Morbidity of Different Treatment Modalities in Advanced Carcinoma Larynx

Objectives: To evaluate morbidity of different modalities of treatment in advanced carcinoma larynx (stage III and IV). Methods: It was a cross sectional study conducted among selected 70 patients of advanced carcinoma larynx treated by different modalities of treatment from April 2009 to April 2010 in different tertiary hospitals in Dhaka. Results:The age of the patients ranged from 30 to 79 years (mean ± SD = 54±10.94), maximum age incidence 5th decade. Almost all were male, habituated in betel nut and leaves chewing and smoking. Mostly (60%) from poor socioeconomic group. 70% cases were supraglottic and 30% cases were glottic carcinoma. Nature of lesion was exophytic 71.43% and ulcerative 28.57%. 22.86% had neck node metastasis. Histopathologically 60% were moderately differentiated and grade II squamous cell carcinoma (SCC). In the total laryngectomy patient pharyngocuteneous fistula (30%), wound infection (10%), haematoma (10%), stomal recurrence (10%), stenosis is tracheostomy (10%), recurrent chest infection (10%) and pharyngeal stenosis (10%) were the morbidities. Mucositis or painful erythematous reaction in larynx and pharynx (95%), periconditis (2.5%), dryness of mouth and throat (100%), loss of test (100%), subcutaneous fibrosis (32.5%), nausea vomiting, skin rashes and alopecia (100%) were the morbidities of chemoradiotherapy and radiotherapy. After analysis the major and minor morbidities of different, modalities of treatment there was no significant (p > 0.05) difference among those modalities. Conclusion: The difference between the morbidity of single modality and combined modalities had not significant. So the combined modalities approach may be advocated for the treatment of advanced carcinoma larynx where required.


Introduction
The larynx is the most common site for primary malignant tumour in head and neck region which accounts for 25-30% of Head and neck malignancy 1,2 It is one of the most common cancers in Bangladesh 3 .It is male predominant 4, >97% are squamous cell carcinoma 7, strongly associated with smoking, alcohol and some environmental factors.Laryngeal carcinomas are diverse in their behavior and prognosis.Topographically it is more supraglottic in nature than other sub sites in this subcontinent 4,5,6,7 as well in Bangladesh (67-73%) 8,9,10,11,12 .Laryngeal carcinoma has high rate of cure in certain sub sites and early stage, may reach over 85% and overall exceeds 50% 13 .. Most of the failures in the treatment of laryngeal cancer are due to the delay in diagnosis can contribute to the presentation with later stage diseases and difficulty in eradicating the loco regional disease 14 .
Laryngeal cancer like all other head and neck cancer are best treated by multidisciplinary approach.The major goal of the treatment of cancer of the larynx is to maximize the cure rate while preserving speech and swallowing function.Treatment is based on the site of involvement and TNM stage of the tumour and some of the patient's factors also remain due consideration.Irradiation and surgery are two main modalities of treatment of cancer larynx.It can be treated by radical radiotherapy, by surgery or by combination of these two modalities.Chemotherapy has previously played a minor adjuvant or palliative role in the treatment of advanced carcinoma, but now it is increasingly used as combined in treatment of early stage of the diseases 15 .Historically, locally advanced carcinoma of the larynx (i.e., T 3 and T 4 and/or N 2 and N 3 disease) has usually been treated with combined surgery and pre-or post-operative RT or RT alone for unresectable disease.The disadvantages of a primary surgical approach include loss of organ function.Locoregional tumor control rates with total laryngectomy and postoperative RT are high (80%-90%).The addition of postoperative RT to a primary surgical approach is crucial to reducing the rate of locoregional failures.For advanced operable carcinoma of the supraglottis, management options include surgery combined with RT, chemotherapy combined with RT, or RT alone.When RT is combined with surgery, it is usually given postoperatively because of the ability to tailor the dose more optimally on the basis of histopathologic information (i.e., the number of positive nodes, the presence of extracapsular extension, and/ or the status of the primary surgical margins) and because there are generally lower rates of complications.
The acute and late effects of RT are directly dependent on such factors as total dose 16 ,dose/fraction, treatment volume, overall treatment time, [ and daily interfraction interval with hyperfractionated RT. 17 Other factors that also influence the late complication rate include the stage of disease, the sequence of RT and surgery (i.e.post operative RT), and chemotherapy 18 .Both acute and late normal tissue effects may be exacerbated in the presence of other medical conditions, such as hypertension, diabetes, immune suppression, and collagen vascular disease.
Acute reactions occurring during fractionated RT for carcinoma of the vocal cords are usually mild.Increases in hoarseness, sore throat, dysphagia, patchy mucositis, erythema, and erythema of the skin in the radiation field may develop, generally beginning during the second to fourth week of RT.Laryngeal edema of varying degrees may persist after RT for carcinoma of the glottis or supraglottis.In patients who have been irradiated for carcinoma of the glottis, the incidence of mild to moderate laryngeal edema persisting for more than 3 months after RT is about 15.4% to 25%. 21 They were grouped and under went different modalities of treatment and attended periodic follow up visit.Patients were treated by either total laryngectomy or total laryngectomy followed by radiotherapy, chemoradiotherapy or radiotherapy alone.These are classified as single modality of treatment (treatment either surgery or chemotherapy or radiotherapy) or Combined modalities of treatment (treatment more than one modalities of treatment like surgery plus chemoradiotherapy/ radiotherapy and chemotherapy plus radiotherapy).The morbidity status of different modalities was classified as major morbidity and minor morbidity.The clinical or physical states which significantly hampered the patient's physiological state and quality of life are grouped as major morbidity.Unavoidable minor complications which are tolerable and regress are defined as minor complications (table-1).During this study ethical implication was thoroughly looked upon.All the data pertinent to the patient kept confidential.The accumulated data analyzed by standard statistical method.Statistical analysis was done by Sigma stat3.5 and SPSS -15 methods.

Discussion
In this study randomly selected 70 cases of advanced laryngeal carcinoma male ware out numbered than female .Male to female ratio was 13:1.This result differ from that of studied of other 7.5:1 1 , 8.5:1 13 , 10:1 16 , 9:1 19 and 4.5:1 20 .Although all other the studies revealed male predominant with carcinoma larynx.The age of the subject range from 30-79(mean 54± SD10.94.) year and the maximum (38.57%) incidence of carcinoma larynx between 50 to 59 years of age.The age incidence is almost identical with the result of others and the results are age group of 55 to 64 years 46.19% 13 .50.29% 16 and 48.33% 25 .
By direct laryngoscopy, supraglottic carcinoma was found 70%, the overall glottic carcinoma 30% and no cases were found subglottic carcinoma..In USA, glottic carcinoma account for 60% of all laryngeal cancer, 35% of supraglottic cancer and 5% of subglottic cancers 21  Treatment is based on the stage of the cancer as well as its location and the health of the individual three types of treatment were givensurgery followed by radiotherapy, chemoradiotherapy and radiotherapy alone (fig.1).
Among the total 70 study cases, 10 cases were done total larygectomy followed by radiotherapy or radiotherapy followed total laryngectomy, 20 cases were treated chemoradiotherapy and rest 40 cases were treated by radiotherapy alone.
In the 10 cases of total laryngectomy, 7(70%) cases received preoperative radiotherapy full dose as curative therapy and 3(30%) cases received radiotherapy after surgery and these were advanced stages (stage III and IV), mean age of patient was 58.90±11.789.Tracheostomy was done preoperatively in 7 patients and in remaining 3 patients; it was done at the time of operation.
In this study, following total laryngectomy pharyngocuteneous fistula developed 30% patients.These patients were irradiated preoperatively with preoperative tracheostomy.It was developed 8 th to 10 th day of operation.This result almost coincide by another study 12.7% 22 and this was not coincide by another studies 67.65% 1 and 51% 23 The fistulas were healed with daily dressing for 3-4 weeks with good nutrition supplied.
Among the 10 cases of 3(30%) patients received radiotherapy after surgery for locoregional treatment and all the patient developed several side effect of radiotherapy like dryness of mouth and throat, loss of taste sensation, pigmentation of skin and subcutaneous fibrosis during study period (table-XI).Another study reveals the same type of morbidity of acute radiation like difficulty in tasting food 76.3%, dryness of mouth 92% 25 and taste changes and dry mouth 26 .
Platinum based chemotherapy particularly the combination of cisplastin and 5 fluorouracil (5FU) were applied prior to radiotherapy.This appears the ability of neoadjuvant chemotherapy to predict radiosensitivity 27 .In this study, 20 patients were treated with chemoradiotherapy, 95% patients developed radiation mucositis in the larynx and pharynx, 5% patients cancel the procedure following chemoradiotherapy, 5% patients developed periconditis(table-XII).All the patients were developed dryness of mouth and throat and loss of taste, nausea, vomiting, skin rashes and alopecia.The same type of morbidity also reveals in another study (Solomon, MN 2009).
In this study out of 70 patients, 40 were treated by radiotherapy alone in Dhaka Medical College Hospital, Dhaka the machine was Telecobalt-60 total dose was received 6600cGY and 33 fractions, once daily, 05 days per week, 200cGY per fraction.The dose to the tumor bed, extra nodal extension or close surgical margins.After the delivery of radiotherapy 92.5% patients develop mucositis in larynx and pharynx, 7.5% developed severe reaction necrosis of skin, 2.5% developed respiratory distress following radiotherapy, 2.5% developed periconditis, 100% patients developed dryness of mouth and throat, and loss of taste, 32.5%, patients developed subcutaneous firbosis.These type of morbidity due to radiation also reveals in another study pain and soreness of mouth 86.8%, pain and itching of the skin 86.8%, difficulty in chewing 55.3% 31 Over all this study shows that major morbidities for surgery plus chemoradiotherapy / radiotherapy major 15 and chemoradiotherapy major was 2 and minor morbidities for surgery plus chemoradiotherapy / radiotherapy were 12 and chemoradiotherapy 139 .The morbidity due to radiotherapy alone were major 5 and minor 93.At the end of the table (table-XVI) it was shown different major and minor morbidities after combined and single modality of treatment.Finally comparison between the single modality and combined modalities were done and the test of significant (the Chi-Square test) was done to see the association between different modalities.But after the Chi-Square test it was found that the difference between the different modalities was not statistically significant (p > 0.05).

Conclusion
By comparing the morbidity of different modalities of treatment as a single or in combination in the treatment of advanced carcinoma larynx, it had found that each modality had its own morbid state which ware differs from others.The morbid state was varies significantly among each of the individuals depending on their different confounding status.In case of total laryngectomy with or without radiotherapy the post operative complications and morbidity were more than organ preservation treatment e,g.radiotherapy with or with out chemotherapy.The difference between the morbidity of single modality and combined modalities had not significant.So the combined modalities approach may be advocated for the treatment of advanced carcinoma larynx where required.

Table - X
Comparison of morbidity between single modality of treatment (radiotherapy alone) and combined modalities of treatment (Surgery+ Chemoradiotherapy or Chemoradiotherapy ) (n= 70)