Major Oncology Journals Research Articles

A multifaceted role of bisphosphonates from palliative care to anti-cancer therapy in solid tumors.

Bisphosphonates (P-C-Ps) also called diphosphonates are the structural analogs of naturally occurring pyrophosphates. Bisphosphonates are traditionally used and shown to provide long-term success in the treatment and prevention of osteoporosis and other bone loss pathologies. Furthermore, bisphosphonates are gaining popularity in the present era of cancer therapeutics and prevention. The usage of bisphosphonates as adjuvant or neoadjuvant therapy, either as a single agent or combined with other chemotherapy, has been studied in different solid tumors. This review aims to present the various roles of bisphosphonates in solid tumors. Articles in MEDLINE/PubMed and the National Institutes of Health Clinical Trials Registry (http://www. Clinicaltrials.gov) between 1 January 2011 and 1 February 2022 were extracted using MeSH terms "bisphosphonates/diphosphosphonates and mechanism," "bisphosphonates and breast cancer," "bisphosphonates and prostate cancer," "bisphosphonates and lung cancer," "bisphosphonates and cancer risk," and "bisphosphonates and adverse events." Manual searches of some major oncology journals were also conducted. This review article focuses on the antitumor activity of bisphosphonates, safety profile, and the role of bisphosphonates as preventive, neoadjuvant, and adjuvant chemotherapy. A significant improvement in overall survival and cancer-specific survival and recurrence-free survival with the usage of bisphosphonates is noted in breast cancer patients, particularly in post-menopausal women. Though great progress has been achieved in over 20 years, further research is needed to identify the subgroup of patients that are most likely to benefit from adjuvant bisphosphonate therapy and to determine regimens with greater efficacy and better safety profile.

How authors select covariates in the multivariate analysis of cancer studies in 10 oncology journals in Korea: a descriptive study

Purpose: Cancer is the leading cause of death in Korea, leading many investigators to focus on cancer research. We present the current practice of variable selection methods for multivariate analyses in cancer studies recently published in major oncology journals in Korea.Methods: We included observational studies investigating associations between exposures and outcomes using multivariate analysis from 10 major oncology journals published in 2021 in KoreaMed, a Korean electronic database. Two reviewers independently and in duplicate performed the reference screening and data extraction. For each study included in this review, we collected important aspects of the variable selection methods in multivariate models, including the study characteristics, analytic methods, and covariate selection methods. The descriptive statistics of the data are presented.Results: In total, 107 studies were included. None used prespecified covariate selection methods, and half of the studies did not provide enough information to classify covariate selection methods. Among the studies reporting selection methods, almost all studies only used data-driven methods, despite having study questions related to causality. The most commonly used method for variable selection was significance in the univariate model, with the outcome as the dependent variable.Conclusion: Half of the included studies did not provide sufficient information to assess the variable selection method, and most used a limited data-driven method. We believe that the reporting of covariate selection methods requires improvement, and our results can be used to educate researchers, editors, and reviewers to increase the transparency and adequacy of covariate selection for multivariable analyses in observational studies.

Analysis of the adequacy of control arms in oncology randomised clinical trials published between 2017 and 2021: a meta-research study

IntroductionRandomised controlled trials (RCTs) are usually considered the highest level of evidence for clinical practice. Patients assigned to control arm in RCTs should always receive the best available treatments to protect participants while also allowing for proper interpretation and applicability of study results. Here we analysed RCTs published in oncology between 2017 and 2021 to describe the frequency of suboptimal control arms. MethodsWe identified phase III studies testing active treatments in patients with solid tumours among 11 major oncology journals. Each control arm was analysed, and the standard of care was determined according to international guidelines and scientific evidence at accrual beginning and until accrual completion. We identified studies with suboptimal control arm from the beginning (type 1) and studies with an initially optimal control arm which became outdated during the accrual period (type 2). ResultsThis analysis included 387 studies. Forty-three (11.1%) control arms were judged as suboptimal: 24 (6.2%) type 1 and 19 (4.9%) type 2. These rates were higher in industry-sponsored compared to academic trials: 9.3% versus 1.9% for type 1 (p = 0.003); 7.9% versus 0.6% for type 2 (p = 0.001). Rates of suboptimal control arms were higher in studies with positive results: 8.1% versus 4.0% for type 1 (p = 0.09); 7.6% versus 1.7% for type 2 (p = 0.007). ConclusionsMany trials have suboptimal control arms, even in journals with high-impact factors, leading to suboptimal treatment of control patients and biased evaluation of trial results.

The trends for the “trend toward significance” in the pediatric literature

PurposeThis study is to examine whether the term “trend toward statistical significance” is used to describe statistically nonsignificant results in biomedical literature. We examined articles published in five high-impact pediatric journals, including The Lancet Child & Adolescent Health, The Journal of Pediatrics, Early Human Development, Frontiers in Pediatrics, and BMC Pediatrics to identify manuscripts where a “trend” was used to describe a statistically nonsignificant result, from January 2020 to December 2021, and, furthermore, for The Journal of Pediatrics, Early Human Development, and BMC Pediatrics from January 2010 to December 2011. We detected that a “trend toward significance” was used to describe a statistically nonsignificant result at least once in 146 articles (2.7%) during the period between 2020 and 2021 and in 97 articles (4.0%) during the period between 2010 and 2011. We found no significant difference in the proportion of published articles with inappropriate use of “trend” across journals belonging to the first quartile of impact compared to the second quartile or across journals publishing under the subscription model or open access policy compared to journals publishing solely under the open access policy, in any period. The overall proportion of the inappropriate use of “trend” declined significantly between 2010 and 2011 to 2020 and 2021 (p = 0.002, RR 0.66 95% CI 0.51–0.86).Conclusion: “Trend” statements were sporadically used to describe statistically nonsignificant results across pediatric literature. The inappropriate use of “trend” to describe almost significant differences could be misleading, and “trend” should be reserved only when a specific statistical test for trend has been performed, or in relation to appropriate scientific definitions.What is Known:•Previously, researchers have reported inappropriate use of “trend” in articles across anaesthesia or major oncology journals.•In many cases, hypothesized results that are close but not lower than the statistical significance threshold are emphasized as “almost” significant.What is New:•“Trend” statements were sporadically used to describe statistically nonsignificant results across pediatric literature.•Inappropriate use of “trend” was similar in journals with a subscription model compared to those having an open access policy and decreased within a 10-year period.

Do Editorialists With Industry-Related Conflicts of Interest Write Unduly Favorable Editorials for Cancer Drugs in Top Journals?

Editorials accompanying the publication of trials in major oncology journals can have a substantial influence on clinical practice. We describe the prevalence of financial conflicts of interest (FCOIs) of authors writing such editorials and the extent to which FCOIs may shape the interpretation of clinical trials. We examined editorials published in 2018 alongside trial reports in the top 5 journals that publish cancer drug trials (New England Journal of Medicine, Lancet, Lancet Oncology, JAMA Oncology, and Journal of Clinical Oncology). An editorial was considered to have an FCOI if at least one of the editorialists had any disclosed FCOI. An FCOI with the same company whose drug was being discussed in the editorial was classified as a direct FCOI. Editorials were reviewed for their content and classified as being unduly favorable (defined as the presence of a positive spin without discussion of limitations) or not. Association of an FCOI and a direct FCOI with writing an unduly favorable editorial was assessed. Of the 90 editorials assessed, 74% (n=67) were classified as having an FCOI with the pharmaceutical industry, and 39% (n=35) had an FCOI with the same company whose product was being discussed in the editorial (direct FCOI). Editorials were classified as being unduly favorable toward the study drug in 12% (8 of 67) and 13% (3 of 23) (P=1.0) of those with and without FCOIs, respectively; corresponding rates with and without direct FCOI were 23% (8 of 35) and 5% (3 of 55), respectively (P=.009). Editorials in top oncology journals were frequently authored by experts with FCOIs, including direct FCOIs. Authoring an unduly favorable editorial for a new cancer drug was significantly associated with the author having a direct FCOI with the same company. These findings support the call for journals to ensure that authors of editorials have no direct FCOIs.

Female leadership in oncology—has progress stalled? Data from the ESMO W4O authorship and monitoring studies

BackgroundExploratory research showed that female oncologists are frequently under-represented in leadership roles. European Society for Medical Oncology (ESMO) Women for Oncology (W4O) therefore implemented gender equality programs in career development and established international studies on female representation at all stages of the oncology career pathway.MethodsFor 2017-2019, data were collected on (i) first and last authorship of publications in five major oncology journals and (ii) representation of women in leadership positions in oncology—as invited speakers at National/International congresses, board members or presidents of National/International societies and ESMO members. The 2015/2016 data from the first published W4O Study were incorporated for comparisons.ResultsAcross 2017-2019, female oncologists were significantly more likely to be first than last authors (P < 0.001). The proportion of female first authors was similar across years: 38.0% in 2017, 37.1% in 2018, 41.0% in 2019 (P = 0.063). The proportion of female last authors decreased from 30.4% in 2017 to 24.2% in 2018 (P = 0.0018) and increased to 28.5% in 2019 (P = 0.018). Across 2015-2019, invited speakers at International/National oncology congresses were significantly less likely to be female than male (P < 0.001; 29.7% in 2015 to 36.8% in 2019). Across 2016-2019, board members of International/National oncology societies were significantly less likely to be female than male (P < 0.001; 26.8% in 2016 to 35.8% in 2019). There were statistically significant increasing trends in female speakers and board members across the study periods (P < 0.001 for both). Societies with a female president had a higher proportion of female board members across these periods (P = 0.026).ConclusionsReported progress towards gender equality in career development in oncology is real but slow. Women in leadership positions are essential for encouraging young women to aspire to and work towards similar or greater success. Therefore, continued monitoring is needed to inform ESMO W4O initiatives to promote gender balance at all stages of the career pathway.

Mind the Gap: Gendered Publication Trends in Academic Oncology

Women now comprise the majority of medical school matriculants (51.6% in 2018), and an increasing number of women are seeking careers in oncology and academic medicine. Yet, men still outrank and outnumber women in academic oncology. Given that scientific publications remain an important metric of academic productivity and expertise, we assessed the gender gap in authorship with three metrics: role in publication, degree credentials, and citation count. We hypothesized women would have lower publication metrics but that the gender gap would decrease over time. This study is a bibliometric analysis of 5 major oncology journals (Cancer, Annals of Surgical Oncology, JAMA Oncology, Journal of Clinical Oncology, and International Journal of Radiation Oncology, Biology, Physics [IJROBP]) for 1990, 2000, 2010, and 2017 using the Web of Science. Full name, credentials, article citation metrics, article type, publication year and journal impact factor were collected. First names were used to identify author gender; ambiguous names were categorized via Google web and image search. In total, 9189 journal articles were identified. Overall, women represented 28.4% of first and 20.7% of senior authors. Across all journals, female representation rose between 1990 and 2017, with first authors increasing from 17.7% in 1990 to 36.6% in 2017 and female senior authors increasing from 11.7% in 1990 to 28.5% in 2017. With male senior authors, the first author was more likely to be male (71.4% male; 25.0% female); with female senior authors, first authors were 50.2% male and 47.6% female. IJROBP had the lowest female representation amongst first (25.1%) and senior (16.7%) authors. Women first-authored 30.5% of reviews, 29.9% of articles, 27.3% of editorials, and 22.3% of letters and notes. Credentials could be identified for 71% of authors. Female authors had more MD/Masters degrees than men, who held more MDs and MD/PhDs; this was more pronounced for senior authors (women: 47.9% MD, 11.6% MD/PhD, 9.6% MD/Masters; men: 61.9% MD, 18.7% MD/PhD, and 4.1% MD/Masters). For the 50 most cited articles per year in each journal, female authors comprised a smaller percent of first (26.5%) and senior (19.9%) authors compared to all articles. Average article citation counts were higher for male first (44.8) and senior (47.1) authors compared to female first (39.7) and senior (44.1) authors. Although female oncologists have made significant strides in closing the gender gap in academic publishing, substantial gendered differences remain. Including more women in oncology research will benefit academic diversity, productivity, and recruitment efforts, especially in technical fields such as radiation oncology. Since our work shows female senior authors play a significant role in mentoring or collaborating with other women academics, it is important to foster the advancement of women in leadership.

PlotROC: A Tool for Plotting ROC Curves.

Plots of the receiver operating characteristic (ROC) curve are ubiquitous in medical research. Designed to simultaneously display the operating characteristics at every possible value of a continuous diagnostic test, ROC curves are used in oncology to evaluate screening, diagnostic, prognostic and predictive biomarkers. I reviewed a sample of ROC curve plots from the major oncology journals in order to assess current trends in usage and design elements. My review suggests that ROC curve plots are often ineffective as statistical charts and that poor design obscures the relevant information the chart is intended to display. I describe my new R package that was created to address the shortcomings of existing tools. The package has functions to create informative ROC curve plots, with sensible defaults and a simple interface, for use in print or as an interactive web-based plot. A web application was developed to reach a broader audience of scientists who do not use R.

Characterization of prostate cancer information available on smartphones.

e15102 Background: When seeking information regarding prostate cancer, patients are often turning to Smartphones. We decided to look at the “top applications” (apps) on the iTunes store to determine the quality of information provided. Methods: In November 2011 on an iPhone the search “Prostate Cancer” was entered. The first page of apps was downloaded and studied (18 in total). They were categorized into apps written at a provider level and apps written for a patient level. The patient apps were then broken into patient support, cancer detection, disease monitoring, advertisements, and patient knowledge. The quality of paid apps was also looked at. Results: Of the 18 apps, two were unrelated to prostate cancer. Of the remaining 16, six were provider apps. Of these six, two were apps for major oncology journals, three were staging guidelines, and one was for a general oncology reference guide. Of the patient directed apps, patient information (general prostate cancer information) apps were four, two were apps to provide support, one was devoted to disease detection which included discussions on prostate specific antigen testing, one for monitoring disease, and one was an advertisement for a radiation technique. One app, once downloaded, required additional payment and personal information prior to giving the promised information. This application was not pursued. Paid apps accounted for eight apps. Two were geared toward providers. Both were prostate cancer staging guidelines. The patient directed paid apps included two apps which provided medically appropriate, level one evidence based information. Two provided information that wasn’t based on accepted medical therapy, including diet advice to prevent cancer and “alternative therapies” including reflexology, roots, and hypnosis as therapies. All free apps that were devoted to prostate cancer were based on level one evidence. Two additional paid apps were unrelated to prostate cancer. Conclusions: The majority of applications available over the iTunes store provide solid evidence and may be a valuable resource to patients and providers. Only the patient directed paid apps provided information that can be deemed questionable.

CONSORT 2010: progress and challenges

State of the literature Poor reporting of the medical literature has been recognized as a serious problem for decades [1,2]. This has a multitude of economic, policy and clinical implications [3]. Worldwide, each year over US$100 billion is spent on health research. This research, in turn, is relied on heavily by clinicians and policy-makers alike to make decisions about patient care. Randomized controlled trials (RCTs) have been the focus of particular scrutiny because of their direct impact on health care. For instance, systematic reviews of RCTs, the widely-recommended vessel for determining efficacy for health care interventions, are often severely and frequently hampered in what they conclude because of inadequate reporting of included RCTs [4]. When authors fail to adequately describe RCT methods (i.e., how treatments should be administered or what outcomes were measured, when and how) and results, their data are of limited use to reviewers, and in turn, cannot be used to make the decisions for which they were intended. Ultimately, the money spent on funding such research goes to waste when their reports do not accurately and/or completely reflect what was done. This is not only unfortunate; some argue, it is unethical, immoral and unacceptable [3,5]. In order to implement successful treatments and thereby, replicate successful outcomes in practice, clinicians need to be presented with complete descriptions about treatments, know which outcomes will be affected and have all the information available to help determine whether bias was present that may affect study findings. As obvious as this may seem, particularly in today’s age of evidence-based healthcare, the majority of RCTs are still largely incompletely reported. In a sample of 80 RCTs and systematic reviews published over a 1-year period (October 2005– October 2006), Glasziou et al. found that only 49% of trials sufficiently described the details of the interventions (i.e., timing, dose, duration and frequency of treatment, route of administration and any monitoring used) [6]. More recently Duff et al., found that the methodological reporting of a sample of RCTs from major oncology journals was inconsistent and deficient in describing at least ten items about cancer therapies deemed essential by oncologists applying them [7]. Only 11% of 262 trials sampled reported all ten items completely. Due to the complex nature of cancer and other treatments, it essential that studies evaluating them provide all the necessary information a clinician might need to implement successful treatments in practice. Reporting of trial outcomes has also been found to be incomplete and inconsistent. A recent systematic review, based on 16 studies, each comparing a median of 54 RCTs to their available protocols or registry entries, found that up to 50% of trial reports omitted, introduced or changed at least one primary outcome from what was stated in the protocol [8]. The review also identified a number of other common

Conflict of interest in oncology publications

Disclosure of conflicts of interest in biomedical research is receiving increased attention. The authors sought to define current disclosure policies and how they relate to disclosure statements provided by authors in major oncology journals. The authors identified all oncology journals listed in the Thomson Institute for Scientific Information and sought their policies on conflict-of-interest disclosure. For a subset of journals with an Impact Factor >2.0, they catalogued the number and type of articles and the details of the published disclosures in all papers from the 2 most recent issues. Disclosure policies were provided by 112 of 131 journals (85%); 99 (88%) of these requested that authors disclose conflicts of interest (mean Impact Factor for these journals: 4.6), whereas the remaining 13 (12%) did not (mean Impact Factor: 2.9). Ninety-three journals (94%) required financial disclosure, and 42 (42%) also sought nonfinancial disclosures. For a subset of 52 higher-impact journals (Impact Factor >2.0), we reviewed 1734 articles and identified published disclosures in 51 journals (98%). Many of these journals (31 of 51, 61%) included some disclosure statement in >90% of their articles. Among 27 journals that published editorials/commentaries, only 14 (52%) included disclosures with such articles. There was no publication of any nonfinancial conflicts of interest in any article reviewed. Disclosure policies and the very definition of conflict of interest varied considerably among journals. Although most journals had some policy in this area, a substantial proportion did not publish disclosure statements consistently, with deficiencies particularly among editorials and commentaries.

Characterization of Published Errors in High-Impact Oncology Journals

To assess the frequency and propagation rate of published errors in the oncology literature and to determine possible contributing factors. We reviewed 10 major oncology journals to determine variability in the online presentation of errata. Canadian oncologists were surveyed regarding characteristics that may influence error propagation. Errors published during 2004-2007 in the Journal of Clinical Oncology (jco) and the Journal of the National Cancer Institute (jnci) were classified as trivial or serious (that is, whether change in outcome was involved). The frequency of citation and error propagation was determined for serious errors. Of the 10 journals reviewed, 9 present links from the original article to the erratum; in 4 of those 9 journals, at least 1 link was missing. Survey results indicate that 33% of oncologists do not read errata, and 45% have read only the abstract when referencing an article. Although 59% of oncologists have noticed errors in cancer publications, only 13% reported the error. Together, jco and jnci published 190 errata, for an error rate of 4% ± 1% (standard deviation) annually; 26 of 190 errors were serious (14%). The median time from publication of the article to the corresponding erratum was 3.5 months for trivial errors as compared with 8.3 months for serious errors (p = 0.03). Error propagation in citations before and after publication of the erratum was 15% and 2% respectively (p < 0.01). Error rates in high-impact oncology journals average 4%, which is likely an underestimate, because errors noticed by readers are not consistently reported. Propagation of serious errors decreases, but still continues, after publication of errata.

Adequacy of Published Oncology Randomized Controlled Trials to Provide Therapeutic Details Needed for Clinical Application

Randomized controlled trials (RCTs) improve clinical care through evidence-based results. Guidelines exist for RCT result reporting, but specific details of therapeutic administration promote clinical application and reproduction of the trial design. We assess the reporting methodology in RCTs published in major oncology journals. Ten essential elements of RCT reporting were identified and included drug name, dose, route, cycle length, maximum number of cycles, premedication, growth factor support, patient monitoring parameters, and dosing adjustments for hematologic and organ-specific toxicity. All therapy-based oncology RCTs published between 2005 and 2008 in the New England Journal of Medicine (NEJM), Journal of Clinical Oncology (JCO), Journal of the National Cancer Institute (JNCI), Blood, and Cancer were analyzed for inclusion of these 10 elements. Of 339 identified articles, 262 were included in the final analysis (165 from JCO, 31 from NEJM, 27 from Cancer, 20 from JNCI, and 19 from Blood). Premedication, growth factor support, and dose adjustments for toxicities were each reported less than half of the time. Only 30 articles (11%) met the main objective of complete data reporting (ie, all 10 essential elements) and was highest in JNCI (5/20; 25%), followed by Cancer (5/27; 18%), JCO (18/165; 11%), Blood (1/19; 5%), and NEJM (1/31; 3%). The presence of an online appendix did not substantially improve complete reporting. RCTs published in major oncology journals do not consistently report essential therapeutic details necessary for translation of the trial findings to clinical practice. Potential solutions to improve reporting include modification of submission guidelines, use of online appendices, and providing open access to trial protocols.

Trends in the application of dynamic allocation methods in multi-arm cancer clinical trials

Dynamic allocation (DA) methods which attempt to balance baseline prognostic factors between treatment arms, can be used in multi-arm clinical trials to sequentially allocate patients to treatment. Although some experts express concern regarding the validity of inference from trials using DA, others believe DA methods produce more credible results. A review of published multi-arm cancer clinical trials was conducted to explore the frequency of DA use in oncology. Multi-arm phase III clinical trials of at least 100 patients per arm, published in 13 major oncology journals from 1995-2005 were manually reviewed. Information about reported use of DA methods, or randomization via random permuted blocks (PB), was extracted along with trial characteristics. Of 476 published clinical trials, 112 (23.5%) reported using some form of DA method, while 103 (21.6%) reported using PB methods. Most trials (403 or 84.7%) reported stratifying on at least one baseline factor. The mean number of stratification factors was 2.70 per trial, and 78.6% of DA trials reported 3 or more stratification factors compared with 30.2% of non-DA trials (p < 0.001). The frequency of DA use increased over time, with 20.2%, 21.3%, 25.8%, 28.8% and 38.9% of trials reported use in 1995-2001, 2002, 2003, 2004, and 2005, respectively. Use of DA methods was more frequently reported in trials involving an academic co-operative group (28.4% vs. 13.8%), however, no difference was observed between industry-funded and other-funded trials (24.0% vs. 23.2%) or geographical region (19.7% of North American trials, 26.2% of European trials and 21.7% of multinational/other trials). As a retrospective analysis, the true frequency of DA use is likely underreported. Few trials gave complete details of the allocation method used, thus it is possible some manuscripts reported incorrect allocation methods. Journals were selected which were assumed to publish most large, multi-arm clinical trials in cancer from 1995-2005, however, some trials were likely reported in journals other than what was reviewed. DA methods are frequently used in multi-arm cancer clinical trials. The use of DA appears to becoming more common over time and are used more frequently when an academic cooperative group is involved. No relationship between industry funded trials or geographic region and allocation method was observed. Clinical Trials 2010; 7: 227-234. http://ctj.sagepub.com.

Abstract A98: Safety, efficacy and efficiency of phase 1 single agent trials using the accelerated titration (ATD) versus modified Fibonacci designs (STD)

Abstract Background: Phase 1 trials of oncology drugs should balance safety, ethics and efficiency; however there is limited consensus on preferred designs for first-in-human studies (FIH). Methods: We conducted a review of the major oncology journals to identify phase 1 oncology trials using ATD and the standard modified Fibonacci design (STD) published between 2000–08. Trials were limited to FIH, single agent, and patients with solid tumors, and used animal toxicology studies to determine starting dose. Data on agent, class, design, starting dose rationale, dose levels, toxicities and responses were abstracted and compared to determine the efficiency, safety, and response rate of the ATD and STD. Results: We identified 46 ATD (1270 patients) and 90 SDT (3035 patients) trials published between 2000–8. Fewer patients were treated at low dose levels (mean difference = 6) and overall (mean n = 28 and 34), there was no significant increase in the number of patients treated above the recommended phase 2 dose (RP2D) or in the mean number of treatment related-deaths on trials using the ATD versus STD (1.3% vs. 1%). Between ATD and STD, the mean number of dose levels evaluated was the same; however, the mean fold dose range evaluated was greater with the ATD. The objective response rate (ORR) was significantly higher among evaluable patients on ATD versus STD trials (2.7% vs. 1.7%, p=.02 1-sided). These results suggest a gain in efficiency both by limiting numbers of patients and numbers of dose levels required to establish the RP2D and by improving the number of patients treated at biological active doses. Most ATD trials used designs 3 and 4, which utilize single patient cohorts and 100% dose escalations and 48% of the ATD trials utilized intra-patient dose escalation (IPDE); thus, more patients overall were treated closer to the RP2D. Both ORR and numbers of treatment-deaths were higher in trials using IPDE. Excess treatment-related deaths did not appear to occur for IPDE patients. Total death rates were 1.71% for STD trials and 1.42% for ATD trials (0.94% for trials without IPDE and 1.90% for trials with IPDE) suggesting either an increase in treatment- versus disease-related deaths in IPDE trials or potential bias in attribution. Proportionately more ATD versus STD trials used 1/10th the LD10 from murine models to determine the starting doses, tested agents that could be classified within traditional chemotherapy classes and reported dose-limiting hepatotoxicity and mucositis. Conclusions: Our results support the safety, efficiency and efficacy of the ATD designs and suggest that the ATD is preferable to the STD. The role of IPDE requires further evaluation. ATD versus STD Trials ATD STD 1-s. p-value Total Trials (n) 46 (22 with IPDE) 90 Total patients (n) 1270 3035 Mean patients/trial 27.6 33.7 p=.01 Overall response rate among evaluable pts [restricted to IPDE trials in ()] 2.73% 1.69% p=.02 (3.49%) (p=.005) Total treatment-related deaths 17 [1.34%] 30 p=.20 [IPDE trials in ()] (11 [1.75%]) [.99%] (p=.08) Mean dose levels/trial 7.8 7.3 Median dose fold-increase/trial 16.8 12.0 Mean pts &amp;gt; recommended dose 8.2 7.2 Mean doses &amp;gt; recommended dose 1.5 1.3 Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A98.

Adequacy of published oncology randomized controlled trials to provide details needed for clinical application

6536 Background: Randomized control trials (RCTs) provide evidence for life-saving and supportive therapies. Although manuscript submissions follow a standard scientific format, major oncology journals have minimal standards for reporting treatment administration. Published data investigating chemo and biologic therapy often lack details needed for effective and safe clinical application. Methods: All therapy-based phase III oncology RCTs published between 2005–2008 in the Journal of Clinical Oncology (JCO), The New England Journal of Medicine (NEJM), Journal of the National Cancer Institute (JNCI), Blood, and Cancer were eligible for inclusion. Physicians and oncology pharmacists were surveyed for details needed for clinical practice. Each article was evaluated for these mandatory elements ( Table ). Differences were calculated using the Chi-squared test. Results: Literature search identified 339 eligible articles, 77 were reviews or meta-analyses. 262 were included in the final analysis (165 JCO; 31 NEJM; 27 Cancer; 20 JNCI; 19 Blood). Only 31 (12%; median score 7.3) met the main objective of complete data reporting. The most consistently reported and missing elements are described in Table 1. Premedications, growth factor support, and dose adjustments for hematologic or organ toxicity were reported less than half the time (p&lt;0.0001). The presence of an online appendix did not significantly improve the results (data not shown). Conclusions: RCTs published in top tier oncology journals fail to consistently report full details needed for clinical application. Manuscript submission guidelines should be modified to promote consistent reporting with potential use of online appendices. Standardized editorial policy may allow safe and effective translation of trial drug findings into clinical practice. [Table: see text] No significant financial relationships to disclose.

The Multi-Institutional Phase I Study: Disadvantages Without Advantages?

The famous Dutch soccer player Johan Cruijf, who now is a commentator for Dutch television, introduced the saying that “Every advantage has its disadvantage” (or vice versa). Does this also apply to the multi-institutional phase I study? Phase I studies are the core of drug development. Among many other aims, they are essential for the identification of safety risks and for the selection of a drug dose that can be used for further development. Drug development is a highly competitive field, and therefore, time is of the essence. This means that every phase I study should provide information as quickly as possible; with the highest possible certainty; and, preferably, with the fewest possible patients, given the limited chance for actual patient benefit. With the assumption that adding more centers would be the optimal strategy to speed patient accrual, pharmaceutical industries in particular are currently pursuing the model of large, multicenter, phase I studies in a continuous drive to further expand these numbers. In addition to this, end points also are changing—from the usual and well-defined maximum-tolerated dose (MTD) to the more obscure and undefined optimal biologic dose (OBD)— because of the shifting focus of mechanism of action of anticancer drugs. In the current issue of theJournalofClinicalOncology, Dowlati et al 1 present an interesting literature review that involves 463 phase I studies that were published during 8 years in two major oncology journals: JCO and Clinical Cancer Research. This selection presents a possible limitation of the analysis, because both journals, although international, are based in the United States. The analysis, therefore, seems to present some publication imbalance, as 70% of the reviewed studies were performed in North America. Although this may cause the performance of phase I studies performed in the rest of the world to be overlooked, it is likely a minor issue when assessing the results of the study. Nearly 60% of the reported studies were pharmaceutical industry–sponsored, which reflects new drug development that largely is—and will likely remain—a pharmaceutical industry–related initiative. Interestingly, only 30% of the studies reported the accrual time. If we first look at the number of sites involved, 55% of phase I studies were performed at a single institution, whereas other studies were performed in two to 16 sites. The large numbers at the upper boundary are surprising, because it is a real challenge to keep all sites informed on a real-time basis about safety issues observed in patients. Although the authors indicated that there was no significant change over time in the proportion of studies that involved multiple institutions, it is notable that 17.3% of the 249 trials reported until 2003 involved three or more sites, whereas 27% of the 214 trials reported in 2003 and beyond involved three or more sites. This is consistent with the collective experience and the concerns of numerous investigators in phase I trials, and it probably indicates that we indeed are involving more and more centers in phase I trials. There was no correlation between the number of participating sites and the mechanism of drug action. One would have expected that, in studies with potentially difficult accrual because of limitations (such as the presence of a specific and infrequently expressed molecular target), more centers would have been required. Apparently, the trend is not to limit the involvement of larger numbers of centers to only such studies but rather to pursue the expansion of the number of participating centers in all phase I studies. In the analysis of Dowlati et al, 1 chemoradiotherapy and gene therapy phase I studies often involved three or more sites. Diseasespecific phase I studies also were more likely to be multi-institutional compared with general solid tumor studies. In contrast, there did not seem to be an association between the involved sponsor and the number of participating institutions. The possibility of bias in this observation may be related to the fact that the analysis basically involved only industry-initiated and NCI-related studies. Other independent organizations, such as the European Organisation for Research and Treatment of Cancer, have always minimized the numbers of sites in phase I studies but were not part of the analysis. Accrual time was not different when comparing trials that in

Confidence Intervals and Survival Estimates

Kaplan-Meier methods generate an estimate of survival when follow-up is less than complete. Confidence intervals (CI) provide a range of values that is likely to contain the true result. We hypothesized that reporting of CI around survival estimates is not uniform. We searched all articles in randomly selected issues of Journal of Clinical Oncology (JCO), Cancer, and International Journal of Radiation Oncology Biology, and Physics (IJROBP) years 1999, 2001, and 2004. Articles reporting overall or median survival were reviewed to determine if CI were reported in text or graphical form. Data regarding disease site, intervention, study size, and type of study were collected. A total of 313 articles reported overall or median survival from 35 issues of the 3 journals (IJROBP 115, JCO 132, Cancer 66). CI were reported in 97/313 (31.0%) articles reviewed. CI reporting was more common in prospective clinical trials (38%) than retrospective reviews (25%), P = 0.018. If patients were treated with chemotherapy the article was more likely to report CI (no chemo 20% versus chemo 40%; P = 0.001). CI reporting varied with journal (IJROBP 20%, Cancer 29%, JCO 42%, P = 0.001). CI reporting increased according to year of publication (25% in 1999, 27% in 2001, and 41% in 2004, P = 0.03). A majority of studies in major oncology journals do not report CI with survival estimates. The likelihood of reporting CI is associated with study type (prospective versus retrospective), use of chemotherapy, journal, and year of publication.