How to measure the net benefit of treatment?

Estimating net benefit makes possible to clarify the basis for therapeutic decisions on an individual and collective level. This clarification is a must in shared medical decision-making and evidence-based medicine. Numerous methods are available, although none outweigh the others. The complex specifications of net benefit estimation should be tailored to the expectations of the central stakeholder, patient or society, and the unlimited range of potential contexts. The challenges, limitations, constraints and skills to be acquired by all stakeholders were discussed by the participants of the round table. They are described in this article, enabling key messages and guidelines to be presented. The essential priority is to ensure that all stakeholders receive the required training.

[Meta-analysis based on individual patient data: example of advanced colorectal cancer]. / Méta-analyses sur données individuelles: exemple des cancers colorectaux métastatiques.

The authors mention the existing methods to perform meta-analysis, and show that meta-analysis based on individual patient data (IPD meta-analyses) are the most reliable. Taking the example of 4 successive meta-analysis of clinical trials in advanced colorectal cancer, they illustrate the possibilities of IPD meta-analysis. They conclude that meta-analysis are a powerful tool not only to confirm small differences between treatment modalities, but also to generate hypothesis, to perform exploratory subgroup analysis, and to study potential surrogate endpoints.

[Management of biliary tract carcinomas]. / Prise en charge thérapeutique des cancers des voies biliaires et de la vésicule biliaire.

Biliary tract carcinomas are rare tumours, counting for less than 5% of cancer. Biliary tract carcinomas comprise gallbladder carcinoma and cholangiocarcinoma, which arise from the intrahepatic or extrahepatic bile ducts. These tumours have a poor prognosis, with a median survival of 6 months for advanced disease. Surgical resection is the only potentially curative therapy. Adjuvant treatement by chemotherapy, radiotherapy or radio-chemotherapy might be an option after surgery, however no standard therapy is define. For advanced disease, despite progress of palliative chemotherapy, there is no standard therapy.

Fixed-dose rate gemcitabine in elderly patients with advanced pancreatic cancer: an observational study.

Pancreatic cancer represents one of the most lethal cancers and treatment of advanced disease remains palliative. Age-related physiologic changes can increase chemotherapy's toxicity but the use of gemcitabine in elderly patients has not been properly evaluated. This observational prospective study evaluated patients aged 70 years and over, receiving gemcitabine for an advanced pancreatic carcinoma. Gemcitabine was delivered according to the usual fixed-dose rate schedule (1000mg/(m(2)week) over 100min, every week, 3 weeks over 4). Thirty-nine patients (median age 74) were treated between November 1999 and August 2004. Twenty-three patients (59%) received 100% of the planned dose-intensity. Grade 3-4 toxicities were neutropenia (38% of patients), thrombocytopenia (28%), anemia (18%) and alopecia (18%). Four partial responses (10%) and 13 stabilizations (33%) were observed. Eight patients (20%) experienced clinical benefit. The median progression free and overall survivals were 7 and 10 months, respectively. Gemcitabine can be administered in selected elderly patients.

Endpoints and surrogate endpoints in colorectal cancer: a review of recent developments.

PURPOSE OF REVIEW: The purpose of this review is to discuss recently published work on endpoints for early and advanced colorectal cancer, as well as the statistical approaches used to validate surrogate endpoints. RECENT FINDINGS: Most attempts to validate surrogate endpoints have estimated the correlation between the surrogate and the true endpoint, and between the treatment effects on these endpoints. The correlation approach has made it possible to validate disease-free survival and progression-free survival as acceptable surrogates for overall survival in early and advanced disease, respectively. SUMMARY: The search for surrogate endpoints will intensify over the coming years. In parallel, efforts to either standardize or extend the endpoints or both will improve the reliability and relevance of clinical trial results.

Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician's perspective.

Surrogate endpoints in oncology research and practice have garnered increasing attention over the past two decades. This activity has largely been driven by the promise surrogate endpoints appear to hold: the potential to get new therapies to seriously ill patients more rapidly. However, uncertainties abound. Even agreeing upon a definition of a "valid" surrogate endpoint has not been a straightforward exercise; this article begins by highlighting differences in how this term has been previously captured and applied, as well as laying out the basic criteria essential for its application in advanced colorectal cancer. Ideally, these elements include (but are not limited to) ease of measurement, rapid indication of treatment effect, and, most importantly, reliable and consistent prediction of the true impact of a treatment on the ultimate outcome of interest: overall survival. The strengths and weaknesses of current potential surrogate endpoints in advanced colorectal cancer, including performance status, carcinoembryonic antigen plasma level, overall response rate, time to progression, and disease-free survival, are each considered in turn. Finally, limitations of surrogate endpoints in the clinical setting, including challenges in extrapolation to new therapies, and the incomplete provision of information about potential adverse effects, are discussed. Work remains to be done between physicians and statisticians to bridge the gap between that which is statistically demonstrable and that which will be clinically useful.The term ;surrogate endpoint' was virtually unknown by most oncologists 15 years ago. A search in PubMed [http://www.ncbi.nlm.nih.gov] based on the words ;surrogate and cancer' shows that more than 2000 papers were published in medical journals in the last 20 years, with a dramatic increase of interest in the last five years. Interestingly, the same trend is observed when the words ;surrogate and heart' are entered into PubMed, suggesting that the issue of surrogate endpoints goes beyond the field of oncology, although the frequency of discussion varies (Figure 1; note different y-axis scales for oncology and cardiology).The goal of the present paper is to discuss the main issues surrounding surrogate endpoints from a clinician's point of view, using as an example surrogate endpoints of overall survival (OS) in advanced colorectal cancer (ACC).

Stents for palliation of obstructive metastatic colon cancer: impact on management and chemotherapy administration.

HYPOTHESIS: The more rapid and less complicated recovery after palliative stent insertion compared with surgery may theoretically facilitate the early administration of chemotherapy. DESIGN: A retrospective study. SETTING: University tertiary care referral center. PATIENTS: From January 1, 1996, to September 15, 2005, 58 patients with obstructing colon cancer and nonresectable synchronous metastases were treated with self-expanding colonic metallic stent (SEMS) (n = 31) or surgery (n = 27). MAIN OUTCOME MEASURES: Comparison of the use of SEMS and emergency surgery as palliative measures to treat obstructing colon cancer with special reference to time to chemotherapy administration and survival. RESULTS: Mortality and morbidity were comparable between the 2 groups. Median hospital stay was shorter after SEMS insertion than after surgery (median, 8.0 vs 13.5 days, respectively; P < .01). Incidence of stoma creation was lower in patients treated with SEMS than in patients treated with surgery (6% vs 37%, respectively; P = .02). The median time to chemotherapy administration was shorter after SEMS insertion than after surgery (14.0 vs 28.5 days, respectively; P = .002). Three patients with SEMS and 0 patients in the surgical group underwent a curative colonic and hepatic resection after downstaging by chemotherapy (P = .27). Two patients (6%) with SEMS and undergoing chemotherapy had a tumor perforation requiring emergency surgery. There was no difference in survival between the 2 groups (median survival, 13.7 months for SEMS vs 11.4 months for surgery; P = .19). CONCLUSIONS: Insertion of SEMS should be the first step to treat obstructing colon cancer with nonresectable synchronous metastases because it allows chemotherapy to be administered earlier, may increase the resectability rate of metastases, and favorably impacts survival. The risk of tumor perforation while receiving chemotherapy requires attention.

A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer.

BACKGROUND: Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. METHODS: A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. RESULTS: Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. CONCLUSION: There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.

Adenocarcinomas of unknown primary (ACUP) of the mediastinum mimicking lymphoma: CT findings at diagnosis and follow-up.

OBJECTIVE: To describe the computed tomography (CT) features at diagnosis and after treatment of adenocarcinoma of unknown primary (ACUP) mimicking lymphoma of the mediastinum. METHODS: Fifteen patients with pathologically proven ACUP and with primarily mediastinal involvement were initially referred to the Hematologic Department of our institution with a suspected diagnosis of lymphoma, and accounted for our study population. Presenting symptoms and baseline biological values were analyzed. All thoraco-abdominal CT studies were reviewed for the location and size of the mediastinal involvement and associated findings. Follow-up chest CT was performed in 14 patients after radiotherapy, chemotherapy or surgical treatment. RESULTS: The most frequent CT feature was a large anterior and middle mediastinal mass (67%), with no calcification. Associated findings included the presence of lung nodules (40%), compression of large mediastinal vessels (33%) and pleural effusion (27%). Follow-up CT, performed in 14 cases, suggested partial or complete responses in 7 patients (50%) 4 weeks after the treatment onset. CONCLUSIONS: Mediastinal ACUP is a differential diagnosis of large mediastinal masses and is frequently associated with lung nodules and mediastinal vascular compression.

Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials.

PURPOSE: Adjuvant therapy of colorectal cancer with oral fluorinated pyrimidines is attractive because of its ease of administration and good tolerability. The purpose of this meta-analysis is to assess the survival and disease-free survival benefits of treating patients after surgical resection of a primary colorectal tumor with oral fluoropyrimidines for 1 year. PATIENTS AND METHODS: This meta-analysis was performed on individual data from three randomized trials conducted by the Japanese Foundation for Multidisciplinary Treatment for Cancer involving a total of 5,233 patients with stages I to III colorectal cancer. RESULTS: The overall hazard ratio in favor of oral therapy was 0.89 for survival (95% CI, 0.80 to 0.99; P =.04), and 0.85 for disease-free survival (95% CI, 0.77 to 0.93; P <.001). Thus oral therapy reduced the risk of death by 11% and the risk of recurrence or death by 15%. There was no significant heterogeneity between trials, nor did the benefit of oral therapy depend on tumor stage (I, II, or III), tumor site (rectum or colon), patient age, or patient sex. CONCLUSION: Oral fluoropyrimidines improve disease-free survival and survival of patients after resection of early-stage colorectal cancer. These observations support the use of these agents alone after resection of early-stage disease, as well as further testing of oral agents in combination with new drugs that have recently shown antitumor activity in advanced colorectal cancer.

Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial.

PURPOSE: This randomized, 2 x 2 factorial study compared a semimonthly (LVFU2) with a monthly (FULV) regimen of fluorouracil and leucovorin and 24 versus 36 weeks of each regimen as adjuvant treatment of patients with stage II (Dukes' B2) and III (Dukes' C) colon cancer. PATIENTS AND METHODS: LVFU2 was administered semi-monthly for 2 consecutive days as dl- or l-leucovorin (200 or 100 mg/m2, respectively) as a 2-hour infusion, followed by a 400 mg/m2 FU bolus and 600 mg/m2 of FU as a 22-hour continuous infusion. FULV was administered monthly for 5 consecutive days as a 15-minute infusion of dl- or l-leucovorin, followed by 400 mg/m2 of FU as a 15-minute infusion. RESULTS: A total of 905 patients were randomly assigned. The median follow-up was 41 months. Disease-free survival was similar between the LVFU2 and FULV groups (127 v 124 events; hazard ratio [HR] = 1.04; P =.74) and between 24 and 36 weeks of therapy (128 v 123 events; HR = 0.94; P =.63). Analysis of overall survival showed a slight excess in the number of deaths in LVFU2 compared with FULV (73 v 59), but this difference was not statistically significant (HR = 1.26; 95% confidence interval, 0.90 to 1.78; P =.18). The most commonly observed grade 3 to 4 toxicities were neutropenia, diarrhea, and mucositis. Toxicities were significantly lower in the LVFU2 group (all toxicities, P <.001). CONCLUSION: Our data confirm that LVFU2 is less toxic than FULV. At a median follow-up of 41 months, no statistically significant difference could be detected in disease-free or overall survival between the treatment groups or treatment durations.

FDG PET in patients with cancer of an unknown primary.

BACKGROUND: This prospective study was undertaken to address the capacity of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) to determine the primary tumour site of carcinomas with unknown primary site. PATIENTS AND METHODS: Twenty-five patients with metastases from adenocarcinoma or undifferentiated carcinoma of unknown primary site (CUP) were included prospectively. For all patients, extensive imaging was unsuccessful in localizing the primary site. Patients received 370 MBq of 18F-FDG intravenously, and whole-body images were acquired 60 min after injection. All hot spots that could not be attributed to a metastatic site were considered as the primary tumour. The evaluation of FDG PET data was based on clinical and radiological outcome or surgery if indicated. RESULTS: Twenty-four patients were eligible for analysis. All known metastases were visualized. In six patients, FDG PET showed a primary tumour site which was confirmed by follow-up or surgery. In five patients, the primary tumour site was suggested by FDG PET but not confirmed by clinical outcome. No primary tumour was found in the other patients, with a mean follow-up of 15 months. CONCLUSION: In our series, FDG PET allowed the identification of primary tumour site in one quarter of patients with CUP (6/24). We conclude that FDG PET has a place in the initial staging of these patients.

Contribution of meta-analyses to the evaluation of treatments for advanced colorectal cancer.

In the last decade, the Meta-Analysis Group in Cancer (formerly Advanced Colorectal Cancer Meta-Analysis Project) has systematically used a meta-analytic to reassess the efficacy and toxicity of various fluoropyrimidine regimens in advanced colorectal cancer, as well as to investigate related questions, such as the relation between tumor response and survival. In this paper, the basic methodology of meta-analysis is reviewed and the findings of seven successive meta-analyses conducted between 1989-2000 by the Meta-Analysis Group in Cancer are summarized. The interested reader can refer to the statistical appendix for details on the methodology used for all meta-analyses.

Progress in the medical treatment of advanced colorectal cancer.

Despite recent progress made in screening, prevention and adjuvant treatment of colorectal cancer, a large proportion of patients with this disease develop local recurrences or distant metastases. The management of these patients requires a multidisciplinary approach. Surgery must be performed whenever possible for metastases confined to the liver or lung. However, in most cases, chemotherapy and supportive care are the only feasible treatments. This review describes the research carried out in this field through randomized trials and meta-analyses aimed at optimizing the efficacy of front-line chemotherapy.

Direct treatment costs for patients with lung cancer from first recurrence to death in france.

OBJECTIVE: To determine the direct treatment cost of lung cancer management from progression to death from the viewpoint of the hospital. METHODS: A retrospective descriptive study was performed. Data from 100 patients who died of lung cancer and who had received treatment from four different types of hospital were used; the hospitals were public hospitals (teaching and non-teaching), private not-for-profit cancer centres, and private hospitals. Resource utilisation/cost data collected included the cost of diagnosis of the recurrence, the cost of hospitalisations or day care treatments and ambulatory surgery. All resources were valued in 2001 euros. RESULTS: In France, the average cost per patient was euro12 518 for the whole group (78% with non-small cell lung cancer [NSCLC], and 22% with small cell lung cancer [SCLC]), euro13 969 for patients with NSCLC and euro7369 for patients with SCLC. The higher cost of treatment in patients with NSCLC is explained by longer survival and duration of chemotherapy. In patients with NSCLC, 51% of the total cost corresponded to terminal care, with up to seven lines of chemotherapy. In patients with SCLC, the costs of diagnosis and terminal care each represented 41% of the total cost. CONCLUSIONS: The cost of treatment of recurrence of lung carcinoma is high, and is related to the number of lines of chemotherapy and the use of radiotherapy and surgery.

[Criteria and endpoints in advanced prostate cancer]. / Critères d'évaluation des thérapeutiques dans les cancers de la prostate avancés.

In castrate-refractory prostate cancers, main efficacy endpoints are progression free survival for phase-II trials and overall survival for phase-III trials. However, various progression criteria have been used, and overall survival may become more difficult to impact due to the recent approval of more effective drugs. PSA is useful in clinical practice, provided it is interpreted with caution, but cannot be used as a surrogate endpoint in clinical trials. Finally, circulating tumor cells represent a promising area of development.

[Randomised phase II trials in oncology]. / Les essais de phase II randomisés en cancérologie.

The purpose of phase II trials is to identify signals in favor of the efficacy of a drug in development. The main pitfall of a phase II study is to conclude by error that a drug has no activity, leading to a stop in the development of a drug which has a real efficacy. In oncology, more and more phase II trials are randomised, even though there are still numerous non randomised studies. Randomisation allows some control on the risk of patient selection bias, inherent to non randomised trials. This bias consists of recruiting by chance a population of patients with high risk or on the contrary low risk of response to the experimental treatment. The present paper describes the various types of randomised phase II trials, their principles, strengths and limits.

Progression-free survival is a surrogate for survival in advanced colorectal cancer.

PURPOSE: The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer is overall survival (OS), but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. We investigated whether progression-free survival (PFS) could be considered a valid surrogate for OS in advanced colorectal cancer. PATIENTS AND METHODS: Individual patient data were available from 10 historical trials comparing fluouracil (FU) + leucovorin with either FU alone (1,744 patients) or with raltitrexed (1,345 patients) and from three validation trials comparing FU + leucovorin with or without irinotecan or oxaliplatin (1,263 patients). Correlation coefficients were estimated in historical trials between the end points of PFS and OS, and between the treatment effects on these end points. Treatment effects on OS were predicted in validation trials, and compared with the observed effects. RESULTS: In historical trials, 1,760 patients (57%) had progressed or died at 6 months, and 1,622 (52%) had died at 12 months. The rank correlation coefficient between PFS and OS was equal to 0.82 (95% CI, 0.82 to 0.83). The correlation coefficient between treatment effects on PFS and on OS ranged from 0.99 (95% CI, 0.94 to 1.04) when all trials were considered to 0.74 (95% CI, 0.44 to 1.04) after exclusion of one highly influential trial. In the validation trials, the observed OS hazard ratios were within the 95% prediction intervals. A hazard ratio of 0.77 or lower in terms of PFS would predict a benefit in terms of OS. CONCLUSION: PFS is an acceptable surrogate for OS in advanced colorectal cancer.