International Recommendations on Postoperative Management for Potentially Resectable Locally Recurrent Nasopharyngeal Carcinoma.

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.

Anatomic prognostic factors and their potential roles in refining M1 classification for de novo metastatic nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: To identify anatomic prognostic factors and their potential roles in refining M1 classification for de novo metastatic nasopharyngeal carcinoma (M1-NPC). MATERIALS AND METHODS: All M1-NPC treated with chemotherapy and/or radiotherapy between 2010 and 2019 from two centers (training and validation cohort) were included. The prognostic value of metastatic disease extent and involved organs for overall survival (OS) were assessed by several multivariable analyses (MVA) models. A new M1 classification was proposed and validated in a separate cohort who received immuno-chemotherapy. RESULTS: A total of 197 M1-NPC in the training and 307 in the validation cohorts were included for M1 subdivision study with median follow-up of 46 and 57 months. MVA model with "≤2 organs/≤5 lesions" as the definition of oligometastasis had the highest C-index (0.623) versus others (0.606-0.621). Patients with oligometastasis had better OS versus polymetastasis (hazard ratio [HR] 0.47/0.63) while liver metastases carried worse OS (HR 1.57/1.45) in MVA in the training/validation cohorts, respectively. We proposed to divide M1-NPC into M1a (oligometastasis without liver metastases) and M1b (liver metastases or polymetastasis) with 3-year OS of 66.5%/31.7% and 64.9%/35.0% in the training/validation cohorts, respectively. M1a subset had a better median progress-free survival (not reach vs. 17 months, p < 0.001) in the immuno-chemotherapy cohort (n = 163). CONCLUSION: Oligometastasis (≤2 organs/≤5 lesions) and liver metastasis are prognostic for M1-NPC. Subdivision of M1-NPC into M1a (oligometastasis without liver metastasis) and M1b (liver metastasis or polymetastasis) depicts the prognosis well in M1-NPC patients who received immuno-chemotherapy.

MRI-based deep learning model predicts distant metastasis and chemotherapy benefit in stage II nasopharyngeal carcinoma.

Chemotherapy remains controversial for stage II nasopharyngeal carcinoma because of its considerable prognostic heterogeneity. We aimed to develop an MRI-based deep learning model for predicting distant metastasis and assessing chemotherapy efficacy in stage II nasopharyngeal carcinoma. This multicenter retrospective study enrolled 1072 patients from three Chinese centers for training (Center 1, n = 575) and external validation (Centers 2 and 3, n = 497). The deep learning model significantly predicted the risk of distant metastases for stage II nasopharyngeal carcinoma and was validated in the external validation cohort. In addition, the deep learning model outperformed the clinical and radiomics models in terms of predictive performance. Furthermore, the deep learning model facilitates the identification of high-risk patients who could benefit from chemotherapy, providing useful additional information for individualized treatment decisions.

Comparison the acute toxicity of two different induction chemotherapy schedules with cisplatin and fluorouracil in nasopharyngeal carcinoma patients.

PURPOSE: To compare the acute toxicity of two different induction chemotherapy (IndCT) regimen followed by the same IMRT in patients with advanced nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: From July 2015 to December 2016, 110 NPC patients with stage III-IV diseases were prospectively randomized to receive either a conventional triweekly cisplatin + 5-fluorouracil (PF) for 3 cycles or weekly P-F for 10 doses, followed by the same IMRT to both arms. The primary endpoints of this study were grade 3/4 and any grade acute toxicities during IndCT period. The secondary endpoints included tumor response and various survivals. RESULTS: Baseline patient characteristics were comparable in both groups. Patients who received weekly P-F experienced significant reduction of grade 3/4 acute toxicities, including neutropenia (12.7% vs. 40.0%, P = 0.0012), anorexia (0% vs. 14.6%, P = 0.0059), mucositis (0% vs. 14.6%, P = 0.0059), and hyponatremia (0% vs. 16.4%, P = 0.0027), compared with the triweekly PF group, resulting in fewer IndCT interruptions (1.8% vs. 16.4%, P = 0.0203), emergency room visits (0% vs. 12.7%, P = 0.0128), and additional hospitalizations (0% vs. 9.1%, P = 0.0568). The acute toxicities during IMRT period were similar. Weekly P-F arm had higher complete response rates (83.6% vs. 61.8%, P = 0.0152) and lower relapse rates (16.4% vs. 33.3%, P = 0.0402) after a median follow-up of 67 months. Kaplan-Meier survival analyses revealed a better trend of locoregional failure-free (P = 0.0892), distant metastasis failure-free (P = 0.0775), and progression-free (P = 0.0709) survivals, favoring the weekly P-F arm. CONCLUSION: IndCT of weekly schedule does reduce acute toxicities without compromised tumor response and survivals.

The role of radiologic extranodal extension in predicting prognosis and chemotherapy benefit for T1-2 N1 nasopharyngeal carcinoma: A multicenter retrospective study.

BACKGROUND AND PURPOSE: This multicenter retrospective study aimed to investigated the prognostic value of unequivocal radiologic extranodal extension (rENE) and the efficacy of chemotherapy for stage T1-2 N1 nasopharyngeal carcinoma (NPC) in the IMRT era. MATERIALS AND METHODS: We included 1,082 patients treated in 2005-2017 from three centers. rENE was recorded as G1 (coalescent nodal mass comprising ≥ 2 inseparable nodes) or G2 (invading beyond perinodal fat to frankly infiltrate adjacent structures). Multivariable analysis (MVA) evaluated the prognostic value of rENE. The value of chemotherapy was assessed in rENE-positive (rENE + ) and rENE-negative (rENE - ) subset separately. RESULTS: Centers 1, 2, and 3 had 139/515 (27.0 %), 100/365 (27.4 %), and 43/202 (21.3 %) cN + patients with rENE, respectively. Compared to rENE-, rENE + patients had a worse distant metastasis-free survival (DMFS) and overall survival (OS) (all p < 0.001). MVA confirmed the prognostic of both G1-rENE and G2-rENE for distant metastasis [G1: hazard ratio (HR): 2.933, G2: HR: 6.942, all p < 0.001] and death (G1: HR: 1.587, p = 0.040; G2: HR: 6.162, p < 0.001). There was no significant difference for DMFS and OS between chemo-radiotherapy and radiotherapy alone in rENE + and rENE - groups (all p > 0.1). However, rENE + patients with a cumulative cisplatin/nedaplatin dose (CCND) of > 160 mg/m2 had an improved DMFS (p = 0.033) but no OS (p = 0.197). CONCLUSION: Unequivocal rENE is prognostic in patients with T1-2 N1 NPC. Addition of chemotherapy to radiotherapy did not affect DMFS and OS in rENE - patients. Chemotherapy with a CCND of > 160 mg/m2 improved DMFS in rENE + patients.

Refining TNM-8 M1 categories with anatomic subgroups for previously untreated de novo metastatic nasopharyngeal carcinoma.

PURPOSE: To propose a refined M1 classification in de novo metastatic nasopharyngeal carcinoma (NPC) based on pooled data from two academic institutions. METHODS: Previously untreated de novo M1 NPC patients prospectively treated at The University of Hong Kong (N = 69) and Fujian Cancer Hospital (N = 114) between 2007 and 2016 were recruited and randomized in a 2:1 ratio to generate training (N = 120) and validation (N = 63) cohorts, respectively. Multivariable analysis (MVA) was performed for the training and validation cohorts to identify anatomic prognostic factors for overall survival (OS). Recursive partitioning analysis (RPA) was performed which incorporated the anatomic prognostic factors identified in the MVA to derive Anatomic-RPA groups which stratified OS in the training cohort, and were then validated in the validation cohort. RESULTS: Median follow-up for the training and validation cohorts was 27.2 and 30.2 months with 3-year OS of 51.6% and 51.1%, respectively. MVA revealed that co-existing liver-bone metastases was the only factor prognostic for OS in both the training and validation cohorts. Anatomic-RPA separated M1 disease into M1a (no co-existing liver-bone metastases) and M1b (co-existing liver-bone metastases) with median OS 39.5 and 23.7 months, respectively (p = 0.004) in the training cohort. RPA for the validation cohort also confirmed good segregation with co-existing liver-bone metastases with median OS 47.7 and 16.0 months, respectively (p = 0.008). CONCLUSION: Our proposal to subdivide de novo M1 NPC into M1a (no co-existing liver-bone metastases) vs. M1b (co-existing liver-bone metastases) provides better OS segregation.

Comparison of radiotherapy combined with nimotuzumab vs. chemoradiotherapy for locally recurrent nasopharyngeal carcinoma.

BACKGROUND: The present study compared the effectiveness and toxicity of two treatment modalities, namely radiotherapy combined with nimotuzumab (N) and chemoradiotherapy (CRT) in patients with locally recurrent nasopharyngeal carcinoma (LR-NPC). METHODS: Patients with LR-NPC who were treated with radiotherapy were retrospectively enrolled from January 2015 to December 2018. The treatment included radiotherapy combined with N or platinum-based induction chemotherapy and/or concurrent chemotherapy. The comparison of survival and toxicity between the two treatment modalities was evaluated using the log-rank and chi-squared tests. Overall survival (OS) was the primary endpoint. RESULTS: A total of 87 patients were included, of whom 32 and 55 were divided into the N group and the CRT group, respectively. No significant differences were noted in the survival rate between the N and the CRT groups (4-year OS rates, 37.1% vs. 40.7%, respectively; P = 0.735). Mild to moderate acute complications were common during the radiation period and mainly included mucositis and xerostomia. The majority of the acute toxic reactions were tolerated well. A total of 48 patients (55.2%) demonstrated late radiation injuries of grade ≥ 3, including 12 patients (37.5%) in the N group and 36 patients (66.5%) in the CRT group. The CRT group exhibited significantly higher incidence of severe late radiation injuries compared with that of the N group (P = 0.011). CONCLUSION: Radiotherapy combined with N did not appear to enhance treatment efficacy compared with CRT in patients with LR-NPC. However, radiotherapy combined with N may be superior to CRT due to its lower incidence of acute and late toxicities. Further studies are required to confirm the current findings.

International Recommendations on Reirradiation by Intensity Modulated Radiation Therapy for Locally Recurrent Nasopharyngeal Carcinoma.

PURPOSE: Reirradiation for locally recurrent nasopharyngeal carcinoma (NPC) is challenging because prior radiation dose delivered in the first course is often close to the tolerance limit of surrounding normal structures. A delicate balance between achieving local salvage and minimizing treatment toxicities is needed. However, high-level evidence is lacking because available reports are mostly retrospective studies on small series of patients. Pragmatic consensus guidelines, based on an extensive literature search and the pooling of opinions by leading specialists, will provide a useful reference to assist decision-making for these difficult decisions. METHODS AND MATERIALS: A thorough review of available literature on recurrent NPC was conducted. A set of questions and preliminary draft guideline was circulated to a panel of international specialists with extensive experience in this field for voting on controversial areas and comments. A refined second proposal, based on a summary of the initial voting and different opinions expressed, was recirculated to the whole panel for review and reconsideration. The current guideline was based on majority voting after repeated iteration for final agreement. RESULTS: The initial round of questions showed variations in clinical practice even among the specialists, reflecting the lack of high-quality supporting data and the difficulties in formulating clinical decisions. Through exchange of comments and iterative revisions, recommendations with high-to-moderate agreement were formulated on general treatment strategies and details of reirradiation (including patient selection, targets contouring, dose prescription, and constraints). CONCLUSION: This paper provides useful reference on radical salvage treatment strategies for recurrent NPC and optimization of reirradiation through review of published evidence and consensus building. However, the final decision by the attending clinician must include full consideration of an individual patient's condition, understanding of the delicate balance between risk and benefits, and acceptance of risk of complications.

Association of Tumor Protein p53 and Ataxia-Telangiectasia Mutated Comutation With Response to Immune Checkpoint Inhibitors and Mortality in Patients With Non-Small Cell Lung Cancer.

Importance: Immune checkpoint inhibitors (ICIs) can elicit durable antitumor responses in patients with non-small cell lung cancer (NSCLC), but only 20% to 25% of patients respond to treatment. As important genes in the DNA damage response pathway, comutation in the tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM) genes may be associated with genomic instability and hypermutation. However, the prevalence of TP53 and ATM comutation and its association with response to ICIs are not fully understood. Objective: To examine the prevalence of the TP53 and ATM comutation, the potential mechanism, and its association with response to ICIs among patients with NSCLC. Design, Setting, and Participants: This multiple-cohort study included patients with NSCLC from the Geneplus Institute, the Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering Cancer Center (MSKCC) databases and from the POPLAR and OAK randomized controlled trials. Samples in the Geneplus cohort were collected and analyzed from April 30, 2015, through February 28, 2019. Data from TCGA, the MSKCC, and the POPLAR and OAK cohorts were obtained on January 1, 2019, and analyzed from January 1 to April 10, 2019. Next-generation sequencing assays were performed on tumor samples by the Geneplus Institute. Genomic, transcriptomic, and clinical data were obtained from TCGA and MSKCC databases. Exposures: Comprehensive genetic profiling was performed to determine the prevalence of TP53 and ATM comutation and its association with prognosis and response to ICIs. Main Outcomes and Measures: The main outcomes were TP53 and ATM comutation frequency, overall survival (OS), progression-free survival, gene set enrichment analysis, and immune profile in NSCLC. Results: Patients with NSCLC analyzed in this study included 2020 patients in the Geneplus cohort (mean [SD] age, 59.5 [10.5] years; 1168 [57.8%] men), 1031 patients in TCGA cohort (mean [SD] age, 66.2 [9.5] years; 579 [56.2%] men), 1527 patients in the MSKCC cohort (662 [43.4%] men), 350 patients in the MSKCC cohort who were treated with ICIs (mean [SD] age, 61.4 [13.8] years; 170 [48.6%] men), and 853 patients in the POPLAR and OAK cohort (mean [SD] age, 63.0 [9.1] years; 527 [61.8%] men). Sites of TP53 and ATM comutation were found scattered throughout the genes, and no significant difference was observed in the frequency of TP53 and ATM comutation within the histologic subtypes and driver genes. In 5 independent cohorts of patients with NSCLC, TP53 and ATM comutation was associated with a significantly higher tumor mutation burden compared with the sole mutation and with no mutation (TCGA, MSKCC, Geneplus, and POPLAR and OAK cohort). Among patients treated with ICIs in the MSKCC cohort, TP53 and ATM comutation was associated with better OS than a single mutation and no mutation among patients with any cancer (median OS: TP53 and ATM comutation, not reached; TP53 mutation alone, 14.0 months; ATM mutation alone, 40.0 months; no mutation, 22.0 months; P = .001; NSCLC median OS: TP53 and ATM comutation, not reached; TP53 mutation alone, 11.0 months; ATM mutation alone, 16.0 months; no mutation, 14.0 months; P = .24). Similar results were found in the POPLAR and OAK cohort in which the disease control benefit rate, progression-free survival, and OS were all greater in patients with the TP53 and ATM comutation compared with the other 3 groups (median progression-free survival: TP53 and ATM comutation, 10.4 months; TP53 mutation, 1.6 months; ATM mutation, 3.5 months; no mutation, 2.8 months; P = .01; median OS: TP53 and ATM comutation, 22.1 months; TP53 mutation, 8.3 months; ATM mutation, 15.8 months; no mutation, 15.3 months; P = .002). Conclusions and Relevance: This study's findings suggest that the TP53 and ATM comutation occurs in a subgroup of patients with NSCLC and is associated with an increased tumor mutation burden and response to ICIs. This suggests that TP53 and ATM comutation may have implications as a biomarker for guiding ICI treatment.

International Guideline on Dose Prioritization and Acceptance Criteria in Radiation Therapy Planning for Nasopharyngeal Carcinoma.

PURPOSE: The treatment of nasopharyngeal carcinoma requires high radiation doses. The balance of the risks of local recurrence owing to inadequate tumor coverage versus the potential damage to the adjacent organs at risk (OARs) is of critical importance. With advancements in technology, high target conformality is possible. Nonetheless, to achieve the best possible dose distribution, optimal setting of dose targets and dose prioritization for tumor volumes and various OARs is fundamental. Radiation doses should always be guided by the As Low As Reasonably Practicable principle. There are marked variations in practice. This study aimed to develop a guideline to serve as a global practical reference. METHODS AND MATERIALS: A literature search on dose tolerances and normal-tissue complications after treatment for nasopharyngeal carcinoma was conducted. In addition, published guidelines and protocols on dose prioritization and constraints were reviewed. A text document and preliminary set of variants was circulated to a panel of international experts with publications or extensive experience in the field. An anonymized voting process was conducted to rank the proposed variants. A summary of the initial voting and different opinions expressed by members were then recirculated to the whole panel for review and reconsideration. Based on the comments of the panel, a refined second proposal was recirculated to the same panel. The current guideline was based on majority voting after repeated iteration for final agreement. RESULTS: Variation in opinion among international experts was repeatedly iterated to develop a guideline describing appropriate dose prioritization and constraints. The percentage of final agreement on the recommended parameters and alternative views is shown. The rationale for the recommendations and the limitations of current evidence are discussed. CONCLUSIONS: Through this comprehensive review of available evidence and interactive exchange of vast experience by international experts, a guideline was developed to provide a practical reference for setting dose prioritization and acceptance criteria for tumor volumes and OARs. The final decision on the treatment prescription should be based on the individual clinical situation and the patient's acceptance of optimal balance of risk.