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ORIGINAL ARTICLE
Year : 2019  |  Volume : 12  |  Issue : 5  |  Page : 391-397  

A study of response to concurrent chemoradiotherapy as primary mode of management for the patients with laryngeal and hypopharyngeal squamous cell carcinoma and correlation of human papillomavirus status


1 Department of Surgery, Burdwan Medical College and Hospital, Burdwan, West Bengal, India
2 Department of Physiology, Rampurhat Government Medical College and Hospital, Rampurhat, West Bengal, India

Date of Submission08-Aug-2018
Date of Acceptance04-Feb-2019
Date of Web Publication19-Sep-2019

Correspondence Address:
Arunima Chaudhuri
Krishnasayar South, Borehat, Burdwan - 713 102, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.mjdrdypu_127_18

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  Abstract 


Background: Successful outcome of concurrent chemotherapy and radiotherapy as organ-preserving protocol in the management of locally advanced laryngeal and hypopharyngeal carcinomas may be a better-accepted modality of management of patients for preservation of the unique functions of the vital organs of communication and deglutition. Aims: The aim of the study is to observe the role of concurrent chemotherapy and radiotherapy as organ-preserving protocol in the management of locally advanced laryngeal and hypopharyngeal carcinomas taking into account the status of human papillomavirus (HPV) in such cases with outcome in a population of Eastern India. Materials and Methods: This cross-sectional observational study was conducted on 73 individuals in Eastern India after taking institutional ethical clearance and informed consent of the individuals in a period of 1 year. Concurrent chemoradiation therapy (CCRT) was the primary mode of treatment. Results: About 49.3% of the patients were smokers and 53.4% were alcoholic. All the patients had squamous cell carcinoma. About 46.6% of the patients had positive HPV in tissue. About 47.9%, 34.2%, and 17.8% of the patients had complete, partial, and no response to the primary treatment after CCRT, respectively. For larynx proportion of complete response was significantly higher for HPV-positive cases (46.2%) as compared to HPV-negative case (19.2%) (P < 0.01). About 22.2% and 11.8% recurrence were found in the hypopharynx and larynx, respectively. Salvage surgery for primary site was performed for 78.4% in the hypopharynx and 56.3% for larynx. The organ was preserved for 29.8% for hypopharynx and 57.7% for larynx during the total follow-up period. Conclusions: HPV was found in tissue of laryngeal and hypopharyngeal squamous cell carcinoma. The response of advanced hypopharyngeal carcinoma to CCRT was the best mode of treatment, as far as the organ preservation was concerned, while the organ preservation rate for advanced laryngeal carcinoma treated with CCRT was found to be a better option of treatment.

Keywords: Carcinoma, human papillomavirus, methods of treatment


How to cite this article:
Sarkar SK, Chaudhuri A. A study of response to concurrent chemoradiotherapy as primary mode of management for the patients with laryngeal and hypopharyngeal squamous cell carcinoma and correlation of human papillomavirus status. Med J DY Patil Vidyapeeth 2019;12:391-7

How to cite this URL:
Sarkar SK, Chaudhuri A. A study of response to concurrent chemoradiotherapy as primary mode of management for the patients with laryngeal and hypopharyngeal squamous cell carcinoma and correlation of human papillomavirus status. Med J DY Patil Vidyapeeth [serial online] 2019 [cited 2019 Oct 22];12:391-7. Available from: http://www.mjdrdypv.org/text.asp?2019/12/5/391/267073




  Introduction Top


Laryngeal carcinoma may occur in glottis in 60% cases, supraglottic area in 35% cases, and remaining cases in subglottic regions.[1] The American Cancer Society's [2] estimation of laryngeal carcinoma in 2012 was 12,360 (9840 in men and 2520 in women). Sixty percent of global incidence of cancer of the larynx is seen in developing countries. In India, the incidence is 1.3–8.8/1 lakh population.[3]

The American Cancer Society estimated in 2012 twenty-four hundred new cases of hypopharyngeal carcinomas.[2] In India, nearly 40,000 cases of oropharyngeal and hypopharyngeal cancers representing 31% of global cases and 29,000 cases of laryngeal cancers (18% of global cases) occur every year.[4]

Apart from smoking, alcohol, and chronic anemia as factors for causation of hypopharyngeal carcinoma, human papillomavirus (HPV), mainly 16 and to a less extent HPV-18, is associated with laryngeal and hypopharyngeal cancer in a significant number of cases.[5],[6],[7],[8],[9]

HPV is found in as many as 20% cases of normal larynx mucosa as has been found in autopsy examination. The prevalence of HPV in laryngeal squamous cell carcinoma is highly varied from 3% to 47% in case–control study series and 0% to 100% in case series.[10],[11],[12],[13] In hypopharyngeal carcinoma, HPV is found almost in the same frequency.[12]

Larynx and hypopharynx are two important organs meant for phonation and deglutition, respectively. Air conduction and prevention of aspiration are also important functions subserved by intact laryngeal mechanism. Treatment of both organs is usually discussed together in relation to cancer as both are close to each other and share almost same symptoms. They are affected in majority of cases by squamous cell carcinoma, shared common etiological association (tobacco, alcohol, and HPV), required almost the same diagnostic workup, and managed in early cases of both by organ-preserving surgery/radiation with comparable results. Locally advanced cancer management in both cases earlier was organ ablation surgery that was potentially morbid and involved sacrifice of phonation and deglutition.[13],[14],[15],[16]

Concurrent chemoradiation therapy (CCRT) came as an alternative mode of management in locally advanced laryngeal and hypopharyngeal cancers in significant number of cases with anatomical and functional organ preservation as reported by Forastiere et al.[14]

The aim of the present cross-sectional study was to observe the role of concurrent chemotherapy and radiotherapy as organ-preserving protocol in the management of locally advanced laryngeal and hypopharyngeal carcinomas taking into account the status of HPV in such cases with outcome in a population of Eastern India. Successful outcome may be a better-accepted modality of the management of patients for preservation of the unique functions of the vital organs of communication and deglutition.


  Materials and Methods Top


This cross-sectional observational study was conducted on 73 individuals at Chittaranjan National Cancer Institute, Kolkata, after taking institutional ethical clearance and informed consent of the individuals in a period of 1 year. Individuals were randomly chosen from outdoor of the hospital using an online randomizer.

Inclusion criteria

  1. T3N0M0, T3N1M0 laryngeal and hypopharyngeal carcinomas (Stage III)
  2. T4aN0M0, T4aN1M0 laryngeal and hypopharyngeal carcinomas (Stage IV)
  3. Positive biopsy report from primary carcinoma
  4. Squamous cell carcinoma cases
  5. Performance status in Karnofsky scale >60
  6. Only treatment naive cases
  7. Patients ready to undergo salvage surgery following failure of CCRT.


Exclusion criteria

  1. Low-performance status <60 in Karnofsky scale
  2. Large nodal disease of N2 or more
  3. High-volume T4 disease of larynx involving >1 cm of invasion of the base of the tongue or tumor penetration of thyroid cartilage into soft tissues
  4. Primary case less than T3
  5. Postcricoid hypopharyngeal growth
  6. Patients who did not like to be treated with salvage surgery should CCRT fail
  7. Patients already treated in some other center for this condition was not included in the study
  8. Renal failure and patients sensitivity to platinum were excluded from the study.


The section written under “Diagnosis” is standard everywhere and need not be written here in extensive form. Similarly, the authors need not to describe in detail the “treatment rendered,” as these protocols are widely accepted and practiced.

Diagnosis was made based on the following:[13],[14],[15],[16],[17]

  1. History
  2. Clinical examination
  3. Ultrasonographic examination of the neck for nodal enlargement and involvement of thyroid gland and soft tissue of the neck
  4. Computed tomography (CT)/magnetic resonance imaging scan of the larynx, pharynx, and neck
  5. Chest X-ray posteroanterior
  6. Ultrasonography (USG) examination of the abdomen.
  7. In relevant cases, positron emission tomography CT (PET-CT) was done.


Diagnosis was confirmed by “Direct Laryngoscopic examination” under general anesthesia in operation theater with punch biopsy from the primary lesion in the larynx or hypopharynx. Part of the tissue was directly sent to the laboratory immediately for HPV detection and rest of the tissue was sent for histopathological examination. Five milliliters of venous blood sample after being clotted was also sent to the laboratory for detection of HPV in blood. All T4 lesions and T3 cases with vocal cord involvement were subjected to tracheostomy.

Classical tumor, node, and metastasis (cTNM) staging was done and based on the opinion from tumor board conforming to the inclusion and exclusion criteria patients were selected for CCRT.

Speech assessment was done at the beginning and in subsequent follow-up and graded as (a) normal (when clearly audible), (b) impaired (when audible but not distinct and also difficult to recognize over telephone), (c) whispering at the beginning and in subsequent follow-up.

Swallowing function was assessed and graded as able to take (a) solid, (b) semisolid, (c) liquid only, and (d) tube dependent at the beginning and in subsequent follow-up.

Human papillomavirus detection methods

  1. Microdissection and tumor enrichment cell
  2. DNA isolation from tissue and blood
  3. HPV detection and HPV16/18 typing.


Similarly, the authors need not to describe in detail the “treatment rendered,” as these protocols are widely accepted and practiced.

Treatment rendered

The patients were transferred to the Radiotherapy Department for CCRT.

Response assessment

Methodology for assessment was as follows:

  1. Noting change of speech quality, swallowing function, and decannulation tolerability from tracheostomy at the end of 3 months of institution of therapy
  2. Palpation of the neck and fiber-optic laryngoscopic examination of the oral cavity, pharynx, and larynx for the presence of lesion and also noting vocal cord movement, etc.
  3. CT scan examination of the neck mostly to note change of size of lesion
  4. Ultrasonographic (7.5–10 MHz) examination of the neck for the assessment of nodal response (size, shape, echogenicity, and vascularity). USG-guided fine-needle aspiration cytology (FNAC) was done for confirmation of nodal persistence. In case of any doubt with cytology, report of PET-CT scan using 18-fluorodeoxyglucose as tracer was taken as a final parameter for persistence.


Response designated as complete response (CR) when no lesion was found, partial response (PR) when primary lesion regressed but persisted, and no response (NR) when the lesion persisted as earlier. This response assessment was done 6 weeks after completion of treatment, i.e., at the end of 12 weeks of institution of treatment to allow sufficient time for regression of edema. Otherwise, assessment might come erroneous.

Follow-up

Total no of cases: 73 (larynx – 26 and hypopharynx – 47).

Nodal persistence was 9 (larynx – 5 and hypopharynx – 4).

CR to CCRT of the primary was 35 (larynx – 17 and hypopharynx – 18).

Nodal persistence was considered within 35 CR group as organ preservation was possible through modified radical neck dissection (MRND) only. Of the 9 persistent enlarged nodal group identified by USG of the neck, 7 reported positive for metastasis when subjected to USG-guided FNAC. Reports of two patients were inconclusive. These two patients were positive 8 weeks after completion of CCRT among all 35 cases in PET-CT. Hence, all 9 cases were put for bilateral MRND operations and postoperative biopsy in all 9 cases reported metastatic deposits. Subsequently, 4 and 2 hypopharyngeal and laryngeal carcinoma cases initially clinically and on PET-CT investigation and biopsy proved to have recurrent lesions and the timing of recurrence was between 12 and 18 months of CCRT. All three modalities were found to be same in terms of confirmation of recurrence.

It was done 3 monthly for the first year and then 6 monthly for the next year. All patients underwent reassessment 12-week posttreatment and no discrepancy was noted between clinical assessment and PET-CT assessment.

Methodology followed was as follows:

  1. Noting change of speech quality, swallowing function, and decannulation tolerability from tracheostomy
  2. Palpation of the neck and laryngoscope examination (Fiberoptic) of the oral cavity, pharynx, and larynx for the presence any lesion and also noting vocal cord movement, etc.
  3. CT scan examination of the neck
  4. Ultrasonogram of the neck done specially for detection of lymph nodal involvement.
  5. For any suspected recurrence, the help of PET-CT was taken
  6. Systemic examination in all follow-up cases was done and recurrent lesion of primary was confirmed by histopathological examination of the tissue
  7. Nodal recurrence was confirmed by USG-guided FNAC from the suspected node.


Data analysis

The computer software “Statistical Package for the Social Sciences (SPSS) version 16 (SPSS Inc., SPSS for Windows, Version 16.0. Chicago, USA)” was used in this study to analyze the data, P < 0.05* was considered as significant and P < 0.01** was considered as highly significant.


  Results Top


The mean age of the patients was 51.97 ± 8.61 years, and the proportion of the patients in the age group 45–54 years (53.4%) were significantly higher than other age group (Z = 2.95; P < 0.01) [Table 1]. Sixty-four participants were male and rest females. Seventy participants were married. Fifty participants were Hindu, twenty Muslim, and three Christian. About 38.3% were agricultural workers, followed by laborer (28.8%) and office workers (24.7%). Patients were having level of education as follows: up to primary school (27.4%), illiterate (24.7%), middle-school level (19.2%), high-school level (17.8%), and graduate (11.0%).
Table 1: Age distribution of the patients

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Data need to be presented in a tabular form so as to make it more clear to grasp and understand. In the present format, it appears to be confusing.

Only 5.5% of the patients were having family history of larynx/hypopharynx cancer [Table 2].
Table 2: Family history of larynx/hypopharynx cancer of the patients

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About 49.3% of the patients were having habit of smoking and 42.5% of them had never smoked [Table 3].
Table 3: Habit of smoking of the patients

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About 53.4% of the patients were having habit of drinking of alcohol. Nearly 56.2% patients had hoarseness of voice and 43.8% dysphagia and the proportion was significantly higher (Z = 4.99; P < 0.01) as compared to other symptoms such as otalgia, cough, and foreign body sensation in throat [Table 4].
Table 4: Chief complaints at presentation of the patients

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Proportion of patient with cancer in hypopharynx (64.4%) was significantly higher than larynx (35.6%); (Z = 3.47; P < 0.01). Proportion of patients with subsite as pyriform sinus (56.2%) was significantly high (Z = 4.24; P < 0.01), followed by the glottis (21.9%) and supraglottic regions (13.7%). Only 8.2% of the patients had cancer in posterior pharyngeal wall [Table 5].
Table 5: Primary site of cancer

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Most of the patients had TNM classification as T3N0M0 (34.2%) and had their cancer with composite Stage at III (57.5%). In hypopharynx, 53.2% and 46.8% were with Stage-III and Stage-IVa, respectively, while in the larynx, 65.4% and 34.6% were with Stage-III and Stage-IVa, respectively [Table 6].
Table 6: Tumor, node, and metastasis classification of cancer of the patients

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All the patients had squamous cell carcinoma. Among the histopathological grading, 28.8% were well differentiated, 21.9% were poorly differentiated, and 49.3% were moderately differentiated. About 46.6% of the patients had positive HPV in tissue. In hypopharynx, 38.3% and 61.7% were with HPV positive and HPV negative, respectively. In larynx, 61.5% and 38.5% were HPV positive and HPV negative, respectively.

All the patients whose blood samples were tested for HPV were found to be HPV negative. Out of 34 HPV-positive cases, 2 (5.9%) were HPV-18 and 31 (94.1%) were HPV-16. All the HPV-18 cases were found in laryngeal carcinoma. Most of the patients had Karnofsky Index between 60 and 80 and only 4.1% had Karnofsky Index of 90 [Table 7].
Table 7: Karnofsky Index of the patients

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About 47.9%, 34.2%, and 17.8% of the patients had CR, PR, and NR to the primary treatment after CCRT. In hypopharynx, 38.3%, 40.4%, and 21.3% had CR, PR, and NR to the primary after CCRT. In larynx, 65.4%, 2.31%, and 11.5% had CR, PR, and NR to the primary treatment after CCRT. Proportion of CR was significantly higher for larynx (46.2%) in comparison with hypopharynx (19.1%). (Z = 4.08; P < 0.01) [Table 8].
Table 8: Response of primary site to concurrent chemoradiation therapy for human papillomavirus-positive cases

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There was no significant difference with respect to response for both the primary sites for HPV-negative cases (P > 0.05). There was no significant difference in CR with respect to HPV status in hypopharynx (P > 0.05). However, for larynx, proportion of CR was significantly higher for HPV-positive cases (46.2%) as compared to HPV-negative case (19.2%) (P < 0.01). About 22.2% and 11.8% recurrence were found in hypopharynx and larynx, respectively. About 14.3% and 21.4% recurrence rate were found in HPV positive and negative, respectively. About 22.2% and 8.3% recurrence were found in HPV-positive cases for hypopharynx and larynx, respectively.

About 22.2% and 20.0% recurrence were found in HPV-negative cases for hypopharynx and larynx, respectively (P > 0.05). Nearly 25% and 16.7% recurrence were found in HPV-positive cases with habit of smoking for hypopharynx and larynx, respectively. About 20% of recurrences were found in HPV-positive cases without habit of smoking for hypopharynx. However, no recurrence was found for larynx in HPV-positive cases without habit of smoking [Table 9].
Table 9: Recurrence in human papillomavirus-positive cases according to primary sites

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Salvage surgery for primary site was performed for 78.4% of patients in the hypopharynx and 56.3% for the larynx. The organ was preserved for 29.8% for hypopharyngeal and 57.7% for laryngeal carcinoma during total follow-up period (after nodal surgery for persistence nodes and for the CR excluding recurrence cases) [Table 10]a, [Table 10]b, [Table 10]c.


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Nearly 45.7% of the patients had normal speech. Out of 35 patients with CR, 26 (74.2%) had tracheostomy at the beginning of the treatment. Log-rank test showed that there was significant difference in pattern of disease-free survival among the patients with HPV-positive tissue as compared to the patients with HPV-negative tissue. (log-rank test –7.44; P = 0.006).


  Discussion Top


Considering the results obtained in this observational study, a detailed discussion is necessary from different angles for final evaluation of CCRT as the organ-preserving modality in laryngeal and hypopharyngeal cancers particularly after correlation to HPV status. Total 73 cases of T3 and T4 laryngeal and hypopharyngeal cancers were included in the present series.

Only 4 out of 73 patients comprising 5.5% had positive family history of laryngeal/hypopharyngeal cancer in first-degree relatives and 57.5% were smokers. Kulkarni [18] reported the incidence of smoking in 57% and 11% among male and female, respectively, in a study on oral cancer among Indians.

In this observational study, 72.6% of the cases were found to be associated with alcohol ingestion. Prasad [19] stated that about 25% of Indian population are taking alcohol in general, and a point of more concern that the age of alcohol consumption has decreased from 21 years to 13 years.

In the present study, 47 (64.4%) belonged to hypopharyngeal cancer and 26 (i.e., 35.6%) were in laryngeal cancer group. On subsite analysis, it was further found that pyriform sinus was involved primarily in 56.2% of cases and posterior pharyngeal wall in 8.2% cases. Glottic and supraglottic carcinoma represented in 21.9% and 13.7% of the total cases, respectively. This higher incidence of hypopharyngeal carcinoma compared to laryngeal carcinoma is a sharp contrast to the picture in the United States where laryngeal carcinoma is almost four times more common than hypopharyngeal carcinomas.[2],[3],[4]

Of the total number of 73 cases, 34 (46.6%) were positive for HPV in tissue of patients with larynx and hypopharynx carcinoma. Further, it was seen that 16 (61.5%) out of 26 laryngeal cancers and 18 (38.3%) out of 47 hypopharyngeal cases were HPV positive in tissue. In no cases, HPV was detectable from venous sample of blood. HPV-16 was found in 32 out of 34 positive cases comprising 94.1% and HPV-18 was detected in 2 (5.9%) out of 34 positive cases. HPV-18 positive cases were all found in larynx cases.

There is a great variation in the reported prevalence with HPV positivity varying from 3% to 47% in larynx cancer cases as found in many case–control studies.[8],[11],[12],[13]

Very few studies are there with focus on HPV in hypopharynx, and in most such cases, it is as a part for head-and-neck carcinoma, and in these studies, hypopharyngeal cancers were found associated with HPV-16 in 0%–29% of cases.[8],[20],[21],[22] Studies have et al.[23] reported that “High-risk” HPV prevalence, i.e., HPV-16 and HPV-18 in hypopharyngeal carcinoma was as high as 82%. HPV infection is focal [3] at times and occurs mostly in differentiated epithelium. This might be one of the reasons for variable percentage of HPV positivity.[6],[7],[8],[10]

PR and NR to CCRT were seen, respectively, in 34.2% and 17.8% of the total cases of hypopharyngeal and larynx cancers.

Recurrence of the primary lesion was found in follow-up of CR group of hypopharyngeal carcinoma in 4 out of 18 cases representing 22.2% and the same for laryngeal cancer was 2 out of 17 representing 11.8%. Recurrence occurred between 12 and 18 months of institution of CCRT. These patients needed salvage surgery in terms of organ ablation.

A randomized study carried out by Radiation Therapy Oncology Group and the head-and-neck intergroup that became a landmark publication in NEJM in November 2003 where Forastiere et al.[14] had conducted a three-arm study, comparing radiotherapy alone versus neoadjuvant chemotherapy (cisplatinum + 5FU) followed by RT versus concurrent radiotherapy (cisplatinum on days 12,243). It included Stage III and Stage IV cases and excluded T1 and T4 cases that had cartilage erosion or invaded the base of tongue for >1 cm depth. At the end of 2 years, proportion of patients with intact larynx was 70%, 75%, and 88%, respectively.

Chang et al.[24] found in his series with 395 patients of hypopharyngeal carcinoma between 1994 and 2004 that the group treated with CCRT had 44.8% and 27% organ preservation rate at 3 years and 5 years, respectively, whereas the group treated with surgery had 5-year survival of 18.8%.

The less number of organ preservation as seen in the present study may be due to the use of external beam radiotherapy rather than intensity modulated radiation therapy. Geographic difference and also the tumor biology might have contributed to this difference in result.


  Conclusions Top


HPV was found in tissue of laryngeal and hypopharyngeal squamous cell carcinoma but not in venous blood samples of patients in the present study. The response of advanced hypopharyngeal carcinoma to CCRT was the best mode of treatment, as far as the organ preservation was concerned, while the organ preservation rate for advanced laryngeal carcinoma treated with CCRT was found to be a better option of treatment. Recurrence after CCRT was more common in hypopharyngeal carcinoma than laryngeal carcinoma. Recurrence was more frequent in HPV-negative cases than HPV-positive cases as found on overall analysis excepting in smokers.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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García-Milián R, Hernández H, Panadé L, Rodríguez C, González N, Valenzuela C, et al. Detection and typing of human papillomavirus DNA in benign and malignant tumours of laryngeal epithelium. Acta Otolaryngol 1998;118:754-8.  Back to cited text no. 11
    
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Dillner J, Knekt P, Schiller JT, Hakulinen T. Prospective seroepidemiological evidence that human papillomavirus type 16 infection is a risk factor for oesophageal squamous cell carcinoma. BMJ 1995;311:1346.  Back to cited text no. 12
    
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Shaughnessy JN, Farghaly H, Wilson L, Redman R, Potts K, Bumpous J, et al. HPV: A factor in organ preservation for locally advanced larynx and hypopharynx cancer? Am J Otolaryngol 2014;35:19-24.  Back to cited text no. 13
    
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Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091-8.  Back to cited text no. 14
    
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Lambert L, Fortin B, Soulières D, Guertin L, Coulombe G, Charpentier D, et al. Organ preservation with concurrent chemoradiation for advanced laryngeal cancer: Are we succeeding? Int J Radiat Oncol Biol Phys 2010;76:398-402.  Back to cited text no. 15
    
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NCCN Guidelines Version 2. Head and Neck Cancers; 2014. p. 98.  Back to cited text no. 17
    
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Kulkarni MR. Head and neck cancer burden in India. IJHNS 2013;4:29-35.  Back to cited text no. 18
    
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Prasad R. Alcohol use on the rise in India. Lancet 2009;373:17-8.  Back to cited text no. 19
    
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Shunyu NB, Syiemlieh J. Prevalence of head and neck cancer in the state of Meghalaya. Hospital based Study. Int J Head Neck Surg 2013;4:1-5.  Back to cited text no. 20
    
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Chang MF, Wang HM, Kang CJ, Huang SF, Lin CY, Fang KH, et al. Treatment results for hypopharyngeal cancer by different treatment strategies and its secondary primary – An experience in Taiwan. Radiat Oncol 2010;5:91.  Back to cited text no. 24
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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