Adequate number of patients are needed to evaluate adjuvant treatment in gastric cancer.
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Chemotherapy, Adjuvant↗
Biomedical subjects
H Bleiberg
Publications and source records attributed to H Bleiberg.
Colorectal cancer--is there an alternative to 5-FU?
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Antidotes↗
Should patients with advanced colorectal cancer be treated with chemotherapy?
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Antimetabolites, Antineoplastic↗
Randomised phase II study of cisplatin and 5-fluorouracil (5-FU) versus cisplatin alone in advanced squamous cell oesophageal cancer.
Patients with measurable or evaluable locally advanced or metastatic squamous cell carcinoma of the oesophagus were treated with cisplatin (CDDP), 100 mg/m2, combined with 5-fluorouracil (5-FU) at a dose of 1000 mg/m2 as a continuous infusion from days 1-5 (Arm A) or with CDDP alone (Arm B). Cycles were repeated every 3 weeks. 92 patients were randomised centrally, 88 were eligible. The response rate was 35% (95% CI (confidence interval), 20-54%) in Arm A and 19% (95% CI, 8-35%) in Arm B. One complete response was observed in each arm. The median duration of survival was 33 weeks and 28 weeks for Arm A and Arm B, respectively. Haematological and non-haematological toxicities were more frequent and more severe in Arm A. The most prominent toxicities were grade 4 aplasia and septicaemia (2), meningeal haemorrhage (1), cerebrovascular accident (3) and ischaemia of the lower limbs (1) all occurring in Arm A. Overall, seven treatment-related deaths (16%) were observed in Arm A, none in Arm B. The severe side-effects induced by the combination suggest that, currently, no standard chemotherapy can be recommended for patients with advanced squamous cell oesophageal cancer.
Adult↗
Gastrointestinal Tract Cancer Liaison Office: an attempt to organise clinical research in Europe.
The Gastrointestinal Tract Cancer Liaison Office (GITCLO) was developed in an attempt to organise the increasing body of clinical research in gastrointestinal tumours in Europe. This paper represents an analysis, by tumour localisation, of the trials collected for the second edition of the GITCLO booklet. The list of cooperative groups, chairmen and study coordinators is given with their respective telephone and telefax numbers. A total of 84 trials were collected, conducted by 46 co-operative groups in 14 countries. For each organ and stage of disease, a summary of concepts investigated is given with the references of the study co-ordinator. Obviously, too many questions are raised at the same time. In colorectal cancer, for example, a total of 41 trials exploring 22 concepts are currently open for patients' registration. We hope that the present attempt to clarify the situation of clinical research in the field of gastrointestinal cancers in Europe will speed up therapeutic progress in the best interest of the patients.
Colorectal Neoplasms↗
Phase IB study of doxorubicin in combination with the multidrug resistance reversing agent S9788 in advanced colorectal and renal cell cancer.
S9788 is a new triazineaminopiperidine derivate capable of reversing multidrug resistance (MDR) in cells resistant to chemotherapeutic agents such as doxorubicin. It does not belong to a known class of MDR revertants, but its action involves the binding of P-glycoprotein. Thirty-eight evaluable patients with advanced colorectal or renal cell cancer were treated with doxorubicin alone (16 patients) followed after disease progression with combination treatment of doxorubicin plus S9788 (12 patients) or upfront with the combination of doxorubicin plus S9788 (22 patients). S9788 was given i.v. as a loading dose of 56 mg m-2 over 30 min followed by doxorubicin given at 50 mg m-2 as a bolus infusion. Thereafter, a 2-h infusion of S9788 was administered at escalating doses ranging from 24 to 120 mg m-2 in subsequent cohorts of 4-10 patients. Pharmacokinetic analysis demonstrated that concentrations of S9788 that are known to reverse MDR in vitro were achieved in patients at non-toxic doses. Compared with treatment with doxorubicin alone, treatment with the combination of doxorubicin and S9788 produced a significant increase in the occurrence of WHO grade 3-4 granulocytopenia. Treatment with S9788 was cardiotoxic as it caused a dose-dependent and reversible increase in corrected QT intervals as well as clinically non-significant arrhythmias on 24- or 48-h Holter recordings. Although clinically relevant cardiac toxicities did not occur, the study was terminated as higher doses of S9788 may increase the risk of severe cardiac arrhythmias. Twenty-nine patients treated with S9788 plus doxorubicin were evaluable for response, and one patient, who progressed after treatment with doxorubicin alone, achieved a partial response. We conclude that S9788 administered at the doses and schedule used in this study results in relevant plasma concentrations in humans and can safely be administered in combination with doxorubicin.
Adult↗
[Colorectal cancer: a controllable disease].
Colorectal cancer is one of the most frequent cancers in western countries. Five years after curative surgery and adjuvant chemotherapy, about 10% more patients with Dukes C colon cancer are free of disease compared to the control group. Several regimens using 5-fluorouracil with folinic acid (5FU/FA) or levamisole are available. For patients with disseminated disease. 5FU/FA based treatments allows a doubling in survival as compared to best supportive care. Moreover, quality of life is significantly improved. New agents are upcoming. Tomudex seems to be equivalent to 5FU/FA but easier to administer. CPT-11 or oxaliplatin have been investigated in second line after failure of 5FU/FA. The available data suggest that median survival is prolonged by ten months, in addition to what was already obtained in first line with 5FU/FA. Colorectal cancer must be revisited. An active approach of our patients should allow to reduce the incidence of the disease, to increase the number of disease free patients 5 years after surgery, to prolong survival and improve the quality of life of those who will develop metastatic disease.
Antimetabolites, Antineoplastic↗
[Role of radiotherapy in cancers of the stomach].
The rational bases for using radiotherapy in gastric cancer are strong since most of the patients will finally die from locoregional recurrence and/or distant metastases. The review of the randomized studies investigating that question failed to demonstrate a benefit from using radiotherapy. Inappropriate methodology could explain the lack of results: the number of patients in the series is too small, the treatment modalities are not standardized, the patients populations are inhomogeneous. Well conceived clinical trials are still required in order to answer that question.
Chemotherapy, Adjuvant↗
[Non surgical treatment of pancreatic cancers].
Pancreatic cancer is a disease difficult to treat. Diagnosis is late, cancer remaining clinically unapparent even if locally advanced or metastatic. Few patients can be submitted to curative surgery. Even if resection is possible, 5-year survival varies from 0% to 18% according to series. Some data suggest that chemotherapy with or without radiotherapy could influence disease free survival but a benefit on overall survival has not been demonstrated. For locally advanced disease, the results of a trial published in 1968, showed that a combination of radiotherapy and 5-Fluorouracil (5FU) improved median survival as compared to radiotherapy alone (5.5 versus 10 months). Since then, no progress has been achieved. At the present time, survival of patients with metastatic pancreatic cancer cannot be improved. Very recently, a new agent, gemcitabine, has been compared to 5FU. Criteria for activity were based on clinical improvement analgesia consumption, performance status and weight gain. Twenty-four percent of the patients treated with gemcitabine had a clinical benefit as compared to 5% for those treated with 5FU. Other studies comparing chemotherapy to best supportive care show a significant decrease of depression and anxiety as well as an improvement in quality of life for patients being treated.
Antineoplastic Combined Chemotherapy Protocols↗
Fotemustine in patients with advanced gastric cancer, a phase II trial from the EORTC-GITCCG (European Organization for Research and Treatment of Cancer, Gastrointestinal Tract Cancer Cooperative Group).
Fotemustine activity was evaluated in 26 patients, mostly pretreated, with advanced gastric cancer. Its main toxicity was haematological with grade 3-4 neutropenia in 32% and grade 3-4 thrombocytopenia in 50% of the patients, complicated by 2 toxicity-related deaths due to haemorrhage. No complete or partial responses were observed in the 26 eligible patients and median survival was only 11 weeks. Fotemustine therefore has no activity in advanced gastric cancer.
Adult↗
Characterisation and clinical management of CPT-11 (irinotecan)-induced adverse events: the European perspective.
CPT-11 (Campto, irinotecan) is a promising new agent in the treatment of advanced colorectal cancer. Its safety has been assessed in light of the results from recent European phase II studies. In a pivotal French study in which CPT-11 350 mg/m2 was administered once every 3 weeks, neutropenia and delayed diarrhoea were the major adverse events: transient neutropenia occurred in 80% of patients, and severe neutropenia and febrile neutropenia in 47 and 15%, respectively. Delayed diarrhoea occurred in 87% of patients, with 39% having severe (grade 3 or 4) diarrhoea and 16% requiring hospitalisation. None of these adverse events was cumulative. Results of a pilot study to elucidate the mechanism of CPT-11-induced delayed diarrhoea suggest that this toxicity has a secretory mechanism with an exudative component. Early appropriate management of delayed diarrhoea may improve the safety profile of CPT-11. Indeed, the safety profile of CPT-11 was clearly improved in a later (currently ongoing) pan-European study: incidences of severe (grade 3 or 4) delayed diarrhoea and febrile neutropenia (+/-infection) were reduced from 39% to 23% (grade 4: 8% to 2.5%) and from 12% to 6%, respectively. Such an improvement could be attributed to a better understanding of the mechanisms of diarrhoea, improved patient selection criteria, better education of patients and physicians about management of delayed diarrhoea and the use of broad spectrum antibiotics when diarrhoea persisted despite loperamide therapy.
Adolescent↗
Colorectal cancer: the challenge.
Colorectal cancer is a common cancer and a common cause of death. The incidence varies widely and is highest in industrialised Western countries. Surgery remains the mainstay of treatment of localised tumours and, in addition, may also play a role in some patients with local recurrence and/or isolated liver or lung metastases. Chemotherapy is required to improve the results of surgery and to treat patients with disseminated disease. For more than 30 years, 5-fluorouracil (5-FU) has been the only active agent in advanced colorectal cancer with an overall response rate of less than 15%. Biomodulation of 5-FU with leucovorin has led to a substantial increase in the response rate, but only a modest benefit in survival. Improvement in palliative effects has also been observed. In adjuvant treatment after curative surgery, 5-FU with levamisole or leucovorin has shown approximately a 10% absolute increase in survival, compared with controls. Despite this progress, there is evidence that an important proportion of colorectal cancer patients remains untreated. New treatments, such as the direct and specific thymidylate synthase inhibitors (e.g. 'Tomudex'--raltitrexed, previously known as ZD1694) in first-line therapy, or CPT-11 or oxaliplatin, along with increased referral and a more consistent treatment approach could improve the outcome of patients with advanced colorectal cancer.
Antimetabolites, Antineoplastic↗
Phase II trial of vinorelbine in metastatic squamous cell esophageal carcinoma. European Organization for Research and Treatment of Cancer Gastrointestinal Treat Cancer Cooperative Group.
PURPOSE: To evaluate the response rate and toxic effects of vinorelbine (VNB) administered as a single agent in metastatic squamous cell esophageal carcinoma. PATIENTS AND METHODS: Forty-six eligible patients with measurable lesions were included and were stratified according to previous chemotherapy. Thirty patients without prior chemotherapy and 16 pretreated with cisplatin-based chemotherapy were assessable for toxicity and response. VNB was administered weekly as a 25-mg/m2 short intravenous (i.v.) infusion. RESULTS: Six of 30 patients (20%) without prior chemotherapy achieved a partial response (PR) (95% confidence interval [CI], 8% to 39%). The median duration of response was 21 weeks (range, 17 to 28). One of 16 patients (6%) with prior chemotherapy had a complete response (CR) of 31 weeks' duration (95% CI, 0% to 30%). The overall response rate (World Health Organization [WHO] criteria) was 15% (CR, 2%; PR 13%; 95% CI, 6% to 29%). The median dose-intensity (DI) was 20 mg/m2/wk. VNB was well tolerated and zero instances of WHO grade 4 nonhematologic toxicity occurred. At least one episode of grade 3 or 4 granulocytopenia was seen in 59% of patients. A grade 2 or 3 infection occurred in 16% of patients, but no toxic deaths occurred. Other side effects were rare, and peripheral neurotoxicity has been minor (26% grade 1). CONCLUSION: These data indicate that VNB is an active agent in metastatic esophageal squamous cell carcinoma. Given its excellent tolerance profile and low toxicity, further evaluation of VNB in combination therapy is warranted.
Abdominal Pain↗
Modulation of high-dose infusional fluorouracil by low-dose methotrexate in patients with advanced or metastatic colorectal cancer: final results of a randomized European Organization for Research and Treatment of Cancer Study.
PURPOSE: Methotrexate (MTX) has been described to modulate the activity of fluorouracil (5-FU) in patients with metastatic colorectal cancer. The European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Cooperative Group (GITCCG) conducted a phase III trial to investigate the efficacy and tolarability of the addition of low-dose MTX (40 mg/m2) to high-dose infusional 5-FU (60 mg/kg over 48 hours) given weekly for 4 weeks and thereafter every 2 (for 4 weeks) and 3 weeks. PATIENTS AND METHODS: Three hundred ten patients were randomized between 1987 and 1992. Eligible patients had measurable advanced or metastatic colorectal cancer and had not been pretreated with antifolates or fluorodinated pyrimidines. All 297 eligible patients were evaluated for survival; toxicity was assessed in 292 patients who received at least one course of treatment. Patients with bidimensionally measurable disease (n = 230) were also evaluated for response according to standard criteria. RESULTS: The addition of low-dose MTX to high-dose infusional 5-FU led to a doubling of the response rate from 10% to 21% (P = .025). The median survival time also increased from 9.3 to 12.5 months, but this difference was not statistically significant (P = .12). High-dose infusional 5-FU with or without low-dose MTX was well tolerated, with grade 3 to 4 toxicity in greater than 10% of patients only occurring for stomatitis with the combination treatment. Performance status was the sole prognostic factor for survival in a multivariate analysis. CONCLUSION: Low-dose MTX effectively modulated high-dose infusional 5-FU in a large, randomized trial in which less than 5% of patients received leucovorin.
Aged↗
Role of chemotherapy for advanced colorectal cancer: new opportunities.
Since the late 1950s, 5-fluorouracil (5-FU) has remained the most effective chemotherapeutic agent in the treatment of advanced colorectal cancer, although response rates to 5-FU monotherapy are typically no more than 15%. However, efforts at improving the response to this agent have involved its administration with biochemical-modulating agents and in protracted infusion schedules. The combination of 5-FU with folinic acid has evinced the most promising results, with an approximate twofold increase in response rate compared with monotherapy (23% versus 11%). Preliminary evidence also suggests further benefits when this regimen is administered by continuous infusion. These results support the current clinical practice of using 5-FU plus folinic acid as first-line therapy in advanced colorectal cancer. However, for those patients refractory to a 5-FU-based chemotherapy, there is no established effective treatment option. Current approaches to enhance second-line therapy involve biochemical modulation of 5-FU and prolongation of its administration schedule or the use of new antitumor agents such as CPT-11 (irinotecan) and oxaliplatin. Among the new agents in development, CPT-11 has demonstrated promising antitumor activity in phase II studies of patients with advanced colorectal cancer, achieving response rates of 15% to 32% and 17% to 25% in chemotherapy-naive and pretreated patients, respectively. Prior disease progression on 5-FU does not affect the response to CPT-11, indicating no cross-resistance between the two agents. This suggests that CPT-11 is a promising new second-line agent for this difficult-to-treat disease. Additional studies will address the benefit of CPT-11 alone in second-line treatment and determine the role of CPT-11 in combination with thymidylate synthase inhibitors in first-line treatment.
Antineoplastic Combined Chemotherapy Protocols↗
A double-blind, randomised comparison of the anti-emetic efficacy of two intravenous doses of dolasetron mesilate and granisetron in patients receiving high dose cisplatin chemotherapy.
This multicentre, double-blind, double-dummy, randomised trial was designed to compare the efficacy and safety of single intravenous doses of dolasetron mesilate and granisetron in the prevention of acute emesis and nausea due to high-dose (> or = 80 mg/m2) cisplatin. Single intravenous doses of 1.8 or 2.4 mg/kg of dolasetron mesilate or 3 mg of granisetron hydrochloride were administered in a volume of 50 ml over a 5-min period, beginning 30 min prior to cisplatin (> or = 80 mg/m2) administration. The number and timing of emetic episodes, time to administration of escape anti-emetic medication, severity of nausea by visual analogue scale (VAS), and safety were monitored for 24 h after the start of cisplatin-containing chemotherapy. Investigators' evaluations of overall efficacy and patients' satisfaction with therapy were recorded at the end of the 24-h study period. Of the 474 patients evaluable for efficacy, complete responses were achieved by 54, 47 and 48% of patients given dolasetron mesilate 1.8 mg/kg, dolasetron mesilate 2.4 mg/kg and granisetron, respectively. Statistically, treatment groups had comparable complete and complete plus major responses, times to first emesis, and use of escape medication; patient maximum nausea severity and treatment satisfaction ratings; and physician nausea severity and overall efficacy assessments. For the majority of efficacy endpoints, 1.8 mg/kg dolasetron mesilate produced numerically superior responses compared with the 2.4 mg/kg dose. Gender and prior chemotherapy were significant predictors of complete response; males and chemotherapy-naive patients had higher responses. The overall incidences of adverse events were comparable among the treatment groups; headache and diarrhoea were most common. In conclusion, 1.8 and 2.4 mg/kg of dolasetron mesilate and granisetron (3 mg) were equally effective in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, because no additional benefit was observed with 2.4 mg/kg of dolasetron mesilate and numerically greater responses were observed with the 1.8 mg/kg dose, the lower dose of 1.8 mg/kg is optimal for further clinical development.
Adult↗
Diagnosis and treatment of gastric cancer.
Despite a decreased incidence, gastric cancer remains a leading cause of death worldwide. The only potentially curative modality for localised gastric cancer is surgery. However, overall 5-year survival does not exceed 40%. Although extensive surgery seems to increase survival in Japanese patients, this has not yet been demonstrated in Western patients. The pattern of recurrence of gastric cancer would suggest that both local and systemic treatment are required to improve survival. To date, there is no evidence that adjuvant treatment is effective. Some trials investigating preoperative chemotherapy with various combinations of etoposide, fluorouracil, cisplatin and doxorubicin in locally advanced disease suggest that a reduction in the bulk of the localised tumour may increase the curative resection rate. Advanced disease remains poorly controlled. The most effective treatments appear to be a combination of fluorouracil, methotrexate and doxorubicin (FAMTX), and of fluorouracil and cisplatin. Response rates range from 25 to 50%, and median survival from 6 to 13 months. New agents and new therapeutic approaches are required to improve the poor prognosis of gastric cancer patients.
Antineoplastic Combined Chemotherapy Protocols↗
Optimal combination therapy with Navoban (tropisetron) in patients with incomplete control of chemotherapy-induced nausea and vomiting. The Belgian Navoban Group.
Even with the availability of potent and selective serotonin antagonists, chemotherapy-induced nausea and vomiting remain a major problem for many patients. This study aims to evaluate the benefit of combination therapy based on Navoban (tropisetron) in patients who had incomplete control of nausea and/or vomiting induced by chemotherapy when using Navoban as a single antiemetic agent. In their first chemotherapy course, 1072 patients planned to receive at least two identical cycles of emetogenic chemotherapy were treated with 5 mg Navoban once daily. To evaluate three treatments additional to the recommended 5 mg once-daily Navoban regimen during Course 2 in those patients who had shown incomplete control of nausea and/or vomiting on any day of Course 1, a 2 x 2 x 2 factorial design was employed. Of these patients, 445 were centrally randomised to receive an additional dose of open-label dexamethasone (Day 1, 0.2 mg/kg i.v.; Days 2-6, 8 mg p.o.) and/or open-label alizapride (Day 1, 100 mg i.v. and 4 x 50 mg p.o.; Days 2-6, 4 x 5 mg p.o.) and/or double-blind Navoban--that is, doubling the dose to 10 mg once daily or placebo. Complete response rates during Course 1 (CRR, no nausea and no vomiting) were, for Day 1, 72% and for Days 1-6, 48%. More complete responders were observed when dexamethasone was added during Course 2, both on Day 1 (76% vs. 66%, p = 0.020) and on Days 1-6 (50% vs. 34%, p = 0.0004).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗