Jeremy Shapiro

BackgroundThis study explores the potential benefits of neoadjuvant chemotherapy in borderline resectable (BR) pancreatic adenocarcinoma. Despite neoadjuvant treatment (NAT) increasingly being utilised, uncertainty remains as to the optimal approach.Patients and methodsThis study assessed clinical outcomes for 218 consecutive BR patients from the PURPLE registry. We compared initial surgery (IS) to NAT overall, and between different chemotherapy regimens.ResultsOf 1314 non-metastatic patients enrolled, 218 (17%) were considered BR. Of 28 planned for IS, 11/28 (39%) had their tumour excised compared to 68/152 (45%) with NAT (P = 0.59). Among those who received NAT and were resected, 52/100 (52%) received FOLFIRINOX (P = 0.234) and 8/28 (29%) received nab-paclitaxel with gemcitabine (nabPGem). There was no difference in median overall survival (OS) [hazard ratio (HR) 0.72, P = 0 …

IntroductionMany clinicians consider carboplatin monotherapy in advanced castrate-resistant prostate cancer (CRPC) patients who have progressed through all available hormonal and standard chemotherapy treatment options, despite the limited evidence to justify its use.Patients and MethodsThis retrospective analysis aimed to evaluate the use of carboplatin monotherapy in patients with refractory prostate cancer in Australia. Efficacy (PSA response, duration, and survival) as well as toxicity was evaluated. Demographic data, PSA response rates, survival data and details of carboplatin treatment protocols, including dose and duration, were collected. Exploratory analyses were conducted on potential prognostic factors.Results51 patients received carboplatin: median age 68 (range 55–86 years). Most patients (78.3%) received carboplatin AUC 5 at 3-week intervals. The median number of cycles of carboplatin …

Introduction While contact days—days with healthcare contact outside home—are increasingly adopted as a measure of time toxicity and treatment burden, they could also serve as a surrogate of treatment-related harm. We sought to assess the association between contact days and patient-reported outcomes, and the prognostic ability of contact days. Methods We conducted a secondary analysis of CO.17 that evaluated cetuximab vs supportive care in patients with advanced colorectal cancer. CO.17 collected EORTC-QLQ-C30 instrument data. We assessed the association between number of contact days in a window and changes in physical function and global health status, and the association between number of contact days in the first 4 weeks with overall survival (OS). Results There was a negative association between the number of contact days …

12Background: Adjuvant chemotherapy (CT) following neoadjuvant chemoradiation and surgery for locally advanced rectal cancer (LARC) is widely adopted, despite uncertain survival benefit. Circulating tumor DNA (ctDNA) detection after surgery has been shown to be a strong prognostic marker in localized colorectal cancer and potentially could inform adjuvant treatment decision making. Methods: AGITG DYNAMIC-Rectal is a multi-centre randomized controlled phase II trial. Eligible patients (pts) had LARC (cT3-4 and/or cN+) treated with neoadjuvant chemoradiation, total mesorectal excision, and were fit for adjuvant CT. Pts were randomly assigned 2:1 to ctDNA-guided management or standard management (clinician decision). A tumor-informed personalized ctDNA assay was used. For the ctDNA-guided group, a positive result at 4 and/or 7 weeks after surgery prompted 4 months of oxaliplatin-based or …

Studies of patients with castrate‐resistant prostate cancer at high risk of developing overt metastases but with no current evidence of evaluable disease on computed tomography or bone scan non‐metastatic castrate‐resistant prostrate cancer have demonstrated increased metastasis‐free survival and overall survival following treatment with the next‐generation oral anti‐androgen apalutamide (in addition to therapies that aim to lower testosterone to castrate levels) or luteinizing hormone‐releasing hormone antagonist or surgical castration. Patients receiving apalutamide can be managed by medical oncologists, radiation oncologists, or urologists, preferably as part of a multidisciplinary team. However, the importance of additional safety monitoring for significant adverse effects and drug interactions should not be underestimated. The toxicities of apalutamide are manageable with experience and should be …

Purpose Sidedness is prognostic and predictive of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). Transverse colon has been historically excluded from several analyses of sidedness and the optimal division between left- and right-sided colorectal cancer is unclear. We investigated transverse colon primary tumor location as a biomarker in mCRC. Experimental Design Pooled analysis of CCTG/AGITG CO.17 and CO.20 trials of cetuximab in chemotherapy-refractory mCRC. Outcomes of patients with RAS/BRAF wild-type (WT) mCRC from CO.17 and KRAS WT mCRC from CO.20 were analyzed according to location. Results A total of 553 patients were analyzed, 32 (5.8%) with cancers from the transverse, 101 (18.3%) from right, and 420 from (75.9%) left colon. Transverse mCRC failed to reach significant benefit from cetuximab versus best …

124Background: Primary tumour location is predictive of anti-EGFR benefit and prognostic in metastatic colorectal cancer (mCRC). Transverse colon cancers are often categorized as right sided, but the optimal cut point is unclear. Canadian Cancer Trials Group (CCTG)/Australasian Gastro-Intestinal Trials Group (AGITG) CO.17 compared Cetuximab (Cet) vs. best supportive care (BSC) in mCRC. CCTG/AGITG CO.20 studied the addition of Brivanib Alaninate to Cet in pre-treated KRAS wildtype (WT) mCRC. We investigated the predictive and prognostic features of transverse colon primary location in a pooled cohort from these trials. Methods: Data from patients with RAS WT mCRC from CO.17 and KRAS WT mCRC from CO.20 randomized to cetux were analyzed for treatment outcomes according to location - right, transverse and left. The cecum to transverse colon was considered right sided, while the splenic …

BackgroundLong course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological CR in 10-30% of patients (pts). Radiotherapy (RT) is immuno-stimulatory by enhancing tumour cell death, but also immunosuppressive stimulating PDL1 production and myeloid-derived suppressor cells. PDL1 inhibition may be required to enhance RT immuno-stimulatory effects. Hypothesis: In pts with resectable LARC, Avelumab given post LCCRT may enhance tumour response rates whilst reducing relapses.MethodsPhase II single arm trial. Pts had LCCRT (50.4 Gy+ 5FU [225mg/m 2/day/CI] or Capecitabine [825mg/m 2 BID]/5.5 weeks). Post LCCRT pts received 4 cycles Avelumab (AV)(10mg/kg, q2 weeks), then resection 10-12 weeks post LCCRT. Fresh tumour biopsy/ctDNA sampling taken at pre LCCRT, pre AV and at surgery. Response by FDG PET and pelvic MRI. Inclusion …

3616Background: Neoadjuvant long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in a complete pathological response rate in 10-30% of patients (pts), but with 20-40% non-responders and 10-15% have local recurrence. Radiotherapy (RT) is immuno-stimulatory by enhancing local/distant tumour cell death, but also immunosuppressive as it stimulates PDL1 production and myeloid-derived suppressor cell activity. Hence PDL1 inhibition may be required to enhance the immuno-stimulatory effects of RT. Hypothesis: In pts with resectable LARC, the anti-PDL1 antibody Avelumab given post LCCRT may enhance the pathological/imaging response rates whilst reducing local/distant relapse rates. Methods: Phase II single arm trial. All pts had standard LCCRT (50.4Gy RT plus 5FU [225mg/m2/day/CI] or Capecitabine [825mg/m2 BID on days of RT] over 5.5 weeks). Post LCCRT …

BackgroundInitial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration.ObjectiveTo present the final data from TRITON2.Design, setting, and participantsTRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy.Outcome measurements and statistical analysisThe primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review [IRR]); prostate-specific antigen (PSA) response rate (≥50% decrease from …

Background Use of neoadjuvant (NA) chemotherapy is recommended when pancreatic ductal adenocarcinoma (PDAC) is borderline resectable Method A retrospective analysis of consecutive patients with localized PDAC between January 2016 and March 2019 within the Australasian Pancreatic Cancer Registry (PURPLE, Pancreatic cancer: Understanding Routine Practice and Lifting End results) was performed. Clinicopathological characteristics, treatment, and outcome were analyzed. Overall survival (OS) comparison was performed using log‐rank model and Kaplan–Meier analysis. Results The PURPLE database included 754 cases with localised PDAC, including 148 (20%) cases with borderline resectable pancreatic cancer (BRPC). Of the 148 BRPC patients, 44 (30%) underwent immediate surgery, 80 (54%) received NA chemotherapy, and 24 (16%) were inoperable. The median age of NA therapy …

PURPOSEThe time spent in pursuing treatments for advanced cancer can be substantial. We have previously proposed a pragmatic and patient-centered metric of these time costs—which we term time toxicity—as any day with physical health care system contact. This includes outpatient visits (eg, bloodwork, scans, etc), emergency department visits, and overnight stays in a health care facility. Herein, we sought to assess time toxicity in a completed randomized controlled trial (RCT).METHODSWe conducted a secondary analysis of the Canadian Cancer Trials Group CO.17 RCT that evaluated weekly cetuximab infusions versus supportive care alone in 572 patients with advanced colorectal cancer. Initial results reported a 6-week improvement in median overall survival (OS) with cetuximab (6.1 v 4.6 months). Subsequent analyses reported that benefit was restricted to patients with K-ras wild-type tumors. We …

PURPOSEThis randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel+ gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials. gov identifier:

Background Treatment with cetuximab provides a survival benefit for patients with RAS wild‐type metastatic colorectal cancer (mCRC). Practice‐defining cetuximab studies utilised weekly (q1w) administration. More convenient second weekly (q2w) administration is supported by pharmacokinetic data and a recent meta‐analysis, but large head‐to‐head studies have not been conducted. Therapeutic Goods Association (TGA) prescribing information states cetuximab be administered q1w for all indications. Aim To assess the real‐world use of q1w versus q2w cetuximab schedule and any difference in outcomes. Methods We analysed data from a prospective mCRC database at seven Melbourne hospitals from January 2010 to August 2019. Characteristics and outcomes for cetuximab‐treated patients were examined, comparing q1w versus q2w schedules. Progression‐free survival (PFS) and overall survival (OS …

Background Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient selection. TKI‐induced hypertension is reportedly a surrogate marker for treatment benefit for some tumor types. Our objective was to determine whether hypertension was associated with benefit in the context of CRC treatment, and also to gain insight on the pathogenesis of TKI‐induced hypertension by monitoring associated changes in the circulating metabolome. Patients and Methods Clinical data were acquired from clinical trial patients with metastatic CRC randomized to cetuximab ± the TKI brivanib (N = 750). Outcomes were evaluated as a function of treatment‐induced hypertension. For metabolomic studies, plasma samples were taken at baseline, as well as at 1, 4, and 12 weeks after treatment initiation. Samples were …

Introduction Analyzing longitudinal cancer quality‐of‐life (QoL) measurements and their impact on clinical outcomes may improve our understanding of patient trajectories during systemic therapy. We applied an unsupervised growth mixture modeling (GMM) approach to identify unobserved subpopulations (“patient clusters”) in the CO.20 clinical trial longitudinal QoL data. Classes were then evaluated for differences in clinico‐epidemiologic characteristics and overall survival (OS). Methods and Materials In CO.20, 750 chemotherapy‐refractory metastatic colorectal cancer (CRC) patients were randomized to receive Brivanib+Cetuximab (n = 376, experimental arm) versus Cetuximab+Placebo (n = 374, standard arm) for 16 weeks. EORTC‐QLQ‐C30 QoL summary scores were calculated for each patient at seven time points, and GMM was applied to identify patient clusters (termed “classes”). Log‐rank/Kaplan …

BackgroundCetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. Limited data suggest a wide variation in cetuximab plasma concentrations after standard dosing regimens. We correlated cetuximab plasma concentrations with survival and toxicity.MethodsThe CO. 20 study randomized patients with RAS WT advanced colorectal cancer in a 1:1 ratio to cetuximab 400 mg/m2 intravenously followed by weekly maintenance of 250 mg/m2, plus brivanib 800 mg orally daily or placebo. Blood samples obtained at week 5 precetuximab treatment were analyzed by ELISA. Patients were grouped into tertiles based on plasma cetuximab concentrations. Cetuximab concentration tertiles were correlated with survival outcomes and toxicity. Patient demographic and biochemical parameters were evaluated as co-variables.ResultsWeek 5 plasma cetuximab concentrations were …

BackgroundPoly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown.ObjectiveTo examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib.Design, setting, and participantsMen with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor–directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed …

Many research studies have investigated the relationship between baseline factors or exposures, such as patient demographic and disease characteristics, and study outcomes such as toxicities or quality of life, but results from most of these studies may be problematic because of potential confounding effects (eg, the imbalance in baseline factors or exposures). It is important to study whether the baseline factors or exposures have causal effects on the clinical outcomes, so that clinicians can have better understanding of the diseases and develop personalized medicine. Mendelian randomization (MR) provides an efficient way to estimate the causal effects using genetic instrumental variables to handle confounders, but most of the existing studies focus on a single outcome at a time and ignores the correlation structure of multiple outcomes. Given that clinical outcomes like toxicities and quality of life are usually a …

BackgroundFirst-line (1L) treatment options for LS RASwt mCRC include the addition of epidermal growth factor receptor inhibitors (EGFRi) to chemotherapy (CT), supported by the overall survival advantage versus CT+ bevacizumab (BEV) demonstrated recently in PARADIGM, the first phase 3 trial with pre-planned analysis by tumour side. Treatment selection and outcomes in Australasian routine practice has yet to be described.MethodsData from 1/2015–5/2023 on patients with LS RASwt mCRC who received 1L doublet CT for palliative intent was reviewed from TRACC, a prospective, multi-site Australasian registry. Baseline clinicopathological characteristics and survival outcomes were analysed with p≤ 0.05 denoted as statistical significance.ResultsOf 676 LS RASwt, palliative intent, mCRC patients, 573 (85%) were actively treated, 404 (60%) receiving 1L doublet CT. Of these, 193 (48%) also received …