Original Research
Risk Factors Associated with Distant Metastasis in Patients with Oral Squamous Cell Carcinoma
Otolaryngology– Head and Neck Surgery 1–8 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599815580980 http://otojournal.org
Takumi Hasegawa, DDS, PhD1, Makiko Tanakura, DDS1, Daisuke Takeda, DDS, PhD1, Akiko Sakakibara, DDS, PhD1, Masaya Akashi, DDS, PhD1, Tsutomu Minamikawa, DDS, PhD1, and Takahide Komori, DDS, PhD1
No sponsorships or competing interests have been disclosed for this article.
Abstract Objective. The purpose of this study was to retrospectively evaluate the incidence of distant metastasis (DM) after curative surgical treatment and assess the multivariate relationships among various risk factors for DM in patients with oral squamous cell carcinoma (OSCC). Study Design. Case series with chart review. Setting. Tertiary referral center. Subjects and Methods. The medical records of all patients with OSCC without DM who underwent curative surgery with or without postoperative adjuvant chemoradiation between January 2001 and February 2014 at our institution were retrospectively reviewed. There were a total of 451 patients, including 271 men and 180 women, with a mean age of 65.9 6 13.5 years. Results. Of these patients, 30 (6.7%) developed DM. During the follow-up period, the 5-year overall survival rate was 76.2%. Sites of DM comprised the lungs (80.0%), skin (13.3%), liver (10.0%), bone (6.7%), and brain (3.3%). We found the T classification and N classification as well as the histologic grade to be significant risk factors associated with the development of DM in the univariate analysis only (P = .003), whereas locoregional failure (odds ratio [OR], 4.03), multiple lymph node metastases (more than 4 positive nodes; OR, 3.32) and positive extracapsular spread (OR, 3.06) were identified to be significant risk factors associated with the development of DM in the multivariate analysis. Conclusion. We demonstrated multivariate relationships among various risk factors for DM in OSCC patients. Clinicians should consider these risk factors and pay special attention to detecting DM early during the postoperative management of OSCC patients with these risk factors. Keywords distant metastasis, oral squamous cell carcinoma, risk factor, oral cancer
Received January 9, 2015; revised March 9, 2015; accepted March 18, 2015.
R
ecently, the treatment of oral squamous cell carcinoma (OSCC) with surgery and/or adjuvant chemoradiation has improved the overall survival (OS) rate of this disease.1 In addition, the control rate for locoregional tumors has also recently improved.2,3 Therefore, controlling distant metastasis (DM) and second primary tumors is becoming increasingly important when treating OSCC. Several investigators have reported that the incidence of DM in patients with head and neck cancer is 4% to 26%.4-8 However, patients in the early stage of DM often exhibit no symptoms. Therefore, achieving the early detection of DM is difficult, and this condition continues to have a poor prognosis. The expected survival time is 4.4 to 7.3 months from the diagnosis of DM of head and neck squamous cell carcinoma (HNSCC).9,10 Hence, providing the early detection of DM and identifying groups at high risk for DM are important for managing HNSCC. Traditionally, locoregional failure (LRF),3,5,11 the T and N classifications,3,5,6,9,12 extracapsular spread (ECS),3,5,13 and poor differentiation14,15 have been shown to be independent risk factors for DM, as reported in several studies of HNSCC,3-15 although some of these factors are controversial as risk factors for DM in OSCC patients.3,13,16-19 In our institution, surgical treatment of the primary tumor is generally performed as the initial treatment. In this study, we retrospectively investigated the multivariate relationships among various risk factors for DM in OSCC patients.
1 Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
Corresponding Author: Takumi Hasegawa, DDS, PhD, Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe 650-0017, Japan. Email: [email protected]
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Patients and Methods
Statistical Analysis
This study was a nonrandomized, retrospective (historic) cohort study of patients and was thus granted exemption from institutional review board approval by our institution. Between January 2001 and February 2014, a total of 451 patients with oral cancer underwent major head and neck surgery at the Department of Oral and Maxillofacial Surgery, Kobe University Hospital. Among the 451 patients, there were 126 (27.9%) subjects with stage I disease, 145 (32.2%) subjects with stage II disease, 54 (12.0%) subjects with stage III disease, and 126 (27.9%) subjects with stage IV disease. All patients underwent wide excision of the primary tumor and/or neck dissection with either modified radical neck dissection or selective neck dissection with or without postoperative adjuvant chemoradiation. In addition, all patients received a preoperative examination, including chest x-ray, computed tomography (CT), and magnetic resonance imaging of the head and neck region. Preoperative DM was excluded based on the findings of chest CT or positron emission tomography (PET)–CT. In our institution, patients exhibiting high-risk characteristics (histological evidence of invasion of 2 or more regional lymph nodes, ECS, and microscopically involved mucosal resection margins) underwent radiotherapy. The concurrent chemotherapy entry criteria included an age of 20 to 75 years, Eastern Cooperative Oncology Group performance status of 0 or 1, and an adequate hematologic and organ function, namely, a white cell count of at least 3500/m3, platelet count of at least 100,000/m3, and creatinine clearance of more than 70 mL/min. Patients with a history of previous chemotherapy or radiotherapy were excluded. For the follow-up for DM after the initial treatment, chest x-ray, chest CT, or PET were performed or when the patient presented with new indicative symptoms. Before 2005, the patients were offered chest x-ray screenings at 3 months of follow-up and chest CT at 6 months of follow-up. After 2006, the patients were offered chest CT at 6 months of follow-up and PET-CT at 1 year of follow-up. The exclusion criteria included patients with other cancers before the diagnosis of OSCC, a history of palliative treatment due to a poor medical condition, and/ or patient refusal of curative surgical treatment, simultaneous second primary cancer, the detection of DM prior to the initial treatment, and previous radiotherapy or chemotherapy for head and neck cancer or other diseases. Clinicopathologic data, including sex, age, subsite, T classification (T1, 2 or T3, 4), N classification (N0 or 1 or N2, 3), treatment modalities, neck dissection, pathologic stage, pathologic nodal status (presence, number of lymph node metastases [0 or 1-3 or more than 4 positive nodes]), histologic grade (well, moderate, or poor), surgical margin, ECS, and LRF were investigated. All factors are listed in Table 1. Also, time of development of DM, location of DM, number of DM lesions (single or multiple), and clinical course were investigated. The endpoint of follow-up was defined as death, loss to follow-up, or February 2014.
Data collection and statistical analyses were carried out with SPSS 15.0 (SPSS, Chicago, Illinois) and Stat-View-J4.5 software (Abacus Concepts, Berkeley, California). The association of each variable with the DM was tested by using the Mann-Whitney U nonparametric test for ordinal variables and the Fisher exact test or x2 test for categorical variables. Cumulative OS was calculated using the KaplanMeier product-limit method. The significant levels among the curves were determined using the log-rank test. A value of P \ .05 was considered statistically significant. All of the variables associated with DM were introduced into a multiple logistic regression model. Forward stepwise algorithms were used, with the rejection of those variables that did not fit the model significantly. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were also calculated for the significant signs. A value of P \ .05 was considered statistically significant.
Results The subjects comprised 451 patients, including 271 men and 180 women, with an age range from 23 to 97 years and a mean age of 65.9 6 13.5 years. Of the 451 patients, 30 (6.7%) individuals developed DM. The mean follow-up time among the 451 patients was 41.9 months (range, 12179 months). During the follow-up period, the 5-year OS rate was 76.2%. Sites of DM included the lungs (80.0%), skin (13.3%), liver (10.0%), bone (6.7%), and brain (3.3%). A total of 27 patients had single sites of DM, and 3 patients had multiple sites of DM. The patients without DM had a mean age of 66.0 6 13.7 years (range, 23-97 years), while the patients with DM had a mean age of 63.8 6 11.1 years (range, 37-86 years); the difference in age was not significant between these 2 groups (Table 1). In addition, there were no significant differences for other factors, including gender, subsite, and surgical margin, between the patients with and without DM (Table 1). In contrast, there were significant differences for factors associated with the preoperative diagnosis, such as the T classification (P = .008) and N classification (P \ .001), between the patients with and without DM in the univariate analysis (Table 1). Of the 28 patients with DM who received neck dissection, there were 4 (14.3%) cases of 0 positive nodes, 10 (35.7%) cases of 1 to 3 positive nodes, and 14 (50.0%) cases of more than 4 positive nodes. Among the 249 patients without DM, there were 122 (49.0%) cases of 0 positive nodes, 98 (39.4%) cases of 1 to 3 positive nodes, and 29 (11.7%) cases of more than 4 positive nodes. The 28 patients with DM included 11 (39.3%) subjects with an ECS– status and 17 (60.7%) subjects with an ECS1 status, whereas there were 206 (82.7%) cases of ECS– and 43 (17.3%) cases of ECS1 among the patients without DM. There were 174 (38.6%) cases of ‘‘not determined,’’ in which the patient did not undergo neck dissection as the initial treatment. In the 30 patients with DM, there were 10
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Table 1. Characteristics and Incidence of Distant Metastasis in Patients with Oral Squamous Cell Carcinoma. Variable Sample size Gender Male Female Age, y Range Mean 6 SD Subsite Buccal mucosa Oral tongue Upper gingiva Lower gingiva Floor of the mouth Other T classification T1-2 T3-4 N classification N0 N1 N2-3 Postoperative radiotherapy No Yes Postoperative chemotherapy No Yes Pathologic nodal status The number of lymph metastasis 0 1-3 More than 4 Status of positive lymph metastasis ECS– ECS1 Not determined Histologic differentiation Well Moderate Poor Surgical margin Negative Involved margins LRF No Yes
DM Number (%)
No DM Number (%)
30 (6.7)
421 (93.3)
19 (63.3) 11 (36.7)
252 (60.0) 169 (40.0)
.848
23-97 66.0 6 13.7
.222
37-86 63.8 6 11.1
P Value
3 (10.0) 13 (43.3) 4 (13.3) 3 (10.0) 6 (20.0) 1 (3.3)
42 (10.0) 209 (49.6) 48 (11.4) 67 (15.9) 33 (7.8) 22 (5.2)
.313
16 (53.3) 14 (46.7)
317 (75.3) 104 (24.7)
.008
11 (36.7) 5 (16.7) 14 (46.7)
306 (72.7) 60 (14.3) 55 (13.0)
\.001
7 (23.3) 23 (76.7)
368 (88.1) 53 (11.9)
\.001
16 (53.3) 14 (46.7)
397 (94.3) 24 (5.7)
\ .001
4 (14.3) 10 (35.7) 14 (50.0)
122 (49.0) 98 (39.4) 29 (11.6)
\.001
11 (36.7) 17 (56.7) 2 (6.7)
206 (48.9) 43 (10.2) 172 (40.9)
\.001 —
10 (33.3) 14 (46.7) 6 (20.0)
274 (65.1) 128 (30.4) 19 (4.5)
\.001
24 (80.0) 6 (20.0)
373 (88.6) 48 (11.4)
.144
13 (43.3) 17 (58.7)
381 (90.5) 40 (9.5)
\.001
Abbreviations: DM, distant metastasis; ECS, extracapsular spread; LRF, locoregional failure; OSCC, oral squamous cell carcinoma.
(33.3%) tumors with well differentiation, 14 (46.7%) tumors with moderate differentiation, and 6 (20.0%) tumors with poor differentiation. Among the 421 patients without DM, there were 274 (65.1%) lesions exhibiting well differentiation, 128
(30.4%) lesions exhibiting moderate differentiation, and 19 (4.5%) lesions exhibiting poor differentiation. Pathologic factors, such as multiple lymph node metastases (more than 4 positive nodes), ECS1, and the histologic grade, were found
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Figure 1. Cumulative rate of distant metastasis in the patients with extracapsular spread (ECS)1 and ECS–.
Figure 2. Cumulative rate of distant metastasis in the patients with lymph node metastases (more than 4 positive nodes) and lymph node metastasis (less than 3 positive nodes).
to be significantly higher risk factors for DM in the univariate analysis (P \ .001; Table 1). Furthermore, the 5-year cumulative DM rates of ECS1 and ECS– were 35.6% and 7.0%, respectively (P \ .001; Figure 1), and the 5-year cumulative DM rates among the patients with multiple lymph node metastases (more than 4 positive nodes) and lymph node metastasis (less than 3 positive nodes) were 50.2% and 7.6%, respectively (P \ .001; Figure 2). Among the 30 patients with DM, there were 13 (43.3%) cases of locoregional control (LRC) and 17 (56.7%) cases of LRF. Of the 421 patients without DM, there were 381 (90.5%) subjects with LRC and 40 (9.5%) subjects with LRF. LRF was identified to be a significant risk factor for DM in the univariate analysis (P \ .001; Table 1). The 5year cumulative DM rates for the LRF and LRC patients were 46.0% and 4.4%, respectively (P \ .001; Figure 3). The 5-year OS rate of DM detection in the patients with LRF was 0%. Only 1 patient with DM survived for more than 5 years, for a 5-year OS rate of DM detection in the patients with LRC of 26.9% (P = .022; Figure 4).
Figure 3. Cumulative rate of distant metastasis in the patients with locoregional failure and locoregional control.
Figure 4. Overall survival after the diagnosis of distant metastasis (DM) in the patients with locoregional control and DM with locoregional failure.
Applying a logistic regression model and forward stepwise algorithms, we determined multiple lymph node metastases (more than 4 positive nodes), LRF, and ECS1 to be significant variables (Table 2). The factors of gender, age, subsite, and surgical margin were excluded from this model, as these factors were not identified to be significant in the univariate analysis. In addition, the factors of radiotherapy and chemotherapy, including the postoperative treatment modality, were excluded. The multivariate adjusted ORs and 95% CIs for the included factors were calculated, and the discriminant hit ratio (89.9%) was considered to be excellent in this study.
Discussion Recently, the treatment of OSCC with surgery and/or adjuvant chemoradiation has improved the LRC and OS rates.1,3 Therefore, controlling DM is becoming a strategy for treating OSCC. Furthermore, it is important to investigate risk factors for DM in OSCC patients to continue providing effective frequent follow-up.5 Many investigators have demonstrated a relationship between certain risk factors and
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Table 2. Results of the Multivariate Logistic Regression Analysis of Risk Factors for Distant Metastasis. 95% Confidence Interval Variable Locoregional failure Multiple lymph metastasis (more than 4 positive nodes) Extracapsular spread
P Value
Odds Ratio
Lower
Upper
.003 .015 .023
4.03 3.32 3.06
1.63 1.26 1.17
9.98 8.73 8.05
the incidence of DM.3-19 However, these studies included cases involving different regional cancers (oropharynx, hypopharynx, larynx, etc) treated with a variety of treatments.3,5-7,9,12-14 Although some studies have investigated only OSCC patients who received radical surgery as the initial treatment with/without postoperative adjuvant chemoradiation therapy,3,13,17,19 the risk factors for DM in the setting of OSCC remain controversial. Several investigators have reported the occurrence of DM of OSCC at a lower rate than that of HNSCC, with a range from 1% to 10%.3,5,7,13-16 In contrast, the incidence of DM in HNSCC patients is reported to range from 4% to 26%.4-8 In this study, 30 (6.7%) patients developed DM. This finding is in accordance with the previous literature on OSCC. LRF is generally considered to be a major risk factor for DM.3,5,11 Leo´n et al5 reported that DM occurs in patients with LRF at a rate of 18%, compared with only 5% for isolated DM. Lim et al11 reported that 31 (18.9%) of their LRF cases involved the development of DM. In studies of OSCC patients only, several investigators have reported an incidence of DM with LRF of 2.3% to 7.4%, in comparison to 3.1% to 5.7% for isolated DM, in all cases.3,13,16 These authors also reported that 9.7% to 17.1% of their patients with LRF exhibited DM.3,13 In the current study, the frequency of DM associated with LRF was 3.8% (17/451 cases) in comparison with 2.9% for isolated DM (13/451 cases), and 17 (29.8%) of our 57 patients with LRF developed DM. Moreover, LRF (OR, 4.03) was found to be associated with the highest risk of DM among the patients with OSCC in a multivariate analysis (Table 2). Our results are in agreement with the findings of the above studies. Jerjes et al18 reported findings of dysplasia at the margin and a positive or close margin in the surgical resection specimens of patients who died from locoregional spread and DM. However, in the current study, there were no significant differences in the surgical margins. Although a positive or close margin is generally associated with increased LRF, the presence of LRF may be a higher risk factor for DM than an involved margin. In HNSCC patients, pathological neck metastasis,3,11,12 multiple lymph node metastases,3,11,12 lower neck metastasis,12 and ECS3,12,13 have been demonstrated to be significant risk factors for DM. Some studies have investigated the relationship between a status of regional metastasis and the development of DM in OSCC patients only.3,13,16,19 These studies included cases of bilateral neck metastasis, pathological neck metastasis, multiple lymph node metastases, and
ECS as risk factors for DM. Huang et al19 demonstrated ECS, the pathological N2 stage, lower neck metastasis, a high human papillomavirus 16/18 E7 viral load, and the tumor depth (more than 11 mm) to be significant risk factors, while Myers et al13 identified ECS as a significant risk factor for DM in OSCC patients treated with surgery for OSCC of the tongue, according to a univariate analysis. These authors also reported a rate of DM among patients without ECS of 8.1%, compared with 24.4% among those with ECS.13 Meanwhile, Liao et al3 found more than 5 positive lymph nodes to be a significant risk factor for DM in OSCC patients who have achieved LRC, while Sumioka et al16 showed more than 4 positive lymph nodes to be a significant risk factor for DM in such patients. In the current study, the presence of multiple lymph node metastases (more than 4 positive lymph nodes; OR, 3.32) and ECS (OR, 3.06) was demonstrated to be associated with a higher risk of DM among patients with OSCC in a multivariate analysis (Table 2). These results are in accordance with the previous literature on OSCC. In addition, in this study, there was a high ‘‘not determined’’ rate for ECS in the group without DM. Almost of the cases involved T1/2 disease in which the patients did not undergo neck dissection as the initial treatment and the pathologic nodal status could not be confirmed. A relationship between the histologic grade and the prognosis has been demonstrated in various cancers,18,20-22 although several investigators consider the histologic grade to not be a significant indicator of the outcome or response to treatment.20,21 On the other hand, some researchers have investigated the value of the histologic grade as a prognostic factor in OSCC and reported this parameter to be a significant predictor of LRF and tumor recurrence.18,22 Therefore, histologic factors may affect the clinical stage and prognosis in patients with OSCC.2,17,18,22 Similar to that observed for the outcome and response to treatment, there is controversy regarding the incidence of DM in patients with HNSCC and OSCC.3,5,12,17 With respect to HNSCC, some investigators have suggested a relationship between the histologic grade and the incidence of DM.7,14,15 Regarding OSCC, Sumioka et al16 reported that a histologic grade of poor differentiation is an independent risk factor for isolated DM in cases of OSCC. In the reports by Chen et al and several researchers, 11 (26.8%) stage III or IV patients (n = 41) with poor differentiation developed DM within 5 years after the initial treatment, with most experiencing DM within 2 years.3,9,17
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Various authors have also suggested that it may be worthwhile to evaluate the survival benefit of more aggressive treatment in patients with poorly differentiated OSCC.17,23 Notably, Jerjes et al18 demonstrated that 10 (90.9%)/11 stage I and II patients who died of DM suffered from moderately, moderately-poorly, and poorly differentiated OSCC. In the present study, poor differentiation was found to be a significantly higher risk factor for DM in the univariate analysis (P \ .001). However, poor differentiation was not identified as a significant risk factor for DM in the multivariate analysis. Further studies are therefore needed to investigate other pathological risk factors, such as perineural, lymphovascular, bone, and cartilage invasion. The most frequent site of DM in cases of HNSCC is the lungs.24 In terms of OSCC, Sumioka et al16 reported that 42 (77.8%) of their 54 DM patients had DM of the lung. Meanwhile, Liao et al3 reported sites of DM (58 [48.3%]/ 120 sites) to include the lungs and pleura. In the current study, the most frequent site of DM was the lungs (80.0%), similar to that observed in other studies.3,16 Therefore, developing treatment for OSCC patients with DM restricted to the lungs may be more important compared with patients with metastases in other locations. Recently developed treatments for pulmonary metastasis of OSCC include novel surgical, radiotherapeutic, and systemic therapies. Platinumbased combination-regimen chemotherapeutics for recurrent or metastatic HNSCC generally elicit higher rates of response (30%-40%).25-29 However, such treatments are associated with severe toxicities. Therefore, platinum-based combination therapies are generally recommended for patients with a maintained functional status. However, the higher response rates to these treatments do not translate into improved DM or survival rates compared with that achieved with cisplatin, 5-fluorouracil, or methotrexate alone. Laramore et al30 demonstrated that neoadjuvant chemotherapy is less frequently associated with DM, while Bachaud et al31 reported the opposite findings and Slotman et al32 reported that this treatment increased the rate of DM. In any case, high-quality studies, such as prospective randomized studies, of neoadjuvant chemotherapy are lacking. As stated above, the development of platinum-based chemotherapeutics may alleviate critical situations regarding the treatment of DM. Cetuximab is a biological agent developed for the treatment of recurrent or metastatic HNSCC. The rate of toxicity to cetuximab is less than that for platinum-based combination therapies, including myelosuppressive effects. However, the response rate is only 10% to 13% in clinical trials.33,34 Shiono et al35 demonstrated the possibility of performing surgical resection for pulmonary metastasis. In addition, Mazer et al36 reported a 5-year survival rate of 43% for pulmonary metastasectomy, compared with the 59% reported by Wedman et al. 37 Meanwhile, Nibu et al38 reported that 32% of 32 patients with HNSCC underwent thoracotomy, while Finley et al39 documented that 29% of 18 patients with HNSCC underwent complete resection. Although previous studies have included limited sample sizes, surgical
resection of single pulmonary metastasis may be an effective treatment compared with conventional systematic therapy.35-39 However, Shiono et al35 suggested that male patients with pulmonary metastasis of OSCC may have a poor prognosis and that pulmonary metastasectomy for these patients may not be beneficial. Therefore, developing adequate selection criteria to identify patients with pulmonary metastasis of OSCC is required in the future. In conclusion, we successfully demonstrated multivariate relationships among various risk factors for DM in OSCC patients. In particular, we identified multiple lymph node metastases, LRF, and ECS1 to be significant factors associated with the development of DM in a multivariate analysis. Clinicians should consider these risk factors and pay special attention to detecting DM early during the postoperative management of OSCC patients with these risk factors. Author Contributions Takumi Hasegawa, conception of the study, designed study, collected data, drafting, analyzed data, agreement to be accountable for all aspects of the work; Makiko Tanakura, collected data, revised article, final approval, agreement to be accountable for all aspects of the work; Daisuke Takeda, collected data, revised article, final approval, agreement to be accountable for all aspects of the work; Akiko Sakakibara, interpretation of data, revised article, final approval, agreement to be accountable for all aspects of the work; Masaya Akashi, interpretation of data, revised article, final approval agreement to be accountable for all aspects of the work; Tsutomu Minamikawa, interpretation of data, revised article, final approval, agreement to be accountable for all aspects of the work; Takahide Komori, conception of the study, interpretation of data, revised article, final approval, agreement to be accountable for all aspects of the work
Disclosures Competing interests: None. Sponsorships: None. Funding source: None.
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6. Ferlito A, Shaha AR, Silver CE, Rinaldo A, Mondin V. Incidence and sites of distant metastases from head and neck cancer. ORL J Otorhinolaryngol Relat Spec. 2001;63:202-207. 7. Garavello W, Ciardo A, Spreafico R, Gaini RM. Risk factors for distant metastases in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2006;132: 762-766. 8. Li X, Di B, Shang Y, Zhou Y, Cheng J, He Z. Clinicopathologic risk factors for distant metastases from head and neck squamous cell carcinomas. Eur J Surg Oncol. 2009;35:1348-1353. 9. Calhoun KH, Fulmer P, Weiss R, Hokanson JA. Distant metastases from head and neck squamous cell carcinomas. Laryngoscope. 1994;104:1199-1205. 10. Troell RJ, Terris DJ. Detection of metastases from head and neck cancers. Laryngoscope. 199;105:247-250. 11. Lim YC, Koo BS, Choi EC. Bilateral neck node metastasis: a predictor of isolated distant metastasis in patients with oral and oropharyngeal squamous cell carcinoma after primary curative surgery. Laryngoscope. 2007;117:1576-1580. 12. Shingaki S, Suzuki I, Kobayashi T, Nakajima T. Predicting factors for distant metastases in head and neck carcinomas: an analysis of 103 patients with locoregional control. J Oral Maxillofac Surg. 1996;54:853-857. 13. Myers JN, Greenberg JS, Mo V, Roberts D. Extracapsular spread: a significant predictor of treatment failure in patients with squamous cell carcinoma of the tongue. Cancer. 2001;92: 3030-3036. 14. Fortin A, Couture C, Doucet R, Albert M, Allard J, Tetu B. Does histologic grade have a role in the management of head and neck cancers? J Clin Oncol. 2001;19:4107-4116. 15. Lim JY, Lim YC, Kim SH, Kim JW, Jeong HM, Choi EC. Predictive factors of isolated distant metastasis after primary definitive surgery without systemic treatment for head and neck squamous cell carcinoma. Oral Oncol. 2010;46:504-508. 16. Sumioka S, Sawai NY, Kishino M, Ishihama K, Minami M, Okura M. Risk factors for distant metastasis in squamous cell carcinoma of the oral cavity. J Oral Maxillofac Surg. 2013;71: 1291-1297. 17. Chen TC, Hsu CW, Lou PJ, et al. The clinical predictive factors for subsequent distant metastasis in patients with locoregionally advanced oral squamous cell carcinoma. Oral Oncol. 2013;49:367-373. 18. Jerjes W, Upile T, Petrie A, et al. Clinicopathological parameters, recurrence, locoregional and distant metastasis in 115 T1-T2 oral squamous cell carcinoma patients. Head Neck Oncol. 2010;2:9. 19. Huang CG, Lee LA, Tsao KC, et al. Human papillomavirus 16/18 E7 viral loads predict distant metastasis in oral cavity squamous cell carcinoma. J Clin Virol. 2014;61:230-236. 20. Po Wing Yuen A, Lam KY, Lam LK, et al. Prognostic factors of clinically stage I and II oral tongue carcinoma: a comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score, and pathologic features. Head Neck. 2002;24:513-520. 21. O-charoenrat P, Pillai G, Patel S, et al. Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer. Oral Oncol. 2003;39:386-390.
22. Kademani D, Bell RB, Bagheri S, et al. Prognostic factors in intraoral squamous cell carcinoma: the influence of histologic grade. J Oral Maxillofac Surg. 2005;63:1599-1605. 23. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27:843-850. 24. Kowalski LP, Carvalho AL, Martins Priante AV, Magrin J. Predictive factors for distant metastasis from oral and oropharyngeal squamous cell carcinoma. Oral Oncol. 2005;41:534-541. 25. Liverpool Head and Neck Oncology Group. A phase III randomised trial of cisplatinum, methotrextate, cisplatinum 1 methotrexate and cisplatinum 1 5- FU in end stage squamous carcinoma of the head and neck. Br J Cancer. 1990;61:311315. 26. Jacobs C, Lyman G, Velez-Garcı´a E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992;10:257-263. 27. Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a southwest oncology group study. J Clin Oncol. 1992;10:1245-1251. 28. Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2005;23:3562-3567. 29. Forastiere AA, Leong T, Rowinsky E, et al. Phase III comparison of high-dose paclitaxel 1 cisplatin 1 granulocyte colonystimulating factor versus low-dose paclitaxel 1 cisplatin in advanced head and neck cancer: Eastern Cooperative Oncology Group study E1393. J Clin Oncol. 2001;19:10881095. 30. Laramore GE, Scott CB, al-Sarraf M, et al. Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: report on Intergroup Study 0034. Int J Radiat Oncol Biol Phys. 1992;23:705-713. 31. Bachaud JM, Cohen-Jonathan E, Alzieu C, David JM, Serrano E, Daly-Schveitzer N. Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys. 1996;36:999-1004. 32. Slotman GJ, Mohit T, Raina S, Swaminathan AP, Ohanian M, Rush BF Jr.The incidence of metastases after multimodal therapy for cancer of the head and neck. Cancer. 1984;54:20092014. 33. Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum refractory metastatic and/ or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23:5568-5577. 34. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity
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of cetuximab as a single agent in patients with recurrent and/ or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007;25:2171-2177. 35. Shiono S, Kawamura M, Sato T, et al. Metastatic Lung Tumor Study Group of Japan. Pulmonary metastasectomy for pulmonary metastases of head and neck squamous cell carcinomas. Ann Thorac Surg. 2009;88:856-860. 36. Mazer TM, Robbins KT, McMurtrey MJ, Byers RM. Resection of pulmonary metastases from squamous carcinoma of the head and neck. Am J Surg. 1988;156:238-242.
37. Wedman J, Balm AJ, Hart AA, et al. Value of resection of pulmonary metastases in head and neck cancer patients. Head Neck. 1996;18:311-316. 38. Nibu K, Nakagawa K, Kamata S, et al. Surgical treatment for pulmonary metastases of squamous cell carcinoma of the head and neck. Am J Otolaryngol. 1997;18:391-395. 39. Finley RK III, Verazin GT, Driscoll DL, et al. Results of surgical resection of pulmonary metastases of squamous cell carcinoma of the head and neck. Am J Surg. 1992;164:594-598.
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Risk Factors Associated with Distant Metastasis in Patients with Oral Squamous Cell Carcinoma
Otolaryngology– Head and Neck Surgery 1–8 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599815580980 http://otojournal.org
Takumi Hasegawa, DDS, PhD1, Makiko Tanakura, DDS1, Daisuke Takeda, DDS, PhD1, Akiko Sakakibara, DDS, PhD1, Masaya Akashi, DDS, PhD1, Tsutomu Minamikawa, DDS, PhD1, and Takahide Komori, DDS, PhD1
No sponsorships or competing interests have been disclosed for this article.
Abstract Objective. The purpose of this study was to retrospectively evaluate the incidence of distant metastasis (DM) after curative surgical treatment and assess the multivariate relationships among various risk factors for DM in patients with oral squamous cell carcinoma (OSCC). Study Design. Case series with chart review. Setting. Tertiary referral center. Subjects and Methods. The medical records of all patients with OSCC without DM who underwent curative surgery with or without postoperative adjuvant chemoradiation between January 2001 and February 2014 at our institution were retrospectively reviewed. There were a total of 451 patients, including 271 men and 180 women, with a mean age of 65.9 6 13.5 years. Results. Of these patients, 30 (6.7%) developed DM. During the follow-up period, the 5-year overall survival rate was 76.2%. Sites of DM comprised the lungs (80.0%), skin (13.3%), liver (10.0%), bone (6.7%), and brain (3.3%). We found the T classification and N classification as well as the histologic grade to be significant risk factors associated with the development of DM in the univariate analysis only (P = .003), whereas locoregional failure (odds ratio [OR], 4.03), multiple lymph node metastases (more than 4 positive nodes; OR, 3.32) and positive extracapsular spread (OR, 3.06) were identified to be significant risk factors associated with the development of DM in the multivariate analysis. Conclusion. We demonstrated multivariate relationships among various risk factors for DM in OSCC patients. Clinicians should consider these risk factors and pay special attention to detecting DM early during the postoperative management of OSCC patients with these risk factors. Keywords distant metastasis, oral squamous cell carcinoma, risk factor, oral cancer
Received January 9, 2015; revised March 9, 2015; accepted March 18, 2015.
R
ecently, the treatment of oral squamous cell carcinoma (OSCC) with surgery and/or adjuvant chemoradiation has improved the overall survival (OS) rate of this disease.1 In addition, the control rate for locoregional tumors has also recently improved.2,3 Therefore, controlling distant metastasis (DM) and second primary tumors is becoming increasingly important when treating OSCC. Several investigators have reported that the incidence of DM in patients with head and neck cancer is 4% to 26%.4-8 However, patients in the early stage of DM often exhibit no symptoms. Therefore, achieving the early detection of DM is difficult, and this condition continues to have a poor prognosis. The expected survival time is 4.4 to 7.3 months from the diagnosis of DM of head and neck squamous cell carcinoma (HNSCC).9,10 Hence, providing the early detection of DM and identifying groups at high risk for DM are important for managing HNSCC. Traditionally, locoregional failure (LRF),3,5,11 the T and N classifications,3,5,6,9,12 extracapsular spread (ECS),3,5,13 and poor differentiation14,15 have been shown to be independent risk factors for DM, as reported in several studies of HNSCC,3-15 although some of these factors are controversial as risk factors for DM in OSCC patients.3,13,16-19 In our institution, surgical treatment of the primary tumor is generally performed as the initial treatment. In this study, we retrospectively investigated the multivariate relationships among various risk factors for DM in OSCC patients.
1 Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
Corresponding Author: Takumi Hasegawa, DDS, PhD, Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe 650-0017, Japan. Email: [email protected]
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Patients and Methods
Statistical Analysis
This study was a nonrandomized, retrospective (historic) cohort study of patients and was thus granted exemption from institutional review board approval by our institution. Between January 2001 and February 2014, a total of 451 patients with oral cancer underwent major head and neck surgery at the Department of Oral and Maxillofacial Surgery, Kobe University Hospital. Among the 451 patients, there were 126 (27.9%) subjects with stage I disease, 145 (32.2%) subjects with stage II disease, 54 (12.0%) subjects with stage III disease, and 126 (27.9%) subjects with stage IV disease. All patients underwent wide excision of the primary tumor and/or neck dissection with either modified radical neck dissection or selective neck dissection with or without postoperative adjuvant chemoradiation. In addition, all patients received a preoperative examination, including chest x-ray, computed tomography (CT), and magnetic resonance imaging of the head and neck region. Preoperative DM was excluded based on the findings of chest CT or positron emission tomography (PET)–CT. In our institution, patients exhibiting high-risk characteristics (histological evidence of invasion of 2 or more regional lymph nodes, ECS, and microscopically involved mucosal resection margins) underwent radiotherapy. The concurrent chemotherapy entry criteria included an age of 20 to 75 years, Eastern Cooperative Oncology Group performance status of 0 or 1, and an adequate hematologic and organ function, namely, a white cell count of at least 3500/m3, platelet count of at least 100,000/m3, and creatinine clearance of more than 70 mL/min. Patients with a history of previous chemotherapy or radiotherapy were excluded. For the follow-up for DM after the initial treatment, chest x-ray, chest CT, or PET were performed or when the patient presented with new indicative symptoms. Before 2005, the patients were offered chest x-ray screenings at 3 months of follow-up and chest CT at 6 months of follow-up. After 2006, the patients were offered chest CT at 6 months of follow-up and PET-CT at 1 year of follow-up. The exclusion criteria included patients with other cancers before the diagnosis of OSCC, a history of palliative treatment due to a poor medical condition, and/ or patient refusal of curative surgical treatment, simultaneous second primary cancer, the detection of DM prior to the initial treatment, and previous radiotherapy or chemotherapy for head and neck cancer or other diseases. Clinicopathologic data, including sex, age, subsite, T classification (T1, 2 or T3, 4), N classification (N0 or 1 or N2, 3), treatment modalities, neck dissection, pathologic stage, pathologic nodal status (presence, number of lymph node metastases [0 or 1-3 or more than 4 positive nodes]), histologic grade (well, moderate, or poor), surgical margin, ECS, and LRF were investigated. All factors are listed in Table 1. Also, time of development of DM, location of DM, number of DM lesions (single or multiple), and clinical course were investigated. The endpoint of follow-up was defined as death, loss to follow-up, or February 2014.
Data collection and statistical analyses were carried out with SPSS 15.0 (SPSS, Chicago, Illinois) and Stat-View-J4.5 software (Abacus Concepts, Berkeley, California). The association of each variable with the DM was tested by using the Mann-Whitney U nonparametric test for ordinal variables and the Fisher exact test or x2 test for categorical variables. Cumulative OS was calculated using the KaplanMeier product-limit method. The significant levels among the curves were determined using the log-rank test. A value of P \ .05 was considered statistically significant. All of the variables associated with DM were introduced into a multiple logistic regression model. Forward stepwise algorithms were used, with the rejection of those variables that did not fit the model significantly. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were also calculated for the significant signs. A value of P \ .05 was considered statistically significant.
Results The subjects comprised 451 patients, including 271 men and 180 women, with an age range from 23 to 97 years and a mean age of 65.9 6 13.5 years. Of the 451 patients, 30 (6.7%) individuals developed DM. The mean follow-up time among the 451 patients was 41.9 months (range, 12179 months). During the follow-up period, the 5-year OS rate was 76.2%. Sites of DM included the lungs (80.0%), skin (13.3%), liver (10.0%), bone (6.7%), and brain (3.3%). A total of 27 patients had single sites of DM, and 3 patients had multiple sites of DM. The patients without DM had a mean age of 66.0 6 13.7 years (range, 23-97 years), while the patients with DM had a mean age of 63.8 6 11.1 years (range, 37-86 years); the difference in age was not significant between these 2 groups (Table 1). In addition, there were no significant differences for other factors, including gender, subsite, and surgical margin, between the patients with and without DM (Table 1). In contrast, there were significant differences for factors associated with the preoperative diagnosis, such as the T classification (P = .008) and N classification (P \ .001), between the patients with and without DM in the univariate analysis (Table 1). Of the 28 patients with DM who received neck dissection, there were 4 (14.3%) cases of 0 positive nodes, 10 (35.7%) cases of 1 to 3 positive nodes, and 14 (50.0%) cases of more than 4 positive nodes. Among the 249 patients without DM, there were 122 (49.0%) cases of 0 positive nodes, 98 (39.4%) cases of 1 to 3 positive nodes, and 29 (11.7%) cases of more than 4 positive nodes. The 28 patients with DM included 11 (39.3%) subjects with an ECS– status and 17 (60.7%) subjects with an ECS1 status, whereas there were 206 (82.7%) cases of ECS– and 43 (17.3%) cases of ECS1 among the patients without DM. There were 174 (38.6%) cases of ‘‘not determined,’’ in which the patient did not undergo neck dissection as the initial treatment. In the 30 patients with DM, there were 10
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Table 1. Characteristics and Incidence of Distant Metastasis in Patients with Oral Squamous Cell Carcinoma. Variable Sample size Gender Male Female Age, y Range Mean 6 SD Subsite Buccal mucosa Oral tongue Upper gingiva Lower gingiva Floor of the mouth Other T classification T1-2 T3-4 N classification N0 N1 N2-3 Postoperative radiotherapy No Yes Postoperative chemotherapy No Yes Pathologic nodal status The number of lymph metastasis 0 1-3 More than 4 Status of positive lymph metastasis ECS– ECS1 Not determined Histologic differentiation Well Moderate Poor Surgical margin Negative Involved margins LRF No Yes
DM Number (%)
No DM Number (%)
30 (6.7)
421 (93.3)
19 (63.3) 11 (36.7)
252 (60.0) 169 (40.0)
.848
23-97 66.0 6 13.7
.222
37-86 63.8 6 11.1
P Value
3 (10.0) 13 (43.3) 4 (13.3) 3 (10.0) 6 (20.0) 1 (3.3)
42 (10.0) 209 (49.6) 48 (11.4) 67 (15.9) 33 (7.8) 22 (5.2)
.313
16 (53.3) 14 (46.7)
317 (75.3) 104 (24.7)
.008
11 (36.7) 5 (16.7) 14 (46.7)
306 (72.7) 60 (14.3) 55 (13.0)
\.001
7 (23.3) 23 (76.7)
368 (88.1) 53 (11.9)
\.001
16 (53.3) 14 (46.7)
397 (94.3) 24 (5.7)
\ .001
4 (14.3) 10 (35.7) 14 (50.0)
122 (49.0) 98 (39.4) 29 (11.6)
\.001
11 (36.7) 17 (56.7) 2 (6.7)
206 (48.9) 43 (10.2) 172 (40.9)
\.001 —
10 (33.3) 14 (46.7) 6 (20.0)
274 (65.1) 128 (30.4) 19 (4.5)
\.001
24 (80.0) 6 (20.0)
373 (88.6) 48 (11.4)
.144
13 (43.3) 17 (58.7)
381 (90.5) 40 (9.5)
\.001
Abbreviations: DM, distant metastasis; ECS, extracapsular spread; LRF, locoregional failure; OSCC, oral squamous cell carcinoma.
(33.3%) tumors with well differentiation, 14 (46.7%) tumors with moderate differentiation, and 6 (20.0%) tumors with poor differentiation. Among the 421 patients without DM, there were 274 (65.1%) lesions exhibiting well differentiation, 128
(30.4%) lesions exhibiting moderate differentiation, and 19 (4.5%) lesions exhibiting poor differentiation. Pathologic factors, such as multiple lymph node metastases (more than 4 positive nodes), ECS1, and the histologic grade, were found
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Figure 1. Cumulative rate of distant metastasis in the patients with extracapsular spread (ECS)1 and ECS–.
Figure 2. Cumulative rate of distant metastasis in the patients with lymph node metastases (more than 4 positive nodes) and lymph node metastasis (less than 3 positive nodes).
to be significantly higher risk factors for DM in the univariate analysis (P \ .001; Table 1). Furthermore, the 5-year cumulative DM rates of ECS1 and ECS– were 35.6% and 7.0%, respectively (P \ .001; Figure 1), and the 5-year cumulative DM rates among the patients with multiple lymph node metastases (more than 4 positive nodes) and lymph node metastasis (less than 3 positive nodes) were 50.2% and 7.6%, respectively (P \ .001; Figure 2). Among the 30 patients with DM, there were 13 (43.3%) cases of locoregional control (LRC) and 17 (56.7%) cases of LRF. Of the 421 patients without DM, there were 381 (90.5%) subjects with LRC and 40 (9.5%) subjects with LRF. LRF was identified to be a significant risk factor for DM in the univariate analysis (P \ .001; Table 1). The 5year cumulative DM rates for the LRF and LRC patients were 46.0% and 4.4%, respectively (P \ .001; Figure 3). The 5-year OS rate of DM detection in the patients with LRF was 0%. Only 1 patient with DM survived for more than 5 years, for a 5-year OS rate of DM detection in the patients with LRC of 26.9% (P = .022; Figure 4).
Figure 3. Cumulative rate of distant metastasis in the patients with locoregional failure and locoregional control.
Figure 4. Overall survival after the diagnosis of distant metastasis (DM) in the patients with locoregional control and DM with locoregional failure.
Applying a logistic regression model and forward stepwise algorithms, we determined multiple lymph node metastases (more than 4 positive nodes), LRF, and ECS1 to be significant variables (Table 2). The factors of gender, age, subsite, and surgical margin were excluded from this model, as these factors were not identified to be significant in the univariate analysis. In addition, the factors of radiotherapy and chemotherapy, including the postoperative treatment modality, were excluded. The multivariate adjusted ORs and 95% CIs for the included factors were calculated, and the discriminant hit ratio (89.9%) was considered to be excellent in this study.
Discussion Recently, the treatment of OSCC with surgery and/or adjuvant chemoradiation has improved the LRC and OS rates.1,3 Therefore, controlling DM is becoming a strategy for treating OSCC. Furthermore, it is important to investigate risk factors for DM in OSCC patients to continue providing effective frequent follow-up.5 Many investigators have demonstrated a relationship between certain risk factors and
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Table 2. Results of the Multivariate Logistic Regression Analysis of Risk Factors for Distant Metastasis. 95% Confidence Interval Variable Locoregional failure Multiple lymph metastasis (more than 4 positive nodes) Extracapsular spread
P Value
Odds Ratio
Lower
Upper
.003 .015 .023
4.03 3.32 3.06
1.63 1.26 1.17
9.98 8.73 8.05
the incidence of DM.3-19 However, these studies included cases involving different regional cancers (oropharynx, hypopharynx, larynx, etc) treated with a variety of treatments.3,5-7,9,12-14 Although some studies have investigated only OSCC patients who received radical surgery as the initial treatment with/without postoperative adjuvant chemoradiation therapy,3,13,17,19 the risk factors for DM in the setting of OSCC remain controversial. Several investigators have reported the occurrence of DM of OSCC at a lower rate than that of HNSCC, with a range from 1% to 10%.3,5,7,13-16 In contrast, the incidence of DM in HNSCC patients is reported to range from 4% to 26%.4-8 In this study, 30 (6.7%) patients developed DM. This finding is in accordance with the previous literature on OSCC. LRF is generally considered to be a major risk factor for DM.3,5,11 Leo´n et al5 reported that DM occurs in patients with LRF at a rate of 18%, compared with only 5% for isolated DM. Lim et al11 reported that 31 (18.9%) of their LRF cases involved the development of DM. In studies of OSCC patients only, several investigators have reported an incidence of DM with LRF of 2.3% to 7.4%, in comparison to 3.1% to 5.7% for isolated DM, in all cases.3,13,16 These authors also reported that 9.7% to 17.1% of their patients with LRF exhibited DM.3,13 In the current study, the frequency of DM associated with LRF was 3.8% (17/451 cases) in comparison with 2.9% for isolated DM (13/451 cases), and 17 (29.8%) of our 57 patients with LRF developed DM. Moreover, LRF (OR, 4.03) was found to be associated with the highest risk of DM among the patients with OSCC in a multivariate analysis (Table 2). Our results are in agreement with the findings of the above studies. Jerjes et al18 reported findings of dysplasia at the margin and a positive or close margin in the surgical resection specimens of patients who died from locoregional spread and DM. However, in the current study, there were no significant differences in the surgical margins. Although a positive or close margin is generally associated with increased LRF, the presence of LRF may be a higher risk factor for DM than an involved margin. In HNSCC patients, pathological neck metastasis,3,11,12 multiple lymph node metastases,3,11,12 lower neck metastasis,12 and ECS3,12,13 have been demonstrated to be significant risk factors for DM. Some studies have investigated the relationship between a status of regional metastasis and the development of DM in OSCC patients only.3,13,16,19 These studies included cases of bilateral neck metastasis, pathological neck metastasis, multiple lymph node metastases, and
ECS as risk factors for DM. Huang et al19 demonstrated ECS, the pathological N2 stage, lower neck metastasis, a high human papillomavirus 16/18 E7 viral load, and the tumor depth (more than 11 mm) to be significant risk factors, while Myers et al13 identified ECS as a significant risk factor for DM in OSCC patients treated with surgery for OSCC of the tongue, according to a univariate analysis. These authors also reported a rate of DM among patients without ECS of 8.1%, compared with 24.4% among those with ECS.13 Meanwhile, Liao et al3 found more than 5 positive lymph nodes to be a significant risk factor for DM in OSCC patients who have achieved LRC, while Sumioka et al16 showed more than 4 positive lymph nodes to be a significant risk factor for DM in such patients. In the current study, the presence of multiple lymph node metastases (more than 4 positive lymph nodes; OR, 3.32) and ECS (OR, 3.06) was demonstrated to be associated with a higher risk of DM among patients with OSCC in a multivariate analysis (Table 2). These results are in accordance with the previous literature on OSCC. In addition, in this study, there was a high ‘‘not determined’’ rate for ECS in the group without DM. Almost of the cases involved T1/2 disease in which the patients did not undergo neck dissection as the initial treatment and the pathologic nodal status could not be confirmed. A relationship between the histologic grade and the prognosis has been demonstrated in various cancers,18,20-22 although several investigators consider the histologic grade to not be a significant indicator of the outcome or response to treatment.20,21 On the other hand, some researchers have investigated the value of the histologic grade as a prognostic factor in OSCC and reported this parameter to be a significant predictor of LRF and tumor recurrence.18,22 Therefore, histologic factors may affect the clinical stage and prognosis in patients with OSCC.2,17,18,22 Similar to that observed for the outcome and response to treatment, there is controversy regarding the incidence of DM in patients with HNSCC and OSCC.3,5,12,17 With respect to HNSCC, some investigators have suggested a relationship between the histologic grade and the incidence of DM.7,14,15 Regarding OSCC, Sumioka et al16 reported that a histologic grade of poor differentiation is an independent risk factor for isolated DM in cases of OSCC. In the reports by Chen et al and several researchers, 11 (26.8%) stage III or IV patients (n = 41) with poor differentiation developed DM within 5 years after the initial treatment, with most experiencing DM within 2 years.3,9,17
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Various authors have also suggested that it may be worthwhile to evaluate the survival benefit of more aggressive treatment in patients with poorly differentiated OSCC.17,23 Notably, Jerjes et al18 demonstrated that 10 (90.9%)/11 stage I and II patients who died of DM suffered from moderately, moderately-poorly, and poorly differentiated OSCC. In the present study, poor differentiation was found to be a significantly higher risk factor for DM in the univariate analysis (P \ .001). However, poor differentiation was not identified as a significant risk factor for DM in the multivariate analysis. Further studies are therefore needed to investigate other pathological risk factors, such as perineural, lymphovascular, bone, and cartilage invasion. The most frequent site of DM in cases of HNSCC is the lungs.24 In terms of OSCC, Sumioka et al16 reported that 42 (77.8%) of their 54 DM patients had DM of the lung. Meanwhile, Liao et al3 reported sites of DM (58 [48.3%]/ 120 sites) to include the lungs and pleura. In the current study, the most frequent site of DM was the lungs (80.0%), similar to that observed in other studies.3,16 Therefore, developing treatment for OSCC patients with DM restricted to the lungs may be more important compared with patients with metastases in other locations. Recently developed treatments for pulmonary metastasis of OSCC include novel surgical, radiotherapeutic, and systemic therapies. Platinumbased combination-regimen chemotherapeutics for recurrent or metastatic HNSCC generally elicit higher rates of response (30%-40%).25-29 However, such treatments are associated with severe toxicities. Therefore, platinum-based combination therapies are generally recommended for patients with a maintained functional status. However, the higher response rates to these treatments do not translate into improved DM or survival rates compared with that achieved with cisplatin, 5-fluorouracil, or methotrexate alone. Laramore et al30 demonstrated that neoadjuvant chemotherapy is less frequently associated with DM, while Bachaud et al31 reported the opposite findings and Slotman et al32 reported that this treatment increased the rate of DM. In any case, high-quality studies, such as prospective randomized studies, of neoadjuvant chemotherapy are lacking. As stated above, the development of platinum-based chemotherapeutics may alleviate critical situations regarding the treatment of DM. Cetuximab is a biological agent developed for the treatment of recurrent or metastatic HNSCC. The rate of toxicity to cetuximab is less than that for platinum-based combination therapies, including myelosuppressive effects. However, the response rate is only 10% to 13% in clinical trials.33,34 Shiono et al35 demonstrated the possibility of performing surgical resection for pulmonary metastasis. In addition, Mazer et al36 reported a 5-year survival rate of 43% for pulmonary metastasectomy, compared with the 59% reported by Wedman et al. 37 Meanwhile, Nibu et al38 reported that 32% of 32 patients with HNSCC underwent thoracotomy, while Finley et al39 documented that 29% of 18 patients with HNSCC underwent complete resection. Although previous studies have included limited sample sizes, surgical
resection of single pulmonary metastasis may be an effective treatment compared with conventional systematic therapy.35-39 However, Shiono et al35 suggested that male patients with pulmonary metastasis of OSCC may have a poor prognosis and that pulmonary metastasectomy for these patients may not be beneficial. Therefore, developing adequate selection criteria to identify patients with pulmonary metastasis of OSCC is required in the future. In conclusion, we successfully demonstrated multivariate relationships among various risk factors for DM in OSCC patients. In particular, we identified multiple lymph node metastases, LRF, and ECS1 to be significant factors associated with the development of DM in a multivariate analysis. Clinicians should consider these risk factors and pay special attention to detecting DM early during the postoperative management of OSCC patients with these risk factors. Author Contributions Takumi Hasegawa, conception of the study, designed study, collected data, drafting, analyzed data, agreement to be accountable for all aspects of the work; Makiko Tanakura, collected data, revised article, final approval, agreement to be accountable for all aspects of the work; Daisuke Takeda, collected data, revised article, final approval, agreement to be accountable for all aspects of the work; Akiko Sakakibara, interpretation of data, revised article, final approval, agreement to be accountable for all aspects of the work; Masaya Akashi, interpretation of data, revised article, final approval agreement to be accountable for all aspects of the work; Tsutomu Minamikawa, interpretation of data, revised article, final approval, agreement to be accountable for all aspects of the work; Takahide Komori, conception of the study, interpretation of data, revised article, final approval, agreement to be accountable for all aspects of the work
Disclosures Competing interests: None. Sponsorships: None. Funding source: None.
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