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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 12  |  Issue : 2  |  Page : 59-64

Dosimetric parameters predicting radiation-induced oral mucositis in head-and-neck cancers in two intensity-modulated radiation therapy protocols: A retrospective analytical study


Department of Radiation Oncology, Father Muller Medical College, Mangalore, Karnataka, India

Date of Submission28-Nov-2020
Date of Acceptance02-Jan-2021
Date of Web Publication04-May-2021

Correspondence Address:
Dr. Sandesh B Rao
Department of Radiation Oncology, Father Muller Medical College, Mangalore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_65_20

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  Abstract 


Background: In locally advanced head-and-neck cancers (HNCs), definitive chemoradiation therapy has emerged as the treatment of choice due to the benefit of organ preservation. Radiation therapy is known to cause significant acute and late toxicities when it is used at radical doses. Studies have shown that more severe toxicities such as mucositis were observed in patients who received radiation therapy with concurrent chemotherapy. Incidental radiation exposure to buccal mucosa during radiation therapy for HNCs contributed to acute radiation-induced oral mucositis (RIOM). Objective: The objective of the study was to dosimetrically evaluate the dose received by buccal mucosa in patients with HNC patients undergoing sequential intensity-modulated radiotherapy technique (SEQ-IMRT) and simultaneous integrated boost intensity-modulated radiotherapy technique (SIB-IMRT). Materials and Methods: Forty patients with histologically proven squamous cell carcinoma of head and neck excluding nasopharyngeal and oral cavity cancers, who received radical chemoradiation therapy by SEQ-IMRT or SIB-IMRT were retrospectively analyzed. The total prescribed dose to the planning target volume was 70 Gy delivered in 2 Gy daily fractions in SEQ-IMRT and 66 Gy in 30 fractions in SIB-IMRT. All patients received concurrent weekly injection cisplatin (35 mg/m2). Dosimetric parameters of right and left buccal mucosa (V 15 Gy, V 30 Gy, and V 45 Gy) were recorded and correlated with grades of RIOM and weight loss as per CTCAE v5.0. Results: Mucositis and weight loss were accessed from week 1 to 7 in the SEQ-IMRT arm and week 1–6 for SIB-IMRT arm. Grade 3 mucositis was observed among 2 patients (10%) and 3 (15%) patients in the SIB-IMRT and none in SEQ-IMRT arm. Grade 2 Weight loss was observed among 35% of patients in SIB-IMRT arm and 5% patients in SEQ-IMRT arm. Conclusion: This study assessed the occurrence of several RIOM as predictive factor with respect to dose received to buccal mucosa in HNC patients, except nasopharyngeal and oral cavity cancer. Our data demonstrated relationship between V30 Gy of buccal mucosa and oral mucosal toxicity with associated weight loss in patients with HNCs undergoing radical chemoradiation therapy.

Keywords: Radiation induced oral mucositis, sequential-intensity-modulated radiotherapy technique, simultaneous integrated boost-intensity-modulated radiotherapy technique


How to cite this article:
Simon P, Fernandes DJ, Rao SB, Athiyamaan M S, Vidyasagar M S, Shankar S, Muhsina V, Sheeba S. Dosimetric parameters predicting radiation-induced oral mucositis in head-and-neck cancers in two intensity-modulated radiation therapy protocols: A retrospective analytical study. J Radiat Cancer Res 2021;12:59-64

How to cite this URL:
Simon P, Fernandes DJ, Rao SB, Athiyamaan M S, Vidyasagar M S, Shankar S, Muhsina V, Sheeba S. Dosimetric parameters predicting radiation-induced oral mucositis in head-and-neck cancers in two intensity-modulated radiation therapy protocols: A retrospective analytical study. J Radiat Cancer Res [serial online] 2021 [cited 2021 Jul 29];12:59-64. Available from: https://www.journalrcr.org/text.asp?2021/12/2/59/315468




  Introduction Top


Radiotherapy (RT) plays a pivotal role in the treatment of patients with head-and-neck cancers (HNCs). Approximately 80% (range 73.9%–84.4%) of all HNC patients will receive RT at least once during the course of their disease. Concurrent chemo-RT is the standard of care due to superior treatment response and survival outcome compared with RT alone for locally advanced cancers of head and neck which are inoperable or unresectable.[1] The use of chemotherapy delivered concomitantly with radiation increases the severity and impacts on the time course of radiation-induced oral mucositis (RIOM). Oral mucositis presents clinically with a spectrum of erythema of the mucosa as an early change, focal mucosal ulcers, and confluent mucosal ulcerations, compromising nutrition due to decreased oral intake as a consequence of severe pain.[2] Ulcerative mucositis leads to unplanned radiation treatment breaks, hampering continuous and uninterrupted concurrent chemo-RT consequently negatively impacting treatment outcomes with detrimental effects appearing greatest in HNCs. The secondary acute effects of oral mucositis include acute and chronic aspiration, inanition, infection, and severe pain. These lead to significant morbidity requiring treatment interruptions.[1] Higher rates of mucosal toxicity are related to intensity of accelerated fractionation or concurrent chemoradiation as ability of normal tissue repair is limited, suggesting a need for aggressive supportive care, leading to acceptable level of toxicity. Mucositis is a dose-limiting toxicity as aggressive treatment regimens have indicated that there is a limit in the ability of mucosa to recover from cytotoxic effects.[3] Volume of the target and RT technique determines the volume of normal tissue irradiated. Dose coverage to the target is achieved by precise collimation with simultaneous modulation of intensity with multiple radiation beams, creating margins of high dose regions with relatively steep dose gradients, avoiding overlap from higher radiation doses with a resultant protection of normal tissues. Delivery of highly conformal radiation techniques to the target tissue also leads to larger amounts of body tissue being irradiated to lower dose. Protection of normal tissue is wholly not achieved by modern techniques as some degree of radiation-associated toxicity will be experienced by patients. Proximity of the target to functionally critical normal tissue leads to excessively high radiation doses, which are above the tolerance threshold levels of organs at risk (OAR).[4]


  Materials and Methods Top


Source of data

Forty patients with histologically proven squamous cell carcinoma of head and neck, excluding nasopharyngeal and oral cavity cancers, with stages T2–T4, N0–3, M0 according to the AJCC 8th edition, who had already received radical treatment with chemoradiation therapy by either sequential intensity-modulated radiotherapy technique (SEQ-IMRT) or simultaneous integrated boost intensity-modulated radiotherapy technique (SIB-IMRT) were considered in the study for evaluation. Patients with prior or synchronous malignancy, metastasis, prior history of radiation therapy, and surgery to head-and-neck region were excluded from the study.

Radiation therapy

Twenty patients were selected in each arm of either SEQ-IMRT or SIB-IMRT with similar patient and disease characteristics. All of them had received weekly injection cisplatin 35 mg/m2.

A thermoplastic head–shoulder mask was applied to immobilize each patient for simulation and treatment. A computed tomography (CT) simulation scan was done with 5 mm slice thickness and intravenous contrast using 16 slice conventional GE CT scan in each patient. Treatment planning was done on eclipse version 13 using (Anisotropic Analytical Algorithm) AAA algorithm.

Treatment protocol

SEQ-IMRT arm received a radical radiation of a total dose of 70 Gy in 35 fractions, 2 Gy/fraction, and 5 fractions per week. Gross tumor volume (GTV) encompassed all macroscopic disease received 70 Gy in 35 fractions, high-risk areas received 66 Gy in 33 fractions, and intermediate risk areas received 60 Gy in 30 fractions, low risk areas received 50 Gy in 25 fractions as per ICRU 62.[5]

SIB-IMRT arm received a radical radiation of a total dose of 66 Gy in 30 fractions, 2.2 Gy/fraction, 5 fractions per week to GTV and high-risk areas, intermediate risk areas received 60 Gy in 30 fractions, 2 Gy per fraction, low-risk areas received 54 Gy in 30 fractions, 1.8 Gy per fraction, as per Chakraborty et al.[6]

All patients were treated on a 6 MV linear photon accelerator, and treatment was delivered using 7 beams.

Assessment of acute radiation-induced oral mucositis

Acute RIOM and weight loss were assessed as per CTCAE 5.0 version in each patient on a weekly basis. In our study, we have correlated dosimetric parameters with respect to buccal mucosa V15, V30, and V45 Gy with severity of mucositis and weight loss. Grade 3 and above RIOM was defined as severe acute RIOM.

Buccal mucosa contouring

Buccal mucosa was contoured as per Brouwer et al., with boundaries cranially bounded by bottom of maxillary sinus, caudally upper edge teeth sockets or lips, anteriorly lips and teeth, posteriorly medial pterygoid muscle, laterally buccal fat, and medially outer surface of the mandible and maxilla, oral cavity [Figure 1] and [Figure 2].[7]
Figure 1: Buccal mucosa contouring (yellow and orange) with dose color wash of planning target volume for sequential intensity-modulated radiotherapy technique

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Figure 2: Buccal mucosa contouring (yellow and orange) with dose color wash of planning for simultaneous integrated boost intensity-modulated radiotherapy technique

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Statistical analysis

The data were entered in computer using MS office excel sheet for statistical analysis. Data were analyzed using IBM SPSS Statistics 23® and Chi-square test. The results were also expressed in percentage. The difference was considered significant if P < 0.05.


  Results Top


Patient characteristics

All patients included in the study were males to avoid gender bias. Major forms of cancers included in the study were cancers of oropharynx; other subsites were hypopharynx and supraglottis. All patients completed the prescribed treatment. All patients characteristcs are given in [Table 1]. Comparison of grades of mucositis and weight loss was accessed from week 1 to 7 in the SEQ-IMRT arm and week 1–6 for SIB-IMRT. There was an earlier onset of Grade 2 mucositis in SIB-IMRT arm with one patient having Grade 2 mucositis at 3rd week of external beam radiation therapy (EBRT), whereas none in SEQ-IMRT arm. Severity of mucositis was more in SIB-IMRT arm compared to SEQ-IMRT arm with Grade 3 occurring in 2 (10%) patients and 3 (15%) patients at week 5 and week 6 in the former compared to none in the latter.
Table 1: Patient characteristics

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[Figure 3] shows trend of RIOM during course of chemo radiation from 1st week to 6th week and progression of RIOM is higher in SIB-IMRT arm compared to SEQ-IMRT arm.
Figure 3: Trend of mucositis in both arms

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Thirty-five percent of patients in SIB-IMRT arm and 5% patients in SEQ-IMRT had developed Grade 2 weight loss posttreatment. The mean values of right and left buccal mucosa are mentioned in [Table 2].
Table 2: Dose Volume parameters of buccal mucosa

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[Table 2] shows the dosimetric parameters of right and left buccal mucosa (V15, V30, and V45 Gy) with the mean values signifying the mean values. The higher dose to right buccal mucosa could be due to the presence of right upper cervical nodes in the majority of the cases in both arms.

Significant correlation between dosimetric parameters and toxicities was observed in the 5th week was observed in SIB-IMRT arm. Higher grades of mucositis were observed at 5th week of SIB-IMRT arm.

[Table 3] shows the grades of RIOM correlated with dosimetric parameters of right and left buccal mucosa (V15, V30, and V45 Gy) at the 5th week in SIB-IMRT arm with statistical significance (P < 0.001). Similar results were seen in SEQ-IMRT also.
Table 3: Mean values of right and left buccal mucosa at 5th week of external beam radiation therapy

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[Figure 4] shows the trend of weight loss during course of chemoradiation from 1st week to 6th week, and progression of weight loss is higher in SIB-IMRT arm compared to SEQ-IMRT arm with statistical significance at the 6th week (P = 0.019).
Figure 4: Trend of weight loss in both arms

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Both SEQ-IMRT and SIB-IMRT arm had similar grades of weight loss till 5th week but at the 6th week of EBRT in SIB-IMRT arm had higher grades of weight loss which was statistically significant (P = 0.019) which may be due to higher grades of mucositis in SIB-IMRT arm.


  Discussion Top


This study was done to evaluate the oral mucosa dose-volume relationship in patients receiving concurrent chemo-RT for cancers of head and neck except nasopharynx and oral cavity. RIOM is the major complication of patients undergoing radiation therapy for HNCs due to inflammation of oral mucosa due to ionizing radiation.[8],[9] Altered fractionation schedules and addition of chemotherapy increase the incidence of oral mucositis, leading to severe RIOM which results in reduction of QOL of patients due to oral pain, odynophagia, reduced oral intake, and secondary infections. This causes interruption of treatment, consequently leading to compromise in disease control and survival.[10],[11] Hence, prevention as well as timely management of RIOM is necessary for optimum tumor outcomes. The severity of RIOM is strongly dependent on the dose, fraction size, radiation portals, fractionation, and type of the ionizing radiation used.[12]

IMRT can reduce the number of hotspots in normal tissue by homogenous dose distribution in and outside the target area using interacting radiation fields and the high-energy beams generated by linear accelerators, thus reducing severity of RIOM. Nutrition, basic oral care, laser therapy, and drug treatments are the areas of utmost focus in the management of radiation-induced mucositis as per the clinical practice guidelines by The European Society for Medical Oncology.[13] In this retrospective study, we compared RIOM and weight loss in SEQ-IMRT with SIB-IMRT.

In our study, SEQ-IMRT and SIB-IMRT plans were generated for twenty patients each, with locally advanced head-and-neck squamous cell cancer without any dose constraints to oral mucosa. In this study, it was observed that patients in SIB-IMRT had an earlier onset of higher grades of RIOM. In the study by Li et al., 26% of the patients developed Grade 3 mucositis, whereas in our study, 15% of patients in SIB-IMRT and 10% in SEQ-IMRT arm developed Grade 3 mucositis.[14] Li et al. concluded that V30 Gy for the buccal mucosa should be <73% to avoid severe RIOM. In our study, V30 in SIB-IMRT arm was 86.648% and 71.556% SEQ-IMRT of the right buccal mucosa, reflecting the occurrence of higher grades of mucositis in SIB-IMRT arm.[14]

SIB-IMRT had higher grades of weight loss at the end of treatment with 35% of patients with Grade 2 weight loss and SEQ-IMRT having only 5% Grade 2 weight loss which was statistically significant (P - 0.018). Occurrence of higher grades of weight loss can be attributed due to higher dose to buccal mucosa in SIB-IMRT arm compared to the SEQ-IMRT arm because of significant more mucositis.

In the current retrospective study, CTCAE version 5.0 criteria were used as an assessment tool, the appearance of oral mucositis could be observed timely, and the symptom of pain on oral mucosa could be recorded exactly, thus making the clinical data we have collected relatively convincing.


  Conclusion Top


This study is to assess the occurrence of RIOM as predictive factor with respect to dose received to buccal mucosa in HNC patients, except nasopharyngeal and oral cavity cancer. This hypothesis-generating study showed that V30% of buccal mucosa should be <73% to avoid severe RIOM. The clinical implications will become increasingly significant as dosimetry will help in defining optimal constraints for this OAR in future. Our data demonstrated similar relationship between V30 Gy of buccal mucosa and oral mucosal toxicity in patients with HNCs. Higher grades of RIOM and weight loss can be correlated to the relatively higher dose received to the buccal mucosa in the SIB-IMRT arm.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Russo G, Haddad R, Posner M, Machtay M. Radiation treatment breaks and ulcerative mucositis in head and neck cancer. Oncologist 2008;13:886-98.  Back to cited text no. 1
    
2.
Bonomi M, Camille N, Misiukiewicz K, Latif A, Gupta V, Blacksburg S, et al. Assessment and management of mucositis in head and neck cancer patients. Clin Investig 2012;2:1231-40.  Back to cited text no. 2
    
3.
Trotti A. Toxicity in head and neck cancer: A review of trends and issues. Int J Radiat Oncol Biol Phys 2000;47:1-2.  Back to cited text no. 3
    
4.
Strojan P, Hutcheson KA, Eisbruch A, Beitler JJ, Langendijk JA, Lee AW, et al. Treatment of late sequelae after radiotherapy for head and neck cancer. Cancer Treat Rev 2017;59:79-92.  Back to cited text no. 4
    
5.
Landberg T, Chavaudra J, Dobbs J, Gerard JP, Hanks G, Horiot JC, et al. Report 62. J Int Comm Radiat Units Meas. 1999;32:1-52.  Back to cited text no. 5
    
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Chakraborty S, Ghoshal S, Patil V, Oinam A, Suresh S. Acute toxicities experienced during simultaneous integrated boost intensity-modulated radiotherapy in head and neck cancers-”experience from a north Indian regional cancer centre. Clin Oncol 2009;21:676-86.  Back to cited text no. 6
    
7.
Brouwer CL, Steenbakkers RJ, Bourhis J, Budach W, Grau C, Grégoire V, et al. 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.  Back to cited text no. 7
    
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Trotti A, Bellm LA, Epstein JB, Frame D, Fuchs HJ, Gwede CK, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: A systematic literature review. Radiother Oncol 2003;66:253-62.  Back to cited text no. 8
    
9.
Bourhis J, Overgaard J, Audry H, Ang KK, Saunders M, Bernier J, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: A meta-analysis. Lancet 2006;368:843-54.  Back to cited text no. 9
    
10.
Scott-Brown M, Miah A, Harrington K, Nutting C. Evidence-based review: quality of life following head and neck intensity-modulate radiotherapy. Radiother Oncol 2010;97:249-57.  Back to cited text no. 10
    
11.
Lee IH, Eisbruch A. Mucositis versus tumor control: The therapeutic index of adding chemotherapy to irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 2009;75:1060-3.  Back to cited text no. 11
    
12.
Werbrouck J, De Ruyck K, Duprez F, Veldeman L, Claes K, Van Eijkeren M, et al. Acute normal tissue reactions in head-and-neck cancer patients treated with IMRT: Influence of dose and association with genetic polymorphisms in DNA DSB repair genes. Int J Radiat Oncol Biol Phys 2009;73:1187-95.  Back to cited text no. 12
    
13.
Peterson DE, Boers-Doets CB, Bensadoun RJ, Herrstedt J, ESMO Guidelines Committee. Management of oral and gastrointestinal mucosal injury: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol 2015;26 Suppl 5:v139-51.  Back to cited text no. 13
    
14.
Li K, Yang L, Xin P, Chen Y, Hu QY, Chen XZ, et al. Impact of dose volume parameters and clinical factors on acute radiation oral mucositis for locally advanced nasopharyngeal carcinoma patients treated with concurrent intensity-modulated radiation therapy and chemoradiotherapy. Oral Oncol 2017;72:32-37.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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