|Ahead of print publication
Comparison of two schedules of hypo-fractionated radiotherapy in locally advanced head-and-neck cancers
Pramila Adlakha1, Guncha Maheshwari2, Aditya Dhanawat3, Rajesh Sinwer1, Mukesh Singhal1, Shankar Lal Jakhar1, Neeti Sharma1, Harvindra Singh Kumar1
1 Department of Radiation Oncology, Sardar Patel Medical College, Bikaner, Rajasthan, India
2 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Submission||15-Dec-2020|
|Date of Decision||17-Nov-2021|
|Date of Acceptance||29-Dec-2021|
|Date of Web Publication||15-Jun-2022|
Department of Radiation Oncology, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Aim: In India, more than 70% patients present as locally advanced head-and-neck cancers (LAHNC), with poor performance status and are suitable candidates for palliative radiotherapy (RT) aimed at symptom relief. This prospective study aims to compare two different short course hypo-fractionated RT regimens in patients of LAHNC at a regional cancer centre of north-west India.
Materials and Methods: A total of 70 patients of LAHNC were randomized to receive palliative RT in two groups of 35 each. Group A received 30 Gy/10# over 2 weeks and Group B received 20 Gy/5# over 1 week. Baseline symptoms of pain, dysphagia, insomnia, dysphonia, bleeding, fungation, and dyspnea were assessed before the start of study. The first assessment for toxicities, subjective and objective response was done at the conclusion of RT and then after 4–6 weeks.
Results: Out of total 70 patients, 71% were males and 29% were females with a median age of 54 years. The most common sites were oropharynx (39%) followed by larynx (24%), oral cavity (20%), and hypopharynx (17%). Nearly 60% of the patients in both groups presented in stage IV and 40% in stage III. At conclusion of RT and at 4–6 weeks follow-up, both groups showed similar results in terms of symptom palliation, objective response, and acute toxicities. Group B showed higher incidence of Grade III and above mucositis (P = 0.027). Median overall survival was found to be 5.9 months (range 1–15 months) in group A and 6.1 months (range 1–18 months) in Group B.
Conclusion: Hypo-fractionated RT promises to effectively relieve symptoms in LAHNC and reduces the need of analgesics and hospital visits. Furthermore, a shorter overall treatment time is beneficial at high volume centers and is also welcomed by patients with shorter life expectancy.
Keywords: Hypo-fractionation, north-west India, palliative radiotherapy, symptom relief
|How to cite this URL:|
Adlakha P, Maheshwari G, Dhanawat A, Sinwer R, Singhal M, Jakhar SL, Sharma N, Kumar HS. Comparison of two schedules of hypo-fractionated radiotherapy in locally advanced head-and-neck cancers. J Can Res Ther [Epub ahead of print] [cited 2022 Jul 2]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=347677
| > Introduction|| |
Head-and-neck cancer accounts for 4.8% of all cancers globally and 14.3% of all cancers in India. The projected incidence of oral cavity and pharyngeal cancers in India is 1 in 60 people. Most of the cancers in developing countries are diagnosed in stages III and IV according to the American Joint Committee on Cancer (AJCC 8th edition, 2017) classification and are considered incurable. The goal of treatment is to palliate symptoms including pain, dysphagia, dyspnea, bleeding, and ulceration and improve quality of life. Radiotherapy (RT) and chemotherapy are useful modalities for symptom management and should be judiciously used in palliative care. Radiation therapy with a curative intent is delivered up to doses of 6000–7000 cGy in 180–200 cGy fractions and is often combined with concurrent chemotherapy. Such regimens, although curative, are often highly toxic. It is widely recognized that palliative RT provides effective symptom control and improved quality of life in advanced incurable and metastatic malignancies due to its radiobiological superiority and shorter overall treatment time. A number of different hypo-fractionated regimens have been used across the globe for the treatment of locally advanced head-and-neck cancers (LAHNC)., The present study was undertaken to compare the efficacy and toxicity of two hypo-fractionated palliative RT regimens in such patients.
| > Materials and Methods|| |
This prospective, simple randomized study was conducted at a regional cancer centre in north-west India between January 2018 and December 2018. A total of 70 biopsy proven cases of squamous cell carcinoma of head-and-neck region, including primaries from oropharynx, oral cavity, larynx, and hypopharynx were enrolled. All patients were aged 18 years or above with locally advanced (stage III or IV) disease and their Karnofsky Performance Status (KPS) ranged from 50 to 70. The patients were staged according to AJCC 8th edition, 2017 TNM classification. Patients with previous history of surgery, RT, or chemotherapy, those with recurrent disease and those who refused to give consent were excluded from the study.
Pretreatment evaluation and symptoms
All the patients underwent a complete staging workup including physical examination, laryngoscopy, computed tomography imaging of the face and neck region and a chest X-ray. Those found unsuitable for curative treatment were planned for palliative RT as a single modality by the multidisciplinary tumor board. Caregivers of the patients were explained about the incurability of the disease and the benefit of short duration of therapy for quick symptom relief and a written informed consent was taken. Baseline symptoms were assessed for pain, dysphagia, insomnia, dyspnea, dysphonia, bleeding, and fungation. Symptoms were scored on a scale of 0–10 and graded as mild (score 1–3), moderate (score 4–6), and severe (score >6). Analgesics were prescribed in accordance with the World Health Organization analgesic ladder. Symptomatic medications were given for cough, insomnia, dysphagia, and mucosal toxicities.
A total of 70 patients were randomized into two groups of 35 patients each. Group A received a total dose of 30 Gy in 10 fractions over 2 weeks while Group B received a total dose of 20 Gy in 5 fractions over 1 week. Target volumes were marked clinically to include the gross tumor (primary and nodal) with an external margin of 1 cm to 1.5 cm all around. Palliative external beam RT was planned and delivered with Theratron 780-C (Cobalt-60) teletherapy unit using appropriate portals. The equivalent dose in 2 Gy fractions (EQD2) was 32.5 Gy for Group A and 23.3 Gy for Group B.
Primary endpoint of the study was prompt symptomatic relief at conclusion and after 4–6 weeks of completion of RT. Secondary endpoints were objective response, toxicity, and survival. All patients were reviewed at least once during treatment, at conclusion and 4–6 weeks post completion of RT for assessing response and toxicity. Tumor response (both primary and nodal response) was assessed as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) as per the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. The radiation therapy oncology group (RTOG) grading was used to document toxicities.
A provision was made in this study to shift the patients who achieved good objective response, i.e., PR (RECIST v1.1) along with symptomatic improvement as assessed by the clinician and reported by the patient, on a curative regime., This was done by escalating the biological EQD to 66 Gy in 2 Gy fractions to the tumor with sparing of the spinal cord after 44 Gy. This dose was calculated using the time-dose-fractionation (TDF) method.
Statistical analyses: The unpaired student-T test was applied for comparing between the two groups in terms of subjective and objective responses and toxicities using IBM SPSS Statistics v. 23. A P value of <0.05 was considered significant.
| > Results|| |
There was equitable distribution of patients in both the groups in terms of age, gender, KPS, and primary site of disease (P > 0.05). The median age of patients in group A was 55 years (range 36–65) and in Group B was 54 years (range 36-68). The commonest subsite of primary in both groups was oropharynx (39%), followed by larynx (24%), oral cavity proper (20%) and hypopharynx (17%) and the most common presenting symptoms were pain (53%) and dysphagia (43%), followed by fungation (29%), dysphonia (27%), insomnia (24%), respiratory symptoms (13%), and bleeding (7%). Nearly 39% patients presented in stage III and 61% in stage IV. Two patients in group A and three in group B expired before completion of 4-6 week post-RT. The various patient characteristics are described in [Table 1].
Out of 19 patients who presented with pain in group A, 8 (42%) showed improvement at completion of RT which decreased to 7 (41%) at the 4-6 weeks follow-up. In group B, 18 patients presented with pain, out of which 10 (56%) improved by RT conclusion and increased to 10 out of 15 (67%) at 4-6 weeks post-RT. Among other complaints, after completion of RT course and at 4-6 weeks follow-up, 8 (57%) showed improvement in dysphagia, 3 (37.5%) showed reduction in fungation, 6 (86%) had improved sleep patterns, 2 (50%) showed improvement in respiratory symptoms, 5 (56%) had betterment in dysphonia and all 3 (100%) patients noted improvement in bleeding among group A. The results of Group B were not statistically different from Group A [Table 2].
The response was assessed at 4-6 weeks post completion of RT course. In Group A, the over all response rate (complete and partial) for primary was 24 (73%) as opposed to 26 (81%) in group B (P = 0.669). For nodal disease it was 21 (64%) in group A and 23 (72%) in group B (P = 0.913). Group A consisted of 15 (45%) patients with SD and 6 (18%) patients with PD which was similar to patients in group B (P > 0.05) [Table 3].
|Table 3: Objective response 4-6 weeks after radiotherapy according to response evaluation criteria in solid tumour v. 1.1|
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Most of the patients presented with mild (Grade I and II) toxicities in both the groups. No significant difference was noted among the two groups in terms of dermatitis (P = 0.443). Grade III or above dermatitis was observed in 3 (9%) versus 4 (11%) patients in Group A and B, respectively. There was significantly higher Grade III and above mucositis in Group B with 9 (26%) patients as compared to 3 (9%) patients in Group A (P = 0.027). Similar results were observed among both groups in terms of dysphagia (P = 0.589) and xerostomia (P = 0.592). A total of 4 (11%) patients in Group A and 5 (14%) in Group B presented with Grade III and above dysphagia for which five patients in Group A and 9 in Group B underwent nasogastric intubation. Two patients (6%) each in both groups had Grade III and above xerostomia by the end of 4–6-week post-RT course [Table 4].
|Table 4: Toxicity profile according to radiation therapy oncology group (4-6 weeks after radiotherapy)|
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Conversion to curative intent
Out of total 35 patients who received RT in Group A, 28 (80%) patients received palliative RT alone, while 7 (20%) patients were escalated to curative dose after completion. On the other hand, among Group B, 29 (83%) patients received palliative RT alone and 6 (17%) received escalated curative dose.
Follow-up period ranged from 1 to 18 months. Median overall survival was found to be 5.9 months (range 1–15 months) in Group A and 6.1 months (range: 1–18 months) in Group B. Survival was mainly recorded telephonically due to logistic issues faced by patients.
| > Discussion|| |
Management of LAHNC has improved over a period of time due to available literature and research. These patients present with large volume disease or fixed fungating nodal masses which makes them inoperable and unsuitable for curative treatment. The median survival of such patients without any treatment is nearly 100 days. Very intense RT regimes have caused unacceptable toxicities in such cases. However, these patients deserve treatment for symptom control which is supported by a few studies available on palliative RT in such type of cancers., The present study tried to compare and quantify the benefits of short course hypo-fractionated RT for LAHNC for sustained local control and symptom alleviation.
In this study, a male preponderance was observed in both the groups with a M:F ratio of 2.5:1 and a median age of 55 years in Group A and 54 years in Group B. These findings are similar to a study by Ali et al. which showed a M:F ratio of 2.7:1 and a median age at presentation of 55 years. Common sites of involvement included oropharynx, larynx, and oral cavity with nearly 60% patients presenting in stage IV and 40% in stage III which were comparable to various other studies.,,
It was observed that after completion of RT course and 4–6 weeks follow-up, a total of 41% patients had relief from pain, 57% showed improvement in dysphagia, 86% patients had improved sleep patterns, 50% had improvement in respiratory symptoms and 37.5% showed reduction in fungating masses in 30 Gy/10# group while in the 20 Gy/5# group, 67% experienced pain relief, 64% had improvement in dysphagia, 71% had betterment in sleep, 50% showed improvement in respiratory symptoms and 44% showed reduction in fungation. Another prospective study which was carried out on 505 patients with stage IV HNSCC to a prescription dose of 20 Gy/5#, once daily over 1 week reported good symptom relief for 57% patients for pain, 53% for dysphagia, 57% for hoarseness, 47% for otalgia and 76% for respiratory distress. The 2-week schedule of 30 Gy/10# used in a pilot study from India provided >50% symptom relief in 90% of the patients who had pain, dysphagia, dyspnoea and disturbed sleep. A retrospective study in 98 patients of stage IV HNSCC utilized 25 Gy/4#, 1#/week schedule and showed all patients to have >50% pain relief. Dysphagia improved in 82% of patients and respiratory distress improved in all the symptomatic patients after 4 weeks of RT conclusion.
On assessment of response, the study found the overall response rate (ORR) at primary site to be 73% in Group A and 81% in Group B and that at the nodal site to be 64% in Group A and 72% in Group B. Various other studies, which used 30 Gy/10# uniform regime found the ORR to be nearly 70%. A large cohort study from India with 505 patients of stage IV HNSCC revealed PR in 37% patients who underwent RT to a dose of 20 Gy/5#. The more intensive QUAD-SHOT delivering 3.5 Gy/#, two times a day for 2 consecutive days to a total of 4 fractions has shown an ORR of 53%. In a recent study by Kumar et al., comparing two groups, one receiving 40 Gy/10#, 2#/week for 5 weeks and another receiving 20 Gy/5# followed by 3-week gap and another shot of 20 Gy/5# in a week, CR at 6 months was observed in 27% and 23% patients at primary site, while in 30% and 24%, respectively at nodal sites which was similar to those obtained in this study. Many patients form low-middle income countries (LMIC) like India have advanced disease at presentation, poor nutritional and performance status and are found unfit for radical therapy wherein a short course of radiation is often preferred by the patients and is effective in palliating symptoms.
In the present study, the radiation toxicities were mild with Grade I dermatitis seen in 37% and 29% of the patients in Group A and B, respectively while Grade I mucositis being observed in 34% and 17% of the patients in Group A and B, respectively. Slightly higher Grades II and III toxicities in terms of dermatitis, dysphagia, and xerostomia were observed in Group B as compared to Group A probably due to higher dose per fraction, but none were statistically significant. However, there was statistically significantly higher mucositis in Group B (P = 0.027). The study by Mohanti et al. found the main acute toxicity of palliative RT to be mild (Grade I and II) patchy oro-pharyngeal mucositis and dermatitis only, wherein a uniform dose of 20 Gy/5# fractions once daily over 1 week was delivered. In the Australian “Hypo trial,” a dose of 30 Gy in 5 fractions was delivered at 2 fractions per week followed by a 6 Gy boost in selected patients, both of whom showed the same rates of Grade III mucositis (26%). Other than mucositis, higher grade radiation toxicities in the present study are less, presumably due to lower total dose and shorter overall treatment time. Due to the palliative nature of treatment, late tissue morbidity is not a significant issue in such patients as the expected lifespan is lesser. The incidence of Grade III or worse toxicity increases when concurrent chemotherapy is combined with conventional radical radiation. Such toxic treatment compromises the quality of life in these patients.
In this study, nearly 80% of the patients completed the planned palliative RT treatment, while five patients (3 from Group A and 2 from Group B) died during or soon after treatment and could not come for the 4–6 weeks follow-up. A total of 13 patients (7 from Group A and 6 from Group B) could be escalated to higher doses for curative treatment. These findings are in accordance with the study done by Murthy et al. in which 74% of the patients completed the planned treatment.
| > Conclusion|| |
The results from our study demonstrate that a short course of palliative RT promises to effectively relieve distressing symptoms in LAHNC unsuitable for curative treatment and may reduce the need of ongoing analgesic therapy and hospital visits, thus improving the quality of life in addition to saving hospital resources in LMICs. It also helps in selecting patients for dose escalation to curative levels using further smaller fraction sizes.
The study was approved by the Institutional Review Board.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al.
Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86.
Mathur P, Sathishkumar K, Chaturvedi M, Das P, Sudarshan KL, Santhappan S, et al.
Cancer statistics, 2020: Report from national cancer registry programme, India. JCO Glob Oncol 2020;6:1063-75.
Joshi P, Dutta S, Chaturvedi P, Nair S. Head and neck cancers in developing countries. Rambam Maimonides Med J 2014;5:e0009.
Chen AM, Vaughan A, Narayan S, Vijayakumar S. Palliative radiation therapy for head and neck cancer: Toward an optimal fractionation scheme. Head Neck 2008;30:1586-91.
Porceddu SV, Rosser B, Burmeister BH, Jones M, Hickey B, Baumann K, et al
. Hypofractionated radiotherapy for the palliation of advanced head and neck cancer in patients unsuitable for curative treatment – “Hypo trial”. Radiother Oncol 2007;85:456-62.
Agarwal JP, Nemade B, Murthy V, Ghosh-Laskar S, Budrukkar A, Gupta T, et al.
Hypofractionated, palliative radiotherapy for advanced head and neck cancer. Radiother Oncol 2008;89:51-6.
Cancer pain relief and palliative care. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 1990;804:1-75.
Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341-6.
Ghoshal S, Patel F, Mudgil N, Bansal M, Sharma S. Palliative radiotherapy in locally advanced head and neck cancer – A prospective trial. Indian J Palliat Care 2004;10:19-23. [Full text]
Ali MY, Alam MS, Mannan MA, Asaduzzaman AK, Khan MA, Islam SM. Short course palliative radiotherapy in locally advanced squamous cell carcinoma of head and neck. J Armed Forces Med Coll 2010;6:5.
Hall EJ. Radiobiology for the Radiologist. 3rd ed. Philadelphia: PA Lippincott; 1998. p. 239-58.
Kowalski LP, Carvalho AL. Natural history of untreated head and neck cancer. Eur J Cancer 2000;36:1032-7.
Jakhar SL, Purohit R, Solanki A, Murali P, Kothari T, Sharma N, et al.
Accelerated hypofractionation (OCTA SHOT): Palliative radiation schedule in advanced head and neck carcinoma. J Cancer Res Ther 2017;13:943-6.
Murthy V, Kumar DP, Budrukkar A, Gupta T, Ghosh-Laskar S, Agarwal J. Twice-weekly palliative radiotherapy for locally very advanced head and neck cancers. Indian J Cancer 2016;53:138-41.
] [Full text]
Mohanti BK, Umapathy H, Bahadur S, Thakar A, Pathy S. Short course palliative radiotherapy of 20 Gy in 5 fractions for advanced and incurable head and neck cancer: AIIMS study. Radiother Oncol 2004;71:275-80.
Ghoshal S, Chakraborty S, Moudgil N, Kaur M, Patel FD. Quad shot: A short but effective schedule for palliative radiation for head and neck carcinoma. Indian J Palliat Care 2009;15:137-40.
] [Full text]
Spartacus RK, Dana R, Rastogi K, Bhatnagar AR, Daga D, Gupta K. Hypofractionated radiotherapy for palliation in locally advanced head and neck cancer. Indian J Palliat Care 2017;23:313-6.
] [Full text]
Gautam D, Shah A. Palliative hypofractionated radiotherapy in advanced squamous cell carcinoma of head and neck. Nepal J Cancer 2020;4:39-44.
Corry J, Peters LJ, Costa ID, Milner AD, Fawns H, Rischin D, et al.
The 'QUAD SHOT' – A phase II study of palliative radiotherapy for incurable head and neck cancer. Radiother Oncol 2005;77:137-42.
Kumar T, Dhull AK, Atri R, Dhankhar R, Kaushal V. Comparison of two palliative radiotherapy schedules of radiotherapy in locally advanced head and neck cancer. J Cancer Prev Curr Res 2018;9:164-7.
Mohanti BK, Sharma DN, Lal P, Biswal BM. Palliative therapy. In: Rath GK, Mohanti BK, editors. Textbook of Radiation Oncology Principles and Practice. New Delhi: BI Churchill Livingstone; 2000. p. 201-12.
Hopewell JW, Nyman J, Turesson I. Time factor for acute tissue reactions following fractionated irradiation: A balance between repopulation and enhanced radiosensitivity. Int J Radiat Biol 2003;79:513-24.
Adelstein DJ, Li Y, Adams GL, Wagner H Jr., Kish JA, Ensley JF, et al.
An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92-8.
[Table 1], [Table 2], [Table 3], [Table 4]