Conventional fractionation versus quad shot in advanced head-and-neck cancers: A randomized controlled trial
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/IJPC.IJPC_209_18
Source of Support: None, Conflict of Interest: None
Keywords: Acute toxicity, hypofractionated palliative radiotherapy, incurable head, neck cancer, Quad Shot regimen, response assessment
Head-and-neck cancer accounts for 14.3% of all cancers in India while globally it is 4.8% of all cancer burden. It contributes to 30% of all cancers in males in India.
Oral cancers are predominant forms of head-and-neck squamous cell cancer in South Asian countries such as Sri Lanka, India, Pakistan, and Bangladesh, whereas in Southeast Asian countries such as China, Malaysia, Indonesia, and Singapore, nasopharyngeal carcinoma is more prevalent. In India, lip, oral cavity, oropharyngeal, and hypopharyngeal cancers constitute >80% of all head-and-neck cancer burden. Histologically head-and-neck cancer is mostly squamous cell carcinoma.
Cigarette smoking and alcohol consumption are the main reasons for head-and-neck squamous cell cancer in the Western population, whereas the use of smokeless tobacco and areca nut is the most common cause in Southeast Asia., The various forms in which smokeless tobacco is used in developing countries include khaini, mava, paan (betel quid), zarda, snuff, and mashiri. The prevalence of HPV in head-and-neck squamous cell cancer is around 50% with the highest prevalence in cancers of the tonsil and base of the tongue, particularly HPV-16 is the most commonly involved type.
A large majority of head-and-neck cancers present in advanced incurable stage because of a very advanced locoregional disease, significant medical comorbidities, poor performance status, distant metastasis, or a combination of these factors. However, they still need some form of treatment to control their locoregional disease which may lie in close proximity to several critical normal tissues such as the spinal cord; salivary glands; mandible; nerves; major blood vessels; and the organs of speech, swallowing, hearing, and respiration.
The management of locoregionally advanced head-and-neck cancers with curative intent is an area of active research and has evolved considerably over time with volumes of research, large randomized control trials, and meta-analysis available for reference. However, there is sparse literature on palliative regimen with several lacunae related to dose and fractionation, identification of patients suitable for palliation, degree or duration of symptom relief, and treatment-related toxicities.,,,
With this background, we had undertaken a study to assess the feasibility of a short course of radiation delivered in 2 days for palliation of locally advanced head-and-neck cancers in comparison to the commonly used dose of 30 Gy/2 weeks/10 fractions. The proposed fractionation schedule is likely to decrease the patient visits to the hospital, reduce the travel expenses, and load on the treatment machines, and this, in turn, would cut down the waiting lists for patients. Therefore, it would be very useful, especially in a developing country like India.
The present prospective randomized controlled study was carried out with 50 previously untreated patients with biopsy-proven squamous cell carcinoma of the head-and-neck region from November 2014 to April 2016. Of a total of 50 patients, 25 patients were selected in each arm. Patients were randomized to receive either 14 Gy/4 fractions/2 days (study group) or 30 Gy/10 fractions/2 weeks (control group) with the help of random number tables. Written informed consent was taken from all the patients.
The inclusion criteria were patients of either sex; age >18 years; histological diagnosis of head-and-neck malignancy; Stage IV B and IV C as per the American Joint Committee on Cancer 2010 classification; Karnofsky Performance Score >60; hemoglobin >10 g%; and blood urea, serum creatinine, serum bilirubin, and serum transaminases within normal limits. The patients with carcinoma of the nasopharynx, salivary gland, nasal cavity, and paranasal sinuses and secondary node with unknown primary site; histology other than squamous cell carcinoma; history of previous oncological treatment; and history of previous malignancy or concomitant second malignancy were excluded from the study.
Technique of radiotherapy
All the patients were subjected to external beam radiation by cobalt-60 teletherapy.
The treatment volume included the primary tumor site with its extensions and lymphatic drainage up to the first station of lymphatic drainage/maximally involved lymphatic along with 1 cm margin on all sides. Dose was delivered using bilateral opposed lateral fields/anteroposterior arrangements in most cases. In certain situations, oblique/unilateral wedge fields were used. Dose was prescribed at mid-separation level in bilateral/anteroposterior plan. Bolus of 0.5 cm was applied only onto cases where the tumor showed fungation/ulceration, to attain a surface dose of 100% in these cases.
Evaluation and follow-up
The response to the treatment was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
The toxicities were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Based on the RECIST criteria for response and the CTCAE criteria for toxicities due to treatment given results were evaluated to assess:
This was done:
Follow-up was done using brief history, clinical examination, and relevant blood investigations.
Categorical variables were presented in number and percentage (%) and continuous variables were presented as mean ± standard deviation and median. Normality of data was tested by the Kolmogorov–Smirnov test. If the normality was rejected, then nonparametric test was used.
Statistical tests were applied as follows:
P< 0.05 was considered statistically significant.
The data were entered in MS Excel spreadsheet, and analysis was done using the Statistical Package for Social Sciences (SPSS) version 21.0. manufactured by IBM, Chicago, Illinois, USA.
The patient characteristics are shown in [Table 1]. Both the groups were similar with respect to baseline parameters. Of 50 patients enrolled, two patients died, one declined treatment, and another one did not come for follow-up. Hence, the results were analyzed for 46 patients.
The response was evaluated according to the RECIST criteria for the primary site as well as nodal disease. At the primary site, 39.13% of patients received a partial response (PR) in the study arm compared to 47.82% in the control arm. About 34.78% of patients had stable disease (SD) in the study arm compared to 30.43% in the control arm at the primary site. Progressive disease (PD) was seen in 26.08% of patients in the study arm compared to 21.73% in the control arm. This was statistically not significant (P = 0.70). At the nodal sites, 43.47% of patients received PR in the study arm compared to 47.82% in the control arm. Almost 39.13% of patients had SD in the study arm compared to 30.43% in the control arm at the nodal site. PD was seen in 17.39% of patients in the study arm compared to 21.73% in the control arm. This was statistically not significant (P = 0.86). Response in two groups was comparable at the primary as well as the nodal site. Response assessment with contrast-enhanced computed tomography is shown in [Figure 1], [Figure 2], [Figure 3].
Acute mucosal toxicity, skin reaction, and xerostomia were evaluated according to CTCAE v 4.02. Mucosal toxicity was more severe in the control group with majority of the patients having Grade 3 reactions (56.52%) in comparison to patients in the study arm where no experienced more than Grade 2 acute mucosal toxicity. The incidence of Grade 2 acute mucosal toxicity was similar in both the arms. Grade 1 mucosal toxicity was seen in 34.78% in the study group and 24.73% in the control group. In the study group, there was no acute mucosal toxicity in majority of the patients, i.e., 52.17%, versus only 8.69% of patients in the control group. This observation was statistically significant, acute mucosal toxicity being more in the control group (P ≤ 0.001, Chi-square test). This was managed conservatively with Betadine and steroid gargles and oral fluids. Only 2 (8.69%) patients in the control group required admission for intravenous fluid administration. There was no treatment-related death.
Acute skin toxicity was minimal. In the study group, there was no acute mucosal toxicity in majority of the patients, i.e., 52.17%, versus only 4.34% of patients in the control group. Maximum skin toxicity was of Grade 1 in the study group (47.82%) while 91.3% in the control group experienced this grade skin toxicity. Grade 2 was seen 4.34% of patients in the control arm. None of the Grade 2 reactions required any treatment other than topical application of gentian violet. This observation was statistically significant, acute skin toxicity being more in the control group (P ≤ 0.001, Chi-square test).
Grade 2 xerostomia was observed more in the control arm (47.82% vs. 34.78%). Grade 1 toxicity was found to be almost similar in both the arms (34.38 and 39.13). No xerostomia was seen in 30.43% in the study arm versus 13.04% in the control arm. This required patient counseling and supplementation in the form of lozenges. This observation was statistically significant, acute skin toxicity being more in the control group (P = 0.044, Chi-square test).
Relief in major symptoms that is pain, dysphagia, and hoarseness were evaluated. Patients' quantification of >50% was taken as symptom relief. Pain and dysphagia were quantified by the patient using a percentage rupee scale.
Pain relief was 52.17% in the study group and 60.86% in the control group. Pain in the patients not relieved by radiotherapy was managed with NSAIDS and weak opioid drugs. Only 4 (17.39%) and 3 (13.04%) patients required oral morphine in the study and control groups, respectively. Pain relief in the two groups was comparable. This observation was statistically not significant (P = 0.656).
Dysphagia relief was 52.17% in the study group and 60.86% in the control group. Dysphagia relief in two groups was comparable. This observation was statistically not significant (P = 0.656). Patients not relieved even after treatment with local anesthetic syrups and steroid gargles required nasogastric tube feeding. Only 2 (8.69%) patients in the control group required admission for intravenous fluid administration.
Hoarseness was present in 91.30% of patients in the study group and control group. Voice was improved in 38% of patients in the study group and 42.85% of patients in the control group. Hoarseness relief in two groups was comparable. This observation was statistically not significant (P = 0.656).
An important aspect of any palliative regimen is to offer symptom relief with minimal toxicity. Hypofractionated radiotherapy is increasingly being studied as palliative treatment in advanced head-and-neck cancers, as it confers an effective dose in a short period in a cohort of patients where the prognosis is guarded and late radiation toxicities less relevant. A number of hypofractionated palliative fractionation regimes in head and and neck cancer that have been used are depicted in the [Table 2].
The Quad Shot regimen described by Corrry et al. designed to giving a biologically equivalent dose below the threshold for producing mucositis. Thirty patients had at least one treatment and sixteen patients completed all three cycles. Sixteen patients (53%) had an objective response and a further seven had SD. No patient experienced Grade 3 or worse toxicity.
Various studies from different parts of India have been carried out. At Chandigarh, two schedules were carried out by Ghoshal et al., 30 Gy in 10 fractions over 2 weeks and Quad Shot. More than 91% patients significant symptom relief with 30 Gy/10 #. 86 % patients had objective response >50% with the quad shot regimen. Fifty-four percent had Grade 1 and 2 mucositis when they carried out Quad Shot regimen.
In a large prospective study from Delhi by Mohanti et al. who used a schedule of 20 Gy in 5 fractions over 1 week for 505 patients, at 1-month assessment, 37% achieved a PR and were suited for further curative-dose radiotherapy. Good symptom relief (50% or more) was found in 50%–60% of patients. A study from Rajasthan demonstrated symptom relief in >65% of patients with 20 Gy/5#/5 days; almost all patients developed Grade 1 or 2 skin and mucosal toxicities. Agarwal et al. used a schedule of 40 Gy in 16 fractions reported from Mumbai. Patients with PR had a dose escalation up to 50 Gy in 20 fractions. More than 50% symptom relief was seen in 74%. The incidence of Grade 3 mucositis was 69%.
Another study from Mumbai, Murthy et al. published twice-weekly palliative radiotherapy regimen of 32 Gy in 8 fractions Overall response rates were 42% at primary disease and 55% at nodal disease. At conclusion of radiotherapy, 76.3% of the patients reported improvement in pain scores (P = 0.001). At the first followup after 612 weeks significant improvement in pain scores persisted. Acute Grade 3 mucositis was seen in one patient (1.2%) while none had Grade 3 skin reactions. From Vellore, Das et al. using a schedule of 40 Gy/10# have reported significant pain relief (>50%) in about 88% of patients and worsening in 9% of patients at the end of radiotherapy. Incidence of grade III mucositis and dermatitis was 18% and 3% in the same study.
Some landmark studies were carried out globally. In a study by Paris et al., good palliation was achieved in 84.6% of patients with minimal acute toxicity and no long-term complications. Erkal et al., in a retrospective study, showed similar response rates and symptom relief. In our study, overall response at 4 months is similar for 73.91% in the study group and 78.26% in the control group as well as nodal site. Mucositis and skin reactions were significantly lower in the Quad Shot arm. Thus, we find that the response and symptom relief in the present study are comparable to previous studies with various time, dose, and fractionation regimens. There are certain limitations of this study. Drawback includes a short follow-up period, small sample size, and inherent biases of a single institutional trial.
The study shows promising results in terms of locoregional control and symptom relief as well as much lesser toxicities for palliation in patients with advanced head-and-neck cancers with heterogeneous subsites when treated with Quad Shot regimen (14 Gy/4 fractions/2 days). Quad Shot regimen lessens the number of hospital visits, shortens loss of working days, and may make treatment more cost-effective. Quad Shot regimen is more suitable for a developing country like India with limited resources in the form of machines and workforce and a large patient load.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]