id
stringlengths 14
28
| title
stringclasses 18
values | content
stringlengths 2
999
| contents
stringlengths 19
1.02k
|
|---|---|---|---|
Surgery_Schwartz_10402
|
Surgery_Schwartz
|
were similar in the two groups. The incidence of wound complications was higher in the preoperative group versus the postoperative group (35% vs. 17%), and the incidence of wound complications was signifi-cantly higher for tumors of the lower extremity (43%) than for those of the upper extremity (5%).114 Late radiation toxic effects (e.g., fibrosis, joint stiffness, and edema) were more common with postoperative than preoperative radiation therapy (48% vs. 32%) because of higher postoperative radiation doses and larger treatment field sizes.115Brachytherapy involves the placement of multiple radioactive seeds through catheters inserted in the tumor resection bed. The primary benefit of brachytherapy is the shorter overall treatment time of 4 to 6 days, compared to the 4 to 6 weeks generally required for preoperative or postoperative Brunicardi_Ch36_p1567-p1598.indd 157701/03/19 6:38 PM 1578SPECIFIC CONSIDERATIONSPART IIradiation therapy regimens. A cost-analysis comparison of
|
Surgery_Schwartz. were similar in the two groups. The incidence of wound complications was higher in the preoperative group versus the postoperative group (35% vs. 17%), and the incidence of wound complications was signifi-cantly higher for tumors of the lower extremity (43%) than for those of the upper extremity (5%).114 Late radiation toxic effects (e.g., fibrosis, joint stiffness, and edema) were more common with postoperative than preoperative radiation therapy (48% vs. 32%) because of higher postoperative radiation doses and larger treatment field sizes.115Brachytherapy involves the placement of multiple radioactive seeds through catheters inserted in the tumor resection bed. The primary benefit of brachytherapy is the shorter overall treatment time of 4 to 6 days, compared to the 4 to 6 weeks generally required for preoperative or postoperative Brunicardi_Ch36_p1567-p1598.indd 157701/03/19 6:38 PM 1578SPECIFIC CONSIDERATIONSPART IIradiation therapy regimens. A cost-analysis comparison of
|
Surgery_Schwartz_10403
|
Surgery_Schwartz
|
required for preoperative or postoperative Brunicardi_Ch36_p1567-p1598.indd 157701/03/19 6:38 PM 1578SPECIFIC CONSIDERATIONSPART IIradiation therapy regimens. A cost-analysis comparison of adjuvant brachytherapy versus adjuvant external-beam irradiation for soft tissue sarcomas showed that costs were lower with brachytherapy.116 The implications of cost have been studied after radical resections and immediate adjuvant brachytherapy with either staged or immediate reconstruction noting a lower cost with staged reconstruction and tissue transfer techniques.117 Brachytherapy can also be used for recurrent disease previously treated with external-beam radiation. Guidelines established at Memorial Sloan-Kettering Cancer Center recommend spacing the afterloading catheters in 1-cm increments while leaving a 2-cm margin around the surgical bed.105 After adequate wound healing is confirmed, usually after the fifth postoperative day, the catheters are loaded with seeds containing
|
Surgery_Schwartz. required for preoperative or postoperative Brunicardi_Ch36_p1567-p1598.indd 157701/03/19 6:38 PM 1578SPECIFIC CONSIDERATIONSPART IIradiation therapy regimens. A cost-analysis comparison of adjuvant brachytherapy versus adjuvant external-beam irradiation for soft tissue sarcomas showed that costs were lower with brachytherapy.116 The implications of cost have been studied after radical resections and immediate adjuvant brachytherapy with either staged or immediate reconstruction noting a lower cost with staged reconstruction and tissue transfer techniques.117 Brachytherapy can also be used for recurrent disease previously treated with external-beam radiation. Guidelines established at Memorial Sloan-Kettering Cancer Center recommend spacing the afterloading catheters in 1-cm increments while leaving a 2-cm margin around the surgical bed.105 After adequate wound healing is confirmed, usually after the fifth postoperative day, the catheters are loaded with seeds containing
|
Surgery_Schwartz_10404
|
Surgery_Schwartz
|
increments while leaving a 2-cm margin around the surgical bed.105 After adequate wound healing is confirmed, usually after the fifth postoperative day, the catheters are loaded with seeds containing iridium-192 that deliver 42 to 45 Gy of radiation to the tumor bed over 4 to 6 days. Subsequent studies at the H. Lee Moffitt Cancer Center that sought to determine outcomes between staged immediate and delayed reconstruction noted advantages in improved local control, wound healing, and less radiation-associated toxicity with staged reconstruction.118 The primary disadvantage of brachytherapy is that it requires significant expertise, extended inpatient hospital stays, and bed rest.IMRT delivers radiation more precisely to the tumor than external-beam irradiation while minimizing the volume of sur-rounding tissues exposed to high radiation doses. The proposed benefits of preoperative IMRT include reduced risk of postop-erative wound infections because of minimization of the dose to the
|
Surgery_Schwartz. increments while leaving a 2-cm margin around the surgical bed.105 After adequate wound healing is confirmed, usually after the fifth postoperative day, the catheters are loaded with seeds containing iridium-192 that deliver 42 to 45 Gy of radiation to the tumor bed over 4 to 6 days. Subsequent studies at the H. Lee Moffitt Cancer Center that sought to determine outcomes between staged immediate and delayed reconstruction noted advantages in improved local control, wound healing, and less radiation-associated toxicity with staged reconstruction.118 The primary disadvantage of brachytherapy is that it requires significant expertise, extended inpatient hospital stays, and bed rest.IMRT delivers radiation more precisely to the tumor than external-beam irradiation while minimizing the volume of sur-rounding tissues exposed to high radiation doses. The proposed benefits of preoperative IMRT include reduced risk of postop-erative wound infections because of minimization of the dose to the
|
Surgery_Schwartz_10405
|
Surgery_Schwartz
|
of sur-rounding tissues exposed to high radiation doses. The proposed benefits of preoperative IMRT include reduced risk of postop-erative wound infections because of minimization of the dose to the skin119 and protection of underlying bone (e.g., femur) as a result of concave dose distributions.120 There have been no prospective randomized trials comparing the long-term out-comes following IMRT versus other types of radiation therapy. In a retrospective analysis of IMRT, patients with negative and positive/close (within 1 mm) margins were found to have 5-year local control rates of 94%.121 In addition, the rates of posttreat-ment edema and joint stiffness with IMRT were lower than the expected rates with conventional radiation therapy.Local toxic effects of radiation therapy vary according to radiation dose, field size, and timing (preoperative or postop-erative). With preoperative radiation therapy, the most frequent wound complications are wound dehiscence, wound necrosis,
|
Surgery_Schwartz. of sur-rounding tissues exposed to high radiation doses. The proposed benefits of preoperative IMRT include reduced risk of postop-erative wound infections because of minimization of the dose to the skin119 and protection of underlying bone (e.g., femur) as a result of concave dose distributions.120 There have been no prospective randomized trials comparing the long-term out-comes following IMRT versus other types of radiation therapy. In a retrospective analysis of IMRT, patients with negative and positive/close (within 1 mm) margins were found to have 5-year local control rates of 94%.121 In addition, the rates of posttreat-ment edema and joint stiffness with IMRT were lower than the expected rates with conventional radiation therapy.Local toxic effects of radiation therapy vary according to radiation dose, field size, and timing (preoperative or postop-erative). With preoperative radiation therapy, the most frequent wound complications are wound dehiscence, wound necrosis,
|
Surgery_Schwartz_10406
|
Surgery_Schwartz
|
according to radiation dose, field size, and timing (preoperative or postop-erative). With preoperative radiation therapy, the most frequent wound complications are wound dehiscence, wound necrosis, persistent drainage, infection, seroma formation, ulceration, and cellulitis.114 Postoperative irradiation of free flaps is often asso-ciated with wound complications, and patients should be advised that secondary surgical repair may be necessary; therefore, con-sideration for preoperative radiation rather than postoperative radiation for larger tumors requiring flap reconstruction is a logical and sound approach. Wound complication rates of 13% to 37% have been reported for preoperative radiation therapy, compared to 5% to 20% for postoperative radiation therapy.121 If catheters are loaded after the fifth postoperative day and/or if staged reconstruction is used, rates of wound complications after brachytherapy are improved if not similar to those after postoperative radiation
|
Surgery_Schwartz. according to radiation dose, field size, and timing (preoperative or postop-erative). With preoperative radiation therapy, the most frequent wound complications are wound dehiscence, wound necrosis, persistent drainage, infection, seroma formation, ulceration, and cellulitis.114 Postoperative irradiation of free flaps is often asso-ciated with wound complications, and patients should be advised that secondary surgical repair may be necessary; therefore, con-sideration for preoperative radiation rather than postoperative radiation for larger tumors requiring flap reconstruction is a logical and sound approach. Wound complication rates of 13% to 37% have been reported for preoperative radiation therapy, compared to 5% to 20% for postoperative radiation therapy.121 If catheters are loaded after the fifth postoperative day and/or if staged reconstruction is used, rates of wound complications after brachytherapy are improved if not similar to those after postoperative radiation
|
Surgery_Schwartz_10407
|
Surgery_Schwartz
|
loaded after the fifth postoperative day and/or if staged reconstruction is used, rates of wound complications after brachytherapy are improved if not similar to those after postoperative radiation therapy.118Long-term (chronic) effects of radiation therapy (those occurring >1 year after completion of therapy) are generally related to fibrosis/contractures, lymphedema, neurologic injury, osteitis, and fractures, all of which can cause substantial func-tional impairment.122 Variables associated with poorer func-tional outcome after radiation therapy include larger tumors, higher doses of radiation (>63 Gy), longer radiation fields (>35 cm), poor radiation technique, neural sacrifice, postop-erative fractures, and wound complications.115,123 Additionally, complications of any kind are less likely after treatment for upper extremity sarcoma than after treatment for lower extremity sarcoma.113,114Definitive radiation therapy that delivers maximal-tissue-tolerance doses of radiation may
|
Surgery_Schwartz. loaded after the fifth postoperative day and/or if staged reconstruction is used, rates of wound complications after brachytherapy are improved if not similar to those after postoperative radiation therapy.118Long-term (chronic) effects of radiation therapy (those occurring >1 year after completion of therapy) are generally related to fibrosis/contractures, lymphedema, neurologic injury, osteitis, and fractures, all of which can cause substantial func-tional impairment.122 Variables associated with poorer func-tional outcome after radiation therapy include larger tumors, higher doses of radiation (>63 Gy), longer radiation fields (>35 cm), poor radiation technique, neural sacrifice, postop-erative fractures, and wound complications.115,123 Additionally, complications of any kind are less likely after treatment for upper extremity sarcoma than after treatment for lower extremity sarcoma.113,114Definitive radiation therapy that delivers maximal-tissue-tolerance doses of radiation may
|
Surgery_Schwartz_10408
|
Surgery_Schwartz
|
likely after treatment for upper extremity sarcoma than after treatment for lower extremity sarcoma.113,114Definitive radiation therapy that delivers maximal-tissue-tolerance doses of radiation may be appropriate for selected patients with unresectable soft tissue sarcomas. In a study of 112 patients with unresectable soft tissue sarcomas, tumor size and radiation dose were found to influence local control and survival.124 The local control rate was 51% for tumors smaller than 5 cm and 9% for tumors larger than 10 cm, and patients who received at least 64 Gy had better local control and survival.Systemic TherapyDespite improvements in local control rates, metastasis and death remain significant problems for patients with high-risk soft tissue sarcomas. Patients considered at high risk of death from sarcoma include those presenting with metastatic disease, localized sarcomas at nonextremity sites, or sarcomas of intermediateor high-grade histology larger than 5 cm.59,105Standard
|
Surgery_Schwartz. likely after treatment for upper extremity sarcoma than after treatment for lower extremity sarcoma.113,114Definitive radiation therapy that delivers maximal-tissue-tolerance doses of radiation may be appropriate for selected patients with unresectable soft tissue sarcomas. In a study of 112 patients with unresectable soft tissue sarcomas, tumor size and radiation dose were found to influence local control and survival.124 The local control rate was 51% for tumors smaller than 5 cm and 9% for tumors larger than 10 cm, and patients who received at least 64 Gy had better local control and survival.Systemic TherapyDespite improvements in local control rates, metastasis and death remain significant problems for patients with high-risk soft tissue sarcomas. Patients considered at high risk of death from sarcoma include those presenting with metastatic disease, localized sarcomas at nonextremity sites, or sarcomas of intermediateor high-grade histology larger than 5 cm.59,105Standard
|
Surgery_Schwartz_10409
|
Surgery_Schwartz
|
of death from sarcoma include those presenting with metastatic disease, localized sarcomas at nonextremity sites, or sarcomas of intermediateor high-grade histology larger than 5 cm.59,105Standard Chemotherapy. For most patients with sarcoma, results of conventional chemotherapy regimens have been poor. The chemosensitivity of soft tissue sarcoma varies by histologic subtype.30 Synovial sarcoma, myxoid/round cell liposarcoma, and uterine leiomyosarcoma are sensitive to chemotherapy,125 whereas pleomorphic liposarcoma, myxofibrosarcoma, epithe-lioid sarcoma, leiomyosarcoma, MPNSTs, angiosarcoma, and desmoplastic round cell tumors have intermediate sensitivity to chemotherapy. Relatively chemoresistant histologic subtypes include clear cell sarcoma, endometrial stromal sarcoma, alveo-lar soft part sarcoma, and extraskeletal myxoid chondrosarcoma. Considering the variability of responses by histologic subtype, it is not surprising that clinical trials of standard chemotherapy, which
|
Surgery_Schwartz. of death from sarcoma include those presenting with metastatic disease, localized sarcomas at nonextremity sites, or sarcomas of intermediateor high-grade histology larger than 5 cm.59,105Standard Chemotherapy. For most patients with sarcoma, results of conventional chemotherapy regimens have been poor. The chemosensitivity of soft tissue sarcoma varies by histologic subtype.30 Synovial sarcoma, myxoid/round cell liposarcoma, and uterine leiomyosarcoma are sensitive to chemotherapy,125 whereas pleomorphic liposarcoma, myxofibrosarcoma, epithe-lioid sarcoma, leiomyosarcoma, MPNSTs, angiosarcoma, and desmoplastic round cell tumors have intermediate sensitivity to chemotherapy. Relatively chemoresistant histologic subtypes include clear cell sarcoma, endometrial stromal sarcoma, alveo-lar soft part sarcoma, and extraskeletal myxoid chondrosarcoma. Considering the variability of responses by histologic subtype, it is not surprising that clinical trials of standard chemotherapy, which
|
Surgery_Schwartz_10410
|
Surgery_Schwartz
|
soft part sarcoma, and extraskeletal myxoid chondrosarcoma. Considering the variability of responses by histologic subtype, it is not surprising that clinical trials of standard chemotherapy, which often include heterogeneous populations with respect to tumor grade and histology, have demonstrated no overall sur-vival benefit.Doxorubicin and ifosfamide are the two most active agents against soft tissue sarcoma, with consistently reported response rates of 20% or greater and positive dose-response curves.126,127 The European guidelines recommend doxorubicin 75 mg/m2 every 3 weeks as first-line treatment for advanced disease.30 Treatment duration is based on response, but a maximum of six cycles is generally recommended because of the risk of cumula-tive cardiotoxicity. Ifosfamide is the recommended second-line treatment and is recommended for first-line treatment in patients with cardiac morbidity. The standard dose of ifosfamide is 9 to 10 g/m2; however, single-institution series
|
Surgery_Schwartz. soft part sarcoma, and extraskeletal myxoid chondrosarcoma. Considering the variability of responses by histologic subtype, it is not surprising that clinical trials of standard chemotherapy, which often include heterogeneous populations with respect to tumor grade and histology, have demonstrated no overall sur-vival benefit.Doxorubicin and ifosfamide are the two most active agents against soft tissue sarcoma, with consistently reported response rates of 20% or greater and positive dose-response curves.126,127 The European guidelines recommend doxorubicin 75 mg/m2 every 3 weeks as first-line treatment for advanced disease.30 Treatment duration is based on response, but a maximum of six cycles is generally recommended because of the risk of cumula-tive cardiotoxicity. Ifosfamide is the recommended second-line treatment and is recommended for first-line treatment in patients with cardiac morbidity. The standard dose of ifosfamide is 9 to 10 g/m2; however, single-institution series
|
Surgery_Schwartz_10411
|
Surgery_Schwartz
|
recommended second-line treatment and is recommended for first-line treatment in patients with cardiac morbidity. The standard dose of ifosfamide is 9 to 10 g/m2; however, single-institution series using higher-dose regimens (>10 g/m2) or standard-dose ifosfamide combined with doxorubicin have shown response rates of 20% to 60%.127 Synovial sarcomas have been shown to be particularly sensi-tive to ifosfamide. Ifosfamide-associated toxic effects include hemorrhagic cystitis, neurotoxicity, and renal tubular acidosis. Historically, combination therapy with doxorubicin plus ifos-famide, dacarbazine, or both has resulted in increased response rates but no improvement in overall survival.128 Dacarbazine as a single agent has also demonstrated activity in clinical trials.Over the past decade, several additional chemotherapeutic agents, including gemcitabine, taxanes, and trabectedin, have been noted to be active against soft tissue sarcomas. Gemcitabine as a single agent was reported to
|
Surgery_Schwartz. recommended second-line treatment and is recommended for first-line treatment in patients with cardiac morbidity. The standard dose of ifosfamide is 9 to 10 g/m2; however, single-institution series using higher-dose regimens (>10 g/m2) or standard-dose ifosfamide combined with doxorubicin have shown response rates of 20% to 60%.127 Synovial sarcomas have been shown to be particularly sensi-tive to ifosfamide. Ifosfamide-associated toxic effects include hemorrhagic cystitis, neurotoxicity, and renal tubular acidosis. Historically, combination therapy with doxorubicin plus ifos-famide, dacarbazine, or both has resulted in increased response rates but no improvement in overall survival.128 Dacarbazine as a single agent has also demonstrated activity in clinical trials.Over the past decade, several additional chemotherapeutic agents, including gemcitabine, taxanes, and trabectedin, have been noted to be active against soft tissue sarcomas. Gemcitabine as a single agent was reported to
|
Surgery_Schwartz_10412
|
Surgery_Schwartz
|
several additional chemotherapeutic agents, including gemcitabine, taxanes, and trabectedin, have been noted to be active against soft tissue sarcomas. Gemcitabine as a single agent was reported to produce responses in 18% of patients with advanced sarcoma.129 Gemcitabine combined with docetaxel has been reported to produce response rates as high as 53% in patients with uterine leiomyosarcoma.129,130 Gemcitabine Brunicardi_Ch36_p1567-p1598.indd 157801/03/19 6:38 PM 1579SOFT TISSUE SARCOMASCHAPTER 36combined with vinorelbine has also been associated with clini-cal benefit in patients with advanced sarcomas.131 The taxanes (docetaxel and paclitaxel) have been found to be active against angiosarcomas, particularly of the face and scalp, likely because of their potent antiangiogenic effects.132,133Novel Chemotherapeutic Agents. Aldoxorubicin is a doxo-rubicin derivative that serves as a prodrug of doxorubicin that covalently binds to albumin in the blood until reaching the acidic
|
Surgery_Schwartz. several additional chemotherapeutic agents, including gemcitabine, taxanes, and trabectedin, have been noted to be active against soft tissue sarcomas. Gemcitabine as a single agent was reported to produce responses in 18% of patients with advanced sarcoma.129 Gemcitabine combined with docetaxel has been reported to produce response rates as high as 53% in patients with uterine leiomyosarcoma.129,130 Gemcitabine Brunicardi_Ch36_p1567-p1598.indd 157801/03/19 6:38 PM 1579SOFT TISSUE SARCOMASCHAPTER 36combined with vinorelbine has also been associated with clini-cal benefit in patients with advanced sarcomas.131 The taxanes (docetaxel and paclitaxel) have been found to be active against angiosarcomas, particularly of the face and scalp, likely because of their potent antiangiogenic effects.132,133Novel Chemotherapeutic Agents. Aldoxorubicin is a doxo-rubicin derivative that serves as a prodrug of doxorubicin that covalently binds to albumin in the blood until reaching the acidic
|
Surgery_Schwartz_10413
|
Surgery_Schwartz
|
Chemotherapeutic Agents. Aldoxorubicin is a doxo-rubicin derivative that serves as a prodrug of doxorubicin that covalently binds to albumin in the blood until reaching the acidic tumor environment releasing doxorubicin into the tis-sue. A recent international, multicenter, phase 2b, open-label, randomized study enrolled 126 patients from 2012 to 2013. Single-agent aldoxorubicin therapy showed superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response, warranting further study.134Trabectedin, a marine-derived alkaloid that binds DNA, affecting transcription and inducing the formation of DNA double-strand breaks, has shown benefit in the treatment of advanced soft tissue sarcomas, particularly leiomyosarcoma, myxoid liposarcoma, and other translocation-related sarcomas.135 Trabectedin is generally well tolerated but can be associated with prolonged and severe neutropenia, thrombocytopenia, and
|
Surgery_Schwartz. Chemotherapeutic Agents. Aldoxorubicin is a doxo-rubicin derivative that serves as a prodrug of doxorubicin that covalently binds to albumin in the blood until reaching the acidic tumor environment releasing doxorubicin into the tis-sue. A recent international, multicenter, phase 2b, open-label, randomized study enrolled 126 patients from 2012 to 2013. Single-agent aldoxorubicin therapy showed superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response, warranting further study.134Trabectedin, a marine-derived alkaloid that binds DNA, affecting transcription and inducing the formation of DNA double-strand breaks, has shown benefit in the treatment of advanced soft tissue sarcomas, particularly leiomyosarcoma, myxoid liposarcoma, and other translocation-related sarcomas.135 Trabectedin is generally well tolerated but can be associated with prolonged and severe neutropenia, thrombocytopenia, and
|
Surgery_Schwartz_10414
|
Surgery_Schwartz
|
myxoid liposarcoma, and other translocation-related sarcomas.135 Trabectedin is generally well tolerated but can be associated with prolonged and severe neutropenia, thrombocytopenia, and hepatic toxic effects.Palifosfamide is a stabilized formulation of the active metabolite of ifosfamide that has been reported to be better tolerated than ifosfamide.136 Early trials have suggested anti-tumor activity comparable or superior to that of ifosfamide without nephrotoxicity; however, recent negative results of the PICASSO III Trial, a phase 3, placebo-controlled study of doxorubicin with or without palifosfamide in patients with metastatic soft tissue sarcoma, have neatly secured the fate of palifosfamide in the treatment of soft tissue sarcoma.137Targeted Therapies. Several targeted agents are being investigated for the treatment of soft tissue sarcomas. Among these are tyrosine kinase inhibitors (e.g., imatinib, suni-tinib, sorafenib, and dasatinib) that have been developed and approved
|
Surgery_Schwartz. myxoid liposarcoma, and other translocation-related sarcomas.135 Trabectedin is generally well tolerated but can be associated with prolonged and severe neutropenia, thrombocytopenia, and hepatic toxic effects.Palifosfamide is a stabilized formulation of the active metabolite of ifosfamide that has been reported to be better tolerated than ifosfamide.136 Early trials have suggested anti-tumor activity comparable or superior to that of ifosfamide without nephrotoxicity; however, recent negative results of the PICASSO III Trial, a phase 3, placebo-controlled study of doxorubicin with or without palifosfamide in patients with metastatic soft tissue sarcoma, have neatly secured the fate of palifosfamide in the treatment of soft tissue sarcoma.137Targeted Therapies. Several targeted agents are being investigated for the treatment of soft tissue sarcomas. Among these are tyrosine kinase inhibitors (e.g., imatinib, suni-tinib, sorafenib, and dasatinib) that have been developed and approved
|
Surgery_Schwartz_10415
|
Surgery_Schwartz
|
being investigated for the treatment of soft tissue sarcomas. Among these are tyrosine kinase inhibitors (e.g., imatinib, suni-tinib, sorafenib, and dasatinib) that have been developed and approved for treatment of GIST. Clinical data accumulated in phase 2 trials also support the use of tyrosine kinase inhibitors (e.g., imatinib, sorafenib, and sunitinib) in the management of other advanced sarcomas.128 Anti–vascular endothelial growth factor antibodies such as bevacizumab have demonstrated activity in patients with metastatic or unresectable angiosar-coma, solitary fibrous tumor, and epithelioid hemangioendo-thelioma.138 Pazopanib is an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptors, platelet-derived growth factor receptor (PDGFR), and c-kit. In a recent phase 3 study, pazopanib showed efficacy against placebo in second or further line of therapy in patients with advanced soft tissue sarcoma.139 Inhibitors of the mammalian target of rapamycin
|
Surgery_Schwartz. being investigated for the treatment of soft tissue sarcomas. Among these are tyrosine kinase inhibitors (e.g., imatinib, suni-tinib, sorafenib, and dasatinib) that have been developed and approved for treatment of GIST. Clinical data accumulated in phase 2 trials also support the use of tyrosine kinase inhibitors (e.g., imatinib, sorafenib, and sunitinib) in the management of other advanced sarcomas.128 Anti–vascular endothelial growth factor antibodies such as bevacizumab have demonstrated activity in patients with metastatic or unresectable angiosar-coma, solitary fibrous tumor, and epithelioid hemangioendo-thelioma.138 Pazopanib is an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptors, platelet-derived growth factor receptor (PDGFR), and c-kit. In a recent phase 3 study, pazopanib showed efficacy against placebo in second or further line of therapy in patients with advanced soft tissue sarcoma.139 Inhibitors of the mammalian target of rapamycin
|
Surgery_Schwartz_10416
|
Surgery_Schwartz
|
recent phase 3 study, pazopanib showed efficacy against placebo in second or further line of therapy in patients with advanced soft tissue sarcoma.139 Inhibitors of the mammalian target of rapamycin pathway, including temsirolimus, everolimus, and ridaforolimus, have also shown activity against some soft tis-sue sarcomas (i.e., PEComas).140Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumor activity in human sarcoma xenografts. Recently, a phase 1b and random-ized phase 2 study of olaratumab and doxorubicin versus doxo-rubicin alone has demonstrated improvements in both objective response rates (18.2% vs. 11.9%, P = 0.34) and median over-all survival (26.5 vs. 14.7 months [stratified hazard ratio 0.46, 0.30–0.71, P = 0.0003]). Additional studies are warranted for this promising combination of agents.141Benefits of Systemic Therapy. The use of adjuvant and neoad-juvant chemotherapy for soft tissue sarcomas remains controver-sial.
|
Surgery_Schwartz. recent phase 3 study, pazopanib showed efficacy against placebo in second or further line of therapy in patients with advanced soft tissue sarcoma.139 Inhibitors of the mammalian target of rapamycin pathway, including temsirolimus, everolimus, and ridaforolimus, have also shown activity against some soft tis-sue sarcomas (i.e., PEComas).140Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumor activity in human sarcoma xenografts. Recently, a phase 1b and random-ized phase 2 study of olaratumab and doxorubicin versus doxo-rubicin alone has demonstrated improvements in both objective response rates (18.2% vs. 11.9%, P = 0.34) and median over-all survival (26.5 vs. 14.7 months [stratified hazard ratio 0.46, 0.30–0.71, P = 0.0003]). Additional studies are warranted for this promising combination of agents.141Benefits of Systemic Therapy. The use of adjuvant and neoad-juvant chemotherapy for soft tissue sarcomas remains controver-sial.
|
Surgery_Schwartz_10417
|
Surgery_Schwartz
|
studies are warranted for this promising combination of agents.141Benefits of Systemic Therapy. The use of adjuvant and neoad-juvant chemotherapy for soft tissue sarcomas remains controver-sial. More than a dozen individual randomized trials of adjuvant chemotherapy have failed to demonstrate improvement in disease-free or overall survival for patients with soft tissue sarcoma. How-ever, several limitations of these individual trials may explain the lack of observed improvement. First, the chemotherapy regimens used were suboptimal, consisting of single-agent therapy (most commonly with doxorubicin) and insufficiently intensive dosing schedules. Second, the patient groups were not large enough to reveal clinically significant differences in survival rates. Finally, most studies included patients at low risk of metastasis and death, namely those with small (<5 cm) and low-grade tumors.The Sarcoma Meta-Analysis Collaboration analyzed 1568 patients from 14 trials of doxorubicin-based
|
Surgery_Schwartz. studies are warranted for this promising combination of agents.141Benefits of Systemic Therapy. The use of adjuvant and neoad-juvant chemotherapy for soft tissue sarcomas remains controver-sial. More than a dozen individual randomized trials of adjuvant chemotherapy have failed to demonstrate improvement in disease-free or overall survival for patients with soft tissue sarcoma. How-ever, several limitations of these individual trials may explain the lack of observed improvement. First, the chemotherapy regimens used were suboptimal, consisting of single-agent therapy (most commonly with doxorubicin) and insufficiently intensive dosing schedules. Second, the patient groups were not large enough to reveal clinically significant differences in survival rates. Finally, most studies included patients at low risk of metastasis and death, namely those with small (<5 cm) and low-grade tumors.The Sarcoma Meta-Analysis Collaboration analyzed 1568 patients from 14 trials of doxorubicin-based
|
Surgery_Schwartz_10418
|
Surgery_Schwartz
|
patients at low risk of metastasis and death, namely those with small (<5 cm) and low-grade tumors.The Sarcoma Meta-Analysis Collaboration analyzed 1568 patients from 14 trials of doxorubicin-based adjuvant chemotherapy to evaluate the effect of adjuvant chemotherapy on localized, resectable soft tissue sarcomas.142 At a median follow-up time of 9.4 years, doxorubicin-based chemotherapy significantly improved the time to local and distant recurrence and recurrence-free survival rates. However, the absolute benefit in overall survival was only 4%, which was not significant (P = .12). In a subset analysis, patients with extremity tumors had a 7% benefit in terms of overall survival (P = .029).142After this meta-analysis, randomized controlled trials of more contemporary anthracycline/ifosfamide dosing combinations with relatively small numbers of patients have yielded conflicting results. In an Italian cooperative trial, adjuvant chemotherapy improved median disease-free and overall
|
Surgery_Schwartz. patients at low risk of metastasis and death, namely those with small (<5 cm) and low-grade tumors.The Sarcoma Meta-Analysis Collaboration analyzed 1568 patients from 14 trials of doxorubicin-based adjuvant chemotherapy to evaluate the effect of adjuvant chemotherapy on localized, resectable soft tissue sarcomas.142 At a median follow-up time of 9.4 years, doxorubicin-based chemotherapy significantly improved the time to local and distant recurrence and recurrence-free survival rates. However, the absolute benefit in overall survival was only 4%, which was not significant (P = .12). In a subset analysis, patients with extremity tumors had a 7% benefit in terms of overall survival (P = .029).142After this meta-analysis, randomized controlled trials of more contemporary anthracycline/ifosfamide dosing combinations with relatively small numbers of patients have yielded conflicting results. In an Italian cooperative trial, adjuvant chemotherapy improved median disease-free and overall
|
Surgery_Schwartz_10419
|
Surgery_Schwartz
|
dosing combinations with relatively small numbers of patients have yielded conflicting results. In an Italian cooperative trial, adjuvant chemotherapy improved median disease-free and overall survival times in patients with high-risk extremity soft tissue sarcomas.143 In that study, 104 patients with high-grade tumors 5 cm or larger were randomized to definitive surgery or surgery plus adjuvant chemotherapy consisting of epirubicin (60 mg/m2 per day on days 1 and 2) and ifosfamide (1.8 g/m2 per day on days 1 through 5) for five cycles. With a median follow-up time of almost 5 years, disease-free survival times were 16 months in the surgery-alone group and 48 months in the combined-treatment group (P = .04), and median overall survival times were 46 months in the surgery-alone group and 75 months in the combined-treatment group (P = .03).143 However, several years later, the surgery-alone and combined-treatment groups had equivalent relapse rates and deaths, which resulted in
|
Surgery_Schwartz. dosing combinations with relatively small numbers of patients have yielded conflicting results. In an Italian cooperative trial, adjuvant chemotherapy improved median disease-free and overall survival times in patients with high-risk extremity soft tissue sarcomas.143 In that study, 104 patients with high-grade tumors 5 cm or larger were randomized to definitive surgery or surgery plus adjuvant chemotherapy consisting of epirubicin (60 mg/m2 per day on days 1 and 2) and ifosfamide (1.8 g/m2 per day on days 1 through 5) for five cycles. With a median follow-up time of almost 5 years, disease-free survival times were 16 months in the surgery-alone group and 48 months in the combined-treatment group (P = .04), and median overall survival times were 46 months in the surgery-alone group and 75 months in the combined-treatment group (P = .03).143 However, several years later, the surgery-alone and combined-treatment groups had equivalent relapse rates and deaths, which resulted in
|
Surgery_Schwartz_10420
|
Surgery_Schwartz
|
and 75 months in the combined-treatment group (P = .03).143 However, several years later, the surgery-alone and combined-treatment groups had equivalent relapse rates and deaths, which resulted in statistically similar overall survival.144In an effort to further assess the role of chemotherapy in patients with stage III extremity sarcoma, a cohort analy-sis of the combined databases of The University of Texas MD Anderson Cancer Center and Memorial Sloan-Kettering Can-cer Center was performed. Data on 674 patients with stage III extremity sarcoma who received either preoperative or postop-erative doxorubicin-based chemotherapy were reviewed. The 5-year disease-specific survival rate was 61%.145 Cox regres-sion analysis showed a time-varying effect of chemotherapy with an associated benefit during the first year while receiving chemotherapy. However, the clinical benefits of chemotherapy in patients with stage III sarcomas were not sustained beyond 1 year. Grobmyer and colleagues
|
Surgery_Schwartz. and 75 months in the combined-treatment group (P = .03).143 However, several years later, the surgery-alone and combined-treatment groups had equivalent relapse rates and deaths, which resulted in statistically similar overall survival.144In an effort to further assess the role of chemotherapy in patients with stage III extremity sarcoma, a cohort analy-sis of the combined databases of The University of Texas MD Anderson Cancer Center and Memorial Sloan-Kettering Can-cer Center was performed. Data on 674 patients with stage III extremity sarcoma who received either preoperative or postop-erative doxorubicin-based chemotherapy were reviewed. The 5-year disease-specific survival rate was 61%.145 Cox regres-sion analysis showed a time-varying effect of chemotherapy with an associated benefit during the first year while receiving chemotherapy. However, the clinical benefits of chemotherapy in patients with stage III sarcomas were not sustained beyond 1 year. Grobmyer and colleagues
|
Surgery_Schwartz_10421
|
Surgery_Schwartz
|
during the first year while receiving chemotherapy. However, the clinical benefits of chemotherapy in patients with stage III sarcomas were not sustained beyond 1 year. Grobmyer and colleagues compared the outcomes of patients treated at two institutions (1990–2001) with surgery only or surgery plus preoperative chemotherapy containing doxorubicin and ifosfamide. In this analysis, chemotherapy was associated with an improvement in the 3-year disease-specific survival rate that was most pronounced in patients with tumors larger than 10 cm (62% for surgery alone vs. 83% for neoadju-vant chemotherapy and surgery).146Brunicardi_Ch36_p1567-p1598.indd 157901/03/19 6:38 PM 1580SPECIFIC CONSIDERATIONSPART IIMore recently, the European Organization for Research and Treatment of Cancer (EORTC) completed a phase 3 ran-domized study (trial EORTC-62931; conducted from 1995 through 2003) comparing surgery alone versus surgery plus adjuvant ifosfamide (5 g/m2) plus doxorubicin (75 mg/m2) with
|
Surgery_Schwartz. during the first year while receiving chemotherapy. However, the clinical benefits of chemotherapy in patients with stage III sarcomas were not sustained beyond 1 year. Grobmyer and colleagues compared the outcomes of patients treated at two institutions (1990–2001) with surgery only or surgery plus preoperative chemotherapy containing doxorubicin and ifosfamide. In this analysis, chemotherapy was associated with an improvement in the 3-year disease-specific survival rate that was most pronounced in patients with tumors larger than 10 cm (62% for surgery alone vs. 83% for neoadju-vant chemotherapy and surgery).146Brunicardi_Ch36_p1567-p1598.indd 157901/03/19 6:38 PM 1580SPECIFIC CONSIDERATIONSPART IIMore recently, the European Organization for Research and Treatment of Cancer (EORTC) completed a phase 3 ran-domized study (trial EORTC-62931; conducted from 1995 through 2003) comparing surgery alone versus surgery plus adjuvant ifosfamide (5 g/m2) plus doxorubicin (75 mg/m2) with
|
Surgery_Schwartz_10422
|
Surgery_Schwartz
|
completed a phase 3 ran-domized study (trial EORTC-62931; conducted from 1995 through 2003) comparing surgery alone versus surgery plus adjuvant ifosfamide (5 g/m2) plus doxorubicin (75 mg/m2) with growth factor support (lenograstim) every 21 days for five cycles in 351 patients with resected grade II or III soft tissue sarcoma at any site. The estimated relapse-free survival rate was 52% in both arms, and the overall survival rate was better in the control arm (69% vs. 64%).147 Although most individual studies are underpowered, data from all of these studies suggest that chemotherapy regimens that incorporate ifosfamide may provide some disease-free survival benefit but do not improve long-term overall survival for the majority of patients with soft tissue sarcoma.In 2008, two updates to the 1997 Sarcoma Meta-Anal-ysis Collaboration were published.148,149 O’Connor and col-leagues included all of the trials in the original meta-analysis and added data from four additional trials, for
|
Surgery_Schwartz. completed a phase 3 ran-domized study (trial EORTC-62931; conducted from 1995 through 2003) comparing surgery alone versus surgery plus adjuvant ifosfamide (5 g/m2) plus doxorubicin (75 mg/m2) with growth factor support (lenograstim) every 21 days for five cycles in 351 patients with resected grade II or III soft tissue sarcoma at any site. The estimated relapse-free survival rate was 52% in both arms, and the overall survival rate was better in the control arm (69% vs. 64%).147 Although most individual studies are underpowered, data from all of these studies suggest that chemotherapy regimens that incorporate ifosfamide may provide some disease-free survival benefit but do not improve long-term overall survival for the majority of patients with soft tissue sarcoma.In 2008, two updates to the 1997 Sarcoma Meta-Anal-ysis Collaboration were published.148,149 O’Connor and col-leagues included all of the trials in the original meta-analysis and added data from four additional trials, for
|
Surgery_Schwartz_10423
|
Surgery_Schwartz
|
the 1997 Sarcoma Meta-Anal-ysis Collaboration were published.148,149 O’Connor and col-leagues included all of the trials in the original meta-analysis and added data from four additional trials, for a total of 18 trials with 2170 patients.148 The results showed a benefit of chemotherapy in terms of disease-free survival at 5 years and recurrence-free survival at 10 years but again failed to demon-strate a benefit in terms of long-term overall survival. The sec-ond update, by Pervaiz and colleagues, which did not include the EORTC-62931 trial, showed that adjuvant chemotherapy was associated with a significant decrease in the risk of death (hazard ratio, 0.77; P = .01).149Because the evidence regarding adjuvant systemic therapy for stage III soft tissue sarcoma is inconclusive, considerable variation still exists in treatment recommendations even though patients with large, stage II or stage III soft tissue sarcomas are at high risk for recurrence and metastasis. Chemotherapy may be
|
Surgery_Schwartz. the 1997 Sarcoma Meta-Anal-ysis Collaboration were published.148,149 O’Connor and col-leagues included all of the trials in the original meta-analysis and added data from four additional trials, for a total of 18 trials with 2170 patients.148 The results showed a benefit of chemotherapy in terms of disease-free survival at 5 years and recurrence-free survival at 10 years but again failed to demon-strate a benefit in terms of long-term overall survival. The sec-ond update, by Pervaiz and colleagues, which did not include the EORTC-62931 trial, showed that adjuvant chemotherapy was associated with a significant decrease in the risk of death (hazard ratio, 0.77; P = .01).149Because the evidence regarding adjuvant systemic therapy for stage III soft tissue sarcoma is inconclusive, considerable variation still exists in treatment recommendations even though patients with large, stage II or stage III soft tissue sarcomas are at high risk for recurrence and metastasis. Chemotherapy may be
|
Surgery_Schwartz_10424
|
Surgery_Schwartz
|
variation still exists in treatment recommendations even though patients with large, stage II or stage III soft tissue sarcomas are at high risk for recurrence and metastasis. Chemotherapy may be considered to downstage large tumors to enable limb-sparing procedures, particularly for tumors known to be chemosensi-tive. It is likely that subsets of high-risk patients with extremity soft tissue sarcoma defined on the basis of tumor size or histol-ogy derive significant benefit from systemic chemotherapy. For example, retrospective cohort analyses have noted a disease-specific survival benefit in patients with large, high-grade lipo-sarcomas and synovial sarcomas of the extremity treated with ifosfamide plus doxorubicin versus no chemotherapy.150Neoadjuvant (Preoperative) Chemotherapy. The use of neoadjuvant (preoperative) chemotherapy for soft tissue sarco-mas is based on the belief that only 30% to 50% of patients respond to standard adjuvant (postoperative) chemotherapy. The rationale
|
Surgery_Schwartz. variation still exists in treatment recommendations even though patients with large, stage II or stage III soft tissue sarcomas are at high risk for recurrence and metastasis. Chemotherapy may be considered to downstage large tumors to enable limb-sparing procedures, particularly for tumors known to be chemosensi-tive. It is likely that subsets of high-risk patients with extremity soft tissue sarcoma defined on the basis of tumor size or histol-ogy derive significant benefit from systemic chemotherapy. For example, retrospective cohort analyses have noted a disease-specific survival benefit in patients with large, high-grade lipo-sarcomas and synovial sarcomas of the extremity treated with ifosfamide plus doxorubicin versus no chemotherapy.150Neoadjuvant (Preoperative) Chemotherapy. The use of neoadjuvant (preoperative) chemotherapy for soft tissue sarco-mas is based on the belief that only 30% to 50% of patients respond to standard adjuvant (postoperative) chemotherapy. The rationale
|
Surgery_Schwartz_10425
|
Surgery_Schwartz
|
of neoadjuvant (preoperative) chemotherapy for soft tissue sarco-mas is based on the belief that only 30% to 50% of patients respond to standard adjuvant (postoperative) chemotherapy. The rationale for using neoadjuvant chemotherapy is that it enables oncologists to identify patients whose disease is sensi-tive to a particular chemotherapy regimen by assessing response while the primary tumor is in situ. Patients whose tumors do not respond to short courses of neoadjuvant chemotherapy can thus be spared the toxic effects of prolonged adjuvant chemotherapy. Another advantage of neoadjuvant chemotherapy is that it may shrink tumors, enabling less morbid operations. The theoreti-cal disadvantages of neoadjuvant chemotherapy are related to myelosuppression and potential postoperative wound healing complications.A recent randomized study comparing three preoperative cycles of full-dose anthracycline-ifosfamide–based chemother-apy with three preoperative plus two postoperative cycles of the
|
Surgery_Schwartz. of neoadjuvant (preoperative) chemotherapy for soft tissue sarco-mas is based on the belief that only 30% to 50% of patients respond to standard adjuvant (postoperative) chemotherapy. The rationale for using neoadjuvant chemotherapy is that it enables oncologists to identify patients whose disease is sensi-tive to a particular chemotherapy regimen by assessing response while the primary tumor is in situ. Patients whose tumors do not respond to short courses of neoadjuvant chemotherapy can thus be spared the toxic effects of prolonged adjuvant chemotherapy. Another advantage of neoadjuvant chemotherapy is that it may shrink tumors, enabling less morbid operations. The theoreti-cal disadvantages of neoadjuvant chemotherapy are related to myelosuppression and potential postoperative wound healing complications.A recent randomized study comparing three preoperative cycles of full-dose anthracycline-ifosfamide–based chemother-apy with three preoperative plus two postoperative cycles of the
|
Surgery_Schwartz_10426
|
Surgery_Schwartz
|
complications.A recent randomized study comparing three preoperative cycles of full-dose anthracycline-ifosfamide–based chemother-apy with three preoperative plus two postoperative cycles of the same regimen in high-risk extremity and trunk wall soft tissue sarcomas showed equivalence between the two approaches, sug-gesting the possibility of limiting chemotherapy administration to the three preoperative courses, improving the ratio between toxicity and expected benefit.151A subanalysis on response showed how tumor attenuation on CT scan and MRI obtained by the administration of such preoperative treatment was associated with a higher percentage of pathologic necrosis152 and better outcome.153Eilber and colleagues examined treatment-induced patho-logic necrosis in patients who received neoadjuvant therapy for high-grade extremity sarcomas.154 The addition of ifosfamide to other agents (doxorubicin alone or doxorubicin and cisplatin) increased the rate of pathologic necrosis to 48%
|
Surgery_Schwartz. complications.A recent randomized study comparing three preoperative cycles of full-dose anthracycline-ifosfamide–based chemother-apy with three preoperative plus two postoperative cycles of the same regimen in high-risk extremity and trunk wall soft tissue sarcomas showed equivalence between the two approaches, sug-gesting the possibility of limiting chemotherapy administration to the three preoperative courses, improving the ratio between toxicity and expected benefit.151A subanalysis on response showed how tumor attenuation on CT scan and MRI obtained by the administration of such preoperative treatment was associated with a higher percentage of pathologic necrosis152 and better outcome.153Eilber and colleagues examined treatment-induced patho-logic necrosis in patients who received neoadjuvant therapy for high-grade extremity sarcomas.154 The addition of ifosfamide to other agents (doxorubicin alone or doxorubicin and cisplatin) increased the rate of pathologic necrosis to 48%
|
Surgery_Schwartz_10427
|
Surgery_Schwartz
|
neoadjuvant therapy for high-grade extremity sarcomas.154 The addition of ifosfamide to other agents (doxorubicin alone or doxorubicin and cisplatin) increased the rate of pathologic necrosis to 48% compared to 13% with other combinations. The 5and 10-year local recur-rence rates were significantly lower for patients with 95% or greater pathologic necrosis (6% and 11%, respectively) than for patients with less than 95% pathologic necrosis (17% and 23%, respectively).Concurrent Chemoradiation TherapyTreatment approaches that combine systemic chemotherapy with radiosensitizers and concurrent external-beam radiation therapy may improve disease-free survival by treating micro-scopic disease and enhancing the treatment of macroscopic disease. Concurrent chemoradiation therapy with doxorubicin-based regimens reportedly produces favorable local control rates for patients with sarcoma.150 Since those findings were published, several groups have evaluated routes of administra-tion, alternative
|
Surgery_Schwartz. neoadjuvant therapy for high-grade extremity sarcomas.154 The addition of ifosfamide to other agents (doxorubicin alone or doxorubicin and cisplatin) increased the rate of pathologic necrosis to 48% compared to 13% with other combinations. The 5and 10-year local recur-rence rates were significantly lower for patients with 95% or greater pathologic necrosis (6% and 11%, respectively) than for patients with less than 95% pathologic necrosis (17% and 23%, respectively).Concurrent Chemoradiation TherapyTreatment approaches that combine systemic chemotherapy with radiosensitizers and concurrent external-beam radiation therapy may improve disease-free survival by treating micro-scopic disease and enhancing the treatment of macroscopic disease. Concurrent chemoradiation therapy with doxorubicin-based regimens reportedly produces favorable local control rates for patients with sarcoma.150 Since those findings were published, several groups have evaluated routes of administra-tion, alternative
|
Surgery_Schwartz_10428
|
Surgery_Schwartz
|
regimens reportedly produces favorable local control rates for patients with sarcoma.150 Since those findings were published, several groups have evaluated routes of administra-tion, alternative chemotherapeutic agents, and the toxicity of combined therapies.Theoretical advantages notwithstanding, concurrent chemoradiation therapy decreases the total treatment time for patients with high-risk sarcoma. This decrease represents a sub-stantial advantage over current sequential combined-modality treatment approaches, for which the total duration of radiation therapy, chemotherapy, surgery, and rehabilitation frequently exceeds 6 to 9 months.Posttreatment SurveillanceCurrently, posttreatment surveillance is recommended for all patients with soft tissue sarcomas based on a few reports involving small numbers of patients, indicating that local recur-rence can be successfully treated with radical reexcision with or without radiation therapy.155,156 Similarly, several groups have reported that
|
Surgery_Schwartz. regimens reportedly produces favorable local control rates for patients with sarcoma.150 Since those findings were published, several groups have evaluated routes of administra-tion, alternative chemotherapeutic agents, and the toxicity of combined therapies.Theoretical advantages notwithstanding, concurrent chemoradiation therapy decreases the total treatment time for patients with high-risk sarcoma. This decrease represents a sub-stantial advantage over current sequential combined-modality treatment approaches, for which the total duration of radiation therapy, chemotherapy, surgery, and rehabilitation frequently exceeds 6 to 9 months.Posttreatment SurveillanceCurrently, posttreatment surveillance is recommended for all patients with soft tissue sarcomas based on a few reports involving small numbers of patients, indicating that local recur-rence can be successfully treated with radical reexcision with or without radiation therapy.155,156 Similarly, several groups have reported that
|
Surgery_Schwartz_10429
|
Surgery_Schwartz
|
small numbers of patients, indicating that local recur-rence can be successfully treated with radical reexcision with or without radiation therapy.155,156 Similarly, several groups have reported that survival can be prolonged by resection of pulmo-nary metastases.157-159The National Comprehensive Cancer Network (NCCN) recommends a history and physical and chest CT or radiog-raphy every 3 to 6 months for 2 to 3 years after completion of treatment. Because most cases of distant metastasis occur within 2 to 3 years of initial diagnosis, the NCCN guidelines indicate that follow-up intervals can be lengthened to every 6 months, and imaging can be done annually during years 2 through 5.1 Consideration should also be given to imaging the primary tumor site; most experts recommend that the tumor site be evaluated every 6 months with MRI for extremity tumors or CT for intra-abdominal or retroperitoneal tumors. Guidelines have been established for using MRI to distinguish recurrences from
|
Surgery_Schwartz. small numbers of patients, indicating that local recur-rence can be successfully treated with radical reexcision with or without radiation therapy.155,156 Similarly, several groups have reported that survival can be prolonged by resection of pulmo-nary metastases.157-159The National Comprehensive Cancer Network (NCCN) recommends a history and physical and chest CT or radiog-raphy every 3 to 6 months for 2 to 3 years after completion of treatment. Because most cases of distant metastasis occur within 2 to 3 years of initial diagnosis, the NCCN guidelines indicate that follow-up intervals can be lengthened to every 6 months, and imaging can be done annually during years 2 through 5.1 Consideration should also be given to imaging the primary tumor site; most experts recommend that the tumor site be evaluated every 6 months with MRI for extremity tumors or CT for intra-abdominal or retroperitoneal tumors. Guidelines have been established for using MRI to distinguish recurrences from
|
Surgery_Schwartz_10430
|
Surgery_Schwartz
|
site be evaluated every 6 months with MRI for extremity tumors or CT for intra-abdominal or retroperitoneal tumors. Guidelines have been established for using MRI to distinguish recurrences from typical postsurgical changes: a discrete nodule with low signal intensity on T1-weighted images and higher signal intensity on T2-weighted images that enhances after adminis-tration of intravenous contrast material is strongly suggestive of recurrence and should be biopsied. Ultrasonography may be an alternative to MRI or CT for assessing for recurrence in the extremities.Brunicardi_Ch36_p1567-p1598.indd 158001/03/19 6:38 PM 1581SOFT TISSUE SARCOMASCHAPTER 36Recurrence is common after surgery for abdominal soft tissue sarcomas. CT is useful for detecting recurrences at primary and distant anatomic sites in the abdomen and pelvis. After surgery, CT every 3 to 6 months during the first 2 years and every 6 months for 3 years thereafter has been recommended. However, today many experienced
|
Surgery_Schwartz. site be evaluated every 6 months with MRI for extremity tumors or CT for intra-abdominal or retroperitoneal tumors. Guidelines have been established for using MRI to distinguish recurrences from typical postsurgical changes: a discrete nodule with low signal intensity on T1-weighted images and higher signal intensity on T2-weighted images that enhances after adminis-tration of intravenous contrast material is strongly suggestive of recurrence and should be biopsied. Ultrasonography may be an alternative to MRI or CT for assessing for recurrence in the extremities.Brunicardi_Ch36_p1567-p1598.indd 158001/03/19 6:38 PM 1581SOFT TISSUE SARCOMASCHAPTER 36Recurrence is common after surgery for abdominal soft tissue sarcomas. CT is useful for detecting recurrences at primary and distant anatomic sites in the abdomen and pelvis. After surgery, CT every 3 to 6 months during the first 2 years and every 6 months for 3 years thereafter has been recommended. However, today many experienced
|
Surgery_Schwartz_10431
|
Surgery_Schwartz
|
sites in the abdomen and pelvis. After surgery, CT every 3 to 6 months during the first 2 years and every 6 months for 3 years thereafter has been recommended. However, today many experienced surgeons are advocating less aggressive imaging for asymptomatic patients, particularly after a second recurrence of retroperitoneal sarcoma, arguing that there is insufficient evidence to suggest that survival is improved by earlier detection.Whooley and colleagues reviewed the efficacy of the sur-veillance strategy used at Roswell Park Cancer Institute for 174 patients with soft tissue sarcomas of the extremities.160 Patients were evaluated every 3 months for the first 2 years, every 4 to 6 months during year 3, and every 6 months during years 4 and 5. Local recurrence occurred in 18% of patients at a median time after completion of treatment of 14 months, and all but one of the recurrences were detected with physical examination alone. Fifty-seven patients had distant recurrences (at a
|
Surgery_Schwartz. sites in the abdomen and pelvis. After surgery, CT every 3 to 6 months during the first 2 years and every 6 months for 3 years thereafter has been recommended. However, today many experienced surgeons are advocating less aggressive imaging for asymptomatic patients, particularly after a second recurrence of retroperitoneal sarcoma, arguing that there is insufficient evidence to suggest that survival is improved by earlier detection.Whooley and colleagues reviewed the efficacy of the sur-veillance strategy used at Roswell Park Cancer Institute for 174 patients with soft tissue sarcomas of the extremities.160 Patients were evaluated every 3 months for the first 2 years, every 4 to 6 months during year 3, and every 6 months during years 4 and 5. Local recurrence occurred in 18% of patients at a median time after completion of treatment of 14 months, and all but one of the recurrences were detected with physical examination alone. Fifty-seven patients had distant recurrences (at a
|
Surgery_Schwartz_10432
|
Surgery_Schwartz
|
at a median time after completion of treatment of 14 months, and all but one of the recurrences were detected with physical examination alone. Fifty-seven patients had distant recurrences (at a median of 18 months after treatment), of which 36 were asymptomatic and diagnosed by surveillance imaging. The investigators determined that the positive predictive value of chest radiography during follow-up was 92%.160 However, evaluation of the primary tumor site by CT or MRI was ineffective in detecting recurrences. The authors recommended that patient characteristics, location of the primary tumor, previous treatment, and physician familiarity with changes after surgery and radiation therapy should all be considered in determining the need for radiographic imaging.Management of Recurrent SarcomaUp to 20% of patients with extremity sarcoma develop locally recurrent disease, which is often accompanied by distant metastases; thus, all patients with recurrent extremity sarcoma should undergo
|
Surgery_Schwartz. at a median time after completion of treatment of 14 months, and all but one of the recurrences were detected with physical examination alone. Fifty-seven patients had distant recurrences (at a median of 18 months after treatment), of which 36 were asymptomatic and diagnosed by surveillance imaging. The investigators determined that the positive predictive value of chest radiography during follow-up was 92%.160 However, evaluation of the primary tumor site by CT or MRI was ineffective in detecting recurrences. The authors recommended that patient characteristics, location of the primary tumor, previous treatment, and physician familiarity with changes after surgery and radiation therapy should all be considered in determining the need for radiographic imaging.Management of Recurrent SarcomaUp to 20% of patients with extremity sarcoma develop locally recurrent disease, which is often accompanied by distant metastases; thus, all patients with recurrent extremity sarcoma should undergo
|
Surgery_Schwartz_10433
|
Surgery_Schwartz
|
to 20% of patients with extremity sarcoma develop locally recurrent disease, which is often accompanied by distant metastases; thus, all patients with recurrent extremity sarcoma should undergo a full staging assessment. Patients with microscopically positive surgical margins are at increased risk of local recurrence. In a series of 179 patients with locally recurrent extremity soft tissue sarcoma at Memorial Sloan-Kettering Cancer Center, the median interval to local recurrence was 16 months; 65% of patients developed a local recurrence by 2 years, and 90% by 4 years.155 The majority of patients (89%) were treated with additional limb-sparing surgery, and 73% received additional adjuvant therapy; the disease-specific survival after treatment of first local recurrence was 55% at 4 years. Independent prognostic factors for disease-specific survival after local recurrence included tumor grade, local recurrence size, and local recurrence-free interval. These data indicate that an
|
Surgery_Schwartz. to 20% of patients with extremity sarcoma develop locally recurrent disease, which is often accompanied by distant metastases; thus, all patients with recurrent extremity sarcoma should undergo a full staging assessment. Patients with microscopically positive surgical margins are at increased risk of local recurrence. In a series of 179 patients with locally recurrent extremity soft tissue sarcoma at Memorial Sloan-Kettering Cancer Center, the median interval to local recurrence was 16 months; 65% of patients developed a local recurrence by 2 years, and 90% by 4 years.155 The majority of patients (89%) were treated with additional limb-sparing surgery, and 73% received additional adjuvant therapy; the disease-specific survival after treatment of first local recurrence was 55% at 4 years. Independent prognostic factors for disease-specific survival after local recurrence included tumor grade, local recurrence size, and local recurrence-free interval. These data indicate that an
|
Surgery_Schwartz_10434
|
Surgery_Schwartz
|
years. Independent prognostic factors for disease-specific survival after local recurrence included tumor grade, local recurrence size, and local recurrence-free interval. These data indicate that an isolated local recurrence should be treated aggressively with resection with negative margins.For patients with extremity sarcomas, achieving negative margins on resection of recurrent disease frequently requires amputation. However, in some patients with recurrent extrem-ity sarcoma, function-preserving resection combined with addi-tional radiation therapy, with or without chemotherapy, can produce acceptable rates of local control.161-163 Nori and col-leagues reported a local control rate of 69% among 40 patients with recurrent tumors treated with reexcision and brachytherapy to a median dose of 45 Gy.163 In a similar series, Midis and col-leagues reported that limb-sparing surgery was possible in 66% of patients, and the 5-year local recurrence-free survival rate was 72% in those
|
Surgery_Schwartz. years. Independent prognostic factors for disease-specific survival after local recurrence included tumor grade, local recurrence size, and local recurrence-free interval. These data indicate that an isolated local recurrence should be treated aggressively with resection with negative margins.For patients with extremity sarcomas, achieving negative margins on resection of recurrent disease frequently requires amputation. However, in some patients with recurrent extrem-ity sarcoma, function-preserving resection combined with addi-tional radiation therapy, with or without chemotherapy, can produce acceptable rates of local control.161-163 Nori and col-leagues reported a local control rate of 69% among 40 patients with recurrent tumors treated with reexcision and brachytherapy to a median dose of 45 Gy.163 In a similar series, Midis and col-leagues reported that limb-sparing surgery was possible in 66% of patients, and the 5-year local recurrence-free survival rate was 72% in those
|
Surgery_Schwartz_10435
|
Surgery_Schwartz
|
dose of 45 Gy.163 In a similar series, Midis and col-leagues reported that limb-sparing surgery was possible in 66% of patients, and the 5-year local recurrence-free survival rate was 72% in those patients.161The primary determinant of survival in patients with soft tissue sarcoma is the development of distant metastases. Patients with extremity sarcomas generally develop pulmonary metastases.160 Less common sites of metastasis for soft tissue sarcomas include bone (7%), liver (4%),49 and lymph nodes (5–7%).28 Myxoid liposarcoma of the extremity is known to metastasize to the abdomen and pelvis; therefore, staging CT of these regions must be performed before definitive local therapy is administered.32Management of Recurrent and Distant Metastatic Sarcoma. In selected individuals with distant metastatic disease, surgical resection of a primary soft tissue sarcoma may be appropriate as a palliative procedure. The decision should be based on the patient’s symptoms, which often include
|
Surgery_Schwartz. dose of 45 Gy.163 In a similar series, Midis and col-leagues reported that limb-sparing surgery was possible in 66% of patients, and the 5-year local recurrence-free survival rate was 72% in those patients.161The primary determinant of survival in patients with soft tissue sarcoma is the development of distant metastases. Patients with extremity sarcomas generally develop pulmonary metastases.160 Less common sites of metastasis for soft tissue sarcomas include bone (7%), liver (4%),49 and lymph nodes (5–7%).28 Myxoid liposarcoma of the extremity is known to metastasize to the abdomen and pelvis; therefore, staging CT of these regions must be performed before definitive local therapy is administered.32Management of Recurrent and Distant Metastatic Sarcoma. In selected individuals with distant metastatic disease, surgical resection of a primary soft tissue sarcoma may be appropriate as a palliative procedure. The decision should be based on the patient’s symptoms, which often include
|
Surgery_Schwartz_10436
|
Surgery_Schwartz
|
metastatic disease, surgical resection of a primary soft tissue sarcoma may be appropriate as a palliative procedure. The decision should be based on the patient’s symptoms, which often include pain; ability to achieve local tumor control; comorbidities; anticipated morbidity of the surgical procedure; and the extent of metastases.The most common initial site of distant metastasis of soft tissue sarcomas is the lung. Selected patients with a limited number of pulmonary nodules (less than four nodules), long disease-free intervals, and no endobronchial invasion may become long-term survivors after pulmonary resection (Fig. 36-8); 15% to 40% of patients with complete resection of metastatic disease confined to the lung are long-term survivors.159,160,164 In a retrospective multi-institutional study of 255 patients with lung metastases, the 5-year overall survival rate after metastasectomy was 38%.157 Favorable prognostic factors in that study included microscopically tumor-free
|
Surgery_Schwartz. metastatic disease, surgical resection of a primary soft tissue sarcoma may be appropriate as a palliative procedure. The decision should be based on the patient’s symptoms, which often include pain; ability to achieve local tumor control; comorbidities; anticipated morbidity of the surgical procedure; and the extent of metastases.The most common initial site of distant metastasis of soft tissue sarcomas is the lung. Selected patients with a limited number of pulmonary nodules (less than four nodules), long disease-free intervals, and no endobronchial invasion may become long-term survivors after pulmonary resection (Fig. 36-8); 15% to 40% of patients with complete resection of metastatic disease confined to the lung are long-term survivors.159,160,164 In a retrospective multi-institutional study of 255 patients with lung metastases, the 5-year overall survival rate after metastasectomy was 38%.157 Favorable prognostic factors in that study included microscopically tumor-free
|
Surgery_Schwartz_10437
|
Surgery_Schwartz
|
study of 255 patients with lung metastases, the 5-year overall survival rate after metastasectomy was 38%.157 Favorable prognostic factors in that study included microscopically tumor-free margins, age younger than 40 years, and grade 1 or 2 tumor.157 For patients who are surgical candidates, pulmonary resection alone can be more cost-effective than watchful waiting, chemotherapy, or chemotherapy plus surgery.158Chemotherapy for Distant Metastatic Sarcoma. Doxorubicin, either alone or combined with other agents, has been the primary treatment modality for patients with advanced or distant metastatic sarcomas for several decades.128 Although most patients with metastatic disease are not curable, some Figure 36-8. A 69-year-old patient with a history of a dedifferenti-ated liposarcoma of the retroperitoneum developed a solitary lung metastasis 6 years after surgical resection.Brunicardi_Ch36_p1567-p1598.indd 158101/03/19 6:38 PM 1582SPECIFIC CONSIDERATIONSPART IIpatients with
|
Surgery_Schwartz. study of 255 patients with lung metastases, the 5-year overall survival rate after metastasectomy was 38%.157 Favorable prognostic factors in that study included microscopically tumor-free margins, age younger than 40 years, and grade 1 or 2 tumor.157 For patients who are surgical candidates, pulmonary resection alone can be more cost-effective than watchful waiting, chemotherapy, or chemotherapy plus surgery.158Chemotherapy for Distant Metastatic Sarcoma. Doxorubicin, either alone or combined with other agents, has been the primary treatment modality for patients with advanced or distant metastatic sarcomas for several decades.128 Although most patients with metastatic disease are not curable, some Figure 36-8. A 69-year-old patient with a history of a dedifferenti-ated liposarcoma of the retroperitoneum developed a solitary lung metastasis 6 years after surgical resection.Brunicardi_Ch36_p1567-p1598.indd 158101/03/19 6:38 PM 1582SPECIFIC CONSIDERATIONSPART IIpatients with
|
Surgery_Schwartz_10438
|
Surgery_Schwartz
|
of the retroperitoneum developed a solitary lung metastasis 6 years after surgical resection.Brunicardi_Ch36_p1567-p1598.indd 158101/03/19 6:38 PM 1582SPECIFIC CONSIDERATIONSPART IIpatients with limited disease experience stabilization of disease with multidisciplinary treatment, which often includes surgery and radiation therapy in addition to chemotherapy. Several factors predict better outcome for patients with recurrent metastatic sarcoma undergoing chemotherapy, including good performance status, previous response to chemotherapy, younger age, absence of hepatic metastases, low-grade tumor, and long disease-free interval.165 Isolated liver metastases, if stable over several months, may be amenable to resection,166 radiofrequency ablation,167 or chemoembolization.168As data accumulate regarding the sensitivity of sarcoma subtypes to particular chemotherapies, it is critical that histologydriven treatment approaches be used. New therapies are also being identified based on the
|
Surgery_Schwartz. of the retroperitoneum developed a solitary lung metastasis 6 years after surgical resection.Brunicardi_Ch36_p1567-p1598.indd 158101/03/19 6:38 PM 1582SPECIFIC CONSIDERATIONSPART IIpatients with limited disease experience stabilization of disease with multidisciplinary treatment, which often includes surgery and radiation therapy in addition to chemotherapy. Several factors predict better outcome for patients with recurrent metastatic sarcoma undergoing chemotherapy, including good performance status, previous response to chemotherapy, younger age, absence of hepatic metastases, low-grade tumor, and long disease-free interval.165 Isolated liver metastases, if stable over several months, may be amenable to resection,166 radiofrequency ablation,167 or chemoembolization.168As data accumulate regarding the sensitivity of sarcoma subtypes to particular chemotherapies, it is critical that histologydriven treatment approaches be used. New therapies are also being identified based on the
|
Surgery_Schwartz_10439
|
Surgery_Schwartz
|
regarding the sensitivity of sarcoma subtypes to particular chemotherapies, it is critical that histologydriven treatment approaches be used. New therapies are also being identified based on the unique molecular signatures of sarcomas.128Palliative Radiation Therapy. Definitive radiation therapy can be considered when no acceptable surgical option is avail-able (e.g., in patients with significant medical comorbidities). In this setting, radiation doses greater than 63 Gy yielded superior tumor control, but doses greater than 68 Gy resulted in increased rates of major complications.169SPECIAL CLINICAL SITUATIONSMyxoid LiposarcomaMyxoid liposarcomas belong to the group of soft tissue sarco-mas with lipomatous differentiation. However, myxoid liposar-comas differ from the other liposarcoma subtypes with respect to morphology (i.e., myxoid stroma and lipomatous differen-tiation) and clinical behavior. Myxoid liposarcomas frequently present as slow-growing, deep tumors in the lower
|
Surgery_Schwartz. regarding the sensitivity of sarcoma subtypes to particular chemotherapies, it is critical that histologydriven treatment approaches be used. New therapies are also being identified based on the unique molecular signatures of sarcomas.128Palliative Radiation Therapy. Definitive radiation therapy can be considered when no acceptable surgical option is avail-able (e.g., in patients with significant medical comorbidities). In this setting, radiation doses greater than 63 Gy yielded superior tumor control, but doses greater than 68 Gy resulted in increased rates of major complications.169SPECIAL CLINICAL SITUATIONSMyxoid LiposarcomaMyxoid liposarcomas belong to the group of soft tissue sarco-mas with lipomatous differentiation. However, myxoid liposar-comas differ from the other liposarcoma subtypes with respect to morphology (i.e., myxoid stroma and lipomatous differen-tiation) and clinical behavior. Myxoid liposarcomas frequently present as slow-growing, deep tumors in the lower
|
Surgery_Schwartz_10440
|
Surgery_Schwartz
|
subtypes with respect to morphology (i.e., myxoid stroma and lipomatous differen-tiation) and clinical behavior. Myxoid liposarcomas frequently present as slow-growing, deep tumors in the lower extremity and can metastasize to other soft tissue locations, including the retroperitoneum and extremities.170,171 For this reason, CT of the chest, abdomen, and pelvis is recommended for adequate stag-ing and surveillance of myxoid liposarcoma.Retroperitoneal SarcomaMost retroperitoneal tumors are malignant, and about one-third are soft tissue sarcomas. Also to be considered in the differen-tial diagnosis of a retroperitoneal tumor are primary germ cell tumors, lymphoma, and metastatic testicular cancer. Approxi-mately 1000 new cases of retroperitoneal sarcoma are diagnosed annually in the United States, and these tumors account for 10% to 15% of all adult tissue sarcomas. Approximately two-thirds of retroperitoneal sarcomas are high grade (either grade 2 or 3), and liposarcoma and
|
Surgery_Schwartz. subtypes with respect to morphology (i.e., myxoid stroma and lipomatous differen-tiation) and clinical behavior. Myxoid liposarcomas frequently present as slow-growing, deep tumors in the lower extremity and can metastasize to other soft tissue locations, including the retroperitoneum and extremities.170,171 For this reason, CT of the chest, abdomen, and pelvis is recommended for adequate stag-ing and surveillance of myxoid liposarcoma.Retroperitoneal SarcomaMost retroperitoneal tumors are malignant, and about one-third are soft tissue sarcomas. Also to be considered in the differen-tial diagnosis of a retroperitoneal tumor are primary germ cell tumors, lymphoma, and metastatic testicular cancer. Approxi-mately 1000 new cases of retroperitoneal sarcoma are diagnosed annually in the United States, and these tumors account for 10% to 15% of all adult tissue sarcomas. Approximately two-thirds of retroperitoneal sarcomas are high grade (either grade 2 or 3), and liposarcoma and
|
Surgery_Schwartz_10441
|
Surgery_Schwartz
|
the United States, and these tumors account for 10% to 15% of all adult tissue sarcomas. Approximately two-thirds of retroperitoneal sarcomas are high grade (either grade 2 or 3), and liposarcoma and leiomyosarcoma are the most common histologies.Retroperitoneal sarcomas generally present as large masses: 70% are larger than 10 cm at diagnosis.172 They typi-cally do not produce symptoms until they grow large enough to compress or invade contiguous structures, although pain, early satiety, and obstructive gastrointestinal symptoms may occur early in the disease course in some patients. Evaluation of a patient with a retroperitoneal mass begins with an accurate his-tory that should exclude signs and symptoms associated with lymphoma (e.g., fever and night sweats). A complete physical examination, with particular attention to all nodal basins and with a testicular examination in men, is critically important. Laboratory assessment can be helpful; elevated lactate dehy-drogenase levels may
|
Surgery_Schwartz. the United States, and these tumors account for 10% to 15% of all adult tissue sarcomas. Approximately two-thirds of retroperitoneal sarcomas are high grade (either grade 2 or 3), and liposarcoma and leiomyosarcoma are the most common histologies.Retroperitoneal sarcomas generally present as large masses: 70% are larger than 10 cm at diagnosis.172 They typi-cally do not produce symptoms until they grow large enough to compress or invade contiguous structures, although pain, early satiety, and obstructive gastrointestinal symptoms may occur early in the disease course in some patients. Evaluation of a patient with a retroperitoneal mass begins with an accurate his-tory that should exclude signs and symptoms associated with lymphoma (e.g., fever and night sweats). A complete physical examination, with particular attention to all nodal basins and with a testicular examination in men, is critically important. Laboratory assessment can be helpful; elevated lactate dehy-drogenase levels may
|
Surgery_Schwartz_10442
|
Surgery_Schwartz
|
with particular attention to all nodal basins and with a testicular examination in men, is critically important. Laboratory assessment can be helpful; elevated lactate dehy-drogenase levels may suggest lymphoma, and elevated β-human chorionic gonadotropin levels or α-fetoprotein levels may indi-cate a germ cell tumor.Figure 36-9. A 50-year-old man with a large right dedifferentiated liposarcoma. Note the atypical fat surrounding the right kidney and displacing the viscera to the left hemiabdomen and the large dedifferentiated mineralized solid nodule lateral to the right kidney.Although the general principles of evaluation and man-agement for retroperitoneal sarcomas are similar to those for extremity sarcomas, there are some differences. Contrast-enhanced CT of the abdomen and pelvis is used to define the extent of the tumor and its relationship to surrounding struc-tures, particularly vascular structures, for surgical planning; contrast-enhanced CT can also often distinguish between
|
Surgery_Schwartz. with particular attention to all nodal basins and with a testicular examination in men, is critically important. Laboratory assessment can be helpful; elevated lactate dehy-drogenase levels may suggest lymphoma, and elevated β-human chorionic gonadotropin levels or α-fetoprotein levels may indi-cate a germ cell tumor.Figure 36-9. A 50-year-old man with a large right dedifferentiated liposarcoma. Note the atypical fat surrounding the right kidney and displacing the viscera to the left hemiabdomen and the large dedifferentiated mineralized solid nodule lateral to the right kidney.Although the general principles of evaluation and man-agement for retroperitoneal sarcomas are similar to those for extremity sarcomas, there are some differences. Contrast-enhanced CT of the abdomen and pelvis is used to define the extent of the tumor and its relationship to surrounding struc-tures, particularly vascular structures, for surgical planning; contrast-enhanced CT can also often distinguish between
|
Surgery_Schwartz_10443
|
Surgery_Schwartz
|
to define the extent of the tumor and its relationship to surrounding struc-tures, particularly vascular structures, for surgical planning; contrast-enhanced CT can also often distinguish between well-differentiated and dedifferentiated liposarcoma. CT imaging is also done to evaluate the liver for the evidence of metastases, the peritoneal cavity for evidence of discontiguous disease, and the kidneys for assessment of function. Angiography or mag-netic resonance arteriography/venography can also be used to delineate vascular anatomy when involvement of critical vascu-lar structures is suspected. Thoracic CT should be performed to evaluate for potential lung metastases because 11% of patients with retroperitoneal sarcoma present with synchronous meta-static disease. CT-guided core needle biopsy is appropriate to provide a tissue diagnosis; however, well-differentiated liposar-coma may be diagnosed with CT imaging alone, and negative biopsy findings should not delay operative
|
Surgery_Schwartz. to define the extent of the tumor and its relationship to surrounding struc-tures, particularly vascular structures, for surgical planning; contrast-enhanced CT can also often distinguish between well-differentiated and dedifferentiated liposarcoma. CT imaging is also done to evaluate the liver for the evidence of metastases, the peritoneal cavity for evidence of discontiguous disease, and the kidneys for assessment of function. Angiography or mag-netic resonance arteriography/venography can also be used to delineate vascular anatomy when involvement of critical vascu-lar structures is suspected. Thoracic CT should be performed to evaluate for potential lung metastases because 11% of patients with retroperitoneal sarcoma present with synchronous meta-static disease. CT-guided core needle biopsy is appropriate to provide a tissue diagnosis; however, well-differentiated liposar-coma may be diagnosed with CT imaging alone, and negative biopsy findings should not delay operative
|
Surgery_Schwartz_10444
|
Surgery_Schwartz
|
needle biopsy is appropriate to provide a tissue diagnosis; however, well-differentiated liposar-coma may be diagnosed with CT imaging alone, and negative biopsy findings should not delay operative intervention.Complete surgical resection is the most effective treatment for primary or recurrent retroperitoneal sarcoma (Fig. 36-9). En bloc resection often necessitates sacrificing contiguous struc-tures such as the colon, kidney, spleen, pancreas, psoas muscle, small bowel, inferior vena cava, and aorta.173 In a review of 25 patients who underwent resection of retroperitoneal sarcoma with major blood vessel involvement in a 16-year time span, postoperative morbidity and mortality rates were 36% and 4%, respectively. Vessel patency rates were greater than 88% with a median follow-up time of 19.3 months.83,174 Local control and survival rates were favorable in patients with tumor-free resec-tion margins. The authors concluded that vascular resection is the treatment of choice in sarcomas
|
Surgery_Schwartz. needle biopsy is appropriate to provide a tissue diagnosis; however, well-differentiated liposar-coma may be diagnosed with CT imaging alone, and negative biopsy findings should not delay operative intervention.Complete surgical resection is the most effective treatment for primary or recurrent retroperitoneal sarcoma (Fig. 36-9). En bloc resection often necessitates sacrificing contiguous struc-tures such as the colon, kidney, spleen, pancreas, psoas muscle, small bowel, inferior vena cava, and aorta.173 In a review of 25 patients who underwent resection of retroperitoneal sarcoma with major blood vessel involvement in a 16-year time span, postoperative morbidity and mortality rates were 36% and 4%, respectively. Vessel patency rates were greater than 88% with a median follow-up time of 19.3 months.83,174 Local control and survival rates were favorable in patients with tumor-free resec-tion margins. The authors concluded that vascular resection is the treatment of choice in sarcomas
|
Surgery_Schwartz_10445
|
Surgery_Schwartz
|
19.3 months.83,174 Local control and survival rates were favorable in patients with tumor-free resec-tion margins. The authors concluded that vascular resection is the treatment of choice in sarcomas that involve major blood vessels in the retroperitoneum.83 Similar considerations were made by other groups reporting specifically on inferior vena cava resection in the context of multivisceral resection for ret-roperitoneal sarcoma and on surgical morbidity after extended surgical resection of retroperitoneal sarcoma. Extended proce-dures, including also vessels, are feasible and safe if carried out in experienced centers. While the goal of sarcoma resection is Brunicardi_Ch36_p1567-p1598.indd 158201/03/19 6:38 PM 1583SOFT TISSUE SARCOMASCHAPTER 36wide excision, this is unlikely to be achievable in most patients with retroperitoneal sarcomas. Surgery is considered marginal in most cases, even when macroscopically complete, but every attempt should be made to minimize this
|
Surgery_Schwartz. 19.3 months.83,174 Local control and survival rates were favorable in patients with tumor-free resec-tion margins. The authors concluded that vascular resection is the treatment of choice in sarcomas that involve major blood vessels in the retroperitoneum.83 Similar considerations were made by other groups reporting specifically on inferior vena cava resection in the context of multivisceral resection for ret-roperitoneal sarcoma and on surgical morbidity after extended surgical resection of retroperitoneal sarcoma. Extended proce-dures, including also vessels, are feasible and safe if carried out in experienced centers. While the goal of sarcoma resection is Brunicardi_Ch36_p1567-p1598.indd 158201/03/19 6:38 PM 1583SOFT TISSUE SARCOMASCHAPTER 36wide excision, this is unlikely to be achievable in most patients with retroperitoneal sarcomas. Surgery is considered marginal in most cases, even when macroscopically complete, but every attempt should be made to minimize this
|
Surgery_Schwartz_10446
|
Surgery_Schwartz
|
to be achievable in most patients with retroperitoneal sarcomas. Surgery is considered marginal in most cases, even when macroscopically complete, but every attempt should be made to minimize this marginality by liberally resecting surrounding organs when involved. The extension of surgery should then take into consideration a trade-off between expected morbidity and benefit and should be best carried out at high-volume centers, where technical skills and knowledge of the natural history of this very rare disease can be found.In an analysis of 500 patients with retroperitoneal soft tissue sarcoma treated at Memorial Sloan-Kettering Cancer Center, the median survival time was 103 months for those who underwent complete resection versus 18 months for those who underwent incomplete resection or observation without resection.172 In general, surgical resection should not be offered unless radiographic evidence indicates the potential for complete resection; however, palliative surgical
|
Surgery_Schwartz. to be achievable in most patients with retroperitoneal sarcomas. Surgery is considered marginal in most cases, even when macroscopically complete, but every attempt should be made to minimize this marginality by liberally resecting surrounding organs when involved. The extension of surgery should then take into consideration a trade-off between expected morbidity and benefit and should be best carried out at high-volume centers, where technical skills and knowledge of the natural history of this very rare disease can be found.In an analysis of 500 patients with retroperitoneal soft tissue sarcoma treated at Memorial Sloan-Kettering Cancer Center, the median survival time was 103 months for those who underwent complete resection versus 18 months for those who underwent incomplete resection or observation without resection.172 In general, surgical resection should not be offered unless radiographic evidence indicates the potential for complete resection; however, palliative surgical
|
Surgery_Schwartz_10447
|
Surgery_Schwartz
|
or observation without resection.172 In general, surgical resection should not be offered unless radiographic evidence indicates the potential for complete resection; however, palliative surgical resection may be considered to reduce symptoms of intestinal obstruction, pain, or bleeding.175 In particular, in patients with atypical lipomatous tumors, an aggressive surgical approach including incomplete resection or debulking is justified to palliate symptoms and may provide a potential survival benefit.176 Such an approach is not justified for dedifferentiated liposarcomas or other high-grade retroperitoneal sarcomas because these tumors have high rates of distant metastasis and local recurrence.Adjuvant Therapy. Most studies have failed to show a sur-vival benefit from adjuvant chemotherapy for retroperitoneal sarcoma.177-179 Because of the high rates of local recurrence, radiation therapy has been proposed for treating microscopic residual disease as an adjunct to surgical resection.
|
Surgery_Schwartz. or observation without resection.172 In general, surgical resection should not be offered unless radiographic evidence indicates the potential for complete resection; however, palliative surgical resection may be considered to reduce symptoms of intestinal obstruction, pain, or bleeding.175 In particular, in patients with atypical lipomatous tumors, an aggressive surgical approach including incomplete resection or debulking is justified to palliate symptoms and may provide a potential survival benefit.176 Such an approach is not justified for dedifferentiated liposarcomas or other high-grade retroperitoneal sarcomas because these tumors have high rates of distant metastasis and local recurrence.Adjuvant Therapy. Most studies have failed to show a sur-vival benefit from adjuvant chemotherapy for retroperitoneal sarcoma.177-179 Because of the high rates of local recurrence, radiation therapy has been proposed for treating microscopic residual disease as an adjunct to surgical resection.
|
Surgery_Schwartz_10448
|
Surgery_Schwartz
|
for retroperitoneal sarcoma.177-179 Because of the high rates of local recurrence, radiation therapy has been proposed for treating microscopic residual disease as an adjunct to surgical resection. However, the optimal technique and timing of radiation therapy have not been established, and the potential benefits of radiation therapy must be weighed against the increased risk of treatment-related toxic effects.Radiation treatment of retroperitoneal sarcomas is com-plex because tumors are usually large, which necessitates large treatment fields close to radiosensitive structures (e.g., bowel). Several techniques have been used, including preoperative and postoperative external-beam radiation therapy, intraoperative radiation therapy, and brachytherapy.180 Preoperative radiation therapy is feasible and well tolerated. Toxic effects may be less severe with preoperative radiation therapy given that the tumor borders are definable, the tumor displaces radiosensitive viscera away from the
|
Surgery_Schwartz. for retroperitoneal sarcoma.177-179 Because of the high rates of local recurrence, radiation therapy has been proposed for treating microscopic residual disease as an adjunct to surgical resection. However, the optimal technique and timing of radiation therapy have not been established, and the potential benefits of radiation therapy must be weighed against the increased risk of treatment-related toxic effects.Radiation treatment of retroperitoneal sarcomas is com-plex because tumors are usually large, which necessitates large treatment fields close to radiosensitive structures (e.g., bowel). Several techniques have been used, including preoperative and postoperative external-beam radiation therapy, intraoperative radiation therapy, and brachytherapy.180 Preoperative radiation therapy is feasible and well tolerated. Toxic effects may be less severe with preoperative radiation therapy given that the tumor borders are definable, the tumor displaces radiosensitive viscera away from the
|
Surgery_Schwartz_10449
|
Surgery_Schwartz
|
feasible and well tolerated. Toxic effects may be less severe with preoperative radiation therapy given that the tumor borders are definable, the tumor displaces radiosensitive viscera away from the treatment field, and effective doses of radiation may be lower preoperatively.181Several studies have shown favorable local control rates for intermediateand high-grade retroperitoneal sarcoma treated with preoperative radiation therapy and complete resection.180 However, most studies have failed to show a survival benefit.182 This situation prompted the initiation of a multicenter, ran-domized trial sponsored by the American College of Surgeons Oncology Group (ACOSOG) comparing surgery to surgery with preoperative radiation (ACOSOG Z9031). Unfortunately, the study was closed prematurely in 2006 because of low patient accrual. A similar study is now ongoing in Europe, sponsored by the Soft Tissue and Bone Sarcoma Group (STBSG) of the EORTC.Current recommendations for radiation therapy for
|
Surgery_Schwartz. feasible and well tolerated. Toxic effects may be less severe with preoperative radiation therapy given that the tumor borders are definable, the tumor displaces radiosensitive viscera away from the treatment field, and effective doses of radiation may be lower preoperatively.181Several studies have shown favorable local control rates for intermediateand high-grade retroperitoneal sarcoma treated with preoperative radiation therapy and complete resection.180 However, most studies have failed to show a survival benefit.182 This situation prompted the initiation of a multicenter, ran-domized trial sponsored by the American College of Surgeons Oncology Group (ACOSOG) comparing surgery to surgery with preoperative radiation (ACOSOG Z9031). Unfortunately, the study was closed prematurely in 2006 because of low patient accrual. A similar study is now ongoing in Europe, sponsored by the Soft Tissue and Bone Sarcoma Group (STBSG) of the EORTC.Current recommendations for radiation therapy for
|
Surgery_Schwartz_10450
|
Surgery_Schwartz
|
because of low patient accrual. A similar study is now ongoing in Europe, sponsored by the Soft Tissue and Bone Sarcoma Group (STBSG) of the EORTC.Current recommendations for radiation therapy for patients with retroperitoneal sarcoma at high volumes centers are based on disease characteristics at presentation.183 For high-risk patients, defined as those with large, high-grade tumors or recurrent low-grade tumors, preoperative radiation therapy to a total dose of 50 Gy followed by surgical resection is considered. Postoperative radiation is discouraged unless the resected tumor bed is clearly away from dose-limiting structures.Treatment of Recurrence. Retroperitoneal sarcomas recur more often than extremity and trunk wall ones. Retroperito-neal leiomyosarcomas, in addition to recurring locally in the tumor bed and metastasizing to the lungs, frequently spread to the liver. Retroperitoneal sarcomas can also recur diffusely throughout the peritoneal cavity (sarcomatosis). Resection of
|
Surgery_Schwartz. because of low patient accrual. A similar study is now ongoing in Europe, sponsored by the Soft Tissue and Bone Sarcoma Group (STBSG) of the EORTC.Current recommendations for radiation therapy for patients with retroperitoneal sarcoma at high volumes centers are based on disease characteristics at presentation.183 For high-risk patients, defined as those with large, high-grade tumors or recurrent low-grade tumors, preoperative radiation therapy to a total dose of 50 Gy followed by surgical resection is considered. Postoperative radiation is discouraged unless the resected tumor bed is clearly away from dose-limiting structures.Treatment of Recurrence. Retroperitoneal sarcomas recur more often than extremity and trunk wall ones. Retroperito-neal leiomyosarcomas, in addition to recurring locally in the tumor bed and metastasizing to the lungs, frequently spread to the liver. Retroperitoneal sarcomas can also recur diffusely throughout the peritoneal cavity (sarcomatosis). Resection of
|
Surgery_Schwartz_10451
|
Surgery_Schwartz
|
in the tumor bed and metastasizing to the lungs, frequently spread to the liver. Retroperitoneal sarcomas can also recur diffusely throughout the peritoneal cavity (sarcomatosis). Resection of recurrent retroperitoneal sarcoma is similar to resection of recurrent extremity sarcoma. However, the likelihood that a recurrent retroperitoneal sarcoma will be resectable declines precipitously with each recurrence. In a large series of patients treated at Memorial Sloan-Kettering Cancer Center, the authors were able to resect recurrent tumors in 57% of patients with a first recurrence but only 20% of patients with a second recur-rence and 10% of patients with a third recurrence.68 In up to 25% of patients, well-differentiated retroperitoneal liposarcoma recurs in a poorly differentiated form or recurs with areas of dedifferentiation. Dedifferentiated retroperitoneal liposarcoma is more aggressive than its well-differentiated precursor and has a greater propensity for distant
|
Surgery_Schwartz. in the tumor bed and metastasizing to the lungs, frequently spread to the liver. Retroperitoneal sarcomas can also recur diffusely throughout the peritoneal cavity (sarcomatosis). Resection of recurrent retroperitoneal sarcoma is similar to resection of recurrent extremity sarcoma. However, the likelihood that a recurrent retroperitoneal sarcoma will be resectable declines precipitously with each recurrence. In a large series of patients treated at Memorial Sloan-Kettering Cancer Center, the authors were able to resect recurrent tumors in 57% of patients with a first recurrence but only 20% of patients with a second recur-rence and 10% of patients with a third recurrence.68 In up to 25% of patients, well-differentiated retroperitoneal liposarcoma recurs in a poorly differentiated form or recurs with areas of dedifferentiation. Dedifferentiated retroperitoneal liposarcoma is more aggressive than its well-differentiated precursor and has a greater propensity for distant
|
Surgery_Schwartz_10452
|
Surgery_Schwartz
|
form or recurs with areas of dedifferentiation. Dedifferentiated retroperitoneal liposarcoma is more aggressive than its well-differentiated precursor and has a greater propensity for distant metastasis.Gastrointestinal SarcomaPatients with gastrointestinal sarcoma most often present with nonspecific gastrointestinal symptoms that are determined by the site of the primary tumor. In a series from Memorial Sloan-Kettering Cancer Center, early satiety and dyspepsia were noted in patients with tumors of the upper gastrointestinal tract, whereas tenesmus and changes in bowel habits were common in patients with tumors of the lower gastrointestinal tract.184 In a series of 80 patients with various smooth-muscle tumors of the gastrointestinal tract, Chou and colleagues185 identified the most common presenting symptoms and signs as gastrointes-tinal bleeding (44%), abdominal mass (38%), and abdominal pain (21%).Establishing the diagnosis of a gastrointestinal sarcoma preoperatively is often
|
Surgery_Schwartz. form or recurs with areas of dedifferentiation. Dedifferentiated retroperitoneal liposarcoma is more aggressive than its well-differentiated precursor and has a greater propensity for distant metastasis.Gastrointestinal SarcomaPatients with gastrointestinal sarcoma most often present with nonspecific gastrointestinal symptoms that are determined by the site of the primary tumor. In a series from Memorial Sloan-Kettering Cancer Center, early satiety and dyspepsia were noted in patients with tumors of the upper gastrointestinal tract, whereas tenesmus and changes in bowel habits were common in patients with tumors of the lower gastrointestinal tract.184 In a series of 80 patients with various smooth-muscle tumors of the gastrointestinal tract, Chou and colleagues185 identified the most common presenting symptoms and signs as gastrointes-tinal bleeding (44%), abdominal mass (38%), and abdominal pain (21%).Establishing the diagnosis of a gastrointestinal sarcoma preoperatively is often
|
Surgery_Schwartz_10453
|
Surgery_Schwartz
|
presenting symptoms and signs as gastrointes-tinal bleeding (44%), abdominal mass (38%), and abdominal pain (21%).Establishing the diagnosis of a gastrointestinal sarcoma preoperatively is often difficult. Radiologic assessment, includ-ing CT of the abdomen or pelvis, is sometimes useful to deter-mine the anatomic location, size, and extent of disease. Patients with localized disease frequently present with a large intra-abdominal mass. However, there is no radiographic evidence of regional lymph node metastases, which would be typical of an adenocarcinoma of similar size and anatomic location. In patients with advanced gastrointestinal sarcoma, CT may dem-onstrate disseminated intra-abdominal masses with or without concomitant ascites and invasion of tissue planes.Endoscopy (esophagoduodenoscopy or colonoscopy) has become the mainstay for evaluating symptoms related to the gastrointestinal tract. For tumors involving the stomach, upper endoscopy with endoscopic ultrasonography and
|
Surgery_Schwartz. presenting symptoms and signs as gastrointes-tinal bleeding (44%), abdominal mass (38%), and abdominal pain (21%).Establishing the diagnosis of a gastrointestinal sarcoma preoperatively is often difficult. Radiologic assessment, includ-ing CT of the abdomen or pelvis, is sometimes useful to deter-mine the anatomic location, size, and extent of disease. Patients with localized disease frequently present with a large intra-abdominal mass. However, there is no radiographic evidence of regional lymph node metastases, which would be typical of an adenocarcinoma of similar size and anatomic location. In patients with advanced gastrointestinal sarcoma, CT may dem-onstrate disseminated intra-abdominal masses with or without concomitant ascites and invasion of tissue planes.Endoscopy (esophagoduodenoscopy or colonoscopy) has become the mainstay for evaluating symptoms related to the gastrointestinal tract. For tumors involving the stomach, upper endoscopy with endoscopic ultrasonography and
|
Surgery_Schwartz_10454
|
Surgery_Schwartz
|
or colonoscopy) has become the mainstay for evaluating symptoms related to the gastrointestinal tract. For tumors involving the stomach, upper endoscopy with endoscopic ultrasonography and biopsy are important diagnostic tests used to distinguish gastrointestinal sarcoma from adenocarcinoma of the stomach. Endoscopic biopsy of these tumors is preferred over CT-guided biopsy if feasible. This distinction is clinically significant because the extent of resection (local excision versus gastrectomy) and the role of regional lymphadenectomy differ for these two condi-tions. For gastrointestinal sarcomas, lymphatic spread is not the primary route of metastasis; consequently, lymphadenectomy is not routinely performed as part of resection. The general rec-ommendation for gastrointestinal sarcoma, based on published data and the primary pattern of distant (vs. local) failure, is to Brunicardi_Ch36_p1567-p1598.indd 158301/03/19 6:38 PM 1584SPECIFIC CONSIDERATIONSPART IIresect the tumor
|
Surgery_Schwartz. or colonoscopy) has become the mainstay for evaluating symptoms related to the gastrointestinal tract. For tumors involving the stomach, upper endoscopy with endoscopic ultrasonography and biopsy are important diagnostic tests used to distinguish gastrointestinal sarcoma from adenocarcinoma of the stomach. Endoscopic biopsy of these tumors is preferred over CT-guided biopsy if feasible. This distinction is clinically significant because the extent of resection (local excision versus gastrectomy) and the role of regional lymphadenectomy differ for these two condi-tions. For gastrointestinal sarcomas, lymphatic spread is not the primary route of metastasis; consequently, lymphadenectomy is not routinely performed as part of resection. The general rec-ommendation for gastrointestinal sarcoma, based on published data and the primary pattern of distant (vs. local) failure, is to Brunicardi_Ch36_p1567-p1598.indd 158301/03/19 6:38 PM 1584SPECIFIC CONSIDERATIONSPART IIresect the tumor
|
Surgery_Schwartz_10455
|
Surgery_Schwartz
|
based on published data and the primary pattern of distant (vs. local) failure, is to Brunicardi_Ch36_p1567-p1598.indd 158301/03/19 6:38 PM 1584SPECIFIC CONSIDERATIONSPART IIresect the tumor with a 2to 4-cm margin of normal tissue. However, some cases may be technically challenging because of the tumor’s anatomic location or size. For example, for gastric tumors located near the gastroesophageal junction, achieving adequate surgical margins may not be possible without a total or proximal subtotal gastrectomy. This recommendation is much different when considering resection of gastrointestinal stromal tumors (GIST) where a gross margin negative resection is rec-ommended are rarely is a total gastrectomy required. Similarly, large leiomyosarcomas arising from the stomach with invasion of adjacent organs should be resected together with the adjacent involved viscera en bloc.For sarcomas of the small or large intestine, segmental bowel resection is the standard treatment. For sarcomas
|
Surgery_Schwartz. based on published data and the primary pattern of distant (vs. local) failure, is to Brunicardi_Ch36_p1567-p1598.indd 158301/03/19 6:38 PM 1584SPECIFIC CONSIDERATIONSPART IIresect the tumor with a 2to 4-cm margin of normal tissue. However, some cases may be technically challenging because of the tumor’s anatomic location or size. For example, for gastric tumors located near the gastroesophageal junction, achieving adequate surgical margins may not be possible without a total or proximal subtotal gastrectomy. This recommendation is much different when considering resection of gastrointestinal stromal tumors (GIST) where a gross margin negative resection is rec-ommended are rarely is a total gastrectomy required. Similarly, large leiomyosarcomas arising from the stomach with invasion of adjacent organs should be resected together with the adjacent involved viscera en bloc.For sarcomas of the small or large intestine, segmental bowel resection is the standard treatment. For sarcomas
|
Surgery_Schwartz_10456
|
Surgery_Schwartz
|
adjacent organs should be resected together with the adjacent involved viscera en bloc.For sarcomas of the small or large intestine, segmental bowel resection is the standard treatment. For sarcomas of the jejunum, ileum, and colon, the tumor is excised en bloc with the involved segment of intestine and its mesentery; radical mesenteric lymphadenectomy is not attempted. For sarcomas originating in the rectum, the tumor resection technique is based on the anatomic location and size of the tumor. For small, low rectal lesions, clear margins may be achievable with a transanal excision. Large or locally invasive lesions may require more extensive operations for complete tumor extirpation.186,187Breast SarcomaSarcomas of the breast are rare tumors, accounting for less than 1% of all breast malignancies and less than 5% of all soft tissue sarcomas. A variety of histologic subtypes have been reported within the breast, including angiosarcoma, stromal sarcoma, fibrosarcoma, and malignant
|
Surgery_Schwartz. adjacent organs should be resected together with the adjacent involved viscera en bloc.For sarcomas of the small or large intestine, segmental bowel resection is the standard treatment. For sarcomas of the jejunum, ileum, and colon, the tumor is excised en bloc with the involved segment of intestine and its mesentery; radical mesenteric lymphadenectomy is not attempted. For sarcomas originating in the rectum, the tumor resection technique is based on the anatomic location and size of the tumor. For small, low rectal lesions, clear margins may be achievable with a transanal excision. Large or locally invasive lesions may require more extensive operations for complete tumor extirpation.186,187Breast SarcomaSarcomas of the breast are rare tumors, accounting for less than 1% of all breast malignancies and less than 5% of all soft tissue sarcomas. A variety of histologic subtypes have been reported within the breast, including angiosarcoma, stromal sarcoma, fibrosarcoma, and malignant
|
Surgery_Schwartz_10457
|
Surgery_Schwartz
|
malignancies and less than 5% of all soft tissue sarcomas. A variety of histologic subtypes have been reported within the breast, including angiosarcoma, stromal sarcoma, fibrosarcoma, and malignant fibrous histiocytoma.Angiosarcoma of the breast accounts for about 50% of all sarcomas of the breast and has increasingly been associated with radiation therapy for treatment of primary breast cancer.10 The period between radiation therapy and diagnosis of radiation-associated breast sarcoma has been reported to range from 3 to 20 years, with an incidence of 0.3% at 10 years and 0.5% at 15 years.188 In a retrospective study of 55 patients with angiosarcoma of the breast, patients with radiation-associated angiosarcoma were on average 30 years older and were less likely to present with distant metastases than radiation-naive patients. Clinically, radiation-associated angiosarcoma of the breast may occur in the irradiated chest wall after mastectomy or in the irradiated breast following
|
Surgery_Schwartz. malignancies and less than 5% of all soft tissue sarcomas. A variety of histologic subtypes have been reported within the breast, including angiosarcoma, stromal sarcoma, fibrosarcoma, and malignant fibrous histiocytoma.Angiosarcoma of the breast accounts for about 50% of all sarcomas of the breast and has increasingly been associated with radiation therapy for treatment of primary breast cancer.10 The period between radiation therapy and diagnosis of radiation-associated breast sarcoma has been reported to range from 3 to 20 years, with an incidence of 0.3% at 10 years and 0.5% at 15 years.188 In a retrospective study of 55 patients with angiosarcoma of the breast, patients with radiation-associated angiosarcoma were on average 30 years older and were less likely to present with distant metastases than radiation-naive patients. Clinically, radiation-associated angiosarcoma of the breast may occur in the irradiated chest wall after mastectomy or in the irradiated breast following
|
Surgery_Schwartz_10458
|
Surgery_Schwartz
|
metastases than radiation-naive patients. Clinically, radiation-associated angiosarcoma of the breast may occur in the irradiated chest wall after mastectomy or in the irradiated breast following segmental resection. The findings at presentation of a patient with cutaneous angiosarcoma often include an expanding erythematous patch, red papular eruptions, bluish-black lesions, or bruise-like discoloration overlying an area of induration. Mammography is often nonspecific, and diagnosis requires punch or incisional biopsy.Cystosarcoma phyllodes are generally not considered to be sarcomas because these tumors are thought to originate from hormonally responsive stromal cells of the breast and are usu-ally benign. In patients with these tumors, infiltrating tumor margins, severe stromal overgrowth, atypia, and cellularity have all been identified as risk factors for metastases.189As with sarcomas at other anatomic sites, histopathologic grade and tumor size are important prognostic factors
|
Surgery_Schwartz. metastases than radiation-naive patients. Clinically, radiation-associated angiosarcoma of the breast may occur in the irradiated chest wall after mastectomy or in the irradiated breast following segmental resection. The findings at presentation of a patient with cutaneous angiosarcoma often include an expanding erythematous patch, red papular eruptions, bluish-black lesions, or bruise-like discoloration overlying an area of induration. Mammography is often nonspecific, and diagnosis requires punch or incisional biopsy.Cystosarcoma phyllodes are generally not considered to be sarcomas because these tumors are thought to originate from hormonally responsive stromal cells of the breast and are usu-ally benign. In patients with these tumors, infiltrating tumor margins, severe stromal overgrowth, atypia, and cellularity have all been identified as risk factors for metastases.189As with sarcomas at other anatomic sites, histopathologic grade and tumor size are important prognostic factors
|
Surgery_Schwartz_10459
|
Surgery_Schwartz
|
atypia, and cellularity have all been identified as risk factors for metastases.189As with sarcomas at other anatomic sites, histopathologic grade and tumor size are important prognostic factors for sarco-mas of the breast. The likelihood of local recurrence increases as tumor size increases; tumors smaller than 5 cm are associated with better overall survival. Local and distant recurrences are more common in patients with high-grade lesions. Complete excision with negative margins is the primary therapy. Simple mastectomy confers no additional benefit if complete excision can be accomplished by segmental mastectomy. Because of low rates of regional lymphatic spread, axillary dissection is not rou-tinely indicated. Neoadjuvant chemotherapy or radiation ther-apy may be considered for patients with large, high-risk tumors.Uterine SarcomaSarcomas account for less than 5% of uterine malignancies. Uterine sarcomas have been classified into four histologic sub-groups: uterine
|
Surgery_Schwartz. atypia, and cellularity have all been identified as risk factors for metastases.189As with sarcomas at other anatomic sites, histopathologic grade and tumor size are important prognostic factors for sarco-mas of the breast. The likelihood of local recurrence increases as tumor size increases; tumors smaller than 5 cm are associated with better overall survival. Local and distant recurrences are more common in patients with high-grade lesions. Complete excision with negative margins is the primary therapy. Simple mastectomy confers no additional benefit if complete excision can be accomplished by segmental mastectomy. Because of low rates of regional lymphatic spread, axillary dissection is not rou-tinely indicated. Neoadjuvant chemotherapy or radiation ther-apy may be considered for patients with large, high-risk tumors.Uterine SarcomaSarcomas account for less than 5% of uterine malignancies. Uterine sarcomas have been classified into four histologic sub-groups: uterine
|
Surgery_Schwartz_10460
|
Surgery_Schwartz
|
for patients with large, high-risk tumors.Uterine SarcomaSarcomas account for less than 5% of uterine malignancies. Uterine sarcomas have been classified into four histologic sub-groups: uterine leiomyosarcoma, endometrial stromal sarcoma, malignant mixed Müllerian tumor (carcinosarcoma), and undif-ferentiated endometrial sarcoma. Five-year overall survival rates for patients with uterine sarcoma are 30% to 50%.190 Total abdominal hysterectomy (TAH) is recommended for localized disease. Bilateral salpingo-oophorectomy is mandatory only in endometrial stromal sarcoma. Because uterine sarcomas are rare, the benefits of adjuvant therapy (e.g., chemotherapy, hor-monal therapy) have not been adequately evaluated. Pelvic post-operative irradiation has been studied instead in a randomized fashion. The results of such study have been reported, showing no benefit in survival in favor of radiation therapy.191Uterine leiomyosarcomas are smooth-muscle tumors and account for 35% to 40% of uterine
|
Surgery_Schwartz. for patients with large, high-risk tumors.Uterine SarcomaSarcomas account for less than 5% of uterine malignancies. Uterine sarcomas have been classified into four histologic sub-groups: uterine leiomyosarcoma, endometrial stromal sarcoma, malignant mixed Müllerian tumor (carcinosarcoma), and undif-ferentiated endometrial sarcoma. Five-year overall survival rates for patients with uterine sarcoma are 30% to 50%.190 Total abdominal hysterectomy (TAH) is recommended for localized disease. Bilateral salpingo-oophorectomy is mandatory only in endometrial stromal sarcoma. Because uterine sarcomas are rare, the benefits of adjuvant therapy (e.g., chemotherapy, hor-monal therapy) have not been adequately evaluated. Pelvic post-operative irradiation has been studied instead in a randomized fashion. The results of such study have been reported, showing no benefit in survival in favor of radiation therapy.191Uterine leiomyosarcomas are smooth-muscle tumors and account for 35% to 40% of uterine
|
Surgery_Schwartz_10461
|
Surgery_Schwartz
|
The results of such study have been reported, showing no benefit in survival in favor of radiation therapy.191Uterine leiomyosarcomas are smooth-muscle tumors and account for 35% to 40% of uterine sarcomas. Leiomyosarcoma can affect women in their twenties, although it is more com-monly diagnosed between 50 and 60 years of age. Standard treatment is TAH with or without ovarian preservation depend-ing on the patient’s wishes and menopausal status. Lymph node metastasis is present in less than 5% of patients at diagnosis, and lymphadenectomy is not recommended. Adjuvant pelvic radia-tion therapy can be considered for selected high-risk patients. Adjuvant chemotherapy is controversial. Gemcitabine plus docetaxel has been noted to be well tolerated and highly active, with a response rate of 53% in patients with unresectable uter-ine leiomyosarcoma.130 Doxorubicin and trabectedin have also demonstrated activity when used as firstor second-line therapy.Endometrial stromal sarcomas account
|
Surgery_Schwartz. The results of such study have been reported, showing no benefit in survival in favor of radiation therapy.191Uterine leiomyosarcomas are smooth-muscle tumors and account for 35% to 40% of uterine sarcomas. Leiomyosarcoma can affect women in their twenties, although it is more com-monly diagnosed between 50 and 60 years of age. Standard treatment is TAH with or without ovarian preservation depend-ing on the patient’s wishes and menopausal status. Lymph node metastasis is present in less than 5% of patients at diagnosis, and lymphadenectomy is not recommended. Adjuvant pelvic radia-tion therapy can be considered for selected high-risk patients. Adjuvant chemotherapy is controversial. Gemcitabine plus docetaxel has been noted to be well tolerated and highly active, with a response rate of 53% in patients with unresectable uter-ine leiomyosarcoma.130 Doxorubicin and trabectedin have also demonstrated activity when used as firstor second-line therapy.Endometrial stromal sarcomas account
|
Surgery_Schwartz_10462
|
Surgery_Schwartz
|
53% in patients with unresectable uter-ine leiomyosarcoma.130 Doxorubicin and trabectedin have also demonstrated activity when used as firstor second-line therapy.Endometrial stromal sarcomas account for approximately 7% to 10% of uterine sarcomas. Mitotic count is used to clas-sify endometrial stromal sarcomas as low grade (<10 mito-ses per 10 high-power fields) or high-grade (>10 mitoses per 10 high-power fields). In general, low-grade tumors demon-strate an indolent clinical course, while high-grade tumors are more aggressive with a poorer prognosis. Unlike other uterine sarcomas subtypes, endometrial stromal sarcomas express pro-gesterone receptors and have been found to be responsive to hormonal manipulation as an adjuvant therapy or for treatment of recurrent disease.192,193 Surgical treatment for these tumors includes TAH and bilateral salpingo-oophorectomy in premeno-pausal women; postoperative hormone replacement therapy is contraindicated.194 Recurrent or advanced disease
|
Surgery_Schwartz. 53% in patients with unresectable uter-ine leiomyosarcoma.130 Doxorubicin and trabectedin have also demonstrated activity when used as firstor second-line therapy.Endometrial stromal sarcomas account for approximately 7% to 10% of uterine sarcomas. Mitotic count is used to clas-sify endometrial stromal sarcomas as low grade (<10 mito-ses per 10 high-power fields) or high-grade (>10 mitoses per 10 high-power fields). In general, low-grade tumors demon-strate an indolent clinical course, while high-grade tumors are more aggressive with a poorer prognosis. Unlike other uterine sarcomas subtypes, endometrial stromal sarcomas express pro-gesterone receptors and have been found to be responsive to hormonal manipulation as an adjuvant therapy or for treatment of recurrent disease.192,193 Surgical treatment for these tumors includes TAH and bilateral salpingo-oophorectomy in premeno-pausal women; postoperative hormone replacement therapy is contraindicated.194 Recurrent or advanced disease
|
Surgery_Schwartz_10463
|
Surgery_Schwartz
|
treatment for these tumors includes TAH and bilateral salpingo-oophorectomy in premeno-pausal women; postoperative hormone replacement therapy is contraindicated.194 Recurrent or advanced disease may respond to antiestrogen therapy. Tamoxifen is not recommended because it may be proestrogenic in this setting.Malignant mixed müllerian tumor accounts for 50% of uterine sarcomas and arises predominantly in postmenopausal women. This tumor is regarded as epithelial and is treated not with agents typically used to treat sarcoma but with agents used to treat ovarian and endometrial cancers.Undifferentiated endometrial sarcoma is an aggressive malignancy that does not express estrogen or progesterone receptors. It is associated with a poor prognosis even in patients presenting with localized disease. TAH with or without pres-ervation of the ovaries is recommended; postoperative pelvic radiation therapy may also be administered. Systemic agents for other soft tissue sarcomas are used for
|
Surgery_Schwartz. treatment for these tumors includes TAH and bilateral salpingo-oophorectomy in premeno-pausal women; postoperative hormone replacement therapy is contraindicated.194 Recurrent or advanced disease may respond to antiestrogen therapy. Tamoxifen is not recommended because it may be proestrogenic in this setting.Malignant mixed müllerian tumor accounts for 50% of uterine sarcomas and arises predominantly in postmenopausal women. This tumor is regarded as epithelial and is treated not with agents typically used to treat sarcoma but with agents used to treat ovarian and endometrial cancers.Undifferentiated endometrial sarcoma is an aggressive malignancy that does not express estrogen or progesterone receptors. It is associated with a poor prognosis even in patients presenting with localized disease. TAH with or without pres-ervation of the ovaries is recommended; postoperative pelvic radiation therapy may also be administered. Systemic agents for other soft tissue sarcomas are used for
|
Surgery_Schwartz_10464
|
Surgery_Schwartz
|
disease. TAH with or without pres-ervation of the ovaries is recommended; postoperative pelvic radiation therapy may also be administered. Systemic agents for other soft tissue sarcomas are used for recurrent and/or meta-static disease.Brunicardi_Ch36_p1567-p1598.indd 158401/03/19 6:38 PM 1585SOFT TISSUE SARCOMASCHAPTER 36GASTROINTESTINAL STROMAL TUMORSGISTs, which account for the majority of gastrointestinal sar-comas, have distinctive molecular features that have been char-acterized over the last decade. These tumors share phenotypic similarities with the intestinal pacemaker cells known as the interstitial cells of Cajal195; interstitial cells of Cajal and GIST cells express the hematopoietic progenitor cell marker CD34 and the growth factor receptor c-Kit.196 Expression of the c-Kit gene protein product, CD117, has emerged as an important defining feature of GISTs. Using these diagnostic criteria, the incidence of GIST has been estimated to be 6 to 15 cases per million
|
Surgery_Schwartz. disease. TAH with or without pres-ervation of the ovaries is recommended; postoperative pelvic radiation therapy may also be administered. Systemic agents for other soft tissue sarcomas are used for recurrent and/or meta-static disease.Brunicardi_Ch36_p1567-p1598.indd 158401/03/19 6:38 PM 1585SOFT TISSUE SARCOMASCHAPTER 36GASTROINTESTINAL STROMAL TUMORSGISTs, which account for the majority of gastrointestinal sar-comas, have distinctive molecular features that have been char-acterized over the last decade. These tumors share phenotypic similarities with the intestinal pacemaker cells known as the interstitial cells of Cajal195; interstitial cells of Cajal and GIST cells express the hematopoietic progenitor cell marker CD34 and the growth factor receptor c-Kit.196 Expression of the c-Kit gene protein product, CD117, has emerged as an important defining feature of GISTs. Using these diagnostic criteria, the incidence of GIST has been estimated to be 6 to 15 cases per million
|
Surgery_Schwartz_10465
|
Surgery_Schwartz
|
the c-Kit gene protein product, CD117, has emerged as an important defining feature of GISTs. Using these diagnostic criteria, the incidence of GIST has been estimated to be 6 to 15 cases per million individuals per year.197-199 Until recently, systemic treat-ment for patients with unresectable or metastatic GIST was of little benefit because these tumors were resistant to conventional chemotherapy. Since the recognition that KIT activation occurs in most GISTs, KIT inhibition has emerged as an adjunct to sur-gery in select patients with resectable disease and as a primary treatment modality for patients with stage IV disease.Approximately 80% of GISTs have a mutation in the gene encoding the KIT receptor tyrosine kinase, and 5% to 10% have a mutation in the gene encoding the related PDGFRA recep-tor tyrosine kinase; such mutations result in the expression of mutant proteins with constitutive tyrosine kinase activity.1 The remaining GISTs do not have a detectable mutation, but lack of
|
Surgery_Schwartz. the c-Kit gene protein product, CD117, has emerged as an important defining feature of GISTs. Using these diagnostic criteria, the incidence of GIST has been estimated to be 6 to 15 cases per million individuals per year.197-199 Until recently, systemic treat-ment for patients with unresectable or metastatic GIST was of little benefit because these tumors were resistant to conventional chemotherapy. Since the recognition that KIT activation occurs in most GISTs, KIT inhibition has emerged as an adjunct to sur-gery in select patients with resectable disease and as a primary treatment modality for patients with stage IV disease.Approximately 80% of GISTs have a mutation in the gene encoding the KIT receptor tyrosine kinase, and 5% to 10% have a mutation in the gene encoding the related PDGFRA recep-tor tyrosine kinase; such mutations result in the expression of mutant proteins with constitutive tyrosine kinase activity.1 The remaining GISTs do not have a detectable mutation, but lack of
|
Surgery_Schwartz_10466
|
Surgery_Schwartz
|
recep-tor tyrosine kinase; such mutations result in the expression of mutant proteins with constitutive tyrosine kinase activity.1 The remaining GISTs do not have a detectable mutation, but lack of a mutation does not preclude a diagnosis of GIST if the tumor is morphologically typical of GIST. The presence and type of KIT (exon 11 or exon 9) or PDGFRA (exon 18) muta-tion has been found to predict tumor response to imatinib. In a phase 2 trial, patients with KIT exon 11 mutations had bet-ter response rates (83.5% vs. 47.8%) and survival than those with KIT exon 9 mutations or those without KIT or PDGFRA mutation.200 These findings have subsequently been confirmed in two additional phase 3 trials conducted by the EORTC– Italian Sarcoma Group–Australasian Gastrointestinal Trials Group (EORTC-62005).201,202The most common locations for GISTs are the stomach (60%) and small intestine (30%), but GISTs can arise anywhere along the gastrointestinal tract.203 Gastric GISTs have been shown to
|
Surgery_Schwartz. recep-tor tyrosine kinase; such mutations result in the expression of mutant proteins with constitutive tyrosine kinase activity.1 The remaining GISTs do not have a detectable mutation, but lack of a mutation does not preclude a diagnosis of GIST if the tumor is morphologically typical of GIST. The presence and type of KIT (exon 11 or exon 9) or PDGFRA (exon 18) muta-tion has been found to predict tumor response to imatinib. In a phase 2 trial, patients with KIT exon 11 mutations had bet-ter response rates (83.5% vs. 47.8%) and survival than those with KIT exon 9 mutations or those without KIT or PDGFRA mutation.200 These findings have subsequently been confirmed in two additional phase 3 trials conducted by the EORTC– Italian Sarcoma Group–Australasian Gastrointestinal Trials Group (EORTC-62005).201,202The most common locations for GISTs are the stomach (60%) and small intestine (30%), but GISTs can arise anywhere along the gastrointestinal tract.203 Gastric GISTs have been shown to
|
Surgery_Schwartz_10467
|
Surgery_Schwartz
|
most common locations for GISTs are the stomach (60%) and small intestine (30%), but GISTs can arise anywhere along the gastrointestinal tract.203 Gastric GISTs have been shown to be associated with a more favorable prognosis than GISTs at other sites.204 GISTs are most commonly diagnosed by upper endoscopy and/or CT of the abdomen as an incidental finding in an asymptomatic patient or in a patient being evalu-ated for symptoms of early satiety, abdominal pain, or gastroin-testinal bleeding. GIST most frequently metastasizes to the liver and/or abdominal cavity.Radiologic AssessmentStandard imaging techniques apply for GIST as for other intraabdominal sarcomas. In general, oral and IV contrast enhanced spiral CT is the staging modality of choice for GIST. CT scan of the abdomen and pelvis allows for assessment of the primary lesion and the presence or absence of intraabdomi-nal disseminated disease or metastatic disease to the liver (the two most common locations for distant
|
Surgery_Schwartz. most common locations for GISTs are the stomach (60%) and small intestine (30%), but GISTs can arise anywhere along the gastrointestinal tract.203 Gastric GISTs have been shown to be associated with a more favorable prognosis than GISTs at other sites.204 GISTs are most commonly diagnosed by upper endoscopy and/or CT of the abdomen as an incidental finding in an asymptomatic patient or in a patient being evalu-ated for symptoms of early satiety, abdominal pain, or gastroin-testinal bleeding. GIST most frequently metastasizes to the liver and/or abdominal cavity.Radiologic AssessmentStandard imaging techniques apply for GIST as for other intraabdominal sarcomas. In general, oral and IV contrast enhanced spiral CT is the staging modality of choice for GIST. CT scan of the abdomen and pelvis allows for assessment of the primary lesion and the presence or absence of intraabdomi-nal disseminated disease or metastatic disease to the liver (the two most common locations for distant
|
Surgery_Schwartz_10468
|
Surgery_Schwartz
|
pelvis allows for assessment of the primary lesion and the presence or absence of intraabdomi-nal disseminated disease or metastatic disease to the liver (the two most common locations for distant metastasis of GIST). FDG-PET has been reported to be useful for preoperative stag-ing of GISTs because it may reveal early metastases and estab-lish baseline metabolic activity and may be considered in select patients where equivocal findings are identified on CT or in the setting of following metabolic response to therapy. PET has been shown to be highly sensitive in detecting early response to imatinib treatment and in predicting long-term response in patients with metastatic GIST. If PET is to be used for moni-toring response to therapy, baseline PET should be performed before initiation of treatment. Useful and effective CT-based criteria by Choi et al for detection of GIST and for predicting prognosis of GIST have also been proposed and may be used readily without incurring the cost and
|
Surgery_Schwartz. pelvis allows for assessment of the primary lesion and the presence or absence of intraabdomi-nal disseminated disease or metastatic disease to the liver (the two most common locations for distant metastasis of GIST). FDG-PET has been reported to be useful for preoperative stag-ing of GISTs because it may reveal early metastases and estab-lish baseline metabolic activity and may be considered in select patients where equivocal findings are identified on CT or in the setting of following metabolic response to therapy. PET has been shown to be highly sensitive in detecting early response to imatinib treatment and in predicting long-term response in patients with metastatic GIST. If PET is to be used for moni-toring response to therapy, baseline PET should be performed before initiation of treatment. Useful and effective CT-based criteria by Choi et al for detection of GIST and for predicting prognosis of GIST have also been proposed and may be used readily without incurring the cost and
|
Surgery_Schwartz_10469
|
Surgery_Schwartz
|
Useful and effective CT-based criteria by Choi et al for detection of GIST and for predicting prognosis of GIST have also been proposed and may be used readily without incurring the cost and radiation exposure of PET/CT.205Management of Localized DiseaseComplete surgical resection with negative margins is the rec-ommended treatment for localized GISTs. Extended anatomic resection, wide margins, and lymphadenectomy are not required; therefore, total gastrectomy for gastric primaries is rarely required even with the largest of lesions. Resection of even locally advanced tumors is associated with improved survival.206 The 5-year survival rate for all patients with GISTs ranges from 20% to 44%, and the 5-year survival rate for patients with com-pletely excised early-stage tumors is up to 75%.206 An analysis of 200 patients by DeMatteo and colleagues found a disease-specific survival rate of 54% for patients with grossly complete resection of primary GIST, and the median survival duration
|
Surgery_Schwartz. Useful and effective CT-based criteria by Choi et al for detection of GIST and for predicting prognosis of GIST have also been proposed and may be used readily without incurring the cost and radiation exposure of PET/CT.205Management of Localized DiseaseComplete surgical resection with negative margins is the rec-ommended treatment for localized GISTs. Extended anatomic resection, wide margins, and lymphadenectomy are not required; therefore, total gastrectomy for gastric primaries is rarely required even with the largest of lesions. Resection of even locally advanced tumors is associated with improved survival.206 The 5-year survival rate for all patients with GISTs ranges from 20% to 44%, and the 5-year survival rate for patients with com-pletely excised early-stage tumors is up to 75%.206 An analysis of 200 patients by DeMatteo and colleagues found a disease-specific survival rate of 54% for patients with grossly complete resection of primary GIST, and the median survival duration
|
Surgery_Schwartz_10470
|
Surgery_Schwartz
|
An analysis of 200 patients by DeMatteo and colleagues found a disease-specific survival rate of 54% for patients with grossly complete resection of primary GIST, and the median survival duration for patients with metastatic disease was only 20 months.58As for other soft tissue sarcomas, tumor size has con-sistently been identified as an important prognostic factor for GIST. Mitotic activity has also been identified as an important prognostic factor and is generally categorized as fewer than 5, 5 to 10, or more than 10 mitoses per high-power field. The National Institutes of Health207 and the Armed Forces Insti-tute of Pathology203 have proposed prognostic criteria for risk stratification of surgically treated, localized primary GIST. Both groups take into account tumor size and mitotic count; the Armed Forces Institute of Pathology also includes tumor site as a prognostic variable. Accurate risk stratification is essential for selecting patients most likely to benefit from adjuvant
|
Surgery_Schwartz. An analysis of 200 patients by DeMatteo and colleagues found a disease-specific survival rate of 54% for patients with grossly complete resection of primary GIST, and the median survival duration for patients with metastatic disease was only 20 months.58As for other soft tissue sarcomas, tumor size has con-sistently been identified as an important prognostic factor for GIST. Mitotic activity has also been identified as an important prognostic factor and is generally categorized as fewer than 5, 5 to 10, or more than 10 mitoses per high-power field. The National Institutes of Health207 and the Armed Forces Insti-tute of Pathology203 have proposed prognostic criteria for risk stratification of surgically treated, localized primary GIST. Both groups take into account tumor size and mitotic count; the Armed Forces Institute of Pathology also includes tumor site as a prognostic variable. Accurate risk stratification is essential for selecting patients most likely to benefit from adjuvant
|
Surgery_Schwartz_10471
|
Surgery_Schwartz
|
count; the Armed Forces Institute of Pathology also includes tumor site as a prognostic variable. Accurate risk stratification is essential for selecting patients most likely to benefit from adjuvant treatment.Management of Locally Advanced or Metastatic DiseaseTreatment with imatinib mesylate (Gleevec, ST1571), a selec-tive inhibitor of the KIT protein tyrosine kinase, has resulted in impressive clinical responses in a large percentage of patients with unresectable or metastatic GISTs. On the basis of the initial results in a single patient with metastatic GIST, the EORTC Soft Tissue and Bone Sarcoma Group initiated a phase 1 study to test the safety and efficacy of imatinib.208 In that study, 53% of patients with GISTs had confirmed partial responses; investiga-tors concluded that imatinib is safe and effective against this disease.208 A multicenter, international trial of imatinib for GIST was begun in July 2000 at four treatment centers: Dana-Farber Cancer Institute, Oregon Health
|
Surgery_Schwartz. count; the Armed Forces Institute of Pathology also includes tumor site as a prognostic variable. Accurate risk stratification is essential for selecting patients most likely to benefit from adjuvant treatment.Management of Locally Advanced or Metastatic DiseaseTreatment with imatinib mesylate (Gleevec, ST1571), a selec-tive inhibitor of the KIT protein tyrosine kinase, has resulted in impressive clinical responses in a large percentage of patients with unresectable or metastatic GISTs. On the basis of the initial results in a single patient with metastatic GIST, the EORTC Soft Tissue and Bone Sarcoma Group initiated a phase 1 study to test the safety and efficacy of imatinib.208 In that study, 53% of patients with GISTs had confirmed partial responses; investiga-tors concluded that imatinib is safe and effective against this disease.208 A multicenter, international trial of imatinib for GIST was begun in July 2000 at four treatment centers: Dana-Farber Cancer Institute, Oregon Health
|
Surgery_Schwartz_10472
|
Surgery_Schwartz
|
is safe and effective against this disease.208 A multicenter, international trial of imatinib for GIST was begun in July 2000 at four treatment centers: Dana-Farber Cancer Institute, Oregon Health Sciences University, Fox Chase Cancer Center, and University Hospital of Helsinki, Finland.209 A total of 147 patients with unresectable or metastatic GISTs were randomized to 400 or 600 mg of imatinib daily for up to 24 months. Objective response was demonstrated in 79 patients (54%); all had partial responses, and there was no significant difference in response rate between imatinib doses.210 Fourteen percent of patients experienced disease progression. The toxic-ity profile was acceptable; the predominant effects were gastro-intestinal effects (diarrhea, nausea), periorbital edema, muscle cramps, and fatigue. However, 21% of patients experienced serious (grade 3 or 4) adverse events, including gastrointestinal bleeding in 5% of patients, most likely related to the rapid tumor response of
|
Surgery_Schwartz. is safe and effective against this disease.208 A multicenter, international trial of imatinib for GIST was begun in July 2000 at four treatment centers: Dana-Farber Cancer Institute, Oregon Health Sciences University, Fox Chase Cancer Center, and University Hospital of Helsinki, Finland.209 A total of 147 patients with unresectable or metastatic GISTs were randomized to 400 or 600 mg of imatinib daily for up to 24 months. Objective response was demonstrated in 79 patients (54%); all had partial responses, and there was no significant difference in response rate between imatinib doses.210 Fourteen percent of patients experienced disease progression. The toxic-ity profile was acceptable; the predominant effects were gastro-intestinal effects (diarrhea, nausea), periorbital edema, muscle cramps, and fatigue. However, 21% of patients experienced serious (grade 3 or 4) adverse events, including gastrointestinal bleeding in 5% of patients, most likely related to the rapid tumor response of
|
Surgery_Schwartz_10473
|
Surgery_Schwartz
|
and fatigue. However, 21% of patients experienced serious (grade 3 or 4) adverse events, including gastrointestinal bleeding in 5% of patients, most likely related to the rapid tumor response of mural lesions.Brunicardi_Ch36_p1567-p1598.indd 158501/03/19 6:38 PM 1586SPECIFIC CONSIDERATIONSPART IIA phase 3 randomized Intergroup trial was simultaneously performed to assess the clinical activity of imatinib at two dose levels for patients with unresectable or metastatic GIST express-ing the c-Kit tyrosine kinase.211 From December 15, 2000, to September 1, 2001, 746 patients were accrued and randomized to low-dose (400 mg/d) or high-dose (800 mg/d) imatinib. The primary endpoint of the trial was survival. Preliminary toxicity data from 325 patients revealed a 23% incidence of grade 3 or 4 adverse events, including nausea and vomiting, gastrointestinal bleeding, abdominal pain, edema, fatigue, and rash.In February 2002, the FDA approved imatinib for treat-ment of GIST based on the
|
Surgery_Schwartz. and fatigue. However, 21% of patients experienced serious (grade 3 or 4) adverse events, including gastrointestinal bleeding in 5% of patients, most likely related to the rapid tumor response of mural lesions.Brunicardi_Ch36_p1567-p1598.indd 158501/03/19 6:38 PM 1586SPECIFIC CONSIDERATIONSPART IIA phase 3 randomized Intergroup trial was simultaneously performed to assess the clinical activity of imatinib at two dose levels for patients with unresectable or metastatic GIST express-ing the c-Kit tyrosine kinase.211 From December 15, 2000, to September 1, 2001, 746 patients were accrued and randomized to low-dose (400 mg/d) or high-dose (800 mg/d) imatinib. The primary endpoint of the trial was survival. Preliminary toxicity data from 325 patients revealed a 23% incidence of grade 3 or 4 adverse events, including nausea and vomiting, gastrointestinal bleeding, abdominal pain, edema, fatigue, and rash.In February 2002, the FDA approved imatinib for treat-ment of GIST based on the
|
Surgery_Schwartz_10474
|
Surgery_Schwartz
|
or 4 adverse events, including nausea and vomiting, gastrointestinal bleeding, abdominal pain, edema, fatigue, and rash.In February 2002, the FDA approved imatinib for treat-ment of GIST based on the results of these promising clinical trials. Both the Intergroup trial mentioned in the preceding paragraph and a separate phase 3 trial compared the efficacy of low-dose (400 mg/d) and high-dose (800 mg/d) imatinib in patients with metastatic or unresectable GISTs.212,213 Both stud-ies showed equivalent response rates and overall survival for the two doses but increased toxicity for the 800-mg/d dose. Current recommendations include consideration of dose escalation to 800 mg/d for patients who experience disease progression at a dose of 400 mg/d and for patients with advanced GIST and KIT exon 9 mutations.1,214The optimal duration of imatinib treatment, the duration of benefit from imatinib, and the long-term toxicity of imatinib have not been established. When feasible, imatinib should
|
Surgery_Schwartz. or 4 adverse events, including nausea and vomiting, gastrointestinal bleeding, abdominal pain, edema, fatigue, and rash.In February 2002, the FDA approved imatinib for treat-ment of GIST based on the results of these promising clinical trials. Both the Intergroup trial mentioned in the preceding paragraph and a separate phase 3 trial compared the efficacy of low-dose (400 mg/d) and high-dose (800 mg/d) imatinib in patients with metastatic or unresectable GISTs.212,213 Both stud-ies showed equivalent response rates and overall survival for the two doses but increased toxicity for the 800-mg/d dose. Current recommendations include consideration of dose escalation to 800 mg/d for patients who experience disease progression at a dose of 400 mg/d and for patients with advanced GIST and KIT exon 9 mutations.1,214The optimal duration of imatinib treatment, the duration of benefit from imatinib, and the long-term toxicity of imatinib have not been established. When feasible, imatinib should
|
Surgery_Schwartz_10475
|
Surgery_Schwartz
|
9 mutations.1,214The optimal duration of imatinib treatment, the duration of benefit from imatinib, and the long-term toxicity of imatinib have not been established. When feasible, imatinib should be continued in the absence of disease progression. A random-ized trial reported worse median progression-free survival in patients who stopped imatinib after 1 year than in patients who continued beyond 1 year (progression-free survival of 6 months vs. 18 months).215 Less than 4% of patients with GISTs have experienced serious adverse events with imatinib. Mild gastrointestinal toxicity is the most frequently reported adverse event, but gastrointestinal tract hemorrhage, presum-ably from rapid tumor necrosis, has also been reported. Thus, all patients with GISTs treated on clinical protocols should be evaluated and followed by a team of medical professionals that includes a surgeon.Many patients with GIST develop resistance to imatinib. Primary resistance is defined as clinical progression
|
Surgery_Schwartz. 9 mutations.1,214The optimal duration of imatinib treatment, the duration of benefit from imatinib, and the long-term toxicity of imatinib have not been established. When feasible, imatinib should be continued in the absence of disease progression. A random-ized trial reported worse median progression-free survival in patients who stopped imatinib after 1 year than in patients who continued beyond 1 year (progression-free survival of 6 months vs. 18 months).215 Less than 4% of patients with GISTs have experienced serious adverse events with imatinib. Mild gastrointestinal toxicity is the most frequently reported adverse event, but gastrointestinal tract hemorrhage, presum-ably from rapid tumor necrosis, has also been reported. Thus, all patients with GISTs treated on clinical protocols should be evaluated and followed by a team of medical professionals that includes a surgeon.Many patients with GIST develop resistance to imatinib. Primary resistance is defined as clinical progression
|
Surgery_Schwartz_10476
|
Surgery_Schwartz
|
be evaluated and followed by a team of medical professionals that includes a surgeon.Many patients with GIST develop resistance to imatinib. Primary resistance is defined as clinical progression that devel-ops during the first 6 months of treatment and is most commonly seen in patients with KIT exon 9 mutation, PDGFRA exon 18 mutation, or no mutations.216 Secondary resistance is defined as progression that develops more than 6 months after the start of treatment in a patient with an initial response.217 Imatinib resis-tance should be managed by either dose escalation or transition to treatment with sunitinib.1In 2006, sunitinib malate (SU11248, Sutent, Pfizer) emerged as an alternative systemic treatment for patients unable to tolerate imatinib and patients with imatinib-refractory GIST. Sunitinib is a tyrosine kinase inhibitor that targets multiple kinases, including the vascular endothelial growth factor receptors, PDGFRA, KIT, and FLT3. Sunitinib has both antiangiogenic and
|
Surgery_Schwartz. be evaluated and followed by a team of medical professionals that includes a surgeon.Many patients with GIST develop resistance to imatinib. Primary resistance is defined as clinical progression that devel-ops during the first 6 months of treatment and is most commonly seen in patients with KIT exon 9 mutation, PDGFRA exon 18 mutation, or no mutations.216 Secondary resistance is defined as progression that develops more than 6 months after the start of treatment in a patient with an initial response.217 Imatinib resis-tance should be managed by either dose escalation or transition to treatment with sunitinib.1In 2006, sunitinib malate (SU11248, Sutent, Pfizer) emerged as an alternative systemic treatment for patients unable to tolerate imatinib and patients with imatinib-refractory GIST. Sunitinib is a tyrosine kinase inhibitor that targets multiple kinases, including the vascular endothelial growth factor receptors, PDGFRA, KIT, and FLT3. Sunitinib has both antiangiogenic and
|
Surgery_Schwartz_10477
|
Surgery_Schwartz
|
GIST. Sunitinib is a tyrosine kinase inhibitor that targets multiple kinases, including the vascular endothelial growth factor receptors, PDGFRA, KIT, and FLT3. Sunitinib has both antiangiogenic and antiproliferative activity. In a phase 3, randomized, placebo-controlled trial, sunitinib was associated with a significant improvement in median time to progression (27.3 weeks vs. 6.4 weeks with placebo) in patients with imatinib-resistant GIST.135 In addition, sunitinib therapy was well tolerated; diarrhea, fatigue, and nausea were the most common adverse effects. Sunitinib has also been associated with hand-foot skin reaction, hypertension, cardiotoxicity, and hypothyroidism.218-220 In 2006, sunitinib was approved by the FDA for treatment of patients with resistance or intolerance to imatinib.The third FDA-approved drug recently made available for treatment of patients with imatiniband sunitinib-resistant GIST is regorafenib. Regorafenib is a structurally unique inhibitor of multiple
|
Surgery_Schwartz. GIST. Sunitinib is a tyrosine kinase inhibitor that targets multiple kinases, including the vascular endothelial growth factor receptors, PDGFRA, KIT, and FLT3. Sunitinib has both antiangiogenic and antiproliferative activity. In a phase 3, randomized, placebo-controlled trial, sunitinib was associated with a significant improvement in median time to progression (27.3 weeks vs. 6.4 weeks with placebo) in patients with imatinib-resistant GIST.135 In addition, sunitinib therapy was well tolerated; diarrhea, fatigue, and nausea were the most common adverse effects. Sunitinib has also been associated with hand-foot skin reaction, hypertension, cardiotoxicity, and hypothyroidism.218-220 In 2006, sunitinib was approved by the FDA for treatment of patients with resistance or intolerance to imatinib.The third FDA-approved drug recently made available for treatment of patients with imatiniband sunitinib-resistant GIST is regorafenib. Regorafenib is a structurally unique inhibitor of multiple
|
Surgery_Schwartz_10478
|
Surgery_Schwartz
|
third FDA-approved drug recently made available for treatment of patients with imatiniband sunitinib-resistant GIST is regorafenib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and PDGFR, with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, a multicenter, single-stage phase 2 trial examined regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib.221 Thirty-four patients were enrolled from February to December 2010 and given regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Clinical benefit was noted in 79% of patients with a median progression-free survival of 10 months. This trial was then followed by a phase 3, international, placebo-controlled, randomized trial of regorafenib for metastatic GIST after failure of imatinib and sunitinib.222 Patients with
|
Surgery_Schwartz. third FDA-approved drug recently made available for treatment of patients with imatiniband sunitinib-resistant GIST is regorafenib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and PDGFR, with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, a multicenter, single-stage phase 2 trial examined regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib.221 Thirty-four patients were enrolled from February to December 2010 and given regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Clinical benefit was noted in 79% of patients with a median progression-free survival of 10 months. This trial was then followed by a phase 3, international, placebo-controlled, randomized trial of regorafenib for metastatic GIST after failure of imatinib and sunitinib.222 Patients with
|
Surgery_Schwartz_10479
|
Surgery_Schwartz
|
10 months. This trial was then followed by a phase 3, international, placebo-controlled, randomized trial of regorafenib for metastatic GIST after failure of imatinib and sunitinib.222 Patients with progres-sion of disease on the placebo arm were crossed to the treatment arm of the study. Patients treated with regorafenib had a median progression-free survival of 4.8 months compared to 0.9 months on the placebo arm. Other tyrosine kinase inhibitors have dem-onstrated modest activity against GIST and target more than one family of protein kinases.223 Among these are sorafenib, dasatinib, and nilotinib for the treatment of imatinib-resistant GIST, and these are now generally reserved for therapy after progression with regorafenib.222Multidisciplinary TreatmentAlthough imatinib has improved survival of patients with advanced GIST, most patients with advanced GIST are not cured with imatinib. Some patients develop secondary resistance to imatinib with one or more sites of disease
|
Surgery_Schwartz. 10 months. This trial was then followed by a phase 3, international, placebo-controlled, randomized trial of regorafenib for metastatic GIST after failure of imatinib and sunitinib.222 Patients with progres-sion of disease on the placebo arm were crossed to the treatment arm of the study. Patients treated with regorafenib had a median progression-free survival of 4.8 months compared to 0.9 months on the placebo arm. Other tyrosine kinase inhibitors have dem-onstrated modest activity against GIST and target more than one family of protein kinases.223 Among these are sorafenib, dasatinib, and nilotinib for the treatment of imatinib-resistant GIST, and these are now generally reserved for therapy after progression with regorafenib.222Multidisciplinary TreatmentAlthough imatinib has improved survival of patients with advanced GIST, most patients with advanced GIST are not cured with imatinib. Some patients develop secondary resistance to imatinib with one or more sites of disease
|
Surgery_Schwartz_10480
|
Surgery_Schwartz
|
survival of patients with advanced GIST, most patients with advanced GIST are not cured with imatinib. Some patients develop secondary resistance to imatinib with one or more sites of disease progression after 6 months of clinical response (Fig. 36-10A [before imatinib], Fig. 36-10B [after imatinib]). The mechanisms of imatinib resistance are currently being investigated. Surgery has been shown to be beneficial for selected patients with isolated disease progression during imatinib therapy.224-227 Surgical resection of residual metastatic disease responding to imatinib-sensitive GIST has also been shown to result in progression-free survival in 70% to 96% of patients with imatinibor sunitinib-sensitive GISTs.226-228 The optimal timing of surgery in relation to ima-tinib therapy for patients with metastatic disease remains to be determined. It is not possible to compare outcomes for patients treated with kinase inhibitors alone and patients treated with kinase inhibitors plus surgical
|
Surgery_Schwartz. survival of patients with advanced GIST, most patients with advanced GIST are not cured with imatinib. Some patients develop secondary resistance to imatinib with one or more sites of disease progression after 6 months of clinical response (Fig. 36-10A [before imatinib], Fig. 36-10B [after imatinib]). The mechanisms of imatinib resistance are currently being investigated. Surgery has been shown to be beneficial for selected patients with isolated disease progression during imatinib therapy.224-227 Surgical resection of residual metastatic disease responding to imatinib-sensitive GIST has also been shown to result in progression-free survival in 70% to 96% of patients with imatinibor sunitinib-sensitive GISTs.226-228 The optimal timing of surgery in relation to ima-tinib therapy for patients with metastatic disease remains to be determined. It is not possible to compare outcomes for patients treated with kinase inhibitors alone and patients treated with kinase inhibitors plus surgical
|
Surgery_Schwartz_10481
|
Surgery_Schwartz
|
with metastatic disease remains to be determined. It is not possible to compare outcomes for patients treated with kinase inhibitors alone and patients treated with kinase inhibitors plus surgical resection outside the context of randomized trials given the heterogeneity of patients and biases associated with selection of patients for surgical resection.Postoperative ImatinibGiven the promising results of imatinib therapy for metastatic and locally advanced GIST, the next step was to study the efficacy of imatinib as adjuvant (postoperative) treatment in patients with surgically resectable disease, particularly those at high risk for recurrence because of large tumor size or high mitotic count. The ACOSOG first evaluated the efficacy of 1 year of postoperative imatinib in a single-arm phase 2 trial with 106 patients with high-risk GIST and compared the results with historical controls. Adjuvant treatment with imatinib for GIST patients was then examined in two key trials. In the
|
Surgery_Schwartz. with metastatic disease remains to be determined. It is not possible to compare outcomes for patients treated with kinase inhibitors alone and patients treated with kinase inhibitors plus surgical resection outside the context of randomized trials given the heterogeneity of patients and biases associated with selection of patients for surgical resection.Postoperative ImatinibGiven the promising results of imatinib therapy for metastatic and locally advanced GIST, the next step was to study the efficacy of imatinib as adjuvant (postoperative) treatment in patients with surgically resectable disease, particularly those at high risk for recurrence because of large tumor size or high mitotic count. The ACOSOG first evaluated the efficacy of 1 year of postoperative imatinib in a single-arm phase 2 trial with 106 patients with high-risk GIST and compared the results with historical controls. Adjuvant treatment with imatinib for GIST patients was then examined in two key trials. In the
|
Surgery_Schwartz_10482
|
Surgery_Schwartz
|
phase 2 trial with 106 patients with high-risk GIST and compared the results with historical controls. Adjuvant treatment with imatinib for GIST patients was then examined in two key trials. In the ACOSOG randomized, double-blind, phase 3 Z9001 study,230 treatment with 12 months of imatinib was compared with placebo, fol-lowing complete resection of a primary GIST smaller than 3 cm. Primary and secondary endpoints were recurrence-free survival Brunicardi_Ch36_p1567-p1598.indd 158601/03/19 6:38 PM 1587SOFT TISSUE SARCOMASCHAPTER 36ABFigure 36-10. A 57-year-old man with a history of a pelvic gastrointestinal stromal tumor involving the small bowel mesen-tery treated preoperatively with 6 months of imatinib (Gleevec). A. Before imatinib. B. After imatinib.(RFS) and overall survival (OS), respectively. Results showed a significant benefit in RFS, but not OS, with 12 months of imatinib. Based on these results, imatinib for the adjuvant treat-ment of adult patients following resection
|
Surgery_Schwartz. phase 2 trial with 106 patients with high-risk GIST and compared the results with historical controls. Adjuvant treatment with imatinib for GIST patients was then examined in two key trials. In the ACOSOG randomized, double-blind, phase 3 Z9001 study,230 treatment with 12 months of imatinib was compared with placebo, fol-lowing complete resection of a primary GIST smaller than 3 cm. Primary and secondary endpoints were recurrence-free survival Brunicardi_Ch36_p1567-p1598.indd 158601/03/19 6:38 PM 1587SOFT TISSUE SARCOMASCHAPTER 36ABFigure 36-10. A 57-year-old man with a history of a pelvic gastrointestinal stromal tumor involving the small bowel mesen-tery treated preoperatively with 6 months of imatinib (Gleevec). A. Before imatinib. B. After imatinib.(RFS) and overall survival (OS), respectively. Results showed a significant benefit in RFS, but not OS, with 12 months of imatinib. Based on these results, imatinib for the adjuvant treat-ment of adult patients following resection
|
Surgery_Schwartz_10483
|
Surgery_Schwartz
|
respectively. Results showed a significant benefit in RFS, but not OS, with 12 months of imatinib. Based on these results, imatinib for the adjuvant treat-ment of adult patients following resection of KIT-positive GIST was approved by the FDA in 2008 and by the European Medical Agency (EMA) in 2009.A more recent study conducted by the Scandinavian Sarcoma Group (SSG) and the Sarcoma Group of the Arbe-itsgemeinschaft Internistische Onkologie (AIO; SSGXVIII/AIO trial) compared 12 versus 36 months of adjuvant imatinib 400 mg/d in patients with GIST at high risk of recurrence (defined as a GIST tumor diameter >10 cm, or mitotic count >10 per 50 high-powered fields, or tumor diameter >5 cm and mitotic count >5 per 50 high-power fields, or tumor rupture).231 Results showed that both RFS and OS significantly improved with 36 months of imatinib: the 5-year RFS rates for patients receiving 36 versus 12 months of imatinib were 65.6% versus 47.9%, respectively, and the 5-year OS rates were 92%
|
Surgery_Schwartz. respectively. Results showed a significant benefit in RFS, but not OS, with 12 months of imatinib. Based on these results, imatinib for the adjuvant treat-ment of adult patients following resection of KIT-positive GIST was approved by the FDA in 2008 and by the European Medical Agency (EMA) in 2009.A more recent study conducted by the Scandinavian Sarcoma Group (SSG) and the Sarcoma Group of the Arbe-itsgemeinschaft Internistische Onkologie (AIO; SSGXVIII/AIO trial) compared 12 versus 36 months of adjuvant imatinib 400 mg/d in patients with GIST at high risk of recurrence (defined as a GIST tumor diameter >10 cm, or mitotic count >10 per 50 high-powered fields, or tumor diameter >5 cm and mitotic count >5 per 50 high-power fields, or tumor rupture).231 Results showed that both RFS and OS significantly improved with 36 months of imatinib: the 5-year RFS rates for patients receiving 36 versus 12 months of imatinib were 65.6% versus 47.9%, respectively, and the 5-year OS rates were 92%
|
Surgery_Schwartz_10484
|
Surgery_Schwartz
|
significantly improved with 36 months of imatinib: the 5-year RFS rates for patients receiving 36 versus 12 months of imatinib were 65.6% versus 47.9%, respectively, and the 5-year OS rates were 92% versus 81.7%, respectively.The NCCN and the European Society of Medical Oncol-ogy now recommend that imatinib be considered for patients at intermediate or high risk of recurrence after resection and that at least 36 months of adjuvant imatinib be considered for patients at high risk of recurrence.232 Further, both the FDA and EMA updated the label, extending the duration of adjuvant therapy to at least 36 months in patients at high risk of recurrence.Whether longer treatment durations may be of further benefit is still an open question that will be addressed by future studies. However, paralleling what is commonly done in the metastatic setting, many investigators believe that even adju-vant imatinib should become a chronic therapy. While moving toward more prolonged adjuvant treatment
|
Surgery_Schwartz. significantly improved with 36 months of imatinib: the 5-year RFS rates for patients receiving 36 versus 12 months of imatinib were 65.6% versus 47.9%, respectively, and the 5-year OS rates were 92% versus 81.7%, respectively.The NCCN and the European Society of Medical Oncol-ogy now recommend that imatinib be considered for patients at intermediate or high risk of recurrence after resection and that at least 36 months of adjuvant imatinib be considered for patients at high risk of recurrence.232 Further, both the FDA and EMA updated the label, extending the duration of adjuvant therapy to at least 36 months in patients at high risk of recurrence.Whether longer treatment durations may be of further benefit is still an open question that will be addressed by future studies. However, paralleling what is commonly done in the metastatic setting, many investigators believe that even adju-vant imatinib should become a chronic therapy. While moving toward more prolonged adjuvant treatment
|
Surgery_Schwartz_10485
|
Surgery_Schwartz
|
what is commonly done in the metastatic setting, many investigators believe that even adju-vant imatinib should become a chronic therapy. While moving toward more prolonged adjuvant treatment durations, it is all the more essential to identify the appropriate patients to treat to avoid the burden of adverse events or increased financial liabil-ity for patients who will not derive therapeutic benefit from imatinib. Risk stratification based on patients’ risk of recur-rence is a key component to optimizing adjuvant treatment. The most practical stratification scheme to use for making a decision for adjuvant therapy is the modified National Insti-tutes of Health consensus criteria.233 High-risk GIST patients, whose tumor harbors a sensitive genotype, should be treated by adjuvant imatinib because they have a poor prognosis. On the contrary, neither low-risk nor intermediate-risk GIST patients need adjuvant therapy, even if their tumor carries a sensitive genotype. In fact, evidence has
|
Surgery_Schwartz. what is commonly done in the metastatic setting, many investigators believe that even adju-vant imatinib should become a chronic therapy. While moving toward more prolonged adjuvant treatment durations, it is all the more essential to identify the appropriate patients to treat to avoid the burden of adverse events or increased financial liabil-ity for patients who will not derive therapeutic benefit from imatinib. Risk stratification based on patients’ risk of recur-rence is a key component to optimizing adjuvant treatment. The most practical stratification scheme to use for making a decision for adjuvant therapy is the modified National Insti-tutes of Health consensus criteria.233 High-risk GIST patients, whose tumor harbors a sensitive genotype, should be treated by adjuvant imatinib because they have a poor prognosis. On the contrary, neither low-risk nor intermediate-risk GIST patients need adjuvant therapy, even if their tumor carries a sensitive genotype. In fact, evidence has
|
Surgery_Schwartz_10486
|
Surgery_Schwartz
|
they have a poor prognosis. On the contrary, neither low-risk nor intermediate-risk GIST patients need adjuvant therapy, even if their tumor carries a sensitive genotype. In fact, evidence has been provided that the out-come of these patients with intermediateor low-risk GIST is good. When using other risk stratification schemes, such as the Armed Forces Institute of Pathology table, Memorial Sloan-Kettering Cancer Center nomogram, or the heat map,204,234,235 there is a consensus to treat all patients having 30% or higher risk of recurrence, if their tumor carries a sensitive genotype. There is also a consensus not to treat patients having 10% or less risk of recurrence, even if their tumor carries a sensitive genotype. All patients having a risk between 10% and 30% should be evaluated on a case-by-case basis, and advantages/disadvantages of treatment should be made clear and discussed with the patient. Whenever a decision for adjuvant therapy is made, treatment duration of at least
|
Surgery_Schwartz. they have a poor prognosis. On the contrary, neither low-risk nor intermediate-risk GIST patients need adjuvant therapy, even if their tumor carries a sensitive genotype. In fact, evidence has been provided that the out-come of these patients with intermediateor low-risk GIST is good. When using other risk stratification schemes, such as the Armed Forces Institute of Pathology table, Memorial Sloan-Kettering Cancer Center nomogram, or the heat map,204,234,235 there is a consensus to treat all patients having 30% or higher risk of recurrence, if their tumor carries a sensitive genotype. There is also a consensus not to treat patients having 10% or less risk of recurrence, even if their tumor carries a sensitive genotype. All patients having a risk between 10% and 30% should be evaluated on a case-by-case basis, and advantages/disadvantages of treatment should be made clear and discussed with the patient. Whenever a decision for adjuvant therapy is made, treatment duration of at least
|
Surgery_Schwartz_10487
|
Surgery_Schwartz
|
a case-by-case basis, and advantages/disadvantages of treatment should be made clear and discussed with the patient. Whenever a decision for adjuvant therapy is made, treatment duration of at least 36 months should be con-sidered independently from the risk.Beside the risk of recurrence, the other important factor to consider is the tumor genotype. In other words, as found in both the metastatic and adjuvant settings, GIST tumors with KIT exon 11 and PDGFRA non-D842V mutations are sensitive to imatinib. Patients with these mutations are suitable for adjuvant imatinib if the risk determined by stratification tools is signifi-cant. Patients with KIT exon 9 mutations should also be treated; a higher dose (800 mg/d) may be more appropriate but remains to be studied clinically. Patients with PDGFRA D842V–mutated tumors should not be treated with adjuvant imatinib, nor should patients with KIT and PDGFRA wild-type tumors associated with neurofibromatosis type 1 or the pediatric
|
Surgery_Schwartz. a case-by-case basis, and advantages/disadvantages of treatment should be made clear and discussed with the patient. Whenever a decision for adjuvant therapy is made, treatment duration of at least 36 months should be con-sidered independently from the risk.Beside the risk of recurrence, the other important factor to consider is the tumor genotype. In other words, as found in both the metastatic and adjuvant settings, GIST tumors with KIT exon 11 and PDGFRA non-D842V mutations are sensitive to imatinib. Patients with these mutations are suitable for adjuvant imatinib if the risk determined by stratification tools is signifi-cant. Patients with KIT exon 9 mutations should also be treated; a higher dose (800 mg/d) may be more appropriate but remains to be studied clinically. Patients with PDGFRA D842V–mutated tumors should not be treated with adjuvant imatinib, nor should patients with KIT and PDGFRA wild-type tumors associated with neurofibromatosis type 1 or the pediatric
|
Surgery_Schwartz_10488
|
Surgery_Schwartz
|
with PDGFRA D842V–mutated tumors should not be treated with adjuvant imatinib, nor should patients with KIT and PDGFRA wild-type tumors associated with neurofibromatosis type 1 or the pediatric GIST/Carney-Stratakis syndromes, whatever the risk. Patients with sporadic wild-type GIST could be treated on an individual basis.Preoperative ImatinibPatients with marginally resectable GIST or at significant risk for operative morbidity should be considered for preoperative imatinib with close monitoring. Since the optimal duration of preoperative therapy is unknown, imatinib should be continued until maximal response is achieved or until there is evidence of progression.236 Preoperative imatinib can be stopped imme-diately before surgery and resumed when oral medications are restarted.Brunicardi_Ch36_p1567-p1598.indd 158701/03/19 6:38 PM 1588SPECIFIC CONSIDERATIONSPART IIPreoperative imatinib in patients with primary GIST or resectable metastatic GIST has been evaluated in the context of
|
Surgery_Schwartz. with PDGFRA D842V–mutated tumors should not be treated with adjuvant imatinib, nor should patients with KIT and PDGFRA wild-type tumors associated with neurofibromatosis type 1 or the pediatric GIST/Carney-Stratakis syndromes, whatever the risk. Patients with sporadic wild-type GIST could be treated on an individual basis.Preoperative ImatinibPatients with marginally resectable GIST or at significant risk for operative morbidity should be considered for preoperative imatinib with close monitoring. Since the optimal duration of preoperative therapy is unknown, imatinib should be continued until maximal response is achieved or until there is evidence of progression.236 Preoperative imatinib can be stopped imme-diately before surgery and resumed when oral medications are restarted.Brunicardi_Ch36_p1567-p1598.indd 158701/03/19 6:38 PM 1588SPECIFIC CONSIDERATIONSPART IIPreoperative imatinib in patients with primary GIST or resectable metastatic GIST has been evaluated in the context of
|
Surgery_Schwartz_10489
|
Surgery_Schwartz
|
158701/03/19 6:38 PM 1588SPECIFIC CONSIDERATIONSPART IIPreoperative imatinib in patients with primary GIST or resectable metastatic GIST has been evaluated in the context of two randomized phase 2 studies. The Radiation Treatment Oncology Group (RTOG 0132/ACRIN 6665) evaluated the efficacy of preoperative imatinib (600 mg/d) for 8 to 10 weeks before surgery and 24 months after surgery in patients with primary (n = 30) or potentially resectable recurrent or metastatic (n = 22) tumors.237 Primarily stable disease was noted during imatinib treatment, and the 2-year progression-free survival rates were 83% for primary GIST and 77% for recurrent or metastatic GIST. In another study, 19 patients undergoing surgical resection at a single institution were randomized to preoperative imatinib (600 mg/d) for 3, 5, or 7 days followed by surgical resection and postoperative imatinib for 24 months. The response rate assessed using FDG-PET was 69%, and the median disease-free survival time
|
Surgery_Schwartz. 158701/03/19 6:38 PM 1588SPECIFIC CONSIDERATIONSPART IIPreoperative imatinib in patients with primary GIST or resectable metastatic GIST has been evaluated in the context of two randomized phase 2 studies. The Radiation Treatment Oncology Group (RTOG 0132/ACRIN 6665) evaluated the efficacy of preoperative imatinib (600 mg/d) for 8 to 10 weeks before surgery and 24 months after surgery in patients with primary (n = 30) or potentially resectable recurrent or metastatic (n = 22) tumors.237 Primarily stable disease was noted during imatinib treatment, and the 2-year progression-free survival rates were 83% for primary GIST and 77% for recurrent or metastatic GIST. In another study, 19 patients undergoing surgical resection at a single institution were randomized to preoperative imatinib (600 mg/d) for 3, 5, or 7 days followed by surgical resection and postoperative imatinib for 24 months. The response rate assessed using FDG-PET was 69%, and the median disease-free survival time
|
Surgery_Schwartz_10490
|
Surgery_Schwartz
|
(600 mg/d) for 3, 5, or 7 days followed by surgical resection and postoperative imatinib for 24 months. The response rate assessed using FDG-PET was 69%, and the median disease-free survival time following treatment with surgery and imatinib was 46 months.238 Similar results were observed in a prospective series of patients treated at a major institution.239All of these studies show that neoadjuvant treatment is feasible, but to maximize the benefit of preoperative therapy, the following factors need to be considered. First, the patient should in principle have a favorable mutational status; other-wise, the treatment would be in vain, allowing the tumor to con-tinue growing. Fortunately, the majority of GISTs will respond, but it should not be forgotten that, especially in gastric loca-tion, the amount of insensitive mutations in the localized setting is less uncommon than what has been previously reported.240 However, we do not absolutely need to know the mutational status in
|
Surgery_Schwartz. (600 mg/d) for 3, 5, or 7 days followed by surgical resection and postoperative imatinib for 24 months. The response rate assessed using FDG-PET was 69%, and the median disease-free survival time following treatment with surgery and imatinib was 46 months.238 Similar results were observed in a prospective series of patients treated at a major institution.239All of these studies show that neoadjuvant treatment is feasible, but to maximize the benefit of preoperative therapy, the following factors need to be considered. First, the patient should in principle have a favorable mutational status; other-wise, the treatment would be in vain, allowing the tumor to con-tinue growing. Fortunately, the majority of GISTs will respond, but it should not be forgotten that, especially in gastric loca-tion, the amount of insensitive mutations in the localized setting is less uncommon than what has been previously reported.240 However, we do not absolutely need to know the mutational status in
|
Surgery_Schwartz_10491
|
Surgery_Schwartz
|
loca-tion, the amount of insensitive mutations in the localized setting is less uncommon than what has been previously reported.240 However, we do not absolutely need to know the mutational status in advance, but we should be aware that mutation is an issue. Alternatively, if mutation status is not determined prior to treatment, we may also check response very early, either by CT, PET, or contrast-enhanced ultrasound. If a radiographic response is detected within a month, then the mutation status is likely favorable, and the treatment could be continued with-out necessarily pursuing mutation testing. If not, then mutation status should be investigated before continuing the treatment.Second, the resectability of the tumor and the extent of resection necessary should be considered. Other than presenta-tions of clearly inoperable tumors (which are usually treated with imatinib upfront) or symptomatic tumors requiring urgent intervention (hemorrhage, perforation, etc), there are few
|
Surgery_Schwartz. loca-tion, the amount of insensitive mutations in the localized setting is less uncommon than what has been previously reported.240 However, we do not absolutely need to know the mutational status in advance, but we should be aware that mutation is an issue. Alternatively, if mutation status is not determined prior to treatment, we may also check response very early, either by CT, PET, or contrast-enhanced ultrasound. If a radiographic response is detected within a month, then the mutation status is likely favorable, and the treatment could be continued with-out necessarily pursuing mutation testing. If not, then mutation status should be investigated before continuing the treatment.Second, the resectability of the tumor and the extent of resection necessary should be considered. Other than presenta-tions of clearly inoperable tumors (which are usually treated with imatinib upfront) or symptomatic tumors requiring urgent intervention (hemorrhage, perforation, etc), there are few
|
Surgery_Schwartz_10492
|
Surgery_Schwartz
|
than presenta-tions of clearly inoperable tumors (which are usually treated with imatinib upfront) or symptomatic tumors requiring urgent intervention (hemorrhage, perforation, etc), there are few rea-sons today to perform extended procedures (i.e., multivisceral resections or formal organ resections) without first attempting preoperative therapy. For instance, patients with large GISTs who may require a long midline incision for resection may benefit from neoadjuvant imatinib to downstage the operation, potentially converting an open laparotomy approach to a laparo-scopic one. Another typical circumstance in which neoadjuvant therapy may be beneficial is in patients with GISTs arising in the esophagus, gastroesophageal junction, duodenum, or distal rectum. Preoperative treatment may shrink the tumor and allow a more conservative local excision. In general, such patients would normally undergo postoperative adjuvant treatment as well because of the expected recurrence risk. The chance
|
Surgery_Schwartz. than presenta-tions of clearly inoperable tumors (which are usually treated with imatinib upfront) or symptomatic tumors requiring urgent intervention (hemorrhage, perforation, etc), there are few rea-sons today to perform extended procedures (i.e., multivisceral resections or formal organ resections) without first attempting preoperative therapy. For instance, patients with large GISTs who may require a long midline incision for resection may benefit from neoadjuvant imatinib to downstage the operation, potentially converting an open laparotomy approach to a laparo-scopic one. Another typical circumstance in which neoadjuvant therapy may be beneficial is in patients with GISTs arising in the esophagus, gastroesophageal junction, duodenum, or distal rectum. Preoperative treatment may shrink the tumor and allow a more conservative local excision. In general, such patients would normally undergo postoperative adjuvant treatment as well because of the expected recurrence risk. The chance
|
Surgery_Schwartz_10493
|
Surgery_Schwartz
|
the tumor and allow a more conservative local excision. In general, such patients would normally undergo postoperative adjuvant treatment as well because of the expected recurrence risk. The chance of obtaining a response is high, and the benefit for tumor shrink-age obvious, so this approach should always be discussed with patients affected by bulky and/or poorly located disease (esoph-agus, gastroesophageal junction, duodenum, distal rectum) as well as for those who would be candidates for an adjuvant treat-ment anyway.Third, in the studies mentioned earlier, patients underwent surgery after a limited treatment duration (3 months at best). It is now well known that the preoperative treatment may result in sustained tumor shrinkage if given for a longer duration. Sur-gical resection may then be performed between 6 and 12 months or sooner if treatment effect plateaus. This allows for optimal tumor shrinkage, or at least shrinkage to the point where there is no further benefit to be
|
Surgery_Schwartz. the tumor and allow a more conservative local excision. In general, such patients would normally undergo postoperative adjuvant treatment as well because of the expected recurrence risk. The chance of obtaining a response is high, and the benefit for tumor shrink-age obvious, so this approach should always be discussed with patients affected by bulky and/or poorly located disease (esoph-agus, gastroesophageal junction, duodenum, distal rectum) as well as for those who would be candidates for an adjuvant treat-ment anyway.Third, in the studies mentioned earlier, patients underwent surgery after a limited treatment duration (3 months at best). It is now well known that the preoperative treatment may result in sustained tumor shrinkage if given for a longer duration. Sur-gical resection may then be performed between 6 and 12 months or sooner if treatment effect plateaus. This allows for optimal tumor shrinkage, or at least shrinkage to the point where there is no further benefit to be
|
Surgery_Schwartz_10494
|
Surgery_Schwartz
|
then be performed between 6 and 12 months or sooner if treatment effect plateaus. This allows for optimal tumor shrinkage, or at least shrinkage to the point where there is no further benefit to be gained by further neoadjuvant therapy without the risk of developing secondary resistance.DESMOIDSDesmoid tumors are not low-grade sarcomas but can be locally aggressive, although they do not metastasize. Approximately half of these tumors arise in the extremities; the remaining lesions are located on the trunk or in the retroperitoneum. Abdominal wall desmoids are associated with pregnancy and are thought to be the result of hormonal influence. Although usually sporadic, desmoids may occur in association with famil-ial adenomatous polyposis, a presentation that is referred to as Gardner’s syndrome and is linked to germline mutations in the APC gene. Sporadic cases of desmoid fibromatosis are com-monly linked to mutations in CTNNB1, the gene for β-catenin.The primary therapy for desmoid
|
Surgery_Schwartz. then be performed between 6 and 12 months or sooner if treatment effect plateaus. This allows for optimal tumor shrinkage, or at least shrinkage to the point where there is no further benefit to be gained by further neoadjuvant therapy without the risk of developing secondary resistance.DESMOIDSDesmoid tumors are not low-grade sarcomas but can be locally aggressive, although they do not metastasize. Approximately half of these tumors arise in the extremities; the remaining lesions are located on the trunk or in the retroperitoneum. Abdominal wall desmoids are associated with pregnancy and are thought to be the result of hormonal influence. Although usually sporadic, desmoids may occur in association with famil-ial adenomatous polyposis, a presentation that is referred to as Gardner’s syndrome and is linked to germline mutations in the APC gene. Sporadic cases of desmoid fibromatosis are com-monly linked to mutations in CTNNB1, the gene for β-catenin.The primary therapy for desmoid
|
Surgery_Schwartz_10495
|
Surgery_Schwartz
|
and is linked to germline mutations in the APC gene. Sporadic cases of desmoid fibromatosis are com-monly linked to mutations in CTNNB1, the gene for β-catenin.The primary therapy for desmoid tumors has long been considered surgical resection with wide local excision to achieve negative margins. However, local recurrence occurs in up to one-third of patients independently of the quality of surgical margins.241-243 Up to two-thirds of the patients operated on with positive margins do not recur. This is why there is growing evidence that the primary approach could be more conservative. Function-sparing operations should be the goal, even if a positive margin is left on a critical structure. Moreover, some authors advocate the possibility to observe patients at presentation, limiting surgery to those who progress or fail medical therapies. It has in fact been reported that by this approach, up to 50% of patients skip surgical resection.244,245 Radiation therapy may be effective in
|
Surgery_Schwartz. and is linked to germline mutations in the APC gene. Sporadic cases of desmoid fibromatosis are com-monly linked to mutations in CTNNB1, the gene for β-catenin.The primary therapy for desmoid tumors has long been considered surgical resection with wide local excision to achieve negative margins. However, local recurrence occurs in up to one-third of patients independently of the quality of surgical margins.241-243 Up to two-thirds of the patients operated on with positive margins do not recur. This is why there is growing evidence that the primary approach could be more conservative. Function-sparing operations should be the goal, even if a positive margin is left on a critical structure. Moreover, some authors advocate the possibility to observe patients at presentation, limiting surgery to those who progress or fail medical therapies. It has in fact been reported that by this approach, up to 50% of patients skip surgical resection.244,245 Radiation therapy may be effective in
|
Surgery_Schwartz_10496
|
Surgery_Schwartz
|
to those who progress or fail medical therapies. It has in fact been reported that by this approach, up to 50% of patients skip surgical resection.244,245 Radiation therapy may be effective in patients with unresectable tumors or as adjuvant therapy following surgery for recurrent disease, although long-term side effects and the risk of radiation-induced sarcoma should always be considered. When used, a dose of 50 to 54 Gy is usually recommended. Systemic treatment is another option when surgery is not indicated. Hormonal therapies such as tamoxifen have been reported to be beneficial, as have nonsteroidal anti-inflammatory drugs, which are known to affect the β-catenin signaling pathways. Chemotherapy is also effective, although usually reserved for patients with tumor-associated symptoms who have not responded to other interventions. Combinations of methotrexate and vinblastine have been shown to have activity, as have single-agent pegylated liposomal doxorubicin246 and
|
Surgery_Schwartz. to those who progress or fail medical therapies. It has in fact been reported that by this approach, up to 50% of patients skip surgical resection.244,245 Radiation therapy may be effective in patients with unresectable tumors or as adjuvant therapy following surgery for recurrent disease, although long-term side effects and the risk of radiation-induced sarcoma should always be considered. When used, a dose of 50 to 54 Gy is usually recommended. Systemic treatment is another option when surgery is not indicated. Hormonal therapies such as tamoxifen have been reported to be beneficial, as have nonsteroidal anti-inflammatory drugs, which are known to affect the β-catenin signaling pathways. Chemotherapy is also effective, although usually reserved for patients with tumor-associated symptoms who have not responded to other interventions. Combinations of methotrexate and vinblastine have been shown to have activity, as have single-agent pegylated liposomal doxorubicin246 and
|
Surgery_Schwartz_10497
|
Surgery_Schwartz
|
symptoms who have not responded to other interventions. Combinations of methotrexate and vinblastine have been shown to have activity, as have single-agent pegylated liposomal doxorubicin246 and sorafenib.247 Imatinib has also been studied with unconvincing results.248-250DERMATOFIBROSARCOMA PROTUBERANSDermatofibrosarcoma protuberans is a rare low-grade sarcoma arising in the dermis that rarely metastasizes but is locally aggressive. The overall annual incidence has been estimated at 4.2 cases per million individuals,251 and the incidence is higher among blacks than whites (6.5 vs. 3.9 per million per year). Approximately 40% of cases arise on the trunk, and most of the remaining tumors are distributed between the head and neck and the extremities. Dermatofibrosarcoma protuberans presents as a nodular, cutaneous mass that grows slowly and persistently. Satellite lesions may be found in patients with larger tumors. Brunicardi_Ch36_p1567-p1598.indd 158801/03/19 6:38 PM 1589SOFT
|
Surgery_Schwartz. symptoms who have not responded to other interventions. Combinations of methotrexate and vinblastine have been shown to have activity, as have single-agent pegylated liposomal doxorubicin246 and sorafenib.247 Imatinib has also been studied with unconvincing results.248-250DERMATOFIBROSARCOMA PROTUBERANSDermatofibrosarcoma protuberans is a rare low-grade sarcoma arising in the dermis that rarely metastasizes but is locally aggressive. The overall annual incidence has been estimated at 4.2 cases per million individuals,251 and the incidence is higher among blacks than whites (6.5 vs. 3.9 per million per year). Approximately 40% of cases arise on the trunk, and most of the remaining tumors are distributed between the head and neck and the extremities. Dermatofibrosarcoma protuberans presents as a nodular, cutaneous mass that grows slowly and persistently. Satellite lesions may be found in patients with larger tumors. Brunicardi_Ch36_p1567-p1598.indd 158801/03/19 6:38 PM 1589SOFT
|
Surgery_Schwartz_10498
|
Surgery_Schwartz
|
as a nodular, cutaneous mass that grows slowly and persistently. Satellite lesions may be found in patients with larger tumors. Brunicardi_Ch36_p1567-p1598.indd 158801/03/19 6:38 PM 1589SOFT TISSUE SARCOMASCHAPTER 36Standard treatment is wide local excision, which generally results in local recurrence rates of less than 10%.252 Although local recurrence rates as high as 30% to 50% have been reported in population-based series, the associated 5-year survival rate is greater than 99%.251Dermatofibrosarcoma protuberans arises from a specific chromosomal translocation involving chromosomes 17 and 22, in which the collagen 1 α 1 gene is fused to the gene for PDGF β-chain (PDGFB).253 The resultant deregulated expression of PDGFB leads to continuous activation of the PDGFR protein tyrosine kinase, which promotes tumor cell growth. The identification of this chromosomal translocation in more than 90% of cases of dermatofibrosarcoma protuberans has led to the development of targeted
|
Surgery_Schwartz. as a nodular, cutaneous mass that grows slowly and persistently. Satellite lesions may be found in patients with larger tumors. Brunicardi_Ch36_p1567-p1598.indd 158801/03/19 6:38 PM 1589SOFT TISSUE SARCOMASCHAPTER 36Standard treatment is wide local excision, which generally results in local recurrence rates of less than 10%.252 Although local recurrence rates as high as 30% to 50% have been reported in population-based series, the associated 5-year survival rate is greater than 99%.251Dermatofibrosarcoma protuberans arises from a specific chromosomal translocation involving chromosomes 17 and 22, in which the collagen 1 α 1 gene is fused to the gene for PDGF β-chain (PDGFB).253 The resultant deregulated expression of PDGFB leads to continuous activation of the PDGFR protein tyrosine kinase, which promotes tumor cell growth. The identification of this chromosomal translocation in more than 90% of cases of dermatofibrosarcoma protuberans has led to the development of targeted
|
Surgery_Schwartz_10499
|
Surgery_Schwartz
|
kinase, which promotes tumor cell growth. The identification of this chromosomal translocation in more than 90% of cases of dermatofibrosarcoma protuberans has led to the development of targeted therapy. Inhibiting PDGFR with imatinib has been shown to induce clinical and radiologic improvement in patients with unresectable dermatofibrosarcoma protuberans.21 These data have resulted in the approval by the FDA of imatinib for treatment of patients with locally advanced dermatofibrosarcoma protuberans.PEDIATRIC SARCOMASSoft tissue sarcomas in children are relatively rare, accounting for 7% to 8% of all pediatric cancers and totaling approximately 600 new cases per year.254 Pediatric sarcomas have traditionally been divided into two groups: rhabdomyosarcoma and nonrhab-domyosarcoma soft tissue sarcomas.RhabdomyosarcomaAssociated with skeletal muscle, rhabdomyosarcomas are the most common soft tissue tumors among children younger than 15 years and can occur at any site comprised of
|
Surgery_Schwartz. kinase, which promotes tumor cell growth. The identification of this chromosomal translocation in more than 90% of cases of dermatofibrosarcoma protuberans has led to the development of targeted therapy. Inhibiting PDGFR with imatinib has been shown to induce clinical and radiologic improvement in patients with unresectable dermatofibrosarcoma protuberans.21 These data have resulted in the approval by the FDA of imatinib for treatment of patients with locally advanced dermatofibrosarcoma protuberans.PEDIATRIC SARCOMASSoft tissue sarcomas in children are relatively rare, accounting for 7% to 8% of all pediatric cancers and totaling approximately 600 new cases per year.254 Pediatric sarcomas have traditionally been divided into two groups: rhabdomyosarcoma and nonrhab-domyosarcoma soft tissue sarcomas.RhabdomyosarcomaAssociated with skeletal muscle, rhabdomyosarcomas are the most common soft tissue tumors among children younger than 15 years and can occur at any site comprised of
|
Surgery_Schwartz_10500
|
Surgery_Schwartz
|
tissue sarcomas.RhabdomyosarcomaAssociated with skeletal muscle, rhabdomyosarcomas are the most common soft tissue tumors among children younger than 15 years and can occur at any site comprised of striated muscle. Patients with these tumors generally present with a painless enlarging mass; about 24% of tumors are located in the geni-tourinary system, 20% in the extremities, 20% in the head and neck, 16% in the parameningeal region, and 22% in other sites.255Rhabdomyosarcoma is a small round cell tumor that dem-onstrates muscle differentiation upon light microscopy and immunohistochemical analysis. Two primary histologic sub-types account for 90% of cases: embryonal (70%) and alveolar (20%). Alveolar rhabdomyosarcoma is associated with cytoge-netic translocation [t(2:13)(q35:q14)] in 85% to 90% of cases and [t(1:13)(p36:q14)] in 10% of cases.256 These translocations affect biologic activity at the levels of protein function and gene expression, thereby affecting the control of cell
|
Surgery_Schwartz. tissue sarcomas.RhabdomyosarcomaAssociated with skeletal muscle, rhabdomyosarcomas are the most common soft tissue tumors among children younger than 15 years and can occur at any site comprised of striated muscle. Patients with these tumors generally present with a painless enlarging mass; about 24% of tumors are located in the geni-tourinary system, 20% in the extremities, 20% in the head and neck, 16% in the parameningeal region, and 22% in other sites.255Rhabdomyosarcoma is a small round cell tumor that dem-onstrates muscle differentiation upon light microscopy and immunohistochemical analysis. Two primary histologic sub-types account for 90% of cases: embryonal (70%) and alveolar (20%). Alveolar rhabdomyosarcoma is associated with cytoge-netic translocation [t(2:13)(q35:q14)] in 85% to 90% of cases and [t(1:13)(p36:q14)] in 10% of cases.256 These translocations affect biologic activity at the levels of protein function and gene expression, thereby affecting the control of cell
|
Surgery_Schwartz_10501
|
Surgery_Schwartz
|
to 90% of cases and [t(1:13)(p36:q14)] in 10% of cases.256 These translocations affect biologic activity at the levels of protein function and gene expression, thereby affecting the control of cell growth, apopto-sis, differentiation, and motility and ultimately contributing to tumorigenic behavior.256 Whereas alveolar rhabdomyosarcomas often have translocations, most embryonal rhabdomyosarcomas have an allelic loss at chromosome 11p15.5 that is thought to inactivate a tumor suppressor gene.256,257 Both of these dis-tinct molecular subtypes of rhabdomyosarcoma are thought to have similar alterations in downstream targets such as the p53 and Rb pathways.256 Further insight into these genetic altera-tions may lead to a better understanding of the pathogenesis of rhabdomyosarcoma and provide novel targets for therapeutic approaches.Extent of disease is the strongest predictor of long-term outcome. Several staging systems for rhabdomyosarcoma are available. The Intergroup Rhabdomyosarcoma
|
Surgery_Schwartz. to 90% of cases and [t(1:13)(p36:q14)] in 10% of cases.256 These translocations affect biologic activity at the levels of protein function and gene expression, thereby affecting the control of cell growth, apopto-sis, differentiation, and motility and ultimately contributing to tumorigenic behavior.256 Whereas alveolar rhabdomyosarcomas often have translocations, most embryonal rhabdomyosarcomas have an allelic loss at chromosome 11p15.5 that is thought to inactivate a tumor suppressor gene.256,257 Both of these dis-tinct molecular subtypes of rhabdomyosarcoma are thought to have similar alterations in downstream targets such as the p53 and Rb pathways.256 Further insight into these genetic altera-tions may lead to a better understanding of the pathogenesis of rhabdomyosarcoma and provide novel targets for therapeutic approaches.Extent of disease is the strongest predictor of long-term outcome. Several staging systems for rhabdomyosarcoma are available. The Intergroup Rhabdomyosarcoma
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.