Haiko J. Bloemendal

Pan-cancer whole genome analyses of metastatic solid tumors

Metastatic cancer is one of the major causes of death and is associated with poor treatment efficiency. A better understanding of the characteristics of late stage cancer is required to help tailor personalised treatment, reduce overtreatment and improve outcomes. Here we describe the largest pan-cancer study of metastatic solid tumor genomes, including 2,520 whole genome-sequenced tumor-normal pairs, analyzed at a median depth of 106x and 38x respectively, and surveying over 70 million somatic variants. Metastatic lesions were found to be very diverse, with mutation characteristics reflecting those of the primary tumor types, although with high rates of whole genome duplication events (56%). Metastatic lesions are relatively homogeneous with the vast majority (96%) of driver mutations being clonal and up to 80% of tumor suppressor genes bi-allelically inactivated through different mutational mechanisms. For 62% of all patients, genetic variants that may be associated with outcome of approved or experimental therapies were detected. These actionable events were distributed across various mutation types underlining the importance of comprehensive genomic tumor profiling for cancer precision medicine.

Tolerability, Safety, and Outcomes of Neoadjuvant Chemoradiotherapy With Capecitabine for Patients Aged ≥ 70 Years With Locally Advanced Rectal Cancer

Micro‐Abstract: In elderly patients with rectal cancer, the application of neoadjuvant chemoradiotherapy (nCRT) is usually determined by the clinical findings because no data on tolerability are available. The present multicenter study identified 447 rectal cancer patients aged ≥ 70 years. Of these, 42 patients (9%) underwent nCRT. If selected by the clinical findings, nCRT is safe and well tolerated and leads to favorable surgical outcomes even in older age groups. Thus, the elderly should not be excluded from nCRT exclusively because of age. Introduction: In studies of colorectal cancer, the elderly have been frequently underrepresented because comorbid conditions and functional status often lead to study exclusion. For elderly patients with an indication for neoadjuvant chemoradiotherapy (nCRT), physicians usually decide using clinical factors whether nCRT should be offered. The aim of the present retrospective study was to assess the tolerability of nCRT with capecitabine and the surgical outcomes in patients aged ≥ 70 years with locally advanced rectal cancer. Patients and Methods: Data from 1372 rectal cancer patients diagnosed from 2002 to 2012 at 4 Dutch hospitals were used. Patients aged ≥ 70 years were included if they had received nCRT, and their data were analyzed for treatment deviations, postoperative complications, mortality, disease‐free survival (DFS), and overall survival (OS). The data were stratified into 3 age groups (ie, 70–74, 75–79, and ≥ 80 years). Results: We identified 447 patients aged ≥ 70 years. Of these patients, 42 had received nCRT, and 37 (88%) had completed nCRT. Radiation dermatitis, fatigue, and diarrhea were reported in 62%, 57%, and 43% of the 42 patients, respectively. Of the 42 patients, 40 (95%) underwent surgery, 1 patient refused resection, and 1 patient died during nCRT of severe mucositis due to dihydropyrimidine dehydrogenase deficiency. The postoperative complication rate was 30%, and the 30‐day mortality rate was 0%. A pathologic complete response was found in 7.5%. The 2‐ and 5‐year DFS and OS rates were 58.5% and 40.7% and 81.0% and 58.2%, respectively. Conclusion: The results of the present multicenter study have shown that if selected on clinical factors, nCRT with capecitabine is safe and well tolerated in elderly patients. No negative effect on surgical outcome was measured, and the beneficial effect (pathologic complete response, DFS, and OS) seemed comparable to that for younger age groups. We believe that elderly patients should not be excluded from nCRT on the basis of age only.

The predictive value of cumulative toxicity for quality of life in patients with metastatic colorectal cancer during first-line palliative chemotherapy

Background Studies evaluating new systemic agents tend to report severe toxicities only, while the cumulative effect of multiple lower grade adverse events (AEs) may have an additional negative impact on patient quality of life (QOL). In the current observational cohort study, we evaluated whether, in patients with metastatic colorectal cancer receiving first-line chemotherapy, cumulative toxicity comprising all grades of AEs is more predictive for QOL than cumulative toxicity due to only high-grade AEs. Methods One hundred and five patients starting treatment completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) questionnaire at baseline and 10 weeks. AEs, clinical outcomes, and demographics were retrieved from patient records. Cumulative toxicity scores were calculated in three ways: total number of high-grade AEs, total number of all-grade AEs, and total number of AEs multiplied by their grade (the severity score). Relations between cumulative toxicity scores and QOL were studied using multivariable linear regression analyses. Results The mean age of patients was 65 years, 68% were male, and 84% received oxaliplatin-based chemotherapy. A higher total number of AEs of all grades (B=−2.4, 95% CI=–3.9; −0.9) and the severity score (B=–1.4, 95% CI=–2.3; −0.5) were predictive for clinically relevant changes in physical QOL, whereas the total high-grade AEs was not. None of the cumulative toxicity scores were predictive for global QOL. Conclusion Cumulative toxicity scores comprising all grades of AEs provide a better measure of treatment burden than a toxicity score comprising high-grade AEs only. Physical QOL seems to be more affected by AEs than global QOL. Our results emphasize that future clinical trials should present cumulative toxicity scores comprising all AE grades as well as physical QOL instead of global QOL.

A Phase 1 Trial of Cabazitaxel Combined With 188 Re–Hydroxyethylidene Diphosphonate in Patients With Metastatic Castration-Resistant Prostate Cancer Who Progressed on or After a Docetaxel-Containing Treatment : The ReCab Trial

Purpose In patients with metastatic castration-resistant prostate cancer (mCRPC), bone-seeking radiopharmaceuticals, such as 188Re–hydroxyethylidene diphosphonate (HEDP), are effective for pain palliation and have a marked antitumor effect. Cabazitaxel is the standard second-line chemotherapy for mCRPC patients. We performed a phase 1 study investigating the safety and feasibility of the combined treatment with 188Re-HEDP and cabazitaxel in mCRPC patients. Methods Patients with mCRPC and documented disease progression on or after docetaxel were eligible for inclusion. In both dose levels, cabazitaxel (4 cycles of cabazitaxel 25 mg/m2 + 2 cycles of cabazitaxel 20 mg/m2 in level 1, and 6 cycles of cabazitaxel 25 mg/m2 in level 2) were combined with 2 cycles of 188Re-HEDP 40 MBq/kg (1.1 mCi/kg) (after the second and fourth cabazitaxel cycles). Three patients were planned for each dose level, expanding to 6 patients in case of a dose-limiting toxicity (DLT). A DLT is defined as any grade 4 toxicity, or grade 3 toxicity delaying the next treatment cycle. Results Twelve patients were included, of whom 3 had progressive disease before the third cycle of cabazitaxel. In total, 1 DLT occurred (dose level 1) after treatment cycle 6 (188Re-HEDP) (thrombopenia grade 3 delaying the next treatment cycle). The cohort was expanded to 6 patients, with no further DLTs. No DLT occurred in dose level 2. The most important adverse events were of hematologic origin, followed by mild fatigue and diarrhea. Conclusions Combination therapy with cabazitaxel and 188Re-HEDP is feasible and generally well tolerated with similar hematologic toxicity compared with cabazitaxel monotherapy.

Abstract CT067: The Prospective Dutch ColoRectal Cancer Cohort (PLCRC): a prospective nationwide observational cohort study providing the infrastructure for registry based trials

Background: Colorectal cancer (CRC) was once considered a single entity, but now appears to exist of multiple, often molecular defined, subclasses. These subclasses have implications for treatment, and hamper the feasibility of prospective randomized clinical trials which require large sample sizes. To anticipate further developments and to obtain more detailed insight in the outcome of daily practice, the Prospective Dutch CRC cohort (PLCRC) was initiated. In this prospective observational multicenter cohort, patients with all stages of colorectal cancer are included, and clinical data, tissue, blood samples and patient-reported outcome measures are collected. The cohort serves as an infrastructure for registry based trials in the Netherlands (CRC incidence approximately 16.000 patients per year). Methods: Patients ≥18 years with histologically proven stage I-IV CRC are eligible to participate. The informed consent includes consent for systematic collection of long-term clinical data and optionally 1) standardized collection of tissue and blood samples; 2) being informed when clinically relevant DNA mutations are detected; 3) patient-reported outcome questionnaires; and 4) invitation for future interventional studies according to (amongst others) the cohort multiple randomized controlled trial design (cmRCT). Results: In 2016 the number of participating hospitals increased from 6 to 17. The number of included patients roughly doubled to more than 1100 patients. The PLCRC infrastructure is used in the execution of fifteen studies, which amongst others focus on the prognostic value of circulating tumor DNA, the quality of life during treatment with new compounds and the influence of nutrition on treatment outcome. The studies use the option to repeatedly withdraw blood, send out PROMs and/or randomize patients according to the cmRCT design. The study populations in the substudies vary from newly diagnosed stage 2 colon cancer to non-liver limited metastatic CRC. In 2017, at least 20 hospitals which are currently in the initiation process will be added with which a 50% coverage of the Dutch hospitals will be reached. Conclusions: PLCRC provides long-term clinical data, tissue, blood samples and patient-reported outcome measures of a large cohort of patients with colorectal cancer. The cohort will be representative of the colorectal cancer population in the Netherlands. Multiple studies are ongoing making use of the infrastructure provided. These studies will make it possible to optimize treatment for specific small subgroups. Citation Format: Geraldine Vink, Robert Coebergh van den Braak, Haiko Bloemendal, Veerle Coupe, Marloes Elferink, Frans Erdkamp, Helma van Grevenstein, Jan-Willem de Groot, Jan Ijzermans, Martijn Intven, Maartje Los, Mirre de Noo, Martijn van Oijen, Cornelis Punt, Ron Rietbroek, Wilfried Roeloffzen, Anandi Schiphorst, Huig Schipper, Hein Stockmann, Manuel Tjin-a-Ton, Ankie van der Velden, Marlies Verhaar, Wouter Vles, David Zimmerman, Gerrit Meijer, Miriam Koopman. The Prospective Dutch ColoRectal Cancer Cohort (PLCRC): a prospective nationwide observational cohort study providing the infrastructure for registry based trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT067. doi:10.1158/1538-7445.AM2017-CT067

Cost-effectiveness analysis of an 18-week exercise programme for patients with breast and colon cancer undergoing adjuvant chemotherapy: The randomised PACT study

Objective Meta-analyses show that exercise interventions during cancer treatment reduce cancer-related fatigue. However, little is known about the cost-effectiveness of such interventions. Here we aim to assess the cost-effectiveness of the 18-week physical activity during cancer treatment (PACT) intervention for patients with breast and colon cancer. The PACT trial showed beneficial effects for fatigue and physical fitness. Design Cost-effectiveness analyses with a 9-month time horizon (18 weeks of intervention and 18 weeks of follow-up) within the randomised controlled multicentre PACT study. Setting Outpatient clinics of 7 hospitals in the Netherlands (1 academic and 6 general hospitals) Participants 204 patients with breast cancer and 33 with colon cancer undergoing adjuvant treatment including chemotherapy. Intervention Supervised 1-hour aerobic and resistance exercise (twice per week for 18 weeks) or usual care. Main outcome measures Costs, quality-adjusted life years (QALY) and the incremental cost-effectiveness ratio. Results For colon cancer, the cost-effectiveness analysis showed beneficial effects of the exercise intervention with incremental costs savings of €4321 and QALY improvements of 0.03. 100% of bootstrap simulations indicated that the intervention is dominant (ie, cheaper and more effective). For breast cancer, the results did not indicate that the exercise intervention was cost-effective. Incremental costs were €2912, and the incremental effect was 0.01 QALY. At a Dutch threshold value of €20 000 per QALY, the probability that the intervention is cost-effective was 2%. Conclusions Our results suggest that the 18-week exercise programme was cost-effective for colon cancer, but not for breast cancer. Trial registration number ISRCTN43801571.