Nicolas Daly-Schveitzer

Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial.

PURPOSE To report the final results of a prospective randomized trial that aimed to evaluate efficacy and toxicity of concomitant postoperative radiotherapy and Cisplatin infusion in patients with Stage III or IV squamous cell carcinoma of the head and neck and histological evidence of extracapsular spread of tumor in lymph node metastase(s). METHODS AND MATERIALS Radiotherapy was delivered using a daily dose of 1.7 Gy for the first 54 Gy and 1.8 to 2 Gy until the completion of the treatment. Cisplatin 50 mg i.v. with forced hydratation was given or not every week (i.e., seven to nine cycles) concurrently with radiotherapy. A total of 44 patients were treated by irradiation only (RT group) and 39 by irradiation with chemotherapy (CM group). RESULTS The RT group displayed a higher rate of loco-regional failures as compared to CM group (41 vs. 23%; p = 0.08). The overall survival, the survival corrected for deaths by intercurrent disease, and the disease-free survival were better in CM group as compared to RT group with statistically significant differences. Survival without loco-regional treatment failure was better in the CM group, the difference being close to the level of significance (p = 0.05). Survival without distant metastases were comparable in the two therapeutic groups. Ten severe late complications were observed, four in the RT group (17%) and six in the CM group (22%). Cox univariate analysis confirmed the importance of the therapeutic modality in predicting the overall survival, the survival corrected for deaths by intercurrent disease, and the disease-free survival. CONCLUSIONS The present final report of this phase III study confirms preliminary results. The concomitant use of 50 mg weekly Cisplatin infusion and postoperative radiation improved loco-regional control and survival. No significant increase of late radiation complications was observed in the CM group.

Impact of radiotherapy on local control and survival in uterine sarcomas: a retrospective study from the Grup Oncologic Català-Occità.

PURPOSE In order to provide more information for the clinician and to analyze the impact of radiation therapy on the loco-regional disease-free interval (LRFI), disease-free interval (DFI) and specific overall survival (OS), a multicentric retrospective study of uterine sarcomas has been undertaken using cases reported to the Grup Oncològic Català-Occità (GOCO). PATIENTS AND METHODS One hundred three patients were selected for this study with a median follow-up period of 49 months. Patients were restaged using the FIGO classification for endometrial adenocarcinoma. Radiotherapy was administered postoperatively to the entire pelvis in 52% of cases (54/103) and was combined with brachytherapy in 24 patients. Mean given dose was 48 Gy, with a 95% confidence interval of 45 to 50 Gy. Variables have been tested for homogeneity between hospitals. Univariate and multivariate analyses have also been carried out. RESULTS Mean age of the selected patients was 59 years (range 35-84). Stages were distributed as follows: 66 patients (64%) in Stage I; 16 in Stage II (15.5%); 12 in Stage III (11.5%); 9 patients in Stage IVa (9%). Pathological distribution was 41.5% leiomyosarcoma, 39% mixed Mullerian tumours, 16.5% stromal sarcomas, and 2.9% of a miscellaneous group. Overall survival for the entire group was 63.7% and 56% at 2 and 5 years, respectively. Probability of LRFI reached 59.8% at 2 years and 57.4 at 5 years. The DFI at 2 and 5 years were 52.9 % and 48.7%, respectively. The LRFI probability was 41% and 36% at 2 and 5 years, respectively, without radiotherapy and reached 76% at 2 and 5 years among those patients treated with radiotherapy. There was also an increase in DFI probability because of the effect of radiotherapy, from 35% to 68.5% and from 33% to 53% at 2 and 5 years, respectively. The overall survival probability for patients treated with radiotherapy was 76% and 73% at 2 and 5 years, respectively and 51% at 2 years and 37% at 5 years without radiotherapy. Multivariate analysis demonstrated that radiotherapy improved LRFI, DFI, and overall survival. CONCLUSION We conclude that postoperative radiotherapy in our series of patients diagnosed with uterine sarcoma has an impact on loco-regional and disease-free progression intervals and survival.

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.

The farnesyltransferase inhibitor FTI-277 suppresses the 24-kDa FGF2- induced radioresistance in HeLa cells expressing wild-type RAS

In this paper, we describe the effect of the inhibitor of farnesyltransferase (FTI-277) on radioresistance induced by the 24-kDa isoform of FGF2 in human cells expressing wild-type RAS. Treatment with FTI-277 (20 microM) for 48 h prior to irradiation led to a significant decrease in survival of radioresistant cells expressing the 24-kDa isoform (HeLa 3A) but had no effect on the survival of control cells (HeLa PINA). The radiosensitizing effect of FTI-277 is accompanied by a stimulation of postmitotic cell death in HeLa 3A cells and by a reduction in G(2)/M-phase arrest in both cell types. These results clearly demonstrate that at least one farnesylated protein is involved in the regulation of the radioresistance induced by the 24-kDa isoform of FGF2. Furthermore, the radiation-induced G(2)/M-phase arrest is also under the control of farnesylated protein. This work also demonstrates that FTase inhibitors may be effective radiosensitizers of certain human tumors with wild-type RAS.

Hyperfractionation in the reirradiation of head and neck cancers. Result of a pilot study

Abstract Between November 1988 and May 1992, 19 patients were enrolled in a pilot study to evaluate feasibility and results of a hyperfractionated reirradiation in the treatment of head and neck recurrences or second primary tumors developed in previously irradiated volume. Patients were divided in two groups according to the initial treatment before reirradiation: group 1 included 14 patients treated with radical surgery and reirradiated because histological evidence of positive margins and/or extra capsular spread of tumor in lymph node metastases; group 2 included five patients treated with three cycles of CDDP-5FU for unresectable tumors and reirradiated because they experienced a complete or good partial (≥80%) response after chemotherapy. The reirradiation planned dose was 60 Gy in 5 weeks, with two daily fractions of 1.2 Gy spaced by 6–8 h intervals. Reirradiation was delivered exclusively with photon beams in 17 cases and with a combination of photon and electron beams in two cases. Follow-up ranged from 3 to 45 months with a median of 17 months. Of the 19 patients, 13 received the reirradiation scheduled dose of 60 Gy. For the six remaining patients, the reirradiation doses ranged from 45.6 to 57.6 Gy. All patients experienced an acute mucositis which never led to interruption of treatment. Of the 14 patients of group 1, 10 died 3–41 months after reirradiation (mean: 14 months), three were disease-free 16–37 months after reirradiation and one patient was alive with local progressive disease 39 months after the reirradiation. The overall local control within reirradiated volume was 36% before and 43% after salvage surgery. For all group 1 patients, 12- and 24-month overall survival was 64 and 36%, respectively (mean: 21 months). All patients of group 2 presented a local failure within the reirradiated volume. Three of them died 12, 16 and 25 months after reirradiation, while two of them were alive with progressive disease 25 and 30 months after reirradiation, respectively. The mean survival was 22 months. Overall, 15 late complications were noted: five grade 1, eight grade 2 and two grade 3. There was no lethal complication. Four patients alive in September 1993, and whose initial technical files were available, were enrolled in an additional study to assess the cumulative doses delivered by the two irradiations. Despite disappointing loco-regional control rates, a reirradiation of 60 Gy using a hyperfractionated schedule is feasible in terms of acute and late toxicity.

Intraoperative interstitial iridium brachytherapy in the management of soft tissue sarcomas: preliminary results of a feasibility Phase II study

Between May 1986 and June 1992, 48 patients with soft tissue sarcomas underwent 50 intraoperative interstitial implants in conjunction with conservative tumoral resections. Brachytherapy was part of the initial treatment in 27 cases and was done in 21 other previously treated patients. For the last ones brachytherapy was, in most of the cases, the only treatment in addition to surgery. The implant dose was 40-65 Gy. When combined with external irradiation the mean prescribed dose was 20 Gy (12-25 Gy). With a median follow-up of 33 months, the 3-year actuarial survival rate was 81% and the local disease-free survival 91.7%. Five local failures were observed only in patients with recurrent sarcomas: two were inside the treated volume and three outside (local failure 5/48 = 10.4%). Acute side-effects occurred in 11 patients (11/48 = 23%), with skin breakdown (two cases) infection and hematoma (one case), infection, lymphocele, secondary skin breakdown and vascular rupture (one case), infection and limited skin breakdown (two cases) and delayed healing (five cases). As a consequence, six patients required reoperation but no amputation was necessary. The functional results were good. Only three patients had a moderate limitation of movement. Late complications occurred in five patients: bone fracture (one case), leg oedemas not interfering with normal activity (three cases), peripheral neuropathy fibrosis related requiring surgery (one case). Therefore, this preliminary report shows that adjuvant intraoperative brachytherapy is feasible and is safe in treating soft tissue sarcomas, even in previously irradiated patients. However, further evaluation is needed to determine the real place of intraoperative implant in the management of soft tissue sarcomas.

Second non-germ cell malignancies in patients treated for stage I-II testicular seminoma.

PURPOSE To measure the incidence of second non-germ cell malignancies (SNGCM) in patients treated for a stage I-II testicular seminoma. MATERIALS AND METHODS From 1970 to 1992, 131 evaluable patients received in the Institut Claudius Regaud a post-orchiectomy treatment for a stage I-II testicular seminoma. The therapeutic modalities, including salvage treatment for six recurrences, were as follows: infradiaphragmatic radiotherapy (IDRT) (n = 55); infra- and supradiaphragmatic radiotherapy (IDRT + SDRT) (n = 64); IDRT + SDRT with chemotherapy (n = 12). The mean follow-up was 11 years. The cumulative incidence of SNGCM was compared to the overall cancer incidence in the general male population on the basis of the Tarn Cancer Registry; the relative risk was expressed as a standardized incidence ratio (SIR). RESULTS Overall, the cumulative incidence of SNGCM was 10.7% (14/131 cases). The SIR was equal to 2.81 (95% confidence interval (CI) 1.54-4.72; P < 0.001) and increased with follow-up duration. The SIR was significantly increased in 64 patients treated with IDRT + SDRT (SIR = 3.08; 95% CI 1.47-5.66; P = 0.002) but not in 55 patients treated with IDRT alone (SIR = 0.62; 95% CI 0.01-3.43; P = 0.8). The 12 patients who received chemotherapy had an SIR of 26.2 (95% CI 5.48-77.69; P < 0.001), while the SIR was 2.26 in the 119 patients who did not receive any chemotherapy (95% CI 1.13-4.04; P = 0.01 ). Of four hematologic malignancies, three appeared in the 12 patients who received chemotherapy. CONCLUSIONS An increased risk of SNGCM after SDRT + IDRT has been demonstrated. After IDRT alone, the risk of second cancer is not incremented after a median follow-up of 6 years, but further observation of the patients is necessary to achieve final conclusions. Our results suggest that the risk of second cancer and especially of hematologic malignancy is increased by the association of chemotherapy and radiation.

Radiotherapy of stage I and II carcinomas of the mobile tongue and/or floor of the mouth.

From 1977 to 1990, 94 evaluable patients were treated with iridium-192 implantation in the Centre Claudius Regaud for a Stage I (52 patients) or a Stage II (42 patients) squamous cell carcinoma of the mobile tongue and/or the floor of the mouth. Interstitial brachytherapy was associated with external irradiation in 68 patients (group 1; mean dose, 48 Gy for external irradiation, 26 Gy for brachytherapy) or was exclusive in 26 patients (group 2; mean dose, 66 Gy). The mean follow-up was 44 months. Eleven acute complications were noted during or immediately after the implant (1 lethal myocardial infarction, 6 hematomas of the tongue which spontaneously resolved, 3 local sepsis). The mean duration of the mucositis was 9 weeks (from 4 to 20 weeks). Ten patients (17%) experienced a late complication (8 in group 1, 2 in group 2): 3 bone necroses requiring hemimandibulectomy (1 post-operative death), 1 tongue necrosis treated by a transoral mucosal excision, 6 bone expositions which recovered after medical treatment. Local control rates for T1 and T2 tumors were 75% (39/52) and 51% (21/41), respectively. Sixteen patients (17%) presented a nodal relapse which was associated in 6 cases with a concomitant local relapse. The local control rate of T1 tumors was 64% (23/36) in group 1 versus 100% (16/16) in group 2 (p < 0.01). For T2 tumors, these figures were 45% (14/31) and 70% (7/10), respectively (p > 0.3). The influence of 13 parameters on the local control was studied in analysis. In the one model analysis, a cox regression tumor size was significantly predictive of actuarial local recurrence (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

A phase I trial combining oral cisplatin (CP Ethypharm) with radiotherapy in patients with locally advanced head and neck squamous cell carcinoma

PURPOSE To determine the maximum tolerated dose (MTD) of oral cisplatin (CP Ethypharm®) in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC) and the recommended dose for phase II trials. PATIENTS AND METHODS Phase I, multicenter, open-labelled, non-comparative and dose escalating trial. CP Ethypharm® was administered on five consecutive days every other week for 7 weeks (4 treatment cycles) in combination with radiotherapy. Eighteen patients with locally advanced HNSCC were allocated to four cisplatin dose levels: 10 mg/m(2)/day: 4 patients; 15 mg/m(2)/day: 4, 20 mg/m(2)/day: 5 and 25 mg/m(2)/day: 5. The inclusion of patients was dictated by occurrence of dose limiting toxicities (DLTs) at each dosing level. RESULTS The most frequently experienced AEs were gastrointestinal (GI) disorders. Five DLTs were observed, including three at 25 mg/m(2) level (two grade 2 renal toxicities, one grade 3 GI and renal toxicities), one at 20 mg/m(2) level (grade 3 GI disorders), one at 10 mg/m(2) level (grade 4 mucositis). PK analysis showed no significant difference of C(max) values between day 1 and day 5 of treatment at each dose level (total & ultrafilterable platinum). CONCLUSION Due to 3 DLTs experienced at 25 mg/m(2)/day, MTD was reached and the recommended dose for phase II studies was determined as 20 mg/m(2)/day.

Phase I trial of oral etoposide in combination with radiotherapy in head and neck squamous cell carcinoma - GORTEC 2004–02

PurposeThis study sought to determine the maximum tolerated dose (MTD) of oral etoposide in combination with radiotherapy in head and neck squamous cell carcinoma (HNSCC).Patients and MethodsPhase I, multicenter, open-labelled, non-comparative and dose escalating trial. Patients with locally advanced HNSCC were enrolled onto cohorts of escalating dose of etoposide. Oral etoposide was administered on five consecutive days every week for 7 weeks (7 treatment cycles) in combination with daily radiotherapy (70 Gy /35 fractions). Two dose levels (25 mg/day and 50 mg/day) of etoposide were planned and three to six patients were to be enrolled at each level according to the potential DLTs.ResultsFourteen patients were allocated to two dose levels: 25 mg/day (3) and 50 mg/day (11). Cisplatin was contra-indicated in all the patients included. Only one patient (50 mg/day) presents a grade 4 neutropenia (DLT), no other DLTs were observed. The most frequently adverse events (AEs) were radiomucositis. Two deaths before 3 months of end of treatment were not related to treatment. Seven patients were still alive with a median follow-up of 30 months (12–58 months). Nine patients had a complete response (CR) at 3 months after the radiotherapy; Among the 9 patients, 3 patients had a local relapse; one patient with local and distant relapse.ConclusionDue to only one DLT experienced, it is possible to a dose of 50 mg/day for phase II studies, however this should be considered with caution.