- Concurrent chemoradiotherapy with cisplatin:
- Is the standard of care for patients with locally advanced head and neck squamous cell carcinoma (HNSCC):
- With the most widely accepted regimen being cisplatin 100 mg/m² administered intravenously every 3 weeks for up to three cycles during radiotherapy
- This approach is supported by multiple large randomized trials demonstrating survival benefit in patients with good performance status and is endorsed by major guidelines, including those from the American Society of Clinical Oncology and NCCN.
- Is the standard of care for patients with locally advanced head and neck squamous cell carcinoma (HNSCC):
- The rationale for exploring low-dose weekly cisplatin (20 to 50 mg/m²):
- Stems from the significant acute and chronic toxicities associated with the high-dose regimen, including:
- Nephrotoxicity, ototoxicity, and myelosuppression:
- Which can limit compliance and preclude delivery of the intended cumulative dose
- Nephrotoxicity, ototoxicity, and myelosuppression:
- Weekly regimens are hypothesized to:
- Improve tolerability and allow more patients to achieve a cumulative cisplatin dose of at least 200 mg/m²:
- Which is considered important for optimal tumor control
- Stems from the significant acute and chronic toxicities associated with the high-dose regimen, including:
- Efficacy: Survival and Disease Control:
- Meta-analyses and large retrospective studies indicate that overall survival and response rates are similar between high-dose and low-dose cisplatin regimens in the definitive chemoradiation setting:
- For example, a large population-based study in US veterans found no significant difference in overall survival between high-dose (100 mg/m² every 3 weeks) and low-dose (40 mg/m² weekly) cisplatin:
- Though high-dose was associated with greater toxicity
- Similarly, systematic reviews and meta-analyses have not demonstrated a meaningful survival difference between the two dosing strategies in either definitive or postoperative settings
- However, some studies and clinical guidelines suggest that high-dose cisplatin may offer superior locoregional control and overall survival:
- Particularly in altered fractionation or postoperative settings
- For instance, randomized trials and meta-analyses have reported improved locoregional control and, in some analyses, overall survival with high-dose regimens, especially when combined with altered fractionation radiotherapy
- For example, a large population-based study in US veterans found no significant difference in overall survival between high-dose (100 mg/m² every 3 weeks) and low-dose (40 mg/m² weekly) cisplatin:
- Meta-analyses and large retrospective studies indicate that overall survival and response rates are similar between high-dose and low-dose cisplatin regimens in the definitive chemoradiation setting:
- The American Society of Clinical Oncology recommends the every-3-week high-dose regimen as the standard:
- Noting that weekly regimens lack level I evidence and may be associated with inferior outcomes in some studies
- Achieving a cumulative cisplatin dose of ≥ 200 mg/m² is consistently associated with better survival and locoregional control:
- Regardless of the dosing schedule
- Toxicity and Compliance:
- High-dose cisplatin regimens are associated with increased rates of severe hematologic, renal, and ototoxic toxicities compared to weekly low-dose regimens
- In contrast, weekly low-dose cisplatin is generally better tolerated and associated with improved compliance, with more patients able to complete the planned cumulative dose
- Notably, patients with low skeletal muscle mass are at higher risk for dose-limiting toxicity with high-dose cisplatin and may particularly benefit from weekly regimens to improve compliance and reduce toxicity
- However, some studies have reported increased rates of grade 3 to 4 dysphagia and weight loss with weekly regimens in the postoperative setting
- Guideline Recommendations and Ongoing Controversies:
- Current US and international guidelines, including those from the American Society of Clinical Oncology:
- Continue to endorse high-dose cisplatin (100 mg/m² every 3 weeks) as the standard regimen for concurrent chemoradiation in eligible patients
- Weekly low-dose cisplatin is widely used in clinical practice, particularly for patients with comorbidities or poor performance status, but is considered investigational pending results from ongoing prospective trials
- The optimal dosing schedule remains an area of active research, and further adequately powered randomized trials are needed to clarify the relative efficacy and toxicity of these regimens, especially in specific subgroups such as HPV-positive, elderly, or comorbid patients
- Current US and international guidelines, including those from the American Society of Clinical Oncology:
- In summary, high-dose cisplatin every 3 weeks remains the standard of care for concurrent chemoradiation in locally advanced HNSCC, with weekly low-dose regimens offering a reasonable alternative for selected patients, particularly those at higher risk for toxicity or with difficulty tolerating high-dose therapy
- References:
- Head and Neck Cancer. Chow LQM. The New England Journal of Medicine. 2020;382(1):60-72. doi:10.1056/NEJMra1715715.
- Management of the Neck in Squamous Cell Carcinoma of the Oral Cavity and Oropharynx: ASCO Clinical Practice Guideline. Koyfman SA, Ismaila N, Crook D, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2019;37(20):1753-1774. doi:10.1200/JCO.18.01921.
- Low-Dose vs. High-Dose Cisplatin: Lessons Learned From 59 Chemoradiotherapy Trials in Head and Neck Cancer. Szturz P, Wouters K, Kiyota N, et al. Frontiers in Oncology. 2019;9:86. doi:10.3389/fonc.2019.00086.
- Concurrent Chemoradiotherapy With Cisplatin Given Once-a-Week Versus Every-Three Weekly in Head and Neck Squamous Cell Carcinoma: Non-Inferior, Equivalent, or Superior?. Gupta T, Kannan S, Ghosh-Laskar S, Agarwal JP. Oral Oncology. 2022;134:106130. doi:10.1016/j.oraloncology.2022.106130.
- Cisplatin Every 3 Weeks Versus Weekly With Definitive Concurrent Radiotherapy for Squamous Cell Carcinoma of the Head and Neck. Bauml JM, Vinnakota R, Anna Park YH, et al. Journal of the National Cancer Institute. 2019;111(5):490-497. doi:10.1093/jnci/djy133.
- Weekly Low-Dose Versus Three-Weekly High-Dose Cisplatin for Concurrent Chemoradiation in Locoregionally Advanced Non-Nasopharyngeal Head and Neck Cancer: A Systematic Review and Meta-Analysis of Aggregate Data. Szturz P, Wouters K, Kiyota N, et al. The Oncologist. 2017;22(9):1056-1066. doi:10.1634/theoncologist.2017-0015.
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- Comparison of Standard-Dose 3-Weekly Cisplatin and Low-Dose Weekly Cisplatin for Concurrent Chemoradiation of Patients With Locally Advanced Head and Neck Squamous Cell Cancer: A Multicenter Retrospective Analysis. Lee SY, Choi YS, Song IC, et al. Medicine. 2018;97(21):e10778. doi:10.1097/MD.0000000000010778.
- Altered Fractionation Radiotherapy Combined With Concurrent Low-Dose or High-Dose Cisplatin in Head and Neck Cancer: A Systematic Review of Literature and Meta-Analysis. Szturz P, Wouters K, Kiyota N, et al. Oral Oncology. 2018;76:52-60. doi:10.1016/j.oraloncology.2017.11.025.
- Comparison of Weekly Administration of Cisplatin Versus Three Courses of Cisplatin 100 mg/M(2) for Definitive Radiochemotherapy of Locally Advanced Head-and-Neck Cancers. Rades D, Seidl D, Janssen S, et al. BMC Cancer. 2016;16:437. doi:10.1186/s12885-016-2478-8.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 