Members of the Colorectal Cancer Collaborative Group are Dr Peter Simmonds (CRC Wessex Medical Oncology Unit, Southampton), Miss Lesley Best (CRC Wessex Medical Oncology Unit, Southampton), Dr Chris Baughan (Royal South Hants Hospital, Southampton), Dr Roger Buchanan (Royal South Hants Hospital, Southampton), Dr Carol Davis (Countess Mountbatten House, Southampton), Professor Ian Fentiman (ICRF Clinical Oncology Unit, London), Dr Steve George (Health Care Research Unit, Southampton), Dr Margot Gosney (Geriatric Medicine, Liverpool), Mr John Northover (St Mark’s Hospital, Middlesex), Dr Chris Williams (Institute of Health Sciences, Oxford).
The trial groups and investigators who contributed individual patient data were invited to comment on the paper: Professor T Allen-Mersh (Imperial College School of Medicine, London), Professor D Cunningham (Royal Marsden Hospital), Professor B Glimelius (Uppsala Hospital, Sweden), Professor L Hafstrom (Sahlgrenska Hospital, Gothenburg, Sweden), Dr P Rougier (Hospital Ambroise Pare, Boulogne, France), and Professor I Taylor (Institute of Surgical Studies, University College, London).
Table 1 Characteristics of included studies
| Study | Participants | Interventions | Outcomes | Notes |
| Allen-Mersh16 Single centre | 100 patients with synchronous or metachronous colorectal liver metastases, excluding those with extensive metastases (>60% liver replacement), less than 4 discrete resectable metastases, ascites, raised bilibubin, evidence of disease outside the liver or a history of systemic chemotherapy. Age <75 years | Hepatic artery infusion floxuridine (0.2 mg/kg body weight). 14 day continuous infusion followed by 14 day rest, and cycle repeated. Treatment continued until progression or toxicity versus Conventional palliation: resection of primary tumour if diagnosed synchronously. Analgesia, corticosteroids, and systemic chemotherapy permitted. Hepatic artery infusion not allowed | Overall survival, quality of life, toxicity | Paper suggests that most of the control group (39/49) did not receive systemic chemotherapy in addition to conventional palliation. Analysis was by intention to treat |
| Beretta10 Multicentre | 88 patients with advanced metastatic colorectal cancer. All patients were 70 years | 5-fluorouracil (500 mg/m2 intravenous infusion) with racemic folinic acid (300 mg/m2 intravenous bolus). Given weekly for 6 months or until progression versus Standard treatment (no further details provided) | Tumour response, overall survival, toxicity | Published only as an abstract. Cannot tell whether analysis was by intention to treat |
| Chisholm19 Single centre | 46 patients with locally advanced or disseminated colorectal cancer | 5-fluorouracil (500-750 mg), methotrexate (25-50 mg), and cyclophosphamide (100-200 mg) intravenously every 2 weeks plus prednisolone (5 mg twice daily, orally) versus Supportive treatment only | Survival, toxicity | Published only as an abstract. Cannot tell whether analysis was by intention to treat |
| Cunningham17 Multicentre | 279 patients with metastatic colorectal cancer, which had progressed within 6 months of treatment with fluorouracil. Age 18-75 years, WHO performance status 0-2, had 1 adjuvant and no more than 2 palliative fluorouracil based regimens. Excluded if had previous treatment with topoisomerase I inhibitors, bulky disease, metastases in central nervous system, or unresolved bowel obstruction or diarrhoea. Specified concentrations of neutrophils, platelets, bilirubin, liver transaminases, and creatinine required for inclusion | Irinotecan 350 mg/m2 over 90 min intravenous infusion every three weeks plus supportive care versus Supportive care alone: antibiotics, analgesics, transfusions, corticosteroids, psychotherapy, and other symptomatic treatment except irinotecan or other topoisomerase I inhibitors. Localised radiotherapy was allowed provided that dose was in palliative range according to institutional standards | Overall survival, disease progression, performance status, body weight, tumour related symptoms, quality of life | In the supportive care group 28 (31%) received chemotherapy, mainly with fluorouracil regimens. Analysis was by intention to treat |
| Gerard11 Multicentre | 74 patients with unresectable colorectal liver metastases. Primary colorectal adenocarcinoma had been previously resected. Age <70 years, Karnofsky performance score 60 | Hepatic artery ligation with portal infusion 5-fluorouracil 600 mg/m2/day for at least 10 days (max 20 days). Treatment repeated every 6 weeks until progression or severe side effects versus Hepatic artery ligation alone | Survival, progression, tumour response, complications, toxicity | Paper does not report whether control patients received subsequent systemic chemotherapy. Analysis not by intention to treat as 7 patients withdrawn from analysis after randomisation |
| Glimelius9 Single centre | 21 patients with surgically non-curable colorectal cancer. Age 75 years. Excluded if Karnofsky performance status <50, previous chemotherapy, other primary tumours, or exceeded specified concentrations of serum creatinine and bilirubin | Primary chemotherapy: 5-fluorouracil (500 mg/m2) and leucovorin (60 mg/m2) on days 1 and 2, every 2nd week. Treatment continued until tumour progression, either objectively or subjectively, as long as toxicity was low. Treatment could be discontinued after 4 months if disease was stable. If a patient had no tumour related symptoms, the planned number of treatments was 10 courses versus Best supportive care including psychosocial support and attempts to relieve any symptoms. Chemotherapy was allowed in this group if supportive measures did not achieve palliation or if patient requested chemotherapy | Survival, tumour response, toxicity, quality of life, costs | These patients are taken from a randomised controlled trial of 61 patients with advanced gastrointestinal cancer (stratified according to primary disease). In the entire group, 15/28 patients who were randomised to supportive care ultimately received chemotherapy. Analysis seems to be intention to treat (not explicitly stated) |
| Hafstrom12 Multicentre | 60 patients with non-resectable liver metastases and no extrahepatic cancer. Age 75 years | Temporary hepatic artery occlusion with intraportal infusion of 5-fluorouracil (1000 mg/m2/day) for 5 days plus allopurinol 300 mg orally for 10 days. Repeated every 6 weeks until progression. After 2 years, interval between treatments was prolonged versus Control: no regional or systemic treatment | Overall survival, tumour response, complications | 57 of 60 randomised patients were treated at one centre. 6 patients were excluded after randomisation because of major protocol violations (not intention to treat). 5/32 in treatment group and 3/28 in control group had subsequent systemic chemotherapy |
| Hunt12 Single centre | 61 patients with unresectable liver metastases and no evidence of extrahepatic disease. Karnofsky score >60. Age 18-75 years. Fit enough to undergo laparotomy. Patients excluded if extensive disease (jaundice, ascites, percentage liver replacement >75%) | Hepatic artery injection of 5-fluorouracil (500 mg) plus degradable starch microspheres (300-900 mg). First course consisted of 4 injections on consecutive days. Each subsequent course consisted of 2 injections on consecutive days, repeated every 28 days versus Hepatic artery embolisation versus No active therapeutic intervention. Symptomatic treatment provided when necessary | Overall survival, extrahepatic disease, toxicity, complications | Analysis was by intention to treat |
| Nordic15 Multicentre | 183 patients with non-curable, asymptomatic colorectal cancer who had received no previous cytostatic therapy. Age 75 years. Normal kidney function, no icterus, no evidence of ascites or pleural effusion | Methotrexate (250 mg/m2 infusion over 2 hours) plus 5-fluorouracil (500 mg/m2 intravenous bolus×2) plus leucovorin rescue (15 mg intramuscular followed by seven oral doses of 15 mg). Treatment repeated every 14 days for 8 courses, every 3 weeks for 2 courses, and every 4 weeks for 2 courses. Therapy continued for 12 courses (6 months) unless tumour progression or severe adverse effects versus Primary expectancy. Chemotherapy was allowed when patients became symptomatic | Survival, symptom-free survival, progression, tumour response, toxicity. Quality of life was studied in a subset at one centre | 51/90 patients in supportive care group received chemotherapy when became symptomatic. Analysis by intention to treat |
| Rougier21 Multicentre | 166 patients with unresectable hepatic metastases from primary colorectal cancer. Primary tumour had been resected. Hepatic metastases unresectable. No evidence of extrahepatic disease or ascites. WHO performance status 0-2. <75% of liver affected by tumour. Specified bilirubin concentration for inclusion | Hepatic artery infusion of floxuridine (0.3 mg/kg/day) for 14 days every 4 weeks versus Observation or systemic bolus 5-fluorouracil infusion (500 mg/m2/day) for 5 days every 4 weeks | Survival, progression, tumour response, complications, toxicity | 24/82 in treatment group and 41/82 in control group had systemic chemotherapy. Analysis by intention to treat |
| Scheithauer14 Single centre | 40 previously untreated patients with inoperable, locally recurrent, or metastatic colorectal cancer. Age <75 years, life expectancy >2 months, ECOG performance status 3. Specified levels of haematological, renal, and hepatic function for inclusion | Leucovorin intravenous bolus (200 mg/m2/day) plus 5-fluorouracil intravenous bolus (550 mg/m2/day) plus cisplatin infusion (20 mg/m2/day). All drugs given on 4 consecutive days at 4 week intervals. Continued for total of 6 months or until evidence of disease progression versus Supportive care: analgesia, nutritional support, blood transfusion, and psychosocial support as required | Survival, quality of life, toxicity | 2/12 evaluable patients in supportive care group received chemotherapy. Analysis not by intention to treat as 4 patients were withdrawn after randomisation |
| Smyth20 Multicentre | 190 patients with recurrent or metastatic colorectal cancer not amenable to curative surgery or radiotherapy. WHO performance status 0-2, life expectancy at least 3 months. Specified levels of haematological and hepatic function required. Excluded if previous chemotherapy or radiotherapy to lesions. Patients with concomitant malignant disease were excluded. Excluded if active uncontrolled infection or poor medical risks because of non-malignant systemic disease | Tauromustine (130 mg/m2 orally every 5 weeks). Continued until evidence of disease progression versus No chemotherapy. Radiotherapy was permitted for palliative treatment. Other cytotoxic agents were not permitted | Survival, progression, tumour response, quality of life, performance status, toxicity | Published only as a short communication. Additional information supplied by Kabi Pharmacia. Analysis was by intention to treat |
| Yorkshire18 Multicentre | 57 patients with minimal residual malignant disease after palliative resection for colorectal cancer | Methyl CCNU (130 mg/m2 intravenous day 1) plus 5-fluorouracil (300 mg/m2/day intravenous days 1-5). Courses repeated every 8 weeks for 2 years unless signs of disease progression versus Symptomatic treatment only | Survival, progression, toxicity | Paper does not report whether patients in the control group received subsequent systemic chemotherapy. Analysis not by intention to treat as some patients were withdrawn from analysis after randomisation |