Carcinoma of unknown primary with gastrointestinal profile: immunohistochemistry and survival data for this favorable subset.

BACKGROUND: Carcinoma of unknown primary with a "gastrointestinal profile" is an emerging, favorable entity. Distinguishing this entity is of increasing significance given the progress in the treatment of colorectal cancer. PATIENTS AND METHODS: 74 carcinoma of unknown primary (CUP) patients with CDX2+ tumors were chosen from the databases at M.D. Anderson and Sarah Cannon Cancer Centers between 2004 and 2010. Data on clinical and pathological characteristics including therapy and survival were recorded. RESULTS: 20 patients had ascites on presentation; the predominant sites of metastases included liver (30 %), carcinomatosis (50 %), and nodes (51 %). Based on immunohistochemistry, 2 cohorts were created: Cohort 1-"consistent with lower GI profile" included 34 patients [CDX-2+, CK20+, CK7-] and Cohort 2-"probable lower GI profile" included 40 patients [CDX2+, irrespective of CK7/CK20 status]. Excluding 6 outliers, Cohorts 1 and 2 had 32 and 36 patients, respectively; their median survivals were 37 and 21 months, respectively. On multivariate Cox regression analysis, only liver metastases were found to negatively influence survival. CONCLUSIONS: Our retrospective study provides encouraging indications that CUP patients with gastrointestinal profiles benefit from site-specific therapy. We recommend all CUP patients, especially those with abdominal nodes, isolated carcinomatosis or liver metastases, to undergo optimal immunohistochemistry (IHC) to check for a gastrointestinal profile of CUP.

Cancer of unknown primary: progress in the search for improved and rapid diagnosis leading toward superior patient outcomes.

This paper explores the enigma of cancer of unknown primary (CUP) in relation to rapidly improving molecular diagnostic approaches. It is based on the first global collaboration meeting on improving research and clinical outcomes in CUP organized by the CUP Foundation. We review the difficulties of classifying this widely heterogeneous disease and the available diagnostic and pathological evaluative techniques, focusing on molecular profiling. Retrospective studies in CUP patients are shown to provide indirect validation of the accuracy of several platforms of gene expression profiling assays that may identify CUP subsets that respond favorably to active chemotherapy regimens. This review concludes that the recent major improvements in pathologic and molecular diagnostics, coupled with new improved therapies for several specific advanced solid tumors, need to be harmonized with more evidence from clinical-translational trials. All patients with CUP could thus be appropriately managed without the constant uncertainty that has previously severely hampered patient care and optimal outcomes. The longer-term objective is to understand the biology of highly metastatic disease, leading to the development of future global therapeutic programs. Current clinical studies, such as CUP-ONE, will address some of these issues.

Molecular assignment of tissue of origin in cancer of unknown primary may not predict response to therapy or outcome: a systematic literature review.

BACKGROUND: Gene expression profiling platforms were recently shown to accurately assign cancer of unknown primary (CUP) to a primary tissue of origin, with unknown impact on patient outcome. We examined chemotherapy activity and outcome in CUP trials and in metastatic solid tumour trials in order to screen for a distinct biological behaviour of CUP. PATIENTS AND METHODS: An online search for autopsy or molecular platform studies on CUP indolent primaries was followed by identification of phase II or III clinical trials enrolling at least thirty patients with poor-risk CUP from 2002 or later. Chemotherapy activity and patient survival data were narratively compared to data from phase III chemotherapy trials on patients with metastatic breast, lung, pancreatic and colon cancer, to which CUP is most commonly classified by molecular profiling. RESULTS: Lung and pancreatic tumours were the primaries most commonly found in CUP autopsy series, whereas microarray platforms assigned CUP to breast, colon in a third and pancreatic, lung primaries in <25% of cases. 14 phase II trials managed 918 CUP patients with platinum-based chemotherapy resulting in objective response rate (ORR) of 32%. Six trials administered anthracycline-containing or gastrointestinal-type chemotherapy in 401 CUP patients, reporting ORR of 22%. The median of quoted median survival times was nine months for platinum and seven for anthracycline or GI-type regimens. Though tumour shrinkage and median survival in CUP patients were similar to those of patients with metastatic lung and pancreatic cancer, they were vastly inferior to response rates of 40-70% and median survival of 15-24 months seen in patients with metastatic breast and bowel cancer. CONCLUSION: This systematic review hints that CUP, though accurately classified by molecular methods, may harbour molecular/genetic traits distinct from tumours of known primaries. These should be sought and the impact of molecularly classified primary site-directed therapy on patient outcome prospectively validated in trials.

Diagnostic and therapeutic management of cancer of an unknown primary.

Metastatic Cancer of Unknown Primary Site (CUP) accounts for approximately 3% of all malignant neoplasms and is therefore one of the 10 most frequent cancer diagnoses in man. Patients with CUP present with metastatic disease for which the site of origin cannot be identified at the time of diagnosis. It is now accepted that CUP represents a heterogeneous group of malignancies that share a unique clinical behaviour and, presumably, unique biology. The following clinicopathological entities have been recognised: (i) metastatic CUP primarily to the liver or to multiple sites, (ii) metastatic CUP to lymph nodes including the sub-sets involving primarily the mediastinal-retroperitoneal, the axillary, the cervical or the inguinal nodes, (iii) metastatic CUP of peritoneal cavity including the peritoneal papillary serous carcinomatosis in females and the peritoneal non-papillary carcinomatosis in males or females, (iv) metastatic CUP to the lungs with parenchymal metastases or isolated malignant pleural effusion, (v) metastatic CUP to the bones, (vi) metastatic CUP to the brain, (vii) metastatic neuroendocrine carcinomas and (viii) metastatic melanoma of an unknown primary. Extensive work-up with specific pathology investigations (immunohistochemistry, electron microscopy, molecular diagnosis) and modern imaging technology (computed tomography (CT), mammography, Positron Emission Tomography (PET) scan) have resulted in some improvements in diagnosis; however, the primary site remains unknown in most patients, even on autopsy. The most frequently detected primaries are carcinomas hidden in the lung or pancreas. Several favourable sub-sets of CUP have been identified, which are responsive to systemic chemotherapy and/or locoregional treatment. Identification and treatment of these patients is of paramount importance. The considered responsive sub-sets to platinum-based chemotherapy are the poorly differentiated carcinomas involving the mediastinal-retroperitoneal nodes, the peritoneal papillary serous adenocarcinomatosis in females and the poorly differentiated neuroendocrine carcinomas. Other tumours successfully managed by locoregional treatment with surgery and/or irradiation are the metastatic adenocarcinoma of isolated axillary nodes, metastatic squamous cell carcinoma of cervical nodes, or any other single metastatic site. Empirical chemotherapy benefits some of the patients who do not fit into any favourable sub-set, and should be considered in patients with a good performance status.

Weekly docetaxel with either gemcitabine or vinorelbine as second-line treatment in patients with advanced nonsmall cell lung carcinoma: Phase II trials of the Minnie Pearl Cancer Research Network.

BACKGROUND: The current study was conducted to evaluate the feasibility, toxicity, and efficacy of weekly docetaxel when paired with either gemcitabine or vinorelbine as the second-line treatment of patients with advanced nonsmall cell lung carcinoma. METHODS: Patients with progressive nonsmall cell lung carcinoma after one previous chemotherapeutic regimen, an Eastern Cooperative Oncology Group performance status of 0-2, and measurable lesions were eligible for treatment in these Phase II trials. Patients who had not received gemcitabine previously were treated with docetaxel, 30 mg/m(2), and gemcitabine, 800 mg/m(2), both of which were administered intravenously (i.v.) on Days 1, 8, and 15 of a 28-day cycle. If the patients had received gemcitabine as part of first-line therapy, they were treated with docetaxel, 30 mg/m(2), and vinorelbine, 20 mg/m(2) i.v., on Days 1, 8, and 15 of a 28-day cycle. Patients were reevaluated after two courses of treatment, and responding patients continued treatment for six courses or until disease progression. RESULTS: Forty patients were treated with a combination of docetaxel and gemcitabine, and 23 patients received docetaxel and vinorelbine. The docetaxel/gemcitabine combination was reasonably well tolerated, with moderate myelosuppression and a few nonhematologic toxicities reported. The objective response rate was 10%, with a 1-year survival rate of 20%. The docetaxel/vinorelbine combination was found to be poorly tolerated, with Grade 3/4 leukopenia reported in 71% of patients and neutropenic fever reported in 70% of patients despite frequent dose reductions and omission of the Day 15 doses. Enrollment onto this regimen was stopped prematurely due to toxicity, and after no major responses were observed in the first 20 evaluable patients. CONCLUSIONS: The combination of weekly docetaxel/gemcitabine appears to be feasible and relatively well tolerated as second-line treatment in patients with advanced nonsmall cell lung carcinoma, whereas a weekly combination of docetaxel and vinorelbine did not appear to be tolerable at the doses and schedule used in the current study. Neither regimen showed a level of activity that suggested any advantage compared with the results obtained with single-agent docetaxel in this setting.

Paclitaxel-based combination chemotherapy in advanced non-small cell lung cancer.

Paclitaxel has proven to be a useful drug for patients with advanced non-small cell lung cancer (NSCLC). Paclitaxel-based combination chemotherapy, particularly with carboplatin, has become a very popular combination in the US. This article will review the conclusions of several studies regarding paclitaxel-based chemotherapy. The data provide evidence that this therapy produces good palliation and prolongation of survival for patients with NSCLC and is superior to older cisplatin-based chemotherapy. These results in patients with advanced disease have important implications for neoadjuvant and/or adjuvant approaches in patients with lower stages of disease, and several studies are ongoing.

Paclitaxel and carboplatin adjuvant therapy alone or with radiotherapy for resected nonsmall cell lung carcinoma: a feasibility study of the Minnie Pearl Cancer Research Network.

BACKGROUND: The objective of this study was to determine the feasibility and toxicity of paclitaxel and carboplatin given in the adjuvant setting alone for patients with resected Stage IB disease and combined with radiotherapy for patients with resected Stages II and IIIA disease and selected patients with Stage IIIB and IV disease (Revised International System for Staging of Lung Cancer). METHODS: One hundred two patients with resected nonsmall cell lung carcinoma were treated in the postoperative period with 3 courses of paclitaxel 200 mg/m(2) intravenously (i.v.) over 1 hour and carboplatin area under the curve of 6 i.v. every 3 weeks for 3 courses. Patients with Stage IB received no further therapy, and those with higher stages also subsequently received radiotherapy plus concurrent weekly paclitaxel and carboplatin over 6 weeks. The median age was 61 years, with 56 men and 46 women, and the predominant histologic type was adenocarcinoma. Twenty pneumonectomies, 80 lobectomies, and 2 other procedures were performed. Ninety percent of the patients (92 of 102) received all 3 courses of adjuvant paclitaxel and carboplatin (84% received full doses). Seventy-three percent received full doses of radiotherapy and concurrent weekly chemotherapy (49 of 67 patients), and 14 others received greater than 75% of the radiotherapy and concurrent chemotherapy. RESULTS: Toxicity of the chemotherapy was mild with only three hospitalizations for neutropenia and fever and no treatment-related deaths. Severe hypersensitivity occurred in six patients (6%). Concurrent radiation therapy and weekly chemotherapy also was well tolerated with the exception of Grade 3-4 esophagitis observed in 27% (17 of 67 patients). Follow-up was short with a median of 10 months, and 65% of all patients remained progression free. CONCLUSIONS: Three courses of paclitaxel and carboplatin is tolerable, feasible, and can be delivered in most patients in the adjuvant setting. Subsequently, in higher stage patients, concurrent postoperative radiation therapy and weekly paclitaxel and carboplatin is well tolerated and delivered in most patients. Definitive prospective randomized Phase III adjuvant trials are warranted.

Paclitaxel, carboplatin, and long-term continuous infusion of 5-fluorouracil in the treatment of advanced squamous and other selected carcinomas: results of a Phase II trial.

BACKGROUND: The purpose of this study was to evaluate the feasibility, toxicity, and efficacy of the combination of paclitaxel, carboplatin, and long-term continuous infusion 5-fluorouracil (5-FU) in the treatment of advanced squamous carcinomas of various primary sites. METHODS: Patients were eligible for this trial if they had metastatic squamous carcinoma at any site except the lung. In addition, patients with locally advanced squamous carcinoma of the head and neck were eligible, if they were considered unlikely to be cured with combined modality therapy. Sixty patients entered this trial between February 1995 and March 1999; 12 patients (20%) had received 1 previous chemotherapy regimen, whereas 48 patients (80%) were previously untreated. All patients received the following regimen: paclitaxel 200 mg/m(2), 1-hour intravenous infusion, Days 1 and 22; carboplatin area under the concentration-time curve (AUC) 6.0 intravenously, Days 1 and 22; 5-FU 225 mg/m(2)/day, by 24-hour continuous intravenous infusion, Days 1-35. Treatment courses were repeated at 6-week intervals; responding patients continued treatment for a maximum of 4 courses (24 weeks). RESULTS: Thirty-nine of 60 patients treated (65%) had objective responses to this regimen, with 25% complete responses. Twelve patients (22%) remain progression free from 7 to 63 months (median, 35 months) after completion of therapy. Complete responses were observed in squamous carcinomas from various primary sites including head and neck, esophagus, cervix, vagina, anus, and unknown primary. The most frequent Grade 3/4 toxicities observed with this 3-drug regimen included leukopenia (48%), diarrhea (17%), mucositis (28%), and portacath-related events (13%). CONCLUSIONS: The combination of paclitaxel, carboplatin, and long-term infusional 5-FU is feasible, well tolerated, and highly efficacious in patients with advanced squamous carcinomas of various primary sites. This regimen merits further investigation.

Paclitaxel-based three-drug combinations for the treatment of small cell lung cancer: a review of the Sarah Cannon Cancer Center experience.

Between June 1993 and September 1999, 217 patients with small cell lung cancer (SCLC) entered three sequential phase II trials evaluating novel paclitaxel-containing three-drug combination chemotherapy regimens. Patients with limited- or extensive-stage SCLC, no previous treatment, and Eastern Cooperative Oncology Group performance status 0 to 2 were eligible. Trials 1 and 2 evaluated the combination of paclitaxel, carboplatin, and etoposide; in the second trial, doses of paclitaxel and carboplatin were higher than in the first trial. Trial 3 evaluated the combination of paclitaxel, carboplatin, and topotecan. Patients with limited-stage disease received radiation therapy to the primary tumor site and mediastinum, beginning concurrently with the third course of chemotherapy. All patients received four courses of chemotherapy, administered at 21-day intervals. All three regimens were highly active and produced high response rates in both limited- and extensive-stage SCLC. Median survivals for regimens 1, 2, and 3 in extensive-stage patients were 8, 10, and 8.5 months, respectively. Median survivals in limited- stage disease were 16, 20, and 15 months, respectively. Although definitive comparisons of these regimens cannot be made on the basis of sequential trials, the higher-dose paclitaxel/carboplatin/etoposide regimen seemed superior; with this regimen, 4-year survival in limited-stage disease was 23%. Paclitaxel-containing three-drug regimens, as evaluated in these three phase II trials, were feasible and highly active in the first-line treatment of SCLC. Randomized trials will be necessary to definitively evaluate the efficacy of these regimens as compared with traditional platinum/etoposide combinations. Semin Oncol 28 (suppl 4):43-47.

Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl Cancer Research Network phase II trial.

PURPOSE: To evaluate the efficacy and toxicity of docetaxel administered weekly to elderly or poor-performance status patients with advanced breast cancer. PATIENTS AND METHODS: Forty-one patients with advanced breast cancer who were either over the age of 65 or considered to be poor candidates for combination chemotherapy received docetaxel 36 mg/m2 weekly for 6 consecutive weeks, followed by 2 weeks without treatment. The median age of patients in this trial was 74 years, and 73% of patients had one or more visceral sites of metastases. Seventy-five percent of patients received weekly docetaxel as first-line treatment for metastatic breast cancer, and the other 25% received it as second-line treatment. Thirty-six patients were assessable for efficacy, and all patients were assessed for toxicity. RESULTS: A total of 448 doses of weekly docetaxel were administered to 41 patients. Thirteen patients (36%) had objective responses to treatment, and an additional 13 patients (36%) had stable disease or minor response. Median time to progression for responding and stable patients was 7 months (range, 3 to 27 months). Median survival for the entire group was 13 months, with 1- and 2-year actuarial survival rates of 61% and 29%, respectively. Severe neutropenia occurred in only 0.4% of courses, and no other hematologic toxicity was observed. Grade 3/4 fatigue was the most common toxicity, occurring in 20% of patients. CONCLUSION: Weekly docetaxel therapy is active and well tolerated by elderly and/or poor-performance status patients with advanced breast cancer. This treatment can be administered with minimal myelosuppression. Weekly docetaxel provides an additional option for treatment in this difficult subgroup of patients with metastatic breast cancer. Well-tolerated combination regimens containing weekly docetaxel merit evaluation for this patient population.

Weekly docetaxel as a single agent and in combination with gemcitabine in elderly and poor performance status patients with advanced non--small cell lung cancer.

Administering docetaxel weekly at a relatively low dose minimizes myelosuppression and reduces nonhematologic toxicities. In a community-based phase II trial conducted in 39 elderly or poor performance status patients with advanced non--small cell lung cancer, weekly 36 mg/m(2) docetaxel produced a response rate of 20%. The response rate was 26% in patients with an Eastern Cooperative Oncology Group performance status of 0 or 1. Actual 1-year survival was 28% and actuarial 2-year survival was 15%. These results are similar to those achieved with other active single agents. The regimen of weekly docetaxel used was associated with minimal hematologic toxicity. There were no cases of grade 4 leukopenia, febrile neutropenia, toxicity-related hospital admissions, or treatment-related death. Nonhematologic toxicities were also mild, even in performance status 2 patients. In a subsequent phase II trial, a similar group of patients received weekly docetaxel at 30 mg/m(2) plus weekly gemcitabine 800 mg/m(2), both drugs given on days 1, 8, and 15 every 28 days. Preliminary analysis of data for the first 41 patients enrolled show an objective response rate of 29%, with an additional 45% of patients having stable disease. Although 26% of patients missed the day 15 dose of gemcitabine and docetaxel because of myelosuppression, the combination regimen was generally well tolerated. There were no hospitalizations caused by complications of myelosuppression. One patient developed bilateral pulmonary infiltrates, possibly treatment-related, and died of respiratory failure. Further evaluation of weekly docetaxel-based combinations is indicated. Semin Oncol 28 (suppl 9):21-25.

Gemcitabine in the second-line therapy of patients with carcinoma of unknown primary site: a phase II trial of the Minnie Pearl Cancer Research Network.

The purpose of this study was to evaluate the activity of single-agent gemcitabine in previously treated patients with carcinoma of unknown primary site. Between January 1997 and October 1998, 39 patients were enrolled in this multicenter Phase II trial performed in the Minnie Pearl Cancer Research Network. Twenty-seven patients (69%) had adenocarcinoma or poorly differentiated adenocarcinoma; 35 patients (90%) had previously received treatment with chemotherapy regimens containing both a platinum agent and a taxane. Only 21% of patients had ever responded to previous therapy. Gemcitabine 1000 mg/m2 was administered intravenously on days 1, 8, and 15 of each 28-day course. Three of 36 evaluable patients (8%) had partial responses, and 9 patients (25%) had minor responses or stable disease with improved symptoms. The median time to progression for patients with partial responses or stable disease/improved symptoms was 5 months. Treatment was well tolerated, with uncommon grade 3 or 4 toxicity. Gemcitabine produced a low objective response rate in this refractory patient population, although approximately one-third of patients experienced symptomatic improvement. Treatment with gemcitabine was well tolerated. Because gemcitabine has activity against a variety of adenocarcinomas, further evaluation of this agent as part of first-line therapy for patients with carcinoma of unknown primary site is appropriate.

Taxane-based chemotherapy for patients with carcinoma of unknown primary site.

BACKGROUND: The purpose of this study was to determine the long-term follow-up on survival of patients with carcinoma of unknown primary site treated with taxane-based chemotherapy in a multicenter community-based setting. PATIENTS AND METHODS: Patients were treated with three sequential phase II trials between 1995 and 1998 as follows: Study I: paclitaxel 200 mg/m2 intravenously (i.v.) Day 1, carboplatin AUC = 6 i.v. Day 1, and oral etoposide 50 mg daily alternating with 100 mg daily days 1-10 every 3 weeks; Study II: docetaxel 75 mg/m2 i.v. Day 1, cisplatin 75 mg/m2 i.v. Day 1, repeated every 3 weeks; Study III: docetaxel 65 mg/m2 i.v. Day 1, carboplatin AUC 6 i.v. Day 1, repeated every 3 weeks. A total of 144 patients (71 on Study I, 26 on Study II, 47 on Study III) were treated (45% had well differentiated carcinoma, 48% had poorly differentiated carcinomas, and 6% poorly differentiated neuroendocrine tumors). The majority of the patients had multiple sites of metastatic disease. RESULTS: Thirty-six percent of all evaluable patients responded to therapy (27% partial and 9% complete responses). The median survival was 10 months with 1-, 2-, 3-, and 4-year survivals of 42%, 22%, 17%, and 17%, respectively. Follow-up ranges from 11 to 50 months. Women survived significantly longer than men. Thirty-one patients remain alive and 14 are progression-free. The primary toxicity was leukopenia with the carboplatin regimens and nausea and vomiting with the cisplatin regimen. A review of the survival of several large previously reported series of patients was compared to results after taxane-based chemotherapy. A compelling argument is made that chemotherapy is superior to best supportive care alone and that taxane-based chemotherapy is superior to other forms of chemotherapy. However, prospective randomized trials will be necessary to definitively demonstrate the superiority of this treatment compared to other therapies for these patients. CONCLUSION: Taxane-based chemotherapy for patients with carcinoma of unknown primary site appears to be clinically beneficial and is associated with long-term survival for a minority of patients at 2-, 3-, and 4-year follow-up.

Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network.

PURPOSE: To evaluate the toxicity and efficacy of combination chemotherapy with paclitaxel and gemcitabine in patients with advanced transitional-cell carcinoma of the urothelial tract. PATIENTS AND METHODS: Fifty-four patients with advanced unresectable urothelial carcinoma entered this multi-centered, community-based, phase II trial between May 1997 and December 1999. All patients were treated with paclitaxel 200 mg/m(2) by 1-hour intravenous (IV) infusion on day 1 and gemcitabine 1,000 mg/m(2) IV on days 1, 8, and 15; courses were repeated every 21 days. Patients who had objective response or stable disease continued treatment for six courses. RESULTS: Twenty-nine of 54 patients (54%; 95% confidence interval, 40% to 67%) had major responses to treatment, including 7% complete responses. With a median follow-up of 24 months, 16 patients (30%) remain alive and nine (17%) are progression-free. The median survival for the entire group was 14.4 months; 1- and 2-year actuarial survival rates were 57% and 25%, respectively. Seven (47%) of 15 patients previously treated with platinum-based chemotherapy responded to paclitaxel/gemcitabine. Grade 3/4 toxicity was primarily hematologic, including leukopenia (46%), thrombocytopenia (13%), and anemia (28%). Ten patients (19%) required hospitalization for neutropenia and fever, and one patient had treatment-related septic death. CONCLUSION: The combination of paclitaxel and gemcitabine is active and well tolerated in the first- or second-line treatment of patients with advanced transitional-cell carcinoma of the urothelial tract. Response rate and duration compare favorably with those produced by other active, first-line regimens. This regimen should be further evaluated in phase II and III studies, as well as in patients with compromised renal function.

Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer.

Two meta-analyses were conducted to quantify the benefit of combining alpha-IFN to 5FU in advanced colorectal cancer in terms of tumour response and survival. Analyses were based on a total of 3254 individual patient data provided by principal investigators of each trial. The meta-analysis of 5FU +/- LV vs. 5FU +/- LV + alpha-IFN combined 12 trials and 1766 patients. The meta-analysis failed to show any statistically significant difference between the two treatment groups in terms of tumour response or survival. Overall tumour response rates were 25% for patients receiving no alpha-IFN vs. 24% for patients receiving alpha-IFN (relative risk, RR = 1.02), and median survivals were 11.4 months for patients receiving no alpha-IFN vs. 11.5 months for patients receiving alpha-IFN (hazard ratio, HR = 0.95). The meta-analysis of 5FU + LV vs. 5FU + alpha-IFN combined 7 trials, and 1488 patients. This meta-analysis showed an advantage for 5FU + LV over 5FU + alpha-IFN which was statistically significant in terms of tumour response (23% vs. 18%; RR = 1.26;P = 0.042), and of a borderline significance for overall survival (HR = 1.11;P = 0.066). Metastases confined to the liver and primary rectal tumours were independent favourable prognostic factors for tumour response, whereas good performance status, metastases confined to the liver or confined to the lung, and primary tumour in the rectum were independent favourable prognostic factors for survival. We conclude that alpha-IFN does not increase the efficacy of 5FU or of 5FU + LV, and that 5FU + alpha-IFN is significantly inferior to 5FU + LV, for patients with advanced colorectal cancer.