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A comparative study of concomitant boost radiation versus concomitant boost with concurrent chemoradiation versus standard fractionation chemoradiation in locally advanced head-and-neck cancer


 Department of Radiation Oncology, Regional Cancer Centre, Pt. B. D. Sharma Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India

Correspondence Address:
Anil Kumar Dhull,
Department of Radiation Oncology, Regional Cancer Centre, Pt. B. D. Sharma PGIMS, P. O. Box: 100, GPO, Rohtak - 124 001, Haryana
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_475_18

 > Abstract 


Context: As the number of head-and-neck cancer (HNC) patients are high in our subcontinent, the study was designed to reduce the treatment time and increase efficacy.
Aims: Comparative evaluation of the efficacy, toxicity, local control, and survival of concomitant boost radiotherapy (CBRT), CBRT with concurrent chemoradiation (CBRT + CCT) and conventionally fractionated radiotherapy with concomitant chemotherapy (CFRT + CCT) in locally advanced HNC (LAHNC).
Materials and Methods: Patients with LAHNC were randomly assigned to 3-groups of 30-patients each. Group I (CBRT) received, 45 Gy/25#/5-weeks and 18 Gy/10# concomitant boost in the last 2-week of treatment, receiving a total dose of 63 Gy. Group II (CBRT + CCT) received CBRT with concomitant cisplatin 75 mg/m 2 on day 1, 17, and 34. Group III (CFRT + CCT) received 64 Gy/32#/6.2 weeks, concurrent with injection cisplatin 75 mg/m 2 on day 1, 22, and 42.
Statistical Analysis Used: Stata 9.0 SPSS and Chi-square test were used for analysis and disease-free survival (DFS) rates were calculated using the Kaplan–Meier method.
Results: The median follow-up period was 8.2 months. At last follow-up, locoregional control was 36%, 57%, and 40% and DFS was seen in 33%, 53%, and 40% of patients in Group I, II, and III, respectively. Grade-3 cutaneous reactions were significantly higher in Group-II as compared to that of Group-III (P = 0.033) and Group-I (P = 0.715).
Conclusion: All three groups have similar response rates and DFS with manageable toxicity.

Keywords: Accelerated hyperfractionation with concomitant boost, concomitant boost RT with concurrent chemotherapy, conventionally fractionated radiotherapy with concomitant chemotherapy, locally advanced head-and-neck carcinoma



How to cite this URL:
Gupta P, Dhull AK, Kaushal V. A comparative study of concomitant boost radiation versus concomitant boost with concurrent chemoradiation versus standard fractionation chemoradiation in locally advanced head-and-neck cancer. J Can Res Ther [Epub ahead of print] [cited 2019 Oct 14]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=263537




 > Introduction Top


Accelerated fractionation (AF) aims at shortening the overall treatment time using conventional or near conventional dose fractionation. The concomitant boost radiotherapy (CBRT) was designed to shorten overall length of treatment, thereby diminishing the opportunity for accelerated repopulation of clonogenic cells during therapy.[1] In a meta-analysis, the use of concurrent chemotherapy with radiotherapy was the most effective modality with a 5-year absolute survival benefit of 8%.[2] In an attempt to assess the potential integration of these two modalities and to minimize accelerated tumor repopulation, the present study was designed to evaluate the feasibility, efficacy, and toxicity of accelerated hyperfractionation with concomitant boost in locally advanced head-and-neck cancer (LAHNC) with and without concurrent chemotherapy versus conventional chemoradiation.


 > Materials and Methods Top


This randomized prospective study was conducted on 90 previously untreated histopathologically proven Stage III/IV patients of the head-and-neck cancer (HNC) with the Karnofsky Performance Status ≥70. The current study was first approved by the Institutional Review Board. Enrolled patients were randomized in three groups of 30 each by draw of lots. In Group I (CBRT), patients received, 45 Gy in 25 fractions over 5-week and 18 Gy/10 fractions concomitant boost in the last 2 weeks of treatment after a gap of 6 h; thus, total radiation dose of 63 Gy was given. Group II (CBRT + CCT) received CBRT as Group I with concomitant chemotherapy of injection cisplatin 75 mg/m 2 on day 1, 17, and 34 over 5-week treatment. Group III conventionally fractionated radiotherapy (CFRT + CCT) received 64 Gy/32 fractions/6.2 weeks (i.e., 2 Gy/fraction), 5 fractions per week concurrent with injection cisplatin 75 mg/m 2 on day 1, 22, and 42. All the patients were treated in supine position and were treated by parallel opposed fields which covered the primary tumor, disease extension, and neck nodes. The dose was prescribed to the mid plane at the central axis. The second daily fraction dose (boost) was delivered by a reduced field to the primary site or primary site along with massive local extension site only, after 15 fractions, in Group I and Group II. The shrinking field technique was used. The patients presenting with neck nodes, away from the primary disease were treated by low-anterior neck field. In all the patients, radiotherapy was delivered by equinox telecobalt machine.

Radiation reactions were assessed using the radiation therapy oncology group (RTOG) criteria. Acute morbidity scoring criteria were considered from day 1, the commencement of radiation, through day 90 and thereafter, the RTOG criteria for late effects were utilized. Tumor response (both primary and nodal response) was assessed by the WHO response criteria 1 month posttreatment completion. It was done by two consecutive assessments 1 month apart by thorough clinical examination as well as contrast-enhanced computerized tomography of the face and neck in all the patients.

Statistical analysis was carried out using Stata 9.0 (IBM SPSS Statistics version 16.0, Chicago, IL, United States) and variables were compared using Chi-square test/Fisher's exact test, and quantitative characteristics were compared using the Student's t-test for independent samples/Wilcoxon rank sum test.

Disease-free survival (DFS) rates were calculated by the Kaplan–Meier method. Cox proportional hazard regression was used to estimate the hazard ratios with 95% confidence intervals for DFS for each arm.


 > Results Top


The median age (range) at presentation of 90 patients enrolled in our study was 58.1 (33–75) years. Male-to-female ratio was 44:1. Most of the patients in our study were from rural background (85%). Chronic smokers in Group I, II, and III were 93.3%, 96.7%, and 90%, respectively. Other patient characteristics as well as detailed TNM staging and grouping are described in [Table 1] and [Table 2]. Patients who completed intended treatment without interruption and without major morbidity in Group I, II, and III respectively were 86.7%, 83.3%, and 76.7%. In 2 (6.7%), 3 (10%), and 1 (3.3%) patients of Group I, II, and III, respectively, EBRT had to be deferred for 1 week; whereas in 2 patients each of Group I and II and in 4 patients of Group III, RT had to be deferred for 2 weeks. Two patients each in Group II and III could not receive the intended 3rd course of CCRT. Interruption in radical treatment as well as on-time completion of treatment in all the enrolled patients was comparable in all the groups without any significant P (P ≥ 0.05).
Table 1: Patient characteristics

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Table 2: Tumor, node, metastasis staging

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Grade-1 acute cutaneous reactions were observed in 4 (13.3%), 2 (6.67%), and 6 (20%) patients of Group-I, II, and III, respectively. Grade-2 acute cutaneous reactions were seen in 12 (40%) patients in Group I and II, whereas 18 (60%) patients in Group III. Grade-3 acute cutaneous reactions were observed in in 14 (46.7%), 16 (53.3%), and 6 (20%) patients of Group-I, II, and III, respectively. Acute mucosal radiation reactions were as follows: Grade-1: 2 (6.7%), 3 (10%), and 5 (16.7%), Grade-2: 18 (60%), 12 (40%) and 17 (56.7%), and Grade-3: 10 (33.3%), 15 (50%), and 8 (26.7%) patients in Group I, II, and III, respectively. All the acute radiation reactions in Group II were higher than in Group III and I, though the difference was not statistically significant except Grade-3 cutaneous reactions which were significantly higher in Group II as compared to Group-III (P = 0.033), and were higher as compared to Group I though the difference was not statistically significant (P = 0.715).

At the end of treatment, locoregional control is described in [Table 3]. It was similar in all the groups and the difference was not statistically significant. Weight loss was assessed as per southwest oncology group criteria and was observed in 6.7%, 10%, and 6.7% of patients of Group I, II, and III, respectively. In late radiation toxicity, Grade 1 salivary gland toxicity was higher in Group I and II than Group III, i.e., in 10 (33.3%), 8 (26.7%), and 1 (3.3%) patients of Group I, II, and III, respectively and P value of the difference between Group III versus I (P = 0.007) and Group III versus II (P = 0.020) was statistically significant. All other late radiation toxicities are described in [Table 4], and the difference in all other late radiation toxicities on intergroup comparison was not statistically significant.
Table 3: Posttreatment response assessment

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Table 4: Late radiation toxicity

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The follow-up period ranged from 6 to 22.7 months with median period of 8.2 months. Disease status at last follow-up is described in [Table 5]. Locoregional control at last follow-up was documented in 36%, 57%, and 40% of patients of Group I, II, and III, respectively [Table 6]. Patterns of failure at last follow-up are described in [Table 6]. DFS was seen in 33.3%, 53.3%, and 40% of patients in Group I, II, and III, respectively. The survival difference between all the groups was not statistically significant and least DFS was seen in Group I [Table 6]. [Figure 1], [Figure 2], [Figure 3], [Figure 4] shows intergroup comparison of DFS as Kaplan–Meier survival curves.
Table 5: Disease status at last follow-up

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Table 6: Pattern of failure, loco-regional control and disease free survival at last follow-up

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Figure 1: Disease free survival of all three groups. Comparison of disease free survival between Group I, II and III i.e. concomitant boost radiation therapy alone versus concomitant boost radiotherapy with concurrent chemotherapy versus conventionally fractionated radiotherapy with concurrent chemotherapy as Kaplan–Meier survival curves. All the patients were surviving till last follow-up

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Figure 2: Disesase free survival of Group I versus II. Comparison of disease free survival between Group I and II i.e. Concomitant boost radiation therapy alone versus concomitant boost radiotherapy with concurrent chemotherapy

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Figure 3: Disesase free survival of Group I versus III. Comparison of disease free survival between Group I and III i.e. concomitant boost radiation therapy alone versus conventionally fractionated radiotherapy with concurrent chemotherapy

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Figure 4: Disesase free survival of Group II versus III. Comparison of disease free survival between Group II and III i.e. concomitant boost radiotherapy with concurrent chemotherapy versus conventionally fractionated radiotherapy with concurrent chemotherapy

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Hazard ratio in Group I versus II was 0.583 with 95% confidence interval 0.297–1.146, P = 0.110; Group III versus II was 0.651 with 95% confidence interval 0.318–1.334, P = 0.241; Group III versus I was 1.129 with 95% confidence interval 0.586–2.176, P = 0.717 [Table 7]. Although the difference was not statistically significant, but the probability of occurrence of residual/recurrent/uncontrolled disease was least in Group II, i.e., CBRT with concurrent chemotherapy and highest in Group I, i.e., CBRT alone as radical treatment.
Table 7: Residual/recurrent hazard ratio

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 > Discussion Top


Worldwide HNC is the seventh most common type of cancer and constitute 5% of the entire cancers. The global burden of HNC accounts for 650,000 new cases and 350,000 deaths worldwide every year and a major proportion of regional malignancies in India.[3],[4],[5] Majority of the HNC patients, i.e., 92.3% presents as (LAHNC Stage III and IV) and accounts for 22.9% of cancer-related mortality in India.[6],[7] Smoking and alcohol consumption are the strong and independent risk factor responsible for increased risk of HNC.[8],[9]

The principle of AF regimens aims to counteract the proliferation of tumor cells by delivering the same dose in less time using multiple fractions per day. Concomitant boost is one of the ways of AF as described above. In oropharyngeal cancers, a 10-day reduction in overall treatment time to around 5-week is estimated to yield a 10%–15% improvement in local control.[10] Applying the concomitant boost concept, which limits the highest radiation doses to tissues involved with clinically detectable tumor, further facilitates relative sparing of normal tissues, thus permitting dose escalation without enhanced toxicity. The shortening of the treatment course through twice daily irradiation during the latter half of the treatment course aims to counteract accelerated repopulation. The use of fractions of 1.8 Gy result in relative sparing of late-reacting normal tissues.[11]

A landmark study by RTOG 90-03 by Fu et al. compared three fractionation schedules with a standard fractionation schedule and demonstrated improved DFS rates of approximately 8% favoring hyperfractionation and accelerated CBRT over standard fractionation with comparable late toxicity. Patients treated with hyperfractionation and AF with concomitant boost had significantly better local-regional control (P = 0.045 and P = 0.050, respectively) than those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation.[12] Similar studies from the literature were reviewed and have shown the superiority of concomitant boost (CBRT) over conventional fractionation [Table 8].[13],[14],[15],[16]
Table 8: Comparison of different studies with disease response, acute and late skin and mucosal reactions

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In our study, 82% of patients completed the intended treatment without interruption. Local control and DFS was similar in all the groups as the difference was not statistically significant. In terms of both acute and late radiation reactions, almost similar results were seen in all the groups. However, acute cutaneous radiation reactions in the Group-II (CBRT with concurrent chemotherapy group) were significantly higher than other two groups.


 > Conclusion Top


The present three arm study design is the first in medical literature, which has assessed concomitant boost radiotherapy with and without chemotherapy in comparison to conventionally fractionated chemoradiation in terms of locoregional control, disease free survival and toxicity. Thus, we conclude that to expedite the treatment time with radical intent in tertiary care centers, it is recommended to use concomitant boost radiotherapy with concurrent chemotherapy. In those patients having contraindications to chemotherapy, concomitant boost radiotherapy alone is recommended in view of the equivocal results with conventional chemoradiation, however, having benefit of shorter treatment time.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Withers HR, Maciejewski B, Taylor JM, Hliniak A. Accelerated repopulation in head and neck cancer. Front Radiat Ther Oncol 1988;22:105-10.  Back to cited text no. 1
    
2.
Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. MACH-NC collaborative group. Meta-analysis of chemotherapy on head and neck cancer. Lancet 2000;355:949-55.  Back to cited text no. 2
    
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Maasland DH, van den Brandt PA, Kremer B, Goldbohm RA, Schouten LJ. Alcohol consumption, cigarette smoking and the risk of subtypes of head-neck cancer: Results from the Netherlands cohort study. BMC Cancer 2014;14:187.  Back to cited text no. 3
    
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Boing AF, Antunes JL, de Carvalho MB, de Góis Filho JF, Kowalski LP, Michaluart P Jr., et al. How much do smoking and alcohol consumption explain socioeconomic inequalities in head and neck cancer risk? J Epidemiol Community Health 2011;65:709-14.  Back to cited text no. 4
    
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Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. GLOBOCAN 2012 Cancer Incidence and Mortality Worldwide. IARC Cancer Base No. 11. Lyon, France: International Agency for Research on Cancer; 2013.  Back to cited text no. 5
    
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Sharma M, Madan M, Manjari M, Bhasin TS, Jain S, Garg S. Prevalence of head and neck squamous cell carcinoma (HNSCC) IN OUR POPULATION: The clinicopathological and morphological description of 198 cases. Int J Adv Res 2015;1:827-33.  Back to cited text no. 6
    
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Dikshit R, Gupta PC, Ramasundarahettige C, Gajalakshmi V, Aleksandrowicz L, Badwe R, et al. Cancer mortality in India: A nationally representative survey. Lancet 2012;379:1807-16.  Back to cited text no. 7
    
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Dhull AK, Atri R, Dhankhar R, Chauhan AK, Kaushal V. Major risk factors in head and neck cancer: A Retrospective analysis of 12-year experiences. World J Oncol 2018;9:80-4.  Back to cited text no. 8
    
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Dhull AK, Atri R, Kaushal V, Malik G, Soni A, Dhankhar R, et al. Alcohol as a risk factor in HNC, an enormous toll on the lives and communities. J Evid Based Med Healthc 2016;3:354-60.  Back to cited text no. 9
    
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Bataini JP, Asselain B, Jaulerry C, Brunin F, Bernier J, Pontvert D, et al. A multivariate primary tumour control analysis in 465 patients treated by radical radiotherapy for cancer of the tonsillar region: Clinical and treatment parameters as prognostic factors. Radiother Oncol 1989;14:265-77.  Back to cited text no. 10
    
11.
Withers HR, Peters LJ, Taylor JM. Dose-response relationship for radiation therapy of subclinical disease. Int J Radiat Oncol Biol Phys 1995;31:353-9.  Back to cited text no. 11
    
12.
Fu KK, Pajak TF, Trotti A, Jones CU, Spencer SA, Phillips TL, et al. A radiation therapy oncology group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas:First report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000;48:7-16.  Back to cited text no. 12
    
13.
Ghoshal S, Goda JS, Mallick I, Kehwar TS, Sharma SC. Concomitant boost radiotherapy compared with conventional radiotherapy in squamous cell carcinoma of the head and neck – A phase III trial from a single institution in India. Clin Oncol (R Coll Radiol) 2008;20:212-20.  Back to cited text no. 13
    
14.
Allal AS, Taussky D, Mach N, Becker M, Bieri S, Dulguerov P, et al. Can concomitant-boost accelerated radiotherapy be adopted as routine treatment for head-and-neck cancers? A 10-year single-institution experience. Int J Radiat Oncol Biol Phys 2004;58:1431-6.  Back to cited text no. 14
    
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MacKenzie R, Balogh J, Choo R, Franssen E. Accelerated radiotherapy with delayed concomitant boost in locally advanced squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1999;45:589-95.  Back to cited text no. 15
    
16.
Rishi A, Ghoshal S, Verma R, Oinam AS, Patil VM, Mohinder R, et al. Comparison of concomitant boost radiotherapy against concurrent chemoradiation in locally advanced oropharyngeal cancers: A phase III randomised trial. Radiother Oncol 2013;107:317-24.  Back to cited text no. 16
    


    Figures

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