Primary site surgical resection in cM1 oral cavity squamous cell carcinoma

1 INTRODUCTION

Surgery and neck dissection is the standard of care for resectable oral cavity squamous cell carcinoma (OCSCC) presenting without clinical evidence of distant metastasis, and advances in adjuvant radiotherapy and chemotherapy have significantly improved survival and locoregional control.^1-11 Approximately 2% of OCSCC presents with clinically distant metastasis (cM1) which often contraindicates definitive local therapies such as surgical resection and radiotherapy.^{12, 13} In cM1 OCSCC, systemic therapies such as chemotherapy and immunotherapy are the standard of care, but response rates are exceedingly poor, with most patients dying of disease progression within months.^14-17 cM1 OCSCC, in particular, is suggested to have a worse prognosis than cM1 squamous cell carcinoma of other head and neck primary sites, highlighting a continued need for more effective targeted and systemic therapies.¹⁸

Recent studies suggest that surgical resection, curative-dose radiotherapy (≥60 Gy to the primary site), and other local therapies have a survival benefit in cM1 head and neck squamous cell carcinoma (HNSCC).^19-29 Surgical resection is included in the management of locoregionally advanced OCSCC, but its utility in cM1 OCSCC remains unclear because of the heterogeneous clinical presentation and lack of high-quality clinical trial data. Considering that the morbidity and mortality of cM1 OCSCC are largely driven by primary tumor progression and poor locoregional control, determining the utility of surgical resection may benefit certain patients. Our study of the National Cancer Database (NCDB) investigates primary site surgical resection and associated survival outcomes in cM1 OCSCC. To our knowledge, our study is also the first to present a cohort of exclusively cM1 OCSCC.

2 METHODS

2.2 Inclusion criteria

The 2006 to 2018 NCDB was retrospectively reviewed for patients with cM1 OCSCC undergoing chemotherapy (Figure 1). OCSCC was identified using the International Classification of Diseases for Oncology, 3rd Edition histology (“8070–8072”), behavior (“3”), and topography (“C00.0–C00.9,” “C02.0–C02.3,” “C02.8,” “C02.9,” “C03.0–C03.9,” “C04.0–C04.9,” “C05.0,” “C05.8,” “C05.9,” “C06.0–C06.9”) codes. Patients were excluded if they had an age <18 years; history of prior malignancy; unknown surgical resection, radiotherapy, or chemotherapy status; treatment with palliative intent; an unknown number of chemotherapy agents; neoadjuvant radiotherapy or chemotherapy; salvage surgery; or unknown vital status or survival time.

3 RESULTS

3.2 Five-year OS

The 5-year OS of patients with primary tumors of the tongue (except base), gingiva, floor of mouth, palate (except soft palate and uvula), and other or unspecified oral cavity sites was 10.2%, 4.3%, 9.1%, 19.0%, and 19.4%, respectively (p = .519). The 5-year OS of patients with metastasis to the bone only, liver only, lung only, and other, multiple, or unknown sites was 9.1%, 0%, 13.2%, and 13.3%, respectively (p = .904) (Figure 2).

Patients undergoing surgical and nonsurgical treatment had similar 5-year OS (17.1% vs. 11.5%, p = .096) (Figure 3). Surgical treatment was associated with higher 5-year OS than nonsurgical treatment in patients with low-grade disease (20.0% vs. 9.8%) and those undergoing single-agent chemotherapy (23.1% vs. 10.1%) (p < .05) (Table 3). When considering all analyzed treatment combinations, the 5-year OS of patients undergoing chemotherapy alone, chemoradiotherapy, surgical resection + adjuvant chemotherapy, and surgical resection + adjuvant chemoradiotherapy was 9.4%, 15.2%, 8.3%, and 23.8%, respectively (p < .001); median survival (95% CI) was 8.3 (6.9–9.8), 16.0 (14.5–17.5), 10.0 (3.0–16.9), and 20.8 (12.4–29.2) months, respectively (Figure 4). Among patients undergoing surgical resection, those also undergoing neck dissection had similar 5-year OS as those not undergoing neck dissection (20.5% vs. 9.1%, p = .237). Patients with PSM had similar 5-year OS as those with negative surgical margins (12.8% vs. 20.0%, p = .668).

TABLE 3. Kaplan–Meier analysis of 5-year overall survival (%) among 278 patients undergoing chemotherapy.

	No surgical resection	Surgical resection	p
Overall	11.5	17.1	.096
Primary site
Tongue (except base)	9.4	13.5	.244
Gingiva	6.3	–	.091
Floor of mouth	9.5	8.1	.617
Palate (except soft palate and uvula)	17.1	–	.328
Other, unspecified	14.8	45.5	.027
Grade
Low	9.8	20.0	.027
High	9.3	–	.379
Unknown	16.2	16.7	.904
cT classification
1	22.2	–	.926
2	17.6	17.2	.447
3	14.3	17.6	.981
4	6.5	16.7	.117
x	23.1	25.0	.691
cN classification
0	–	27.3	.048
1–3	11.2	15.7	.132
x	29.0	–	.051
Site of distant metastasis
Bone	8.7	–	.740
Liver	–	–	.448
Lung	12.7	15.2	.228
Other, multiple, unknown	12.0	18.2	.309
Pathologic extranodal extension
No	–	18.8	.497
Yes	–	18.9	.619
Lymphovascular invasion
No	–	31.0	.034
Yes	–	12.5	.600
Radiotherapy
No	9.4	8.3	.972
Yes	15.2	23.8	.175
Chemotherapy
Single-agent	10.1	23.1	.020
Multiple agents	12.0	8.7	.505

• Note: Bold values are statistically significant (p < 0.05).
• Abbreviations: cN, clinical nodal; cT, clinical tumor.

Age at diagnosis (adjusted hazard ratio [aHR] 1.03, 95% CI 1.01–1.04, p < .001) was associated with decreased OS on multivariable Cox regression (Table 4). Floor of the mouth (aHR 0.61, 95% CI 0.40–0.93), palate (0.42, 0.22–0.80), other or unspecified primary sites (0.64, 0.43–0.95), chemoradiotherapy (0.56, 0.38–0.83), surgical resection + adjuvant chemoradiotherapy (0.37, 0.21–0.66), and immunotherapy (0.48, 0.28–0.81) were associated with improved OS (p < .05).

TABLE 4. Univariable and multivariable Cox proportional hazard regression models of 5-year overall survival among 278 patients undergoing chemotherapy.

	Univariable		Multivariable
	HR (95% CI)	p	aHRa (95% CI)	p
Age at diagnosis	1.02 (1.01–1.04)	<.001	1.03 (1.01–1.04)	<.001
Sex
Male	Ref	.230	Ref	.142
Female	1.19 (0.90–1.58)		1.27 (0.92–1.75)
Race
White	Ref		Ref
Black	1.23 (0.84–1.79)	.289	1.22 (0.81–1.82)	.343
Other	0.52 (0.26–1.01)	.052	0.61 (0.3–1.23)	.170
Facility type
Academic	1.08 (0.83–1.40)	.566	1.06 (0.79–1.42)	.694
Nonacademic	Ref		Ref
Charlson-Deyo comorbidity score
0	Ref	.496	Ref	.658
≥1	1.11 (0.82–1.50)		1.08 (0.77–1.52)
Primary site
Tongue (except base)	Ref		Ref
Gingiva	1.00 (0.62–1.60)	.999	0.61 (0.33–1.14)	.121
Floor of mouth	0.87 (0.62–1.22)	.420	0.61 (0.40–0.93)	.023
Palate (except soft palate and uvula)	0.73 (0.44–1.22)	.230	0.42 (0.22–0.80)	.008
Other, unspecified	0.77 (0.55–1.09)	.140	0.64 (0.43–0.95)	.027
Grade
Low	Ref		Ref
High	1.40 (1.02–1.92)	.037	1.15 (0.81–1.63)	.440
Unknown	0.90 (0.66–1.24)	.535	0.85 (0.59–1.23)	.397
cT classification
1	Ref		Ref
2	1.26 (0.64–2.5)	.504	1.48 (0.70–3.12)	.304
3	1.47 (0.74–2.96)	.273	1.42 (0.66–3.05)	.367
4	1.75 (0.94–3.24)	.076	1.91 (0.95–3.84)	.068
x	1.19 (0.58–2.44)	.627	1.12 (0.51–2.47)	.772
cN classification
0	Ref		Ref
1–3	1.08 (0.74–1.57)	.703	0.87 (0.57–1.33)	.514
x	0.74 (0.40–1.40)	.357	0.65 (0.30–1.38)	.259
Site of distant metastasis
Bone	Ref		Ref
Liver	0.97 (0.42–2.25)	.946	0.81 (0.33–1.98)	.649
Lung	0.93 (0.59–1.47)	.763	0.79 (0.48–1.30)	.356
Other, multiple, unknown	0.87 (0.57–1.33)	.519	0.66 (0.41–1.08)	.099
Treatment
Chemotherapy alone	Ref		Ref
Chemoradiotherapy	0.63 (0.46–0.85)	.002	0.56 (0.38–0.83)	.004
Surgical resection + adjuvant chemotherapy	1.01 (0.64–1.59)	.963	0.80 (0.45–1.39)	.423
Surgical resection + adjuvant chemoradiotherapy	0.47 (0.31–0.73)	.001	0.37 (0.21–0.66)	<.001
Chemotherapy
Single-agent	Ref		Ref
Multiple agents	1.27 (0.96–1.67)	.093	0.88 (0.61–1.27)	.499
Immunotherapy
No	Ref		Ref
Yes	0.72 (0.44–1.16)	.175	0.48 (0.28–0.81)	.006

• Note: Bold values are statistically significant (p < 0.05).
• Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval; cN, clinical nodal; HR, hazard ratio; Ref, reference.
• ^a N = 272; number of uncensored deaths: 229.

4 DISCUSSION

For the approximately 2% of OCSCC presenting with distant metastasis, systemic therapies remain the standard of care.^{12, 22} Despite aggressive treatment, most patients have uncontrolled pain, bleeding, respiratory obstruction, cachexia, and death within months.^{22, 40} Although local therapies are often withheld in cM1 disease, studies of cM1 HNSCC suggest that definitive local treatment may improve survival in appropriately selected patients.^19-29 In addition to the morbidity of locoregional disease, mortality in cM1 OCSCC has strong associations with primary tumor progression and poor locoregional control which raises the possibility that some patients may benefit from surgical resection. Given the lack of high-quality clinical trial data, our study utilizes the NCDB to investigate primary site surgical resection in cM1 OCSCC.

Our study identified 278 patients with cM1 OCSCC undergoing chemotherapy. Most patients had cT3-4 (68.3%) and clinical nodal disease (79.9%), which is often seen with aggressive tumor biology and high metastatic potential. Among patients with 1 known site of distant metastasis, the most frequent site was the lung (69.7%) which accounts for approximately 70% of all distant metastases in HNSCC.⁴¹ A minority of patients (21.2%) underwent primary site surgical resection in addition to chemotherapy. Although surgical resection is more often considered in patients with fewer comorbidities, those with CDCS ≥1 had increased odds of undergoing surgical resection. Academic facility was also associated with increased odds of undergoing surgical resection. Academic facilities often have increased access to additional personnel, resources, and multidisciplinary specialists, which assists in coordinating the aggressive, multimodal treatments that patients with cM1 disease may require. Of note, higher cTN classification was not associated with decreased odds of undergoing surgical resection. Although locoregionally advanced tumors are sometimes less amenable to surgical resection because of the difficulty in safely achieving negative margins and extent of surgery required, resecting these tumors often improves quality of life (eg, pain palliation and restoration of critical functions such as breathing and swallowing) which is prioritized in cM1 disease.

The five-year OS in our cohort was 13%; studies report 5-year OS in metastatic OCSCC ranging from 9% to 19% depending on tumor location, size, extent of metastasis, and treatment.^42-45 Despite the high rate of PSM (36.2%), patients undergoing surgical resection + adjuvant chemoradiotherapy had the highest OS, followed by those undergoing chemoradiotherapy alone; treatment combinations without radiotherapy were associated with the poorest OS, even if surgical resection was performed. The survival benefit of surgical resection + chemoradiotherapy persisted in sensitivity analysis including patients undergoing neoadjuvant therapy. Our study suggests that surgical resection is not associated with higher OS in cM1 OCSCC unless offered with chemoradiotherapy. A hypothesized abscopal effect in which radiotherapy enhances systemic antitumor immune responses and reduces tumor burden in nonirradiated distant sites may account for this finding.^{36, 46-49} Our findings are consistent with clinical trials and meta-analyses of cM1 HNSCC which demonstrate the survival benefit of curative-dose radiotherapy in cM1 HNSCC.^{20, 46, 50-52} Studies of cM1 HNSCC utilizing the NCDB similarly conclude that chemoradiotherapy with a dose ≥60 Gy is associated with higher OS than either chemotherapy alone or chemoradiotherapy with a dose <60 Gy.^{20, 22} Locoregional radiotherapy, however, is often not utilized in cM1 HNSCC because of poor disease prognosis, the inconvenience of daily radiotherapy sessions, and treatment-related toxicities such as mucositis, dermatitis, xerostomia, dysphagia, and feeding tube dependence.²² Although studies attributing a survival benefit to radiotherapy in cM1 HNSCC excluded patients undergoing surgical resection, our study suggests that the survival benefit of radiotherapy persists in the adjuvant setting.²² The roles of altered fractionation, stereotactic body radiotherapy, radio-sensitizing chemotherapy, and biologic agents in optimizing response to radiotherapy remain areas of future investigation not explored in our study because of limitations in the NCDB.^{22, 46, 53-55}

Patients undergoing surgical resection + adjuvant chemotherapy (without radiotherapy) had similar OS as those undergoing chemotherapy alone. Interruptions or delays in chemotherapy may have mitigated any potential benefit of surgical resection because systemic therapy is typically withheld prior to and immediately following surgery to allow for appropriate wound healing.⁴⁶ Poor baseline health and the known immunosuppressive effects of surgery may also have mitigated any benefit of locoregional control, contributing to further disease progression.⁴⁶ Surgical resection may have more benefit in oligometastatic HNSCC, especially if the primary tumor and distant metastases can be removed concomitantly.^{24, 46, 54-58} Regardless, progression of cM1 disease has significant functional morbidity and despite the risks of surgery, resection may improve quality of life in select patients. Further studies are needed to determine whether the possible survival benefit of definitive local therapy is associated with symptom palliation.

Our study did not identify an association between the number of chemotherapy agents and OS, aligning well with studies of cM1 HNSCC.^{21, 46} Current chemotherapy agents are often ineffective in slowing the progression of cM1 disease, even when administered in combination, highlighting a continued need for more effective targeted and systemic therapies. Interestingly, surgical resection was associated with higher OS in patients undergoing single-agent chemotherapy suggesting that the possibly improved locoregional control that surgery offers does not benefit patients undergoing multiple-agent chemotherapy. However, there are likely other factors responsible including the specific details surrounding why patients underwent single-agent versus multiple-agent chemotherapy (eg, patients undergoing multiple-agent chemotherapy may not have been candidates for preferred regimens with high-dose cisplatin).

Our study identified an association between immunotherapy and higher OS, aligning with the results of the EXTREME, CheckMate 141, and KEYNOTE-048 clinical trials which demonstrated the survival benefit of cetuximab, nivolumab, and pembrolizumab, respectively, in recurrent or metastatic HNSCC.^{17, 26, 59-63} Of note, immunotherapy was not routinely utilized in HNSCC during the earlier years of our study period (2006–2018) which may account for a minority of patients (9%) in our cohort undergoing immunotherapy. Interestingly, on landmark survival analysis censoring survival time <3, <6, and <12 months, chemoradiotherapy, surgical resection + chemoradiotherapy, and immunotherapy, respectively, were no longer associated with higher OS, possibly suggesting that the survival benefit of aggressive treatment is specific to advanced cM1 disease with particularly poor prognosis.^{20, 46} The survival benefit of multiagent chemotherapy and immunotherapy in cM1 HNSCC, specifically in patients undergoing definitive local therapy, warrants further investigation in well-designed clinical trials.⁶⁴

Limitations inherent in retrospective review of the NCDB include the possibility of inaccurate histologic diagnosis and variable miscoding. The NCDB does not report medical comorbidities, specific site and size of metastases, imaging studies, quality of life, tumor board recommendations, surgeries besides resection (eg, tracheostomy and endovascular procedures), types of chemotherapy and immunotherapy agents, postoperative complications, benefits of surgery besides higher OS (eg, pain palliation and restoration of function), locoregional recurrence, and progression-free survival. The NCDB does not reliably confirm if patients had biopsy-proven pM1 disease. Selection bias is inherent in retrospective analysis comparing primary surgical resection with primary nonsurgical therapy because patients responding to systemic therapy may have been more likely to undergo definitive local therapies or have better performance status. Participation in palliative care, clinical trials, and experimental therapies may have impacted treatment decisions. Our study is unable to comment on the management of cM0 OCSCC that is unresponsive to initial definitive treatment or later presents with distant metastasis. Lastly, the retrospective, hypothesis-generating design of our study prevents us from making firm, evidence-based treatment recommendations.

5 CONCLUSION

A minority of patients with cM1 OCSCC undergoing chemotherapy also underwent primary site surgical resection. Patients undergoing surgical resection more frequently were treated at academic facilities, had CDCS ≥1, and higher incidence of cT1-2 disease. Despite the high rate of PSM, patients undergoing surgical resection + adjuvant chemoradiotherapy had the highest OS, followed by those undergoing chemoradiotherapy alone; treatment combinations without radiotherapy were associated with the poorest OS, even if surgical resection was performed. Our study suggests that surgical resection + adjuvant chemoradiotherapy may have a survival benefit in select patients. cM1 OCSCC is typically considered incurable, and management requires multidisciplinary physicians capable of weighing the potential survival benefit of aggressive treatment with patient-directed goals of care, quality of life, and probability of cure.

CONFLICT OF INTEREST STATEMENT

The authors declare that there is no conflict of interest.