BRAF mutation correlates with worse local–regional control following radiation therapy in patients with stage III melanoma

Background In patients with stage III melanoma, the use of adjuvant radiation therapy (RT) after lymph node dissection (LND) may be currently considered in selected high-risk patients to improve tumor control. Melanomas harbor BRAF mutations (BRAF+) in 40–50% of cases, the majority of which are on the V600E residue. This study sought to compare the clinical outcomes after RT between patients with BRAF+ and BRAF− melanoma. Methods This was a retrospective review of 105 Stage III melanoma patients treated at our institution with LND followed by adjuvant RT from 2006 to 2019. BRAF mutational status was determined on the primary skin or nodal tissue samples from all patients. We compared characteristics of the BRAF+ and BRAF− groups using Fisher’s exact test and Wilcoxon rank sum test and performed univariate and multivariate analysis using Kaplan–Meier estimates, log-rank tests, and Cox proportional hazards modeling with the clinical outcomes of local–regional lymph node control, distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS). Results Fifty-three (50%) patients harbored a BRAF mutation (92%, pV600E). BRAF+ patients were younger and had primary tumors more commonly found in the trunk vs head and neck compared to BRAF- patients (p < 0.05). The 5 year local–regional control in the BRAF + patients was 60% compared to 81% in the BRAF- patients (HR 4.5, 95% CI 1.3–15.5, p = 0.02). There were no significant differences in 5-year DMFS, RFS, and OS rates between the two BRAF patient groups. The presence of 4 or more positive LNs remained a significant prognostic factor for local–regional lymph node control, RFS, and OS in multivariate analysis. Conclusions Stage III melanoma patients with BRAF mutation treated with adjuvant RT had > 4 times increased risk of local recurrence or regional lymph node recurrence. These results could be useful for adjuvant RT consideration in lymph node positive melanoma patients and supports other data that BRAF mutation confers radiation resistance.

Passively Scattered Proton Therapy for Nonmelanoma Skin Cancer with Clinical Perineural Invasion

Purpose To report our experience with the delivery of passively scattered proton therapy in the management of nonmelanoma skin cancers with clinical perineural invasion. Materials and Methods We reviewed the medical records of patients who received definitive or postoperative proton therapy for nonmelanoma skin cancer with clinical perineural invasion at our institution and updated patient follow-up when possible. All patients were treated with curative intent with or without the delivery of concurrent systemic therapy. We report disease control rates and the rates of late toxicity among this cohort. Results Twenty-six patients treated between 2008 and 2017 were included in the analysis. Following proton therapy, the 3-year overall, cause-specific, and disease-free survival rates were 59%, 73%, and 60%, respectively. The 3-year local control, local regional control, and distant metastasis-free survival rates were 80%, 65%, and 96%, respectively. On univariate analysis, surgical resection before radiation therapy significantly improved local regional control rates at 3 years (55% versus 86%; P = .04). Grade 3+ late toxicities occurred in 13 patients (50%) and the most common toxicities included grade 3+ keratitis of the ipsilateral eye, which occurred in 4 patients (15%) and grade 3+ brain necrosis in 4 patients (15%). Conclusion Proton therapy is effective in the management of nonmelanoma skin cancer with clinical perineural invasion. Although disease control and complication rates compare favorably to those previously published for photon-based radiation therapy, the risk for late toxicity is significant and patients should be appropriately counseled.

Long-term Outcomes from Proton Therapy for Sinonasal Cancers

Purpose To report long-term disease control, survival, and toxicity after proton therapy for sinonasal cancer. Patients and Methods We reviewed 143 cases of adults with nonmetastatic sinonasal cancers treated with primary (18%; n = 26) or adjuvant (82%; n = 117) proton therapy. The most common histologies were squamous cell carcinoma (29%; n = 42), olfactory neuroblastoma (23%; n = 33), and adenoid cystic carcinoma (16%; n = 23). Patients had predominantly advanced-stage disease (T3, 24%, n = 35; T4, 66%, n = 94) and high-grade histology (52%; n = 74). Surgery included endoscopic resection alone (50%) with craniotomy (10%) or open resection (40%), and 31% had gross disease present at radiotherapy. Most (91%) received high-dose (median, 73.6 Gy radiobiological equivalent [GyRBE]; 84% &gt;70 GyRBE) passive-scatter proton therapy using accelerated hyperfractionation (1.2 GyRBE twice daily) and concurrent chemotherapy (70%). Univariate and multivariate models assessed prognostic factors. Grade 3+ toxicities were recorded per Common Terminology Criteria, version 4. Median follow-up was 3.4 years (range, 0.1–12.5 years) overall and 4.9 years (range, 0.9–12.5 years) for living patients. Results The 5-year outcomes were as follows: local control (LC), 80%; neck control, 96%; local-regional control, 78%; freedom from distant metastases, 71%; and disease-free survival, 62%; cause-specific survival, 64%; and overall survival, 59%. Surgery improved LC, but only with gross total resection (5-year LC 87% versus subtotal resection 62.9%, and biopsy alone 55% (P &lt; 0.001). Gross residual disease was the only significant prognostic factor for local-regional control on multivariate analysis. High-grade, T4, and local recurrence were associated with decreased overall survival. Late (G3+) toxicity occurred in 22% (32 of 143), including central nervous system necrosis and vision loss in 6% (9 of 143) and 3.5% (5 of 143), respectively. Conclusion Proton therapy after gross-total resection provides excellent long-term LC in patients with locally advanced, high-grade sinonasal cancer. Moreover, LC remains strongly associated with long-term survival. With gross disease, about 60% of patients had long-term LC with proton therapy and induction or concurrent chemotherapy.

Proton Therapy for Head and Neck Cancer: A 12-Year, Single-Institution Experience

Purpose To characterize our experience and the disease control and toxicity of proton therapy (PT) for patients with head and neck cancer (HNC). Patients and Methods Clinical outcomes for patients with HNC treated with PT at our institution were prospectively collected in 2 institutional review board–approved prospective studies. Descriptive statistics were used to summarize patient characteristics and outcomes. Overall survival, local-regional control, and disease-free survival were estimated by the Kaplan-Meier method. Treatment-related toxicities were recorded according to the Common Terminology Criteria for Adverse Events (version 4.03) scale. Results The cohort consisted of 573 patients treated from February 2006 to June 2018. Median patient age was 61 years. Oropharynx (33.3%; n = 191), paranasal sinus (11%; n = 63), and periorbital tissues (11%; n = 62) were the most common primary sites. Patients with T3/T4 or recurrent disease comprised 46% (n = 262) of the cohort. The intent of PT was definitive in 53% (n = 303), postoperative in 37% (n = 211), and reirradiation in 10% (n = 59). Median dose was 66 Gy (radiobiological equivalent). Regarding systemic therapy, 43% had received concurrent (n = 244), 3% induction (n = 19), and 15% (n = 86) had both. At a median follow-up of 2.4 years, 88 patients (15%) had died and 127 (22%) developed disease recurrence. The overall survival, local-regional control, and disease-free survival at 2 and 5 years were, respectively, 87% and 75%, 87% and 78%, and 74% and 63%. Maximum toxicity (acute or late) was grade 3 in 293 patients (51%), grade 2 in 234 patients (41%), and grade 1 in 31 patients (5%). There were 381 acute grade 3 and 190 late grade 3 unique toxicities across 212 (37%) and 150 (26%) patients, respectively. There were 3 late-grade 4 events across 2 patients (0.3%), 2 (0.3%) acute-grade 5, and no (0%) late-grade 5 events. Conclusions The overall results from this prospective study of our initial decade of experience with PT for HNC show favorable disease control and toxicity outcomes in a multidisease-site cohort and provide a reference benchmark for future comparison and study.

Survival (OS) and progression-free survival (PFS) results after induction chemotherapy (IC) followed by de-escalated chemoradiotherapy (RDCRT) for locally advanced (LA) HPV positive oropharynx cancer (HPVOPC.

6058 Background: HPVOPC has a significantly better prognosis and survival than HPV negative cancer resulting in overtreatment with significant acute and late toxicities and mortality. Radiation therapy is the single greatest determinant of toxicity. Studies to support reduction of radiation dose are a high priority. IC improves local regional control, reduces distant metastases, and may support radiotherapy de-escalation. Patients with T4, ECE, and N2c disease have poorer local regional control (LRC) and a higher rate of distant metastases (DM) and may be suitable for this option. Methods: Data was combined for the experimental arm of a previously reported Phase 3 trial (12 subjects, NCT01706939) and a continuation Phase 2 trial (20 subjects, NCT02945631). After informed consent subjects who were PCR+ HPVOPC, smoked < 20 py, and were LA or functionally unresectable were treated with Taxotere, cisplatin and reduced 5-fluorouracil (mTPF) for 3 cycles and then assessed for response. Responders were treated with 5600 cGy and weekly carboplatin, and then followed for LRC, DM, PFS, OAS and toxicity. Data was analyzed as of 2/1/21. 85% LRC at 3 years was considered non inferior to standard of care chemoradiotherapy. An acceptable end point was predetermined to be 80% PFS and 85% LRC at 3 years in this LA population. Results: 32 subjects were entered and included in the analysis, all responded to IC and had RDCRT. 2 patients with non-HPV16 subtypes were initially entered, treated with IC, responded, and then were taken off study and excluded from the analysis due to non-HPV 16 subtype. They were treated with 7000 cGy and are alive and well. Poor risk factors (ECE, T4, N2c, Non-HPV16 subtype) were present in 72% of 32 subjects; 22 (69%) never smoked. At data cutoff with a median follow up of 50m (21-95m), 28/32 (87.5%) have LRC, 1/32 DM (3.1%), OS is 28/32 (87.5%) and PFS is 27/32 (84.4%). All 5 patients who recurred did so in the first 12m (median 8m); all had 1 or more poor risk factors and 1 is alive with disease 42m post recurrence. 2 year LRC, PFS and OS are 87.4% [95% CI: 69.8%, 95.1%], 84.4% [95% CI: 66.5%, 93.2%] and 90.6% [95% CI: 73.7%, 96.9%] respectively. There was no therapy-related mortality, generally rapid recovery from CRT and minimal long term consequences (to be reported). Conclusions: Induction with mTPF followed by RDCRT resulted in excellent LRC, PFS and OS in patients with LA HPV OPC and significant risk factors. These results compare favorably to standard of care and other dose de-escalation trials in high and low risk categories. This treatment paradigm is highly effective in a LA, high risk HPVOPC patients and is a reasonable treatment option to be compared to other de-escalation treatment plans in Phase 3 trials for this higher risk population. Clinical trial information: NCT02945631, NCT01706939.

BRAF Mutation Correlates with Worse Local-regional Control Following Radiation Therapy in Patients with Stage III Melanoma

Background In patients with stage III melanoma, the use of adjuvant radiation therapy (RT) after lymph node dissection (LND) may be currently considered in selected high-risk patients to improve local-regional control. Melanomas harbor BRAF mutations (BRAF+) in 40–50% of cases, the majority of which are on the V600E residue. This study sought to compare the clinical outcomes after RT between patients with BRAF + and BRAF- melanoma. Methods This was a retrospective review of 105 Stage III melanoma patients treated at our institution with LND followed by adjuvant RT from 2006–2019. BRAF mutational status was determined on the primary skin or nodal tissue samples from all patients. We compared characteristics of the BRAF + and BRAF- groups using Fisher’s exact test and Wilcoxon rank sum test and performed univariate and multivariate analysis using Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards modeling with the clinical outcomes of local-regional control (LRC), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS). Results Fifty-three (50%) patients harbored a BRAF mutation (92%, pV600E). BRAF + patients were younger and had primary tumors more commonly found in the trunk vs head and neck compared to BRAF- patients (p < 0.05). The 5 year local-regional control in the BRAF + patients was 60% compared to 81% in the BRAF- patients (HR 4.5, 95% CI 1.3–15.5, p = 0.02). There were no significant differences in 5-year DMFS, DFS, and OS rates between the two BRAF patient groups. The presence of 4 or more positive LNs remained a significant prognostic factor for LRC, DFS, and OS in multivariate analysis. Conclusions Stage III melanoma patients with BRAF mutation treated with adjuvant RT had > 4 times increased risk of loco-regional recurrence. These results could be useful for adjuvant RT consideration in lymph node positive melanoma patients and supports other data that BRAF mutation confers radiation resistance.

Durvalumab after Chemoradiotherapy for PD-L1 Expressing Inoperable Stage III NSCLC Leads to Significant Improvement of Local-Regional Control and Overall Survival in the Real-World Setting

Concurrent chemoradiotherapy (CRT) followed by maintenance treatment with the PD-L1 inhibitor durvalumab is a new standard of care for inoperable stage III NSCLC. The present study compares the oncological outcome of patients treated with CRT to those treated with CRT and durvalumab (CRT-IO) in the real-world setting. The analysis was performed based on the retro- and prospectively collected data of 144 consecutive inoperable stage III NSCLC patients treated between 2011–2020. Local-regional-progression-free-survival (LRPFS—defined as progression in the mediastinum, hilum and/or supraclavicular region at both sites and the involved lung), progression-free survival (PFS), and overall survival (OS) were evaluated from the last day of thoracic radiotherapy (TRT). Median follow-up for the entire cohort was 33.1 months (range: 6.3–111.8) and median overall survival was 27.2 (95% CI: 19.5–34.9) months. In the CRT-IO cohort after a median follow-up of 20.9 (range: 6.3–27.4) months, median PFS was not reached, LRPFS (p = 0.002), PFS (p = 0.018), and OS (p = 0.005) were significantly improved vs. the historical cohort of conventional CRT patients. After propensity-score matching (PSM) analysis with age, gender, histology, tumor volume, and treatment mode, and exact matching for T-and N-stage, 22 CRT-IO patients were matched 1:2 to 44 CRT patients. Twelve-month LRPFS, PFS, and OS rates in the CRT-IO vs. CRT cohort were 78.9 vs. 45.5% (p = 0.002), 60.0 vs. 31.8% (p = 0.007), and 100 vs. 70.5% (p = 0.003), respectively. This real-world analysis demonstrated that durvalumab after CRT led to significant improvement of local-regional control, PFS, and OS in PD-L1 expressing inoperable stage III NSCLC patients compared to a historical cohort.

279 Durvalumab after chemoradiotherapy for PD-L1 expressing inoperable stage III NSCLC impacts local-regional control and overall survival

BackgroundChemoradiotherapy (CRT) followed by maintenance treatment with the PD-L1 inhibitor durvalumab is a new standard of care for inoperable stage III NSCLC. The present study aims to evaluate the oncological outcome of patients treated with CRT alone to those treated with CRT and durvalumab (CRT-IO) in the real-world setting.MethodsRetro- and prospectively collected data of 133 consecutive inoperable stage III NSCLC patients treated between 2011–2019 were evaluated. Local-regional-recurrence-free-survival (LRPFS - defined as progression in the mediastinum, hilum and/or supraclavicular region at both sides and the involved lung), progression-free survival (PFS) and overall survival (OS) were evaluated from last day of thoracic radiotherapy (TRT).ResultsMedian age at diagnosis was 68.5 years; 44 (33%) were female; 58 (44%) were diagnosed with adenocarcinoma. All patients were irradiated to a total dose of at least 60 Gy (EQD2). Median PTV was 709.8 cc (range: 181–1958 cc). 113 (85%) patients were treated with CRT and 20 (15%) PD-L1 expressing patients with CRT-IO. 83% of patients received two cycles of concomitant platinum-based chemotherapy. Median time to initiation of durvalumab after CRT was 0.8 months (range: 0.4–2.1). Median follow-up for entire cohort was 33.3 months (range: 4.8–111.8) and median overall survival (OS) was 24.7 (95% CI: 18.9–30.4) months. In the CRT-IO cohort after a median follow-up of 15.5 (range: 5.1–20.2) months, no deaths were reported at the time of evaluation (August 2020). Improved LRPFS (p=0.013), PFS (p=0.033) and OS (p=0.002) were correlated with CRT-IO compared to the historical cohort of conventional CRT patients.After propensity-score matching (PSM) analysis with age, gender, histology, tumor volume and treatment mode and exact matching for T-and N-stage, 18 CRT-IO patients were matched 1:2 to 36 CRT patients. 12-month LRPFS, PFS and OS rates in the CRT-IO vs CRT cohort were 80% vs 38.8% (p=0.001), 50% vs 22% (p=0.013) and 100% vs 75% (p=0.002), respectively. Also regarding intracranial failure, 6-month brain metastases rates were 0% vs. 6% in the CRT-IO vs CRT cohort (p=0.290).ConclusionsThis real-world analysis demonstrates that durvalumab after CRT has led to significant improvement of local-regional control, PFS and OS in PD-L1 expressing inoperable stage III NSCLC patients compared to a historical cohort.AcknowledgementsThe study was partly presented at 2020 Annual Meeting of the American Society of Clinical Oncology (ASCO).Trial RegistrationN/AEthics ApprovalThe study was approved by Ludwig-Maximilians-University (LMU), Munich, Germany: Institution’s Ethics Board, approval number 17-230.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Salvage Resection for Isolated Local and/or Regional Failure of Head/Neck Cancer Following Definitive Concurrent Chemoradiotherapy Case Series and Review of the Literature

Background: Primary management of advanced head/neck cancers involves concurrent chemoradiotherapy . Subsequently, regional and local failures are managed with resection but there have been few reports that describe the morbidity and disease control outcomes of surgical salvage in this setting. Methods: Retrospective analysis describes complications, survival, and patterns of failure after salvage resection of isolated local and/or regional failures of head/neck cancer following definitive concurrent chemoradiotherapy. Results: Sixteen patients were identified for inclusion: laryngectomy in 11 patients, oral cavity/oropharynx resection in 2 patients, and neck dissection alone in 4 patients. Ten patients required graft tissue reconstruction (6 pedicle and 4 free flap). Median post-operative hospitalization was 7 days (range 3-19), and 4 patients required hospital re-admission. At a median survivor follow-up of 15.8 months (range 4.3-34.9), 10 patients were alive (6 without evidence of disease). Seven patients experienced disease recurrence at a median 6.7 months (range 0-12.6) following salvage resection (2 with isolated distant failures). Estimated 2-year local/regional control, freedom from failure, and overall survival were 58%, 39%, and 58%, respectively. Conclusions: Surgical salvage after primary definitive concurrent chemoradiotherapy is feasible with toxicity and outcomes similar to prior radiotherapy alone or sequential chemotherapy and radiation. Local andregional recurrence remains the predominant pattern of failure.