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.
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.
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.
ClinicalTrials.gov Identifiers: NCT01562210 (registered March 23, 2012), NCT02227082 (retrospectively registered August 27, 2014), NCT02229656 (registered September 1, 2014).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Radiotherapy might augment systemic antitumoral responses to immunotherapy. In the PEMBRO-RT (phase 2) and MDACC (phase 1/2) trials, patients with metastatic non-small-cell lung cancer were randomly ...allocated immunotherapy (pembrolizumab) with or without radiotherapy. When the trials were analysed individually, a potential benefit was noted in the combination treatment arm. However, owing to the small sample size of each trial, differences in response rates and outcomes were not statistically significant but remained clinically notable. We therefore did a pooled analysis to infer whether radiotherapy improves responses to immunotherapy in patients with metastatic non-small-cell lung cancer.
Inclusion criteria for the PEMBRO-RT and MDACC trials were patients (aged ≥18 years) with metastatic non-small-cell lung cancer and at least one unirradiated lesion to monitor for out-of-field response. In the PEMBRO-RT trial, patients had previously received chemotherapy, whereas in the MDACC trial, patients could be either previously treated or newly diagnosed. Patients in both trials were immunotherapy-naive. In the PEMBRO-RT trial, patients were randomly assigned (1:1) and stratified by smoking status (<10 vs ≥10 pack-years). In the MDACC trial, patients were entered into one of two cohorts based on radiotherapy schedule feasibility and randomly assigned (1:1). Because of the nature of the intervention in the combination treatment arm, blinding to radiotherapy was not feasible in either trial. Pembrolizumab was administered intravenously (200 mg every 3 weeks) with or without radiotherapy in both trials. In the PEMBRO-RT trial, the first dose of pembrolizumab was given sequentially less than 1 week after the last dose of radiotherapy (24 Gy in three fractions), whereas in the MDACC trial, pembrolizumab was given concurrently with the first dose of radiotherapy (50 Gy in four fractions or 45 Gy in 15 fractions). Only unirradiated lesions were measured for response. The endpoints for this pooled analysis were best out-of-field (abscopal) response rate (ARR), best abscopal disease control rate (ACR), ARR at 12 weeks, ACR at 12 weeks, progression-free survival, and overall survival. The intention-to-treat populations from both trials were included in analyses. The PEMBRO-RT trial (NCT02492568) and the MDACC trial (NCT02444741) are registered with ClinicalTrials.gov.
Overall, 148 patients were included in the pooled analysis, 76 of whom had been assigned pembrolizumab and 72 who had been assigned pembrolizumab plus radiotherapy. Median follow-up for all patients was 33 months (IQR 32·4-33·6). 124 (84%) of 148 patients had non-squamous histological features and 111 (75%) had previously received chemotherapy. Baseline variables did not differ between treatment groups, including PD-L1 status and metastatic disease volume. The most frequently irradiated sites were lung metastases (28 of 72 39%), intrathoracic lymph nodes (15 of 72 21%), and lung primary disease (12 of 72 17%). Best ARR was 19·7% (15 of 76) with pembrolizumab versus 41·7% (30 of 72) with pembrolizumab plus radiotherapy (odds ratio OR 2·96, 95% CI 1·42-6·20; p=0·0039), and best ACR was 43·4% (33 of 76) with pembrolizumab versus 65·3% (47 of 72) with pembrolizumab plus radiotherapy (2·51, 1·28-4·91; p=0·0071). Median progression-free survival was 4·4 months (IQR 2·9-5·9) with pembrolizumab alone versus 9·0 months (6·8-11·2) with pembrolizumab plus radiotherapy (hazard ratio HR 0·67, 95% CI 0·45-0·99; p=0·045), and median overall survival was 8·7 months (6·4-11·0) with pembrolizumab versus 19·2 months (14·6-23·8) with pembrolizumab plus radiotherapy (0·67, 0·54-0·84; p=0·0004). No new safety concerns were noted in the pooled analysis.
Adding radiotherapy to pembrolizumab immunotherapy significantly increased responses and outcomes in patients with metastatic non-small-cell lung cancer. These results warrant validation in a randomised phase 3 trial.
Merck Sharp & Dohme.
Background
Despite improvements in the multimodality treatment for patients with locally recurrent rectal cancer (LRRC), oncological outcomes remain poor. This study evaluated the effect of induction ...chemotherapy and subsequent chemo(re)irradiation on the pathologic response and the rate of resections with clear margins (R0 resection) in relation to long-term oncological outcomes.
Methods
All consecutive patients with LRRC treated in the Catharina Hospital Eindhoven who underwent a resection after treatment with induction chemotherapy and subsequent chemo(re)irradiation between January 2010 and December 2018 were retrospectively reviewed. Induction chemotherapy consisted of CAPOX/FOLFOX. Endpoints were pathologic response, resection margin and overall survival (OS), disease free survival (DFS), local recurrence free survival (LRFS), and metastasis free survival (MFS).
Results
A pathologic complete response was observed in 22 patients (17%), a “good” response (Mandard 2–3) in 74 patients (56%), and a “poor” response (Mandard 4–5) in 36 patients (27%). An R0 resection was obtained in 83 patients (63%). The degree of pathologic response was linearly correlated with the R0 resection rate (
p
= 0.026). In patients without synchronous metastases, pathologic response was an independent predictor for LRFS, MFS, and DFS (
p
= 0.004,
p
= 0.003, and
p
= 0.024, respectively), whereas R0 resection was an independent predictor for LRFS and OS (
p
= 0.020 and
p
= 0.028, respectively).
Conclusions
Induction chemotherapy in addition to neoadjuvant chemo(re)irradiation is a promising treatment strategy for patients with LRRC with high pathologic response rates that translate into improved oncological outcomes, especially when an R0 resection has been achieved.
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).
Olaparib dose was ...escalated in two groups: radiotherapy (66 Gy/24 fractions in 2.75 Gy/fraction) with and without daily cisplatin (6 mg/m
), 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.
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.
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.
•Delineation in LRRC is complex due to heterogeneous disease and absence of guidelines.•Inter-observer variation in LRRC is large.•Multidisciplinary target volume definition is essential.•QA data ...from PelvEx II trial will provide further insight in target volumes.
Neoadjuvant chemoradiotherapy (nCRT) is used in locally recurrent rectal cancer (LRRC) to increase chances of a radical surgical resection. Delineation in LRRC is hampered by complex disease presentation and limited clinical exposure. Within the PelvEx II trial, evaluating the benefit of chemotherapy preceding nCRT for LRRC, a delineation guideline was developed by an expert LRRC team.
Eight radiation oncologists, from Dutch and Swedish expert centres, participated in two meetings, delineating GTV and CTV in six cases. Regions at-risk for re-recurrence or irradical resection were identified by eleven expert surgeons and one expert radiologist. Target volumes were evaluated multidisciplinary. Inter-observer variation was analysed.
Inter-observer variation in delineation of LRRC appeared large. Multidisciplinary evaluation per case is beneficial in determining target volumes. The following consensus regarding target volumes was reached. GTV should encompass all tumour, including extension into OAR if applicable. If the tumour is in fibrosis, GTV should encompass the entire fibrotic area. Only if tumour can clearly be distinguished from fibrosis, GTV may be reduced, as long as the entire fibrotic area is covered by the CTV. CTV is GTV with a 1 cm margin and should encompass all at-risk regions for irradical resection or re-recurrence. CTV should not be adjusted towards other organs. Multifocal recurrences should be encompassed in one CTV. Elective nodal delineation is only advised in radiotherapy-naïve patients.
This study provides a first consensus-based delineation guideline for LRRC. Analyses of re-recurrences is needed to understand disease behaviour and to optimize delineation guidelines accordingly.
The addition of induction chemotherapy (ICT) to neoadjuvant chemoradiotherapy (CRT) has the potential to improve outcomes in patients with locally advanced rectal cancer (LARC). However, patient ...selection is essential to prevent overtreatment. This study compared the complete response (CR) rate after treatment with and without ICT of LARC patients with prognostically poor characteristics.
All LARC patients who were treated with neoadjuvant CRT, whether or not preceded by ICT, and who underwent surgery or were considered for a wait-and-see strategy between January 2016 and March 2020 in the Catharina Hospital Eindhoven, were retrospectively selected. LARC was defined as any T4 tumour, or a T2/T3 tumour with extramural venous invasion and/or tumour deposits and/or N2 lymph node status, and/or mesorectal fascia involvement (T3 tumours only). Case-control matching was performed based on the aforementioned characteristics.
Of 242 patients, 178 (74%) received CRT (CRT-group) and 64 patients (26%) received ICT followed by CRT (ICT-group). In the ICT-group, 3 patients (5%) did not receive the minimum of three cycles. In addition, in this selected cohort, compliance with radiotherapy was 100% in the ICT-group and 97% in the CRT-group. The CR rate was 30% in the ICT-group and 15% in the CRT-group (p = 0.011). After case-control matching, the CR rate was 28% and 9%, respectively (p = 0.013).
Treatment including ICT seemed well tolerated and resulted in a high CR rate. Hence, this treatment strategy may facilitate organ preservation and improve survival in LARC patients with prognostically poor characteristics.
In the Netherlands, use of neoadjuvant radiotherapy for rectal cancer declined after guideline revision in 2014. This decline is thought to affect the clinical nature and treatability of locally ...recurrent rectal cancer (LRRC). Therefore, this study compared two national cross-sectional cohorts before and after the guideline revision with the aim to determine the changes in treatment and survival of LRRC patients over time.
Patients who underwent resection of primary rectal cancer in 2011 (n = 2094) and 2016 (n = 2855) from two nationwide cohorts with a 4-year follow up were included. Main outcomes included time to LRRC, synchronous metastases at time of LRRC diagnosis, intention of treatment and 2-year overall survival after LRRC.
Use of neoadjuvant (chemo)radiotherapy for the primary tumour decreased from 88.5% to 60.0% from 2011 to 2016. The 3-year LRRC rate was not significantly different with 5.1% in 2011 (n = 114, median time to LRRC 16 months) and 6.3% in 2016 (n = 202, median time to LRRC 16 months). Synchronous metastasis rate did not significantly differ (27.2% vs 33.7%, p = 0.257). Treatment intent of the LRRC shifted towards more curative treatment (30.4% vs. 47.0%, p = 0.009). In the curatively treated group, two-year overall survival after LRRC diagnoses increased from 47.5% to 78.7% (p = 0.013).
Primary rectal cancer patients in 2016 were treated less often with neoadjuvant (chemo)radiotherapy, while LRRC rates remained similar. Those who developed LRRC were more often candidate for curative intent treatment compared to the 2011 cohort, and survival after curative intent treatment also improved substantially.
•In 2016 less primary rectal cancer patients were treated with neoadjuvant (chemo)radiotherapy.•The LRRC rate remained the same between 2011 and 2016.•In 2016 LRRC patients were more often candidate for curative treatment.•In 2016 LRRC patients received full course chemoradiotherapy more often.•Survival of curatively treated LRRC patients increased significantly over time.
Solitary fibrous tumour is a rare mesenchymal tumour of uncertain origin that occurs most frequently in the pleura, although it has also been described in extraserosal sites. The biological behaviour ...of the tumour is unpredictable. The case history is described of a patient diagnosed with a large symptomatic irresectable mediastinal solitary fibrous tumour who achieved a clinical, radiological and metabolic response after concurrent chemotherapy and radiotherapy.
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