Twice-daily Thoracic Radiotherapy Research Articles

Evaluation of Radiation Therapy Treatment Plans in a Randomized Phase 2 Trial Comparing 2 Schedules of Twice-Daily Thoracic Radiation Therapy in Limited Stage Small Cell Lung Cancer

PurposeThere is limited clinical data for recommendations on how to deliver thoracic radiotherapy (TRT) concurrently with chemotherapy in limited stage (LS) small-cell lung cancer (SCLC). We reviewed radiotherapy treatment plans in a randomized phase II trial comparing high-dose with standard-dose twice-daily TRT to assess treatment planning techniques, dose-volume data for target volumes and organs at risk (OARs), evaluate compliance with the protocol, associations with radiation-induced toxicity and whether an imbalance in treatment planning parameters might be a reason for the large survival benefit of the higher dose (median overall survival 43.6 vs. 22.6 months). Methods and Materials170 patients were to receive four courses of platinum/etoposide and randomized to receive twice-daily TRT of 60 Gy/40 fractions (fx) or 45 Gy/30 fx. TRT treatment plans for those who received one or more fx of TRT (n=166) were analyzed. ResultsThe most common treatment planning technique was 3DCRT (67%). The 75th percentile of the reported dose-volume parameters for the OARs were within the protocol-recommended limits for both groups. Mean doses to the esophagus of 25.5 Gy (IQR: 20.2-31.3) [60 Gy/40 fx] and 24.3 Gy (IQR: 20.3-27.5) [45 Gy/30 fx] were associated with 21% and 18% ≥ grade 3 acute esophagitis, respectively. In the 60 Gy/40 fx group, a mean dose to the lungs of 16.5 Gy (IQR: 15.8-16.9), V20Gy of 29.5% (IQR: 28.8-30.4), and V5Gy of 65.6% (IQR: 61.5-68.7) led to ≥ grade 3 pneumonitis in 4% of the patients. There was no ≥ grade 3 pneumonitis in the 45 Gy group. Treatment planning techniques, the percentage change in volumes between original and re-delineated OARs, PTV volumes, relative doses, and laterality were well balanced between the randomly assigned groups. ConclusionConsidering that the incidences of severe radiation-induced toxicities were within the range of other recent trials, the reported doses to the OARs appear to be safe. Treatment planning parameters were well balanced between the randomly assigned groups, supporting that the survival benefit of the twice-daily 60 Gy/ 40 fx TRT schedule was due to the higher dose.

Associations between patient-reported nutritional status, survival, and toxicity among patients with limited stage small-cell lung cancer (LS SCLC) in a randomized trial of high-dose, twice-daily (BID) thoracic radiotherapy (TRT).

8519 Background: Up to 1/3 of LS SCLC patients are cured by chemoradiotherapy (CRT), but severe toxicity is frequent and population-based studies show that many patients do not receive standard CRT. More knowledge on how to predict who experiences side-effects or achieves long term disease control is needed. Poor nutritional status is strongly associated with inferior survival in many types of cancer including non-small cell lung cancer, but little is known about whether this is the case in LS SCLC. We investigated whether nutritional status reported by patients on the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) was associated with toxicity and survival among participants in a trial comparing high dose with standard dose twice-daily TRT in LS-SCLC (NCT02041845, n=170). Methods: Patients received four courses of platinum/etoposide chemotherapy and were randomized to TRT of 60 Gy/40 fractions or 45 Gy/30 fractions. Patients completed PG-SGA SF before treatment commenced and were categorized as having low (PG-SGA SF score 0–3.9), intermediate (4.0–8.9) and high (≥9) risk of malnutrition. Toxicity was graded according to CTCAE 4.0. Median follow-up for survival was 49 months. Results: 113/170 (66.5%) patients completed PG-SGA SF at baseline. Median age was 65 years, 46.0% were men, 88.5% had PS 0-1, 87.6% stage III disease and 22.1% weight loss of >5% the three months before inclusion. Median PG-SGA SF score was 3.0, 52.2% of patients had low, 29.2% intermediate, and 18.6% high risk of malnutrition. Numerically, there were more patients with stage III, PS 1-2 and pleural fluid among those at high risk. There was no difference in mean no. of chemotherapy courses (low: 3.85, intermediate: 3.88, high: 3.90, p=0.95) or TRT completion (low: 96.6%, intermediate: 97.0%, high: 95.2%, p=1.0). There were no statistically significant differences in proportions who experienced grade 3-4 toxicity (low: 88%, intermediate: 91%, high: 86%, p=0.86), median PFS (low: 15.1 months, intermediate: 11.8 months, high: NR, p=0.23), 2-year survival (low: 68%, intermediate: 52%, high: 67%, p=0.28) or median OS (low: 38.1 months, intermediate: 25.8 months, high: NR, p=0.15). Patients with weight loss >5% did not experience more grade 3-4 toxicity (92% vs. 87%, p=0.73), had similar median PFS (24.0 vs. 15.9 months, p=0.69), 2-year survival (64.0% vs. 66.2%, p=0.84) and median OS (30.6 vs. 35.1 months, p=0.93) as those without. Conclusions: Our study suggest that LS SCLC patients tolerate and should receive concurrent chemotherapy and twice-daily TRT regardless of nutritional status and weight loss.

Final survival data from a randomized phase II trial comparing high-dose with standard-dose twice-daily (BID) thoracic radiotherapy (TRT) in limited stage small-cell lung cancer (LS SCLC).

8512 Background: Concurrent chemotherapy and TRT is standard treatment of LS SCLC. BID TRT of 45 Gy/30 fractions is the most recommended schedule. Trials report 5-year survival rates of up to 36%, illustrating that some are cured but also need for better treatment. Many treatment failures are due to relapses within TRT fields, and it has been proposed that higher TRT doses might improve local control and consequently survival. However, high-dose once-daily (QD) TRT of 66-70 Gy do not prolong survival. We investigated whether high-dose BID TRT of 60 Gy/40 fractions was tolerable and improved survival compared with the established 45 Gy schedule (NCT02041845). Primary analyses presented at ASCO 2020 showed that the trial was highly positive for the primary endpoint, 2-year survival (60 Gy: 74.2%, 45 Gy: 48.1%, OR 3.09 [95% CI 1.62-5.89]; p=0.0005). We now present updated and final survival data. Methods: Patients ≥18 years with PS 0-2, confirmed SCLC, LS according to the IASLC definition after PET CT staging received 4 courses of platinum/etoposide and were randomized to receive 60 Gy or 45 Gy to PET CT positive lesions. TRT started concurrently with the 2nd chemotherapy course. Responders were offered QD prophylactic cranial irradiation of 25-30 Gy. All patients were followed for 5 years or until death. Results: 170 eligible patients were randomized at 22 Scandinavian hospitals from 2014-2018 (60 Gy: n=89, 45 Gy: n=81). Median age was 65, 31.2% were ≥70 years, 57.1% women, 89.4% had PS 0-1, 83.5% stage III disease, 7.6% pleural effusion and 20.0% ≥5% weight loss last three months before enrollment. Baseline patient and disease characteristics and TRT planning target volumes were well balanced between treatment arms. Completion rates of chemotherapy (60 Gy: 92.1%, 45 Gy: 87.7%) and TRT (60 Gy: 96.6%, 45 Gy: 91.4%) were similar. Patients on the high-dose arm did not experience more grade 3-4 esophagitis (60 Gy: 21.2%, 45 Gy: 18.2%; p=0.83) or pneumonitis (60 Gy: 3.4%, 45 Gy: 0.0%; p=0.39), other grade 3-4 toxicity or treatment related deaths. The 60 Gy group had numerically longer PFS (median PFS 60 Gy: 18.6 months [95% CI 11.6-25.6], 45 Gy: 10.9 months [95% CI 8.7-13.2], HR 0.76 [95% CI 0.53-1.08]; p=0.13). Results for the primary endpoint remain unchanged. The higher TRT dose significantly prolonged survival (median OS 60 Gy: 43.5 months [95% CI 30.4-56.6], 45 Gy: 22.6 months [95% CI 17.2-28.0], HR 0.69 [0.48-0.99]; p=0.043) and provided higher 4.5 year survival rate (60 Gy: 41.6% [95% CI 30.4-56.6], 45 Gy: 28.4% [95% CI 18.9-39.5], OR: 1.79 [95% CI 0.95-3.41]). 5-year survival rates will be presented at the meeting. Conclusions: Compared with LS SCLC patients who received standard TRT, patients receiving high-dose BID TRT of 60 Gy did not experience more toxicity, had a substantial prolongation of survival and a much higher long term survival rate. Clinical trial information: NCT02041845 .

Efficacy and safety of high dose twice-daily thoracic radiotherapy versus standard dose for limited stage small-cell lung cancer: A multicentre, open-label randomised, phase 3 trial.

8587 Background: We aimed to assess the efficacy and safety of high-dose, hyperfractionated thoracic radiotherapy of 54 Gy in 30 fractions compared with standard dose(45 Gy in 30 fractions) as a first-line treatment for LS-SCLC. Methods: The study was an open-label, randomised, phase 3 trial, done at 16 public hospitals in China.Key inclusion criteria were patients aged 18-70 years, with previously histologically or cytologically confirmed LS-SCLC, previously untreated or received 1-2 courses of intravenous cisplatin (75 mg/m²of body-surface area, on day 1 or divided into two days of each cycle) or carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle)and intravenous etoposide (100 mg/m²of body-surface area, on days 1-3 of each cycle), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.Eligible patients were randomly assigned (1:1) to receive receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions or the simultaneous integrated boost VMAT (SIB-VMAT) of 54 Gy in 30 fractions to the primary lung tumour and lymph node metastases starting 0-42 days after the first chemotherapy course. Both groups of patients received thoracic radiotherapy twice per day and 10 fractions per week.Prophylactic cranial radiation (PCI, 25Gy in 10 fractions) was implemented to patients with responsive disease. The primary endpoint was overall survival. Safety was analysed in the as-treated population. This study is complete and registered with ClinicalTrials.gov,NCT03214003. Results: Between June 30, 2017, and April 6, 2021, 224 eligible patients were enrolled and randomly assigned to 54 Gy (n = 108) or 45 Gy (n = 116).Median follow-up for the primary analysis was 45 months (IQR 41-48). Median overall survival was significantly improved in the 54 Gy group (62.4 months ) compared with the 45 Gy group (43.1 months; p = 0.001). Median progression-free survival was significantly improved in the 54 Gy group (30.5 months) compared with the 45 Gy group (16.7 months; p = 0.044). The most common grade 3-4 adverse events were neutropenia (30 [28%] of 108 patients in the 54 Gy group vs 27 [23%] of 116 patients in the 45 Gy group), neutropenic infections (6 [6%] vs 2 [2%]), thrombocytopenia (13 [12%] vs 12 [10%]), anaemia (6 [6%] vs 4 [3%]), and oesophagitis (1 [1%] vs 3 [3%]). There were one treatment-related deaths in 54 Gy group (myocardial infarction). Conclusions: Compared with standard thoracic radiotherapy dose of 45 Gy, the high dose dose of 54 Gy improved overall survival and progression-free survival without increasing toxicities in patients with LS-SCLC, supporting twice-daily hyperfractionated thoracic radiotherapy of 54 Gy with concurrent chemotherapy is an alternative treatment option for LS-SCLC. Clinical trial information: NCT03214003 .

172 - A feasibility study of high-dose twice-daily thoracic radiotherapy in limited stage small-cell lung cancer (LS-SCLC) at Barking, Havering and Redbridge University Hospitals NHS Trust (BHRUT)

172 - A feasibility study of high-dose twice-daily thoracic radiotherapy in limited stage small-cell lung cancer (LS-SCLC) at Barking, Havering and Redbridge University Hospitals NHS Trust (BHRUT)

Treatment Outcomes of Older Participants in a Randomized Trial Comparing Two Schedules of Twice-Daily Thoracic Radiotherapy in Limited-Stage SCLC

IntroductionHalf of the patients with limited-stage SCLC (LS SCLC) are above or equal to 70 years old, but they account for less than 20% of participants in most trials. Comorbidities and reduced organ and physical function might lead to more treatment toxicity, and population-based studies indicate that fewer older than younger patients with LS SCLC receive standard chemoradiotherapy, although there is limited evidence for such a policy. MethodsWe compared baseline characteristics, comorbidity, survival, treatment completion, toxicity, health-related quality of life, and treatment outcomes between patients above or equal to 70 years old and those younger than 70 years old in an open-label, randomized phase II trial comparing twice-daily thoracic radiotherapy of 45 Gy in 30 fractions with 60 Gy in 40 fractions in LS SCLC. All patients received concurrent i.v. cisplatin (75mg/m2) or carboplatin (AUC 5-6 mg/ml x min) day 1 and i.v. etoposide (100 mg/m2) day 1-3 chemotherapy. This trial is registered at ClinicalTrials.gov (NCT02041845). ResultsA total of 170 patients who were above or equal to 18 years old and had performance status of 0 to 2 were randomized. Of these, 53 patients (60 Gy: 25, 45 Gy: 28) were above or equal to 70 years old and 117 (60 Gy: 64, 45 Gy: 53) were younger. There were no differences in baseline characteristics, treatment completion rates, toxicity, or response rates across the age groups. Health-related quality of life mean scores were similar during year one, but older patients reported more decline on functional scales than younger patients during year two. Overall survival was shorter for older patients, whereas there was no difference in progression-free survival or time to progression. ConclusionsPatients above or equal to 70 years old tolerated concurrent twice-daily chemoradiotherapy and achieved similar disease control as younger patients, indicating older patients should receive the same treatment as younger patients.

Twice-Daily Thoracic Radiotherapy for Patients with Locally Advanced or Oligometastatic Non-Small Cell Lung Cancer: A Single-Center Observational Study

<h3>Purpose/Objective(s)</h3> Radiotherapy is standard treatment for locally advanced or oligometastatic non-small cell lung cancer (NSCLC). Once-daily thoracic radiotherapy of 60ཞ66 Gy in 30ཞ33 fractions is considered to be the most effective schedule in the past. The aim of this study was to investigate whether twice-daily thoracic radiotherapy improves survival and reduces toxicity. <h3>Materials/Methods</h3> Patients aged 18 years and older with treatment-naive confirmed locally advanced or oligometastatic NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 were eligible. Participants received thoracic radiotherapy of 40ཞ80 Gy (2ཞ4Gy/fraction, bid) and 30ཞ60 Gy (1.5ཞ2.0Gy/fraction, bid) to the primary lung tumor and positive lymph node metastases respectively. Patients received 2-4 cycles of chemotherapy or oral targeted drugs if the driver genes are positive. <h3>Results</h3> In total, 124 patients were included in this study between February 2016 to March 2020. The median patient age was 61 years old and 113 (91.1%) patients were male. The patient group included 72 patients with stage IIBཞIIIC, and 52 patients with stage IV disease. Histological diagnosis was squamous cell carcinoma in 68 patients, adenocarcinoma in 56 patients. Median follow-up was 24.8 months (range 1.5-59.7months). The 1, 2, 3-year OS were 83.1% and 70.6%, 60.6%, respectively. The incidence of ≥Grade 2 radiation pneumonitis and esophagitis was 25.6% and 15.2%, respectively. The most common grade 3-4 adverse events were leukopenia (17 [13.7%]), thrombocytopenia (5 [4.0%]), anemia (15[12.0%]) and lymphopenia (30[24.2%]). None of the patients experienced fatal bronchopulmonary hemorrhage or tracheal fistula. <h3>Conclusion</h3> Twice-daily thoracic radiotherapy is feasible and well tolerated for locally advanced or oligometastatic NSCLC. It needs to be further confirmed by large randomized controlled clinical studies.

Comparison of Simultaneous Integrated Boost IMRT for Dose Escalation (54 Gy) and Conventional IMRT (45 Gy) Twice Daily Combined with Concurrent Chemotherapy for Limited-Stage Small-Cell Lung Cancer: Analysis of Two Prospective Trials

<h3>Purpose/Objective(s)</h3> Twice-daily thoracic radiotherapy (TRT) with concurrent chemotherapy is standard for limited-stage small-cell lung cancer (LS-SCLC). However, the importance of twice-daily simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) has not been clearly defined in LS-SCLC. Therefore, we conducted a prospective single arm, multicenter phase II study of SIB-IMRT for dose escalation (54 Gy) to the gross tumor volume for LS-SCLC. Here, we compared SIB-IMRT for dose escalation (54 Gy) to the gross tumor volume versus conventional intensity-modulated radiotherapy (IMRT) of standard-dose (45 Gy) twice-daily combined with concurrent chemotherapy in patients with LS-SCLC. <h3>Materials/Methods</h3> Sixty patients with LS-SCLC were entered from 2015 to 2021 in the phase II study of SIB-IMRT, and all 60 patients were treated with SIB-IMRT to the postchemotherapy tumor volume, as the SIB-IMRT group. In the SIB-IMRT group, the prescribed dose was 54Gy at 1.8 Gy twice daily to PGTV, and 45 Gy at 1.5 Gy twice daily to PCTV. We previously conducted a prospective phase III study on thoracic radiotherapy (TRT) target volumes for LS-SCLC (Cancer, 2020, 126(4), 840-849). In that study, from 2012-2017, 85 patients received thoracic IMRT to the postchemotherapy tumor volume, as the IMRT group. In the IMRT group, the prescribed dose was 45 Gy at 1.5 Gy per twice-daily fraction to both the planning gross tumor volume (PGTV) and the planning clinical tumor volume (PCTV). All of the 145 patients in both groups received concurrent chemoradiotherapy (CCRT) after completion of 2 cycles of induction cisplatin-etoposide chemotherapy, and received chemotherapy for 4 to 6 cycles in total. We compared progression free survival (PFS) and overall survival (OS) between the treatment groups by using the Kaplan-Meier method. <h3>Results</h3> Overall, with a median follow-up of 34.6 months, the median PFS and OS were 11.9 and 23.7 months, respectively. The patients in the SIB-IMRT group showed marginal longer PFS than those in the IMRT group (13.3 months versus 11.5 months; <i>p</i> = 0.08). The median OS of the SIB-IMRT and IMRT groups were 35.0 and 20.3 months, with the 2-year OS rate of 66.1% and 38.8%, respectively (<i>p</i> =0.007). For radiotherapy toxicity, grade 2 acute esophagitis was more common in the SIB-IMRT group, but grade≥3 esophagitis and grade≥2 pneumonitis was no difference in both two groups. <h3>Conclusion</h3> For LS-SCLC patients, SIB-IMRT for dose escalation (54 Gy at 1.8Gy twice daily) to PGTV benefited survival greatly. Our results suggest that SIR-IMRT is safe and effective for patients with LS-SCLC and should be further evaluated in a large prospective clinical trial.

Twice-daily thoracic radiotherapy for patients with locally advanced or oligometastatic non-small cell lung cancer: A single-center observational study.

e21070 Background: Radiotherapy is standard treatment for locally advanced or oligometastatic non-small cell lung cancer (NSCLC). Once-daily thoracic radiotherapy of 60～66 Gy in 30～33 fractions is considered to be the most effective schedule in the past. The aim of this study was to investigate whether twice-daily thoracic radiotherapy improves survival and reduces toxicity. Methods: Patients aged 18 years and older with treatment-naive confirmed locally advanced or oligometastatic NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1 were eligible. Participants received thoracic radiotherapy of 40～80 Gy(2～4Gy/fraction, bid) and 30～60 Gy (1.5～2.0Gy/fraction, bid) to the primary lung tumour and positive lymph node metastases respectively. Patients received 2-4 cycles of chemotherapy or oral targeted drugs if the driver genes is positive. Results: In total, 124 patients were included in this study between February 2016 to March 2020. The median patient age was 61 years old and 113(91.1%) patients were male. The patient group included 72 patients with stage IIB～IIIC, and 52 patients with stage IV disease. Histological diagnosis was squamous cell carcinoma in 68 patients, adenocarcinoma in 56 patients. Median follow-up was 24.8 months (range 1.5-59.7months). The 1, 2, 3-year OS were 83.1% and 70.6%, 60.6%, respectively. The incidence of ≥Grade 2 radiation pneumonitis and esophagitis were was 25.6% and 15.2%, respectively. The most common grade 3-4 adverse events were leukopenia (17 [13.7%]), thrombocytopenia (5 [4.0%]), anaemia (15[12.0%]) and lymphopenia (30[24.2%]). None of the patients experienced fatal bronchopulmonary hemorrhage or tracheal fistula. Conclusions: Twice-daily thoracic radiotherapy is feasible and well tolerated for locally advanced or oligometastatic NSCLC. It needs to be further confirmed by large randomized controlled clinical studies. Clinical trial information: ChiCTR2100055096.

Twice-daily thoracic radiotherapy by intensity-modulated radiation therapy (IMRT) compared with simultaneous integrated boost IMRT (SIB-IMRT) with concurrent chemotherapy for patients with limited-stage small cell lung cancer. A propensity-score matched analysis

BackgroundConcurrent chemoradiotherapy is the standard treatment for limited-stage small-cell lung cancer patients (SCLC). However, the optimal dose and schedule of thoracic radiotherapy (TRT) has not been established. MethodsWe retrospectively reviewed the clinical records of limited-stage SCLC patients treated with twice-daily TRT and concurrent chemotherapy between December 2009 and December 2017. Patients were divided into two groups according to radiotherapy dose: the intensity modulated radiotherapy (IMRT) group [45 Gy to the planning target volume (PTV)] and the simultaneous integrated boost IMRT (SIB-IMRT) group (57 Gy to the gross tumour volume, 51 Gy to the clinical target volume, and 45 Gy to PTV). A 1:1 propensity score matching (PSM) was applied to balance the observable potential confounding factors between the two groups. Primary endpoint was progression-free survival (PFS). ResultsA total of 112 patients were enrolled in our study, including 71 patients in the IMRT group and 41 patients in the SIB-IMRT group. After PSM, the clinical features were well balanced between the groups, including 37 patients each. The median PFS was 17.54 months in the IMRT group versus 34.92 months in the SIB-IMRT group (P = 0.047). The median overall survival (OS) was 38.52 months in the IMRT group versus 63.41 months in the SIB-IMRT group (P = 0.261). ConclusionsCompared with IMRT, a high dose of twice-daily TRT by the SIB-IMRT approach with concurrent chemotherapy for limited-stage SCLC patients may improve PFS without increasing toxicities. However, PFS improvement failed to result in significant advantages in OS.

Radiation and Systemic Therapy for Limited-Stage Small-Cell Lung Cancer.

Progress in the overall treatment of small-cell lung cancer (SCLC) has moved at a slower pace than non-small-cell lung cancer. In fact, the standard treatment regimen for limited stage SCLC has not appreciably shifted in more than 20 years, consisting of four to six cycles of cisplatin and etoposide chemotherapy concurrent with thoracic radiotherapy (TRT) followed by prophylactic cranial irradiation (PCI) for responsive disease. Nevertheless, long-term outcomes have improved with median survival approaching 25-30 months, and approximately one third of patients now survive 5 years. This is likely attributable in part to improvements in staging, including use of brain magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography imaging, advances in radiation treatment planning, and supportive care. The CONVERT and CALGB 30610 phase III trials failed to demonstrate a survival advantage for high-dose, once-daily TRT compared with standard 45 Gy twice-daily TRT, although high-dose, once-daily TRT remains common in practice. A phase III comparison of high-dose 60 Gy twice-daily TRT versus 45 Gy twice-daily TRT aims to confirm the provocative outcomes reported with 60 Gy twice daily in the phase II setting. Efforts over time have shifted from intensifying PCI, to attempting to reduce treatment-related neurotoxicity, to more recently questioning whether careful magnetic resonance imaging surveillance may obviate the routine need for PCI. The addition of immunotherapy has resulted in mixed success in extensive-stage SCLC with modest benefit observed with programmed death-ligand 1 inhibitors, and several ongoing trials assess programmed death-ligand 1 inhibition concurrent or adjuvant to chemoradiotherapy in limited-stage SCLC. Major advances in future treatment will likely depend on a better understanding and exploiting of molecular characteristics of SCLC with increasing personalization of therapy.

Twice-Daily Thoracic Radiotherapy by Intensity-Modulated Radiation Therapy (IMRT) or Simultaneous Integrated Boost (SIB) IMRT With Concurrent Chemotherapy for Limited-Stage Small Cell Lung Cancer Patients? A Propensity-Score Matched Analysis

<h3>Purpose/Objective(s)</h3> Concurrent chemoradiotherapy is the standard treatment for limited-stage small-cell lung cancer patients (SCLC), but the optimal dose and schedule of radiotherapy have not been established. <h3>Materials/Methods</h3> We retrospectively reviewed the clinical records of limited-stage SCLC patients treated with twice-daily thoracic radiotherapy by intensity modulated radiotherapy (IMRT) or Simultaneous integrated boost IMRT (SIB-IMRT) with concurrent chemotherapy between December 2009 to December 2017. The patients were divided into two groups according to the radiotherapy dose. The patients of SIB-IMRT group received 57Gy at 1.9Gy twice-daily to the gross tumor volume (GTV), 51Gy at 1.7Gy twice-daily to the clinical target volume (CTV) and 45Gy at 1.5Gy twice-daily to the planning target volume (PTV), and the patients of IMRT group received 45Gy at 1.5Gy twice-daily to PTV. A 1:1 propensity score matching (PSM) was applied to balance observable potential confounding factors between two groups. Primary endpoint was progression-free survival (PFS). Overall survival (OS), objective tumor response (ORR) and treatment-related toxicities were also evaluated. Statistical analyses were conducted using SPSS version 22.0 and statistical significance was defined as <b>P</b> < 0.05. <h3>Results</h3> A total of 112 patients were enrolled in our study, including 71 patients in IMRT group and 41 patients in SIB-IMRT group. After PSM, the clinical features were well balanced between two groups included 37 patients each. ORR in IMRT group and SIB-IMRT group were 94.6% (35/37) and 97.3% (36/37), respectively. Median PFS was 17.54 months in IMRT group <b>vs</b> 34.92 months in SIB-IMRT group (<b>P</b> = 0.047). Median OS was 38.52 months in IMRT group <b>vs</b> 63.41 months in SIB-IMRT group (<b>P</b> = 0.261). The incidence of grade 3-4 treatment-related toxicities was 43.24% (32/74), and there was no significant difference between two groups (<b>P</b> = 0.639). <h3>Conclusion</h3> Compared with IMRT, the high dose of twice-daily thoracic radiotherapy by SIB-IMRT approach with concurrent chemotherapy for the patients with limited-stage SCLC were well-tolerated and may improve PFS, but PFS improvement didn't result in significant advantage in OS.

ES11.02 Advances in Thoracic Radiation in SCLC

ES11.02 Advances in Thoracic Radiation in SCLC

A Comparison of Hypofractionated and Twice-Daily Thoracic Irradiation in Limited-Stage Small-Cell Lung Cancer: An Overlap-Weighted Analysis.

Simple SummaryThe optimal thoracic radiotherapy schedule for limited-stage small cell lung cancer (LS-SCLC) patients remains controversial. We conducted a propensity score adjusted analysis of LS-SCLC patients treated at our institutions with 40Gy/15 fractions versus 45Gy/30 twice daily. After overlap weighting for clinical and treatment variables and attaining good balance, we did not find a significant difference in overall survival, locoregional recurrence risk, thoracic response, or ≥grade 3 toxicity. Moderate hypofractionation, with its similar outcomes and logistical advantages, may present a reasonable alternative to twice daily radiotherapy.Despite evidence for the superiority of twice-daily (BID) radiotherapy schedules, their utilization in practice remains logistically challenging. Hypofractionation (HFRT) is a commonly implemented alternative. We aim to compare the outcomes and toxicities in limited-stage small-cell lung cancer (LS-SCLC) patients treated with hypofractionated versus BID schedules. A bi-institutional retrospective cohort review was conducted of LS-SCLC patients treated with BID (45 Gy/30 fractions) or HFRT (40 Gy/15 fractions) schedules from 2007 to 2019. Overlap weighting using propensity scores was performed to balance observed covariates between the two radiotherapy schedule groups. Effect estimates of radiotherapy schedule on overall survival (OS), locoregional recurrence (LRR) risk, thoracic response, any ≥grade 3 (including lung, and esophageal) toxicity were determined using multivariable regression modelling. A total of 173 patients were included in the overlap-weighted analysis, with 110 patients having received BID treatment, and 63 treated by HFRT. The median follow-up was 20.4 months. Multivariable regression modelling did not reveal any significant differences in OS (hazard ratio [HR] 1.67, p = 0.38), LRR risk (HR 1.48, p = 0.38), thoracic response (odds ratio [OR] 0.23, p = 0.21), any ≥grade 3+ toxicity (OR 1.67, p = 0.33), ≥grade 3 pneumonitis (OR 1.14, p = 0.84), or ≥grade 3 esophagitis (OR 1.41, p = 0.62). HFRT, in comparison to BID radiotherapy schedules, does not appear to result in significantly different survival, locoregional control, or toxicity outcomes.

Randomized phase II trial comparing the efficacy of standard-dose with high-dose twice-daily thoracic radiotherapy (TRT) in limited disease small-cell lung cancer (LD SCLC).

9007 Background: Concurrent chemoradiotherapy is the standard treatment of LD SCLC. Some patients are cured, but most relapse and better treatment is needed. 45 Gy in 30 fractions BID is the most recommended TRT-schedule. Studies suggest that a higher TRT-dose might prolong survival, but hitherto, this has not been confirmed in randomized trials. We aimed to investigate whether high-dose BID TRT of 60 Gy in 40 fractions was feasible, tolerated, and improved survival. Methods: Patients &gt; 18 years, performance status (PS) 0-2 and confirmed LD SCLC were to receive 4 courses of platinum/etoposide and were randomized to BID TRT of 60 or 45 Gy. Responders were offered prophylactic cranial irradiation of 25-30 Gy. Primary endpoint was 2-year survival; secondary endpoints were toxicity, progression free survival (PFS), and overall survival (OS). To demonstrate a 25% improvement of 2-year survival from 53% to 66% with a one-sided α = .10 and β = .80, 75 patients were required on each arm. Results: Between 2014-2018, 176 patients were enrolled at 22 Scandinavian hospitals. 160 completed TRT per protocol and were eligible for the present analyses (60 Gy: n = 84, 45 Gy: n = 76). Median age was 65, 58% women, 90% PS 0-1. There were no significant differences in grade 3–4 esophagitis (60 Gy: 19%, 45 Gy: 18%, p = .92) or grade 3–4 pneumonitis (60 Gy: 4%, 45 Gy: 0%, p = .10). There was a trend towards more neutropenic infections on the 45 Gy arm (60 Gy: 21%, 45 Gy: 36%, p = .05). There were no significant differences in other grade 3-4 toxicity. Three patients died during the study treatment period (60 Gy: one neutropenic infection and one aortic dissection; 45 Gy: one thrombocytopenic bleeding). There were no statistically significant differences in response rates (60 Gy: 88% [95% CI 81-95], 45 Gy: 85% [95% CI 76-93], p = .52) or median PFS (60 Gy: 20 months [95% CI 11-29], 45 Gy: 14 months [95% CI 10-19], p = .31). Significantly more patients on the 60 Gy arm were alive after 2 years (60 Gy: 73% [95% CI 63-83], 45 Gy: 46% [95% CI 36-60], p = .001), and they had a significantly longer median overall survival (60 Gy: 42 months [95% CI 32-51], 45 Gy: 23 months [95% CI 17-28], HR .63 [95% CI .41-.96], p = .031). Conclusions: LD SCLC patients who received BID TRT of 60 Gy had a statistically significant and numerically substantial benefit in terms of 2-year survival (primary endpoint) and median overall survival compared with those who received BID TRT of 45 Gy. The higher TRT dose did not cause more toxicity than the standard dose. Clinical trial information: NCT02041845.

Twice-daily Thoracic Radiotherapy for Limited-stage Small-cell Lung Cancer Does Not Increase the Incidence of Acute Severe Esophagitis

PurposeAcute esophagitis is common after thoracic radiation therapy (TRT) given with chemotherapy for limited-stage small-cell lung cancer (LS SCLC). Although twice-daily TRT to 45 Gy in 30 fractions is considered standard, some clinicians are reluctant to use this schedule because of its perceived impracticality and risk of severe esophagitis. We reviewed a single-institution experience with severe (grade ≥ 3) esophagitis after TRT with chemotherapy for LS SCLC. Patients and MethodsA total of 504 patients were identified as having received TRT (≥45 Gy) with platinum-containing chemotherapy for LS SCLC at MD Anderson Cancer Center in 1987 through 2012. Patients with complete or good partial response were offered prophylactic cranial irradiation. Esophagitis was scored retrospectively with the Common Terminology Criteria for Adverse Events, V3.0. Clinical variables were analyzed for possible association with acute grade ≥ 3 esophagitis. ResultsAt a median follow-up time of 23.9 months (range, 1.2-240.8 months), 103 (20%) patients had experienced grade ≥ 3 esophagitis. In univariate analysis, TRT dose ≥ 60 Gy was the only factor associated with severe esophagitis (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.02-3.30; P = .043); use of twice-daily TRT was not (OR, 0.96; 95% CI, 0.61-1.52; P = .867). The significance of TRT to ≥ 60 Gy was maintained in multivariate Cox regression analysis adjusted for tumor size (OR, 1.91; 95% CI, 1.05-3.46; P = .034). ConclusionsTRT to ≥ 60 Gy predicted acute severe esophagitis, but twice-daily fractionation did not. Standard-dose 45-Gy twice-daily TRT should not be avoided for fear of severe esophagitis.

MTE 04.01 Role of Radiotherapy in Multimodality Treatment for SCLC

Major advances in SCLC include improvements in RT techniques, the use of prophylactic cranial irradiation (PCI) for all stages of SCLC and the improved combination of chemotherapy and RT (Califano). The role of thoracic radiotherapy is well established in the management of stage I-III SCLC (Pignon). There is increasing evidence in the literature in favor of early concurrent chemo-radiotherapy, and a standard of care for patients with a good performance status is twice-daily thoracic radiotherapy (45 Gy in 3 weeks) with concurrent cisplatin and etoposide (Turrisi). Although current clinical trials are exploring the efficacy of new chemotherapeutic strategies, essential questions related to the optimization of thoracic radiotherapy and the benefit of chemo-radiotherapy in sub-groups of patients remain unanswered, e.g. the elderly (Blackhall). The CONVERT trial (twice-daily (BD) versus once daily (OD) radiotherapy given concurrently with chemotherapy in stage I-III SCLC) was reported at ASCO 2016 (Faivre-Finn). OD RT did not result in a superior survival or worse toxicity than BD RT (two-year survival was 56% (95% CI 50-61) vs 51% (95% CI 45-57), p= 0.14). The survival for both regimens was higher than previously reported and using modern RT techniques radiation toxicities were lower than expected. In the stage IV setting the CREST trial as shown that the addition on thoracic RT to chemotherapy and PCI leads to a significant reduction in intrathoracic recurrence and, despite the lack of a significant benefit in overall survival at 1 year, there were significant improvements in overall survival at 2 years (Slotman). It is crucial that patients with SCLC are given the opportunity to participate in clinical research in order to continue to improve the survival of this disease. Molecular studies are ongoing aiming to gain improved insight into the molecular biology of SCLC, discover and/or validate candidate biomarkers for response, resistance to or toxicity of systemic treatment and radiation. It is expected that this understanding will lead to the development of targeted therapies that will not only prove efficacious but also less toxic than more conventional chemotherapy treatments. In combination with advanced RT techniques and better imaging, it is hoped that the rates of long term survivors will increase significantly in the future. We will address the following controversial questions: 1) Should BDRT be considered standard of care in stage I-III SCLC? 2) Role of CTRT in stage I-II SCLC 3) Role of CTRT in elderly patients with LS-SCLC 4) Should thoracic RT be given to all patients with stage IV SCLC? 1. Califano R, et al. Management of small cell lung cancer: recent developments for optimal care. Drugs. 2012 5;72(4):471-90. 2. Pignon JP, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992; 327:1618-1622. 3. Turrisi AT, et al. Twice daily compared to once-daily thoracic radiotherapy in limited-stage small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999; 340: 265-271. 4. Auperin A, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 1999;341(7):476-84. 5. Blanchard P, et al. Prophylactic cranial irradiation in lung cancer. Curr Opin Oncol. 2010; 22(2):94-101. 6. Blackhall F et al. Treatment of limited small cell lung cancer: an old or new challenge? Curr Opin Oncol. 2011; 23(2):158-62. 7. Faivre-Finn C, 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. 8. Slotman BJ, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet. 2015 3;385(9962):36-42. 9. Slotman BJ, et al. Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the Phase III CREST trial. Lung Cancer. 2017; 108:150-153. small-cell, radiotherapy, thoracic

Duration of Twice-Daily Thoracic Radiotherapy and Time From the Start of Any Treatment to the End of Chest Irradiation as Significant Predictors of Outcomes in Limited-Disease Small-Cell Lung Cancer

BackgroundThe hypothesis of this retrospective study was that the duration of twice-daily (BID) thoracic radiotherapy (TRT) and time from the start of any treatment to the end of chest irradiation (SER) would predict outcomes in limited-disease small-cell lung cancer. Materials and MethodsAll 81 patients received 45 Gy in 30 fractions BID with a ≥ 6-hour interval and concurrent chemotherapy of platinum and etoposide. ResultsThe median radiotherapy duration was 25 days (range, 21-38 days). The 5-year overall survival rates were 26.2% (95% confidence interval [CI], 14.3%-38.0%), and the median survival time was 30 months (95% CI, 15.5-44.5 months). Using multivariate regression analysis, the significant predictors of survival were the sum of the diameters of the primary tumor and metastatic lymph nodes, male gender, age ≥ 60 years, and the duration of BID-TRT (hazard ratio [HR], 1.15; 95% CI, 1.06-1.25; HR, 2.38; 95% CI, 1.13-5.02; HR, 2.38; 95% CI, 1.10-5.17; and HR, 1.08; 95% CI, 1.01-1.15, respectively). A total of 70 of 81 patients (86%) received radiotherapy during the first chemotherapy cycle. The median SER was 29 days (range, 21-109 days). The 5-year local control rate was 48.7% (95% CI, 33.9%-63.6%). The significant predictors of local control were the sum of the diameters of the primary tumor and metastatic lymph nodes, age ≥ 60 years, and SER (HR, 1.18; 95% CI, 1.06-1.31; HR, 4.18; 95% CI, 1.23-14.24; and HR, 1.02; 95% CI, 1-1.04, respectively). ConclusionsThe duration of BID-TRT and SER were identified as one of the significant predictors of survival and local control in limited-disease small-cell lung cancer treated with concurrent chemoradiotherapy at 45 Gy in 30 fractions, respectively.

A Phase I Study of Chemoradiotherapy With Use of Involved-Field Conformal Radiotherapy and Accelerated Hyperfractionation for Stage III Non-Small Cell Lung Cancer: WJTOG 3305

A Phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non-small-cell lung cancer was conducted. Patients with unresectable Stage III non-small-cell lung cancer were treated intravenously with carboplatin (area under the concentration curve 2) and paclitaxel (40 mg/m(2)) on Days 1, 8, 15, and 22 with concurrent twice-daily thoracic radiotherapy (1.5 Gy per fraction) beginning on Day 1 followed by two cycles of consolidation chemotherapy using carboplatin (area under the concentration curve 5) and paclitaxel (200 mg/m(2)). Total doses were 54 Gy in 36 fractions, 60 Gy in 40 fractions, 66 Gy in 44 fractions, and 72 Gy in 48 fractions at Levels 1 to 4. The dose-limiting toxicity, defined as Grade ≥4 esophagitis and neutropenic fever and Grade ≥3 other nonhematologic toxicities, was monitored for 90 days. Of 26 patients enrolled, 22 patients were assessable for response and toxicity. When 4 patients entered Level 4, enrollment was closed to avoid severe late toxicities. Dose-limiting toxicities occurred in 3 patients. They were Grade 3 neuropathy at Level 1 and Level 3 and Grade 3 infection at Level 1. However, the maximum tolerated dose was not reached. The median survival time was 28.6 months for all patients. The maximum tolerated dose was not reached, although the dose of radiation was escalated to 72 Gy in 48 fractions. However, a dose of 66 Gy in 44 fractions was adopted for this study because late toxicity data were insufficient.

Cisplatin and Etoposide Chemotherapy Combined with Early Concurrent Twice-daily Thoracic Radiotherapy for Limited-disease Small Cell Lung Cancer in Elderly Patients

The optimal management of elderly patients with limited-disease small cell lung cancer (LD-SCLC) has not been established. The records of elderly (>or=70 years of age) patients with LD-SCLC who had been treated with etoposide and cisplatin chemotherapy with early concurrent twice-daily thoracic radiotherapy (TRT) were reviewed retrospectively. Of the 25 elderly patients with LD-SCLC identified, 12 (48%) individuals received etoposide-cisplatin chemotherapy with early concurrent twice-daily TRT. The main toxicities of this treatment regimen were hematologic, with neutropenia of Grade 4 being observed in all patients and febrile neutropenia of Grade 3 in eight patients during the first cycle of chemoradiotherapy. The toxicity of TRT was acceptable, with all patients completing the planned radiotherapy within a median of 29 days (range, 19-33). No treatment-related deaths were observed. The median progression-free survival and overall survival times were 14.2 months (95% confidence interval, 4.3-18.2) and 24.1 months (95% confidence interval, 11.3-27.2), respectively. Etoposide-cisplatin chemotherapy with early concurrent twice-daily TRT was highly myelotoxic in elderly patients with LD-SCLC, although no treatment-related deaths were observed in our cohort. Prospective studies are required to establish the optimal schedule and dose of chemotherapy and TRT in such patients.