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Hypofractionated radiotherapy versus conventional radiotherapy in early glottic cancer T1-2N0M0: A randomized study


1 Department of Radiation Oncology, Acharya Tulsi Regional Cancer Treatment and Research Institute, S. P. Medical College, Bikaner, Rajasthan, India
2 Department of Radiation Oncology, Acharya Tulsi Regional Cancer Treatment and Research Institute, Bikaner, Rajasthan, India

Date of Submission25-Oct-2019
Date of Decision16-Dec-2019
Date of Acceptance22-Apr-2020
Date of Web Publication28-May-2021

Correspondence Address:
Shankar Lal Jakhar,
Department of Radiation Oncology, Acharya Tulsi Regional Cancer Treatment and Research Institute, Bikaner - 334 001, Rajasthan
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_867_19

 > Abstract 


Objective: Glottic cancer has an excellent probability of cure. The early glottic cancer is usually treated by radiotherapy with different fractionation schedules. The aim of this study was to compare conventional versus hypofractionated radiotherapy with respect to overall survival and disease-free survival.
Materials and Methods: A total of fifty patients with T1-2N0M0 glottic cancer with no previous treatment history were prospectively randomized into two arms. In Arm A (Study), patients received a total of 55 Gy in 20# at 2.75 Gy/#, 5 days a week. In Arm B (Control), patients received a total of 66 Gy in 33# at 2 Gy/#, 5 days a week. Disease response was evaluated by the WHO criteria at the end of treatment, then at 1, 2, and 3 months to complete their 6-month follow-up. Overall survival and disease-free survival were evaluated at 1, 2, and 3 years.
Results: Overall, 100% of patients in the study arm and 96% of patients in the control arm had complete response after 6 months. Overall survival rates at 1, 2, and 3 years were 96%, 96%, and 88%, respectively, in the study arm, while in the control arm, these values were 92%, 84%, and 80%, respectively, and the difference was not statistically significant (P > 0.05). Disease-free survival at 3 years was 88% in the study arm and 80% in the control arm.
Conclusion: The study suggests that hypofractionated regimen may be better in local control and symptomatic relief with the added advantage of shorter treatment time, which offers better patient compliance and advantageous in busy setups where there is heavy patient load.

Keywords: Conventional, glottic carcinoma, hypofractionated, overall survival, radiotherapy



How to cite this URL:
Kachhwaha A, Jakhar SL, Syiem T, Sharma N, Kumar HS, Sharma A. Hypofractionated radiotherapy versus conventional radiotherapy in early glottic cancer T1-2N0M0: A randomized study. J Can Res Ther [Epub ahead of print] [cited 2021 Jun 22]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=317068




 > Introduction Top


Cancer of the larynx represents about 2% of the total cancer risk; about 51% of the cases remain localized, 29% have regional spread, and 15% have distant metastasis.[1]

Laryngeal cancer remains a common head-and-neck cancer, with 3580 cases diagnosed within the UK in 2016. At our institute, there were 247 cases of laryngeal cancer out of 6942 cases registered in 2016, accounting for 3.5% of total malignancies.

Laryngeal cancer is mainly a disease of middle-aged and elderly men with peak incidence during the seventh decade of life. Women appear to be affected earlier in life than men, and the proportion of women is higher in younger age group.[2],[3]

The vocal cords (glottis) are the most commonly involved subsite, representing approximately 75% of larynx carcinoma.[4] Glottic carcinoma commonly presents early, and unlike many other head-and-neck cancer subsites, the paucity of lymphatic drainage in the glottis mucosa conveys a low risk of lymphatic dissemination.[5]

The aim of treatment for early glottic carcinoma is generally cure with larynx preservation and adequate/good voice quality. Definitive radiotherapy and transoral laser resection are both widely employed, with the choice depending on tumor factors including involvement of one or both cords, anterior commissure involvement, physician choice and expertise, and patient preference. Reviews of the outcomes of radiotherapy and laser resections suggest comparable local control and survival with similarly low risks of major complications.[5],[6],[7] In the modern era, open partial laryngectomies are usually reserved to salvage local recurrences, which remain suitable for laryngeal preservation.[8]

A wide range of radiotherapy dose-fractionation schedules have been employed for the treatment of early glottic carcinoma.[9],[10],[11],[12],[13],[14] Recommended schedules included 64–70 Gy in daily 2 Gy fractions over 6.5–7 weeks, 54–55 Gy in 20 daily fractions over 4 weeks, and 50–52.5 Gy in 16 daily fractions over 3 weeks for small-volume disease only.[15] Hypofractionation to minimize the potential for tumor repopulation during radiotherapy is particularly appealing for early larynx in view of small field sizes, potentially allowing larger doses per fraction without excessive late morbidity.[11]

Aims

The aim of this study was to compare the efficacy and safety of two fractionation schedules of radiotherapy in early-stage carcinoma vocal cord. The primary endpoint is overall survival and disease-free survival.


 > Materials and Methods Top


This was a randomized prospective study conducted at Acharya Tulsi Regional Cancer Treatment and Research Institute, Sardar Patel Medical College, and associated group of hospitals, Bikaner.

The study protocol included fifty histologically proven new cases of early glottic cancer of T1-2N0M0 stage, who were enrolled from January 2014 to August 2015.

Inclusion criteria

  1. Age <70 years
  2. ECOG 0–2
  3. No previous history of malignancy-oriented treatment
  4. Adequate baseline organ functions (hematological, renal function test, liver function test, and others)
  5. Baseline computed tomography scan/magnetic resonance imaging head and neck was done to exclude node involvement and for tumor extension.


Exclusion criteria

  1. Distant metastasis
  2. Other concurrent malignancies
  3. History of previous treatment with any of the following modalities – surgery, radiotherapy, and chemotherapy
  4. Pregnant and lactating women.


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

Fifty patients who fit the inclusion criteria were randomized to two groups of 25 each by using the website (http:/www.randomisation.com). The groups are shown in [Figure 1].
Figure 1: Hierarchy showing the two arms

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  1. Hypofractionated radiotherapy as the study arm
  2. Conventional radiotherapy as the control arm.


Biological effective dose (BED) of the hypofractionated arm was compared with that of the conventional arm.

BED = Nd (1 + d/[alpha/beta])

Where N is the total number of doses and d is dose per fraction. In laryngeal carcinoma, alpha/beta for early reactions is 10 and late reactions is 3 [Table 1].
Table 1: BED calculation

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Treatment with radiation therapy was given using Cobalt-60 energy source on Theratron 780 E/780 C, Bhabhatron II, or by using a 6 MV photon beam on linear accelerator. Patients were not randomized for the allotted machines. Field size taken was 5 cm × 5 cm or 6 cm × 6 cm. The treatment field size was not reduced or increased at any time during the treatment period. Patients were observed on a weekly basis during the course of treatment for acute toxicity. Disease response and radiation toxicity were assessed at the end of radiotherapy, 1st month, 3rd month, and 6th month, and then yearly at 1, 2, and 3 years. Patients were examined by direct and indirect laryngoscopy, assessed for local response using the WHO criteria and toxicities using RTOG guidelines. P < 0.05 was considered statistically significant.


 > Results Top


Patient characteristics [Table 2], treatment response [Table 3], and toxicities [Table 4] are shown in tabulated format.
Table 2: Patient characteristics

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Table 3: Treatment response at the 6th month

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Table 4: Late toxicities

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From the evaluation of fifty patients for treatment response by the WHO criteria, 25 patients in the study arm and 24 patients in the control arm had complete response at the end of treatment, 1-patient had partial response at end of treatment and 1st month follow-up then lost to follow-up. Overall survival rates at 1, 2, and 3 years were 96%, 96%, and 88%, respectively, in the study arm, while in the control arm, those values were 92%, 84%, and 80%, respectively, and not statistically significant (P > 0.05). Disease-free survival at 3 years was 88% in the study arm and 80% in the control arm.

Toxicities

There was no statistical difference in the grades of toxicities. At the end of 3 years, laryngeal edema ranged from Grade I to II. Grade II edema was 44% and 52%, respectively, in the study and control arm (χ2 = 0.762, P = 0.383). Hoarseness of voice was mainly Grade I–II. Grade II hoarseness was 64% versus 68% in the study and control arm, respectively (χ2 = 0.000, P = 1.000). Dysphagia ranged from Grade 0 to II. Grade II dysphagia was seen in 4% versus 8% patients (χ2 = 3.125, P = 0.210).


 > Discussion Top


Glottic cancer is the most common laryngeal cancer with curative intent. Literature supports that the most common age of presentation is at the sixth to seventh decade of life, with a median age of 54 years.[2],[3] In our study, males were 94% and females were 6%, which is in accordance to literature finding of M:F ratio of 4:1 to 20:1.[16]

In the present study, 100% of patients were histologically proven of squamous cell carcinoma, of which the most common is moderately differentiated carcinoma.

The main complaint at presentation given by 88% of patients was hoarseness and 12% complained of hoarseness and dysphagia in this study.

In this study, 56% of patients had anterior commissure involvement, in which one patient in the control arm had a partial response. Le et al. stated that 5-year local control was 80% for patients with AC involvement and 88% for those without.[11]

Cigarette/bidi smoking was the most common associated habit (80%) of the patients in our study. Browman et al., in their study, concluded that patients with head-and-neck cancer who continued to smoke during treatment had reduced response to radiation.[17] Gowda et al. found that severe late radiation complication was seen in only one patient who continued to smoke heavily after treatment.[14]

The choice of treatment modality usually depends on T-stage, anterior commissure involvement, preference of the patient and physician, and general status of the patient. For early glottic cancer, treatment options include open partial laryngectomy, transoral laser excision, and radiotherapy. However, radiotherapy is generally preferred over surgery due to organ preservation.

Of the total fifty patients that were enrolled for the study, 25 patients were subjected to receive radiotherapy of 55 Gy total dose, 2.75 Gy/#, 5 days a week and 25 patients of 66 Gy total dose, 2 Gy/#, 5 days a week. Patients in the study arm completed their treatment in a range of 27–30 days, whereas those in the control arm in a range of 47–51 days. Literature reports that overall treatment time affects local control.[11]

In our study, 100% of patients showed local control in the study arm and 96% in the control arm within the follow-up period of 6 months. Overall survival rates at 1, 2, and 3 years were 96%, 96%, and 88%, respectively, in the study arm, whereas in the control arm, those values were 92%, 84%, and 80%, respectively, and statistically not significant. Disease-free survival at 3 years was 88% in the study arm and 80% in the control arm.

Jamshed et al. in their study of T1 cancer with hypofractionated radiotherapy reported local control rate at 5 years of 91% and 5-year overall survival of 86%.[18]

Late toxicity occurs in the form of laryngeal edema, hoarseness of voice, and dysphagia. There was no statistical difference in grades of toxicities, in our study. At the end of 3 years, laryngeal edema ranged from Grade I to II. Grade II edema was 44% and 52%, respectively, in the study and control arms. Hoarseness of voice was mainly of Grade I to II. Grade II hoarseness was 64% versus 68% in the study and control arms, respectively. Dysphagia ranged from Grade 0 to II. Grade II dysphagia was seen in 4% versus 8% patients. This is in correspondence to literature.

Khan et al. reported in their 5-year study of early glottis cancer by hypofractionated radiotherapy that chronic laryngeal edema and chronic dysphagia were observed in 18.4% and 6.4% of cases, respectively.[19]


 > Conclusion Top


From this prospective, randomized, single-institutional study, both regimens were found to be safe with high local control rates and acceptable long-term toxicities. However, the hypofractionated regimen is slightly superior in local control and symptomatic relief with the added advantage of shorter treatment time, which offers better patient compliance. In busy setups where there is heavy patient load in the outpatient department and machines, a hypofractionated regimen may be recommended.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
William MM, Anthony AM, Robert JA, Brian JB, Peter TD. Perez and Brady's Principles and Practice of Radiation Oncology. 6th ed. 2018;2:852-3.  Back to cited text no. 1
    
2.
Rothman KJ, Cann CI, Flanders D, Fried P. Epidemiology of laryngeal cancer. Epidemiol Rev 1980;2:195-209.  Back to cited text no. 2
    
3.
Robin PE, Reid A, Powell DJ, McConkey CC. The incidence of cancer of the larynx. Clin Otolaryngol 1991;16:198-201.  Back to cited text no. 3
    
4.
Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin 2012;62:10-29.  Back to cited text no. 4
    
5.
Mendenhall WM, Werning JW, Hinerman RW, Amdur RJ, Villaret DB. Management of T1-T2 glottic carcinomas. Cancer 2004;100:1786-92.  Back to cited text no. 5
    
6.
Luscher MS, Pedersen U, Johansen LV. Treatment outcome after laser excision of early glottic squamous cell carcinoma--a literature survey. Acta Oncol 2001;40:796-800.  Back to cited text no. 6
    
7.
Delsupehe KG, Zink I, Lejaegere M, Bastian RW. Voice quality after narrow-margin laser cordectomy compared with laryngeal irradiation. Otolaryngol Head Neck Surg 1999;121:528-33.  Back to cited text no. 7
    
8.
Mendenhall WM, Mancuso AA, Hinerman RW, Malyapa RS, Werning JW, Amdur RJ, et al. Multidisciplinary management of laryngeal carcinoma. Int J Radiat Oncol Biol Phys 2007;69 Suppl 2:S12-4.  Back to cited text no. 8
    
9.
Mendenhall WM, Amdur RJ, Morris CG, Hinerman RW. T1-T2N0 squamous cell carcinoma of the glottic larynx treated with radiation therapy. J Clin Oncol 2001;19:4029-36.  Back to cited text no. 9
    
10.
Yamazaki H, Nishiyama K, Tanaka E, Koizumi M, Chatani M. Radiotherapy for early glottic carcinoma (T1N0M0): Results of prospective randomized study of radiation fraction size and overall treatment time. Int J Radiat Oncol Biol Phys 2006;64:77-82.  Back to cited text no. 10
    
11.
Le QT, Fu KK, Kroll S, Ryu JK, Quivey JM, Meyler TS, et al. Influence of fraction size, total dose, and overall time on local control of T1-T2 glottic carcinoma. Int J Radiat Oncol Biol Phys 1997;39:115-26.  Back to cited text no. 11
    
12.
Trotti A 3rd, Zhang Q, Bentzen SM, Emami B, Hammond ME, Jones CU, et al. Randomized trial of hyperfractionation versus conventional fractionation in T2 squamous cell carcinoma of the vocal cord (RTOG 9512). Int J Radiat Oncol Biol Phys 2014;89:958-63.  Back to cited text no. 12
    
13.
Cheah NL, Lupton S, Marshall A, Hartley A, Glaholm J. Outcome of T1N0M0 squamous cell carcinoma of the larynx treated with short-course radiotherapy to a total dose of 50 Gy in 16 fractions: The Birmingham experience. Clin Oncol (R Coll Radiol) 2009;21:494-501.  Back to cited text no. 13
    
14.
Gowda RV, Henk JM, Mais KL, Sykes AJ, Swindell R, Slevin NJ. Three weeks radiotherapy for T1 glottic cancer: The Christie and Royal Marsden Hospital experience. Radiother Oncol 2003;68:105-11.  Back to cited text no. 14
    
15.
Kim RY, Marks ME, Salter MM. Early stage glottis cancer: Importance of dose fractionation in radiation therapy. Radiology 1992;182:273-5.  Back to cited text no. 15
    
16.
Stephenson WT, Barnes DE, Holmes EF, Norris CW. Gender influences subsite or origin of laryngeal carcinoma. Arch Otolaryngol Head Neck Surg 1991;117:774-8.  Back to cited text no. 16
    
17.
Browman GP, Wong G, Hodson I, Sathya J, Russel R, McAlpine L, et al. Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 1993;328:159-63.  Back to cited text no. 17
    
18.
Jamshed A, Hussain R, Jamshed S, Iqbal H, Hameed N, Ali M, et al. Hypofractionated radiotherapy in the treatment of early glottic carcinoma: Int Sci J 2011;1069-71.  Back to cited text no. 18
    
19.
Khan MK, Koyfman SA, Hunter GK, Reddy CA, Saxton JP. Definitive radiotherapy for early (T1-T2) glottis squamous cell carcinoma: A 20 year Cleveland clinic experience. Radiat Oncol 2012;7:193-200.  Back to cited text no. 19
    


    Figures

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    Tables

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



 

 
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