Twice-daily Radiotherapy Research Articles

Prognostic value of the TGFβ1 rs4803455 single nucleotide polymorphism in small cell lung cancer.

Small cell lung cancer (SCLC) is one of the greatest therapeutic challenges of oncology. Potential associations between single nucleotide polymorphisms in heat shock protein β1 (HSPB1) and transforming growth factor β1 (TGFβ1) and survival have been investigated. A prospective multicenter study of 94 patients with SCLC treated between 2013 and 2016 was conducted. Clinical, tumour-related, therapeutic, and genetic (9 SNPs of TGFβ1 gene and 5 of HSPB1 gene) variables were analyzed. The cohort included 77 men and 17 women with a median age of 61 years. Eighty percent presented with limited stage at diagnosis and received thoracic radiation with a median dose of 45 Gy (twice-daily radiation in 42%). Forty-seven percent received concurrent platinum-based chemotherapy and 57% received prophylactic cranial irradiation (PCI). Overall survival (OS) was 34% at 2 years and 16% at 3 years. In multivariate analysis, the rs4803455:CA genotype of the TGFβ1 gene showed a statistically significant association with lower disease-free survival (DFS; hazard ratio [HR] 3.13; confidence interval [CI] 1.19-8.17; p = 0.020) and higher local recurrence (HR 3.80; CI 1.37-10.5; p = 0.048), and a marginal association with lower OS (HR 1.94; CI 0.98-3.83; p = 0.057). A combined analysis showed that patients receiving PCI and carrying the rs4803455:CA genotype had statistically significant lower OS (p < 0.001) and DFS (p < 0.001) than patients receiving PCI and carrying the rs4803455:AA genotype. Genetic analysis showed the CA genotype of TGFβ1 SNP rs4803455 was associated with worse prognosis in patients with SCLC and could be considered as a potential biomarker.

Once daily versus twice-daily radiotherapy in the management of limited disease small cell lung cancer – Decision criteria in routine practise

BackgroundIn limited disease small cell lung cancer (LD-SCLC), the CONVERT trial has not demonstrated superiority of once-daily (QD) radiotherapy (66 Gy) over twice-daily (BID) radiotherapy (45 Gy). We explored the factors influencing the selection between QD and BID regimens. MethodsThirteen experienced European thoracic radiation oncologists as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) were asked to describe their strategies in the management of LD-SCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies. ResultsLogistic reasons, patients’ performance status and radiotherapy dose constraints were the three major decision criteria used by most experts in decision making. The use of QD and BID regimens was balanced among European experts, but there was a trend towards the BID regimen for fit patients able to travel twice a day to the radiotherapy site. ConclusionBID and QD radiotherapy are both accepted regimens among experts and the decision is influenced by pragmatic factors such as availability of transportation.

Long-term outcome comparison for standard fractionation (>59 Gy) versus hyperfractionated (>45 Gy) radiotherapy plus concurrent chemotherapy for limited-stage small-cell lung cancer.

Concurrent chemoradiotherapy (CCRT) is commonly employed in limited-stage small-cell lung cancer (LS-SCLC); however, the optimal radiotherapy regimen is still unknown. This 3-institution analysis compares long-term disease control and survival outcomes for once- (QD) versus twice-daily (BID) radiotherapy at contemporary doses. Data were collected for LS-SCLC patients treated with platinum-based CCRT and planned RT doses of >5940 cGy at >180 cGy QD or >4500 cGy at 150 cGy BID. Comparative outcome analyses were performed for treatment groups. From 2005 through 2014, 132 patients met inclusion criteria for analysis (80 QD, 52 BID). Treatment groups were well-balanced, excepting higher rate of advanced mediastinal staging, longer interval from biopsy to treatment initiation, and lower rate of prophylactic cranial irradiation for the QD group, as well as institutional practice variation. At median survivor follow-up of 33.5 months (range, 4.6-105.8), 80 patients experienced disease failure (44 QD, 36 BID), and 106 died (62 QD, 44 BID). No differences in disease control or survival were demonstrated between treatment groups. The present analysis did not detect a difference in disease control or survival outcomes for contemporary dose QD versus BID CCRT in LS-SCLC.

IBS19.02 Novel Radiotherapy Approaches in Small Cell Lung Carcinoma – Has SABR and Radionuclide Therapy Got a Role to Play?

Thoracic radiotherapy has been shown in to increase overall survival when added to systemic therapy in patients with small cell lung carcinoma (SCLC) and M0 stage. The dose, fractionation, treatment time and timing issues have not been fully resolved. A recent study did not show the superiority of 66Gy in 33 daily fractions over 6.5 weeks over twice-daily radiotherapy to a dose of 45 Gy in 30 fractions over 3 weeks twice daily [1]. For stage I non-small cell lung carcinoma (NSCLC), stereotactic ablative body radiotherapy (SABR) has been clearly shown to be superior to conventional fractionation [2]. Given the clear benefit seen in early stage NSCLC, it is postulated that SABR may have a role to play in early stage SCLC. A recent multi-institutional cohort study has reported favourable outcomes in this setting [3]. However, randomised data of equivalence or indeed superiority are lacking. Furthermore, questions remain as the timing and role of systemic therapy and prophylactic cranial irradiation when SABR is used in this setting. In advanced SCLC, many tumors display neuroendocrine clinical and cytological features and many SCLC tumors express somatostatin receptor and this can be imaged using radiolabeled somatostatin analogs such as 68Ga-DOTATATE [4]. Given the uptake by some SCLC tumors of 68Ga-DOTATATE, higher doses of the tracer have been used in an attempt to provide radiolabelled radiotherapy treatment in metastatic disease in what has been described as peptide receptor radionuclide therapy (PRRT) [5]. This molecularly target radiotherapy is a potentially exciting therapeutic approach, but the ideal positioning of such therapy in tumors which are suitable for treatment with PRRT and the safety of PRRT with systemic therapy have yet to be determined. 1. Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017;18(8):1116–1125. https://doi.org/10.1016/S1470-2045(1730318-2) 2. Ball D, Mai GT, Vinod S, et al. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small cell lung cancer (TROG 09.02. CHISEL): a phase 3, open-label, randomised controlled trial. The Lancet. 2019; 20: 494-503 3. Verma V, Simone CB, 2nd, Allen PK, et al. Multi-Institutional Experience of Stereotactic Ablative Radiation Therapy for Stage I Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2017;97:362-71 4. Sollini M, Farioli D, Froio A, et al. Brief Report on the Use of Radiolabeled Somatostatin Analogs for the Diagnosis and Treatment of Metastatic Small-Cell Lung Cancer Patients. J Thor Oncol 2013;8(8):1095-1101. 5. Lapa C, Hänscheid H, Wild V, et al. Somatostatin receptor expression in small cell lung cancer as a prognostic marker and a target for peptide receptor radionuclide therapy. Oncotarget. 2016 Apr 12;7(15):20033-40. SCLC, SABR, radiotherapy

Risk of brainstem necrosis in pediatric patients with central nervous system malignancies after pencil beam scanning proton therapy

Background: Radiation therapy (RT) plays an important role in management of pediatric central nervous system (CNS) malignancies. Centers are increasingly utilizing pencil beam scanning proton therapy (PBS-PT). However, the risk of brainstem necrosis has not yet been reported. In this study, we evaluate the rate of brainstem necrosis in pediatric patients with CNS malignancies treated with PBS-PT.Material and methods: Pediatric patients with non-hematologic CNS malignancies treated with PBS-PT who received dose to the brainstem were included. All procedures were approved by the institutional review board. Brainstem necrosis was defined as symptomatic toxicity. The actuarial rate was analyzed by the Kaplan Meier method.Results: One hundred and sixty-six consecutive patients were reviewed. Median age was 10 years (range 0.5–21 years). Four patients (2.4%) had prior radiation. Median maximum brainstem dose in the treated course was 55.4 Gy[RBE] (range 0.15–61.4 Gy[RBE]). In patients with prior RT, cumulative median maximum brainstem dose was 98.0 Gy [RBE] (range 17.0–111.0 Gy [RBE]). Median follow up was 19.6 months (range, 2.0–63.0). One patient who had previously been treated with twice-daily radiation therapy and intrathecal (IT) methotrexate experienced brainstem necrosis. The actuarial incidence of brainstem necrosis was 0.7% at 24 months (95% CI 0.1–5.1%).Conclusion: The rate of symptomatic brainstem necrosis was extremely low after treatment with PBS-PT in this study. Further work to clarify clinical and dosimetric parameters associated with risk of brainstem necrosis after PBS-PT is needed.

Analysis of Radiotherapy to Recurrent Nasopharyngeal Carcinoma (NPC) in Hong Kong

To investigate the effect of intensity modulated radiotherapy (IMRT) dose and tumor volume on the outcomes in patients with recurrent NPC in Hong Kong. A total of 91 patients (22% rT1-2, 38% rT3, and 40% rT4) from six oncology centers in Hong Kong were included. These patients had recurrent NPC at least 12 months after their primary treatment, and were given a second course of radiotherapy. The median follow-up period was 47.7 months (1.8 to 110.6) measured from the start of the re-irradiation. IMRT of various types including conventional fractionation scheme, stereotactic radiotherapy, twice-daily (BID) radiation were used to deliver the second course of radiotherapy. The prescribed doses delivered from the different fractionation schemes were converted into Equivalent Dose at 2 Gy per fractions (EQD2) using α/β ratios of 10 Gy and 3 Gy for the disease and fatal complication respectively. The variations of the accrual local control and overall survival at 24 months versus the dose as well as the recurrent GTV volume were analyzed. The relationship between the fatal complication rate and the dose were also studied. Logistic regression was used to fit the dose and volume responses (if applicable) using a computer algorithm software. The significance of the responses were evaluated using the likelihood ratio test at a significance level of p=0.05. The dose delivered to the tumor ranged from 44.3 Gy to 72 Gy (EQD2). Local control and the rate of fatal complication appear to rise with the dose, but the relationships are not statistically significant (p = 0.147 and p=0.054 respectively). The overall survival rises with the dose until around 60 Gy (EQD2) and then falls again. The size of GTV varied significantly from 1.8 cc to 194 cc. The local control shows a significant decreasing trend with GTV volume (p<0.001). A similar trend can be seen on overall survival but has not reached statistical significance (p=0.061). There is no clear trend or correlation between the fatal complication rate and the GTV volume. A multi-dimensional logistic model was also fitted to the local control versus the target dose and GTV volume. The result suggests that the local control is predominantly affected by the GTV volume as expected from the individual analyses. While local control also has an increasing trend with prescribed dose for smaller GTV, higher prescribed dose does not lead to higher control for large tumors, probably due to both the large tumor mass and the resulting deterioration of dose coverage in a recurrent radiotherapy setting. The GTV volume plays a significant role in the local control of the recurrent diseases. 60 Gy (EQD2) appears to be the optimal dose for achieving the best survival outcome while balancing the probability of local control and fatal complication, but a higher personalized dose based on the multi-dimensional logistic model might be considered for smaller tumors.

Thoracic twice-daily radiotherapy and brain metastasis in patients with small cell lung cancer.

8560 Background: Although thoracic twice-daily radiotherapy (TDRT) is one of standards of care for small cell lung cancer, its impact on brain metastases remains unknown. This study aimed to compare TDRT with once-daily radiotherapy (ODRT) for the brain metastases rate after prophylactic cranial irradiation in patients with small cell lung cancer. Methods: Consecutive patients received TDRT (45Gy/30f)/ODRT(50-66Gy/25-33f), chemotherapy and prophylactic cranial irradiation were retrieved from eight hospitals’ databases between 2003 and 2016. The endpoints included brain metastases, progression-free survival and overall survival. Brain metastases rate was evaluated using competing risk analysis. A 1:1 propensity score matching approach was used to control confounding between these two groups. Confounding covariates included eight demographic variables and eight treatment related covariates. Results: Of the 778 eligible patients with median age of 55-year (IQR, 48-61), 204 (26.2%) were female. At a median follow-up time of 23.6 months (IQR, 14.2- 38.2), 131 (16.8%) experienced brain metastases. The rates in TDRT were significantly higher than ODRT (3-year, 26.0% vs. 16.9%; HR = 1.55, 95%CI 1.06-2.26, P = 0.03). Of the 338 matched patients (169 in ODRT vs. 169 in TDRT), 60 (17.8%) experienced brain metastases with 3-year rate of 14.9% in ODRT vs 26.0% in TDRT (HR = 1.71, 95%CI 1.02-2.88, P = 0.04). Progression-free survival was similar in both the whole cohort and the matched one. Overall survival in ODRT tended to be significantly longer after matching (median, 47.2 months in ODRT vs. 32.8 months in TDRT; HR = 1.41, 95%CI 0.99-2.01, P = 0.06). When jointly evaluated biologically effective dose (BED), start of any therapy to the end of radiotherapy (SER) and TDRT/ODRT in the multivariable analysis, the impact of ODRT/TDRT on overall survival become more significant (HR = 1.69, 95%CI 1.05-2.71, P = 0.03). Conclusions: Patients with small cell lung cancer who were treated with thoracic TDRT appeared to have higher risk of brain metastases than those with ODRT, which strongly supports the need for further prospective randomized clinical trials, especially in China or other parts of Asia.

Association of Twice-Daily Radiotherapy With Subsequent Brain Metastases in Adults With Small Cell Lung Cancer

ImportanceAlthough thoracic twice-daily radiotherapy (TDRT) is one of the standards of care for small cell lung cancer, its association with brain metastases remains unknown.ObjectiveTo investigate the association of TDRT vs once-daily radiotherapy (ODRT) with brain metastases after prophylactic cranial irradiation in patients with small cell lung cancer.Design, Setting, and ParticipantsIn this multicenter cohort study, data on 778 consecutive patients with small cell lung cancer who had undergone thoracic radiotherapy (609 received ODRT and 169 received TDRT), chemotherapy, and prophylactic cranial irradiation were retrieved from the databases of 8 hospitals in China between July 1, 2003, and June 30, 2016. A 1:1 propensity score matching approach was used to control for confounding between the ODRT and TDRT groups. Confounding covariates included 8 demographic variables and 8 treatment-related covariates. Data analysis was conducted from November 1, 2017, to May 31, 2018, and reanalyzed for revision.ExposuresThe ODRT group received 50 to 66 Gy given in 25 to 33 fractions. The TDRT group received 45 Gy given in 30 fractions.Main Outcomes and MeasuresThe primary end point was brain metastases. Secondary end points included progression-free survival and overall survival.ResultsOf the 778 patients (median age, 55 years [interquartile range, 48-61 years]), 204 were women and 574 were men. At a median follow-up of 23.6 months (interquartile range, 14.2-38.2 months), 131 patients (16.8%) experienced brain metastases. The rate of brain metastasis at 3 years in the TDRT group was significantly higher than in the ODRT group (26.0% vs 16.9%; hazard ratio, 1.55; 95% CI, 1.06-2.26; P = .03). Of the 338 matched patients (169 in the ODRT group vs 169 in the TDRT group), 60 (17.8%) experienced brain metastases, with a rate at 3 years of 14.9% in the ODRT group vs 26.0% in the TDRT group (hazard ratio, 1.71; 95% CI, 1.02-2.88; P = .04). Progression-free survival was similar in both the whole cohort and the matched cohort. Median overall survival in the ODRT group tended to be significantly longer than in the TDRT group after matching (47.2 vs 32.8 months; hazard ratio, 1.41; 95% CI, 0.99-2.01; P = .06).Conclusions and RelevanceIn this study, patients with small cell lung cancer who received thoracic TDRT appeared to have a higher risk of brain metastases than those who received ODRT, which supports the need for further prospective randomized clinical trials, especially in China and other parts of Asia.

Twice-daily Radiation for Metastatic Malignant Melanoma: A Different Approach Resulting in a Significant Response.

The aim of this study was to discern an abscopal effect by modifying the delivery of radiation for metastatic malignant melanoma. The effect would be directly evident with visible/radiographic regression of the disease and indirectly shown with an overall extension in survival and potential cure. Patients with locally advanced, metastatic palpable, or radiographic visible metastatic malignant melanoma were treated with twice-daily radiation therapy using a dose range of 100-135 centigray (cGy) per fraction. A 100% complete response/continued regression with no recurrence was achieved within the region of delivery for every patient so treated. Of those alive at three years, few demonstrate a progression of the disease. These results were achieved without the use of immunotherapy, created few side effects, and were accomplished at a fraction of the alternative’s cost. Evidence of an immune-mediated response (abscopal effect) was commonly seen. Treatment was administered within acceptable dose ranges, historically used twice daily for other malignancies known to be sensitive to the effects of radiation.

Association of Chemoradiotherapy With Outcomes Among Patients With Stage I to II vs Stage III Small Cell Lung Cancer

There is limited evidence to guide stage I to II small cell lung cancer (SCLC) treatment. To examine the characteristics and outcomes among patients with stage I to II SCLC treated with modern chemoradiotherapy. In this post hoc secondary analysis of the Concurrent Once-Daily vs Twice-Daily Radiotherapy Trial (CONVERT), a multicenter phase 3 trial conducted in patients with limited-stage SCLC from April 7, 2008, to November 29, 2013, patients with TNM stage I to II SCLC were compared with those with stage III disease. Data analysis was performed from November 1, 2017, to February 28, 2018. In CONVERT, patients were randomized to receive twice-daily (45 Gy in 30 fractions) or once-daily (66 Gy in 33 fractions) chemoradiotherapy. Prophylactic cranial irradiation (PCI) was offered, if indicated. The primary trial end point was overall survival (OS). TNM staging information was collected prospectively; this was an unplanned analysis because stratification was not performed according to TNM stage. A total of 509 (277 [54.4%] men; mean [SD] age, 61.5 [8.3] years) of 543 patients (93.7%) with TNM staging information were eligible for this subgroup analysis, and 86 of the 509 (16.9%) had TNM stage I to II disease. The median gross tumor volume was smaller in patients with stage I to II disease (38.4 cm3; range, 2.2-593.0 cm3) compared with patients with stage III disease (93 cm3; range, 0.5-513.4 cm3) (P < .001). No other significant differences were found in baseline and treatment characteristics and chemoradiotherapy adherence between the 2 groups or the number of patients with stage I to II disease (78 [90.7%]) and stage III disease (346 [81.8%]) who received PCI (P = .10). Patients with stage I to II disease achieved longer OS (median, 50 months [95% CI, 38 to not reached months] vs 25 months [95% CI, 21-29 months]; hazard ratio, 0.60 [95% CI, 0.44-0.83]; P = .001) compared with patients with stage III disease. In patients with stage I to II disease, no significant survival difference was found between the trial arms (median, 39 months in the once-daily arm vs 72 months in the twice-daily arm; P = .38). Apart from lower incidence of acute esophagitis in patients with stage I to II disease compared with patients with stage III disease (grade ≥3, 9 [11.3%] vs 82 [21.1%]; P < .001), the incidences of acute and late toxic effects were not significantly different. Patients with stage I to II SCLC in CONVERT achieved long-term survival with acceptable toxic effects after chemoradiotherapy and PCI. This study suggests that patients with stage I to II small cell lung cancer treated with modern chemoradiotherapy have better outcomes compared with patients with stage III disease, providing information that practitioners can potentially give their patients to aid clinical decisions. ClinicalTrials.gov identifier: NCT00433563.

Compliance and Outcome of Elderly Patients Treated in the Concurrent Once-Daily Versus Twice-Daily Radiotherapy (CONVERT) Trial

IntroductionThere is a lack of data on the efficacy and safety of concurrent chemoradiotherapy in elderly, limited-stage, patients with SCLC. MethodsWe compared outcomes of patients 70 years of age or older versus younger patients within the Concurrent Once-daily Versus twice-daily RadioTherapy (CONVERT) trial. Patients were randomized to receive 45 Gy/30 twice-daily fractions/19 days or 66 Gy/33 once-daily fractions/45 days concurrently with platinum-based chemotherapy. Overall survival and progression-free survival were evaluated using Kaplan-Meier methodology and Cox proportional hazards regression. ResultsOf 547 patients randomized between April 2008 and November 2013, 57 did not receive protocol treatment and were excluded. Of the 490 patients included, 67 (14%) were 70 years of age or older (median age: 73 years; range: 70–82). Fewer older patients received the optimal number of radiotherapy fractions (73% versus 85%; p = 0.03); however, chemotherapy compliance was similar in both groups (p = 0.24). Neutropenia grade 3/4 occurred more frequently in the elderly (84% versus 70%; p = 0.02) but rates of neutropenic sepsis (4% versus 7%; p = 0.07) and death (3% versus 1.4%; p = 0.67) were similar in both groups. With a median follow-up of 46 months; median survival in the elderly versus younger groups was 29 (95% confidence interval [CI]: 21–39) versus 30 months (95% CI: 26–35), respectively; (hazard ratio: 1.15, 95% CI: 0.84–1.59; p = 0.38). Median time to progression in the elderly versus younger groups was 18 months (95% CI: 13–31) versus 16 months (95% CI: 14–19), respectively (hazard ratio: 1.04, 95% CI: 0.76–1.41; p = 0.81). ConclusionsConcurrent chemoradiotherapy with modern radiotherapy techniques should be a treatment option for fit, older patients.

P2.12-15 Prognostic and Predictive Covariates in Limited-Stage Small-Cell Lung Cancer: Analysis of the Phase 3 CONVERT Trial

The majority of patients with limited-stage small cell lung cancer (LS-SCLC) progress after concurrent chemo-radiotherapy (cCTRT). Data from the CONVERT trial was analysed to investigate prognostic and predictive covariates in LS-SCLC patients. CONVERT is an international multi-centre phase III trial that randomly assigned fit patients to receive either twice-daily (45Gy in 30 fractions) or once-daily (66Gy in 33 fractions) radiotherapy starting on day 22 of chemotherapy cycle 1 (ClinicalTrials.gov NCT00433563). Chemotherapy consisted of 4 or 6 cycles (centres choice) of cisplatin and etoposide. Prophylactic cranial irradiation was offered, if indicated. The following covariates were investigated for prognostic and predictive significance (benefit from twice-daily radiotherapy and completion of cCTRT): clinical (age, performance score, TNM staging, smoking status, weight loss >10% and lung function), laboratory (alkaline phosphatase, sodium and lactate dehydrogenase) and dosimetric (gross tumour volume (GTV), heart and lung dose). Completion of chemotherapy was defined as delivery of all planned cycles while completion of radiotherapy was defined as delivery of all fractions. Results of the multivariate regression analysis of overall survival (OS) and progression-free survival (PFS) were reported after correcting for multiple comparisons. Of 547 patients recruited to CONVERT, 449 with complete covariate and outcome data were eligible for this analysis. GTV was the strongest prognostic covariate of OS (hazard ratio (HR) 1.37 (95% confidence interval (CI) 1.21-1.56); p<0.001). The addition of weight loss and performance score modestly improved the concordance probability (0.59 to 0.61) of this model. The HR for OS between high and low risk groups using this model was 2.72 (95% CI 1.94-3.81), median OS: 21 months (95% CI 19-26) vs 44 months (95% CI 36-not reached), respectively. For PFS, the HR between high and low risk groups was 2.55 (95% CI 1.86-3.5), median PFS: 13 months (95% CI 12-15) vs 26 months (95% CI 18-48), respectively. None of the tested covariates predicted patient benefit from twice-daily radiotherapy. Increase in patient age (continuous variable) predicted non-completion of planned chemotherapy (p=0.002). Due to the high completion of radiotherapy (86% in twice-daily and 80% in once-daily group), a multivariate analysis to predict radiotherapy completion was not performed. We report a clinical prognostic model in LS-SCLC, providing information that clinicians can relay to their patients to aid clinical decisions. The addition of biological covariates could help refine these prognostic models in the future.

PC02.04 BID Radiation - PRO

The optimal thoracic radiotherapy dose for treating limited stage small cell lung cancer remains to be defined. Given the radiosensitivity of small cell lung cancer cell lines in preclinical studies in the 1980's it was postulated that twice daily radiotherapy would result in improved efficacy. Subsequent clinical experience included the landmark Intergroup 0096 trial, which demonstrated improved overall survival for patients assigned to twice daily radiotherapy (45 Gy) compared with once daily radiotherapy to the same total dose. Despite being one of the few randomized trials showing that changing the radiotherapy regimen impacts overall survival, the twice-daily regimen was slow to be adopted in clinical practice and many NCI cooperative group studies continued to use once-daily radiotherapy. Reluctance to routinely use the twice-daily regimen likely relate to concerns with acute toxicity, logistic issues, and use of a modest radiotherapy dose of only 45 Gy on the standard arm. In addition, a contemporaneous study from NCCTG did not show an advantage to twice-daily radiotherapy, although a planned treatment break was included such that radiotherapy was not accelerated. Alternate strategies to improve the efficacy of thoracic radiotherapy have included the development of high dose once-daily regimens with a 70 Gy regimen utilized in several phase II trials from the Cancer and Leukemia Group B. These trials are somewhat difficult to interpret, as radiotherapy was not initiated until the 3rd cycle of chemotherapy and novel induction chemotherapy regimens were included. The RTOG has also studied a concomitant boost regimen, though overall survival was lower than expected in the phase II experience. Results from the CONVERT trial, comparing 45 Gy twice-daily and 66 Gy once-daily radiotherapy, were recently published. The trial was powered to show superiority of high dose daily radiotherapy and failed to do so, and thus the authors concluded that 45 Gy twice-daily remain the standard of care. The CALGB 30610 trial, which uses 70 Gy in the once-daily arm, is near completion and will provide further data regarding the therapeutic ratio of these regimens. For the time being it should be kept in mind that the long held assumption that increasing radiotherapy dose with conventional fractionation will result in improved outcomes may not be justified – particularly in the setting of concurrent chemotherapy. For example, increasing the radiotherapy dose from 50.4 Gy to 64.8 Gy, with cisplatin and 5-FU, did not improve outcomes for patients with esophageal cancer on the phase 3 Intergroup 0123 trial. Perhaps even more suprising are the results of RTOG 0617, where even in the era of advanced radiotherapy treatment planning raising the radiotherapy dose resulted in worse outcomes. accelerated, thoracic radiotherapy, twice daily

Selective bladder preservation with twice-daily radiation plus 5-flourouracil/cisplatin (FCT) or daily radiation plus gemcitabine (GD) for patients with muscle invasive bladder cancer: Primary results of NRG/RTOG 0712—A randomized phase 2 multicenter trial.

408 Background: To assess GD or FCT as the chemoradiation (CRT) component of a bladder sparing regimen. Methods: Patients with T2-4a bladder cancer were randomized. Patients had a maximal transurethral resection and induction CRT to 40 Gy followed by cystoscopic assessment. Patients with a complete response (CR) received consolidation CRT to 64 Gy. Others were offered cystectomy and no further CRT. Adjuvant gemcitabine/cisplatin chemotherapy was subsequently administered. The primary endpoint was the rate of distant metastasis at 3 years (DM3). Toxicity and other efficacy related endpoints including CR and bladder intact distant metastasis free survival at 3 years (BI-DMFS3) were also assessed. Using the Clopper-Pearson method, the study required 32 patients per arm, with a benchmark DM3 of 25% and a 1-sided significance level of 0.1. If both arms meet this benchmark, toxicity will be used to select a regimen for future study. This study was not designed to compare arms. Results: From 12/2008 to 4/2014, 70 patients were enrolled; 66 were eligible for analysis (33 per arm). Median follow-up was 4.3 years. DM3 was 22% and 16% for FCT and GD, respectively. BI-DMFS3 was 67% and 72%, respectively. CR rates were 88% and 78%, respectively. Of 33 patients in the FCT group, 32 (97%) completed induction, 27 (93%) completed induction and consolidation, and 18 (55%) completed the entire protocol. Of 33 patients in the GD group, these figures were 31 (94%), 23 (92%), and 16 (49%), respectively. Of 33 patients in the FCT group, 21 (64%) had grade 3-4 toxicity during protocol treatment with 18 (55%), 2 (6%) and 2 (6%) experiencing hematologic, GI and GU toxicity, respectively. For 33 patients in the GD group, these figures were 18 (55%) overall and 14 (43%), 3 (9%) and 2 (6%), respectively. Conclusions: Both regimens are promising, given DM3 rates &lt; 25%. As there was less toxicity in the GD arm, it would be reasonable to consider a gemcitabine based option as well as a cisplatin based regimen for future trials. Daily radiation may be as effective as twice-daily radiation, which may broaden appeal. Clinical trial information: NCT00777491.

Selective Bladder Preservation with Twice-Daily Radiation Plus 5-Flourouracil/Cisplatin or Daily Radiation Plus Gemcitabine for Patients with Muscle Invasive Bladder Cancer—Primary Results of NRG/RTOG 0712: A Randomized Phase 2 Multicenter Trial

Selective Bladder Preservation with Twice-Daily Radiation Plus 5-Flourouracil/Cisplatin or Daily Radiation Plus Gemcitabine for Patients with Muscle Invasive Bladder Cancer—Primary Results of NRG/RTOG 0712: A Randomized Phase 2 Multicenter Trial

Population-based Results of Chemoradiotherapy for Limited Stage Small Cell Lung Cancer in The Netherlands

AimsTreatment guidelines for limited stage small cell lung cancer (LS-SCLC) favour early concurrent chemoradiotherapy (CRT). Little is known about contemporary, real-world treatment patterns and outcome. We evaluated population-based practice patterns of CRT and corresponding survival in the Netherlands, focusing on the impact of the 2011 national guidelines recommending use of twice-daily (BID) radiotherapy, and treatment outcomes in elderly patients. Materials and methodsData for 1635 patients with LS-SCLC treated with CRT from 2010 to 2014 were retrieved from the Netherlands Cancer Registry. The type of CRT was designated as either concurrent BID, concurrent once-daily (OD), concurrent atypical or sequential. Overall survival was the primary end point and prognostic factors were evaluated with multivariable Cox regression and represented by hazard ratios and 95% confidence intervals. ResultsThe most common form of CRT used was sequential (41%). The proportion of patients treated BID increased from 13% in 2010–2011 to 36% in 2013–2014 (P < 0.001). The median survival was 21 months and did not improve with time (P = 0.58). Five year survival was 16% for sequential, 31% for BID (hazard ratio = 0.67, confidence interval 0.57–0.79) and 28% for OD (hazard ratio = 0.73, confidence interval 0.63–0.85). In patients aged 70 years and older, concurrent CRT was less often used than in younger patients (45% versus 66%) and 5 year survival after concurrent CRT was less favourable; 18% versus 32%, respectively. ConclusionsOutcome data at the population level for LS-SCLC are equivalent to those reported in clinical trials. The increased use of BID schemes since 2011 did not improve survival.

Comparison of Twice-Daily Radiation Therapy to 54 Gy by Simultaneous Integrated Boosting Technique and Once-Daily Radiation Therapy to 60 Gy for Limited Stage Small Cell Lung Cancer

Comparison of Twice-Daily Radiation Therapy to 54 Gy by Simultaneous Integrated Boosting Technique and Once-Daily Radiation Therapy to 60 Gy for Limited Stage Small Cell Lung Cancer

Twice-Daily Radiation Therapy for Recurrent or Resistant Breast Cancer

Hyperfractionated radiotherapy offers radiobiological advantages including increased biologically effective dose and more between-treatment intervals for reoxygenation and reassortment. We report on outcomes from an initial cohort of patients with resistant or recurrent breast cancer treated with a hyperfractionated radiotherapy regimen delivered twice daily. Fourteen patients with breast cancer either resistant to neoadjuvant chemotherapy or recurrent after previous treatment were treated between January 2009 and December 2014. All patients received 65 Gy in 50 fractions, delivered twice daily, to the breast, chest wall, gross disease (including involved lymph nodes), and first three internal mammary chain lymph nodes, if warranted. Regional nodal irradiation to the supraclavicular/axillary lymph nodes regions was delivered to a dose of 49.4 Gy in 38 fractions, twice daily, concurrently with the first 38 fractions of the 50 fraction regimen. Recurrence and survival outcomes were calculated from the date of start of radiotherapy. Toxicity was reported based on the CTCAE version 4 criteria. Survival without local recurrence (SWLF) was 83% at 1 year and 69% at 2 years. Survival without distant failure (SWDF) was 29% at 1 year and 7% at 2 years. Median overall survival (OS) was 15 months with OS rates of 64% at 1 year and 36% at 2 years. Twelve of fourteen patients (86%) suffered acute toxicity, all of which were dermatitis. Of these reactions, Four were classified as grade 1 dermatitis (29% of all patients treated), two were grade 2 (14%), five grade 3 (36%), and one grade 4 (7%). Three patients (21%) had subacute or late toxicities consisting of one case each of grade 1 pneumonitis, grade 2 pneumonitis, and grade 3 radiation recall (on Eribulin). Hyperfractionated radiotherapy given as 65 Gy in 50 fractions, twice daily, is a feasible and effective treatment regimen for resistant or recurrent breast cancer with acceptable toxicity profile. Larger populations and prospective trials will better define the effectiveness and side effect profiles compared with other treatment options.

Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial

SummaryBackgroundConcurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer.MethodsThe CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0–2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin–etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up.FindingsBetween April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35–58), median overall survival was 30 months (95% CI 24–34) in the twice-daily group versus 25 months (21–31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95–1·45]; p=0·14). 2-year overall survival was 56% (95% CI 50–62) in the twice-daily group and 51% (45–57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI −3·2% to 13·7%]). The most common grade 3–4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3–4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3–4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group).InterpretationSurvival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting.FundingCancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups).

Once- (QD) Versus Twice-Daily (BID) Radiation Therapy (RT) Plus Concurrent Chemotherapy for Limited-Stage (LS) Small-Cell Lung Cancer (SCLC): A Comparative Outcomes Analysis

Once- (QD) Versus Twice-Daily (BID) Radiation Therapy (RT) Plus Concurrent Chemotherapy for Limited-Stage (LS) Small-Cell Lung Cancer (SCLC): A Comparative Outcomes Analysis