Post-Operative Adjuvant Concurrent Chemoradiotherapy For High Risk Oral Cavity Squamous Cell Carcinoma Patients
Post-Operative Adjuvant Concurrent Chemoradiotherapy For High Risk Oral Cavity Squamous Cell Carcinoma Patients
The purpose of this study is to confirm the value of concurrent chemoradiotherapy in
 improving the locoregional control and survival of patients with resected locally advanced
 HNSCC, a phase III randomized study is proposed. The population studied in this trial is
 limited to patients of oral cavity cancer; this could reduce the confounding factor of
 varying prognosis in patients of different primary sites of HNSCC.
Potentially resectable Stage III or IV squamous cell carcinomas of the head and neck (HNSCC)
 are treated by operation and adjuvant radiotherapy. The 5-year survival rate is approximating
 30%. Recurrence typically occurs within 3 years, 60-80% in locoregional sites, and 20-30%
 systemically. Patients who are found to have tumors at the margins of surgical specimens far
 particularly poorly.

 Chemotherapy has been added in the hope to improve this situation. Induction and adjuvant
 chemotherapy has resulted in a decrease in the appearance of systemic metastases in most
 trials, but has not improved locoregional control and survival.

 For cases with unresectable head and neck cancers, concurrent chemoradiotherapy appears to
 have improved locoregional control, disease-free survival, and possibly overall survival, as
 compared to radiotherapy alone. Bachaud et al. reported a randomized trial of postoperative
 cisplatin and radiotherapy vs. radiotherapy alone for patients with Stage III or IV head and
 neck cancer. Cisplatin was administered 50 mg weekly during radiotherapy. There was a
 significant improvement in locoregional control (70% vs. 55%) as well as overall survival
 (median 36m vs. 20m) in patients who received concurrent chemoradiotherapy. Al-Sarraf et al.
 also reported a phase II concurrent chemoradiotherapy trial, using cisplatin 100 mg/m2 every
 three weeks. Based on comparison with similar patients treated in a prior RTOG trial, they
 conclude that postoperative radiotherapy with concurrent cisplatin may improve locoregional
 control rates10. The superiority of adjuvant concurrent chemoradiotherapy (CCRT) to RT alone
 or sequential adjuvant RT and chemotherapy has been further confirmed in an analysis of data
 of RTOG 85-03 and RTOG 88-24. Comparing high-risk patients of RTOG 85-03 with prognostically
 similar patients from RTOG 88-24, the data suggest that sequential surgery, RT, and
 chemotherapy produced better locoregional control than surgery plus RT, but that surgery
 followed by CCRT produced even higher locoregional control. Independent of the differences in
 the amount of RT delivered, the Cox proportional hazards model suggests that the addition of
 CCRT resulted in a 50% decrease in locoregional relapse rates compared with surgery plus
 postoperative RT with no chemotherapy. The reduction in mortality was 18%.

 Although CCRT may be better than RT alone or sequential treatment, the 3 year survival in
 both adjuvant CCRT studies were only around 50%. Is more aggressive treatment warranted?
 Tolerance to CCRT is a major concern. In the French study, severe acute toxicity occurred in
 18% of RT only patients and 41% of patients received CCRT. In the RTOG 88-24 trial, severe
 and life-threatening toxicities occurred in 20% and 12% of patients, respectively; the most
 common drug-related toxicities were leukopenia, anemia, nausea, and vomiting . Theoretically,
 to optimize CCRT, continuous presence of chemotherapeutic drug or drug effect is necessary to
 maximize the effect of radiosensitization. For radiosensitization purpose, daily chemotherapy
 may be better than weekly and weekly may be better than tri-weekly. French study used weekly
 cisplatin with a dose of 30 mg/m2. RTOG 88-24 used different treatment dose and schedule 100
 mg/m2 of cisplatin on radiotherapy days 1, 23 and 43. We choose weekly for convenience and
 hope this can increase the recruitment of patients. In the pilot study, we observed a
 remarkable toxicity with this treatment schedule. Considering the remarkable toxicity
 reported and our preliminary experience, more drugs, higher dosage, or extended schedule may
 not be justified.
Inclusion Criteria:

 Clinically free of disease after having undergone surgery for histologically confirmed
 primary keratinizing SCC of the oral cavity.

 buccal mucosa upper lip (140.3) lower lip (140.4) cheek (145.0) retromolar area (145.6)
 bucco-alveolar sulci upper and lower (145.1) oral tongue dorsum (141.1) lateral border
 (141.2) inferior surface (141.3)

 With any one of the risk factors of recurrence listed below:

 Nodal extracapsular spread of disease (ECS) Number of positive node > 2 Perineural
 involvement Lymphovascular emboli/permeation in resected surgical specimen Histologically
 positive surgical margin

 Exclusion Criteria:

 Karnofsky performance status of <50 Concurrent or previous second primary cancer (excluding
 non-melanoma skin cancer) Gross residual disease following surgery Distant metastasis
 before or at the time of adjuvant treatment Serum creatinine > 1.4 mg/dl, WBC <3500/mm3,
 platelet <100,000/mm3

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