Comparative Evaluation of Octa Shot Versus Quad Shot Palliative Radiotherapy for Advanced Head and Neck Cancer Patients

Abstract

Background: Majority of Head and Neck Squamous Cell Cancer patients in India present in advanced stages. They are not candidates for multimodality treatment due to loco-regionally advanced disease and poor performance status. Hypo-fractionated regimens have been used for palliation of advanced head and neck cancers.
Purpose: The purpose of this study to compare the acute and late toxicity and overall response of octa shot and quad shot radiation therapy as palliative regime in locally advanced head and neck cancers.
Materials and methods: A hospital based prospective, randomized study was conducted with 50 patients of advanced Squamous cell carcinoma of head and neck, 25 patients taken in each arm. Two fractions(3.5Gy/#) per day six hours apart was given in four consecutive days (Octa shot). Two fractions (3.5Gy/#) per day six hours apart was given in two consecutive days repeated for one more cycle with a interval of two weeks (Quad shot). Acute toxicities monitored at day 15 &30 and late at 3 & 6 months after the treatment started.
Results: Octa shot had slightly better loco-regional control but the difference was statistically insignificant. Octa shot had more grade 2 skin and mucosal reaction than Quad shot. Symptomatic relief, subjective regression and improved QOL were better in Octa shot than Quad shot.
Conclusion: The study concludes that “octa shot” is an effective palliative radiotherapy regime with greater yet manageable toxicity in comparison to Quad shot regimen. This regime not only strikes a balance between the economic burden, treatment time, machine load but also helps in selecting patients for further dose escalation based on treatment response and symptomatic relief. However more such trials with longer follow up and larger sample size are required for stronger evidences.

Introduction

Head and neck cancers accounts for almost 2,54,287 new cases annually, among this nearly 60% have non metastatic locally advanced disease [1]. Most of the cancers in developing countries are diagnosed in advanced stages according to the American Joint Committee on Cancer (AJCC 8^th edition, 2017) classification and are considered incurable [2]. The goal of the treatment is to palliate symptoms like pain, dysphagia, dyspnea , bleeding, and ulceration and improve quality of life. Radiotherapy (RT) and chemotherapy are the useful modality of treatment for management of advanced head and neck cancer [3]. It is widely recognized that the 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 globally for treatment of advanced head and neck cancer [4-5]. Usually these patients are treated with schedule of 30Gy / 10 fractions/ two weeks [6]. The present study was undertaken to compare the efficacy and toxicity of two hypo-fractionated palliative RT regimens in such patients. Comparison of QOL in Octa shot regimen and Quad shot regimen by FACT H & N SCORING SYSTEM.

Materials and Methods

This was a prospective simple randomized study conducted at Acharya Tulsi Regional Cancer Treatment and Research Institute (ATRCTRI), Sardar Patel Medical College and Associated group of hospitals, Bikaner, Rajasthan.

Eligibility criteria

The study protocol included 50 patients of biopsy proven previously untreated advanced head and neck cancer who were enrolled from January 2021 to June 2022.

Inclusion Criteria

1. Surgical unresectable stage IVA, B cancers with poor ECOG score.

2. Age <80year of either sex

3. Adequate baseline hematological, cardiac, renal or liver function tests.

4. Fungating mass of head and neck. Exclusion Criteria

1. Evidence of second malignancy.

2. Prior history of radiotherapy to head and neck region

3. Pregnant or lactating patient

4. Severe stridor at presentation.

The protocol was approved by hospital’s institutional ethical committee, and all patients were properly informed and consented for treatment study. Study design was intent to treat.

Fifty patients who fit the inclusion criteria were randomized into two arms of 25 each, by using the website(http:www.randomisation.com). The arms were

Arm A - Two fractions of 3.5 Gy/# per day atleast six hours apart given in four consecutive days (Octa shot arm). Arm B - Two fractions of 3.5Gy/# per day atleast six hours apart were given in two consecutive days followed by same cycle repeated two weeks later (Quad shot arm).

Treatment plan

25 patients were planned for an “Octa Shot” schedule, total 28 Gy in eight fractions; 3.5Gy/fr, two such fractions were delivered in four consecutive days, two fractions per day at-least 6 hours apart. The radiotherapy was planned for Cobalt-60 tele-therapy unit, and marking of patients was done around gross tumor volume (primary tumor and involved nodes) with an additional margin of two cm all around. The biologically equivalent dose (BED) for this Octa Shot regimen for tumor and late reacting tissue is 37.8 Gy10 and 60.48 Gy3, respectively. The equivalent dose to 2 Gy/fraction schedule is 31.5 Gy10 for tumor and 36.43 Gy3 for late reacting tissue.

25 patients planned for Quad shot” regime with total 14 Gy in four fractions in two days,3.5Gy/fr, two such fractions per day at-least six hrs apart then same cycle repeated after 14 days. BED of two quad shots is equal to one OCTA shot. After completion of treatment, patients were called for review at 15 days and one month, two months, three months and six months. The assessment of tumor response and toxicity namely mucositis and dermatitis were done according to RECIST criteria and RTOG and CTCAE grading system.

Results

The baseline patients and tumor characteristics are described in Table 1.

Table 1. Patients Characteristics.

Characters	Octa-shot group (Arm A)		Quad-shot group (Arm B)
Age (years)
<40	3		5
>40	22		19
Mean	54.24		53.52
SD	10.32		12.26
AJCC Stages
Stage IV A	8		9
Stage IV B	17		16
Chi square		4.051
P value		0.344
ECOG
0	0		0
1	1		1
2	9		11
3	15		13
Chi square		0.343
p value		0.842
Primary site
Oral cavity	6		5
Oropharynx	15		14
Hypopharynx	4		6
Chi square	2.534
P value	0.639

ECOG, Eastern cooperative oncology group; AJCC, American Joint Committee on Cancer

All characteristics were balanced. The treatment response described in Table 2 and the treatment-related toxicities are described in Table 3-4.

Table 2. Treatment Response.

Response			Octa Shot Group					Quad Shot Group
	2 weeks	4 weeks	2 months	3 months	6 months	2 weeks	4 weeks	2 months	3 months	6 months	p value
PR	21	21	17	15	13	22	22	18	16	17	0.847
CR	0	0	4	4	4	0	0	1	1	1	0.045
SD	3	3	1	1	1	3	3	3	3	3	0.618
PD	1	1	2	2	3	0	0	3	3	2	0.409
Death	0	0	1	3	4	0	0	1	2	3	0.143
TOTAL	25	25	25	25	25	25	25	25	25	25

CR, Complete Response; PR, Partial Response; SD, Stable Disease; PD, Progressive disease

Table 3. Toxicity Skin (Dermatitis).

Toxicity			Octa Shot Group					Quad Shot Group
Skin Reaction	2 weeks	4 weeks	2 months	3 months	6 months	2 weeks	4 weeks	2 months	3 months	6 months	p value
Grade 0	0	0	3	12	21	0	0	13	13	22	0.0001
Grade 1	9	8	16	10	0	24	24	11	10	0	0.0001
Grade 2	16	16	5	0	0	1	1	0	0	0	0.0001
Grade 3	0	1	0	0	0	0	0	0	0	0	0.476
Death	0	0	1	3	4	0	0	1	2	3	0.143
Total	25	25	25	25	25	25	25	25	25	25

Table 4.Toxicity Mucositis.

Toxicity Mucositis			Octa Shot Group					Quad Shot Group
	2 weeks	4 weeks	2 months	3 months	6 months	2 weeks	4 weeks	2 months	3 months	6 months	p value
Grade 0	0	0	2	11	21	0	0	15	22	22	0.0001
Grade 1	6	0	15	10	0	10	9	8	1	0	0.0001
Grade 2	17	18	7	1	0	15	16	1	0	0	0.0001
Grade 3	2	7	0	0	0	0	0	0	0	0	0.0001
Death	0	0	1	3	4	0	0	1	2	3	0.143
Total	25	25	25	25	25	25	25	25	25	25

21 patients (84%) had an objective response (4 CR,17PR) 1 stable disease, 2 progressive disease and 1 death in Octa shot at 2 months of follow up, In Quad shot 19 patients (76%) had an objective response (1CR,18PR) 3 stable disease, 2 progressive disease and 1 death in Quad shot at 6 months of follow up CR in Octa shot and Quad shot 16% & 4% respectively, which is statistically significant P value (0.045). QOL improved better in Octa shot than Quad shot (Table 2).

Dermatitis was not a significant problem in this study. Most of them had grade 1&2 reaction. Grade I skin toxicity was seen in 9, 8, 16 ,10 patients in Octa Shot &24,24 ,11,10 Quad Shot at 2 weeks, 1 month, 2 months, 3 months and 6 months respectively (p Value=0.0001). Grade 3 skin toxicity in 1 pt in Octa shot vs 0 in Quad shot. (p Value=0.476). Skin toxicities grade 2 &3 more in Octa shot then Quad shot (Table 3).

Majority of the patients developed grade 2 mucositis. 2 patients developed grade 3 mucositis in Octa shot group at weeks 2 and 7 patients at weeks 4 No one developed grade 3 mucositis in Quad shot. The difference was statistically significant (P value-0.0001).

Discussion

In this study we compared the acute and late toxicity, overall response and quality of life (QOL) of Octa shot and Quad shot palliative radiotherapy in advanced Squamous Cell Cancers of head and neck by using validated appropriate tools. This study included of fifty consecutive inoperable head and neck cancer patients, who were recruited after getting an informed consent, over a time period of 18 months.

In Octa shot group, 3.5 Gy per fraction, two fraction each day atleast six hours apart were delivered for four consecutive days. In Quad shot group, 3.5 Gy per fraction, two fraction per day atleast six hours apart were delivered for two consecutive days then same cycle was repeated after 14 days interval.

Mean age in Octa shot group was 54.24 years and in quad shot group 53.52 years, in which youngest age 32 year and oldest 79 years old. Patients characteristics like age, TNM staging, primary site, gender, smoking status are similar to previous studies like Lok study, paris et al, Jakhar et al, Mohanti et al, Ghosal et al, Das et al (Table 5).

Table 5. Similar Studies of Different Hypo Fractionation Schedules in Head and Neck Cancers.

Study	Patients	Dose/Fraction (Gy)	Number of fractions	Schedule	Efficacy	Toxicity
Corry et al [7]	30	3.7 BID	4	Monthly x 3	53% RR 44% Improved QOL	No³Grade 3 toxicity
Paris et al [8]	37	3.7 BID	4	Monthly x 3	77% RR	No late toxicity
Monnier et al [9]	78	3	8	Day 1 and 3 Repeated	54% RR	31% needed break
				weeks 1, 3, 5, 7 cisplatin		4% acute grade 3-4
						12% late grade 3-4
Das et al [10]	33	4	10	Twice/Week	88% Pain Relief 60% Improved PS	Grade 3 mucositis 18% Dermatitis 3%
Kancherla et al [11]	33	4	5	Repeated after 2 weeks	7% Symptom Relief 72% RR	18% Grade 3 acute
Murthy et al [12]	505	4	5	Additional RT for responders	37 % RR 47%-59% Symptom relief	Not stated for palliative RT
Porceddu et al [5] single arm	37	6	5-6	Twice Weekly	80% RR 62% Improved QOL 67% Improved pain	Grade 3 mucositis 26% Grade 3 dysphagia 11%
Velarasan et al [13]	64	2	30-35	Daily Daily	No difference between arms	No difference between arms
		4	10-12
Jakhar et al. [14]	22	3.5 BID	8	Daily	73% RR	9% Grade 3 Mucositis No Grade 3 dermatitis
Neeraj Kumar et al [15]	60	3.5	8	Daily	--	No Grade 3 Toxicity
Ghosal et al [16]	15	3.5	8	Daily	86% RR	No Grade 3 Toxicity
Present Study (Octa Shot V/S Quad Shot)	50	3.5	8	Daily	16 % CR in Octa Shot 4% CR in Quad Shot 68% PR in Octa Shot 72% PR in Quad Shot	Grade 2 Skin Reactions 64 % in Octa Shot 4% Quad Shot Grade 3 4% in Octa Grade 3 Mucositis 28% in Octa shot

BID, twice a day; RR, relative response (CR+PR); QOL, quality of life; PS, performance status; CR, complete response; PR, partial response

In this study, objective response (complete response + partial response) was 84% (21 patients) in Octa shot group and 76% (19 patients) in Quad shot group at two months.

The objective response found in this study is comparable or slightly better than similar previous studies.

Corry et al [l6] and Ghoshal et al have performed studies describing “Quad Shot” in which a short course of palliative radiation 3.5 Gy/fraction is given in four fractions in two days. Such two days regime has shown objective response, i.e., complete and partial response in 53% patients at the end of six weeks. Ghoshal et al. in their study have given two successive “quad shots” to responding patients and have reported partial response in 66.67% patients.

Jakhar et al [14] Octa shot study, first response evaluation at 15 days after the day of treatment started, showed >50 % objective response in 63.33% (14 patients). At one month this objective response increased to >75 % in 73% (16 patients) and 50%-75% in 13.63% (three patients).

In this study grade 2 mucositis was developed in majority of cases, as 72 % patients in Octa shot group and 64 % patients in Quad shot group patients. Grade 3 mucositis developed in Octa shot group 28% but none in Quad shot group.

Majority of patients developed grade 1 and 2 skin toxicity in Octa shot group but in Quad shot group majority of patients developed grade 1 skin toxicity. Grade 3 skin toxicity developed in only one patient in Octa shot group, these toxicities are comparable with previous studies.

Previous studies have concluded that due to palliative nature of the treatment, late tissue toxicities were not a significant problem in the patients received short course palliative radiotherapy. So, patients received further radiotherapy did not have any worst late toxicity as compared to patients received initial palliative radiotherapy alone.

In this study QOL measured by FACT H& N, QOL improved better in Octa shot group then Quad shot group but statistically insignificant.

Mean FACT H& N TOI observed in Octa shot group before radiotherapy was 58.92 with SD 7.95 and in Quad shot 56.54 with SD 8.06. After 3 months of radiotherapy in Octa shot mean FACT H&N TOI were 64.92 with SD 13.95 and in Quad shot mean 60.54 with SD 12.06.

Mean FACT -G TOTAL SCORE in Octa shot group before radiotherapy were 63.05 with SD 8.33 and in Quad shot group 58.77 with SD 12.00. After 3 months of radiotherapy Mean FACT-G TOTAL SCORE in Octa shot 69.05 with SD 14.33 and in Quad shot 62.77 with SD 16.00.

Mean FACT H&N TOTAL SCORE in Octa shot group before radiotherapy were 90.18 with SD 10.91 and in Quad shot 86.35 with SD 13.92. After 3 months of radiotherapy Mean FACT H&N TOTAL SCORE 98.18 with SD 18.91 and in Quad shot group 92.35 with SD 19.92.

In conclusion, Octa shot is an effective palliative radiotherapy regimen with greater yet manageable toxicity in comparison to Quad shot regimen. This regime not only strikes a balance between the economic burden, treatment time, machine load but also helps in selecting patients for further dose escalation based on treatment response and symptomatic relief. However more such trials with longer follow up and larger sample size are required for stronger evidences.