Preliminary results of a randomized study of adjuvant radiation therapy in resectable adult retroperitoneal soft tissue sarcomas

Between January 1980 and September 1985, 35 adult patients with resectable retroperitoneal soft tissue sarcomas were entered on a randomized trial comparing two forms of adjuvant radiation therapy. Fifteen patients received the experimental therapy consisting of intraoperative radiotherapy (IORT) to 20 Gy using high-energy electrons followed by low-dose (35 to 40 Gy) postoperative external beam irradiation. Twenty patients received standard therapy consisting of high-dose (50 to 55 Gy) postoperative external beam irradiation. With a minimum follow-up of 15 months, there is no significant difference in the actuarial disease-free survival (DFS) and overall survival (OS) comparing the two groups (median DFS, 34 months; median OS, 38 months). At 5 years follow-up, approximately 40% of patients are alive and 20% of patients remain disease-free. Although there is a trend towards an improvement in in-field local control in the experimental arm, the predominant pattern of failure in both groups was locoregional within the retroperitoneum and/or peritoneal cavity. Acute and late radiation enteritis were significantly reduced in the experimental group. However, four experimental patients developed late (greater than 6 months following treatment) peripheral neuropathy believed related to the use of IORT; all four recovered. We conclude that there is no difference in the therapeutic effectiveness of the combination of IORT and low-dose external beam radiation compared with conventional high-dose radiation as adjuvant treatment in retroperitoneal sarcomas, although the former appears to be less toxic. Newer combined modality treatment strategies are discussed to improve the prognosis in these patients.     

Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group study

One hundred ninety-one patients with pathologically confirmed, locally unresectable adenocarcinoma of the stomach (57 patients) and pancreas (91 patients), were randomly allocated to therapy with 5-fluorouracil (5-FU) alone, 600 mg/m2 intravenously (IV) once weekly, or radiation therapy, 4,000 rad, plus adjuvant 5-FU, 600 mg/m2 IV, the first three days of radiotherapy, then follow-up maintenance 5-FU, 600 mg/m2, weekly. Forty-three patients (22%) could not be analyzed because of ineligibility or cancellation, thus 148 patients were evaluable. The median survival time was similar for both treatment programs and for both types of primary carcinoma, and was as follows: gastric primary carcinoma, 5-FU, 9.3 months; 5-FU plus radiotherapy, 8.2 months; pancreatic primary carcinoma, 5-FU, 8.2 months; 5-FU plus radiotherapy, 8.3 months. Substantially more toxicity was experienced by patients treated with the combined modality arm than by those patients receiving 5-FU alone. Severe or worse toxicity experienced by patients with gastric primary carcinoma treated by 5-FU was 19%, and the combined modality arm was 31%. The toxicity experienced by patients with pancreatic primary carcinoma treated with 5-FU was 27%, and the combined modality arm was 51%. Significant prognostic variables included: weight loss in stomach-cancer patients; and performance status, degree of anaplasia, and reduced appetite in pancreas-cancer patients.     

Radiotherapy alone in patients with advanced nasopharyngeal cancer: comparison with an intergroup study. Is combined modality treatment really necessary?

PURPOSE: To examine the outcome of radiotherapy (RT) alone in patients with advanced nasopharyngeal cancer (NPC) and to compare the results with those reported by the Intergroup study 0099 (IGS) comparing RT to combined modality therapy (CMT). MATERIALS AND METHODS: During the period 1985-1992, 198 NPC patients presenting without distant metastatic disease were treated for cure. Of these, 172 had stage III/IV (UICC 1987, 1992). Planned RT was 2 Gy/day fraction to 60-66 Gy to the primary tumor, with 50 and 60 Gy to the node negative and to palpable nodes, respectively. Outcomes included overall survival (OS) and disease-free survival (DFS), defined from the time of registration at our institution. RESULTS: The TNM categories and other prognostic factors were similar to the IGS, though 80% had stage IV compared to 91% in IGS. The 5 year OS and DFS for the 172 patients with stage III/IV disease were 62 and 48%, respectively, as compared to the IGS results of OS 37% and DFS 29% for RT alone, and OS 67% and DFS 58% for the CMT arm of IGS. When the distribution of adverse prognostic factors was balanced between both studies the comparative results were unchanged. CONCLUSIONS: The early results for RT alone of this single institution experience are superior to those of the IGS control arm (RT), while somewhat inferior to those reported in the chemo-radiotherapy arm. The surprisingly poor outcome of the IGS/RT control arm may have resulted by chance, suggesting the need for a confirmatory randomized trial to fully establish the role of combined chemotherapy and radiation, as used in the IGS.     

紫杉醇加顺铂同步放化疗治疗局部晚期食管癌的临床研究

目的:探讨紫杉醇加顺铂(TP)同步放化疗治疗局部晚期食管癌的疗效及毒副反应。方法:48例局部晚期食管癌患者,随机分成两组,每组24例,A组为单纯放疗组,B组为每周紫杉醇加顺铂同步放化疗组。两组均采用6MV或者18MVX射线放射治疗,食管癌原发灶剂量60～68Gy,区域淋巴结剂量50～60Gy。B组放疗同时给予紫杉醇40mg/m2 DDP20mg/m2,均于d1、d8、d15、d22、d29、d36静滴。结果:单纯放疗组和紫杉醇加顺铂组的有效率(CR PR)分别为75%和88%,差异有显著性意义(P<0.05)。两组的1、3、5年局部无进展生存率分别为60.7%、21.0%和9.5%,71.2%、49.3%和19.2%,两组局部无进展生存率差异有显著性意义(P=0.034);两组的1、3、5年生存率分别为66.7%、25.0%和12.5%,79.2%、58.3%和29.2%,总生存率差异有显著性意义(P=0.041)。同步放化疗组的Ⅲ、Ⅳ级毒副反应高于单纯放疗组。结论:同步放化疗可提高局部晚期食管癌的无进展生存率和总生存率,但毒副反应有增加的趋势。     

A randomized study of two doses of abdominopelvic radiation therapy for patients with optimally debulked stage I,II, and III ovarian cancer

Purpose: To determine whether an increased dose of abdominal radiation therapy results in improved disease control and survival in patients with early ovarian cancer.Methods and Patients: Between 1981 and 1990, 125 patients with optimally debulked Stage I, II, and III ovarian cancer were entered into a prospective randomized clinical trial of abdominopelvic radiation therapy. Patients were stratified and randomized to either the control arm, treated with an abdominal dose of 22.5 Gy in 22 fractions, or the experimental arm of 27.5 Gy in 27 fractions. A pelvic boost dose of 22.5 Gy was used in both arms. There were 43 patients with Stage I tumors, 71 Stage II tumors, and 11 Stage III tumors. Nineteen patients had grade 1 histology, 77 grade 2, and 29 grade 3. Three patients had small-volume residual disease (<2 cm) in the pelvis alone and the remainder had no gross tumor following surgery. Median follow-up was 6.6 years (range 1.4–9.9).Results: Overall survival (OS) at 5 years was 83% in the low-dose arm and 72% in the high-dose arm (p = 0.3). Disease-free survival (DFS) at 5 years was 74% and 67% in the low-dose and high-dose arms, respectively (p = 0.5). The difference in OS between the two arms was −11%, with 95% confidence intervals of −26% (favoring low-dose treatment) to 4% (in favor of high dose). The difference in DFS was −7% (95% confidence interval, −23 to 9%). Failure in the pelvis alone predominated (n = 15); six patients had abdominal and pelvic failure and seven patients failed in the abdomen alone. There were no differences in patterns of relapse, hematologic toxicity, or late complications between the two arms. Serious bowel toxicity was seen in three patients: two in the low-dose and one in the high-dose arm. A Cox proportional hazards model was used to assess the effect of treatment when adjusting for other prognostic variables. Ascites (p = 0.03, relative risk 2.05) was the only significant covariate in predicting disease-free survival, but was not prognostic for overall survival.Conclusions: There was no difference in survival, tumor control, or toxicity between high-dose and low-dose abdominopelvic radiation therapy. High-dose abdominopelvic radiation therapy is unlikely to be associated with an increase in OS of more than 4% or DFS of more than 9%.     

Postoperative irinotecan in resected stage II–III rectal cancer: final analysis of the French R98 Intergroup trial

BackgroudThe R98 trial explores the addition of irinotecan to a 5-fluorouracil (5-FU) plus leucovorin (5-FU/LV) adjuvant regimen in optimally resected stages II–III rectal cancers. We report the updated long-term results. Disease-free survival (DFS) was the primary end point.Patienst and methodsBetween March 1999 and December 2005, 357 patients were randomized: 178 in 5-FU/LV and 179 in LV5-FU2 + irinotecan arm. The trial was stratified by control arm: Mayo Clinic regimen or LV5-FU2 regimen.ResultsThree hundred and fifty-seven randomized patients were evaluable for efficacy. With a follow-up of 156 months, the DFS was in favour of experimental arm but did not reach statistical significance [hazard ratio (HR) = 0.80, P = 0.154]. The same was observed for overall survival (OS) (HR = 0.87, P = 0.433). The 5-year DFS was 58% in the control arm and 63% in the experimental arm. The 5-year OS was 74% in the control arm and 75% in the experimental arm. Patients allocated to the experimental arm had more grade 3–4 neutropenia when compared with the LV5-FU2 arm (33% versus 6%, P = 0.03), but not when compared with the Mayo Clinic arm (33% versus 36%, P = 0.84). Grade 3–4 diarrhoea tended to be higher in the experimental arm, but analyses stratified by control arm or by radiotherapy failed to show significant differences across strata (test for interaction P = 0.44).ConclusionEven though a benefit of irinotecan in subgroups of patients cannot be excluded, due to early termination and lack of power, the study does not support the addition of irinotecan to 5-FU/LV in routine in patients with resected stage II–III rectal cancer.     

单药顺铂在局部晚期鼻咽癌同步放化疗中的临床应用分析

目的：评价局部晚期鼻咽癌PDD同步化疗的疗效及毒副反应。方法：52例局部晚期鼻咽癌接受顺铂同步放疗,PDD化疗的第1天就开始实施同步放疗,顺铂30 mg/m2静脉滴注,每周1次,共7次;鼻咽部病灶及阳性的淋巴结给予放疗总量为70Gy,颈部预防性照射给予放疗量50Gy,每周5次,每次2Gy。结果：全部患者均可评价,近期有效率为100%;1年、3年和5年OS分别为100%、88.5%、25%;3年、5年的无病生存率分别为80.8%和19.2%;平均生存时间和中位生存时间分别为48.7月和47月。无病平均生存时间和无病中位生存时间分别为45.7月和45月。结论：局部晚期鼻咽癌含PDD方案的CCRT有较好的疗效,毒性反应可耐受,长期生存需要进一步观察。     

French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC-GORTEC)

BACKGROUND: Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis. Following a previous phase II study, this phase III multicenter trial was conducted between November 1997 and March 2002. METHODS: Nontreated, strictly unresectable cases were eligible. Twice-daily radiation: two fractions of 1.2 Gy/day, 5 days per week, with no split (D1-->D46). Total tumor doses: 80.4 Gy/46 day (oropharynx), 75.6 Gy/44 day (hypopharynx). Chemotherapy (arm B): Cisplatin 100 mg/m2 (D1, D22, D43); 5FU, continuous infusion (D1-->D5), 750 mg/m2/day cycle 1; 430 mg/m2/day cycles 2 and 3. RESULTS: A total of 163 evaluable patients. Grade 3-4 acute mucositis 82.6% arm B/69.5% arm A (NS); Grade 3-4 neutropenia 33.3% arm B/2.4% arm A (p < 0.05). Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months (p < 0.01). At 24 months, overall survival (OS), disease-free survival (DFS), and specific survival (SS) were significantly better in arm B. OS: 37.8% arm B vs. 20.1% arm A (p = 0.038); DFS: 48.2% vs. 25.2% (p = 0.002); SS: 44.5% vs. 30.2% (p = 0.021). No significant difference between the two arms in the amount of side effects at 1 and 2 years. CONCLUSION: For these unresectable cases, chemoradiation provides better outcome than radiation alone, even with an "aggressive" dose-intensity radiotherapy schedule.     

Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: survival results and observations regarding patterns of failure, radiotherapy dose and CA19-9 levels

Purpose: Primary endpoints were 1. To determine if, in the context of postoperative adjuvant therapy of pancreatic and nonpancreatic periampullary adenocarcinoma, continuous infusion (C.I.) 5-fluorouracil (5-FU) and leucovorin (Lv), combined with continuous-course external-beam radiotherapy (EBRT) to liver (23.4–27.0 Gy), regional lymph nodes (50.4–54.0 Gy) and tumor bed (50.4–57.6 Gy), followed by 4 months of C.I. 5-FU/Lv without EBRT could be given with acceptable toxicity. 2. To determine an estimate of disease-free and overall survival (DFS, OS) with this treatment in this context. Secondary endpoints were 1. To observe the effects of therapy at two different dose levels of irradiation, and 2. To observe for correlations among DFS, OS and CA 19-9 levels during therapy.

Methods: Patients received C.I. 5-FU 200 mg/m² and Lv 5 mg/m² Monday through Friday during EBRT, and 4 cycles of the same chemotherapy without EBRT were planned for each 2 weeks of 4, beginning 1 month following the completion of EBRT. Therapy was to begin within 10 weeks of surgery and patients were monitored for disease recurrence, toxicity, and CA 19-9 levels before the start of EBRT/5-FU/Lv, before each cycle of C.I. 5-FU/Lv, and periodically after the completion of therapy. There were two EBRT dosage groups: Low EBRT, 23.4 Gy to the whole liver, 50.4 Gy to regional nodes and 50.4 Gy to the tumor bed; High EBRT, 27.0 Gy to the whole liver, 54.0 Gy to regional nodes, and 57.6 Gy to the tumor bed.

Results: 29 patients were enrolled and treated (23 with pancreatic cancer, and 6 with nonpancreatic periampullary cancer). Of these, 18 had tumor sizes ≥ 3 cm and 23 had at least one histologically involved lymph node; 6 had histologically positive resection margins. Mean time to start of EBRT/5-FU/Lv was 53 ± 2 days following surgery. The first 18 patients were in the Low EBRT Group and the last 11 in the High EBRT Group. Toxicity was moderate and manageable, including a possible case of late radiation hepatitis. Median DFS was 8.3 months (pancreatic cancer patients 8.5 months) and OS was 14.1 months (pancreatic cancer patients 15.9 months). Among patients with pancreatic cancer, results were similar for the Low and High EBRT Groups (DFS: 8.3 vs. 8.6 months; OS: 14.4 vs. 16.9 months, respectively). With a mean follow up of 2.6 ± 0.3 years for the surviving patients and a minimal follow-up of 2.5 years, 27 of 29 pts have relapsed and 25 pts have died. A rise in CA 19-9 levels preceded clinical relapse by 9.1 ± 1.5 months. Time to first relapse by site showed inverse correlation with dose of radiotherapy to that site: peritoneal (5 ± 1 month), hepatic (7 ± 0.9 months), regional nodes/tumor bed (9.6 ± 1.8 months). Mean postresection CA 19-9 level was 63.3 ± 16.2 U/ml. Postresection CA 19-9 values did not correlate with survival, margin status, or with the identification of metastatic carcinoma in resected lymph nodes. However, among patients with histologically involved nodes in the resected specimen, postresection CA 19-9 values did correlate with the number of positive nodes identified (p = 0.05).

Conclusions: Although toxicity was acceptable, survival results were not improved over those seen with standard adjuvant treatment. Most patients relapsed before the planned chemotherapy cycles were completed, or within 100 days thereof, suggesting disease resistance to C.I. 5-FU/Lv as used in this study. Although this regimen is not recommended for further study, the doses of EBRT utilized may be suitable for evaluation with other chemotherapy combinations. Postoperative CA 19-9 levels did not correlate with survival, but did correlate with the number of histologically involved lymph nodes found in the resected specimen among node-positive patients. Moreover, rising CA 19-9 levels anticipated ultimate clinical failure by 9 months.     

Long-term results of combined-modality therapy for inflammatory breast carcinoma

Sixty-eight patients with inflammatory breast carcinoma (IBC) received treatment in 2 prospective randomized trials of multimodality therapy for locally advanced breast cancer. The treatment plan consisted of 3 courses of neoadjuvant chemotherapy with CAF (cyclophosphamide/doxorubicin/5-fluorouracil [5-FU]) or CEF (cyclophosphamide/epirubicin/5-FU) followed by surgery and 6 adjuvant courses of CAF or CEF alternated with CMF (cyclophosphamide/methotrexate/5-FU). Radiation therapy was administered at the end of adjuvant treatment. All patients with estrogen receptor-positive tumors received tamoxifen 20 mg daily for 5 years. The response rate to induction chemotherapy was 73.6% (95% CI, 61.4%-83.5%): 4 of 68 patients (6%) exhibited a pathologic remission of primary breast tumor (persistent disease in the axilla), and 2 patients (3%) exhibited a pathologic complete response. Median follow-up was 10 years (range, 5 months to 14.7 years). Disease-free survival (DFS) rates at 5 and 10 years were 29% and 20%, respectively, and median DFS was 2.2 years (range, 3.8 months to 11.5 years). Overall survival (OS) rates at 5 and 10 years were 44% and 32%, respectively, and median OS was 4 years (range, 5 months to 14.7 years). Significant prognostic factors for DFS and OS were the number of axillary nodes and residual disease in the breast at surgery. This analysis confirmed that patients with IBC obtained significant long-term survival benefit from combined-modality therapy.     

Phase I study of hyperfractionated radiation therapy with protracted 5-fluorouracil infusion in patients with locally advanced pancreatic cancer

OBJECTIVE: This study investigated the maximum-tolerated dose of hyperfractionated radiation therapy with protracted 5-fluorouracil (5-FU) infusion in patients with locally advanced, unresectable pancreatic cancer. METHODS: Five cohorts of patients were scheduled to receive escalating doses of hyperfractionated radiation therapy (range, 45.6-64.8 Gy). All patients received two fractions of 1.2 Gy each (separated by 6 h) per day for 5 days a week, and received protracted 5-FU infusion (200 mg/m2/day) during the radiation course. The maximum-tolerated dose was defined as one dose level below the dose at which more than one third of 3-6 patients experienced dose-limiting toxicity. RESULTS: Twenty-nine patients were enrolled in this study. The most common toxicities were nausea/vomiting and anorexia. Although 1 patient developed bleeding from a gastric ulcer 3 months after the completion of chemoradiotherapy, the maximum-tolerated dose was not reached even at the highest dose level (level 5, 64.8 Gy). The median survival time was 12.2 months and the 1-year survival rate was 55.0%. CONCLUSION: The toxicity associated with our regimen was tolerable up to dose level 5 (64.8 Gy). We are currently conducting a phase II study of this hyperfractionated radiation therapy with protracted 5-FU infusion at a dose of 64.8 Gy.     

调强放疗模式下局部晚期鼻咽癌诱导化疗后同期化疗与单纯放疗疗效比较

目的:探讨调强放疗模式下局部晚期鼻咽癌诱导化疗后同期化疗与单纯放疗临床疗效的比较。方法:回顾性分析2010年-2012年期间在本院采用调强放疗技术治疗的局部晚期鼻咽癌,分期为Ⅲ-Ⅳ期的鼻咽癌患者共120例。所有患者都进行过诱导化疗。放疗范围及剂量为鼻咽原发灶、阳性淋巴结的大体肿瘤体积处方剂量为T1、T2期69.96Gy,T3、T4期72~74Gy;亚临床高危区靶体积处方剂量为60~64Gy;淋巴结阴性引流区处方剂量为50~54Gy。分为单纯放疗组60例,同期化疗组60例。同期化疗方案为单药顺铂为基础的方案。主要观察两组的近期疗效、3年无瘤生存率(DFS)、3年无局部区域复发生存率（LRFS）、3年无远处转移生存率（MFS）、3年总生存率（OS）及治疗的毒副反应情况。结果:两组性别、年龄、病理类型及临床分期的构成比均有可比性。两组患者中位随访36个月。治疗结束3个月两组患者的完全缓解率分别为83.3％、80.0％,3年无瘤生存率分别为78.3％、75.0％,3年的无局部区域复发生存率分别为93.3％、90.0％,3年无远处转移生存分别为81.7％、83.3％,3年总生存率分别为88.3％、86.7％,两组统计学无明显差异。同期化疗组急性毒副反应高于单纯放疗组。结论:在调强放疗治疗模式下,局部晚期鼻咽癌同期化疗与单纯放疗相比,患者的3年总生存率及无瘤生存率未能进一步提高,而急性毒副反应增加,同期化疗在调强放疗模式下治疗策略需要行进一步的临床研究。     

Multicenter randomized phase III trial comparing protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin in inoperable pancreatic cancer.

PURPOSE: To compare protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin (MMC) in patients with advanced pancreatic cancer in a multicenter, prospectively randomized study. PATIENTS AND METHODS: Two hundred eight patients were randomized to PVI 5-FU (300 mg/m(2)/d for a maximum of 24 weeks) or PVI 5-FU plus MMC (7 mg/m(2) every 6 weeks for four courses). The major end points were tumor response, survival, toxicity, and quality of life (QOL). RESULTS: The two treatment groups were balanced for baseline demographic factors, and 62% had metastatic disease. The overall response rate was 8.4% (95% confidence interval [CI]) 3.2% to 13.7% for patients treated with PVI 5-FU alone compared with 17.6%; 95% CI 10.3% to 25.1% for PVI 5-FU plus MMC (P =.04). Median failure-free survival was 2.8 months for PVI 5-FU and 3.8 months for PVI 5-FU plus MMC (P =.14). Median survival was 5.1 months for PVI 5-FU and 6.5 months for PVI 5-FU plus MMC (P =.34). Toxicities in both arms were mild. There was an increased incidence of neutropenia in the 5-FU plus MMC arm (P <.01), although no differences in infection were seen. No patients developed hemolytic uremic syndrome. Global QOL improved significantly after 24 weeks of treatment compared with baseline for patients receiving 5-FU plus MMC, although there was no statistically significant difference in QOL between arms. CONCLUSION: PVI 5-FU plus MMC resulted in a superior response rate in comparison with PVI 5-FU alone in advanced pancreatic cancer, but this did not translate into a survival advantage. These results emphasize the importance of chemotherapy in this setting and the continuing value of the fluoropyrimidines in pancreatic cancer.     

A phase III randomized study of misonidazole plus radiation vs. radiation alone for cervix cancer

BACKGROUND AND PURPOSE: A randomized-controlled study of radical radiotherapy for cervical cancer with or without the hypoxic sensitizer, misonidazole was conducted from 1981 to 1984 to investigate its therapeutic benefit. PATIENTS AND METHODS: Seventy-three patients were accrued from the Princess Margaret Hospital, and St John Regional Cancer Centre and randomized to either misonidazole (MISO, n = 39) or placebo (P, n = 34) in addition to radiotherapy. MISO was given orally each day 4 h prior to external beam radiation treatment (45Gy to midplane in 20 daily fractions) at a dose of 0.45 g/m(2), as well as during intra-uterine brachytherapy (40Gy). RESULTS: The 10-year overall survival (OS) for the entire group was 46%, and the disease-free survival (DFS) was 39%. The 10-year OS for patients in the MISO arm was 45%, compared to 49% for the P arm (P = 0.89). The corresponding DFS figures were 36 and 43%, respectively, (P = 0.6). Ten patients (14%) developed severe late complications (grade 3 or 4). The 10-year serious late complication rate was 14% for MISO and 12% for P (P = 0.51). CONCLUSIONS: Misonidazole failed to improve the outcome of patients with cervix cancer treated with radiotherapy.     

Chemoradiotherapy in the treatment of regional pancreatic carcinoma: a phase II study

In locally advanced pancreatic cancer, the utilization of chemotherapy and radiotherapy is increasing, although in view of the reported long-term results of several contemporary trials, further improvements are certainly needed. Encouraging results using the combination of cisplatin, cytarabine, caffeine, and continuous infusion (CI) 5-fluorouracil (5-FU) (PACE) for the treatment of advanced pancreatic carcinoma prompted a phase II study using PACE followed by external beam radiotherapy with CI of 5-FU (PACE-RT) for localized disease. Forty-one patients were treated with PACE-RT as adjuvant therapy after surgical resection (21 patients), or as primary therapy for locally advanced, unresectable disease (20 patients), with reevaluation for resection after completion of treatment. PACE consisted of cisplatin 100 mg/m2 IV on day 1, cytarabine 2 g/m2 IV every 12 hours x 2 doses, and caffeine 400 mg/m2 subcutaneously after each cytarabine dose; and days 3 to 21, 5-FU 250 mg/m2/d given by CI. Cycles were repeated every 28 days. After 2 cycles of PACE, radiation therapy was given concurrently with 5-FU at 200 mg/m2/d. In the adjuvant setting, the tumor bed and the draining lymph node basin received 50.4 Gy and 45 Gy, respectively. In the neoadjuvant setting, the primary and regional lymph nodes were to receive 39.6 Gy followed by a neutron boost of 8 NGy to the gross tumor volume. Photon therapy was delivered at 1.8 Gy per fraction and neutron therapy at 0.8 NGy per fraction, 5 days a week. All patients were evaluable for toxicity and survival. The most common toxicity was myelosuppression, with grade III to IV neutropenia occurring in 59% of the patients. The median survival times in the locally advanced and adjuvant patients were 13.4 and 18.1 months, with 1-year survival rates of 52% and 65%, respectively. Nine of 20 patients receiving PACE-RT for unresectable carcinoma had sufficient tumor regression to meet clinical criteria for exploration; three were resected with curative intent. The survival of these three patients undergoing resection after neo-adjuvant therapy was 22.4, 24.3 and 40 months. The treatment program was active, but only moderately well tolerated. Modification of this regimen with newer, less toxic drugs may provide better results and reduced toxicity.     

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.     

Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02.

PURPOSE: Radiation Therapy Oncology Group (RTOG) Protocol 92-02 was a randomized trial testing long-term (LT) adjuvant androgen deprivation (AD) after initial AD with external-beam radiotherapy (RT) in patients with locally advanced prostate cancer (PC; T2c-4) and with prostate-specific antigen level less than 150 ng/mL. PATIENTS AND METHODS: Patients received a total of 4 months of goserelin and flutamide, 2 months before and 2 months during RT. A radiation dose of 65 to 70 Gy was given to the prostate and a dose of 44 to 50 Gy to the pelvic lymph nodes. Patients were randomly assigned to receive no additional therapy (short-term [ST]AD-RT) or 24 months of goserelin (LTAD-RT); 1,554 patients were entered onto the study. RESULTS: The LTAD-RT arm showed significant improvement in all efficacy end points except overall survival (OS; 80.0% v 78.5% at 5 years, P =.73), compared with the STAD-RT arm. In a subset of patients not part of the original study design, with tumors assigned Gleason scores of 8 to 10 by the contributing institutions, the LTAD-RT arm had significantly better OS (81.0% v 70.7%, P =.044). There was a small but significant increase in the frequency of late radiation grades 3, 4, and 5 gastrointestinal toxicity ascribed to the LTAD-RT arm (2.6% v 1.2% at 5 years, P =.037), the cause of which is not clear. CONCLUSION: The RTOG 92-02 trial supports the addition of LT adjuvant AD to STAD with RT for T2c-4 PC. In the exploratory subset analysis of patients with Gleason scores 8 to 10, LT adjuvant AD resulted in a survival advantage.     

Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report

Purpose: To compare the efficacy of concomitant irradiation with mitomycin C and bleomycin in patients with inoperable head and neck carcinoma with radiotherapy alone.

Methods and materials: Between March 1991 and December 1993, 64 patients with inoperable head and neck carcinoma (41 with oropharyngeal site) were randomized to radiotherapy alone (group A) or radiotherapy combined with simultaneous application of mitomycin C and bleomycin (group B). In both groups patients were irradiated five times weekly with 2 Gy to a total dose of 66–70 Gy. The planned concomitant treatment in group B was: bleomycin 5 units twice a week IM, total dose 70 units, mitomycin C 15 mg/m² IV after delivery of 10 Gy, and 10 mg/m² IV on the last day of radiotherapy. To enhance the effect of these two drugs, patients received also nicotinamide, chlorpromazine, and dicoumarol.

Because significantly better results were achieved in arm B for patients with inoperable oropharyngeal carcinoma, the study was closed and such patients were after December 1993 routinely treated with the combined therapy (as in arm B). Until October 1996, we treated and followed up 48 such consecutive patients.

Results: Median follow-up of our study patients is 42 months. Complete remission (CR) rate in group A was 31% and in group B 59% (p = 0.04); disease-free survival (DFS) in group A was 8% and in group B 37% (P = 0.01); and overall survival (OS) was 7% in group A and 26% in group B (p = 0.08). CR rate for patients with oropharyngeal carcinoma was 29% in group A (N = 21) and 75% in group B (N = 20) (p = 0.007); DFS in group A was 10% and in group B 48% (p = 0.001); and the OS was 10% in group A and 38% in group B (p = 0.019). In patients with inoperable oropharyngeal carcinoma treated after December 1993, complete remission was achieved in 32/48 (67%, 95% CI: 52%–80%). DFS at the median follow-up of 14 months was 60% (95% CI 43–77%) and OS 58% (95% CI 42–74%).

Conclusion: From the results of our study it seems that the concomitant treatment significantly improves CR rate, DFS, and OS in patients with inoperable oropharyngeal carcinoma in comparison with radiotherapy alone.     

The 5-year results of a randomized trial of adjuvant radiation therapy after chemotherapy in breast cancer patients treated with mastectomy

The use of adjuvant radiation therapy in breast cancer patients treated with mastectomy and adjuvant chemotherapy has been controversial. In order to assess the necessity and effectiveness of adjuvant radiation therapy in this setting, we reviewed the results in 510 patients with T1-T3 tumors and pathologically positive nodes or tumors larger than 5 cm and negative nodes who were treated with adjuvant chemotherapy. Patients with four or more positive nodes or at least one positive apical node were randomized to receive either five or ten cycles of cyclophosphamide/Adriamycin (Adria Laboratories, Columbus, OH) (CA) and patients with one to three positive nodes or operable tumors larger than 5 cm and pathologically negative nodes were randomized to receive eight cycles of either cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF) or methotrexate and 5-FU (MF) chemotherapy. Two hundred six of these patients were subsequently rerandomized to receive either no further treatment or adjuvant radiotherapy. Thirty-five patients withdrew after randomization, including 34 who declined to receive radiotherapy. Radiation therapy consisted of 4,500 cGy in 5 weeks to the chest wall and appropriate draining lymph nodes. Median follow-up from chemotherapy randomization is 45 months for patients in the CA arm and 53 months for those in the CMF/MF arm. The crude rate of local failure (chest wall or draining lymph node areas) as first site of failure for patients randomized to receive chemotherapy only was 14%; for those randomized to receive both chemotherapy and radiotherapy it was 5% (P = .03). For patients in the CMF/MF arm, the rate of local failure as the first site of failure was nearly the same for patients randomized to chemotherapy only as for those randomized to adjuvant radiotherapy as well (5% v 2%). For patients in the CA arm, the crude rate of local failure was 20% for patients randomized to receive chemotherapy only, and 6% for those randomized to both types of adjuvant treatment (P = .03). Among the 43 patients treated with CA who actually received radiotherapy, there was only one local failure, compared with 12 local failures among the 59 patients (20%) who actually did not receive radiotherapy (P = .007). No significant difference was seen in disease-free survival or overall survival in either the CA or the CMF/MF arm between patients randomized to receive radiation therapy and those randomized to no further treatment.(ABSTRACT TRUNCATED AT 400 WORDS)     

Results of radiation therapy for unresected soft-tissue sarcomas

PURPOSE: Definitive radiotherapy is uncommonly used in the management of soft-tissue sarcoma (STS). The purpose of the study was to evaluate the results of radiotherapy for unresected STSs treated in a single institution. METHODS AND MATERIALS: Between 1970 and 2001, 112 patients with STSs underwent radiotherapy for gross disease. Locations of the tumor were 43% in the extremities, 26% retroperitoneal, 24% in the head and neck, and 7% in the truncal wall. Histologic grades were 11% G1 and 89% G2 to G3. Median size of tumor at radiotherapy was 8 cm (range, 1-30 cm). Median radiation dose was 64 Gy (range, 25-87.5 Gy). Twenty percent of patients received chemotherapy. Local control (LC), disease-free survival (DFS), and overall survival (OS) rates were evaluated in univariate (log-rank) and then multivariate (Cox model) analysis to determine prognostic factors for STS. RESULTS: Median follow-up for patients is 139 months (range, 30-365 months). The 5-year actuarial LC, DFS, and OS were 45%, 24%, and 35%, respectively. Tumor size at radiotherapy and radiation dose influenced LC, DFS, and OS in univariate analysis. LC at 5 years was 51%, 45%, and 9% for tumors less than 5 cm, 5 to 10 cm, and greater than 10 cm, respectively. Patients who received doses of less than 63 Gy had 5-year LC, DFS, and OS rates of 22%, 10%, and 14%, respectively, compared with 5-year LC, DFS, and OS rates of 60%, 36%, and 52%, respectively, for patients who received doses of 63 Gy or more. AJCC stage was related to the OS and DFS without statistically significant influence on LC. Use of chemotherapy, histologic grade, age, and location did not influence results. In multivariate analysis, LC was related to total dose (p = 0.02), T size at radiotherapy (p = 0.003), and AJCC stage (p = 0.04); DFS was related to total dose (p = 0.007), T size at radiotherapy (p = 0.01), and AJCC stage (p < 0.0001); and OS was related to AJCC stage (p = 0.0001) and total dose (p = 0.002), but not to T size, at radiotherapy. Major radiotherapy complications were noted in 14% of patients; 27% of patients who received doses of 68 Gy or more had these complications compared with 8% of patients treated with doses of less than 68 Gy. CONCLUSIONS: Definitive radiotherapy for STS should be considered in clinical situations where no acceptable surgical option is available. Higher radiation doses yield superior tumor control and survival. A rise in complications occurs in patients who receive doses of 68 Gy or more, which provides a therapeutic window for benefit in these patients.