B. Rhein

Randomized Trial of Radiation Therapy Versus Concomitant Chemotherapy and Radiation Therapy for Advanced-Stage Oropharynx Carcinoma

Background: We designed a randomized clinical trial to test whether the addition of three cycles of chemotherapy during standard radiation therapy would improve disease-free survival in patients with stages III and IV (i.e., advanced oropharynx carcinoma). Methods: A total of 226 patients have been entered in a phase III multicenter, randomized trial comparing radiotherapy alone (arm A) with radiotherapy with concomitant chemotherapy (arm B). Radiotherapy was identical in the two arms, delivering, with conventional fractionation, 70 Gy in 35 fractions. In arm B, patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin (70 mg/m 2 per day) and 5-fluorouracil (600 mg/m 2 per day) by continuous infusion. The two arms were equally balanced with regard to age, sex, stage, performance status, histology, and primary tumor site. Results: Radiotherapy compliance was similar in the two arms with respect to total dose, treatment duration, and treatment interruption. The rate of grades 3 and 4 mucositis was statistically significantly higher in arm B (71%; 95% confidence interval [CI] = 54%-85%) than in arm A (39%; 95% CI = 29%-56%). Skin toxicity was not different between the two arms. Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level. Three-year overall actuarial survival and disease-free survival rates were, respectively, 51% (95% CI = 39%-68%) versus 31% (95% CI = 18%-49%) and 42% (95% CI = 30%-57%) versus 20% (95% CI = 10%-33%) for patients treated with combined modality versus radiation therapy alone (P = .02 and .04, respectively). The locoregional control rate was improved in arm B (66%; 95% CI = 51%-78%) versus arm A (42%; 95% CI = 31%-56%). Conclusion: The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx.

Final Results of the 94–01 French Head and Neck Oncology and Radiotherapy Group Randomized Trial Comparing Radiotherapy Alone With Concomitant Radiochemotherapy in Advanced-Stage Oropharynx Carcinoma

PURPOSE We report the 5-year survival and late toxicity results of a randomized clinical trial, which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma, using concomitant radiochemotherapy (arm B), compared with standard radiotherapy (arm A). PATIENTS AND METHODS A total of 226 patients were entered onto a phase III multicenter randomized trial comparing radiotherapy alone (70 Gy in 35 fractions; arm A) with concomitant radiochemotherapy (70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil; arm B). Prognostic factors were evaluated by univariate and multivariate analysis. Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity, hearing, taste, mandibula, and teeth damage, and Radiation Therapy Oncology Group toxicity criteria for skin, salivary gland, and mucosa. RESULTS Five-year overall survival, specific disease-free survival, and locoregional control rates were 22% and 16% (log-rank P =.05), 27% and 15% (P =.01), and 48% and 25% (P =.002), in arm B and arm A, respectively. Stage IV, hemoglobin level lower than 125 g/L, and standard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis. One or more grade 3 to 4 complications occurred in 56% of the patients in arm B, compared with 30% in arm A (P was not significant). CONCLUSION Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity. Anemia was the most important prognostic factor for survival in both arms.

Late toxicity results of the gortec 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: Comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems

PURPOSE To prospectively assess 5-year late toxicity in patients treated by concomitant radiochemotherapy for locally advanced oropharynx carcinoma using three different toxicity scales. METHODS AND MATERIALS A total of 226 patients were entered in a Phase III multicenter, randomized trial comparing radiotherapy alone (70 Gy in 35 fractions: Arm A) with concomitant radiochemotherapy (70 Gy in 35 fractions with three cycles of a 4-day regimen containing carboplatin and 5-fluorouracil: Arm B). Five living patients, free of local or distant recurrences, could not be evaluated for late toxicity. Forty-four patients were eligible for late toxicity with a median follow-up of 5 years. Late toxicity was evaluated by the radiation oncologist using a large questionnaire containing 120 mixed items of three scales (NCI-CTC, LENT/SOMA, and RTOG). The data were then transposed on separate scales using corresponding grades. RESULTS The 5-year overall survival rate was 22% in Arm B and 16% in Arm A (p = 0.05). The 5-year locoregional control rate was 48% in Arm B and 25% in Arm A (p = 0.002). The spinal cord was not affected by the concomitant adjunct of chemotherapy, and no deaths were caused by late toxicity. Using the three late toxicity scales, 100% of the patients treated with the combined modality (Arm B) developed one or more late complications vs. 94% in the radiotherapy-alone arm (Arm A). The difference was not statistically significant. The most commonly damaged organs (all Grade 1-4) were the salivary glands (100% in Arm B vs. 82% in Arm A, p <0.05), skin (78% vs. 47%, p <0.05), teeth (67% vs. 18%, p <0.05), mucosa (59% vs. 63% p = not significant), and mandible (44% vs. 12%, p <0.05). One or more Grade 3-4 complications occurred in 82% of the patients in Arm B vs. 47% in Arm A (p = 0.02) but concerned only the teeth. The correlation between the RTOG and LENT/SOMA scale and between the NCI-CTC and LENT/SOMA scale were low for Grade 1-4 toxicity (near 30%). The transposability of a patients symptoms was significantly greater using the LENT/SOMA or RTOG/EORTC scaling systems than using the NCI-CTC system. CONCLUSION Concomitant radiochemotherapy increased overall survival and locoregional control rates. The difference between the two treatment groups for Grade 3-4 complications was only significant for the teeth. The late toxicity assessment of a treatment may depend on the toxicity scale used. The LENT/SOMA scale seems to be the most accurate scale, but most of the score results were not concordant with those obtained with other scales. The results of this study confirm the necessity of using a common late toxicity scale in clinical trials.

RADIOTHERAPY WITH CONCOMITANT WEEKLY DOCETAXEL FOR STAGES III/IV OROPHARYNX CARCINOMA. RESULTS OF THE 98-02 GORTEC PHASE II TRIAL

PURPOSE We designed a prospective Phase II clinical trial to evaluate the addition of weekly chemotherapy using Docetaxel during standard radiation therapy in patients with Stages III and IV oropharynx carcinoma. METHODS A total of 63 patients have been entered in a Phase II multicenter trial. Radiotherapy delivered, with conventional fractionation, 70 Gy in 35 fractions. Patients received during the period of radiotherapy seven cycles of Docetaxel (20 mg/m2 each week). RESULTS Radiotherapy compliance was good in respect to total dose, treatment duration, and treatment interruption. The rate of Grade 3 and 4 mucositis was 84%. Grade 3 and 4 skin toxicity occurred in 53% of the patients. Hematologic toxicity was infrequent, with only a 5% rate of Grade 3 or 4 neutropenia. Three-year overall actuarial survival and disease-free survival rates were, respectively, 47% (95% CI = 39-68%) and 39% (95% CI = 30-57%). The local and regional control rate was 64%. CONCLUSION The adjunction of weekly Docetaxel to conventional radiotherapy is feasible. Mucositis and skin toxicity were the major acute toxic effects. Therapeutic results were similar to those observed with concomitant chemotherapy using platinum and/or 5-FU. Further trials using Docetaxel in combination with other cytotoxic agents are needed.

Preliminary data of the GORTEC 2000-02 phase III trial comparing intravenous and subcutaneous administration of amifostine for head and neck tumors treated by external radiotherapy☆

A prospective randomized study is comparing intravenous (IV; arm A) versus subcutaneous (SC; arm B) administration of amifostine in patients receiving radiotherapy for head and neck cancer. Main eligibility criteria were newly diagnosed squamous cell head and neck cancer, inclusion of at least 75% of both parotid glands within radiation fields that would receive at least 40 Gy, and no evidence of distant metastasis. Prophylactic use of pilocarpine and concomitant chemotherapy were prohibited. Intravenous administration of amifostine is 200 mg/m2/d in a short 3-minute infusion 15 to 30 minutes before each fraction of radiotherapy. Subcutaneous administration is 500 mg/d in two, slow 1.25-mL injections at two different sites 20 to 60 minutes before each radiotherapy fraction. Antiemetic treatment and blood pressure monitoring are required in both arms. As of April 25, 2002, 111 of the 292 required patients were included. Data are available for the first 54 patients. Acute toxicity included nausea/vomiting (12% for arm A; 13% for arm B), hypotension (6% in arm A; 0% in arm B), skin rash (15% in arm A; 16% in arm B), and asthenia (4% in arm A; 0% in arm B). Compliance with amifostine administration was 70% in arm A (IV) and 80% in arm B (SC). The rate of acute xerostomia (> or = grade 2) was 23% in arm A and 19% in arm B. These preliminary results indicate that tolerance is better with SC than IV administration, particularly because of the absence of hypotension. The absence of hypotension with SC administration facilitates patient monitoring and management in radiotherapy departments. More patients and data are required to assess the long-term efficacy of SC administration on acute and late xerostomia.