Correlation of oral mucositis with timing of radiation in head and neck cancer - A prospective randomized study on chronoradiotherapy

Lithika M Lavanya; TR Arulponni

doi:10.4103/jrcr.jrcr_62_20

ORIGINAL ARTICLE

Year : 2021 | Volume : 12 | Issue : 1 | Page : 10-14

Correlation of oral mucositis with timing of radiation in head and neck cancer - A prospective randomized study on chronoradiotherapy

Lithika M Lavanya¹, TR Arulponni²
¹ Department of Radiation Oncology, BGS Clinical Global Hospital, Bengaluru, Karnataka, India
² Department of Radiation Oncology, Ramaiah Medical College, Bengaluru, Karnataka, India

Date of Submission	20-Nov-2020
Date of Acceptance	24-Dec-2020
Date of Web Publication	27-Jan-2021

Correspondence Address:
Dr. T R Arulponni
Department of Radiation Oncology, Ramaiah Medical College, Bengaluru, Karnataka
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jrcr.jrcr_62_20

Abstract

Context: Study to reduce oral mucositis using chronoradiotherapy. Aims: This study aims to assess and compare oral mucositis and weight loss between two groups of patients on radiation-morning and evening group. Settings and Design: Prospective randomized study. Subjects and Methods: Sixty-four head and neck cancer patients were enrolled in the study. They were allotted into two arms, i.e., morning-arm A and evening-arm B using randomization. Baseline weight was recorded for all the patients. Weight and the grade of mucositis were recorded weekly during radiotherapy (RT) and at 2^nd and 6^th week post treatment in both the arms. Mucositis was graded based on the Radiation Therapy Oncology Group acute radiation morbidity scoring criteria. Statistical Analysis Used: The analysis of different grades and the incidence of mucositis at weekly intervals and follow-up were compared using Chi-square test. Weight loss was compared using t-test. Results: The progression of mucositis to higher grades was delayed by a week in the morning arm compared to the evening arm. Arm A (morning arm) developed Grade 3 mucositis in 21.9% patients versus 25% in the arm B (evening arm). Conclusions: Circadian rhythm has an impact on mucositis trending toward morning RT being less toxic with delayed progression and thereby decreased weight loss and better tolerance to radiation.

Keywords: Cell cycle, chronoradiotherapy, head and neck cancer, oral mucositis, radiotherapy

How to cite this article:
Lavanya LM, Arulponni T R. Correlation of oral mucositis with timing of radiation in head and neck cancer - A prospective randomized study on chronoradiotherapy. J Radiat Cancer Res 2021;12:10-4

How to cite this URL:
Lavanya LM, Arulponni T R. Correlation of oral mucositis with timing of radiation in head and neck cancer - A prospective randomized study on chronoradiotherapy. J Radiat Cancer Res [serial online] 2021 [cited 2021 Apr 17];12:10-4. Available from: https://www.journalrcr.org/text.asp?2021/12/1/10/308108

Introduction

Head and neck cancers (HNCs) are one of the most common malignancies in India accounting for 21.2% of all cancers with 30% and 11% incidence in male and female population, respectively.^[1],[2] Due to aggressive multimodality therapy in HNC, though the mortality has reduced, patients experience increased morbidity.^[3] Oral mucositis is a dose limiting toxicity leading to treatment breaks resulting in increased overall treatment time thereby affecting the potential for cure.^[3] Interventions such as excellent oral prophylaxis, care during radiation treatment, oral cryotherapy using ice, exposure to soft laser, and systemic administration of keratinocyte growth factor have produced some benefit. However, each of these approaches has its own limitations.^[4]

The actively dividing epithelial cells of the oral mucosa exist in different phases of the cell cycle during different times of the day in accordance with the molecular circadian clock.^[5] The use of this knowledge in the administration of radiation in coordination with the circadian rhythm of the body to maximize effectiveness and minimize toxicities is called chronotherapeutics. Chronochemotherapy has been proven to be effective,^[6] however, there are not many studies on chronoradiotherapy. It has been observed that correlation exists between circadian variation in cells and the incidence of mucositis.^[7] Most of the mucosal cells are in G₁ phase of the cell cycle in the morning and G₂-M phase in the late afternoon. Radiotherapy (RT) in the morning with most cells in G₁ phase would be associated with less mucositis than RT in late afternoon (with most cells in G₂M phase).^[7] There are not many studies on Indian patients to reduce mucositis based on this concept. Hence, the aim of this study is to correlate the grade of oral mucositis and weight loss with timing of radiation.

Subjects and Methods

This prospective study was conducted on 64 histologically proven HNC patients receiving definitive or adjuvant RT with or without concurrent chemotherapy from October 2016 to March 2018 following ethical clearance and informed consent. All the patients were immobilized using aquaplast cast with appropriate head rest. Contrast-enhanced computerized tomography planning scan was done with images of 3 mm slice thickness from the vertex to carina.

The allotment of patients into morning (Arm A) and evening (Arm B) group was done using chit method which is a simple random allocation sequence. The patients in the Arm A received radiation between 8 AM and 11 AM and the Arm B received radiation between 5 PM and 8 PM.

The target volumes were delineated based on Grégoire et al.^[8] and Chao et al.^[9] contouring guidelines and the organs at risk as per Radiation Therapy Oncology Group (RTOG) guidelines.^[10] The radiation dose in the definitive setting was 66 Gy in 30–33 fractions (fr) using intensity-modulated RT (IMRT) technique along with concurrent weekly cisplatin to a dose of 40 mg/m² body surface area. In the postoperative (adjuvant) setting, the dose was 60 Gy in 30 fr with five fractions per week ± concurrent weekly cisplatin chemotherapy based on the margin status and perinodal spread. IMRT technique was planned using the oncentra treatment planning system. Baseline weight was recorded for all the patients. Patients were not on any mouth washes or gargles prior to the start of radiation therapy. However, all the patients underwent oral/dental prophylaxis as per our department protocol. Weight and grade of the oral mucositis were assessed at regular weekly intervals during radiation, at 2^nd and 6^th week after completion of radiation using RTOG acute radiation morbidity scoring criteria.^[11] Both the arms were treated similarly for mucositis and weight loss. They were started on local applications such as gentian violet, benzocaine gel, sucralfate gargle, and oral analgesics along with serratiopeptidase. On the development of Grade III mucositis, Ryle's tube was placed for feeding purposes in both the arms.

Results

In this prospective study on 64 patients, Arm A and B consisted of 32 patients each. The patient characteristics are shown in [Table 1]. The mean age in the arm A was 58 years (standard deviation [SD] of 12) and in the arm B was 54 years (SD of 11.76), with no statistical significant difference between the two groups (P = 0.176). The performance status of the patients in both the arms was similar with majority belonging to Eastern Cooperative Oncology Group 2.

Table 1: Characteristics of patients in both the groups

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Radiotherapy and concurrent chemotherapy

The median RT dose was 66 Gy in 30 fractions in both the groups. Ninety-one percent of patients in the morning arm and 75% in the evening arm received concurrent weekly chemotherapy. Among them 83% of the patients completed six cycles and the remaining 17% received ≤5 cycles with minimum of 4 cycles.

Grades of mucositis during treatment

The various grades of mucositis in both the arms during radiation and follow-up are shown in [Figure 1]. In the 1^st week, 93% of patients in both the arms did not develop mucositis, P = 1. In the 2^nd week, 40.6% patients in the morning arm developed Grade I mucositis and none progressed to Grade II, whereas 31.2% developed Grade I mucositis in the evening group with 3.10% progressing to Grade II. Thus, both the arms developed grade one mucositis in the 2^nd week; however, the evening arm progressed to Grade II (3.2%) unlike the morning arm which remained in the Grade I. The trend continued from 3^rd week onward up to the end of treatment, where more patients progressed to higher grade of mucositis in evening group although not statistically significant.

Figure 1: Trend of mucositis in patients belonging to Arm A-morning (a) and Arm B-evening (b)

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Grade III mucositis was 0%, 21.90% in the morning group and 6.20%, 25% in the evening group during 5^th and 6^th week of RT, respectively. Thus, even during the 5^th week of radiation, the morning group showed Grade II mucositis whereas 6.2% of the evening group progressed to Grade III. However, none of the patients in either group developed Grade IV mucositis. The percentage of Grade III mucositis in the morning group was comparatively less at end of treatment.

In the nonoral cavity sites, the mean volume of oral cavity receiving 20 Gy in both the groups was 44 cc and the mean dose was 27.7 Gy in the morning group and 26 Gy in the evening group which did not show statistical significance.

In the nonoral cavity subsites eliminating the bias of T and N stage, the morning group consisted of more number of patients (9.4%) compared to the evening group (9%), however, none in the morning group showed Grade III mucositis at the 5^th week. This may be attributable to the propitious effect of morning irradiation. Overall, though the morning RT arm showed low incidence of Grade III mucositis and low mean weight loss, it did not translate into significant result at any given time of assessment (P = 0.7) as shown in [Table 2].

Table 2: Percentage of Grade III mucositis in morning and evening group

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During the first follow-up, i.e., at the 2^nd week following completion of radiation, the trend continued and Grade III mucositis was less in morning group compared to the evening group with 25% and 34.4%, respectively.

During the second follow-up, i.e., at the 6^th week post irradiation, predominantly Grade II mucositis was observed which was 84.4% in the morning group and 90.6% in the evening group.

Assessment of weight

The morning group showed lower mean weight loss (mean weight loss = 3.91 kg) as compared to evening group (mean weight loss = 4.25 kgs) though not statistically significant (P = 0.3), thus correlating with the grades of mucositis.

Discussion

There are very few studies in the literature exploring the preventive aspect of chronotherapy in relation to radiation-induced mucositis. Harper and Talbot had done a literature survey on chronoradiotherapy in various cancers including HNC.^[12]

The mean age of patients in our study was 55.5 years and in both the groups males were twice the number of females, similar to the studies by Bjarnason et al., and Goyal et al., respectively.^[7],[13] Significant gender-specific circadian rhythm studies for hundreds of genes involving the cell cycle pathway and multiple other pathways were studied and they suggested that the optimal timing of RT to reduce mucositis were not the same for males and females.^[14] As both the arms in the our study had higher percentage of males (81.3% in arm A and 62.5% in arm B), the comparison of mucositis among the genders was not done.

Majority of the patients belonged to oral cavity and oropharyngeal cancers in the study done by Bjarnason et al.^[7] However, our study consisted of oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers. Majority of our patients belonged to Stages III and IV, similar to the the study by Goyal et al.^[13]

Concurrent chemotherapy and smoking

Bernier et al. and Cooper et al. showed that the incidence of acute toxicity, including mucositis, increased by two folds in patients who underwent concurrent chemotherapy in either groups compared with those who underwent RT alone.^[15],[16] In the present study, though the morning arm patients received higher percentage (91% in Group A and 75% in Group B) of concurrent chemotherapy, they presented with less oral mucositis. This observation may be attributed to the propitious effect of morning irradiation.

Smoking is an important confounding factor and many trials including the study by Bjarnason have shown that patients with chronic history of smoking showed higher incidence of radiation-induced mucositis irrespective of the timing of radiation.^[14] This particular subset analysis of smokers in both the arms was not performed in our trial as the nonsmokers were only 22% and 38% respectively in arms A and B.

Chronoradiotherapy on other cancers

Chronoradiotherapy is a promising concept and is being explored in different cancers such as carcinoma cervix and breast cancers by Shukla et al.^[17] and Myoung et al. respectively^[18] apart from HNC. Different RT techniques were also collaborated with chronotherapy to improve tumor control and reduce toxicity. Rahn et al.^[19] in his retrospective study on non-small cell lung cancer patients with brain metastasis showed that the use of Gamma knife radiosurgery to the brain had better local control, better survival and lower rate of CNS-related death when treated earlier in the day compared to later in the day. Local control at 3 months was achieved in 97% of patients treated before 12:30 pm compared with 67% of those treated after 12:30 pm which was statistically significant (P = 0.014).^[19]

Chronoradiotherapy on tumor control

It is logical to assume that the chronoradiotheray may reduce the tumor control, but this aspect has been addressed in the trial done by Jae Myoung Noh et al., in which carcinoma breast patients were divided to receive morning or afternoon RT.^[18] There was no difference in the failure patterns or survival outcomes between the two treatment groups after a follow-up for 83 months.^[20] They noticed that among the 39 patients (9.9%) who developed Grade II (RTOG Grade) or more acute skin reaction, higher percentage was seen in the afternoon RT group than the morning RT group (13.7% vs. 5.8%, respectively) with significant P = 0.0088. Similar were the results in the studies conducted by Goyal et al. and Shukla et al. on HNC patients and carcinoma cervix patients, respectively.^[13],[17]

One of the unique observations in our study was that the onset of mucositis was delayed in the morning group as compared to the evening group which no other studies have quoted. Grade III mucositis was 21.9% in the morning RT group versus 25% in the evening group in our study, however, it was not statistically significant (P = 0.07), similar to the study by Bjarnason et al. in which the P = 0.17.^[7] As inconsistencies in the literature exist regarding the exact timing of RT and its outcome, further investigation is warranted on the lines of dosimetric correlation of the observed mucositis and for higher level of evidences for their therapeutic efficacy.

Strengths and limitations

This is one of the very few studies done worldwide, analyzing the effect of chronoradiotherapy on toxicities in HNC patients. It is a prospective randomized study, with equal number of patients in both the groups. Along with the assessment of oral mucositis, one of its objective outcomes, i.e., variation in weight was also recorded on weekly basis.

The limitation is that the long-term follow-up to assess the effect of chronoradiotherapy on tumor control and late toxicities are lacking. Another major limitation of this study was that all HNC sites were combined and compared. Comparison of similar sites of the HNC would have yielded statistically significant results. As both the arms in the present study had higher percentage of males (81.3% in arm A and 62.5% in arm B), the effect of chronoradiation on males versus females could not be correlated.

This study seeds in our mind a unique way to reduce radiation-induced mucositis, however, requires more research with more number of patients.

Conclusions

Circadian rhythm has an impact on radiation mucositis trending toward morning RT being less toxic with delayed onset and slower progression and there by decreased weight loss compared to evening RT. Long-term study including more number of patients, with subsite division in HNC would yield a significant result. Furthermore, future research is required to delineate the differences between the circadian gene profile between the normal cells and tumor cells to appropriately apply chronoradiotherapy in patients undergoing radiation with or without chemotherapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Alam MS, Siddiqui SA, Perween R. Epidemiological profile of head and neck cancer patients in Western Uttar Pradesh and analysis of distributions of risk factors in relation to site of tumor. J Cancer Res Ther 2017;13:430-5.
2.	National Cancer Registry Programme (ICMR). Consolidated Report of Population Based Cancer Registries: 2004-2005, Bangalore, India; 2008.
3.	Maria OM, Eliopoulos N, Muanza T. Radiation-induced oral mucositis. Front Oncol 2017;7:89.
4.	Sonis ST. Mucositis: The impact, biology and therapeutic opportunities of oral mucositis. Oral Oncol 2009;45:1015-20.
5.	Lévi F. From circadian rhythms to cancer chronotherapeutics. Chronobiol Int 2002;19:1-9.
6.	Laerum OD, Smaaland R, Abrahamsen JF. Current concepts for chronochemotherapy of cancer. J Infus Chemother 1995;5:159-70.
7.	Bjarnason GA, Mackenzie RG, Nabid A, Hodson ID, El-Sayed S, Grimard L, et al. Comparison of toxicity associated with early morning versus late afternoon radiotherapy in patients with head and neck cancer: A prospective randomized trial of the national cancer institute of Canada clinical trials group (HN3). Int J Radiat Oncol Biol Phys 2009;73:166-72.
8.	Grégoire V, Levendag P, Ang KK, Bernier J, Braaksma M, Budach V, et al. CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC, RTOG consensus guidelines. Radiother Oncol 2003;69:227-36.
9.	Chao KS, Wippold FJ, Ozyigit G, Tran BN, Dempsey JF. Determination and delineation of nodal target volumes for head-and-neck cancer based on patterns of failure in patients receiving definitive and postoperative IMRT. Int J Radiat Oncol Biol Phys 2002;53:1174-84.
10.	Brouwer CL, Steenbakkers RJ, Bourhis J, Budach W, Grau C, Grégoire V, et al. Head and neck guidelines CT-based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines. Radiother Oncol 2015;117:83-90.
11.	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.
12.	Harper E, Talbot CJ. Is it time to change radiotherapy: The dawning of chronoradiotherapy? Clin Oncol (R Coll Radiol) 2019;31:326-35.
13.	Goyal M, Shukla P, Gupta D, Bisht SS, Dhawan A, Gupta S, et al. Oral mucositis in morning vs. evening irradiated patients: A randomised prospective study. Int J Radiat Biol 2009;85:504-9.
14.	Bjarnason GA, Seth A, Wang Z. Diurnal rhythms (DR) in gene expression in human oral mucosa: Implications for gender differences in toxicity, response and survival and optimal timing of targeted therapy (Rx). Journal of clinical oncology 2007;25:Abstract 2507 suppl.
15.	Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-52.
16.	Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-44.
17.	Shukla P, Gupta D, Bisht SS, Pant MC, Bhatt ML, Gupta R, et al. Circadian variation in radiation-induced intestinal mucositis in patients with cervical carcinoma. Cancer 2010;116:2031-5.
18.	Jae Myoung Noh, Choi DH, Park H, Huh SJ, Park W, Seol SW, et al. Comparison of acute skin reaction following morning versus late afternoon radiotherapy in patients with breast cancer who have undergone curative surgical resection. J Radiat Res 2014;55:553-8.
19.	Rahn DA 3^rd, Ray DK, Schlesinger DJ, Steiner L, Sheehan JP, O' Quigley JM, et al. Gamma knife radiosurgery for brain metastasis of non-small cell lung cancer: Is there a difference in outcome between morning and afternoon treatment? Cancer 2011;117:414-20.
20.	Chan S, Rowbottom L, McDonald R, Bjarnason GA, Tsao M, Danjoux C, et al. Does the time of radiotherapy affect treatment outcomes? A review of the literature. Clin Oncol (R Coll Radiol) 2017;29:231-8.