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Background: The dynamic effects of immune checkpoint inhibitors (ICIs) are a challenge when designing and analysing data in non-proportional hazards (PH) scenarios. Herein, we present the risk of making type II errors, affecting pharmacotherapeutic development when methods that assume constant effects are applied., Patients and Methods: Individual patient data from six clinical trials (KEYNOTE-062/061, IMvigor211, CA184-143 y CheckMate-057/037) were extracted. The most relevant time-varying effects were examined using the Royston-Parmar spline model (RPSM), time-driven analyses and weighted log-rank and Renyi tests., Results: The RPSM yields an appropriate fit in non-PH contexts, enabling dynamic descriptions of the hazard rate, and time-varying differences of overall survival (OS)/progression-free survival. In the KEYNOTE-061, CheckMate-057 and 037 trials, 12-, 18-, and 24-month OS rates were higher with immunotherapy (differences of some 10%) (P-value <0.05). In KEYNOTE-062, CA184-043 and IMvigor-211 trials, OS rate differences were significant for past 20 months. Flemming-Harrington and Renyi tests with late weighting (e.g. with ρ-value = 0 and γ-value = 1) captured the existence of significant differences on all curves. The Cox models and log-rank tests were inefficient at detecting the effect., Conclusion: This analysis highlights the risk of declaring studies with ICIs negative, despite associating substantial OS benefits. Effort and consensus are needed with respect to methodology to design and evaluate trials with ICIs in non-PH settings., Competing Interests: Conflict of interest statement A.S-.A. reports collaborating professionally with Roche Pharma S.A. E.C. reports receiving travel grants from AstraZeneca, Spain, BMS, MSD and Roche, Spain and serving a consulting/advisory role for AstraZeneca, BMS, MSD and Roche, all outside of the scope of this work. F.A.M. reports no conflict of interest. P.J-.F. reports receiving travel grants from Ipsen and serving a consulting/advisory role for Roche, Celgene, Bristol, MSD, Mylan, Rovi and LeoPharma, all outside of the scope of this work. A.C-.B. reports receiving travel grants from Ipsen, Spain, Roche, Spain and Novartis, Spain and serving a consulting/advisory role for Roche, Merck, Rovi, LeoPharma, Pfizer and Esteve, all outside of the scope of this work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Sarcomatoid renal cell carcinoma (sRCC) represents a rare form of renal cell carcinoma marked by an aggressive biology, poor prognosis and little benefit from anti-angiogenic targeted therapy. More promising results come from the recent therapeutic strategy based on immune checkpoint inhibitor (ICI) combinations., Materials and Methods: For this meta-analysis, we searched MEDLINE/PubMed, the Cochrane Library and American Society of Medical Oncology (ASCO) Meeting abstracts for phase II or III randomised clinical trials. Data extraction was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. The hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) with the relative 95% confidence intervals were extracted from studies. Summary HRs were calculated using random- or fixed-effects models, depending on the heterogeneity of the included studies., Results: Four studies were selected for final analysis, including 467 patients (226 treated in with ICI combinations and 241 received sunitinib in the control arms). ICI-based combinations were associated with an improved PFS and OS compared with sunitinib, with a reduction of more than 40% of progression (HR = 0.56; p < 0.0001) and mortality (HR = 0.56; p = 0.001) risk. Moreover, ICI-based combinations are associated with a objective response rate (ORR) of more than 50% (versus 20% with sunitinib), corresponding to a doubled risk of achieving an ORR compared with controls (relative risk [RR] = 2.15; p < 0.00001). Finally, immunotherapy significantly increased the possibility to obtain complete responses (RR = 8.15, p = 0.0002) with an incidence of 11%., Conclusion: Our data support the efficacy of ICI-based combinations for sRCC therapy, redefining the first-line treatment., Competing Interests: Conflict of interest statement R.I. reports serving as a consultant or playing an advisory role for Pfizer, Janssen, Sanofi, IPSEN, MSD and Novartis and receiving travel accommodations from Pfizer, Janssen and Ipsen. C.C. reports serving as a consultant of IPSEN and Merk. E.B. reports receiving funds from the Italian Association for Cancer Research AIRC-IG20583, the International Association for Lung Cancer (IASLC), the LILT (Lega Italiana per la Lotta contro i Tumori) and Fondazione Cariverona; receiving fee for speak’ and travel’ from MSD, AstraZeneca, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis and Roche; receiving consultant fee from Roche and Pfizer and receiving institutional research grants from Astra-Zeneca and Roche. S.B. reports serving as a consultant or playing an advisory role for Pfizer, BMS, MSD, Roche, Astellas, Janssen, Ipsen, Bayer, Merck and AstraZeneca and reports receiving travel accommodations from Pfizer, BMS, Roche, Astellas, Janssen, Ipsen, AstraZeneca and Exelixis. G.P. reports serving as a consultant or playing an advisory role for AstraZeneca, Bayer, BMS, Ipsen, MSD, Novartis and Pfizer. C.P. reports serving a consultant and speaker for EUSA, Bristol-Myers Squibb, MSD, Pfizer, Ipsen, Eisai, AstraZeneca, Janssen, Novartis and General Electrics and reports receiving honoraria from Roche. G.T. reports serving a consultant or playing an advisory role for BMS and Novartis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The use of overall survival (OS) as the gold standard primary end-point (PEP) in metastatic oncologic randomised controlled trials (RCTs) has declined in favour of progression-free survival (PFS) without a complete understanding of the degree to which PFS reliably predicts for OS., Methods: Using ClinicalTrials.gov, we identified 1239 phase III oncologic RCTs, 260 of which were metastatic solid tumour trials with a superiority-design investigating a therapeutic intervention by using either a PFS or OS PEP. Each individual trial was reviewed to quantify RCT design factors and disease-related outcomes., Results: A total of 172,133 patients were enrolled from the year 1999 to 2015 in RCTs that used PFS (56.2%, 146/260) or OS (43.8%, 114/260) as the PEP. PFS trials were more likely to restrict patient eligibility by using molecular criteria (15.1% versus 4.4%, p = 0.005) use targeted therapy (80.1% versus 67.5%, p = 0.048), accrue fewer patients (median 495 versus 619, p = 0.03), and successfully meet the trial PEP (66.9% versus 33.3%, p < 0.0001). On multiple binary logistic regression analysis, factors that predicted for PFS or OS PEP trial success included choice of PFS PEP (p < 0.0001), molecular profile restriction (p = 0.02) and single agent therapy (p = 0.02). Notably, there was only a 38% (31/82) conversion rate of positive PFS-to-OS benefit; lack of industry sponsorship predicted for PFS-to-OS signal conversion (80.0% without industry sponsorship versus 35.1% with industry sponsorship, p = 0.045)., Conclusions: A PFS PEP has suboptimal positive predictive value for OS among phase III metastatic solid tumour RCTs. Regulatory agency decisions should be judicious in using PFS results as the primary basis for approval., Competing Interests: Conflict of interest statement The authors report no financial disclosures or conflicts of interests related to this work. Dr. Jagsi reports stock ownership and an advisory role in Equity Quotient; personal fees from Amgen and Vizient; grants from the National Institutes of Health, the Doris Duke Foundation, the Greenwall Foundation, and Blue Cross Blue Shield of Michigan. Dr. Das reports personal fees from Adlai Nortye. Dr. Fuller reports honoraria from the University of Texas Health Science Center San Antonio and Elekta AB; royalties from Demos Medical Publishing; travel expenses/accommodations from Oregon Health & Science University, Great Baltimore Medical Center, University of Illinois Chicago, Elekta AB, the Translational Research Institute of Australia; grants from the National Science Foundation and National Institutes of Health. Dr. Thomas reports receiving a stipend as deputy editor of JAMA Oncology. Dr. V. Subbiah reports funding for clinical trials from Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning point therapeutics, Boston Pharmaceuticals; for travel from Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte; for consultancy from Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED pharma, Medimmune, Novartis; and for other duties from Medscape., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: T-DM1 has been approved for the treatment of HER2+ breast cancer. Cardiac dysfunction is a side effect of trastuzumab, a component of T-DM1. However, little is known about T-DM1-associated cardiotoxicity., Methods: We have conducted a pooled analysis of T-DM1 trials in advanced HER2+ breast cancer cases to understand the incidence, clinical presentation as well as to establish possible risk factors for T-DM1-associated cardiotoxicity. The primary endpoint was the incidence of cardiac events (CEs). CEs were categorized as follows: (1) congestive heart failure (CHF) or grade 3/4 LVEF drop; (2) cardiac ischemia, (3) cardiac arrhythmia, (4) grade 1/2 LVEF drop. Secondary endpoints included CE recovery rate and impact of CEs on treatment discontinuation. Logistic regression was used to assess possible risk factors for CEs., Results: Individual patient-level data from 1961 patients exposed to T-DM1 in seven trials were pooled. Of these, 1544 received T-DM1 and 417 T-DM1 + pertuzumab. CHF/LVEF drop grade 3/4 was reported in 0.71%, cardiac ischemia in 0.1%, cardiac arrhythmia in 0.71% and grade 1/2 LVEF drop in 2.04%. The total CE rate was 3.37% (95% confidence interval (CI), 2.6%-4.3%). Multivariate analysis showed patient's age ≥65 (OR 3.0; 95% CI, 1.77-5.14; P-value <0.001) and baseline LVEF<55% (OR 2.62; 95% CI, 1.29-5.32; P-value 0.008) as risk factors. CEs resolved in most (79%) patients after treatment discontinuation., Conclusion: The incidence of CEs in patients receiving T-DM1 was low. Older patients receiving T-DM1 should be carefully followed for cardiac safety during treatment., Competing Interests: Conflict of interest Noam Pondé has received fees from Mundipharma and AstraZeneca, and travel grants from Novartis, Roche/Genentech and Mundipharma. Lieveke Ameye has no conflicts to report. Matteo Lambertini has received honoraria from Theramex, Takeda and Roche and served as consultant for Roche Diagnostic. Marianne Paesmans has no conflicts to report. Martine Piccart is a board member for Oncolytics and Radius. She has received honoraria from AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Oncolytics, Periphagen, Pfizer, Roche PharmaMar, and Seattle Genetics. Her institute has received research grants from AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier and Synthon. Evandro de Azambuja has received honoraria and is a member of advisory boards for Roche/Genetench; she received travel grants from Novartis, GSK and Roche/Genentech. The institution she works for has received research grants for Roche/Genentech, AstraZeneca, GSK, Novartis and Servier., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Concomitant external-beam radiochemotherapy (5-fluorouracil-mitomycin C) has become the standard of care in anal cancer since the '90s. A pooled analysis of individual patient data from 7 major trials was performed quantifying the effect of radiation therapy (RT)-related parameters on the outcome of patients with anal cancer., Materials and Methods: Pooling databases from combined modality trials, the impact of RT parameters (total dose, gap duration, OTT: overall treatment time) on outcome including locoregional failure (LRF), 5-year progression free survival (PFS) and toxicities were investigated. Individual patient data were received for 10/13 identified published studies conducted from 1987 to 2008 (n = 3031). A Cox regression model was used (landmark = 3 months after RT for first follow-up)., Results: After data inspection indicating severe heterogeneity between trials, only 1343 patients from 7/10 studies received were analysed (the most recent ones, since 1994; median follow-up = 4.1 years). A higher overall 5-year LRF rate [22.8% (95% confidence interval [CI] 22.3-27.3%)] significantly correlated with longer OTT (p = 0.03), larger tumour size (p < 0.001) and male gender (p = 0.045). Although significant differences were not observed, subset analyses for LRF (dose range: 50.4-59 Gy) seemed to favour lower doses (p = 0.412), and when comparing a 2-week gap versus 3 (dose: 59.4 Gy), results suggested 3 weeks might be detrimental (p = 0.245). For a 2-week gap versus none (dose range: 55-59.4 Gy), no difference was observed (p = 0.89). Five-year PFS was 65.7% (95% CI: 62.8-68.5%). Higher PFS rates were observed in women (p < 0.001), smaller tumour sizes (p < 0.001) and shorter OTT (p = 0.025). Five-year overall survival [76.7% (95% CI: 73.9%-79.3%)] correlated positively with female gender (p < 0.001), small tumour size (p = 0.027) and short OTT (p = 0.026). Descriptive toxicity data are presented., Conclusion: For patients receiving concurrent external-beam doublet chemoradiation, a longer OTT seems detrimental to outcome. Further trials involving modern techniques may better define optimal OTT and total dose., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: We aimed to determine whether treatment effect size differed between randomised controlled phase II trials and subsequent phase III trials and examine potential predictor of positive phase III trials., Methods: We searched MEDLINE for randomised controlled phase II studies published from January 2006 to December 2015. Matched phase III trials that investigated same intervention in the same setting of the same cancer were identified through Web of Science, ClinicalTrials.gov and conference proceedings. For each pair of phase II and phase III trials, we extracted hazard ratios (HRs) with 95% confidence intervals (CIs) for both overall survival (OS) and progression-free survival (PFS) and evaluated the differences by ratio of HRs (rHRs): the HR for phase II trial to that for phase III trial. A summary rHR was obtained through a random-effect meta-analysis. Univariable analyses were conducted to identify predictors of positive phase III trials., Results: We identified 57 pairs of phase II and phase III trials. Compared with phase III trials, treatment effect sizes of PFS were, on average, 26% larger in phase II trials (rHR = 0.74, P < 0.001, 95% CI: 0.68-0.80). Treatment effect sizes of OS were 27% greater in phase II trials than in phase III trials (rHR = 0.73, P < 0.001, 95% CI: 0.66-0.79). Fifteen (26.3%) phase III trials were positive, and the only predictor of positive phase III trials was positive phase II trials CONCLUSION: Treatment effects in randomised controlled phase II trials were greater than those in matched phase III trials. Caution must be taken when interpreting promising results from randomised controlled phase II trials., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Health-related quality of life (HRQOL) is increasingly recognised as an important end-point in cancer clinical trials. The concept of minimally important difference (MID) enables interpreting differences and changes in HRQOL scores in terms of clinical meaningfulness. We aimed to estimate MIDs for interpreting group-level change of European Organisation for Research and Treatment for Cancer Quality of life Questionnaire core 30 (EORTC QLQ-C30) scores in patients with malignant melanoma., Methods: Data were pooled from three published melanoma phase III trials. Anchors relying on clinician's ratings, e.g. performance status, were selected using correlation strength and clinical plausibility of associating the anchor/EORTC QLQ-C30 scale pair. HRQOL change was evaluated between time periods that were common to all trials: start of treatment to end of treatment and end of treatment to end of follow-up. Three change status groups were formed: deteriorated by one anchor category, improved by one anchor category and no change. Patients with greater anchor change were excluded. The mean change method and linear regression were used to estimate MIDs for change in HRQOL scores within the group and between the groups of patients, respectively., Results: MIDs varied according to QLQ-C30 scale, direction (improvement versus deterioration), anchor and period. MIDs for within-group change ranged from 4 to 18 points (improvement) and -16 to -4 points (deterioration), and MIDs for between-group change ranged from 3 to 16 points and from -16 to -3 points. MIDs for most of QLQ-C30 scales ranged from 5 to 10 points in absolute values., Conclusions: These results are useful for interpreting changes in EORTC QLQ-C30 scores over time and for performing more accurate sample size calculations in adjuvant melanoma settings., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Little is known about the extent of selective publication in contemporary oncology randomised controlled trials (RCTs) worldwide. This study aimed to evaluate the rates of publication and timely publication (within 24 months) for contemporary oncology RCTs from all over the world. We also investigated the trial characteristics associated with publication and timely publication., Patients and Methods: We identified all phase III oncology RCTs registered on ClinicalTrials.gov with a primary completion date between January 2008 and December 2012. We searched PubMed and EMBASE to identify publications. The final search date was 31 December 2015. Our primary outcome measure was the time to publication from the primary completion date to the date of primary publication in a peer-reviewed journal., Results: We identified 598 completed oncology RCTs; overall, 398 (66.6%) had been published. For published trials, the median time to publication was 25 months (interquartile range, 16-37 months). Only 192 trials (32.1%) were published within 24 months. Timely publication was independently associated with trials completed late in 2012. Trials conducted in Asia and other regions were less likely to have timely publication, but trials conducted in different locations were all equally likely to be published. Industry- and NIH-funded trials were equally likely to be published timely or at any time after trial completion. Among 391 published trials with clear primary outcomes, there was a trend for timely publication of positive trials compared with negative trials., Conclusions: Despite the ethical obligations and societal expectations of disclosing findings promptly, oncology RCTs performed poorly., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Correct interpretation of subgroup analyses (SGA) is important as it influences selection of therapeutic interventions for patient subsets. The primary aim of our study was to compare reporting of SGA between industry and non-industry sponsored trials., Methods: We performed a systematic literature review and extracted data from journal articles (JA) and conference abstracts (CA) published over a decade reporting SGA results of phase III randomised controlled gastrointestinal (GI) oncology trials with patient participants of ≥150., Results: In JA, SGA was reported in 100/145 (69%) trials: 41/54 industry sponsored (76%; 95% confidence interval [CI]: 63-86%) and 59/91 non-industry sponsored (65%; 95% CI: 55-74%) trials (p = 0.16). In CA, SGA was reported in 86/204 (42%) trials: 43/83 industry sponsored (52%; 95% CI: 41-62%) and 43/121 non-industry sponsored (36%; 95% CI: 28-44%) trials (p = 0.02). Number of SGA performed per trial was significantly larger for industry compared to non-industry sponsored trials in both JA (median 6 versus 2, p = 0.003) and CA (median 1 versus 0, p = 0.023). Claims of subgroup effect were made in 52% of trials in JA and 50% in CA, with significant test of interaction evident in only 25% of JA and 16% of CA, with no difference between industry and non-industry trials. Industry sponsored trials with a significant primary end-point reported more SGA (p < 0.001 JA; p = 0.046 CA)., Conclusions: Industry sponsored trials reported more SGA. Claimed subgroup effects were often not accompanied by significant interaction test; thus circumspection should be adopted when using SGA to deviate from standard therapeutic decision-making in GI oncology., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Although participation in cancer clinical trials is low, little is known about the number of available clinical trials, and open spots for patients. Moreover, it is unclear what the relationship is between clinical trial openings and the incidence and mortality of cancer subtypes., Methodology: We identified the number of phase I, phase II and phase III registered at clinicaltrials.gov by cancer (tumour) type. All counts were over the preceding 5 years (2008-2013). We compared these counts against the incidence and prevalence of disease reported by Surveillance, Epidemiology and End Results (SEER) database for 32 common cancers., Results: From 2008 to 2013, 3879 phase I trials, 4982 phase II trials and 1379 phase III trials concerning a cancer subtype were registered in clinicaltrials.gov. These trials had a cumulative proposed recruitment of 203,396, 421,502 and 697,787 patients, respectively. Trial enrollment varied by tumour type, with both over and under-representation occurring., Conclusion: Opportunities to enroll in clinical trials vary by phase and tumour type. Oncologists must remain committed to clinical trials., (Published by Elsevier Ltd.)

Purpose: Alopecia is a common side-effect of chemotherapy and affects quality of life of cancer patients. Some patients and physicians believe that alopecia could be a surrogate marker for response to chemotherapy and impact on prognosis. However, this was never been tested in a sufficiently large cohort of ovarian cancer patients., Patients and Methods: We analysed retrospectively the meta-databank of four prospective randomised phase-III-trials with platinum- and taxane-based 1st-line-chemotherapy in patients with advanced epithelial ovarian cancer (EOC) regarding the impact of alopecia overall outcome., Results: For 4705 (92.0%) of a total of 5114 EOC-patients alopecia was documented. They had received on median six cycle platinum-taxane chemotherapy (range 0-11) with 4186 (89.0%) having completed ⩾ 6 cycles. Worst alopecia grade was 0 in 2.4%, 1 in 2.9% and 2 in 94.7% of the patients. In a univariate analysis, including all patients, grade-0/1 alopecia was associated with significantly lower progression free survival (PFS) and overall survival (OS) compared to grade-2 alopecia. However when assessing only those patients who completed ⩾ 6 chemotherapy-cycles and hence eliminating the bias of lower total dose of treatment, alopecia failed to retain any significant impact on survival in the multivariate analysis. Merely the time point of alopecia onset was an independent prognostic factor of survival: patients who developed grade-2 alopecia up to cycle 3 had a significantly longer OS compared to patients who experienced alopecia later during therapy (hazard ratio (HR): 1.25; 95% confidence interval (CI): 1.04-1.50)., Conclusions: Within a large EOC-patient cohort with 1st-line platinum- and taxane-based chemotherapy early onset alopecia appears to be significantly associated with a more favourable outcome in those patients who completed ⩾ 6 chemotherapy cycles. It remains to be elucidated if early onset alopecia is just a surrogate marker for higher sensitivity to chemotherapy or if other biological effects are underlying., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aim: To describe the proportion of women in Tayside, Scotland diagnosed with early breast cancer who would have been eligible for influential adjuvant breast cancer trials., Methods: Phase III trials of adjuvant treatment for breast cancer referenced in five national guidelines were shortlisted by breast cancer specialists to identify the twelve considered most influential. Eligibility criteria were extracted from protocols and applied to a 16-year cohort of women who had received a diagnosis of breast cancer and the proportion meeting trial criteria calculated. The criteria used clinically in Tayside to make decisions about use of the trial treatments were also applied to the cohort. Finally, the proportion of women receiving adjuvant endocrine therapy as part of their care and who would have been eligible for the trial evaluating that therapy was calculated., Results: Of the cohort's 4811 women, 3535 (73%) were eligible for at least one trial but eligibility for an individual trial rarely exceeded 45%. There were substantial differences between the proportion of women meeting trial eligibility criteria and the proportion considered clinically eligible for the same treatment. The proportion of women receiving an endocrine therapy as part of their care who would also have been eligible for the trial evaluating that treatment ranged from 17% to 56%., Conclusion: Clinical eligibility criteria may be at variance with trial criteria. For adjuvant endocrine therapy, a substantial proportion of women who would have been ineligible for a trial nevertheless received the trial treatment as part of their care., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: We sought to estimate worst-case, typical and best-case scenarios for survival in men starting systemic therapies for castration resistant prostate cancer (CRPC)., Methods: We sought randomised phase 3 trials of systemic therapies for CRPC and recorded the following percentiles (represented scenario) from Kaplan-Meier overall survival (OS) curves: 90th (worst-case), 75th (lower-typical), 50th (median), 25th (upper-typical) and 10th (best-case). We determined the accuracy of using simple multiples of the median OS to estimate the other selected percentiles from each curve: 0.25 for 90th, 0.5 for 75th, 2 for 25th and 3 for 10th. Estimates were deemed accurate if within 0.75-1.33 times the actual value., Findings: We reviewed 23 trials (13,909 men) with 48 treatment groups including 28 of chemotherapy, and three of novel hormonal agents. In trials of first-line docetaxel, the mean (interquartile range) for median OS was 19 months (17-20), and for each scenario was: worst-case 7 months (6-8); lower-typical 12 months (11-13); upper-typical 29 months (27-31); and best-case 40 months (34-44). For trials of novel hormonal agents after chemotherapy the mean values were: median OS 17 months, worst-case 5 months, lower-typical 9 months, upper-typical 24 months and best-case not reported. Simple multiples of the median gave accurate estimates of the worst-case scenario in 72% of OS curves, lower-typical in 89%, upper-typical in 84% and best-case in 84%., Interpretation: Simple multiples of the median OS from randomised trials provided accurate estimates of worst-case, typical and best-case scenarios for survival time in men starting systemic therapies for CRPC., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Mucinous histology of metastatic colorectal cancer (CRC) has been associated with poor prognosis, however this has never been assessed in large well-defined study populations treated with the current used systemic agents. We investigated the prognostic value of mucinous histology in two large phase III studies in metastatic CRC., Patients and Methods: The study population included 1010 metastatic CRC patients who were treated with chemotherapy and targeted therapies in two phase III studies. Patients were classified according to the histology of the primary tumour in mucinous adenocarcinomas (MC) and non-mucinous adenocarcinomas (AC)., Results: Patients with MC (n=99) were older, had more often a normal serum lactate dehydrogenase (LDH), extrahepatic localisation of metastases, larger primary tumour diameter and a higher T classification compared to patients with AC (n=911). A deficient mismatch repair system and BRAF mutations were observed in 17% and 22% of patients with MC, compared to 3% and 7% in patients with AC, respectively. Clinical outcome was investigated in both studies separately, showing a worse overall survival (OS), progression free survival and overall response rate in patients with MC compared to patients with AC. Patients with MC received less cycles of treatment compared to AC, but did not suffer from a higher incidence of grade 3/4 toxicity. In multivariate analysis, mucinous histology was as an independent negative prognostic factor for OS, resulting in a combined hazard ratio of 1.78 (95%confidence interval (CI) 1.35-2.35)., Conclusions: Patients with metastatic mucinous CRC have distinct clinicopathological features and poor response to chemotherapy and targeted agents. The strong negative prognostic value of MC warrants the use of this pathological feature as a stratification factor for clinical trials in metastatic CRC., (Copyright © 2011 Elsevier Ltd. All rights reserved.)