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Stereotactic body radiation therapy (SBRT) improves complete pain response for painful spinal metastases compared with conventional external beam radiation therapy (cEBRT). We report mature local control and reirradiation rates in a large cohort of patients treated with SBRT versus cEBRT enrolled previously in the Canadian Clinical Trials Group Symptom Control 24 phase 2/3 trial.One hundred thirty-seven of 229 (60%) patients randomized to 24 Gy in 2 SBRT fractions or 20 Gy in 5 cEBRT fractions were retrospectively reviewed. By including all treated spinal segments, we report on 66 patients (119 spine segments) treated with SBRT and 71 patients (169 segments) treated with cEBRT. The primary outcomes were magnetic resonance-based local control and reirradiation rates for each treated spine segment.The median follow-up was 11.3 months (interquartile range, 5.3-27.7 months), and median overall survival in the SBRT and cEBRT cohorts were 21.6 (95% confidence interval [CI], 11.3, upper bound not reached) and 18.9 (95% CI, 12.2-29.1) months (P = .428), respectively. The cohorts were balanced with respect to radioresistant histology and presence of mass (paraspinal and/or epidural disease extension). Risk of local failure after SBRT versus cEBRT at 6, 12, and 24 months were 2.8% (95% CI, 0.8%-7.4%) versus 11.2% (95% CI, 6.9%-16.6%), 6.1% (95% CI, 2.5%-12.1%) versus 28.4% (95% CI, 21.3%-35.9%), and 14.8% (95% CI, 8.2-23.1%) versus 35.6% (95% CI, 27.8%-43.6%), respectively (P.001). cEBRT (hazard ratio [HR], 3.48; 95% CI, 1.94-6.25; P.001) and presence of mass (HR, 2.07; 95% CI, 1.29-3.31; P = .002) independently predicted local failure on multivariable analysis. The 1-year reirradiation rates and median times to reirradiation after SBRT versus cEBRT were 2.2% (95% CI, 0.4-7.0%) versus 15.8% (95% CI, 10.4%-22.3%) (P = .002) and 22.9 months versus 9.5 months, respectively. cEBRT (HR, 2.60; 95% CI, 1.27-5.30; P = .009) and radioresistant histology (HR, 2.00; 95% CI, 1.12-3.60; P = .020) independently predicted for reirradiation. Eight of 12 iatrogenic vertebral compression fractures were after SBRT and 4 of 12 after cEBRT; grade 3 adverse fracture effects were isolated to the SBRT cohort (5 of 12).Risk of local failure and reirradiation is lower with SBRT compared with cEBRT for spinal metastases. Although the iatrogenic vertebral compression fracture rates were within expectations, grade 3 vertebral compression fractures were isolated to the SBRT cohort.

PURPOSE We previously reported that enzalutamide improved overall survival when added to standard of care in metastatic, hormone-sensitive prostate cancer. Here, we report its effects on aspects of health-related quality of life (HRQL). METHODS HRQL was assessed with the European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire and QLM-PR25 at weeks 0, 4, 12, and then every 12 weeks until progression. Scores from week 4 to 156 were analyzed with repeated measures modeling to calculate group means and differences. Deterioration-free survival was from random assignment until the earliest of death, clinical progression, discontinuation of study treatment, or a worsening of 10 points or more from baseline in fatigue, physical function, cognitive function, or overall health and quality of life (OHQL). HRQL scores range from 0 (lowest possible) to 100 (highest possible). RESULTS HRQL was assessed in 1,042 of 1,125 participants (93%). Differences in means favored control over enzalutamide for fatigue (5.2, 95% CI, 3.6 to 6.9; P < .001), cognitive function (4.0, 95% CI, 2.5 to 5.5; P < .001), and physical function (2.6, 95% CI, 1.3 to 3.9; P < .001), but not OHQL (1.2, 95% CI, −0.2 to 2.7; P = .1). Deterioration-free survival rates at 3 years, and log-rank P values comparing the whole distributions, favored enzalutamide over control for OHQL (31% v 17%; P < .0001), cognitive function (31% v 20%; P = .001), and physical function (31% v 22%; P < .001), but not fatigue (24% v 18%; P = .16). The effects of enzalutamide on HRQL were independent of baseline characteristics. CONCLUSION Enzalutamide was associated with worsening of self-reported fatigue, cognitive function, and physical function, but not OHQL. Enzalutamide was associated with improved deterioration-free survival for OHQL, physical function, and cognitive function because delays in disease progression outweighed early deteriorations in these aspects of HRQL.

Background Complementary medicines (CM) are frequently used by patients with cancer. Controversy exists over the effectiveness and risk that CM may add to conventional cancer therapy. The incidence of CM use among patients enrolled in phase III clinical trials is unknown. Methods Medication lists from 6 international phase III clinical trials were retrospectively reviewed to identify patients using CM. Patients had metastatic breast, colorectal, or lung cancers. Quality of life, adverse events, overall survival, and progression-free survival were compared between CM users and non-users. Baseline differences between groups were adjusted with propensity score matching groups. Results Seven hundred and six of 3446 patients (20.5%) used at least one CM. CM use was highest among patients with breast cancer (35.6%). CM users had more favorable baseline prognostic factors (ECOG 0-1, non-smoking status, younger age, and fewer metastases). CM use was associated with lower rates of adverse events (50% vs. 62%, P = .002) and quality of life was similar between both groups. After adjustment with propensity score matching, CM use was also associated with longer overall survival in patients with lung cancer (adjusted hazard ratio 0.80, 95%CI, 0.68-0.94, P =.0054). However, several key control variables like EGFR status were not available. Conclusion One in 5 patients in phase III clinical trials report using CM. CM was not associated with worse cancer-specific outcomes. However, CM users had more favorable baseline prognostic factors, and likely other confounders that may have contributed to improved outcomes observed in the lung cohort. Physicians should monitor for CM use and potential interactions with clinical trial drugs.

Background: MET has been associated with beneficial anti-cancer effects in epidemiologic and preclinical research. It may act indirectly by reversing obesity associated physiologic changes or directly via mitochondrial mediated effects on LKB1/AMPK/mTOR and other mechanisms. MA.32 investigated the effect of MET vs PLAC (in addition to standard therapy) on adjuvant BC outcomes. Design: Randomized, placebo-controlled double-blind Phase III clinical trial conducted within the NCI US National Clinical Trials Network, NCRI (UK) BG, IBCSG. Methods: Between 2010-2013 BC patients < 75 yo without diabetes (DM) with high risk T1-3, N0-3 M0 BC regardless of ER, PgR, HER2 and with adequate cardiac, renal and hepatic function were randomized (stratified for ER/PgR + vs -, BMI < vs > 30 kg/m2, HER2 +ve vs -ve, any vs no chemo) within 1 year of BC diagnosis to MET 850 mg po bid or PLAC bid for 5 years. Dose was reduced for toxicity with re-escalation when possible. Subjects were followed for Invasive Disease-Free Survival (IDFS primary outcome; events included invasive local/regional recurrences, distant recurrences, new ipsilateral/contralateral invasive BCs, new non-breast primary cancers, any death), Overall Survival (OS), Distant Relapse Free Survival (DRFS), BC Specific Survival (BCSS), BC Free Interval (BCFI), contralateral BC and cardiovascular (CV) events/new DM. 3582 subjects were required for 80% power to detect HR 0.76 (431 events). In 2011, entry was restricted to higher risk BC, leading to 80% power to detect HR 0.785 (544 events). In 2016, after the 2nd interim analysis at 29.5 months median F/U, the DSMB recommended (i) the intervention be continued with primary analysis triggered at 544 events be conducted in ER/PgR +ve (any HER2) subjects only and (ii) ER/PgR -ve subjects stop study drug for futility but blinding and follow-up continue. In 2021, a time driven analysis in ER/PgR +ve BC was approved (465 events providing 80% power to detect the original HR 0.76). Time to event survival described by the Kaplan-Meier method. Two-sided log-rank tests adjusting for stratification factors were primarily used to compare IDFS between arms. Cox proportional hazards models were used to identify and adjust for factors significantly related to IDFS. Results: 3649 subjects were enrolled. In the 2533 ER/PgR +ve subjects included in the primary analysis, baseline mean (± SD) age was 52.7 (±9.9 yrs); mean BMI 28.8 (±6.4) kg/m2. Baseline tumor characteristics were balanced: T stage 1/2/3/4 = 832/1351/349/1; N stage 0/1/2/3 = 964/1097/449/23; HER2+ 429. 1901 (75%) received XRT. 2150 (84.9%) received (neo)adj chemo, 2223 (87.8%) (neo)adj hormones and 434 (17.1%) HER2 targeted therapy. Any Grade ≥ 3 toxicity was similar in MET and PLAC arms (21.7% and 18.7%, P = 0.06). Median follow-up was 96.2 (range 0.2-121.0) months with 465 IDFS events (234 MET, 231 PLAC, 76% due to BC). Efficacy results are shown below. MET vs PLACMET vs PLACIDFSOSPopulation Included# subjectsHR (95% CI)HR (95% CI)PRIMARY ANALYSISER/PgR +ve (any HER2)*25331.01 (0.84-1.21). P=0.920.89 (0.64-1.23). P=0.46ER/PgR -ve (any HER211161.01 (0.79-1.30. P=0.92)0.89 (0.64-1.23). P=0.46Exploratory. AnalysisHER2 +ve (any ER/PgR)6200.64 (0.43-0.95. P=0.0260.53 (0.30-0.98. P=0.0398**in ER/PgR pos BC HRs were similar for BCFI, DRFS, BCSS (ranging from 0.98-1.09)Conclusions: MET did not improve IDFS or other BC outcomes in ER/PgR positive or ER/PgR negative BC and should not be used as adjuvant treatment. Exploratory findings suggesting benefit in HER2+ve BC should be further investigated. Funded by: CCSRI, NCI (US), CBCF, BCRF, CRUK, Hold’Em for Life Charity, Apotex (Canada) Citation Format: Pamela J. Goodwin, Bingshu E Chen, Karen A Gelmon, Timothy J Whelan, Marguerite Ennis, Julie Lemieux, Jennifer A Ligibel, Dawn L Hershman, Ingrid A Mayer, Timothy J Hobday, Judith M Bliss, Priya Rastogi, Manuela Rabaglio-Poretti, Som D. Mukherjee, Robert R Mackey, Vandana G Abramson, Conrad Oja, Robert Wesolowski, Alastair M Thompson, Daniel W Rea, Paul M Stos, Lois E Shepherd, Vuk Stambolic, Wendy R Parulekar. CCTGMA.32, a phase III randomized double-blind placebo controlled adjuvant trial of metformin (MET) vs placebo (PLAC) in early breast cancer (BC): Results of the primary efficacy analysis (clinical trials.gov NCT01101438) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-08.

Women with hormone receptor positive breast cancer may receive 5 years of treatment with aromatase inhibitors but the magnitude of benefit was relatively small. Our goal was to develop a tool for identification of women with limited treatment benefit. Regression analyses were applied to women treated by placebo in CCTG MA.17R trial (NCT00754845) to identify important prognostic factors associated with distant recurrence and develop a nomogram for predicting 5-year likelihood of distant recurrence, which was internally validated using bootstrap resampling method. Differential treatment effects between risk categories derived from the nomogram were evaluated among all women enrolled through interaction test between treatment and risk category. A total of 1735 women were included and the final model from 866 women treated by placebo identified the following three factors associate with distant recurrence: tumor size, nodal status, and presence of cardiovascular disease. The nomogram derived from the final model exhibited good discrimination power with a bootstrap-corrected concordance index of 0.71 and, importantly, identified 64% of low risk patients in whom extended treatment has limited benefit. Interaction between treatment and risk category derived from the nomogram was significant (p = 0.04). A nomogram with good performance may be used to accurately predict distant recurrence risk and also benefits with extended treatment after 5 years of aromatase inhibitors. Future independent validation of the proposed nomogram is warranted. NCT00754845

Men who initially present with localized prostate cancer and later develop metachronous metastases have a better prognosis than men with de novo metastatic disease and often have a low burden of disease on conventional imaging. Some have disease amenable to metastasis-directed therapy for lymph node or bone metastases, a strategy used by some because no documented overall survival (OS) benefit of combination systemic therapy in this setting. We report data for patients prospectively classified as "M0" at initial diagnosis from the interim analysis of the ENZAMET trial, with 34 mo of median follow-up for survivors. A total of 312 (28%) of the 1125 enrolled patients were classified as M0 at diagnosis, and 205 (66%) of the 312 patients had low-volume disease at study entry as per the CHAARTED criteria. The hazard ratio for OS, that is, HR(OS), was 0.56 (95% confidence interval [CI]: 0.29-1.06) with the addition of enzalutamide for all patients with metachronous metastatic hormone-sensitive prostate cancer, and for the low-volume subset the HR(OS) was 0.40 (95% CI: 0.16-0.97). The 3-yr OS was 83% without and 89% with enzalutamide for all patients with metachronous metastases, and 83% and 92%, respectively, for the low-volume subset. Intensification of hormonal therapy should strongly be considered for these men. PATIENT SUMMARY: Many men present with prostate cancer that has spread to distant sites beyond the prostate gland years after their initial diagnosis and treatment, while others have distant spread at the time the cancer is diagnosed. On average, men whose cancer comes back years after the initial diagnosis often survive much longer than men whose cancer has been found to spread to distant sites when it is first diagnosed. In this report, we demonstrate strong evidence for the first time that the survival of men whose cancer comes back years later is improved when drugs such as enzalutamide or apalutamide are added to testosterone suppression in this setting.

Summary Background Conventional external beam radiotherapy is the standard palliative treatment for spinal metastases; however, complete response rates for pain are as low as 10–20%. Stereotactic body radiotherapy delivers high-dose, ablative radiotherapy. We aimed to compare complete response rates for pain after stereotactic body radiotherapy or conventional external beam radiotherapy in patients with painful spinal metastasis. Methods This open-label, multicentre, randomised, controlled, phase 2/3 trial was done at 13 hospitals in Canada and five hospitals in Australia. Patients were eligible if they were aged 18 years and older, and had painful (defined as ≥2 points with the Brief Pain Inventory) MRI-confirmed spinal metastasis, no more than three consecutive vertebral segments to be included in the treatment volume, an Eastern Cooperative Oncology Group performance status of 0–2, a Spinal Instability Neoplasia Score of less than 12, and no neurologically symptomatic spinal cord or cauda equina compression. Patients were randomly assigned (1:1) with a web-based, computer-generated allocation sequence to receive either stereotactic body radiotherapy at a dose of 24 Gy in two daily fractions or conventional external beam radiotherapy at a dose of 20 Gy in five daily fractions using standard techniques. Treatment assignment was done centrally by use of a minimisation method to achieve balance for the stratification factors of radiosensitivity, the presence or absence of mass-type tumour (extraosseous or epidural disease extension, or both) on imaging, and centre. The primary endpoint was the proportion of patients with a complete response for pain at 3 months after radiotherapy. The primary endpoint was analysed in the intention-to-treat population and all safety and quality assurance analyses were done in the as-treated population (ie, all patients who received at least one fraction of radiotherapy). The trial is registered with ClinicalTrials.gov , NCT02512965 . Findings Between Jan 4, 2016, and Sept 27, 2019, 229 patients were enrolled and randomly assigned to receive conventional external beam radiotherapy (n=115) or stereotactic body radiotherapy (n=114). All 229 patients were included in the intention-to-treat analysis. The median follow-up was 6·7 months (IQR 6·3–6·9). At 3 months, 40 (35%) of 114 patients in the stereotactic body radiotherapy group, and 16 (14%) of 115 patients in the conventional external beam radiotherapy group had a complete response for pain (risk ratio 1·33, 95% CI 1·14–1·55; p=0·0002). This significant difference was maintained in multivariable-adjusted analyses (odds ratio 3·47, 95% CI 1·77–6·80; p=0·0003). The most common grade 3–4 adverse event was grade 3 pain (five [4%] of 115 patients in the conventional external beam radiotherapy group vs five (5%) of 110 patients in the stereotactic body radiotherapy group). No treatment-related deaths were observed. Interpretation Stereotactic body radiotherapy at a dose of 24 Gy in two daily fractions was superior to conventional external beam radiotherapy at a dose of 20 Gy in five daily fractions in improving the complete response rate for pain. These results suggest that use of conformal, image-guided, stereotactically dose-escalated radiotherapy is appropriate in the palliative setting for symptom control for selected patients with painful spinal metastases, and an increased awareness of the need for specialised and multidisciplinary involvement in the delivery of end-of-life care is needed. Funding Canadian Cancer Society and the Australian National Health and Medical Research Council.

Metformin may exert anticancer effects through indirect (mediated by metabolic changes) or direct mechanisms. The goal was to examine metformin impact on metabolic factors in non-diabetic subjects and determine whether this impact varies by baseline BMI, insulin, and rs11212617 SNP in CCTG MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer (BC) trial. 3649 subjects with T1-3, N0-3, M0 BC were randomized; pretreatment and 6-month on-treatment fasting plasma was centrally assayed for insulin, leptin, highly sensitive C-reactive protein (hsCRP). Glucose was measured locally and homeostasis model assessment (HOMA) calculated. Genomic DNA was analyzed for the rs11212617 SNP. Absolute and relative change of metabolic factors (metformin versus placebo) were compared using Wilcoxon rank and t-tests. Regression models were adjusted for baseline differences and assessed interactions with baseline BMI, insulin, and the SNP. Mean age was 52 years. The majority had T2/3, node positive, hormone receptor positive, HER2 negative BC treated with (neo)adjuvant chemotherapy and hormone therapy. Median baseline body mass index (BMI) was 27.4 kg/m2 (metformin) and 27.3 kg/m2 (placebo). Median weight change was −1.4 kg (metformin) vs +0.5 kg (placebo). Significant improvements were seen in all metabolic factors, with 6 month standardized ratios (metformin/placebo) of 0.85 (insulin), 0.83 (HOMA), 0.80 (leptin), and 0.84 (hsCRP), with no qualitative interactions with baseline BMI or insulin. Changes did not differ by rs11212617 allele. Metformin (vs placebo) led to significant improvements in weight and metabolic factors; these changes did not differ by rs11212617 allele status.

Importance Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies. Objective To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. Design, Setting, and Participants MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. Interventions Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. Main Outcomes and Measures The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed. Results Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). Conclusions and Relevance Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival. Trial Registration ClinicalTrials.gov Identifier: NCT01101438.

Anthracyclines are frequently used in adjuvant treatment for early-stage breast cancer (ESBC). The purpose of this study was to evaluate cardiotoxic effects in the first five years after treatment with different anthracycline-based regimens. CCTG MA.21 (NCT000142) was a phase III trial in ESBC that compared cyclophosphamide (75 mg/m2) orally for 14 days, epirubicin (60 mg/m2) and fluorouracil, IV days one and eight (CEF) for six cycles; dose-dense epirubicin (120 mg/m2) and cyclophosphamide, IV every 2 weeks for six cycles with concurrent G-CSF then paclitaxel every 2 weeks for four cycles (ddEC/T); doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks for four cycles then four cycles q3 weekly paclitaxel (175 mg/m2) (AC/T). Endpoints: LVEF decline; LV function changes (heart failure), or Grade 3–4 cardiac ischemia/infarction. A competing risk analysis was performed with endpoints of cardiotoxicity or recurrence in first 5 years after completion of chemotherapy. 2104 women were randomized. Compliance with cardiac LVEF assessments was 70% at 5 years in all arms. The 5-year cumulative risks of any cardiac event for CEF, ddECT, and AC/T were 22.3% (95%CI 18.9 to 25.7), 14.2% (95%CI 11.0 to 17.3), and 8.1% (95%CI 5.8 to 10.4), respectively, p

Background The purpose of this retrospective biomarker study of the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial (lapatinib vs trastuzumab) of HER2-positive metastatic breast cancer (MBC) was to evaluate the prognostic and predictive biomarker utility of pretreatment serum programmed death ligand 1 (PD-L1) levels. Methods CCTG MA.31 accrued 652 HER2-positive patients; 387 had serum available (185 in the trastuzumab arm and 202 in the lapatinib arm). The Ella immunoassay platform (ProteinSimple, San Jose, California) was used to quantitate serum PD-L1 levels. Stepwise forward Cox multivariable analyses were performed for progression-free survival and overall survival (OS). Results In the whole trial population, continuous pretreatment serum PD-L1 levels were not associated with OS. However, within the trastuzumab arm, a higher continuous pretreatment serum PD-L1 level was significant for shorter OS (hazard ratio [HR], 3.85; P = .04), but within the lapatinib arm, pretreatment serum PD-L1 was not associated with OS (P = .37). In the whole trial, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate (HR, 2.38; P = .001). There was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P = .0025): at or above 214.2 pg/mL (the 89th percentile), serum PD-L1 was associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment. Conclusions In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: a higher pretreatment serum PD-L1 level was associated with shorter OS with trastuzumab treatment but with longer OS with lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in advanced breast cancer is warranted to identify patients with HER2-positive MBC who may benefit from novel immune-targeted therapies in addition to trastuzumab.

Women with hormone receptor positive breast cancer may receive 5 years of treatment with aromatase inhibitors but the magnitude of benefit was relatively small. Our goal was to develop a tool for identification of women with limited treatment benefit.Regression analyses were applied to women treated by placebo in CCTG MA.17R trial (NCT00754845) to identify important prognostic factors associated with distant recurrence and develop a nomogram for predicting 5-year likelihood of distant recurrence, which was internally validated using bootstrap resampling method. Differential treatment effects between risk categories derived from the nomogram were evaluated among all women enrolled through interaction test between treatment and risk category.A total of 1735 women were included and the final model from 866 women treated by placebo identified the following three factors associate with distant recurrence: tumor size, nodal status, and presence of cardiovascular disease. The nomogram derived from the final model exhibited good discrimination power with a bootstrap-corrected concordance index of 0.71 and, importantly, identified 64% of low risk patients in whom extended treatment has limited benefit. Interaction between treatment and risk category derived from the nomogram was significant (p = 0.04).A nomogram with good performance may be used to accurately predict distant recurrence risk and also benefits with extended treatment after 5 years of aromatase inhibitors. Future independent validation of the proposed nomogram is warranted.NCT00754845.

An interim analysis is commonly used in phase III superiority trials to compare treatment arms, with the goal of terminating exposure of patients to ineffective or unsafe drugs or to identify highly effective therapies for earlier public disclosure. Traditionally, interim analyses have been designed to identify early evidence of extremely large benefit of the experimental approach, potentially leading to early dissemination of effective treatments. Increasingly, interim analysis has also involved analysis of futility, which may lead to early termination of a trial that will not yield additional useful information. This presents an important challenge in early stage hormone receptor–positive breast cancer, where recurrence often occurs late, with a steady annual event rate up to 20 years. Early analysis of events may miss late treatment effects that can be observed only with longer follow-up. We discuss approaches to futility analysis in adjuvant clinical trials in hormone receptor–positive breast cancer, the role of the Data Safety Monitoring Committee in such analyses, considerations of the potential harms vs benefits of treatment, and the risks of continuing vs early termination of a trial.

Background Circulating levels of cancer antigen (CA) 15–3, a tumor marker and regulator of cellular metabolism, were reduced by metformin in a nonrandomized neoadjuvant study. We examined the effects of metformin (vs placebo) on CA 15–3 in participants of MA.32, a phase III randomized trial in early-stage breast cancer. Methods A total of 3649 patients with T1-3, N0-3, M0 breast cancer were randomly assigned; pretreatment and 6-month on-treatment fasting plasma were centrally assayed for CA 15–3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism. Absolute and relative change of CA 15–3 (metformin vs placebo) were compared using Wilcoxon rank and t tests. Regression models adjusted for baseline differences and assessed key interactions. All statistical tests were 2-sided. Results Mean (SD) age was 52.4 (10.0) years. The majority of patients had T2/3, node-positive, hormone receptor–positive, HER2-negative breast cancer treated with (neo)adjuvant chemotherapy and hormone therapy. Mean (SD) baseline CA 15–3 was 17.7 (7.6) and 18.0 (8.1 U/mL). At 6 months, CA 15–3 was statistically significantly reduced in metformin vs placebo arms (absolute geometric mean reduction in CA 15–3 = 7.7% vs 2.0%, P .11). Conclusions Our observation that metformin reduces CA 15–3 by approximately 6% was corroborated in a large placebo-controlled randomized trial. The clinical implications of this reduction in CA 15–3 will be explored in upcoming efficacy analyses of breast cancer outcomes in MA.32.

High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Treatment is not uniform, with some patients undergoing primary debulking surgery followed by chemotherapy (PDS) and others being treated directly with chemotherapy and only having surgery after three to four cycles (NACT). Which strategy is optimal remains controversial. We developed a mathematical framework that simulates hierarchical or stochastic models of tumor initiation and reproduces the clinical course of HGSC. After estimating parameter values, we infer that most patients harbor chemoresistant HGSC cells at diagnosis and that, if the tumor burden is not too large and complete debulking can be achieved, PDS is superior to NACT due to better depletion of resistant cells. We further predict that earlier diagnosis of primary HGSC, followed by complete debulking, could improve survival, but its benefit in relapsed patients is likely to be limited. These predictions are supported by primary clinical data from multiple cohorts. Our results have clear implications for these key issues in HGSC management.

Regional nodal irradiation for women with breast cancer is known to be an important risk factor for the development of upper extremity lymphedema, but tools to accurately predict lymphedema risks for individual patients are lacking. This study sought to develop and validate a nomogram to predict lymphedema risk after axillary surgery and radiation therapy in women with breast cancer.Data from 1832 women accrued on the MA.20 trial between March 2000 and February 2007 were used to create a prognostic model with National Cancer Institute Common Toxicity Criteria Version 2.0 grade 2 or higher lymphedema as the primary endpoint. Multivariable logistic regression estimated model performance. External validation was performed on data from a single large academic cancer center (N = 785).In the MA.20 trial cohort, 3 risk factors were predictive of lymphedema risk: body mass index (adjusted odds ratio, 1.05 per unit body mass index; 95% confidence interval [CI], 1.03-1.08, P.001), extent of axillary surgery (adjusted odds radio for 8-11 lymph nodes removed, 3.28 [95% CI, 1.53-7.89] P = .004; 12-15 lymph nodes, 4.04 [95% CI, 1.76-10.26] P = .002; ≥16 nodes, 5.08 [95% CI, 2.26-12.70] P.001), and extent of nodal irradiation (adjusted odds radio for limited, 1.66 [95% CI, 1.08-2.56] P = .02; for extensive, 2.31 [95% CI, 1.28-4.10] P = .004). A nomogram was created from these data that predicted lymphedema risk with reasonable accuracy confirmed by both internal (concordance index, 0.69; 95% CI, 0.64-0.74) and external validation (concordance index, 0.71; 95% CI, 0.66-0.76).The nomogram created from the MA.20 randomized trial data using clinical information may be useful for lymphedema screening and risk stratification for therapeutic intervention trials.

Background: Early stage, hormone sensitive breast cancer is associated generally with a good prognosis, with only a minority of patients expected to die of breast cancer. Death from causes other than breast cancer can dilute the patients at risk of breast cancer events and result in over-estimation of risk of recurrence and consequently the benefit from breast cancer therapy, a so-called immortal time bias. The MA.17R trial (Goss et al 2016) evaluated the role of extending adjuvant treatment with letrozole from 5 to 10 years. Here we determine the effect of analyzing the MA.17R trial using methods accounting for competing risks. Methods: We compared conventional and competing risk methods for disease-free survival (DFS) and for distant recurrence-free survival (DRFS). In Kaplan-Meier analyses death from any cause was considered an event while cumulative incidence functions (CIFs) assumed death without recurrence to be a competing risk. The complement of the survival function (one minus the survival function) was used to estimate incidence of the primary event of interest. This was compared to estimates obtained using CIFs accounting for the occurrence of competing events. Results: Non-breast cancer death was the most common event defining DFS and DRFS. Over the course of follow-up, there was increasing discrepancy between the risk of disease recurrence measured using Kaplan-Meier and CIF. Among letrozole treated patients the estimated distant recurrence at 5 years of follow-up was 5.4% using CIF and 9.6% using Kaplan-Meier. At 10 years of follow-up, the estimated distant recurrence was 8.4% using CIF and 20.0% using Kaplan-Meier. Similar results were observed for the placebo group (8.5% vs 12.1% at 5 years and 14.8% vs 27.3% at 10 years), and in patients with baseline cardiovascular disease (see Table). Benefit from letrozole on DFS and DRFS was greater when accounting for competing risk (hazard ratio [HR] for DFS 0.66, 95%CI 0.48-0.90; DFRS HR 0.75, 0.50-1.14) compared to the conventional method (DFS HR 0.79, 0.62-0.99; DRFS HR 0.91, 0.70-1.18). In women with baseline cardiovascular risk, the benefits of extended adjuvant letrozole when considering competing risk (DFS HR 0.38, 0.16-0.89; DRFS HR 0.46, 0.16-1.35) were also greater than those observed in the conventional analysis (DFS HR 0.55, 0.32-0.93; DRFS HR 0.59, 0.33-1.04). Treatment with extended letrozole did not influence non-breast cancer death in women who died with disease recurrence (HR 1.06, 0.74 -1.50) or in those with competing risk or censored from the analysis (HR 1.05, 0.73 -1.49). Conclusion: Over the course of follow-up, estimates of DFS and DRFS differ increasingly if measured using Kaplan-Meier or CIF, with CIF estimates of risk being substantially lower. Using a competing risk model, the reduction in distant recurrence at 8 years with extended letrozole is less than 1%. Additional competing risk analyses of the MA.17 (Goss 2006) and MA.27 (Goss 2013) trials are ongoing. Cumulative incidence of disease recurrence in patients with baseline cardiovascular riskTime (years)CIF (%)1-KM (%)Letrozole11.51.534.46.555.813.8Placebo13.53.538.311.8512.520.3 Citation Format: Ethier J-L, Parulekar W, Shepherd L, Summers L, Strasser-Weippl K, Tu D, Amir E. Influence of competing risks of death on the interpretation of adjuvant endocrine therapy trials for breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-03.

Background: Palbociclib is approved for treatment of ER+, HER2- ABC at a standard dose of 125 mg po daily 3 weeks on/1 week off (STD). We evaluated the efficacy, safety, quality of life (QOL) and compliance of a 100 mg continuous daily dose (CDD) of palbociclib based on modeling data that suggested efficacy and tolerability. Methods: Canadian Cancer Trials Group (CCTG) led a randomized phase II trial (CCTG MA38) to estimate the efficacy of palbociclib 100 mg po on CDD schedule (Arm 1) relative to 125 mg po STD schedule (Arm 2) with physician choice endocrine therapy. Eligible patients had ER+, HER2- ABC, post progression on first line metastatic endocrine therapy or progressed while on/within 12 months of completion of adjuvant endocrine therapy. One line of palliative chemotherapy in ABC was allowed. Stratification factors were: visceral metastases, duration of prior endocrine therapy and planned endocrine therapy. Primary Outcome measure was investigator reported PFS; secondary outcome measures included: RR, OS, safety (CTCAE V4.0), and QOL (EORTC QLQ-C30). The sample size was 180 to enable estimation of the HR between arms with the upper bound of the 90% CI 1.36 times the estimated HR and the lower bound is 0.74 times the estimated HR. Results: 180 patients were enrolled across Canada from Dec 2015 to Feb 2017. The database was locked April 16 2018 after prespecified PFS events reached at a median follow-up of 19 months for all patients. For the whole population: median age was 60.5 years (21% ≥ 70 years); ECOG 0/1 95%; postmenopausal 91%; visceral metastases 67%. Planned endocrine therapy: aromatase inhibitor 33%, fulvestrant 57%, tamoxifen 10%. Efficacy analyses CDD vs STD: PFS stratified univariate HR 0.93 (90% CI 0.66-1.30); multivariate Cox model analysis (covariates ECOG PS, age, histology, grade): HR 0.92 (90% CI 0.67-1.25). Median PFS CDD: 9.33 months (90% CI 6.93-13.90) and STD: 11.30 months (90% CI 8.08- 13.83) Secondary analyses CDD vs STD: OS stratified univariate HR: 1.07 (90% CI 0.67-1.69); multivariate HR 1.14 (90%CI 0.75-1.75); median OS for CDD: 20.73 months (90% CI 19.29-23.30) and 21.39 months (90% CI 19.65 to 26.68) for STD. RR and median duration of response: 11.1% vs 12.4% (p=0.84) and 126 vs 169 days (p=0.86), respectively. Palbociclib drug exposure CDD vs STD: median daily dose (mg) 87 vs 125; median dose intensity (mg/week) 571.2 vs 613.5; ≥ 90% planned dose intensity, 41% vs 54%. Dose modification (withhold and/or reduction) rate CDD vs STD for neutropenia was 70% vs 40%. Grade 3/4 neutropenia 69% vs 53%; febrile neutropenia 3% each arm. Non-hematological toxicity profiles were comparable for both arms. No significant differences were seen in QOL domains. Conclusion: Palbociclib is active and tolerable when administered on either a 100 mg CDD or a 125 mg STD schedule. CDD schedule had higher rates of grade 3/4 neutropenia and dose modifications. Post approval evaluation of alternate dosing schedules for targeted therapies provides useful information regarding drug activity, toxicity and adherence. Citation Format: Parulekar WR, Joy AA, Gelmon K, Mates M, Desbiens C, Clemons M, Taylor S, Lemieux J, Bartlett J, Whelan T, Ayoub J-P, Cescon D, Bordeleau L, Rahim Y, Winch C, Chen BE. Randomized phase II study comparing two different schedules of palbociclib plus second line endocrine therapy in women with estrogen receptor positive, HER2 negative advanced/metastatic breast cancer: CCTG MA38 (NCT02630693) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-10.

TPS5110 Background: [177Lu]Lu-PSMA-617 improves outcome in men with metastatic, PSMA positive CRPC post androgen pathway inhibitor therapy and taxane chemotherapy compared to standard care (excluding chemotherapy, immunotherapy, radium-223 and investigational drugs; Sartor et al, NEJM 2021). The relative efficacy, adverse event experience and impact on QOL of [177Lu]Lu-PSMA-617 compared to docetaxel chemotherapy in this patient population is unknown. We hypothesize that [177Lu]Lu-PSMA-617 will improve radiographic PFS (rPFS) compared to docetaxel chemotherapy with a favourable safety and tolerability profile. Methods: CCTG PR21 is a Canadian Cancer Trials Group randomized phase II trial with a primary objective to compare rPFS between [177Lu]Lu-PSMA-617 7.4 GBq (+/- 10%) IV q 6 weekly (maximum 6 cycles) versus docetaxel 75 mg/m2 q 3 weekly (maximum 12 cycles). Secondary objectives are to compare the two arms with respect to: 6-month PFS rate (PCWG3 and RECIST 1.1), second rPFS after crossover to the alternate therapy, time to commencement of 3rd line systemic therapy, OS, PSA decline from baseline, clinical benefit rate and adverse events. Tertiary objectives include evaluation of QOL (FACT-P and EQ5D-5L), cost effectiveness, ctDNA and radiographic based prognostic and predictive biomarkers, dosimetry based approach to measurement of [177Lu]Lu-PSMA-617 activity and creation of tissue and image biobanks. Key eligibility criteria include: mCRPC with PSMA positive disease using 18F or 68Ga radionuclide label, progression on ADT + ARPI therapy (using PSA, RECIST 1.1 or PCWG3 criteria) and adequate organ function. Statistical Design: Patients are allocated in 1:1 ratio to [177Lu]Lu-PSMA-617 or docetaxel balanced for stratification factors of ECOG PS, LDH, visceral metastases, previous docetaxel in the castration sensitive setting > 1 year prior to enrollment as well as centre. Assuming a 6-month median rPFS for the control group, the detection of a hazard ratio (HR) of 0.67 with 80% power using a 1-sided 5% level test will require accrual of 200 participants in 24 months with 12-month follow-up to trigger the primary analysis. Conduct to Date: Study activation Dec 17 2020. Enrollment as of January 31 2022: 25. The DSMC last reviewed and recommended continuation of the trial in December 2021. Clinical trial information: NCT04663997.

526 Background: The MA32 study (NCT01101438) investigated whether 5-years of metformin improves invasive disease-free survival in early-stage breast cancer (BC). Non-adherence to endocrine therapy (ET) and medications for chronic conditions is common, and increases with drug toxicity and polypharmacy. This secondary analysis evaluates rates and predictors of early discontinuation of metformin, placebo, and ET among participants with HR positive BC. Methods: Patients with high-risk non-metastatic BC were randomized to 60 months of metformin (850 mg BID) or placebo. Patients were administered bottles of metformin/placebo every 180 days. Metformin/placebo compliance was defined as a bottle dispensed at month 48 or later (i.e., medication supplied for 54 months). The ET compliance analysis included patients with HR positive BC who received adjuvant ET with start and stop date reported and was defined as > 48 months of use. Associations of baseline covariates with drug compliance and with ET adherence were examined using multivariable models. Results: Among the 2,521 HR-positive BC patients, 32.9% were non-compliant to study drug. Non-compliance was higher among patients on metformin vs. placebo (37.1% vs. 28.7%, p 30, OR=1.49, 95% CI, 1.25 - 1.77; p

TPS4619 Background: Immunotherapy improves outcomes in the advanced (Bellmunt 2019; Powles 2020) as well as in the adjuvant setting post cystectomy (Bajorin 2021) for muscle invasive bladder cancer (MIBC) patients. Trimodality treatment (TMT) consisting of transurethral resection of bladder tumor (TURBT) followed by chemoradiotherapy (CRT) may be considered an alternative to radical cystectomy in MIBC. The role of radiotherapy and chemotherapy as immune system stimulants provides a rationale to evaluate the anticancer activity of checkpoint inhibitors in this patient population. Durvalumab, an anti PDL1 inhibitor, administered after CRT leads to improvement in PFS and OS in patients with locally advanced NSCLC, which further supports the rationale for this study (Antonia 2017, 2018). We hypothesized that durvalumab will improve outcomes in patients with MIBC when administered in the adjuvant setting after completion of trimodality therapy. Methods: CCTG BL13 is a Canadian Cancer Trials Group, randomized phase II trial in patients with stage T2-T4a N0M0, urothelial carcinoma treated with TURBT followed by radiotherapy with concurrent chemotherapy. Treatment arms consist of durvalumab 1500 mg IV q 4 weeks for 12 months versus surveillance. The primary objective: to compare disease free survival (DFS) between arms (RECIST 1.1, investigator assessed). Secondary endpoints include a non muscle-invasive bladder cancer recurrence rate (< T2); locoregional control rate; overall survival; bladder intact DFS, patterns of disease recurrence; metastasis free survival; safety; quality of life ; economics evaluation. A pilot sub study (BL13F) has been activated and will evaluate the feasibility of electronic real-time patient self-reporting of immunotherapy related symptomatic adverse events using the SYMPTOM-IQ Tool on the uMotif Mobile Health Application (APP). Statistical Design: Randomization 1:1 balanced for stratification factors: ECOG PS; neoadjuvant chemotherapy; radiation field extent; T2 vs T3/T4; centre. Assuming a 2-year DFS rate 65% for patients on the control arm and estimated 12% improvement in the 2-year DFS rate (65% to 77% (HR 0.61)) with 80% power using a 1-sided 10% level test requires a sample size of 190 including 5% drop out rate. Conduct to Date: Study activation Dec 2018. Enrollment as of January 31 2022: 49. The DSMC reviewed and recommended trial continuation in November 2021. Clinical trial information: NCT03768570.

Background: Conventional external beam radiation (CRT) is standard palliative treatment for spinal metastases; however, complete response rates for pain are low. Stereotactic body radiotherapy (SBRT) delivers high dose ablative radiotherapy. We aimed to compare complete response rates (CR) for pain between SBRT and CRT to painful spinal metastases. Methods: We did this multicenter, phase 2/3, randomised controlled trial in 13 hospitals in Canada and 5 in Australia and New Zealand. Patients were eligible if they were aged 18 years and older, a spine MRI confirmed painful (pain measured as ≥2 points using the Brief Pain Inventory) site of spinal metastasis, no more than three consecutive vertebral segments to be included in the treatment volume, an Eastern Cooperative Oncology Group performance status of 0 to 2, and no frank instability or neurologically symptomatic spinal cord or cauda equina compression. Patients were randomized (1:1) to receive either 24Gy in 2 SBRT fractions or 20Gy in 5 CRT fractions using standard techniques. Treatment assignment was performed centrally using a minimization method to achieve balance for the stratification factors of radioresistant (gastrointestinal, sarcoma, melanoma and renal cell cancer metastases) vs. radiosensitive (all other histologies) histologic type, presence or absence of “Mass” on imaging (extra-osseous paraspinal and/or epidural disease extension), and center. Patients, caregivers and investigators were not masked to the treatment allocation. The primary endpoint was the CR rate for pain at 3 months post-radiation. Final analysis populations included the intent-to-treat (ITT) population for all efficacy endpoints, and the as-treated population for safety and quality assurance analyses. The trial is registered with ClinicalTrials.gov (NCT02512965). Findings: Patients were enrolled from January 2016 to September 2019. All 229 patients were included in the ITT analyses including 4 of the 114 patients randomized to SBRT who did not initiate the study intervention, 2 of the 115 in the CRT arm that initiated at least one fraction of radiation treatment but withdrew prior to completion, 22 (19%) patients in the CRT arm and 16 (14%) patients in the SBRT arm who were in-evaluable at the primary endpoint assessment at 3 months, and 39 (34%) patients in the CRT arm and 36 (32%) patients in the SBRT arm who were inevaluable at the 6 month endpoint. The median baseline worst pain score was 5 (range, 2-10) in both arms, and the median follow-up was 6.7 months (range, 0.2-8.9). At 3 months, 16/115 (14%) in the CRT arm vs. 40/114 (36%) in the SBRT arm (p=0.0002) achieved a CR for pain. Significance was retained on multivariable analyses (MVA, p=0.0003) and the risk ratio (RR) was 1.33 (95% C.I., 1.14 – 1.55) favoring SBRT. At 6 months, 18/115 (16%) in the CRT arm vs. 37/114 patients (33%) in the SBRT arm achieved a CR (p=0.004), significance was retained on MVA (p=0.007), and the RR was 1.24 (95% C.I., 1.07 – 1.44) favoring SBRT. The 3 month radiation site specific progression-free-survival rates for CRT vs. SBRT were 86% vs. 92% and, at 6 months, 69% vs. 75%, respectively. Quality-of-life outcomes were comparable with only financial perception at 1 month (p=0.03) favoring SBRT. Grade 2+ adverse events were observed in 12% and 11% in the CRT and SBRT arms, respectively. Interpretation: SBRT is superior to CRT in improving the CR rate for pain in selected patients with spinal metastases. Trial Registration: (NCT02512965). Funding: Canadian Cancer Society (CCS) and the National Health and Medical Research Council (NHMRC). Declaration of Interests: AS declares prior consulting services and/or honorarium for past educational seminars for Varian Medical Systems, Elekta AB, Astra Zeneca, Medtronic Kyphon, and BrainLAB, and research grants from Elekta AB and Varian Medical Systems. SS declares research grants from Varian Medical Systems, Merck-Sharp-Dohme and Bayer Pharmaceuticals and honorarium for past educational seminars and advisory board participation from Astra Zeneca and Reflexion. SDM declares grant support from Novartis/AAA and honorarium from Ipsen. MF declares grants from Elekta AB and honorarium for past educational seminars from Elekta AB and Varian Medical Systems. JG, IT, MK, MGF, ML, PJM, YL, MB, JB, KD, GLM, RKW, SKL, WRP, and ZG have no conflicts of interests to declare. Ethics Approval Statement: Each participating center obtained approval from their local research ethics board, and each patient provided written informed consent. All data were collected, maintained and analyzed by the Canadian Cancer Trials Group (CCTG) in Kingston, Ontario, Canada. The trial was sponsored in Canada by the CCTG and in Australia and New Zealand by the Trans Tasman Radiation Oncology Group (TROG), and independently monitored by the independent CCTG Data Safety Monitoring Board.

IMPORTANCE: Treatment options for platinum-refractory metastatic urothelial cancer (mUC) are limited, and outcomes remain poor. Nab-paclitaxel is an albumin-bound formulation of paclitaxel showing promising activity and tolerability in a prior single-arm trial. OBJECTIVES: To evaluate the efficacy and safety of nab-paclitaxel vs paclitaxel in platinum-refractory mUC. DESIGN, SETTING, AND PARTICIPANTS: In this investigator-initiated, open-label, phase 2 randomized clinical trial conducted across Canada and Australia from January 2014 to April 2017, eligible patients had histologically confirmed, radiologically evident mUC of the urinary tract. Mixed histologic findings, except small cell, were permitted provided UC was the predominant histologic finding. All patients had received platinum-based chemotherapy either in the metastatic setting or were within 12 months of perioperative chemotherapy. Patients with prior taxane chemotherapy were not included. Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2 and adequate organ function. INTERVENTIONS: Patients were randomized to nab-paclitaxel, 260 mg/m(2), or paclitaxel, 175 mg/m(2), every 3 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS). RESULTS: Among 199 patients, median age was 67 (range, 24-88) years; 144 (72%) were men; 167 (84%) were ECOG PS 0-1; 59 (30%) had liver metastases; and 110 (55%) were within 6 months of prior platinum-based chemotherapy. At a median follow-up of 16.4 months, there was no significant difference between nab-paclitaxel vs paclitaxel for median PFS (3.4 months vs 3.0 months; hazard ratio [HR], 0.92; 90% CI, 0.68-1.23; 1-sided P = .31). Median overall survival was 7.5 months for nab-paclitaxel vs 8.8 months for paclitaxel (HR, 0.95; 90% CI, 0.70-1.30; 1-sided P = .40); and objective response rate (ORR) was 22% for nab-paclitaxel vs 25% for paclitaxel (P = .97). Grade 3/4 adverse events were more frequent with nab-paclitaxel (64/97 [66%]) compared with paclitaxel (45/97 [46%]), P = .009; but peripheral sensory neuropathy was similar (all grades, 72/97 [74%] vs 64/97 [66%]; grade 3/4, 7/97 [7%] vs 3/97 [3%]; P = .27). There were no apparent differences in scores for health-related quality of life. CONCLUSIONS AND RELEVANCE: In this open-label, phase 2 randomized clinical trial of patients with platinum-refractory mUC, nab-paclitaxel had similar efficacy to paclitaxel; but worse toxic effects. The ORR with either taxane, however, was higher than previously reported and similar to those reported for the immune checkpoint inhibitors, suggesting that the taxanes remain a reasonable option in this setting. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02033993

Summary Background The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. Methods We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7–10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60–68). Median follow-up was 4·9 years (IQR 3·0–6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81–1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58–1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3–4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). Interpretation These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy. Funding Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.

BACKGROUND: The purpose of this multistage, adaptively, designed randomized phase II study was to evaluate the role of intraperitoneal (i.p.) chemotherapy following neoadjuvant chemotherapy (NACT) and optimal debulking surgery in women with epithelial ovarian cancer (EOC). PATIENTS AND METHODS: We carried out a multicenter, two-stage, phase II trial. Eligible patients with stage IIB–IVA EOC treated with platinum-based intravenous (i.v.) NACT followed by optimal (

Background We hypothesized that increased baseline BMI and BMI change would negatively impact clinical outcomes with adjuvant breast cancer systemic therapy. Methods Data from chemotherapy trials MA.5 and MA.21; endocrine therapy MA.12, MA.14 and MA.27; and trastuzumab HERA/MA.24 were analyzed. The primary objective was to examine the effect of BMI change on breast cancer-free interval (BCFI) landmarked at 5 years; secondary objectives included BMI changes at 1 and 3 years; BMI changes on disease-specific survival (DSS) and overall survival (OS); and effects of baseline BMI. Stratified analyses included trial therapy and composite trial stratification factors. Results In pre-/peri-/early post-menopausal chemotherapy trials (N = 2793), baseline BMI did not impact any endpoint and increased BMI from baseline did not significantly affect BCFI (P = 0.85) after 5 years although it was associated with worse BCFI (P = 0.03) and DSS (P = 0.07) after 1 year. BMI increase by 3 and 5 years was associated with better DSS (P = 0.01; 0.01) and OS (P = 0.003; 0.05). In pre-menopausal endocrine therapy trial MA.12 (N = 672), patients with higher baseline BMI had worse BCFI (P = 0.02) after 1 year, worse DSS (P = 0.05; 0.004) after 1 and 5 years and worse OS (P = 0.01) after 5 years. Increased BMI did not impact BCFI (P = 0.90) after 5 years, although it was associated with worse BCFI (P = 0.01) after 1 year. In post-menopausal endocrine therapy trials MA.14 and MA.27 (N = 8236), baseline BMI did not significantly impact outcome for any endpoint. BMI change did not impact BCFI or DSS after 1 or 3 years, although a mean increased BMI of 0.3 was associated with better OS (P = 0.02) after 1 year. With the administration of trastuzumab (N = 1395) baseline BMI and BMI change did not significantly impact outcomes. Conclusions Higher baseline BMI and BMI increases negatively affected outcomes only in pre-/peri-/early post-menopausal trial patients. Otherwise, BMI increases similar to those expected in healthy women either did not impact outcome or were associated with better outcomes. Clinical Trials numbers CAN-NCIC-MA5; National Cancer Institute (NCI)-V90-0027; MA.12-NCT00002542; MA.14-NCT00002864; MA.21-NCT00014222; HERA, NCT00045032;CAN-NCIC-MA24; MA-27-NCT00066573.

The lapatinib–taxane combination led to shorter PFS than trastuzumab–taxane in HER2+ metastatic breast cancer. We investigated the prognostic and predictive effects of pretreatment serum HER2, CAIX, and TIMP-1. MA.31 accrued 652 patients; 537 (82%) were centrally confirmed HER2+. Biomarkers were categorized for univariate and multivariable predictive investigations with a median cut-point, ULN cut-points (15 ng/ml for HER2; 506 pg/ml for CAIX; 454 pg/ml for TIMP-1), and custom cut-points (30 and 100 ng/ml for HER2). Stratified step-wise forward Cox multivariable analysis examined continuous and categorical effects of biomarkers on PFS in the ITT and central HER2+ populations; central HER2+ biomarker results are shown. Serum was banked for 472 (72%) of 652 patients. Higher serum HER2 (>median; >15; >30; or >100 ng/ml; p = 0.05–0.002); higher CAIX (>median; >506 pg/ml; p = 0.02; p = 0.001); and higher TIMP-1 (> median; > 454 pg/ml; p = 0.001; p = 0.02) had shorter univariate PFS. In multivariable analysis, higher continuous TIMP-1 was associated with significantly shorter PFS: HR = 1.001 (95% CI = 1.00–01.002; p = 0.004). Continuous serum HER2 and CAIX were not significantly associated with PFS. HER2 of 15 ng/ml or higher had shorter PFS (p = 0.02); higher categorical CAIX had shorter PFS (p = 0.01–0.08). Interaction terms of HER2, CAIX, and TIMP-1 with treatment were not significant; the predictive test power was low. Higher levels of serum TIMP-1, CAIX, and HER2 were significant prognostic biomarkers of shorter PFS. We found no significant interaction between serum biomarkers and response to lapatinib versus trastuzumab. Evaluation of TIMP-1 and CAIX-targeted therapy in addition to HER2-targeted therapy appears warranted in patients with elevated serum levels of these biomarkers.

Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates the effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high-risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples.VitB12 was analyzed centrally in baseline and 6-month fasting plasma. Levels 181 pmol/L were considered deficient, 181-221 pmol/L borderline, and ≥222 pmol/L sufficient. Methylmalonic acid (MMA) and homocysteine (HC) were assayed in those with VitB12 levels 222 pmol/L. Statistical analyses used Spearman's rank correlation coefficients and Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables.237 patients received metformin and 255 received placebo; median (inter quartile range) baseline VitB12 levels were 390 (290, 552) and 370 (290, 552) pmol/L in the metformin and placebo arms, respectively (p = 0.97). At 6 months, the median levels were 320 (244, 419) in the metformin versus 380 (286, 546) pmol/L in the placebo arm (p = 0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12 181 pmol/L, and at 6 months, 18 patients (15 metformin and 3 placebo) (p = 0.004). Median hemoglobin was similar at baseline, metformin, 130 g/L (124-137), and placebo arms, 131 g/L (124-137) (p = 0.38), and at 6 months, metformin, 131 g/L (91-162), and 131 g/L (106-169) in placebo group (p = 0.11). Of the 74 subjects with vitamin B12 222 pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and two had elevated HC (15μmol/L). At 6 months, one patient (metformin) had MMA0.4μmol/L and 3 (2 metformin, 1 placebo) had HC 15μmol/L.There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline and at 6 and 60 months.

Background and Objectives: The presence of tumor infiltrating lymphocytes (TILs), particularly CD8+ cytotoxic T-cells, has been associated with improved prognosis in patients with HER2+ breast cancer. Increasing levels of TILs also appear to predict response to adjuvant trastuzumab in early breast cancer, although they did not predict benefit of combined trastuzumab-lapatinib neoadjuvant dual therapy over monotherapy in NeoALLTO. CCTG MA.31 randomized 652 women with HER2+ metastatic breast cancer to treatment with trastuzumab (T) vs. lapatinib (L), in combination with taxane (Tax) chemotherapy for 24 weeks, followed by the same HER2-targeted monotherapy. Final results from MA.31 found trastuzumab was superior to lapatinib for the primary endpoint of progression free survival (PFS): the hazard ratio (HR) for lapatinib to trastuzumab was 1.37 (95% CI, 1.13-1.65). Although both agents block HER2 signaling, trastuzumab has additional mechanisms of action via the immune system. We hypothesized that TIL levels may predict response to HER2-targeted therapy (trastuzumab vs. lapatinib). Methods: MA.31 included HER2+ metastatic breast cancer patients, median age 55 years, and median follow-up 21.5 months. Overall TILs were counted per published guidelines on the original H&E stained sections used for pathology review at study entry. Immunohistochemistry (IHC) was performed on unstained sections from tissue microarrays or individual formalin-fixed paraffin-embedded blocks to test expression of lymphocyte biomarkers CD8, FOXP3, CD56 and PD-1 on stromal and intra-tumoral TILs (sTILs, iTILs). Statistical analysis was conducted by CCTG for a total of 9 prespecified biomarker tests. Associations of TILs with PFS were evaluated by univariate stratified log-rank test with graphical Kaplan-Meier curves, and by stratified multivariate Cox proportional hazards regression analysis. Predictive effect was examined with a test of interaction between treatment allocation and biomarker classification (high vs. low, using pre-established cutpoints). Results: Of the 652 cases, 614 had slides for overall TIL assessment and 427 for IHC biomarker assessments. In this correlative study set, superiority of trastuzumab over lapatinib for PFS was confirmed in multivariate analysis (LTax/T vs. TTax/L: HR = 2.55, 95% CI = 1.43-4.55, p = 0.001). TIL counts by H&E were neither prognostic nor predictive in this set of metastatic HER2+ breast cancers. Lymphocyte IHC markers were not prognostic. However, prespecified stratified univariate analysis detected a significantly higher risk for lapatinib over trastuzumab (HR = 2.94, 95% CI = 1.40-6.17, p = 0.003) in patients with low CD8+ sTIL (< 3) than was observed among those with high CD8+ sTIL (HR = 1.36, 95% CI = 1.05-1.75, p = 0.019). This differential effect was confirmed in multivariate analysis (interaction test p = 0.042). The other tested biomarkers did not demonstrate significant predictive effects. Conclusions: In this correlative study of metastatic HER2+ breast cancer, a low level of pre-existing stromal cytotoxic T cell infiltration predicts women who benefit most from trastuzumab over lapatinib. Overall TIL counts were neither prognostic nor predictive. Citation Format: Liu S, Chen B, Burugu S, Leung S, Gao D, Virk S, Kos Z, Parulekar WR, Shepherd L, Gelmon K, Nielsen TO. Predictive effect of cytotoxic tumor infiltrating lymphocytes in HER2-positive metastatic breast cancer: A correlative study with CCTG MA.31 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-08.

High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Whether treatment order—primary debulking surgery followed by adjuvant chemotherapy (PDS) or neo-adjuvant chemotherapy with interval surgery (NACT)—affects outcome is controversial. We developed a mathematical framework that holds for hierarchical or stochastic models of tumor initiation and reproduces HGSC clinical course. After estimating parameter values, we infer that most patients harbor chemo-resistant HGSC cells at diagnosis, and that if complete debulking (Significance StatementThe optimal order and timing of surgery and chemotherapy, and the potential benefits of earlier diagnosis of HGSC, remain controversial. We developed a mathematical framework of tumor dynamics to address such issues, populated the model with primary clinical data and reliably recapitulated clinical observations. Our model prospectively predicts that: (1) PDS is superior to NACT when complete debulking is feasible; (2) timely adjuvant chemotherapy is critical for the outcome of PDS with 1mm, residual tumors; (3) earlier detection of relapse is unlikely to be beneficial with current therapies; (4) earlier detection of primary HGSC, followed by complete debulking, could have substantial benefit. Our model provides insights into the evolutionary dynamics of HGSC, argues for new clinical trials to optimize HGSC therapy, and is potentially applicable to other tumor types.

Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies.

Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer.In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events.A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group.Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).

Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor–positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor–positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.

Management of the neck in oropharyngeal carcinoma varies due to a lack of clarity of patterns of lymphatic drainage and concern of failure in the contralateral neck. With recent advances in transoral surgical techniques, surgical management has become increasingly prevalent as the primary treatment modality. We compare international practice patterns between surgical and radiation oncologists.A survey of neck management practice patterns was developed and pilot tested by 6 experts. The survey comprised items eliciting the nature of clinical practice, as well as patterns of neck management depending on extent of nodal disease and location and extent of primary site disease. Proportions of surgical and radiation oncologists treating the neck bilaterally were compared using the chi-squared statistic.Two-hundred and twenty-two responses were received from 172 surgical oncologists, 44 radiation oncologists, 3 medical oncologists, and 3 non-oncologists from 32 different countries. For tongue base cancers within 1 cm of midline (67% vs. 100%, p 0.001), and for tonsil cancers with extension to the medial 1/3 of the soft palate (65% vs. 100%, p 0.001) or tongue base (77% vs. 100%, p 0.001), surgical oncologists were less likely to treat the neck bilaterally. For isolated tonsil fossa cancers with no nodal disease, both surgical and radiation oncologists were similarly likely to treat unilaterally (99% vs. 97%, p = NS). However, with increasing nodal burden, radiation oncologists were more likely to treat bilaterally for scenarios with a single node 3 cm (15% vs. 2%, p 0.001), a single node with extranodal extension (41% vs. 18%, p 0.001), multiple positive nodes (55% vs. 23% p 0.001), and node(s) 6 cm (86% vs. 33%, p 0.001). For tumors with midline extension, even with a negative PET in the contralateral neck, the majority of surgical and radiation oncologists would still treat the neck bilaterally (53% and 84% respectively).The present study demonstrates significant practice pattern variability for management of the neck in patients with lateralized oropharyngeal carcinoma. Surgical oncologists are less likely to treat the neck bilaterally, regardless of tumor location or nodal burden. Even in the absence of disease in the contralateral neck on imaging, them majority of practitioners are likely to treat bilaterally when the disease approaches midline.

TPS266 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analogue (LHRHA), is standard of care for men with very high-risk localized prostate cancer (PC), or with very high- risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of men with very high-risk features. Darolutamide is a structurally distinct oral androgen receptor antagonist with low blood-brain-barrier penetration, a demonstrated favorable safety profile and low potential for drug-drug interactions. Our aim is to determine the efficacy of adding darolutamide to ADT and RT in the setting of either primary definitive therapy, or adjuvant therapy for very high-risk PC. Methods: This study is a randomized (1:1) phase III placebo-controlled, double-blind trial for men planned for RT who have very high-risk localized PC; or very high-risk features with PSA persistence or rise within one year following RP. The trial will be stratified by: RP; use of adjuvant docetaxel; pelvic nodal involvement. 1100 participants will be randomized to darolutamide 600 mg or placebo twice daily for 96 weeks. Participants will receive LHRHA for 96 weeks, plus RT starting week 8-24 from randomisation. Participants are allowed nonsteroidal antiandrogen (up to 90 days) in addition to LHRHA up until randomisation. Early treatment with up to 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival (ICECaP-validated), with secondary endpoints overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety and resistance to study treatment. Clinical trial information: NCT04136353.

Canadian Cancer Society Research Institute [021039, 015469]; National Cancer Institute [CA180888, CA189953, CA180828, CA13612, CA37981, CA077202, CA180863, CA67753, CA189805, CA16116, CA180802]; Canadian Cancer Trials Group [CA077202, CA180863]; ECOG-ACRIN Cancer Research Group [CA180820, CA21115]; Novartis Pharmaceuticals; Avon Foundation; AstraZeneca; Pfizer; Roche; Amgen; Novartis; Glaxo-SmithKline; Eisai; Genomic Health; NanoString; Genentech; BioMarin

TPS6592 Background: Treatment for HPV positive(+) oropharyngeal squamous cell carcinoma (OSCC) is highly effective but associated with significant short and long term treatment related morbidity. We hypothesize that decreasing the regions of elective nodal irradiation (ENI) in the neck will lead to less toxicity and better quality of life/functional outcomes while maintaining high disease control rates in patients with favourable prognosis HPV+ OSCC. Methods: HN.10 is a Canadian Cancer Trials Group phase II trial with a primary objective to evaluate the efficacy of primary definitive radiotherapy (RT) or chemoradiotherapy (CRT) utilizing volume reduced ENI as measured by 2-year event-free survival (EFS) in patients with low-risk HPV+ OPSCC. Secondary objectives include to evaluate overall survival, local control, regional control, locoregional control, out-of-field regional control, distant metastasis free survival, early and late toxicities of treatment, subjective swallowing functions, quality of life, utilization of healthcare resources, work productivity, and prognostic biomarkers. An imaging and biospecimen bank will be compiled as part of trial conduct. Key eligibility criteria include: pathologically proven diagnosis of HPV+ OPSCC; HPV association determined locally by either p16 immunohistochemistry or direct detection of HPV DNA sequences (e.g. by PCR or in situ hybridization) performed on a core needle or surgical biopsy specimen of the primary tumour or involved cervical lymph node; clinical stage T1-3 N0-1 M0 (UICC/AJCC 8th Ed.); fit for radiotherapy +/-chemoradiotherapy. Statistical Design: The primary endpoint is 2-year EFS. Assuming 2-year EFS to be 91% (Ha) for low-risk HPV-related OPSCC with standard treatment, and that the experimental treatment will be considered as ineffective if the 2-year EFS is ≤ 85% (H0), with one-sided alpha of 0.1, a sample size of 100 patients will have 80% power to detect a 6% difference of 2-year EFS. With 3 years of accrual and 2 years of follow-up, the total duration of this study will be 5 years. A total of 304.7 person-years of follow-up is needed for the final analysis. The null hypothesis (H0) will be rejected when the observed survival rate is 88.85% or higher (i.e. if there are 18 or fewer EFS events observed). Conduct to Date: Study activation February 20, 2019. Enrollment as of January 29 2020: 23. Clinical trial information: NCT03822897 .

TPS385 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinising hormone releasing hormone analogue (LHRHA) for at least one year, is standard of care for men with very high-risk localised prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of men with very high risk features. Darolutamide is an androgen receptor antagonist with favourable tolerability. Our aim is to determine the efficacy of adding darolutamide to ADT and RT given in the setting of either primary definitive therapy (RP or RT), or adjuvant therapy for very high-risk PC. Methods: This study is a randomised (1:1) phase III placebo-controlled, double-blind trial for men planned for RT who have very high-risk localised PC, or very high-risk features with PSA persistence or rise within one year following RP. The trial will be stratified by: use of adjuvant docetaxel; pelvic nodal involvement; RP. 1100 participants will be randomised to darolutamide 600 mg or placebo twice daily for 96 weeks. Participants will receive LHRHA for 96 weeks, plus RT starting week 8-24 from randomisation. Participants are allowed nonsteroidal antiandrogen (up to 90 days) in addition to LHRHA up until randomisation. Early treatment with 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival, with secondary endpoints overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety and resistance to study treatment. Clinical trial information: NCT04136353.

Background:Approximately 40% of metastatic cancer patients will develop spinal metastases. The current report provides recommendations for standardization of metrics used for spinal oncology patient population description and outcome assessment beyond local control endpoints on behalf of the SPIne response assessment in Neuro-Oncology (SPINO) group. Methods:The SPINO group survey was conducted in order to determine the preferences for utilization of clinician-based and patient-reported outcome measures for description of patients with spinal metastases. Subsequently, ClinicalTrials.gov registry was searched for spinal oncology clinical trials, and measures for patient description and outcome reporting were identified for each trial. These two searches were used to identify currently used descriptors and instruments. A literature search was performed focusing on the measures identified in the survey and clinical trial search in order to assess their validity in the metastatic spinal tumor patient population. References for this manuscript were identified through PubMed and Medline searches. Results:Published literature, expert survey, and ongoing clinical trials were used to synthesize recommendations for instruments for reporting of spinal stability, epidural tumor extension, neurological and functional status, and symptom severity. Conclusions:Accurate description of patient population and therapy effects requires a combination of clinician-based and patient-reported outcome measures. The current report provides international consensus recommendations for the systematic reporting of patient- and clinician-reported measures required to develop trials applicable to surgery for spinal metastases and postoperative spine stereotactic body radiotherapy (SBRT).

Purpose MA.17R was a Canadian Cancer Trials Group–led phase III randomized controlled trial comparing letrozole to placebo after 5 years of aromatase inhibitor as adjuvant therapy for hormone receptor–positive breast cancer. Quality of life (QOL) was a secondary outcome measure of the study, and here, we report the results of these analyses. Methods QOL was measured using the Short Form-36 (SF-36; two summary scores and eight domains) and menopause-specific QOL (MENQOL; four symptom domains) at baseline and every 12 months up to 60 months. QOL assessment was mandatory for Canadian Cancer Trials Group centers but optional for centers in other groups. Mean change scores from baseline were calculated. Results One thousand nine hundred eighteen women were randomly assigned, and 1,428 women completed the baseline QOL assessment. Compliance with QOL measures was > 85%. Baseline summary scores for the SF-36 physical component summary (47.5 for letrozole and 47.9 for placebo) and mental component summary (55.5 for letrozole and 54.8 for placebo) were close to the population norms of 50. No differences were seen between groups in mean change scores for the SF-36 physical and mental component summaries and the other eight QOL domains except for the role-physical subscale. No difference was found in any of the four domains of the MENQOL Conclusion No clinically significant differences were seen in overall QOL measured by the SF-36 summary measures and MENQOL between the letrozole and placebo groups. The data indicate that continuation of aromatase inhibitor therapy after 5 years of prior treatment in the trial population was not associated with a deterioration of overall QOL.

The objective of our study was to determine the optimal cut points for classification of pain scores as mild, moderate, and severe based on interference with function and quality of life (QOL). We evaluated 822 patients who completed the Brief Pain Inventory (BPI) and/or the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 30 (QLQ-C30) prior to receiving repeat radiation therapy for previously irradiated painful bone metastases. Optimal cut points for mild, moderate, and severe pain were determined by the MANOVA that yielded the largest F ratio for the between category effect on the seven interference items of BPI and the six functional domains of QOL (physical, role, emotional, cognitive, social functioning, and global QOL) as indicated by Pillai’s Trace, Wilk’s λ, and Hostelling’s Trace F statistics. For BPI and for QOL domains separately, the two largest F ratios for Wilk’s λ, Pillai’s Trace, and Hotelling’s Trace F statistics were from the cut points 4, 8 and 6, 8. When combining both, the optimal cut points were 4, 8 with 1–4 (mild), 5–8 (moderate), and 9–10 (severe). With this classification, the mean scores of all the seven interference items in BPI and the six functional domains were all highly statistically different. Patients with severe pain survived significantly shorter than those with mild and moderate pain (p