Long-term results of a randomized phase III trial of TPF induction chemotherapy followed by surgery and radiation in locally advanced oral squamous cell carcinoma

Previously, we conducted a randomized phase III trial of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy in surgically managed locally advanced oral squamous cell carcinoma (OSCC) and found no improvement in overall survival. This study reports long-term follow-up results from our initial trial. All patients had clinical stage III or IVA locally advanced OSCC. In the experimental group, patients received two cycles of TPF induction chemotherapy (75mg/m2 docetaxel d1, 75mg/m2 cisplatin d1, and 750mg/m2/day 5-fluorouracil d1-5) followed by radical surgery and post-operative radiotherapy; in the control group, patients received upfront radical surgery and post-operative radiotherapy. The primary endpoint was overall survival. Among 256 enrolled patients with a median follow-up of 70 months, estimated 5-year overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival rates were 61.1%, 52.7%, 55.2%, and 60.4%, respectively. There were no significant differences in survival rates between experimental and control groups. However, patients with favorable pathologic responses had improved outcomes compared to those with unfavorable pathologic responses and to those in the control group. Although TPF induction chemotherapy did not improve long-term survival compared to surgery upfront in patients with stage III and IVA OSCC, a favorable pathologic response after induction chemotherapy may be used as a major endpoint and prognosticator in future studies. Furthermore, the negative results observed in this trial may be represent type II error from an underpowered study. Future larger scale phase III trials are warranted to investigate whether a significant benefit exists for TPF induction chemotherapy in surgically managed OSCC.

. Comparison of (A) overall survival, (B) disease-free survival, (C) locoregional recurrence-free survival, and (D) distant metastasis free-survival between the patients with favorable and unfavorable pathologic responses. The landmark point was set at the time of response evaluation. Table S1. Comparison of the incidences of locoregional recurrence, distant metastasis, and secondary neoplasm between experimental and control groups. Table S2. Summary of 68 patients with oral squamous cell carcinoma for pancytokeratin expression detection in surgical margins. Table S3. Immunohistochemical results of pan-cytokeratin expression detection in the surgical margins from 68 patients with oral squamous cell carcinoma.

STUDY PROTOCOL REDACTION Introduction
Induction chemotherapy is regarded as an effective way to reduce or downgrade the locally advanced or aggressive cancers, and to improve the chance of eradication of the locoregional lesions by radical surgery and/or radiotherapy. However, there are still debates on the clinical value of induction chemotherapy for patients with advanced and resectable oral squamous cell carcinoma. Recently, an induction chemotherapy protocol of docetaxel, cisplatin and 5-fluorouracil (TPF) combination followed by chemoradiotherapy has been reported to be superior to cisplatin and 5-fluorouracil (PF) in two randomized phase III trials on the aspect of survival rate, and it is suggested as a better treatment strategy of induction chemotherapy for head and neck squamous cell carcinoma patients. However, there is still few direct evidence from large sample clinical trials on the survival rate, that confirming the benefit of TPF induction chemotherapy between the patients with and without TPF in oral squamous cell carcinoma (OSCC). The hypothesis of this study is that the induction chemotherapy of TPF protocol could benefit the patients with locally advanced OSCC.

Study design
This prospective, open label, parallel, interventional, randomized control trial was to evaluate the TPF induction chemotherapy in the patients with locally advanced and resectable OSCC. The patients would receive TPF induction chemotherapy followed by radical surgery and post-operative radiotherapy (the experimental group) or radical surgery and post-operative radiotherapy (the control group).

Primary endpoint: Survival rate.
Secondary endpoints: Local control and safety.

Sample size consideration
The study had a power of 83% on the basis of an assumed 5-year survival rate of 55% in the experiment group and 35% in the control group, with use of a two-sided log-rank test at a level of significance of 0.05. The recruitment period would be 3 years, and the follow-up period would be 3 years, and 15% of patients would drop out early or be lost to follow-up. A maximum of 128 patients per group were to be recruited.

Inclusion criteria
 Age: 18 to 75 years old.
 Sex: both males and females.  Previous radiotherapy or chemotherapy.
 Other previous malignancies within 5 years.
 Can not tolerate the treatment protocol with systematic diseases such as history of severe pulmonary or cardiac diseases.
 Legal incapacity or limited legal capacity.

Treatment procedures
The patients in the experimental group received the TPF induction chemotherapy for 2 cycles followed by radical surgery and post-operative radiotherapy. The palpable edges of the primary lesion (both the longest and shortest axis) were marked before induction chemotherapy by at least four points, which were 0.5cm away. The patients in the control group received the radical surgery and post-operative radiotherapy.
Induction chemotherapy: For the patients who were randomly assigned to receive TPF induction chemotherapy, peripherally inserted central catheter was firstly inserted before intravenous infusion, docetaxel (at a dose of 75mg/m 2 of body surface area) was administered as a 2-hour intravenous infusion, followed by intravenous cisplatin (75 mg/m 2 ), administered during a period of 2 to 3 hours. Then, 5-Fu (750 mg/m 2 /day) was administered as a 120-hour continuous intravenous infusion for 5 days. Induction chemotherapy was given every 3 weeks for 2 cycles, unless there was disease progression, unacceptable toxic effects, or withdrawal of consent by the patients. Dexamethasone was given before docetaxel infusion to prevent docetaxel-related hypersensitivity reactions, skin toxic effects, and fluid retention; prophylactic antibiotics were also given starting on day 5 of each cycle for 3 days. Hydration with diuretic and antiemetic treatment was also performed. Primary prophylaxis with recombinant granulocyte colony-stimulating factor was not suggested. Chemotherapy dose reductions were allowed for grade 3/4 toxicities occurring after cycle 1: 25% and 50% dose reductions of the three chemotherapy agents were suggested for grade 3 and grade 4 hematologic toxicities or gastrointestinal toxicities, respectively; 25% and 50% cisplatin dose reductions were suggested for grade 3 and grade 4 renal toxicities, respectively. Surgery was performed at least 2 weeks after completion of induction chemotherapy.
Surgery: Radical resection of the primary lesion and full neck dissection (functional or radical) with proper reconstruction (pedicle or free flap) were performed. The safety margins of the primary lesion were 1.5cm far away from the palpable margins of the lesion; for patients who received induction chemotherapy, the safety margins were 1.0cm away from the marks that were placed before induction chemotherapy, to ensure the same extent surgery in both arms. Frozen sections during surgery were performed to confirm adequate margins.
Post-operative radiotherapy: Radiotherapy was arranged 4 to 6 weeks after surgery.
Routine external beam radiotherapy, such as conformal or intensity modulated radiotherapy was performed, and the dose was 1.8-2 Gy/day, 5 days/week for 6 weeks, and totally 54-60 Gy, in the patient with high risk features, such as positive surgical margin, extra capsular nodal spread, vascular embolism, total dose of 66 Gy was suggested.

Assessment
A complete medical history was obtained and tumor assessment was performed at baseline. Clinical tumor response was assessed by clinical evaluation and imaging study and was characterized according to the criteria of response evaluation criteria in solid rumors (version 1.0) before surgery. Post-operative pathologic response was assessed by post-operative pathologic examination as good and bad response. A good response was defined as absence of any tumor cells (pathologic complete response) or presence of scattered foci of a few tumor cells (minimal residual disease with <10% viable tumor cells); otherwise, a bad pathologic response was defined. Toxic effects were assessed weekly during and after completion of induction chemotherapy and radiotherapy according to the common terminology criteria for adverse events (version 3.0).

Outcome measures
Overall survival was calculated from the date of randomization to the date of death; disease free survival was calculated from the date of randomization to tumor recurrence or distant metastasis or death from any cause; locoregional recurrence/distant metastasis free survival was calculated from the date of randomization to locoregional recurrence/distant metastasis of tumor or death from any cause. Time to locoregional recurrence/distant metastasis was calculated from the date of finishing treatment to tumor locoregional recurrence/distant metastasis. Patients were