A new supplementary analysis of data from a phase II/III randomized controlled trial has found that acute kidney injury (AKI) impacted overall survival in head and neck cancer patients receiving postoperative chemoradiotherapy with 3-weekly cisplatin, but not in those receiving weekly cisplatin. The study, published in Cancer Medicine on September 2, 2024, provides further support for the use of weekly cisplatin in this patient population.
The analysis examined data from JCOG1008, a multicenter, non-inferiority, phase II/III randomized controlled trial conducted in Japan. JCOG1008 compared weekly cisplatin (40 mg/m2) to 3-weekly cisplatin (100 mg/m2) given concurrently with postoperative radiotherapy in patients with high-risk head and neck squamous cell carcinoma (HNSCC). The trial was funded by the National Cancer Center Research and Development Funds and grants from the Ministry of Health, Labor and Welfare of Japan and the Japan Agency for Medical Research and Development.
The primary aim of this supplementary analysis was to investigate how the development of AKI, a major dose-limiting toxicity of cisplatin, affected overall survival (OS) in the two treatment arms. The study included 251 patients from the original JCOG1008 trial who received chemoradiotherapy between October 2012 and December 2018. Patients were eligible if they had histologically proven squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx; pathological stage III, IVA, or IVB disease; and creatinine clearance ≥60 mL/min. The median age was 62 years in the 3-weekly arm and 61.5 years in the weekly arm, with over 80% of patients being male in both groups.
AKI was defined based on Acute Kidney Injury Network criteria as an increase in serum creatinine of ≥0.3 mg/dL or ≥1.5-fold from baseline within 30 days after completing chemoradiotherapy. The analysis found that the overall incidence of AKI was lower in the weekly cisplatin arm compared to the 3-weekly arm (31.1% vs 43.4%). Additionally, moderate-to-severe AKI (stage II/III) occurred less frequently with weekly dosing (6.6% vs 14.7%).
A key finding was that in the weekly cisplatin arm, there was no significant difference in OS between patients who developed AKI and those who did not (hazard ratio [HR] 1.06, 95% CI 0.53-2.10). However, in the 3-weekly arm, patients who developed AKI had significantly poorer OS compared to those without AKI (HR 1.83, 95% CI 1.04-3.21). Similar trends were observed for recurrence-free survival.
The analysis also revealed important differences in treatment delivery between the arms. In the weekly cisplatin arm, the total cisplatin dose was similar regardless of whether patients developed AKI (median 238.6 mg/m2 vs 239.2 mg/m2). However, in the 3-weekly arm, patients who developed AKI received a lower total cisplatin dose compared to those without AKI (median 276.3 mg/m2 vs 297.4 mg/m2).
These findings suggest that weekly cisplatin administration may allow for better maintenance of dose intensity even when AKI occurs. The authors propose that this could explain the lack of impact of AKI on survival outcomes in the weekly arm. In contrast, AKI in the 3-weekly arm often led to dose reductions or treatment discontinuation, potentially compromising treatment efficacy.
The study had some limitations, including its retrospective nature and the fact that reasons for cisplatin dose modifications were not limited to AKI alone. Additionally, the analysis was restricted to patients receiving postoperative chemoradiotherapy, so the findings may not be generalizable to patients with inoperable disease receiving definitive chemoradiotherapy.
Nevertheless, the authors conclude that their results provide further support for the use of weekly cisplatin at 40 mg/m2 in the postoperative chemoradiotherapy setting for high-risk HNSCC. They suggest that weekly administration may improve renal safety while maintaining treatment intensity and efficacy.
The potential clinical impact of these findings is significant. AKI is a common and serious complication of cisplatin-based chemoradiotherapy that can lead to long-term renal dysfunction and impact survival outcomes. If weekly cisplatin administration can reduce the incidence and severity of AKI while maintaining treatment efficacy, it could improve both short-term tolerability and long-term outcomes for patients with HNSCC.
This analysis adds to a growing body of evidence supporting alternative cisplatin dosing schedules in head and neck cancer. Previous studies have yielded conflicting results, with some showing non-inferiority of weekly regimens and others suggesting inferior outcomes compared to 3-weekly dosing. The JCOG1008 trial itself demonstrated non-inferiority of weekly cisplatin for OS, with a hazard ratio of 0.69 (99.1% CI 0.37-1.27) favoring the weekly arm.
The current analysis provides a potential mechanistic explanation for these findings by highlighting the impact of AKI on treatment delivery and survival outcomes. It suggests that the ability to maintain dose intensity with weekly administration may be a key factor in achieving equivalent or potentially superior outcomes.
However, it is important to note that questions remain regarding optimal cisplatin dosing in HNSCC. Some experts argue that a cumulative cisplatin dose of at least 200-300 mg/m2 is necessary to achieve maximal benefit, which may be more challenging to achieve with weekly dosing. The median cumulative dose in the weekly arm of this study was approximately 240 mg/m2, which is at the lower end of this range.
Additionally, while this analysis focused on postoperative chemoradiotherapy, the optimal cisplatin regimen may differ for patients receiving definitive chemoradiotherapy for inoperable disease. Further research is needed to clarify these issues and determine whether weekly cisplatin should become the new standard of care across HNSCC treatment settings.
In conclusion, this supplementary analysis of the JCOG1008 trial provides important insights into the relationship between cisplatin-induced AKI and survival outcomes in patients with HNSCC receiving postoperative chemoradiotherapy. The findings suggest that weekly cisplatin administration may offer advantages in terms of renal safety and maintenance of treatment intensity. As the field of head and neck oncology continues to evolve, these results may inform future treatment guidelines and clinical decision-making, potentially improving outcomes for patients with this challenging disease.
References
Imamura Y, Kiyota N, Tahara M, et al. Effect of acute kidney injury and overall survival in patients with postoperative head and neck cancer who received chemoradiotherapy with cisplatin: A supplementary analysis of the phase II/III trial of JCOG1008. Cancer Med. 2024;13(18):e70235. doi:10.1002/cam4.70235
