SURVIVAL OUTCOMES IN SURGICALLY TREATED PATIENTS WITH ADVANCED LARYNGEAL CANCER IN SERBIA PREŽIVLJAVANJE HIRURŠKI LEČENIH PACIJENATA SA ODMAKLIM

Backround/Aim. Laryngeal carcinomas make 1-3% of all head and neck malignancies.Treatment outcome and survival rates depend greatly on established stage of the disease. The purpose of this paper was to examine the survival of the patients with advanced laryngeal carcinoma depending on gender, age, common risk factors (tobacco and alcohol use), primary tumor localization, histopathological tumor grade, clinical TNM stage and surgical treatment of the disease. Methods. Retrospective study included 252 patients treated surgically for advanced squamocellular carcinoma of the larynx in a threeyear period with five-year follow up. Patients included in the study were treated primary with surgery, with postoperative radiotherapy and chemotherapy depending on the stage of the disease, intraoperative findings and tumor resection borders. Overall survival and disease-specific five-year survival of patients was calculated for demographical and clinical characteristics of the patients. Results. Overall 5-year survival for patients with operable advanced laryngeal cancer included in the study was 86.14% and disease-specific survival 86.51%. Lower overall and disease-specific survival was associated with age, higher histological tumor grade and more extensive neck dissections. Conclusion Primary total laryngectomy results in higher survival outcomes in cases of transglottic T3 and T4a laryngeal tumors. Patients should be informed of the likely increased mortality risks tied to the choice of surgical resection and treatment modality before their decision.


Introduction
Laryngeal carcinomas make 1-3% of all head and neck malignancies. 1Treatment outcome and survival rates depend greatly on established stage of the disease.In the recent decades treatment concept of advanced laryngeal cancer was shifted toward organ preservation therapy, suggesting radiotherapy with concurrent chemotherapy as a preferable method for laryngeal preservation. 2Some studies suggested that in clinical setting, organ preservation protocols weren't as efficient in providing high enough rates of survival as the surgical treatment combined with radiotherapy or chemoradiotherapy. 3Some authors argue that traditional treatment of advanced laryngeal cancer, which most commonly includes total laryngectomy with postoperative radiotherapy, isstill the best for ensuring most favorable oncological results . 4,5 The purpose of this study was to examine the overall and diseasespecific survival of the patients surgically treated of operable advanced laryngeal carcinoma depending on gender, common risk factors (tobacco and alcohol use), histopathological tumor grade, clinical TNM stage and treatment of the disease.

Methods
A retrospective study was conducted on 252 patientstreated at the Clinic for Otorhinolaryngology and Maxillofacial Surgery, Clinical Center of Serbia in Belgrade.The data were obtained by processing medical chartsof the patients with squamocellular carcinoma of the larynx surgically treated inthe period from January 1st, 2010 to January 1st, 2012.This study was approved by the Institutional Ethical Committee (440/IX-3/09), and all patients signed the informed consent form prior to their inclusion in the study.Patients were divided into age groups according to International Cancer Survival Standard (ICSS) using the Five Default Age Groups (15-44, 45-54, 55-64, 65-74, 75+). 6e diagnosis of laryngeal carcinoma was confirmed by otorhinolaryngological clinical examination and laryngomicroscopic examination of the larynx with the biopsy and histopathologic examination of the tissue.Additional diagnostics, likeultrasonography of the neck and of the abdomen, chest x-ray and computed (CT) tomography of the neck were performed to determine the TNM stage of the disease. 7Study included patients diagnosed with advanced stages of operable laryngeal carcinoma (T2N1-N2, T3N0-N2 and T4aN0-N2), without previous treated malignancies and distant metastases.The modality of treatment for every patient was decided on the Oncological board (consisting of radiotherapist, head and neck surgeons, oncologist and histopathologist).Choice of primary and adjuvant treatment was decided based on NCCN and ASTRO guidelines 7,8 which are recommended and used at Clinic for Otorhinolaryngology and Maxillofacial surgery and Institute for Oncology and Radiology of Serbia in Belgrade.Surgical therapy involved resection of the tumor with some form of neck dissection in case of cervical lymphadenopathy.Radiotherapy consisted of external radiotherapy with total dose of 60 to 70Gy in 30-35 fractions for 6-7 weeks.Patients received concomitant chemotherapy consisted of at least three courses of cisplatin (CDDP) with 5-fluorouracil (5-FU) intravenously.Follow-up period was from 63 to 82 months.Demographic characteristics (age and gender) and risk factors (cigarette and alcohol consumption) were noted.Histopathological tumor grade, the beginning of treatment with or without tracheotomy, TNM classification, type of surgical treatment, type of neck dissection, and therapy modalitywere also examined.Five-year overall and disease-specific survival of patients was determined depending on all previously mentioned factors.
For statistical analysis of the data in this paper used the program SPSS v20 (Statistical Package for Social Sciences, SPSS Inc, Chicago, Illinois).Descriptive statistics were calculated for demographic characteristics, risk factors and other followed parametersand are presented as frequencies and proportions.Overall survival (OS) and disease-specific survival (DSS) rates were calculated using the Kaplan-Meier method.A Cox proportional hazards regression model was used for univariate and multivariable was usedto evaluate the impact of prognostic factors on disease-specific survival.Risk estimates are presented as hazard ratios (HR) with 95% confidence intervals (CI).Statistical significance was considered at p ˂0.05.

Results
The study comprised 230 (91.3%) males and 22 (8.7%) females of an average age of 59.98 years (SD ±8.85 years).The youngest patient was 38, and the oldest 84 years old.233 (92.5%) of the patients were smokers, and 19 (7.5%) were non-smokers.Alcohol consumption was noted in 87 (34.5%) of the patients, while 165 (65.5%) were nondrinkers.Diagnostics of the tumor started with tracheotomy in 51 (20.2%) of the patients.Majority of carcinomas were histologically moderately differentiated tumors (74.2%) and were transglottic tumors (40.9%)Out of all surgical procedures used to treat advanced laryngeal carcinoma in our study, total laryngectomy was most frequently done procedure in 216 patients (85.7%).59 (23.4%) of the patients underwent neck dissection.Most of the patients were treated with surgery followed by postoperative radiotherapy, while there were only small number of patients treated only surgically (3.6%), or with surgery with concomitant chemo-radiotherapy (5.2%).(table 1) Table 1.Demographic and clinical characteristics of the patients Overall 5-year survival for patients with operable advanced laryngeal cancer included in the study was 86.14% and disease-specific survival 86.51%.Overall survival didn't differ much from disease-specific survival comparing different age groups, except in the group of patients older the 75 year, mostly because of other comorbidities.(table 2 and 3) Females had lower 3-year and 5-year survival rates comparing to male patients (3-year OS and DSS 81.8 vs. 87.4;5-year OS 72.7 vs 80.9. and DSS 72.7 vs. 81.2).Non-smokers had better disease-specific survival rates compared to smokers included in the study, but the difference wasn't statistically significant.Patients who didn't consumed alcohol had higher overall and disease-specific survival compering to those who consumed alcohol.
Patients with poorly differentiated tumors had lower survival rates comparing to patients with good and moderately differentiated tumors.Tumor localization significantly influenced on overall (Log rank, p=0.017) and disease-specific survival (Log rank, p=0.025).Tumors with primary supraglottic localization had significantly lower survival rates comparing to other localization.20.1% of patients started their diagnostic process with tracheotomy, which significantly influenced their disease-specific survival(Log rank, p=0.041).Patients with T2 advanced laryngeal tumors had lower overall and disease specific survival comparing to T3 and T4a tumors (3-year DSS 77.8 vs. 88.2 vs. 83.3;5year DSS 66.7 vs. 81.1 vs. 80) , but the regional spreading of the disease present in these patients should be taken in account explaining the results.Overall (Log rank p=0.046) and disease-specific survival (Log rank p=0.037) was significantly lower in patients with N2 nodal disease comparing to those N0 and N1 stage of nodal disease (3-year OS and DSS 88.1 vs. 86 vs. 66.7;5-year OS and DSS 82.7 vs. 74.4 vs. 50).5-year overall and diseasespecific survival was lower in patients who underwent partial supraglottic laryngectomy comparing to other conducted operative procedures.5-year overall (Log rank p=0.032) and disease-specific survival (Log rank p=0.024) in patients who underwent radical and expanded radical neck dissection was significantly lower comparing other patients, which is in direct contact with the advancement of nodal disease.Patients who were treated only surgically, without postoperative radiotherapy or chemotherapy had higher overall and disease-specific survival one year, three years and five years after the treatment.Table 2. Overall and disease-free survival for patients included in the study Table 3. Disease-specific survival for patients included in the study Multivariate analysis revealed that age, histological grade of the tumor and undertaken selective or modified radical neck dissection were significant prognostic factors for DSS in patients with advanced laryngeal cancer (table 4).Age of the patients (HR 1.042, p=0.013), histological G2 (moderately differentiated) (HR 3.453, p=0.027) and G3 (poorly differentiated) (HR 4.069, p=0.036) tumor grade had a negative impact on DSS.Undertaken selective or modified radical neck dissection had a positive impact on DSS (HR 0.132, p=0.02).DSS was significantly better for patients with supraglottic (HR 0.405, p=0.009) and glottic localization of the tumor (HR 0.478, p=0.023), but only by univariate analysis.

Discussion
In our study overall and disease-specific survival was significantly lowered with age.Age of the patients proven to be an importantrisk factor which other studies confirmed as well. 9,10 n female patients in our study, 3-year and 5-year survival was lower comparing to male patients, which differs from other studies where females had significantly higher survival rates. 11,12Smoking and alcohol consumption were also associated with lower survival in our patients.In this study gender, smoking and alcohol consumption weren't significan prognostic factors fr disease specific survival.Less differentiated advancer carcinoma had higher risk of mortality.These data don't differentiate significantly from other research data available. 9,10This study involved patients with advanced laryngeal carcinoma which included T2 stage with nodal disease, T3 and T4 stage with and without nodal disease.Patients with higher T stage of the disease had, as expected, lower overall and disease-specific survival.Presence of nodal disease also lowered survival in the patients included in our study.
The evolution of treatment for advanced laryngeal carcinoma in Serbia was interesting during the last half of the century.In the 1960s' radiotherapy was considered to be primary treatment for laryngeal cancer.In the 1970s' functional and radical laryngeal surgery started to emerge as the primary curative treatment, with postoperative radiotherapy and chemotherapy. 13It was considered that extended surgery was needed for successful oncological treatment of advanced laryngeal cancer.With the advances of chemotherapeutic drugs and radiotherapy, new treatment protocol for organ preservation were presented in the last three decades. 2,14,15Nonsurgical therapy was suggested to be as efficient as surgical therapy in treating advanced laryngeal cancer.Since then, numerous studies showed that in the clinical settings, surgical therapy still resulted in better overall and disease-specific survival in patients treated for advanced laryngeal cancer comparing to chemoradiotherapy and radiotherapy alone. 3,16,17tients with T4a tumors in our study had high 3-year and 5-year overall and disease-specific survival (83.3% and 80%) and were all treated with total laryngectomy with postoperative chemoradiotherapy.In the recent systematic review paper which included 24 studies, Francis et al. reported overall survival for T4a laryngeal carcinoma treated with total laryngectomy varied from 30 to 100% at 2-years and from 10% to 80.9% at 5-years. 18In 2010, Olsen stated that tumors that extend through the laryngeal cartilage should be treated with total laryngectomy, followed by postoperative RT or chemoradiotherapy depending on primary tumor pathologic findings and presence of neck metastasizes. 19n Serbian leading medical centers, surgery is considered the preferable primary method of treatment for advanced laryngeal carcinomas.Adherence to new recommended protocols for treating advanced laryngeal carcinoma is significantly influenced by health care organization.Small number of radiology and oncology centers and prolonged waiting period for radiotherapy, is surely influencing the decision on treatment choice, leaving surgery as the best and reliable method.There are limited number of papers written on the matter, without significant stratification of data.In older studies done in Serbia, 3-year overall survival in patients with advanced laryngeal carcinoma treated with total laryngectomy from 1971 to 1981 was 68.49%. 13In the period from 1990 to 1997, 5-year overall survival for patients with advanced laryngeal carcinomas who underwent total laryngectomy reported to be 63%. 20Stankovic et al. reported disease-specific survival of 61.3% for 387 patients with advanced laryngeal cancer who underwent total laryngectomy from 1995 to 2007. 21In this study, patients treated with total laryngectomy had 3-year overall survival of 86.6% and disease-specific survival of 87%, and 5-year overall survival of 80.1% and disease-specific survival of 80.5%.
Most of the patients included in the study had clinically negative enlarged lymph nodes of the neck (203 patients, 80.6%), and neck dissection wasn't done in 193 patients (76.6%).Current recommendations support selective neck dissection in advanced laryngeal carcinoma without clinically positive neck 22,23 which should be implemented in our clinical practice.In our study 31 patients (12.7%) underwent radical of extended radical neck dissection.5-year overall survival was significantly lower in these patients, which is surely connected with the advanced regional spread of the disease.Selective or modified radical neck dissection positively influenced disease-specific survival.There are few studies that suggest that with the careful selection of patients without massive lymphadenopathy, nodal fixation, gross extracapsular spread and history of previous neck surgery or radiotherapy, selective neck dissection could resolve N1 to N3 nodal disease. 24.

Conclusion
This study indicates that lower overall and disease-specific-survival was significantly associated with patients' age, higher histological grade of the disease and more extensive neck dissections.Primary total laryngectomy results in higher survival outcomes in cases of transglottic T3 and T4a laryngeal tumors.Patients should be informed of the likely increased mortality risks tied to the choice of surgical resection and treatment modality before their decision.