ASPiRATION: Australian observational cohort study of comprehensive genomic profiling in metastatic lung cancer tissue.

ASPiRATION is a national prospective observational cohort study assessing the feasibility, clinical and economic value of up-front tissue-based comprehensive genomic profiling (CGP) to identify actionable genomic alterations in participants with newly diagnosed metastatic non-squamous non-small-cell lung cancer in Australia. This study will enrol 1000 participants with tumor available for CGP and standard of care molecular testing (EGFR/ALK/ROS1). Participants with actionable variants may receive novel targeted treatments through ASPiRATION-specific substudies, other trials/programs. Clinical outcome data will be collected for a minimum of 2 years. Study outcomes are descriptive, including the ability of CGP to identify additional actionable variants, leading to personalized treatment recommendations, and will describe the feasibility, efficiency, cost and utility of implementation of CGP nationally.

Lung cancer is the most common cause of cancer death in Australia and worldwide. This disease often happens due to alterations in specific genes that allow cancer cells to develop and spread. Scientists have designed targeted drugs that are better at attacking cancer cells that have specific 'actionable' gene alterations and have less effect on other cells in the body. The result is often more benefit from treatment and fewer side effects than other standard treatments (chemotherapy or immunotherapy). The targeted drugs are well established as the best initial treatments for some gene alterations, but more research is needed to know if this is true for some of the less common or recently identified gene alterations, and where the targeted drugs are very new. Comprehensive genomic profiling is a new way of testing lung cancer cells for all the gene alterations (the well-known ones as well as the rare ones) in a single test. It is expected that this test will find many more of these gene alterations, which will allow more people to have safer and more effective targeted treatments leading to potentially better outcomes, and will allow some people to join clinical trials testing newer targeted treatments. The ASPiRATION study will help work out whether comprehensive genomic profiling is better than the current way of testing for gene alterations in Australia, and if it is feasible to use in all people diagnosed with advanced lung cancer in Australia. Clinical Trial Registration: ACTRN12621000221853 (ANZCTR).

Patient-Reported Bowel, Urinary, and Sexual Outcomes After Laparoscopic-Assisted Resection or Open Resection for Rectal Cancer: The Australasian Laparoscopic Cancer of the Rectum Randomized Clinical Trial (ALaCart).

OBJECTIVE: The aim of this study was to compare patient-reported urinary, bowel, and sexual functioning of ALaCaRT Trial participants randomized to open or laparoscopic surgery for rectal cancer. SUMMARY BACKGROUND DATA: The primary endpoint, noninferiority of laparoscopic surgical resection adequacy, was not established. METHODS: Participants completed QLQ-CR29 at baseline, 3, and 12 months post-surgery. Additionally, women completed Rosen's Female Sexual Functioning Index (FSFI). Men completed the International Index of Erectile Function (IIEF) and QLQ-PR25. We compared the proportions of participants in each group who experienced moderate/severe symptoms/dysfunction at each time-point and compared mean difference scores from baseline to 12 months between groups. All analyses were intention-to-treat. Sexual functioning analyses included only the participants who expressed sexual interest at baseline. RESULTS: Baseline PRO compliance of 475 randomized participants was 88%. At 12 months, a lower proportion of open surgery participants experienced moderate-severe fecal incontinence and sore skin, compared to Laparoscopic participants, and a lower proportion of men randomized to open surgery experienced moderate-severe urinary symptoms. There were no differences at 3 months for bowel or urinary symptoms. Sexual functioning among sexually interested participants was similar between groups at 3 and 12 months; however, a lower proportion of women reported moderate to severe sexual dissatisfaction at 3 months in the open as compared to the laparoscopic group, (Rebecca.mercieca@sydney.edu.au., 95% CI 0.03-0.39). DISCUSSION: Despite the slightly lower proportions of open surgery participants self-reporting moderate-severe symptoms for 3 of 16 urinary/bowel domains, and lack of differences in sexual domains, it remains difficult to recommend one surgical approach over another for rectal resection.

The validity of progression-free survival 2 as a surrogate trial end point for overall survival.

BACKGROUND: Overall survival (OS) is the gold-standard end point for oncology trials. However, the availability of multiple therapeutic options after progression and crossover to receive investigational agents confound and delay OS data maturation. Progression-free survival 2 (PFS-2), defined as the time from randomization to progression on first subsequent therapy, has been proposed as a surrogate for OS. Using a meta-analytic approach, the authors aimed to assess the association between OS and PFS-2 and compare this with progression-free survival 1 (PFS-1) and the objective response rate (ORR). METHODS: An electronic literature search was performed to identify randomized trials of systemic therapies in advanced solid tumors that reported PFS-2 as a prespecified end point. Correlations between OS and PFS-2, OS and PFS-1, and OS and ORR as hazard ratios (HRs) or odds ratios (ORs) were assessed via linear regression weighted by trial size. RESULTS: Thirty-eight trials were included, and they comprised 19,031 patients across 8 tumor types. PFS-2 displayed a moderate correlation with OS (r = 0.67; 95% confidence interval [CI], 0.08-0.69). Conversely, correlations of ORR (r = 0.12; 95% CI, 0.00-0.13) and PFS-1 (r = 0.21; 95% CI, 0.00-0.33) were poor. The findings for PFS-2 were consistent for subgroup analyses by treatment type (immunotherapy vs nonimmunotherapy: r = 0.67 vs 0.67), survival post progression (<12 vs ≥12 months: r = 0.86 vs 0.79), and percentage not receiving subsequent treatment (<50% vs ≥50%: r = 0.70 vs 0.63). CONCLUSIONS: Across diverse tumors and therapies, the treatment effect on PFS-2 correlated moderately with the treatment effect on OS. PFS-2 performed consistently better than PFS-1 and ORR, regardless of postprogression treatment and postprogression survival. PFS-2 should be included as a key trial end point in future randomized trials of solid tumors.

Changes to design and analysis elements of research plans during randomised controlled trials in Australia.

OBJECTIVES: To investigate the frequency and legitimacy of substantive changes to the research plans of published randomised controlled trials (RCTs) undertaken in Australia. DESIGN: Comparison of methodology and analysis plans for RCTs specified in protocol documents (full protocols, published protocol articles, statistical analysis plans, Australian New Zealand Clinical Trials Registry [ANZCTR] registration entries) and described in publications of primary results. SETTING, PARTICIPANTS: 181 RCTs registered with the ANZCTR, 1 September 2007 - 31 December 2013, for which primary results had been published. MAIN OUTCOME MEASURE: Changes made to research plan, both overall and by specific item (primary outcome, analysis set, eligibility criteria, sample size, primary analysis method, and treatment arms included in the primary comparison in multi-arm trials); trial characteristics associated with changes. RESULTS: Protocol documents were available for 124 of 181 eligible RCTs (69%; 46 publicly available, 78 provided by trial groups on request). Full audit of RCTs with protocols found clear or probable changes in 111 trials (90%), for 101 of which (91%) it was unclear whether changes had been made blinded to treatment outcomes. After seeking clarification from investigators, changes to 78 trials were confirmed (63%), for 61 of which (78%) changes were made blinded to treatment outcomes. Any change was less likely for trials with publicly available protocols than for trials for which we needed to request protocols (odds ratio, 0.22; 95% CI, 0.06-0.77). Limited reviews of trials without protocols identified that changes had been made to 42 of 57 trials (74%). CONCLUSION: Changes to RCT study plans in Australia are both frequent and usually made appropriately blinded to treatment outcomes. However, the documentation of changes made to RCT protocols should be formalised to improve transparency.

Common genetic variants do not predict recurrent events in coronary heart disease patients.

BACKGROUND: It is unclear whether genetic variants identified from single nucleotide polymorphisms (SNPs) strongly associated with coronary heart disease (CHD) in genome-wide association studies (GWAS), or a genetic risk score (GRS) derived from them, can help stratify risk of recurrent events in patients with CHD. METHODS: Study subjects were enrolled at the close-out of the LIPID randomised controlled trial of pravastatin vs placebo. Entry to the trial had required a history of acute coronary syndrome 3-36 months previously, and patients were in the trial for a mean of 36 months. Patients who consented to a blood sample were genotyped with a custom designed array chip with SNPs chosen from known CHD-associated loci identified in previous GWAS. We evaluated outcomes in these patients over the following 10 years. RESULTS: Over the 10-year follow-up of the cohort of 4932 patients, 1558 deaths, 898 cardiovascular deaths, 727 CHD deaths and 375 cancer deaths occurred. There were no significant associations between individual SNPs and outcomes before or after adjustment for confounding variables and for multiple testing. A previously validated 27 SNP GRS derived from SNPs with the strongest associations with CHD also did not show any independent association with recurrent major cardiovascular events. CONCLUSIONS: Genetic variants based on individual single nucleotide polymorphisms strongly associated with coronary heart disease in genome wide association studies or an abbreviated genetic risk score derived from them did not help risk profiling in this well-characterised cohort with 10-year follow-up. Other approaches will be needed to incorporate genetic profiling into clinically relevant stratification of long-term risk of recurrent events in CHD patients.

Outcomes of Two Trials of Oxygen-Saturation Targets in Preterm Infants.

BACKGROUND: The safest ranges of oxygen saturation in preterm infants have been the subject of debate. METHODS: In two trials, conducted in Australia and the United Kingdom, infants born before 28 weeks' gestation were randomly assigned to either a lower (85 to 89%) or a higher (91 to 95%) oxygen-saturation range. During enrollment, the oximeters were revised to correct a calibration-algorithm artifact. The primary outcome was death or disability at a corrected gestational age of 2 years; this outcome was evaluated among infants whose oxygen saturation was measured with any study oximeter in the Australian trial and those whose oxygen saturation was measured with a revised oximeter in the U.K. trial. RESULTS: After 1135 infants in Australia and 973 infants in the United Kingdom had been enrolled in the trial, an interim analysis showed increased mortality at a corrected gestational age of 36 weeks, and enrollment was stopped. Death or disability in the Australian trial (with all oximeters included) occurred in 247 of 549 infants (45.0%) in the lower-target group versus 217 of 545 infants (39.8%) in the higher-target group (adjusted relative risk, 1.12; 95% confidence interval [CI], 0.98 to 1.27; P=0.10); death or disability in the U.K. trial (with only revised oximeters included) occurred in 185 of 366 infants (50.5%) in the lower-target group versus 164 of 357 infants (45.9%) in the higher-target group (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.24; P=0.15). In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02), and death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04). In the group in which revised oximeters were used, death or disability occurred in 287 of 580 infants (49.5%) in the lower-target group versus 248 of 563 infants (44.0%) in the higher-target group (relative risk, 1.12; 95% CI, 0.99 to 1.27; P=0.07), and death occurred in 144 of 587 infants (24.5%) versus 99 of 586 infants (16.9%) (relative risk, 1.45; 95% CI, 1.16 to 1.82; P=0.001). CONCLUSIONS: Use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial but in significantly increased risks of this combined outcome and of death alone in post hoc combined analyses. (Funded by the Australian National Health and Medical Research Council and others; BOOST-II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry number, ACTRN12605000055606.).

Dose intensity in anthracycline-based chemotherapy for metastatic breast cancer: mature results of the randomised clinical trial ANZ 9311.

PURPOSE: The separate impacts of dose and dose intensity of chemotherapy for metastatic breast cancer remain uncertain. The primary objective of this trial was to compare a short, high-dose, intensive course of epirubicin and cyclophosphamide (EC) with a longer conventional dose regimen delivering the same total dose of chemotherapy. METHODS: This open label trial randomised 235 women with metastatic breast cancer to receive either high-dose epirubicin 150 mg/m2 and cyclophosphamide 1500 mg/m2 with filgrastim support every 3 weeks for 3 cycles (HDEC) or standard dose epirubicin 75 mg/m2 and cyclophosphamide 750 mg/m2 every 3 weeks for 6 cycles (SDEC). Primary outcomes were time to progression, overall survival and quality of life. RESULTS: In 118 patients allocated HDEC 90% of the planned dose was delivered, compared to 96% in the 117 participants allocated SDEC. There were no significant differences in the time to disease progression (5.7 vs. 5.8 months, P = 0.19) or overall survival (14.5 vs. 16.5 months, P = 0.29) between HDEC and SDEC, respectively. Patients on HDEC reported worse quality of life during therapy, but scores improved after completion to approximate those reported by patients allocated SDEC. Objective tumour response was recorded in 33 (28%) on HDEC and 42 patients (36%) on SDEC. HDEC produced more haematologic toxicity. CONCLUSION: For women with metastatic breast cancer, disease progression, survival or quality of life were no better with high-dose intensity compared to standard dose EC chemotherapy. Australian Clinical Trials Registry registration number ACTRN12605000478617.

Cancer Molecular Screening and Therapeutics (MoST): a framework for multiple, parallel signal-seeking studies of targeted therapies for rare and neglected cancers.

BACKGROUND: Precision medicine aims to link molecular targets in tumours with corresponding therapies, particularly for patients with rare cancers. Innovative approaches are needed to translate molecular opportunities into clinical care. The Cancer Molecular Screening and Therapeutics (MoST) program employs a molecular screening platform to identify molecular changes of therapeutic relevance (actionable changes) and a master protocol for multiple, parallel signal-seeking clinical substudies, focused on therapies for patients with rare and neglected cancers. Methods and analysis: Archival pathology laboratory samples from patients with treatment-refractory advanced solid cancer of any histologic type undergo molecular tumour profiling. Following review by a Molecular Tumour Board, eligible patients are offered treatment in therapeutic substudies. This novel master protocol allows expedited addition of individual substudies; at least 12 open label, single arm, signal-seeking substudies during the initial 4 years of MoST are planned. The primary objectives are to identify signals of efficacy for developing biomarker-driven therapies and biomarkers that more accurately predict response to therapy, as well as to evaluate the MoST design. Ethics approval: The program has been approved by the St Vincent's Hospital Sydney Human Research Ethics Committee (reference, HREC/16/SVH/23). Dissemination of results: A report summarising and interpreting collected study data will be published. Our findings will be presented at national and international conferences and scientific meetings, and published in peer-reviewed journals. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry: ACTRN12616000908437 (8 July 2016).

Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage.

BACKGROUND: Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known. METHODS: We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician's choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups. RESULTS: Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P=0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively. CONCLUSIONS: In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure. (Funded by the National Health and Medical Research Council of Australia; INTERACT2 ClinicalTrials.gov number, NCT00716079.).

Hope, optimism and survival in a randomised trial of chemotherapy for metastatic colorectal cancer.

PURPOSE: Psychological responses to cancer are widely believed to affect survival. We investigated associations between hope, optimism, anxiety, depression, health utility and survival in patients starting first-line chemotherapy for metastatic colorectal cancer. METHODS: Four hundred twenty-nine subjects with metastatic colorectal cancer in a randomised controlled trial of chemotherapy completed baseline questionnaires assessing the following: hopefulness, optimism, anxiety and depression and health utility. Hazard ratios (HRs) and P values were calculated with Cox models for overall survival (OS) and progression-free survival (PFS) in univariable and multivariable analyses. RESULTS: Median follow-up was 31 months. Univariable analyses showed that OS was associated negatively with depression (HR 2.04, P < 0.001) and positively with health utility (HR 0.56, P < 0.001) and hopefulness (HR 0.75, P = 0.013). In multivariable analysis, OS was also associated negatively with depression (HR 1.72, P < 0.001) and positively with health utility (HR 0.73, P = 0.014), but not with optimism, anxiety or hopefulness. PFS was not associated with hope, optimism, anxiety or depression in any analyses. CONCLUSIONS: Depression and health utility, but not optimism, hope or anxiety, were associated with survival after controlling for known prognostic factors in patients with advanced colorectal cancer. Further research is required to understand the nature of the relationship between depression and survival. If a causal mechanism is identified, this may lead to interventional possibilities.

Sentinel lymph node based management or routine axillary clearance? Three-year outcomes of the RACS sentinel node biopsy versus axillary clearance (SNAC) 1 trial.

PURPOSE: To determine whether the benefits of sentinel node based management (SNBM) over routine axillary clearance (RAC) at 1 year persisted to 3 years of follow-up. METHODS: A total of 1,088 women with clinically node-negative breast cancer were randomly assigned to the SNBM or RAC group. Upper limb volume, symptoms, and function were assessed at 1, 6, 12, 24, and 36 months after surgery objectively with upper limb measurements by clinicians and subjectively by patients' using validated self-rating scales. RESULTS: Upper limb volume increased in both groups over the first 2 years and differed between the two groups all time points beyond 1 month (P < 0.02) but then plateaued. Upper limb swelling was no worse in women who had axillary clearance as a two-stage procedure than in women assigned RAC as a one-stage procedure. Upper limb volume had increased 15 % or more in 6.0 % at 6 months and 17.6 % at 3 years in those assigned RAC versus 4.2 and 11.9 % in those assigned SNBM. Reductions in upper limb movement were also greater, with RAC than SNBM over 6 months, but improved and were similar in the two groups from 1 to 3 years. Subjective ratings of upper limb swelling, symptoms, dysfunction, and disability over 3 years were worse in the RAC group. Upper limb swelling at 3 years was rated severe by few women (1.1 %) but was rated as moderate by 9.4 % in the RAC group and 2.5 % in the SNBM group (P < 0.001). CONCLUSIONS: The benefits of SNBM over RAC persist 3 years after surgery.

Australian clinical trial activity and burden of disease: an analysis of registered trials in National Health Priority Areas.

OBJECTIVE: To assess whether Australian clinical trials activity in National Health Priority Areas (NHPAs) reflects the relative disease burden. DESIGN AND SETTING: Analysis of trials registered on the Australian New Zealand Clinical Trials Registry (ANZCTR) or ClinicalTrials.gov from January 2008 to December 2012 that planned recruitment in Australia and investigated interventions for NHPA conditions (cancer control, cardiovascular health, mental health, obesity, injury prevention/control, diabetes mellitus, arthritis and musculoskeletal conditions, dementia and asthma). Australian estimates of disability-adjusted life-years (DALYs) were used to quantify the burden of disease for each NHPA. MAIN OUTCOME MEASURES: For each NHPA, the total number of registered trials, planned recruitment, and the predicted numbers based on disability-adjusted life-years expressed as a proportion of the total burden of disease in Australia (%DALY). RESULTS: 5143 trials with Australian sites were registered in the 5-year study period with total planned recruitment of 2 404 609 participants. Of these, 3032 trials (59%) with planned recruitment of 1 532 064 participants (64%) investigated NHPA conditions. Trial numbers and planned recruitment were highest for cancer, cardiovascular and mental health - reflecting their higher disease burden. In contrast, planned recruitment into obesity and dementia trials was ≤ 50% of that predicted from total trial activity based on their relative disease burden. The number of registered trials for these conditions was also lower than predicted. Overall, of 3032 NHPA trials, 2335 (77%) used randomisation and 1520 (50%) planned to recruit > 100 participants. CONCLUSIONS: Australian clinical trial activity for obesity and dementia interventions is lower that would be expected based on their relative disease burden. Trial registries provide a valuable public database to identify and monitor gaps in research activity.

Epiregulin gene expression as a biomarker of benefit from cetuximab in the treatment of advanced colorectal cancer.

BACKGROUND: Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy-refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression may further predict cetuximab benefit. METHODS: Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment-biomarker interaction. RESULTS: Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status ('co-biomarker')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P<0.0001), and median OS was 9.8 vs 5.1 months (HR 0.43; P<0.001) for cetuximab vs BSC, respectively. In the rest (n=246, 64%), PFS (HR 0.82; P=0.12) and OS (HR 0.90; P=0.45) were not significantly different. Test for treatment interaction showed a larger cetuximab effect on OS (HR 0.52; P=0.007) and PFS (HR 0.49; P=0.001) in the co-biomarker-positive group. CONCLUSION: In pre-treated K-ras wild-type status colorectal cancer, patients with high EREG gene expression appear to benefit more from cetuximab therapy compared with low expression. Epiregulin as a selective biomarker requires further evaluation.

Final results of Australasian Gastrointestinal Trials Group ARCTIC study: an audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines.

BACKGROUND: Cardiac toxicity an uncommon but serious side-effect of some fluoropyrimides. Cardiac toxicity from raltitrexed is rarely reported. With this background, we initiated this study to investigate the incidence of cardiac events in patients who had switched to raltitrexed following cardiac toxicity from fluoropyrimidines (5-fluorouracil or capecitabine). PATIENTS AND METHODS: Pharmacy records were used to identify patients receiving raltitrexed from January 2004 till March 2012. Medical records were then reviewed to confirm the use of raltitrexed after cardiac toxicity from 5-fluorouracil or capecitabine. The primary end point was the rate of further cardiac events after commencing raltitrexed. RESULTS: Forty-two patients were identified and the majority had colorectal cancer. Prior regimens included 5-fluorouracil ± leucovorin, capecitabine alone, FOLFOX, FOLFIRI, epirubicin/cisplatin/5-fluorouracil, and capecitabine/oxaliplatin. Seven patients (17%) had bolus 5-fluorouracil regimens, 26 patients (62%) had infusion 5-fluorouracil regimens, and 9 patients (21%) had capecitabine alone or in combination. Angina was the most common cardiac toxicity from 5-fluorouracil or capecitabine and usually occurred in the first or the second cycle. Four patients after their first cardiac event continued with the same 5-fluorouracil or capecitabine regimen with the addition of nitrates and calcium antagonists but still had further cardiac events. After changing to raltitrexed, either as a single agent or a continuing combination regimen, no patients experienced further cardiac toxicity. CONCLUSION: Raltitrexed is associated with no significant cardiac toxicity in patients who have experienced prior cardiac toxicity from 5-fluorouracil or capecitabine. Raltitrexed, alone or in combination with oxaliplatin or irinotecan, provides a safe option in terms of cardiac toxicity for such patients.

Semiparametric methods for multistate survival models in randomised trials.

Transform methods have proved effective for networks describing a progression of events. In semi-Markov networks, we calculated the transform of time to a terminating event from corresponding transforms of intermediate steps. Saddlepoint inversion then provided survival and hazard functions, which integrated, and fully utilised, the network data. However, the presence of censored data introduces significant difficulties for these methods. Many participants in controlled trials commonly remain event-free at study completion, a consequence of the limited period of follow-up specified in the trial design. Transforms are not estimable using nonparametric methods in states with survival truncated by end-of-study censoring. We propose the use of parametric models specifying residual survival to next event. As a simple approach to extrapolation with competing alternative states, we imposed a proportional incidence (constant relative hazard) assumption beyond the range of study data. No proportional hazards assumptions are necessary for inferences concerning time to endpoint; indeed, estimation of survival and hazard functions can proceed in a single study arm. We demonstrate feasibility and efficiency of transform inversion in a large randomised controlled trial of cholesterol-lowering therapy, the Long-Term Intervention with Pravastatin in Ischaemic Disease study. Transform inversion integrates information available in components of multistate models: estimates of transition probabilities and empirical survival distributions. As a by-product, it provides some ability to forecast survival and hazard functions forward, beyond the time horizon of available follow-up. Functionals of survival and hazard functions provide inference, which proves sharper than that of log-rank and related methods for survival comparisons ignoring intermediate events.

Framework for the Use of External Controls to Evaluate Treatment Outcomes in Precision Oncology Trials.

Advances in genomics have enabled anticancer therapies to be tailored to target specific genomic alterations. Single-arm trials (SATs), including those incorporated within umbrella, basket, and platform trials, are widely adopted when it is not feasible to conduct randomized controlled trials in rare biomarker-defined subpopulations. External controls (ECs), defined as control arm data derived outside the clinical trial, have gained renewed interest as a strategy to supplement evidence generated from SATs to allow comparative analysis. There are increasing examples demonstrating the application of EC in precision oncology trials. The prospective application of EC in conducting comparative studies is associated with distinct methodological challenges, the specific considerations for EC use in biomarker-defined subpopulations have not been adequately discussed, and a formal framework is yet to be established. In this review, we present a framework for conducting a prospective comparative analysis using EC. Key steps are (1) defining the purpose of using EC to address the study question, (2) determining if the external data are fit for purpose, (3) developing a transparent study protocol and a statistical analysis plan, and (iv) interpreting results and drawing conclusions on the basis of a prespecified hypothesis. We specify the considerations required for the biomarker-defined subpopulations, which include (1) specifying the comparator and biomarker status of the comparator group, (2) defining lines of treatment, (3) assessment of the biomarker testing panels used, and (4) assessment of cohort stratification in tumor-agnostic studies. We further discuss novel clinical trial designs and statistical techniques leveraging EC to propose future directions to advance evidence generation and facilitate drug development in precision oncology.

Validity and Efficiency of Progression-Free Survival-2 as a Surrogate End Point for Overall Survival in Advanced Cancer Randomized Trials.

PURPOSE: Progression-free survival (PFS)-2, defined as the time from randomization to progression on second-line therapy, is potentially a more reliable surrogate than PFS for overall survival (OS), but will require longer follow-up and a larger sample size. We sought to compare the validity and efficiency, defined as proportional increase in follow-up time and sample size, of PFS-2 to PFS. METHODS: We performed an electronic search to identify randomized trials of advanced solid tumors reporting PFS, PFS-2, and OS as prespecified end points. Only studies that had protocols that defined measurement of PFS-2 and follow-up for patients after first disease progression were included. We compared correlations in the relative treatment effect for OS with PFS and PFS-2. We reconstructed individual patient data from survival curves to estimate time to statistical significance (TSS) of the relative treatment effect. We further computed the sample size (person-year [PY] follow-up) required to reach statistical significance. RESULTS: Across the 42 analysis units and 21,255 patients, the correlation of the relative treatment effect between OS and PFS-2, r, was 0.70 (95% CI, 0.41 to 0.80) and r = 0.46 (95% CI, 0.26 to 0.74) for OS and PFS. The median differences in TSS between OS with PFS, OS with PFS-2, and PFS with PFS-2 were 16.59 (95% CI, 4.48 to not reached [NR]), 10.0 (95% CI, 2.2 to NR), and 4.31 (95% CI, 2.92 to 13.13) months, respectively. The median difference in PYs required to reach statistical significance for PFS-2 over PFS was 156 (95% CI, 82 to 500) PYs, equivalent to an estimated median 12.7% increase in PYs. CONCLUSION: PFS-2 offers improved correlation with OS than PFS with a modest increase in follow-up time and sample size. PFS-2 should be considered as a primary end point in future trials of advanced cancers.

Oral Cannabis Extract for Secondary Prevention of Chemotherapy-Induced Nausea and Vomiting: Final Results of a Randomized, Placebo-Controlled, Phase II/III Trial.

PURPOSE: The aim of this randomized, placebo-controlled, two-stage, phase II/III trial was to determine the efficacy of an oral cannabis extract in adults with refractory nausea and/or vomiting during moderately or highly emetogenic, intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Here, we report results of the prespecified combined analysis including the initial phase II and subsequent phase III components. PATIENTS AND METHODS: Study treatment consisted of oral capsules containing either tetrahydrocannabinol 2.5 mg plus cannabidiol 2.5 mg capsules (THC:CBD) or matching placebo, taken three times a day from days -1 to 5, in addition to guideline-consistent antiemetics. The primary measure of effect was the difference in the proportions of participants with no vomiting or retching and no use of rescue medications (a complete response) during hours 0-120 after the first cycle of chemotherapy on study (cycle A). RESULTS: We recruited 147 evaluable of a planned 250 participants from 2016 to 2022. Background antiemetic prophylaxis included a corticosteroid and 5-hydroxytryptamine antagonist in 97%, a neurokinin-1 antagonist in 80%, and olanzapine in 10%. THC:CBD compared with placebo improved the complete response rate from 8% to 24% (absolute difference 16%, 95% CI, 4 to 28, P = .01), with similar effects for absence of significant nausea, use of rescue medications, daily vomits, and the nausea scale on the Functional Living Index-Emesis quality-of-life questionnaire. More frequent bothersome adverse events of special interest included sedation (18% v 7%), dizziness (10% v 0%), and transient anxiety (4% v 1%). There were no serious adverse events attributed to THC:CBD. CONCLUSION: THC:CBD is an effective adjunct for chemotherapy-induced nausea and vomiting despite standard antiemetic prophylaxis, but was associated with additional adverse events. Drug availability, cultural attitudes, legal status, and preferences may affect implementation. Future analyses will evaluate the cost-effectiveness of THC:CBD.