Extended vs. Small Field Irradiation in High Risk Post Esophagectomy Patients Receiving Combined Chemoradiation Therapy: A Decade Experience in Treatment of Esophageal Cancer

OBJECTIVE: To assess the impact of extended field irradiation with anastomotic coverage on local recurrence in high risk resected esophageal cancerpatients. METHODS: From 1989-1999, high risk resected esophageal cancer cases receiving post-resection chemoradiation were reviewed. Adjuvant chemotherapy consisted of four cycles of fluorouracil-based regimens. Loco-regional irradiation with or without coverage of anastomotic site had radiation a dose range from 45-60 Gyat 1.8-2.0 Gy/fraction given with initial anterior-posterior/posterior-anterior arrangement with either extended (with anastomotic coverage), or small (without anastomotic coverage) field followed by oblique fields for boost. RESULTS: One hundred eighty-eight charts were reviewed. Seventy-two patients were eligible for post-resection chemoradiation. Three patients had disease progression prior to therapy, and 69 patients were analyzed. The median age was 60 years (range 35-82 years) with 94% T2-3N1 and 65% were adenocarcinoma. As of January 2005 median followup was 30.5 months (range 3-142 months), the two-and five-year overall survival rates were 50% and 31%, respectively. First relapse rate after adjuvant therapy was 71% (n=49) and median time to relapse was about 30 months. Loco-regional relapse with small field was 25/35 (71.4%) and 2/14 (14.2%) with extended field (P\u3c0.001). Recurrence locally to anastomosis or adjacent site was 10/35 (28.6%) with small field and 0/14 (0%) with extended field (P=0.04). CONCLUSION: At a minimum of 5-year followup, there is significant decrease in loco-regional relapse with the use of extended field in high risk resected esophageal cancer patients. This important improvement trend deserves further exploration in prospective randomized clinical trials

Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937

Introduction—RTOG-0937 is a randomized phase-II trial evaluating 1-year OS with PCI or PCI plus consolidative radiation therapy (cRT) to intra-thoracic disease and extracranial metastases for ED-SCLC. Methods—Patients with 1–4 extracranial metastases were eligible after CR or PR to chemotherapy. Randomization was to PCI or PCI+cRT to the thorax and metastases. Original stratification included PR vs CR after chemotherapy and 1 vs 2–4 metastases; age \u3c 65 vs ≥ 65 was added after an observed imbalance. PCI was 25GY/10 fractions. cRT was 45GY/15 fractions. To detect an OS improvement from 30% to 45% with a 34% hazard reduction (HR=0·66) under a 0.1 type-1 error (1-sided) and 80% power, 154 patients were required. Results—Ninety-seven patients were randomized between March, 2010 and February, 2015. Eleven patients were ineligible (nine PCI, two PCI+cRT), leaving 42 randomized to PCI and 44 to PCI+cRT. At planned interim analysis the study crossed the futility boundary for OS and was closed prior to meeting accrual target. Median follow-up was 9 months. One-year OS was not different between the groups: 60.1% [95% CI: 41.2–74.7%] for PCI and 50.8% [95% CI:34.0–65.3%] for PCI+cRT (p=0.21). Three and 12-month rates of progression were 53.3% and 79.6% for PCI, and 14.5% and 75% for PCI+cRT. Time to progression favored PCI+cRT, HR=0.53 (95% CI: 0.32–0.87, p=0.01). One-patient in each arm had Grade-4 therapy related toxicity and one had Grade-5 therapy related pneumonitis with PCI+cRT. Conclusions—OS exceeded predictions for both arms. Consolidative RT delayed progression but did not improve 1-year OS

Association of Radiotherapy Duration With Clinical Outcomes in Patients With Esophageal Cancer Treated in NRG Oncology Trials: A Secondary Analysis of NRG Oncology Randomized Clinical Trials

IMPORTANCE: For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes. OBJECTIVE: To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT). DESIGN, SETTING, AND PARTICIPANTS: This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy Oncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023. EXPOSURES: Treatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy. MAIN OUTCOMES AND MEASURES: The outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable. RESULTS: The analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs ≤39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07). CONCLUSIONS AND RELEVANCE: Results of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes

Shifting from Hypofractionated to Conventionally Fractionated Thoracic Radiotherapy: A Single Institution\u27s 10-year Experience in the Management of Limited-stage Small-cell Lung Cancer Using Concurrent Chemoradiation

PURPOSE: To perform a retrospective review of a single institution\u27s 10-year experience in treating limited-stage small-cell lung cancer (LS-SCLC) with a concurrent chemoradiation regimen modeled after the experimental arm of a randomized National Cancer Institute of Canada trial in which hypofractionated radiotherapy started with cycle 2 of chemotherapy. We then looked at the impact on patient outcomes of changing the RT during the course of the decade to a conventionally (2 Gy) fractionated regimen, with a focus on toxicity and survival rates. METHODS AND MATERIALS: Between 1989 and 1999, 215 LS-SCLC patients received six cycles of chemotherapy consisting of cyclophosphamide, doxorubicin, and vincristine alternating with etoposide and cisplatin every 3 weeks. Thoracic RT was administered concurrently with etoposide and cisplatin (at cycle 2 or 3) only and consisted of either 40 Gy in 15 fractions for 3 weeks or 50 Gy in 25 fractions for 5 weeks. RT fields encompassed gross and suspected microscopic disease with 2-cm margins. Prophylactic cranial irradiation (PCI) was offered to complete responders according to clinician preference. RT interruption during concurrent chemoradiation was used as the marker for treatment toxicity. The analysis compared the RT schedules for differences in toxicity, survival, and recurrence patterns. RESULTS: The overall survival rate for 215 patients at 2 and 5 years was 22.7% and 7.2%, respectively, with a median survival of 14.7 months. Thoracic RT consisted of 40 Gy in 3 weeks for 122 patients (57%) and 50 Gy in 5 weeks for 92 patients (43%). PCI was administered to 21 (44%) and 47 (56%) patients receiving 40 Gy and 50 Gy, respectively. The patient- and treatment-related variables were comparable between the two cohorts treated with the different RT prescriptions. RT interruptions during concurrent chemoradiation were recorded in 56 cases (26%), with a median duration of 5 days (range 1-18). No differences in treatment-related toxicity rates were demonstrated between the two dose cohorts (p = 0.35). The overall and disease-free survival rates (patients stratified by PCI use) at 5 years for the 40- and 50-Gy schedules were 14.3% and 12.0% (p = 0.71) and 20.7% and 22.2% (p = 0.76), respectively. Sites of first failure were recorded in 132 patients (61%). Comparing the 40-Gy and 50-Gy cohorts, the rate of any first relapse was 40% vs. 42% and the chest as the first relapse site was 34% vs. 45% (patients stratified by PCI use), respectively. The brain failure rate reflected PCI use and was not related to the thoracic RT schedule. CONCLUSION: Changing from a hypofractionated to a conventionally fractionated RT thoracic prescription did not alter outcomes because the survival, thoracic control, and toxicity rates were statistically similar. This suggests that the hypofractionated schedule remains practicable and should be considered in the setting of randomized clinical trials. In view of the benefits that accelerated schedules provide for both patients and cost containment, clinicians may opt to use this tolerable regimen in managing LS-SCLC. Regarding the future development of novel chemoradiation programs, the most critical factor in ensuring improved outcomes for LS-SCLC may be limiting the duration of RT and overall treatment time

Impaired Diffusion Capacity Predicts for Decreased Treatment Tolerance and Survival in Limited Stage Small Cell Lung Cancer Patients Treated with Concurrent Chemoradiation

PURPOSE: To determine if stratification of limited stage small cell lung cancer (LSCLC) patients by pre-treatment pulmonary function test (PFT) prognostic indicators predicts for treatment-related toxicity risks and survival following concurrent chemoradiation. MATERIALS AND METHODS: From 1989 to 1999, 215 LSCLC patients received six cycles of alternating cyclophosphamide/doxorubicin/vincristine and etoposide/cisplatin (EP). Thoracic radiation (RT) was initiated only with EP and at cycle 2 or 3. RT dose was: 40 Gy/15 fractions/3 weeks or 50 Gy/25 fractions/5 weeks. RT fields encompassed gross and suspected microscopic disease with a 2 cm margin. Pre-treatment PFT values analyzed included forced expiratory volume in 1s (FEV1) (in liter and as % predicted) and diffusion capacity for carbon monoxide (DLCO) (as % predicted). The marker for toxicity during concurrent chemoradiation was the duration of any RT breaks initiated for severe hematologic or locoregional symptomatology. Patient outcomes were analyzed for associations between recognized PFT cut-offs (FEV1 \u3c2l, \u3e or =2l; FEV1 \u3c60%, \u3e or =60% predicted; DLCO \u3c60%, \u3e or =60% predicted), toxicity rates, and survival. RESULTS: For the whole study cohort, median, 2- and 5-year overall survivals were: 14.7 months, 22.7 and 7.2%, respectively. Fifty-six patients (26%) required treatment breaks due to toxicity. FEV1 and DLCO results were available for 96 (45%) and 86 (40%) patients, respectively. Two thirds of FEV1s measured were \u3c2l. On statistical analysis, the incidence of toxicity-related interruptions was significant for DLCO\u3c60% (P=0.043), suggestive for FEV1\u3c2l (P=0.1) and non-significant for FEV1\u3c60%. Patients with simultaneous DLCO\u3c60% and FEV1\u3c2l showed a trend toward increase toxicity risk (P=0.1). For selected PFT measures, median overall survivals were: 12.7 months versus 14.8 months for DLCO\u3c60% versus \u3e or =60%; 13.4 months versus 17.7 months for FEV1\u3c2l versus\u3e or =2l; 15.4 months versus 19.9 months for DLCO\u3c60% + FEV1\u3c2l versus DLCO\u3e or =60% + FEV1\u3e or =2l. Although absolute differences favored all patients with PFT values above the prognostic cut-offs, differences were not statistically significant on this analysis. Patients with both a treatment break and a DLCO\u3c60% had the poorest median survival of all patient subsets, at 11.4 months (P=0.09). CONCLUSIONS: Impaired DLCO (i.e. \u3c60%) is a novel predictor of increased treatment-related toxicity leading to interruptions. The present study suggests a probable role for DLCO and FEV1 (in l) as prognostic factors for predicting survival but larger patient samples are required for confirmation. Patients with impaired DLCOs experiencing treatment interruptions have the poorest survival. Assessment of pre-treatment PFTs contributes to determining optimal management strategies for LSCLC patients receiving definitive chemoradiation