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The article offers information on randomized clinical trials (RCTs) and their impact on defining the efficacy of new cancer treatments, while also examining the debated benefits of trial participation for individual patients. Topics include the existence of a participation effect in cancer RCTs, as explored by Iskander et al, which initially suggested lower mortality risk among trial participants but found this effect diminished when adjusting for confounders and publication bias.

There are limited effective therapies for most patients with relapsed diffuse large B-cell lymphoma (DLBCL). We conducted a phase II trial of the multi-targeted vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, sunitinib, 37.5 mg given orally once daily in adult patients with relapsed or refractory DLBCL. Of 19 enrolled patients, 17 eligible patients were evaluable for toxicity and 15 for response. No objective responses were seen and nine patients achieved stable disease (median duration 3.4 months). As a result, the study was closed at the end of the first stage. Grades 3--4 neutropenia and thrombocytopenia were observed in 29%% and 35%%, respectively. There was no relationship between change in circulating endothelial cell numbers (CECs) and bidimensional tumor burden over time. Despite some activity in solid tumors, sunitinib showed no evidence of response in relapsed/refractory DLBCL and had greater than expected hematologic toxicity. [ABSTRACT FROM AUTHOR]

Bortezomib and gemcitabine have each shown activity as single agents in mantle cell lymphoma (MCL), which is incurable. The purpose of this phase II study was to determine the efficacy and safety of the previously unstudied combination of bortezomib and gemcitabine in patients with relapsed or refractory MCL. Patients were eligible if they had relapsed MCL with 1--3 prior therapies. Patients were treated with gemcitabine 1000 mg/m2 on days 1 and 8 and bortezomib 1.0 mg/m2 IV on days 1, 4, 8, and 11, on a 21-day schedule. Twenty-six patients were evaluable for toxicity and 25 for response. The overall response rate was 60%% and the median progression free survival was 11.4 months. The main adverse effects were hematological, with 40%% and 48%% of patients experiencing grade 3/4 thrombocytopenia and granulocytopenia, respectively. Bortezomib and gemcitabine is an active combination in relapsed and refractory MCL with clinically meaningful results. It offers a chemotherapy backbone to which other agents, less myelosuppressive, may be added. [ABSTRACT FROM AUTHOR]

The Gynecological Cancer Intergroup (GCIG) has previously reached consensus regarding the criteria that should be used in clinical trial protocols to define progression-free survival after first-line therapy as well as the criteria to define response to treatment in recurrent disease using the serum marker CA 125 and has specified the situations where these criteria should be used. However, the publications did not include detailed definitions, nor were they written to accommodate the new version of Response Evaluation Criteria In Solid Tumors (RECIST) criteria (version 1.1) now available. Thus, we recommend that the definitions described later in detail are incorporated into clinical trial protocols to maintain consistency. The criteria for defining progression are now acceptable in clinical trials of recurrent disease as they have since been validated (Pujade-Lauraine, personal communication, 2010). The GCIG requests that data from all clinical trials using these definitions are made available to GCIG trial centers so that continual validation and improvement can be accomplished. These definitions were developed from analyzing patients receiving cytotoxic chemotherapy and have not yet been validated in patients receiving molecular targeting agents. [ABSTRACT FROM AUTHOR]

Sorafenib is a small molecule inhibitor of RAF kinase, VEGFR-2, c-KIT, and FLT3. In this randomized phase I study, eligible patients had relapsed/refractory acute myeloid leukemia (AML), and one prior induction regimen, or were age >65 with untreated myelodysplastic syndrome (MDS) or secondary AML. Sorafenib was given orally for 28 days (cont) or 14 days (int) every 4 weeks at three dose levels (100, 200, and 400 mg BID); 300 mg cont was also tested. Forty-two patients were enrolled (median age 71 [37–82]; prior chemotherapy: 22). Dose-limiting toxicity (DLT) was: 100 mg BID: 0/7 patients; 200 mg BID: 2/12 patients; 400 mg BID: 1/17 patients. Sorafenib 400 mg cont was not tolerated in this population: 6/8 received <14 days of treatment due to toxicity; no DLT was seen with 300 mg cont. One CR was seen in a patient with AML with FLT3-ITD. Flow cytometry studies suggest that sorafenib inhibits ERK phosphorylation via c-KIT. The recommended phase II dose in AML is 300 mg BID continuously, and testing in combination and in FLT3-ITD AML is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Background: Clinical benefit (CB) was first successfully used as an end-point in 1997 in the pivotal study of gemcitabine in advanced pancreas cancer. In the trial by Burris et al. CB was a composite measure of pain, performance status and weight. Here we describe how CB has been used in oncology trials since that time. Methods: We performed an electronic search (www.jco.org) for reports of all clinical trials (phase I, II and III) published in the Journal of Clinical Oncology 1997–2008 citing ‘clinical benefit’. Eligible trials were those reporting clinical benefit as an end-point. Details related to study methodology, sponsorship and end-points were abstracted. Use of CB was classified as patient centred if it referred to improvement in the clinical parameters used by Burris et al. or in other disease-related symptoms. CB was classified as tumour centred if it relatedtoobjective tumour criteria for partial/complete response and/or stable disease. Descriptive statistics were used to summarise findings and the chi-square test was used to compare proportions. Results: Seventy-one trials reporting CB as an end-point were identified: 37in breast, 8in pancreasand 26 in other cancers. The definition of CB was patient centred in 20 trials (28%) and tumour centred in 51 trials (72%). Only 20% (14/71) of trials (including all 8 pancreas studies) used the original Burris definition. Among the 71 trials reporting clinical benefit, in only 31 (44%) cases was the end-point defined as a primary or secondary study objective. Trials with a patient-centred definition of CB were considerably more likely to do so than trials with a tumour-centred definition (19/20, 95% versus 12/51, 24%, p <0.0001). Study variables associated with the use of a tumour-centred definition include: disease site (breast 35/37, 95%; all others 16/34, 47%, p <0.001) andintervention (hormone or targeted agent 38/40, 95%; chemotherapy 13/31, 42%, p <0.001). There has been a steady increase in the number of trials using CB as an end-point; in the second half of the study period the number of trials increased from 17 to 54, along with the proportion of trials with a tumour-centred definition (10/17, 59% to 41/54, 76%, p =0.09). Conclusions: Despite its initial definition, clinical benefit is often used to describe objective tumour findings. Clinical trials should use end-points in a consistent manner to enable clear communication between investigators, clinicians and patients about the benefit of novel therapies. [Copyright &y& Elsevier]

Despite both the increase in basic biologic knowledge and the fact that many new agents have reached various stages of development during the last 10 years, the number of new treatments that have been approved for patients has not increased as expected. We propose the multi-arm, multi-stage trial design as a way to evaluate treatments faster and more efficiently than current standard trial designs. By using intermediate outcomes and testing a number of new agents (and combinations) simultaneously, the new design requires fewer patients. Three trials using this methodology are presented. [ABSTRACT FROM AUTHOR]

RECIST (response evaluation criteria in solid tumours) uses a unidimensional approach to tumour measurement and has been widely adopted for assessing the response rate of new therapies in solid tumour clinical trials. For lymphoma, the IWC (International Workshop Criteria), based on bidimensional product assessment, is generally utilised. We adapted RECIST for use in lymphoma and compared responses with the IWC in three Phase II lymphoma trials (n = 115). Measures of agreement estimated the concordance between the adapted RECIST and the IWC response assessments. A Pearson's coefficient estimated the correlation between changes in uni- and bidimensional measurements in a subset of patients (n = 75). All measures of agreement were very high [κ = 0.86 (95% CI: 0.76 - 0.95), percent agreement 0.93 (95% CI: 0.87 - 0.97), positive agreement 0.90 (95% CI: 0.87 - 0.98), negative agreement 0.92 (95% CI: 0.89 - 0.98)]. Pearson's coefficient was 0.92 (95% CI: 0.87, 0.95). The lymphoma-adapted RECIST is simpler to apply than the IWC and yields near identical response rates. The adapted RECIST should be considered for inclusion into any new draft of the IWC. [ABSTRACT FROM AUTHOR]

Flavopiridol is a potent cyclin-dependent kinase (CDK) inhibitor that has preclinical activity in many tumours. This synthetic flavonoid was tested in a phase II nonrandomized, nonblinded multicentre clinical trial to determine its activity and toxicity in patients with previously untreated metastatic or locally advanced soft tissue sarcoma. Methods. A total of 18 patients with histologically confirmed nonoperable soft tissue was treated with flavopiridol administered at a dose of 50 mg/m2 IV over 1 hour daily x3 days every 3 weeks. Results. Eighteen patients were accrued to the study over a period of 6 months. No objective responses were noted in the seventeen evaluable patients. Eight patients (47%) exhibited stable disease after 2 cycles (median duration of 4.3 months (range 1.4--6.9 months). Kaplan-Meier estimates for 3-and 6-month progression-free survival rates were 44 percent and 22 percent, respectively. The only grade 3 toxicities were diarrhea (N = 2), nausea (N = 2), gastritis (N = 1), and fatigue (N = 1). Ninety-four percent of patients received ≥90% of the planned dose intensity, during 55 treatment cycles. Conclusions. Flavopiridol was well tolerated at the dose and schedule used in this study, however, no objective treatment responses were seen and thus our results do not support further exploration of flavopiridol as a monotherapy at this dose and schedule in soft tissue sarcomas. [ABSTRACT FROM AUTHOR]

Background: New targeted, non-cytotoxic anticancer agents, such as small-molecule kinase inhibitors, pose challenges to the current phase I paradigm of dose selection based on toxicity. Moreover, increasing the drug dose to toxicity may be unnecessary for drug effect, making the use of maximum tolerated dose as a surrogate of effective dose inappropriate in the phase I setting. Because little is known about the optimal methods of recommended phase II dose selection of targeted, non-cytotoxic therapies, we reviewed the strategies that were used in completed phase I studies of these drugs. Methods: We retrieved 60 publications of phase I studies involving 31 single agents representative of the most common targets of interest in the oncology literature. For each publication, we abstracted data regarding patient population, starting dose, methods of dose escalation and determination of recommended phase II dose, and inclusion of correlative studies in study conduct. Results: Of the 60 completed phase I studies, 36 used toxicity and eight used pharmacokinetics data as endpoints for selection of the recommended phase II dose. Nontraditional endpoints, such as measures of molecular drug effects in tumor or surrogate tissue or functional imaging studies, were not routinely incorporated into the study design and rarely formed the primary basis for dose selection. Conclusions: To date, phase I studies of targeted anticancer agents have generally used traditional endpoints for selection of the recommended phase II dose. More research is needed to define suitable molecular measures of drug effect and the means to incorporate them in the early drug development process. [ABSTRACT FROM AUTHOR]

Summarizes the issues discussed at the workshop 10th National Cancer Institute-European Organization for Research and Treatment of Cancer Symposium on New Drugs in Cancer Therapy held in the United States. Preclinical assessment; Phase I trial design of an anticancer drug; Lessons from nononcology drugs.

The objective of a phase II clinical trial in oncology is to assess the antitumor activity of a specific treatment regimen. A multiple-testing procedure is commonly used to decide whether the experimental treatment warrants further investigation based on patients’ tumor response. There are ethical concerns about exposing patients to a new drug when the response rate is low and a relatively large number of patients have early progressive disease. Ensign et al. () proposed a stopping rule that rejects a drug early when there is a long run of early treatment failures. However, this approach may not be sensitive to pick up early progressors mixed with other nonresponders. In this paper, we present a multiple-stage stopping rule for a single-arm trial of an experimental treatment in which both tumor response and early progression are considered simultaneously. We use a multinomial model to accommodate an outcome of discrete multivariate responses in order to improve the efficiency of the stopping rule. The proposed multiple-testing procedure requires that both the numbers of responses and early progressions fall within the boundaries satisfying the stopping criteria in order to stop the study. Simulation is performed to validate these results and to compare them with other commonly used designs. Other applications of this method are also discussed. [ABSTRACT FROM AUTHOR]

Explains the Gynaecologic Cancer Intergroup's stand that definitions for response and progression of ovarian cancer according to serum CA 125 levels should be incorporated into ovarian cancer clinical trial protocols for relapse therapy. Definition of response; Rules for calculating CA 125 levels; Recommendation that CA 125 measurements be taken at specific time intervals.

Progression-free survival (PFS) is an end-point in an increasing number of cancer clinical trials, informing both regulatory bodies and clinical practice. PFS is utilised both as a surrogate end-point for overall survival and as a primary trial end-point in itself. Understanding the history of clinical trial definitions of progression provides some context for how PFS may be applied to clinical practice as well as some of its limitations that need to be considered in patient care decisions. This commentary reviews recent drug approval for anti-cancer agents in solid tumours, reviews various concepts of progression in clinical trials and outlines some future directions for patient care and clinical trial research using progression free survival. [ABSTRACT FROM AUTHOR]

Disease-free survival (DFS) is an end-point for an increasing number of clinical trials in adjuvant and curative intent cancer treatment informing both regulatory bodies and clinical practice. DFS is seen both as a surrogate end-point and as an end-point in itself in clinical trials. Understanding the history of DFS, and some of the assumptions, limitations, and vulnerabilities for studies designed with this primary end-point are required. This commentary reviews recent drug approvals for anti-cancer agents in solid tumours in the adjuvant and curative settings, and considers the meaning of DFS from the perspectives of clinical trials and clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: Cancer for many patients is still a lethal disease, and we are at the edge of the time that it will be the leading cause of death in the western world. One of the hallmarks of cancer is its ability to spread to other organs, turning cancer in essence to a systemic disease. For this reason, systemic therapy plays an important role in our efforts to either obtain cure or to prolong life and palliate symptoms. The ultimate goal in the development of such new treatments is cure or prolongation of life, but the process to ascertain this may be lengthy. This presents a limitation to the rapid assessment of the potential benefit of new cancer treatments, which is why investigators and regulators have been interested in clinical trial measures that could provide early readouts of drug activity or efficacy, in other words for surrogate indicators for the ultimately desired outcome. [Copyright &y& Elsevier]

Background: Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1-3 inhibitor that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer.Methods: In this randomised, three-arm, double-blind, placebo-controlled phase 3 trial, we randomly assigned patients aged 18 years or older with relapsed platinum-sensitive ovarian cancer at 63 centres in Australia, Canada, New Zealand, Spain, and the UK. Participants received up to six cycles of platinum-based chemotherapy (once every 3 weeks) then entered a maintenance phase. Participants were randomly allocated (2:3:3), with five stratification factors and in alternating blocks, to receive placebo alongside chemotherapy and then placebo only maintenance (arm A; reference), cediranib 20 mg once-daily alongside chemotherapy then placebo only maintenance (arm B; concurrent), or cediranib 20 mg once-daily alongside chemotherapy then cediranib 20 mg once-daily maintenance (arm C; maintenance). Patients continued treatment to progression or excessive toxic effects. The primary efficacy endpoint was progression-free survival between arms A and C. Efficacy analysis was by intention to treat. Safety was assessed in all patients who received the allocated study drug. This trial is registered with ClinicalTrials.gov, number NCT00532194; the ISRCTN registry, number ISRCTN68510403; and ANZ Clinical Trials Registry, number ACTRN1261000016003.Findings: We randomly assigned 486 [corrected] women between Nov 13, 2007, and Dec 23, 2011; results presented are for 456 patients randomly assigned subsequent to the 30mg safety phase. During a median of 19·5 months (IQR 14-26) follow-up, 113 (96%) of 118 women assigned to arm A and 141 (86%) of 164 assigned to arm C had disease progression. Median progression-free survival was 11·0 months (95% CI 10·4-11·7) in arm C and 8·7 months (7·7-9·4) in arm A (hazard ratio 0·56, 0·44-0·72, p<0·0001). 156 (90%) of 174 patients in arm B had disease progression, and median progression-free survival was 9·9 months (95% CI 9·4-10·5). Diarrhoea, neutropenia, hypertension, and voice changes were significantly more common, during chemotherapy with cediranib, and diarrhoea, hypothyroidism and voice changes were more common during maintenance. Poor compliance with cediranib was noted during maintenance treatment with toxic effects being the most common cause for discontinuation.Interpretation: Cediranib, when given orally with chemotherapy and continued as maintenance, yielded a meaningful improvement [corrected] in progression-free survival in women with recurrent platinum-sensitive ovarian cancer, albeit with added toxic effects. The positive results in ICON6 could provide women with a new therapeutic option for recurrent ovarian cancer. Assessment of the secondary endpoint of overall survival will need longer follow-up.Funding: Medical Research Council, Cancer Research UK, Canadian Cancer Society Research Institute, Cancer Australia, National Gynecological Cancer Centre, and AstraZeneca. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Vascular endothethial growth factor (VEGF) and stem cell factor (c-KIT) signaling may play a role in the development and progression of cervical carcinoma. Sunitinib malate is an oral, multi-targeted tyrosine kinase inhibitor that inhibits receptors for VEGF, c-Kit and platelet-derived growth factor. This multi-centre phase II study was performed to evaluate the activity of sunitinib in women with locally advanced or metastatic cervical carcinoma who had received up to one prior line of chemotherapy for advanced disease. Methods: Sunitinib, 50 mg/day, was administered in 6-week cycles (4 weeks on followed by 2 weeks off treatment). The primary endpoint was the objective response rate. Results: Sixteen (84%) of 19 patients enrolled had stable disease (median duration 4.4 months, 2.3–17 months), but no objective response was observed. Median time to progression was 3.5 months (range, 2.7–7.0 months). Four patients had fistulae develop on study treatment and an additional patient developed a fistula 3.5 months after discontinuation of therapy. All five patients had received either prior chemoradiation or radiation. Conclusions: A higher rate of fistula formation (26.3%) was observed than would be expected and is of concern. Sunitinib has insufficient activity as a single agent in cervical cancer to warrant further investigation. [Copyright &y& Elsevier]

Abstract: Background: After the initial RECIST 1.0 were published in 2000, the criteria were widely implemented in the scientific oncology community. Since then, the RECIST working group has identified several issues to examine further. Two key issues that required careful, data-based assessment were the maximum number of lesions that should be assessed at each evaluation and the added value of requiring confirmation of response. Methods: To address these questions, data were obtained from 16 clinical trials in metastatic cancer, with patients enrolled between 1993 and 2005. A total of 6512 patients were included in the primary analysis dataset, accounting for over 18,000 potential target lesions. Nine percent of the included patients (n =585) had six or more reported target lesions. The response and progression outcomes in the database were calculated using an adjusted RECIST methodology with a maximum of 5 (or 3) target lesions with/without confirmation and this was compared to the original RECIST version 1.0 which required up to 10 target lesions plus confirmation of response. Results: Assessment of 5 lesions per patient led to a difference in best overall response assignment for an estimated 209 (3.2%) patients as compared to RECIST version 1.0. However, these changes did not affect the overall response rate. Progression-free survival was only minimally affected by measuring fewer lesions. In contrast, removing the requirement for response confirmation led to a significant increase in the numbers of patients classified as responders, resulting in a relative increase of approximately 19% in response rate. An algorithm using a maximum of three target lesions shows high concordance with the 10 lesions requirement in terms of response and TTP assignment. Concern that appropriate assessment of disease within an organ requires two lesions to be followed per organ suggests the approach of following two target lesions per organ, up to a maximum of five target lesions overall. Both strategies seem reasonable based on the data warehouse. The requirement of response confirmation in trials where this is a primary end-point is recommended to be maintained as its removal would substantially increase reported response rates. [Copyright &y& Elsevier]

Summary: Background: A randomised trial published by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group (trial 26981-22981/CE.3) showed that addition of temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma significantly improved survival. We aimed to undertake an exploratory subanalysis of the EORTC and NCIC data to confirm or identify new prognostic factors for survival in adult patients with glioblastoma, derive nomograms that predict an individual patient''s prognosis, and suggest stratification factors for future trials. Methods: Data from 573 patients with newly diagnosed glioblastoma who were randomly assigned to radiotherapy alone or to the same radiotherapy plus temozolomide in the EORTC and NCIC trial were included in this subanalysis. Survival modelling was done in three patient populations: intention-to-treat population of all randomised patients (population 1); patients assigned temozolomide and radiotherapy (population 2, n=287); and patients assigned temozolomide and radiotherapy who had assessment of MGMT promoter methylation status and who had undergone tumour resection (population 3, n=103). Cox proportional hazards models were fitted with and without O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Nomograms were developed to predict an individual patient''s median and 2-year survival probabilities. No nomogram was developed in the radiotherapy-alone group because combined treatment is now the new standard of care. Findings: Independent of the MGMT promoter methylation status, analysis in all randomised patients (population 1) identified combined treatment with temozolomide, more extensive tumour resection, younger age, Mini-Mental State Examination (MMSE) score of 27 or higher, and no corticosteroid treatment at baseline as independent prognostic factors correlated with improved survival outcome. In patients assigned temozolomide and radiotherapy (population 2), younger age, better performance status, more extensive tumour resection, and MMSE score of 27 or higher were associated with better survival. In patients who had tumours resected, who were assigned temozolomide and radiotherapy, and who had available MGMT promoter methylation status (population 3), methylated MGMT, better performance status, and MMSE score of 27 or higher were associated with improved survival. Nomograms were developed and are available at http://www.eortc.be/tools/gbmcalculator. Interpretation: MGMT promoter methylation status, age, performance status, extent of resection, and MMSE are suggested as eligibility or stratification factors for future trials in patients with newly diagnosed glioblastoma. Stratifying by MGMT promoter methylation status should be mandatory in all glioblastoma trials that use alkylating chemotherapy. Nomograms can be used to predict an individual patient''s prognosis, and they integrate pertinent molecular information that is consistent with a paradigm shift towards individualised patient management. [Copyright &y& Elsevier]