Treatment and prognosis of patients with recurrent laryngeal carcinoma: a retrospective study

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1 Page 1 of 7 Treatment and prognosis of patients with recurrent laryngeal carcinoma: a retrospective study T Jin 1, H Lin 2,3, HX Lin 2,3, XY Cai 2,3, HZ Wang 2,3, WH Hu 2,3, LB Guo 4, JZ Zhao 5 * Abstract Introduction Although recurrent laryngeal carcinoma is a common clinical problem, the data regarding its natural history and prognostic factors are limited. The aims of this study were to evaluate the treatment outcomes of patients with recurrent laryngeal carcinoma and to identify the value of several prognostic factors. Methods A retrospective analysis of 224 consecutive cases of recurrent laryngeal carcinoma, treated between 1996 and 2009, was performed. Overall survival was estimated using the Kaplan Meier method. Log-rank test was employed to identify significant prognostic factors for overall survival. The Cox proportional hazards model was applied to identify covariates significantly associated with the aforementioned endpoint. Results The estimated 3-, 5- and 10-year survival rates of the entire patient sample were 56.6%, 46.4% and 39.2%, respectively. On univariate analysis, the age, smoking index, grade, primary * Corresponding author jinting22222@163.com 1 Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People s Republic of China 2 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People s Republic of China 3 State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, People s Republic of China 4 Department of Oncology, Guangdong Second Provincial People s Hospital, Guangzhou, Guangdong, People s Republic of China 5 Department of Head and Neck Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People s Republic of China site, initial T stage, initial Union for International Cancer Control (UICC) stage and nodal status of the primary tumour, as well as disease-free interval, extent of recurrence and suitability for surgery were all powerful prognostic factors for survival. On multivariate analysis, four variables retained statistical significance: the initial T stage, nodal status, extent of recurrence and suitability for surgery. Conclusion Our results suggest that lower initial T stage, no initial cervical lymph node metastasis, only local recurrence and patients suitable for salvage surgery are favourable prognostic factors for overall survival of patients with recurrent laryngeal cancer. Introduction In the United States, it is estimated that about 49,260 new cases of oral cavity, pharyngeal and laryngeal cancers occurred in An estimated 11,480 deaths from head and neck cancers occurred during the same time 1. Of all head and neck tumours, 20% originate in the larynx. Recurrences are common in laryngeal cancer. The rate of recurrence in patients with T1 tumours of the larynx ranges from 5% to 13%, and in patients with T2 tumours, from 25% to 30% 2. For patients with advanced laryngeal cancer, the rate of recurrence is approximately 30% 50% as reported by some studies 3 5. The most frequent site of recurrence is the larynx itself, including the peristomal area followed by the regional lymph nodes and, less often, distant sites 6,7. The options for patients who have failed definitive treatment for squamous cell carcinoma (SCC) of the larynx include (1) salvage surgery; (2) repeat radiation therapy (reirradiation), with or without chemotherapy; (3) palliative chemotherapy and (4) supportive care. Surgery is recommended for resectable recurrent locoregional disease. Surgical treatment can either be endoscopic laser treatment or laryngectomy (partial or total), depending on the size and site of the tumour. Small recurrences can be treated by endoscopic laser treatment. Larger tumours and those with subglottic extension are generally treated by total laryngectomy. Adjuvant therapy depends on the risk factors. If the recurrence is unresectable and the patient did not have prior radiotherapy, then radiotherapy with concurrent systemic therapy is recommended, depending on the performance status. For patients with recurrent disease not amenable to curative-intent radiation or surgery, the treatment approach is the same as that for patients with metastatic disease. Enrolment in a clinical trial is preferred. Choice of treatment also depends on age, general health and preference of the patient. The survival rate after local recurrence and salvage surgery varies greatly from 22% to 66% Some authors even report an overall 5-year survival rate of as low as 2% in this patient population 4. This retrospective study reviews a series of 224 consecutive recurrent laryngeal carcinomas observed at our institutions and managed with the aforementioned therapeutic choices. The aim of this study was to report our results and try to identify, in a retrospective analysis, potential prognostic factors and possible guidelines in tailoring the most appropriate treatment for patients with recurrent laryngeal carcinoma.

2 Page 2 of 7 Table 1 Patient characteristics Features No. of patients % Gender Female Male Age (years) a < Histological grade Well Moderately Poorly Smoking index b < Alcohol consumption No Yes Primary site Glottic Supraglottic Subglottic T Stage 1 and and Cervical lymph node metastasis Positive Negative TNM Stage I and II III and IV Blood type A B AB O a Patients were divided according to the median age. b Smoking index is defined as the number of cigarettes used per day the total smoking time (years). Materials and methods Characteristics of patient enrolment criteria Between 1996 and 2009, 1621 consecutive patients with neoplasms of the larynx were observed at the Sun Yat-sen University Cancer Center, China. Of these, 1556 patients had biopsy-proven SCC of the larynx. With a median follow-up time of 49.5 months (range, months), recurrent disease was diagnosed in 253 patients (16.3%). Among these 253 patients, the enrolment criteria were as follows: (a) each patient s complete clinical and pathological data including age, gender, blood type, stage, smoking index, alcohol consumption, histological differentiation and treatment status; (b) patients were restaged according to the guidelines of the 2002 Union for International Cancer Control (UICC) by the cancer staging system; (c) no patient had distant metastasis at the time of initial staging and (d) patients were initially treated with the goal of a cure at our institution by one or a combination of three modalities: surgery, radiation therapy and chemotherapy. The study was approved by the Research Ethics Committee of the Sun Yat-sen University Cancer Center. A total of 224 patients were evaluated in this analysis according to the above criteria. Patient characteristics are summarized in Table 1. There were 216 male (96.4%) and 8 female (3.6%) patients. The median age at diagnosis was 60 years (range, 16 83). There were 79 cases of T1, 67 cases of T2, 43 cases of T3 and 35 cases of T4. There were 105 cases of good differentiation, 94 cases of moderate differentiation and 25 cases of poor differentiation. Treatment approaches for initial tumours When selecting treatment approaches, a comprehensive consideration of each individual patient, their economic situation and their treatment preferences was made by the multidisciplinary team at our cancer centre.

3 Page 3 of 7 For the treatment modality of the primary site, 120 patients received surgery alone; 22 patients received Gy radiation alone; 64 patients received surgery plus Gy post-operative radiotherapy; 1 patient received 66 Gy radiotherapy plus surgery and 17 patients were treated with combined cisplatin-based chemotherapy, including 4 cases of neoadjuvant chemotherapy plus radiotherapy, 6 cases of surgery plus adjuvant chemotherapy, 1 case of concurrent chemoradiotherapy, 2 cases of surgery with concurrent chemoradiotherapy, 2 cases of neoadjuvant chemotherapy plus surgery plus 60 Gy post-operative radiotherapy and 2 cases of surgery plus adjuvant chemotherapy plus 66 Gy post-operative radiotherapy. In the surgical treatment of the neck, 72 patients were managed by neck dissection, including 27 cases with modified radical neck dissection (MRND) and 45 cases with selective neck dissection (SND). Further, 7 patients underwent Gy neck radiation alone; 22 patients had combined neck dissection with Gy post-operative radiotherapy; 3 patients were given cisplatin-based chemotherapy alone; 106 patients received no active therapy and were observed; 14 patients had combined cisplatinbased chemotherapy, including 5 cases of neoadjuvant chemotherapy plus radiotherapy; 3 cases of surgery plus adjuvant chemotherapy; 1 case of concurrent chemo-radiotherapy; 2 cases of surgery with concurrent chemoradiotherapy; 2 cases of neoadjuvant chemotherapy plus surgery plus 54 Gy post-operative radiotherapy and 1 patient received surgery plus 60 Gy post-operative radiotherapy plus adjuvant chemotherapy. Follow-up time and method Follow-ups were conducted mainly via outpatient check-ups. The followup examination was started after treatment. Patients were seen every 2 months during the first year, every 3 months for the subsequent 2 years and then every 6 months thereafter until death. All loco-regional tumours were diagnosed by clinical examination, magnetic resonance imaging (MRI) or intensive computed tomography (CT), fiberoptic endoscopy and biopsy. Distant metastases were diagnosed by clinical symptoms, physical examinations and imaging methods, including chest X-ray, bone scan, abdominal sonography, MRI, intensive CT or positron emission CT. Statistical analyses Survival was defined as the interval between the date of diagnosis of recurrent disease and date of death or the last date on which the patient was known to be alive. Patients who died of no other documented cause were considered to have died from recurrent laryngeal cancer. SPSS 13.0 statistical software was used (SPSS Inc., Chicago, IL) for analysis. The survival rate and univariate analysis were performed by the Kaplan Meier method 12 and log-rank test. Multivariate analyses with the Cox proportional hazards model 13 were used to test the independent significance by forward elimination of insignificant explanatory variables of different parameters. A two-tailed P value of <0.05 was considered statistically significant. Results Site of recurrence As many as 151 patients (67.4%) had local recurrence, either alone (140 patients) or with regional (11 patients) recurrence. In 57 patients (25.4%), there was a failure in the regional lymph nodes only, whereas 14 patients (6.3%) had isolated distant metastases. However, 2 patients (0.9%) had regional lymph node recurrence and distant metastases. The median disease free interval for all 224 patients was 11 months (range, 3 124). Treatment for recurrent tumour The treatments given at recurrence are summarized in Table 2. Surgery was performed in 142 patients (63.4%) for Table 2 Treatment at recurrent tumour No. of patients % Surgery (n = 142) Partial laryngectomy Total laryngectomy Unilateral neck node dissection Bilateral neck node dissection Laryngectomy and neck node dissection Radiation (n = 26) Radiation alone Surgery plus post-operative radiotherapy Chemotherapy (n = 39) Chemotherapy alone Radiotherapy plus adjuvant chemotherapy Surgery plus adjuvant chemotherapy Surgery plus post-operative radiotherapy plus adjuvant chemotherapy No active therapy (n = 17) No active therapy

4 Page 4 of 7 Table 3 Univariate analysis of prognostic factors for overall survival Prognostic factor No. of patients 5-year OS χ 2 P a Gender Female % Male % Age b < % % Smoking index c < % % Alcohol consumption No % Yes % Grade <0.001 Well % Moderately % Poorly % Primary site Glottic % Supraglottic % Subglottic % Blood type A % B % AB % O % Initial T stage < and % 3 and % Initial UICC stage <0.001 I and II % III and IV % Initial nodal status <0.001 Positive % Negative % Disease-free interval d <11 months % 11 months % Extent of recurrence <0.001 Local only % Regional (±local) % (Continued) locoregional disease. Further, 62 and 33 patients were treated with partial and total laryngectomy, respectively. Unilateral neck node dissection was performed in 25 patients, whereas bilateral neck node dissection was performed in 5 patients. Further, 17 patients were treated with both laryngectomy and neck node dissection; 12 patients received Gy radiation alone; 14 patients received surgery plus Gy post-operative radiotherapy; 30 patients were given cisplatin-based chemotherapy alone; 9 patients were treated with combined cisplatin-based chemotherapy, including 1 case of radiotherapy plus adjuvant chemotherapy, 6 cases of surgery plus chemotherapy, 2 cases of surgery plus 60 Gy post-operative radiotherapy plus adjuvant chemotherapy and 17 patients refused active therapy and hence received only supportive care. Survival The last follow-up was on 31 December 2012, with a median follow-up time of 49.5 months (range, 7 176). No patients were lost during the follow-up. In total, 118 patients were alive and 106 patients died. The estimated 3-, 5- and 10-year survival rates of the entire patient sample were 56.6%, 46.4% and 39.2%, respectively. Univariate analysis As shown in Table 3, survival after recurrence was significantly influenced by variables related to both primary and recurrent tumour. The age, smoking index, grade, primary site, initial T stage, initial UICC stage and nodal status of the primary tumour, as well as the disease-free interval, extent of the recurrence and suitable for surgery were powerful prognostic factors for survival (Figure 1). Multivariate analysis Multivariate survival analysis was performed using the Cox regression model to calculate the odds ratio and 95% confidence intervals. Results of multivariate analysis are shown in

5 Page 5 of 7 Table 3 (Continued) Prognostic factor No. of patients 5-year OS χ 2 P a Distant (±regional) 16 0% Suitable for surgery <0.001 No % Yes % a Log-rank test. b Patients were divided into two groups according to the median age. c Smoking index is defined as the number of cigarettes smoked per day the total smoking time (years). d Patients were divided into two groups according to the median duration of disease-free interval. Table 4. Model A included variables related to both primary and recurrent tumour, while model B was composed of only the former and model C was composed of only the latter. Because the initial UICC stage depends on the initial T stage and nodal status, this variable was omitted from the analysis. According to model A, the initial T stage, nodal status and suitability for surgery strongly predicted patient outcome. When the analysis was limited Figure 1: Survival curves of various groups of patients. (a) Overall survival by age. (b) Overall survival by smoking index. (c) Overall survival by grade. (d) Overall survival by primary site. (e) Overall survival by initial T stage. (f) Overall survival by initial nodal status. (g) Overall survival by disease-free interval. (h) Overall survival by extent of recurrence. (i) Overall survival by suitable for surgery.

6 Page 6 of 7 Table 4 Multivariate analysis of the effect of clinico-pathological factors on OS in recurrent laryngeal carcinoma patients Variables OS Odds ratio 95% CI P values Model A Age Smoking index Grade Primary site Initial T stage Nodal status Extent of the recurrence Suitable for surgery <0.001 Disease-free interval Model B Age Smoking index Grade Primary site Initial T stage <0.001 Nodal status Model C Disease-free interval Suitable for surgery <0.001 Extent of the recurrence <0.001 to factors related with primary tumour (model B), initial T stage and nodal status were the only factors that predicted survival. When the analysis was limited to recurrence-related factors (model C), extent of recurrence and suitability for surgery were independent prognostic factors in recurrent laryngeal SCC patients. Discussion Dealing with recurrent laryngeal cancer is arguably the greatest challenge faced by the physicians who treat these patients. This group of patients presents a unique set of dilemmas because the chance for a cure is low, and prior treatment generally has a negative impact on all current therapeutic options. In this study, we retrospectively evaluated the significance of various prognostic factors related to both primary and recurrent tumour in 224 patients with recurrent laryngeal cancer treated at the Sun Yat-sen University Cancer Center, China to gain a better understanding of the natural course of this entity and the factors predicting outcome. The estimated 3-, 5- and 10-year survival rates of the entire patient sample were 56.6%, 46.4% and 39.2%, respectively. Our results are similar to those previously reported 11,14. The estimated 5-year survival rate of the patients that had local recurrence was only 55.8%. When regional disease was involved, the survival rate decreased to 40.2%, with a further decline to 0% when distant metastases were present. On multivariate analysis, our results showed the 5-year overall survival (OS) was significantly related to the initial T stage, nodal status, extent of recurrence and operability of the recurrent tumour. Further, univariate analysis indicated that age 60 years, smoking index 600, poor degree of tumour differentiation (moderately or poorly), primary site (supraglottic cancer) and disease-free interval <11 months correlates with poor prognosis. These results are partly similar to those previously reported 11,14. In a similar research, Brenner et al. 14 found that six prognostic factors related to survival of patients with recurrent laryngeal cancer on univariate analysis: T stage and nodal status of the primary tumour, primary tumour site, duration of disease-free interval, site of recurrence and operability of the recurrent tumour. Multivariate analysis only revealed that the initial site and site of recurrence retained statistical significance. When factors related to the primary disease were excluded from the analysis, the site of recurrence and its operability were the only predictors of survival. In addition, Lacy et al. 15 found that the site of recurrence was a significant prognostic factor for survival, in addition to the method of treatment of the primary tumour and original TNM stage. The operability of the recurrent tumour was also found to predict survival, but only on univariate analysis. Goodwin et al. 16 reported a prospective review of 109 consecutive patients (larynx with 46 patients) undergoing salvage surgery for recurrent SCC of the upper aerodigestive tract; they reported some contrasting results. They found that good prognosis was strongly dependent on the TNM stage of recurrent disease at the time of surgical salvage, weakly dependent on the site of disease and not dependent on the time to recurrence after initial therapy.

7 Page 7 of 7 Our results showed that 92.8% patients had a locoregional recurrence, which accounted for the high rate (71.0%) of salvage surgery. Our rate of salvage surgery was comparable with that reported by Lacy et al. (rate of salvage surgery = 78%) 15 and Brenner et al. (rate of salvage surgery = 69%) 14. However, the rate was much higher than that reported by Yuen et al. (rate of salvage surgery = 21% only) 4. Salvage surgery is generally considered to be the first option if the recurrent disease is resectable and the patient is able to undergo the required surgery. Fortunately, due to natural barriers to tumour spread, the ability to remove the entire larynx without threatening vital function and the relatively early onset of symptoms associated with recurrent disease, surgical salvage is highly successful 17. The relationship between salvage surgery and OS has been examined in many patient series; this includes the results of studies conducted by Brenner et al. 14 (76% patients who underwent salvage surgery were alive at the time of their analysis compared with 35% of those with inoperable recurrent disease, P < 0.05) and Yuen et al. 4 (42% 5-year survival rate for patients who underwent surgery for recurrence compared with 2% of those who did not, P < 0.05). These results were substantially confirmed by our study, in which the estimated 5-year survival rate of the patients suitable for salvage surgery was 55.8%, which was much higher than those who were unsuitable for salvage surgery (17.4% only, P < 0.001). The major criticism of retrospective studies is that the data collected were not originally designed for a research application. Therefore, some factors responsible for the ultimate treatment outcome might be omitted in the analysis, thereby contributing to bias. Such censure correctly refers to the present study, in which the data were heterogeneous and of lesser quality according to present standards. Considering these factors, one should realize that conclusions from this study should be validated by future projects. Conclusion Above all, our data suggest that initial lower T stage, no initial cervical lymph node metastasis, only local recurrence and patients suitable for salvage surgery are favourable prognostic factors for OS of patients with recurrent laryngeal cancer. Acknowledgements This work was supported by the Excellent Talents Project of Zhejiang Cancer Hospital, P. R. China (To: T Jin, No. 2013). References 1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, CA Cancer J Clin Sep Oct;60: Barthel SW, Esclamado RM. Primary radiation therapy for early glottic cancer. Otolaryngol Head Neck Surg Jan; 124(1): The Department of Veterans Affairs Laryngeal Cancer Study Group. 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