Hypofractionated radiation therapy for head and neck cancers in the era of intensity-modulated radiation therapy
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Definitive or postoperative radiation therapy (RT) for head and neck (H&N) cancer typically involves delivering 2 Gy doses five times a week over a period of 6–7 weeks. However, concerns regarding tumor repopulation have spurred research into methods to reduce the treatment duration compared to conventional RT [1-3]. Hypofractionated RT (HFRT) offers several advantages in this regard. A condensed treatment schedule reduces the overall treatment duration and enhances patient convenience and compliance. Additionally, HFRT may result in cost savings for healthcare systems and patients by decreasing the number of hospital visits and the associated expenses. Moreover, the higher biological effectiveness of HFRT may improve tumor control rates, potentially leading to enhanced survival outcomes. However, HFRT poses challenges, including an increased risk of acute and late toxicity. During the era of two-dimensional or three-dimensional conformal RT, significant radiation exposure to normal tissues associated with HFRT has resulted in a notable increase in toxicity, making it less attractive as a treatment option, except in select cases. However, with the advent of intensity-modulated RT (IMRT), it has become possible to maintain uniform radiation doses to tumors, while drastically reducing radiation exposure to adjacent normal tissues [4,5]. Consequently, compared to previous RT techniques, IMRT has significantly decreased toxicity, making HFRT more feasible. Against the backdrop of the coronavirus disease 2019 pandemic, interest in HFRT for various types of cancer has increased.
H&N cancers pose unique challenges owing to the complex intertwining of various organs in the region, making RT difficult and leading to a higher incidence of serious side effects. Oral mucositis is a prominent side effect that induces pain and significantly affects the patient’s ability to eat, consequently reducing treatment compliance. In addition, xerostomia, taste changes, or loss of taste due to RT, dysphagia, or dermatitis can often lead to treatment delays. Long-term side effects may include inflammation and fibrosis in areas exposed to high-dose radiation, resulting in weakening of the swallowing muscles or damage to the surrounding nerves, leading to symptoms. These side effects may be exacerbated in the case of HFRT, as described earlier, leading to relatively little research on HFRT for H&N cancer.
Tripathy et al. [6] conducted a retrospective analysis comparing conventional RT administered at 2.0 Gy over 7 weeks with moderate HFRT delivered at 2.2 Gy over 6 weeks. The study period spanned from 2013 to 2018 for conventional RT, and from 2018 to 2021 for HFRT. Treatment compliance with planned RT was slightly higher in the HFRT group (80% vs. 89.1%; p = 0.174). With a median follow-up of 18.9 months, there was no significant difference in progression-free survival between the two groups (15.9 months vs. 26.9 months; hazard ratio = 0.801, 95% confidence interval 0.49–1.28; p = 0.357). Regarding toxicity, the frequency of unplanned RT breaks exceeding 2 days was higher in the HFRT group than in the conventional RT group (36.9% vs. 43.9%; p = 0.454). The authors claimed a trend towards benefits in terms of locoregional control in the HFRT arm and similar overall survival rates. However, differences in patient age, sex distribution, subsite involvement, and chemotherapy regimens between the two groups made it difficult to draw conclusions.
The National Comprehensive Cancer Network Guidelines [7] describe various HFRT regimens for palliative RT, catering to patients who are often older or have compromised Eastern Cooperative Oncology Group performance, making hospital visits challenging and limiting access to medical facilities. In such cases, HFRT can achieve the RT goals by shortening the treatment duration and reducing patient visits, thereby increasing convenience. Various regimens, such as 50 Gy in 20 fractions; 37.5 Gy in 15 fractions; 30 Gy in 10 fractions; or 30 Gy in 5 fractions, with a minimum of 3 days between treatments; or 44.4 Gy delivered in 12 fractions over three cycles, with each cycle separated by 2 to 3 weeks (QUAD SHOT) [8], are available for use.
For definitive or postoperative RT, various dose fractionation schedules utilizing dose-painting techniques, such as simultaneous integrated boost, sequential boost, or accelerated concomitant boost, can be prescribed. Radiation prescription schedules vary by subsite, but typically involve administering 2.0–2.2 Gy per fraction to the high-risk planning target volume, resulting in total doses ranging from 66–72 Gy over 6–7 weeks. HFRT with single-fraction doses greater than 2.4 Gy is still experimentally used for H&N cancers, with the exception of early-stage glottic cancer, but its adoption is limited by a lack of high-quality evidence and concerns about potential long-term late toxicity. In early glottic cancer, several published studies have demonstrated the effectiveness of HFRT at doses above 2.4 Gy [9-11]. Clinical trials applying stereotactic RT to this cancer are also underway; however, concerns regarding toxicity persist [12-14]. Recently, Bentzen et al. [15] presented an abstract of the results from a randomized non-inferiority phase III trial (HYPNO) comparing HFRT and normofractionated accelerated RT (NFX) in locally advanced H&N squamous cell carcinoma. The trial was conducted at 12 centers across 10 low- and middle-income countries. In total, 792 patients were enrolled, with 395 and 397 allocated to the HFRT and NFX groups, respectively. HFRT demonstrated non-inferiority compared to NFX in terms of the 3-year locoregional control rate (50.7% vs. 51.2%; p = 0.36) and the occurrence of late-grade 3+ adverse events (18.8% vs. 20.2%; p = 0.68). Although detailed results are yet to be published, these findings underscore the potential utility of HFRT and warrant further attention.
In summary, HFRT offers benefits, such as a shorter treatment duration, increased patient convenience, and potential cost savings. The advent of IMRT has improved its feasibility by reducing toxicity. However, HFRT for H&N cancer remains relatively underexplored owing to the unique challenges in the complexity of treatment and frequent severe side effects. Careful consideration of dose fractionation and vigilant management of treatment-related toxicities are essential to maximize the benefits of HFRT while minimizing potential risks. This highlights the importance of personalized treatment planning and ongoing research in this evolving field.
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Conflict of Interest
No potential conflict of interest relevant to this article was reported.