Purpose: To identify an MTD of olaparib, a PARP inhibitor, in combination with loco-regional radiotherapy with/without cisplatin for the treatment of non–small cell lung cancer (NSCLC). Patients and Methods: Olaparib dose was escalated in two groups: radiotherapy (66 Gy/24 fractions in 2.75 Gy/fraction) with and without daily cisplatin (6 mg/m2), using time-to-event continual reassessment method with a 1-year dose-limiting toxicity (DLT) period. The highest dose level with a DLT probability <15% was defined as MTD. Poly ADP-ribose (PAR) inhibition and radiation-induced PAR-ribosylation (PARylation) were determined in peripheral blood mononuclear cells. Results: Twenty-eight patients with loco-regional or oligometastatic disease (39%) were treated: 11 at olaparib 25 mg twice daily and 17 at 25 mg once daily. The lowest dose level with cisplatin was above the MTD due to hematologic and late esophageal DLT. The MTD without cisplatin was olaparib 25 mg once daily. At a latency of 1–2.8 years, severe pulmonary adverse events (AE) were observed in 5 patients across all dose levels, resulting in 18% grade 5 pulmonary AEs. Exploratory analyses indicate an association with the radiation dose to the lungs. At the MTD, olaparib reduced PAR levels by more than 95% and abolished radiation-induced PARylation. Median follow-up of survivors was 4.1 years. Two-year loco-regional control was 84%, median overall survival in patients with locally advanced NSCLC was 28 months. Conclusions: Combined mildly hypofractionated radiotherapy and low-dose daily cisplatin and olaparib was not tolerable due to esophageal and hematologic toxicity. Severe pulmonary toxicity was observed as well, even without cisplatin. More conformal radiotherapy schedules with improved pulmonary and esophageal sparing should be explored.

Purpose: To systematically review all current evidence into the dose-response relation of yttrium-90 and holmium-166 selective internal radiation therapy (SIRT) in primary and secondary liver cancer. Methods: A standardized search was performed in PubMed (MEDLINE), Embase, and the Cochrane Library in order to identify all published articles on dose-response evaluation in SIRT. In order to limit the results, all articles that investigated SIRT in combination with other therapy modalities (such as chemotherapy) were excluded. Results: A total of 3038 records were identified of which 487 were screened based on the full text. Ultimately, 37 studies were included for narrative analysis. Meta-analysis could not be performed due to the large heterogeneity in study and reporting designs. Out of 37 studies, 30 reported a ‘mean dose threshold’ that needs to be achieved in order to expect a response. This threshold appears to be higher for hepatocellular carcinoma (HCC, 100–250 Gy) than for colorectal cancer metastases (CRC, 40–60 Gy). Reported thresholds tend to be lower for resin microspheres than when glass microspheres are used. Conclusion: Although the existing evidence demonstrates a dose-response relationship in SIRT for both primary liver tumours and liver metastases, many pieces of the puzzle are still missing, hampering the definition of standardized dose thresholds. Nonetheless, most current evidence points towards a target mean dose of 100–250 Gy for HCC and 40–60 Gy for CRC. The field would greatly benefit from a reporting standard and prospective studies designed to elucidate the dose-response relation in different tumour types.

Background: Poly (ADP-ribose) Polymerase (PARP) inhibitors are promising novel radiosensitisers. Pre-clinical models have demonstrated potent and tumour-specific radiosensitisation by PARP inhibitors. Olaparib is a PARP inhibitor with a favourable safety profile in comparison to clinically used radiosensitisers including cisplatin when used as single agent. However, data on safety, tolerability and efficacy of olaparib in combination with radiotherapy are limited.Methods: Olaparib is dose escalated in combination with radical (chemo-)radiotherapy regimens for non-small cell lung cancer (NSCLC), breast cancer and head and neck squamous cell carcinoma (HNSCC) in three parallel single institution phase 1 trials. All trials investigate a combination treatment of olaparib and radiotherapy, the NSCLC trial also investigates a triple combination of olaparib, radiotherapy and concurrent low dose cisplatin. The primary objective is to identify the maximum tolerated dose of olaparib in these combination treatments, defined as the dose closest to but not exceeding a 15% probability of dose limiting toxicity. Each trial has a separate dose limiting toxicity definition, taking into account incidence, duration and severity of expected toxicities without olaparib. Dose escalation is performed using a time-to-event continual reassessment method (TITE-CRM). TITE-CRM enables the incorporation of late onset toxicity until one year after treatment in the dose limiting toxicity definition while maintaining an acceptable trial duration. Olaparib treatment starts two days before radiotherapy and continues during weekends until two days after radiotherapy. Olaparib will also be given two weeks and one week before radiotherapy in the breast cancer trial and HNSCC trial respectively to allow for translational research. Toxicity is scored using common terminology criteria for adverse events (CTCAE) version 4.03. Blood samples, and tumour biopsies in the breast cancer trial, are collected for pharmacokinetic and pharmacodynamic analyses.Discussion: We designed three parallel phase 1 trials to assess the safety and tolerability of the PARP inhibitor olaparib in combination with radical (chemo-)radiotherapy treatment regimens. PARP inhibitors have the potential to improve outcomes in patients treated with radical (chemo-)radiotherapy, by achieving higher locoregional control rates and/or less treatment associated toxicity.Trial registration: ClinicalTrials.govIdentifiers: NCT01562210 (registered March 23, 2012), NCT02227082 (retrospectively registered August 27, 2014), NCT02229656 (registered September 1, 2014).

Aim: To evaluate the prognostic value of tumor markers in a European cohort of patients with resectable gastric cancer. Methods: We performed a post hoc analysis of the CRITICS trial, in which 788 patients received perioperative therapy. Association between survival and pretreatment CEA, CA 19-9, alkaline phosphatase, neutrophils, hemoglobin and lactate dehydrogenase were explored in uni- and multivariable Cox regression analyses. Likelihoods to receive potentially curative surgery were investigated for patients without elevated tumor markers versus one of the tumor markers elevated versus both tumor markers elevated. The association between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 patients with available ctDNA data. Results: In multivariable analysis, in which we corrected for allocated treatment and other baseline characteristics, elevated pretreatment CEA (HR 1.43; 95% CI 1.11–1.85, p < 0.001) and CA 19-9 (HR 1.79; 95% CI 1.42–2.25, p < 0.001) were associated with worse OS. Likelihoods to receive potentially curative surgery were 86%, 77% and 60% for patients without elevated tumor marker versus either elevated CEA or CA 19-9 versus both elevated, respectively (p < 0.001). Although both preoperative presence of ctDNA and tumor markers were prognostic for survival, no association was found between these two parameters. Conclusion: CEA and CA 19-9 were independent prognostic factors for survival in a large cohort of European patients with resectable gastric cancer. No relationship was found between tumor markers and ctDNA. These factors could potentially guide treatment choices and should be included in future trials to determine their definitive position. Trial registration: ClinicalTrial.gov identifier: NCT00407186. EudraCT number: 2006-00413032.

To evaluate treatment-related toxicity, treatment compliance, surgical complications and event-free survival (EFS) in older (≥70 years) versus younger (<70 years) adults who underwent perioperative treatment for gastric cancer. In the CRITICS trial, 788 patients with resectable gastric cancer were randomised before start of any treatment and received preoperative chemotherapy (3 cycles of epirubicin, cisplatin or oxaliplatin and capecitabine), followed by surgery, followed by either postoperative chemotherapy or chemoradiotherapy (45Gy + cisplatin + capecitabine). 172 (22%) patients were older adults. During preoperative chemotherapy, 131 (77%) older adults versus 380 (62%) younger adults experienced severe toxicity (p < 0.001); older adults received significantly lower relative dose intensities (RDIs) for all chemotherapeutic drugs. Equal proportions of older versus younger adults underwent curative surgery: 137 (80%) versus 499 (81%), with comparable postoperative complications and postoperative mortality. Postoperative therapy after curative surgery started in 87 (64%) older adults versus 391 (78%) younger adults (p < 0.001). Incidence of severe toxicity during postoperative chemotherapy was 22 (54%) in older adults versus 113 (59%) in younger adults (p = 0.541); older adults received significantly lower RDIs for all chemotherapeutic drugs. Severe toxicity rates for postoperative chemoradiotherapy were 22 (48%) older adults versus 89 (45%) for younger adults (p = 0.703), with comparable chemotherapy RDIs and radiotherapy dose. Two-year EFS was 53% for older adults versus 51% for younger adults. Perioperative treatment compliance, especially in the postoperative phase, was poorer in older adults compared with younger adults. As comparable proportions of patients underwent curative surgery, future studies should focus on neo-adjuvant treatment. ClinicalTrials.gov identifier: NCT00407186. EudraCT number: 2006-00413032.