Tongue conservation treatment for oral tongue squamous cell carcinoma with induction chemotherapy, surgery, and risk‐adapted adjuvant therapy: A phase II trial

Abstract Background To assess the feasibility of tongue conservation treatment with induction chemotherapy (ICT), tongue conservation surgery, and risk‐adapted postoperative adjuvant therapy in oral tongue squamous cell carcinoma (OTSCC). Methods Patients with newly diagnosed OTSCC cT2‐4 N0‐2 M0 were recruited. The ICT with a regimen of docetaxel, cisplatin, and oral tegafur/uracil (DCU) was administrated every 21 days. After the first cycle of ICT (DCU1), patients with a more than 30% decrease in the longest diameter of primary tumor underwent a second cycle of ICT (DCU2). Tongue conservation surgery was performed after ICT, and risk‐adapted adjuvant therapy was organized based on pathological features. Results From July 2011 to December 2015, a total of 23 patients were enrolled, 87% of whom were classified as stage III–IV. Clinical responders to DCU1 and DCU2 were determined in 90.5% (19/21) and 88.2% (15/17) of patients. Tongue conservation surgery was performed in 16 responders to ICT. Only one patient had a positive margin (6.3%), and a complete pathologic response was achieved in eight patients (50%). Only one patient developed local recurrence after a median follow‐up of 58.6 months (range, 7.9–105.2). The 5‐year overall survival (0% vs. 87.5%, P = 0.001) and disease‐specific survival (0% vs. 93.3%, P = 0.000) were significantly different between the DCU1 nonresponders and responders. Conclusion Tongue conservation treatment with ICT, followed by conservation surgery and risk‐adapted adjuvant therapy, is feasible for patients with OTSCC who are good responders to ICT. However, the outcomes of nonresponders are dismal. Further study in a larger patient population is warranted.


| INTRODUCTION
Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy in Taiwan, with over 5000 new cases annually. Oral tongue squamous cell carcinoma (OTSCC) is a major oral cavity cancer, 1 and radical surgery is the standard treatment for patients with OTSCC. 2 Early T1-2 tumors can be treated by transoral excision, while larger T3-4 tumors may require mandibulotomy, mandibulectomy, or flap reconstruction. In addition, postoperative adjuvant radiotherapy or chemoradiotherapy (POCCRT) is indicated for patients with advanced T3-4 tumors, cervical lymph node metastasis, or adverse pathologic features. Such intensive treatment for OTSCC inevitably leads to functional sequelae.
Temporo-spatially coordinated motility of the oral tongue is critical for normal swallow and speech functions. Greater volumetric or motility loss of oral tongue tissue after surgery can lead to poor quality of life with profound swallowing and speech impairments, especially in patients with large tumors and adjuvant radiation. 3 Despite the availability of modern free tissue transfer reconstruction, the benefit for residual tongue functions is still controversial. 2,4 Conserving the oral tongue without jeopardizing tumor control is the primary treatment goal for OTSCC, but is not easily attained. Although organ preservation with chemoradiotherapy has been widely applied for head and neck cancers in the past two decades, patients with resectable OTSCC are usually excluded due to concerns about poorer responses and outcomes compared to radical surgery. 5,6 Induction chemotherapy (ICT) has been applied as an important component in the treatment of various advanced human cancers, including cancers of the rectum, cervix, and breast. For organ or tissue conservation purposes, and under appropriate circumstances, limited surgical excision of residual tumors after ICT is performed, followed by adjuvant therapy. In cervical cancers, the possibility of attempting a less extensive surgery after ICT has been investigated to improve the quality of life. 7 Breast conservation treatment with ICT has become one of the standard treatments for breast cancer. 8,9 The main purpose of ICT is to downsize large primary breast tumors (> 3 cm) for breast-conserving surgery, which involves resection of the gross residual tumor mass with a safe margin, instead of the original tumor extent. 10,11 A similar concept of organ or tissue conservation treatment with ICT has not yet been investigated in OSCC. For locally advanced head and neck cancers, a combination of docetaxel, cisplatin, and fluorouracil (TPF) has been shown by TAX323 and TAX324 studies to be the most effective ICT regimen. ICT consisting of paclitaxel and carboplatin with cetuximab is another feasible, effective, and well-tolerated regimen. 12 However, all aforementioned studies only included a small number of OSCC patients, [12][13][14][15] and the benefits of ICT in OSCC remain unclear. [16][17][18][19][20] Because TPF has been shown to be superior to PF in randomized trials, for reasons of tolerance in Asian patients, we modified it to the docetaxel, cisplatin and oral tegafur/uracil (DCU) regimen, as published earlier in Asian papers. 21,22 We conducted this phase II study to assess the feasibility and safety of ICT, followed by tongue conservation surgery and risk-adapted postoperative adjuvant therapy in the management of OTSCC. This was an open-label, noncomparative phase II trial to evaluate the   feasibility of tongue conservation treatment comprising ICT, tongue conservation surgery, and risk-adapted adjuvant chemoradiotherapy.

| Study design
The primary end point was the response to ICT, and the secondary endpoints included the oncologic controls and survival. The sample size was calculated based on the two-stage design by Simon. 23 The first step was planned to include 11 patients, and if >7 responders were recorded, an additional 39 patients would be enrolled. However, the study was prematurely closed due to slow patient recruitment. The study protocol is registered in ClinicalTrials.gov (No. NCT03161548), and was approved by the Institutional Review Board of Taipei Veterans General Hospital.

| Patients
Between July 2011 and December 2015, patients with newly diagnosed and histologically proven OTSCC, who were to receive curative treatment at Taipei Veterans General Hospital, a tertiary referral medical center, were screened. The inclusion criteria were as follows 1 : cT2-4, N0-2M0 by clinical and radiographic examinations 2 ; postoperative tongue defect >4 cm by initial surgical planning 3 ; age between 20 and 70 years 4 ; ECOG performance status of 0-1 5 ; adequate hematopoietic, hepatic, and renal functions; and 6 signed informed consent.
Patients were excluded if they had any of the following conditions 1 : history of head and neck or esophageal cancer 2 ; prior head and neck chemoradiotherapy 3 ; synchronous cancer history within 6 months 4 ; tumor invasion to the mandible, tonsils, or > 1/3 base of tongue; and 5 N3 or M1 disease. Patients who had a history of previous tongue surgery, who had developed distant metastasis or those who were physically or mentally unfit were also excluded.
Comprehensive pretreatment evaluation was performed and included physical examination with photographic documentation, endoscopy, computed tomography (CT) or magnetic resonance imaging, chest X-ray or chest CT, and routine laboratory studies. Patients were staged in the 3 weeks prior to recruitment using the seventh edition of the AJCC TNM staging system. 24 The original surgical planning upon screening, including the approach and reconstruction, was recorded by the responsible surgeons.

| Statistical analysis
All analyzes were performed using the Statistical Package of Social Sciences software version 17.0 (SPSS, Inc., Chicago, IL). Descriptive statistics were used for most primary and secondary end points. Overall survival (OS) was defined as the interval between the start of ICT and the date of death or last contact. Disease-specific survival (DSS) was defined as the interval between the start of ICT and the date of death from the index tumor or treatment-related events. Kaplan-Meier analysis and the log-rank test were used for survival analyzes. All tests were two-sided, and results were considered significant at P < 0.05.   (Table 2).

| Patient characteristics and treatment course
After DCU1, one patient developed severe adverse events (SAE) with liver function deterioration and ascites despite a good response, and immediate surgery was arranged. Another patient died from F I G U R E 1 Flowchart of the Phase II trial for oral tongue squamous cell carcinoma. Induction chemotherapy, followed by conservative surgery and riskadapted adjuvant therapy febrile neutropenia and sepsis. Seventeen patients completed the entire course of DCU2. One patient refused scheduled surgery after DCU2, and another developed lung metastasis after surgery; these two patients were excluded from subsequent analyzes. Among the 17 included patients, 15 (88.2%) were determined as clinical DCU2 responders (Table 2).
Ultimately, 16 patients underwent surgery, one after DCU1 and 15 after DCU2; POCCRT was waived in 6 patients according to our risk-adapted criteria.

| Safety and adverse events of DCU induction chemotherapy
Cumulative severe hematologic and nonhematologic toxicities or SAE (grade 3-4) during DCU1 and/or DCU 2 are listed in Table 3. Grade 3 to 4 leukopenia being the most common SAE (42.9%, 9/21), and grade 4 neutropenia (< 500/mm 3 ) occurred in two patients. One patient had early signs of sepsis after DCU1, which required intensive concomitantly with a mean of six cycles of weekly chemotherapy with cisplatin administration (range, 5-7 cycles).

| DISCUSSION
There has been a paucity of data about chemoradiotherapy in OSCC due to the poorer response and inferior outcome compared with surgery. 5,6 Our results of this phase II trial suggest that conservation surgery after ICT is feasible in resectable OTSCC and may lower the need for mandibulotomy, free flap reconstruction, and adjuvant chemoradiotherapy. Good oncological outcomes can be observed in ICT responders. The DCU regimen in this study was easy to administer and carried a low rate of SAE.
Several studies have reported the use of ICT with different regimens in OSCC patients. Zhong et al. 17 reported a phase III trial of ICT with TPF followed by surgery in locally advanced OSCC, in which they achieved a clinical response rate of 80.6% after two cycles of TPF, including a pCR rate of 13.4%. Licitra et al. 16 also reported a clinical response rate of 82% and a pCR rate of 27% with a PF regimen (cisplatin and fluorouracil) in OSCC. Compared with these two studies, the DCU regimen in our study achieved better response rates (90.5% and 88.3% for DCU1 and DCU2, respectively) ( Table 2) and an impressive pCR rate (50%). These positive results may partly be explained by the fact that the DCU regimen was used in a patient group with a substantial proportion of cT2 tumors (43.5%).
In our study, daily oral UFUR was given at an equivalent dose to ameliorate stomatitis induced by the continuous 5-fluorouracial infusions of the TPF regimen. 1,26,27 The lower rate of grade 3-4 mucositis (14.3%) and convenient administration without the need for hospitalization also improved patient compliance. The mean clearance of docetaxel has been reported to be lower in Asian populations than in Caucasian populations. 28,29 Therefore, a dose modification with docetaxel in Asian populations had been used in the treatment of various kinds of cancers. [30][31][32][33] In our study, grade 3/4 leukopenia and febrile neutropenia were noted in 42.9% and 9.5% of the patients, respectively, slightly higher than those reported in the studies using ICT with The limitation of our study is the relative small sample size. Since this was a phase II trial, more patients should be recruited with a comparison group in the future study. In addition, DCU1 nonresponders had extremely poor oncologic outcomes. Treatment delay from ineffective ICT in nonresponders, although determined after just one cycle of DCU, is also a concern. Therefore, molecular markers should be further investigated to predict the response to ICT and allow proper selection of candidates for ICT. Until then, the benefit of ICT may be fully exploited in responders, and nonresponders will be spared from treatment delay and toxicities. Finally, functional outcomes, other than tracheostomy and tube feeding, were not addressed in this study. The details of functional improvement and quality of life require further study.

| CONCLUSION
In conclusion, tongue conservation treatment by ICT with a DCU regimen, followed by surgery and risk-adapted adjuvant therapy, is feasible for OTSCC. A good oncological outcome could be achieved in ICT responders with risk-adapted adjuvant therapy. However, the outcomes of nonresponders are dismal. Further study in a larger patient population with a control group is required to explore the oncologic and functional benefit of this treatment.

ACKNOWLEDGMENTS
Research for the present study was supported in part by Ministry of

CONFLICT OF INTEREST
The authors declare that they have no potential conflicts of interest.

ETHICS STATEMENT
All procedures performed in studies involving human participant were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Signed informed consent was obtained from patients.

DATA AVAILABILITY STATEMENT
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