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Objective: Rapid access to neurosurgical decisions and definitive management are vital for the outcome of neurocritical patients. There are unique challenges associated with the provision of services required to maintain critical infrastructure for rural citizens. Given that a relationship between rurality, marginalization, and health outcomes has been identified as associated with higher mortality rates and higher rates of many diseases, the authors studied whether worse clinical outcomes were associated with rurality in pediatric neuro-oncological disease., Methods: Using linked administrative databases, the authors retrospectively analyzed a population-based cohort of patients diagnosed with a pediatric brain tumor between 1996 and 2017 in Ontario, Canada. The main variable of interest was the Rurality Index for Ontario (RIO; larger value denotes more rural); the main outcome was survival, while controlling for surgery and tumor type., Results: Of the 1428 patients included, 53.9% were male. Overall survival of all the children (controlling for surgery and tumor type) at 1, 5, and 10 years was 84.7%, 65.1%, and 58.4%, respectively. A total of 11.5% were classified as living in a rural area of Ontario. The distance to the nearest pediatric neurosurgical hospital ranged from 25.6 to 167.4 km. The RIO score was 0 in 38.7% of children, and the majority of patients had a RIO score < 40. A higher RIO score was not a significant factor (continuous p = 0.12/ordinal p = 0.18) associated with length of follow-up, indicating that rurality was not significantly linked to compliance with clinical follow-up., Conclusions: Rurality of the region in which pediatric neuro-oncological patients reside was not associated with patient outcome (HR 0.83, p = 0.39).

The Canadian Cancer Clinical Trials Network (3CTN) was established in 2014 to address the decline in academic cancer clinical trials (ACCT) activity. Funding was provided to cancer centres to conduct a Portfolio of ACCTs. Larger centres received core funding and were paired with smaller centres to enable support and sharing of resources. All centres were eligible for incentive-based funding for recruitment above pre-3CTN baseline. Established performance measures were collected and tracked. The overall recruitment target was 50% above pre-3CTN baseline by Year 4. An analysis was completed to identify predictive success factors and descriptive statistics were used to summarize site characteristics and outcomes. From 2014-2018, a total of 11,275 patients were recruited to 559 Portfolio trials, an overall increase of 59.6% above pre-3CTN baseline was observed in Year 4. Twenty-five (51%) adult centres met the Year 4 recruitment target and the overall recruitment target was met within three years. Three factors that correlated with sites' achieving recruitment targets were: time period, region and number of baseline trials. 3CTN was successful in meeting its objectives and will continue to support ACCTs and member cancer centres, monitor performance over time and seek continued funding to ensure success, better trial access and outcomes for patients.

Traditionally, drug development has evaluated dose, safety, activity, and comparative benefit in a sequence of phases using trial designs and endpoints specifically devised for each phase. Innovations in drug development seek to consolidate the phases and rapidly expand accrual with "seamless" trial designs. Although consolidation and rapid accrual may yield efficiencies, widespread use of seamless first-in-human (FiH) trials without careful consideration of objectives, statistical analysis plans, or trial oversight raises concerns. A working group formed by the National Cancer Institute convened to consider and discuss opportunities and challenges for such trials as well as encourage responsible use of these designs. We reviewed all abstracts presented at American Society of Clinical Oncology annual meetings from 2010 to 2017 for FiH trials enrolling at least 100 patients. We identified 1786 early-phase trials enrolling 57 559 adult patients. Fifty-one of the trials (2.9%) investigated 50 investigational new drugs, were seamless, and accounted for 14.6% of the total patients. The seamless trials included a median of 3 (range = 1-13) expansion cohorts. The overall risk of clinically significant treatment-related adverse events (grade 3-4) was 49.1% (range = 0.0-100%), and seven studies reported at least one toxic death. Rapid expansion of FiH trials may lead to earlier drug approval and corresponding widespread patient access to active therapeutics. Nevertheless, seamless designs must adhere to established ethical, scientific, and statistical standards. Protocols should include prospectively planned analyses of efficacy in disease- or biomarker-defined cohorts of sufficient rigor to support accelerated approval., (© The Author(s) 2018. Published by Oxford University Press.)

Chemotherapy fails to provide durable cure for the majority of cancer patients. To identify mechanisms associated with chemotherapy resistance, we identified genes differentially expressed before and after chemotherapeutic treatment of breast cancer patients. Treatment response resulted in either increased or decreased cell cycle gene expression. Tumors in which cell cycle gene expression was increased by chemotherapy were likely to be chemotherapy sensitive, whereas tumors in which cell cycle gene transcripts were decreased by chemotherapy were resistant to these agents. A gene expression signature that predicted these changes proved to be a robust and novel index that predicted the response of patients with breast, ovarian, and colon tumors to chemotherapy. Investigations in tumor cell lines supported these findings, and linked treatment induced cell cycle changes with p53 signaling and G1/G0 arrest. Hence, chemotherapy resistance, which can be predicted based on dynamics in cell cycle gene expression, is associated with TP53 integrity.

Background: Substantial staff time and costs are incurred in the collection of data for cancer clinical trials. Anecdotal experience suggests that much of these data are never used in the analysis or reporting of a trial., Purpose: To quantify data items collected in cancer clinical trials and calculate what percentage is used in subsequent published manuscripts., Methods: Cancer clinical trials completed by the Ontario Clinical Oncology Group (OCOG) between 2003 and 2012 and the corresponding primary outcome publication were identified. The number of data items collected on each trial's case report form (CRF) was counted and sorted into 18 categories including eligibility, baseline characteristics, medical history, toxicity, and recurrence. The data items were then counted within the corresponding published manuscripts to determine percent of data used overall and within each section., Results: In all, 8 trials, with 9 corresponding publications, were evaluated. The CRF analysis revealed that the total collected items per subject ranged from 186 to 1035 per trial with a median of 599. Across all the publications, a median of 96 data items (18%) were reported in each manuscript, ranging from 11% to 27% per trial. In 8 of the 18 categories, 4% or less of collected data items were used., Limitations: The number of trials reviewed is small and were conducted from a single clinical trial coordinating centre. The main outcome of the number of data items used in the published manuscript is a surrogate for trial information considered valuable by investigators. Some data may be deemed important by investigators but not included in manuscripts., Conclusions: In this analysis of publications from 8 clinical trials, a small amount of data collected was ultimately used in peer-reviewed journal manuscripts. A large amount of data collected in cancer trials appears to go unused and could be omitted from CRFs, thus simplifying data collection and improving trial efficiency.

Background: In designing phase III randomized clinical trials (RCTs), the expected magnitude of the benefit of the experimental therapy (δ) determines the number of patients required and the number of person-years of follow-up. We conducted a systematic review to evaluate how reliably δ approximates the observed benefit (B) in RCTs that evaluated cancer treatment., Methods: RCTs evaluating systemic therapy in adult cancer patients published in 10 journals from January 1, 2005, through December 31, 2009, were identified. Data were extracted from each publication independently by two investigators. The related-samples Sign test was used to determine whether the median difference between δ and B was statistically significant in different study subsets and was two-sided., Results: A total of 253 RCTs met the eligibility criteria and were included in the analysis. Regardless of whether benefit was defined as proportional change (median difference between δ and B = -13.0%, 95% confidence interval [CI] = -21.0% to -8.0%), absolute change (median difference between δ and B = -8.0%, 95% CI = -9.9% to -5.1%), or median increase in a time-to-event endpoint (median difference between δ and B = -1.4 months, 95% CI = -2.1 to -0.8 months), δ was consistently and statistically significantly larger than B (P < .001, for each, respectively). This relationship between δ and B was independent of year of publication, industry funding, management by cooperative trial groups, type of control arm, type of experimental arm, disease site, adjuvant treatment, or treatment for advanced disease, and likely contributed to the high proportion of negative RCTs (158 [62.5%] of 253 studies)., Conclusions: Investigators consistently make overly optimistic assumptions regarding treatment benefits when designing RCTs. Attempts to reduce the number of negative RCTs should focus on more realistic estimations of δ. Increased use of interim analyses, certain adaptive trial designs, and better biological characterization of patients are potential ways of mitigating this problem.

Objective: There appears to be considerable confusion about the interpretation of phase II clinical trial conclusions as contrasted with the alternative (HA) and null (H0) hypotheses. This study was conducted to evaluate whether there is congruence with numerical results of phase II trials and their overall verbal conclusions., Methods: A literature search of 2006 and 2007 phase II clinical trials was conducted. The alternative and null hypotheses were noted as were point estimates with confidence intervals (CIs). These were compared with the final conclusions and concordance and discordance rates were calculated., Results: A total of 152 eligible analyses were reviewed. The point estimates were below H0 in 42 (27.6%) trials, above HA in 60 (39.4%) trials and between H0 and HA (i.e. the grey zone) in 50 (32.9%) trials. Thirty-three (21.7%) trials reported negative conclusions, 111 (73.0%) reported positive conclusions and 8 (5.3%) were ambiguous. All 60 trials in which the point estimate was greater than HA reported positive conclusions, as did 40/50 (80.0%) of trials with point estimates in the grey zone., Conclusions: There exist inconsistencies and ambiguities in the conclusions drawn from phase II trials, particularly when results are in the grey zone (greater than H0 but less than HA). This may make the integration of phase II trials in phase III trial development strategies difficult and better understanding of the statistical properties of phase II clinical trials is required., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objectives: To compare the quality of informed consent forms (ICF) for different trial phases, funding sources, oncology subspecialties, disease settings, and intervention modalities., Methods: ICF for prospectively conducted clinical trials were examined for their descriptions of benefits and risks, study alternatives, voluntary participation, and confidentiality. Readability was assessed with Flesch Reading Ease (FRE) score and Flesch-Kincaid Reading Grade Level., Results: Among 262 evaluable trials, ICF contained an average of 3982 words, 379 sentences, and 10.5 pages. The mean FRE score and Reading Grade Level were 61.2 and 7.4, respectively. All ICF explicitly stated that the intervention was investigational. Only 2 (1%) promised direct personal benefits, 16 (6%) suggested the chance of cure or prolonged survival, and 89 (34%) indicated a potential for tumor response. Conversely, 239 (91%) mentioned the risk of serious harms, 217 (83%) admitted that some side effects could be unknown or unpredictable, and 126 (48%) reported hospitalization or death as a possibility. Alternatives to participation, right to withdraw from study, and data confidentiality were addressed in 242 (92%), 254 (97%), and 260 (99%) ICF, respectively. Hematology, industry-funded, metastatic, and systemic therapy trials were most likely to highlight major risks (P < 0.05). Readability was better in phase I trials and in studies, which were performed by medical oncologists, sponsored by governmental agencies, conducted in the metastatic setting, and involved systemic therapy (P < 0.05)., Conclusions: ICF had acceptable readability and provided a realistic overview of the benefits and risks of clinical trials, but the potential for hospitalization or fatality was underreported.

Background: Evaluation of therapeutic outcomes and risk factors was undertaken for patients with primary solid tumors (PST) developing acute leukemia or myelodysplasia (MDS) as a second malignancy., Methods: In all, 131 consecutive patients presenting to a single institution with leukemia or MDS after treatment for PST with surgery or chemotherapy/radiotherapy were examined. Management of the secondary acute leukemia and MDS consisted either of intensive therapy including allogeneic blood and marrow transplants or supportive measures., Results: The time from diagnosis of PST to development of acute leukemia or MDS, the cytogenetic profile of patients, and their survival were similar irrespective of PST therapy with surgery alone or strategies involving chemotherapy and/or radiation. The median survival of all 131 patients was 10.5 months with a 5-year survival of 15.6%. Induction therapy and/or transplantation resulted in a median survival of 13.6 months and a 5-year survival of 26.6% compared with 6.5 months and 2% with supportive measures. Subset analysis of transplant recipients revealed a median survival of 17.6 months and a 37.9% 5-year survival. Despite a significantly lower recurrence rate the survival of transplant recipients was not improved secondary to a higher treatment-related mortality (TRM) rate., Conclusions: Patients developing acute leukemia or MDS after PST demonstrated similar cytogenetic profiles and clinical outcomes independent of the type of treatment. Survival was significantly better for patients able to undergo intensive therapy compared with supportive measures. The low recurrence rate for allograft recipients was consistent with a potent antileukemic effect that may translate into a survival benefit if TRM could be reduced.

Purpose: Conference abstracts of phase I trials (P1T) communicate important anticancer drug development information. Our objectives were to determine elements essential for good P1T abstract reporting, to assess the quality of P1T abstracts submitted to American Society of Clinical Oncology (ASCO) meetings, and to propose reporting guidelines., Experimental Design: A survey of developmental therapeutics experts established elements of P1T reporting quality, and a scoring system was generated. All P1T abstracts published in ASCO Annual Proceedings from 1997 to 2006 were reviewed, and the scoring system was applied., Results: A survey was distributed twice to 69 experts, with a response rate of 39% (27 of 69). Experts rated 37 elements using a five-point scale, and elements with mean ratings over 3.75 were included in the final scoring system. One thousand six hundred and eighty three P1T abstracts were reviewed. A positive and linear association was observed between average expert rating of the elements and the proportion of P1T abstracts including those elements (Spearman correlation coefficient, rho = 0.60, P < 0.001). The median for all 1,683 abstracts was 62.5% (range, 25-95%; SD, 12.3%). Year of presentation was found to be significantly associated with higher quality scores (rho = 0.20, P < 0.001), with later years possessing better quality scores. The quality score was statistically significant as a predictor of type of presentation (odds ratio, 1.10; 95% confidence interval, 1.02-1.19 per 10% increase; P = 0.014), with oral presentations having the highest scores., Conclusions: The quality of P1T abstract reporting at ASCO has improved over time, although there is room for optimization. The quality of P1T abstract reporting may be enhanced using guidelines derived from our expert consensus.

Purpose: A tool that quantifies the risk of treatment-related toxicity based on individual patient characteristics can augment the informed consent process and safety monitoring in the setting of phase II cancer treatment trials of molecularly targeted agents (MTAs)., Methods: A regression model was constructed to predict the risk of a serious adverse event (SAE) with an MTA and presented as a nomogram. Estimation of risk can be performed by integrating risk estimates from the nomogram and from a reference or average patient. Internal validation was performed using bootstrapping techniques., Results: A total of 578 patients were treated with one of 14 MTAs given alone or in combination on one of 27 clinical trials performed by the Princess Margaret Hospital Drug Development Program between 2001 and 2006. Approximately 50% and 24% of patients experienced an SAE and an attributable SAE (SAEatt) during cycle 1, respectively. Albumin, lactate dehydrogenase (LDH), number of target lesions, prior radiotherapy, Charlson score, age, and performance status were included in the optimal model as predictors of a cycle 1 SAE, whereas the number of prior chemotherapy regimens, baseline creatinine, LDH, prior radiotherapy, Charlson score, body-surface area, and performance status were included as predictors of an SAEatt. Moderate-good internal validity was demonstrated, with area under the curve estimates ranging from 56.7% to 86.1% for all SAEs and 63.0% to 89.7% for SAEatts., Conclusion: A regression model was constructed that predicts the SAE and SAEatt risk for an individual patient during cycle 1 of phase II trial treatment with moderate to good internal validity. External validation is still required.

Purpose: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities., Experimental Design: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed., Results: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response., Conclusions: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.

Goals of Work: The quality of informed consent in phase I trials is controversial, partially due to gaps in patient understanding. We assessed an educational DVD's impact on knowledge and satisfaction in cancer patients newly referred to a phase I clinic., Materials and Methods: Forty-nine patients were randomly assigned to view an educational DVD (n = 22) which explained phase I trials or a placebo DVD (n = 27). Patients completed a questionnaire assessing knowledge of phase I studies and satisfaction with the DVD. The blinded interviewing physician (n = 8) rated the patient's understanding of phase I trials., Main Results: The mean patient age was 56; 61% were male. Patients who viewed the educational DVD were less likely to believe that phase I trials determine drug efficacy (p = 0.019), more likely to know that phase I drugs have not been thoroughly studied in humans (p = 0.003), and less likely to believe that these agents have proven activity against human cancers (p = 0.008). More patients who viewed the educational DVD agreed/strongly agreed that the DVD provided useful information (p < 0.001), were confident in their knowledge of phase I trials (p = 0.031), felt aided in their decision to enter a phase I study (p = 0.011), and would have more questions for their physicians because of the DVD (p = 0.017). No statistically significant difference in physician perception of patient understanding or phase I trial accrual was observed between the educational and placebo DVD groups., Conclusions: An educational DVD increased patient knowledge and satisfaction regarding participation in phase I clinical trials.

Background: There is a paucity of literature on the referral outcome of patients seen in phase I trial clinics in academic oncology centres. This study aims to provide information on the accrual rate and to identify obstacles in the recruitment process., Methods: A retrospective chart review was performed for all new patients referred and seen in the phase I clinic at the Princess Margaret Hospital between January 2000 and June 2005. Data on their demographics, medical history, and details of trial participation or non-entry were recorded., Results: A total of 667 new phase I referrals were seen during the stated period. Of these patients, 197 (29.5%) patients were enrolled into a phase I trial, and 64.5% of them started trial within 1 month of the initial visit. About a quarter (165 of 667) of the patients referred were deemed ineligible at their first visit, with the most frequent reasons for ineligibility being poor performance status, unacceptable bloodwork, too many prior treatments and rapid disease progression. The remaining 305 patients (45.7%) were potentially eligible at their initial visit, but never entered a phase I trial. The main reasons for their non-entry were patient refusal, other treatment recommended first, and lack of available trials or trial spots., Conclusion: This study provides information on the clinical realities underlying a referral to a phase I clinic and eventual trial enrollment. Better selection of patients, appropriate education of referring physicians, and opening phase I trials with fewer restrictions on some criteria such as prior therapy may enhance their recruitment rates.

Background: The tolerability of molecularly targeted agents in older patients has not been specifically examined. Adverse event data from clinical trials in the Princess Margaret Hospital Phase II Consortium database were analyzed to address this question., Methods: The Consortium database collects trial information on all patients treated with either a molecularly targeted agent alone or in combination since 2001. The frequency of adverse events was determined and analyzed by two different age groups, <65 years and >/=65 years. Toxicity indices (TI) and frequencies of dose-limiting toxicities (DLT), based on adverse events of all causalities (TI(ALL) and DLT(ALL)), and on adverse events that were at least possibly related to the molecularly targeted agent (TI(MTA) and DLT(MTA)), were calculated for both age groups., Results: Four hundred and one patients who received 1,252 treatment cycles were analyzed from 19 different studies. Baseline performance status was similar between both age groups, but fewer older patients have had multiple prior regimens of chemotherapy or prior radiation therapy. A comparison of the proportions of younger and older patients experiencing DLT(ALL) and DLT(MTA) showed similar results. The TI(MTA) values were comparable between the two age groups in both single agent (3.25 versus 3.00, for <65 versus >/=65 years) and multi-agent (3.65 versus 3.00, for <65 versus >/=65 years) trials., Conclusions: Older patients seem to tolerate molecularly targeted therapies either alone or in combination with chemotherapy as well as younger patients. Age alone should not be a barrier in the administration of targeted agents.

Background: The optimal cancer treatment for an older population is largely unknown because of the low numbers of elderly patients accrued into clinical trials. This project focuses on the attitudes of the elderly about participation in clinical trials to determine if this is one of the barriers to the involvement of this population in clinical trials., Methods: The first phase of this study was a self-administered questionnaire mailed to 425 elderly persons with cancer, selected from Princess Margaret Hospital oncology clinics. The second phase consisted of individual semi-structured interviews with cancer patients to assess their attitudes towards cancer, its management and enrolment into cancer clinical trials., Results: Ninety-four patients responded to the survey giving a response rate of 22.1%. Three quarters of respondents stated that they would be willing to participate in a clinical trial. The factors that most influenced older patients' willingness to participate in a cancer study were recommendations from a cancer doctor and the chance that the study treatment may help them feel better. Seventeen survey responders participated in interviews. Common themes from these interviews included patient-physician communication, the referral process, and the role of age in cancer care decision-making., Conclusion: Most elderly people, who responded to this survey, are willing to consider participation in cancer clinical trials however, elderly patients do not appear to actively seek clinical trials and few were informed of the availability of clinical trials. Physician barriers and availability of appropriate clinical trials may play a bigger role in preventing accrual of elderly cancer patients into trials.

A phase I study was conducted to determine the recommended phase II dose, safety profile and anti-tumor activity of a combination regimen of gemcitabine, doxorubicin and cisplatin (GAP). Gemcitabine (G) and doxorubicin (A) were administered on days 1 and 8 at increasing doses (starting level 800 and 15 mg/m, respectively). Cisplatin (P) was given at a fixed dose of 50 mg/m2 (day 1). Treatment cycles were repeated every 3 weeks. Nineteen patients received 76 cycles of treatment. A and G were escalated up to 20 and 1000 mg/m2, and finally de-escalated to 15 and 800 mg/m2. The dose-limiting toxicity was neutropenic fever that was observed in 21% of the patients. Non-hematological toxicities included mild/moderate nausea, vomiting, diarrhea and fatigue, observed in 58, 37, 21 and 95% of the patients, respectively. Of 19 patients with evaluable disease, six patients had a partial response yielding an overall response rate of 31.6 % (95% confidence interval 12.6-56.6%) by intention-to-treat. We conclude that GAP is an active and tolerable treatment combination, with minimal visceral organ toxicities.

Purpose: Understanding why older patients are frequently underrepresented in cancer services use and clinical research may help to increase their participation in clinical trials and eventually result in better cancer care for this vulnerable population., Methods: To identify potential barriers that may prevent older cancer patients from being referred from a primary care physician (PCP) to an oncology specialist, a self-administered questionnaire was mailed to 9,312 PCPs throughout Ontario., Results: With a one-time mailing, 2,240 questionnaires were returned (response rate, 24%) of which 2,089 (93%) were assessable. Although 86% of respondents would refer most older patients with early-stage, potentially curable cancers to oncologists, only 65% would refer those with advanced-stage, potentially incurable cancers. The factors that most influence referral decisions of PCPs are patient's desire to be referred (69%), type (54%) and stage (49%) of cancer, and severity of cancer symptoms (49%). Other factors including age do not seem to influence the referral decision. Approximately 9% of respondents found it difficult to refer older cancer patients to oncology specialists, with the most commonly cited barriers being the length of waiting lists, mandatory tissue diagnosis before referral, and the belief that oncologists seldom relate to PCPs., Conclusion: Most PCPs stated that they would refer all elderly patients with cancer to oncologists and that referral decisions were based mainly on patients' wishes. Continued efforts are needed to overcome barriers in the referral process and to understand the perspectives of elderly patients to enhance their cancer care.