Neoadjuvant chemotherapy followed by surgery versus definitive chemoradiotherapy in locally advanced head-and-neck cancer

INTRODUCTION

Locally advanced head-and-neck squamous cell cancers (LAHNSCCs) represent a significant clinical challenge due to their aggressive behavior, anatomical complexity, and impact on vital functions such as speech, swallowing, and respiration. At diagnosis, a substantial proportion of head-and-neck squamous cell carcinoma (HNSCC) patients present at this stage, characterized by large primary tumors (T3, T4), regional lymph node involvement (N2, N3), or both. The optimal management of LAHNSCC remains a subject of ongoing clinical debate, particularly regarding the choice between surgical and non-surgical treatment modalities, especially definitive chemoradiotherapy (CRT). Despite both approaches being supported by clinical data, they differ in toxicity profiles, functional outcomes, and long-term control rates. This review critically evaluates the advantages and limitations of both treatment modalities, incorporating evidence from relevant clinical studies, with the objective of facilitating informed decision-making and promoting individualized treatment strategies to optimize patient outcomes.

ROLE OF NEOADJUVANT CHEMOTHERAPY (NACT) IN HEAD-AND-NECK CANCERS

LAHNSCC comprises a significant proportion of patients who require aggressive multimodal treatment approaches, including surgery, radiotherapy, and chemotherapy. NACT administered before definitive local therapy in LAHNSCC hinges on three primary objectives: to shrink tumor volume and enhance resectability, particularly in borderline unresectable cases; to eliminate micrometastases and reduce distant failure; and to identify chemotherapy-responsive tumors and tailor further treatment accordingly. Landmark trials such as TAX 323 and TAX 324 reinvigorated interest in this strategy by showing that a docetaxel, cisplatin, and 5-fluorouracil (FU) (TPF) regimen outperformed the traditional cisplatin + 5-FU (PF) regimen in terms of response rates and survival in unresectable head-and-neck cancers.^[1]

NACT in resectable head-and-neck cancers remains a debated strategy, as multiple randomized trials have not shown significant gains in overall survival (OS) or locoregional control (LRC) for patients undergoing upfront surgery.^[1] Meta-analyses indicate that NACT may reduce distant metastasis rates modestly, particularly benefiting high-risk groups such as those with N2 nodal disease or hypopharyngeal primaries. The most compelling evidence for NACT’s benefit lies in technically unresectable oral cavity cancers. Studies from institutions such as Tata Memorial Hospital and CMC Vellore revealed that up to one-third of these cases became resectable following two to three cycles of TPF-based NACT, leading to improved surgical outcomes and survival.^[2,3] Supporting this, real-world data from Varanasi showed that NACT enabled surgery in 27.7% of previously unresectable cases, doubling median survival from 9 to 18 months in those successfully resected.^[4] These findings affirm the role of NACT in select patients, particularly for downstaging and enabling curative surgery in unresectable disease.

One of the notable benefits of NACT in oral cancers, especially of the tongue and gingivobuccal complex, is its potential to facilitate less morbid surgical resections. In a retrospective study at CMC Vellore, about 85% of tongue cancer patients required smaller resections than initially anticipated post-NACT.^[3] This aligns with the organ-preservation hypothesis proposed by Licitra et al., potentially improving postoperative speech and swallowing outcomes.^[5]

CRT AS A DEFINITIVE TREATMENT MODALITY IN LAHNSCC

Definitive CRT remains a cornerstone of curative-intent treatment in patients with unresectable disease or where organ preservation is desirable. It combines the LRC offered by radiation therapy (RT) with the systemic benefit of chemotherapy, primarily cisplatin-based regimens.^[6] The landmark meta-analysis of chemotherapy in head-and-neck cancer (MACH-NC) provided compelling evidence supporting the addition of chemotherapy to RT, particularly in the concurrent setting. Intensity-modulated radiotherapy (IMRT) has revolutionized HNSCC treatment by enabling precise dose delivery to tumor tissues while sparing adjacent critical structures such as salivary glands, spinal cord, and pharyngeal musculature.^[7] IMRT facilitates dose escalation strategies and better toxicity profiles, thus supporting its use in combination with chemotherapy. In definitive settings, RT doses of 70 Gy in 35 fractions are typically used.^[6]

The addition of platinum-based chemotherapy to RT demonstrated an absolute survival benefit of approximately 6.5% at 5 years. This synergy is attributed to chemotherapy’s ability to sensitize tumor cells to radiation, eradicate microscopic systemic disease, and enhance overall LRC. Cisplatin, owing to its radiosensitizing properties and established efficacy, has been the mainstay of concurrent regimens. The standard regimen involves high-dose cisplatin at 100 mg/m² administered every 3 weeks during the radiation course.^[7] However, alternative schedules, such as weekly cisplatin (40 mg/m²), have been investigated for their better tolerability and comparable efficacy.^[8] Other chemotherapeutic combinations include carboplatin with 5-FU or paclitaxel, particularly in cisplatin-ineligible patients.^[6]

NACT FOLLOWED BY SURGERY VERSUS DEFINITIVE CRT: HEAD TO HEAD

Each of the two approaches: NACT followed by surgery, and definitive CRT has distinct biological rationales, patterns of adoption based on tumor subsite, and varying degrees of clinical evidence supporting its use.

NACT is often applied in technically unresectable oral cavity cancers where tumor bulk or location initially precludes surgery. Studies have shown that 30–40% of such patients can be downstaged to undergo successful surgical resection with clear margins, which translates into improved survival compared to non-responders.^[1] Although pathological complete response rates up to 27% were reported in studies by Licitra et al. and Zhong et al., these did not uniformly translate into OS benefits for the entire cohort. However, responders did show significantly better outcomes in the form of early tumor shrinkage post-NACT, allowing for less extensive surgery and better functional preservation.^[5,9] Toxicities, including neutropenia and renal impairment, may cause treatment delays and jeopardize timely surgery.^[3] Moreover, the lack of biomarker-driven patient selection has hindered its wider implementation.

Definitive CRT has become the standard for many LAHNSCCs, particularly those of the oropharynx, hypopharynx, and larynx. High-level evidence from randomized controlled trials and the MACH-NC meta-analysis supports definitive CRT as the most effective non-surgical modality for excellent LRC while preserving speech and swallowing and improving survival.^[6] However, CRT is associated with a range of acute and delayed toxicities such as mucositis, dermatitis, nephrotoxicity, ototoxicity, and hematologic suppression. Long-term toxicities, such as xerostomia, dysphagia, and fibrosis, can severely impact quality of life. In a study by Iqbal et al., over 60% of patients completed all planned CRT with manageable side effects, but more than 40% required hospitalization for supportive care.^[8]

Subsite-specific considerations are crucial in treatment selection. For example, surgery remains the gold standard for oral cavity cancers. NACT may help convert unresectable tumors to resectable tumors, but it is not routinely used in resectable cases. CRT is preferred in oropharyngeal and laryngeal cancers, particularly in human papillomavirus-positive patients, due to better response and survival with organ preservation.^[10,11] Patient factors such as age, comorbidities, performance status, and preferences also influence modality choice. In elderly or frail patients, CRT with weekly cisplatin or alternative agents may be more feasible than surgery post-NACT.^[12] Biomarker-based selection and prospective validation are necessary to justify the routine use of NACT.

CONCLUSION

In the management of locally advanced head-and-neck cancers, both NACT followed by surgery and definitive CRT are curative options. CRT remains the mainstay for most patients, especially those with oropharyngeal, hypopharyngeal, and laryngeal primaries, due to its proven efficacy and organ-preserving potential. Conversely, NACT followed by surgery offers value in selected patients with technically unresectable oral cavity cancers by enabling curative resection and improving outcomes. There is no one-size-fits-all solution, and treatment must be individualized based on tumor subsite, stage, patient performance status, and institutional expertise. Future advances, including biomarker-guided therapy, organoid models, and integrated immunotherapy, may further refine these paradigms. Until then, multidisciplinary evaluation remains critical to achieving optimal oncologic and functional outcomes.