2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on first line/second and further lines of treatment in advanced disease.

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study.

BACKGROUND: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). RESULTS: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.

Patient satisfaction with GP-led melanoma follow-up: a randomised controlled trial.

BACKGROUND: There are no universally accepted guidelines for the follow-up of individuals with cutaneous melanoma. Furthermore, to date, there have been no randomised controlled trials of different models of melanoma follow-up care. This randomised controlled trial was conducted to evaluate the effects of GP-led melanoma follow-up on patient satisfaction, follow-up guideline compliance, anxiety and depression, as well as health status. METHODS: A randomised controlled trial of GP-led follow-up of cutaneous melanoma was conducted over a period of 1 year with assessment by self-completed questionnaires and review of general practice-held medical records at baseline and 12 months later. It took place in 35 general practices in North-east Scotland. Subjects were 142 individuals (51.4% women 48.6% men; mean (s.d.) age 59.2 (15.2) years previously treated for cutaneous melanoma and free of recurrent disease. The intervention consisted of protocol-driven melanoma reviews in primary care, conducted by trained GPs and supported by centralised recall, rapid access pathway to secondary care and a patient information booklet. The main outcome measure was patient satisfaction measured by questionnaire. Secondary outcomes were adherence to guidelines, health status measured by Short Form-36 and the Hospital Anxiety and Depression Scale. RESULTS: There were significant improvements in 5 out of 15 aspects of patient satisfaction during the study year in those receiving GP-led melanoma follow-up (all P

Factors contributing to the time taken to consult with symptoms of lung cancer: a cross-sectional study.

OBJECTIVES: To determine what factors are associated with the time people take to consult with symptoms of lung cancer, with a focus on those from rural and socially deprived areas. METHODS: A cross-sectional quantitative interview survey was performed of 360 patients with newly diagnosed primary lung cancer in three Scottish hospitals (two in Glasgow, one in NE Scotland). Supplementary data were obtained from medical case notes. The main outcome measures were the number of days from (1) the date participant defined first symptom until date of presentation to a medical practitioner; and (2) the date of earliest symptom from a symptom checklist (derived from clinical guidelines) until date of presentation to a medical practitioner. RESULTS: 179 participants (50%) had symptoms for more than 14 weeks before presenting to a medical practitioner (median 99 days; interquartile range 31-381). 270 participants (75%) had unrecognised symptoms of lung cancer. There were no significant differences in time taken to consult with symptoms of lung cancer between rural and/or deprived participants compared with urban and/or affluent participants. Factors independently associated with increased time before consulting about symptoms were living alone, a history of chronic obstructive pulmonary disease (COPD) and longer pack years of smoking. Haemoptysis, new onset of shortness of breath, cough and loss of appetite were significantly associated with earlier consulting, as were a history of chest infection and renal failure. CONCLUSION: For many people with lung cancer, regardless of location and socioeconomic status, the time between symptom onset and consultation was long enough to plausibly affect prognosis. Long-term smokers, those with COPD and/or those living alone are at particular risk of taking longer to consult with symptoms of lung cancer and practitioners should be alert to this.

The impact of primary tumour origins in patients with advanced oesophageal, oesophago-gastric junction and gastric adenocarcinoma--individual patient data from 1775 patients in four randomised controlled trials.

BACKGROUND: It is unclear if differential chemotherapy effects exist on overall survival (OS), response rate (RR) and toxicity depending on primary tumour origin [oesophageal versus oesophago-gastric junction (OGJ) versus gastric adenocarcinoma]. PATIENTS AND METHODS: A total of 2110 patients were enrolled in four randomised controlled trials (RCTs) assessing fluoropyrimidine +/- platinum-based chemotherapy. This analysis used individual patient data and restricted to patients with adenocarcinoma who received one or more dose of chemotherapy. Gastric origin was the control in comparisons of tumour origin. RESULTS: Of the 2110 patients randomised, 1775 (84%) patients had adenocarcinoma with oesophageal (n = 485), OGJ (n = 457) and gastric (n = 833) origins. The median OS was 9.5 months in oesophageal, 9.3 months in OGJ and 8.7 months in gastric cancer (P = 0.68). RR was 44.1% in oesophageal, 41.1% in OGJ and 35.6% in gastric cancers (P = 0.11 and 0.27, respectively, compared with gastric cancer on multivariate analysis). Toxicity composite end point occurred in 46%, 47% and 45% in oesophageal, OGJ and gastric cancers, respectively (P = 0.85 and 0.62 compared with gastric). CONCLUSIONS: In our large multicentre RCT dataset, no significant differences were demonstrated on multivariate analyses in OS, RR and toxic effects among patients with advanced oesophageal, OGJ and gastric adenocarcinoma. Future RCTs should not exclude oesophageal adenocarcinoma.

Identification of a BALB/c H-2Ld gene by DNA-mediated gene transfer.

Gene transfer and immunoselection were used in the identification of a BALB/c genomic clone containing an H-2Ld gene (clone 27.5). Transformation of thymidine kinase-negative C3H mouse L cells with the cloned 27.5 DNA together with the herpes simplex virus tk gene produced transformants expressing Ld molecules detected by radioimmune assay with monoclonal hybridoma antibodies to Ld antigens. The foreign Ld gene products expressed by cloned mouse L cell transformants were shown to be virtually indistinguishable from BALB/c spleen Ld molecules by two-dimensional electrophoretic analysis of H-2Ld immunoprecipitates. These results indicate that the genomic clone 27.5 contains a functional BALB/c H-2Ld gene and demonstrate the usefulness of this approach for identifying the gene products encoded by cloned genes which are members of a multigene family. Furthermore, the ability to place cell-surface recognition molecules on the surfaces of foreign cells provides a powerful opportunity for functional analyses of these molecules.

Scientific knowledge and clinical authority in dentistry: James Sim Wallace and dental caries.

Once the germ theory had become generally accepted within medicine, the importance of experimental science to the improvement of medical practice could no longer be reasonably doubted. However, clinicians still sought to retain control of how knowledge that had originated in the laboratory was interpreted and applied within practical diagnostics and therapeutics. Thus how practitioners incorporated new scientific knowledge into their medical discourse and practice is a matter for careful empirical inquiry. James Sim Wallace, born in Renfrewshire in 1869 and a graduate in medicine from the University of Glasgow, was a leading figure in British dentistry throughout the first half of the twentieth century. Through an examination of his voluminous writings, we explore how the new 'chemico-parasitical' theory of dental caries was accommodated within dentists' understanding of oral hygiene. The paper also looks at the controversies that surrounded the application of the vitamin theory to the problems of rickets and dental caries, focusing on the contentious interaction between Sim Wallace and his colleagues, on the one hand, and the eminent physiologists May and Edward Mellanby, on the other.

James Willocks and the innovation of fetal cephalometry.

James Willocks (1928-2004), a Glasgow obstetrician, was an important pioneer of obstetric ultrasound and the originator of the first clinically useful technique of fetal cephalometry. He collaborated with Tom Duggan, an engineer, who designed and built an electronic cephalometer to be used in conjunction with a Kelvin Hughes industrial flaw detector. Working in the Royal Maternity Hospital, Willocks was able to measure the biparietal diameter to an accuracy of better than 2mm. This major innovation enabled fetal growth in the third trimester to be accurately charted and thus greatly improved the detection of placental insufficiency, as well as the management of antepartum haemorrhage, hypertension and other complications of late pregnancy.

Total energy expenditure and the level of physical activity correlate with plasma leptin concentrations in five-year-old children.

Leptin, the product of the ob gene, is a hormone secreted by adipocytes that is known to decrease food intake and increase energy expenditure in ob/ob mice. In humans, variants in the OB gene have not been detected and very little is known about the action of leptin on food intake and energy expenditure, although circulating leptin concentrations are positively correlated to body fat stores. The purpose of this study was to assess the relationship between fasting plasma leptin concentrations and energy expenditure in 123 5-yr-old Pima Indian children (67 males/76 females). Body composition was assessed by isotopic water dilution (18O) whereas total energy expenditure (TEE) and resting metabolic rate (RMR) were measured using doubly labeled water and indirect calorimetry, respectively. The physical activity level was calculated as the ratio of TEE:RMR. Plasma leptin concentrations were positively correlated to percent body fat (r = 0.84, P < 0.0001), but were similar in boys and girls after adjusting for percent body fat. Most importantly, we found that, independent of the percentage of body fat, plasma leptin concentrations correlated with TEE (in absolute values, r = 0.37, P < 0.0001, or adjusted for body size r = 0.42; P < 0.0001) and with physical activity level (r = 0.26, P < 0.01), but not RMR. These results suggest that, as in animal models, leptin plays a role in energy expenditure in humans.

Replication-defective chimeric helper proviruses and factors affecting generation of competent virus: expression of Moloney murine leukemia virus structural genes via the metallothionein promoter.

Two chimeric helper proviruses were derived from the provirus of the ecotropic Moloney murine leukemia virus by replacing the 5'long terminal repeat and adjacent proviral sequences with the mouse metallothionein I promoter. One of these chimeric proviruses was designed to express the gag-pol genes of the virus, whereas the other was designed to express only the env gene. When transfected into NIH 3T3 cells, these helper proviruses failed to generate competent virus but did express Zn2+-inducible trans-acting viral functions needed to assemble infectious vectors. One helper cell line (clone 32) supported vector assembly at levels comparable to those supported by the Psi-2 and PA317 cell lines transfected with the same vector. Defective proviruses which carry the neomycin phosphotransferase gene and which lack overlapping sequence homology with the 5' end of the chimeric helper proviruses could be transfected into the helper cell line without generation of replication-competent virus. Mass cultures of transfected helper cells produced titers of about 10(4) G418r CFU/ml, whereas individual clones produced titers between 0 and 2.6 X 10(4) CFU/ml. In contrast, defective proviruses which share homologous overlapping viral sequences with the 5' end of the chimeric helper proviruses readily generated infectious virus when transfected into the helper cell line. The deletion of multiple cis-acting functions from the helper provirus and elimination of sequence homology overlapping at the 5' ends of helper and vector proviruses both contribute to the increased genetic stability of this system.

Efficacy and tolerability of chemotherapy in elderly patients with advanced oesophago-gastric cancer: A pooled analysis of three clinical trials.

The aim of this study was to determine the benefits of chemotherapy for oesophago-gastric cancer (OGC) in patients 70 years and above (> or =70) in comparison to younger patients. 1080 patients were enrolled into three randomised controlled trials assessing fluorouracil-based combination chemotherapy. Patients received either a platinum-containing regimen (ECF, MCF), PVI 5-FU (protracted venous infusion of 5-fluorouracil)+/-mitomycin C (MMC), or FAMTX. Of the 1080 patients randomised, 257 (23.8%) were aged > or =70 years. There were no significant differences in the incidence of grades 3/4 toxicity between the two cohorts. Objective and symptomatic response rates, failure-free and overall survival were not significantly different. In a multivariate analysis, independent prognostic factors for survival were performance status and locally advanced disease, not age. Patients > or =70 years with OGC obtained similar benefits from palliative chemotherapy with respect to symptomatic response, tumour regression and survival, without increased toxicities.

Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer.

BACKGROUND: In phase II trials, paclitaxel has been shown to have antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). However, the survival and quality-of-life (QOL) benefits of paclitaxel used as a single agent compared with supportive care alone have not been assessed in a randomized clinical trial. METHODS: A total of 157 patients with stage IIIB or IV NSCLC who had received no prior chemotherapy were randomly assigned to receive either best supportive care alone (78 patients) or paclitaxel plus supportive care (79 patients). Paclitaxel was administered as a 3-hour intravenous infusion every 3 weeks. Supportive care included palliative radiotherapy and supportive therapy with corticosteroids, antibiotics, analgesics, antiemetics, transfusions, and other symptomatic therapy as required. The primary end point of the study was survival. Time to disease progression, response rate, adverse events, and QOL were secondary end points. RESULTS: Pretreatment characteristics were evenly distributed between the two arms. Survival was statistically significantly better in the paclitaxel plus supportive care arm than in the supportive care alone arm (two-sided P =.037) (median survival = 6.8 months versus 4.8 months). Cox multivariate analysis showed paclitaxel plus supportive care to be statistically significantly associated with improved survival (two-sided P =.048). QOL was similar for both treatment arms, except for the functional activity score of the Rotterdam Symptom Checklist, where QOL data statistically significantly favored the paclitaxel plus supportive care arm (two-sided P =.043). CONCLUSION: The addition of paclitaxel to best supportive care significantly improved survival and time to disease progression compared with best supportive care in patients with advanced NSCLC and may improve some aspects of QOL.

Genomic instability at the BUB1 locus in colorectal cancer, but not in non-small cell lung cancer.

Genomic instability is observed in the majority of human tumors. Dysregulation of the mitotic spindle checkpoint is thought to be one of the mechanisms that facilitate aneuploidy in tumor cells. Mutations in the mitotic spindle checkpoint kinase BLUB1 cause a dominant negative disruption of the spindle, leading to chromosome instability in cancer cell lines. However, little is known about chromosome 2q14, the genomic region containing BUB1, in human tumors. The BUB1 locus was evaluated in 32 colorectal cancer (CRC) and 20 non-small cell lung cancer (NSCLC) primary tumors using a panel of seven microsatellite repeats for 2q, two CA repeats in BUB1, and gene mutation analysis. The 2q locus was allelically stable in NSCLC but relatively unstable in colorectal primary tumors (20 of 32 tumors, 62.5%). In addition, 14.5% of CRC patients displayed instability within BUB1. Previously described BUB1 mutations and polymorphisms were rare (< 1%) in the CRC or NSCLC tumors. Our data demonstrate 2q and BUB1 allelic instability in CRC and indicate that mutations in BUB1 are rare causes of chromosome instability in CRC or NSCLC. Additional investigations may shed light on the mechanistic impact of the mitotic spindle checkpoint pathway in colorectal tumor initiation and progression.

Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin.

PURPOSE: So far there are no published data on optimal duration of chemotherapy for advanced non-small-cell lung cancer (NSCLC); six or more courses are usually recommended. We have carried out a multicenter randomized trial comparing three versus six courses of chemotherapy. PATIENTS AND METHODS: Patients with stage IIIb or IV NSCLC were randomized at start of treatment to receive either three or six courses of mitomycin 8 mg/m(2) (courses 1, 2, 4, and 6), vinblastine 6 mg/m(2), and cisplatin 50 mg/m(2) (MVP) every 21 days. Treatment was stopped early in both arms for progressive disease or unacceptable toxicity. Key end points were overall survival, duration of symptom relief, and quality-of-life assessment using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 with lung cancer-specific module QLQ-LC13. RESULTS: Three hundred eight patients were randomized. Seventy-two percent of the 155 patients randomized to three courses completed treatment. In the 153 patients randomized to six courses, 73% completed three courses and 31% six courses. Median survival was 6 versus 7 months, respectively, and 1-year survival 22% versus 25% (P =.2). Median duration of symptom relief was 4.5 months (both arms), and 8% versus 18% had continuing symptom relief (P =.4). Quality-of-life parameters were the same or improved for patients randomized to only three courses, including significantly decreased fatigue (P =.03) and a trend toward decreased nausea and vomiting (P =.06). CONCLUSION: Our findings show no evidence for additional clinical benefit by continuing MVP chemotherapy beyond three courses. This challenges current orthodoxy of six courses or more. Further trials addressing duration of chemotherapy are now warranted, particularly with newer chemotherapy schedules.

Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer.

PURPOSE: We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) (ECF) with the combination of mitomycin, cisplatin, and PVI 5-FU (MCF) in previously untreated patients with advanced esophagogastric cancer. PATIENTS AND METHODS: Five hundred eighty patients with adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma were randomized to receive either ECF (epirubicin 50 mg/m(2) every 3 weeks, cisplatin 60 mg/m(2) every 3 weeks and PVI 5-FU 200 mg/m(2)/d) or MCF (mitomycin 7 mg/m(2) every 6 weeks, cisplatin 60 mg/m(2) every 3 weeks, and PVI 5-FU 300 mg/m(2)/d) and analyzed for survival, response, toxicity, and quality of life (QOL). RESULTS: The overall response rate was 42.4% (95% confidence interval [CI], 37% to 48%) with ECF and 44.1% (95% CI, 38% to 50%) with MCF (P =.692). Toxicity was tolerable, and there were only two toxic deaths. ECF resulted in more grade 3/4 neutropenia and grade 2 alopecia, but MCF caused more thrombocytopenia and plantar-palmar erythema. Median survival was 9.4 months with ECF and 8.7 months with MCF (P =.315); at 1 year, 40.2% (95% CI, 34% to 46%) of ECF and 32.7% (95% CI, 27% to 38%) of MCF patients were alive. Median failure-free survival was 7 months with both regimens. Global QOL scores were better with ECF at 3 and 6 months. CONCLUSION: This study confirms response, survival, and QOL benefits of ECF observed in a previous randomized study. The equivalent efficacy of MCF was demonstrated, but QOL was superior with ECF. ECF remains one of the reference treatments for advanced esophagogastric cancer.

High-dose melphalan and autologous bone marrow transplantation as consolidation in previously untreated myeloma.

PURPOSE: We report the results of intensive chemotherapy with high-dose melphalan (HDM) following conventional-dose cytoreductive chemotherapy in previously untreated patients with myeloma. PATIENTS AND METHODS: From 1986 to 1991, 53 previously untreated patients with myeloma received HDM 200 mg/m2 plus methylprednisolone 1.5 g daily (MP) for 5 days with autologous bone marrow transplantation (ABMT) after cytoreductive chemotherapy. RESULTS: At the time of HDM administration, responses to induction therapy were complete remission (CR) in nine patients, partial remission (PR) in 38, and no response (NR) in six. Following HDM, all but one patient responded, with 40 patients achieving a CR (75%). There was one treatment-related death following HDM. The median time to reach a WBC count more than 1,000/microL and platelet count more than 25,000/microL was 19 days (range, 13 to 30) and 24 days (range, 15 to 55), respectively. The median duration of response has not been reached at 20 months, and it is significantly longer for patients in CR than for those in PR (P < .025). Currently, with a median follow-up duration of 31 months (range, 6 to 58), 12 patients are dead and 40 are alive, and the estimated probability of survival at 54 months is 63%. Multivariate analysis found hemoglobin (Hb) more than 10 g/dL (P = .012), and stage A disease (P = .001) at diagnosis to be favorable indicators for survival. CONCLUSION: Myeloma patients who are able to receive HDM plus ABMT following conventional chemotherapy achieve a high proportion of CRs, which may be associated with prolonged survival.

High-dose melphalan for multiple myeloma: long-term follow-up data.

PURPOSE: To present long-term follow-up data of patients with myeloma treated with high-dose melphalan HDM, including an assessment of prognostic factors. PATIENTS AND METHODS: Between November 1981 and April 1986, 63 previously untreated patients with multiple myeloma received HDM 140 mg/m2 without autologous bone marrow transplantation. RESULTS: The overall response rate was 82% (51 of 62), with 32% (20 of 62) patients entering complete remission (CR). The median duration of response was 18 months, and six patients remain alive and free from disease progression at 60+ to 84+ months. Improvements in quality of life associated with remission were immediate in terms of pain grade (89% of patients) and performance status (92%), and later in terms of bone healing (29%). Currently, at a median follow-up duration of 74 months (range, 63 to 100) since HDM, 23 patients are alive with a median survival duration of 47 months, and 35% of patients are expected to be alive at 9 years. Apart from early-stage disease, no factors were found to predict long-term survival. No second malignancies or other late side effects have been recorded. CONCLUSION: Single-agent HDM without autologous bone marrow transplantation is a feasible therapeutic option in myeloma, and is associated with a high objective response rate, relatively long remission durations, and good symptom control.

Royal Marsden phase III trial of fluorouracil with or without interferon alfa-2b in advanced colorectal cancer.

PURPOSE: Phase II studies have shown that the combination of interferon alfa-2b (IFN) and fluorouracil (5-FU) is active in patients with metastatic colon cancer. This study was designed to investigate whether treatment with the combination of IFN and 5-FU could improve the response rate, duration of response, or survival compared with treatment with 5-FU alone. PATIENTS AND METHODS: Patients with histologically confirmed advanced colorectal cancer were randomized to receive 5-FU 750 mg/m2/d by continuous infusion for 5 consecutive days followed by weekly bolus 5-FU 750 mg/m2 either with or without IFN 10 MU subcutaneously three times weekly. Treatment was continued until disease progression or unacceptable toxicity for up to 12 months. RESULTS: Radiologic response was observed in 26 of 106 assessable patients (25%): 10 of 52 (19%) in the group that received 5-FU plus IFN (all partial responses [PRs]) and 16 of 54 (30%) in the 5-FU-alone group (three complete responses [CRs] and 13 PRs) (P = .21). There was similarly no significant difference between the two groups in progression-free survival (median, 3 months), 1-year survival, or overall survival (median, 8 months). However, patients who received IFN did experience significantly more toxicity in the form of leukopenia (P = .013), lymphopenia (P = .01), depression (P = .014), and alopecia (P = .002), and were significantly more likely to be withdrawn due to adverse events (P = .003). There were four toxic deaths, all of which occurred in patients who had received IFN. CONCLUSION: At the doses and schedules used in this study, IFN affords no benefit to 5-FU in terms of response and survival and significantly increases toxicity for patients with advanced colorectal cancer.

Phase II study of continuous infusion fluorouracil and interferon alfa-2b in the palliation of malignant neuroendocrine tumors.

PURPOSE AND METHODS: Twenty-four patients with rapidly progressive neuroendocrine tumors were treated with a new regimen of continuous infusion fluorouracil for 20 weeks (200 mg/m2/d) together with interferon alfa-2b (5 MU three times per week). Maintenance interferon alfa at the same dose was continued after the initial 20-week period. RESULTS: Of 15 patients with carcinoid tumors, seven (47%) had an objective response, with a median duration of 20.5 months (range, 8.5 to 41), and five (33%) had stabilization of disease for between 3.5 and 42 months. Improvement in symptoms was reported by 10 patients (67%). Three early deaths occurred, all in patients with advanced disease. Of nine patients with neuroendocrine tumors other than carcinoid, three (33%) had an objective response that lasted 2.5 to 24.5 months, and five had disease stabilization for between 2.5 and 16 months. CONCLUSION: These data, particularly in respect to carcinoid tumors, are encouraging, especially since serious complications from treatment were limited. This regimen is not generally toxic, is well tolerated, and offers useful palliation and symptom control in patients with disease that does not respond to simple pharmacologic manipulations.

Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer.

PURPOSE: We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin, and methotrexate (FAMTX) in previously untreated patients with advanced esophagogastric cancer. PATIENTS AND METHODS: Two hundred seventy-four patients with adenocarcinoma or undifferentiated carcinoma were randomized and analyzed for survival, tumor response, toxicity, and quality of life (QL). RESULTS: The overall response rate was 45% (95% confidence interval [CI], 36% to 54%) with ECF and 21% (95% CI, 13% to 29%) with FAMTX (P = .0002). Toxicity was tolerable and there were only three toxic deaths. The FAMTX regimen caused more hematologic toxicity and serious infections, but ECF caused more emesis and alopecia. The median survival duration was 8.9 months with ECF and 5.7 months with FAMTX (P = .0009); at 1 year, 36% (95% CI, 27% to 45%) of ECF and 21% (95% CI, 14% to 29%) of FAMTX patients were alive. The median failure-free survival duration was 7.4 months with ECF and 3.4 months with FAMTX (P = .00006). The global QL scores were better for ECF at 24 weeks, but the remaining QL data showed no differences between either arm of the study. Hospital-based cost analysis on a subset of patients was similar for each arm and translated into an increment cost of $975 per life-year gained. CONCLUSION: The ECF regimen results in a survival and response advantage, tolerable toxicity, better QL and cost-effectiveness compared with FAMTX chemotherapy. This regimen should now be considered the standard treatment for advanced esophagogastric cancer.