V. Pernin

Comparison of passive-beam proton therapy, helical tomotherapy and 3D conformal radiation therapy in Hodgkin's lymphoma female patients receiving involved-field or involved site radiation therapy

PURPOSE Second cancers and cardiovascular toxicities are long term radiation toxicity in locally advanced Hodgkins lymphomas. In this study, we evaluate the potential reduction of dose to normal tissue with helical tomotherapy and proton therapy for Hodgkins lymphoma involved-field or involved-site irradiation compared to standard 3D conformal radiation therapy. PATIENTS AND METHODS Fourteen female patients with supradiaphragmatic Hodgkins lymphoma were treated at our institution with 3D conformal radiation therapy or helical tomotherapy to a dose of 30Gy in 15 fractions. A planning comparison was achieved including proton therapy with anterior/posterior passive scattered beams weighted 20Gy/10Gy. RESULTS Mean doses to breasts, lung tissue and heart with proton therapy were significantly lower compared to helical tomotherapy and to 3D conformal radiation therapy. Helical tomotherapy assured the best protection of lungs from doses above 15Gy with the V20Gy equal to 16.4%, compared to 19.7% for proton therapy (P=0.01) or 22.4% with 3D conformal radiation therapy (P<0.01). Volumes of lung receiving doses below 15Gy were significantly larger for helical tomotherapy than for proton therapy or 3D conformal radiation therapy, with respective lung doses V10Gy=37.2%, 24.6% and 27.4%. Also, in the domain of low doses, the volumes of breast that received more than 10Gy or more than 4Gy with helical tomotherapy were double the corresponding volumes for proton therapy, with V4Gy representing more than a third of one breast volume with helical tomotherapy. CONCLUSIONS Helical tomotherapy achieved a better protection to the lungs for doses above 15Gy than passive proton therapy or 3D conformal radiation therapy. However, dose distributions could generally be improved by using protons even with our current passive-beam technology, especially allowing less low dose spreading and better breast tissue sparing, which is an important factor to consider when treating Hodgkins lymphomas in female patients. Prospective clinical study is needed to evaluate the tolerance and confirm these findings.

Can we Reduce the Toxicity of the Mediastinal Irradiation Using NewHighly Conformal Techniques

Objectives: Three-Dimensional Conformal Radiotherapy (3DCRT) has been successfully used to treat Hodgkin’s Lymphoma (HL) but treatment delivery is often complex and requires large fields that may result in significant exposure of normal tissues to ionizing radiation. The present study was undertaken to compare the dosimetry of Involved Field (IF) 3DCRT to HT in female patients treated for HL. Materials/Methods: A total of 10 young female patients affected with early stage mediastinal HL and treated with IF radiotherapy after chemotherapy were selected from our database. For each patient, 3DCRT and HT plans were designed to deliver 30 Gy to the target volume and 36 Gy in case of residual masses. HT planning solutions were optimized by inverse planning with specific dose-volume constraints on OAR (breasts, lungs, heart). Dose- Volume Histograms (DVHs) were calculated and then compared, both for target and OAR by a statistical analysis (Wilcoxon’s Test). Results: Mean doses to the PTV were almost identical for all plans. Conformity index was better with HT and homogeneity index didn’t differ. Mean dose to the breasts were increased with HT compared to 33DCRT (right breast: 3.28 vs 2.19, p<0.05; left breast: 3.76 vs 2.81, p<0.05) whereas no difference in mean doses appeared for heart, coronary arteries, lungs, thyroid and normal tissue. Maximal doses were reduced with HT for breasts (right breast: 19.9 vs 28.87, p<0.05; left breast: 24.76 vs 30.29, p<0.05) and spinal cord (20.87 vs 33.88, p<0.05). Volume exposed to high doses was smaller with HT whereas volume exposed to low doses was smaller with 3DCRT. Pronounced benefits of HT in terms of heart sparing were observed for patients with lymph nodes anterior to the heart. Conclusions: Although high dose to organ at risk was reduced with HT, increasing low dose especially to the breasts must be taken into account for IF HT. HT may be considered for large PTV especially when the anterior mediastinum is involved.

Late toxicities and outcomes of adjuvant radiotherapy combined with concurrent bevacizumab in patients with triple-negative non-metastatic breast cancer

OBJECTIVE To evaluate the safety of the concurrent combination of bevacizumab with adjuvant radiotherapy (B-RT) in breast cancer (BC). METHODS Multicentre, prospective study, of the toxicity of adjuvant radiotherapy (RT) alone or B-RT in patients with non-metastatic BC enrolled in randomized Phase 3 BEATRICE trial. Early and late toxicities were assessed by the Common Terminology Criteria for Adverse Events v. 3.0 during and 12 months after the completion of RT. RESULTS From 2007 to 2012, 39 females received adjuvant B-RT and 45 received adjuvant RT alone. Median follow-up was 21.5 months. All patients had triple-negative non-metastatic BC and received adjuvant chemotherapy followed by RT. 90% of the 39 females treated by concurrent B-RT received whole breast irradiation (WBI) with a boost and 4 (10%) received post-mastectomy RT. Lymph node RT was delivered in 49% of the females with internal mammary chain irradiation. The mean duration of bevacizumab was 11.7 months. 38 (84%) females treated by RT alone received WBI with a boost and 16% of the females received post-mastectomy RT. Lymph node RT was delivered in 47% of the females with internal mammary chain RT in 31%. Grade 3 acute dermatitis was observed in 9% of patients receiving B-RT and 5% of patients receiving RT alone with no significant difference. 1 year after the completion of RT, the most common late grade 1-2 toxicities in the B-RT group were pain (18%), fibrosis (8%) and telangiectasia (5%). CONCLUSION The concurrent bevacizumab with locoregional RT is associated with acceptable early and late 1-year toxicities in patients with BC. ADVANCES IN KNOWLEDGE The largest series of this association.

Radiotherapy associated with concurrent bevacizumab in patients with non-metastatic breast cancer *

The purpose of this multicenter prospective and descriptive study was to determine late toxicities and outcomes among patients with non-metastatic breast cancer receiving concurrent bevacizumab (BV) and radiation therapy (RT) in the clinical trials. Early and late toxicities were assessed and evaluation was available for 63 patients (pts) at 12 months. Acute radiation dermatitis was observed in 48 (76%): grade 1 for 27, grade 2 for 17 and grade 3 for 4 pts. Grade 2 acute oesophagitis was observed in one patient (2%). Little toxicity was described 1 year after the completion of RT: 7 pts (12%): grade 1-2 pain, 3 (5%) presented grade 1 fibrosis, and 2 pts (4%) - telangiectasia. One patient (2%) experienced grade 1 dyspnoea. Five grade 1-2 lymphoedema occurred. Only one patient experienced a LEVF value less than 50% one year after the end of RT. In conclusion, the concurrent BV with locoregional RT provides acceptable toxicities.

Evolution of radiation techniques in the treatment of mediastinal lymphoma: from 3D conformal radiotherapy (3DCRT) to intensity-modulated RT (IMRT) using helical tomotherapy (HT): a single-centre experience and review of the literature.

OBJECTIVE To evaluate radiation techniques and their toxicity in the treatment of Hodgkins lymphoma (HL) and non-Hodgkins lymphoma (NHL) with mediastinal disease over a 10-year period. METHODS Between 2003 and 2015, 173 patients with Stage I-III nodal lymphoma were treated in our institution: some of these patients were irradiated for HL or NHL with mediastinal disease. Some of the patients were treated by three-dimensional conformal radiotherapy (3DCRT), others by intensity-modulated radiotherapy (IMRT). RESULTS We studied 26 males and 43 females with a median age of 26 years. The median follow-up was 43 months. 49 patients were treated by 3DCRT and 20 patients by IMRT. The median dose received by patients treated for NHL was 40 Gy (range: 36-44 Gy), and the median dose received by patients with HL was 30 Gy (range: 30-36 Gy). Between 2003 and 2006, 16 patients were treated by 3DCRT vs 0 patients by IMRT. Between 2007 and 2009, 16 patients received 3DCRT and one patient received IMRT. Between 2010 and 2015, 19 patients received IMRT, and no patients received 3DCRT. 11 of the 20 (55%) patients treated by IMRT and 35 of the 49 (71.4%) patients treated by 3DCRT experienced acute toxicity. Among the patients treated by 3DCRT, one patient experienced Grade 1 radiation pneumonitis and two patients experienced Grade 1 acute mucositis. No late toxicity was observed in patients treated by IMRT. CONCLUSION Improvement of radiation techniques for HL and NHL appears to have improved acute and late clinical safety. Longer follow-up is necessary to evaluate very late toxicity. ADVANCES IN KNOWLEDGE Improvement of radiation techniques for HL and NHL appears to improve the tolerance.

Abstract 4428: Pre-clinical studies of the therpaeutic effect of a PARP inhibitor combined with radiotherapy for breast cancer treatment.

Introduction: Triple negative breast cancer (TNBC) is an aggressive disease associated with a high risk of distant recurrence and poor overall survival and, as for other BC sub-types, loco-regional treatment relies on surgery and radiotherapy (RT). Small molecules inhibitors of poly(ADP-ribose) polymerases (PARP) can potentially be exploited to sensitise breast tumour cells either when used in combination with chemo- and radiotherapy or in certain genetic backgrounds. In order to test this hypothesis, pre-clinical studies of the therapeutic effects of the combination of a PARP inhibitor and RT in human breast cancer xenograft models have been initiated using two TNBC models. Experimental design: Two human TNBC models, HBCx-17 and HBCx-12A xenografts were subcutaneously transplanted into the flanks of nude mice. The PARP inhibitor, 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (PARPi), suspended in 0.5% methylcellulose was administered by tube feeding at 100 mg/kg for 3 or 28 days. After tumors reached a calculated average volume of 125 mm3 (HBCx-12A) or 300 mm3 (HBCx-17), the animals were randomized into 8 treatment groups (10 mice/group): (1, 2) methylcellulose alone for 3 or 28 days, (3,4) methylcellulose for 3 or 28 days with 3 days radiotherapy, (5, 6) PARPi alone for 3 or 28 days, (7) PARPi combined with RT for 3 days and (8) PARPi for 3 days, then PARPi combined with 3 days RT followed by 22 days of PARPi. To mimic the clinical application of RT, the tumors were locally irradiated with X-Rays (200 kV, mean energy 80 keV) with a fractionated (3.25 Gy per fraction) schedule. Preliminary Results: In both TNBC models, individual group comparisons showed that after 28 days of treatment with PARPi alone tumour growth was markedly slowed, an effect that has persisted to day 60. Treatment with RT alone or RT combined with PARPi also resulted in significant growth inhibition over the same period. Animals are being followed to assess tumour regrowth and determine the long-term outcome of these treatment protocols. Conclusion: Our preclinical results show the susceptibility of TNBCs to the PARP inhibitor alone or combined with RT. However whether the response seen when the PARP inhibitor was combined with RT is due exclusively to impaired DNA damage responses or whether tumor re-oxygenation via the vasoactive effects of the PARP inhibitors contributes remains to be fully determined in further preclinical and clinical studies. Acknowledgments: This project is in-part financially supported by Institut Curie9s (IC) CEST program. V.P. was supported by an IC translational studentship (MD-Master2 science) and T.Z. by IC9s International Postodoctoral fellowship program and the Fondation PGG. Citation Format: Frederic Pouzoulet, Victor Pernin, Christophe Roulin, Helene Alcade, Franck Assayag, Frederique Megnin-Chanet, Laurence Vaslin-Lepetit, Sophie Heinrich, Florence Mahuteau-Betzer, Aurelie Thuleau, Tomasz Zaremba, Vincent Favaudon, Elisabetta Marangoni, Youlia Kirova, Alain Fourquet, Janet Hall, Didier Decaudin. Pre-clinical studies of the therpaeutic effect of a PARP inhibitor combined with radiotherapy for breast cancer treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4428. doi:10.1158/1538-7445.AM2013-4428

Radiotherapy for breast cancer and erythrokeratodermia variabilis.

We report the first case report indicating that locoregional radiotherapy provide acceptable early and late toxicities in patient with erythrokeratodermia variabilis after 2 years of follow-up. However, preclinical data showing radiation-induced tumor genesis in case of deficiency of some connexins point out the need of a careful surveillance of these patients.