Effect of temozolomide on male gametes: an epigenetic risk to the offspring?

INTRODUCTION: Temozolomide is an oral alkylating agent with proven efficacy in recurrent high-grade glioma. The antitumour activity of this molecule is attributed to the inhibition of replication through DNA methylation. However, this methylation may also perturb other DNA-dependent processes, such as spermatogenesis. The ability to father a child may be affected by having this treatment. Here we report a pregnancy and a baby born after 6 cures of temozolomide. METHODS: The quality of gametes of the father has been studied through these cures and after the cessation of treatment. Sperm parameters, chromosomal content and epigenetic profiles of H19, MEST and MGMT have been analysed. RESULTS: Sperm counts decrease significantly and hypomethylation of the H19 locus increase with time even staying in the normal range. CONCLUSION: This is the first report of an epigenetic modification in sperm after temozolomide treatment suggesting a potential risk for the offspring. A sperm cryopreservation before the initiation of temozolomide treatment should be recommended.

[Progress in radiation therapy and integration in Tenon hospital (AP-HP) of new advances in routine practices of radiotherapy for non-small-cell lung cancer]. / Evolution de la radiothérapie externe et intégration à l'hôpital Tenon (AP-HP) des innovations technologiques récentes dans la pratique de la radiothérapie externe des carcinomes bronchiques non à petites cellules.

Much progress has been made in recent years in administration modalities for external radiotherapy of non-small-cell lung carcinoma. Three-dimensional conformal radiotherapy with or without intensity modulation, with respiratory gated radio-therapy (4D radiotherapy), and image-guided radiotherapy (IGRT) can be considered as a third revolution in radiation therapy after total dose fractionation and the development of megavoltage radiation therapy equipment. We describe progress in the three-dimensional radiotherapy technique and the integration of this technique in the department of Radiation Oncology at Tenon hospital (AP-HP).

[Ductal carcinoma in situ treated with radiation therapy and additional boost]. / Carcinomes canalaires in situ du sein traités par chirurgie conservatrice et irradiation avec complément dans le lit opératoire.

PURPOSE: Women with ductal carcinoma in situ are treated with breast-conserving surgery and radiation therapy. The impact of an additive boost radiation is under evaluation. PATIENTS AND METHODS: All women treated for ductal carcinoma in situ with breast-conserving surgery and whole breast radiation therapy at a total dose of 45Gy with a boost radiation from 1990 to 2008 have been included in this retrospective monocentric retrospective study. RESULTS: We included 171 patients. Boost radiation to the surgical bed was delivered by brachytherapy in 66 patients (39%), by direct en-face electron beam in 86 patients (50%), and by tangential fields using photon beams in 19 patients (11%). Median follow-up was 95.1months. Eight local relapses (4.6%) have occurred. The 10-year local recurrence-free survival rate was 97%. The 10-year overall survival rate was 98%. On multivariable analysis, brachytherapy (P=0.05; HR=5.15; IC=1-26.3) was associated with a reduction risk of local recurrence-free survival. CONCLUSION: In our experience, women treated for a ductal carcinoma in situ with breast-conserving surgery and whole breast radiation therapy with a boost radiation have a high 10-year local recurrence-free survival rate.

[Postoperative radiotherapy after complete resection of stage II (N1) non-small-cell lung cancer: reasons for not proposing it]. / La radiothérapie post-opératoire dans les cancers bronchiques non à petites cellules en résection complète stade pathologique II (N1). Des arguments pour ne pas la proposer.

Postoperative external radiation in non-small-cell lung cancer has remained a topic of debate since the first randomized study examining the potential contribution of postoperative radiotherapy published more than 35 years ago and despite a recent meta-analysis published in 1998 that included 9 randomized prospective studies. Among the 4 eligible randomized studies including non-small-cell lung cancer patients in complete remission of stage II (N1) disease, none demonstrated a significant advantage on survival. In addition, some of these studies disclosed an apparently deleterious effect after postoperative radiotherpy. Although the modalities and the technical quality of radiotherapy and surgical resection were different for the different studies or within a given study, or in some of the older studies even obsolete, and although the precision of the outcome evaluation can be criticized, there is currently no argument for proposing postoperative radiotherapy as a routine systematic practice with conventional methods of bidimensional dosimetric planification after complete surgical resection with good quality mediastinal node dissection for non-small-cell lung cancer patients with stage II (N1) disease. However, the contribution of postoperative radiotherpy with sufficient means for performing tridimensional conformational radiotherapy with individual optimization of computerized dosimetric planification taking into account the residual respiratory function after surgery remains to be evaluated in randomized prospective studies with rigorous control of the technical quality of the surgical resection and the radiotherapy and a precise statistical analysis of the locoregional and distant events in case of incomplete surgical resection and in more advanced stage disease (parietal T3, N0, stage III N2).

[New administration modalities for radiotherapy in lung cancer]. / Les nouvelles modalités d'administration de la radiothérapie dans les cancers broncho-pulmonaires.

Much progress has been made in recent years in administration modalities for radiotherapy for lung cancer. Exposure time to external irradiation was the first parameter to be modified: hyperfractionated radiotherapy, hyperfractionated accelerated radiotherapy with or without concomitant irradiation, synchronous or asynchronous protocols, split course radiotherapy. Radiosensitizing agents have also been the subject of much research: radiosensitization of hypoxic cells, modifiers of the biological response, concomitant radiochemotherapy. The main drugs used are 5-fluorouracil, platinum salts, etoposide, hydroxyurea, taxanes, topotecan, vinorelbin, and gemcitabine. Outcome with these combinations is discussed, both for non-small-cell and small-cell lung cancer. 3D conformational radiotherapy can enable increased dosing in the tumoral target while better preserving healthy tissues. High dose endoluminal brachytherapy is used particularly as a palliative treatment for bronchial obstructions or as curative treatment for weakly infiltrative small endoluminal tumors.

[Dropped Head Syndrome after whiplash injury in a patient treated for a Hodgkin's lymphoma by mantle field radiotherapy]. / Syndrome de la tête tombante après traumatisme cervical dans le cadre d'un lymphome de Hodgkin irradié en mantelet.

The authors report a case of Dropped Head Syndrome with an unusually rapid onset after an accident in a patient with a history of Hodgkin's lymphoma cured by chemotherapy and mantle field radiotherapy and compare this case to the rare published cases of chronic Dropped Head Syndrome occurring after this type of treatment. A 56-year-old man was treated at the age 36 years for supra-diaphragmatic Hodgkin's lymphoma by chemotherapy and mantle field radiotherapy according to a standard technique and standard doses (40Gy, 20 fractions, 27 days). Seventeen years after the end of treatment, he experienced a violent whiplash injury, rapidly followed by a Dropped Head Syndrome, similar to the cases of chronic Dropped Head Syndrome already described in the context of Hodgkin's lymphoma (permanent flexion of the head, only reduced in the supine position). Physical and neurophysiological examination, electromyogram, and magnetic resonance imaging confirmed the diagnosis of Dropped Head Syndrome. Very few treatment options are available for the major disability related to Dropped Head Syndrome. This type of subacute onset of Dropped Head Syndrome has not been previously described. The good results of radiation therapy after chemotherapy allow a dose reduction to 30Gy in the involved regions. This, together with recent progress in treatment planning, should allow eradication of these complications.

[Large volume stage I and II epidermoid carcinoma of the uterine cervix treated with primary radiotherapy and surgery]. / Carcinomes épidermoïdes du col utérin stades I et II de gros volume traités par radiothérapie première et chirurgie.

Fifty-two women with stage Ib2 and II bulky squamous cell carcinoma of the uterine cervix (mean size: 5.65 +/- 0.12 cm, range: 5-8 cm) were treated between July 1982 and December 1993. The median follow-up was 73 months. Their patient's age ranged from 25 to 77 years (median: 45 years). There were 18 stage Ib2, 8 stage IIa and 26 stage IIb operable patients. External radiotherapy was delivered using photons of 6 MV to 25 MV and a four-field "box" technique (upper limit situated between L4-L5). Mean total dose at mid-plane to the whole pelvis was 38.6 Gy (range: 37.4-40.6 Gy) in 18 fractions over 30 days. A boost dose of 20 Gy was given by intracavitary brachytherapy (utero-vaginal). After a mean rest of 48 days, total abdominal hysterectomy and bilateral salpingo-oophorectomy combined with bilateral pelvic lymphadenectomy was performed. Following surgery, no remaining tumor on pathological examination of uterine cervix was observed in 39 cases (75%) and positive external iliac nodes were found in 4 cases. Five- and 10-year specific survival rates were 80% and 75%, respectively. The 5- year local tumour recurrence and nodal recurrence rates were 18% and 15%, respectively. There were 7 para-aortic nodal recurrences (3 were isolated para-aortic nodal relapses). There were five late severe complications necessiting surgical intervention. A combination of preoperative radiation therapy and concomitant chemotherapy, and the extended dissection of common iliac and para-aortic lymph nodes or a post operative prophylactic extended field irradiation including para-aortic lymph nodes is now being attempted in order to improve the locoregional tumour and para-aortic lymph node control rates.