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Purpose: Conservative treatment of soft tissue sarcomas most often implies combination of surgical resection and irradiation. The aim of this study was to evaluate low-dose-rate intraoperative brachytherapy, delivered as a boost, in the local control of primary tumors, with special concern about treatment complications. Methods and Materials: Between 1986 and 1995, 112 patients underwent intraoperative implant. This report focuses on the group of 58 patients with primary sarcomas treated by combination of conservative surgery, intraoperative brachytherapy, and external irradiation. Most of the tumors were located in the lower limbs (46/58—79%). Median size of the tumor was 10 cm, most of the lesions being T2–T3 (51/58—88%), Grade 2 or 3 (48/58—83%). The mean brachytherapy dose was 20 Gy and external beam irradiation dose 45 Gy. In 36/58 cases, iridium wires had to be placed on contact with neurovascular structures. Results: With a median follow-up of 54 months, the 5-year actuarial survival was 64.9%, with a 5-year actuarial local control of 89%. Of the 6 patients with local relapse, 3 were salvaged. Acute side effects, essentially wound healing problems, occurred in 20/58 patients, late side effects in 16/58 patients (7 neuropathies G2 to G4). No amputation was required. The only significant factor correlated with early side effects was the location of the tumor in the lower limb ( p = 0.003), and with late side effects the vicinity of the tumor with neurovascular structures ( p = 0.009). Conclusion: Brachytherapy allows early delivery of a boost dose in a reduced volume of tissue, precisely mapped by the intraoperative procedure. Combined with external beam irradiation, it is a safe and efficient treatment technique leading to high local control rates and limited functional impairment.

Resume L'association chirurgie-radiotherapie postoperatoire est le traitement de reference de nombreux cancers des voies aerodigestives superieures. Les echecs de ce traitement sont surtout, mais non exclusivement, locoregionaux. Les parametres histologiques permettent d'identifier les tumeurs a haut risque de rechute. La revue des donnees disponibles indique que la chimiotherapie, delivree de facon concomitante a la radiotherapie, est susceptible d'ameliorer le controle locoregional chez ces patients. Cela devra etre confirme par les essais en cours, de meme que l'eventuelle efficacite d'une polychimiotherapie sur la prevention du risque metastatique.

Purpose: To determine the effect of low-dose splenic irradiation on severe Zidovudine-resistant, HIV-1–associated thrombocytopenia (HAT). Methods and Materials: Between September 1994 and October 1996, 17 patients were included in a prospective study. The patients met the following criteria for inclusion: hemorrhagic symptoms or a platelet count below or equal to 50 × 10 9 /l and normal numbers of megakaryocytes on bone aspiration. The mean baseline platelet count was 20.3 (± 14.4) × 10 9 /l; four patients had a platelet count inferior to 10 × 10 9 /l. Splenic volume was defined by ultrasonography. A total dose of 9 Gy was given using an isocentric parallel pair field technique. Results: One month after the end of treatment six patients had a significant rise in their platelet count. Clinically, hemorrhagic symptoms stopped for all patients that were symptomatic. Unfortunately, duration of response was short because for one patient only the platelet count remains stable with a follow-up of 6 months. All patients are alive and in recent evaluation, with four out of eight patients receiving a combination of antiretroviral therapy had a platelet count above 50 × 10 9 /l. Conclusion: Our results are disappointing concerning the duration of response, especially comparatively to those reported in autoimmune thrombocytopenia. Mechanisms of HAT are more complex, and megakaryocytes' infection may play an important role. Splenic irradiation should be considered as palliative treatment for the minority of patients with severe bleeding that does not respond to standard medical treatment.

Resume But de l'etude Entre novembre 1988 et mai 1992, 14 patients ont participe a une etude pilote dans le but d'evaluer la faisabilite d'une reirradiation hyperfractionnee sur des recidives ou des seconds cancers developpes en volume irradie. Materiel et methodes Chaque patient inclus dans l'etude avait fait l'objet d'une intervention chirurgicale et, en raison de marges envahies et/ou d'adenopathies en rupture capsulaire, une reirradiation leur a ete proposee au cours de laquelle une dose de 60 Cy a ete delivree en 5 semaines a raison de deux seances quotidiennes de 1,2 Gy espacees d'au moins 6 heures. Resultats Sur les 14 patients, dix ont termine leur irradiation. Tous les patients ont eu une reaction muqueuse ne necessitant pas d'interruption de la radiotherapie. Dix patients sont decedes entre 3 et 41 mois apres la fin de la reirradiation (moyenne: 14 mois), trois etaient en remission clinique complete au moment de l'analyse, soit 48 et 71 mois apres la reirradiation, et un patient etait vivant 74 mois apres la reirradiation mais avec une poursuite evolutive. Le taux de controle local en volume irradie etait de 43 %. Les taux de survie globale a 2 et 3 ans etaient respectivement de 50 et 35 %. Treize complications tardives ont ete observees: quatre de grade 1, sept de grade 2 et deux de grade 3. Chez trois patients (ceux vivants lors du recueil des donnees) ont pu etre realises des histogrammes dose-volume et ainsi determineees les doses cumulees des deux irradiations. Conclusion En depit de resultats carcinologiques mediocres, il est possible de delivrer 60 Cy selon un schema hyperfractionne sans crainte de complications rhedibitoires.

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 histological evidence of extracapsular spread of tumor in lymph node metastases(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 comfirned the importance of the therapeutic modality in predicting the overall surviva, 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 loc-regional control and survival. No significant increase of laet radiation complications was observed in the CM group.

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 11(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 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 p = 0.06). The other variables (age, sex, anatomic site, macroscopic aspect of the tumor, pathologic differentiation, technique of implant, intersource spacing and dose rate) had no significant influence. This retrospective study suggests that exclusive brachytherapy is the best modality in terms of local control and functional results.

To measure the incidence of second non-germ cell malignancies (SNGCM) in patients treated for a stage I-II testicular seminoma.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).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; P0.001) 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; P0.001), 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.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.

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.

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 548=10.4%). Acute side-effects occurred in 11 patients (1148 = 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.

Duration of the G 2 -phase delay and arrest after exposure to ionizing radiation is thought to influence radiosensitivity. The kinase activity of the p34 cdc2 -cyclin B complex and the p34 cdc2 -cyclin A complex is implicated in G 2 - to M-phase transition and in G 2 -phase arrest after exposure to ionizing radiation. We analyzed the expression level and the subcellular location of p34 cdc2 , cyclin A and cyclin B in head and neck squamous cell carcinoma (SCC) tumors; samples were obtained from patients with locally nonrecurrent and recurrent tumors that had been treated by surgery and radiotherapy. No significant difference was noticed in cyclin A, cyclin B and p34 cdc2 expression. However, we noted a significant preferential cytoplasmic location of p34 cdc2 in recurring tumors compared to the nonrecurring ones (P < 0.001). This abnormal location of p34 cdc2 occurs even in primary tumors in patients with recurring tumors, suggesting that a default in the activation of p34 cdc2 kinase could be implicated in clinical radioresistance.

After exposure to ionizing radiation, eukaryotic cells undergo a G2 delay which contributes to the ability of cells to survive irradiation. For some radioresistant cell lines, this delay is prolonged. Entry of cells into mitosis is regulated by a complex of two proteins cyclin B, and the serine-threonine p34cdc2 kinase. When this complex is activated, it undergoes a transport from cytoplasm into the nucleus and phosphorylates proteins which lead to mitosis. P34cdc2 kinase is activated by binding to cyclin B and by phosphorylation/dephosphorylation of p34cdc2. Since G2 delay after irradiation has been correlated with a rapid inhibition of p34cdc2 activity and an enhanced tyrosine phosphorylation, we hypothesized that radioresistant tumors could have a lack in regulation of p34cdc2 kinase activity. In this study, we entered 32 patients treated, from 1983 through 1989 at the Claudius Regaud Center, for head and neck squamous cell carcinoma by surgery and standard post-operative doses of radiotherapy. The paraffin embedded tumor specimens had been sampled before radiotherapy for long term controlled patients (n = 7) and before and after radiotherapy for patients who had developed a recurrence in the irradiation fields (n = 25). Immunohistochemical staining was performed with monoclonal antibodies against p34cdc2 (sc-54) and cyclin B (sc-245). A semi-quantitative score was used. For p34cdc2 analysis, no difference in intensity of staining was observed between long term controlled patients and those who recurred or, when there was a recurrence before and after radiotherapy. However, there was a highly significant difference (P