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Introduction: Because a dose-response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors., Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005-2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available., Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%-80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003)., Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%-80% of MTD)., (©2014 American Association for Cancer Research.)

Introduction: Traditional dose-limiting toxicity (DLT) definition, which uses grade (G) 3-4 toxicity data from cycle 1 (C1) only, may not be appropriate for molecularly targeted agents (MTAs) of prolonged administration, for which late or lower grade toxicities also deserve attention., Patients and Methods: In collaboration with pharmaceutical companies and academia, an European Organisation for Research and Treatment of Cancer (EORTC)-led initiative, Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies (DLT-TARGETT), collected data from completed phase 1 trials evaluating MTAs as monotherapy. All toxicities at least possibly related to the study drugs that occurred during C1-6, their type, grade (CTCAEv3.0), and duration as well as patients' relative dose-intensity (RDI), were recorded., Results: The 54 eligible trials enrolled 2084 evaluable adult patients with solid tumours between 1999 and 2013, and evaluated small molecules (40), antibodies (seven), recombinant peptides (five) and antisense oligodeoxynucleotides (two). A maximum tolerated dose was set in 43 trials. Fifteen percent of the patients received <75% of the intended RDI in C1, but only 9.1% of them presented protocol-defined DLTs. After C1, 16-19% of patients received <75% of the intended RDI. A similar proportion of G ⩾ 3 toxicities was recorded in C1 and after C1 (936 and 1087 toxicities, respectively), with the first G⩾3 toxicity occurring after C1 in 18.6% of patients., Conclusion: Although protocol-defined DLT period is traditionally limited to C1, almost 20% of patients present significant reductions in RDI at any time in phase 1 trials of MTAs. Recommended phase 2 dose assessment should incorporate all available information from any cycle (notably lower grade toxicities leading to such RDI decrease), and be based on achieving >75% RDI., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Although sarcomas account for only 1% of all solid tumours, patients with sarcomas comprise a larger proportion of patients entering phase I trials, due to the limited number of registered or active drugs for these diseases. To help in patient selection, we evaluated the utility of the predictive Royal Marsden Score which had been derived in carcinoma patients. In addition, we analysed efficacy and toxicity regarding the sarcoma population enrolled in phase I trials., Patients and Methods: We used data from a European Database comprising 2182 patients treated in phase I trials in 14 European institutions between 2005 and 2007., Results: One hundred and seventy-eight patients diagnosed with advanced sarcoma or other mesenchymal tumours were identified and accounted for 217 phase I trial participations during the study period. Histological type, class of drug, number of metastatic sites, high serum lactate dehydrogenase activity (LDH), low albumin and high white blood cell count were independent prognostic factors. Poor performance status (PS), liver metastases and high leucocyte count were associated with increased risk of early death. The class of drug used was the strongest predictor of progression-free survival (PFS) duration, inhibitors of angiogenesis and histone deacetylase giving the best results. Poor PS, high serum LDH and low lymphocyte count correlated with shorter PFS. In this heterogeneous population, PFS with investigational agents appeared comparable with that previously published for patients receiving standard treatments beyond first line., Conclusion: Prognostic factors in sarcoma patients do not differ from a broader phase I population. Efficacy measures suggest that some patients with sarcoma derive benefit from therapy in this setting which could therefore be considered for patients with no remaining standard therapeutic option., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Studies indicate that ovarian cancer patients who have been optimally debulked survive longer. Although chemotherapy has been variable, they have defined standards of care. Additionally, it is suggested that patients from the United Kingdom (UK) have inferior survival compared with some other countries. We explored this within the context of a large, international, prospective, randomized trial of first-line chemotherapy in advanced ovarian cancer (docetaxel-carboplatin v paclitaxel-carboplatin; SCOTROC-1). The Scottish Randomised Trial in Ovarian Cancer surgical study is a prospective observational study examining the impact on progression-free survival (PFS) of cytoreductive surgery and international variations in surgical practice., Patients and Methods: One thousand seventy-seven patients were recruited (UK, n = 689; Europe, United States, and Australasia, n = 388). Surgical data were available for 889 patients. These data were analyzed within a Cox model., Results: There were three main observations. First, more extensive surgery was performed in non-UK patients, who were more likely to be optimally debulked (< or = 2 cm residual disease) than UK patients [corrected] (71.3% v 58.4%, respectively; P < .001). Second, optimal debulking was associated with increased PFS mainly for patients with less extensive disease at the outset (test for interaction, P = .003). Third, UK patients with no visible residual disease had a less favorable PFS compared with patients recruited from non-UK centers who were similarly debulked (hazard ratio = 1.85; 95% CI, 1.16 to 2.97; P = .010). This observation seems to be related to surgical practice, primarily lymphadenectomy., Conclusion: Increased PFS associated with optimal surgery is limited to patients with less advanced disease, arguing for case selection rather than aggressive debulking in all patients irrespective of disease extent. Lymphadenectomy may have beneficial effects on PFS in optimally debulked patients.

Background: Because metastatic nonseminomatous germ cell cancer is a rare but treatable cancer, we have explored whether there is an association between the experience of the treating institution with this disease and the long-term clinical outcome of the patients, particularly patients with a poor prognosis., Methods: We analyzed data on 380 patients treated in one of 49 institutions participating in the European Organization for Research and Treatment of Cancer/ Medical Research Council randomized trial of four cycles of bleomycin-etoposide-cisplatin followed by two cycles of etoposide-cisplatin versus three cycles of bleomycin-vincristine-cisplatin followed by three cycles of etoposide-ifosfamide-cisplatin-bleomycin, both treatment regimens given with or without filgrastim (granulocyte colony-stimulating factor). Institutions were divided into four groups based on the total number of patients entered in the trial. The groups were compared by use of the Cox proportional hazards model stratified for treatment with filgrastim and for patient prognosis as defined by the International Germ Cell Consensus Classification Group. With the use of this classification, only 65 % of the patients had a poor prognosis., Results: Patients treated in the 26 institutions that entered fewer than five patients into the trial had an overall survival that was statistically significantly worse (two-sided P = .010; hazard ratio = 1.85; 95% confidence interval = 1.16-3.03) than that of patients treated in the 23 institutions that entered five patients or more. Overall survival and failure-free survival were similar among institutions that entered at least five patients. The observed effect may be related to differences in adherence to the chemotherapy protocol and in the frequency and extent of surgery for residual masses, although only the differences in dose intensity achieved statistical significance., Conclusions: Patients treated in institutions that entered fewer than five patients into the trial appeared to have poorer survival than those treated in institutions that entered a larger number of patients with "poor-prognosis" nonseminoma.

This article deals with new antitumor agents currently in Phase I or II evaluation in various European centers. Drugs reviewed in this article include Taxotere, Camptothecin analogues, CPT-11, and Topotecan. Rhizoxin, D1694, and Bryostatin are among other agents reviewed in this article.

Trends in mortality from Hodgkin's disease between mid 1950s and the late 1980s have been analysed for 16 western European and seven eastern European countries. In all western countries there were substantial falls in mortality from the late 1960s onwards, for an overall mean decline of 50% in both sexes, although these falls were somewhat larger in Nordic countries (approaching 70% in Denmark and Sweden), and more limited (20 to 30%) in Portugal, Spain and Greece. The reductions in Hodgkin's disease mortality were evident both in younger (under 35) and middle age (35 to 64 years), as well as in children under 15 and, in several countries, in the elderly (above 65), too. They were persistent up to the most recent calendar periods, with no evidence of flattening off. The pattern of trends in Hodgkin's disease mortality was largely different in Eastern Europe. Among seven countries examined, some fall was observed only in Bulgaria and Czechoslovakia, but other countries showed no consistent pattern and there was some increase, too. In absolute terms, the reductions in Hodgkin's disease mortality in Western Europe correspond to the avoidance of over 3,000 deaths per year. This stresses the importance and urgency of improving the availability of currently defined knowledge and resources for treatment of Hodgkin's disease in Eastern Europe.

Two hundred and twenty-eight patients with advanced testicular cancer were entered into a randomized study of chemotherapy comprising cis-platinum (P) 20 mg/m2-, days 1-5 every 3 weeks for four courses, bleomycin (B) 30 mg weekly for 12 weeks, and vinblastine (V) at either the low dose of 0.15 mg/kg or the high dose of 0.20 mg/kg on days 1 and 2 every 3 weeks for four courses. In this interim analysis, 64 patients were randomized to high dose PVB. Forty-five (71%) achieved a complete response, and 13 (25%) a partial response. Seventy patients received low dose PVB of whom 50 (71%) achieved a complete response and 16 (23%) a partial response. Thus there is no difference in the efficacy of this combination chemotherapy with respect to the dose of vinblastine, but the low dose schedule was less toxic (particularly to bone marrow). It was also apparent that the response rate varied with the volume of metastatic disease, irrespective of the dose of vinblastine. Patients with low volume metastases had a complete response rate (CR) of 88%, while those with high volume had a CR rate of 60%. In a second randomization, 68 patients achieving CR were randomized to receive either 1 year of further (maintenance) chemotherapy with cis-platinum and vinblastine, or no further chemotherapy. One of 37 patients (3%) receiving treatment and 2 of 31 patients (6%) not receiving treatment relapsed, with a follow-up of at least 10 months. Thus maintenance chemotherapy appears not to be necessary in the treatment of advanced testicular cancer.