Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer.

PURPOSE: The primary objective of this phase I trial was to determine the maximum-tolerated dose of radiation that could be delivered to the primary tumor concurrent with full-dose gemcitabine in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Thirty seven patients with unresectable (n = 34) or incompletely resected pancreatic cancer (n = 3) were treated. Gemcitabine was administered as a 30-minute intravenous infusion at a dose of 1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Radiation therapy was initiated on day 1 and directed at the primary tumor alone, without prophylactic nodal coverage. The starting radiation dose was 24 Gy in 1.6-Gy fractions. Escalation was achieved by increasing the fraction size in increments of 0.2 Gy, keeping the duration of radiation constant at 3 weeks. A second cycle of gemcitabine alone was intended after a 1-week rest. RESULTS: Two of six assessable patients experienced dose-limiting toxicity at the final planned dose level of the trial (42 Gy in 2.8-Gy fractions), one with grade 4 vomiting and one with gastric/duodenal ulceration. Two additional patients at this dose level experienced late gastrointestinal toxicity that required surgical management. CONCLUSION: The final dose investigated (42 Gy) is not recommended for further study considering the occurrence of both acute and late toxicity. However, a phase II trial of this novel gemcitabine-based chemoradiotherapy approach, at a radiation dose of 36 Gy in 2.4-Gy fractions, is recommended on the basis of tolerance, patterns of failure, and survival data.     

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.     

A phase I trial of weekly gemcitabine and concurrent radiotherapy in patients with locally advanced pancreatic cancer

This study investigated the maximum-tolerated dose of gemcitabine based on the frequency of dose-limiting toxicities of weekly gemcitabine treatment with concurrent radiotherapy in patients with locally advanced pancreatic cancer. Fifteen patients with locally advanced pancreatic cancer that was histologically confirmed as adenocarcinoma were enrolled in this phase I trial of weekly gemcitabine (150-350 mg x m(-2)) with concurrent radiotherapy (50.4 Gy in 28 fractions). Gemcitabine was administered weekly as an intravenous 30-min infusion before radiotherapy for 6 weeks. Three of six patients at the dose of 350 mg x m(-2) of gemicitabine demonstrated dose-limiting toxicities involving neutropenia/ leukocytopenia and elevated transaminase, while nine patients at doses of 150 mg x m(-2) and 250 mg x m(-2) did not demonstrate any sign of dose-limiting toxicity. Of all 15 enrolled patients, six patients (40.0%) showed a partial response. More than 50% reduction of serum carbohydrate antigen 19-9 level was observed in 13 (92.9%) of 14 patients who had pretreatment carbohydrate antigen 19-9 levels of 100 U x ml(-1) or greater. The maximum-tolerated dose of weekly gemcitabine with concurrent radiotherapy was 250 mg x m(-2), and this regimen may have substantial antitumour activity for patients with locally advanced pancreatic cancer. A phase II trial of weekly gemcitabine at the dose of 250 mg x m(-2) with concurrent radiation in patients with locally advanced pancreatic cancer is now underway.     

Low-dose gemcitabine concurrent with radiation therapy for locally advanced pancreatic carcinoma

We evaluated the efficacy and feasibility of low-dose gemcitabine concurrent with radiation as adjuvant therapy. Nine cases of locally far advanced unresectable pancreatic cancer were enrolled in this study. Intraoperative radiation was carried out in every case using eight or ten centimeter cones with a radiation dose of twenty to twenty five Gy. Postoperative radiation was two Gy per day on weekdays for five weeks. Low-dose gemcitabine (40 mg/m2) once a week was administered prior to radiation. A grade 3 adverse event occurred in three cases. CA19-9 decreased 60.1% and DUPAN-2, 52.6%. CT scan confirmed a necrotic change and a decrease of the tumor size. Average survival time was ten months. Peritoneal dissemination was the recurrence pattern. In conclusion, low-dose gemcitabine concurrent with radiation therapy may contribute to local control of the disease. However, peritoneal dissemination must be overcome to prolong survival.     

Phase I trial of gefitinib with concurrent radiotherapy and fixed 2-h gemcitabine infusion, in locally advanced pancreatic cancer

PURPOSE: Pancreatic cancers are resistant to radiotherapy (RT) and current chemotherapy agents. Epidermal growth factor receptor is overexpressed in pancreatic cancer, and in vitro studies have shown that epidermal growth factor receptor inhibitors can overcome radio- and chemoresistance. The aim of the study was to determine whether the addition of gefitinib to RT and gemcitabine for patients with locally advanced pancreatic carcinoma (LAPC) was feasible and safe. METHODS AND MATERIALS: Eighteen patients with pathologically proven LAPC, based on major vascular invasion based on helical computed tomography (CT) and endoscopic ultrasound, were entered into the study. The targeted irradiated volume included the tumor and 2-cm margin. Prophylactic irradiation of regional nodes was not allowed. Patients with >500 cm(3) of planning tumor volume were excluded. An initial cohort of 6 patients was treated with RT (45 Gy/25 fractions/5 weeks) plus concomitant gefitinib (250 mg/day). Successive cohorts of patients received 100, 150, and 200 mg/m(2)/day of gemcitabine in a 2-h infusion over Weeks 1, 2, 3, 4, and 5 with gefitinib (250 mg/day) and RT. Gefitinib was continued after RT until progression. A pharmacodynamic study of angiogenic markers was also performed to evaluate a possible antiangiogenic effect. RESULTS: There were no dose-limiting toxicities. Common toxicities were mild neutropenia, asthenia, diarrhea, cutaneous rash and nausea/vomiting. The median (95% confidence interval [CI]) progression-free survival was 3.7 (95% CI = 1.9-5.5) months, and the median overall survival was 7.5 (95% CI = 5.2-9.9) months. No significant reduction of vascular endothelial growth factor and interleukin-8 was observed after treatment. CONCLUSION: Our results support that the combination of gefitinib, RT, and gemcitabine has an acceptable toxicity but with modest activity in LAPC.     

Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297.

PURPOSE: Gemcitabine is generally considered to constitute first-line therapy for pancreatic cancer. To determine whether the addition of fluorouracil (5-FU) improves on the results from single-agent gemcitabine, the Eastern Cooperative Oncology Group (ECOG) compared gemcitabine plus bolus 5-FU with gemcitabine alone for patients with advanced pancreatic carcinoma. PATIENTS AND METHODS: This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients were randomized to receive either gemcitabine alone (1,000 mg/m(2)/wk) weekly for 3 weeks of every 4 or to receive gemcitabine (1,000 mg/m(2)/wk) followed by 5-FU (600 mg/m(2)/wk) weekly on the same schedule. The primary end point of the trial was survival, with secondary end points of time to progression and response rate. RESULTS: Of 327 patients enrolled over 18 months, 322 were eligible. Overall, the median survival was 5.4 months for gemcitabine alone and 6.7 months for gemcitabine plus 5-FU (P =.09). Progression-free survival for gemcitabine alone was 2.2 months, compared with 3.4 months for gemcitabine plus 5-FU (P =.022). Objective responses were uncommon and were observed in only 5.6% of patients treated with gemcitabine and 6.9% of patients treated with gemcitabine plus 5-FU. Most toxicities were hematologic or gastrointestinal; no significant differences were noted between the two treatment arms. CONCLUSION: 5-FU, administered in conjunction with gemcitabine, did not improve the median survival of patients with advanced pancreatic carcinoma compared with single-agent gemcitabine. Further studies with other combinations of gemcitabine and 5-FU are not compelling, and clinical trial resources should address other combinations and novel agents.     

Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of the Eastern Cooperative Oncology Group

BACKGROUND: The current study was conducted to evaluate the antitumor activity and toxicity of gemcitabine in patients with advanced sarcoma. METHODS: Twenty-five patients with advanced sarcomas, who previously were untreated for metastatic disease, were treated on an Eastern Cooperative Oncology Group Phase II study. Patients ranged in age from 27 to 79 years, with a median age of 59 years. The most common histology was leiomyosarcoma (54%). The grades of the tumors were high in 40%, moderate in 24% and low in 12%. Gemcitabine was given at a dose of 1250 mg/m(2) as a 30-minute infusion weekly for 3 weeks followed by 1 week of rest. RESULTS: One of the 25 patients (4%) (90% confidence interval [90% CI], 0-18%) achieved a partial response lasting 8 months. The estimated overall median survival was 15 months. The 1-year estimated survival rate was 63% (90% CI, 47-84%). The estimated median progression-free survival (PFS) was 13 months with a 1-year PFS rate of 56% (90% CI, 41-76%). Grade 3-4 toxicities (by CTC criteria) were observed in all 25 patients. No lethal toxicity (Grade 5) related to treatment was found. CONCLUSIONS: The results of the current study demonstrated that gemcitabine given at this schedule and dose in this population of patients with advanced sarcoma had limited activity.     

Phase II trial of gemcitabine and docetaxel in patients with advanced carcinoma of the urothelium: a trial of the Eastern Cooperative Oncology Group

BACKGROUND: Gemcitabine and docetaxel are active agents in advanced urothelial carcinoma. A Phase II trial of this combination was performed to determine the activity and toxicity of these agents in a multiinstitutional setting in patients previously treated with one prior chemotherapy regimen. METHODS: Twenty-nine eligible patients with advanced urothelial carcinoma were treated with docetaxel at a dose of 40 mg/m(2) over 1 hour followed by gemcitabine, 800 mg/m(2), over 30 minutes, both intravenously (i.v.) on Days 1 and 8. Cycles were repeated every 21 days until disease progression or a maximum of 6 cycles. RESULTS: Five patients obtained an objective response for an overall response rate of 17% (90% confidence interval, 7-33%). One patient achieved a complete clinical response. The median overall survival of the group was 7.7 months. Toxicity was moderate with granulocytopenia, anorexia, and fatigue being the most commonly noted side effects. CONCLUSIONS: Gemcitabine and docetaxel is an active second-line combination in patients with advanced urothelial carcinoma. Responses in visceral, lymph node, and soft tissues sites were observed. Granulocytopenia without fever, fatigue, and anorexia was common. Thromboembolic symptoms were reported and are of concern. The combination of gemcitabine and docetaxel has the potential to palliate a subset of previously treated patients with an adequate performance status.     

Phase I/II study of weekly irinotecan and concurrent radiation therapy for locally advanced non-small cell lung cancer

A study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities, and the response rate of irinotecan administered weekly with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, surgically unresectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) were enrolled. Irinotecan was administered as a 90 min intravenous infusion once weekly for 6 weeks. The starting dose was 30 mg m(-2) and dose escalation was done in 15 mg m(-2) increments. Dose-limiting toxicity was defined as grade 3 nonhaematologic toxicity (excluding nausea, vomiting and alopecia) or grade 4 haematologic toxicity according to the WHO criteria. Radiation was delivered to the primary tumour and regional lymph nodes (40 Gy), followed by a boost to the primary tumour (20 Gy). Twenty-seven patients were entered into this study at three irinotecan dose levels (30, 45 and 60 mg m(-2)). Twenty-six eligible patients were evaluated for toxic effects and clinical outcome. Severe oesophagitis, pneumonitis, and diarrhoea occurred at 45 and 60 mg m(-2). Three of the five patients given 60 mg m(-2) developed grade 3 or 4 oesophagitis and pneumonitis. In addition, one patient died of pneumonitis after completing therapy at 45 mg m(-2) in the phase II study. The objective response rate was 76.9% (95% CI, 53.0-88.9%). Oesophagitis, pneumonitis, and diarrhoea are the dose-limiting toxicities of weekly irinotecan combined with thoracic irradiation. The maximum tolerated dose and the dose for the phase II study were 60 and 45 mg m(-2) wk(-1), respectively. This combined therapy for locally advanced non-small cell lung cancer is promising and shows acceptable toxicity.     

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.     

调强放疗联合TP方案同期化疗治疗局部晚期鼻咽癌的初步研究

 目的　分析调强放疗（IMRT）联合TP方案[多西紫杉醇（DOC）+顺铂（DDP）] 同期治疗鼻咽癌的近期疗效及患者不良反应,初步探讨该方案的可行性与有效性。方法　回顾性分析32例初诊Ⅲ～ⅣB期鼻咽癌患者临床资料,IMRT处方剂量：鼻咽肿瘤区计划靶区（PTVnx）总剂量7000 cGy,分31～32次;转移淋巴结计划靶区（PTVnd）总剂量6600 Gy,分31～32次;高危临床肿瘤区的计划靶区（PTV1）总剂量6000 cGy;PTVnx分次剂量220～228 cGy,31～32次。同期予2个疗程TP方案化疗,DOC 75 mg／m2 第1天静脉滴注,DDP 75 mg／m2 第1天静脉滴注（或者DDP 25 mg／m2 第1天至第3天静脉滴注）,2个疗程化疗开始的时间间隔为21～28 d。结果　全组32例患者均完成全量IMRT放疗及2个疗程TP方案化疗。无治疗相关死亡。主要不良反应为血液毒性及口腔黏膜反应,Ⅲ～Ⅳ度白细胞减少占46.9 %（15／32）,Ⅲ～Ⅳ度中性粒细胞减少占59.4 %（19／32）,Ⅲ度急性黏膜反应占40.6 %（13／32）。本组病例的完全缓解（CR）率为96.9 %（31／32）。治疗过程中有29例（90.6 %）患者使用粒细胞集落刺激因子（G-CSF）。中位随访13个月,全组患者1年总生存（OS）率、无局部复发生存（LRFS）率、无区域复发生存（RRFS）率及无远处转移生存（DMFS）率分别为100.0 %（32／32）、96.9 %（31／32）、96.9 %（31／32）、96.9 %（31／32）。结论　IMRT联合同期TP方案治疗局部晚期鼻咽癌近期疗效好,CR率高,主要不良反应为白细胞及中性粒细胞减少,在G-CSF支持下患者能耐受。该方案的远期疗效值得进一步探讨。     

Phase II trial of fluorouracil and recombinant interferon alfa-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group study

In a pilot clinical trial, treatment of patients with advanced colorectal carcinoma with the combination of fluorouracil (5FU) and recombinant interferon alfa-2a (IFN) resulted in objective tumor regression in 62% of patients. To confirm these findings in a multiinstitutional setting, a phase II clinical trial was initiated by the Eastern Cooperative Oncology Group (ECOG) in 1989. The treatment regimen was identical to that used in the earlier study: 5FU 750 mg/m2/d for 5 days as a continuous infusion followed by weekly outpatient bolus therapy and IFN 9MU subcutaneously beginning day 1 and administered three times per week. Doses were modified for gastrointestinal, hematologic, and neurologic toxicity and for fatigue, similarly to those used in the previous pilot trial. Thirty-eight patients were registered; 36 are evaluable for response (one lost to follow-up and one with nonmeasurable disease). All patients had metastatic or locally recurrent disease beyond the scope of resection; 31 of 38 had liver metastases, and 20 of 38 had two or more sites of involvement. Eight patients had grade 4 toxicities, including sepsis (nonneutropenic) (one), watery diarrhea (two), and granulocytopenia (six). Grade 3 neurologic toxicities were observed in two (5%) patients and included slurred speech and gait disturbance. Objective response was 42% (95% confidence interval [Cl], 27% to 58%), including one clinical complete responder and 14 partial responders. Among the responding patients, the median time to treatment failure was 8 months. Two patients remain on treatment at 10+ and 16+ months: median survival has not been reached. The results of this multiinstitutional trial suggest that the addition of IFN to 5FU enhances the objective response rates achieved in patients with advanced colorectal carcinoma and that the toxicities of this regimen are acceptable.     

Phase I study of weekly cisplatin, vinorelbine, and concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer

Background The combination of chemotherapy and thoracic radiation therapy (TRT) is considered as a standard treatment for locally advanced non-small-cell lung cancer (NSCLC). Although the frequent interaction of anticancer agents and irradiation may produce stronger radio-sensitizing effects, the daily administration of these agents is complicated. We therefore used weekly administration of these agents, and conducted a phase I study of weekly cisplatin, vinorelbine, and concurrent TRT. The purpose of this study was to identify the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the recommended dose of this treatment. Methods Patients with locally advanced NSCLC were enrolled in this study. Both cisplatin and vinorelbine were given intravenously on a weekly schedule for 6 weeks, starting on the first day of TRT, i.e., on days 1, 8, 15, 22, 29, and 36. The total dose of TRT was 60 Gy. The dose of cisplatin was fixed at 20 mg/m² per week. The starting dose of vinorelbine was 15 mg/m² per week (dose level 1). Results Nine patients were enrolled in this study. All three patients at dose level 1 experienced DLTs. We decreased the dose of vinorelbine to 10 mg/m² per week (dose level 0). Two of the six patients at dose level 0 experienced DLTs. Therefore, dose level 1 was considered as the MTD, and dose level 0 as the recommended dose. The DLTs of this treatment were esophagitis, fatigue, infection, and hyponatremia. Conclusion The recommended dose of cisplatin is 20 mg/m² per week and that of vinorelbine is 10 mg/m² per week with standard TRT. A phase II study of this treatment is warranted. The results of this study were presented in part at the 43rd Annual Meeting of the Japan Lung Cancer Society in Fukuoka, Japan, November 21–22, 2002.     

Phase I trial of strictly time-scheduled gemcitabine and cisplatin with concurrent radiotherapy in patients with locally advanced pancreatic cancer

PURPOSE: Maximal therapeutic gain in xenograft sarcoma and toxicity for jejunal mucosa is time dependent for concurrent gemcitabine and radiotherapy (RT). We used a time-dependent schedule to determine the maximal-tolerated dose and dose-limiting toxicities (DLTs; Grade 4 hematologic or Grade 3 other toxicity). METHODS AND MATERIALS: Patients with pancreatic cancer (n = 33), periampullary carcinoma (n = 1), or bile duct cancer (n = 2) were treated with 3-day conformal RT with 50.4 Gy (tumor, lymphatics) plus a 5.4-Gy boost. Concurrent cisplatin (20 mg/m(2)/d on Days 1-5 and 29-33) and gemcitabine (initially 600 mg/m(2), weekly on Fridays 68 h before RT) were administered. Because of DLT, the doses were reduced to 500 mg/m(2) weekly and then 500, 400, or 300 mg/m(2) on Days 2, 5, 26, 33. RESULTS: DLT occurred at all dose levels of gemcitabine >300 mg/m(2). Fourteen patients were treated at the recommended Phase II dose of gemcitabine (300 mg/m(2)) without DLT. The response to chemoradiation allowed 10 of 30 initially unresectable patients with primary pancreatic carcinoma to undergo radical surgery, including a complete response in 2 cases. CONCLUSIONS: At the recommended Phase II dose, chemoradiation with gemcitabine and cisplatin can be administered safely in pancreatic carcinoma. However, at higher dose levels, toxicity is severe and frequent. Patients with a chance for conversion to resection could benefit from this schedule.     

Phase I study of conformal radiotherapy with concurrent gemcitabine in locally advanced bladder cancer

PURPOSE: A prospective phase I trial was conducted to determine the maximal tolerated dose of gemcitabine given once weekly during hypofractionated conformal radiotherapy to patients with locally advanced transitional cell carcinoma of the bladder. Eight male patients, median age 69 years, with Stage T2 (n = 4) or T3 (n = 4) N0M0, were enrolled in cohorts of 3. Treatment comprised conformal radiotherapy (52.5 Gy in 20 fractions) within 4 weeks, with concurrent gemcitabine once weekly for four cycles. The weekly gemcitabine dose was escalated from 100 mg/m(2) in increments of 50 mg/m(2) per cohort. Dose-limiting toxicity was defined as any acute Radiation Therapy Oncology Group (RTOG) toxicity Grade 3 or greater arising in >1 of 3 patients in each cohort. Tumor response was assessed cystoscopically and radiologically at 3 months. RESULTS: All 8 patients completed radiotherapy, and 6 of 8 completed chemoradiotherapy. No acute toxicity greater than RTOG Grade 1 was seen with gemcitabine at 100 mg/m(2). Dose-limiting toxicity was observed at 150 mg/m(2) with Grade 3 toxicity seen in 2 of 2 patients (one bladder, one bowel). An additional 3 patients received 100 mg/m(2) with minimal toxicity. No hematologic toxicity was encountered. A complete response was seen in 7 (87.5%) of 8 patients, all of whom were disease free at a median follow-up of 19.5 months (range, 14-23 months). No late toxicity (greater than RTOG Grade 0) has been observed. CONCLUSION: The maximal tolerated dose for gemcitabine given once weekly with concurrent hypofractionated conformal bladder radiotherapy was 150 mg/m(2), with a maximal recommended dose of 100 mg/m(2). This dose regimen has now entered Phase II clinical trials.     

Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma.

Gemcitabine has modest activity in the treatment of advanced pancreatic cancer and is a potent radiosensitizer. We conducted a Phase I trial to determine the maximum tolerated dose of weekly gemcitabine delivered concurrently with radiation therapy for the treatment of locally advanced adenocarcinoma of the pancreatic head and to assess the treatment-related toxic effects associated with such a regimen. Eighteen patients with pathologically proven, locally advanced adenocarcinoma of the pancreatic head were enrolled in this study. Patients received seven weekly doses of gemcitabine with 3000 cGy of external beam radiation therapy delivered during the first 2 weeks of therapy. Six patients received gemcitabine at 350 mg/m(2)/week, nine at 400 mg/m(2)/week, and three at 500 mg/m(2)/week. Grade 3-4 hematological toxicity was observed in over half the patients treated. Nonhematological toxicities were significant and included fatigue, anorexia, nausea, vomiting, and dehydration. Forty-four % of the patients required admission to the hospital for management of nausea/vomiting and dehydration. The risk of hospitalization appeared to be dose-related; all of the three patients treated at 500 mg/m(2)/week required hospital admission during treatment. Seventeen patients were evaluated for response, and eight patients (47%) had evidence of a local anticancer effect. Four of these eight patients (24%) had a partial response to therapy. The median survival for the entire group was 6 months. The 1-year survival rate for patients with an objective response to therapy was 66%. The clinical responses observed in this group of patients suggest gemcitabine is a clinically relevant radiosensitizer in patients with pancreatic adenocarcinoma. However, the toxic effects are significant, suggesting that until dose and scheduling issues are explored further, concomitant administration of gemcitabine and radiation therapy should still be considered investigational.     

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.