Effects of tumor staging and treatment modality on functional outcome and quality of life after treatment for laryngeal cancer

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1 ORIGINAL ARTICLE Effects of tumor staging and treatment modality on functional outcome and quality of life after treatment for laryngeal cancer Stuart M. Robertson, FRCSGlasg(ORL-HNS), 1,2 * Justin C. L. Yeo, MRCS, 1 Lesley Sabey, MSc(Med Sci), 1,2 David Young, PhD, 3 Kenneth MacKenzie, FRCS(Ed) 1,2 1 Department of Otolaryngology, Head and Neck Surgery, Glasgow Royal Infirmary, United Kingdom, 2 West of Scotland Managed Clinical Network for Head and Neck Cancer, United Kingdom, 3 Department of Mathematics and Statistics, Strathclyde University, United Kingdom. Accepted 26 November 2012 Published online 9 March 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. An earlier stage of primary disease at diagnosis is associated with better survival from laryngeal cancer. It remains unproven whether earlier stage is also associated with improved end-organ function and quality of life after treatment. Methods. Questionnaire packs were posted to 250 patients with laryngeal cancer treated between January 2006 and December 2008 within the West of Scotland. Packs contained the Voice Symptom Scale (VoiSS), MD Anderson Dysphagia Inventory (MDADI), and University of Washington Quality of Life Questionnaire (UW-QOL). Results. One hundred forty-seven eligible patients provided data for analysis (59% of original cohort). Patients with an earlier stage of primary disease reported significantly better VoiSS, MDADI, and UW-QOL scores (p <.05). No differences were found between scores of patients with T1 laryngeal disease treated with endoscopic laser resection (ELR) and radiotherapy. Conclusion. An earlier stage at diagnosis is associated with significantly better end-organ function and quality of life after treatment for laryngeal cancer. VC 2013 Wiley Periodicals, Inc. Head Neck 35: , 2013 KEY WORDS: laryngeal cancer, voice, swallowing, quality of life, treatment modality INTRODUCTION Comprehensive changes have been made to the clinical management of patients with head and neck cancer in recent decades. The implementation of evidence-based guidelines has been widespread and multidisciplinary team (MDT) management is now the accepted standard of care. 1 3 Data from North America and Europe have confirmed significant changes in treatment patterns for laryngeal cancer with an increase in primary nonsurgical treatment during this time. 4 Despite all of these changes in practice, survival from laryngeal cancer has not improved. 4 The importance of achieving a cancer diagnosis at the earliest possible stage of disease has been widely publicized and it is accepted that survival and stage at diagnosis share an inverse relationship. 1 3 It is also presumed that a better functional outcome and quality of life after treatment will be achieved if cancer is diagnosed at an earlier stage of disease. 2 The latter hypothesis remains unproven to date and the literature contains conflicting evidence about the relationship between stage of laryngeal disease at diagnosis and posttreatment function and quality of life. 5 7 In Scotland, the incidence of laryngeal cancer is rising. 8 With the realization that MDT-driven practice has not improved survival, the importance of maximizing functional *Corresponding author: S. M. Robertson, Department of Otolaryngology, Head and Neck Surgery, Glasgow Royal Infirmary, Alexandra Parade, Glasgow G4 0SF, United Kingdom. stuartrobertson1@nhs.net outcome and quality of life for patients is greater than ever. 3 For an MDT to reach an evidence-based consensus on recommended treatment in circumstances in which different treatment options offer similar chances of cure, the estimated end-organ function and quality of life that will be achieved after each treatment must be taken into consideration. As an example, treatment options for early laryngeal disease include endoscopic laser resection (ELR) and radiotherapy. ELR leaves the option of radiotherapy in reserve for future salvage, whereas both options offer an equal chance of achieving cure. The relative voice and swallowing outcome achievable with these treatments modalities are key factors in the decision-making process. 1,2 The principal purpose of this study was to determine the association between primary tumor staging and treatment modality on the functional outcome of patients 3 years after completing treatment for laryngeal cancer. The secondary purpose was to compare the functional outcome and quality of life of patients with T1 laryngeal disease treated with ELR and radiotherapy. Approval to conduct this study was granted by the Research Committee and Advisory Board of the West of Scotland Managed Clinical Network (MCN) for Head and Neck Cancer. MATERIALS AND METHODS Participants In January 2010, the West of Scotland MCN database confirmed that 300 patients with laryngeal cancer were HEAD & NECK DOI /HED DECEMBER

2 ROBERTSON ET AL. treated within the MCN between January 2006 and December The West of Scotland MCN comprises 8 clinical units providing head and neck cancer services to approximately 2.8 million patients, approximately 60% of the Scottish population. Patients who had undergone laryngectomy surgery within this 2-year period were excluded as it was considered that this small but significant cohort might have specific end organ and quality of life issues that could skew the results. In addition, the functional outcome and quality of life of surviving laryngectomy patients within the West of Scotland MCN has already been analyzed in a recently published study. 8 Patients diagnosed with metachronous tumors, a histological diagnosis other than squamous cell carcinoma, and those dying during the study period were also excluded. All eligible patients were posted a questionnaire packet, as detailed below. Informed consent was assumed by the return and completion of the questionnaires. Patients were asked to complete a data collection form and confirm which primary treatments they received (surgery, radiotherapy, and/or chemotherapy) and whether they received further treatment (salvage surgery, radiotherapy, and/or chemotherapy). Both paper and electronic case records were accessed to confirm data on T classification, primary treatment modality, disease-free status, and salvage treatments received. Questionnaires To assess voice, swallowing, and quality of life, the Voice Symptoms Scale (VoiSS), MD Anderson Dysphagia Inventory (MDADI), and the University of Washington Quality of Life (UW-QOL) questionnaires were used, respectively. Voice Symptoms Scale VoiSS is a well-established and psychometrically robust outcome measure to assess voice outcome. VoiSS has a significant correlation with perceptual voice analysis performed by speech and language therapists. 9,10 It is a 30-item questionnaire with a total score ranging from 0 to 120. Patients select 1 of 5 possible responses for each statement (never, occasionally, some of the time, most of the time, and always). A higher total score reflects a greater severity of dysphonia and poorer voice-related quality of life. 9,10 MD Anderson Dysphagia Inventory The MDADI comprises 20 statements related to dysphagia in 4 subscales (global, emotional, functional, and physical) and has been rigorously validated in populations of patients with head and neck cancer. 11 Patients select 1 of 5 possible responses for each statement (strongly agree, agree, no opinion, disagree, and strongly disagree). This yields individual scores for each statement on a scale of 1 to 5 and a total score of 20 to 100. The MDADI total score was used for analysis in this study. A higher MDADI total score reflects better swallowing function and swallowing-related quality of life. TABLE 1. Variables Exclusions from original sample. Initial cohort 300 Excluded laryngectomy 42 Excluded metachronous SCC head and neck 3 Excluded metachronous lung 1 Excluded laryngeal sarcoma (not SCC) 1 Excluded died 3 Final eligible study group 250 Abbreviation: SCC, squamous cell carcinoma. No. of patients University of Washington Quality of Life questionnaire The UW-QOL is a well-validated quality of life outcomes measure with 3 distinct parts. 12 The first part is comprised of single questions addressing 12 domains that include pain, appearance, activity, recreation, swallowing, chewing, speech, shoulder function, taste, saliva, mood, and anxiety. There are 3 to 5 possible responses yielding a score from 0 to 100 for each domain. The second part of UW-QOL enables the patient to choose which 3 of the 12 domains have been the most important in the past 7 days. The final part of the questionnaire is composed of 3 general questions concerning health-related and overall quality of life. 12 Higher questionnaire scores in each of the 3 domains reflect better quality of life. The overall composite UW-QOL score was used for data analysis in this study. Statistical analysis Between group comparisons of questionnaire scores were done using Kruskal Wallis tests or Mann Whitney U tests. All analyses were performed using Minitab (version 15) at a significance level of 5%. Data from the recently published West of Scotland Laryngectomy Audit 8 were also used to facilitate a comparison between the functional outcome of patients with advanced laryngeal disease treated with primary surgical treatment and organ-preserving chemoradiotherapy. RESULTS Demographics and treatment groups After applying the exclusion criteria described above, 250 of 300 patients (83%) were identified as eligible for study participation as detailed in Table 1. Patient record data were available for 222 of 250 patients (89%) and fully completed questionnaires were returned by 185 of 250 patients (74%). Staging, treatment, and questionnaire data were collated yielding a complete dataset for 161 of 250 patients (64%). Ten patients (6%) had received salvage treatment after failure of primary treatment and 4 patients (2%) had received multimodality primary treatment (ie, surgery, radiotherapy, and chemotherapy). These patients were also excluded because meaningful comparative statistical analysis between these small groups and the rest of the study population was not possible. Therefore, final dataset for analysis comprised data for 147 patients (59% of original eligible cohort). The median age in the cohort was 68 years (range, HEAD & NECK DOI /HED DECEMBER 2013

3 DETERMINANTS OF FUNCTIONAL OUTCOME AFTER TREATMENT FOR LARYNGEAL CANCER TABLE 2. T classification of patients. T classification (AJCC) No. of patients % T T T T4 5 4 Total Abbreviation: AJCC, American Joint Committee on Cancer. years) and the male-to-female ratio was 4:1. There were no significant differences between the median ages of patients in any of the treatment groups analyzed. Staging data All laryngectomy patients were excluded from this study as detailed above and only 5 of 147 patients in the final study group had T4 disease. To enable meaningful statistical analysis to be undertaken, patients with T3 and T4 disease were grouped together. Patients were therefore divided into 3 primary staging groups in accord with T classification, as detailed in Table Voice outcome The median total VoiSS score for the cohort was 22 (range, 0 100). There was a significant difference between the median total VoiSS scores of patients when analyzed in accord with T classification (Kruskal Wallis, p ¼.002). Significantly better median VoiSS scores were reported by patients with T1 disease than by patients with T2 disease or T3/4 disease (Mann Whitney, both p <.05, Table 3). There was no significant difference between the median VoiSS scores of patients with T2 and T3/4 disease (Mann Whitney, p ¼.08, Table 3). Swallowing outcome The median total MDADI score was 78 (range, 0 100). There was a significant difference between the median MDADI scores of patients when analyzed according to T classification (Kruskal Wallis, p <.001). Significantly better median MDADI scores were reported by patients with T1 disease in comparison with T2 disease (Mann Whitney, p <.05) and by patients with T2 disease in comparison with T3/4 disease (Mann Whitney, p <.01, Table 4). Quality of life The median composite UW-QOL score was 100 (range, ). There was a significant difference between the TABLE 3. total Voice Symptom Scale scores by T classification (Kruskal Wallis p 5.002). T classification No. of patients total VoiSS T (0 93) T (0 100) T3/ (3 92) All (0 100) Abbreviation: VoiSS, Voice Symptom Scale. TABLE 4. total MD Anderson Dysphagia Inventory scores by T classification (Kruskal Wallis p <.001). T classification No. of patients total MDADI T (0 97) T (20 100) T3/ (0 92) All (0 100) Abbreviation: MDADI, MD Anderson Dysphagia Inventory. median composite UW-QOL scores of patients when analyzed by T classification (Kruskal Wallis, p <.001). Significantly better composite median UW-QOL scores were reported by patients with T1 disease in comparison with T2 disease (Mann Whitney, p <.01) and by patients with T2 disease in comparison with T3/4 disease (Mann Whitney, p <.01, Table 5). Treatment group data Patients were divided into 3 treatment groups (surgery, radiotherapy, and chemoradiotherapy) according to the primary treatment modality undertaken. Ninety-one of 149 patients had been treated with radiotherapy only, 29 had been treated with surgery only, and 27 had been treated with chemoradiotherapy. Significant differences were demonstrated among the median total VoiSS, MDADI, and composite UW-QOL scores of patients when analyzed by treatment group (all Kruskal Wallis, p.007). Patients treated with chemoradiotherapy reported significantly worse median VoiSS (Mann Whitney, p <.01), MDADI (Mann Whitney, p <.001), and composite UW-QOL scores (Mann Whitney, p <.001) than patients treated with surgery or radiotherapy (Table 6). However, when the primary T classification of patients in these treatment groups was taken into account, it was evident that these comparisons were not clinically relevant. Twenty-one of 27 patients (78%) treated with primary chemoradiotherapy had advanced (T3 or T4) disease, whereas only 5 of 120 patients (4%) treated with surgery or radiotherapy had advanced disease (Table 7). As we had already excluded laryngectomy patients from this study, the number of patients in the T3/4 group in this study was unrepresentatively low. Analysis of T1 classification group according to primary treatment Forty-three of 69 patients with T1 disease underwent ELR and 26 received radiotherapy. No significant TABLE 5. composite University of Washington Quality of Life scores by T classification (Kruskal Wallis p <.001). T classification No. of patients composite UW-QOL T (28 100) T (30 100) T3/ (30 100) All (0 100) Abbreviation: UW-QOL, University of Washington Quality of Life. HEAD & NECK DOI /HED DECEMBER

4 ROBERTSON ET AL. TABLE 6. total Voice Symptom Scale, MD Anderson Dysphagia Inventory, and composite University of Washington Quality of Life scores by treatment group. Treatment group No. of patients total VoiSS total MDADI composite UW-QOL Surgery (2 88) 80 (0 98) 100 (30 100) Radiotherapy (0 100) 80 (0 100) 100 (28 100) Chemoradiotherapy (3 92) 65 (0 100) 70 (30 100) Total (0 100) 78 (0 100) 100 (30 100) Kruskal Wallis p ¼.007 p <.001 p <.001 Abbreviations: VoiSS, Voice Symptom Scale; MDADI, MD Anderson Dysphagia Inventory; UW-QOL, University of Washington Quality of Life. differences were found between the median VoiSS scores of ELR (20.5; range, 2 62) and radiotherapy patients (15; range, 0 93, Mann Whitney, p ¼.331), median MDADI scores of ELR (88.5; range, 0 100), radiotherapy patients (85; range, 0 100, Mann Whitney, p ¼.602), median composite UW-QOL scores of ELR (100; range, ), and radiotherapy patients (100; range, , Mann Whitney, p ¼.586). Analysis of organ-preservation cohort Sixteen patients in the current study had received primary chemoradiotherapy for T3N0 laryngeal disease. Statistical analysis was undertaken to compare these organpreserved survivors with surviving laryngectomy patients recruited during the recent West of Scotland Laryngectomy Audit. 8 As shown in Table 8, no significant difference in median total VoiSS was found between the organ-preservation group and the "historical laryngectomy group (p ¼.826). Significant differences were found between the median total MDADI scores (p <.01) and median composite UW-QOL scores of these groups (p ¼.02; Table 8). DISCUSSION The literature contains conflicting evidence regarding the correlation between tumor stage and both healthrelated quality of life and functional outcome in patients with laryngeal cancer. 5 7 Our study suggests that 3 years after successful primary treatment for laryngeal cancer, significantly better voice, swallowing, and quality of life outcomes are reported after treatment by patients with an earlier T classification of disease at diagnosis. That an earlier tumor stage is associated with significant functional and quality of life benefits after treatment adds further support to rapid-access referral pathways for patients with specific symptoms and risk factors for head and neck cancer. Limitations of the current study include the fact that data collection on nonresponders to the questionnaire TABLE 7. Population divided into T classification and treatment groups. T classification Radiotherapy Surgery Chemoradiotherapy Total T T T T Total mailshot was not undertaken. This was in accordance with the specification of ethical approval granted for this study. Other limitations include absence of data on ethnic origin, education, smoking status, and comorbidity. A future prospective audit of patients with laryngeal cancer in the West of Scotland is planned to enable more comprehensive data collection and include these important variables. When analyzing laryngeal cancer cohorts in this way, it is accepted that treatment modality may be a confounding variable. It is difficult to determine the relative importance of T classification and treatment morbidity in terms of the effects these variables have on the functional and quality of life outcomes reported by patients. It is also difficult to compensate for changes in outcome that may occur with time when analyzing cohorts of patients with laryngeal cancer in observational studies. All patients in the current study were treated within a single MCN within the same 3-year period in accord with accepted and published management protocols. Once again, future prospective analysis of functional outcome and quality of life data reported by patients with laryngeal cancer before treatment commences is likely to contribute further to this interesting debate. The current study also contributes to the key debate surrounding the management of T1 laryngeal cancer. The literature contains conflicting evidence regarding the relative functional outcome of ELR and radiotherapy for early laryngeal disease. Some studies propose that the voice and swallowing outcomes reported by patients are not related to treatment modality, 14,15 whereas others propose that better swallowing outcomes are achieved with ELR. 16 Although our study did not include a power analysis, the sample size achieved was relatively large in TABLE 8. total Voice Symptom Scale, MD Anderson Dysphagia Inventory, and composite University of Washington Quality of Life scores of T3N0 patients treated with chemoradiotherapy vs historical controls managed with laryngectomy alone. Treatment modality No. of patients total VoiSS total MDADI composite UW-QOL Total laryngectomy (10 96) 79 (45 100) 94 (70 100) Chemoradiotherapy (3 92) 63 (41 91) 73 (40 100) Mann Whitney p ¼.826 p <.010 p ¼.020 Abbreviations: VoiSS, Voice Symptom Scale; MDADI, MD Anderson Dysphagia Inventory; UW- QOL, University of Washington Quality of Life HEAD & NECK DOI /HED DECEMBER 2013

5 DETERMINANTS OF FUNCTIONAL OUTCOME AFTER TREATMENT FOR LARYNGEAL CANCER comparison to other studies Our study proposes that similar voice, swallowing, and quality of life outcomes are reported by patients from the same geographic area with T1 disease treated with ELR and radiotherapy. All patients in the current study were treated within the same MCN in accordance with agreed national guidelines. Accordingly, these findings support current protocols advocating ELR for low-volume, early laryngeal disease that does not involve the anterior commissure and is not associated with extensive dysplastic field change in patients with acceptable anatomic access and sufficient performance status. 1,2 A second key debate within laryngeal cancer management of relevance to the current study is the controversy surrounding treatment options for advanced laryngeal cancer. 1,2 The decision-making process between primary chemoradiotherapy and primary surgery as treatment modalities for T3 disease remains difficult. 17 The popularity of organ preservation is based primarily on the knowledge that the success rate of this modality is comparable with that of primary laryngectomy in terms of survival. 18 By retaining an intact larynx, patients functional outcome and quality of life are likely to be superior to that of laryngectomy patients, as proposed by the landmark Veterans Affairs study. 18 Yet there remain significant concerns regarding the mucosal toxicity of modern chemoradiotherapy regimens and the resulting functional deficits. 17 There is a lack of evidence directly comparing the functional outcome and quality of life of patients with T3N0 laryngeal disease treated with surgical and nonsurgical modalities. Sixteen patients in the current study had received primary chemoradiotherapy for T3N0 laryngeal disease. It is acknowledged that these patients represent a very small group of organ-preserved survivors and, once again, power analysis was not undertaken. Nevertheless, it is useful to compare the functional outcome and quality of life reported by these patients with that of historical controls managed with surgery alone within the same geographic area. Statistical analysis was undertaken to compare these organ-preserved survivors with surviving laryngectomy patients recruited during the recent West of Scotland Laryngectomy Audit. 8 Although no significant difference in reported voice outcome was found between the organ-preservation group and the historical laryngectomy group, significant differences were found between the swallowing and quality of life outcomes. A significantly better swallowing outcome and quality of life was reported by the historical laryngectomy group. It is not possible to determine whether these patient groups are comparable in terms of age, sex, performance status, subsite, or stage of disease due to the limitations of these retrospective and observational studies. The laryngectomy group comprises a historical cohort of laryngectomy patients cured with surgery alone over 5 years ago, whereas the organ-preserved survivors from the current study were treated within the last 3 years and have avoided surgical salvage to date. It is known that the functional outcome and quality of life of laryngectomy patients in the West of Scotland is not related to time elapsed since undergoing surgery. 8 Whether patients voice, swallowing, or quality of life outcomes after chemoradiotherapy improve after 3 years is unknown. Although no conclusions can be drawn from this final analysis, it is clear that the mucosal toxicity of modern chemoradiotherapy regimes has a measurable and clinically significant effect on patients functional outcome and quality of life. Whether these detrimental effects are outweighed by the anatomic advantages of laryngeal preservation remains unproven. Prospective research comparing the outcome of patients with advanced laryngeal cancer treated with surgical and nonsurgical modalities must be the subject of future research if head and neck surgical oncologists are to continue improving the functional outcome of patients with laryngeal cancer. REFERENCES 1. EBP Compendium: summary of clinical practice guideline. Diagnosis and management of head and neck cancer: a national clinical guideline. 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