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We conducted an individual-patient-data meta-analysis of the efficacy of chemotherapy on overall survival (OS) and progression-free survival (PFS) in advanced/recurrent gastric cancer (AGC). Our primary research question was whether the experimental arms of the trials included in the meta-analysis showed a benefit as compared with their corresponding control arms. MEDLINE (up to 2010), Cochrane Central Register of Controlled Trials, National Institutes of Health (NIH) trial registry and proceedings of major oncologic and gastrointestinal cancer meetings were searched. Randomised controlled trials for AGC closed to patient accrual before the end of 2006 were eligible. As of December 2010, individual patient data were available from 22 trials (4245 patients, representing 47% of the targeted data) of 55 eligible trials. The overall comparison of experimental arms with the corresponding control arms showed statistically significant differences in terms of both OS and PFS. Hazard ratio was 0.88 (95% confidence interval 0.82-0.94, P<0.0001) for OS and 0.81 (0.76-0.88, P<0.0001) for PFS. The results of the sub-analysis of adding a given chemotherapeutic agent to any chemotherapy confirm the results of the overall analysis, with a hazard reduction of 11% for OS (P<0.01) and 26% for PFS (P<0.0001). This meta-analysis of individual patient data shows that the additions of experimental chemotherapeutic agents to pre-existing control or standard regimens have produced a modest improvement in OS and PFS. Median survival remained below 1 year for all investigated chemotherapy regimens and none emerged as a clear standard., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.

Accurate assessment of health-related quality of life (HRQoL) in patients with advanced colorectal cancer is essential to improve our understanding of how cancer and chemotherapy influence patients' life and to adapt treatment strategies. Specific questionnaires have descriptive and predictive value and can be used to evaluate new therapies. Results from HRQoL assessments in randomised trials help patients and physicians to choose between treatment options. More than half of the patients treated with palliative chemotherapy have an improvement or at least a preservation of their HRQoL. However, several trials have found small differences in HRQoL between treatment groups. This may be due to the insufficient sensitivity of tools, low numbers of patients or missing data. An international consensus on the methods of measurement of HRQoL in oncology is warranted to enhance compliance, to better interpret results and to optimise the publication of precise HRQoL data.

A single-agent dose-escalating phase I study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile and recommended dose for phase II studies. Plasma pharmacokinetics were determined as well as the SCH 66336-induced inhibition of farnesyl protein transferase in vivo. SCH 66336 was given orally once daily (OD) without interruption to patients with histologically-confirmed solid tumours. Routine antiemetics were not prescribed. 12 patients were enrolled into the study. Dose levels studied were 300 mg (6 patients) and 400 mg (6 patients) OD. Pharmacokinetic sampling was performed on days 1 and 15. Although at 400 mg OD only 1 patient had a grade 3 diarrhoea, 3 out of 6 patients interrupted treatment early due to a combination of various grade 1-3 toxicities (diarrhoea, uremiacreatinine, asthenia, vomiting, weight loss) indicating that this dose was not tolerable for a prolonged period of time. At 300 mg OD, the same pattern of toxicities was observed, but all were grade 1-2. Therefore, this dose can be recommended for phase II studies. Pharmacokinetic analysis showed that peak plasma concentrations as well as the AUCs were dose-related, with increased parameters at day 15 compared with day 1, indicating some accumulation upon multiple dosing. Plasma half-life ranged from 5 to 9 h and appeared to increase with increasing dose. Steady state plasma concentrations were attained by day 14. A large volume of distribution at steady state suggested extensive distribution outside the plasma compartment. There is evidence of inhibition of protein prenylation in some patients after OD oral administration of SCH 66336. SCH 66336 can be safely administered using a continuous oral OD dosing regimen. The recommended dose for phase II studies using this regimen is 300 mg OD.

In patients with non-colon digestive carcinomas, various schedules and doses of 5-fluorouracil (5-FU) and leucovorin combined with cisplatin (CDDP) have been used extensively. The present study explored the toxicity and activity of a weekly 24-h infusion of high dose 5-FU modulated by high dose leucovorin with bi-weekly CDDP. 59 patients with measurable disease were treated with a weekly infusion of high dose 5-FU (2 or 2.6 g/m2)+leucovorin 500 mg/m2 for 6 weeks and a bi-weekly dose of CDDP (50 mg/m2). All patients had metastatic or locoregionally advanced disease and had a performance status < or =3. All patients were evaluable for toxicity and 58 for response. Toxicity was different according to the schedule of 5-FU. Serious adverse events occurred most frequently when 5-FU was given at a dose of 2.6 g/m2 with a high incidence of grade 3/4 neutropenia (16%) and febrile neutropenia (13%), and led to dose reductions in both CDDP and 5-FU in 13 patients (34%). For patients who started 5-FU at a dose of 2 g/m2, no reduction in 5-FU was required, and only 4 patients required a dose reduction of CDDP (19%). Grade 3/4 neutropenia was seen in 10% of patients of this group and only 1 patient required hospitalisation for febrile neutropenia. Other grade 3/4 toxicities were rare in both groups. Renal toxicity was infrequent and mild and did not require dose adjustments. The overall response rate was 33%; 19 patients achieved a partial responses (PR). No patient had a complete response (CR). The median duration of response was 5.7 months (range 2-24 months) and the median survival was 7.9 months ( range: 1-30, 95% confidence interval (CI): 7-9). The combination of weekly 24-h infusion of high dose 5-FU with leucovorin and bi-weekly cisplatin seems a well-tolerated and active treatment in non-colon digestive carcinomas. A dose of 2 g/m2 of 5-FU seems to be recommended.

Univariate and multivariate analyses were performed on data from 370 5-fluorouracil (5-FU)-resistant advanced colorectal cancer patients treated with oxaliplatin (Eloxatin)/5-FU+/-folinic acid (FA) to identify prognostic factors for oxaliplatin-based treatment. The response rate was 14.6% (95% confidence interval (CI): 11.0-18.2%), median time to progression was 4.3 months (95% CI: 3.9-4.7), and median overall survival 9.7 months (95% CI: 8.5-10.8). Multivariate analysis indicated < 2 prior chemotherapy regimens, bi-weekly treatment administration schedule (versus tri-weekly) and continuous chronomodulated delivery (CCM) as significantly associated (P < 0.05) with a higher overall response rate. Performance status (PS) < 2, having only one involved organ, biweekly schedule and CCM were associated (P < 0.05) with a longer time to progression. Good PS, one involved organ, low alkaline phosphatase (AP) serum levels, bi-weekly schedule and CCM were significantly correlated with longer overall survival, while confirming the efficacy of oxaliplatin/5-FU+/-FA in this indication.

Colorectal, gastric and pancreatic cancers are major health problems worldwide. Although surgery is a curative option in 50% of patients with colorectal cancer, it is much less effective in gastric cancer (< 20% of patients) and virtually ineffective in pancreatic cancer. These three cancer types also respond poorly to chemotherapy. CPT-11 (irinotecan), a novel cytotoxic drug, is now available in many countries as a single agent for second-line therapy in metastatic colorectal cancer. The response rate in the pivotal European study of metastatic colorectal cancer patients was 14%, with a median duration of response of 8.5 months. There was also a high rate of disease stabilisation (44%), with a median duration of 4.8 months. Median survival time was 10.4 months. The dose-limiting toxicities (DLT) for CPT-11 are delayed diarrhoea and neutropenia, both of which are schedule dependent and non-cumulative. These encouraging data in second-line therapy support the further study of CPT-11 as first-line therapy for colorectal cancer in combination with other agents. Four Japanese trials of CPT-11 as first- and/or second-line single-agent therapy for advanced gastric cancer report response rates of 18-43%. The median durations for response and survival time in the late phase II trial were 2.3 months and 5.8 months, respectively. These results are in the range of those reported for sequential high-dose methotrexate and 5-fluorouracil (5-FU)/doxorubicin (FAMTX), etoposide/leucovorin/5-FU (ELF) or cisplatin/5-FU therapy in gastric cancer. Data are currently available from five phase II studies of CPT-11 in advanced pancreatic cancer: four Japanese and one European. The response rates ranged from 9 to 19%. The median duration of survival for all treated patients in the European study was 5.2 months. CPT-11 in combination with 5-FU is currently being investigated in Japan, the U.S.A. and Europe in patients with gastrointestinal tumours. CPT-11 is also being evaluated in combination with each of the following agents: oxaliplatin, docetaxel, raltitrexed, etoposide and mitomycin C. Japanese studies of CPT-11 plus cisplatin in patients with gastric cancer have produced response rates of 48-59%. These encouraging data highlight the potential for CPT-11 in combination therapy for gastrointestinal tumours.

The aim of this prospective study was to assess the efficacy, clinical benefit and safety of CPT-11 (irinotecan) in patients with stringently-defined 5-fluorouracil-resistant metastatic colorectal cancer (CRC). 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m2 once every 3 weeks in a multicentre phase II study. Tumour response and toxicity were assessed using WHO criteria. Changes in performance status (PS), weight and pain were also measured. The WHO response rate was 13/95 (13.7%, 95% CI 7.5% to 22.3%) eligible patients with a median duration of response of 8.5 months (37 weeks, range: 18-53+). There was also a high rate of disease stabilisation (44.2%) with a median duration of 4.8 months. The probability of being free of progression at 4 months was 50%. Median survival from first administration of CPT-11 was 10.4 months or 45 weeks (range: 3-66+ weeks). There was weight stabilisation or gain in 81% (73/90) of patients, a favourable outcome in PS in 91% (82/90) (improvement of WHO PS 2 or stabilisation of PS 0-1), and pain relief in 54% (26/48). There were no toxic deaths. Neutropenia was short-lasting and non-cumulative. Diarrhoea grade > or = 3 occurred in 7% of cycles and 28/107 (26%) of patients. CPT-11 350 mg/m2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical benefit. The toxicity profile of CPT-11 is becoming better understood and has been considerably improved.

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.

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.

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.

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.

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.

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.

Sections were obtained from archival colorectal tissue samples preserved in paraffin since 1974, after an in vitro incubation with [3H]thymidine and fixation in formaldehyde. These sections were submitted to immunohistochemical staining with the 19A2 monoclonal antibody against proliferating cell nuclear antigen (PCNA) (i.e. the PCNA identified as the auxiliary protein to DNA polymerase delta), followed by autoradiography. Analysis of this double-labelled material revealed an excess of PCNA-labelled over 3H-labelled nuclei, as expected from our previous studies with this fixative. On the other hand, PCNA positive nuclei showed the same overall topographical distribution as the [3H]thymidine-labelled ones, eventually revealing the same heterogeneity or abnormality in the spatial distribution of proliferative cells. Finally, there was a highly significant correlation (r = 0.898; P < 0.0001) between the [3H]thymidine labelling index (TLI) and the proportion of PCNA-positive nuclei (PCNAF-LI). PCNA immunostaining after formaldehyde fixation thus appears as a valid approach for mapping the proliferative compartment and demonstrating tumour heterogeneity or abnormalities in the distribution of proliferative cells. The excellent correlation between the PCNAF-LI and the TLI also makes PCNA immunostaining a simple tool for retrospective or prospective studies on pathological material aimed at evaluating the potential relevance of proliferative indices to clinical prognosis or prediction of cancer risk.