Phase I/II trial of pre-operative radiation therapy and coloanal anastomosis in distal invasive resectable rectal cancer.

A total of 22 patients with the diagnosis of invasive, resectable, primary adenocarcinoma of the rectum limited to the pelvis were enrolled on a Phase I/II trial of pre-operative radiation therapy+low anterior resection/coloanal anastomosis. By pre-operative assessment, all patients had invasive tumors involving the distal half of the rectum and required an abdominoperineal resection. The median tumor size was 4 cm (1.5-6 cm) and the median distance from the anal verge was 4 cm (3-7 cm). The whole pelvis received 4680 cGy followed by a 360 cGy boost to the primary tumor bed. The median follow-up was 29 months (10-60 months). Of the 21 patients who underwent resection, 10% had a complete pathologic response and 90% were able to successfully undergo a low anterior resection/coloanal anastomosis. The incidence of local failure as a component of failure was crude: 23% and 4-year actuarial: 32%. The 4-year actuarial survival was 61%. No patients experienced Grade 3 or 4 toxicity while receiving radiation therapy, and 6% developed a partial disruption of the anastomosis. Of the patients who underwent a low anterior resection/coloanal anastomosis, 89% had a good or excellent functional result. This technique may be an alternative to an abdominoperineal resection in selected patients. Further follow-up is needed in order to determine if this approach ultimately has similar local control and survival rates as an abdominoperineal resection.     

Phase I study of preoperative oral uracil and tegafur plus leucovorin and radiation therapy in rectal cancer.

PURPOSE: Preoperative combined-modality therapy for rectal cancer may allow for sphincter preservation, while decreasing recurrence rates and improving the overall prognosis. Oral chemotherapy with uracil and tegafur (UFT) plus leucovorin (LV) may reduce costs and complications associated with protracted infusions of fluorouracil. Our goal was to evaluate the safety of UFT plus LV combined with preoperative radiation and determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of UFT plus LV in this setting. PATIENTS AND METHODS: Patients with tumor-node-metastasis stage II or III rectal cancer received escalating doses of UFT (starting at 250mg/m(2)/d, with 50-mg/m(2)/d increments between consecutive cohorts) and fixed doses of LV (90 mg/d). The UFT and LV combination was given 5 days per week concurrently with a 5-week course of preoperative radiation totaling 45 Gy (1.8 Gy/fraction). Surgery was performed 4 to 6 weeks after radiation and was followed by four 35-day cycles of fixed doses of UFT and LV (28 days of therapy each cycle). RESULTS: Fifteen patients were treated, and 13 received the full preoperative chemotherapy. All planned radiation was delivered successfully. The MTD of UFT with radiation was 350 mg/m(2)/d with 90 mg/d of LV. Diarrhea was the DLT. Sphincter-preserving surgery was performed in 12 of 14 patients. One patient had progressive disease before surgery. Pathologic evaluation of 14 resected specimens showed a complete response in three cases. CONCLUSION: Preoperative chemoradiation with oral UFT plus LV is feasible and well tolerated and should be further investigated.     

Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer.

PURPOSE: The purpose of this study was to establish the feasibility and efficacy of preoperative radiotherapy (RT) with concurrent capecitabine and oxaliplatin (XELOX-RT) in patients with rectal cancer. PATIENTS AND METHODS: Thirty-two patients with locally advanced (T3/T4) or low-lying rectal cancer received preoperative RT (total dose, 50.4 Gy). Capecitabine was administered concurrently at 825 mg/m2 bid on days 1 to 14 and 22 to 35, with oxaliplatin starting at 50 mg/m2 on days 1, 8, 22, and 29 with planned escalation steps of 10 mg/m2. End points of the phase II study included downstaging, histopathologic tumor regression, resectability of T4 disease, and sphincter preservation in patients with low-lying tumors. RESULTS: Dose-limiting grade 3 gastrointestinal toxicity was observed in two of six patients treated with 60 mg/m2 of oxaliplatin. Thus, 50 mg/m2 was the recommended dose for the phase II study. Toxicities observed at this dose level were generally mild, with only two cases of short-lived grade 3 diarrhea. Myelosuppression, mainly leukopenia, was restricted to grade 2 in 19% of patients. T-category downstaging was achieved in 17 (55%) of 31 operated patients, and 68% of patients had negative lymph nodes. Pathologic complete response was found in 19% of the resected specimens. Radical surgery with free margins could be performed in 79% of patients with T4 disease, and 36% of patients with tumors < or = 2 cm from the dentate line had sphincter-saving surgery. CONCLUSION: Preoperative XELOX-RT is a feasible and well tolerated treatment. This regimen is proposed for phase III evaluation comparing standard fluorouracil-based therapy with XELOX chemoradiotherapy.     

Preoperative high-dose leucovorin/5-fluorouracil and radiation therapy for unresectable rectal cancer

Twenty patients with primary or recurrent unresectable rectal cancer limited to the pelvis were entered on a Phase I trial of preoperative pelvic radiation therapy (RT) (5040 cGy) and two cycles of combined high-dose leucovorin (LV) and 5-fluorouracil (5-FU), followed by surgery and ten cycles of postoperative LV/5-FU (sequential). Maximum tolerated doses (MTD) were determined for preoperative combined LV/5-FU and RT and for postoperative sequential LV/5-FU. 5-FU was escalated 50 mg/m2 while the LV remained constant at 200 mg/m2. The initial doses of 5-FU were combined LV/5-FU and RT (200 mg/m2) and sequential LV/5-FU (325 mg/m2). The median follow-up time was 14 months. The resectability rate was 89%, and the pathologic complete response rate was 21%. The MTD for combined LV/5-FU and RT was 300 mg/m2; therefore, the recommended dose of 5-FU is 250 mg/m2. The recommended dose of 5-FU for sequential LV/5-FU is 375 mg/m2. The dose-limiting toxicities in this trial were diarrhea, tenesmus, increased bowel movements, dysuria, and myelosuppression. For the six patients who received 5-FU at the recommended dose level, the median low counts were leukocyte count, 3.7/microliters (range, 2.4 to 4.9/microliters); hemoglobin, 9.0 g/dl (range, 8.2 to 11.9 g/dl); and platelet count (X1000), 146/microliters (range, 89 to 182/microliters). The incidence rate of any Grade 3 toxicity was 17% (diarrhea and frequent bowel movements). The recommended doses of 5-FU used in this protocol were well tolerated. Because there was a long delay before optimal doses of 5-FU could be delivered, the authors do not recommend that high-dose LV be used in conjunction with combined 5-FU and RT with the treatment regimen as currently designed. However, because the resectability and complete response rates were higher than those previously reported for preoperative RT alone, the authors are encouraged by the combined technique approach. New trials are currently being undertaken to determine if the use of a low-dose LV regimen is more tolerable.     

Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: Phase I trial results

PURPOSE: The overexpression of vascular endothelial growth factor (VEGF) is associated with poor outcomes in colorectal cancer patients. Bevacizumab, a VEGF inhibitor, enhances the effects of chemotherapy and radiation therapy on tumor cytotoxicity in preclinical models, including colorectal cancer. A Phase I trial was undertaken to evaluate the combination of bevacizumab, capecitabine, oxaliplatin, and radiation therapy in patients with rectal cancer. METHODS AND MATERIALS: Patients with pathologically confirmed adenocarcinoma of the rectum were eligible. Pretreatment staging included computerized tomography, endoscopic ultrasound, and surgical evaluation. Patients received 50.4 Gy of external beam radiation therapy (EBRT) to the tumor in 28 fractions. Capecitabine, oxaliplatin, and bevacizumab were administered concurrently with radiation therapy. After EBRT completion, patients were restaged and evaluated for surgery. Primary endpoints included the determination of dose-limiting toxicity and a recommended Phase II dose, non dose-limiting toxicity, and preliminary radiographic and pathologic response rates. RESULTS: Eleven patients were enrolled. All were evaluable for toxicity and efficacy. Dose level 2 was associated with unacceptable toxicity (primarily diarrhea). Dose level 1 had an acceptable toxicity profile. The recommended Phase II dose in our study was bevacizumab 15 mg/kg Day 1 + 10 mg/kg Days 8 and 22, oxaliplatin 50 mg/m2 weekly, and capecitabine 625 mg/m2 bid during radiation days. Six patients had clinical responses. Two patients had a pathologic complete response, and 3 had microscopic disease only. One patient experienced a postoperative abscess, one a syncopal episode during adjuvant chemotherapy, and one a subclinical myocardial infarction during adjuvant chemotherapy. CONCLUSIONS: The combination of bevacizumab, capecitabine, oxaliplatin, and radiation therapy in rectal cancer was tolerable, with encouraging response rates. Further investigation with this regimen is being pursued in a Phase II setting.     

Preliminary analysis of a randomized clinical trial of adjuvant postoperative RT vs. postoperative RT plus 5-FU and levamisole in patients with TNM stage II-III resectable rectal cancer

OBJECTIVES: Two-hundred eighteen patients with TNM stage II-III resectable rectal cancer, enrolled into a randomized clinical trial, were assessed for efficacy and toxicity of adjuvant postoperative radiation therapy (RT) vs. those of combined RT and chemotherapy (CT), with 5-fluorouracil (5-FU) plus levamisole. End points were overall survival, disease-free survival, the rate of loco-regional recurrence, and treatment-related toxicity. METHODS: Patients in arm I underwent RT (50 Gy) in daily fractions of 2 Gy, 5 days/week for 5 weeks. Patients in arm II began with 5-FU (450 mg/m(2)/day intravenous bolus, days 1-5) plus levamisole (150 mg/day orally, days 1-3); postoperative RT was delivered during week 2 at the same dosage and schedule as in arm I. The other five cycles of CT (5-FU every 28 days and levamisole every 15 days for the length of 5-FU administration) continued after the end of RT if clinical and hemato-biochemical parameters were normal. RESULTS: RT was completed or modified in 170 (90%) of 189 evaluable patients undergoing RT (both treatment groups). Only 44 (59%) of 75 evaluable patients of arm II completed or had an adjustment of the CT schedule; the remaining 31 patients (41%) had to stop or never started the CT regimen. Patients undergoing combined RT and CT had more severe toxicity (enteritis, P = 0.03). There was one CT-related death (gastrointestinal bleeding) in this subset. No significant difference was observed in outcome of patients in the two study groups, nor for pattern of recurrence (heterogeneity chi(2) = 4.82; d.f. = 2; P = 0.08). CONCLUSIONS: These preliminary findings suggest a similar efficacy, coupled with less morbidity, of postoperative RT alone compared with a combined regimen of postoperative RT and CT in patients undergoing radical surgery for stage II-III rectal cancer.     

Phase I study of 5-fluorouracil administered by protracted venous infusion, leucovorin, and pelvic radiation therapy.

BACKGROUND: This study was designed to assess the toxicity of pelvic radiation therapy, 5-fluorouracil (5-FU) administered by protracted venous infusion, and leucovorin. METHODS: Pelvic radiation therapy consisted of 50.4-54 gray (Gy) administered in 28-30 fractions. Systemic treatment consisted of leucovorin (10 mg daily) administered orally and protracted venous infusion of 5-FU. The initial daily 5-FU dose was 150 mg/m(2). Dose escalations were planned in increments of 25 mg/m(2). RESULTS: Forty eligible patients were registered, of whom 37 were evaluable for chemoradiotherapy-related toxicity. Grade 3 or 4 toxicity secondary to radiation therapy, protracted venous infusion of 5-FU, and leucovorin occurred in 2 of 17 patients at a daily 5-FU dose of 150 mg/m(2), in 5 of 10 patients at a daily 5-FU dose of 175 mg/m(2), and in 5 of 10 patients at a daily 5-FU dose of 200 mg/m(2). Diarrhea was dose-limiting in 7 of 8 patients with Grade 4 toxicity. Venous thrombosis, a treatment-related complication not directly related to chemotherapy or radiation therapy, occurred in 5 of the 40 patients entered into this study. Four thromboses occurred at the site of a central catheter. No thrombotic complications occurred in the last 7 patients, who were given warfarin orally (1 mg daily) during treatment. CONCLUSIONS: Toxicity due to radiation therapy, protracted venous infusion of 5-FU, and leucovorin when 5-FU is given daily at a dose of 150 mg/m(2) is similar to that observed in current chemoradiotherapy regimens for patients with rectal carcinoma. This regimen will be considered as a possible investigational treatment arm of a future trial of adjuvant therapy for rectal carcinoma patients.     

Randomised clinical trial of adjuvant postoperative RT vs. sequential postoperative RT plus 5-FU and levamisole in patients with stage II-III resectable rectal cancer: a final report

BACKGROUND AND OBJECTIVES: A randomised clinical trial was performed in patients undergoing radical surgery for rectal cancer to compare the efficacy and toxicity of adjuvant postoperative radiation therapy (RT) to sequential RT and chemotherapy (CT) with 5-fluorouracil (5-FU) plus levamisole (LEV). The primary end point was overall survival (OS); secondary end points were disease-free survival (DFS), the rate of loco-regional recurrence, and treatment-related toxicity; the final results of this trial are reported. METHODS: Patients in arm I underwent RT (50 Gy) in daily fractions of 2 Gy, 5 days/week for 5 weeks. Patients in arm II began with 5-FU (450 mg/sqm/day intravenous (i.v.) bolus, days 1-5) plus LEV (150 mg/day orally, days 1-3); postoperative RT was delivered during week 2 at the same dosage and schedule as in arm I. The other five cycles of CT (5-FU every 28 days and LEV every 15 days for the length of 5-FU administration) continued after the end of RT if clinical and hemato-biochemical parameters were in the normal range. RESULTS: From May 1992 to December 1998, 218 patients were enrolled into the randomised clinical trial (144 men, 74 women; age range: 28-75, median 64 years). The median follow-up time was 58.1 months (range: 1-3,271 days). No significant difference was observed between the two arms of treatment as regards OS and DFS (P = 0.18 and P = 0.66, respectively). Cox regression analysis for OS confirmed what was observed by univariate analysis for all variables except age. Older age (>60 years) and pathologic lymph-node involvement defined the subgroups with the worst prognosis. Cox regression analysis for DFS confirmed what was observed by univariate analysis for all variables: the only independent variable in predicting DFS was pathologic lymph-node involvement. CONCLUSIONS: Our findings suggest no difference in OS, loco-regional and distant site progressions of postoperative RT alone compared to sequential postoperative RT and CT; notably, this latter regimen was associated with higher toxicity which seriously impaired the patient's compliance to CT. The low loco-regional recurrence rate (9.2%) observed in our patients undergoing postoperative RT alone compared to similarly treated patients in previously performed clinical trials (20-25%) underline the role of radical surgery (mesorectal excision) coupled with a complete postoperative RT regimen. On the other hand, the similar efficacy of these two adjuvant modalities of treatment might be conditioned by both the low compliance (59%) to the CT regimen as well as the sequential, instead of concurrent, schedule of administration of RT and CT, which may have decreased further the expected efficacy of the combined regimen.     

Optimal therapy for resectable rectal cancer

Alot can be gained by improving our understanding of the optimal sequence of existing therapies in rectal cancer, with the more difficult task of balancing the morbidity of recurrence with the morbidity of prescribed therapies that are particularly toxic owing to tumour location. This review aims to highlight a recent shift in treatment strategies in the opposite direction, with a focus on earlier, more intense systemic treatments with reduced local therapies. Understanding the rationale for and evidence to support this shift will help identify gaps, shape future trials, and ultimately answer the question of whether this is indeed the right path to follow with regards to maintaining local control rates and long-term outcomes for patients, and improving distal disease control and local treatment-related morbidities without compromising quality of life.     

Phase I trial of 5-fluorouracil,leucovorin, and cisplatin in combination

Summary The ongoing evaluation of combination chemotherapy with 5-fluorouracil (5-FU) and cisplatin in several tumors prompted a phase I clinical trial of cisplatin with 5-FU modulated by leucovorin. A total of 26 patients were treated with varying doses of 5-FU by continuous i.v. infusion for 5 days; 200 mg/m² leucovorin was given by daily bolus injection for 5 days; and 20 mg/m² cisplatin was infused over 2 h on each day of treatment. Courses were repeated every 21–28 days. The starting dose of 5-FU was 300 mg/m². Poor-risk patients (extensive prior radiation, performance status of 2 or worse) did not tolerate the initial dose; the maximum tolerated dose of 5-FU in this group was 200 mg/m² daily. Good-risk patients tolerated 300 mg/m², but a majority had excessive toxicity at higher doses. The dose-limiting toxicity was gastrointestinal (mucositis/diarrhea) and/or myelosuppression; additional side effects included were nausea and vomiting (grade 2) and ataxia (one patient). Among 13 patients with colorectal cancer, 4 partial responses were observed. The marked reduction in the tolerable dose of 5-FU occasioned by the addition of modulating doses of leucovorin is noteworthy. The response observed support further investigation of this regimen in phase II trials.     

Phase I dose escalating trial of hyperfractionated pre-operative chemoradiation for locally advanced rectal cancer

Purpose: To determine the acute toxicity, post-operative complications, pathologic response and extent of downstaging to high dose pre-operative radiation using a hyperfractionated radiation boost and concurrent chemotherapy in a prospective Phase I trial.Materials & Methods: To be eligible for this study, patients had to have adenocarcinoma of the rectum less than 12 cm from the anal verge with either Stage T4 or T3 but greater than 4 cm or greater than 40% of the bowel circumference. All patients received 45 Gy pelvic radiation (1.8 Gy per fraction). Subsequent radiation was given to the region of the gross tumor with a 2 cm margin. This “boost” treatment was given at 1.2 Gy twice daily to a total dose of 54.6 Gy for Level I, 57 Gy for Level II, and 61.8 Gy for Level III. 5-FU was given at 1g/m² over 24 hours for a four day infusion during the first and sixth weeks of radiation, with the second course concurrent with the hyperfractionated radiation. Surgical resection was carried out 4–6 weeks following completion of chemoradiation (in curative cases) and additional adjuvant chemotherapy consisting of 5-FU and Leucovorin was given for an additional 4 monthly cycles Days 1 through 5 beginning four weeks post surgery.Results: Twenty-seven patients, age 40–82 (median 61), completed the initial course of chemoradiation and are included in the analysis of toxicity. The median follow-up is 27 months (range 8–68). Eleven patients were treated to a dose of 54.6 Gy, nine patients to 57 Gy, and seven patients to 61.8 Gy. Twenty-one patients had T3 tumors, and six patients T4 tumors. Grade III acute toxicity from chemoradiation included proctitis (5 patients), dermatitis (9), diarrhea (five), leukopenia (1), cardiac (1). Grade IV toxicities included one patient with diarrhea (on dose Level I) and one patient (on dose Level III) with cardiac toxicity (unrelated to radiation). Surgical resection consisted of abdominal perineal resection in 16 and low anterior resection in 7. Four patients did not undergo a curative resection; three initially presented with metastases and one developed metastasis during the pre-operative regimen. Post-operative complications included pelvic or perineal abscess in two (on dose Levels I & II), and delayed wound healing in two (one of whom, on dose Level III, developed perineal wound dehiscence requiring surgical reconstruction). Of the 23 patients who had a curative resection, four manifested pathologic complete responses (17.4%). Thirteen of 23 patients (57%) had evidence of pathologic downstaging and only 1/23 patients (on dose Level I) had a positive resection margin. Of these 23 patients (with a minimum follow-up of 8 months), the patient with positive margins was the only one who developed a local failure (Fisher’s Exact p = .04). The 3-year actuarial OS, DFS and LC rates are 82%, 72% and 96%, respectively. Twelve of 13 patients (92% at 3 years) ≥ 61 years vs. 5/10 patients (45% at 3 years) < 61 years remained disease-free (log-rank p = 0.017).Conclusion: This regimen of high dose pre-operative chemoradiation employing a hyperfractionated radiation boost is feasible and tolerable and results in significant downstaging in locally advanced rectal cancer. The vast majority of patients (96%) achieved negative margins, which appears to be a prerequisite for local control (p = 0.04). Older age (≥61 years) was a significant predictor for improved DFS. This regimen (at dose Level III, 61.8 Gy) is currently being tested in a Phase II setting.     

Preoperative irinotecan/5-FU/leucovorin plus concurrent radiotherapy in rectal cancer

PURPOSE: To evaluate results of preoperative irinotecan/5-FU/leucovorin plus radiotherapy for locally-advanced rectal cancer. METHODS: Thirty-five patients with locally-advanced rectal cancer were treated with preoperative irradiation 46 Gy plus concurrent chemotherapy(irinotecan 10 mg/m(2)/d d1-d5, d22-d26, 5-FU 350 mg/m(2)/d d1-d5, d22-d26, and leucovorin 20 mg/m(2) d1-d5, d22-d26), followed by radical surgery. RESULTS: There were no treatment-related deaths. Acute toxicity was mainly in neutropenia and diarrhea, with both grade 4 neutropenia and grade 3 diarrhea observed in 4 patients(11%). Radical resectability was performed in 29 patients(83%)with sphincter preservation surgery in 7 patients. Six patients did not undergo the planned surgery due to patient refusal and disease progression. A complete pathological response was observed in 14%(4/29). Pathological T-downstaging was observed in 55%(16/29). CONCLUSIONS: These results suggest that preoperative radiochemotherapy with irinotecan/5-FU/leucovorin is safe and effective in tumor downstaging and allows sphincter-saving resection to be performed in locally-advanced rectal cancer.     

Effect of nedaplatin, 5-FU,and leucovorin combined with radiation therapy in unresectable esophageal carcinoma

A 51-year-old male was assessed as having esophageal squamous cell carcinoma with trachea invasion and cervical lymph node metastasis. After one course of chemotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU) and Leucovorin (LV), the patient had progressive disease (PD) of the primary lesion and metastatic lymph nodes, and a side effect of severe nausea. One course of nedaplatin, 5-FU and LV combined with radiation was performed alternatively. The effect was evaluated as a partial response (PR) of the primary lesion and metastatic lymph nodes. There were no adverse side effects such as nausea or renal dysfunction except for pancytopenia of grade 2. Increased serum levels of vascular endothelial growth factor (s-VEGF) decreased after the chemoradiotherapy and increased again during continued radiotherapy alone. More information is needed as to whether changes in s-VEGF relate to the clinical effects of the treatment.     

A case of postoperative pelvic metastasis and multiple liver metastases of the rectal cancer successfully treated by arterial infusion therapy with 5-FU/leucovorin

A 55-year-old man underwent a rectal amputation for rectal cancer in 1994. As the tumor marker was elevated in 2002, we performed an abdominal CT scan and detected local and multiple liver recurrences. We treated the patient with intra-arterial infusion of 5-FU/LV via the internal iliac artery and the hepatic artery. The chemotherapy was performed on a weekly basis; it consisted of 5-FU (500 mg/body), administered for 5 hours to bilateral reservoirs through an infusion pump and l-leucovorin (400 mg/body), administered intravenously for 2 hours. After 18 administrations of this regimen during a hospital stay and after a discharge from the hospital as an outpatient, the multiple liver metastases that were observed have disappeared. Further, the local recurrences showed a partial reduction in tumor size with a decrease in perineal pain. Subsequently, the patient did not require further doses of morphine. He exhibited no severe side effects except for grade 1 nausea, and his QOL was also good. Therefore, local intra-arterial infusion chemotherapy with 5-FU/LV appears to have been effective for rectal cancer recurrences.     

非小细胞肺癌立体适形放疗的Ⅰ期临床剂量递增试验

目的 建立非小细胞肺癌适形放疗技术,试图获得患者适形放疗的最大耐受剂量（ＭＴＤ）,并观察其即期疗效。方法 １９９９年６月至２０００年６月,３８例Ⅱ～ⅢＢ期非小细胞肺癌患者进入本研究。常规放疗４２Ｇｙ后用适形放疗做肿瘤剂量递增。根据接受２０Ｇｙ照射的总肺体积面分比,计划的肿瘤剂量递增水平分别为６９、７２、７５、７８和８１Ｇｙ。大于ＲＴＯＧⅢ级放射性肺损伤为停止剂量递增的标准。结果 已完成放疗计划者有     

Adjuvant postoperative radiation therapy for rectal adenocarcinoma.

From October 1975 to August 1988, 261 patients at high risk for local recurrence after curative resection of rectal carcinoma underwent high-dose postoperative irradiation. Patients received 45 Gy by a 4-field box usually followed by a boost to 50.4 Gy or higher when small bowel could be excluded from the reduced field. Since January 1986, patients also received 5-fluorouracil (5-FU) for 3 consecutive days during the first and last week of radiotherapy. Five-year actuarial local control and disease-free survival decreased with increasing stage of disease; patients with Stage B2 and B3 disease had local control rates of 83% and 87% and disease-free survivals of 55% and 74%, respectively. In patients with Stage C1 through C3 tumors, local control rates ranged from 76% to 23%, and disease-free survivals ranged from 62% to 10%, respectively. For patients with Stage C disease, disease-free survival decreased progressively with increasing lymph node involvement, but local control was independent of the extent of lymph node involvement. For each stage of disease, local control and disease-free survival did not correlate with the dose of pelvic irradiation. Preliminary data from this study suggest a trend toward improved local control for patients with Stage B2, C1, and C2 tumors who receive 5-FU for 3 consecutive days during the first and last weeks of irradiation compared with patients who do not receive 5-FU. Current prospective randomized studies are addressing questions regarding the optimum administration of chemotherapy with pelvic irradiation for patients following resection of rectal carcinoma.     

Phase I trial of Orzel (UFT plus leucovorin), cisplatin, and radiotherapy in the treatment of potentially resectable esophageal cancer

PURPOSE: Fluorinated pyrimidines have been established as radiosensitizers in the combined modality therapy of esophageal cancer. UFT, an oral combination of a 5-fluorouracil pro-drug (uracil) and a dihydropyrimidine dehydrogenase inhibitor (ftorafur), may provide improvement in the ease of administration with equal efficacy. This Phase I study was designed to determine the maximal tolerated dose and dose-limiting toxicity of UFT, leucovorin, and cisplatin when given with radiotherapy in the neoadjuvant treatment of resectable esophageal cancer. METHODS: Chemotherapy consisted of i.v. cisplatin 80 mg/m(2) (Days 1 and 22) and UFT with leucovorin orally on Days 1-35. UFT was escalated in 50-mg/m(2) increments, starting at 200 mg/m(2)/d. Radiotherapy consisted of 4500 cGy in 25 fractions. Patients underwent resection 4-6 weeks after chemoradiotherapy. RESULTS: Ten patients with resectable esophageal cancer were enrolled. Of the 7 patients entered at dose level 1, 1 developed a dose-limiting toxicity of nausea. All 3 patients entered at dose level 2 developed dose-limiting toxicity. The maximal tolerated dose for UFT was the starting level, 200 mg/m(2)/d. Of the 10 patients enrolled, 8 underwent esophagectomy and 2 developed progressive disease and did not undergo surgery. The disease of 6 of the 8 patients was downstaged at surgery. CONCLUSION: The recommended UFT dose for Phase II studies is 200 mg/m(2)/d given orally in two divided doses when given with leucovorin, cisplatin, and radiotherapy.