Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. Treatment of patients with advanced gastric carcinoma with a 5-fluorouracil-based or a cisplatin-based regimen: two parallel randomized phase II studies. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. Quality of life in patients with advanced gastric cancer: a randomized trial comparing docetaxel, cisplatin, 5-FU (TCF) with epirubicin, cisplatin, 5-FU (ECF). Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. A randomized trial between two neoadjuvant chemotherapy protocols: CDDP + 5-FU versus CDDP + VP16 in advanced cancer of the head and neck. Controlled evaluation of three drug combination regimens versus fluorouracil alone for the therapy of advanced gastric cancer. North Central Cancer Treatment Group. A randomized, comparative study of combination chemotherapies in advanced gastric cancer: 5-fluorouracil and cisplatin (FP) versus 5-fluorouracil, cisplatin, and 4'-epirubicin (FPEPIR). Kyoto Research Group for Chemotherapy of Gastric Cancer (KRGCGC). Mature results from a randomized Phase II trial of cisplatin plus 5-fluorouracil and radiotherapy with or without tirapazamine in patients with resectable Stage IV head and neck squamous cell carcinomas. A randomized study comparing two regimens of neoadjuvant and adjuvant chemotherapy in multimodal therapy for locally advanced head and neck cancer.
This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy.
                Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric carcinoma, a performance status <or= 1, and adequate hematologic, hepatic, and renal function randomly received <or= eight 3-weekly cycles of ECF (epirubicin 50 mg/m(2) on day 1, cisplatin 60 mg/m(2) on day 1, and fluorouracil [FU] 200 mg/m(2)/d on days 1 to 21), TC (docetaxel initially 85 mg/m(2) on day 1 [later reduced to 75 mg/m(2) as a result of toxicity] and cisplatin 75 mg/m(2) on day 1), or TCF (TC plus FU 300 mg/m(2)/d on days 1 to 14). Study objectives included response (primary), survival, toxicity, and quality of life (QOL).
                ORR was 25.0% (95% CI, 13% to 41%) for ECF, 18.5% (95% CI, 9% to 34%) for TC, and 36.6% (95% CI, 23% to 53%) for TCF (n = 119). Median overall survival times were 8.3, 11.0, and 10.4 months for ECF, TC, and TCF, respectively. Toxicity was acceptable, with one toxic death (TC arm). Grade 3 or 4 neutropenia occurred in more treatment cycles with docetaxel (TC, 49%; TCF, 57%; ECF, 34%). Global health status/QOL substantially improved with ECF and remained similar to baseline with both docetaxel regimens.
                Time to response and ORR favor TCF over TC for further evaluation, particularly in the neoadjuvant setting. A trend towards increased myelosuppression and infectious complications with TCF versus TC or ECF was observed. Although many drug combination therapies have been proposed, there is no standard therapy for patients with advanced gastric carcinoma. The superiority of combination therapy over monochemotherapy has not been demonstrated convincingly. To explore the role of monochemotherapy, the authors evaluated 5-fluorouracil (5-FU), modulated by 6S-leucovorin (6S-LV) and a cisplatin-containing regimen, which was comprised of epirubicin, etoposide, and cisplatin with the addition of the reversal agent lonidamine (EEP-L).
                After stratification according to performance status (PS) and resection of the primary tumor, 72 patients with advanced gastric carcinoma were randomized to 2 parallel Phase II trials with 5-FU/6S-LV and EEP-L, respectively. Thirty-six patients in Study A received bolus 6S-LV, 100 mg/m2, followed by bolus 5-FU, 370 mg/m2, on Days 1-5 and 36 others in Study B received epirubicin, 30 mg/m2, on Days 1 and 5; etoposide, 100 mg/m2, on Days 1, 3, and 5; cisplatin, 30 mg/m2, on Days 2 and 4; and lonidamine, 150 mg/day.
                There were 6 partial responses (18.2%) (95% confidence interval [CI] +/- 13.2) in Study A and 7 partial responses (21.9%) (95% CI +/- 14.3) in Study B. Partial responses were more frequent in patients with resected tumors or with an Eastern Cooperative Oncology Group PS of 0-1. The median duration of response was 8.8 and 8.3 months, respectively, in Study A and Study B. The median survival reached 8 months in Study A and 9 months in Study B. In the whole population of patients survival was significantly higher in patients with a PS of 0-1 (P < 0.05). Patients with a PS of 0-1 and a resected tumor had the significantly longest survival both in EEP-L treated patients and in all evaluable patients in the two studies. The most frequent World Health Organization Grade 3-4 toxic effects were gastrointestinal in Study A and hematologic in Study B. No treatment-related death was observed.
                The efficacy of 5-FU, modulated with 6S-LV, is moderate in patients with advanced gastric carcinoma, similar to cisplatin-containing regimens. PS and other prognostic factors could influence the response rate, which does not appear to be a reliable parameter for evaluating the outcome of chemotherapy trials. To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life.
                Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m(2) (49 patients) or 75 mg/m(2) (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks.
                One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7. 1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P <.001), as was median survival (7.0 v 4.6 months; log-rank test, P =.047). The difference was more significant for docetaxel 75 mg/m(2) patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P =.010; 1-year survival, 37% v 11%; chi(2) test, P =.003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m(2), three of whom died, and in one patient treated with docetaxel 75 mg/m(2). Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups.
                Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m(2), the benefits of docetaxel therapy outweigh the risks. To determine the efficacy and safety of a biweekly regimen of leucovorin (LV) plus fluorouracil (FU) alone or in combination with cisplatin or irinotecan in patients with previously untreated metastatic gastric adenocarcinoma and to select the best arm for a phase III study.
                One hundred thirty-six patients (two were ineligible) were enrolled onto the randomized multicenter phase II trial. Patients received LV 200 mg/m(2) (2-hour infusion) followed by FU 400 mg/m(2) (bolus) and FU 600 mg/m(2) (22-hour continuous infusion) on days 1 and 2 every 14 days (LV5FU2; arm A), LV5FU2 plus cisplatin 50 mg/m(2) (1-hour infusion) on day 1 or 2 (arm B), or LV5FU2 plus irinotecan 180 mg/m(2) (2-hour infusion) on day 1 (arm C).
                The overall response rates, which were confirmed by an independent expert panel, were 13% (95% CI, 3.4% to 23.3%), 27% (95% CI, 14.1% to 40.4%), and 40% (95% CI, 25.7% to 54.3%) for arms A, B, and C, respectively. Median progression-free survival and overall survival times were 3.2 months (95% CI, 1.8 to 4.6 months) and 6.8 months (95% CI, 2.6 to 11.1 months) with LV5FU2, respectively; 4.9 months (95% CI, 3.5 to 6.3 months) and 9.5 months (95% CI, 6.9 to 12.2 months) with LV5FU2-cisplatin, respectively; and 6.9 months (95% CI, 5.5 to 8.3 months) and 11.3 months (95% CI, 9.3 to 13.3 months) with LV5FU2-irinotecan, respectively.
                Of the three regimens tested, the combination of LV5FU2-irinotecan is the most promising and will be assessed in a phase III trial. Health related quality of life (HRQOL) is an important outcome after treatment for upper gastrointestinal carcinoma. This study aimed to compare HRQOL in patients with advanced gastric cancer (GC) receiving either a standard or an experimental treatment.
                Seventy-one patients have been treated in Cancer Institute (Tehran, Iran) with docetaxel, cisplatin, 5 FU (TCF) or epirubicin, cisplatin, 5-FU (ECF) and were followed from Jan 2002 to Jan 2005. End points were response rate, HRQOL and survival. HRQOL was assessed using the EORCT QLQ-C30 at baseline and after the third cycle of chemotherapy.
                The baseline HRQOL scores were comparable between two groups. After treatment improvement was seen in a number of items and domains except for cognitive functioning, and diarrhoea. Pain decreased and physical functioning improved in both groups. However, only the TCF group showed statistically and clinically meaningful improvement in global QOL (P = 0.001). Surgical and pathologic response was better with TCF but there was no difference in survival rate between two groups.
                Docetaxel based treatment (TCF) showed better palliation and improvement of global QOL as compared with epirubicin based treatment (ECF). However, it seems that regardless of treatment offered, effective chemotherapy was the most important factor affecting QOL in these patients. The monoclonal antibody trastuzumab has survival benefit when given with chemotherapy to patients with early, operable, and metastatic breast cancer that has HER2 (also known as ERBB2) overexpression or amplification. We aimed to assess event-free survival in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without 1 year of trastuzumab.
                We compared 1 year of treatment with trastuzumab (given as neoadjuvant and adjuvant treatment; n=117) with no trastuzumab (118), in women with HER2-positive locally advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Randomisation was done with a computer program and minimisation technique, taking account of geographical area, disease stage, and hormone receptor status. Investigators were informed of treatment allocation. A parallel cohort of 99 patients with HER2-negative disease was included and treated with the same chemotherapy regimen. Primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered, number ISRCTN86043495.
                Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer (3-year event-free survival, 71% [95% CI 61-78; n=36 events] with trastuzumab, vs 56% [46-65; n=51 events] without; hazard ratio 0.59 [95% CI 0.38-0.90]; p=0.013). Trastuzumab was well tolerated and, despite concurrent administration with doxorubicin, only two patients (2%) developed symptomatic cardiac failure. Both responded to cardiac drugs.
                The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve event-free survival, survival, and clinical and pathological tumour responses.
                F Hoffmann-La Roche.
                Copyright 2010 Elsevier Ltd. All rights reserved. We investigated a phase III randomized trial to compare efficacy and tolerance of CDDP + 5-FU to CDDP + VP16, both given intravenously in patients with unresectable advanced head and neck cancer. The 197 eligible patients were paired off successively on the basis of tumor sites and UICC stage. Comparisons were made through sequential closed plans. In 179 patients, tumor beds and cervical lymph nodes were irradiated, and 20 patients underwent salvage surgical procedures. Cisplatin plus 5-fluorouracil showed a response (CR + PR) rate of 15% greater than that observed with cisplatin plus etoposide (alpha=0.05, power 70%). Complete responses played a major role in the CDDP + 5-FU regimen. Furthermore, we noted a higher cervical node regression with this chemotherapy combination. Because radiotherapy was administered after chemotherapy, we could not analyze the mean duration response for each protocol. No significant difference in survival existed between the two groups. Myelosuppression was the most frequent sign of toxicity observed, especially with the CDDP + VP16 regimen. Mucositis was rare with allopurinol protection. In the CDDP + 5-FU group, one patient had grade 4 cardiac dysfunction, and 3 patients exhibited unconsciousness that may be related to cerebral vascular damage. Thirteen patients died, with 8 cases related to septic shock (5 CPPP + VP16 and 3 CDDP + 5-FU). Cisplatin plus 5-FU chemotherapy showed a satisfactory efficacy and acceptable toxicity profile compared with CDDP + VP16, with caution to patients with a cardiac or vascular history. Although we could not show a benefit in survival with the CDDP + 5-FU protocol, this trial supports literature data and confirms that this regimen may be proposed as a first-line therapy in advanced cancer of the head and neck. The purpose of this study was to evaluate the therapeutic effectiveness of fluorouracil (5-FU), doxorubicin, and methyl lomustine (CCNU) (FAMe), 5-FU, doxorubicin, and cisplatin (FAP), and FAMe alternating with triazinate (TZT) when compared with a standard therapy of 5-FU alone in patients with advanced gastric cancer.
                Two hundred fifty-two eligible patients selected for study had proven locally unresectable and/or metastatic gastric adenocarcinoma. The majority had nonmeasureable disease. They were randomly assigned to receive one of the three drug combination regimens or to 5-FU alone administered by rapid injection in 5-day course. Survival was the primary study end point.
                None of the three drug combinations showed a significant advantage over 5-FU alone in improved performance score, weight gain, or patient survival. Each of the three combinations was more toxic than 5-FU alone.
                FAMe, FAP, or FAMe alternating with TZT cannot be recommended for the therapy of advanced gastric carcinoma. Therapy of this disease should remain an experimental endeavor. It would seem reasonable to prove the value of any new treatment approach by a randomized comparison to simple therapy with 5-FU alone. Sixty patients with inoperable or recurrent gastric cancers were randomly assigned into 2 treatment regimens: the FP regimen, consisting of cisplatin (CDDP, 50 mg/body, d1) + 5-fluorouracil (5-FU, 250 mg/body, d2-d5), or the FPEPIR regimen, CDDP+5-FU (FP) + 4'-epirubicin (EPIR, 30 mg/m2, d2), administered intravenously every 2 weeks. The objective responses were evaluated in 43 patients (FP: 21; FPEPIR: 22). The response rates were 24% (5PR/21) for FP and 27% (6PR/22) for FPEPIR. Objective responses were seen in 1 primary lesion and 4 metastatic lesions in patients on the FP regimen, and in 3 primary lesions and 4 metastatic lesions in patients on the FPEPIR regimen. The 6 month and 1 year survival rates were 34% and 13% for FP, and 55% and 27% for FPEPIR, respectively (not significant). Significantly higher survival rates were demonstrated in those patients with recurrent cancers (p < 0.01) and those who responded to the FPEPIR regimen (p < 0.05). Drug toxicities were assessed in 56 patients, and were in general mild and well tolerated. However, the FP regimen induced significantly less neutropenia (p < 0.01) and less complete alopecia (p < 0.01) than the did FPEPIR regimen. These results suggest that FPEPIR may be a more beneficial regimen for the treatment of gastric cancer than FP, and may be indicated for further clinical trials. The objective of this article was to report the results from a randomized trial that evaluated the efficacy and toxicity of adding tirapazamine (TPZ) to chemoradiotherapy in the treatment of patients with head and neck squamous cell carcinomas (HNSCC).
                Sixty-two patients with lymph node-positive, resectable, TNM Stage IV HNSCC were randomized to receive either 2 cycles of induction chemotherapy (TPZ, cisplatin, and 5-fluorouracil [5-FU]) followed by simultaneous chemoradiotherapy (TPZ, cisplatin, and 5-FU) or to receive the same regimen without TPZ. Patients who did not achieve a complete response at 50 Grays underwent surgical treatment. Stratification factors for randomization included tumor site, TNM stage, and median tumor oxygen tension. The primary endpoint was complete lymph node response.
                The addition of TPZ resulted in increased hematologic toxicity. There was 1 treatment-related death from induction chemotherapy. The complete clinical and pathologic response rate in the lymph nodes was 90% and 74% for the standard treatment arm and the TPZ arm, respectively (P = .08) and 89% and 90% at the primary site in the respective treatment arms (P = .71). The 5-year overall survival rate was 59%, the cause-specific survival rate was 68%, the rate of freedom from recurrence was 69%, and the locoregional control rate was 77% for the entire group. There was no difference with regard to any of the outcome parameters between the 2 treatment arms. The significant long-term toxicity rate also was found to be similar between the 2 arms.
                The addition of TPZ increased hematologic toxicity but did not improve outcomes in patients with resectable, Stage IV HNSCC using the protocol administered this small randomized study. The combination of induction and simultaneous chemoradiotherapy resulted in excellent survival in these patients. Two regimens of neoadjuvant chemotherapy for previously untreated patients with locally advanced head and neck cancer were compared with the goal of identifying a regimen with a greater than 50% complete response (CR) rate. Patients with a performance status of 0 to 2 and normal end-organ function were randomized to receive either four cycles of neoadjuvant methotrexate, cisplatin, and continuous infusion 5-fluorouracil (5-FU) (MPF) (arm A), or four cycles of bleomycin, cisplatin, and methotrexate (PBM) alternating with cisplatin and 5-FU (PF) (arm B). Patients with a performance status of greater than 2 or a carbon monoxide diffusion capacity of less than 50% of the predicted value were assigned to the arm A regimen but were analyzed separately (arm C). Local therapy consisted of surgery (for patients with resectable disease) or radiation therapy followed by two cycles of adjuvant chemotherapy with the regimen that was administered initially. Of the 42 patients who were evaluated, 16 were randomized to arm A, 13 to arm B, and 13 to arm C. The clinical CR rate was 19% on arm A (95% confidence interval, 0% to 38%), 39% on arm B (95% confidence interval, 12% to 66%) (P = 0.41), and 54% on arm C (95% confidence interval, 27% to 81%). At a median follow-up time of 35 months, the 2-year actuarial survival rate was 61% on arm A, 69% on arm B (the P value was not significant), and 38% on arm C. The 2-year survival rate for all 42 patients who were treated was 57% and the median survival time was 31 months. Toxicities of neoadjuvant chemotherapy on all arms consisted of mild to moderate myelosuppression and renal toxicity. The incidence of moderate to severe mucositis was significantly higher on arm A than arm B (P = 0.02). Two cycles of adjuvant chemotherapy were administered to only 11 of 42 patients due to patient refusal or cumulative toxicity. In conclusion, both neoadjuvant chemotherapy regimens resulted in similar response and survival rates, but mucositis was more severe with arm A. However, since neither regimen was likely to cause a CR rate of greater than 50%, this study was closed to further patient accrual.
Chemotherapy significantly improves survival in comparison to best supportive care. In addition, combination chemotherapy improves survival compared to single-agent 5-FU. All patients should be tested for their HER-2 status and trastuzumab should be added to a standard fluoropyrimidine/cisplatin regimen in patients with HER-2 positive tumours. Two and three-drug regimens including 5-FU, cisplatin, with or without an anthracycline, as well as irinotecan or docetaxel-containing regimens are reasonable treatment options for HER-2 negative patients.