Head-and-neck squamous cell carcinoma (HNSCC) is a major global health concern, ranking among the most common malignancies worldwide and accounting for a disproportionate burden in low- and middle-income countries (LMICs). In India, HNSCC constitutes nearly one-fourth of all male cancers and over one-tenth of female cancers, largely driven by tobacco, alcohol, and socioeconomic exposures. Most patients present with locally advanced, non-metastatic disease requiring multimodality therapy.1 Concurrent chemoradiotherapy (CCRT) with cisplatin and conventionally fractionated radiotherapy (70 Gy in 35 fractions over 7 weeks) has long been the standard of care, offering both organ preservation and improved survival.2,3 Meta-analyses such as MACH-NC and MARCH have demonstrated that chemotherapy improves survival (~6.5% absolute OS at 5 years)4,5, and that altered fractionation provides a modest survival advantage, especially when overall treatment time (OTT) is shortened.6,7 However, conventional schedules are protracted, vulnerable to interruptions, and strain on oncology resources.8 The COVID-19 pandemic amplified these challenges. Lockdowns, travel restrictions, and infection risks necessitated pragmatic adaptations in cancer care. Professional societies including ASTRO (American Society for Radiation Oncology) and ESTRO (European Society for Radiotherapy and Oncology) issued consensus recommendations endorsing mild hypofractionation (≤2.4 Gy/fraction) to reduce visits while maintaining curative intent.9,10 Several centers reported early experiences with these approaches, particularly in high-volume or resource-limited settings.11-13 From a radiobiological perspective, the six-week hypofractionated regimen of 66 Gy in 30 fractions (2.2 Gy/fraction) provides a biologically effective dose (BED) for tumor control (α/β = 10) of approximately 79.2 Gy, compared with 84 Gy for the conventional 70 Gy/35# regimen. Although slightly lower in nominal BED, this difference is counterbalanced by the reduction in OTT, which mitigates accelerated tumor repopulation. For late-reacting tissues (α/β = 3), the BED is higher than conventional fractionation, necessitating vigilance for late toxicities.14,15 Thus, the regimen represents a rational compromise between maintaining tumor control, limiting treatment duration, and preserving tolerability. In this context, our institution introduced the six-week hypofractionated CCRT protocol as a deviation from the routine seven-week regimen. The primary endpoint of this study was the complete response (CR) rate at six months. Secondary endpoints included acute and late toxicities (graded using CTCAE v5.0), treatment compliance, and logistic outcomes such as fractions avoided and OTT reduction. The novelty of this work lies in demonstrating the real-world feasibility of this fractionation strategy with concurrent cisplatin in an LMIC setting, while also quantifying operational benefits such as patient visits averted and reduced treatment duration—dimensions rarely captured in formal clinical trials.

Study Design and Setting This prospective, single-arm study was conducted in the Department of Radiation Oncology at a tertiary cancer center between August 2020 and June 2021. Patients with biopsy-confirmed, locally advanced head-and-neck squamous cell carcinoma (HNSCC) were enrolled and treated with a six-week hypofractionated concurrent chemoradiotherapy (CCRT) regimen. Written informed consent was obtained from all participants prior to initiation of therapy. Eligibility Criteria Inclusion criteria: • Age between 18 and 70 years. • Karnofsky Performance Score (KPS) ≥70. • Histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx. • Non-metastatic, locally advanced disease (Stage II–IV) Exclusion criteria: • Prior radiotherapy to the head and neck region. • Prior systemic chemotherapy for any malignancy. • Evidence of distant metastasis. • Non-SCC histologies, including sinonasal or nasopharyngeal primaries. Radiotherapy Protocol All patients were immobilized using a five-point thermoplastic head–neck–shoulder mask, with individualized positioning aids such as shoulder traction or bite blocks when indicated. Planning computed tomography (CT) simulation was performed with ≤3 mm slice thickness, with intravenous contrast enhancement. Magnetic resonance imaging (MRI) or positron emission tomography (PET) fusion was incorporated when available for improved target delineation. Target volumes were defined in accordance with ICRU-83 recommendations. The gross tumor volume (GTV) included the primary lesion and gross nodal disease. Clinical target volume (CTV) margins of 0.5–1.0 cm were applied, with anatomical editing to exclude uninvolved structures. A planning target volume (PTV) margin of 5 mm was added to account for setup uncertainties. Elective nodal regions were contoured based on international consensus guidelines. The prescribed dose was 66 Gy in 30 fractions (2.2 Gy per fraction, 5 fractions per week, over 6 weeks) delivered to the high-risk PTV. Radiotherapy was delivered using linear accelerators with three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT), depending on patient and machine availability. Planning aimed for ≥95% of the PTV to receive 100% of the prescription dose, while minimizing hot spots >110%. OAR dose constraints followed QUANTEC/ESTRO recommendations: spinal cord Dmax ≤45 Gy, brainstem Dmax ≤54 Gy, parotid mean <26 Gy when feasible, mandible V70 <20%, larynx mean <40 Gy, and pharyngeal constrictors Dmean <50 Gy. Image guidance included daily setup verification with portal imaging or weekly cone-beam CT, with corrections applied if shifts exceeded institutional thresholds (>3 mm). Plans underwent standard quality assurance, including gamma evaluation (3%/3 mm). Concurrent Chemotherapy Cisplatin was the standard concurrent agent and was delivered either weekly at 40 mg/m² or tri-weekly at 100 mg/m², according to patient performance status and tolerance. Pre- and post-hydration, magnesium supplementation, and antiemetics (5-HT3 antagonists with dexamethasone) were administered per institutional protocol. Dose modifications were permitted in the event of grade ≥3 hematologic or non-hematologic toxicities, renal dysfunction, or persistent grade ≥3 mucositis/dysphagia. For patients deemed cisplatin-ineligible particularly those with advanced age, borderline performance status, impaired creatinine clearance (<60 mL/min), or significant comorbidities, concurrent carboplatin (AUC 2 weekly) was considered as an alternative radiosensitizer. This substitution ensured that systemic therapy could be maintained without excessive renal or gastrointestinal toxicity, aligning with real-world practice for patients unable to tolerate cisplatin. Supportive Care All patients were evaluated weekly by a multidisciplinary team comprising radiation oncologists, dieticians, and nursing staff. Standard supportive measures included analgesics, topical anesthetic agents, oral hygiene counseling, antifungals when required, and nutritional supplementation. Patients with >5–10% body weight loss or grade ≥3 dysphagia were considered for nasogastric tube placement. Prophylactic hospital admission for intravenous fluids was instituted in patients with severe mucositis or dehydration. Assessments • Acute toxicities (mucositis, dermatitis, dysphagia) were assessed weekly during radiotherapy and graded per CTCAE version 5.0. • Late toxicities (xerostomia, dysphagia, mucositis) were defined as events persisting or arising ≥4 weeks after completion of radiotherapy and graded per CTCAE v5.0. • Tumor response was evaluated clinically using direct laryngoscopy and radiologically with contrast-enhanced CT at 3 and 6 months, classified according to RECIST version 1.1: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). • Compliance was recorded as: treatment completed without interruptions; treatment completed with gaps; defaulted before completion; or death during treatment. Endpoints The primary endpoint was the complete response (CR) rate at 6 months. Secondary endpoints included acute and late toxicities, compliance, and logistic outcomes (fractions avoided and OTT reduction). Statistical Analysis Analyses were descriptive in nature. Frequencies and percentages summarized categorical variables, while medians and ranges were used for continuous variables. Binomial 95% confidence intervals (CIs) were calculated for key proportions (e.g., CR, overall response rate, grade ≥3 toxicities). All analyses were conducted using standard statistical software. No formal hypothesis testing against conventional regimens was performed, given the single-arm design.

A total of 65 patients were assessed for eligibility, of whom five were excluded (three did not meet inclusion criteria and two declined participation). Sixty patients were enrolled and initiated on hypofractionated concurrent chemoradiotherapy. The median age at diagnosis was 62 years (range, 31–70 years). There was a clear male predominance (n=54, 90%), while females comprised 10% (n=6). The majority presented with locally advanced disease: Stage III in 16 patients (26.6%) and Stage IV in 36 patients (60%). Only 8 patients (13.3%) had early Stage II disease. Tumor differentiation was moderate in half the cases (n=30, 50%), well-differentiated in 26 (43.3%), and poorly differentiated in 4 (6.6%). The subsite distribution showed predominance of laryngeal (n=24, 40%) and oropharyngeal cancers (n=22, 36.6%), followed by oral cavity (n=10, 16.6%) and hypopharynx (n=4, 6.7%). Performance status was good in most patients, with KPS ≥80 in 52 (86.6%). Treatment Delivery and Compliance Among the 60 patients initiated on hypofractionated chemoradiotherapy, treatment adherence was encouraging. A large majority, 50 patients (83.3%), completed the prescribed 66 Gy in 30 fractions with concurrent cisplatin without any unplanned interruptions. Six patients (10%) experienced short treatment breaks of 3–7 days, most commonly due to acute grade III mucositis or dysphagia, but were able to resume and complete the course after supportive interventions. Two patients (3.3%) defaulted partway through treatment because of logistical challenges, while two patients (3.3%) died during therapy, both related to sepsis in the setting of severe mucosal toxicity and poor nutritional reserve. These events reflect the clinical vulnerability of this population when exposed to intensive chemoradiation. Chemotherapy compliance was also satisfactory. More than four-fifths of the cohort (≥80%) received at least five weekly cycles of cisplatin, corresponding to a cumulative dose of ≥200 mg/m², a threshold associated with improved outcomes in concurrent chemoradiotherapy. Chemotherapy omissions, when necessary, were driven by acute toxicities rather than patient refusal. Overall, the compliance profile in this study demonstrates that a condensed six-week hypofractionated regimen can be delivered with high feasibility and without compromising systemic therapy intensity, while still maintaining adherence rates comparable to conventional seven-week protocols. Table 1. Baseline demographic and disease characteristics (n=60) Characteristic Category N (%) Age, years Median (range) 62 (31–70) Sex Male 54 (90) Female 6 (10) Performance status (KPS) ≥80 52 (86.6) 70 8 (13.3) Stage II 8 (13.3) III 16 (26.6) IV 36 (60) Histological differentiation Well differentiated 26 (43.3) Moderately differentiated 30 (50) Poorly differentiated 4 (6.6) Primary subsite Larynx 24 (40) Oropharynx 22 (36.6) Oral cavity 10 (16.6) Hypopharynx 4 (6.7) Toxicity Profile Acute Toxicities: The heatmap visualization highlights the clustering of higher-grade toxicities in mucositis and dysphagia compared with dermatitis. More than half of the cohort experienced grade III mucositis (53.3%) and grade III dysphagia (50%), whereas grade IV events were rare (≤7%). In contrast, dermatitis was predominantly grade I–II, with only 2 patients (3.3%) developing grade III changes. This pattern underscores that mucosal and swallowing structures were the principal dose-limiting toxicities in this hypofractionated regimen, while skin reactions remained largely mild. Late Toxicities: At six months, the toxicity profile had substantially improved, with the majority of late effects being low grade. Xerostomia was the most frequently reported symptom, affecting 40% of patients (grade I–II in 20 patients, grade III in 4). Late dysphagia and mucositis were largely grade I–II, with no grade III–IV events recorded. This suggests that, despite the intensity of acute mucosal reactions, late toxicity remained acceptable in the short follow-up period, supporting the tolerability of this hypofractionated schedule. This heatmap is shown in Figure 1. Table 2. Late toxicity distribution at 6 months (n=60) Toxicity Grade I Grade II Grade III Mucositis 4 (6.6) 1 (1.6) 0 Dysphagia 10 (16.6) 6 (8.3) 0 Xerostomia 12 (20) 8 (13.3) 4 (6.6) Sustained Early Tumor Response The waterfall plot clearly demonstrates the predominance of favorable responses following hypofractionated chemoradiotherapy. At the first assessment, 47 patients (78.3%) achieved a complete response, and this proportion increased marginally to 48 patients (80%) by six months, indicating durable early disease control. Partial responses were observed in a small subset (11.6% at three months and 10% at six months), while stable disease (6.6%) and progressive disease (3.3%) remained infrequent. The visual distribution highlights a clear skew toward tumor regression, with only two patients showing progression at both time points. Collectively, these findings emphasize that the hypofractionated regimen provided robust and sustained locoregional control in the majority of treated patients. The adoption of the hypofractionated chemoradiotherapy protocol translated into measurable logistic advantages at both the patient and institutional levels. Compared with the conventional 70 Gy in 35 fractions delivered over 7 weeks, the six-week hypofractionated regimen reduced the number of treatment fractions by five per patient. When extrapolated across the entire cohort of 60 patients, this corresponded to nearly 300 hospital visits averted. In addition to minimizing the frequency of hospital attendance, the overall treatment time was shortened from seven to six weeks (49 days versus 42 days). This reduction is of particular importance in the context of the COVID-19 pandemic, where decreasing cumulative exposure risk for immunocompromised patients was a critical priority. Furthermore, the decrease in total fractions alleviated machine burden and improved departmental throughput, enabling more efficient use of limited radiotherapy resources. From the patient perspective, fewer visits and a shorter treatment schedule translated into decreased travel requirements, reduced indirect costs, and improved convenience without compromising oncologic intent.

The present study demonstrates that a six-week hypofractionated chemoradiotherapy regimen (66 Gy in 30 fractions with concurrent cisplatin) is feasible, yields high early response rates, and offers operational advantages in the context of a pandemic. With an 80% complete response rate at six months, 90% overall response rate, and acceptable acute and late toxicity, our findings suggest that hypofractionation can maintain oncologic intent while reducing overall treatment time (OTT) and hospital visits. The results align with and extend evidence from landmark altered fractionation trials. RTOG 9003 compared conventional fractionation with hyperfractionation and accelerated regimens in HNSCC, showing that altered schedules improved locoregional control but at the cost of increased acute mucosal toxicity.16 Similarly, the MARCH meta-analysis (Meta-Analysis of Radiotherapy in Head and Neck Cancer) demonstrated a modest but significant absolute survival benefit (~3.4% at 5 years) with altered fractionation, particularly hyperfractionation, reinforcing the principle that reducing OTT can translate into improved outcomes.6 Our 6-week regimen reduced OTT by one week compared with conventional 70 Gy/35#, which may help counter accelerated repopulation starting around week 4–5 of treatment. The MACH-NC meta-analysis further confirmed the survival advantage of adding concurrent chemotherapy to radiotherapy in HNSCC, with cisplatin-based regimens offering the strongest benefit (~6.5% absolute OS at 5 years)4. By integrating concurrent cisplatin with hypofractionation, our study aligns with the highest level of evidence favouring combined modality therapy. The rationale for the selected schedule is supported by radiobiological modelling. A regimen of 66 Gy in 30 fractions (2.2 Gy/fraction) corresponds to a tumour control BED10 of ~79.2 Gy, compared with 84 Gy for conventional 70 Gy/35#. Although nominally lower, this is counterbalanced by reduced OTT, mitigating clonogenic repopulation.14,15 For late-reacting tissues (α/β = 3), the BED is higher, necessitating monitoring for late toxicity. At six months, late effects were largely grade I–II, with only 6.6% xerostomia grade III, suggesting early tolerability. Long-term outcomes remain to be evaluated. In our cohort, grade III mucositis (53.3%) and grade III dysphagia (50%) were the dominant acute toxicities, consistent with reports from altered fractionation trials. For example, in RTOG 9003, grade 3 mucositis occurred in ~40–56% of accelerated/hyperfractionated arms.16 Dermatitis was predominantly low-grade in our series, highlighting mucosal and swallowing structures as the primary dose-limiting sites. Importantly, late toxicities were mild at early follow-up, with no grade IV events recorded, supporting the short-term safety of this approach. Comparable findings have been reported in hypofractionated chemoradiation cohorts from Brazil (Jacinto et al., 55 Gy/20#, ORR 70%)12 and Egypt (Abdelhafiz et al., 60 Gy/25#, weekly cisplatin, feasible toxicity profile).13 Treatment adherence was favorable, with 83.3% completing therapy without gaps and >80% achieving a cisplatin cumulative dose ≥200 mg/m², the threshold associated with improved outcomes.9,17, Two patients (3.3%) died during therapy from septic complications, reflecting the clinical vulnerability of patients undergoing intensive chemoradiation, but consistent with reported treatment-related mortality rates (2–5%) in large trials.18 Laryngeal and oropharyngeal primaries predominated in our cohort. Evidence suggests that tumor subsites may influence outcomes with altered fractionation. In the MARCH meta-analysis, the greatest benefit of accelerated fractionation was seen in non-oropharyngeal tumors. Although our study was not powered for subsite-specific conclusions, the high CR rates across subsites suggest broad applicability. Cisplatin was the standard systemic agent, but weekly carboplatin (AUC 2) was substituted in patients with poor renal function, advanced age, or comorbidities. This pragmatic adaptation is endorsed by NCCN guidelines, which recognize carboplatin as a reasonable alternative for cisplatin-ineligible patients.19

Pandemic-Era Adaptations and Global Guidelines Our findings are consistent with the ASTRO–ESTRO consensus recommendations issued during the COVID-19 pandemic, which emphasized that radical head and neck radiotherapy should remain a high-priority intervention and should not be postponed by more than 4–6 weeks, even in resource-strained settings.9,10 The panel strongly supported the use of mildly hypofractionated schedules (≤2.4 Gy/fraction) in scenarios of reduced departmental capacity, while reserving concomitant chemotherapy for conventional or mildly hypofractionated regimens. These guidelines also acknowledged the role of pragmatic adaptations—including reduction in hospital visits, prioritization of curative over elective or low-risk cases, and omission of chemotherapy in select situations of severe resource constraints. By implementing a 66 Gy/30# regimen with concurrent cisplatin, our institution aligned with the risk-adapted strategy endorsed internationally, achieving both oncologic feasibility and operational gains. Importantly, our results reinforce that such hypofractionated chemoradiation regimens can be delivered safely in LMIC settings without compromising early response, while simultaneously reducing ~300 hospital visits and shortening OTT by one week. This dual oncologic and logistic benefit reflects the core rationale of ASTRO–ESTRO recommendations, ensuring continuity of high-quality cancer care under pandemic conditions. Similar pragmatic adaptations were reported at Princess Margaret (2.4 Gy/fx hypofractionation)11 and AIIMS Patna (60 Gy/25#, CR 55%, but higher mucosal toxicity).12 Together, these findings strengthen the case for hypofractionation as a safe, resource-conscious alternative in crisis settings.

1. Thomson DJ, Palma D, Guckenberger M, Balermpas P, Beitler JJ, Blanchard P et.al. Practice recommendations for risk-adapted head and neck cancer radiotherapy during the COVID-19 pandemic: an ASTRO–ESTRO consensus statement. Int J Radiat Oncol Biol Phys. 2020;107(4):618–27. 2. Bourhis J, Overgaard J, Audry H, Ang KK, Saunders M, Bernier J et.al. MARCH meta-analysis collaborators. Hyperfractionated or accelerated radiotherapy in head and neck cancers: a meta-analysis. Lancet Oncol. 2006;7(3):226–37. 3. Lacas B, Bourhis J, Overgaard J, Zhang Q, Grégoire V, Nankivell Met al.; MARCH meta-analysis collaborators. Role of radiotherapy fractionation in head and neck cancers: an update. Lancet Oncol. 2017;18(11):1221–7. 4. Tripathy A, Muzumder S, Srikantia N, Babu A, Sebastian MJ, Udayashankar AH et.al. A comparison of conventional and accelerated hypofractionated radiotherapy in definitive chemoradiation for locally advanced head and neck carcinoma: a retrospective cohort study. Radiat Oncol J. 2023;41(4):248. 5. Pignon JP, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): update on randomized trials. Radiother Oncol. 2009;92(1):4–14. 6. Shuryak I, Wang E, Brenner DJ. Understanding the impact of radiotherapy fractionation on overall survival in a large head and neck squamous cell carcinoma dataset: a comprehensive approach combining mechanistic and machine learning models. Front in Oncol. 2024;14:1422211. 7. Jacinto AA, Batalha Filho ES, Viana LD, De Marchi P, Capuzzo RD, Gama RR, et.al. Feasibility of concomitant cisplatin with hypofractionated radiotherapy for locally advanced HNSCC. BMC Cancer. 2018;18:1026. 8. Huang SH, O'Sullivan B, Su J, Ringash J, Bratman SV, Kim J, et.al. Hypofractionated radiotherapy alone with 2.4 Gy per fraction for head and neck cancer during the COVID-19 pandemic: The Princess Margaret experience and proposal. Cancer. 2020;126(15):3426-37 9. Abdelhafiz N, Mahmoud D, Gad M, Essa H, Morsy A. Effect of definitive hypo-fractionated radiotherapy concurrent with weekly cisplatin in locally advanced squamous cell carcinoma of the head and neck. J Med Life. 2023;16(5):743-50 10. Budach W, Hehr T, Budach V, Belka C, Dietz K. A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck. BMC Cancer. 2006;6:28. 11. Gupta T, Amer SB, Kumar R, Murthy V. Radiobiological basis of curative hypofractionated-accelerated RT (55 Gy/20fx). Cancer Treat Rev. 2020;68:102–9. 12. Agarwal S, Jaiswal I, Shahi UP, Mandal A, Aggarwal LM, Singh A, et.al. Accelerated hypofractionated chemoradiation for locally advanced head and neck cancer during COVID 19 pandemic: A tertiary care experience. J Cancer Res Ther. 2024;20(1):404–9. 13. Beitler JJ, Zhang Q, Fu KK, Trotti A, Spencer SA, Jones CU et.al. Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Clin Cancer Res. 2014;20(4):990–7. 14. Lee ML, Jung K, Kang CM, et al. Impact of COVID-19 pandemic on treatment delays for HNSCC. J Clin Med. 2025;14(5):1424. 15. Mireștean CC, Crisan A, Mitrea A, Buzea C, Iancu RI, Teodor Inacu DP . Hypofractionated radiotherapy for HNC during COVID-19: center experience. Clin JCancer. 2021;10(4):587. 16. Petit C, Lacas B, Pignon JP, Le QT, Grégoire V, Grau C, et.al. Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis. Lancet Oncol. 2021;22(5):727-36. 17. Guckenberger M, Belka C, Bezjak A, Bradley J, Daly ME, DeRuysscher D et.al. ESTRO–ASTRO consensus statement on COVID-19–adapted HNC RT. Radiother Oncol. 2020;148:192–9. 18. Lacas B, Carmel A, Landais C, Wong SJ, Licitra L, Tobias JS, et.al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group. Radiother Oncol. 2021;156:281-93. 19. Pignon JP, Bourhis J, Domenge CO, Designé LL. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. The Lancet. 2000;355(9208):949-55.