Sequential Therapy of Advanced Buccal Mucosa Squamous Cell Carcinoma: Three-Year Outcome

SURGICAL ONCOLOGY AND RECONSTRUCTION

Sequential Therapy of Advanced Buccal Mucosa Squamous Cell Carcinoma: Three-Year Outcome Jiong Lyu, PhD,* Chaojun Li, PhD,y Yunteng Wu, MD,z Runxiang Wang, MD,x Guoxin Ren, PhD,k and Wei Guo, PhD{ Purpose:

Squamous cell carcinoma (SCC) of the buccal mucosa is aggressive and requires multimodal treatment. The objective of this study was to evaluate the outcome of sequential therapy (neoadjuvant therapy plus surgery plus radiotherapy) in advanced buccal SCC and explore the prognostic factors.

Patients and Methods:

In this retrospective cohort study, patients with advanced buccal cancer who received neoadjuvant chemotherapy (cisplatin, docetaxel, and 5-fluorouracil) followed by surgery and radiotherapy in the authors’ department were reviewed. The outcomes of chemotherapy and surgery were analyzed. Overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method. The prognostic values of age, gender, histologic grade, lymph node status, tumor stage, pathologic response, and adverse pathologic features were explored using the log-rank test and the Cox regression model.

Results:

From 2008 to 2011, data from 22 patients were analyzed. The overall response rate of chemotherapy was 72.7%. The pathologic complete or partial response rate was 40.9%. The median follow-up was 36 months. The 2-year DFS and OS rates were 63.3% and 67.2%, respectively. Male and younger patients showed an association with poor outcome. Multivariate analysis showed that gender was a predictive factor with respect to DFS and OS (P = .023 and .014, respectively).

Conclusion:

Sequential therapy (neoadjuvant therapy plus surgery plus radiotherapy) tends to be effective for advanced buccal cancer. Female patients have better survival. Ó 2014 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 72:606-610, 2014

Squamous cell carcinoma (SCC) of the head and neck region often originates in the oral cavity, where the tongue and buccal mucosa are the most frequently affected sites. According to the database of tumors in the authors’ department, SCC of the buccal mucosa represents approximately 20% of oral SCCs. Tobacco, alcohol, and betel chewing are considered major risk factors.1,2 There are several management options for patients with buccal mucosa SCC, such as surgery and

radiotherapy. However, many patients show an association with a high frequency of recurrence or metastasis, especially those at an advanced stage. Recently, some studies have reported that in advanced cases, multimodal treatment (surgery plus radiotherapy or radio-chemotherapy) yield better outcomes than surgery alone or radiotherapy alone; thus, these investigators recommended multimodal treatment for patients with advanced cancer.1,3-5 In

Received from the Department of Oral and Maxillofacial–Head and

Conflict of Interest Disclosures: None of the authors reported any

Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

disclosures. Address correspondence and reprint requests to Dr Guo: Depart-

*Doctor.

ment of Oral and Maxillofacial–Head and Neck Oncology, Ninth Peo-

yDoctor.

ple’s Hospital, College of Stomatology, Shanghai Jiao Tong University

zDoctor.

School of Medicine, No 639 Zhizaoju Road, Shanghai 200011, Peo-

xDoctor.

ple’s Republic of China; e-mail: [email protected]

kAssociate Professor.

Received May 30 2013

{Professor.

Accepted September 7 2013

This work was supported by the Project of Science and Technol-

Ó 2014 American Association of Oral and Maxillofacial Surgeons

ogy Commission of Shanghai Municipality (grants 10410711200,

0278-2391/13/01196-8$36.00/0

08140902100, and 11495802000).

http://dx.doi.org/10.1016/j.joms.2013.09.009

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LYU ET AL

recent years, the authors have been interested in performing neoadjuvant chemotherapy before surgery and radiotherapy in advanced oral cancer, to facilitate local therapy and eliminate potential micrometastasis. The purpose of this study was to evaluate the outcome of sequential therapy (neoadjuvant chemotherapy plus surgery plus postoperative radiotherapy) for advanced buccal mucosa SCC. The authors hypothesized that advanced buccal mucosa SCC would be responsive to neoadjuvant chemotherapy and that the outcome of sequential therapy would be good. The specific aim of the study was to explore prognostic factors.

Patients and Methods PATIENTS

Owing to the retrospective nature of this study, it was granted an exemption from informed consent in writing by the institutional review board of Shanghai Jiao Tong University (Shanghai, China). To address the research purpose, the authors designed and implemented a retrospective cohort study. The authors reviewed the records of all patients with advanced buccal mucosa SCC who were treated with sequential therapy (chemotherapy using docetaxel, cisplatin, and 5-fluorouracil [5-FU; altogether, TPF] followed by surgery and radiotherapy) in their department from May 2008 through April 2011. Evaluation of stage (according to the American Joint Committee on Cancer staging system) was based on computed tomography or magnetic resonance imaging and chest radiography. TREATMENTS

Before local therapy, all patients received neoadjuvant chemotherapy (TPF regimen), which consisted of docetaxel (75 mg/m2 administered intravenously on day 1), cisplatin (75 mg/m2 administered intravenously on day 1), and 5-FU (750 mg/m2 per day using a continuous intravenous infusion on days 1 to 5). Neoadjuvant chemotherapy was provided every 3 weeks for 2 cycles. Radical surgery was performed 2 to 3 weeks after completion of the second cycle. All patients underwent extended excision of the primary tumor and neck dissection with appropriate reconstruction. Radiotherapy was initiated 4 to 6 weeks after surgery using standard conformal or intensity-modulated radiotherapy (total dose range, 54 to 66 Gy). STATISTICAL METHODS

Descriptive statistics were used to describe the patients’ demographic, pathologic, and clinical characteristics. The primary outcome variables were diseasefree survival (DFS) and overall survival (OS). OS was measured from the date of initial diagnosis to death of any cause. DFS was measured from the completion

of surgery to recurrence or metastasis. OS and DFS were analyzed using the Kaplan-Meier method. The prognostic values of age, gender, histologic grade, lymph node status, tumor stage, pathologic response, and adverse pathologic features were investigated. The log-rank test was performed to test the difference in survival between subgroups. Multivariate analysis was performed using the Cox regression model. All tests were 2-sided, and a P value equal to .05 was set as the level of statistical significance. All statistical analyses were performed using SPSS 13 (SPSS, Inc, Chicago, IL).

Results RESPONSE TO NEOADJUVANT CHEMOTHERAPY

In total, 22 patients were analyzed. All patients had stage III or IVa buccal mucosa SCC. No patients had received prior radiotherapy, chemotherapy, or surgery (except diagnostic biopsy). The patients’ characteristics are listed in Table 1. Common adverse reactions included alopecia, nausea, hematologic toxicity, and altered liver function, but serious adverse effects or death did not occur. Assessment of clinical response to neoadjuvant chemotherapy by clinical examination and imaging scans was performed 2 weeks after the completion of chemotherapy. The response was characterized according to RECIST 1.0.6 In 22 patients, the overall response rate was 72.7% (complete response [CR], 4.5%; partial response, 68.2%; stable disease,

Table 1. PATIENTS’ CHARACTERISTICS (N = 22)

Characteristics Age (yr), median (range) Gender Male Female Stage at time of diagnosis III IVa Tumor size T1-2 T3 T4 Nodal status N0 N1 N2 Histologic grade (biopsy) I II III

n (%) 55.4 (37-75) 9 (40.9%) 13 (59.1%) 4 (18.2%) 18 (81.8%) 2 (9.1%) 4 (18.2%) 16 (72.7%) 4 (18.2%) 13 (59.1%) 5 (22.7%) 4 (18.2%) 17 (77.3%) 1 (4.5%)

Lyu et al. Sequential Therapy of Buccal Cancer. J Oral Maxillofac Surg 2014.

608 18.2%; progression of disease, 9.1%). Pathologic response was assessed by examining the postoperative specimen. Pathologic CR (pCR) or major response (MR) was defined as fewer than 10% residual cancer cells in the resected specimen.7 In 22 patients, a pCR/MR was observed in 40.9% of patients. SURGICAL CHARACTERISTICS

All patients underwent extended excision of the primary tumor and neck dissection. The reconstructive measures included an antebrachial flap (in 10 patients), a pectoralis major myocutaneous flap (in 5 patients), and an anterolateral thigh flap (in 7 patients). By examining the postoperative specimens, lymph node metastasis was found in 14 cases, in which the number of positive nodes ranged from 1 to 19. In the other 8 patients with negative lymph nodes, 5 were staged as clinical N+ before chemotherapy. Adverse pathologic features were present in 5 cases: 1 patient had a positive margin, 3 patients had extracapsular extension of lymph nodes, and 1 patient had nerve and vessel invasion. FOLLOW-UP AND SURVIVAL

For this report, patients were followed until November 2012. The median follow-up time was 36 months. Locoregional recurrence occurred in 8 patients (36.3%), 7 of whom died and 1 who underwent salvage surgery and has survived. No patient developed metastasis. One patient died of cerebral hemorrhage. The 2-year DFS and OS rates were 63.3% and 67.2%, respectively (Fig 1).

FIGURE 1. Overall survival analyzed by the Kaplan-Meier method. Lyu et al. Sequential Therapy of Buccal Cancer. J Oral Maxillofac Surg 2014.

SEQUENTIAL THERAPY OF BUCCAL CANCER PROGNOSTIC FACTORS

Univariate analysis of the clinical variables (age, gender, histologic grade, tumor stage, adverse feature, pathologic lymph node status, and pathologic response) for DFS and OS is presented in Table 2. Age and gender showed significant prognostic effects on DFS (P = .019 for the 2 comparisons). When concerning OS, age was associated with prognosis (P = .020). In multivariate analysis (Table 3), gender had significant prognostic value with respect to DFS (P = .023) and OS (P = .014).

Discussion Buccal cancer is considered an aggressive cancer because of its high locoregional failure rate. The major treatment alternatives for buccal cancer are surgery and radiotherapy. Recently, some studies have reported that treatment with combined modalities (surgery plus radiotherapy with or without chemotherapy) yield better outcomes than surgery or radiotherapy alone for advanced buccal cancer. Considering these results, combined therapy is the best choice for patients with advanced disease. Because SCC of the head and neck is known to be responsive to tumoricidal agents, several strategies combining chemotherapy and radiotherapy with surgery have been explored to achieve better results, such as concurrent chemoradiotherapy and neoadjuvant therapy. Concurrent chemoradiotherapy can produce a significant response, but with the disadvantage of substantial toxicity. Moreover, some studies have reported that concurrent chemoradiotherapy does not produce a significantly better result than radiotherapy alone when an extracapsular spread of lymph nodes is not present.8 Neoadjuvant chemotherapy is used before other modalities and may facilitate subsequent surgery or radiotherapy. Although neoadjuvant chemotherapy has not had a decisive impact on the survival rate in the studies conducted to date, it has several advantages: it induces tumor shrinkage, which allows more effective local therapy; it potentially decreases distant metastatic disease because of systemic exposure; and it induces tumor cell death independently of the effect of radiotherapy with different toxicity profiles.9 Any literature evaluating neoadjuvant chemotherapy plus surgery and radiotherapy in buccal cancer seems to be absent. In this study, the purpose was to evaluate the outcome of sequential therapy (neoadjuvant chemotherapy plus surgery plus postoperative radiotherapy) for advanced buccal mucosa SCC and investigate the prognostic factors. In this series, the overall response rate was 72.7% and pCR/MR was observed in 40.9% of patients. The 2-year DFS and OS rates were 63.3% and 67.2%, respectively. Male and younger

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Table 2. UNIVARIATE ANALYSIS OF SUBGROUP FOR DISEASE-FREE AND OVERALL SURVIVAL

P Value by Log-Rank Test DFS

OS

12 10

.019*

.020*

13 9

.019*

.077

4 18

.746

.583

4 18

.488

.466

5 17

.546

.445

14 8

.108

.387

9 13

.818

.589

n Entire group Age (yr) <55 $55 Gender Female Male Histology grade I II/III Tumor stage III IVa Adverse feature Yes No Positive lymph node Yes No Pathologic response pCR/MR Other

22

Abbreviations: DFS, disease-free survival; OS, overall survival; pCR/MR, pathologic complete or major response. * P < .05 Lyu et al. Sequential Therapy of Buccal Cancer. J Oral Maxillofac Surg 2014.

patients showed an association with poor outcomes. Gender was an independent prognostic factor. In the authors’ department, buccal mucosa cancer accounts for approximately 20% of all SCC cases. A higher incidence has been reported in some South Asian countries, such as India and Malaysia, with a male predilection. Reasons for the male predominance in these countries may be associated with smoking and betel chewing.1,5,10,11 However, in this study, male patients accounted for only 40.9%, whereas female patients accounted for 59.1%. This discrepancy in gender is similar to that in North American populations, in which men account for only 14% to 55%.2 The high incidence of buccal mucosa cancer in North American women has been attributed to the use of snuff. Nevertheless, most Chinese female patients are not tobacco users, alcohol drinkers, or snuff users. This differs from patients in South Asia and North America, which may reflect different risk factors. In the present series, 8 patients developed locoregional failure, with recurrence ranging from 4 to 21 months after surgery. This result concurs with

other studies indicating locoregional failure as the main cause of death.5 In univariate analysis, age was a prognostic factor of DFS and OS. Gender was a significant prognostic factor of DFS in univariate and multivariate analyses. Most patients with recurrence were younger than 55 years. The higher recurrence rate in younger patients may be due to the fact that cancer in young adults tends to be more anaplastic, resulting in more aggressive behavior and a poor prognosis.12 In this study, the recurrence rate in male patients was significantly higher than that in female patients (66.7% vs 15.4%; P = .026); comparable data were not present in other studies. This gender difference may be attributed to different etiologic factors between genders. In the present series, 2 patients who did not achieve an objective response showed pCR/MR in resected specimens. This phenomenon might be due to the reconstruction of destroyed cancer tissues. This suggests that pathologic response is more accurate for evaluating the response to chemotherapy. The overall clinical response rate in this study was 72.7%. Comparable data were limited. Wang et al13 reported an 80% overall response rate of intra-arterial plus intravenous chemotherapy for bulky buccal cancer with the cisplatin and 5-FU regimen. However, toxicity was high. In the present series, the DFS and OS rates at 2 years were 63.3% and 67.2%, respectively, compared with the literature on multimodal treatment: Lin et al1 reported 61% and 60% 5-year DFS rates for patients with stage III and IV cancer and Lin et al5 reported a 23.5% 5-year DFS rate for patients with advanced cancer. Distant metastasis was absent in the present study in contrast to the studies by Lin et al5 (15.7%) and Lin et al1 (10.3%). This result might be attributed to an effective systemic chemotherapy that eliminated potential micrometastasis.14 In a report by Jan et al,15 tumor stage, surgical margin status, and extracapsular spread of cervical nodal metastasis were the most important prognostic factors in patients with buccal SCC, whereas these factors did not show significant value in the present study. The authors suggest it may be attributed to the rigorous treatment (radical surgery plus adequate adjuvant therapy) that lowers the relapse rate in patients with those risk factors. In the previous literature involving neoadjuvant chemotherapy, pathologic response to chemotherapy was a prognostic factor of survival.7,16 In the present study, the difference in survival between patients with an excellent pathologic response and those with a poor response was not significant. Neoadjuvant chemotherapy may play a role in decreasing distant metastasis, but not in decreasing local recurrence,17 and the most common cause of treatment failure in buccal cancer is local recurrence. As a result, the survival advantage of patients with an excellent pathologic response was not significant in the present study.

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SEQUENTIAL THERAPY OF BUCCAL CANCER

Table 3. REGRESSION MODEL FOR OS AND DFS

DFS

Age (<55 vs $55 yr) Gender (female vs male) Histologic grade (well vs moderate-poor differentiation) Tumor stage (III vs IVa) Adverse feature (no vs yes) Lymph nodes status (N0 vs N+) Pathologic response (CR/MR vs limited response)

OS

P Value

HR (95.0% CI)

P Value

HR (95.0% CI)

.293 .023* .253

3.492 (0.340-35.861) 0.060 (0.005-0.684) 0.251 (0.023-2.689)

.061 .014* .118

9.747 (0.901-105.429) 0.038 (0.003-0.523) 0.122 (0.009-1.712)

.206 .225 .269 .318

5.810 (0.379-88.979) 7.594 (0.287-201.244) 0.276 (0.028-2.705) 0.374 (0.054-2.582)

.138 .282 .812 .110

6.328 (0.551-72.615) 5.900 (0.233-149.688) 0.800 (0.127-5.037) 0.195 (0.026-1.449)

Abbreviations: CI, confidence interval; CR/MR, complete or major response; DFS, disease-free survival; HR, hazard ratio; OS, overall survival. * P < .05 Lyu et al. Sequential Therapy of Buccal Cancer. J Oral Maxillofac Surg 2014.

The present study showed that sequential therapy tends to be effective in advanced buccal cancer. The response rate was high, and long-term outcome was good. Limitations of this study include a small sample and no comparison cohort against which to analyze chance alone. Although the incidence of distant metastasis in the present series seems to be lower than that in other studies, conclusions cannot be drawn because of the small sample and absence of a control cohort. In conclusion, sequential therapy (neoadjuvant chemotherapy plus surgery plus radiotherapy) for buccal mucosa SCC tends to be effective. Gender is an independent prognostic factor. Further efforts should be made to decrease locoregional failure.

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6. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205, 2000 7. Licitra L, Grandi C, Guzzo M, et al: Primary chemotherapy in resectable oral cavity squamous cell cancer: A randomized controlled trial. J Clin Oncol 21:327, 2003 8. Fan KH, Lin CY, Kang CJ, et al: Combined-modality treatment for advanced oral tongue squamous cell carcinoma. Int J Radiat Oncol Biol Phys 67:453, 2007 9. Pointreau Y, Atean I, Fayette J, et al: Induction chemotherapy in head and neck cancer: A new paradigm. Anticancer Drugs 22: 613, 2011 10. Iype EM, Pandey M, Mathew A, et al: Squamous cell cancer of the buccal mucosa in young adults. Br J Oral Maxillofac Surg 42:185, 2004 11. Pathak KA, Nason RW, Talole SD, et al: Are buccal cancers in India and Canada any different? J Surg Oncol 97:529, 2008 12. Byers RM: Squamous cell carcinoma of the oral tongue in patients less than thirty years of age. Am J Surg 130:475, 1975 13. Wang HM, Ng SH, Wang CH, et al: Intra-arterial plus i.v. chemotherapy for advanced bulky squamous cell carcinoma of the buccal mucosa. Anticancer Drugs 12:331, 2001 14. Ma J, Liu Y, Yang X, et al: Induction chemotherapy in patients with resectable head and neck squamous cell carcinoma: A meta-analysis. World J Surg Oncol 11:67, 2013 15. Jan JC, Hsu WH, Liu SA, et al: Prognostic factors in patients with buccal squamous cell carcinoma: 10-Year experience. J Oral Maxillofac Surg 69:396, 2011 16. Kies MS, Boatright DH, Li GJ, et al: Phase II trial of induction chemotherapy followed by surgery for squamous cell carcinoma of the oral tongue in young adults. Head Neck 34:1255, 2012 17. Liu J, Xie X, Zhou C, et al: Which factors are associated with actual 5-year survival of oesophageal squamous cell carcinoma? Eur J Cardiothorac Surg 41:e7, 2012