Introduction
Cancer of the hypopharynx is a poor predictive cancer. The survival rate (OS) of five years is about 35%. Even if the survival rate has enhanced dramatically, the overall survival rate has been dramatically reduced for decades than oropharyngeal cancer related to the human papillomavirus. 1, 2, 3, 4, 5
Compared with conventional radiation therapy treatment, good treatment results can be achieved with the hyperfractionated technique. Theoretically, this substitute could increase the total amount of radiation dose without increasing the frequency of toxic substances or extending the duration of general treatment. 6, 7 In addition, random clinical trials have shown that HFRT was better than CFRT in the treatment of head and neck cancers, mainly in local controls. 8, 9
The reasons for the rise in hyperfractionation than other modified variants remain unclear, and hyperfractionation has not been the standard of care, mainly due to mobility problems, difficulty in finding 2 slots per day on machines or management of patient between fractions, which preferred the delivery of simultaneous chemoradiotherapy over hyperfractionation. 10
This study aimed to investigate tumor response in hypopharynx cancer using hyperfractionated radiotherapy compared with conventional fractionation with concurrent chemotherapy.
Materials and Methods
Data of 56 patients with biopsy-proven cancer of hypopharynx squamous cell (Stage II to IVA), who received either hyperfractionated (n = 34) or conventional fractionation (n = 22) radiotherapy, with concurrent chemotherapy, between July 2018 to January 2020 are analyzed.
The patient data includes patient age, stage, chemotherapy used with regimen details and the number of cycles administered, the radiation dose administered, overall treatment time, pre-and post-therapy contrast-enhanced computed tomography (CT) scan findings of head and neck, hematological, biochemical and chest X-ray findings, acute toxicity data.
Table 1 depictsthe characteristics of patients. The mean age in the case of the HFRT group was 58.29 years. As per the classification of staging by UICC-TNM, 11 stage II cases were 19; stage III were 9 and 6 cases were of stage IVA. The mean age in the CFRT group was 56.45 years. As per the classification of staging by UICC-TNM, stage II cases were 13; stage III were 5 and stage IVA was 4. All cases are histologically proven to be cancers of squamous cells in both the HFRT and CFRT groups.
Table 1
Characteristics of patient’s
|
|
HFRT group |
CFRT group |
|
Number of patients |
34 |
22 |
|
Mean age (years) |
58.29 |
56.45 |
|
Gender (Male:Female) |
29:5 |
19:3 |
|
Stage II |
19 |
13 |
|
Stage III |
9 |
5 |
|
Stage IVA |
6 |
4 |
The treatment protocol is shown in Table 2. This study hyperfractionated radiation technique comprises 2 fractions per day at an interval of six hours apart of 1.2 Gy per fraction, 5 days in a week up to a total dose of 72 Gy in 6 weeks (Average of 6.3 to 7.4 weeks). Conventional fractionated radiation therapy comprises 1 fraction per day with 2.0 Gy per fraction, 5 days in a week up to the total dose of 66 Gy in 6.3 weeks (Average of 7.1 to 8.2 weeks). Chemotherapy was administered in all patients and received weekly Cisplatin 30 MG per m2. Radiotherapy was delivered using CO 60 Teletherapy machine.
The outcome measures studied were tumor response and emphasis on toxicities as the primary outcome. Response evaluation was done periodically after completing treatment based on contrast-enhanced CT scan of neck and head, clinical examination and chest X-ray findings in each patient. Biopsy or fine-needle aspiration cytology was taken from any suspicious clinical and or radiological residual tumor or to confirm recurrence at the primary and/ or nodal areas. Patients were then categorized as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) as having complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Patients were evaluated for toxicity weekly during radiation and after that during follow-up, initially monthly and subsequently at longer intervals.
Results
Response evaluation was done periodically after the completion of treatment. After completing radiation therapy, the rate of responses of hypopharynx lesions was determined and shown in Table 3. As for hypopharynx lesions, there were 29 CRs and 3 PRs, 1 SDs and 1 PDs in the HFRT group. In the CFRT group, there are 15 CRs, 2 PRs and 3 SDs and 2 PDs. So the rate of complete response in the HFRT group was 85.29% and 68.18% in the CFRT group.
Table 3
Radiation response
The rate of local control in the N0-N1 stages in the HFRT group was 88.24% and it was 72.72% for the CFRT group. Also, the rate of local control in node N3 was 0% for the HFRT group and 4.55% for the CFRT group (Table 4).
The most prevalent acute toxicities were skin, mucosal and dysphagia related. The acute skin toxicity was significantly higher in CFRT (54.55%) than in HFRT (44.12%). Acute oral mucositis was higher in HFRT (50%), while in CFRT, it was less (45.45%). Acute dysphagia was noticed in 22.72% in CFRT compared to HFRT. It was lesser to 17.65% (Table 5).
Discussion
For various types of cancer, dose-escalation radiation therapy achieves improved local control, according to many reports. To achieve dose escalation, a good knowledge of the biology and physics of radiation therapy is needed.12, 13 Because of advances in physics, there is intensity-modulated radiation therapy (IMRT) and 3-dimensional conformal radiation therapy (3D-CRT) for the treatment of head and neck, prostate and lung cancers; by improved dose distributions, escalation of the dose was attained. 14, 15, 16 Conversely, developments in biology have to steer to modified fractionated radiation techniques, including hyperfractionation therapy. Since the 1980s, HFRT has been performed to increase the total dose without extending general treatment.
Some recent experiments further supported the clinical efficacy of modified radiation therapy to treat carcinomas of the head and neck, mainly in their local control. 8, 9 Fu et al. showed that the rate of local control within two years for hyperfractionation at 81.6 Gy total dose with 1.2 Gy each fraction was 54.4% which shows statistically significant enhancement when compared to conventional fractionation at 70 Gy total dose with 2 Gy each fraction was 46.0% (P = 0.045).8 They further investigated and compared conventional fractionation, as per the protocol of Wang et al two modified fractionated radiation therapies that are accelerated fractionation and concomitant boost fractionation. 17
This comparison showed that only concomitant boost fractionation was better than conventional fractionation. When compared to conventional fractionation, severe late toxicity in concomitant boost fractionation was more. These studies proposed that one of the best modified fractionated radiation therapies is hyperfractionated radiation therapy.
In our study, complete response (CR) was detected in 85.29% of patients receiving hyperfractionated radiation therapy, which is much higher than patients receiving conventional radiation therapy showing only CR of 68.18%. The rate of local control at the N0-N1 nodes in the HFRT (88.24%) was also better when compared to CFRT (72.72%) group.
In terms of acute toxicity, pharyngeal toxicity in the HFRT group had a greater tendency than in the CFRT group. Nevertheless, the hematological and skin toxicities were comparable between the groups (Table 5), indicating acceptable acute toxicity of the HFRT group. However, further research is needed to lessen acute toxicity.
Conclusion
To conclude, this study showed that hyperfractionated radiation treatment for hypopharyngeal cancer had achieved superior local control, better survival rates, acceptable toxicity and pharyngeal preservation. These findings indicate that HFRT is a promising treatment for hypopharyngeal cancer.
