Radiation therapy is one of the recommended treatment options for localized prostate cancer. In randomized trials, dose escalation was correlated with better biochemical control but also with higher rectal toxicity. A prospective multicenter phase II study was carried out to evaluate the safety, clinical and dosimetric effects of the hydrogel prostate-rectum spacer. Here we present the 12 months toxicity results of this trial.

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.

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).

To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival. In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated. 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute ≥ grade 3 toxicities were regarding skin/mucosa and pain (54% and 37%). Late ≥grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years. Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity.

Clinical introduction of magnetic resonance (MR)-guided radiotherapy involves treatment planning while taking into account machine-specific characteristics. Our aim was to investigate the feasibility of high-quality MR-linac treatment planning for an MR-linac and to benchmark MR-linac plan quality (IMRT) against current clinical practice (VMAT). Data of eight rectal and eight prostate cancer patients, who received radiotherapy on a conventional CBCT-integrated linac, were selected. Clinically acquired CTs and associated delineations of target volumes and organs-at-risk (OARs) were used for MR-linac treatment planning in Monaco. To investigate treatment planning software bias ‘quasi MR-linac plans’ were generated in Pinnacle3 by mimicking MR-linac specific beam characteristics. MR-linac, quasi MR-linac, and clinical plans were compared and differences in target and OAR doses assessed. Differences in plan complexity were determined by the number of segments and monitor units. Compared to clinical plans, MR-linac plans showed a statistically significant decrease in plan homogeneity, an increase in PTV Dmean (prostate: 0.6 Gy; rectum: 0.8 Gy) and D1% (prostate: 1.9 Gy; rectum: 2.0 Gy), and increases in OAR dose. Quasi MR-linac plans were comparable to MR-linac plans with respect to OAR dose and plan homogeneity. For rectal cancer an increase was seen in PTV Dmean (0.12 Gy) and D1% (0.5 Gy) compared to regular MR-linac plans. All created plans were clinically equivalent to current clinical practice. This study demonstrates the feasibility of creating high-quality MR-linac treatment plans. The results supported the clinical introduction of an MR-linac.

Total mesorectal excision for rectal cancer is a major operation associated with morbidity and mortality. For older or inoperable patients, alternatives are necessary. This prospective study evaluated the oncological and functional outcome and quality of life of older or inoperable rectal cancer patients treated with a contact X-ray brachytherapy boost to avoid major surgery. During follow-up, tumor response and toxicity on endoscopy were scored. Functional outcome and quality of life were assessed with self-administered questionnaires. Additionally, in-depth interviews regarding patients’ experiences were conducted. Nineteen patients were included with a median age of 80 years (range 72–91); nine patients achieved a clinical complete response and in another four local control of the tumor was established. The 12 month organ-preservation rate, progression-free survival, and overall survival were 88%, 78%, and 100%, respectively. A transient decrease in quality of life and bowel function was observed at 3 months, which was generally restored at 6 months. In-depth interviews revealed that patients’ experience was positive despite the side-effects shortly after treatment. In older or inoperable rectal cancer patients, contact X-ray brachytherapy can be considered an option to avoid total mesorectal excision. Contact X-ray brachytherapy is well-tolerated and can provide good tumor control.