Discussion

In India, a significant proportion of HNC cases present with locally advanced or metastatic disease and do not merit receiving radical therapy. ^{Reference Mathur, Sathishkumar and Chaturvedi6} Although these patients are not suited for receiving prolonged and definitive therapy, they often require PRT as uncontrolled tumour growth in the head and neck region can negatively affect an individual’s nutrition, respiration and social interaction. In most RT centres, palliative therapy comprises between 40 and 50% of the workload. ^{Reference Lutz, Chow, Hartsell and Konski13}

HNCs can invade the aerodigestive tract giving rise to symptoms like pain, dysphagia, change in voice, bleeding, etc. The basic goal of treatment in such cases becomes palliation of symptoms by control of the local disease. The principles of effective palliation entail the use of therapeutic modalities that relieve a patient’s symptoms with minimal side effects and with minimal time spent in the hospital, to facilitate both the patients’ and their caregivers’ early return to their residence.

Short-course hypofractionated RT has been extensively and effectively used for palliation of HNCs over the years by institutions all over the world. The radiobiological principle that supports PRT is as follows. By using a large dose per fraction, a moderately high biologically effective dose (BED) can be built up within the tumour in a few treatment fractions. This dose will be sufficient to cause enough tumour cell kill to reduce the bulk of the tumour mass and relive the symptoms being caused by it. The acute toxicity associated is usually minimal and easily manageable. ^{Reference Velarasan and Ramasundaram7–Reference Corry, Peters and Costa11,Reference Miller, Hoogstraten, Staquet and Winkler14} The risks of increased late toxicity due to larger doses per fraction and of increased chances of recurrence due to insufficient total dose can be neglected due to limited life expectancy in this patient group.

As far back as 1983, Weissberg et al. reported on a randomised controlled trial comparing a schedule of 70 Gy delivered in 35 fractions over 7 weeks versus another of 80 Gy in 12 fractions over 3 weeks in patients of stage III and IV HNCs. The study reported that both schedules had equal palliative benefit and toxicity. ^{Reference Weissberg, Pillsbury, Sasaki, Son and Fischer15} In India, a large study of more than 500 HNC patients, conducted at AIIMS, New Delhi, showed that even a dose of 20 Gy delivered in 5 fractions over 1 week achieved a tumour response rate of 37% and relief from symptoms in 47–59% of patients. ^{Reference Mohanti, Umapathy, Bahadur, Thakar and Pathy16} Over the last few decades, a myriad variety of dose fractionation schemes have been tried and reported in the literature, with tumour response rates ranging from 53% to 83%. ^{Reference Velarasan and Ramasundaram7–Reference Corry, Peters and Costa11,Reference Kancherla, Oksuz and Prestwich17–Reference Stevens, Huang and Fung29} Table 2 compares some of these PRT schedules with the present study’s results. With a tumour response rate of 73% and symptomatic relief in 72% cases, the results are comparable to those that have been reported in previous trials.

Table 2.

Chart showing relative radiobiological doses, treatment durations and results of various PRT regimens in HNCs

However, the optimal regimen of hypofractionated RT for palliation of HNCs is yet to be agreed upon, and there are no available guidelines for preferring one regimen over the other. This is primarily because of the heterogeneity of clinical characteristics of patients and treatment environments in the various studies leading to a situation where it would be difficult to compare the regimens used in two different clinical trials. This is combined with the lack of any randomised controlled trials comparing two or more treatment schedules. Nevertheless, as is clear from Table 2, most of the regimens achieve gratifying results with symptom relief of patients ranging from 44% to 82% in various studies. The dose–outcome relationship, at least in terms of symptom relief, is not automatically evident, even if it exists. The situation is also confused by the concurrent use of painkillers and other medications that most trials allow. Symptom relief in our study, at 72%, is comparable to what has been described in the literature.

It has been previously suggested that the total dose delivered in a RT schedule may have a significant impact on the treatment response rates as well as OS rates. ^{Reference Monnier, Touboul, Durdux, Lang, St Guily and Huguet28} The study also attempted to compare the BEDs of the major trials involving hypofractionated RT. The underlying hypothesis was that a higher BED may achieve a greater tumour cell kill leading to a more durable response, thus delaying disease recurrence and potentially improving OS. This would imply that regimens with a higher BED should show a greater tumour response rate and should be preferred where clinically and logistically feasible. BED and EQD₂ (Equivalent Dose at 2Gy per fraction) were calculated for all the studies using the formulas based on the linear-quadratic model and compared with the study regimen (Table 2). No corrections were used for the time duration over which the dose was delivered.

Though no statistical test was carried out, a visual comparison of BEDs of various regimens and the tumour response rates reported suggests that a simple BED calculation may not help choose one PRT regimen over another. The regimen used in the present study had the second-highest BED and EQD₂, but higher response rates and symptom relief rates have been reported by at least four studies with lower values of these parameters.

The mean OS calculated in this study population is 9·72 months, which was as expected for the patient demographic as per available literature. ^{Reference Sharma, Baishya, Kataki, Kalita, Das and Rahman2–Reference Chen, Vaughan, Narayan and Vijayakumar10} It was interesting to see that among patients with significant tumour response (CR or PR), the mean OS was higher than those with no tumour response (SD or PD). This supports the theory that a higher tumour cell kill may potentially improve OS. It may be prudent to further research in this direction.

The skin, mucosal toxicities and treatment-induced dysphagia reported were similar to those described in other studies from India and were easily managed. ^{Reference Grewal, Jones and Lin8,Reference Agarwal, Nemade and Murthy9,Reference Paliwal, Kumar-Patidar, Walke, Hirapara, Jain and Raj-Bardia26,Reference Shishodia, Divakar and Al Kheraif27} Higher number of grade 3 toxicities have been described when chemotherapy has been delivered concurrently with hypofractionated RT. ^{Reference Minatel, Gigante and Franchin30}

The question of preference for one PRT regimen over another remains unanswered. Shorter regimens may be preferable when logistic and economic issues of daily travel to the RT centre and overnight stay in a new city for treatment are considered. This is especially relevant in countries like ours where the majority of patients receiving RT are outstation residents. One- or 2-day schedules are also the better choices for patients with extremely poor performance status or general condition. On the other hand, longer schedules with higher total BED may potentially be superior in giving longer recurrence-free survival and OS in patients who have a life expectancy greater than a year. Thus, the decision should be taken by the treating radiation oncologist after considering all clinical, radiobiological and logistic factors. The available RT technology should also be considered in the selection of the treatment schedule.

In a recent French study by Benhmida et al., intensity-modulated radiotherapy (IMRT) was used to deliver hypofractionated PRT in two phases of 30 Gy in 10 fractions each separated by 2–4 weeks to a study population similar to ours. ^{Reference Benhmida, Sun and Gherga31} Thus, an overall higher dose compared to our schedule could be delivered by using the conformal IMRT technique. The OS at 12 and 24 months was 60% and 41%, and a median OS of 19·3 months was reported. Acute skin toxicity (grades 1 and 2) was seen in 31% of patients, acute mucosal toxicity (grades 1, 2 and 3) in 35% of patients, while acute dysphagia (grades 1, 2 and 3) was seen in 36% of patients. Only three patients showed grade 3 reactions. Though the OS at 12 months of the French study (60%) was similar to what was seen in the present study (57%) which used 2D RT delivery, the incidence of acute toxicity is evidently lower. Use of modern conformal RT techniques, when available, can certainly reduce treatment toxicities and improve quality of life of patients undergoing PRT. Conformal techniques may also allow use of even shorter and more hypofractionated schedules which can deliver a substantially high dose of radiation to a relatively small target. This may also contribute to greater treatment compliance with higher radiation doses delivered and improvement in survival rates.

Finally, the management of incurable HNCs patients should always be multimodality. While PRT has a vital role, the importance of nutritional support, airway management, pain and infection control, psychological counselling and social support should not be neglected. Similarly, the use of chemotherapy, immunotherapy or targeted therapy where indicated and feasible is acceptable in management of such patients.

The limitations of this and similar trials reported in literature are that they are single-armed studies with a relatively short follow-up period, which preclude any analysis or comparison among each other for long-term outcomes and toxicities.