Diabetes mellitus affects response to neoadjuvant chemoradiotherapy in the management of rectal cancer.

INTRODUCTION: Although diabetic patients with rectal cancer have poorer outcomes than their nondiabetic counterparts, few studies have looked at diabetics' response to therapy as an explanation for this disparity. This study compares the neoadjuvant chemoradiotherapy (CRT) response in diabetic and nondiabetic patients with locally advanced rectal cancers. METHODS: This is a single-institution, retrospective review of rectal cancer patients who received CRT followed by resection from 1995 to 2006. Pretreatment tumor-node-metastasis (TNM) staging was determined using endorectal ultrasound, computed tomography (CT) scan, and magnetic resonance imaging (MRI); post-treatment staging was determined by pathological review. RESULTS: 110 patients were included; seventeen had diabetes and 93 were nondiabetics. Pretreatment staging was similar in both groups. Sixteen of the diabetics (94%) completed CRT compared to 92% (86/93) of the nondiabetics. Tumor downstaging rates were similar in the two groups (53% in diabetics, 52% in nondiabetics). Nondiabetic patients had a higher rate of nodal downstaging although not statistically significant (67% versus 27%, P = 0.80). While none of the diabetics patients achieved a pathologic complete response (pCR), 23% (21/93) of the nondiabetics did (P = 0.039). Local progression rates were higher in the diabetic group (24% versus 5%, P = 0.046). CONCLUSION: Our study shows that neoadjuvant chemoradiotherapy in rectal cancer is less effective in diabetic patients than in nondiabetics. While minimal differences are found in the rate of downstaging, the rate of achieving a complete pathologic response was significantly higher in nondiabetic patients, and in fact was not seen in any of our diabetic patients. This may explain the poorer outcomes seen in diabetic patients with rectal cancer.

Adjuvant gemcitabine and concurrent radiation for patients with resected pancreatic cancer: a phase II study.

The safety and efficacy of gemcitabine and concurrent radiation to the upper abdomen followed by weekly gemcitabine in patients with resected pancreatic cancer was determined. Patients with resected adenocarcinoma of the pancreas were treated with intravenous gemcitabine administered twice-weekly (40 mg m(-2)) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy in 5(1/2) weeks). At the completion of the chemoradiation, patients without disease progression were given gemcitabine (1000 mg m(-2)) weekly for two cycles. Each cycle consisted of 3 weeks of treatment followed by 1 week without treatment. Forty-seven patients were entered, 46 of whom are included in this analysis. Characteristics: median age 61 years (range 35-79); 24 females (58%); 73% stage T3/T4; and 70% lymph node positive. Grade III/IV gastrointestinal or haematologic toxicities were infrequent. The median survival was 18.3 months, while the median time to disease recurrence was 10.3 months. Twenty-four percent of patients were alive at 3 years. Only six of 34 patients with progression experienced local regional relapse as a component of the first site of failure. These results confirm the feasibility of delivering adjuvant concurrent gemcitabine and radiation to the upper abdomen. This strategy produced good local regional tumour control.

Analysis of surgical salvage after failure of primary therapy in rectal cancer: results from Intergroup Study 0114.

PURPOSE: Intergroup Study 0114 was designed to study the effect of various chemotherapy regimens delivered after potentially curative surgical resection of T3, T4, and/or node-positive rectal cancer. A subset analysis was undertaken to investigate the prevalence and influence of salvage therapy among patients with recurrent disease. PATIENTS AND METHODS: Adjuvant therapy consisted of two cycles of fluorouracil (FU)-based chemotherapy followed by pelvic irradiation with chemotherapy and two more cycles of chemotherapy after radiation therapy. A total of 1,792 patients were entered onto the study and 1,696 were assessable. After a median of 8.9 years of follow-up, 715 patients (42%) had disease recurrence, and an additional 10% died without evidence of disease. Five hundred patients with follow-up information available had a single organ or single site of first recurrence (73.5% of all recurrences). RESULTS: A total of 171 patients (34% of those with a single organ or single site of recurrence) had a potentially curative resection of the metastatic or locally recurrent disease. Single-site first recurrences in the liver, lung, or pelvis occurred in 448 patients (90% of the single-site recurrences), with 159 (35%) of these undergoing surgical resection for attempted cure. Overall survival differed significantly between the resected and nonresected groups (P <.0001), with overall 5-year probabilities of.27 and.06, respectively. Controlling for worst performance status at the time of recurrence does not alter this relationship. Patients who underwent salvage surgery had significantly increased survival (P <.001) for each site. CONCLUSION: Attempted surgical salvage of rectal cancer recurrence is performed commonly in the United States. The chance of a long-term cure with such intervention is approximately 27%.

Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114.

PURPOSE: The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure. PATIENTS AND METHODS: All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy. Chemotherapy regimens were bolus fluorouracil (5-FU), 5-FU and leucovorin, 5-FU and levamisole, and 5-FU, leucovorin, and levamisole. Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy. RESULTS: One thousand six hundred ninety-five patients were entered and fully assessable, with a median follow-up of 7.4 years. There was no difference in overall survival (OS) or disease-free survival (DFS) by drug regimen. DFS and OS decreased between years 5 and 7 (from 54% to 50% and 64% to 56%, respectively), although recurrence-free rates had only a small decrease. The local recurrence rate was 14% (9% in low-risk [T1 to N2+] and 18% in high-risk patients [T3N+, T4N]). Overall, 7-year survival rates were 70% and 45% for the low-risk and high-risk groups, respectively. Males had a poorer overall survival rate than females. CONCLUSION: There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates are still high, especially in T3N+ and T4 patients, even with full adjuvant chemoradiation therapy.

Chemoradiation for locally advanced squamous cell carcinoma of the head and neck for organ preservation and palliation.

OBJECTIVES: To measure the efficacy and toxic effects of our chemoradiotherapy regimen by means of response and survival in patients with advanced squamous cell carcinoma of the head and neck (HNSCC) for organ preservation in resectable disease or palliation in unresectable disease. DESIGN: All patients underwent evaluation by the multidisciplinary head and neck cancer team, with pathological diagnosis and staging. All patients underwent assessment for response to therapy using results of physical examination and radiologic imaging. Patients were followed up at 3-month intervals for a planned period of 5 years. SETTING: Academic center. PATIENTS: Thirty-eight previously untreated patients with newly diagnosed HNSCC were treated from June 1, 1996, through December 31, 1998, of whom 20 had resectable and 18 had unresectable tumors. INTERVENTION: Patients received intravenous cisplatin, 100 mg/m(2) for 1 hour on days 1 and 29; a 24-hour continuous infusion of fluorouracil, 1000 mg/m(2) on days 1 through 4 and 29 through 32; and radiation therapy, 150 rad twice daily for 12 days. The patients were given a 7- to 10-day break, and radiation therapy was restarted on day 29 for 12 additional days (total dose, 7200 rad). MAIN OUTCOME MEASURES: Complete, partial, and total response rates; disease-free survival; overall survival; and toxic effects. RESULTS: Toxic effects of treatment were moderately severe, including grades III to IV mucositis (89%), neutropenia (71%), and renal toxic effects (8%). In the 18 patients in the unresectable group, complete response in the 17 primary tumors and 15 cervical nodal metastases was achieved in 12 (71%) and 9 (60%), respectively; in the 20 patients undergoing organ preservation, complete response rates were 100% in the 23 primary tumors and 15 cervical nodal metastases. Complete response for all 38 patients was achieved in 31 (82%). In the unresectable group, the Kaplan-Meier relapse-free survival estimate is 56%, with follow-up from 29 to 45 months. In the organ preservation group, 75% of patients are alive without disease, and 8 have been followed up for 36 to 48 months. Of the 5 patients who have died, only 2 died of disease, with recurrences at 13.0 and 16.5 months. CONCLUSIONS: Chemoradiotherapy consisting of cisplatin, fluorouracil, and twice-daily external beam radiation is highly effective in achieving durable complete responses in patients with resectable HNSCC undergoing organ preservation and patients with unresectable HNSCC undergoing palliation. Toxic effects of this regimen were moderate to severe.

Tumor uptake and elimination of 2',2'-difluoro-2'-deoxycytidine (gemcitabine) after deoxycytidine kinase gene transfer: correlation with in vivo tumor response.

PURPOSE: We hypothesized that tumor uptake and elimination of 2',2'-difluoro-2'-deoxycytidine/2',2'-difluoro-2'-deoxycytidine 5'-triphosphate (dFdCyd/dFdCTP) would be altered after dCK gene transfer and that this change would result in an enhanced cytotoxic effect. To test this hypothesis, we examined dFdCyd/dFdCTP uptake and clearance in HT-29 human colon carcinoma xenografts in nude mice by high-performance liquid chromatography (HPLC) and fluorine-19 magnetic resonance spectroscopy (F-19 MRS). EXPERIMENTAL DESIGN: HT-29 tumors were grown from cells infected with either the retroviral vector alone (LNPO-LacZ) or vector containing the dCK gene (LNPO-dCK). HPLC and F-19 MRS analyses were performed after a single 160 mg/kg i.p. injection of dFdCyd. Tumor response was determined in animals receiving a similar dosing schedule of dFdCyd. RESULTS: HPLC experiments revealed an increased tumor accumulation of dFdCTP in xenografts overexpressing dCK compared with wild-type controls (P < or = 0.05). dFdCTP in the dCK-infected tumors was easily identified at 24 h postinjection. Conversely, no dFdCTP could be detected in the control xenografts 14 h postinjection. Subsequent F-19 MRS experiments confirmed an altered uptake, revealing a 2.5-fold greater accumulation of dFdCyd/dFdCTP in the dCK xenografts. Whereas a modest tumor growth delay was observed in the wild-type tumors receiving dFdCyd, dCK xenografts demonstrated a marked tumor growth delay following treatment (P < or = 0.05). CONCLUSIONS: These data support the hypothesis that increased expression of dCK cDNA in HT-29 xenografts results in an enhanced dFdCTP accumulation and prolonged elimination kinetics, and ultimately a potentiated in vivo tumor response to dFdCyd. Related to these effects, changes in the overall tumor metabolism of dFdCyd/dFdCTP was detectable by noninvasive F-19 MRS. These data are relevant to future preclinical and clinical studies evaluating dCK gene transfer and dFdCyd therapy.

Impact of surgical and pathologic variables in rectal cancer: a United States community and cooperative group report.

PURPOSE: Substantial and successful effort has been focused on decreasing the risk of local failure after rectal cancer surgery through the use of adjuvant therapies. Our study examined data from studies conducted by United States cooperative groups to investigate the impact of surgical and pathologic variables in rectal cancer outcomes. PATIENTS AND METHODS: Surgical and pathologic reports from 673 patients with stage II/III rectal cancer enrolled onto three adjuvant clinical trials were reviewed for tumor and surgical variables. Additional information on individual institutions and operating surgeon was collected. Variables were tested for association with 5-year local recurrence and survival after adjustment for adjuvant treatments and other important prognostic factors. RESULTS: Five-year local recurrence and survival rates were 16% and 59%, respectively. Surgeons treating more than 10 study cases had lower local recurrence rates than those treating < or = 10 (11% v 17%, P =.02). Free radial margins also correlated with local recurrence (P =.01). Type of surgery, distal margins, and tumor radial spread were not significant. Tumor adherence to adjacent structures predicted local recurrence (35% v 14%, P <.001) and survival (30% v 63%, P <.001), regardless of en bloc resection. Although T and N classification predicted survival (P <.001), only N classification correlated with local recurrence. The number and percentage of positive nodes correlated with survival, but only the percentage independently predicted local recurrence. Several pathologic and surgical variables were reported suboptimally. CONCLUSION: Moderate variability in outcomes among surgeons was detected in this high-risk population. Efforts to improve surgical results will require changes in reporting practices to allow for more accurate assessment of the quality of surgery.

Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-kappaB.

PURPOSE: NF-kappaB is activated by tumor necrosis factor, certain chemotherapeutic agents, and ionizing radiation, leading to inhibition of apoptosis. NF-kappaB activation is regulated by phosphorylation of IkappaB inhibitor molecules that are subsequently targeted for degradation by the ubiquitin-proteasome pathway. PS-341 is a specific and selective inhibitor of the proteasome that inhibits NF-kappaB activation and enhances cytotoxic effects of chemotherapy in vitro and in vivo. The objective of this study was to determine if proteasome inhibition leads to enhanced radiation sensitivity. METHODS AND MATERIALS: Inhibition of NF-kappaB activation in colorectal cancer cells was performed by treatment of LOVO cells with PS-341 or infection with an adenovirus encoding IkappaB super-repressor, a selective NF-kappaB inhibitor. Cells were irradiated at 0, 2, 4, 6, 8, and 10 Gy with or without inhibition of NF-kappaB. NF-kappaB activation was determined by electrophoretic mobility gel shift assay, and apoptosis was evaluated using the TUNEL assay. Growth and clonogenic survival data were obtained to assess effects of treatment on radiosensitization. In vitro results were tested in vivo using a LOVO xenograft model. RESULTS: NF-kappaB activation was induced by radiation and inhibited by pretreatment with either PS-341 or IkappaBalpha super-repressor in all cell lines. Inhibition of radiation-induced NF-kappaB activation resulted in increased apoptosis and decreased cell growth and clonogenic survival. A 7-41% increase in radiosensitivity was observed for cells treated with PS-341 or IkappaBalpha. An 84% reduction in initial tumor volume was obtained in LOVO xenografts receiving radiation and PS-341. CONCLUSIONS: Inhibition of NF-kappaB activation increases radiation-induced apoptosis and enhances radiosensitivity in colorectal cancer cells in vitro and in vivo. Results are encouraging for the use of PS-341 as a radiosensitizing agent in the treatment of colorectal cancer.

Impact of number of nodes retrieved on outcome in patients with rectal cancer.

PURPOSE: We postulated that the pathologic evaluation of the lymph nodes of surgical specimens from patients with rectal cancer can have a substantial impact on time to relapse and survival. PATIENTS AND METHODS: We analyzed data from 1,664 patients with T3, T4, or node-positive rectal cancer treated in a national intergroup trial of adjuvant therapy with chemotherapy and radiation therapy. Associations between the number of lymph nodes found by the pathologist in the surgical specimen and the time to relapse and survival outcomes were investigated. RESULTS: Patients were divided into groups by nodal status and the corresponding quartiles of numbers of nodes examined. The number of nodes examined was significantly associated with time to relapse and survival among patients who were node-negative. For the first through fourth quartiles, the 5-year relapse rates were 0.37, 0.34, 0.26, and 0.19 (P: = .003), and the 5-year survival rates were 0.68, 0.73, 0.72, and 0.82 (P: = .02). No significant differences were found by quartiles among patients determined to be node-positive. We propose that observed differences are primarily related to the incorrect determination of nodal status in node-negative patients. Approximately 14 nodes need to be studied to define nodal status accurately. CONCLUSION: These results suggest that the pathologic assessment of lymph nodes in surgical specimens is often inaccurate and that examining greater number of nodes increases the likelihood of proper staging. Some patients who might benefit from adjuvant therapy are misclassified as node-negative due to incomplete sampling of lymph nodes.

Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer.

PURPOSE: To determine the maximum-tolerated dose, dose-limiting toxicities, and potential antitumor activity of twice-weekly gemcitabine and concurrent radiation in patients with locally advanced pancreatic cancer. PATIENTS AND METHODS: Nineteen patients with histologically confirmed adenocarcinoma of the pancreas were studied at the Wake Forest University Baptist Medical Center and the University of North Carolina at Chapel Hill. The initial dose of gemcitabine was 20 mg/m(2) by 30-minute intravenous infusion each Monday and Thursday for 5 weeks concurrent with 50.4 Gy of radiation to the pancreas. Gemcitabine doses were escalated in 20-mg/m(2) increments in successive cohorts of three to six additional patients until dose-limiting toxicity was observed. RESULTS: The dose-limiting toxicities at 60 mg/m(2) given twice-weekly were nausea/vomiting, neutropenia, and thrombocytopenia. Twice-weekly gemcitabine at a 40-mg/m(2) dose was well tolerated. Of the eight patients eligible for a minimum follow-up of 12 months, three remain alive, one of whom has no evidence of disease progression. CONCLUSION: A dose of twice-weekly gemcitabine at 40 mg/m(2) produced mild thrombocytopenia, neutropenia, nausea, and vomiting when delivered with concurrent radiation to the upper abdomen in patients with advanced pancreatic cancer. These data suggest this regimen is well tolerated and may possess significant activity. These data and other observations have resulted in a phase II Cancer and Leukemia Group B study to ascertain the efficacy of this treatment regimen in patients with locally advanced pancreatic cancer.

Outcomes of patients receiving radiation for carcinoma of the rectum. Results of the 1988-1989 patterns of care study.

BACKGROUND: Clinical trials of surgical adjuvant treatment for patients with rectal carcinoma (RC) indicate that postoperative radiation therapy with concurrent chemotherapy (CRT) is superior to postoperative radiation alone (RT) or surgery alone. Whether preoperative treatment is superior to postoperative treatment is controversial. This Patterns of Care Study (PCS) surveyed patients with RC treated with radiation during the years 1988-1989 to determine the national practice standards and outcomes and to compare these results with those of clinical trials. METHODS: A national survey of 73 institutions was conducted using 2-stage cluster sampling, and specific information on 406 patients with RC who received radiation at 69 facilities was collected. Follow-up information on 215 patients was subsequently collected by mail survey. There were no significant differences between the known prognostic indicators or treatment-related variables for patients for whom follow-up was available compared with the variables for patients for whom follow-up was not available. Follow-up ranged from 0 to 8.44 years with a median of 4 years. One hundred fifty-four patients (71%) received postoperative treatment, either RT (37%) or CRT (34%); and 40 (18%) received preoperative treatment, either RT (15%) or CRT (3%). Ninety-six patients (45%) received chemotherapy, and for 86% of those patients chemotherapy was administered concurrently with radiation. RESULTS: Survival was stage-dependent (85% Stage I, 69% Stage II, and 54% Stage III at 5 years, P = 0.04). Survival was also substage-dependent, and patients with C(1) cancer had significantly higher 5-year survival than those with C(2)/C(3) cancer (89% vs. 48%, P = 0.008). Local failure was similar for Stage II and Stage III patients (10% vs. 11% at 5 years, respectively). In multivariate analyses, only stage and use of chemotherapy were significant to survival (Stage III vs. Stage I and II, relative risk [RR] = 2.52, and chemotherapy vs. no chemotherapy, RR = 0.46). A significantly higher 5-year survival rate was seen with postoperative CRT than with postoperative RT (69% vs. 50%, P = 0. 011). Preoperative radiation resulted in a significantly higher 5-year survival rate than postoperative radiation (85% vs. 50%, P = 0.0006), but not compared with postoperative CRT. Survival and local failure did not differ according to radiation therapy interruption or the interval between surgery and radiation. CONCLUSIONS: Stage is an important prognostic indicator for survival, and among patients with Stage III malignancies survival in the substage C(1) is significantly higher than in the substages C(2) and C(3). As has been demonstrated in randomized trials, adjuvant postoperative CRT is superior to postoperative RT for patients with RC in this national study. These nationwide results of adjuvant treatment are comparable to those reported in randomized trials. The use of CRT was the only treatment-related factor that resulted in a significant reduction in the risk of death.

Sphincter-sparing treatment for distal rectal adenocarcinoma.

BACKGROUND: Studies suggest that the anal sphincter can be preserved in some patients with distal rectal adenocarcinoma (DRA), but this has not been validated in any prospective multi-institutional trial. METHODS: To test the hypothesis that the anal sphincter can be preserved in some patients with DRA, the Cancer and Leukemia Group B and collaborators reviewed 177 patients who had T1/T2 adenocarcinomas < or = 4 cm in diameter, which encompassed < or = 40% of bowel wall circumference, and were < or = 10 cm from the dentate line. Of the 177 patients, 59 patients who were eligible for the study had T1 adenocarcinomas and received no further treatment; 51 eligible T2 patients received external beam irradiation (5400 cGY/30 fractions 5 days/week) and 5-fluorouracil (500 mg/m2 IV d1-3, d29-31) after local excision. RESULTS: At 48 months median follow-up, 6-year survival and failure-free survival rates of the eligible patients are 85% and 78% respectively. Three patients died of unrelated disease. Two patients were treated for second primary colorectal tumors; both remain disease free (NED). Another eight patients died of disease, four with distant recurrence only. One T1 patient is alive with distant disease. Two T1 and seven T2 patients experienced isolated local recurrences; all underwent salvage abdominoperineal resection (APR). After APR, one T1 and four of seven T2 patients were NED at the time of last visit (2-7 years). One T1 patient died of local and distant disease. Three of seven T2 patients died with distant disease. CONCLUSIONS: We conclude that sphincter preservation can be achieved with excellent cancer control without initial sacrifice of anal function in most patients. After local recurrence, salvage resection appears effective, but longer follow-up time of local and distant disease-free survival is advised before extrapolation to patients with T3 primaries.

Induction chemoradiotherapy followed by esophagectomy in patients with carcinoma of the esophagus.

BACKGROUND: Induction chemoradiotherapy followed by esophagectomy may provide results superior to those of single-modality treatment in patients with esophageal cancer. The purpose of this study was to review our experience with this approach for esophageal cancer. METHODS: From 1988 to 1996, 166 consecutive patients with esophageal cancer were evaluated; 66 entered a protocol of chemotherapy (5-fluorouracil, cisplatin) concurrent with radiation (45 Gy) followed by esophagectomy. Fifty-four patients completed the protocol. RESULTS: Toxicity associated with induction chemoradiotherapy was minimal. The actuarial survival at 12, 24, and 36 months was 59%, 42%, and 32%, respectively. The pathologic complete response (pCR) rate was 41%, with 12-, 24-, and 36-month survivals of 77%, 50%, and 45%, whereas non-pCR patients had survivals of 46%, 35%, and 23%. The difference in survival between pCR and non-pCR patients was not significant (p = 0.13), but the difference in recurrence-free survival was significant (p = 0.007). CONCLUSIONS: This well-tolerated protocol resulted in a high pCR. Trimodality treatment for esophageal cancer may provide long-term survival in some patients regardless of their pCR status.

Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114.

PURPOSE: The combination of radiation therapy with fluorouracil (5-FU)-based chemotherapy is generally accepted as appropriate postoperative therapy for patients with adenocarcinomas of the rectum that extend through the bowel wall or with lymph nodes positive for tumor. We attempted to determine whether the efficacy of this postoperative therapy could be improved by the addition of leucovorin and/or levamisole. METHODS: A total of 1,696 patients were randomized and eligible for treatment with one of four treatment schemes. All patients received two cycles of bolus 5-FU-based systemic chemotherapy followed by pelvic radiation therapy with chemotherapy and two more cycles of the same systemic chemotherapy. Chemotherapy was either 5-FU alone, 5-FU with leucovorin, 5-FU with levamisole, or 5-FU with leucovorin and levamisole. RESULTS: With a median follow-up duration of 48 months, there is no statistically significant advantage to any of the treatment regimens compared with bolus 5-FU alone. There is evidence of increased gastrointestinal toxicity with the three-drug combination compared with bolus 5-FU alone. Statistical analysis suggests it is very unlikely that either levamisole-containing combination will be shown to be of value with further follow-up evaluation. CONCLUSION: There is no evidence at present for a beneficial effect of levamisole in the adjuvant treatment of rectal cancer. Definitive evaluation of the effect of the addition of leucovorin to 5-FU and pelvic radiation will require further follow-up evaluation.

Role of radiation therapy in retroperitoneal sarcomas.

Historically, patients with retroperitoneal sarcomas have had a poor prognosis. Surgical resection continues to be the standard treatment for these tumors. However, their anatomic location and large size at presentation often make complete surgical resection infeasible. Even with complete gross removal of tumor, most patients will experience local failure. Adjuvant radiation therapy has been used to improve local control rates. In the postoperative setting, radiation doses to the tumor bed are limited by radiation tolerances of surrounding normal tissues. Extrapolation of data from soft-tissue sarcomas at other sites suggests that delivery of higher radiation doses, in combination with surgery, may favorably affect local control. Preoperative radiation therapy, in combination with brachytherapy or intraoperative radiation therapy at the time of surgical resection, allows for the safe delivery of higher doses of radiation than is possible in the postoperative setting. These approaches make it possible to maximize the likelihood of local control and cure while minimizing normal tissue toxicity.