Generalisability of Common Oncology Clinical Trial Eligibility Criteria in the Real World

AimsStrict oncology clinical trial eligibility criteria can contribute to low accrual and result in poorly generalisable study findings. Using common eligibility criteria, we sought to (i) determine how many patients would be eligible versus ineligible and (ii) describe real-world patterns of treatments and outcomes between those considered trial eligible and ineligible.Materials and methodsThe Alberta Cancer Registry was used to assemble a population-based cohort of patients diagnosed with 11 common malignancies between 2004 and 2015. We considered age >75 years, anaemia, comorbid conditions (heart disease, uncontrolled diabetes, kidney disease, liver disease) and history of a prior malignancy or immunosuppression to be exclusion criteria. Logistic regression was used to characterise the likelihood of receiving treatment. Cox regression models were constructed to determine cancer-specific and overall survival.ResultsWe identified 125 316 cancer patients, of whom 53% were men; the median age was 66 (interquartile range 48–84) years. Approximately 38% of patients were considered trial ineligible. The most common reasons for ineligibility were advanced age (24%) and heart disease (16%). In this ineligible group, 12, 47 and 19% still underwent chemotherapy, surgery and radiotherapy, respectively. Compared with ineligible patients, eligible patients were more likely to undergo chemotherapy (odds ratio 1.98, 95% confidence interval 1.89–2.07, P < 0.0001), surgery (odds ratio 1.39, 95% confidence interval 1.32–1.46, P < 0.0001) and radiotherapy (odds ratio 1.46, 95% confidence interval 1.4–1.52, P < 0.0001). Compared with ineligible patients who did not receive treatment, those considered ineligible but who still received treatment experienced improved cancer-specific survival (hazard ratio 0.75, 95% confidence interval 0.74–0.77, P < 0.0001) and overall survival (hazard ratio 0.89, 95% confidence interval 0.87–0.90, P < 0.0001).ConclusionsA significant proportion of real-world patients are unable to participate in clinical trials due to stringent exclusion criteria, but many still receive treatment in routine practice. The eligibility criteria of oncology clinical trials should be broadened.     

Survival Outcomes for Patients with Metastatic Triple-Negative Breast Cancer: Implications for Clinical Practice and Trial Design

BackgroundClinical experience suggests that many women with triple-negative metastatic breast cancer (MBC) relapse quickly. This has implications for clinical practice and trial design. We evaluated the duration of first-, second-, and third-line chemotherapy as a surrogate for duration of treatment response.Patients and MethodsWe performed a retrospective multicenter chart review of patients with triple-negative MBC receiving palliative chemotherapy. Primary outcome was duration of palliative chemotherapy, and secondary outcome was to identify prognostic variables.ResultsA total of 111 patients were analyzed. Median age at diagnosis was 51 years (range, 26–82 years). Fourteen percent of patients presented with MBC. Twenty-seven percent received neoadjuvant chemotherapy, and 48% received adjuvant chemotherapy. Median distant disease-free interval (DDFI) was 18 months (range, 0–172 months). At presentation of MBC, 68% had visceral and 71% had multiple sites of disease. Median survival with MBC was 13.3 months (range, 0.8–99.8 months). Median duration of first-line palliative therapy was 11.9 weeks (range, 0–73.1 weeks). Eighty-seven patients (78%) went on to receive second-line therapy with a median duration of 9 weeks (range, 0–120.9 weeks), and 55 (49%) received third-line therapy with a median duration of 4 weeks (range, 0–59 weeks). Multivariate analysis revealed that age < 50 years, ALP > 120 U/L, history of previous chemotherapy, DDFI < 12 months, and visceral presentation were all independently associated with a poor prognosis.ConclusionDespite the poorer overall prognosis of patients with triple-negative disease, there remains considerable heterogeneity in individual outcomes. Many women with recurrent triple-negative disease will progress quickly on first-, second-, and third-line palliative treatment. Future clinical trials in this population must take into account their shorter time to progression when determining optimal trial design.     

Factors Involved in Delaying Initiation of Adjuvant Chemotherapy After Breast Cancer Surgery

BackgroundDelays in initiating adjuvant chemotherapy after breast cancer surgery seems to have an impact on patients’ risk of relapse and their survival rate. The aim of this retrospective study was to identify factors delaying initiation of adjuvant chemotherapy after breast surgery.Material and methodsAll patients undergoing surgical treatment for mammary cancer between June 2014 and June 2015 and receiving adjuvant chemotherapy were selected retrospectively.ResultsIn multivariate analysis, 3 factors significantly delay initiation of adjuvant chemotherapy: a secondary procedure (odds ratio [OR], 6.67; P = .00012), inclusion in a therapeutic trial (OR, 8.46; P = .0013), and a positive HER2 status (OR, 3.02; P = .063 [statistically significant]).DiscussionThis study provides a brief overview of the population most likely to experience a delay in the initiation of their adjuvant chemotherapy after cancer surgery. Our findings should assist interventions during initial management.     

Study Protocol of the Bladder Adjuvant RadioTherapy (BART) Trial: A Randomised Phase III Trial of Adjuvant Radiotherapy Following Cystectomy in Bladder Cancer

AimsTo assess the efficacy and safety of adjuvant radiotherapy in patients with high-risk muscle-invasive bladder cancer (MIBC) following radical cystectomy (RC) and chemotherapy.Materials and methodsThe BART (Bladder Adjuvant RadioTherapy) trial is an ongoing multicentric, randomised, phase III trial comparing the efficacy and safety of adjuvant radiotherapy versus observation in patients with high-risk MIBC. The key eligibility criteria include ≥pT3, node-positive (pN+), positive margins and/or nodal yield <10, or, neoadjuvant chemotherapy for cT3/T4/N+ disease. In total, 153 patients will be accrued and randomised, in a 1:1 ratio, to either observation (standard arm) or adjuvant radiotherapy (test arm) following surgery and chemotherapy. Stratification parameters include nodal status (N+ versus N0) and chemotherapy (neoadjuvant chemotherapy versus adjuvant chemotherapy versus no chemotherapy). For patients in the test arm, adjuvant radiotherapy to cystectomy bed and pelvic nodes is planned with intensity-modulated radiotherapy to a dose of 50.4 Gy in 28 fractions using daily image guidance. All patients will follow-up with 3-monthly clinical review and urine cytology for 2 years and subsequently 6 monthly until 5 years, with contrast-enhanced computed tomography abdomen pelvis 6 monthly for 2 years and annually until 5 years. Physician-scored toxicity using Common Terminology Criteria for Adverse Events version 5.0 and patient-reported quality of life using the Functional Assessment of Cancer Therapy – Colorectal questionnaire is recorded pre-treatment and at follow-up.Endpoints and statisticsThe primary endpoint is 2-year locoregional recurrence-free survival. The sample size calculation was based on the estimated improvement in 2-year locoregional recurrence-free survival from 70% in the standard arm to 85% in the test arm (hazard ratio 0.45) using 80% statistical power and a two-sided alpha error of 0.05. Secondary endpoints include disease-free survival, overall survival, acute and late toxicity, patterns of failure and quality of life.ConclusionThe BART trial aims to evaluate whether contemporary radiotherapy after standard-of-care surgery and chemotherapy reduces pelvic recurrences safely and also potentially affects survival in high-risk MIBC.     

Three Versus Six Months of Adjuvant Doublet Chemotherapy for Patients With Colorectal Cancer: A Multi-Country Cost-Effectiveness and Budget Impact Analysis

BackgroundThe Short Course Oncology Treatment (SCOT) trial demonstrated non-inferiority, less toxicity, and cost-effectiveness from a UK perspective of 3 versus 6 months of oxaliplatin-based chemotherapy for patients with colorectal cancer. This study assessed the cost-effectiveness of shorter treatment and the budget impact of implementing trial findings from the perspectives of all countries recruited to SCOT: Australia, Denmark, New Zealand, Spain, Sweden, and the United Kingdom.Patients and MethodsIndividual cost–utility analyses were performed from the perspective of each country. Resource, quality of life, and survival estimates from the SCOT trial (N = 6065) were used. Probabilistic sensitivity analysis and subgroup analyses were undertaken. Using undiscounted costs from these cost–utility analyses, the impact on country-specific healthcare budgets of implementing the SCOT trial findings was calculated over a 5-year period. The currency used was US dollars (US$), and 2019 was the base year. One-way and scenario sensitivity analysis addressed uncertainty within the budget impact analysis.ResultsThree months of treatment were cost saving and cost-effective compared to 6 months from the perspective of all countries. The incremental net monetary benefit per patient ranged from US$8972 (Spain) to US$13,884 (Denmark). The healthcare budget impact over 5 years for the base-case scenario ranged from US$3.6 million (New Zealand) to US$61.4 million (UK) and totaled over US$150 million across all countries.ConclusionThis study has widened the transferability of results from the SCOT trial, showing that shorter treatment is cost-effective from a multi-country perspective. The vast savings from implementation could fully justify the investment in conducting the SCOT trial.     

SCOT: Tumor Sidedness and the Influence of Adjuvant Chemotherapy Duration on Disease Free Survival (DFS)

AimPatients with loco-regional right-sided colorectal tumors have a worse overall survival (OS). Here we investigate the difference in disease free survival (DFS) between colorectal patients with right and left sided tumors in the SCOT study.MethodsThe SCOT study showed 3-months of oxaliplatin-containing adjuvant chemotherapy (OxFp) is non-inferior to 6-months for patients with stage III and high-risk stage II colorectal cancer. We divided the cohort into patients with left and right sided tumors, and evaluated the effect on DFS and the principle 3 versus 6-months analysis.Results6088 patients with Stage III/high risk Stage II colorectal cancers were randomized between 27^th March 2008 and 29^th November 2013 from 244 centers internationally. In February 2017 (3-years FU) information on sidedness was available for 3309 patients (1238 R-sided, 2071 L-sided). Patients with right-sided tumors had a significantly worse DFS (3-year DFS right: 73.3% (se = 1.3%), left: 80.2% (se = 0.9%) HR 1.423 (95% CI 1.237-1.637; P < .0001). Adjusting for T and N-stage reduced the HR to 1.230 (95% CI 1.066-1.420, P = .005). The data did not suggest that sidedness affected the impact of chemotherapy duration on 3-year DFS (R: HR 1.024 [0.831-1.261], L: HR 0.944 [0.783-1.139]). Test for heterogeneity, P = .571. Further sub-set analysis was limited due to cohort size.ConclusionsThis is the first study to show that unselected patients with right-sided tumors had a worse DFS compared to left-sided tumors. Tumor sidedness did not impact upon the 3-months versus 6-months comparison in SCOT.     

Eligibility of Real-World Patients With Stage II and III Colon Cancer for Adjuvant Chemotherapy Trials

IntroductionThe results of adjuvant chemotherapy trials in stage II and III colon cancer are often extrapolated to real-world patients. This study was conducted to determine the proportion of real-world patients with stage II/III colon cancer who would be eligible for adjuvant chemotherapy trials and to compare the outcomes among eligible versus ineligible patients.Patients and MethodsWe identified all patients diagnosed with stage II/III colon cancer between 2004 and 2015 from a large province in Canada. Patients meeting any one of the following criteria were considered ineligible: age > 75 years, anemia, comorbid conditions (heart disease, uncontrolled diabetes, kidney disease, liver disease), and a history of malignancy or immunosuppression. Cox regression models were constructed to determine the factors predicting overall and cancer-specific survival.ResultsA total of 7841 patients with stage II/III colon cancer were identified, of whom 52.0% were men and median age at diagnosis was 71 years. Approximately 58.6% of patients were deemed trial ineligible; the most common reasons for ineligibility included advanced age (36.2%), renal dysfunction (26.9%), and cardiac disease (17.4%). In the real-world setting, 54.0% of eligible patients received adjuvant chemotherapy compared to 23.2% of ineligible patients (odds ratio, 3.89; 95% confidence interval, 3.53-4.28; P < .0001). The 5-year overall and cancer-specific survival of trial-ineligible patients who received adjuvant chemotherapy was significantly better than those treated with surgery alone.ConclusionThe eligibility criteria of adjuvant chemotherapy trials in colon cancer should be broadened to be more representative of real-world patients.     

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer

IntruductionRadiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ESCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiotherapy (TRT) after induction chemotherapy for SCLC.MethodsPatients with ESCLC who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity in the 35 days following initiation of treatment.ResultsThirty-eight patients with ESCLC (median age 65 years, range: 37–79 years) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100 to 200 mg with no dose-limiting toxicity in the 35-day window. There were no grade 4-5 toxicities; 2 (6%) patients experienced grade 3 events (n = 1 rash, n = 1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range: 1–13 months); median progression-free and overall survival times were 6.1 months (95% confidence interval: 4.1–8.1) and 8.4 months (95% confidence interval: 6.7-10.1).ConclusionsConcurrent pembrolizumab-TRT was tolerated well with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g., enrolling progressors on induction chemotherapy). Although randomized studies have shown benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.     

Comparison of Neoadjuvant and Adjuvant Chemotherapy in Muscle-invasive Bladder Cancer

BackgroundWe use observational methods to compare impact of perioperative chemotherapy timing (ie, neoadjuvant and adjuvant) on overall survival (OS) in muscle-invasive bladder cancer because there is no head-to-head randomized trial, and patient factors may influence decision-making.Patients and MethodsUsing Surveillance, Epidemiology, and End Results-Medicare data, we identified patients receiving cystectomy for muscle-invasive bladder cancer diagnosed between 2004 and 2013. Patients were classified as receiving neoadjuvant or adjuvant chemotherapy. Propensity of receiving neoadjuvant chemotherapy was determined using gradient boosted models. Inverse probability of treatment weighted survival curves were adjusted for 13 demographic, socioeconomic, temporal, and oncologic covariates.ResultsWe identified 1342 patients who received neoadjuvant (n = 676) or adjuvant chemotherapy (n = 666) with a median follow-up of 23 months (interquartile range, 9-55 months). Inverse probability of treatment weighted adjustment allows comparison of the groups head-to-head as well as counterfactual scenarios (eg, effect if those getting one treatment were to receive the other). The average treatment effect (ie, “head-to-head” comparison) of adjuvant compared with neoadjuvant on OS was not significant (hazard ratio, 1.14; 95% confidence interval, 0.99-1.31). However, the average treatment effect of the treated (ie, the effect if the neoadjuvant patients were to receive adjuvant instead) was associated with a 33% increase in risk of mortality if they were given adjuvant therapy instead (hazard ratio, 1.33; 95% confidence interval, 1.12-1.57).ConclusionSignificant treatment selection bias was noted in peri-cystectomy timing, which limits the ability to discriminate differential efficacy of these 2 approaches with observational data. However, patients with higher propensity to receive neoadjuvant therapy were predicted to have increased OS with approach, in keeping with existing paradigms from trial data.     

Trastuzumab Retreatment after Relapse on Adjuvant Trastuzumab Therapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Final Results of the Retreatment after Herceptin Adjuvant Trial

AimsTrastuzumab, in combination with chemotherapy, is the standard of care for patients with early and metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The Retreatment after HErceptin Adjuvant trial assessed the efficacy and safety of trastuzumab plus a taxane as first-line treatment for patients with metastatic breast cancer (MBC) who had relapsed after adjuvant trastuzumab for HER2-positive early breast cancer.Materials and methodsIn total, 43 patients with HER2-positive MBC who had received previous adjuvant trastuzumab for ≥10 months, with a relapse-free interval of ≥6 months after the last adjuvant trastuzumab dose, were recruited. Eligible patients (n = 41) were assigned to receive trastuzumab, either weekly or every 3 weeks, in combination with docetaxel or paclitaxel until disease progression.ResultsAt the final analysis, with a median follow-up time of 40 months, a positive response was observed in 25/41 patients (61%; 95% confidence interval: 48.7–80.4%), stable disease in 7/41 (17.1%) and progressive disease in 6/41 (14.6%). Three patients had missing response assessments (one had no measurable lesions at baseline and two had no post-baseline tumour assessments). The median progression-free survival (PFS) was 8.0 months (95% confidence interval: 6–11 months) and the median overall survival was 25.0 months (16–33 months). No correlation was found between response rate, PFS or overall survival and the duration of adjuvant trastuzumab treatment, trastuzumab-free interval, relapse-free interval, hormone receptor status or type of pre-metastatic treatment. The most common adverse events (all grades) were alopecia (32%) and diarrhoea (32%). Six patients (14.6%) developed at least one serious adverse event. No congestive heart failure or any unexpected adverse events were reported.ConclusionTrastuzumab, in combination with a taxane, is an effective and well-tolerated first-line treatment for MBC in patients who relapse after trastuzumab-based adjuvant therapy.     

Single Versus Maintenance Intravesical Chemotherapy for the Prevention of Bladder Recurrence after Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Randomized Clinical Trial

IntroductionThe objective of this study was to determine the efficiency of 1-year maintenance intravesical chemotherapy (MIC) in reducing bladder recurrence (BR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma compared with single intravesical instillation (SIC).Patients and MethodsBetween January 2015 and May 2017, patients who underwent RNU were randomized to receive SIC (epirubicin 50 mg) or MIC (once weekly for 6 weeks plus once monthly for 1 year). The primary outcome was the rate of histologically proven BR. The secondary outcomes included chemotherapy-related toxicities and disease-specific survival (DSS). Thirty-five patients in each arm were required to achieve a power of 80%.ResultsA total of 38 (SIC) and 36 (MIC) patients were analyzed. In SIC, BR developed in 5 (13.2%) over a median follow-up of 3 months (range, 3-6 months) compared with 9 (25%) patients over 12 months (range, 3-28 months) in MIC (P = .08). The 6- and 12-month BR-free survivals were the same (86.8%) in SIC versus 88.9% and 83.3% in MIC, respectively (P = .2). Lymphovascular invasion was significantly associated with BR (P = .04). Post-RNU intravesical chemotherapy regimens did not alter DSS. Blood transfusion and advanced tumor stage were independent predictors for DSS. No significant medication toxicity was reported.ConclusionsFollowing RNU, MIC did not change the natural course of BR beyond a single instillation apart from potentially delaying its occurrence. Lymphovascular invasion and blood transfusion were associated with worse BR and DSS outcomes, respectively.     

Smoking Behavior in Patients With Early-Stage NSCLC: A Report From ECOG-ACRIN 1505 Trial

IntroductionSmoking cessation has been reported to benefit patients even after a diagnosis of lung cancer. We studied the smoking behavior of patients who participated in a phase 3 trial of adjuvant therapy following resection of stages IB–IIIA NSCLC.MethodsThe ECOG-ACRIN 1505 was conducted to determine whether the addition of bevacizumab to adjuvant chemotherapy would improve overall survival (OS) for patients with early-stage NSCLC. Studying the association between smoking status and OS was a secondary end point. Patients completed a questionnaire on their smoking habits at baseline, 3, 6, 9, and 12 months.ResultsA total of 1501 patients were enrolled, and 99.8%, 95%, 94%, 93%, and 93% responded to the questionnaire at baseline, 3, 6, 9, and 12 months, respectively. A total of 90% reported a current or previous history of cigarette smoking. In addition, 60% of nonsmokers at enrollment reported smoking after diagnosis (before randomization); however, 1% of them reported smoking at 12 months. Furthermore, 94% of the respondents smoked none/fewer cigarettes daily at 12 months. The incidence of grades 3–5 toxicity on treatment was 68%, 76%, and 72% in never, former, and current smokers, respectively (p = 0.05). The disease-free survival for never-smokers relative to current and former smokers was (hazard ratio [HR] 0.93, p = 0.64 and HR 1.05, p = 0.72), and OS was (adjusted HR for death 0.54, p = 0.005 and adjusted HR for death 0.68, p = 0.03), respectively.ConclusionsThis is the first comprehensive, prospective report of smoking habits in patients with NSCLC patients from a phase III early-stage trial. There was a high rate of smoking reduction and cessation following study entry. The disease-free survival did not differ significantly between smokers and never smokers, though there were less grade 3–5 toxicities and more favorable OS in never-smokers.     

Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA–N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy

This prospective, randomized, phase III trial shows that prophylactic cranial irradiation prolongs disease-free survival, decreases the rate of cerebral metastases and does not affect quality-of-life for patients with fully resected postoperative pathologically confirmed stage IIIA-N2 non-small-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy.BackgroundThis study compared prophylactic cranial irradiation (PCI) with observation in patients with resected stage IIIA–N2 non-small-cell lung cancer (NSCLC) and high risk of cerebral metastases after adjuvant chemotherapy.Patients and methodsIn this open-label, randomized, phase III trial, patients with fully resected postoperative pathologically confirmed stage IIIA–N2 NSCLC and high cerebral metastases risk without recurrence after postoperative adjuvant chemotherapy were randomly assigned to receive PCI (30 Gy in 10 fractions) or observation. The primary end point was disease-free survival (DFS). The secondary end points included the incidence of brain metastases, overall survival (OS), toxicity and quality of life.ResultsThis trial was terminated early after the random assignment of 156 patients (81 to PCI group and 75 to control group). The PCI group had significantly lengthened DFS compared with the control group, with a median DFS of 28.5 months versus 21.2 months [hazard ratio (HR), 0.67; 95% confidence interval (CI) 0.46–0.98;P = 0.037]. PCI was associated with a decrease in risk of brain metastases (the actuarial 5-year brain metastases rate, 20.3% versus 49.9%; HR, 0.28; 95% CI 0.14–0.57;P < 0.001). The median OS was 31.2 months in the PCI group and 27.4 months in the control group (HR, 0.81; 95% CI 0.56–1.16;P = 0.310). While main toxicities were headache, nausea/vomiting and fatigue in the PCI group, they were generally mild.ConclusionIn patients with fully resected postoperative pathologically confirmed stage IIIA–N2 NSCLC and high risk of cerebral metastases after adjuvant chemotherapy, PCI prolongs DFS and decreases the incidence of brain metastases.     

Decreasing incidence of upper age restriction enrollment criteria among cancer clinical trials

BackgroundAge disparities among cancer clinical trial participants are pervasive and worsening over time. Identification of factors associated with age disparities is critical to improve enrollment of older patients on trials. The incidence and impact of trial eligibility criteria that exclude patients on the basis of age remains opaque.MethodsClinicalTrials.gov was queried for completed oncologic randomized controlled trials (RCTs). Phase 3 RCTs assessing a therapeutic intervention among adult cancer patients were included. Trial eligibility criteria were assessed using the ClinicalTrials.gov website as well as trial publications and protocol documentation.ResultsSeven hundred and forty-two trials met inclusion criteria, with a total combined enrollment of 449,720 patients. Upper age restriction enrollment criteria were identified for 10.1% of RCTs; the median age cutoff for restricted trials was 72 years (interquartile range 70–80 years). Linear regression modeling revealed decreasing incidence of age restriction criteria over time, at a rate of −1.1% annually (p = .03); trials initiating enrollment in 2002–2005, for example, had a 16.1% rate of age-restrictive eligibility criteria, compared with 7.6% for trials initiating enrollment in 2010–2014.ConclusionUse of eligibility criteria that explicitly exclude patients on the basis of age appears to be decreasing with time. Future efforts should aim to better characterize the relationship between eligibility criteria (such as those that exclude patients on the basis of specific organ function) and their association with age disparities among enrolled patients.     

Tumor marker kinetics predict outcome in patients with relapsed disseminated non-seminomatous germ-cell tumors

BackgroundAn early serum tumor marker (TM) decline during chemotherapy was shown to independently predict survival in patients with poor-prognosis disseminated non-seminomatous germ-cell tumors (NSGCTs). The aim of this study was to assess whether a TM decline (TMD) also correlates with the outcome in the salvage setting.Patients and methodsData regarding 400 patients with progressive or relapsed disseminated NSGCTs after first-line chemotherapy prospectively accrued onto two phase III clinical trials were obtained. Serum alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (hCG) were assessed at baseline and after 6 weeks of chemotherapy. A total of 297 patients, 185 and 112 in the training and validation sets, with initially abnormal TMs for whom a change from baseline could be established were used for this analysis.ResultsAn unfavorable decline in either AFP or hCG was predictive of progression-free survival (PFS) [hazard ratio, HR = 2.15, (95% CI 1.48–3.11); P < 0.001; 2-year PFS rate: 50% versus 26%] as was the Lorch prognostic score (LPS). In the multivariate analysis, an unfavorable TMD, stratified based on the LPS, was an independent adverse prognostic factor for PFS and OS.ConclusionAn unfavorable TMD during the first 6 weeks after chemotherapy is associated with a poorer outcome in patients with relapsed disseminated NSGCTs.     

Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial

The results of the PROCTOR-SCRIPT trial could not demonstrate a significant benefit of adjuvant chemotherapy with fluoropyrimidine monotherapy regarding overall survival, disease-free survival, and recurrence rates after preoperative (chemo)radiotherapy and TME surgery in yp stage II and III rectal cancer patients.BackgroundThe discussion on the role of adjuvant chemotherapy for rectal cancer patients treated according to current guidelines is still ongoing. A multicentre, randomized phase III trial, PROCTOR-SCRIPT, was conducted to compare adjuvant chemotherapy with observation for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision (TME).Patients and methodsThe PROCTOR-SCRIPT trial recruited patients from 52 hospitals. Patients with histologically proven stage II or III rectal adenocarcinoma were randomly assigned (1:1) to observation or adjuvant chemotherapy after preoperative (chemo)radiotherapy and TME. Radiotherapy consisted of 5 × 5 Gy. Chemoradiotherapy consisted of 25 × 1.8–2 Gy combined with 5-FU-based chemotherapy. Adjuvant chemotherapy consisted of 5-FU/LV (PROCTOR) or eight courses capecitabine (SCRIPT). Randomization was based on permuted blocks of six, stratified according to centre, residual tumour, time between last irradiation and surgery, and preoperative treatment. The primary end point was overall survival.ResultsOf 470 enrolled patients, 437 were eligible. The trial closed prematurely because of slow patient accrual. Patients were randomly assigned to observation (n = 221) or adjuvant chemotherapy (n = 216). After a median follow-up of 5.0 years, 5-year overall survival was 79.2% in the observation group and 80.4% in the chemotherapy group [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.62–1.39;P = 0.73]. The HR for disease-free survival was 0.80 (95% CI 0.60–1.07;P = 0.13). Five-year cumulative incidence for locoregional recurrences was 7.8% in both groups. Five-year cumulative incidence for distant recurrences was 38.5% and 34.7%, respectively (P = 0.39).ConclusionThe PROCTOR-SCRIPT trial could not demonstrate a significant benefit of adjuvant chemotherapy with fluoropyrimidine monotherapy after preoperative (chemo)radiotherapy and TME on overall survival, disease-free survival, and recurrence rate. However, this trial did not complete planned accrual.Registration numberDutch Colorectal Cancer group, CKTO 2003-16, ISRCTN36266738.     

Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT

BackgroundRecent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation.Design and methodsWe analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling.ResultsDistributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72–1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69–1.84) who are less likely to develop chemotherapy-induced amenorrhea.ConclusionBased on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected.Clinicaltrials.govNCT00066690 and NCT00066703.     

Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502

BackgroundWhile adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer.Patients and methodsPatients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety.ResultA total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group.ConclusionEighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer.Clinical trial numberUMIN-CTR C000000245.     

Thoracic Oncology Clinical Trial Eligibility Criteria and Requirements Continue to Increase in Number and Complexity

IntroductionEligibility criteria and screening procedures are designed to optimize the scientific yield and maximize the safety of clinical trials. However, they may also heighten trial complexity, hinder enrollment, decrease generalizability, and increase costs. We analyzed the types and number of eligibility criteria and screening procedures among thoracic oncology clinical trials sponsored or endorsed by the Eastern Cooperative Oncology Group.MethodsWe identified trials and obtained protocols from the Eastern Cooperative Oncology Group website. Eligibility criteria were grouped and categorized as comorbidity (classified by organ system), administrative requirements, prior treatment, and measurable disease requirements. Associations between trial characteristics and eligibility criteria were analyzed by using the Kruskal-Wallis and Wilcoxon tests.ResultsA total of 74 lung cancer trials activated in 1986–2016 were identified. The total number of eligibility criteria was associated with trial principal therapy (a median of nine for surgical, 18 for radiation, and 20 for medical therapy [p = 0.02]), trial primary end point (a median of 20 for overall survival, 28 for progression-free survival, and 17 for other [p = 0.001]), number of therapies (p = 0.05), and year of activation (a median of 16 for 1986–1995, 19 for 1996–2005, and 27 for 2006–2016 [P < 0.001]). The increase in trial eligibility requirements over time was limited to medical therapy trials. Over time, there was also an increase in blood test screening procedures (p = 0.05) but not in imaging, cardiac assessment, or pulmonary function screening procedures.ConclusionsThe number of eligibility criteria and screening procedures in medical therapy lung cancer clinical trials continues to rise. Continued efforts to simplify protocol eligibility and procedures are warranted to promote trial adherence, enrollment, completion, and generalizability.