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ORIGINAL ARTICLE
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Study of comparison of acute toxicities between sequential intensity-modulated radiation therapy and simultaneous integrated boost intensity-modulated radiation therapy in head-and-neck cancers


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

Date of Submission04-Aug-2022
Date of Acceptance09-Aug-2022
Date of Web Publication01-Nov-2022

Correspondence Address:
Lanisha Jolitha Sequeira,
Department of Radiation Oncology, Father Muller Medical College, Mangaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jrcr.jrcr_48_22

  Abstract 

Purpose: The purpose of this study is to assess and compare the acute toxicities between sequential intensity-modulated radiation therapy and simultaneous integrated boost (SIB) intensity-modulated radiation therapy in head-and-neck cancers using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Materials and Methods: Patients with histologically proven squamous cell carcinoma of head and neck at the department of radiotherapy (RT), from December 2018 to July 2020, were taken up for this study. Patients were divided into sequential intensity-modulated RT (IMRT) arm and SIB-IMRT arm. Patients treated with sequential IMRT were treated so as to receive a total dose of 70 Gy in 35 fractions, 2 Gy/fractions, 5 fractions per week – 70 Gy in 35 fractions to the primary tumor, 66 Gy in 33 fractions to high-risk clinical target volume (CTV1), 60 Gy in 30 fractions to high-risk CTV2 and 50 Gy in 25 fractions to elective nodes/low-risk CTV3. Patients treated with SIB-IMRT were treated so as to receive a total dose of 66 Gy in 30 fractions – 2.2 Gy/fraction to gross tumor volume/PTV 66, 60 Gy in 30 fractions – 2.0 Gy/fraction to high-risk nodes (PTV 60), 54 Gy in 30 fractions – 1.8 Gy/fraction to elective nodes (PTV 54), respectively. Patients received concurrent chemotherapy with weekly injections cisplatin (35mg/m2) or injection carboplatin (AUC 2). Toxicities were assessed using CTCAE v 4.03. Results: Higher grades of radiation-induced dermatitis and mucositis were observed in patients in SIB-IMRT. No patients experienced Grade 4 toxicity. The results confirm that irradiation according to our SIB-IMRT protocol is a treatment option with acceptable toxicity. Conclusion: SIB-IMRT is feasible, although associated with increased rates of skin and mucosal toxicity.

Keywords: Head-and-neck squamous cell carcinomas, radiotherapy, sequential intensity-modulated radiotherapy, simultaneous integrated boost sequential intensity-modulated radiotherapy



How to cite this URL:
Sequeira LJ, Shankar S, Rao SB, Fernandes D, Jacob T, Krishnaraj H. Study of comparison of acute toxicities between sequential intensity-modulated radiation therapy and simultaneous integrated boost intensity-modulated radiation therapy in head-and-neck cancers. J Radiat Cancer Res [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.journalrcr.org/preprintarticle.asp?id=360287


  Introduction Top


Head-and-neck cancers (HNCs) include epithelial malignancies of the upper aerodigestive tract, nasal cavity, oral cavity, pharynx, larynx, and paranasal sinuses; and are the sixth leading cancer worldwide which accounts for about 650,000 cases and 330,000 deaths annually.[1]

Head-and-neck squamous cell carcinomas contribute to approximately 5% for all cancers worldwide.[2] Worldwide alcohol and tobacco consumption were associated with an increased incidence of oral cavity cancers, but presently many countries noticed a decline in oral cavity cancer incidence due to a decline in the use of tobacco. Countries like Canada, Netherlands, Denmark, Sweden, Norway, the United States, and the United Kingdom have witnessed a rising trend in oropharyngeal and oral cavity cancers due to HPV infection.[3]

In 2018, GLOBOCAN estimated that more than 1,157,294 new cancer cases and nearly 700,000 deaths occurred in India. HNCs are among the most common cancers diagnosed in the Indian subcontinent and account for approximately 30%–40% of all cancer sites, in India. New cases in 2018 were 16.1% in males and 4.8% in females. Lip and oral cavity accounts for 10.4% and rank second-most common malignancy in India. Larynx accounts for 2.5%, hypopharynx 2.2%, oropharynx 1.5%, salivary gland 0.66%, and nasopharynx 0.44%.[1]

HNCs occur due to variations in exposure to major environmental and behavioral risk factors, the most common being smoking tobacco, smokeless tobacco (betel quid chewing), alcohol, diet poor in vegetables and fruits, occupational hazards, microorganisms, dental risk factors, and genetic risk factors.

Surgery and radiation therapy are two curative options in the treatment of HNCs. Almost one-third of patients present with early-stage disease (Stages I and II) which can be treated with single modality surgery or radiotherapy (RT) with similar results. Five-year overall survival is 70%–90%. Two-thirds of patients present with locally advanced disease (Stages III and IV) and are treated with multimodality management which includes surgery, RT, chemotherapy, and targeted therapy. Locally advanced cancers constitute a major burden. Treatment of such cancers involves the use of RT in most patients at one point in time or other. Combined concomitant chemoradiation is the standard treatment in locally advanced carcinomas of the head and neck with a 5-year overall survival of 30%–40%. Concurrent chemoradiation increases absolute benefit by 6.5% at 5 years.[4]

As intensity-modulated RT (IMRT) was introduced, the improved high-dose conformality reduced the dose to normal tissues and produced minimal radiation toxicity while maintaining similar rates of control.[5] There is well-established steep dose-response relationship in head-and-neck carcinoma for local tumor control which translates into improved survival.[6]

The simultaneous integrated boost (SIB)-IMRT technique allows for the simultaneous delivery of different dose levels to different target volumes within a single treatment fraction. SIB-IMRT technique is a new way to investigate the accelerated fractionation in the definitive treatment of head-and-neck (H and N) cancers.[7] Acceleration was achieved by delivering a higher daily fraction dose to the gross tumor volume from the very 1st day of treatment. The overall treatment time was shortened to 6 weeks and RT acceleration began at treatment inception.[8]

RT causes significant acute and late toxicities when used at doses required to sterilize the locoregional disease. The acute toxicities of RT include mucositis, dysphagia, xerostomia, dermatitis, and weight loss. In this study, we compare acute toxicities between SEQ-IMRT and SIB in HNCs using the CTCAE version 4.03.


  Materials and Methods Top


History and clinical examination of the primary tumor and neck nodes were done for all the patients in this study. Investigations such as complete hemogram, renal function tests, and liver function tests, were done. Biopsy from the primary tumor and/or fine-needle aspiration cytology of metastatic lymph nodes was done. Diagnostic imaging computed tomography (CT)/magnetic resonance imaging scan, chest X-ray PA view, and ultrasonography of the abdomen and pelvis were done to rule out metastasis. All patients were staged according to TNM staging system (AJCC Staging Manual 8th Edition).

A written informed consent was obtained after explaining the nature of disease, its treatment, and side effects in their own language before starting the study. Patients were also counseled about maintaining good oral hygiene and nutrition throughout the treatment.

Treatment plan

After the institutions ethical committee approval patients were allocated to SEQ-IMRT arm and SIB-IMRT arm. Patients were treated in supine position with their neck slightly extended with a thermoplastic mold which covered the head-and-neck region. A bite block was used. Contrast-enhanced CT of the head and neck, of 5 mm thickness were taken. CT scans were then sent to eclipse TPS. Target volume delineation was done and for each patient, target volumes with their respective planning target volumes were defined as per ICRU 62 guidelines.[9] Gross tumor volume included all clinically and radiologically demonstrable tumors including the involved nodes. Positive lymph nodes were defined as any lymph node of size more than or equal to 1 cm which was palpable clinically/noted on CT scan. Following clinical target volumes were defined:

Patients treated with sequential IMRT were planned to receive a total dose of 70 Gy in 35 fractions, 2 Gy/fractions, and 5 fractions per week [Table 1]:
Table 1: Clinical target volumes for patients treated with sequential intensity modulated radiation therapy

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Patients treated with SIB-IMRT were planned so that prescribed doses were 66 Gy, 60 Gy, and 54 Gy to PTV 66, PTV 60, and PTV 54, respectively, at daily fraction sizes of 2.2 Gy, 2 Gy, and 1.8 Gy, per fraction, 5 days a week, over 6 weeks, delivered simultaneously over 30 fractions [Table 2].
Table 2: Clinical target volumes for patients treated with simultaneous integrated boost intensity modulated radiation therapy

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Treatment of patients

Orthogonal electronic portal imaging devices were used in the treatment position to match with the DRR for delineation of setup errors to verify the treatment field. Patients received concurrent chemotherapy with weekly injection cisplatin (injection cisplatin: 35 mg/m2)/carboplatin (AUC 2).

Data collection

All patients were assessed for acute toxicity during the treatment period on a weekly basis and at follow-up after the completion of RT at 4 weeks, 8 weeks, and 12 weeks using CTCAE version 4.03.

Statistical analysis

A sample size of 50 (25 in each arm), was included in time bound manner for the specified period, and allocation was done by the Lottery method. Data were entered into the computer using a Microsoft Office Excel sheet for statistical analysis. Data were analyzed using IBM SPSS Statistics version 23.0, Chi-square test, Fisher's exact test, and phi test. The results were also expressed in percentages. The difference was considered significant if P < 0.05.


  Results Top


Considering stage-wise distribution, Stage II was seen in 16% and 20%, Stage III was seen in 28% and 24%, and Stage IV was seen in 56% in SEQ-IMRT and SIB-IMRT arms, respectively. The majority of patients in both arms were in the Stage IV group as shown in [Table 3].
Table 3: Stage group distribution of patients in each arm

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The observation made on symptoms is shown in [Table 4]. Dysphagia to solids was seen in the majority of patients (32% v/s 36% in SEQ v/s SIB). Other symptoms included swelling in the neck, odynophagia, change in voice, ulcer over the tongue and pain in the throat.
Table 4: Clinical spectrum of the disease in each arm

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Grade 1 dermatitis was seen in most patients in both arms by week 3 (P = 0.713 ns). By week 5, 20 (80%) patients in SEQ-IMRT and 23 patients (92%) in SIB-IMRT developed Grade 2 skin reactions (P = 0.144 ns). Grade 3 reactions were seen in 3 (12%) patients in SEQ arm and 4 (16%) patients in SIB arm by the week 6 (P = 0.384 ns). No patients had Grade 4 dermatitis. Radiation-induced mucositis of Grade 1 was seen in the majority of the patients by week 3 in both arms (P = 0.529 ns). Grade 3 mucositis was seen in 5 (20%) patients in SEQ-IMRT arm and 6 (24%) patients in SIB-IMRT arm (P = 0.269 ns). No patients had Grade 4 mucositis. Dysphagia of Grade 2 was seen in 18 (72%) patients in SEQ and 20 (80%) patients in SIB arm by week 4 during treatment (P = 0.5 ns). Fourteen (56%) patients in SEQ-IMRT arm and 16 (64%) patients in SIB-IMRT arm required Ryle's tube insertion. Xerostomia of grade 1 was seen by the 4th week in most patients. Grade 2 xerostomia was seen in one patient each (4%) in SEQ and SIB-IMRT arm (P = 0.2 ns). Grade 1 weight loss was seen in the majority of the patients by week 5 (P = 1 ns). Grade 2 weight loss was seen in 2 (8%) patients in each arm at the end of treatment (P = 0.011 ns).


  Discussion Top


Locally advanced HNCs treated with surgery have been associated with functional loss and increased morbidity. Hence, chemoradiation has emerged as the treatment of choice based on several meta-analyses. Concurrent chemoradiotherapy is the standard of care for locally advanced HNCs with a 5-year survival benefit of 8% over RT alone.[4]

The standard of care is concurrent chemoradiation with a radiation dose of 66–70 Gy in 33–35 fractions in 2 Gy per fraction 5 days a week along with chemotherapy injection cisplatin. Several studies have reported that SIB-IMRT is a safe and effective treatment for HNC and offers the following advantages: (i) Shortening of the overall treatment time; (ii) increase in biologically equivalent dose to the tumor with a dose per fraction slightly >2 Gy; (iii) more conformal dose distributions compared with that of SEQ-IMRT where planning was done sequentially in three phases.

SIB-IMRT technique allows simultaneous delivery of different doses to different target volumes within a single treatment fraction. Acceleration was achieved by delivering a higher daily fraction dose to the gross tumor volume from the very first day of treatment. The overall treatment time was shortened to 6 weeks and RT acceleration began at treatment inception.

Radiation therapy is known to cause significant acute and late toxicities when it is used at radical doses.[10] Studies have shown that more severe toxicities were observed in patients who received radiation therapy with concurrent chemotherapy.

This study was done to assess and compare the acute toxicities between sequential intensity modulated radiation therapy and SIB intensity-modulated radiation therapy in HNCs using CTCAE version 4.03 and also to assess and compare the response to radiation therapy.

Grade 2 skin reactions were seen in 40% of the patients in SEQ arm and 46% of patients in SIB arm and Grade 3 in 12% in SEQ v/s 16% in the SIB arm in this study. Vlacich et al.,[11] reported that rates of acute Grade 2 dermatitis of 40% v/s 15% in SEQ v/s SIB and Grade 3 dermatitis of 56% v/s 71% were significantly higher in the SIB group than in the SEQ group. This incidence has been observed by Lee et al.,[12] who have highlighted the additive influence of the thermoplastic mask by the tangential beams towards the increase in skin dosage. Another factor that may be of some importance in the production of skin toxicity might have been weight loss that patients suffered during treatment, with the attendant thinning of subcutaneous fat during the course of therapy resulting in an increase in skin dose as observed by Chakraborty et al.[13]

Our study also showed an increase in dermatitis in SIB arm which could probably be due to the weight loss leading to thinning of subcutaneous fat during radiation therapy, but to assess thinning of s/c fat, no reimaging was done as SIB was a single treatment plan.

Grade III oral mucositis was seen in 20% of patients in SEQ-IMRT arm and 24% of patients in SIB-IMRT arm. In the study conducted by Raghunathan et al.,[14] Grade 3 mucositis occurred in 23% and 28% of the patients, respectively. The high frequency of Grades 1 and 2 mucositis noted in our study was in the 3rd and 4th weeks of treatment. The use of mouth bite during the treatment for better setup reproducibility might have led to an increased reaction in the region of oral cavity by unintentional trauma on the irradiated region during the process of insertion and removal, which could have been a cause for increased oral mucositis in our patients. The addition of concurrent chemotherapy to definitive radiation is also known to increase toxicity compared to radiation alone, which is another cause of the increased rate of mucositis in our patients.

Grade 3 dysphagia was seen in 56% of patients in SEQ-IMRT arm and 64% (P = 0.001) of patients in SIB-IMRT arm, who required feeding tubes, which was significant. Similar results were seen in the study by Vlacich et al.[11] who reported grade 3 dysphagia in 55% of patients in SEQ-IMRT arm and 79% of patients in SIB-IMRT arm. Fifty-six percent of the patients in our study were stage IV a, due to which a higher dose might have been received by the constrictor muscles which might have been a confounding factor for dysphagia.

In our study, Grade 1 xerostomia was seen by the 4th week in most patients (96%). Grade 2 xerostomia was seen in 8% of patients in SEQ and SIB arms. Raghunathan et al.[14] reported Grade 2 xerostomia in 12% of patients and 17% of patients in SEQ-IMRT and SIB-IMRT groups which was a study done in patients with carcinoma hypopharynx. Our evaluation of xerostomia was done based on symptomatic evaluation and there was no objective measurement of the salivary flow.

Grade 1 weight loss was seen in most patients by week 5. Grade 2 weight loss was seen in two patients in each arm at the end of treatment. In the study conducted by Vlachich et al.,[11] there were no significant differences in weight loss in the two arms. The weight loss might have been due to mucositis and dysphagia which led to nutritional impairment during treatment.

Our study revealed that patients who were treated with SIB-IMRT had a slower recovery from toxicities, though not statistically significant.

In our subset analysis, we did not find any correlation between tumor and nodal stages with the toxicities.

Although our study had a small sample size; with respect to patient selection criteria, the methods and materials used are comparable to studies in the literature[11] and showed that SIB-IMRT was associated with a similar risk of acute side effects compared with SEQ-IMRT. Although Grade II and III reactions were slightly higher in SIB patients, they were manageable and did not lead to a significant treatment gap or increased overall treatment time, which would otherwise lead to compromised local control. In our study, we found that these techniques appear equivalent with respect to response though sequential boost IMRT is associated with lesser rates of acute toxicity.

The merits of the study:

All patients were treated with concurrent chemoradiation, which is the treatment of choice in patients with unresectable, inoperable HNCs.

All toxicities that occurred during the treatment were manageable. No treatment-related death occurred in this study. Toxicities were graded according to CTCAE version 4.03.

SIB-IMRT may have advantages due to its convenience and comparatively shorter overall treatment duration and the use of a single treatment plan during the entire radiation treatment.

This study had several limitations, one of the most important being the small sample size, which was adequate for considering toxicities and not any other variable.

Varied regimen of concurrent chemotherapy was used in this study which might have been a cause for variable toxicities.


  Conclusion Top


SIB-IMRT provided similar treatment outcomes without compromising on the risk of severe acute adverse events, compared with SEQ-IMRT in HNC patients. Both IMRT techniques tended to cause comparable frequent and manageable adverse side effects. SIB-IMRT may be considered noninferior to SEQ-IMRT in its convenience and a short course of treatment duration. Hence, SIB-IMRT and SEQ-IMRT can be prescribed as a technique of RT for HNC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.  Back to cited text no. 1
    
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Machiels JP, Lambrecht M, Hanin FX, Duprez T, Gregoire V, Schmitz S, et al. Advances in the management of squamous cell carcinoma of the head and neck. F1000Prime Rep 2014;6:44.  Back to cited text no. 2
    
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Chaturvedi AK, Anderson WF, Lortet-Tieulent J, Curado MP, Ferlay J, Franceschi S, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol 2013;31:4550-9.  Back to cited text no. 3
    
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Pignon JP, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14.  Back to cited text no. 4
    
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Spiotto MT, Weichselbaum RR. Comparison of 3D confromal radiotherapy and intensity modulated radiotherapy with or without simultaneous integrated boost during concurrent chemoradiation for locally advanced head and neck cancers. PLoS One 2014;9:e94456.  Back to cited text no. 5
    
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Ho KF, Fowler JF, Sykes AJ, Yap BK, Lee LW, Slevin NJ. IMRT dose fractionation for head and neck cancer: Variation in current approaches will make standardisation difficult. Acta Oncol 2009;48:431-9.  Back to cited text no. 6
    
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Orlandi E, Palazzi M, Pignoli E, Fallai C, Giostra A, Olmi P. Radiobiological basis and clinical results of the simultaneous integrated boost (SIB) in intensity modulated radiotherapy (IMRT) for head and neck cancer: A review. Crit Rev Oncol Hematol 2010;73:111-25.  Back to cited text no. 7
    
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Montejo ME, Shrieve DC, Bentz BG, Hunt JP, Buchman LO, Agarwal N, et al. IMRT with simultaneous integrated boost and concurrent chemotherapy for locoregionally advanced squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2011;81:e845-52.  Back to cited text no. 8
    
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Landberg T, Chavaudra J, Dobbs J, Gerard JP, Hanks G, Horiot JC, et al. Reports of the International Commission on Radiation Units and Measurements. 1999. p. 48-51.  Back to cited text no. 9
    
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Vlacich G, Stavas MJ, Pendyala P, Chen SC, Shyr Y, Cmelak AJ. A comparative analysis between sequential boost and integrated boost intensity-modulated radiation therapy with concurrent chemotherapy for locally-advanced head and neck cancer. Radiat Oncol 2017;12:13.  Back to cited text no. 11
    
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Lee N, Chuang C, Quivey JM, Phillips TL, Akazawa P, Verhey LJ, et al. Skin toxicity due to intensity-modulated radiotherapy for head-and-neck carcinoma. Int J Radiat Oncol Biol Phys 2002;53:630-7.  Back to cited text no. 12
    
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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 (R Coll Radiol) 2009;21:676-86.  Back to cited text no. 13
    
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Raghunathan MS, Subramaniam R, Vaz A, Kumar NS. EP-1097: Comparison of outcomes and toxicities between IMRT and SIB-IMRT in cancers of hypopharynx. Radiother Oncol 2016;1:S528.  Back to cited text no. 14
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

 
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