Publication status of contemporary oncology randomised controlled trials worldwide

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

Bias in reporting of randomised clinical trials in oncology

BackgroundBias in reporting efficacy and toxicity in clinical trials may impact treatment decisions. Here, we report quality of reporting of efficacy and of toxicity in articles describing randomised controlled trials (RCTs) of cancer therapy and the association between biased reporting and study results, funding and financial relationships of the authors with the sponsor.Materials and methodsWe reviewed articles published from July 2010 to December 2012 in six high-impact journals reporting RCTs of systemic treatment for cancer. Bias in reporting of the primary end-point and toxicity were assessed. Associations between biased reporting and study results, funding source and financial ties of the author with the funding source were evaluated using logistic regression.ResultsTwo hundred articles were identified. Among 107 RCTs where there was no statistically significant difference in the primary end-point between the two arms, 50 (47%) reports used biased reporting in the abstract of the paper to imply benefit of the experimental treatment. Toxicity was not reported in the abstract in 18.5% of the studies and this was associated with a positive primary end-point. Source of funding and financial ties were not associated with biased reporting.ConclusionsBias in reporting of efficacy outcomes is common for studies with a negative primary end-point and can lead to off-label misuse of experimental therapies, if they are approved for other indications. Toxicity is under-reported, especially for studies with a positive primary end-point, leading to a biased view of the safety of new treatments.     

Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: A phase III multicentre randomised controlled trial

BackgroundThe role of neoadjuvant chemotherapy (NACT) for locoregionally advanced nasopharyngeal carcinoma (NPC) is unclear. We aimed to evaluate the feasibility and efficacy of NACT followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone in locoregionally advanced NPC.MethodsPatients with stage III–IVB (excluding T3N0-1) NPC were randomly assigned to receive NACT followed by CCRT (investigational arm) or CCRT alone (control arm). Both arms were treated with 80 mg/m² cisplatin every 3 weeks concurrently with radiotherapy. The investigational arm received cisplatin (80 mg/m² d1) and fluorouracil (800 mg/m² civ d1–5) every 3 weeks for two cycles before CCRT. The primary end-point was disease-free survival (DFS) and distant metastasis-free survival (DMFS). Secondary end-point was overall survival (OS). Survival curves for the time-to-event endpoints were analyzed by the Kaplan–Meier method and compared using the log-rank test. The P value was calculated using the 5-year endpoints.ResultsFour hundred seventy six patients were randomly assigned to the investigational (n = 238) and control arms (n = 238). The investigational arm achieved higher 3-year DFS rate (82.0%, 95% CI = 0.77–0.87) than the control arm (74.1%, 95% CI = 0.68–0.80, P = 0.028). The 3-year DMFS rate was 86.0% for the investigational arm versus 82.0% for the control arm, with marginal statistical significance (P = 0.056). However, there were no statistically significant differences in OS or locoregional relapse-free survival (LRRFS) rates between two arms (OS: 88.2% versus 88.5%, P = 0.815; LRRFS: 94.3% versus 90.8%, P = 0.430). The most common grade 3–4 toxicity during NACT was neutropenia (16.0%). During CCRT, the investigational arm experienced statistically significantly more grade 3–4 toxicities (P < 0.001).ConclusionNACT improved tumour control compared with CCRT alone in locoregionally advanced NPC, particularly at distant sites. However, there was no early gain in OS. Longer follow-up is needed to determine the eventual therapeutic efficacy.     

Cardiac toxicity events in the PHARE trial,an adjuvant trastuzumab randomised phase III study

BackgroundThis article reports, the cardiac toxicity according to 6- versus 12-month durations of adjuvant trastuzumab in PHARE randomised trial (NCT00381901).Patients and methodsCardiac follow-up and Left Ventricular Ejection Fraction (LVEF) assessment by echocardiography or multigated acquisition scan were performed every 3 months while patients received trastuzumab and after completion of treatment over the first 2 years and every 6 months afterwards. The primary cardiac end-point was Cardiac Heart Failure (CHF) defined as New York Heart Association (NYHA) class III or IV. The secondary cardiac end-points were: cardiac events, cardiac dysfunctions defined by NYHA class I and II; LVEF decreases, cardiac recoveries. The cardiac subcommittee reviewed cardiac events and assessed if patients had favourable outcomes or not on the basis of trends from LVEF measurements.ResultsAmong 3380 patients the cardiac dysfunction assessment included 14,055 and 13,218 LVEF measurements in the 12- and 6-month arms. The overall incidences of CHF were 0.65% (11/1690) and 0.53% (9/1690) in the 12 and 6 month arms, respectively (p > 0.05). Cardiac dysfunction occurred in 5.9% (100/1690) and 3.4% (58/1690) of patients in the 12 and 6 month arms, respectively (p = 0.001). Recoveries were observed for the majority patients and 0.79% (27/3380) of patients experienced an unfavourable cardiac outcome.ConclusionPHARE confirm that the incidence of cardiac end-points remains low and mostly reversible after trastuzumab. Identification at baseline of cardiac risk categories of patients should be of interest to provide an optimal adaptation of adjuvant modalities and a shorter duration might be an option.     

The impact of bevacizumab on health-related quality of life in patients treated for recurrent glioblastoma: Results of the randomised controlled phase 2 BELOB trial

BackgroundThe BELOB study, a randomised controlled phase 2 trial comparing lomustine, bevacizumab and combined lomustine and bevacizumab in patients with recurrent glioblastoma, showed that the 9-month overall survival rate was most promising in the combination arm. Here we report the health-related quality of life (HRQoL) results, a secondary trial end-point.MethodsHRQoL was measured at baseline and every 6 weeks until progression using the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20). HRQoL was assessed over time for five preselected scales (global health (GH), physical (PF) and social functioning (SF), motor dysfunction (MD) and communication deficit (CD)). Moreover, mean changes in HRQoL from baseline until progression were determined.Results138/148 patients with at least a baseline HRQoL assessment were analysed. Over time, HRQoL remained relatively stable in all treatment arms for all five scales, at least during the first three treatment cycles. More than half (54–61%) of the patients showed stable (<10 point change) or improved (⩾10 point change) HRQoL during their progression-free time, except for SF (43%), irrespective of treatment arm. Deterioration of mean HRQoL was most profound at disease progression for all scales except SF, which deteriorated earlier in disease course. Compared to baseline, 40% of patients had clinically relevant (⩾10 points) worse GH, PF and SF, while 44% and 31% had increased MD and CD at disease progression, irrespective of treatment arm.ConclusionsBevacizumab, whether or not in combination with lomustine, did not negatively affect HRQoL in patients treated for recurrent glioblastoma in this randomised study.     

Tamoxifen reduces the risk of contralateral breast cancer in premenopausal women: Results from a controlled randomised trial

BackgroundAdjuvant treatment with tamoxifen reduces the risk of contralateral breast cancer in hormone-responsive postmenopausal patients, whereas the effect in premenopausal women has not been fully elucidated. We have therefore studied the effect of tamoxifen on contralateral breast cancer in premenopausal women in a controlled randomised trial.Patients and methodsPremenopausal women (564) with stage II breast cancers were randomised to 2 years of tamoxifen versus control irrespective of oestrogen receptor (ER) and progesterone receptor (PgR) status. The median follow-up for patients not developing a contralateral cancer was 14 years.ResultsIn the control group 35 women, and in the tamoxifen group 17 women, developed a contralateral breast cancer as a primary event. Tamoxifen significantly reduced the risk of contralateral breast cancer in all women regardless of age (hazard ratio (HR) 0.5, p = 0.02). In subgroup analysis the risk reduction was most pronounced in patients <40 years of age (HR 0.09, p = 0.02). A risk reduction was also seen in women 40–49 years of age or ?50 years of age, although in these subgroups this did not reach statistical significance. The reduced risk of contralateral breast cancer was persistent during the whole follow-up time.ConclusionIn this randomised trial, adjuvant treatment using tamoxifen for 2 years reduced the incidence of contralateral breast cancer by 50% in all premenopausal women, and by 90% in women <40 years of age. The effect of tamoxifen was not significantly dependent on time.     

Unequal allotment of patients in phase III oncology clinical trials

Patient enrollment in cancer clinical trials has traditionally been limited to an equal distribution between cases and controls, however recently some clinical trials have utilized an unequal distribution between the case and control arms. Trends and proportion of phase 3 cancer clinical trials that have an unequal allocation between the years 2010 and 2019 were studied from data extracted from clinicaltrials.gov. 323 trials with two arms and 35 trials with 3 arms were identified as randomized control trials with the primary purpose of a cancer-related treatment that provided allocation data. Amongst the trials with two arms, 238 trials had equal allocation and 85 trials had unequal allocation. Therefore, cancer clinical trials with unequal allocation represent about one in four 2-arm phase 3 trials. Amongst the eligible trials with three arms, 26 trials had equal allocation and 9 trials had unequal allocation. There was no significant difference in the annual proportion of trials with unequal allocation from 2010 to 2019. The categories of cancer which had the highest number of unequally allotted two-arm clinical trials were: gastrointestinal, breast, and genitourinary malignancies. This shift may represent a new trend in clinical trial design to help enhance closer monitoring of adverse events despite higher costs and lower statistical power attached to this method.     

Disclosing information about randomised controlled trials in oncology: training concept and evaluation of an individualised communication skills training for physicians COM-ON-rct

When physicians disclose information about randomised controlled trials, they have to balance the requirements of conducting high standard research and the respect for patients' rights. Physicians need training in this difficult matter. An individualised communication skills training (CST) about randomised controlled trials for oncologists has been developed. The aim of this publication is to describe the concept of our CST and present data of evaluation by the participants: First, a theoretical introduction about a communication model and important ethical and legal issues was presented. Individual learning goals of participants were then derived through video assessment with actor-patients. The learning goals were the basis for practicing in role play. Individual coaching helped physicians to transfer the made experience into their daily work. Forty physicians have been trained. The acceptance of the training concept was assessed by a questionnaire consisting of 14 items and using a 6-point scale from 1 (very best) to 6 (very bad): the individualised CST was highly accepted (mean = 1.33). Practicing with actor-patients (mean = 1.4), providing constructive feedback (mean = 1.3) and assessing individual learning goals (mean = 1.85) were seen as helpful. Our CST trains physicians to realise best research standards and incorporate patients' rights.     

Incomplete follow-up of positive HPV tests: overview of randomised controlled trials on primary cervical screening

Background:

It has been suggested that adjustment for incomplete compliance with follow-up in women with positive human papillomavirus (HPV) tests would be appropriate for estimating the true sensitivity of cervical screening with HPV testing. We assessed the compliance and its impact on ⩾CIN3 detection in all eight randomised controlled trials (RCT) with published baseline-round data.

Methods:

We extracted data on recommended follow-up procedures, follow-up compliance, and ⩾CIN3 detection for both arms of each RCT, and assessed their correlation.

Results:

Compliance with a direct referral for colposcopy was around 90% in all RCTs, whereas compliance with repeated testing among HPV-positive/cytology-negative women was around 60% in three RCTs and 73% in one RCT. Detection of ⩾CIN3 was significantly increased in two out of six RCTs with reported data. The correlation between compliance with follow-up in HPV-positive women and relative ⩾CIN3 detection was 0.48 (P=0.33).

Conclusion:

There is at present scant evidence to support the view that the measured sensitivity of HPV screening is a simple reflection of compliance with follow-up. Adjustment of measured cervical intraepithelial neoplasia detection on the basis of compliance data may not always be justifiable, and if adjustment is made, it should be used very judiciously.     

The challenge of conducting pharmacoeconomic evaluations in oncology using crossover trials: the example of sunitinib for gastrointestinal stromal tumour

This paper examines the challenge of conducting economic evaluations to support patient access to cancer therapies when the cost-effectiveness estimation is hampered by crossover trial design.To demonstrate these limitations, we present the submission to the Canadian Drug Review (CDR) of a cost-effectiveness evaluation of sunitinib versus best supportive care (BSC) for the treatment of gastrointestinal stromal tumour in patients intolerant or resistant to imatinib.The economic model generated an incremental cost-effectiveness ratio for sunitinib versus BSC of $79,884/quality-adjusted life-year gained. Eight months after initial submission, CDR granted a final recommendation to fund sunitinib following the manufacturer’s appeal against their first recommendation. Although cost-effectiveness is an important consideration in reimbursement decisions, there is a need for improved decision-making processes for cancer drugs, as well as a better understanding of the limitations of clinical trial design.     

Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: A randomised clinical trial on overall survival

BackgroundThe unfavourable side-effects of late-stage pancreatic cancer treatments call for non-toxic and effective therapeutic approaches. We compared the overall survival (OS) of patients receiving an extract of Viscum album [L.] (VaL) or no antineoplastic therapy.MethodsThis is a prospective, parallel, open label, monocentre, group-sequential, randomised phase III study. Patients with locally advanced or metastatic cancer of the pancreas were stratified according to a binary prognosis index, composed of tumour stage, age and performance status; and were evenly randomised to subcutaneous injections of VaL extracts or no antineoplastic therapy (control). VaL was applied in a dose-escalating manner from 0.01 mg up to 10 mg three times per week. Patients in both groups received best supportive care. The primary end-point was 12-month OS, assessed in a group-sequential analysis.FindingsWe present the first interim analysis, including data from 220 patients. Baseline characteristics were well balanced between the study arms. Median OS was 4.8 for VaL and 2.7 months for control patients (prognosis-adjusted hazard ratio, HR = 0.49; p < 0.0001). Within the ‘good’ prognosis subgroup, median OS was 6.6 versus 3.2 months (HR = 0.43; p < 0.0001), within the ‘poor’ prognosis subgroup, it was 3.4 versus 2.0 months respectively (HR = 0.55; p = 0.0031). No VaL-related adverse events were observed.ConclusionVaL therapy showed a significant and clinically relevant prolongation of OS. The study findings suggest VaL to be a non-toxic and effective second-line therapy that offers a prolongation of OS as well as less disease-related symptoms for patients with locally advanced or metastatic pancreatic cancer.     

Barriers to inclusion of older adults in randomised controlled clinical trials on Non-Hodgkin’s lymphoma: A systematic review

Background

The majority of Non-Hodgkin’s lymphoma (NHL) patients are over 65 years. Management is challenging, especially for aggressive lymphoma, and appropriate assessment of efficacy and tolerance specific to this population is crucial.

Objectives

To assess the representation of older patients in randomised controlled trials (RCT) in NHL, examining whether trial eligibility criteria prevent participation, and whether appropriate primary endpoints such as toxicity, quality of life, or geriatric assessment scores are used.

Methods

We searched Medline for articles published in English or French between 1 January 2005 and 31 December 2011 reporting on phase II/III RCT evaluating therapeutic strategies for NHL. Articles were categorised as including or excluding (directly or indirectly) older adults, and features of RCT that included or excluded older patients are compared.

Results

We identified 87 relevant RCT: 9 (10.3%) focussed exclusively on patients >65 years, 22 (25.3%) directly excluded patients >65 years, 47 (54.0%) indirectly excluded older adults through selective inclusion criteria (ECOG status, liver or kidney function, and comorbidities), and 9 (10.3%) did not directly or indirectly exclude patients >65 years (although two excluded patients >70 years). Proportions of older patients included do not reflect incidence. Trials including older adults were published in journals with lower impact factors and few RCT used appropriate endpoints for older adults.

Conclusions

Older adults are poorly represented in NHL RCT both due to direct age-based exclusion and restrictive inclusion criteria. This situation needs rapid correction to better represent older patients and thus improve cancer management in this highly prevalent population.     

Evaluating the relationship between erectile dysfunction and dose received by the penile bulb: Using data from a randomised controlled trial of conformal radiotherapy in prostate cancer (MRC RT01, ISRCTN47772397)

AIM: To evaluate the relationship between erectile function and the radiation dose to the penile bulb and other proximal penile structures in men receiving conformal radiotherapy (CFRT) for prostate cancer (PCa). METHODS: The Medical Research Council (MRC) RT01 trial randomised 843 men who had localised PCa to receive either 64 or 74 Gy after 3 - 6 months neoadjuvant hormonal treatment. Fifty-one men were selected who were potent prior to hormonal treatment, having completed both pre-hormone and 2-year post-CFRT Quality of Life assessments, and on whom dose volume data were available for analysis. The men were divided into three groups according to 2-year follow-up: potent, reduced potency, and impotent. The bulb of the penis together with the crura, were outlined on restored treatment plans. Dose - volume histograms were generated and compared between the three groups. An ordered logistic regression model was used to calculate the odds ratio of a range of dose - volume parameters to the penile bulb and effect on erectile dysfunction. The dose to the penile bulb was correlated to the dose received by the crura. RESULTS: Of the 51 patients, 12 remained potent, 22 had reduced potency, and 17 were impotent at 2 years. No differences were seen in mean dose to the penile bulb by allocated treatment (t test = 1.61, p = 0.11). The mean doses to the penile bulb received by the potent, reduced potency, and impotent groups were 45.5 Gy (SD 17.1), 48 Gy (SD 16.1), and 59.2 Gy (SD 13.8), respectively. There was a strong correlation between the mean dose received by the penile bulb and dose to the crura (r = 0.82, p < 0.0001). 83.3% of impotent patients received a D90 > or = 50 Gy to the penile bulb compared with 29.4% of patients who maintained potency at 2 years (p = 0.006). CONCLUSION: There is evidence from this study to suggest a dose volume effect on the penile bulb and erectile dysfunction. A D90 > or = 50 Gy is associated with a significant risk of erectile dysfunction and this should form a basis for selecting dose constraints in future dose escalation studies.     

The level of patient-reported outcome reporting in randomised controlled trials of brain tumour patients: A systematic review

BackgroundTo determine the net clinical benefit of a new treatment strategy, information on both survival and patient-reported outcomes (PROs) is required. However, to make an adequately informed decision, PRO evidence should be of sufficiently high quality.ObjectiveTo investigate the methodological quality of PRO reporting in randomised controlled trials (RCTs) in patients with brain tumours, and to assess the proportion of studies that should impact clinical decision-making.MethodsWe conducted a systematic literature search in several databases covering January 2004 to March 2012. We selected relevant RCTs and retrieved the following data: (1) basic trial demographics and PRO characteristics, (2) quality of PRO reporting and (3) risk of bias. Studies that should impact clinical decision-making based on their methodological robustness were analysed systematically.ResultsWe identified 14 RCTs, representing over 3000 glioma patients. Only two RCTs (14%) satisfied sufficiently many key methodological criteria to provide high-quality PRO evidence, and should therefore impact clinical decision-making. Important methodological limitations in other studies were lack of reporting of the extent (43%) and reasons (86%) of missing data and statistical approaches to handle this (71%). PRO results were not interpreted in 79% of the studies and clinical significance was not discussed in 86%. Studies with high-quality PRO evidence generally showed lower risk of bias.ConclusionsInvestigators involved in brain tumour research should pay special attention to methodological challenges identified in current work. The level of PRO reporting should continue to improve in order to facilitate a critical appraisal of study results.     

Adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: Long-term results of a phase 3 multicentre randomised controlled trial

Aim of the studyPrevious results from our trial showed that adjuvant cisplatin and fluorouracil chemotherapy did not significantly improve survival after concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we present the data of long-term survival and late toxicities to further assess the ultimate therapeutic index of adjuvant chemotherapy (AC).MethodsPatients with stage III–IVB (except T3-4N0) NPC were randomly assigned to receive CCRT plus AC or CCRT only at seven institutions in China. Patients in both groups received cisplatin 40 mg/m² weekly up to 7 weeks concurrently with radiotherapy. The CCRT plus AC group subsequently received adjuvant cisplatin 80 mg/m² and fluorouracil 800 mg/m²/d for 120 h every 4 weeks for three cycles. The primary end-point was failure-free survival.ResultsTwo hundred and fifty-one patients were randomised to the CCRT plus AC group and 257 to the CCRT only group. After a median follow-up of 68.4 months, estimated 5-year failure-free survival rate was 75% in the CCRT plus AC group and 71% in the CCRT only group (hazard ratio 0.88, 95% confidence interval 0.64–1.22; p = 0.45). 66 (27%) of 249 patients in the CCRT plus AC group and 53 (21%) of 254 patients in the CCRT only group developed one or more late grade 3–4 toxicities (p = 0.14).ConclusionAdjuvant cisplatin and fluorouracil chemotherapy still failed to demonstrate significant survival benefit after CCRT in locoregionally advanced NPC based on the long-term follow-up data, and addition of adjuvant cisplatin and fluorouracil did not significantly increase late toxicities.Registration numberNCT00677118.     

Early surgery for failure after chemoradiation in operable thoracic oesophageal cancer. Analysis of the non-randomised patients in FFCD 9102 phase III trial: Chemoradiation followed by surgery versus chemoradiation alone

BackgroundTwo randomised trials concerning thoracic oesophageal cancer concluded that for squamous cell carcinoma, chemoradiation alone leads to the same overall survival (OS) as chemoradiation followed by surgery. One of these trials, FFCD 9102, randomised only fit, compliant and operable responders to induction chemoradiation between continuation of chemoradiation and surgery. In the present analysis, the outcome in the patients not eligible for randomisation was calculated to determine if attempt of surgery should be recommended.MethodsEligible patients had operable T3-N0/N1-M0 thoracic oesophageal cancer. After initial chemoradiation, patients with no clinical response, or with contraindication to follow any attributed treatment, were not randomised. OS was studied first in the whole population of not randomised patients, and then specifically in clinical non-responders. The impact of surgery on OS was studied in these two populations.FindingsOf the 451 registered patients in the trial, 192 were not randomised. Among them, 111 were clinical non-responders. Median OS was significantly shorter for non-randomised patients (11.5 months) than for randomised patients (18.9 months; p = 0.0024). However, for the 112 non-randomised patients who underwent surgery, median OS was not different from that in randomised patients: 17.3 versus 18.9 months (p = 0.58).Concerning clinical non-responders, median OS was longer for those who underwent surgery compared to non-operated patients: 17.0 versus 5.5 months (hazard ratio (HR) = 0.39 [0.25–0.61]; p < 0.0001), and again was not different from that in responding, randomised patients (p = 0.40).InterpretationIn patients with locally advanced thoracic oesophageal cancer, overall survival did not differ between responders to induction chemoradiation and patients having surgery after clinical failure of chemoradiation. Surgery should therefore be considered in those patients who are still operable.