Chemoradiotherapy of locally-advanced non-small cell lung cancer: Analysis of radiation dose-response, chemotherapy and survival-limiting toxicity effects indicates a low alpha/beta ratio

Purpose To analyse changes in 2-year overall survival (OS2yr) with radiotherapy (RT) dose, dose-per-fraction, treatment duration and chemotherapy use, in data compiled from prospective trials of RT and chemo-RT (CRT) for locally-advanced non-small cell lung cancer (LA-NSCLC). Material and methods OS2yr data was analysed for 6957 patients treated on 68 trial arms (21 RT-only, 27 sequential CRT, 20 concurrent CRT) delivering doses-per-fraction ≤4.0 Gy. An initial model considering dose, dose-per-fraction and RT duration was fitted using maximum-likelihood techniques. Model extensions describing chemotherapy effects and survival-limiting toxicity at high doses were assessed using likelihood-ratio testing, the Akaike Information Criterion (AIC) and cross-validation. Results A model including chemotherapy effects and survival-limiting toxicity described the data significantly better than simpler models (p < 10−14), and had better AIC and cross-validation scores. The fitted α/β ratio for LA-NSCLC was 4.0 Gy (95%CI: 2.8–6.0 Gy), repopulation negated 0.38 (95%CI: 0.31–0.47) Gy EQD2/day beyond day 12 of RT, and concurrent CRT increased the effective tumour EQD2 by 23% (95%CI: 16–31%). For schedules delivered in 2 Gy fractions over 40 days, maximum modelled OS2yr for RT was 52% and 38% for stages IIIA and IIIB NSCLC respectively, rising to 59% and 42% for CRT. These survival rates required 80 and 87 Gy (RT or sequential CRT) and 67 and 73 Gy (concurrent CRT). Modelled OS2yr rates fell at higher doses. Conclusions Fitted dose–response curves indicate that gains of ~10% in OS2yr can be made by escalating RT and sequential CRT beyond 64 Gy, with smaller gains for concurrent CRT. Schedule acceleration achieved via hypofractionation potentially offers an additional 5–10% improvement in OS2yr. Further 10–20% OS2yr gains might be made, according to the model fit, if critical normal structures in which survival-limiting toxicities arise can be identified and selectively spared

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p&lt;0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p&lt;0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (&lt;1%) with standard of care in the abiraterone trial). Interpretation: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas

Widening the therapeutic window of thoracic radiotherapy: cardiopulmonary toxicity modelling

Introduction: Prognosis for locally advanced non-small cell lung cancer (LANSCLC) remain poor despite attempts with radiation dose escalation to improve overall survival (OS). A major limitation of radiation dose escalation is normal tissue toxicity. Here, I investigate the hypothesis that cardiac and its substructure irradiation impact OS in LA-NSCLC patients with a dose-volume-time effect. As cardiac avoidance can potentially increase lung toxicity (radiation pneumonitis (RP) acutely) the hypothesis that novel predictive models for RP combining clinical and dosimetric factors accounting for potential heart and lung irradiation synergistic effect are better than mean lung dose alone as a predictor was also tested. Methods: Complementary methodologies were utilised to provide additional knowledge and derive novel Cox regression OS models and logistic regression RP models. The highly correlated dose volume data were best analysed through principal component analysis. 1) A post hoc analysis of a prospective phase 1/2 isotoxic dose escalation study of 78 patients was conducted to derive an OS model incorporating clinical and cardiac substructure dosimetric factors, and electrocardiographic (ECG) changes. 2) OS model identified in part 1 was validated and refined in an independent retrospective 64 patient cohort where direct impact of cardiac dosimetry on cardiac-morbidity and cardiac-related-death was also assessed. 3) The further refined OS model from part 2 was validated in another independent cohort and the model refined using a large combined cohort and a dose-volume-time effect was tested. 4) A modelling study to predict ≥ grade 2 RP (G2RP) risk combining clinical and dosimetric factors including heart and lung irradiation interaction was conducted. Results: High volume of left atrial wall receiving high doses (64-73 Gy in equivalent 2 Gy per fraction (EQD2)), coronary ostia region receiving intermediate doses (29- 38 Gy EQD2), large planning target volume size, younger age and any ECG changes or recorded cardiac events after RT were associated with poorer OS. A prognostic index was derived from these factors with good performance. High whole heart volume receiving low doses (3-12 Gy EQD2) was associated with poorer OS with the low dose effect seen later than high or intermediate dose effects. Poorer performance status, higher baseline forced vital capacity, higher contralateral tumour free lung volumes, especially lower and middle sections, receiving 2-5 Gy EQD2 and high heart volume receiving 37-55 Gy EQD2 were associated with higher G2RP risk. A model combining these factors performed better at predicting G2RP than the standard mean lung dose model in isotoxically dose escalated patients. Conclusions: This work adds to the knowledge about the nature, magnitude and timing of cardiac and its substructure irradiation on OS and derived novel survival and lung toxicity models combining clinical and dosimetric factors. This can be used to help future management of LA-NSCLC and personalisation of radiation dose escalation. The planned in-silico study and the prospective cardiopulmonary functional imaging study will contribute further knowledge regarding the practical implications and underlying mechanism of damage.</p

Cardiac-sparing radiotherapy for locally advanced non-small cell lung cancer.

BACKGROUND: We have carried out a study to determine the scope for reducing heart doses in photon beam radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC). MATERIALS AND METHODS: Baseline VMAT plans were created for 20 LA-NSCLC patients following the IDEAL-CRT isotoxic protocol, and were re-optimized after adding an objective limiting heart mean dose (MD(Heart)). Reductions in MD(Heart) achievable without breaching limits on target coverage or normal tissue irradiation were determined. The process was repeated for objectives limiting the heart volume receiving???50 Gy (V(Heart-50-Gy)) and left atrial wall volume receiving???63 Gy (V(LAwall-63-Gy)). RESULTS: Following re-optimization, mean MD(Heart), V(Heart-50-Gy) and V(LAwall-63-Gy) values fell by 4.8 Gy and 2.2% and 2.4% absolute respectively. On the basis of associations observed between survival and cardiac irradiation in an independent dataset, the purposefully-achieved reduction in MD(Heart) is expected to lead to the largest improvement in overall survival. It also led to useful knock-on reductions in many measures of cardiac irradiation including V(Heart-50-Gy) and V(LAwall-63-Gy), providing some insurance against survival being more strongly related to these measures than to MD(Heart). The predicted hazard ratio (HR) for death corresponding to the purposefully-achieved mean reduction in MD(Heart) was 0.806, according to which a randomized trial would require 1140 patients to test improved survival with 0.05 significance and 80% power. In patients whose baseline MD(Heart) values exceeded the median value in a published series, the average MD(Heart) reduction was particularly large, 8.8 Gy. The corresponding predicted HR is potentially testable in trials recruiting 359 patients enriched for greater MD(Heart) values. CONCLUSIONS: Cardiac irradiation in RT of LA-NSCLC can be reduced substantially. Of the measures studied, reduction of MD(Heart) led to the greatest predicted increase in survival, and to useful knock-on reductions in other cardiac irradiation measures reported to be associated with survival. Potential improvements in survival can be trialled more efficiently in a population enriched for patients with greater baseline MD(Heart) levels, for whom larger reductions in heart doses can be achieved.The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version, accepted versio

A cardiac contouring atlas for radiotherapy

Background and Purpose: The heart is a complex anatomical organ and contouring the cardiac substructures is challenging. This study presents a reproducible method for contouring left ventricular and coronary arterial segments on radiotherapy CT-planning scans. Material and Methods: Segments were defined from cardiology models and agreed by two cardiologists. Reference atlas contours were delineated and written guidelines prepared. Six radiation oncologists tested the atlas. Spatial variation was assessed using the DICE similarity coefficient (DSC) and the directed Hausdorff average distance (⃗,). The effect of spatial variation on doses was assessed using six different breast cancer regimens. Results: The atlas enabled contouring of 15 cardiac segments. Inter-observer contour overlap (mean DSC) was 0.60-0.73 for five left ventricular segments and 0.10-0.53 for ten coronary arterial segments. Inter-observer contour separation (mean ⃗, ) was 1.5-2.2 mm for left ventricular segments and 1.3-5.1 mm for coronary artery segments. This spatial variation resulted in &lt;1 Gy dose variation for most regimens and segments, but 1.2-21.8 Gy variation for segments close to a field edge. Conclusions: This cardiac atlas enables reproducible contouring of segments of the left ventricle and main coronary arteries to facilitate future studies relating cardiac radiation doses to clinical outcomes.</p

The UK experience of a treatment strategy for pediatric metastatic medulloblastoma comprising intensive induction chemotherapy, hyperfractionated accelerated radiotherapy and response directed high dose myeloablative chemotherapy or maintenance chemotherapy (Milan Strategy)

BACKGROUND: Historically, the 5-year overall survival (OS) for metastatic medulloblastoma (MMB) was less than 40%. The strategy of post-operative induction chemotherapy (IC) followed by hyperfractionated accelerated radiotherapy (HART) and response directed high dose chemotherapy (HDC) was reported in a single center study to improve 5-year OS to 73%. We report outcomes of this strategy in UK. METHODS: Questionnaires were sent to all 20 UK pediatric oncology primary treatment centers to collect retrospective data on delivered treatment, toxicity and survival with this strategy in children aged 3-19 years with MMB. RESULTS: Between February 2009 and October 2011, 34 patients fulfilled the entry criteria of the original study. The median age was 7 years (range 3-15). Median interval from surgery to HART was 109 versus 85 days in the original series. The incidence of grade 3 or 4 hematological toxicities with IC and HDC was 83-100%. All 16 patients who achieved complete response by the end of the regimen remain in remission but only three of 18 patients with lesser responses are still alive (P < 0.0001). With a median follow-up of 45 months for survivors, the estimated 3-year OS is 56% (95% CI 38, 71). This result is outside the 95% CI of the original study results and encompasses the historical survival result of 40%. CONCLUSION: Within the limits of statistical significance, we did not replicate the improved survival results reported in the original series. The reasons include differences in patient sub-groups and protocol administration. International randomized phase III studies are needed

Long-Term Results from the IDEAL-CRT Phase 1/2 Trial of Isotoxically Dose-Escalated Radiation Therapy and Concurrent Chemotherapy for Stage II/III Non-small Cell Lung Cancer

Purpose: The IDEAL-CRT phase 1/2 multicenter trial of isotoxically dose-escalated concurrent chemoradiation for stage II/III non-small cell lung cancer investigated two 30-fraction schedules of 5 and 6 weeks' duration. We report toxicity, tumor response, progression-free survival (PFS), and overall survival (OS) for both schedules, with long-term follow-up for the 6-week schedule. Methods and Materials: Patients received isotoxically individualized tumor radiation doses of 63 to 71 Gy in 5 weeks or 63 to 73 Gy in 6 weeks, delivered concurrently with 2 cycles of cisplatin and vinorelbine. Eligibility criteria were the same for both schedules. Results: One-hundred twenty patients (6% stage IIB, 68% IIIA, 26% IIIB, 1% IV) were recruited from 9 UK centers, 118 starting treatment. Median prescribed doses were 64.5 and 67.6 Gy for the 36 and 82 patients treated using the 5- and 6-week schedules. Grade >= 3 pneumonitis and early esophagitis rates were 3.4% and 5.9% overall and similar for each schedule individually. Late grade 2 esophageal toxicity occurred in 11.1% and 17.1% of 5- and 6-week patients. Grade >= 4 adverse events occurred in 17 (20.7%) 6-week patients but no 5-week patients. Four adverse events were grade 5, with 2 considered radiation therapy related. After median follow-up of 51.8 and 26.4 months for the 6- and 5-week schedules, median OS was 41.2 and 22.1 months, respectively, and median PFS was 21.1 and 8.0 months. In exploratory analyses, OS was significantly associated with schedule (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.32-0.98; P = .04) and fractional clinical/internal target volume receiving >= 95% of the prescribed dose (HR, 0.88; 95% CI, 0.77-1.00; P = .05). PFS was also significantly associated with schedule (HR, 0.53; 95% CI, 0.33-0.86; P = .01). Conclusions: Toxicity in IDEAL-CRT was acceptable. Survival was promising for 6-week patients and significantly longer than for 5-week patients. Survival might be further lengthened by following the 6-week schedule with an immune agent, motivating further study of such combined optimized treatments