Carboplatin–capecitabine in concurrent chemoradiation for LA-HNSCC: could it be a safer alternative to high-dose cisplatin?

Abstract

This letter discusses the findings of the CARCAP-HN trial by Mohanty et al, which compared concurrent chemoradiation (CRT) with carboplatin plus capecitabine versus standard 3-weekly high-dose cisplatin in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). The Phase II randomized study demonstrated that the experimental regimen offered comparable efficacy in terms of progression-free survival and objective response rates while significantly reducing severe toxicities, including grade ≥3 oral mucositis, vomiting, and nephropathy. Importantly, the carboplatin–capecitabine arm showed fewer treatment interruptions, addressing a critical factor for therapeutic success in LA-HNSCC. We highlight the potential of this regimen as a safer, effective alternative for cisplatin-ineligible patients, leveraging the radiosensitizing properties of capecitabine and the favorable toxicity profile of carboplatin. However, heterogeneity in patient baseline characteristics and the single-center nature of the study warrant cautious interpretation. We advocate for future large-scale, multi-center Phase III trials incorporating quality-of-life metrics and molecular subtyping to validate these findings. If confirmed, this regimen could become a standard of care for vulnerable populations, offering improved compliance and outcomes.

To the Editor,

We read with considerable interest the paper by Mohanty et al titled, “Phase II randomized study of carboplatin plus capecitabine versus 3-weekly cisplatin in locally advanced head and neck cancer patients undergoing concurrent chemoradiation (CARCAPHN).” This Phase II trial addresses a critical and long-standing clinical challenge: identifying a less toxic yet equally effective concurrent chemoradiation (CRT) regimen for the substantial proportion of locally advanced head-and-nek squamous cell carcinoma (LAHNSCC) patients who are ineligible for standard 3-weekly high-dose cisplatin due to comorbidities or risk of sever toxicity^[1^].

The authors’ findings were comparable efficacy with a significantly superior toxicity profile. Make a compelling case for carboplatin plus capecitabine combination as a pragmatic alternative. Specifically, the median progression-Free survival (PFS) was similar (14 months vs 12.5 months; P = 0.715), the objective response rate (ORR) was nearly identical (97.5% vs 94.7%) to the control arm.

The clinical imperative: reducing toxicity and treatment interruptions

The primary strength of the CARCAP-HN trial lies in its demonstration of reduced treatment-related adverse events. The experimental arm showed significantly lower rates of Grade ≥ 3 oral mucositis (P ≤ 0.0001), vomiting (P ≤ 0.0001), nephropathy (P = 0.003), and electrolyte imbalance (P = 0.013). These toxicities are hallmark challenges of high-dose cisplatin^[2^], frequently leading to dose delays, reductions, or cessation. Crucially, the regimen translated this improved tolerability into a significantly lower treatment interruption rate (TIR) for both chemotherapy and radiation therapy (P ≤ 0.001). This factor is arguably one of the most clinically relevant observations, as adherence of the prescribed radiation schedule is paramount. Prolongation of overall treatment time (OTT) is a well-established negative prognostic indicator in LAHNSCC, strongly correlating with impaired locoregional control and reduced survival^[3,4^]. The carboplatin/capecitabine approach appears to facilitate treatment completion, thereby minimizing a major preventable cause of treatment failure.

Placing capecitabine-base regimens in context

The rationale for using capecitabine is strong: it acts as a prodrug for 5-fluorouracil (5-FU), exploiting the high activity of thymidine phosphorylase (TP) is tumor tissues, and is known to be a potent radiosensitizer^[5^]. While carboplatin monotherapy is generally considered inferior to 3-weekly cisplatin in terms of toxicity profile compared to infusional 5-FU^[6,7^]. It appears to close the efficacy gap. This combination offers an all-oral, non-nephrotoxic backbone for patients who would otherwise be relegated to less intensive weekly regimens, which have demonstrated inferior outcomes compared to high-dose cisplatin^[8^].

Potential sources of heterogeneity

The study delivers promising results; however, specific elements of the research methodology may have contributed to heterogeneity. Differences in baseline patient characteristics like performance status, nutritional status, comorbid conditions, and kidney function, could affect how well a treatment works and how well a patient tolerates it. Variations in radiation treatment, division plans, and supportive treatments may also influence the outcome. Also, since this is a single-center study with a small sample size, the way the institution treats patients and the preferences of the clinicians could affect both toxicity and compliance rates. It will be necessary to address these factors in future multicenter trials using standardized protocols to confirm the accuracy and usefulness of these findings.

Next step for validation and future research

While the CARCAP-HN trial provides robust data for Phase II study, the observed equivalence efficacy with superior tolerability must be validated in larger, multi-institutional Phase II non-inferiority trial with longer follow-up data. Future studies should focus on:

• Quality of Life metrics: Formally integrating patient-reported outcome measures (PROMs) To assess the advantages of diminished Grade ≥ 3 toxicities and TIR on patient quality of life and functional outcomes, such as swallowing, which are vital endpoints in organ-preservation strategies^[9^].

• Molecular Subtyping and De-intensification: Allocating treatment according to LAHNSCC molecular features, especially p16 status of oropharyngeal cancer. In p16-positive disease with a better prognosis that frequently occurs, this lower toxic regimen might be investigated as a candidate for de-intensification.

• The Addition of Innovative Agents: Exploring such a backbone’s ability, with lower myelosuppressive and nephrotoxicity profiles, to readily accommodate addition of newer immunotherapeutic agents such as anti-PD-1 antibodies that are challenging when added to high-dose cisplatin.

This letter to the editor adheres to the TITAN Guidelines 2025 on transparency, integrity, and the use of AI in medical writing and publishing^[10^].

Conclusion

Mohanty et al offered compelling data that would persuade physicians to accept carboplatin with capecitabine as a standard concomitant regimen in cisplatin-ineligible LAHNSCC patients. Their retrospective analysis strongly recommends that this combination attains the desired efficacy for definitive CRT while significantly reducing acute toxicity and minimizing therapy delay. We support the view of the authors that a Phase III study is essential to make this combination an invaluable substitute in our armamentarium so that we can finally witness improved compliance from patients as well as possibly better longer-term outcomes with strict compliance with the desired schedule of therapy.

Ethical approval

No ethical approval was required for the study.

Consent

No consent was needed.

Sources of funding

No financial support was received for the study.

Author contributions

F.A.R. and A.G.: designed the study and performed the data collection. F.A.R. and M.H.J.A.: drafted the manuscript. D.M. and A.H.M.: performed the statistical analysis and validation of the data. A.H.M.: supervised the project and provided final approval of the version to be published. All authors read and approved the final manuscript.

Conflicts of interest disclosure

The authors declare no competing interests that could have influenced the objectivity or outcome of this research.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Mohammed Hammad Jaber Amin.

Provenance and peer review

Not applicable.