The purpose of this study is to investigate whether the addition of metronomic capecitabine to the standard treatment can improve prognosis in locoregionally advanced head and neck squamous cell carcinoma.

The standard treatment for resectable locoregionally advanced squamous cell carcinoma of the head and the neck (LAHNSCC) is a regimen consisting of radical surgery plus radiotherapy or concurrent chemoradiotherapy. And induction chemotherapy plus radical radiotherapy or concurrent chemoradiotherapy is also recommended for locoregionally advanced squamous cell carcinoma of larynx and hypopharynx. With the extensive application of comprehensive treatment, the 5-year overall survival of LAHNSCC has not reached 50% yet. So, it is urgent to explore a regimen with high efficiency and low toxicity on the basis of existing standard treatment.

Two retrospective studies found that the metronomic use of orally administered fluorouracil drugs following the reference treatment significantly improved prognosis in LAHNSCC. And capecitabine is one kind of the oral fluorouracil drugs, which has high efficiency and low toxicity. Indeed, metronomic capecitabine maintenance was shown to be effective in patients with breast cancer, colorectal cancer, and nasopharyngeal carcinoma in phase III trials.

The abovementioned studies suggested the promising use of metronomic capecitabine in LAHNSCC. However, there has been no randomized trials in this field. Therefore, we initiated a randomized phase III trial to investigate the efficacy and safety of the addition of metronomic capecitabine to the standard treatment in LAHNSCC.

Inclusion Criteria:

1. Performance status of ECOG grade 0 or 1.

2. Tumor staged as III-IV (as defined by the 8th AJCC edition), with newly histologically confirmed squamous cell carcinoma of oral cavity, oropharynx, larynx or hypopharynx.

3. Complete one of the following treatments:

   1. Radical surgery plus radiotherapy or concurrent chemoradiotherapy
   2. Neoadjuvant therapy plus radical radiotherapy or concurrent chemoradiotherapy
   3. Concurrent chemoradiotherapy

4. Postoperative radiotherapy started within 4 to 8 weeks after completion of radical surgery.

5. Within 4 to 8 weeks after completion of the last radiation dose.

6. No clinical evidence of persistent locoregional disease or distant metastases before enrollment.

7. Adequate hematologic (neutrophil count > 1.5×10^9/L, hemoglobin > 90g/L and platelet count > 100×10^9/L), hepatic (alanine aminotransferase, aspartate aminotransferase ≤ 1.5×ULN, bilirubin ≤ 1.5×ULN, alkaline phosphatase ≤ 2.5×ULN) and renal function (creatinine clearance ≥ 50 ml/min).

8. Patients must be appraised of the investigational nature of the study and provide written informed consent.

Exclusion Criteria:

1. p16 positive.
2. Patients who were known to be intolerable or allergic to capecitabine.
3. Illness that would interfere with oral medication, including dysphagia, chronic diarrhea, or ileus.
4. Prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer.
5. Pregnancy or lactation (consider pregnancy test in women of child-bearing age and emphasize effective contraception during the treatment period).
6. Prior surgery, chemotherapy, radiotherapy or other anti-tumor treatments (except diagnostic) to primary tumor or nodes before the standard therapy.
7. Patients who received surgery treatment, biotherapy or immunotherapy during radiotherapy.
8. Patients who are receiving or highly likely to receive other chemotherapy treatment, biotherapy or immunotherapy after radiotherapy.
9. Any severe intercurrent disease, which may bring unacceptable risk or affect the compliance of the trial, for example, unstable cardiac disease requiring treatment, renal disease, chronic hepatitis, diabetes with poor control (fasting plasma glucose > 1.5×ULN), and emotional disturbance.