Mark R. Green

Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.

PURPOSE Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. PATIENTS AND METHODS One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. RESULTS Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. CONCLUSION This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.

A Randomized Trial of Induction Chemotherapy plus High-Dose Radiation versus Radiation Alone in Stage III Non-Small-Cell Lung Cancer

BACKGROUND For patients with locally or regionally advanced non-small-cell lung cancer radiation is the standard treatment, but survival remains poor. We therefore conducted a randomized trial to determine whether induction chemotherapy before irradiation improves survival. METHODS All the patients had documented non-small-cell cancer of the lung with Stage III disease established by clinical or surgical staging. Eligibility requirements included excellent performance status, minimal weight loss, and visible disease on radiography. Patients randomly assigned to group 1 received cisplatin (100 mg per square meter of body-surface area given intravenously on days 1 and 29) and vinblastine (5 mg per square meter given intravenously on days 1, 8, 15, 22, and 29) and then began radiation therapy on day 50 (60 Gy over a 6-week period). Patients assigned to group 2 received the same radiation therapy but began it immediately and received no chemotherapy. RESULTS The eligible patients in group 1 (n = 78) and group 2 (n = 77) were comparable in terms of age (median, 60 years), sex, performance status, histologic features, stage of disease, and completeness of radiation therapy. The median survival was greater for those in group 1-13.8 versus 9.7 months (P = 0.0066 by log-rank test). Rates of survival in group 1 were 55 percent after one year, 26 percent after two years, and 23 percent after three years, as compared with 40, 13, and 11 percent, respectively, in group 2. Those in group 1 had a higher incidence of serious infections requiring hospitalization (7 percent, vs. 3 percent in group 2) and severe weight loss (14 percent vs. 6 percent), but there were no treatment-related deaths. CONCLUSIONS In patients with Stage III non-small-cell lung cancer, induction chemotherapy with cisplatin and vinblastine before radiation significantly improves median survival (by about four months) and doubles the number of long-term survivors, as compared with radiation therapy alone. Since three quarters of the patients still die within three years, however, further improvements in systemic and local therapy are needed.

Chemotherapy of Advanced Hodgkin's Disease with MOPP, ABVD, or MOPP Alternating with ABVD

BACKGROUND AND METHODS MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) has been the standard treatment for Hodgkins disease for almost 20 years. In a randomized, multicenter trial, we compared three regimens of primary systemic therapy for newly diagnosed advanced Hodgkins disease in Stages IIIA2, IIIB, and IVA or IVB: (1) MOPP alone given for 6 to 8 cycles, (2) MOPP alternating with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for 12 cycles, and (3) ABVD alone for 6 to 8 cycles. Patients in a first relapse after radiation therapy were eligible. No additional radiation therapy was given. Patients who did not have a complete response or who had a relapse with either MOPP alone or ABVD alone were switched to the opposite regimen. RESULTS Of 361 eligible patients, 123 received MOPP, 123 received MOPP alternating with ABVD, and 115 received ABVD alone. The patients were stratified according to age, stage, previous radiation, histologic features, and performance status. The overall response rate was 93 percent, with complete responses in 77 percent: 67 percent in the MOPP group, 82 percent in the ABVD group, and 83 percent in the MOPP-ABVD group (P = 0.006 for the comparison of MOPP with the other two regimens, both of which contained doxorubicin). The rates of failure-free survival at five years were 50 percent for MOPP, 61 percent for ABVD, and 65 percent for MOPP-ABVD. Age, stage (III vs. IV), and regimen influenced failure-free survival significantly. Overall survival at five years was 66 percent for MOPP, 73 percent for ABVD, and 75 percent for MOPP-ABVD (P = 0.28 for the comparison of MOPP with the doxorubicin regimens). MOPP had more severe toxic effects on bone marrow than ABVD and was associated with greater reductions in the prescribed dose. CONCLUSIONS In this trial, ABVD therapy for 6 to 8 months was as effective as 12 months of MOPP alternating with ABVD, and both were superior to MOPP alone in the treatment of advanced Hodgkins disease. ABVD was less myelotoxic than MOPP or ABVD alternating with MOPP.

Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial

BACKGROUND Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection. METHODS Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin [50 mg/m(2) on days 1, 8, 29, and 36] and etoposide [50 mg/m(2) on days 1-5 and 29-33]) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002550. FINDINGS 202 patients (median age 59 years, range 31-77) were assigned to group 1 and 194 (61 years, 32-78) to group 2. Median OS was 23.6 months (IQR 9.0-not reached) in group 1 versus 22.2 months (9.4-52.7) in group 2 (hazard ratio [HR] 0.87 [0.70-1.10]; p=0.24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0.63 [0.36-1.10]; p=0.10). With N0 status at thoracotomy, the median OS was 34.4 months (IQR 15.7-not reached; 19 [point estimate 41%] patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12.8 months (5.3-42.2) vs 10.5 months (4.8-20.6), HR 0.77 [0.62-0.96]; p=0.017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38%] and 20 [10%], respectively) and group 2 (80 [41%] and 44 [23%], respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy. INTERPRETATION Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer. FUNDING National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.

Adjuvant Paclitaxel Plus Carboplatin Compared With Observation in Stage IB Non–Small-Cell Lung Cancer: CALGB 9633 With the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups

PURPOSE Adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC. PATIENTS AND METHODS Within 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m(2) intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival. RESULTS Three hundred-forty-four patients were randomly assigned. Median follow-up was 74 months. Groups were well-balanced with regard to demographics, histology, and extent of surgery. Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths. Survival was not significantly different (hazard ratio [HR], 0.83; CI, 0.64 to 1.08; P = .12). However, exploratory analysis demonstrated a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors > or = 4 cm in diameter (HR, 0.69; CI, 0.48 to 0.99; P = .043). CONCLUSION Because a significant survival advantage was not observed across the entire cohort, adjuvant chemotherapy should not be considered standard care in stage IB NSCLC. Given the magnitude of observed survival differences, CALGB 9633 was underpowered to detect small but clinically meaningful improvements. A statistically significant survival advantage for patients who had tumors > or = 4 cm supports consideration of adjuvant paclitaxel/carboplatin for stage IB patients who have large tumors.

Irinotecan Plus Gemcitabine Results in No Survival Advantage Compared With Gemcitabine Monotherapy in Patients With Locally Advanced or Metastatic Pancreatic Cancer Despite Increased Tumor Response Rate

PURPOSE This phase III, randomized, open-label, multicenter study compared the overall survival associated with irinotecan plus gemcitabine (IRINOGEM) versus gemcitabine monotherapy (GEM) in patients with chemotherapy-naive, locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS IRINOGEM patients received starting doses of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 given weekly for 2 weeks every 3-week cycle. GEM patients received gemcitabine 1,000 mg/m2 weekly for 7 of 8 weeks (induction) and then weekly for 3 of 4 weeks. The primary end point of the trial was survival. Secondary end points included tumor response, time to tumor progression (TTP), changes in CA 19-9, and safety. RESULTS In each arm, 180 randomly assigned patients comprised the intent-to-treat population evaluated for efficacy; 173 IRINOGEM and 169 GEM patients were treated. Median survival times were 6.3 months for IRINOGEM (95% CI, 4.7 to 7.5 months) and 6.6 months for GEM (95% CI, 5.2 to 7.8 months; log-rank P =.789). Tumor response rates were 16.1% (95% CI, 11.1% to 22.3%) for IRINOGEM and 4.4% (95% CI, 1.9% to 8.6%) for GEM (chi2 P <.001). Median TTP was 3.5 months for IRINOGEM versus 3.0 months for GEM (log-rank P =.352). However, subset analyses in patients with locally advanced disease suggested a TTP advantage with IRINOGEM versus GEM (median, 7.7 v 3.9 months). CA 19-9 progression was positively correlated with tumor progression. The incidence of grade 3 diarrhea was higher in the IRINOGEM group but grade 3 to 4 hematologic toxicities and quality-of-life outcomes were similar. CONCLUSION IRINOGEM safely improved the tumor response rate compared with GEM but did not alter overall survival.

Intraperitoneal Cisplatin with Systemic Thiosulfate Protection

Seventeen patients with intraperitoneal tumors were treated by 4-hour intraperitoneal dialysis with cisplatin alone, or in combination with an intravenous neutralizing agent, sodium thiosulfate. Cisplatin alone, 90 mg/m2 body surface area intraperitoneally, produced nephrotoxicity. When intraperitoneal cisplatin therapy was combined with intravenous thiosulfate treatment, the dose of cisplatin could be escalated to 270 mg/m2 body surface area without causing an increase in serum creatinine levels or undue myelosuppression. Even at doses up to 270 mg/m2, no local toxicity occurred. The peak peritoneal concentration of free reactive cisplatin averaged 21-fold higher than the plasma level, and the area under the peritoneal cisplatin elimination curve averaged 12-fold more than the area under the plasma curve. Neither of these ratios varied significantly with cisplatin dose. Regression of intraperitoneal tumor masses was observed in patients with far-advanced ovarian carcinoma, mesothelioma, and malignant carcinoid.

Phase II trial of gemcitabine (2,2'-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas.

Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical acitivity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m2 was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2–20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 × 103/μl (range 1.6–9.3) and the median absolute neutrophil (ANC) nadir was 2.0 × 103/μl (range 0.4–7.2). Thrombocytopenia - 100.0 × 103/μl was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0–245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemcitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.

Single-Agent Versus Combination Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The Cancer and Leukemia Group B (study 9730)

PURPOSE We compared the efficacy of combination chemotherapy versus single-agent therapy in patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS A total of 561 eligible patients were randomly assigned to receive paclitaxel alone or in combination with carboplatin. RESULTS The response rate was 17% in the paclitaxel arm and 30% in the carboplatin-paclitaxel arm (P < .0001). Median failure-free survival was 2.5 months in the paclitaxel arm and 4.6 months in the carboplatin-paclitaxel arm (P = .0002). Median survival times were 6.7 months (95% CI, 5.8 to 7.8) and 8.8 months (95% CI, 8.0 to 9.9), and 1-year survival rates were 32% (95% CI, 27% to 38%), and 37% (95% CI, 32% to 43%), respectively. The overall survival distributions were not statistically different: hazard ratio = 0.91 (95% CI, 0.77 to 1.17; P = .25). Hematological toxicity and nausea were more frequent in the combination arm, but febrile neutropenia and toxic deaths were equally low in both arms. There was no significant survival difference in elderly patients. Performance status 2 patients treated with combination chemotherapy had a better survival rate than those treated with single-agent therapy (P = .019). CONCLUSION Combination chemotherapy improves response rate and failure-free survival compared with single-agent therapy, but there was no statistically significant difference in the primary end point of overall survival. The results in elderly patients were similar to younger patients. Performance status 2 patients had a superior outcome when treated with combination chemotherapy.

Randomized Phase II Study of Cisplatin With Gemcitabine or Paclitaxel or Vinorelbine as Induction Chemotherapy Followed by Concomitant Chemoradiotherapy for Stage IIIB Non–Small-Cell Lung Cancer: Cancer and Leukemia Group B Study 9431

PURPOSE To evaluate new drugs in combination with cisplatin in unresectable stage III non-small-cell lung cancer, Cancer and Leukemia Group B (CALGB) conducted a randomized phase II study of two cycles of induction chemotherapy followed by two additional cycles of the same drugs with concomitant radiotherapy. PATIENTS AND METHODS Eligible patients received four cycles of cisplatin at 80 mg/m(2) on days 1, 22, 43, and 64 with arm 1: gemcitabine 1,250 mg/m(2) on days 1, 8, 22, and 29 and 600 mg/m(2) on days 43, 50, 64, and 71; arm 2: paclitaxel 225 mg/m(2) for 3 hours on days 1 and 22 and 135 mg/m(2) on days 43 and 64; and arm 3: vinorelbine 25 mg/m(2) on days 1, 8, 15, 22, and 29 and 15 mg/m(2) on days 43, 50, 64, and 71. Radiotherapy was initiated on day 43 at 2 Gy/d (total dose, 66 Gy). RESULTS One hundred seventy-five eligible patients were analyzed. Toxicities during induction chemotherapy consisted primarily of grade 3 or 4 granulocytopenia. Grade 3 or 4 toxicities during concomitant chemoradiotherapy consisted of thrombocytopenia, granulo-cytopenia, and esophagitis. Response rates after completion of radiotherapy were 74%, 67%, and 73% for arms 1, 2, and 3, respectively. Median survival for all patients was 17 months. One-, 2-, and 3-year survival rates for the patients on the three arms were 68%/37%/28%, 62%/29%/19%, and 65%/40%/23%. CONCLUSION Four cycles of gemcitabine, vinorelbine, or paclitaxel in combination with cisplatin can be administered at these doses and schedules. The observed survival rates exceed those of previous CALGB trials and may be attributable to the use of concomitant chemoradiotherapy. Induction chemotherapy added to concomitant chemoradiotherapy is being evaluated in a phase III randomized trial.