Defining and analysing symptom palliation in cancer clinical trials: a deceptively difficult exercise

The assessment of symptom palliation is an essential component of many treatment comparisons in clinical trials, yet an extensive literature search revealed no consensus as to its precise definition, which could embrace relief of symptoms, time to their onset, duration, degree, as well as symptom control and prevention. In an attempt to assess the importance of these aspects and to compare different methods of analysis, we used one symptom (cough) from a patient self-assessment questionnaire (the Rotterdam Symptom Checklist) in a large (>300 patient) multicentre randomized clinical trial (conducted by the Medical Research Council Lung Cancer Working Party) of palliative chemotherapy in small-cell lung cancer. The regimens compared were a two-drug regimen (2D) and a four-drug regimen (4D). No differences were seen between the regimens in time of onset of palliation or its duration. The degree of palliation was strongly related to the initial severity: 90% of the patients with moderate or severe cough at baseline reported improvement, compared with only 53% of those with mild cough. Analyses using different landmark time points gave conflicting results: the 4D regimen was superior at 1 month and at 3 months, whereas at 2 months the 2D regimen appeared superior. When improvement at any time up to 3 months was considered, the 4D regimen showed a significant benefit (4D 79%, 2D 60%, P = 0.02). These findings emphasize the need for caution in interpreting results, and the importance of working towards a standard definition of symptom palliation. The current lack of specified criteria makes analysis and interpretation of trial results difficult, and comparison across trials impossible. A standard definition of palliation for use in the analysis of clinical trials data is proposed, which takes into account aspects of onset, duration and degree of palliation, and symptom improvement, control and prevention. © 1999 Cancer Research Campaig

A meta-analysis of two randomised trials of early chemotherapy in asymptomatic metastatic colorectal cancer

This report constitutes a prospectively planned meta-analysis combining two almost identical trials undertaken in Australasia and Canada to study the effect of starting chemotherapy immediately in asymptomatic patients with metastatic colorectal cancer. Patients (n=168) were randomised to receive either immediate or delayed treatment (at onset of predefined symptoms). Australasian patients received either weekly 5-fluorouracil and leucovorin (500 and 20 mg m−2, respectively) (n=59) or the daily × 5 Mayo Clinic schedule (425 and 20 mg m−2, respectively) (n=42). Canadian patients were treated with the Mayo schedule (n=67). Otherwise, the two studies were almost identical in design and each used the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 instrument for measuring quality of life (QoL). Treatment was continued until 6 months had elapsed or disease progression occurred. Low accrual led to trial suspension before the predetermined sample size for either study was reached. Median survival was not significantly better with immediate treatment (median 13.0 vs 11.0 months; hazard ratio, 1.15; 95% confidence interval (CI) 0.79–1.72; P=0.49). There was no statistically significant difference in progression-free survival (time from randomisation until first evidence of progression after chemotherapy, 10.2 vs 10.8 months; hazard ratio, 1.08; 95% CI 0.71–1.64; P=0.73). There was no difference in overall QoL or its individual domains between the two treatment strategies at baseline or at any subsequent time point. Early treatment of asymptomatic patients with metastatic colorectal cancer did not provide a survival benefit or improved QoL compared to withholding treatment until symptoms occurred

A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer

The purpose of this trial was to examine the efficacy of the addition of levamisole (LEV) or interferon alfa (IFN) to an adjuvant chemotherapy with 5-fluorouracil (5-FU) in patients with stage III colon cancer. According to a 2 × 2 factorial study design, 598 patients were randomly assigned to one of four adjuvant treatment arms. Patients in arm one received 5-FU weekly for 1 year, patients in arm two 5-FU plus LEV, in arm three 5-FU plus IFN and patients in arm four 5-FU, LEV and IFN. The relative risk of relapse and the relative risk of death were significantly higher for patients treated with LEV compared with those without LEV treatment (HR 1.452, 95% CI 1.135–1.856, P=0.0028; HR 1.506, 95% CI 1.150–1.973, P=0.0027, respectively). No significant impact on survival was observed for therapy with IFN in the univariate analysis. The addition of LEV to adjuvant 5-FU significantly worsened the prognosis of patients with stage III colon cancer. Interferon alfa had no significant influence on survival when combined with adjuvant 5-FU, but increased the toxicity of therapy substantially

Phase I/II study of first-line irinotecan combined with 5-fluorouracil and folinic acid Mayo Clinic schedule in patients with advanced colorectal cancer

BACKGROUND: This multicentre phase I/II study was designed to determine the maximum tolerated dose of irinotecan when combined with 5-fluorouracil and folinic acid according to the Mayo Clinic schedule and to evaluate the activity of this combination as first-line therapy in patients with advanced colorectal cancer. METHODS: Sixty-three patients received irinotecan (250 or 300 mg/m(2), 30- to 90-minute intravenous infusion on day 1), immediately followed by folinic acid (20 mg/m(2)/day) and 5-fluorouracil (425 mg/m(2), 15-minute bolus infusion) days 1 to 5, every four weeks. RESULTS: Diarrhoea was dose limiting at 300 mg/m(2 )irinotecan in combination with 5-fluorouracil and folinic acid, and this was determined to be the maximum tolerated dose. Grade 3–4 neutropenia was the most frequently reported toxicity. The recommended dose of irinotecan for the phase II part of the study was 250 mg/m(2). The response rate for the evaluable patient population was 36% (13/36), and 44% (16 patients) had stable disease (including 19% of minor response). For the intention-to-treat population, the response rate was 29% (14/49) and 35% (17 patients) stable disease (including 14% of minor response). The median time to progression was 7.0 months and the median survival was 12.0 months. Grade 3–4 non-haematological drug-related toxicities included delayed diarrhoea, stomatitis, fatigue, and nausea/vomiting. There were three deaths due to septic shock that were possibly or probably treatment-related. CONCLUSIONS: This regimen of irinotecan in combination with the Mayo Clinic schedule of bolus 5-fluorouracil/folinic acid every four weeks showed activity as first-line therapy in patients with advanced colorectal cancer. In keeping with other published results of studies using bolus 5-fluorouracil combined with irinotecan, the use of this regimen is limited by a relatively high rate of grade 3–4 neutropenia, and the combination of irinotecan and infusional 5-fluorouracil / folinic acid should remain the regimen of first choice