Identifying an oligometastatic phenotype in HPV-associated oropharyngeal squamous cell cancer: Implications for clinical trial design

Oral Oncology 112 (2021) 105046

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Identifying an oligometastatic phenotype in HPV-associated oropharyngeal squamous cell cancer: Implications for clinical trial design

T

Christopher W. Fleminga, , Matthew C. Wardb, Neil M. Woodya, Nikhil P. Joshia, John F. Greskovich Jrc, Lisa Rybickid, David Xionge, Kevin Contreraf, Deborah J. Chuteg, Zvonimir L. Milash, Catherine H. Frenkelh, Daniel S. Brickmanh, Daniel R. Carrizosai, Jamie Kuf, Brandon Prendesf, Eric Lamarref, Robert R. Lorenzf, Joseph Scharpff, Brian B. Burkeyf, Larisa Schwartzmanj, Jessica L. Geigerj, David J. Adelsteinj, Shlomo A. Koyfmana ⁎

a

Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States Department of Radiation Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC, United States c Department of Radiation Oncology, Cleveland Clinic Florida, Weston, FL, United States d Department of Quantitative Health Sciences, Cleveland Clinic Learner Research Institute, Cleveland, OH, United States e Cleveland Clinic Lerner College of Medicine, Cleveland, OH, United States f Department of Otolaryngology, Head and Neck Institute, Cleveland Clinic, Cleveland, OH, United States g Department of Pathology, Cleveland Clinic, Cleveland, OH, United States h Department of Surgical Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC, United States i Department of Medical Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC, United States j Department of Hematology/Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States b

ARTICLE INFO

ABSTRACT

Keywords: Head and neck cancer Oligometastatic SBRT Clinical trials Oropharyngeal Squamous cell carcinoma HPV

Objectives: Patients with human papillomavirus (HPV) associated squamous cell carcinoma of the oropharynx (SCC-OP) have improved overall survival (OS) after distant metastasis (DM) compared to HPV negative patients. These patients may be appropriate candidates for enrollment on clinical trials evaluating the efficacy of metastasis-directed therapy (MDT). This study seeks to identify prognostic factors associated with OS after DM, which could serve as enrollment criteria for such trials. Materials and methods: From an IRB approved multi-institutional database, we retrospectively identified patients with HPV/p16 positive SCC-OP diagnosed between 2001 and 2018. Patterns of distant failure were assessed, including number of lesions at diagnosis and sites of involvement. The primary outcome was OS after DM. Prognostic factors for OS after DM were identified with Cox proportional hazards. Stepwise approach was used for multivariable analysis. Results: We identified 621 patients with HPV-associated SCC-OP, of whom 82 (13.2%) were diagnosed with DM. Median OS after DM was 14.6 months. On multivariable analysis, smoking history and number of lesions were significantly associated with prolonged OS. Median OS after DM by smoking (never vs ever) was 37.6 vs 11.2 months (p = 0.006), and by lesion number (1 vs 2–4 vs 5 or more) was 41.2 vs 17.2 vs 10.8 months (p = 0.007). Conclusion: Among patients with newly diagnosed metastatic HPV-associated SCC-OP, lesion number and smoking status were associated with significantly prolonged overall survival. These factors should be incorporated into the design of clinical trials investigating the utility of MDT, with or without systemic therapy, in this population.

Introduction Management of metastatic patients is undergoing a paradigm shift

in oncology. Recent randomized trials have found significant improvements in overall survival (OS) in oligometastatic patients undergoing metastasis-directed therapy (MDT), specifically stereotactic body

⁎ Corresponding author at: Cleveland Clinic, Department of Radiation Oncology, Taussig Cancer Institute, 9500 Euclid Avenue/CA-50, Cleveland, OH 44195, United States. E-mail address: [email protected] (C.W. Fleming).

https://doi.org/10.1016/j.oraloncology.2020.105046 Received 8 May 2020; Received in revised form 7 October 2020; Accepted 8 October 2020 1368-8375/ © 2020 Elsevier Ltd. All rights reserved.

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radiotherapy (SBRT) [1,2]. The success of these initial phase II trials has spurred the development of further trials assessing the role of local therapy for distant metastases (DM) from various primary tumor sites [3–7]. Eligibility criteria for these trials generally enrich for patients thought to have the highest chance of benefitting from MDT, i.e. those patients with improved prognosis due to their limited number of DM and/or indolent histology. Oligometastatic trials have generally excluded patients with head and neck cancer, leaving unanswered questions regarding the indications for and benefit of MDT in this population. Squamous cell carcinoma of the head and neck is a common malignancy, with 890,000 new cases diagnosed worldwide in 2018 [8]. Within the United States, approximately 75% of oropharynx cancers are HPV-associated, a dramatic increase from 16% in the 1980s [9]. HPVassociated squamous cell carcinomas of the oropharynx (SCC-OP) have improved prognosis compared to HPV negative SCC-OP [10]. This improved prognosis persists even after failure of definitive treatment [11,12]. In addition to prognosis, patterns of failure differ between the two etiologies of SCC-OP, with HPV association conferring significantly improved locoregional control but similar rates of DM [10]. As such the likelihood of isolated DM has increased, accounting for 37% of recurrences on the recently published RTOG 1016 [13]. Altogether, this data suggests that patients with HPV-associated SCC-OP, or at least a favorable subgroup of these patients, may benefit from MDT and would be reasonable candidates for enrollment on MDT trials. This study seeks to characterize the outcomes of patients with HPVassociated SCC-OP after diagnosis of distant metastasis and identify prognostic factors for prolonged survival. In doing so, our findings could have important implications for clinical decision making regarding how to manage these patients, most specifically, but not limited to, the use of MDT. Perhaps most importantly, this study can inform the inclusion criteria for future clinical trials examining the potential value of MDT in this unique disease.

positive p16 staining of the lung biopsy specimen was desirable, though the final determination for inclusion in this study was based on the favored origin reported in the treating oncologist’s clinical documentation. Treatment after DM was recorded, including receipt of MDT, defined as either surgery or stereotactic radiotherapy (SRT). We defined surgery as an operation attempting complete resection of the tumor. SRT included stereotactic radiosurgery (SRS) and SBRT, also known as stereotactic ablative radiotherapy (SABR). To be considered as MDT, only one lesion required treatment fitting the above criteria, meaning we did not require consolidation of all sites of metastatic disease for patients with multiple lesions. The primary outcome was OS after DM. OS was estimated with the Kaplan-Meier method. Prognostic factors for OS were identified with Cox proportional hazards analysis. Stepwise analysis with a variable entry criterion of p < 0.10 and a variable retention criterion of p < 0.05 was used to identify multivariable prognostic factors. All tests were two-sided, and a p value of < 0.05 was considered statistically significant. Results We identified 621 patients with HPV-associated SCC-OP, of whom 82 (13.2%) were diagnosed with DM. Patient characteristics and tumor characteristics are summarized in Table 1. All stage I-III patients had completed definitive or postoperative radiotherapy (RT) between 2002 and 2018; no patients underwent surgery alone. Median age at initial diagnosis was 60 years (range 42–82). Median pack-years smoking was 16 (range 0–100). The most common sites of DM were lung/mediastinum (n = 61, Table 1 Patient and tumor characteristics.

Methods and materials After institutional review board and legal approval, patients were identified retrospectively from a 2‐institution head and neck cancer database with identical data dictionaries. Demographic and treatment data were maintained independently at each institution with REDCap software (version 5.8.2; Vanderbilt University, Nashville, Tennessee) and then exported for central analysis. We identified patients with HPV/p16 positive SCC-OP diagnosed between 2001 and 2018 who were diagnosed with DM at any point in their disease course. Patient, tumor, and treatment factors were recorded at the time of diagnosis of initial and metastatic disease. HPV-positivity was defined as strong (3+) and diffuse (70% or more tumor cells) nuclear and cytoplasmic staining for p16 by immunohistochemistry. Initial clinical group stage was recorded using AJCC 8th edition criteria. Smoking information was obtained from records at initial diagnosis, as this information was poorly documented at time of DM. Patients initially diagnosed with stage I-III disease completed definitive therapy, consisting of surgery and postoperative (chemo)radiation or definitive (chemo) radiation. After completion of definitive therapy, patients generally underwent routine follow up every three months for the first two years, then every four to six months for years 3–5, then annually. PET/CT or CT of the neck and chest was performed three months after the completion of definitive treatment. Neck/chest imaging was variably performed over the follow-up period. DM was determined by either biopsy or unequivocal imaging consistent with metastasis. Patterns of distant failure were assessed, including number of lesions at diagnosis of DM, as well as individual sites of involvement. Concomitant locoregional failure (LRF) at time of DM was documented for initially stage I-III patients. Lesion number, site, and LRF were determined by review of radiology reports. For lesions of the lung of uncertain origin, i.e. primary versus secondary lung cancers,

%

Gender

Male Female

76 6

92.7 7.3

Smoking history

Current Former Never

24 33 25

29.3 40.2 30.5

Smoking pack-years

< 20 ≥20

42 40

51.2 48.8

Initial clinical stage (AJCC 8th edition)

I II III IV

25 32 17 8

30.5 39.0 20.7 9.8

Initial concurrent systemic therapy

Cisplatin Cetuximab Other None

43 21 11 7

52.4 25.6 13.4 8.5

ECOG performance status (n = 81)

0 1 2

54 25 2

66.7 30.9 2.5

Age at DM (median, range in years) Time to distant metastasis (median, range in months)

2

N

61 (44–82) 14.3 (1.4–83)

Number of metastatic lesions

1 2–4 ≥5

25 19 38

30.5 23.2 46.3

Number of distant sites

1 2 ≥3

62 14 6

75.6 17.1 7.3

Largest size of metastatic lesion (n = 77)

≤2 cm > 2 cm

41 36

53.2 46.8

Concomitant locoregional failure (n = 74, stage IIII)

Yes No

26 48

35.1 64.9

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Fig. 1. Overall survival after distant metastasis, entire cohort.

74%), bone (n = 23, 28%), liver (n = 10, 12%), axillary lymph nodes (n = 5, 6%), and brain (n = 3, 4%). 62 patients (76%) had lesions involving only one site. 42 patients (51%) had lung-only disease and 13 (16%) had bone-only disease. Overall, 25 patients (30%) presented with a solitary metastasis, of which 13 (52%) were in the lung, 6 (24%) in bone, 2 (8%) in liver, 1 (4%) in skin, and 1 (4%) in the axilla. MDT was administered to 30 patients (37%). At the time of analysis, 24 (29%) were alive with median follow up of 26 months (range 0.4–67). Median OS after DM was 14.6 months (Fig. 1). Table 2 shows results of univariable (UVA) and multivariable (MVA) analyses for factors associated with OS after DM. On UVA, any history of smoking, 5 or more distant lesions, two or more distant sites, and LRF were associated with worse OS, while receipt of MDT was associated with improved OS. Multivariable analysis found only smoking history and number of lesions to remain significant. OS was significantly inferior for smokers compared to never smokers (median

11.2 vs. 37.6 months; HR 2.21; p = 0.018; Fig. 2). Patients with ≥5 metastases had significantly inferior OS compared to those with one solitary metastatic lesion (median 10.8 vs. 41.2 months; HR 2.59; 95% CI 1.30–5.14; p = 0.007). OS for patients with 2–4 metastases was not significantly different from those with a single lesion (median 17.2 months; HR 1.45; 95% CI 0.65–3.23; p = 0.36) (Fig. 3). After accounting for smoking and lesion number, none of the remaining variables were statistically significant. There was no difference in OS after diagnosis of DM between patients presenting with stage IV disease (n = 8) and those with initial stage I-III disease (p = 0.90). Detailed survival estimates are shown in Table 3. Regarding long-term survivors, 14 patients (17%) lived 3 or more years after DM. Of these, 11 (79%) were never smokers. 9 (64%) presented with a single lesion, while 3 (21%) presented with 5 or more. All had only one site of initial involvement. 7 (50%) had lung metastases, 3 (21%) bone, 2 (14%) brain, 1 (7%) liver, and 1 (7%) axilla. 2 (14%)

Table 2 Univariable and multivariable analyses for factors associated with overall survival.

Gender Performance status Smoking

Initial clinical stage Initial concurrent systemic therapy Age at DM Time interval to DM # Distant lesions # Distant sites Lesion diameter Locoregional failure Metastasis-directed therapy

Female/Male Per 1 point increase Current/Never Former/Never Ever/Never ≥20/ < 20 pack years II/I III/I IV/I Yes/No Per 10 yr increase Per 6 month increase 2–4/1 ≥5/1 ≥2/1 > 2 cm/≤2 cm Yes/No Yes/No

UVA HR

95% CI

P

2.07 1.23 2.32 2.33 2.32 1.56 1.00 1.21 1.10 1.02 1.07 0.94 1.91 2.86 2.54 1.67 1.86 0.48

0.88–4.86 0.79–1.90 1.14–4.70 1.18–4.59 1.25–4.32 0.92–2.66 0.53–1.92 0.57–2.56 0.45–2.68 0.41–2.56 0.80–1.44 0.82–1.07 0.88–4.14 1.46–5.60 1.38–4.68 0.96–2.89 1.05–3.30 0.27–0.84

0.09 0.36 0.020 0.015 0.008 0.10 0.99 0.62 0.83 0.97 0.64 0.33 0.10 0.002 0.003 0.07 0.034 0.011

3

MVA HR

95% CI

P

2.21

1.15–4.24

0.018

1.45 2.59

0.65–3.23 1.30–5.14

0.36 0.007

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Fig. 2. Overall survival after distant metastasis, stratified by smoking history.

were stage IV at diagnosis.

tripled (37.6 months) in the never-smoking group and nearly quadrupled (41.2 months) in those patients presenting with only a single metastasis. These results have important implications for trials enrolling patients with metastatic SCC-OP, for which these factors merit consideration as stratification variables. Furthermore, for MDT trials, which have generally excluded head and neck patients in favor of more traditionally indolent histologies [2,3,7], this data shows that well selected SCC-OP patients have prolonged survival after DM, suggesting they would be appropriate candidates for such trials. Other studies have corroborated the effect of lesion number on

Discussion This study reports a relatively large experience of 82 patients with metastatic HPV-associated SCC-OP treated at two separate institutions. We found significant associations between survival after DM and both lesion number and smoking status. Patients with any history of smoking, as well as those presenting with 5 or more lesions, had a median survival of 11 months after distant metastasis. Survival was

Fig. 3. Overall survival after distant metastasis, stratified by lesion number. 4

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board honorarium from AstraZeneca outside the submitted work. Daniel R. Carrizosa reports institutional research support from Merck, Celgene, AstraZeneca/MedImmune, Loxo, Aeglea Biotherapeutics, and GlaxoSmithKline outside the submitted work. Jessica L. Geiger reports institutional research support from Regeneron and Genentech and an advisory board honorarium from Regeneron outside the submitted work. Shlomo A. Koyfman reports research support from Merck outside the submitted work. All other coauthors have no relevant conflicts of interest.

Table 3 Overall survival estimates. Years after treatment 1 All patients

2

3

Median (months)

55%

33%

28%

14.6

Smoking history

Never Ever

72% 47%

59% 19%

54% 14%

37.6 11.2

Number of metastatic lesions

1 2–4 ≥5

72% 62% 40%

57% 33% 16%

51% 26% 12%

41.2 17.2 10.8

Acknowledgment Supported in part by the Melvin Markey Discovery Fund at Cleveland Clinic.

survival in metastatic head and neck cancer. Albergotti et al. found a median survival of 45 months for patients with 1–2 metastatic lesions confined to one organ system versus 10 months for patients not meeting those criteria [14]. Beckham et al found that patients presenting with a single metastasis had a 5-year OS of 35%, compared to 4% for patients with multiple metastases [15]. Interestingly, although lesion number was highly significant in our study, 3 of the 14 patients that lived 3 years or longer presented with 5 or more lesions, hinting at an underlying favorable biologic profile. Previous studies have found smoking to be a negative prognostic factor in newly diagnosed HPVassociated SCC-OP [16–18]. It has been theorized that smoking alters the mutation profile of HPV+ head and neck cancers, in turn conferring resistance to standard therapies; however, to date, studies investigating this hypothesis have been almost universally negative [19], leaving unanswered questions regarding the mechanism of treatment resistance. While receipt of MDT was associated with improved OS on univariable analysis, this was not significant on multivariable analysis. The MSKCC group did however find a statistically significant benefit to MDT (HR for death 0.36, p = 0.006) [15]. Other retrospective studies have also found survival benefit to aggressive local therapies in metastatic head and neck cancer [20–22]. Many studies have included both HPV positive and negative patients, which may have fundamentally different behaviors. Also, MDT is itself a selection bias, which obscures making firm conclusions about its benefit. This study is limited by its retrospective nature over a long period of time, during which the understanding and management of HPV-associated SCC-OP evolved. Also, not all patients had biopsy proven confirmation of DM, although patients in whom there was a high suspicion for a second primary cancer (e.g. solitary lung lesion in a heavy smoker) were excluded to minimize the chance for this error. Selection bias is inherent in the management of these patients, especially the use of MDT, which is generally selected for those patients presenting with a limited number of lesions, more indolent metastatic disease course, or generally an improved prognosis after DM. While our findings are compelling, our moderate sample size will need to be increased to validate these findings on larger cohorts. Finally, biological drivers of these varying phenotypes are unaccounted for in this study and should be elucidated in future studies to help better understand this patient population. Due to the inherent biases of retrospective research, questions regarding the benefit of MDT will likely only be definitively answered through prospective trials. Our study suggests that patients with limited smoking history and number of metastatic lesions are more likely to experience long term survival after DM, and therefore would be reasonable candidates for enrollment on such trials. These factors should also be used as stratification tools in systemic therapy trials in metastatic HPV-associated SCC-OP.

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Declaration of Competing Interest Matthew C. Ward reports research grants from Varian and advisory 5