Oncologic Outcomes Following Transoral Robotic Surgery for Human Papillomavirus–Associated Oropharyngeal Carcinoma in Older Patients | Geriatrics | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
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Figure 1.  Patient Selection Flowchart of Patients With Human Papillomavirus–Associated Oropharyngeal Cancers Undergoing Transoral Robotic Surgery (TORS), Neck Dissection, and Pathologic Characteristic–Guided Adjuvant Therapy
Patient Selection Flowchart of Patients With Human Papillomavirus–Associated Oropharyngeal Cancers Undergoing Transoral Robotic Surgery (TORS), Neck Dissection, and Pathologic Characteristic–Guided Adjuvant Therapy
Figure 2.  Estimates of Survival for Human Papillomavirus–Associated Oropharyngeal Cancers
Estimates of Survival for Human Papillomavirus–Associated Oropharyngeal Cancers
Figure 3.  Estimates of Survival for Human Papillomavirus–Associated Oropharyngeal Cancers Stratified by Treatment Modality
Estimates of Survival for Human Papillomavirus–Associated Oropharyngeal Cancers Stratified by Treatment Modality
Table 1.  Baseline Clinical and Demographic Patient Characteristics
Baseline Clinical and Demographic Patient Characteristics
Table 2.  Univariate Analysis of Factors Associated With Survival Outcomes
Univariate Analysis of Factors Associated With Survival Outcomes
1.
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Pignon  J-P, le Maître  A, Maillard  E, Bourhis  J; MACH-NC Collaborative Group.  Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients.   Radiother Oncol. 2009;92(1):4-14. doi:10.1016/j.radonc.2009.04.014 PubMedGoogle ScholarCrossref
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de Almeida  JR, Li  R, Magnuson  JS,  et al.  Oncologic outcomes after transoral robotic surgery: a multi-institutional study.   JAMA Otolaryngol Head Neck Surg. 2015;141(12):1043-1051. doi:10.1001/jamaoto.2015.1508 PubMedGoogle ScholarCrossref
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de Almeida  JR, Byrd  JK, Wu  R,  et al.  A systematic review of transoral robotic surgery and radiotherapy for early oropharynx cancer: a systematic review.   Laryngoscope. 2014;124(9):2096-2102. doi:10.1002/lary.24712 PubMedGoogle ScholarCrossref
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Weinstein  GS, O’Malley  BW  Jr, Magnuson  JS,  et al.  Transoral robotic surgery: a multicenter study to assess feasibility, safety, and surgical margins.   Laryngoscope. 2012;122(8):1701-1707. doi:10.1002/lary.23294 PubMedGoogle ScholarCrossref
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Weinstein  GS, Quon  H, Newman  HJ,  et al.  Transoral robotic surgery alone for oropharyngeal cancer: an analysis of local control.   Arch Otolaryngol Head Neck Surg. 2012;138(7):628-634. doi:10.1001/archoto.2012.1166 PubMedGoogle ScholarCrossref
17.
Cracchiolo  JR, Roman  BR, Kutler  DI, Kuhel  WI, Cohen  MA.  Adoption of transoral robotic surgery compared with other surgical modalities for treatment of oropharyngeal squamous cell carcinoma.   J Surg Oncol. 2016;114(4):405-411. doi:10.1002/jso.24353 PubMedGoogle ScholarCrossref
18.
Lam  JS, Scott  GM, Palma  DA, Fung  K, Louie  AV.  Development of an online, patient-centred decision aid for patients with oropharyngeal cancer in the transoral robotic surgery era.   Curr Oncol. 2017;24(5):318-323. doi:10.3747/co.24.3669 PubMedGoogle ScholarCrossref
19.
Vandenbroucke  JP, von Elm  E, Altman  DG,  et al; STROBE Initiative.  Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration.   Int J Surg. 2014;12(12):1500-1524. doi:10.1016/j.ijsu.2014.07.014 PubMedGoogle ScholarCrossref
20.
Swisher-McClure  S, Lukens  JN, Aggarwal  C,  et al.  A phase 2 trial of Alternative Volumes of Oropharyngeal Irradiation for De-intensification (AVOID): omission of the resected primary tumor bed after transoral robotic surgery for human papilloma virus–related squamous cell carcinoma of the oropharynx.   Int J Radiat Oncol Biol Phys. 2020;106(4):725-732. doi:10.1016/j.ijrobp.2019.11.021 PubMedGoogle ScholarCrossref
21.
Ferris  RL, Flamand  Y, Weinstein  GS,  et al.  Transoral robotic surgical resection followed by randomization to low- or standard-dose IMRT in resectable p16+ locally advanced oropharynx cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3311).   J Clin Oncol. 2020;38(15)(suppl):6500. doi:10.1200/JCO.2020.38.15_suppl.6500Google ScholarCrossref
22.
Charlson  ME, Pompei  P, Ales  KL, MacKenzie  CR.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.   J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8 PubMedGoogle ScholarCrossref
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Janssen-Heijnen  ML, Maas  HA, Houterman  S, Lemmens  VE, Rutten  HJ, Coebergh  JW.  Comorbidity in older surgical cancer patients: influence on patient care and outcome.   Eur J Cancer. 2007;43(15):2179-2193. doi:10.1016/j.ejca.2007.06.008PubMedGoogle ScholarCrossref
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Singh  B, Bhaya  M, Stern  J,  et al.  Validation of the Charlson comorbidity index in patients with head and neck cancer: a multi-institutional study.   Laryngoscope. 1997;107(11, pt 1):1469-1475. doi:10.1097/00005537-199711000-00009 PubMedGoogle ScholarCrossref
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Parhar  HS, Gausden  E, Patel  J,  et al.  Analysis of readmissions after transoral robotic surgery for oropharyngeal squamous cell carcinoma.   Head Neck. 2018;40(11):2416-2423. doi:10.1002/hed.25362 PubMedGoogle ScholarCrossref
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Amin  MB, Edge  S, Greene  F,  et al, eds.  AJCC Cancer Staging Manual. 8th ed. American Joint Commission on Cancer; 2017. doi:10.1007/978-3-319-40618-3
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Stokes  W, Ramadan  J, Lawson  G, Ferris  FRL, Holsinger  FC, Turner  MT.  Bleeding complications after transoral robotic surgery: a meta-analysis and systematic review.   Laryngoscope. 2020. doi:10.1002/lary.28580 PubMedGoogle Scholar
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Jackson  RS, Chen  S, Last  A,  et al.  Multi-institutional analysis of outcomes following transoral surgery for HPV-positive oropharyngeal squamous cell carcinoma in elderly patients.   Head Neck. 2019;41(11):3933-3939. doi:10.1002/hed.25946 PubMedGoogle ScholarCrossref
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Hanasoge  S, Magliocca  KR, Switchenko  JM,  et al.  Clinical outcomes in elderly patients with human papillomavirus–positive squamous cell carcinoma of the oropharynx treated with definitive chemoradiation therapy.   Head Neck. 2016;38(6):846-851. doi:10.1002/hed.24073 PubMedGoogle ScholarCrossref
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Zumsteg  ZS, Lok  BH, Ho  AS,  et al.  The toxicity and efficacy of concomitant chemoradiotherapy in patients aged 70 years and older with oropharyngeal carcinoma in the intensity-modulated radiotherapy era.   Cancer. 2017;123(8):1345-1353. doi:10.1002/cncr.30495 PubMedGoogle ScholarCrossref
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Lu  DJ, Luu  M, Nguyen  AT,  et al.  Survival outcomes with concomitant chemoradiotherapy in older adults with oropharyngeal carcinoma in an era of increasing human papillomavirus (HPV) prevalence.   Oral Oncol. 2019;99:104472. doi:10.1016/j.oraloncology.2019.104472 PubMedGoogle Scholar
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    Original Investigation
    October 29, 2020

    Oncologic Outcomes Following Transoral Robotic Surgery for Human Papillomavirus–Associated Oropharyngeal Carcinoma in Older Patients

    Author Affiliations
    • 1Department of Otorhinolaryngology–Head & Neck Surgery, University of Pennsylvania, Philadelphia
    • 2Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia
    • 3Department of Radiation Oncology, University of Pennsylvania, Philadelphia
    JAMA Otolaryngol Head Neck Surg. 2020;146(12):1167-1175. doi:10.1001/jamaoto.2020.3787
    Key Points

    Question  What are the oncologic outcomes of an upfront transoral robotic surgery approach to human papillomavirus–associated oropharyngeal carcinoma in older adults?

    Findings  In a cohort study including 77 older patients with oropharyngeal carcinoma, 3-year estimated survival outcomes were 92.4% for disease-specific, 90.0% for overall, and 84.3% for disease-free survival over a median follow-up period of 39.6 months. Twenty-seven patients (35.1%) underwent postoperative radiotherapy and 20 patients (26.0%) underwent postoperative chemoradiotherapy.

    Meaning  The findings of this study suggest that the transoral robotic surgery approach can provide positive survival outcomes for carefully selected older adults with oropharyngeal carcinoma and, in many of these patients, obviate the need for chemotherapy.

    Abstract

    Importance  While early epidemiologic studies ascribed increases in the incidence of human papillomavirus–associated oropharyngeal cancers to middle-aged patients, recent analyses have demonstrated an increasing median age of diagnosis. Treatment of patients older than 70 years is controversial as their inclusion in the practice-defining clinical trials has been limited and the survival benefit conferred by chemotherapy may be outweighed by treatment toxic effects.

    Objective  To assess the oncologic outcomes of older adults with human papillomavirus–associated oropharyngeal cancer who underwent upfront transoral robotic surgery and pathologic characteristics–guided adjuvant therapy in a large cohort of patients with close follow-up.

    Design, Setting, and Participants  A retrospective cohort analysis was conducted in a tertiary care academic medical center between January 1, 2010, and December 30, 2017. Patients aged 70 years or older at time of diagnosis with biopsy-proven and surgically resectable p16-positive oropharyngeal cancers were included. Data analysis was conducted from March 1 to June 1, 2020.

    Exposures  Transoral robotic surgery oropharyngeal resection and neck dissection with pathologic characteristic-guided adjuvant therapy.

    Main Outcomes and Measures  Three-year estimates of disease-specific survival, overall survival, and disease-free survival, as well as rates of adjuvant therapy (radiotherapy and chemoradiotherapy) and perioperative complications.

    Results  Seventy-seven patients were included (median age, 73.0; interquartile range, 71.0-76.0; range, 70-89 years); of these, 58 were men (75.3%). Perioperative mortality was 1.3% and the rate of oropharyngeal hemorrhage was 2.6%. Twenty-seven patients (35.1%) underwent postoperative radiotherapy and 20 patients (26.0%) underwent postoperative chemoradiotherapy. The median length of follow-up was 39.6 (range, 0.1-96.2) months, and the 3-year estimates of survival were 92.4% (95% CI, 82.4%-96.9%) for disease-specific survival, 90.0% (95% CI, 79.4%-95.0%) for overall survival, and 84.3% (95% CI, 73.4%-91.0%) for disease-free survival.

    Conclusions and Relevance  The findings of this cohort study suggest that transoral robotic surgery and pathologic characteristic–guided adjuvant therapy can provide beneficial survival outcomes, infrequent perioperative mortality, and, for most carefully selected older adults, obviate the need for chemotherapy.

    Introduction

    Early epidemiologic studies not only demonstrated a substantial increase in the incidence of human papillomavirus (HPV)-associated oropharyngeal cancers (OPSCCs) in North America, but also described these cancers as occurring in a uniquely younger cohort of patients compared with historical HPV-negative cohorts who acquired cancers due to long-term alcohol and tobacco exposure.1-3 Using nationally representative databases, it was demonstrated that the median age of diagnosis for OPSCC decreased substantially between 1973 and 2004, which was thought to be attributable to HPV oncogenicity impacting younger individuals.1 By contrast, more contemporary studies (2002-2012) have demonstrated increasing rates of OPSCCs in individuals older than 65 years, despite demonstrable decreases in nonoropharyngeal head and neck cancers in this cohort.4 This finding was supported in a recent multicenter study (1995-2013) that identified, through confirmatory p16 testing, that the incidence of HPV-associated OPSCC is increasing among older adults and should no longer be considered a disease of younger patients.5 Another large registry-based study (1992-2015) not only found substantial increases in OPSCC incidence among individuals born between 1939 and 1955, but also projected that by 2029 most new cases will be in older adults.6

    The treatment of HPV-related OPSCC, which may include upfront surgery with pathologic characteristic–guided postoperative adjuvant therapy or concurrent chemoradiotherapy, is controversial in patients older than 70 years. First, older patients are often underrepresented in practice-defining clinical trials, making therapeutic decisions in this population a challenge.7 Second, older patients frequently have a high burden of coexisting comorbidity, making it difficult to tolerate multimodality therapy, with high rates of unexpected inpatient hospitalization and frequent treatment breaks.7-9 Third, analyses of large, concurrent head and neck chemoradiotherapy trials have shown that the most statistically significant pretreatment predictor for severe late toxic effects has been increasing age.10 Fourth, and most important, several subgroup analyses of chemotherapy trials have demonstrated no survival benefit of chemotherapy in patients older than 70 years, which is thought to be related to toxic effects due to cisplatin potentially outweighing oncologic benefit.11,12

    Transoral robotic surgery (TORS), followed by pathologic characteristic–guided adjuvant therapy, has emerged as an alternative to definitive concurrent chemoradiotherapy during the past decade.13-16 Surgery is not only preferred by patients but has demonstrated excellent oncologic outcomes for localized HPV-associated OPSCC and is the most commonly used upfront treatment modality among contemporary American cohorts.13-18 A benefit of the TORS approach is that it is well tolerated among patients with HPV-associated OPSCC and can, in selected cases, obviate the need for adjuvant therapy; however, to our knowledge, TORS has yet to be formally studied in the older adults, who will make up an increasing proportion of patients in the coming years. The purpose of this study was to investigate the oncologic and survival outcomes in older adults (age ≥70 years) with HPV-associated OPSCC who underwent upfront TORS and pathologic characteristic–guided adjuvant therapy in a large cohort of patients with close follow-up. We hypothesized that a TORS and pathologic characteristic–guided adjuvant therapy approach would demonstrate acceptable oncologic outcomes and infrequent perioperative mortality, and often avoid the need for adjuvant therapy, particularly chemotherapy.

    Methods
    Cohort Selection

    Electronic medical records for patients 70 years or older who had biopsy-proven OPSCC and had undergone primary surgical therapy consisting of TORS and neck dissection followed by pathologic characteristic–guided adjuvant therapy were retrospectively abstracted between January 1, 2010, and December 30, 2017. Data analysis was performed from March 1 to June 1, 2020. All patients had provided both oral and written informed consent for inclusion in this study at their initial preoperative clinic visit. This study was conducted following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort studies.19 Research ethics approval was obtained from the University of Pennsylvania institutional review board.

    All patients underwent surgery between 2010 and 2017, which allowed for a minimum of 2 years’ follow-up for all patients. Patients with HPV-negative cancers were excluded. As a part of standard institutional protocol, all patients had undergone a preoperative clinical examination, physical examination, and radiologic workup for staging. In-house review of outside biopsy pathologic reports by a dedicated head and neck pathologist and radiologic reports by a dedicated neuroradiologist was performed when possible. All patients underwent panendoscopy to assess operative candidacy. Patient cases were subsequently presented at a multidisciplinary tumor board to discuss management options. Surgery consisted of TORS-assisted primary resection with ipsilateral or bilateral neck dissection as indicated. Neck dissection was performed either concurrently or in a staged fashion depending on surgeon/patient preference. When staged, neck dissection was performed beforehand to allow for arterial ligation before primary resection. Postoperatively, discussions regarding adjunct therapy were again made in the context of a multidisciplinary tumor board and consistent with guideline-based protocols unless patients were enrolled in a clinical trial (ECOG 3311 or AVOID).20,21 Postoperative radiotherapy was generally recommended for all those with greater than 1 metastatic node, perineural invasion, lymphovascular invasion, or pT3 or pT4 disease. Postoperative chemoradiotherapy was generally recommended for all those with positive margins, greater than 5 metastatic lymph nodes, and/or extranodal extension. Unless the patient had a medical contraindication, cisplatin was used when chemotherapy was recommended. A patient selection diagram is presented in Figure 1.

    Covariates

    The following patient-level demographic and baseline clinical characteristics were abstracted from the electronic patient medical records: age, sex, smoking status (never, <10 pack-years, and ≥10 pack-years), and comorbidity burden. Comorbidity status was assessed using the Charlson Comorbidity Index (CCI), which is a weighted index that has been well validated in predicting in-hospital mortality for patients with cancer who undergo surgery.22-24 We modified the original index (mCCI) to remove the effect of the current oropharyngeal cancer in a previously described manner, leaving 15 chronic conditions weighted for effect on mortality.25 Preoperative oncologic covariates included tumor subsite and clinical or radiographic tumor and nodal staging. Where required, the patient’s diagnosis was restaged using American Joint Committee on Cancer, 8th edition26 (AJCC-8) for consistency. The final pathologic test report was used to abstract pathologic tumor and nodal stage (AJCC-8), final margin status, lymphovascular invasion, perineural invasion, and extranodal extension. Margin assessment was performed using a previously described institutional approach.15 In addition, the use of adjuvant therapy was abstracted (no adjuvant therapy, radiotherapy, and chemoradiotherapy). The 30-day perioperative complications of interest were selected a priori and included postoperative bleed, postoperative neck hematoma, perioperative mortality, and reoperation. In addition, we abstracted the median length of hospitalization. To perform survival analysis, we reviewed records for timing of recurrence/metastases, cause of death, and date of last follow-up.

    Statistical Analysis

    All clinical data were deidentified, tabulated, and compiled for statistical review. Survival analyses, including disease-specific survival (DSS), overall survival (OS), and disease-free survival (DFS), were performed using nonparametric Kaplan-Meier methods. The cohort was grouped by treatment modality (surgery, surgery and radiotherapy, and surgery and chemoradiotherapy) and log-rank tests were used to compare DSS, OS, and DFS between strata. The association between prognostic clinical and pathologic variables and DSS, OS, and DFS was explored through univariate analyses using Cox proportional hazards models. All statistical testing was performed with a 2-sided α level of .05 and/or 95% CIs with SAS, version 9.4 (SAS Institute Inc).

    Results
    Patient Characteristics

    A total of 77 patients aged 70 years and older underwent TORS, neck dissection, and pathologic characteristic–guided adjuvant therapy for HPV-associated oropharyngeal carcinoma between 2010 and 2017. These patients had a median age of 73.0 years (interquartile range, 71.0-76.0; range, 70-89 years), and most patients were men (58 [75.3%] vs 19 [24.7%] women). Thirty patients (39.0%) had no history of smoking, 17 patients (22.1%) had smoked less than 10 pack-years, and 30 patients (39.0%) had smoked 10 or more pack-years. Most patients had a low burden of comorbidity (mCCI 0: 51 [66.2%]; mCCI 1: 15 [19.5%]; and mCCI≥2: 11 [14.3%]). Fifty-two patients (67.5%) had primary tumors of the tongue base; 24 tumors (31.2%) were of the tonsil, and 1 tumor (1.3%) was deemed to be an unknown primary even after TORS-assisted workup. The preoperative clinical tumor and nodal staging can be found in Table 1. Tumor staging was as follows: 11 (14.3%) cT0, 22 (28.6%) cT1, 37 (48.1%) cT2, 2 (2.6%) cT3, and 5 (6.5%) cT4. Most patients (55 [71.4%]) had cN1 nodal disease. Overall clinical staging was 68 (88.3%) stage I, 4 (5.2%) stage II, and 5 (6.5%) stage III.

    Of the 77 included patients who underwent TORS and neck dissection, 69 patients (89.6%) required only secondary healing or local myomucosal closure, while 8 patients (10.4%) required a TORS-assisted lateral pharyngotomy with free tissue transfer. No patient required a mandibulotomy for access. Four patients (5.2%) returned to the operating room within 30 days of index surgery. Two patients (2.6%) developed oropharyngeal hemorrhage requiring operative intervention, and 1 patient (1.3%) required reoperation to evacuate a cervical hematoma. One patient (1.3%) returned to the operating room for exploration and successful revision of a clotted venous anastomosis. There was 1 death (1.3%) within 30 days of the index surgery. This patient developed pulseless electrical activity and cardiovascular arrest on postoperative day 3 following an uneventful surgery. The median length of acute care hospitalization was 4.0 days (interquartile range, 4.0-5.0).

    Detailed postoperative pathologic tumor and nodal staging can be found in Table 1. The pathologic tumor staging of the cohort was as follows: 1 (1.3%) pT0, 32 (41.6%) pT1, 34 (44.2%) pT2, 8 (10.4%) pT3, and 2 (2.6%) pT4. Most patients had a pN1 (50 [64.9%]) nodal burden. Overall pathologic staging was 59 (76.6%) stage I, 17 (22.1%) stage II, and 1 (1.3%) stage III. Nineteen patients (24.7%) had evidence of extranodal extension, 11 patients (14.3%) had evidence of perineural invasion, and 28 patients (36.4%) had evidence of lymphovascular invasion. Six patients (7.8%) had a positive margin on final pathologic testing. Thirty patients (39.0%) underwent no postoperative adjuvant therapy, 27 patients (35.1%) underwent postoperative adjuvant radiotherapy, and 20 patients (26.0%) underwent postoperative adjuvant chemoradiotherapy. Of the 19 patients with extranodal extension, 17 patients (89.5%) underwent chemoradiotherapy, as did 3 of the 6 patients (50.0%) with positive margins.

    Survival Analysis

    The median length of follow-up for the 77 older adults with HPV-positive OPSCC undergoing TORS and neck dissection was 39.6 (range, 0.1-96.2) months. Eight patients (10.4%) had a locoregional recurrence and 4 patients (5.2%) had a distant recurrence during the follow-up period. Eleven patients (14.3%) died during the follow-up period, 5 of whom (45.5%) died from events unrelated to their diagnosis of oropharyngeal cancer. One patient (1.3%) died from leukemia, 1 patient (1.3%) from sepsis and multiorgan failure, 1 patient (1.3%) from intracranial hemorrhage, and 3 patients (3.9%) from unknown causes without evidence of cancer recurrence.

    Kaplan-Meier analyses for the overall cohort survival are displayed in Figure 2. Survival estimates were calculated for DSS, OS, and DFS. The 3-year estimates of survival were 92.4% (95% CI, 82.4%-96.9%) for DSS, 90.0% (95% CI, 79.4%-95.0%) for OS, and 84.3% (95% CI, 73.4%-91.0%) for DFS. Nonparametric Kaplan-Meier methods demonstrated similar survival outcomes in terms of DSS, OS, or DFS among the cohort after being stratified by treatment modality: surgery, surgery and adjuvant radiotherapy, and surgery and adjuvant chemoradiotherapy. The results of the treatment-stratified analysis are displayed in Figure 3. On univariate analysis, OS was negatively impacted by increasing age (hazard ratio, 1.18; 95% CI, 1.05-1.33) but DFS and DSS were not. In the comparison of survival by stage, DFS and DSS were found to be lower in patients with stage II disease compared with patients with stage I disease (DFS: hazard ratio, 5.27; 95% CI, 1.61-17.32 and DSS: hazard ratio, 6.99; 95% CI, 1.28-38.36) and other negative pathologic indicators (lymphovascular invasion, perineural invasion, and extranodal extension). The results of the univariate analysis of covariates impacting survival are displayed in Table 2. Multivariable analyses for OS, DSS, and DFS could not be performed because the events of interest were too infrequent to reach minimum statistical thresholds.

    Discussion

    To our knowledge, this analysis represents the largest cohort of septuagenarians and octogenarians with HPV-associated OPSCC treated with upfront TORS and pathologic characteristic–guided adjuvant therapy with long-term follow-up. This strategy yielded 3-year survival rates of 92.4% for DSS, 90.0% for OS, and 84.3% for DFS. In addition, the cohort experienced an acceptable safety profile with a perioperative mortality rate of 1.3% and postoperative oropharyngeal hemorrhage rate of 2.6%, which compares favorably with literature estimates of hemorrhage after TORS (4.0%-5.8%).25,27

    Our results expand on the work of Jackson et al28 that examined oncologic outcomes in 75 older patients with HPV-associated OPSCC who underwent either transoral laser microsurgery or TORS. In that study (2003-2016), 3-year survival rates were 94.3% for DSS, 81.5% for OS, and 79.3% for DFS. Similarly, the investigators suggested that transoral techniques are safe in older adults. It is unclear, however, how many patients underwent transoral laser microsurgery as opposed to TORS, which are different techniques and have distinct advantages and disadvantages. Any outcome differences may therefore be the result of variations in patient population or technique or potentially reflect that our study looked at a more consistent and contemporary data set. In addition, the Jackson et al28 analyses found that more advanced comorbidity was negatively associated with both OS and DFS, but this finding was not corroborated in our investigation. Our results also compare favorably with those of a small number of studies examining survival of older adults with HPV-associated OPSCC undergoing primary chemoradiotherapy. Hanasoge et al29 treated 21 such patients older than 70 years with chemoradiotherapy and reported 5-year survival rates of 76.0% for OS and 40.0% for DFS, with acute mortality in 1 patient (4.8%). In 2017, Zumsteg et al30 compared different chemotherapy agents as a constituent component of chemoradiotherapy in a cohort of 74 patients older than 70 years. The best results were obtained among 28 patients who received cisplatin-based chemoradiotherapy (5-year OS, 87%).30 In addition, a recent National Cancer Database–based study of T1/2N1-3 or T3/4N0-3 HPV-associated OPSCC showed a 3-year OS of 70.3% among patients older than 70 years undergoing chemoradiotherapy.31

    Any survival analysis in an older adult cohort needs to be interpreted in the context of competing risks of mortality. In our study, nearly half (45.5%) of the deaths in the cohort (median age, 74.2 years; 75.3% men) were attributed to causes other than OPSCC. With a median follow-up of 39.6 months, our cohort had a 3-year DSS rate of 93.4% and OS rate of 90.0%. These rates are similar to estimates from actuarial calculators for all-cause population-level mortality based on Social Security data in the US.32 For example, a 74-year-old American man had a 3-year OS of 94.7% from all-cause mortality in 2014 (the midpoint of our study period).

    The upfront TORS strategy that we have used not only suggests high rates of oncologic control in a cohort of septuagenarians and octogenarians but also can obviate the need for adjuvant therapy (particularly chemotherapy) in many cases. In this cohort, 39.0% of the patients avoided all adjuvant therapy and 74.0% avoided chemotherapy. The rate of triple-modality therapy in our cohort was commensurate with other institutional experiences.13,14,33 Triple-modality therapy might be best avoided with appropriate patient selection (perhaps excluding those with a high burden of or obvious matted nodes and/or those at high risk for positive margin), although preoperative estimation of need for adjuvant therapy remains challenging based on clinicoradiologic factors.34-36 Any potential role for triple-modality therapy in the treatment of HPV-related OPSCC is currently being defined in the literature, and the decision to use triple-modality therapy is all the more important in older patients as advancing age is known to be a strong predictor for severe toxic effects with chemotherapy.10,33,37 Our treatment-stratified subgroup analysis showed no statistically significant survival differences by treatment modality (ie, surgery, surgery and adjuvant radiotherapy, and surgery and adjuvant chemoradiotherapy), which may be expected as patients generally adhered to treatment guidelines. However, the sample sizes after stratification were small and the subgroups were heterogeneous in terms of pathologic variables so further prospective comparative studies with standardized inclusion criteria should be undertaken for inferential analysis of survival according to treatment modality. Univariate analysis suggests that increasing age had a detrimental impact for OS but not DSS or DFS, highlighting the association of age with competing mortality rather than disease progression. Conversely, DSS and DFS were negatively impacted by poor pathologic prognostic features, such as higher pathologic stage, rather than age.

    Multiple factors motivated this inquiry into the oncologic outcomes following TORS for HPV-associated OPSCC in the older adult population. We know that older adults will compose an ever-increasing proportion of patients with cancer as the North American population ages. This expansion is expected to become particularly relevant for HPV-related OPSCC because of a rapid increase in incidence that is expected in the coming decade, which is thought to be related to a delayed cohort effect on patients whose sexual behaviors changed in the mid- to late 20th century, which increased their potential exposure to HPV.5,6,38,39 Older adults generally are an underinvestigated cohort in all aspects of cancer care, are particularly susceptible to treatment-related morbidity, and often receive nonstandard treatment approaches.7,37,40-42 The results of the data presented herein suggest that upfront TORS may provide good survival outcomes that approach actuarial estimates of survival in the absence of a cancer diagnosis, with infrequent perioperative mortality, and in many cases a reduced need for adjuvant therapy. Future study should focus on investigating the functional results and quality-of-life outcome measures following TORS in older adults. Baseline rates of dysphagia in septuagenarians are high and there has been a renewed interest in investigating swallowing function following TORS in light of the ORATOR trial, which showed nonclinically meaningful differences in swallowing between TORS-based and conventional radiation therapy–based approaches to HPV-associated OPSCC.43,44Because aging is an inherently heterogeneous process, future efforts should also focus on methods of patient selection, perhaps starting with a formal geriatric assessment, to select patients who can tolerate and benefit from multimodality therapy.

    Limitations

    This study has limitations. First, with the design being retrospective and observational, we were limited to the information gleaned through medical records review, which may be susceptible to misclassification. Second, our cohort underwent TORS, neck dissection, and adjuvant therapy as indicated at a high volume and experienced center and there was no comparative conventional radiation therapy cohort, which may limit the generalizability of this study. Future studies might be improved by having a prospectively enrolled chemoradiotherapy control arm to reduce the reliance on literature-based comparisons. Third, detailed data regarding radiotherapy treatment dose, volume, and completion were unavailable for review. The study period overlapped the accrual period for inclusion in the ECOG 3311 and the AVOID de-escalation trials for which this center was a participant; some of the included patients were therefore subject to trial-based adjuvant therapy protocols.20,21 The variability in radiotherapy may impact the interpretation of survival outcomes presented herein. Fourth, this cohort, while older, had a low burden of comorbidity, which was probably the result of a selection bias favoring healthier patients for upfront surgery. Fifth, the sample size and relative infrequency of recurrence, metastasis, and death during the study period not only led to wide 95% CIs, they also did not allow for a meaningful multivariate Cox proportional hazards analysis of survival predictors because minimum event-to-variable thresholds were not met.45 Sixth, an assessment of functional outcomes, in terms of speech and swallowing, was beyond the scope of our investigation and could not be performed based on the lack of availability of the needed data; efforts are currently in place to increase the collection of these variables to strengthen future analyses. Still, to our knowledge, this cohort is the largest of HPV-associated OPSCC in patients 70 years or older treated with upfront TORS, neck dissection, and pathologic characteristic–guided adjuvant therapy. We believe it may be helpful to patients and clinicians to be aware of the oncologic outcomes that may be achieved using this strategy in carefully selected patients. This approach may aid in therapeutic decision-making in an increasing population.

    Conclusions

    In this analysis, a TORS, neck dissection, and pathologic findings–guided adjuvant therapy approach demonstrated positive oncologic and survival outcomes among patients 70 years or older with HPV-associated OPSCC. Perioperative mortality was rare and postoperative oropharyngeal hemorrhages occurred infrequently. For carefully selected older adults, this approach may be safe and obviate the need for chemotherapy.

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    Article Information

    Accepted for Publication: August 19, 2020.

    Published Online: October 29, 2020. doi:10.1001/jamaoto.2020.3787

    Corresponding Author: Robert M. Brody, MD, Department of Otorhinolaryngology–Head & Neck Surgery, University of Pennsylvania, 3400 Spruce St, 5 Ravdin, Philadelphia, PA 19104 (robert.brody2@pennmedicine.upenn.edu).

    Author Contributions: Dr Parhar and Mr Shimunov had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Parhar, Shimunov, Newman, Cannady, Rajasekaran, O'Malley, Chalian, Weinstein, Brody.

    Acquisition, analysis, or interpretation of data: Parhar, Shimunov, Newman, Rajasekaran, O'Malley, Rassekh, Cohen, Lin, Lukens, Swisher-McClure, Bauml, Aggarwal, Weinstein, Brody.

    Drafting of the manuscript: Parhar, Shimunov, O'Malley, Bauml, Brody.

    Critical revision of the manuscript for important intellectual content: Parhar, Newman, Cannady, Rajasekaran, O'Malley, Chalian, Rassekh, Cohen, Lin, Lukens, Swisher-McClure, Aggarwal, Weinstein, Brody.

    Statistical analysis: Parhar, Shimunov, O'Malley, Brody.

    Administrative, technical, or material support: Parhar, Shimunov, Newman, Rajasekaran, O'Malley, Bauml, Aggarwal, Brody.

    Supervision: Newman, Cannady, O'Malley, Chalian, Lin, Weinstein, Brody.

    Conflict of Interest Disclosures: Dr Newman reported consulting for Castle Biosciences, Bolder Surgical Inc, and VisionSense Inc. Dr O'Malley reported other support from Olympus during the conduct of the study. Dr Rassekh reported receiving grants from Cook Medical outside the submitted work. Dr Bauml reported receiving grants and personal fees from Merck; grants from Incyte, Novartis, and Bayer; grants and personal fees from Janssen, AstraZeneca, and Takeda; grants from Amgen; personal fees from BMS, Celgene, Genentech, Guardant Health, Boehringer Ingelheim, Regeneron, Inivata, and Ayala outside the submitted work. Dr Aggarwal reported other support from AstraZeneca, Celgene, Eli Lilly, Merck, and Roche outside the submitted work. Dr Weinstein reported other support from Olympus Corporation outside the submitted work. No other disclosures were reported.

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