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Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. Although postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60 Gy, and hyperfractionation has shown promise in reducing toxicity. These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for clinical experts involved in the treatment of locally recurrent NPC.
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BACKGROUND: A synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma. PATIENTS AND METHODS: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics. RESULTS: 19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5-2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2-1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS. CONCLUSION: When combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation. TRIAL REGISTRATION NUMBER: NCT01557114.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno CTLA-4/metabolismo , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Relación Dosis-Respuesta en la Radiación , Humanos , Ipilimumab/farmacología , Dosis Máxima Tolerada , Persona de Mediana EdadRESUMEN
PURPOSE: Addition of CDK4/6 inhibitors to a variety of established treatments in squamous cell carcinoma of the head and neck (SCCHN) has the potential to improve responses to other therapies and may help overcome treatment resistance. The SCCHN is a heterogeneous group of cancers of the oral cavity, the pharynx and the larynx with poor prognosis despite the aggressive multimodal therapies. In the past decade, significant advances were made in understanding of the molecular and genetic abnormalities leading to oncogenesis in SCCHN. RECENT FINDINGS: Besides EGFR targeting agents, antiangiogenic agents have been shown to produce antitumor activity in these tumors. The cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway regulates cellular proliferation by controlling the G1 to S cell cycle checkpoint. In SCCHN, the Rb pathway is frequently altered through amplification of CCND1 (cyclin D1) or deletion of CDKN2A (cyclin-dependent kinase inhibitor 2A) coding for p16INK4A, and thus promoting proliferation. This article summarizes what we actually know of the place of CDK4/6 inhibitors in the therapeutic arsenal of SCCHN. CDK4/6 inhibitors could serve as a method to target these tumors, and both p16 loss and CCND1 amplification could be investigated as biomarkers.
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Carcinoma de Células Escamosas , Quinasa 4 Dependiente de la Ciclina , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Carcinoma de Células Escamosas/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológicoRESUMEN
IMPORTANCE: The BRAF inhibitor, vemurafenib, was recently approved for the treatment of patients with BRAFV600 metastatic melanoma. Wider use of this drug and longer follow-up periods of treatment are resulting in the emergence of a growing number of reports detailing new adverse effects. Cutaneous adverse effects are preeminent with UV-A-dependent phototoxicity, hyperkeratotic folliculitis, hand-foot skin reaction, hair changes, verrucous papillomas, keratoacanthomas, and squamous cell carcinomas. OBSERVATIONS: We report 2 cases of dermatitis occurring on a previously irradiated skin area in patients treated with vemurafenib for a BRAFV600-mutated metastatic melanoma. The first case occurred 10 days after a low dose of radiation was delivered that usually does not induce any radiodermatitis, suggesting radiosensitization by vemurafenib. The second case occurred 30 days after radiotherapy and was diagnosed as radiation recall dermatitis. CONCLUSIONS AND RELEVANCE: Vemurafenib should be considered a potential cutaneous radiosensitizer and an inducer of radiation recall dermatitis. However, these adverse effects are easily managed with topical corticosteroids. Dose reduction or interruption of vemurafenib is not required. Further studies and reports will enlighten us as to whether this pharmacodynamic interaction between x-rays and vemurafenib is also seen with other BRAF or MEK inhibitors on the same mitogen-activated protein kinase pathway currently under development.
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Indoles/efectos adversos , Melanoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Tolerancia a Radiación/efectos de los fármacos , Neoplasias Cutáneas/tratamiento farmacológico , Sulfonamidas/efectos adversos , Adulto , Femenino , Humanos , Indoles/uso terapéutico , Masculino , Melanoma/radioterapia , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Neoplasias Cutáneas/radioterapia , Sulfonamidas/uso terapéutico , VemurafenibRESUMEN
BACKGROUND: Concomitant chemoradiotherapy and accelerated radiotherapy independently improve outcomes for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC). We aimed to assess the efficacy and safety of a combination of these approaches. METHODS: In our open-label phase 3 randomised trial, we enrolled patients with locally advanced, stage III and IV (non-metastatic) HNSCC and an Eastern Cooperative Oncology Group performance status of 0-2. We randomly allocated patients centrally with a computer program (with centre, T stage, N stage, and localisation as minimisation factors) in a 1:1:1 ratio to receive conventional chemoradiotherapy (70 Gy in 7 weeks plus three cycles of 4 days' concomitant carboplatin-fluorouracil), accelerated radiotherapy-chemotherapy (70 Gy in 6 weeks plus two cycles of 5 days' concomitant carboplatin-fluorouracil), or very accelerated radiotherapy alone (64·8 Gy [1·8 Gy twice daily] in 3·5 weeks). The primary endpoint, progression-free survival (PFS), was assessed in all enrolled patients. This trial is completed. The trial is registered with ClinicalTrials.gov, number NCT00828386. FINDINGS: Between Feb 29, 2000, and May 9, 2007, we randomly allocated 279 patients to receive conventional chemoradiotherapy, 280 to accelerated radiotherapy-chemotherapy, and 281 to very accelerated radiotherapy. Median follow-up was 5·2 years (IQR 4·9-6·2); rates of chemotherapy and radiotherapy compliance were good in all groups. Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional chemoradiotherapy (HR 1·02, 95% CI 0·84-1·23; p=0·88) or very accelerated radiotherapy (0·83, 0·69-1·01; p=0·060); conventional chemoradiotherapy improved PFS compared with very accelerated radiotherapy (0·82, 0·67-0·99; p=0·041). 3-year PFS was 37·6% (95% CI 32·1-43·4) after conventional chemoradiotherapy, 34·1% (28·7-39·8) after accelerated radiotherapy-chemotherapy, and 32·2% (27·0-37·9) after very accelerated radiotherapy. More patients in the very accelerated radiotherapy group had RTOG grade 3-4 acute mucosal toxicity (226 [84%] of 268 patients) compared with accelerated radiotherapy-chemotherapy (205 [76%] of 271 patients) or conventional chemoradiotherapy (180 [69%] of 262; p=0·0001). 158 (60%) of 265 patients in the conventional chemoradiotherapy group, 176 (64%) of 276 patients in the accelerated radiotherapy-chemotherapy group, and 190 (70%) of 272 patients in the very accelerated radiotherapy group were intubated with feeding tubes during treatment (p=0·045). INTERPRETATION: Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy cannot compensate for the absence of chemotherapy. We noted the most favourable outcomes for conventional chemoradiotherapy, suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules. FUNDING: French Ministry of Health.