This cohort study evaluates the incidence of postoperative adverse events in treatment-naive patients receiving neoadjuvant pembrolizumab for advanced oral cavity cancer when compared with matched controls.
Key Points
Question
Is neoadjuvant pembrolizumab for local regionally advanced oral cavity squamous cell carcinoma associated with adverse events after surgery?
Findings
In this cohort study of 32 treatment-naive patients with local regionally advanced oral cavity squamous cell carcinoma and 32 matched controls, there was not an increase in adverse events when patients were treated with neoadjuvant pembrolizumab. Patients who received preoperative immunotherapy had a decreased incidence of trismus following surgery compared with matched controls.
Meaning
Neoadjuvant pembrolizumab does not appear to be associated with higher rates of adverse events in the setting of advanced head and neck cancer and does not appear to increase perioperative morbidity.
Abstract
Importance
Pembrolizumab, a monoclonal antibody targeting programmed cell death 1, is currently approved by the US Food and Drug Administration for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The potential neoadjuvant role of programmed cell death 1 inhibitors in primary surgical management of HNSCC and effects on surgical outcomes are poorly understood.
Objective
To evaluate the incidence of postoperative adverse events in treatment-naive patients with advanced oral cavity cancer receiving neoadjuvant pembrolizumab when compared with matched controls, as part of a window-of-opportunity multi-institutional clinical trial assessing neoadjuvant pembrolizumab for locally advanced HNSCC.
Design, Setting, and Participants
This retrospective cohort study at a single tertiary academic institution included treatment-naive patients with local regionally advanced oral cavity squamous cell carcinoma (OCSCC) who were undergoing surgical resection.
Exposures
Patients with local regionally advanced resectable OCSCC who received neoadjuvant pembrolizumab were retrospectively reviewed for postoperative adverse events. Controls were matched by age, race, smoking status, and overall cancer stage based on historical data at the same institution. Matched-cohort analysis was performed using a McNemar test to assess differences between the groups.
Main Outcomes and Measures
Incidence of adverse events following surgical resection of advanced OCSCC within 30 days of surgery and on continued follow-up.
Results
A total of 64 patients (32 as part of the prospective clinical trial and 32 as controls; mean [SD] age, 59.6 [10.3] years; 28 [44%] women) were included in the analysis. Postoperative adverse events in the 32 patients receiving pembrolizumab included lymphedema (n = 20 [63%]), trismus (n = 7 [22%]), return to operating room (n = 7 [22%]), wound infection (n = 7 [22%]), fistula (n = 6 [19%]), wound dehiscence (n = 4 [13%]), flap failure (n = 3 [9%]), and hematoma (n = 2 [6%]). The matched control group demonstrated similar complication rates without considerable differences, except for trismus (n = 16 [50%]), which was greater by a difference of 28.1% (95% CI, 5.6%-50.6%) in the control group.
Conclusions and Relevance
This cohort study examined surgical complications among patients with local regionally advanced OCSCC treated with neoadjuvant pembrolizumab and found that serious adverse events were similar to those in patients who underwent standard-of-care treatment. This suggests that there is no increased perioperative morbidity in the use of preoperative treatment with immunotherapy. Further prospective studies are needed to validate these findings for oral cavity cancer and other subsites of the head and neck.
Introduction
Although the use of immune checkpoint inhibitors has grown in recent years, surgical resection followed by adjuvant chemoradiation remains the standard of care for advanced-stage oral cancers with high-risk features.1,2 In 2020, there were 377 713 new cases of oral cavity cancer worldwide.3 The 5-year overall survival rate for local regionally advanced oral cavity squamous cell carcinoma (OCSCC) is reportedly as low as 50%.3
Immunotherapy demonstrates promise in treating many types of cancer, including head and neck squamous cell carcinoma (HNSCC).4,5 T cells are one of many types of cells in the body that express programmed cell death 1 (PD-1). This protein acts as a receptor that allows T cells to bind to its ligands and induce death of aberrant cells.6 When neoplastic cells express PD-1 ligand 1, they hijack the PD-1 pathway and block the signal by binding to PD-1 on T cells. In doing so, neoplastic cells evade the body’s immune system and are allowed to proliferate. This pathway thereby represents a major avenue for cancer progression.6,7 Pembrolizumab is an anti–PD-1 antibody that blocks the PD-1 pathway and inhibits cancer cells’ ability to evade the immune system through this mechanism.7
Pembrolizumab and nivolumab are approved by the US Food and Drug Administration for the treatment of recurrent or metastatic HNSCC, including cancer of the oral cavity.5,8,9,10,11 Recently, neoadjuvant and adjuvant pembrolizumab were shown to increase 1- year disease-free survival in local regionally advanced HNSCC for patients with intermediate risk factors.4 The potential neoadjuvant role of PD-1 inhibitors in primary surgical management of HNSCC and its effects on surgical outcomes are incompletely understood at present. Previously, a large multi-institutional retrospective study reported an increase in surgical complications with the use of preoperative immunotherapy in HNSCC, suggesting poor wound healing resulting from those receiving treatment.12
Given the increasing role of neoadjuvant and adjuvant immunotherapy for the treatment of HNSCC, the aim of this cohort study was to determine if there is an increased risk of perioperative morbidity in patients who received neoadjuvant pembrolizumab compared with historical controls for treatment-naive patients with advanced oral cavity cancer.
Methods
Study Design and Population
Institutional review board approval through the University of Cincinnati College of Medicine was granted for a retrospective review of the multicenter, open-label, nonrandomized, phase 2 prospective clinical trial evaluating neoadjuvant and adjuvant pembrolizumab in patients with surgically resectable head and neck cancer that concluded in 2020.4 Patient informed consent was given for the trial and then data were deidentified for the current study. Patients reviewed for this study (1) were 18 years or older; (2) had previously untreated local regionally advanced stage III or IV (as determined by the American Joint Committee on Cancer staging system, 8th edition) T3 or T4, or N2 or higher, disease that was surgically resectable; (3) were treated only at the University of Cincinnati Cancer Center, and (4) only with the subsite of oral cavity cancer. As per trial protocol, these patients received 1 dose of pembrolizumab (200 mg intravenously) 7 to 21 days before their scheduled resection date. The time period of when adverse events were collected ended when adjuvant treatment began (approximately 4-6 weeks following surgical resection). Full details of the trial protocol can be found in the primary publication.4
Statistical Analysis
To identify historical controls to match clinical trial patients, medical records were reviewed through the head and neck cancer RedCap (Vanderbilt University) database of patients treated at the University of Cincinnati Cancer Center from 2015 to 2021. The University of Cincinnati prospectively collects demographic and clinical information of patients treated for head and neck cancer at the University of Cincinnati Cancer Center for research purposes and stores the data in a secure RedCap database. Patients were matched by cancer subsite (OCSCC), age (±5 years), sex, race and ethnicity, smoking status, and overall pathological stage of cancer. Medical records were then reviewed for postoperative adverse events that included edema/lymphedema, trismus, flap failure, fistula, wound dehiscence (of both primary surgical and donor sites), wound infection, hematoma, or return to the operating room within 30 days of initial surgery. Trismus was assessed before and after surgical intervention. A McNemar test was conducted on each adverse event separately, comparing the 2 groups. Statistical analysis was conducted using SAS, version 9.4 (SAS Institute), and statistical significance was set at 95% with P<.05.
Results
In total, 66 patients were included in this study, with 34 patients as part of the prospective clinical trial and 32 patients identified as historical controls. When comparing the 2 groups for differences in postoperative adverse events, 2 patients who received neoadjuvant pembrolizumab were excluded because a control was not able to be identified for those specific patients. The demographics of each group are summarized in Table 1. All but 1 of the patients in the clinical trial underwent free-flap reconstruction following surgical resection. The sole patient who did not require free tissue transfer experienced enough disease regression with neoadjuvant pembrolizumab to avoid free-flap reconstruction. Within the control group, 28 patients underwent free tissue transfer, while 1 required a regional flap (submental island rotational flap) and 3 patients received primary closure of their defects.
Table 1. Baseline Patient and Disease Characteristicsa.
Characteristic | No. (%) | |
---|---|---|
Pembrolizumab group (n = 32) | Control group (n = 32) | |
Age, mean (SD) | 58 (3.9) | 59.6 (3.8) |
Sex | ||
Female | 14 (44) | 14 (44) |
Male | 18 (56) | 18 (56) |
Race and ethnicity | ||
Black | 1 (3) | 1 (3) |
White | 30 (94) | 30 (94) |
Unknown/otherb | 1 (3) | 1 (3) |
Smoker (>10 packs/y) | 19 (60) | 19 (60) |
Overall cancer stage | ||
I | 2 (6) | 2 (6) |
II | 1 (3) | 1 (3) |
III | 2 (6) | 2 (6) |
IV | 29 (91) | 29 (91) |
Reconstruction | ||
Free flap | 31 (97) | 28 (88) |
Rotational flap | 0 | 1 (3) |
Total | 31 (97) | 29 (91) |
Demographics are of patients who received neoadjuvant pembrolizumab compared with matched controls with treatment-naive local regionally advanced oral cavity squamous cell carcinoma treated with surgical resection. The University of Cincinnati prospectively collects demographic and clinical information of patients treated for head and neck cancer at the University of Cincinnati Cancer Center for research purposes and stores the data in a secure database.
Other was a self-reported response in the secure database.
Among the 32 patients receiving neoadjuvant immunotherapy, edema/lymphedema was the most common adverse event (n = 20 [63%]), followed by trismus (n = 7 [22%]), wound infection (n = 7 [22%]), and return to the operating room within 30 days (n = 7 [22%]). The most common postsurgical complication noted in the control group was also edema/lymphedema (n = 20 [63%]). Trismus was considerably more prevalent by a difference of 28.1% (95% CI, 5.6%-50.6%) among historical control patients (n = 16 [50%]). There were no clinically meaningful differences between the pembrolizumab group and the historical control group in rates of flap failure (−3.1%; 95% CI, −16.6% to 10.0%), fistula (3.1%; 95% CI, −16.6% to 22.8%), hematoma (−3.1%; 95% CI, −13.5% to 7.2%), wound dehiscence (9.0%; 95% CI, −9.6% to 27.5%), lymphedema (0.0%; 95% CI, −23.7% to 23.7%), or wound infection (0.0%; 95% CI, −20.3% to 20.3%), nor in rates of return to the operating room within 30 days after the initial surgery (0.0%; 95% CI, −20.3% to 20.3%) (Table 2).
Table 2. Postoperative Adverse Events.
Adverse event | No. (%) | Effect size (95% CI), % | |
---|---|---|---|
Pembrolizumab group (n = 32) | Control group (n = 32) | ||
Edema/lymphedema | 20 (63) | 20 (63) | 0.0 (−23.7 to 23.7) |
Trismus | 7 (22) | 16 (50) | 28.1 (5.6 to 50.6) |
Flap failure | 3 (9) | 2 (6) | −3.1 (−16.6 to 10.0) |
Fistula | 6 (19) | 7 (22) | 3.1 (−16.6 to 22.8) |
Wound dehiscence | 4 (13) | 7 (22) | 9.0 (−9.6 to 27.5) |
Wound infection | 7 (22) | 7 (22) | 0.0 (−20.3 to 20.3) |
Hematoma | 2 (6) | 1 (3) | −3.1 (−13.5 to 7.2) |
Return to operating room within 30 d | 7 (22) | 7 (22) | 0.0 (−20.3 to 20.3) |
Discussion
In this study, the use of neoadjuvant pembrolizumab therapy for advanced-stage OCSCC was not associated with an increase in the incidence of postoperative adverse events. Except for trismus, which was more common in the historical control group, the complications assessed were similar between groups, suggesting that preoperative pembrolizumab in treatment-naive patients does not considerably increase perioperative morbidity.
The safety and efficacy of neoadjuvant immunotherapy for cancer treatment is an area of active research.13,14,15,16,17 In locally advanced esophageal cancer, the addition of immunotherapy to standard chemoradiotherapy prior to esophagectomy did not increase 30-day major complications (including readmission rate and mortality).14 Preoperative use of immune checkpoint inhibitors did not increase the risk of intraoperative or postoperative complications in melanoma.18 In a window-of-opportunity clinical trial evaluating neoadjuvant tadalafil and nivolumab in resectable HNSCC, Luginbuhl et al16 reported no appreciable wound-healing delays, although this was not their primary outcome.
For HNSCC specifically, Mays et al12 performed a multi-institutional retrospective case series that evaluated patients undergoing free tissue transfer treated with immunotherapy. In their study, they reported a 33% wound complication rate among 51 patients with preoperative targeted therapy for oral cavity cancer compared with 21% in historical controls. For all subsites of HNSCC, they also reported a higher likelihood of developing major complications requiring invasive surgical treatment among patients receiving neoadjuvant immunotherapy, concluding that preoperative immunotherapy contributed to poor wound healing and the need for treatment for such complications. However, their analysis included a heterogenous patient cohort, with some receiving immunotherapy for recurrence and many having undergone radiotherapy previously, suggesting an interplay of multimodality treatment with confounding contributions to poor wound healing. Furthermore, while patients in their study were considerably more likely to experience major complications after receiving preoperative immunotherapy, these complications were not specifically in patients with OCSCC. It is likely that these additional complications were present in patients with pharyngeal or laryngeal defects or more extensive head and neck resections. Patients included in the present study were treatment naive, from a single institution, and carefully matched by disease subsite and clinical stage, likely explaining the differences observed between these 2 studies.
A rather surprising finding in this study was the substantially lower rate of postoperative trismus among patients who received preoperative immunotherapy. Trismus is a common adverse effect of head and neck cancer treatment and is a distressing symptom that can drastically diminish one’s quality of life.19,20 Trismus from surgery results from the disruption of the muscles of mastication, particularly the pterygoids, or the temporomandibular joint. If neoadjuvant treatment resulted in a real-time shrinkage of tumor size, then a smaller and less disrupted resection could be expected, thereby decreasing the risk of trismus. In total, 6 patients in the clinical trial were down-staged following pretreatment with pembrolizumab to a lower final pathologic stage (eTable in the Supplement). Although the protocol of the clinical trial called for the surgeon to resect from the boundaries of the original tumor, it theoretically would be difficult to discern the original margins in the setting of a considerable treatment effect, potentially resulting in a less radical resection. Others have also similarly reported that for some patients, T stage was down-staged from pretreatment clinical stage to postoperative final stage after receiving neoadjuvant treatment.16,17
Wise-Draper et al4 described that patients who demonstrated pathologic response (PR) to neoadjuvant pembrolizumab had a meaningful improvement in disease-free survival compared with those without PR, particularly in those tumors with high PD-1 ligand 1 positivity. While it remains unclear how PR may predict long-term prognosis, the immediate effect of this tumor response may have been observed in the surgical field and consequently reduced morbidity of the surgical resection.
Limitations
There are several limitations of this study. The small sample size was determined by the number of enrolled patients in the larger clinical trial at the time of data collection, and it is possible that more differences in clinical outcomes might have been detected with a greater sample size. For the control group, a 2:1 or 3:1 comparison was considered, but after extensive medical record review and earnest effort, it became apparent that there was not a large enough group of similar patients to match during this time period. It was decided that including patients from farther back in time would introduce additional noteworthy factors that play a role in surgical complications, such as different treating health care professionals and surgeons. Thus, the control group was matched at a 1:1 ratio. This highlights the importance of multi-institutional collaboration to study these questions.
Additionally, the adverse events assessed herein were limited to those easily discoverable in the historical control group through a retrospective medical record review because adverse events in standard-of-care treatment are not as meticulously documented as they are in a clinical trial. Accordingly, there are likely differences in complication rates between treatment groups not captured in this study. Finally, trismus was documented in the medical records as either being present or absent as it relates to clinical significance determined by the health care professional. Owing to a lack of regular, standardized measurements of the degree of trismus in this study, this study was limited to a qualitative definition of trismus.
Despite these limitations, this study demonstrated that there was no increase in perioperative morbidity among patients with advanced oral cavity cancer treated with neoadjuvant pembrolizumab. Trismus was considerably less common in the immunotherapy group, suggesting a perioperative benefit from receiving neoadjuvant treatment. Further prospective studies are needed to expand on the possible adverse events that may arise so that physicians may anticipate and better manage the potential surgical adverse effects of novel agents.
Conclusions
This cohort study found that the use of neoadjuvant pembrolizumab therapy in treatment-naive, local regionally advanced OCSCC was not associated with an increase in the incidence of most postoperative adverse events studied, with trismus being the only complication more prevalent in the control group. These findings suggest that preoperative treatment with pembrolizumab does not increase prevalence of postoperative adverse events.
eTable. Pretreatment Clinical Stage and Postoperative Pathological Stage
References
- 1.Bernier J, Domenge C, Ozsahin M, et al. ; European Organization for Research and Treatment of Cancer Trial 22931 . Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350(19):1945-1952. doi: 10.1056/NEJMoa032641 [DOI] [PubMed] [Google Scholar]
- 2.Omura K. Current status of oral cancer treatment strategies: surgical treatments for oral squamous cell carcinoma. Int J Clin Oncol. 2014;19(3):423-430. doi: 10.1007/s10147-014-0689-z [DOI] [PubMed] [Google Scholar]
- 3.Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660 [DOI] [PubMed] [Google Scholar]
- 4.Wise-Draper TM, Gulati S, Palackdharry S, et al. Phase II clinical trial of neoadjuvant and adjuvant pembrolizumab in resectable local-regionally advanced head and neck squamous cell carcinoma. Clin Cancer Res. 2022;28(7):1345-1352. doi: 10.1158/1078-0432.CCR-21-3351 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856-1867. doi: 10.1056/NEJMoa1602252 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. doi: 10.1146/annurev.immunol.26.021607.090331 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kwok G, Yau TC, Chiu JW, Tse E, Kwong YL. Pembrolizumab (Keytruda). Hum Vaccin Immunother. 2016;12(11):2777-2789. doi: 10.1080/21645515.2016.1199310 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol. 2018;81:45-51. doi: 10.1016/j.oraloncology.2018.04.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Ferris RL, Licitra L, Fayette J, et al. Nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: efficacy and safety in CheckMate 141 by prior cetuximab use. Clin Cancer Res. 2019;25(17):5221-5230. doi: 10.1158/1078-0432.CCR-18-3944 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956-965. doi: 10.1016/S1470-2045(16)30066-3 [DOI] [PubMed] [Google Scholar]
- 11.Rischin D, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: health-related quality-of-life results from KEYNOTE-048. Oral Oncol. 2022;128:105815. doi: 10.1016/j.oraloncology.2022.105815 [DOI] [PubMed] [Google Scholar]
- 12.Mays AC, Yarlagadda B, Achim V, et al. ; American Head and Neck Society Reconstructive Microsurgery Committee . Examining the relationship of immunotherapy and wound complications following flap reconstruction in patients with head and neck cancer. Head Neck. 2021;43(5):1509-1520. doi: 10.1002/hed.26601 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Cheng J, Guo M, Yang Y, et al. Perioperative outcomes of minimally invasive esophagectomy after neoadjuvant immunotherapy for patients with locally advanced esophageal squamous cell carcinoma. Front Immunol. 2022;13:848881. doi: 10.3389/fimmu.2022.848881 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Sihag S, Ku GY, Tan KS, et al. Safety and feasibility of esophagectomy following combined immunotherapy and chemoradiotherapy for esophageal cancer. J Thorac Cardiovasc Surg. 2021;161(3):836-843.e1. doi: 10.1016/j.jtcvs.2020.11.106 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Ge S, Huang C. Immune checkpoint inhibitors in neoadjuvant therapy of non-small cell lung cancer: a systematic review and meta-analysis. J Thorac Dis. 2022;14(2):333-342. doi: 10.21037/jtd-21-1664 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Luginbuhl AJ, Johnson JM, Harshyne LA, et al. Tadalafil enhances immune signatures in response to neoadjuvant nivolumab in resectable head and neck squamous cell carcinoma. Clin Cancer Res. 2022;28(5):915-927. doi: 10.1158/1078-0432.CCR-21-1816 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Uppaluri R, Campbell KM, Egloff AM, et al. Neoadjuvant and adjuvant pembrolizumab in resectable locally advanced, human papillomavirus-unrelated head and neck cancer: a multicenter, phase II trial. Clin Cancer Res. 2020;26(19):5140-5152. doi: 10.1158/1078-0432.CCR-20-1695 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Sun J, Kirichenko DA, Chung JL, et al. Perioperative outcomes of melanoma patients undergoing surgery after receiving immunotherapy or targeted therapy. World J Surg. 2020;44(4):1283-1293. doi: 10.1007/s00268-019-05314-2 [DOI] [PubMed] [Google Scholar]
- 19.Loh SY, Mcleod RWJ, Elhassan HA. Trismus following different treatment modalities for head and neck cancer: a systematic review of subjective measures. Eur Arch Otorhinolaryngol. 2017;274(7):2695-2707. doi: 10.1007/s00405-017-4519-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Gondivkar SM, Gadbail AR, Sarode SC, et al. Prevalence of trismus and its impact on oral health-related quality of life in patients treated for oral squamous cell carcinoma. Asian Pac J Cancer Prev. 2021;22(8):2437-2444. doi: 10.31557/APJCP.2021.22.8.2437 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable. Pretreatment Clinical Stage and Postoperative Pathological Stage