Accelerated radiotherapy and concomitant high dose chemotherapy in non resectable stage IV locally advanced HNSCC: results of a GORTEC randomized trial.

BACKGROUND: The objective was to evaluate the efficacy of a strong increase of the dose-intensity of concomitant radio-chemotherapy (RT-CT) in patients with far advanced non metastatic HNSCC. METHODS: Eligible patients had N3 disease (UICC 1997) and the primary tumor and/or the node(s) had to be strictly unresectable. Patients with palpable N2B-C were also eligible if massive nodal involvement was present. 109 patients were included, with 53 randomized to RT-CT and 56 to accelerated RT. In the RT-CT arm, the RT regimen consisted of 64Gy in 5weeks and the CT regimen consisted of synchronous CDDP 100mg/m(2) on days 2, 16, and 30 and 5FU 1000mg/m(2) on days1-5 and 29-33 of the RT course. After RT-CT, two adjuvant cycles of CDDP-5FU were delivered in good responders. A control arm was using a very accelerated RT, delivering 64Gy in 3weeks. RESULTS: The most common tumor sites were oropharynx and hypopharynx. Most of the patients had T4 disease (70%) and 100% had a massive nodal involvement (mainly N3 with a mean nodal size >7cm in both arms). A significant difference was observed in favor of the RT-CT arm (p=0.005) in terms of cumulative incidence of local regional failure or distant metastases. However, the overall survival and event free survival rates were not significantly different between the two arms (p=0.70 and 0.16, respectively). The lack of survival benefit in favor of the RT-CT was partly due to an excess of initial early treatment related death in the RT-CT arm. CONCLUSION: The very intense RT-CT schedule was more efficient on disease control, but was also more toxic than accelerated RT alone, pointing out that there was no clear improvement of the therapeutic index. This study shows the limits of dose-intensification, with regard to concomitant RT-CT.

Randomized phase III trial (GORTEC 98-03) comparing re-irradiation plus chemotherapy versus methotrexate in patients with recurrent or a second primary head and neck squamous cell carcinoma, treated with a palliative intent.

PURPOSE: This randomized phase III trial investigated the potential benefit of concurrent re-irradiation, fluorouracil and hydroxyurea versus methotrexate for patients treated with palliative intent for recurrent or second primary head and neck squamous cell carcinoma (HNSCC) in previously irradiated area. PATIENTS AND METHODS: Patients with recurrent HNSCC or a second primary not amenable to curative-intent treatment were randomized to the R-RT arm (concurrent re-irradiation, fluorouracil and hydroxyurea) or to the Ch-T arm (methotrexate). The primary endpoint was overall survival (OS). Due to a very slow accrual, the trial was closed after inclusion of 57 patients. RESULTS: Fifty-seven patients were included. All patients died in the two arms with a maximal follow-up of 5years. Although four complete responses were achieved in R-RT arm, (none in Ch-T arm) re-irradiation did not improve OS compared with methotrexate (23% versus 22% at 1year, NS). Sixteen patients experienced clinical grade ⩾3 late toxicities (>6months), 11 in R-RT arm and five in Ch-T arm. CONCLUSIONS: Premature discontinuation of the trial did not allow us to draw firm conclusions. However, there was no suggestion that concurrent re-irradiation, fluorouracil and hydroxyurea improved OS compared to methotrexate alone in patients treated with palliative intent for a recurrent or second primary HNSCC.

Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation.

BACKGROUND: Chemotherapy with cisplatin (P) and 5-fluorouracil (F) followed by radiotherapy in patients who respond to chemotherapy is an alternative to total laryngectomy for patients with locally advanced larynx and hypopharynx cancer. Data suggest that docetaxel (T) may add to the efficacy of PF. The objective of this trial was to determine whether adding T to PF could increase the larynx preservation rate. METHODS: Patients who had larynx and hypopharynx cancer that required total laryngectomy were randomly assigned to receive three cycles of TPF or PF. Patients who responded to chemotherapy received radiotherapy with or without additional chemotherapy. Patients who did not respond to chemotherapy underwent total laryngectomy followed by radiotherapy with or without additional chemotherapy. The primary endpoint was 3-year larynx preservation rate. Secondary endpoints included acute toxicities and overall response. All statistical tests were two-sided. RESULTS: Baseline patient and tumor characteristics were well balanced between the TPF (n = 110) and PF (n = 103) groups. With a median follow-up of 36 months, the 3-year actuarial larynx preservation rate was 70.3% with TPF vs 57.5% with PF (difference = 12.8%; P = .03). Patients in the TPF group had more grade 2 alopecia, grade 4 neutropenia, and febrile neutropenia, whereas patients in the PF group had more grade 3 and 4 stomatitis, thrombocytopenia, and grade 4 creatinine elevation. The overall response was 80.0% in the TPF group vs 59.2% in the PF group (difference = 20.8%; P = .002). CONCLUSIONS: In patients with advanced larynx and hypopharynx carcinomas, TPF induction chemotherapy was superior to the PF regimen in terms of overall response rate. These results suggest that larynx preservation could be achieved for a higher proportion of patients.

Achieving higher pathological complete response rates in HER-2-positive patients with induction chemotherapy without trastuzumab in operable breast cancer.

Recent trials of induction chemotherapy in bulky operable breast cancer have shown much higher pathological complete response (pCR) rates with trastuzumab-driven combinations. However, it is useful to take into account the specific chemosensitivity of HER-2-positive tumors. The aim of this study was to assess the pCR rate according to HER-2 status in response to chemotherapy, without an anti-HER-2 specific biological agent, in 710 operable breast cancer patients. Since 1982, these patients have been treated with several different neoadjuvant chemotherapy combinations. During this period, HER-2 overexpression was most often not assessed. Subsequently, we assessed HER-2 expression using archival paraffin-embedded tissue. A technically usable specimen was available for 413 of the 710 patients. Before treatment, 51 patients were HER-2 positive, 287 patients were HER-2 negative, and the results were inconclusive for 75 patients. Of these patients, a pCR in breast and nodes was obtained in 94 patients (14.3%), but this event was threefold more frequent for HER-2-positive patients (23.5%) than for HER-2-negative patients (7%). The overall survival (OS) and disease-free survival (DFS) rates at 10 years were 66.6% and 57.4%, respectively. The DFS rate was, as expected, better for HER-2-negative patients, with HER-2 status assessed before as well as after chemotherapy. A significant difference was found for OS in favor of HER-2-negative patients only with postchemotherapy assessment of HER-2, a fact similar to our previous findings. Finally, there was a tendency toward a higher DFS rate for HER-2-positive patients who achieved a pCR compared with HER-2-positive patients who did not.

Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial.

PURPOSE: With the aim to increase the dose intensity of radiation therapy (RT), and subsequently the locoregional control rate, a very accelerated RT regimen was compared with conventional RT in a series of patients with head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Between 1994 and 1998, 268 patients with T3 or T4, N0 to N3 HNSCC (staged by 1997 International Union Against Cancer criteria) that was not eligible for surgery were randomly assigned to receive either conventional RT, delivering 70 Gy in 7 weeks to the primary tumor and 35 fractions of 2 Gy over 49 days, or to receive very accelerated RT, delivering 62 to 64 Gy in 31 to 32 fractions of 2 Gy over 22 to 23 days (2 Gy/fraction bid). RESULTS: The most common tumor site was the oropharynx and most of the patients (70%) had T4 and N1 to N3 tumors in 72% of patients. The main patient and tumor characteristics were well-balanced between the two arms. The median total doses were 63 Gy (accelerated) and 70 Gy (conventional), with a median overall time of 22 days and 48 days, respectively. Acute mucositis was markedly increased in the accelerated-RT arm (P < .001). The locoregional control rate was improved by 24% at 6 years with accelerated RT. In contrast, disease-free survival and overall survival were not significantly different between the two arms. There was no difference in late effects between the two arms. CONCLUSION: The very accelerated RT regimen was feasible and provided a major benefit in locoregional control but had a modest effect on survival.

French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC-GORTEC).

BACKGROUND: Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis. Following a previous phase II study, this phase III multicenter trial was conducted between November 1997 and March 2002. METHODS: Nontreated, strictly unresectable cases were eligible. Twice-daily radiation: two fractions of 1.2 Gy/day, 5 days per week, with no split (D1-->D46). Total tumor doses: 80.4 Gy/46 day (oropharynx), 75.6 Gy/44 day (hypopharynx). Chemotherapy (arm B): Cisplatin 100 mg/m2 (D1, D22, D43); 5FU, continuous infusion (D1-->D5), 750 mg/m2/day cycle 1; 430 mg/m2/day cycles 2 and 3. RESULTS: A total of 163 evaluable patients. Grade 3-4 acute mucositis 82.6% arm B/69.5% arm A (NS); Grade 3-4 neutropenia 33.3% arm B/2.4% arm A (p < 0.05). Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months (p < 0.01). At 24 months, overall survival (OS), disease-free survival (DFS), and specific survival (SS) were significantly better in arm B. OS: 37.8% arm B vs. 20.1% arm A (p = 0.038); DFS: 48.2% vs. 25.2% (p = 0.002); SS: 44.5% vs. 30.2% (p = 0.021). No significant difference between the two arms in the amount of side effects at 1 and 2 years. CONCLUSION: For these unresectable cases, chemoradiation provides better outcome than radiation alone, even with an "aggressive" dose-intensity radiotherapy schedule.

Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck.

PURPOSE: To evaluate the efficacy and safety of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Ninety-six eligible patients received cetuximab (initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) followed by platinum chemotherapy at the same dose and schedule at which progressive disease was documented before entry onto the study. RESULTS: The response rate, based on an independently read assessment, in the intent-to-treat population was 10%, with a disease control rate (complete response, partial response [PR], and stable disease) of 53%. The median time to progression and overall survival were 85 and 183 days, respectively; both were longest in patients achieving a PR (median, 203.5 and 294 days, respectively). Treatment was well tolerated. The most common cetuximab-related adverse events were skin reactions, particularly an acne-like rash. CONCLUSION: The combination of cetuximab and platinum chemotherapy is an active and well-tolerated approach to the treatment of this poor-prognosis patient population with platinum-refractory recurrent or metastatic SCCHN for whom there are no recommended standard therapeutic options.

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.

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.

[Targeting of epidermal growth factor receptor and applications in ORL cancer]. / Ciblage du récepteur du facteur de croissance épidermique et applications en cancérologie ORL.

EGFR (epidermal growth factor receptor) is a transmembrane glycoprotein highly expressed in head and neck squamous cell carcinoma (HNSCC). Once triggered by ligands, tyrosine kinase located at their inner part is phosphorylated, initiating signal transduction pathways towards the nucleus. Two categories of EGFR inhibitors are affordable: the former group includes monoclonal antibodies whereas the latter regards tyrosine kinase inhibitors (ITK). Acting more as cytostatic than cytotoxic agents, they may potentiate both chemotherapy (CT) and radiation therapy (RT). Characterized by a spectrum of toxicity that does not overlap that of CT or RT, they may be associated with these treatments. First clinical trials have demonstrated the feasibility of their administration. Side-effects merely consist of skin reactions and digestive symptoms; their intensity is generally mild and they resolve at the completion of treatment. As of yet, response rates are sometimes astounding but are still disparate. Randomized studies are ongoing. A better definition of EGFR status is warranted. Other data regarding interactions between her-family members, ligands parameters and the cascade regulation of signal transduction would certainly enable to better define the clinical applications of this new therapeutical approach.

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 patient's 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.