Final survival analysis of induction chemotherapy with lobaplatin and fluorouracil versus cisplatin and fluorouracil followed by concurrent chemoradiotherapy in nasopharyngeal carcinoma: a multicenter, randomized, phase 3 trial

Domain: neuroscience
Published: 2026-02-10
Editorial outcome: minor_revision

Abstract
In nasopharyngeal carcinoma, cisplatin is known to be associated with poor treatment compliance and notable side effects. More effective and safer platinum drugs are needed for the treatment of patients with nasopharyngeal carcinoma. In 2021, our multicenter, randomized, phase 3 trial reported that lobaplatin and fluorouracil induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than did cisplatin-based therapy in nasopharyngeal carcinoma. Data from the 10-year survival analysis are updated here. With a median follow-up of 10.6 years in the intention-to-treat population, 10-year progression-free survival is 70.7% in the lobaplatin-based therapy group vs. 71.9% in the cisplatin-based therapy group (HR 1.02, 95% CI 0.72–1.43; log-rank p = 0.885). The difference between the groups is 1.2% (95% CI −6.7–9.1, p = 0.015), which is lower than the prespecified non-inferiority margin of 10%. The results are similar when we analyze patients in the per-protocol population. In the univariable and multivariable analyses, stage is an independent prognostic factor for progression-free survival (p = 0.001). The subgroup analyses suggest that the non-inferiority of lobaplatin-based therapy did not differ among specific populations. The incidence of late toxic effects is similar between the therapy groups, except for grades 1–2 peripheral neuropathy (p = 0.033), grades 1–2 deafness/otitis (p = 0.021), and grades 1–2/3 nephrotoxicity (p = 0.005; p = 0.021), the incidence of which is greater in the cisplatin-based therapy group than in the lobaplatin-based therapy group. Our findings suggest that lobaplatin and fluorouracil induction chemotherapy plus lobaplatin-based concurrent chemoradiotherapy is an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.

Introduction
Approximately 129,000 new cases of nasopharyngeal carcinoma were diagnosed globally in 2018, accounting for 0.7% of all cancers diagnosed 1–3. Nevertheless, its global geographical distribution is extremely unbalanced; >70% of new cases are in Southern China, southeast Asia, and northern Africa 1,2,4. Despite recent improvements in the survival of patients with locoregionally advanced nasopharyngeal carcinoma, notable side effects and therapy compliance are still not satisfactory in patients with this disease 4,5.

Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy is generally recommended as the standard first-line therapy for locoregionally advanced nasopharyngeal carcinoma. Nevertheless, cisplatin-based therapy is known to be related to poor toxicity. Thus, effective and safer platinum drugs for treating locoregionally advanced nasopharyngeal carcinoma are needed. Lobaplatin, a third-generation platinum-based drug, leads to the formation of DNA adducts and causes cell apoptosis 6,7. Our phase 2 trial regarding lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy for stage III–IVB nasopharyngeal carcinoma reported encouraging antitumor activity and safer treatment-related toxicity 8. In 2021, our multicenter, randomized, phase 3 trial (No. ChiCTR-TRC-13003285) compared the efficacy and safety of lobaplatin and induction chemotherapy plus concurrent chemoradiotherapy with cisplatin and fluorouracil induction chemotherapy plus concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma, with non-inferior 5-year progression-free survival and fewer treatment-related toxicities 4. A durable long-term survival benefit is imperative.

In this work, we sought to determine the 10-year survival and late toxicity of lobaplatin and fluorouracil induction chemotherapy plus lobaplatin-based concurrent chemoradiotherapy compared with those of cisplatin and fluorouracil induction chemotherapy plus cisplatin-based concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. The associated late toxic effects of these therapies were also reported.

Results
Between June 7, 2013, and June 16, 2015, 515 patients were screened for eligibility, 502 of whom were randomly assigned to receive lobaplatin-based therapy (n = 252) or cisplatin-based therapy (n = 250) (Fig. 1). Measurements of plasma Epstein-Barr virus DNA (EBV-DNA) were available for 478 patients (237 patients [94%] in the lobaplatin-based therapy group and 241 patients [96.4%] in the cisplatin-based therapy group). Baseline characteristics were balanced between the two therapy groups (Table 1).

The data cutoff date for this updated analysis was April 30, 2025. The median follow-up was 10.6 years (IQR 10.5–10.7) for the intention-to-treat population. In the intention-to-treat population, 10-year progression-free survival rate was 70.7% (95% CI 65.1–76.8) in the lobaplatin-based therapy group vs. 71.9% (95% CI 66.4–77.8) in the cisplatin-based therapy group (HR 1.02, 95% CI 0.72–1.43, log-rank p = 0.885). The difference between the therapy groups was 1.2% (95% CI −6.7–9.1%, p = 0.015), which was lower than the prespecified non-inferiority margin of 10% (Fig. 2A; Supplementary Table 1). Sixty-nine of 252 patients (27%) in the lobaplatin-based therapy group and 68 of 250 patients (27.2%) in the cisplatin-based therapy group experienced a progression-free survival event in the intention-to-treat population. The proportional hazards assumption was met (Supplementary Table 2). There were no differences between the therapy groups regarding the secondary endpoints of overall survival, locoregional recurrence-free survival, and distant metastasis-free survival in the intention-to-treat population (Fig. 2B–D; Supplementary Table 1).

In the per-protocol population, 10-year progression-free survival rate was 70.1% (95% CI 64.3–76.3) in the lobaplatin-based therapy group vs. 72.5% (95% CI 66.9–78.5) in the cisplatin-based therapy group (HR 1.08, 95% CI 0.77–1.52, log-rank p = 0.664) (Supplementary Fig. 1A; Supplementary Table 1). The difference between the therapy groups was 2.4% (95% CI −5.6–9.5, p = 0.033), which was lower than the pre-specified non-inferiority margin of 10% (Supplementary Fig. 1B–D; Supplementary Table 1). Sixty-eight of 252 patients (27%) in the lobaplatin-based therapy group and 66 of 250 patients (26.4%) in the cisplatin-based therapy group experienced a progression-free survival event in the per-protocol population. The proportional hazards assumption was met (Supplementary Table 2). Differences were not observed between the therapy groups in the per-protocol analysis for the secondary endpoints (Supplementary Fig. 1B–1D, Supplementary Table 1). Summaries and timepoints of patients lost to follow-up after treatment are presented in Supplementary Table 3–4.

In the univariable and multivariable analyses, stage was an independent prognostic factor for progression-free survival, locoregional recurrence-free survival, and distant metastasis-free survival in the intention-to-treat population and the per-protocol population, marginal significance for overall survival in the intention-to-treat population (Table 2, Supplementary Table 5). Results were similar when we excluded patients lost to follow-up in the sensitivity analyses (Supplementary Table 6).

At the last follow-up on April 30, 2025, total of 71 (14.1%) patients of local recurrence (35 of 252 patients [13.9%] in the lobaplatin-based therapy group vs. 36 of 250 patients [14.4%] in the cisplatin-based therapy group) and 85 (16.9%) patients of distant metastasis (42 of 252 patients [16.7%] in the lobaplatin-based therapy group vs. 43 of 250 patients [17.2%] in the cisplatin-based therapy group) were observed (Supplementary Table 7). Fourteen new cases of local recurrence (2.8%) were observed, including 5 of 252 cases (2.1%) in the lobaplatin-based therapy group vs. 9 of 250 patients (3.6%) in the cisplatin-based therapy group. In addition, 12 new cases of distant metastasis (2.4%) were reported, comprising 8 of 252 cases (3.1%) in the lobaplatin-based therapy group vs. 4 of 250 cases (1.6%) in the cisplatin-based therapy group. Furthermore, 70 of 502 cases (16.9%) died, with 35 of 252 cases (14%) in the lobaplatin-based therapy group vs. 35 of 250 cases (14%) in the cisplatin-based therapy group (Supplementary Table 8).

We performed subgroup analyses for progression-free survival, overall survival, locoregional recurrence-free survival, and distant metastasis-free survival in patients stratified by the following covariates: sex, age, Karnofsky scale, stage, EBV-DNA, and hospital. No interactions between these covariates and therapy were observed, irrespective of the intention-to-treat population or the per-protocol population, suggesting that the non-inferiority of lobaplatin-based therapy did not differ among specific populations. The details of the analyses are shown in Fig. 3 and Supplementary Fig. 2.

During the entire therapy and follow-up course, the proportions of the most common late adverse events (i.e., those occurring in >10% of patients) were similar between the lobaplatin-based therapy group and the cisplatin-based therapy group (dry mouth: 189 patients [75%] vs. 184 patients [73.5%]; deafness/otitis: 104 patients [41.3%] vs. 138 patients [55.5%]; neck tissue damage: 90 patients [35.7%] vs. 97 patients [38.9%]). After multivariable analyses, the incidence of grades 1–2 peripheral neuropathy (28 patients [11.2%] vs. 15 patients [6%], p = 0.033), grades 1–2 deafness/otitis (116 patients [46%] vs. 88 patients [34.9%], p = 0.021), and grades 1–2 nephrotoxicity (22 patients [8.8%] vs. 6 patients [2.4%], p = 0.005) was higher in the cisplatin-based therapy group than in the lobaplatin-based therapy group. In addition, the incidence of grade 3 nephrotoxicity (10 patients [4%] vs. 1 patient [0.4%], p = 0.021) was also higher in the cisplatin-based therapy group compared with the lobaplatin-based therapy group (Table 3). No grade 4–5 late adverse events were recorded. Details of the acute adverse events in the two therapy groups were reported in our previous study 4. Temporal trends in late toxicities are presented in Supplementary Fig. 3. Descriptions of patients with missing toxicity data in each therapy group are showed in Supplementary Table 9.

Details regarding radiotherapy compliance, relative dose intensity, and dose reductions are provided in Supplementary Table 10.

Methods
Study design and participants
This is a multicenter, open-label, non-inferiority, randomized, controlled, phase 3 trial. The Institutional Ethics Review Board of Sun Yat-sen University Cancer Center approved the trial protocol (No. B2012-003-01). The trial was performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. Written informed consent was obtained from all patients before enrollment. Patients could withdraw consent at any time after enrollment and could discontinue the trial if severe coexisting conditions occurred. The study design was previously reported 4. We enrolled patients from hospitals in China with previously untreated, non-distant-metastatic, non-keratinizing, stage III–IVB nasopharyngeal carcinoma (7th edition of the International Union Against Cancer Staging System). To be eligible for the study, the following inclusion criteria had to be met: age 18–60 years; a Karnofsky performance status score of at least 70; loss of no more than 10% of body weight; adequate hematological parameters (absolute neutrophil count ≥ 2000/μL, platelet count ≥ 100,000/μL, and hemoglobin concentration ≥ 90g/L); adequate renal function (creatinine clearance ≥ 80mL/min); and adequate hepatic function (serum bilirubin, alanine aminotransferase, and aspartate aminotransferase concentrations ≤ 2.0 times the upper limit of normal). The main exclusion criteria were previous malignancies; the presence of recurrent or distant metastasis; previous radiotherapy, chemotherapy, immunotherapy, or surgery; severe coexisting illness; and pregnancy or lactation. The full list of eligibility and ineligibility criteria is provided in the Protocol (Supplementary Note 2).

Randomization and masking
Patients were randomly assigned (1:1) to one of four blocks to receive lobaplatin and fluorouracil induction chemotherapy plus lobaplatin-based concurrent chemoradiotherapy (lobaplatin-based therapy group) or cisplatin and fluorouracil induction chemotherapy plus cisplatin-based concurrent chemoradiotherapy (cisplatin-based therapy group). The identity of each group was known only to the statistician. The clinical trial center of Sun Yat-sen University Cancer Center conducted the centralized randomization procedure using a computer-generated random number code. The investigators and patients were aware of the therapy group assignment (open-label), whereas the Central Imaging Review Committee was masked to the treatment assignment. Several quality control measures were implemented to ensure scientific integrity (Protocol [Supplementary Note 2]).

Randomization was conducted at the Clinical Trial Center of Sun Yat-sen University Cancer Center. The computer-generated random number sequence was generated using a block design with a block size of four 27–29. In our trial, the stage and hospital could significantly influence the treatment. If these characteristics were unevenly distributed between therapy groups, the evaluation of the results could be affected. Stratified randomization is an important trial design that divides participants into several levels on the basis of certain important characteristics and then randomly assigns them within each level. Stratified analysis is the analysis of survival data using this method, considering the effect of different stratification factors on survival, which can be used to accurately evaluate treatment effects 30. Blocks of four have been used in several trials of nasopharyngeal carcinoma 5,14,31,32.

Procedures
Pretreatment evaluation included a complete medical history; physical examination; hematologic and biochemical analyses; nasal endoscopy or rhinosinusal endoscopy; contrast-enhanced MRI or CT of the nasopharynx and neck (CT was indicated only in patients with contraindications to MRI); chest imaging (X-ray or CT); and liver imaging (external ultrasonography or CT), a bone scan or 18F-FDG PET-CT was mandatory for distant metastasis staging. All patients were referred for a dental examination before therapy. Pretreatment evaluations were performed within 2 weeks before randomization.

Patients in the lobaplatin-based therapy group received two cycles of induction lobaplatin (30 mg/m², 2 h intravenously, on days 1 and 22) and fluorouracil (800 mg/m², continuous 120 h infusion, on days 1–5 and 22–26), administered once every 3 weeks. For patients assigned to the cisplatin-based therapy group, induction chemotherapy was given at 3 week intervals as follows: cisplatin at a dose of 100 mg/m², 4 h intravenously on days 1 and 22, and fluorouracil at a dose of 800 mg/m² as a continuous 120 h infusion on days 1–5 and 22–26. Subsequently, both groups received concurrent chemoradiotherapy with either lobaplatin (30 mg/m², 2 h intravenously) or cisplatin (100 mg/m², 4 h intravenously) every 3 weeks on days 43 and 64. Two cycles were given concurrently with intensity-modulated radiotherapy (IMRT), according to previously published guidelines 4. The radiotherapy plans were centrally administered and reviewed in accordance with the criteria recommended in international guidelines 33. Dose modifications of chemotherapy due to adverse events were permitted as specified in the Protocol (Supplementary Note 2).

Acute toxic effects observed during treatment were graded in accordance with the Common Toxicity Criteria for Adverse Events (version 3.0). Radiotherapy toxicity was assessed using the late Radiation Morbidity Scoring Scheme of the Radiation Therapy Oncology Group (Supplementary Data 1) 34. Patients were removed from the trial if they experienced disease progression or severe comorbidities or if they refused to receive therapy at any time during the trial. After the primary treatment was completed, the patients were followed up every 3 months for the first 3 years, every 6 months for 4–5 years, and annually thereafter. The nasopharynx was assessed by nasal endoscopy or rhinosinusal endoscopy approximately 4 weeks after the completion of radiotherapy. During routine follow-up, hematological and biochemical analyses, nasal endoscopy or rhinosinusal endoscopy, enhanced MRI or CT of the nasopharynx and neck, chest radiography, and abdominal scan were performed, or when tumor recurrence or metastasis was clinically suspected. Tumor recurrence or metastasis was confirmed on the basis of the results of biopsy or fine needle aspiration. For lesions that were not accessible, the clinical diagnosis was also accepted on the basis of the presence of at least two classic radiological features on CT, MRI, abdominal ultrasonography, or ¹⁸F-FDG PET-CT (Protocol).

Outcomes
The primary endpoint was progression-free survival, which was defined as the time from the date of randomization to the date of locoregional recurrence, distant metastasis, or death from any cause, whichever occurred first. The following secondary endpoints were also analyzed: overall survival (interval between randomization and the date of death), locoregional recurrence-free survival (interval between randomization and the date of locoregional recurrence or death from any cause), distant metastasis-free survival (interval between randomization and the date of distant metastasis or death from any cause), toxicity profile, and treatment compliance.

Statistical analysis
The present trial adopted a non-inferiority margin of 10% 4,35. This margin was selected to ensure preservation of an appropriate proportion of the treatment effect of the standard regimen 36–42. Non-inferiority would be concluded if the upper limit of the 95% confidence interval (CI) for the difference in progression-free survival between the lobaplatin-based group and the cisplatin-based group did not exceed 10%. Based on these assumptions, a minimum of 246 patients per group (492 in total, allowing for a 10% dropout or loss to follow-up) was required to provide 80% power with a one-sided type I error rate of 2.5% 4.

Efficacy analyses were performed in patients who received at least one cycle of concurrent chemoradiotherapy. The safety analysis population comprised patients who received at least one cycle of induction chemotherapy 4.

Survival was estimated via the Kaplan-Meier method, with Greenwood’s formula used to calculate 95% CIs and the log-rank test used to establish significance. Time-to-event data were censored for patients who were lost to follow-up and patients with no events observed at the date of the last follow-up. For patients who had no observed events, the follow-up times and statuses were recorded according to the final follow-up visit (April 30, 2025). We generated hazard ratios with the Cox proportional-hazards model with the assumption of proportional hazards and assessed them on the basis of Schoenfeld residuals. The Bonferroni method was applied to control the type I error in multiple toxicity comparisons.

SPSS (IBM, version 26.0) and SAS (version 9.4) were used for statistical analyses. The statistical test for the primary endpoint was one-sided, and p < 0.025 was considered significant. All statistical tests for the other endpoints were two-sided, and p < 0.05 was considered significant. The database is preserved on the Research Data Deposit public platform (No. RDDA2021002107). The trial is registered with the Chinese Clinical Trial Registry (No. ChiCTR-TRC-13003285).

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "Reviewer Comments (Design and Statistical Considerations)\nOverall, this manuscript is well-written, clearly structured, and easy to follow. The long-term follow-up and randomized, multi-center design are major strengths, and the trial addresses an important clinical question in the management of nasopharyngeal carcinoma. I have several comments for the authors to consider:\nClarification of Randomization Method\nThe manuscript states that “Patients were randomly assigned (1:1) to one of four blocks…,” but it is unclear what “four blocks” means in this context. I assume this refers to permuted block randomization with a block size of four, but this should be stated explicitly. If this is the case, please clarify the block size and the rationale for this choice, along with how stratification by stage and hospital was incorporated into the randomization scheme.\nSample Size and Power Justification\nThe current description (“The trial required at least a sample size of 492 patients…”) is not standard for time-to-event non-inferiority trials. A complete justification should include: the non-inferiority margin, type I error level, target power, the difference in PFS at which power was calculated, the required number of events, and assumptions about accrual and follow-up periods. This information is essential for assessing whether the study was adequately powered to meet its primary objective.\nNon-Inferiority Margin\nThe choice of a 10% absolute margin for 10-year PFS appears relatively wide, particularly given the high baseline survival rate (~71%). While I defer to clinical experts for the ultimate acceptability of this margin, a brief rationale based on prior literature, expected effect sizes, and clinical relevance would help readers interpret this choice.\nMultiplicity in Toxicity Comparisons\nMultiple toxicity endpoints were tested, with statistically significant results reported for grade 1–2 deafness/otitis and peripheral neuropathy. No adjustment for multiple comparisons is mentioned. Given the number of toxicity outcomes evaluated, these findings may not remain significant after correction for multiplicity. I recommend clarifying whether multiplicity adjustments were considered and, if not, noting this as a limitation.\nToxicity as a Motivation for Non-Inferiority Design\nThe original rationale for pursuing a non-inferiority design was the expectation that lobaplatin-based therapy would offer a better toxicity profile. However, the long-term toxicity data presented here do not clearly support this premise. A brief discussion of potential reasons (e.g., limitations in long-term toxicity data collection, competing late effects) would help contextualize the findings.\nHandling of Missing Data in Long-Term Follow-Up\nIn a 10-year follow-up study, losses to follow-up and missing data are inevitable. The manuscript should report the number (and percentage) of patients lost to follow-up, the reasons where available, and whether any sensitivity analyses (e.g., worst-case scenario) were performed to assess the potential impact on the results.", "reviewer_2": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts.", "reviewer_3": "This manuscript presents the final 10-year follow-up results of a randomized phase III non-inferiority trial comparing lobaplatin versus cisplatin as induction and concurrent chemotherapy in locally advanced nasopharyngeal carcinoma (LA-NPC). The updated analysis confirms the non-inferiority of lobaplatin with respect to progression-free survival, consistent with their prior report, and demonstrates no significant differences in locoregional recurrence-free survival, distant metastasis-free survival, or overall survival. Importantly, in addition to previously reported reductions in acute toxicities (hematologic, nausea, vomiting, weight loss, nephrotoxicity), this long-term analysis highlights lower rates of late grade 1–2 ototoxicity and peripheral neuropathy with lobaplatin. This is clinically meaningful given the survivorship implications in LA-NPC. This publication also adds invaluable insight into the long-term outcome of LA-NPC in the era of induction chemotherapy.\nI have several points and suggestions for improvement:\n1. Statistical Analysis: The study design and the non-inferiority margin should be explicitly stated in the Methods section.\n2. Results:\n- Outcomes: Always good to indicate the additional number of events (both local and distant) were observed with the longer follow-up since the last report?\n- This reviewer will also request that the investigators indicate the cumulative number of locoregional and distant relapse events in both group.\n- Line 194: The statement that “in the per-protocol analysis, the PFS difference was 2.4% (95% CI -5.6% to 10.5%), which was lower than the non-inferiority margin of 10%” is potentially misleading. The 95% CI should be higher than the pre-specified margin.\n- Line 200: The analysis should be described as univariable and multivariable, instead of univariate and multivariate.\n- Line 214: The value of “115%” is likely a typo\n3. Discussion\n- Line 229: The authors should consider specifying progression-free survival (primary endpoint of this study) rather than “survival”\n- This study used a “de-escalated” chemotherapy schedule with 2 cycles of IC and 2 cycles of concurrent chemotherapy, in place of the commonly used regimen of 3 cycles IC+ 3 cycles concurrent. Furthermore, the control arm was PF, rather than the current standard GP or taxane-based triplet chemotherapy (per NCCN, CSCO guidelines). The implications should be addressed explicitly in the discussion section.\n4. Follow-up and Missing Data\n- Attrition is a potential issue for long term follow-up. The authors should provide information on loss to follow-up and the extent of missing toxicity data.\n- It would be more informative if the authors can provide a breakdown of progression and/or death events.\n5. Toxicity Reporting\n- For such a study, the key would be long-term toxicities. In particular, this reviewer would be interested to assess the long-term effects on nephrotoxicity between lobaplatin vs cisplatin. The reporting of late adverse events deserves further elaboration. Specifically, can the authors specify the assessment scale used for late toxicities? The RTOG/ EORTC late toxicity grading 1 did not capture peripheral neuropathy and ototoxicity (which are the two main findings here) (appendix P32 in original publication). This information is critical for readers to interpret the clinical benefit of lobaplatin.\n- Please indicate the number of patients assessed for toxicity at each follow-up timepoint.\n- How was follow-up ensured for monitoring of late effects?\n- As this reviewer alluded to, was nephrotoxicity assessed since this is one of the main debilitating long-term toxicity of cisplatin (Grant, et al. JAMA Oncology, 2025).\n- Reporting of the “worst grade toxicity” may not fully capture the clinical relevance of long-term adverse effects in NPC survivors. For example, ototoxicity can fluctuate and may partially recover 2. Also, peripheral neuropathy may also improve over time, although there may not be complete recovery 3. To better depict these dynamics, the authors may consider using time stream plots or longitudinal toxicity curves to show how these late toxicities evolve.\nWithout those, it is a missed opportunity for the readers to appraise the long-term “benefits”, if any, of lobaplatin and its advantage over cisplatin. In fact, based on the key results highlighted in Table 2, this reviewer may contest that there are little to no added benefits of administering lobaplatin vs cisplatin. Compliance may be improved with lobaplatin, but yet with the reduced compliance, the outcomes and late toxicities appear comparable, and not necessarily fewer than cisplatin. Which brings me to my key point – Cisplatin remains the dominant platinum agent in head and neck cancer. Thus far, substitutes like nedaplatin, carboplatin, oxaliplatin have been shown to be “comparable” in clinical trials, but most have not penetrated the clinic. In fact, for cisplatin eligible patients, cisplatin remains the preferred choice. The investigators ought to discuss why this may be the case. Perhaps, the long term data of this trial will be helpful to inform the community about the cross-utility of the platinum class of drugs.\nREFERENCES\n1. Cox, J. D., Stetz, J., & Pajak, T. F. (1995). Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). International journal of radiation oncology, biology, physics, 31(5), 1341–1346. https://doi.org/10.1016/0360-3016(95)00060-C\n2. Low, W. K., Toh, S. T., Wee, J., Fook-Chong, S. M., & Wang, D. Y. (2006). Sensorineural hearing loss after radiotherapy and chemoradiotherapy: a single, blinded, randomized study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 24(12), 1904–1909. https://doi.org/10.1200/JCO.2005.05.0096\n3. Miltenburg, N. C., & Boogerd, W. (2014). Chemotherapy-induced neuropathy: A comprehensive survey. Cancer treatment reviews, 40(7), 872–882. https://doi.org/10.1016/j.ctrv.2014.04.004", "reviewer_4": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts.", "reviewer_5": "Review suggestion: minor\nComments：\nThe data from the 10-year survival analysis of multi-center, randomized, phase 3 trial (no. ChiCTR-TRC13003285) which reported that lobaplatin and fluorouracil induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than did cisplatin-based therapy in nasopharyngeal carcinoma is updated in this article.10-year progression-free survival in the lobaplatin-based therapy group and the incidence of late toxic effects was similar with the progression-free survival in the cisplatin-based therapy group，except grade 1–2 deafness/otitis and grade 1–2 peripheral neuropathy .In the univariate and multivariate analyses, stage was an independent prognostic factor for progression-free survival.\nThe 10-year follow-up data from the article support the use of lobaplatin in patients with nasopharyngeal carcinoma. It enriches the types of chemotherapy drugs and provides multiple options for physicians in various chemotherapy treatments\nA question needs to be answered:\nIs deafness/otitis media related to radiotherapy?"}, "author_response": "1 Response to Reviewer# 1\n3 providing constructive feedback. These insightful comments were highly valuable and have\n4 significantly improved the clarity and overall quality of our study.\n5 1. Clarification of Randomization Method\n7 but it is unclear what “four blocks” means in this context. I assume this refers to permuted\n8 block randomization with a block size of four, but this should be stated explicitly. If this\n9 is the case, please clarify the block size and the rationale for this choice, along with how\n10 stratification by stage and hospital was incorporated into the randomization scheme.\n14 design with a block size of four. For both clinical implementation and statistical\n15 considerations, we believe that a block size of four represents an optimal compromise for\n16 the following reasons 1-3: (1) ensures group balance—block randomization with a block\n17 size of four effectively prevents imbalances in the number of participants between\n18 treatment groups; (2) controls for known and unknown confounders—keeping treatment\n19 groups balanced with respect to predefined variables (e.g., sex, age, and disease stage)\n20 reduces the risk of confounding bias; (3) improves statistical power—balanced allocation\n21 across treatment groups enhances the statistical power of the trial, making the results more\n22 reliable; and (4) allows prespecification of the randomization scheme—unlike some\n23 adaptive randomization methods, permuted block randomization schemes can be fully\n24 prespecified before the trial begins, which facilitates implementation, arrangement, and\n25 management.\n27 significantly influence the treatment allocation. An unbalanced distribution of these\n28 variables across treatment groups would compromise the validity of the comparison of the\n29 outcomes between the groups. Therefore, we adopted stratified randomization, a widely\n1\n1 used clinical trial design that allocates patients within strata defined by important\n2 prognostic variables. Survival analyses were conducted accordingly, accounting for the\n3 effects of stratification variables on outcomes to ensure a more accurate evaluation of the\n4 treatment effects 4,5.\n6 trials of nasopharyngeal carcinoma 6-9. We have added these details to the Supplementary\n8\n9 2. Sample Size and Power Justification\n11 standard for time-to-event non-inferiority trials. A complete justification should include:\n12 the non-inferiority margin, type I error level, target power, the difference in PFS at which\n13 power was calculated, the required number of events, and assumptions about accrual and\n14 follow-up periods. This information is essential for assessing whether the study was\n15 adequately powered to meet its primary objective.\n19 established if the upper limit of the 95% confidence interval (CI) for the difference in\n20 progression-free survival between the two groups did not exceed 10%. A minimum of 246\n21 patients per group (492 in total, allowing for a 10% dropout or loss to follow-up) was\n22 needed to provide 80% power with a one-sided type I error rate of 2.5%.11 In response to\n23 this comment, we have added this information to the revised manuscript (lines 21–22,\n24 page 18, and lines 1–5, page 19 in “Methods—Statistical analysis” section).\n25\n26 3. Non-Inferiority Margin\n28 given the high baseline survival rate (~71%). While I defer to clinical experts for the\n29 ultimate acceptability of this margin, a brief rationale based on prior literature, expected\n30 effect sizes, and clinical relevance would help readers interpret this choice.\n2\n3 noninferiority margin to our attention.\n6 (1) clinical acceptability: a 10% difference is generally considered clinically acceptable,\n7 as it represents a reasonable balance between a benefit for patients and the treatment risk;\n8 (2) historical data and placebo effect: the margin is derived from historical placebo-\n9 controlled trials, where 10% often falls within a reasonable range 10; (3) statistical\n10 considerations: very small margins require excessively large sample sizes; a 10% margin\n11 balances statistical feasibility with clinical reliability; (4) regulatory guidance 15,16: the\n13 10% is widely adopted in practice 10.\n15\n16 𝐻0: 𝛿 ≥ 0.1,𝜋1 < 𝜋0\n17 𝐻1: 𝜋1 < 0.1\n∗\n(𝑃1−𝑃2)+0.1\n18 𝑍* T=he noninferiority margin we chose.\nSp.\n20 ratio (HR) (HR=1.39; p<0.05). Therefore, we believe that both sets of results—the\n21 absolute difference with its 95% CI and the HR with its 95% CI—provide consistent\n22 support for our findings(Supplementary Method_2).\n23\n24 4. Multiplicity in Toxicity Comparisons\n26 grade 1–2 deafness/otitis and peripheral neuropathy. No adjustment for multiple\n27 comparisons is mentioned. Given the number of toxicity outcomes evaluated, these\n28 findings may not remain significant after correction for multiplicity. I recommend\n29 clarifying whether multiplicity adjustments were considered and, if not, noting this as a\n3\n1 limitation.\n5 have performed multivariable analyses, and present the corresponding results in the\n6 revised manuscript(Table 3).\n7\n8 5. Toxicity as a Motivation for Non-Inferiority Design\n10 lobaplatin-based therapy would offer a better toxicity profile. However, the long-term\n11 toxicity data presented here do not clearly support this premise. A brief discussion of\n12 potential reasons (e.g., limitations in long-term toxicity data collection, competing late\n13 effects) would help contextualize the findings.\n17 completeness of long-term toxicity data collection over a span of 10 years of follow-up\n18 and the influence of competing late effects on long-term toxicity. Our findings suggested\n19 that the incidence of grade 1–2 peripheral neuropathy, grade 1–2 deafness/otitis, and grade\n20 1–2 of nephrotoxicity was higher in the cisplatin-based therapy group than in the\n21 lobaplatin-based therapy group. In addition, the incidence of grade 3 of nephrotoxicity was\n22 also higher in the cisplatin-based therapy group compared with the lobaplatin-based\n23 therapy group(Table 3).\n25 these potential explanations in the “Discussion” section (lines 8–12, page 15) to provide\n26 a better context for the results.\n27\n28 6. Handling of Missing Data in Long-Term Follow-Up\n30 manuscript should report the number (and percentage) of patients lost to follow-up, the\n4\n1 reasons where available, and whether any sensitivity analyses (e.g., worst-case scenario)\n2 were performed to assess the potential impact on the results.\n6 as the results of sensitivity analyses, is important for a comprehensive understanding of\n7 our study. In accordance with your suggestion, we have addressed these points in the\n8 revised manuscript(Supplementary Tables 6).\n5\n3 is part of the Nature Communications initiative to facilitate training in peer review and to\n4 provide appropriate recognition for Early Career Researchers who co-review manuscripts.\n7 feedback. These valuable comments have substantially improved the clarity and quality of our\n8 study(see our revised manuscript).\n9\n6\n3 is important, as this analysis represents the key points assessed in our work.\n4 1. Statistical Analysis\n6 section.\n9 of the noninferiority margin.\n11 design and a detailed explanation of the selected noninferiority margin(lines 21–22, page\n12 18; lines 1–8, page 19).\n13\n14 2. Results\n15 (1) Outcomes: Always good to indicate the additional number of events (both local and\n16 distant) were observed with the longer follow-up since the last report?\n20 be specified. In total, 14 new cases of local recurrence (2.8%) were observed,\n21 including 5 of 252 patients (2.1%) in the lobaplatin-based therapy group and 9 of 250\n22 patients (3.6%) in the cisplatin-based therapy group. In addition, 12 new cases of distant\n23 metastases (2.4%) were reported,including 8 of 252 patients (3.1%) in the lobaplatin-\n24 based therapy group and 4 of 250 patients (1.6%) in the cisplatin-based therapy group\n25 (lines 17–21, page 9).\n26 (2) This reviewer will also request that the investigators indicate the cumulative number\n27 of locoregional and distant relapse events in both groups\n7\n2 local recurrence, including 35 of 252 patients (13.9%) in the lobaplatin-based therapy\n3 group and 36 of 250 patients (14.4%) in the cisplatin-based therapy group. In addition,\n4 85 patients (16.9%) developed distant metastasis, including 42 of 252 patients (16.7%)\n5 in the lobaplatin-based therapy group and 43 of 250 patients (17.2%) in the cisplatin-\n6 based therapy group(lines 13–17, page 9; Supplementary Table 7).\n7 (3) Line 194\n10 potentially misleading. The 95% CI should be higher than the pre-specified margin.\n15 value should be 9.5%, which is below the noninferiority margin of 10%. We have\n16 corrected this error in the revised version (line 22, page 8; Supplementary Table 1).\n17 (4) Line 200\n19 univariate and multivariate.\n23 8, page 9).\n24 (5) Line 214\n28 the revised version. We are grateful you for carefully identifying this issue (Table 3).\n29\n30 3. Discussion\n8\n1 (1) Line 229: The authors should consider specifying progression-free survival (primary\n2 endpoint of this study) rather than “survival”\n6 (2) This study used a “de-escalated” chemotherapy schedule with 2 cycles of IC and 2\n7 cycles of concurrent chemotherapy, in place of the commonly used regimen of 3\n8 cycles IC+3 cycles concurrent. Furthermore, the control arm was PF, rather than the\n9 current standard GP or taxane-based triplet chemotherapy (per NCCN, CSCO\n10 guidelines). The implications should be addressed explicitly in the discussion section.\n13 suggestions.\n15 supporting gemcitabine plus cisplatin [GP] induction chemotherapy [IC] was\n16 available and before GP entered guideline-preferred status) 11. In 2012–2015, the\n18 concurrent chemoradiotherapy (CCRT) and referenced cisplatin plus fluorouracil (PF)\n19 as standards. Our choice of the PF regimen in this protocol therefore aligned with\n20 prevailing practice when enrollment started 17. A phase 3 trial showing that docetaxel,\n21 cisplatin, and fluorouracil (TPF) IC followed by CCRT improves failure-free survival\n22 over CCRT alone was published in 2016 (after our trial initiated), reinforcing the role\n23 of induction chemotherapy with TPF 7. A phase 3 trial demonstrating that GP\n24 induction chemotherapy plus CCRT improves recurrence-free survival and overall\n25 survival compared with CCRT alone was published in 2019 9. A series of trials\n26 conducted before 2013 used induction chemotherapy with a cisplatin plus\n27 fluorouracil regimen (Tang et al., 2012; Cao et al., 2008; Yang et al., 2008) 10,18,19.\n29 locally advanced nasopharyngeal carcinoma who were treated with two or three\n30 cycles of IC plus CCRT. After propensity score matching, the study revealed no\n9\n1 statistically significant difference between the two groups in terms of progression-free\n2 survival, distant metastasis-free survival, or overall survival; however, patients in the\n3 3-cycle IC group had a significantly higher incidence of grades 1–2 toxicity 20. Study\n4 by Peng et al. further revealed that among stage N2/3 patients, those who received 2\n5 cycles of IC had significantly higher 3-year OS rate than those who received 3 cycles\n6 or 4 cycles of IC did (92.4% vs. 80.8%, p=0.029). They suggested that 2 cycles of IC\n7 may be sufficient and that additional cycles are not associated with improved survival\n8 among patients with locoregionally advanced nasopharyngeal carcinoma in the era of\n11 more IC cycles without proportional gains in survival when 2 vs. 3 cycles are\n12 compared. These findings suggest that beyond 2 cycles, the incremental benefit may\n13 plateau while the rate of toxicity continues to increase 22.\n15 regimens at that time. GP IC was still under prospective evaluation and did not\n16 become a guideline-supported preferred regimen until evidence from a phase 3 trial\n17 was reported in 2019 9. Accordingly, the use of PF in our protocol is consistent with\n18 contemporaneous evidence and should not be considered a de-escalated or inferior\n19 choice.\n21\n22 4. Follow-up and Missing Data\n23 (1) Attrition is a potential issue for long term follow-up. The authors should provide\n24 information on loss to follow-up and the extent of missing toxicity data\n28 extent of missing toxicity data is essential for a more transparent interpretation. In\n29 response, we have added the relevant details to the revised manuscript as follows:\n10\n(n=252) (n=250)\nNumber (no.) 34 31\nPercentage (%) 13.5% 12.4%\n4 least one cycle of induction chemotherapy. Toxicity was recorded in 252 patients in the\n5 lobaplatin-based therapy group and 249 patients in the cisplatin-based therapy group.\nLobaplatin-based therapy group Cisplatin-based therapy group\n(n=252) (n=249)\nNumber 0 1\nPercentage (%) 0% 0.4%\n8 (2) It would be more informative if the authors can provide a breakdown of progression\n9 and/or death events.\n13 will make the results more informative. In response, we have revised the manuscript\n14 to include these data. Specifically, the numbers and proportions of local recurrence,\n15 distant metastasis, and death events are now presented in the “Results” section(lines\n16 13–22, page 9; line 1, page 10)and summarized inSupplementary Tables 7–8of the\n17 revised version. These additions should allow readers to better understand the event\n18 distribution between treatment groups.\nLobaplatin-based therapy Cisplatin-based therapy\nProgression events (%) group (n=252) group (n=250)\nDistant metastases (n=85 [16.9%]) 42 (16.7%) 43 (17.2%)\nLobaplatin-based therapy Cisplatin-based therapy\ngroup (n=252) group (n=250)\nDeath events (n=70 [16.9%]) 35 (14%) 35 (14%)\n4\n5 5. Toxicity Reporting\n6 (1) For such a study, the key would be long-term toxicities. In particular, this reviewer\n7 would be interested to assess the long-term effects on nephrotoxicity between\n8 lobaplatin vs cisplatin. The reporting of late adverse events deserves further\n9 elaboration. Specifically, can the authors specify the assessment scale used for late\n10 toxicities? The RTOG/EORTC late toxicity grading 1 did not capture peripheral\n11 neuropathy and ototoxicity (which are the two main findings here) (appendix P32 in\n12 original publication). This information is critical for readers to interpret the clinical\n13 benefit of lobaplatin.\n16 of the interpretation of this finding, which is the key point assessed in our work, is\n17 important.\n19 concerning long-term nephrotoxicity in our revised manuscript (Table 3). Radiation\n20 or chemoradiotherapy inevitably induces late toxicity, which can emerge months or\n21 even years after treatment completion 23. In our trial, late radiotherapy toxicity was\n22 assessed using the Late Radiation Morbidity Scoring Scheme of the Radiation\n12\n1 4 reactions can persist and lead to consequential late effects 23. Common late toxicities\n2 induced by treatment include xerostomia, sensorineural hearing loss,\n3 osteoradionecrosis, trismus, and CNS/peripheral abnormalities, which are\n4 summarized in the study by Chen et al. 23. In our trial, the proportions of patients with\n5 grades 1–2 peripheral neuropathy, grades 1–2 deafness/otitis, grades 1–2 of\n6 nephrotoxicity, and grade 3 of nephrotoxicity were significantly higher in the cisplatin-\n7 based therapy group than in the lobaplatin-based therapy group (lines 12–18, page\n8 10; Table 3). As late toxic effects, peripheral neuropathy, nephrotoxicity and\n9 ototoxicity were also evaluated in previous important trials 7,9,10,25-29.\n10 (2) Please indicate the number of patients assessed for toxicity at each follow-up\n11 timepoint.\n15 induction chemotherapy(lines 6–8, page 19).\n17 assessed. Specifically, toxicity assessments were available for all patient in the\n18 lobaplatin-based therapy group and 249 patients in the cisplatin-based therapy group.\n20 clarity.\n21 (3) How was follow-up ensured for monitoring of late effects?\n24 telephone calls and messages based on the outpatient and inpatient records of the\n25 physicians to accurately evaluate patient outcomes and toxicities. The follow-up data\n26 will be managed according to the guidelines for nasopharyngeal carcinoma.\n28 the completion of treatment. After the primary treatment was completed, the patients\n29 were followed every 3 months for the first 3 years, every 6 months for 4–5 years, and\n30 annually thereafter(protocol).\n13\nTime points Items\n1–3 years (every 3 months) Patient complaints\nPhysical examination\nHematological and biochemical analyses\nFlexible nasopharyngoscopy\nPlasma Epstein‒Barr virus DNA load\nEnhanced MRI of the nasopharynx and neck a\nCT or X-ray of the chest\nUltrasonography or CT scan of the abdomen\nBone scan (if necessary)\nAssessment of thyroid function\n4–5 years (every 6 months) Patient complaints\nPhysical examination\nHematological and biochemical analyses\nFlexible nasopharyngoscopy\nPlasma Epstein‒Barr virus DNA load\nEnhanced MRI of the nasopharynx and neck\nCT or X-ray of the chest\nUltrasonography or CT scan of the abdomen\nBone scan (if necessary)\nAssessment of thyroid function\nAfter 5 years (every 12 months) Patient complaints\nPhysical examination\nHematological and biochemical analyses\nFlexible nasopharyngoscopy\nPlasma Epstein‒Barr virus DNA load\nEnhanced MRI of the nasopharynx and neck\nCT or X-ray of the chest\nBone scan (if necessary)\nAssessment of thyroid function\n1 a Enhanced CT of the nasopharynx and neck was conducted if patients had contraindications\n2 to MRI.\n4 biopsy or fine needle aspiration. Even in patient with long-term disease-free survival, skull\n5 base bone destruction might persist on MRI. Clinical features and laboratory/imaging\n6 examinations, including symptoms, signs, EBV-DNA level, PET-CT, and dynamic\n7 changes in MRI, should be combined to determine whether treatment failure has occurred.\n9 imaging findings are typical of treatment failure (e.g., progression of skull base bone\n10 destruction, recurrent primary lesion, necrosis, or progressive enlargement of lymph\n11 nodes), local or regional failure may be clinically diagnosed once approved by the\n12 investigators at each center. Records should be kept of the dates of diagnosis of local and\n13 distant failures; the sites should also be recorded. All enrolled patients will be followed\n14 until death. The cause of death will be recorded. Deaths from unknown causes will be\n15 considered deaths caused by nasopharyngeal carcinoma if the disease is still present at the\n16 final follow-up assessment(protocol).\n17 (4) As this reviewer alluded to, was nephrotoxicity assessed since this is one of the main\n18 debilitating long- term toxicity of cisplatin (Grant, et al. JAMA Oncology, 2025).\n22 kidney. Although pharmacological interventions are often used, grades 2–4 reactions\n23 can persist and lead to consequential late effects 23. Late toxic effects on the kidney\n24 were graded in accordance with the RTOG/EORTC late radiation morbidity scoring\n25 scheme 24. In accordance with the Reviewer’s suggestion, we have enriched the\n26 description of the results concerning long-term nephrotoxicity in our revised\n27 manuscript (Table 3).\n15\nGrade 0 None\nGrade 1 Transient albuminuria; no hypertension; mild impairment of renal function;\nUrea 25–35 mg %; creatinine 1.5–2.0 mg %; creatinine clearance > 75%\nGrade 2 Persistent moderate albuminuria (2+); mild hypertension; no related\nanemia; moderate impairment of renal function;\nUrea > 36–60 mg %; creatinine clearance (50–74%)\nGrade 3 Severe albuminuria; severe hypertension; persistent anemia (< 10 g %);\nsevere renal failure; urea > 60 mg %; creatine > 4.0 mg %; creatinine\nclearance < 50%\nGrade 4 Malignant hypertension\nUremic coma\nUrea > 100%\n2 (5) Reporting of the “worst grade toxicity” may not fully capture the clinical relevance\n3 of long-term adverse effects in NPC survivors. For example, ototoxicity can fluctuate\n4 and may partially recover 2. Also, peripheral neuropathy may also improve over time,\n5 although there may not be complete recovery 3. To better depict these dynamics, the\n6 authors may consider using time stream plots or longitudinal toxicity curves to show\n7 how these late toxicities evolve.\n11 after treatment completion 23. The Reviewer is correct that some toxic effects can\n12 fluctuate during long-term follow-up. In some cases, grades 2–4 reactions can persist\n13 and evolve into consequential late effects 23.\n15 data completeness over the 10-year follow-up was inevitably limited and potentially\n16 underestimated some late adverse events, and competing late effects may dilute\n17 differences between groups. This limitation is also described in the “Discussion”\n16\n1 section(lines 8–12, page 15).\n2\n3 6. Without those, it is a missed opportunity for the readers to appraise the long-term\n4 “benefits”, if any, of lobaplatin and its advantage over cisplatin. In fact, based on the key\n5 results highlighted in Table 2, this reviewer may contest that there are little to no added\n6 benefits of administering lobaplatin vs. cisplatin. Compliance may be improved with\n7 lobaplatin, but yet with the reduced compliance, the outcomes and late toxicities appear\n8 comparable, and not necessarily fewer than cisplatin.\n12 chemotherapy plus concurrent chemoradiotherapy compared with a cisplatin-based\n13 regimen in patients with locoregional, advanced nasopharyngeal carcinoma. With respect\n14 to radiotherapy compliance, 252 (100%) patients in the lobaplatin-based group and 247\n15 (99%) patients in the cisplatin-based group completed the scheduled radiotherapy course;\n16 the dose and fraction of radiotherapy were similar between the treatment groups. Under\n17 these circumstances, as shown in Table 3, the incidences of grades 1–2 peripheral\n18 neuropathy, grades 1–2 deafness/otitis, grades 1–2 of nephrotoxicity, and grade 3 of\n19 nephrotoxicity were higher in the cisplatin-based therapy group than in the lobaplatin-based\n20 therapy group. These results suggest that the lobaplatin-based group had a better safety\n21 profile.\nLobaplatin-based group Cisplatin-based group p\n(n=252) (n=250)\nvalue\nCompleted (%) 252 (100%) 247 (98.8)\nDose of radiotherapy (Gy) 70 (70–70) 70 (70–70) 0.25\n(median [IQR])\nDose per fraction (Gy) 2.33 (2.19–2.33) 2.33 (2.19–2.33) 2.33\n(median [IQR])\n17\n2 p values were calculated with Fisher’s exact test.\n3\n4 7. Which brings me to my key point – Cisplatin remains the dominant platinum agent in head\n5 and neck cancer. Thus far, substitutes like nedaplatin, carboplatin, oxaliplatin have been\n6 shown to be “comparable” in clinical trials, but most have not penetrated the clinic. In fact,\n7 for cisplatin eligible patients, cisplatin remains the preferred choice. The investigators\n8 ought to discuss why this may be the case. Perhaps, the long-term data of this trial will be\n9 helpful to inform the community about the cross-utility of the platinum class of drugs.\n13 adducts and causes apoptosis 30,31. In previous studies, compared with cisplatin, lobaplatin\n14 has been shown to have robust antitumor activity against several malignancies with less\n15 toxicities 31,32. Furthermore, in laboratory tumor models, lobaplatin was found to overcome\n16 some forms of multidrug resistance caused by other platinum drugs (e.g., cisplatin or\n17 carboplatin) 31. In a phase 2 study of recurrent and metastatic nasopharyngeal carcinoma,\n18 lobaplatin and docetaxel-based chemotherapy showed clinical activity 33. Our phase 2 trial\n19 of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy for\n20 patients with stage III–IVB nasopharyngeal carcinoma showed encouraging antitumor\n21 activity and tolerable treatment-related toxicity 34. The Chinese Society of Clinical\n23 concurrent chemoradiation as level IB evidence, especially for patients with impaired\n24 cardiac and pulmonary functions (www.csco.org.cn).\n26 used diuretics (mannitol and furosemide) on the day of cisplatin administration in each\n27 cycle to prevent nephrotoxicity. The use of lobaplatin, which does not require hydration or\n28 diuretics, is associated with less fluid overload, especially for patients with inadequate\n29 organ function (lung and heart). Moreover, the low number of hospital beds and prolonged\n30 hospital stay are some of the most difficult challenges encountered in areas with a high\n18\n1 prevalence of nasopharyngeal carcinoma. Patients who are waiting for treatment not only\n2 experience worsening disease but also experience psychological pressure. Lobaplatin-\n3 based induction chemotherapy plus concurrent chemoradiotherapy, which may be used in\n4 southern China, does not require parallel hydration treatment and could shorten the\n5 duration of the hospital stay, helping to solve these problems. Compared with cisplatin-\n6 based therapy, lobaplatin-based induction chemotherapy plus concurrent\n7 chemoradiotherapy resulted in noninferior survival and fewer toxic effects and thus may\n8 be a promising alternative regimen to cisplatin-based treatment in patients with\n9 locoregional, advanced nasopharyngeal carcinoma.\n10\n19\n3 is part of the Nature Communications initiative to facilitate training in peer review and to\n4 provide appropriate recognition for Early Career Researchers who co-review manuscripts.\n8 study(see our revised manuscript).\n20\n3 we have enriched our revised manuscript.\n4 1. Is deafness/otitis media related to radiotherapy?\n7 the radiation field is near the ear or includes ear structures, the risk of side effects to the\n8 ear increases. These side effects are commonly observed in patients receiving radiotherapy\n9 for head and neck cancers, such as nasopharyngeal carcinoma. The risk of hearing damage\n10 increases greatly if radiotherapy is combined with ototoxic chemotherapy drugs (e.g.,\n11 cisplatin).\n13 simultaneously 35,36: (1) external ear damage—direct radiation effect on the skin and skin\n14 appendages; (2) middle ear damage—radiation causes swelling and dysfunction of the\n15 eustachian tube, preventing normal pressure regulation and leading to fluid buildup, and\n16 can cause tympanosclerosis or fixation of the ossicular chain; (3) inner ear damage—direct\n17 toxicity of radiation to the auditory cells of the inner ear and the cochlear nerve, as well as\n18 damage to vascular and neural tissues.\n20 modified(lines 1–7, page 14).\n21\n21\n2 1 Bruce, C. L. et al. Choosing and evaluating randomisation methods in clinical trials: a\n3 qualitative study. Trials. 25, 199 (2024).\n4 2 Efird, J. Blocked randomization with randomly selected block sizes. Int J Environ Res\n6 3 Kernan, W. N., Viscoli, C. M., Makuch, R. W., Brass, L. M. & Horwitz, R. I. Stratified\n7 randomization for clinical trials. J Clin Epidemiol. 52, 19-26 (1999).\n8 4 Guidelines for random allocation in drug clinical trials of China. 5 (2022).\n9 5 R.P., W. Statistical elements in the design of clinical trial research protocol. Shanghai\n11 6 Chen, Y. P. et al. Metronomic capecitabine as adjuvant therapy in locoregionally\n12 advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group,\n13 randomised, controlled, phase 3 trial. Lancet. 398, 303-313 (2021).\n14 7 Sun, Y. et al. Induction chemotherapy plus concurrent chemoradiotherapy versus\n15 concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal\n16 carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol. 17, 1509-\n17 1520 (2016).\n18 8 Yang, Y. et al. Camrelizumab versus placebo in combination with gemcitabine and\n19 cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma\n20 (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol.\n21 22, 1162-1174 (2021).\n22 9 Zhang, Y. et al. Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal\n24 10 Tang, L. Q. et al. Concurrent chemoradiotherapy with nedaplatin versus cisplatin in\n25 stage II-IVB nasopharyngeal carcinoma: an open-label, non-inferiority, randomised\n26 phase 3 trial. Lancet Oncol. 19, 461-473 (2018).\n27 11 Lv, X. et al. Induction chemotherapy with lobaplatin and fluorouracil versus cisplatin\n28 and fluorouracil followed by chemoradiotherapy in patients with stage III-IVB\n29 nasopharyngeal carcinoma: an open-label, non-inferiority, randomised, controlled,\n30 phase 3 trial. Lancet Oncol. 22, 716-726 (2021).\n22\n1 12 D’Agostino, R. B. Non-inferiority clinical trials: concepts and issues. Stat Med. 22,\n2 169–186 (2003).\n3 13 Kay, R. Statistical principles for clinical trials. J Int Med Res. 26, 57-65 (1998).\n4 14 Piaggio, G. et al. Reporting of noninferiority and equivalence randomized trials:\n5 extension of the CONSORT 2010 statement. JAMA. 308, 2594-2604 (2012).\n6 15 EMA. Guideline on the Choice of the Non-inferiority Margin. (2005).\n7 16 FDA. Guidance for Industry: Non-Inferiority Clinical Trials. (2016).\n8 17 Chan, A. T. et al. Nasopharyngeal cancer: EHNS-ESMO-ESTRO Clinical Practice\n10 (2012).\n11 18 Cao, S. M. et al. Neoadjuvant chemotherapy followed by concurrent\n12 chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally\n13 advanced nasopharyngeal carcinoma: A phase III multicentre randomised controlled\n14 trial. Eur J Cancer. 75, 14-23 (2017).\n15 19 Yang, Q. et al. Induction chemotherapy followed by concurrent chemoradiotherapy\n16 versus concurrent chemoradiotherapy alone in locoregionally advanced\n17 nasopharyngeal carcinoma: long-term results of a phase III multicentre randomised\n18 controlled trial. Eur J Cancer. 119, 87-96 (2019).\n19 20 Guo, L. F., Yu, Y. F., Lu, Z. Z., Lin, Q. & Wu, S. G. Two or three cycles of induction\n20 chemotherapy in locoregionally advanced nasopharyngeal carcinoma? BMC Cancer.\n21 25, 1268 (2025).\n22 21 Peng, H. et al. Optimize the cycle of neoadjuvant chemotherapy for locoregionally\n23 advanced nasopharyngeal carcinoma treated with intensity-modulated radiotherapy: A\n24 propensity score matching analysis. Oral Oncol. 62, 78-84 (2016).\n25 22 Xu, Y. C., Chen, K. H., Liang, Z. G. & Zhu, X. D. A Systematic Review and Meta-\n28 843675 (2022).\n29 23 Chen, Y. P. et al. Nasopharyngeal carcinoma. Lancet. 394, 64-80 (2019).\n30 24 Cox, J. D., Stetz, J. & Pajak, T. F. Toxicity criteria of the Radiation Therapy Oncology\n23\n2 (EORTC). Int J Radiat Oncol Biol Phys. 31, 1341-1346 (1995).\n3 25 Tang, Q. N. et al. Effect of Concurrent Chemoradiotherapy With Nedaplatin vs\n7 26 Li, W. F. et al. Concurrent chemoradiotherapy with/without induction chemotherapy in\n8 locoregionally advanced nasopharyngeal carcinoma: Long-term results of phase 3\n9 randomized controlled trial. Int J Cancer. 145, 295-305 (2019).\n10 27 Zhang, Y. et al. Final Overall Survival Analysis of Gemcitabine and Cisplatin Induction\n13 28 Liu, X. et al. Induction-concurrent chemoradiotherapy with or without sintilimab in\n14 patients with locoregionally advanced nasopharyngeal carcinoma in China\n15 (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled,\n16 phase 3 trial. Lancet. 403, 2720-2731 (2024).\n17 29 Hui, E. P. et al. Randomized phase II trial of concurrent cisplatin-radiotherapy with or\n18 without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J\n20 30 Welink, J., Boven, E., Vermorken, J. B., Gall, H. E. & van der Vijgh, W. J.\n22 advanced solid tumors, including patients with impaired renal of liver function. Clin\n24 31 McKeage, M. J. Lobaplatin: a new antitumour platinum drug. Expert Opin Investig\n26 32 Perabo, F. G. & Muller, S. C. New agents for treatment of advanced transitional cell\n27 carcinoma. Ann Oncol. 18, 835-843 (2007).\n28 33 Long, G. X. et al. Single-arm, multi-centre phase II study of lobaplatin combined with\n29 docetaxel for recurrent and metastatic nasopharyngeal carcinoma patients. Oral Oncol.\n30 50, 717-720 (2014).\n24\n1 34 Ke, L. R. et al. Safety and efficacy of lobaplatin combined with 5-fluorouracil as first-\n2 line induction chemotherapy followed by lobaplatin-radiotherapy in locally advanced\n3 nasopharyngeal carcinoma: preliminary results of a prospective phase II trial. BMC\n5 35 Mujica-Mota, M. A., Lehnert, S., Devic, S., Gasbarrino, K. & Daniel, S. J. Mechanisms\n6 of radiation-induced sensorineural hearing loss and radioprotection. Hear Res. 312, 60-\n7 68 (2014).\n8 36 Ishak, E. M., Gallitto, M., Golub, J. S., Sisti, M. B. & Wang, T. J. C. Radiation-Induced\n10 215 (2024).\n11\n25"}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors responded quite well to most of my questions and comments.\nThere may have been a misunderstanding regarding comment 4, Multiplicity in toxicity comparisons. I did not ask for multivariable regression analyses, but rather clarification on how type I error was controlled across multiple toxicity comparisons.", "reviewer_2": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts.", "reviewer_3": "Thank you for the supplementary information, including the breakdown of events and additional details on late toxicity outcomes. This reviewer has a few points that require clarification:\n1. Supplementary Table 9 is confusing. It appears to indicate that only one patient had missing toxicity data, whereas Supplementary Table 4 shows that approximately 13% of patients were lost to follow-up and therefore should also have missing toxicity data.\n2. This reviewer acknowledges that at the time of this trial’s conception, PF may have been the standard of care. However, as noted by the authors, current preferred regimens have shifted to TPF or GP (category 1) based on recent evidence (Li 2019; Zhang 2019). Both landmark trials employed three cycles of induction chemotherapy. As platinum dose intensity can influence the incidence of acute and late toxicity, this is particularly relevant in the present study. The authors are encouraged to discuss the generalizability of their findings in the context of these current standard regimens.\n3. Toxicity grading scales\nThe authors reported that acute toxicity was graded using CTCAE v3, while late toxicity was assessed using the RTOG/EORTC criteria (Cox 1994, details in the Supplementary Appendix). However, this reviewer notes that deafness/otitis and peripheral neuropathy are not included in the RTOG/EORTC late toxicity scale. Please clarify which specific toxicity grading scales were used for these endpoints.\nIn addition, the authors stated that late nephrotoxicity was graded according to the RTOG/EORTC criteria, and that lobaplatin was associated with improved late nephrotoxicity outcomes. This reviewer questions the rationale for using the RTOG scale rather than CTCAE, as renal injury is typically chemotherapy-related rather than due to radiotherapy effects. The RTOG/EORTC scale includes parameters such as blood pressure, urinalysis, and renal function tests—please clarify whether all these assessments were performed routinely during long-term follow-up. This information is essential to evaluate the robustness of the finding.\n4. Supplementary Figure 1 contains garbled text.\n5. Supplementary Figure 3 appears blurred.", "reviewer_4": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts.", "reviewer_5": "comments：\n1. What I mean is how to distinguish whether ototoxicity is caused by cisplatin or radiotherapy. As the author mentioned, different radiotherapy locations have different impacts on hearing loss. So, is the part of the ear canal damaged by cisplatin the same as that damaged by radiotherapy? Is the less damage caused by lobaplatin due to different radiotherapy locations?"}, "author_response": "Response to Reviewer #1\nWe sincerely thank you for the time and effort devoted to carefully reading our revised\nmanuscript and providing feedback. This insightful comment is highly valuable and\nsignificantly improved the clarity and overall quality of our study.\n1. There may have been a misunderstanding regarding comment 4, Multiplicity in toxicity\ncomparisons. I did not ask for multivariable regression analyses, but rather clarification on\nhow type I error was controlled across multiple toxicity comparisons.\nREPLY:\nWe thank the Reviewer for this insightful comment.\nThe Bonferroni method is one of the most used approaches for multiplicity adjustment.\nIt controls the probability of type I error in multiple testing by adjusting the significance\nlevel. In our trial, we used Bonferroni method to control the type I error in multiple toxicity\ncomparisons (lines 21–22, page 20 in “Methods—Statistical analysis” section).\nI co-reviewed this manuscript with one of the reviewers who provided the listed reports. This\nis part of the Nature Communications initiative to facilitate training in peer review and to\nprovide appropriate recognition for Early Career Researchers who co-review manuscripts.\nREPLY:\nWe sincerely thank you for carefully reading our revised manuscript and providing feedback.\nThese valuable comments improve the clarity and quality of our study (see our revised\nmanuscript).\nThank you for the suggestions to improve our study. We agree that interpreting these points are\nimportant, as these analyses represent the key points assessed in our work.\n1. Supplementary Table 9 is confusing. It appears to indicate that only one patient had\nmissing toxicity data, whereas Supplementary Table 4 shows that approximately 13% of\npatients were lost to follow-up and therefore should also have missing toxicity data.\nREPLY:\nWe thank you for bringing this important point regarding the toxicities during the follow-\nup phase.\nThe toxicity analysis population included patients who received at least one cycle of\ninduction chemotherapy 1 (lines 14–15, page 20 in “Methods—Statistical analysis”\nsection, and Figure 1). A total of 31 patients (13%) were lost to follow-up in cisplatin-\nbased therapy group. Among them, 1 patient (0.4%) did not receive any toxicity\nassessment, while 30 patients (12%) had at least one toxicity evaluation before lost to\nfollow-up.\n2. This reviewer acknowledges that at the time of this trial’s conception, PF may have been\nthe standard of care. However, as noted by the authors, current preferred regimens have\nshifted to TPF or GP (category 1) based on recent evidence (Li 2019; Zhang 2019). Both\nlandmark trials employed three cycles of induction chemotherapy. As platinum dose\nintensity can influence the incidence of acute and late toxicity, this is particularly relevant\nin the present study. The authors are encouraged to discuss the generalizability of their\nfindings in the context of these current standard regimens.\nREPLY:\nWe appreciate your valuable comment.\nIn accordance with the Reviewer’s suggestion, we have enriched the generalizability of\nour findings in our revised manuscript (lines 17–18, page 13, and lines 1–4, page 14 in\n“Discussion” section).\n3. Toxicity grading scales\nThe authors reported that acute toxicity was graded using CTCAE v3, while late toxicity\n3\nwas assessed using the RTOG/EORTC criteria (Cox 1994, details in the Supplementary\nAppendix). However, this reviewer notes that deafness/otitis and peripheral neuropathy\nare not included in the RTOG/EORTC late toxicity scale. Please clarify which specific\ntoxicity grading scales were used for these endpoints.\nREPLY:\nThank you for reviewing our paper and providing this constructive and supportive\nsuggestion.\nOtotoxicity and neurotoxicity were graded using the Late Radiation Morbidity Scoring\nScheme of RTOG/EORTC 2(Supplementary Datasets).\nGrades Definition\ndesquamation not requiring medication. Audiogram unchanged\nmedius/hypoacusis on testing only\nhypoacusis/tinnitus, not drug related\nIn term of a comparative study, late toxicities were graded using the Late Radiation\nMorbidity Scoring Scheme of RTOG/EORTC 3. Although this scheme is originally\ndeveloped for the assessment of long-term radiation-induced toxicities, it also been applied\nin studies combining chemotherapy and radiotherapy to maintain a consistent scoring\nsystem for grading late adverse events across all organ systems 3,4. This approach was\nallowed for standardized assessment of both radiotherapy- and chemotherapy-related late\ntoxicities in our study. Radiation or chemoradiotherapy inevitably induces acute and late\ntoxicities, and the latter can emerge and persist months or even years after treatment\ncompletion 2,5. Furthermore, toxicities refer to adverse events that persist after the acute\nphase, often months to years following chemoradiotherapy 6-8. The late toxicities about\nperipheral neuropathy have been reported in several previous clinical trials of\n4\nnasopharyngeal carcinoma 9-11.\n4. In addition, the authors stated that late nephrotoxicity was graded according to the\nRTOG/EORTC criteria, and that lobaplatin was associated with improved late\nnephrotoxicity outcomes. This reviewer questions the rationale for using the RTOG scale\nrather than CTCAE, as renal injury is typically chemotherapy-related rather than due to\nradiotherapy effects. The RTOG/EORTC scale includes parameters such as blood pressure,\nurinalysis, and renal function tests—please clarify whether all these assessments were\nperformed routinely during long-term follow-up. This information is essential to evaluate\nthe robustness of the finding.\nREPLY:\nThank you for this suggestion to improve our paper. We agree that a brief description of\nthe information, which is the key point in our study.\nIn accordance with your valuable suggestion, we have added a description in the\n“Methods—Procedures” section(lines 9–18, page 19).\nThe assessments will include the following (protocol)：\nTime points Items\n1–3 years (every 3 months) Patient complaints\nPhysical examination a\nHematological and biochemical analyses b\nFlexible nasopharyngoscopy\nPlasma Epstein‒Barr virus DNA load\nEnhanced MRI of the nasopharynx and neck c\nCT or X-ray of the chest\nUltrasonography or CT scan of the abdomen\nBone scan (if necessary)\nAssessment of thyroid function\n4–5 years (every 6 months) Patient complaints\nPhysical examination\nHematological and biochemical analyses\nPlasma Epstein‒Barr virus DNA load\nEnhanced MRI of the nasopharynx and neck\nCT or X-ray of the chest\nUltrasonography or CT scan of the abdomen\nBone scan (if necessary)\nAssessment of thyroid function\nAfter 5 years (every 12 months) Patient complaints\nPhysical examination\nHematological and biochemical analyses\nFlexible nasopharyngoscopy\nPlasma Epstein‒Barr virus DNA load\nEnhanced MRI of the nasopharynx and neck\nCT or X-ray of the chest\nUltrasonography or CT scan of the abdomen\nBone scan (if necessary)\nAssessment of thyroid function\na Physical examination included blood pressure.\nb Biochemical analyses included renal function, and hepatic function.\nc Enhanced CT of the nasopharynx and neck was conducted if patients had\ncontraindications to MRI.\n5. Supplementary Figure 1 contains garbled text.\nREPLY:\nWe acknowledge these were edited error and we have corrected them in the revised version.\nWe are grateful you for carefully identifying this issue (Supplementary Figure 1).\n6. Supplementary Figure 3 appears blurred.\nREPLY:\nWe sincerely thank you for bringing these errors to our attention.\nWe have revised the Supplementary Figure 3 (Supplementary Figure 3).\nI co-reviewed this manuscript with one of the reviewers who provided the listed reports. This\nis part of the Nature Communications initiative to facilitate training in peer review and to\nprovide appropriate recognition for Early Career Researchers who co-review manuscripts.\nREPLY:\nWe thank you for investing your time in carefully reading and commenting on our manuscript.\nThese comments are very valuable and help us to increase the clarity and quality of our study\n(see our revised manuscript).\nThank you for reviewing our paper and providing this suggestion. According to your suggestion,\nwe enriched our revised manuscript.\n1. What I mean is how to distinguish whether ototoxicity is caused by cisplatin or\nradiotherapy. As the author mentioned, different radiotherapy locations have different\nimpacts on hearing loss. So, is the part of the ear canal damaged by cisplatin the same as\nthat damaged by radiotherapy? Is the less damage caused by lobaplatin due to different\nradiotherapy locations?\nREPLY:\nIn radiotherapy for nasopharyngeal carcinoma, the radiation field is near the ear or\nincludes ear structures. Radiation-induced oxidative stress destroy inner ear cells and\npromote cell damage, inflammation and other post-irradiation effects 12. Cisplatin induces\napoptosis by inhibiting the activity of antioxidant enzymes 13. In addition, cisplatin has a\ntoxic effect on the stria vascularis, resulting in a reduction in the endocochlear potential\nrelated to striatal edema 14. The Reviewer is right that these observations suggest a possibly\ndifficult mechanism. Future work is needed to understand the mechanisms contributing to\nthese observations in the clinic practices.\nIn the trial, for radiotherapy, intensity-modulated radiotherapy (IMRT) was mandatory\nin both lobaplatin and fluorouracil induction chemotherapy plus lobaplatin-based\nconcurrent chemoradiotherapy group and cisplatin and fluorouracil induction\nchemotherapy plus cisplatin-based concurrent chemoradiotherapy group. Gross tumor\nvolume (GTV) included the primary tumor and enlarged lymph nodes (GTVnx, the sum\nof the volumes of the primary tumor and enlarged retropharyngeal nodes; GTVnd, the\nvolume of clinically involved gross cervical lymph nodes). For the planning target\nvolumes of GTVnx, GTVnd, CTV1, and CTV2, total radiation doses of 68–70 Gy, 62–68\nGy, 60 Gy, and 54 Gy, respectively, were administered in 30–32 fractions, 5 days per week,\nstarting on the first day of the first concurrent chemoradiotherapy cycle. The details were\nprovided in our previous report 1. The region of the ear canal affected by platinum drug is\nthe same as that affected by radiotherapy. Taken together, these observations suggest that\n8\nlobaplatin induces less injury than cisplatin (lines 9–12, page 15).\nfluorouracil followed by chemoradiotherapy in patients with stage III-IVB nasopharyngeal\ncarcinoma: an open-label, non-inferiority, randomised, controlled, phase 3 trial. Lancet Oncol.\n22, 716-726 (2021).\n(RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J\nRadiat Oncol Biol Phys. 31, 1341-1346 (1995).\nradiation-induced lung toxicity. Clin Oncol (R Coll Radiol). 21, 371-375 (2009).\nmean lung dose and risk of radiation pneumonitis in a large cohort of patients with non-small\ncell lung cancer. Int J Radiat Oncol Biol Phys. 77, 691-698 (2010).\nCriteria.\nChemotherapy in Nasopharyngeal Carcinoma: A Multicenter, Randomized Phase III Trial. J\nClin Oncol. 40, 2420-2425 (2022).\nlocoregionally advanced nasopharyngeal carcinoma: Long-term results of phase 3 randomized\ncontrolled trial. Int J Cancer. 145, 295-305 (2019).\nchemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3,\nmulticentre, randomised controlled trial. Lancet Oncol. 17, 1509-1520 (2016).\nin Locally Advanced Nasopharyngeal Carcinoma: Early to Mid-Term Findings. Clin\nPrevention. Semin Hear. 40, 197-204 (2019).\ninduced ototoxicity and prevention. Hear Res. 226, 157-167 (2007).\n11"}]

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