Statistical controversies in clinical research: should schedules of tumor size assessments be changed?

BACKGROUND: Time to progression (TTP) is often used as a primary end point in phase II clinical trials. Since the actual date of nadir and progression is never known, most calculated TTP are overestimated. This study evaluates the imprecision on the estimate of TTP under two hypothetical tumor kinetic settings and various assessment schedules. DESIGN: A two-component tumor growth model was used to account for treatment effect assuming exponential decay for tumor shrinkage and linear growth for progression. Evolution of tumor burden (TB) was modelized according to two scenarios using either a cytotoxic or a cytostatic agent and several assessment schedules. TB, nadir, progression and TTP were simulated for each visit schedule. RESULTS: For cytotoxic agents, our model predicted response at 1.5 weeks, a TB at nadir of 40.2 mm (starting from 100 mm) occurring at 6.7 weeks and true progression at 11.2 weeks with a TB of 48.2 mm. For cytostatic agents, our model predicted no response, a TB at nadir of 77 mm occurring at 9.2 weeks and true progression at 19.4 weeks with a TB of 92 mm. Depending on the assessment schedule, estimated TTP was increased from 0.8 to 36.8 weeks and from 0.6 to 28.6 weeks when compared with the true TTP and varied from 5.2% to 298% and from 1.66 to 109.58% when compared with the true TB at progression for cytotoxic and cytostatic agents, respectively. Our model further shows that for cytotoxic agents, evaluation of TB every 6 weeks is optimal to capture the true nadir, the time to nadir, the true progression and the true TTP, whereas for cytostatic agents, this evaluation is optimal every 10 weeks. CONCLUSIONS: Our results emphasize the importance to estimate the effects of tested drugs on tumor shrinkage before design any phase II clinical trials to choose optimal TB evaluation's timing.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

Trastuzumab duration effects within patient prognostic subgroups in the PHARE trial.

BACKGROUND: At 42.5 months of median follow-up, PHARE failed to show that 6 was non-inferior to 12 months of adjuvant trastuzumab. From the results of PHARE, questions remain regarding whether the magnitude of benefit derived from 1 year is sufficient to justify its systematic use for different patient subgroups. METHODS: Treatment effects were evaluated according to various tumour characteristics, and the multivariate Cox proportional hazards regression models were carried out on metastases-free survival (MFS) in the 12 months control arm. A prognostic score was defined providing the identification of patient categories with similar risks. The 6-month arm was used as a validation set in order to test for heterogeneity. This study is registered at clinicaltrials.gov, number NCT00381901. RESULTS: A total of 261 metastatic events were observed and four prognostic groups were defined: very low, low, intermediate and high risk in the 12-month arm. The corresponding 3-year MFS rates were 98.3%, 95.8%, 90.4% and 78.4% in the four prognostic groups, respectively. In the 6-month arm, the 3-year MFS rates were 98.3%, 94.2%, 85.7% and 74.8% in the four prognostic groups, respectively. CONCLUSION: In the very low-risk group, the potential absolute benefit of standard duration of trastuzumab was small enough to indicate that optimal standard treatment might be clinically questionable. On the other hand, the 3-year metastasis occurrence rates strongly support the need for a search of a more efficient treatment in the low-, intermediate- and high-risk groups.

Tumor marker kinetics predict outcome in patients with relapsed disseminated non-seminomatous germ-cell tumors.

BACKGROUND: An early serum tumor marker (TM) decline during chemotherapy was shown to independently predict survival in patients with poor-prognosis disseminated non-seminomatous germ-cell tumors (NSGCTs). The aim of this study was to assess whether a TM decline (TMD) also correlates with the outcome in the salvage setting. PATIENTS AND METHODS: Data regarding 400 patients with progressive or relapsed disseminated NSGCTs after first-line chemotherapy prospectively accrued onto two phase III clinical trials were obtained. Serum alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (hCG) were assessed at baseline and after 6 weeks of chemotherapy. A total of 297 patients, 185 and 112 in the training and validation sets, with initially abnormal TMs for whom a change from baseline could be established were used for this analysis. RESULTS: An unfavorable decline in either AFP or hCG was predictive of progression-free survival (PFS) [hazard ratio, HR = 2.15, (95% CI 1.48-3.11); P < 0.001; 2-year PFS rate: 50% versus 26%] as was the Lorch prognostic score (LPS). In the multivariate analysis, an unfavorable TMD, stratified based on the LPS, was an independent adverse prognostic factor for PFS and OS. CONCLUSION: An unfavorable TMD during the first 6 weeks after chemotherapy is associated with a poorer outcome in patients with relapsed disseminated NSGCTs.

Prediction of early death among patients enrolled in phase I trials: development and validation of a new model based on platelet count and albumin.

BACKGROUND: Selecting patients with 'sufficient life expectancy' for Phase I oncology trials remains challenging. The Royal Marsden Hospital Score (RMS) previously identified high-risk patients as those with ≥ 2 of the following: albumin <35 g l(-1); LDH > upper limit of normal; >2 metastatic sites. This study developed an alternative prognostic model, and compared its performance with that of the RMS. METHODS: The primary end point was the 90-day mortality rate. The new model was developed from the same database as RMS, but it used Chi-squared Automatic Interaction Detection (CHAID). The ROC characteristics of both methods were then validated in an independent database of 324 patients enrolled in European Organization on Research and Treatment of Cancer Phase I trials of cytotoxic agents between 2000 and 2009. RESULTS: The CHAID method identified high-risk patients as those with albumin <33 g l(-1) or ≥ 33 g l(-1), but platelet counts ≥ 400.000 mm(-3). In the validation data set, the rates of correctly classified patients were 0.79 vs 0.67 for the CHAID model and RMS, respectively. The negative predictive values (NPV) were similar for the CHAID model and RMS. CONCLUSION: The CHAID model and RMS provided a similarly high level of NPV, but the CHAID model gave a better accuracy in the validation set. Both CHAID model and RMS may improve the screening process in phase I trials.

A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802).

BACKGROUND: This multicenter adjuvant phase III trial evaluated the addition of irinotecan to LV5FU2 in colon cancer patients at high risk of relapse. PATIENTS AND METHODS: A total of 400 patients with histologically proven primary colon cancer with postoperative N1 detected by occlusion/perforation or N2 were randomised to: A-LV5FU2 [leucovorin 200 mg/m(2), 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m(2) bolus, 600 mg/m(2) 22-h continuous infusion, days 1 and 2] or B-LV5FU2 + IRI (irinotecan 180 mg/m(2) 90-min infusion day 1 + LV5FU2) fortnightly for 12 cycles. Primary end point was disease-free survival (DFS). RESULTS: Median follow-up was 63 months. Significantly more T4 tumours and 15 or more positive lymph nodes were observed in arm B. 5-FU relative dose intensity (RDI) was >0.80 for 94% and 77% in arms A and B, respectively (P < 0.001). Irinotecan RDI was >0.80 for 70% patients. There were more grades 3 and 4 neutropenia in arm B (4% versus 28%, P < 0.001). The 3-year DFS was 60% [95% confidence interval (CI) 53% to 66%] and 51% (95% CI 44% to 58) in arms A and B, respectively. No difference was observed [hazard ratio (HR) = 1.12, 95% CI 0.85-1.47, P = 0.42] even when adjusted for prognostic factors (adjusted HR = 0.98, 95% CI 0.74-1.31, P = 0.92). The 5-year overall survival (OS) was 67% (95% CI 59% to 73%) and 61% (95% CI 53% to 67%) in arms A and B, respectively. CONCLUSION: Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.

A comparison of model choices for the Continual Reassessment Method in phase I cancer trials.

Determination of the maximum tolerated dose (MTD) is the main objective of phase I trials. Trials are typically carried out with restricted sample sizes. Model-based approaches proposed to identify the MTD (including the Continual Reassessment Method or CRM) suppose a simple model for the dose-toxicity relation. At this early stage of clinical development, the true family of models is not known and several proposals have been done. Asymptotic convergence of the recommendation to the true MTD can be obtained with a one-parameter model even in case of model misspecification. Nevertheless, operating characteristics with finite sample sizes can be largely affected by the choice of the model. In this paper, we evaluate and compare several models in a simulation framework. This framework includes a large class of dose-toxicity relations against which to test the competing models, an 'optimal' method that provides efficient non-parametric estimates of the probability of dose limiting toxicity to serve as a benchmark and as a graphic representation. In particular we explore the use of a one-parameter versus a two-parameter model, we compare the power and the logistic models and finally we investigate the impact of dose recoding on the operating characteristics. Comparisons are carried out with both a likelihood approach and a Bayesian approach for model estimations. We show that average performances of a one-parameter model are superior and that the power model has good operating characteristics. Some models can speed up dose escalation and lead to more aggressive designs. We derive some behavior related to the choice of model and insist on the use of simulations under several scenarios before the initiation of each new trial in order to determine the best model to be used.

Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases.

PURPOSE: To assess the rate of R(0) resection of liver metastases achieved after chemotherapy with FOLFIRINOX. PATIENTS AND METHODS: Patients with histologically proven primary colorectal cancer and bidimensionally measurable liver metastasis, not fully resectable based on technical inability to achieve R(0) resection, but potentially resectable after tumor reduction, were given FOLFIRINOX: oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), bolus fluorouracil 400 mg/m(2) and fluorouracil 46-h continuous IV infusion 2,400 mg/m(2), every 2 weeks for a maximum of 12 cycles. RESULTS: Thirty-four patients were enrolled. Response rate before surgery was 70.6% (95%CI: 52.5-84.9). Twenty-eight patients (82.4%) underwent hepatic resection and nine achieved R(0) resection [26.5% (95% CI: 12.9-44.4%)]. The rate of clinical complete remission after surgery was 79.4%. Two-year overall survival was 83%. The most frequent grade 3 or 4 toxicities were neutropenia (64.8%), diarrhea (29.4%), fatigue (23.5%), abdominal cramps (14.7%), neuropathy and nausea (11.8% each), and AST/ALT elevation (14.7/11.8%). Only one patient experienced febrile neutropenia, four patients withdrew due to toxicity and no toxic death was observed. CONCLUSION: FOLFIRINOX, with an acceptable toxicity profile, shows a high response rate in liver metastases from colorectal cancer. The rate of hepatic resection in patients initially not resectable, is attractive and warrants further assessment of this regimen in randomized studies compared to standard regimens.

Peritoneal fluid cytokines and the differential diagnosis of benign and malignant ovarian tumors and residual/recurrent disease examination.

This study aimed to assess the potential value of peritoneal fluid cytokine examination for the differential diagnosis of ovarian tumors and for evaluating residual or recurrent disease after treatment. The cytokines that are commonly elevated in ovarian cancer, VEGF, IL-6, bFGF, IL-8 and M-CSF, and a reference ovarian tumor marker, CA 125, were measured in peritoneal fluids of 53 previously untreated patients with epithelial ovarian cancer, 18 ovarian cancer patients after surgical treatment and chemotherapy, and 17 patients with benign epithelial ovarian tumors. Non-parametric statistical analysis of data was performed. Ovarian cancer peritoneal fluids, as compared to peritoneal fluids of patients with benign ovarian tumors, contained significantly higher concentrations of IL-6, VEGF and CA 125, and significantly lower concentrations of bFGF and M-CSF, but only the levels of IL-6 and VEGF were significantly higher in peritoneal fluids of stage I and II ovarian cancer patients than of patients with benign ovarian conditions. IL-6 at the cutoff level of 400 pg/mL discriminated benign and malignant ovarian tumors with 92% sensitivity and 60% specificity, while VEGF at the cutoff of 400 pg/mL had 90% sensitivity and 80% specificity. At the cutoff level of 1200 pg/mL, IL-6 had 84% sensitivity and 87% specificity. A radical decrease in local cytokine and CA 125 levels in patients after treatment was independent of therapy outcome. IL-6 and VEGF measurements in peritoneal fluids might be useful for the differential diagnosis of malignant and benign ovarian conditions, but not for residual or recurrent disease examination.

Measuring agreement for ordered ratings in 3 x 3 tables.

OBJECTIVES: When two raters consider a qualitative variable ordered according to three categories, the qualitative agreement is commonly assessed with a symmetrically weighted kappa statistic. However, these statistics can present paradoxes, since they may be insensitive to variations of either complete agreements or disagreements. METHODS: Agreement may be summarized by the relative amounts of complete agreements, partial and maximal disagreements beyond chance. Fixing the marginal totals and the trace, we computed symmetrically weighted kappa statistics and we developed a new statistic for qualitative agreements. Data sets from the literature were used to illustrate the methods. RESULTS: We show that agreement may be better assessed with the unweighted kappa index, kappa(c), and a new statistic zeta, which assesses the excess of maximal disagreements with respect to the partial ones, and does not depend on a particular weighting system. When zeta is equal to zero, maximal and partial disagreements beyond chance are equal. With its estimated large sample variance, we compared the values of two contingency tables. CONCLUSIONS: The (kappa(c), zeta) pair is sensitive to variations in agreements and/or disagreements and enables locating the difference between two qualitative agreements. The qualitative agreement is better with increasing values of kappa(c) and zeta.

Consumption of dairy produce and alcohol in a case-control study of breast cancer.

In a French case-control study of 1,010 breast cancer cases and 1,950 controls with nonmalignant diseases, the risk of breast cancer was found to be positively associated with frequency of cheese consumption and the level of fat in the milk consumed. A negative association was found between frequency of yogurt consumption and the risk of breast cancer. No association was found between the consumption of butter and the risk of breast cancer. The positive association between a daily consumption of alcohol and the risk of breast cancer previously reported was not altered when dairy produce consumption was taken into account.

Relating genotype and phenotype in breast cancer: an analysis of the prognostic significance of amplification at eight different genes or loci and of p53 mutations.

Breast cancer heterogeneity can be related directly to its variability at the genetic level. Thus, tumor genotyping could be a valuable approach to define breast tumor subtypes. It has been shown that it is possible to delineate subgroups of breast tumors according to specific sets of DNA amplifications. The aim of the present work was to study the prognostic significance of these DNA amplifications. We studied DNA amplification at eight genes or loci (AIB1, CCND1, EMS1, ERBB2, FGFR1, MDM2, MYC, and RMC20C001) as well as p53 mutations in a series of 640 breast cancer patients who had not received presurgical therapy and analyzed the correlations with survival DNA amplification was assessed by Southern blotting and was scored positive when exceeding three to five copies. Mutations in the p53 gene were searched by four-color fluorescent single. strand conformational polymorphism, using an automated sequencer. Of the nine genetic alterations tested, four (CCND1, EMS1, FGFR1, and p53 mutations) showed a significant association with reduced disease-free (DFS) and/or overall survival (OVS) in the unselected set of patients by univariate test. Correlations for p53 were found only when selecting mutations in exons 5 or 7. Analysis of node-negative and -positive subgroups of patients showed that MDM2 amplification and p53 mutations bore prognostic significance in node-negative patients, whereas amplification of CCND1, EMS1, and FGFR1 correlated with poor outcome in node-positive patients. Multivariate analysis on an unselected set of patients retained significance for the amplification of EMS1, FGFR1, and MDM2 with DFS, of CCND1 with OVS, and of RMC20C001 with both DFS and OVS. Interestingly, stratified analysis according to nodal status confirmed results obtained in the univariate tests: significance of MDM2 amplification and p53 mutations in node-negative and that of CCND1, EMS1, and FGFR1 in node-positive patients. We also observed an association between the number of genetic alterations observed in a tumor and poor prognosis. Patients with two or more amplified loci had a worsened outcome. Strongly correlating coamplifications such as CCND1 and FGFR1, as well as ERBB2 and MYC, were associated with a significant reduction of patient survival, thus indicating cooperative effects. Our data support the idea that genetic alterations in breast cancer are not only helpful for phenotyping purposes, but can also represent powerful prognostic indicators in the clinical practice.

Adequate locoregional treatment for early breast cancer may prevent secondary dissemination.

PURPOSE: To analyze different events that determine event-free survival (EFS) in a randomized trial on adjuvant radiotherapy in early breast cancer patients with more than 15 years of follow-up evaluation. PATIENTS AND METHODS: The trial included 960 patients with a unilateral, operable breast cancer. Surgery consisted of a modified radical mastectomy. The trial compared three arms, as follows: preoperative radiotherapy, postoperative radiotherapy, and no adjuvant treatment. Events were analyzed by a competing-risk approach. A proportional hazards multiple regression model was used to analyze the effects of radiotherapy on the risk of distant metastasis. Similar analyses were performed separately for node-negative [N(-)] and node-positive [N(+)] patients in the two groups that did not include preoperative radiotherapy. RESULTS: Radiotherapy produced a fivefold decrease of the risk of local recurrence (P < .0001). In N(+) patients, postoperative radiotherapy decreased the risk of distant dissemination (relative risk, 0.63). When local recurrence was introduced in the model as a time-dependent covariate, this factor was predictive of distant dissemination (P < .0001) and nullified the effect of postoperative radiotherapy. This finding suggests that the decrease of distant metastases was related to the prevention of local recurrence. A similar effect was found in models that used overall survival as an end point. CONCLUSION: This study shows that postmastectomy radiotherapy in N(+) breast cancer patients may decrease the distant metastasis rate by preventing local recurrences and thus avoiding secondary dissemination.

Competing events determining relapse-free survival in limited small-cell lung carcinoma. The French Cancer Centers' Lung Group.

PURPOSE: We report results in terms of relapse-free survival (RFS), obtained in patients with limited small-cell lung carcinoma (SCLC) treated by four consecutive alternating protocols, using a competing risk approach with local recurrences, distant metastases, and death unrelated to cancer as competing events. PATIENTS AND METHODS: Two hundred two patients with limited SCLC were included in four consecutive protocols alternating radiotherapy and chemotherapy (CT). The alternating schedule consisted of six cycles of CT (doxorubicin, etoposide [VP16213], and cyclophosphamide [CAVP16], plus methotrexate in the first protocol; cisplatin replaced methotrexate in the other three protocols) and three courses of thoracic radiotherapy at a total dose of 45, 55, 65, and 61 Gy in the four consecutive protocols, respectively (accelerated hyperfractionation was used in the first course of the fourth protocol). A 1-week rest followed each CT cycle and each course of radiotherapy. Seventy-six percent of patients were in complete remission at the end of the induction treatment. RFS variables were determined according to a model assuming competing risks to define the first cause of failure (local disease, distant metastasis, or intercurrent death). RESULTS: No significant differences were observed between the four treatment groups. Overall results showed a 2-year cumulative incidence rate of failure of 75%. When analyzed, the first cause of failure was local recurrence only, 33%; distant only, 25%; distant and local simultaneously, 9%; and intercurrent death, 8%. CONCLUSIONS: The methodology of competing risks allowed an unequivocal description of first events in limited SCLC. The extent of the local problem has been relatively overshadowed by the use of conventional descriptive methods.

Primary mediastinal nonseminomatous germ cell tumors: results of modern therapy including cisplatin-based chemotherapy.

PURPOSE: Primary mediastinal nonseminomatous germ cell tumors (NSGCT) are uncommon neoplasms and clinically and biologically distinct from other germ cell tumors (GCT). We describe the clinical and biologic features of these patients and evaluate the results of treatment during the cisplatin era. PATIENTS AND METHODS: Between 1976 and 1993, 38 patients with mediastinal NSGCT received cisplatin-based chemotherapy as part of their primary treatment. Twenty-nine of them were initially treated at the Institut Gustave-Roussy (IGR), VillejuiF, France, and nine were referred for salvage treatment. RESULTS: Of the 29 patients initially treated at IGR, 11 (39%) had metastasis. A complete response (CR) to therapy was obtained in 19 of 29 patients (66%) after chemotherapy and surgery. Ten patients (34.5%) have remained free of disease with a median follow-up of 89 months. All patients who did not achieve a CR died of disease. The 2-year overall survival rate for the IGR patients is 45% and the 2-year disease-free survival is 37%. Only the presence of extrapulmonary metastasis was of prognostic significance in the univariate analysis (P = .0095). None of the 20 patients who required salvage therapy is currently disease-free. Five patients developed and subsequently died of a hematologic malignancy at an interval range of 1 to 47 months from treatment of mediastinal NSGCT. Cytogenetic analysis of leukemic cells found an isochromosome of the short arm of chromosome 12 (12p) in two cases. The incidence of leukemia was 21% in patients who attained a CR. CONCLUSION: Primary mediastinal NSGCT is a clinical and biologic entity that should be distinguished from other GCT. About 40% of these patients can envisage long-term survival with modern therapy that includes cisplatin-based chemotherapy followed by surgical resection of residual masses. New strategies are required for patients who do not attain a CR. Predictive factors and improvement in therapy are required for mediastinal NSGCT-associated leukemia.

Prognostic factors in children with localized malignant nonseminomatous germ cell tumors.

PURPOSE: Prognostic factors were studied in children older than 1 year who were treated with chemotherapy for extracranial localized malignant non seminomatous germ cell tumors. PATIENTS AND METHODS: Data from two consecutive protocols were pooled. The TGM 85 (1985-1989) protocol consisted of alternating courses of cyclophosphamide, dactinomycin and vinblastine, bleomycin, and cisplatin at a dose of 100 mg/m(2) per course. The TGM 90 (1990-1994) protocol was initiated with carboplatin 400 mg/m(2) substituted for cisplatin as the only modification to the previous protocol. RESULTS: We examined alpha-fetoprotein (AFP) levels, disease stage, and primary site and identified three prognostic groups. Patients with a poor prognosis had either an AFP level >/= 10,000 ng/mL or stage III disease and a sacrococcygeal or mediastinal primary site; such patients represented 46% of the patient population and experienced a 43% 3-year failure-free survival rate and a 77% overall survival rate. Patients with a good prognosis had an AFP level less than 10,000 ng/mL, stage I or II disease, and a testicular, ovarian, perineal, or retroperitoneal primary site; such patients represented 22% of the patient population and experienced no treatment failures. The other patients were classified in the intermediate prognosis group and represented 37% of the patient population, with an 81% 3-year failure-free survival rate and a 92% overall survival rate. CONCLUSION: Initial AFP level, disease stage, and primary site are the most important prognostic factors in this analysis. Prognostic models for pediatric germ cell tumors should allow the stratification of patients for a risk-adapted approach to treatment.

High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables.

PURPOSE: To identify prognostic variables for response and survival in male patients with relapsed or refractory germ cell tumors treated with high-dose chemotherapy (HDCT) and hematopoietic progenitor cell support. PATIENTS AND METHODS: Three hundred ten patients treated with HDCT at four centers in the United States and Europe were retrospectively evaluated. Univariate and multivariate analysis of patient, disease, and treatment characteristics were used for comparisons of response rates and failure-free survival (FFS). RESULTS: The actuarial FFS rate was 32% at 1, 30% at 2, and 29% at 3 years. Multivariate analysis identified progressive disease before HDCT, mediastinal nonseminomatous primary tumor, refractory or absolute refractory disease to conventional-dose cisplatin, and human chorionic gonadotropin (HCG) levels greater than 1,000 U/L before HDCT as independent adverse prognostic variables for FFS after HDCT. These variables were used to identify patients with good, intermediate, and poor prognoses. In the good-risk category, the predicted FFS rate at 2 years was 51%, compared with 27% and 5% in the intermediate-risk and poor-risk categories (P < .001). The increased risk for treatment failure was due to both a significantly lower rate of favorable responses and a significantly higher rate of relapses. Within the prognostic categories, the particular HDCT regimen or higher dosages of carboplatin or etoposide did not have a significant influence on treatment outcome. CONCLUSION: Prognostic variables for treatment response after HDCT can be identified. The proposed prognostic model might help to optimize the use of HDCT in germ cell tumors and warrants validation in future trials.

Assessment of health status over time by Prevalence and Weighted Prevalence functions: Interface in R.

The importance of evaluating complications and toxicity during and following treatment has been stressed in many publications. In most studies, these endpoints are presented descriptively and summarized by numbers and percentages but descriptive methods are rarely sufficient to evaluate treatment-related complications. Pepe and Lancar developed Prevalence and Weighted Prevalence functions which take into account the duration and the severity of complication unlike conventional methods of survival analysis or competing risks which are limited to the time to first event. The purpose of this paper is to describe features and use of two R functions, main.preval.func and main.wpreval.func, which were designed for the analysis of survival adjusted for quality of life. These functions compute descriptive statistics, survival and competing risks analysis and especially Prevalence and Weighted Prevalence estimations with confidence intervals and associated test statistics. The use of these functions is illustrated by several examples.

Prognostic factors and survival in patients with metastatic renal cell carcinoma treated with chemotherapy or interferon-alpha.

Prognostic factors and survival were analysed in 295 patients with metastatic renal cell carcinoma (MRCC), treated with either chemotherapy (1975-1990) or interferon (IFN) (1983-1990). The 3-year survival was 8 and 24% in the chemotherapy and IFN groups, respectively (P < 0.001). In the univariate analysis, age < or = 60 years, prior nephrectomy, more than 1 year since initial diagnosis and treatment for metastatic disease, ECOG performance status 0 or 1, absence of liver metastases, lower erythrocyte sedimentation rate (first hour), and < or = 10% weight loss, within the past 6 months, were correlated with improved survival. Sedimentation rate, performance status and weight loss remained independent prognostic factors from the results of a Cox regression analysis. Three prognostic groups were identified from a combination of these factors. In the poor and intermediate risk groups, no significant survival difference was observed between patients treated with chemotherapy and those treated with IFN. The 3-year survival estimates for good risk patients were 15 and 48% in the chemotherapy and IFN groups, respectively. Therefore, in MRCC, sedimentation rate, performance status and weight loss are easily assessable and reproducible prognostic variables for the identification of risk groups. We hypothesise that IFN may increase survival in good risk patients, but is as ineffective as chemotherapy in poor risk patients with MRCC.