F. Janot

Induction Chemotherapy Followed by Either Chemoradiotherapy or Bioradiotherapy for Larynx Preservation: The TREMPLIN Randomized Phase II Study

PURPOSE To compare the efficacy and safety of induction chemotherapy (ICT) followed by chemoradiotherapy (CRT) or bioradiotherapy (BRT) for larynx preservation (LP). PATIENTS AND METHODS Previously untreated patients with stage III to IV larynx/hypopharynx squamous cell carcinoma received three cycles of ICT-docetaxel and cisplatin 75 mg/m(2) each on day 1 and fluorouracil 750 mg/m(2) per day on days 1 through 5. Poor responders (< 50% response) underwent salvage surgery. Responders (≥ 50% response) were randomly assigned to conventional radiotherapy (RT; 70 Gy) with concurrent cisplatin 100 mg/m(2) per day on days 1, 22, and 43 of RT (arm A) or concurrent cetuximab 400 mg/m(2) loading dose and 250 mg/m(2) per week during RT (arm B). Primary end point was LP at 3 months. Secondary end points were larynx function preservation (LFP) and overall survival (OS) at 18 months. RESULTS Of the 153 enrolled patients, 116 were randomly assigned after ICT (60, arm A; 56, arm B). Overall toxicity of both CRT and BRT was substantial following ICT. However, treatment compliance was higher in the BRT arm. In an intent-to-treat analysis, there was no significant difference in LP at 3 months between arms A and B (95% and 93%, respectively), LFP (87% and 82%, respectively), and OS at 18 months (92% and 89%, respectively). There were fewer local treatment failures in arm A than in arm B; salvage surgery was feasible in arm B only. CONCLUSION There is no evidence that one treatment was superior to the other or could improve the outcome reported with ICT followed by RT alone (French Groupe Oncologie Radiothérapie Tête et Cou [GORTEC] 2000-01 trial [Induction CT by Cisplatin, 5FU With or Without Docetaxel in Patients With T3 and T4 Larynx and Hypopharynx Carcinoma]). The protocol that can best compare with RT alone after ICT is still to be determined.

Treatment of Early-Stage Glottic Cancer by Transoral Laser Resection

Objectives: We reviewed outcomes of treatment of early glottic carcinoma by transoral laser resection. Methods: We performed a retrospective study of tumor stage, type of cordectomy (European Laryngological Society), resection margins, local control, and laryngeal preservation. Results: Of 142 patients treated with curative intent, 79 (92% male; average age, 63 years) were retained for this study, on the basis of availability of information regarding resection margins, the absence of adjuvant radiotherapy, and follow-up of at least 2 years. The tumors were classified pTis (n = 21), pT1a (n = 51), or pT1b (n = 7) and were treated by cordectomy types I (23%), II (30%), III (27%), IV (6%), and V (14%). The average follow-up was 56 months (range, 24 to 150 months). The overall 5-year actuarial recurrence-free survival rate was 89%, and the 5-year actuarial disease-specific survival rate was 97.3%. There were 11 local recurrences (14%); 7 were treated by another laser resection, 1 by radiotherapy, 1 by supracricoid partial laryngectomy, and 2 by total laryngectomy. The overall rate of final local control with the laser alone was 100% for patients with initially positive margins, 95% for those with initially suspicious margins, and 94% for those with free margins. The overall rate of organ preservation was 100% for patients with positive or suspicious margins and 96% for those with free margins. Margin status (p = .39), cordectomy type (p = .67), and anterior commissure involvement (p = .16) were not statistically related to recurrence (Kaplan-Meier calculations with nonparametric univariate analysis). The recurrence rate was significantly higher for T1b tumors, however (p = .001). Conclusions: Laser microresection provides high rates of local control and organ preservation for early glottic cancer. Positive or suspicious margins were not related to recurrence, nor was anterior commissure involvement. This study implies that suspicious margins can be managed with a “watch-and-wait” attitude. Re-treatment with laser, external partial laryngectomy, and radiotherapy remain therapeutic options for recurrences.

Potential doubling time and clinical outcome in head and neck squamous cell carcinoma treated with 70 GY in 7 weeks

PURPOSE To study the predictive value of pretreatment potential doubling time and labeling index, as measured by flow cytometry in patients with head and neck squamous cell carcinoma treated with conventional radiotherapy. METHODS AND MATERIALS 70 patients with a squamous cell carcinoma of the oropharynx and 4 patients with another involved head and neck site were entered in this prospective study. The duration of the S phase (TS), the labeling index (LI), and the potential doubling time (Tpot) were obtained by flow cytometry measurements of a tumor biopsy obtained after i.v. injection of 200 mg bromodeoxyuridine to the patient. The treatment consisted of 70 Gy in 7 weeks, 2 Gy per fraction and five fractions per week. RESULTS The mean and median LI were 7.7% (standard deviation, SD: 5.0) and 6.3%, respectively. The mean and median TS were 9.3 h (SD: 3.6) and 8.3 h, respectively. The mean and median Tpot were 5.6 days (SD: 5.4) and 4.6 days, respectively. No significant relationship was found between the Tpot or LI and the tumor stage (T), nodal status (N), histological grade, and the site of the primary within the oropharynx. The only parameter significantly associated with an increased risk of local relapse was the tumor stage (p < 0.001). The mean Tpot for the group of tumors that relapsed locally was 5.3 days (SD: 3.3), compared to 6.1 days (SD: 4.08) for those who did not relapse locally (NS). Two parameters were significantly associated with a decrease in disease-free (DFS) and overall survival, namely the tumor stage (p < 0.005, and p < 0.001, respectively, for DFS and overall survival) and nodal involvement (p = 0.02 and (p < 0.005, respectively, for DFS and overall survival). The TS, LI, DNA index, and Tpot were not significantly associated with local relapse, DFS, and survival, either in the univariate or in the multivariate analysis. CONCLUSIONS The method used to evaluate tumor cell kinetics did not provide clinically relevant kinetic parameters for this type of cancer. The classic prognostic factors (tumor stage and nodal status) were strongly associated with clinical outcome.

Rapid tumor cell proliferation after induction chemotherapy in oropharyngeal cancer

Tumor cell kinetics were studied in vivo in a series of 97 patients with oropharyngeal cancer. The duration of S phase (tS), the labeling index (LI), and the potential doubling time (Tpot) were obtained by flow cytometry measurements of a tumor biopsy obtained after intravenous injection of 200 mg 5‐bromodeoxyuridine to the patient. The mean LI was 9.7% (standard deviation [SD], 5.4), the mean tS was 10.1 hours (SD, 3.6), and the mean Tpot was 4.6 days (SD, 3.5). No significant relationship was found between the Tpot or LI and the size of the tumor, nodal status, histological grade, or the site of the primary within the oropharynx. Conversely, aneuploid tumors had longer tS (P<.001), higher LI (P<.001), and shorter Tpot (P<.05) than the diploid tumors. The mean LI and Tpot of the tumors obtained after induction chemotherapy were significantly higher and shorter, respectively, than those measured before any treatment. The data strongly suggest that rapid tumor cell proliferation frequently occurs in oropharyngeal cancer which had responded poorly to chemotherapy.

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.

In vivo measurement of the potential doubling time by flowcytometry in oropharyngeal cancer treated by conventional radiotherapy

PURPOSE Experimental and clinical studies suggest that the pre-treatment potential doubling time could be predictive of tumor control in patients treated by conventional radiotherapy and could help to identify the rapidly growing tumors for which accelerated radiotherapy is required. METHODS AND MATERIALS To test this hypothesis, we studied prospectively 48 patients with a squamous cell carcinoma of the oropharynx and treated by conventional radiotherapy (70 Gy/7 weeks). The duration of S phase, the labeling index and the potential doubling time were obtained by flowcytometry measurements of a tumor biopsy obtained after injection of 200 mg bromodeoxyuridine to the patient. RESULTS Three parameters were significantly associated with an increased risk of relapse namely the tumors size (T4; p < 0.01), the nodal status (> or = N2; p < 0.05) and the site of the primary within the oropharynx (p = 0.08). The S phase, labeling index, DNA index and potential doubling time were not significantly associated with an increased risk of relapse. However when considering only the T2 subgroup of patients, high labeling indexes and short potential doubling time were associated with an increased risk of relapse: the mean pre-treatment potential doubling time of the tumors which relapsed was 3.21 versus 5.5 days when there was no evidence of local relapse (p < 0.05). The mean labeling index for the group of tumors associated with a tumor recurrence was 11.7% compared to 7.3% when there was no evidence of relapse (p = 0.02). CONCLUSION Factors other than proliferation play a role in determining the outcome of oropharyngeal cancers treated by conventional radiotherapy. However there was a significant correlation between short potential doubling time, high labeling index and tumor recurrence in the T2 subgroup of patients. The finding of significance for potential doubling time and labeling index in the T2 subset of tumors may be a reflexion of the more homogeneous nature of these tumors with regard to prognostic variables.

Sentinel node biopsy in early oral squamous cell carcinomas: A 10‐year experience

To evaluate the reliability of the sentinel node (SN) biopsy in early oral squamous cell carcinomas.

Treatment of the N0 neck during salvage surgery after radiotherapy of head and neck squamous cell carcinoma.

The morbidity and mortality rates of salvage surgery in patients with local recurrence of head and neck squamous cell carcinoma (HNSCC) after radiotherapy are high. The aim of this study was to determine the rate of occult neck node metastasis and the surgical morbidity of patients after salvage surgery for local relapse after definitive radiotherapy.

Subtotal laryngectomy with cricohyoidopexy as first treatment procedure for supraglottic carcinoma: Institut Gustave-Roussy experience (146 cases, 1974-1997).

Patients and methods: Between 1974 and 1997, 297 patients underwent a subtotal laryngectomy at the Institut Gustave-Roussy; 146 of these patients underwent cricohyoidopexy (CHP) for a supraglottic primary as their first treatment. The majority of patients were men (137) aged from 33 to 78 years (median 54 years). The tumour stage at presentation was T1 in 2, T2 in 87, T3 in 53 (pre-epiglottic space involvement), and T4 (minimal thyroid cartilage invasion) in 4 patients. One hundred and twenty-five patients were N0 (86%) and 21 patients were Np (palpable); 98% had homolateral and 55% had bilateral neck dissections. Results: One patient died postoperatively of a myocardial infarction and 68% patients had an uneventful course. Aspiration was the commonest complication (23 patients, 19%). The median time to removal of the tracheotomy cannula was 10 days and for the nasogastric tube 21 days during the past 10 years. Completion of subtotal laryngectomy into total laryngectomy was done in 21 cases (15%): eight times because of oncological events [five local failures, two second primary (hypopharynx), one positive margin] and 13 times because of aspiration (9%). There were six local failures (4%) and eight nodal failures (5%). The rates of distant metastases and second primaries were 6% and 16% respectively. Half of the local and nodal failures were subsequently sterilized. Findings at death were two local recurrences, four nodal recurrences, eight distant metastases, and 11 second primaries. The 3- and 5-year overall survival rates were 92% and 88% respectively, with an overall laryngeal preservation rate of 86%. Conclusion: When supraglottic laryngectomy is not feasible for supraglottic cancer, subtotal laryngectomy with CHP is a safe and effective oncological procedure, with preservation of satisfactory laryngeal function.

In vitro parameters and treatment outcome in head and neck cancers treated with surgery and/or radiation: Cell characterization and correlations with local control and overall survival

PURPOSE To determine whether in vivo parameters (surviving fraction at 2 Gy, alpha values, and calculated cell growth fraction) were predictive of the treatment outcome. METHODS AND MATERIALS Biopsies were obtained from patients with a head and neck tumor. In vitro parameters were determined using the CAM plate assay. Cell characterization by cytogenetic analysis was performed on 19 different cell cultures. In 25 additional cell cultures, cell clonogenicity was tested using the Courtenay Mills assay. RESULTS Biopsies were obtained from 156 patients with a head and neck tumor and the oropharynx was the predominant primary site. In vitro parameters were obtained in 113 cases (72%) (SF2 in 93 cases and calculated cell growth fraction in 103 cases). Cell characterization showed that cells in CAM plates were diploid with no clonal chromosome abnormalities and gave colonies in soft agar with a mean cloning efficiency of 1.610(-3). Only patients treated with surgery and/or radiation (76), were considered eligible for in vitro parameters and treatment outcome correlation studies. The mean follow-up is over 2 years (range 9-47 months). The local control rate was significantly higher (p = 0.04) for patients with alpha values above the cut-off point of 0.07 Gy-1 (69% vs. 38% at 2 years). The local control rate was also significantly higher (p = 0.04) for patients with calculated cell growth fraction values about the cut-off point of 0.06% (70% vs. 48% at 2 years). Moreover for these latter patients the overall survival rate was also significantly higher (p = 0.004) (54% vs. 26% at 2 years). It is worth noting that alpha and calculated cell growth fraction values below the cut-off points identified a small group of patients (about 20%) who were at a significantly high risk of local failure. From a pragmatic point of view, as only radiosensitivity or calculated cell growth fraction values could be obtained in a certain number of experiments due to technical reasons, the treatment outcome of patients who had either alpha and/or calculated cell growth fraction values below the cut-off levels (about 30% of all patients) was analyzed. This group of patients fared significantly worse (p = 0.02) in terms of local control (50% vs. 68% at 2 years) and (p = 0.04) overall survival (36% vs. 50% at 2 years). CONCLUSION These results suggest that in vitro parameters using the CAM plate assay, might be useful in predicting the treatment outcome of patients with a head and neck tumor treated with surgery and postoperative radiation, or radiation alone. However, they must be considered as preliminary because the cut offs used in the study were chosen for exploratory purposes. Only a multivariate analysis including all clinical and biologic factors will allow us to draw any firm conclusions.