Quality of Life in Head and Neck Cancer Patients: Impact of HPV and Primary Treatment Modality

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1 The Laryngoscope VC 2013 The American Laryngological, Rhinological and Otological Society, Inc. Quality of Life in Head and Neck Cancer Patients: Impact of HPV and Primary Treatment Modality Jessica H. Maxwell, MD, MPH; Vikas Mehta, MD; Hong Wang, PhD; Diana Cunningham, MS; Umamaheswar Duvvuri, MD, PhD; Seungwon Kim, MD; Jonas T. Johnson, MD; Robert L. Ferris, MD, PhD Objectives/Hypothesis: To determine posttreatment quality of life (QOL) in head and neck cancer patients, stratifying by human papillomavirus (HPV)/p16 status and primary treatment modality. Study Design: Retrospective study. Methods: One hundred and seventy-seven patients (N 5 177) with head and neck squamous cell carcinoma and known HPV/p16 status were included. All patients completed at least one baseline or posttreatment University of Washington QOL survey. QOL scores were averaged and compared across patients, stratifying by HPV/p16 status and primary treatment modality (surgical vs. nonsurgical). In the analysis, p16 was used as a surrogate marker for HPV. Results: Of the 177 patients, 80 (45.2%) were p16-positive and 49.7% of subsites were oropharyngeal. Nearly 60% (105/177) of patients underwent primary surgery, 26.7% (28/105) of patients with transoral robotic or laser techniques. The remainder 40.7% of patients underwent primary radiation and/or chemotherapy. Overall, QOL scores were better for p16-positive patients compared to p16-negative patients at baseline (P ), at 6 months posttreatment (P ), and at greater than 1 year posttreatment (P ). P16-positive patients had better QOL scores in speech (P ), chewing (P ), and swallowing (P ) after 1 year posttreatment compared to p16-negative patients. Primary treatment modality did not affect overall QOL or any of the 12 QOL categories in p16-positive patients at any time point. At over 1 year posttreatment, QOL was at or above baseline in both p16-positive treatment groups. Conclusion: The p16-positive patients had better baseline and posttreatment overall QOL compared to p16-negative patients. The overall and category specific QOL scores for p16-positive patients were not affected by primary treatment modality. Key Words: Quality of life, HPV, p16, head and neck squamous cell carcinoma. Level of Evidence: 4. Laryngoscope, 124: , 2014 INTRODUCTION Human papillomavirus (HPV) is a recently discovered cause of oropharyngeal squamous cell carcinoma (OPSCC) and portends a favorable prognosis. 1,2 Patients with HPV-positive OPSCC tend to be younger, 3 less likely to smoke, 3,4 and have an improved disease-specific and overall survival compared to their HPV-negative counterparts. 1,2,4 The improved survival benefit is seen in HPV-positive patients regardless of primary treatment modality, including primary surgery with or without adjuvant therapy 5 or definitive chemoradiation. 1,2 Because survival is expected among HPV-positive patients and the incidence of HPV-positive OPSCC is increasing, 6 8 the factors that contribute to posttreatment quality of life (QOL) become more important for this particular group of patients. Understanding the relationship between QOL and HPV can also help guide clinicians in clinical management and treatment options. While OPSCC was traditionally treated with upfront chemoradiation, 9 11 primary surgical management is returning to the forefront with the use of transoral, minimally invasive techniques. 12,13 It has yet to be determined how QOL is affected by primary treatment modality among HPVpositive patients. The goal of this study was to determine the role of HPV status and primary treatment modality on QOL in patients with head and neck squamous cell carcinoma. From the Department of Otolaryngology, University of Pittsburgh Medical Center (J.H.M., U.D., S.K., J.J., R.L.F.); the University of Pittsburgh Cancer Institute, Biostatistics Facility (H.W., D.C.), Pittsburgh, Pennsylvania; and the Department of Otolaryngology/Head and Neck surgery, LSUHSC Shreveport (V.M.), Shreveport, Louisiana, U.S.A. Editor s Note: This Manuscript was accepted for publication November 1, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Robert L. Ferris, MD, PhD, Suite 500, 203 Lothrop Street, Pittsburgh, PA 15213; ferrrl@upmc.edu DOI: /lary MATERIALS AND METHODS Study Population After approval was obtained from the institutional review board of the University of Pittsburgh Medical Center (IRB - PRO ), patients with a primary head and neck squamous cell carcinoma diagnosed between 2006 and 2012 at the University of Pittsburgh Medical Center were included in this study. Patients were included only if they had completed at least one University of Washington QOL version 4 (UW-QOL v4) survey at specific time points before and/or after treatment. Known HPV and p16 status by in situ hybridization and

2 immunohistochemistry, respectively, was an additional inclusion criterion for this study. Demographic and clinical data obtained from our prospectively collected head and neck database included age, gender, primary tumor site, clinical and pathological tumor stage, HPV and p16 status, treatment modality, and follow-up time. Tumor stage was defined by the American Joint Committee on Cancer (AJCC version 6). Survival data was not collected or included in the analysis. Among patients who were treated with primary surgery, differences in QOL were analyzed among those who underwent open versus minimally invasive techniques. Minimally invasive techniques included transoral robotic surgery and microsuspension laryngoscopy with laser. Neck dissections were performed, when appropriate, in patients who underwent both open and minimally invasive techniques. HPV and p16 Analysis All patients tumors included in this study were tested for HPV by in-situ hybridization (ISH) and p16 by immunohistochemistry (IHC) at the time of initial diagnosis. HPV detection by in situ hybridization was performed using probes targeting 37 distinct HPV subtypes, including 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, and 52 (Y1404; Dako, Carpinteria, CA). Cases with punctate nuclear signal were considered positive. 14 For p16 analysis, heat-induced epitope retrieval of deparaffinized tumor sections was then performed in a citrate buffer. Immunohistochemistry for p16 (G ; BD Pharmingen, San Diego, CA) was performed as per the manufacturer s protocol. Cases were reviewed by specialized head and neck pathologists and were considered positive if > 70% to 80% of tumor cells showed diffuse, strong cytoplasmic and nuclear staining. 14 P16 status by IHC was used for the statistical analysis. QOL Assessment QOL was assessed using the UW-QOL v4 survey administered before and after treatment. The UW-QOL v4 survey is a validated head and neck cancer-specific health related questionnaire that consists of 12 domain-specific items The 12 domains include pain, appearance, activity, recreation, swallowing, chewing, speech, shoulder function, taste, saliva, mood, and anxiety. The QOL survey also includes the most important domains as perceived by the patient. Each domain item is scored from 0 to 100 with 100 being the best possible response. An overall QOL score was determined by averaging across all 12 domains. Investigators have shown that a 7-point difference in overall QOL score represents the minimal clinically important difference. 18 Patients in the head and neck cancer clinic at the University of Pittsburgh are routinely offered the UW-QOL v4 survey during their clinic visit. Patient QOL surveys were only included for this study if they fell into one of five time periods. These time periods included a baseline survey prior to treatment (within 60 days pretreatment) and four surveys posttreatment at 2 months (6 30 days), 6 months (6 40 days), 1 year (6 60 days), and between 1 and 3 years. Patients with QOL surveys that were completed outside of these time periods were excluded from this study. Patients had to have completed at least one survey in a specified time period to be included in the study, but there was no upper limit to the number of surveys they could complete. To obtain a sufficient sample size, patients were not required to have completed consecutive surveys at each time period in order to be included in the study. Most patients responded to more than one survey; however, only three patients responded to surveys at all five time periods. A change in QOL was calculated by subtracting the difference in QOL scores between two time periods of interest. Statistical Analysis Statistical analysis was performed in SAS 9.3 software (SAS Corp, Cary, NC). To examine differences in patient characteristics by p16 status, primary treatment modality and oropharynx subsite, both Fisher s exact tests and Wilcoxon Mann Whitney tests were used for categorical variables and continuous variables, respectively. When examining changes from baseline, the change in score for each domain was calculated by subtracting the baseline score from the score for the corresponding month for each patient. A positive value would indicate an improvement and a negative value would indicate that conditions worsened for that domain. To determine if the change from baseline was significant, we applied the Wilcoxon sign test. To determine if there were significant differences in scores at each time point between patients with and without surgery, with open versus minimally invasive techniques, by p16 status and oropharynx subsite, Wilcoxon-Mann Whitney exact tests were used. P values of less than 0.05 were considered statistically significant. To determine if there were significant differences in scores at each time point between patients with and without surgery, by p16 status and oropharynx subsite, Wilcoxon-Mann Whitney exact tests were used. P values of less than 0.05 were considered statistically significant. RESULTS One hundred and seventy-seven patients (N 5 177) were included in this study. Nearly half of all patients were p16-positive (45.2%; 80/177). Nearly half of all patients had an oropharyngeal primary tumor (88/177; 49.7%). Approximately 30% of p16-positive patients underwent primary surgical resection (24/80; 30%) compared to 83.5% of p16-negative patients (81/97; P < ). Table I demonstrates clinical and pathological data for all patients in this cohort. Of the 177 patients, 33 responded to a survey at baseline, 62 at 2 months, 86 at 6 months, 77 at 1 year, and 54 at greater than 1 year after initial treatment. There was no statistical difference in the proportion of p16-positive patients with QOL data at each time point. The proportion of p16-positive patients with QOL data ranged from a low of 39.5% at the 1-year time point to a high of 53.8% at the 1- to 3-year time point. Baseline QOL scores differed among p16-positive and p16-negative patients in that p16-positive patients had significantly better scores in overall QOL (P ; Fig. 1), recreation (P 5.004), and chewing (P ; Fig. 2a). At 2 months posttreatment, p16-positive patients had better scores in chewing (P ; Fig. 2a) and speech (P ; Fig. 2b) compared to p16-negative patients. At 6 months posttreatment, p16-positive patients had better activity (P ), recreation (P ), swallowing (P ; Fig. 2c), speech (P ; Fig. 2b), and overall QOL (P ; Fig. 1) compared to p16-negative patients. The benefit for p16- positive patients in activity (P ), recreation (P ), swallowing (P ), chewing (P ), speech (P ), and overall QOL (P ) was maintained between 1 and 3 years posttreatment. In contrast, saliva production was the only domain that 1593

3 TABLE I. Clinical and Pathologic Data of All Patients by p16 Status. p16-positive (n 5 80) p16-negative (n 5 97) Characteristic No. % No. % P value Age (mean) Gender.217 Male Female Tumor subsite <.0001 Oropharynx Nonoropharynx HPV <.0001 Positive Negative Not evaluated T class Tis T T T T Unknown N class <.0001 N N N N Unknown AJCC stage*.001 I II III IV Unknown Primary Treatment <.0001 Surgical Nonsurgical Radiation <.0001 Yes No Chemotherapy <.0001 Yes No *AJCC stage 5 American Joint Committee on Cancer stage. Radiation 5 Includes patients treated with primary radiation and postoperative radiation. Chemotherapy 5 Includes patients treated with primary chemotherapy and postoperative chemotherapy. was significantly better for p16-negative patients compared to p16-positive patients (P ; Fig. 2d) at 2, 6, and 12 months posttreatment. However, this difference was no longer significant after 1 year posttreatment. Among p16-positive patients only, overall QOL scores did not differ by primary treatment modality. Furthermore, primary surgery versus chemoradiation did not affect QOL in any of the 12 domains at any time point among p16-positive patients. Similarly, among p16-negative patients, primary treatment modality did not affect baseline or posttreatment overall QOL. However, at 2 months posttreatment for p16-negative 1594

4 techniques. In p16-positive patients only, those who underwent minimally invasive techniques had better scores in recreation and mood at 6 months only (P for both domains) compared to those who underwent open techniques. In p16-negative patients, appearance was the only significantly better domain among those who underwent minimally invasive techniques compared to open techniques (at 6 months only; P ). Fig. 1. Overall QOL by p16 status at each time point. [Color figure can be viewed in the online issue, which is available at patients, shoulder function was better in the chemoradiation group (P ); this difference resolved by 6 months posttreatment. There were no long-term differences in QOL for p16-negative patients treated with primary surgery versus chemoradiation. Patients who underwent primary surgical management were further stratified into two categories, open versus minimally invasive techniques that included use of either the robot or laser. Among all patients who underwent primary surgery, 26.7% (28/105) underwent minimally invasive surgery. Regardless of primary tumor site or p16 status, those who underwent minimally invasive techniques had better scores in chewing at 2 months (P ) and appearance at 6 months (P ) compared to those who underwent open DISCUSSION It is now recognized that patients with HPV-positive OPSCC have an improved survival when compared to their HPV-negative counterparts. 1,2 This improved survival is demonstrated in patients treated with both chemoradiation 1,4 and primary surgery, 5 including transoral robotic surgery 12 and transoral laser surgery. 13 With a growing number of HPV-positive OPSCC patients and a remarkable cure rate, their potential vulnerability to treatment intensity becomes more important, and the emphasis on QOL is thus essential to quantify. This is the first study to our knowledge that analyzes QOL using a validated survey and stratifying for both p16 status and primary treatment modality. Our findings reveal that QOL scores in each of 12 domains, including overall QOL, do not differ by primary treatment modality among the p16-positive OPSCC patients. In other words, there was no difference in QOL scores among those treated with primary surgery with or without adjuvant therapy compared to those treated with primary chemoradiation. Although only 30% of p16-positive patients underwent primary surgical Fig. 2. (a) Chewing by p16 status at each time point. (b) Speech by p16 status at each time point. (c) Swallowing by p16 status at each time point. (d) Saliva by p16 status at each time point. [Color figure can be viewed in the online issue, which is available at

5 management in our cohort, nearly all of those patients received adjuvant radiation. Even with double modality treatment, QOL was unaffected, suggesting that the addition of surgery has a minimal, if any, effect on longterm QOL scores in p16-positive patients. Furthermore, there were no QOL differences at 1 to 3 years posttreatment among the p16-positive patients managed with minimally invasive techniques versus open surgery. This apparent lack of QOL differences may, however, be due to small sample sizes after controlling for p16 status and treatment modality at each of the five time points. As expected, p16-positive patients in our study had better baseline and posttreatment QOL scores compared to p16-negative patients. This is most likely due to the fact that p16-positive patients are more often young, nonsmokers. 3 Investigators from the University of Washington demonstrated that baseline QOL scores were higher for HPV-positive patients compared to their HPVnegative counterparts. 19 They found a decrease in pretreatment to posttreatment QOL scores that was greater for the HPV-positive patients compared to the HPVnegative patients. By 1 year posttreatment, however, there was no association between HPV status and QOL. This is in contrast to our findings, which demonstrated that although overall QOL initially decreased for HPVpositive patients following treatment, it then returned to levels that were higher than baseline after 1 year posttreatment. They were also significantly better when compared to the HPV-negative cohort. Reasons for these discrepancies are unclear. In the study by Sharma et al., 19 the HPV-negative cohort was limited to patients with oropharyngeal or oral cavity squamous cell carcinoma. It is possible that our long-term QOL scores were lower for HPV-negative patients because other head and neck subsites were included. Of interest, the only domain in which HPV-positive patients fared worse than HPV-negative patients was in saliva. This is most likely attributable to the increased use of both primary and adjuvant radiation therapy among patients with HPV-positive compared to HPVnegative patients (95% versus 67%). Furthermore, the location of radiation exposure among OPSCC patients, who are more often HPV-positive, is more likely to involve the salivary glands than other subsites of the head and neck such as the larynx. Despite the initial discrepancy in posttreatment saliva scores among HPVpositive and HPV-negative patients, this difference became insignificant after 1 year of posttreatment QOL follow-up. With the advent of minimally invasive techniques to manage OPSCC, several investigators have analyzed QOL outcomes among patients treated with transoral robotic surgery (TORS) Two studies from Ohio State University on TORS patients revealed that QOL scores initially deteriorated after surgery in speech, eating, aesthetics, social disruption, and overall QOL. 20,23 However, they noted a return of QOL to high levels in all categories except for eating after 1 year posttreatment. 20,23 These studies utilized the Head and Neck Cancer Inventory HNCI grading system for QOL, which includes four domains. This is in contrast to the UW QOL v4 survey used in our study, which includes 12 domains and does not include eating as a distinct category. Swallowing, however, is a comparable UW- QOL v4 category; among our p16-positive patients, swallowing scores declined from an average baseline of 86 to 66 at 6 months posttreatment, but rebounded to 87 after 1 year posttreatment (Fig. 2c). Otherwise, our results among p16-positive patients parallel the findings in TORS cohorts, which contained approximately 84% to 85% p16-positive patients. 20,23 Our findings among the p16-positive patients are also similar to TORS trials in that overall QOL initially decreased from an average pretreatment score of 77 to a nadir of 57 at 2 months after treatment. The average overall QOL score then returned to even better than baseline at 82 (Fig. 1). A major difference between the prior investigations on TORS patients and our current study is that our cohort was stratified by p16 status and primary treatment modality. This stratification enabled us to conclude that primary surgery with adjuvant therapy does not lead to a difference in QOL compared to standard chemoradiation therapy among p16-positive patients. There are several limitations of our study that deserve mention. For one, to ensure a large sample size, patients were included if they completed at least one survey at a specified time period. It was not feasible to obtain serial QOL surveys from the same patient. In fact, only three patients responded to surveys at all five time periods. It is possible that patients who fared poorly were not well enough to go to their clinic visits, or even passed away following treatment would not have completed posttreatment surveys. This bias may have led to falsely elevated QOL scores, especially in the patients with HPV-negative head and neck cancer who were much more likely to recur or die from the disease during the study time period. While we estimate a very low number of deceased patients, we were unable to account for this in our methodology. Furthermore, 92.7% (164/177) of patients submitted surveys within their first year of posttreatment, which would likely reflect most of those with disease recurrence. In addition, there were not enough p16-positive, surgically treated patients to stratify by type of adjuvant therapy. Therefore, we were unable to determine a difference in QOL scores among those who received surgery alone, surgery plus radiation, and surgery plus chemoradiation. Since most patients (95%) underwent adjuvant therapy, we are able to conclude that QOL did not differ among those who underwent surgery plus adjuvant therapy versus chemoradiation alone. Similarly, age and other potential confounders were not controlled for in the QOL analysis at each time point because this would have further limited the sample size. A larger, prospectively mandated cohort and future deintensification of adjuvant therapy would allow for more in-depth stratification by treatment modality. CONCLUSION Ultimately, p16-positive patients in our cohort had better baseline and posttreatment overall QOL compared

6 to p16-negative patients. The overall and category specific QOL scores for p16-positive patients were not affected by primary treatment modality. Specifically, patients treated with primary surgery and adjuvant radiation had similar quality of life scores compared to those treated with primary chemoradiation, regardless of HPV/p16 status. BIBLIOGRAPHY 1. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363: Fakhry C, Westra WH, Lis S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008;100: Gillison ML, D Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 2008;100: Maxwell JH, Kumar B, Feng FY, et al. Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res 2010;16: Maxwell JH, Ferris RL, Gooding W, et al. Extracapsular spread in head and neck carcinoma: impact of site and human papillomavirus status. Cancer 2013;119: Chaturvedi AK, Engels EA, Pfeiffe, RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011;29: Ernster JA, Sciotto CG, O Brien MM, et al. Rising incidence of oropharyngeal cancer and the role of oncogenic human papilloma virus. Laryngoscope 2007;117: Chenevert J, Chiosea S. Incidence of human papillomavirus in oropharyngeal squamous cell carcinomas: now and 50 years ago. Hum Pathol 2012;43: Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350: Bernier J. Chemoradiation in locally advanced head and neck cancer: new evidence, new challenges. Expert Rev Anticancer Ther 2004;4: Bernier J, Cooper JS, Pajak RF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC ( 22931) and RTOG ( 9501). Head Neck 2005;27: Cohen MA, Weinstein GS, O Malley BW Jr, Feldman M, Quon H. Transoral robotic surgery and human papillomavirus status: oncologic results. Head Neck 2011;33: Haughey BH, Hinni ML, Salassa JR, et al. Transoral laser microsurgery as primary treatment for advanced-stage oropharyngeal cancer: a United States multicenter study. Head Neck 2011;33: Singhi AD, Westra WH. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. Cancer 2010;116: D Cruz AK, Yueh B, Das AK, McDowell JA, Chaukar DA, Ernest AW. Validation of the University of Washington quality of life questionnaires for head and neck cancer patients in India. Indian J Cancer 2007;44: Vartanian JG, Carvalho AL, Yueh B, et al. Brazilian-Portuguese validation of the University of Washington Quality of Life Questionnaire for patients with head and neck cancer. Head Neck 2006;28: Rogers SN, Gwanne S, Lowe D, Humphris G, Yueh B, Weymuller EA Jr. The addition of mood and anxiety domains to the University of Washington quality of life scale. Head Neck 2002;24: El-Deiry MW, Futran ND, McDowell JA, Weymuller EA Jr. Influences and predictors of long-term quality of life in head and neck cancer survivors. Arch Otolaryngol Head Neck Surg 2009;135: Sharma A, Mendez E, Yueh B, et al. Human papillomavirus-positive oral cavity and oropharyngeal cancer patients do not have better quality-oflife trajectories. Otolaryngol Head Neck Surg 2012;146: Hurtuk AM, Marcinow A, Agrawal A, Old M, Teknos TN, Ozer E. Qualityof-life outcomes in transoral robotic surgery. Otolaryngol Head Neck Surg 2012;146: Leonhardt FD, Quon H, Abrahao M, O Malley BW Jr, Weinstein GS. Transoral robotic surgery for oropharyngeal carcinoma and its impact on patient-reported quality of life and function. Head Neck 2012;34: Sinclair CF, McColloch NL, Carroll WR, Rosenthal EL, Desmond RA, Magnuson JS. Patient-perceived and objective functional outcomes following transoral robotic surgery for early oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 2011;137: Dziegielewski PT, Teknos TN, Durmus K, et al. Transoral robotic surgery for oropharyngeal cancer: long-term quality of life and functional outcomes. JAMA Otolaryngol Head Neck Surg 2013;10:1 9. doi: / jamaoto [Epub ahead of print]. 1597