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  Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 3  |  Page : 402-407
 

Accelerated versus conventional radiation fractionation in early stage carcinoma larynx


1 Department of Radiotherapy, J. N. Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
2 Department of Obstetrics and Gynecology, J. N. Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Date of Web Publication24-Feb-2017

Correspondence Address:
MS Alam
Department of Radiotherapy, J. N. Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.200677

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 » Abstract 

INTRODUCTION: In our study, we have treated cases of early glottic carcinoma by two different dose-fractionation schedules in relation to overall treatment time. MATERIALS AND METHODS: This is an analysis of 29 patients with invasive, previously untreated T1and T2squamous cell carcinoma of true vocal cord that was treated by radical radiation therapy. DOSE AND FRACTIONATION: All patients were treated with a continuous course of radiation therapy with once-daily fractionation. All the patients were treated 5 days a week from Monday to Friday. The fractionation regime was either: (1) 62.5 Gy/25fractions/5 weeks at 2.5 Gy fractions (Regimen 1), (2) 70 Gy/35 fractions/7 weeks at 2 Gy/fraction (Regimen 2). Regimen 1 included 15/29 patients (51.72%) and Regimen 2 included 14/29 patients (48.27%). Patients were evaluated for: (1) Locoregional control, (2) acute and late radiation toxicities, (3) quality of voice. RESULTS AND OBSERVATION: There was no significant difference in terms of locoregional control rate, acute and late radiation toxicities in both groups. Voice quality during and after radiation was comparable in both arms. CONCLUSION: Use of high dose per fraction schedule with shorter duration of treatment results in comparable local control as well as the quality of voice to the protracted course of radiotherapy without increase in treatment-related toxicities. Shorter overall treatment time can be of great advantage in terms of time, cost, comfort, and acceptability by the patients.


Keywords: Accelerated hypofractionated radiation, carcinoma larynx, early glottic cancer, radiation fractionation schedule, radiation therapy


How to cite this article:
Alam M, Perween R, Siddiqui S. Accelerated versus conventional radiation fractionation in early stage carcinoma larynx. Indian J Cancer 2016;53:402-7

How to cite this URL:
Alam M, Perween R, Siddiqui S. Accelerated versus conventional radiation fractionation in early stage carcinoma larynx. Indian J Cancer [serial online] 2016 [cited 2017 May 1];53:402-7. Available from: http://www.indianjcancer.com/text.asp?2016/53/3/402/200677



 » Introduction Top


Carcinoma of the larynx, along with carcinoma of the oral cavity, is the most common primary head and neck malignancy. Laryngeal tumors represent 2% of total cancer risk.[1] Laryngeal cancers are important since it affects organ of voice, and disease, as well as treatment, can alter the functional aspects of the voice. Carcinoma of larynx is strongly related to smoking.[2] Alcohol has synergistic effect if consumed along with smoking. On an average, world statistics quotes the incidence of laryngeal carcinoma as 4–5/lac of population. In India, the population-based registry estimates an annual incidence of nearly 25,000 new cases of laryngeal carcinomas. The incidence of laryngeal cancers in India is 8.5/lac in males and constitutes 7.4% of all cancers in men. The male:female ratio is 4:1. In the Indian subcontinent, supraglottic carcinomas are twice more common compared to glottic carcinomas. Globally, the ratio of glottic to supraglottic carcinoma is approximately 3:1.[1] Laryngeal carcinoma is predominantly a male disease. The male:female ratio is 12:1 for glottic cancer and 4:1 for supraglottic cancers. Our institution records approximately 150 cases of carcinoma larynx in a year. More than two-third of these cases are supraglottic carcinomas. It has been estimated that 70%–80% of the supraglottic carcinoma present in stage III and IV. In the treatment of vocal cord carcinoma, goal is to maximize control rates with voice preservation using radiation therapy and surgery, either alone or in combination. Early stage carcinomas can be treated by radical radiation therapy or in selected cases, by partial laryngectomy or endoscopic CO2 laser cordectomy. The advanced stage disease is treated by combined modality in the form of total laryngectomy and neck dissection with or without adjuvant radiotherapy or by radiation therapy and concomitant chemotherapy.[3],[4]

In our study, we have treated cases of early glottic carcinoma by two different dose-fractionation schedules, i.e., (62.5 Gy in 25 fractions at the rate of 2.5 Gy/fraction and 70 Gy in 35 fractions at the rate of 2 Gy/fraction) in relation to overall treatment time. Use of high dose per fraction schedule with shorter duration of treatment results in comparable local control as well as quality of voice to the protracted course of radiotherapy without increase in treatment-related toxicities.

Aims and objectives

Our study was designed to:

  1. To assess the response of two different fractionation schedules, i.e., (62.5 Gy in 25 fractions at the rate of 2.5 Gy/fraction and 70 Gy in 35 fractions at the rate of 2 Gy/fraction)
  2. To evaluate, locoregional control in relation to total dose, fractionation schedule, dose per fraction, and overall treatment time
  3. To determine certain tumor-related parameters that may influence local control
  4. To analyze early and late toxicities of radiation therapy
  5. To examine the functional quality of voice following radiation therapy and influence of various treatment parameters.



 » Materials and Methods Top


Patient characteristics

This is an analysis of 29 patients with invasive, previously untreated T1 and T2 squamous cell carcinoma of true vocal cord that was treated by radical radiation therapy. All patients were treated with curative intent with a continuous course of radiation therapy with telecobalt. All the patients are alive and are on regular follow-up.

Staging

Pretreatment evaluation included history, physical examination, chest X-ray, complete blood count, fiber optic direct laryngoscopy with biopsy and diagnostic computed tomography scan of the neck.

After meticulous work up, the patients were staged. Patients with T1N0M0 (stage I) and T2N0M0 (Stage II) were included in our study. The patient's agreement and a written consent to participate in the study were taken. All the cases had to undergo an approval of the tumor board.

Inclusion criteria

  1. Good Karnofsky performance scale (>70%)
  2. T1N0M0 and T2N0M0 disease
  3. Biopsy proven carcinoma
  4. Patient willing to be enrolled in study
  5. Willing for long-term follow-up.


Treatment procedure

All patients received continuous course of radiation therapy with once-daily fractionation. All the patients were treated 5 days a week from Monday to Friday.

Dose and fractionation

The fractionation regime was either:

  • 62.5 Gy/25fractions/5 weeks at 2.5 Gy/fraction (Regimen 1)
  • 70 Gy/35 fractions/7 weeks at 2 Gy/fraction (Regimen 2)


It was 2.5 Gy/fraction (Regimen 1) in 15/29 patients (51.72%) and 2 Gy/fraction (Regimen 2) in 14/29 patients (48.27%).

Monitoring of the patients on radiotherapy

The patient acute morbidities were charted on radiation therapy oncology group morbidity criteria chart. The late toxicity was assessed by LENT-SOMA score. At least, five parameters were noted, and grading (Grade 0–IV) was done every week. The parameters were related to skin, mucous membrane, salivary gland, pharynx and esophagus, and larynx.

All the patients completed their planned treatment in stipulated time and none had to discontinue their treatment due to acute toxicity.

Follow-up after treatment

Patient was followed up regularly at increasing intervals and was evaluated for:

  • Locoregional control
  • Quality of voice
  • Late toxicity of radiation therapy.


Voice assessment

Voice assessment after radiation therapy was done by:

  1. Voice quality
  2. Vocal function
  3. Vocal performance.


To assess the vocal performance, the patients were given a questionnaire, which they had to answer at first, second, and third follow-up posttreatment. Our questionnaire was based on the pattern of University Medical Center, Amsterdam, Netherlands. The questions were:

  1. Do you have to strain to produce voice?
  2. Do you have problem in shouting?
  3. Do you have problem in making a telephone call due to voice?
  4. Do you encounter problems holding conversation due to your voice?
  5. Does your voice change from day-to-day?


Scoring as follows:

  • 0 – Yes
  • 1 – Occasional
  • 2 – No.


Score vocal performance:

  • 0–3 – Impaired
  • 4–6 – Satisfactory
  • 7–10 – Good.


Voice quality assessment was done as follows:

  1. Unpleasant or pleasant
  2. Breathy or not breathy
  3. Dull or clear
  4. high or low
  5. Shrill of deep


  • Score 1 – Unfavorable answer
  • Score 2 – Favorable answer.


The minimum and maximum scores were 5 and 10, respectively. The higher the score, better the voice quality.

Score voice quality:

  • 5–7 – Normal
  • 8–10 – Deviant.


Statistical analysis

Analysis was done using statistical tool SPSS 11.0 (IBM). Two-tailed corrected Chi-square test and unpaired t-test were used for P value calculation. The results were studied on an intention-to-treat basis.


 » Results and Observation Top


Twenty-nine patients of early glottic carcinoma were found eligible for radical radiation therapy. All the patients successfully completed the treatment within the stipulated time and are on regular follow-up. The overall treatment time ranged from 34 to 37 days for Regimen 1 while it was between 48 days to 53 days in Regimen 2. The patient and tumor-related characteristics are detailed in [Table 1].
Table 1: Patient and tumor characteristics

Click here to view


Outcome

Follow-up period of patients ranged from 6 months to 2 years with a median follow-up of 18 months.

The local control rate with radical radiation therapy at 18 months was 90% as 26 out of 29 patients had complete response to radical radiation therapy. Thus, the local control rate in Regimen 1 was 93% (14/15 patients had local control). The locoregional control rate in Regimen 2 was 85% (12/14 patients had local control).

These three patients who had local failure underwent total laryngectomy. None of the patients developed recurrence after total laryngectomy, neither at the primary site nor in the neck nodes. All the patients are on regular follow-up and are controlled for the disease.

The tumor variables tested for an association with local control included:

  1. T1 and T2 stage
  2. Extensions to supraglottic and subglottis
  3. Impaired vocal cord mobility
  4. Anterior commissure involvement
  5. Field size
  6. Regimen 1 and 2.


T1 and T2 stage

The local control rate for T1 lesion was 92% and for T2 lesion was 88% (P = 0.05).

Supraglottic and subglottic extension

Of the 17 patients with T2 stage, six patients (35%) had supraglottic spread. Out of these six patients, one patient had failure (1/6 = 16%). The subglottic extension was present in only 1 patient with the involvement of whole cord and this patient also patient developed local failure (P < 0.01).

Locoregional control in patients with localized disease was 95%, and it was 71% for disease with extension beyond glottis.

Impaired vocal cord mobility

Out of 17 patients of T2 tumors, 11 patients (65%) had impaired vocal cord mobility. Of these 11 patients, three patients had supraglottic extension as well as impaired mobility of vocal cord. The other eight patients had localized disease with impaired mobility. One of the patients with supraglottic extension as well as impaired mobility developed local failure.

The local control rate with impaired mobility and normal mobility was 82% and 94%, respectively (P = 0.04).

Anterior commissure involvement

In our study, 14 out of 29 patients had anterior commissure involvement. The local control rate with or without anterior commissure involvement is 86% and 93%, respectively (P = 0.5).

Field size

Radiation field did not influence local control. The 2-year local control rate treated with:

  • 36 cm 2 – 94%
  • 42cm 2 – 86%
  • 49 cm 2 – 86%.


Radiation toxicities

Comparison of acute toxicities of Regimen 1 and 2 is detailed in [Table 2].
Table 2: Acute toxicity grading in regimen I and II

Click here to view


  • The difference in the acute and late toxicities in both the arms was statistically nonsignificant. High dose per fraction was well tolerated by the patients although the toxicity was marginally, yet it was very much acceptable, as none of the patients had to discontinue their treatment due to acute morbidity
  • Majority of the patients had Grade 1 late toxicity. No severe late complication was observed in either of the Regimens. None of the patients developed radionecrosis or second primary in our set up. However, long-term follow-up is warranted to come to a definite conclusion.


Voice quality during and after treatment

The majority of the patients showed improvement in voice in the first 2–3 weeks after commencing of radiation therapy. In general, the hoarseness reappeared in subsequent weeks. The voice started to improve again approximately 2–3 weeks after completion of radiotherapy and voice reached a plateau in 2–3 months. The improvement of voice was almost comparable in both groups.

Results of voice quality

Majority (86%) of the patients on follow-up had normal voice quality.

The 4/29 (14%) patients did not had a satisfactory improvement in their voice. Three of the patients among these had local treatment failure. Thus, poor voice or deterioration of voice can be the first sign of local failure or recurrence of laryngeal cancers.


 » Discussion Top


Radiation therapy for early glottic cancers offers an excellent probability of cure. The dual objective of treatment: controlling the malignant tumor and preserving a functionally useful voice is best optimized by the use of radical radiotherapy in early glottic cancers. Although surgery can undoubtedly offer good results, it is best reserved in the event of radiation failures, with patients still given a second chance of cure.[5],[6] Comparative data of incidence, sex distribution, and site-wise distribution of carcinoma larynx are detailed in [Table 3].
Table 3: Comparative data of incidence, sex distribution, and site-wise distribution

Click here to view


Management of early glottic lesions

Radical radiation therapy is the standard treatment option for stage T1–T2 glottic cancers. Staplers et al. observed that while radiotherapeutic techniques and schedules varied in different centers, the 5-year overall Survival rates only varied from 85% to 95% for T1 lesions and 80%–90% for T2 lesions. The disease-free survival at 5 years averaged at a mean of 84% for T1 and 70% for T2 lesions.

In our study, the local control and overall local control including surgical salvage at 2 years were 92% and 100% for T1 whereas it was 88% and 100% for T2 lesions.

Factors influencing local control

Stage

Earlier the stage, the better is local control and overall survival. Mendenhall et al., in 2003, reported a local control rate of 93% and 75% for T1 and T2, respectively.[7]

Our study results (according to stage)

The local control rate of our study at 2 years follow-up was 92% for T1 and 88% for T2 lesions. The 2 years overall local control with surgical salvage and survival were 100%.

Anterior commissure involvement

Some authors including Mantravadi et al. and Kirchner et al. reported decreased local control rates when there was anterior commissure extension, and the primary lesion was treated with radiotherapy alone.[8] Fein et al. found no significant relationship between the likelihood of local control and tumor involvement of anterior commissure. In a study at Tata Memorial Hospital by Dinshaw et al., anterior commissure did not adversely affect the local control: 82% as compared to 85% with or without the involvement of anterior commissure (P value not statistically significant).

In our study, local control was not significantly influenced by the presence of anterior commissure involvement. The local control rate with or without the involvement of anterior commissure was 86% and 93%, respectively (P = 0.5).

Impaired vocal cord mobility

Impaired mobility had been shown by various authors to result in increased local failures [Table 4].[5] Harwood et al. reported a 21% difference in 5-year survival and a 25% difference in local control depending on whether the cord was mobile or not.[9],[10],[11],[12] Dinshaw et al. reported that impaired cord mobility did not adversely affect the local control rates at 10 years, having 75% control rates in comparison to the mobile vocal cord group with 58% (P = 0.48). Murakami et al. reported no difference in the 5 years local control rate with impaired cord mobility. They reported local control rate of 76% and 75% with mobile and impaired vocal cord (P = 0.8).
Table 4: Control rate of T1 and T2 glottic cancers treated at various institutes with radical radiotherapy

Click here to view


In our study, the local control rate for with or without impaired mobility of the vocal cord was 82% and 94%, respectively (P = 0.2).

Subglottic extension

The T2 lesion with subglottic extension of glottic Carcinoma also has adverse prognostic outcome. Le et al. reported local control of 77% for lesions without subglottic extension compared with 58% for subglottic extension (P = 0.55).[13] Dinshaw et al. reported a local control rate of 64% with subglottic extension as compared to 77% without subglottic extension (P = 0.71). However, Murakami et al. reported 5-year local control rate of 66% and 80% with or without the involvement of subglottis, respectively (P = 0.0001).

In our study, only two patients had subglottic extensions, and both of them had local treatment failure (P = 0.001).

Dose, fractionation schedule, and overall treatment time

Mendenhall et al. reported that for patients treated once daily, 5 days/week, fractionation schedules using dose >2 Gy/fraction are superior to those using 1.8 Gy/fraction.[14] Million et al. reported a trend of improved local control rates in patients treated with higher dose per fractions and shorter over all treatment time.[15],[16],[17] Harwood et al. suggested that the dose-response curve for local control of T1 tumors is almost flat between 55 and 66 Gy and that increasing the dose will not results in any improvement.[9],[10],[11],[12]

Wang reported 5-year local control rates of 95% for patients with T1 laryngeal tumor whose OTT was 60 days or less versus 60% for patients whose treatment time was >60 days (P = 0.0056).[18],[19],[20]

Rudoltz et al. reported local control rates of 100% if treatment was completed within 42 days, 91% for 43–46 days, 74% for 45–50 days, 65% for 51–54 days, and 50% for 55–56 days (P = 0.0001).

Mendenhall et al. reported a local control rate of 100% when T1 tumor was treated with total dose of 61–67 Gy in 2.25 Gy/fraction. In contrast, the local control rate was only 80% for patient treated with 2–2.2 Gy/fractions.[3]

Chatani and Nishiyama et al., from Japan, concluded that 2.25 Gy/fraction scheme with a shorter overall treatment time is superior to 2 Gy/fraction for local control of T1 glottic carcinoma (92% vs. 77%, P = 0.003).

In our study, the result was definitely better in Regimen 1 (62.5 Gy in 25 fractions), in which local control rate was 93% as compared to 85% in Regimen 2 (70 Gy in 35 fractions) (P = 0.5).

Field size

The importance of field size in the treatment of T1 and T2 glottic carcinoma remains controversial. Teshima and Chatani et al. reported field size has an influence in the local control after radiotherapy. Locoregional control remains same irrespective of field size as long as entire target is covered well. Chatani et al. reported 3-year recurrence-free survival of 88% in a randomized study of 273 patients of T1N0M0 tumors using field size of 5 cm × 5 cm or 6 cm × 6 cm field size, and 80% local control rate with field size of more than 6 cm × 6 cm (P value statistically significant). Fein et al. reported 2 years local control of 90% for field size of <36 cm 2 as compared with 86% for >36 cm 2 (P = 0.001). Historically, the University of Florida and the Massachusetts General Hospital have used field size of ≤5 cm × 5 cm, and they have reported an excellent local control rates with minimal complications.[5],[19]

In our study, large field size had an adverse effect. Local control rate for field size <36 cm 2 was 94% while it was 86% for field size more than 36 cm 2 (P value not statistically significant).

Beam energy

In our set up, all the patients were treated by telecobalt-60. However, early glottic carcinoma can also be treated by 4–6 MV LINAC machine. Mendenhall et al. compared cobalt-60 with 6 MV and found no significant difference in the dose received at any point along the vocal cords.[5] Cobalt-60 was the beam of choice for Mendenhall et al., in their series.[5]


 » Conclusion Top


Radical radiotherapy is the standard of care for early carcinoma glottis. It is well tolerated by patients without any significant complications. Radiotherapy has major advantage in terms of preservation of natural voice, high local control rate, and overall survival. In our study, use of high dose per fraction schedule with shorter duration of treatment results in comparable local control as well as the quality of voice to the protracted course of radiotherapy without increase in treatment-related toxicities. Shorter overall treatment time can be of great advantage in terms of time, cost, comfort, and acceptability by the patients. Shorter treatment time reduces the burden in a busy department and also decreases the cost of treatment in relation to time and money. This form of treatment demands a stringent criterion of patient selection, and quality assurance in terms of target volume delineation, treatment technique, treatment planning, verification, and execution.[21][22][23][24]

Acknowledgment

We are thankful and would like to acknowledge the contributions of the doctors and staffs of the Department of Radiotherapy and Gynaecology of J. N. Medical College and Hospital, Aligarh, Uttar Pradesh, India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

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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. 5
    
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Harwood AR, Beale FA, Cummings BJ, Hawkins NV, Keane TJ, Rider WD. T3 glottic cancer: An analysis of dose time-volume factors. Int J Radiat Oncol Biol Phys 1980;6:675-80.  Back to cited text no. 9
    
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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. 13
    
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Million RR, Cassisi NJ, editors. Larynx. In: Management of Head and Neck Cancer: A Multidisciplinary Approach. 1st ed. Philadelphia: JB Lippincott; 1984. p. 315-64.  Back to cited text no. 15
    
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Million RR, Cassisi NJ, Mancuso AA. Larynx. In: Million RR, Cassisi NJ, editors. Management of Head and Neck Cancer: A Multidisciplinary Approach. 2nd ed. Philadelphia: JB Lippincott; 1994. p. 431-97.  Back to cited text no. 16
    
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Million RR, Cassisi NJ, Mancuso AA. Management of the neck for squamous cell carcinoma. In: Million RR, Cassisi NJ, editors. Management of Head and Neck Cancer: A Multidisciplinary Approach. 2nd ed. Philadelphia: JB Lippincott; 1994. p. 75-142.  Back to cited text no. 17
    
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Warde P, O'Sullivan B, Bristow RG, Panzarella T, Keane TJ, Gullane PJ, et al. T1/T2 glottic cancer managed by external beam radiotherapy: The influence of pretreatment hemoglobin on local control. Int J Radiat Oncol Biol Phys 1998;41:347-53.  Back to cited text no. 21
    
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Garden AS, Forster K, Wong PF, Morrison WH, Schechter NR, Ang KK. Results of radiotherapy for T2N0 glottic carcinoma: Does the “2” stand for twice-daily treatment? Int J Radiat Oncol Biol Phys 2003;55:322-8.  Back to cited text no. 22
    
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Pradhan SA, Pai PS, Neeli SI, D'Cruz AK. Transoral laser surgery for early glottic cancers. Arch Otolaryngol Head Neck Surg 2003;129:623-5.  Back to cited text no. 23
    
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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. 24
    



 
 
    Tables

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



 

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