Treatment outcomes of squamous cell carcinoma of the oral cavity in young adults

Oral Oncology 87 (2018) 43–48

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Treatment outcomes of squamous cell carcinoma of the oral cavity in young adults☆

T

Mauricio E. Gameza,1, Ryan Krausc,1, Michael L. Hinnib, Eric J. Moored, Daniel J. Mae, Stephen J. Kof, Jean Claude M. Rwigemaa, Lisa A. McGeea, Michele Y. Halyarda, ⁎ Matthew R. Burasg, Robert L. Footee, Samir H. Patela, a

Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, AZ, United States Department of Otolaryngology-Head and Neck Surgery/Audiology, Mayo Clinic Hospital, Phoenix, AZ, United States c University of Southern California Keck School of Medicine, Los Angeles, CA, United States d Department of Otorhinolaryngology-Head and Neck Surgery, Mayo Clinic, Rochester, MN, United States e Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States f Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, United States g Biostatistics, Mayo Clinic, Scottsdale, AZ, United States b

A R T I C LE I N FO

A B S T R A C T

Keywords: Head and neck cancer Oral cavity Oral tongue

Objectives: The natural history of squamous cell carcinoma (SCC) of the oral cavity (OC) in young adults is unknown. We sought to provide an updated report on treatment outcomes of patients with OC SCC who were 40 years or younger. Materials and methods: We performed a retrospective analysis of 124 consecutive patients with primary OC SCC treated at Mayo Clinic (1980–2014). Patient and tumor characteristics and treatment approach were abstracted from patient charts. Results: Median patient age was 35 years (range, 19–40 years). The most common primary site was oral tongue (107 patients; 86.3%). Most patients (101; 81.5%) underwent wide local excision. Surgery alone was curative in 77 patients (62.1%); 47 (37.9%) received radiotherapy, and 26 (21%) received chemotherapy. Five-year overall survival (OS) was 78.1%; 10-year OS was 76.9%. Five-year disease-free survival (DFS) was 66.6%; 5-year local control was 87.6%; and 5-year locoregional control was 78.5%. On multivariable analysis, factors associated with worse OS and DFS were higher pathologic T stage (P = .008), lymph node positivity (P < .001), and disease recurrence (P < .001). Conclusion: Young adults with primary OC SCC may be treated with a similar treatment approach as older adults.

Introduction Oral cavity cancer (OCC) includes cancers that involve the lip, floor of the mouth, oral tongue, buccal mucosa, upper and lower gingivae, hard palate, and retromolar trigone, with the oral tongue being the most commonly affected subsite [1,2]. More than 90% of cancers in the oral cavity (OC) are squamous cell carcinomas (SCCs) [3]. In 2018, an estimated 33,950 cases of OCC and 6800 deaths are expected to occur

[4]. Historically, OCC has been thought of as a disease of older men who have a history of tobacco and alcohol use; the average age at diagnosis is 60 years; approximately 95% of OCC occurs after age 45 years [5]. Although the overall incidence of OCC has decreased over the past 30 years in the United States [6,7], the incidence of OCC in younger patients increased over the same period, peaked in the late 1980s, and has remained at an elevated level [2]. Of all patients with OCC, 4% to 6% are younger than 40 years [2,8–10], and most recent studies report

Abbreviations: AJCC, American Joint Committee on Cancer; DFS, disease-free survival; EGFR, epidermal growth factor receptor; HR, hazard ratio; LC, local control; LRC, locoregional control; MVA, multivariable analysis; OC, oral cavity; OCC, oral cavity cancer; OS, overall survival; SCC, squamous cell carcinoma; UVA, univariable analysis ☆ Portions of this manuscript have been published in abstract form: Int J Radiat Oncol Biol Phys. 2018;100(5):1340–1. ⁎ Corresponding author at: Department of Radiation Oncology, Mayo Clinic Hospital, 5777 E Mayo Blvd, Phoenix, AZ 85054, United States. E-mail address: [email protected] (S.H. Patel). 1 Both authors equally contributed to this manuscript. https://doi.org/10.1016/j.oraloncology.2018.10.014 Received 30 August 2018; Received in revised form 10 October 2018; Accepted 14 October 2018 1368-8375/ © 2018 Elsevier Ltd. All rights reserved.

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a female predominance [11]. The incidence of OCC in younger patients has increased worldwide, and most of these cancers involve the oral tongue [12]. The cause of the increased incidence of oral tongue cancers in younger patients is unclear. Studies on OCC risk factors in younger patients have yielded mixed results. Several studies have indicated that OCC occurs in younger patients who do not have a history of alcohol or tobacco use [11,13], but alcohol and tobacco use is considered the main risk factor for OCC in older patients [14]. Although some studies have indicated that alcohol and tobacco use may be similar between older and younger patients [9], some have speculated that the duration of exposure in younger patients may not be sufficient for development of OCC [15]. Risk factors that may be more relevant for younger patients include genetic factors, family history of neoplasm, immunodeficiency, oral hygiene, viral infections, and dietary factors, but consensus is lacking on these risk factors [16–18]. Similarly, reports on the prognosis for younger patients with OCC compared with older patients have been inconclusive; studies have reported no difference [19,20], a worse prognosis [12,21], and a better prognosis [8]. Similarities and differences between younger and older patients with OCC may be unclear for many reasons. Many studies have had a small number of patients, so drawing meaningful conclusions is difficult. Additionally, the definition of young patients is somewhat arbitrary, and different studies have used different ages, making it difficult to compare studies and identify differences between patients younger or older than 40 years. Given the lack of consensus on whether the OCC risk factors, recommended treatments, and prognosis for patients younger than 40 years are the same as for older patients, we wanted to perform a retrospective chart review of primary OC SCC in patients 40 years or younger at Mayo Clinic. A similar retrospective study performed at Mayo Clinic in Rochester, Minnesota, reported on the risk factors and prognosis for 62 patients 18–40 years old [22]. Our goal was to update the results of that study by identifying patient demographics, disease stage at presentation, treatments, prognostic indicators, and treatment outcomes for a larger cohort of patients.

Table 1 Patient, tumor, and treatment characteristics for 124 patients. Feature

Value

Age at diagnosis, y Mean (SD) Median (range) Quartile 1, quartile 3

33.8 (5.4) 35.0 (19.0–40.0) 30.5, 38.0

Sex, No. (%) Male Female

74 (59.7) 50 (40.3)

Smoker (> 10-pack-year history) Missing data, No. Nonsmoker, No. (%) Smoker, No. (%)

37 61 (70.1) 26 (29.9)

Primary site, No. (%) Oral tongue Other

107 (86.3) 17 (13.7)

Surgery type, No. (%) Wide local excision Excisional biopsy only

113 (91.1) 4 (3.2)

Radiotherapy, No. (%) Did not receive Received

77 (62.1) 47 (37.9)

Chemotherapy, No. (%) Did not receive Received

98 (79.0) 26 (21.0)

Pathologic T stage Missing data, No. 1, No. (%) 2, No. (%) 3, No. (%) 4, No. (%)

9 65 (56.5) 29 (25.2) 9 (7.8) 12 (10.4)

Lymph node Missing data, No. Negative, No. (%) Positive, No. (%)

24 54 (54.0) 46 (46.0)

physicians. Materials and methods Statistical analysis

The Mayo Clinic Institutional Review Board approved this study of 124 consecutive patients who were no older than 40 years, who had pathologically confirmed primary OC SCC, and who were treated from 1980 through 2014 at Mayo Clinic’s campuses in Phoenix, Arizona; Jacksonville, Florida; and Rochester, Minnesota. Patient charts were retrospectively reviewed to identify patient and tumor characteristics and treatment (Table 1). The stage of disease was initially determined with the American Joint Committee on Cancer (AJCC) staging criteria that were current at the time of diagnosis, but for the present analysis, staging followed the AJCC Cancer Staging Manual, Seventh Edition. At presentation, all patients underwent a complete history and physical examination, and all underwent biopsy of the OC primary tumor. All histopathologic diagnoses were confirmed at Mayo Clinic. Imaging studies, such as computed tomography, magnetic resonance imaging, and positron emission tomography, were performed at the discretion of the treating physician. Surgical approaches varied according to disease location and initial extension and included wide local excision and hemiglossectomy. Radiotherapy was delivered with linear accelerator–based photon therapy using 2-dimensional, 3-dimensional conformal, or intensitymodulated radiotherapy techniques. The radiotherapy planning target volume was the surgical bed of the primary tumor site along with neck lymph nodes that were involved or neck lymphatics if radiographic or pathologic findings were negative. The median prescribed total radiotherapy dose was 60 Gy in 30 fractions (range, 50–70 Gy). After treatment, follow-up evaluations included a history, physical examination, and imaging studies at the discretion of the treating

Kaplan-Meier survival curves were calculated for overall survival (OS), disease-free survival (DFS), locoregional control (LRC), and local control (LC) from the date of diagnosis to the date of the censoring event. Local failure was calculated from the date of first recurrence. All statistical tests were 2-sided; P values less than .05 were considered significant. Univariable analysis (UVA) log-rank tests and multivariable analysis (MVA) Cox proportional hazard regressions were performed to associate patient characteristics with treatment outcomes. Variables considered for analysis were patient sex, smoking history, primary site (oral tongue or other), pathologic T and N stages, treatment type (surgery alone or surgery in combination with other treatment), tumor grade (grades 1 and 2 or grades 3 and 4), margin status (negative margins or close or positive margins), perineural invasion, extracapsular extension, and development of disease recurrence after curative treatment. Analyses were performed with SAS version 9.4 (SAS Institute Inc). Results Patient characteristics and treatment regimens are reported in Table 1. The median patient age was 35 years (range, 19–40 years); 74 patients (59.7%) were male; 26 (29.9%) were smokers (> 10-pack-year smoking history). The most common primary site was oral tongue (107 patients; 86.3%); most tumors had an early T stage (stage 1 in 56.6% 44

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Figure 1. Five-Year Survival. A, Five-year overall survival. B, Five-year disease-free survival. C, Five-year local control. D, Five-year locoregional control.

1 predominantly male study in which the floor of the mouth was the most commonly affected subsite [8]. Additionally, our cohort was similar to cohorts in previous studies in the use of surgery alone as curative treatment for most patients [8,22,24] and in the resulting pathologic TNM staging [22,23]. For patient outcomes, our cohort had higher LC [24,28] but similar 5-year OS [22,28] and similar 5-year DFS [22,24] compared with other published studies of patients 40 years or younger. Table 2 summarizes the outcomes in previously reported series of younger patients with SCC of the OC.

[65 of 115] and stage 2 in 25.2% [29 of 115]); and lymph nodes were positive in 46% of patients (46 of 100). Surgery was performed in 117 patients (94.4%), with 113 (91.1%) undergoing wide local excision. Surgery alone was the curative treatment in 77 patients (62.1%); 47 patients (37.9%) received radiotherapy (5 of the 47 received radiotherapy with a definitive intent without surgical resection); and 26 (21%) received chemotherapy as part of their treatment. Two patients elected to have no treatment. The median follow-up was 9 years (range, 0.1–36.1 years). The 5year OS was 78.1% (95% CI, 71–85.9%), and the 10-year OS was 76.9% (95% CI, 69.7–85%) (Figure 1). The 5-year DFS was 66.6% (95% CI, 58.2–76.2%); the 5-year LC was 87.6% (95% CI, 81.4–94.4%); and the 5-year LRC was 78.5% (95% CI, 78.5–86.6%) (Figure 1). Factors associated with worse OS on UVA were higher pathologic T stage (T3 or T4) (hazard ratio [HR], 3.19; 95% CI, 3.44–22.04; P = .003); lymph node positivity (HR, 7.33; 95% CI, 2.72–19.81; P < .001); higher tumor grade (G3 or G4) (HR, 3.36; 95% CI, 1.52–7.42; P = .002); positive margins (HR, 5.58; 95% CI, 1.25–24.91; P = .01); need for adjuvant therapy (HR, 8.71; 95% CI, 3.44–22.04; P < .001); and disease recurrence (HR, 11.05; 95% CI, 3.87–31.52; P < .001). The same variables were also associated with a statistically worse DFS on UVA except for tumor grade and margin status. LC and LRC were not associated with any significant factors on UVA. On MVA, factors associated with worse OS and DFS were higher pathologic T stage (P = .008), lymph node positivity (P < .001), and disease recurrence (P < .001).

Treatment outcomes compared with studies of patients older than 40 years Given the discrepancies in published outcomes data, the appropriate management of patients 40 years or younger who have SCC of the OC has been the subject of much debate. Historic reports that looked at small samples of patients 40 years or younger who had SCC of the OC suggested poor overall treatment outcomes and more aggressive disease compared with patients older than 40 years [21,30,33,37]. Such results led to the use of a more aggressive approach for younger patients. However, more recent studies have shown that patients 40 years or younger may have similar or better outcomes than patients older than 40 years [8,20,23,24,38]. The outcomes data of the present study support the notion that patients 40 years or younger have similar treatment outcomes compared with patients older than 40 years and may be treated with the same treatment approach. Our findings for 5-year OS (78.1%), DFS (66.6%), LC (87.6%), and LRC (78.5%) were similar to or higher than what has been reported in other studies of patients older than 40 years, in which the reported OS was 57.6% to 76% [8,39]; DFS was 55% to 75% [20,23,24,38,39]; LC was 73.3% to 86% [20,24,37,38]; and LRC was 65.4% to 78% [24,40]. From these results and the current literature, it appears that the same treatment approach applies to patients 40 years or younger with SCC of the OC: single-modality therapy with surgery and consideration for adjuvant multimodality therapy on the basis of high-risk pathologic features (positive or close margins, perineural invasion, lymphovascular invasion, multiple nodes, extracapsular extension, or advanced T stage).

Discussion This study included 1 of the largest cohorts of patients who were no older than 40 years when they received the diagnosis of SCC of the OC. Our results indicate that the majority of OCCs occur in the anterior twothirds of the oral tongue and can be managed as for patients older than 40 years with similar treatment outcomes. Comparison with other studies of younger patients with SCC of the OC The patients in our cohort had similar age [22–24], sex distribution [2,22,25–27], and OC subsite distribution [22,28,29] as previously published studies of patients 40 years or younger with the exception of 45

12

39

27

11

6

Amsterdam and Strawitz [30] Lipkin et al. [31]

Son and Kapp [32]

Jones et al. [33]

Sarkaria and Harari [21] Friedlander et al. [24]

46

18

16

38

34

63

124

Goepfert et al. [23]

Hilly et al. [35]

Udeabor et al. [8]

Atula et al. [36]

Blanchard et al. [28]

Current series

40; median age, 35 y

40; mean age, 32 y 40

40

40; mean age, 32 y 40; median age, 30.8 y 49; median age, 39 y 45; mean age, 37 y 30

40

35; median age, 29 y 40; median age, 36 y 40

Age cutoff, y

66% were male 87% were male 56% were male 64% were female 83% were male 56% were male 56% were female 100% were female 56% were male 79% were male 65% were male 75% were male 60% were male

Sex

Retrospective Retrospective

1980–2014

Retrospective

1999–2011

1980–1989

Retrospective

Retrospective

1996–2012 1980–1999

Retrospective

Phase 2

Retrospective

Retrospective

Retrospective

Retrospective

Retrospective

Retrospective

Study design

1997–2011

2001–2004

1984–1993

1971–1991

1976–1988

1958–1980

1964–1983

1954–1979

Period of study

OC (oral tongue, 67%) OC (38%), pharynx, larynx OC (63%), oropharynx OC (oral tongue, 100%) OC (oral tongue, 100%) OC (oral tongue, 100%) OC (oral tongue, 100%) OC (oral tongue, 100%) OC (oral tongue, 100%) OC (FOM, 39%), oropharynx OC (oral tongue, 100%) OC (oral tongue, 86%) OC (oral tongue, 86%)

Primary site

Surgery

Surgery

Surgery

Surgery

Surgery and radiotherapy

Induction chemotherapy followed by surgery with or without radiotherapy Surgery and radiotherapy

Surgery

Surgery

Surgery and radiotherapy

Surgery or radiotherapy

Surgery

Surgery

Primary treatment

Abbreviations: DFS, disease-free survival; FOM, floor of mouth; NA, data not available; OC, oral cavity; SCC, squamous cell carcinoma. a According to histologic results, all participants had SCC.

23

Kies et al. [34]

36

N

Author

Table 2 Outcomes of SCC of the oral cavity in young adultsa.

88

80

NA

NA

50

NA

NA

72

17

NA

19

NA

82

Local control, %

78% (5 y)

80% (5 y)

71% (5 y)

66% (5 y)

About 60% (3 y)

About 75% (2.7 y)

48%

DFS, 62% (5 y)

About 62%; no significant difference with respect to older patients 33%

17% (3 y)

NA

75% (2 y)

Overall survival

9y

64 mo

≥5 y

NA

30 mo

64 mo

52 mo

25 mo

NA

NA

NA

≥1 y

2y

Follow-up

M.E. Gamez et al.

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M.E. Gamez et al.

Prognostic factors identified in younger patients with SCC of the OC [3]

The earlier Mayo Clinic experience with 62 patients identified a trend toward poor cause-specific survival and high rates of recurrence in patients with overexpression of epidermal growth factor receptor (EGFR) [22]. Although we could not assess for EGFR overexpression, we did identify that pathologic T stage, lymph node positivity, and recurrent disease were associated with significantly worse OS and DFS on MVA. This finding expanded on the previous Mayo Clinic study in which only lymph node positivity was associated with OS on MVA.

[4] [5] [6]

[7]

Cause of SCC of the OC in younger patients

[8]

The cause of SCC of the OC in patients 40 years or younger is unclear. It is difficult to compare the role of smoking in the development of SCC of the OC in patients 40 years or younger because studies report smoking history in various ways. In the present study, nearly one-third of patients reported that they were smokers (> 10-pack-year smoking history), but other studies have reported that 40.3–65.9% of patients 40 years or younger who had SCC of the OC had a smoking history [20,22,24,33,40], and 1 study reported a mean smoking history of 13.1 pack-years [23]. The difference in the smoking histories may simply reflect various ways of reporting or the general decreased prevalence of tobacco use in the United States. The time of exposure in younger patients, however, may not be sufficient for development of OCC [15]. Additionally, a study at the University of Texas MD Anderson Cancer Center reported that SCC of the oral tongue in nonsmoking patients 45 years or younger appeared genomically similar to tumors of older patients who had a smoking history [41]. Additional research is needed to better understand the etiologic origins of SCC of the OC in patients 40 years or younger.

[9]

[10] [11]

[12] [13] [14]

[15] [16]

[17] [18]

Limitations [19]

This study has several limitations, including the relatively small number of patients, lack of matched controls or biomarkers for comparison of outcomes data, and the limitations associated with a retrospective study design. Additionally, we compared the results of this study, which included patients with SCC of any OC subsite, with results of studies that looked exclusively at cancer of the oral tongue. Despite these limitations, our study is one of the largest studies of patients 40 years or younger with SCC of the OC.

[20] [21] [22]

[23]

Conclusions [24]

SCC of the OC in young adults may be managed with a treatment approach similar to that for older adults. A decision-making strategy for adjuvant therapy based on pathologic criteria is justified. Further study is warranted to better understand the etiologic factors responsible for OCC in young adults.

[25]

[26]

[27]

Role of the funding source [28]

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

[29]

Conflict of interest

[30]

None declared.

[31] [32]

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