B. Diletto

Low-dose fractionated radiotherapy and concomitant chemotherapy in glioblastoma multiforme with poor prognosis: a feasibility study

We explored the feasibility of concurrent palliative chemotherapy and low-dose fractionated radiotherapy (LD-FRT) in glioblastoma multiforme (GBM). Patients with recurrent/progressive GBM at least 3 months after the end of primary radiotherapy received 0.3 Gy twice daily with cisplatin and fotemustine if progressing on temozolomide, or 0.4 Gy twice daily with temozolomide if recurrent 4-6 months later (retreatment group). Newly diagnosed GBM with gross residual mass received 30 Gy with concomitant and adjuvant temozolomide and 0.4 Gy twice daily from the second adjuvant cycle (naive group) for 2-4 cycles. Twenty-six patients were enrolled. In the retreatment group (n = 17; median LD-FRT total dose 7.2 Gy [range 2.4-11.6]), grade 3 or 4 hematological toxicity was observed in 5.9% of patients. Median follow-up time was 20 months (range 4-35). Median progression-free survival (PFS) and overall survival (OS) from the time of recurrence or progression were 4 and 8 months, respectively (OS at 6 months, 69%; at 12 months, 16.7%). In the naive group (n = 9; median LD-FRT total dose 8 Gy [range 3.2-16]), grade 3 or 4 hematological toxicity was observed in 11.1% of patients. Median follow-up time was 17 months (range 8-20)-median PFS was 9 months, with PFS at 6 months and at 1 year of 66.7% and 26.7%, respectively; and median OS was 12 months, with OS at 6 months and at 1 year of 77.8% and 34.6%, respectively. LD-FRT with concurrent chemotherapy was well tolerated.

Final results of the second prospective AIEOP protocol for pediatric intracranial ependymoma

BACKGROUND This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). METHODS WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. RESULTS From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. CONCLUSIONS In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports.

Can Elderly Patients With Newly Diagnosed Glioblastoma be Enrolled in Radiochemotherapy Trials

Objectives:Age is an unfavorable prognostic factor in glioblastoma multiforme (GBM). To assess the possibility and the advantage of radiotherapy (RT) plus concomitant/sequential temozolomide (TMZ) in patients over 65 years with GBM, we analyzed 4 prospective trials in terms of compliance and outcomes. Methods:Elderly patients with histologically proven GBM, included in 4 prospective phase II studies with a Karnofsky Performance Status (KPS) >70 and a Charlson Comorbidity Index (CCI) <3, were selected for these analyses. Patients were treated by 3D-conformal RT (60 Gy), fractionated stereotactic conformal-RT (69.4 Gy), or intensity-modulated RT with simultaneous integrated boost (63 Gy). Concomitant (standard modality, first and last week, or from the Monday to Friday) and adjuvant chemotherapy with TMZ was administered. To stratify patients, recursive partitioning analysis was used. Safety and tolerability were measured by the National Cancer Institute Common Criteria. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier method. Results:From 2001 to 2011, 201 patients were enrolled in 4 trials and 111 elderly patients were recruited for this analysis. Compliance was 96.4%: 4/111 patients discontinued treatment, prevalently for disease progression. During radiochemotherapy, acute toxicity was mild. At a median follow-up of 64 months (range, 9 to 122 mo), median PFS and OS were 10 and 13 months, respectively. Extent of surgery (P=0.009) and radiation dose (P=0.01) significantly improved survival. Conclusions:Radiochemotherapy is effective and well tolerated by elderly patients when KPS >70 and CCI <3; therefore these criterions should be considered to enroll elderly patients in combined prospective study.

Surgical approach to primary tumors of the chest wall in children and adolescents: 30 years of mono-institutional experience.

Aims and background Chest wall reconstruction after surgical resection for malignancies in children is a challenge for surgeons because of growth-related complications. The aim of this study is to analyze the surgical treatment and outcomes of 30 pediatric and adolescent patients treated at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, over a 30-year period. Methods Pediatric patients undergoing chest wall resection were retrospectively reviewed and selected for malignant primary tumor. Endpoints were survival, recurrences, and long-term results. We also reported the use of the innovative rib-like technique in 2 young patients. Results Twenty-one patients were male. Median age was 13.7 years. Eleven patients (37%) presented with a chest wall mass. Twenty-six (87%) had Ewing sarcoma family tumors. Twenty-eight (94%) received neoadjuvant chemotherapy after histologic diagnosis. One rib was resected in 13 cases; 2 or 3 contiguous ribs in 8 cases. No postoperative mortality was observed and the complication rate was 40%. Overall survival was 85.2% (95% confidence interval [CI] 65.2%-94.2%) at 5 and 10 years. Relapse occurred in 7 patients. The 5-year disease-free survival rate was 82% (95% CI 62%-92%). Conclusions Long-term survival is achievable for chest wall tumors in a high-volume referral center where a multimodal treatment should be set to reach the best result. As advances in medical treatment have increased survival, surgical techniques must ensure a lasting functional result. When refining the reconstruction techniques, such as the rib-like approach, it is necessary to expand the options of curative surgery for young patients.

Primary systemic treatment and concomitant low dose radiotherapy for breast cancer: final results of a prospective phase II study.

BACKGROUND To evaluate the efficacy of preoperative low dose fractionated radiotherapy (LD-FRT) and chemotherapy in breast cancer. MATERIALS AND METHODS Patients with stage IIA-IIIA breast cancer, received LD-FRT (0.40 Gy bid, on day 1 and 2, for 6 cycles) to primary tumor volume and concurrent chemotherapy with non-pegylated liposomal anthracycline and docetaxel. Pathological response was assessed by Mandard Tumor Regression Grade (TRG). We evaluated the pathological major response rate (PMRR) as TRG1 and TRG2. The expected outcome was a PMRR of 60%. The accrual was determined by the single proportion powered analysis (α = 0.05, power = 0.8). RESULTS Twentyone patients were enrolled. No grade 2-4 acute skin and hematological toxicity was observed. TRG1 was obtained in 3 patients (14.3%), TRG2 in 4 patients (19%). The PMRR was 33.3%; it does not concur with the expected result, but is similar to that of chemotherapy alone. According to molecular subtype, 2/11 luminal A patients and 4/6 luminal B patients obtained a PMRR to preoperative treatment (35.3%); 1/4 basal like patients reported TRG1 (25%). CONCLUSIONS LD-FRT concomitant with primary systemic treatment has a good toxicity profile. The response rate is consistent with that of chemotherapy alone, and suggests different interactions between low dose radiotherapy and molecular subtypes. Additional investigations are planned.

Axillary coverage by whole breast irradiation in 1 to 2 positive sentinel lymph nodes in breast cancer patients.

Purpose To evaluate the dosimetric coverage of axillary levels I, II, and III obtained with standard whole breast irradiation in 1 to 2 positive sentinel lymph nodes (SLNs) patients not submitted to axillary lymph nodes dissection (ALND), and to compare the lymph nodes areas coverage obtained with 3D conformal radiation therapy, intensity-modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT). Methods Patients with 1 to 2 positive SLNs undergoing breast-conserving therapy, without ALND, were included in the analysis. For each patient, 3 treatment plans were performed: a 3D conventional tangential plan, a static IMRT plan, and a volumetric IMRT, designed to encompass the entire breast parenchyma. The volumes of axillary levels I, II, and III receiving 90% and 95% (V90, V95) of the whole breast prescribed dose were evaluated. Dose-volume histograms were compared by means of the Friedman test. Results Ten patients were enrolled. All defined breast volumes received >95% of the prescribed dose with the 3 techniques. Median V95 for axillary level I was 26.4% (range 4.7%-61.3%) for 3D plans, 8.6% (range 0.64%-19.1%) for static IMRT plans, and 2.6% (range 0.4%-4.7%) for volumetric IMRT plans (p<0.001). Median V95 for axillary level II was 5.4% (range 0%-14.6%), 1.9% (range 0%-15%), and 2.6% (range 0.4%-4.7%) for 3D, static IMRT, and volumetric IMRT, respectively (p<0.001). Conclusions Results of our analysis showed that standard 3D tangential whole breast irradiation failed to deliver a therapeutic dose to axillary levels I and II. The coverage was even lower using static and volumetric IMRT techniques.

Reducing heart dose during left breast cancer radiotherapy: comparison among 3 radiation techniques

Purpose Breast cancer survivors have a high risk of cardiac death as a consequence of heart irradiation during left breast tangential radiotherapy (RT). This study compares the cardiac dose delivered by standard 3D conformal tangential RT (CRT) to that delivered by prospective-gating RT (PGRT) or 5-field intensity-modulated RT (IMRT). Methods Patients with early left breast cancer, referred for adjuvant RT to our institution, were enrolled in this study. For each patient, 2 simulation computed tomography scans were acquired: the first during free breathing, and the second on prospective gating during deep inspiration breath-hold. The scans were monitored by the Varian RPM™ respiratory gating system. For each patient, 3 treatment plans were performed: a 3D-CRT and an IMRT plan, each based on the free-breathing scan, and a PGRT plan, based on the deep inspiration breath-hold scan. Dose-volume histograms were compared by means of the Friedman test. Results The median mean heart dose was 3 Gy (range 0.9-7.3 Gy) in the CRT plans, 1.9 Gy (range 0.5-3.6 Gy) in the PGRT plans, and 4.5 Gy (range 1.1-10.5 Gy) in the IMRT plans (p = 0.001). The mean heart V25 was 1.2% (range 0%-9.7%), 0% (range 0%-2.0%), and 0.2% (range 0%-7.3%) for CRT, PGRT, and IMRT plans, respectively (p<0.001). Conclusions Prospective-gating RT to the left breast offered the best protection of heart and lung, as well as a lower irradiation of the contralateral breast, compared to CRT or IMRT.

Hypofractionated stereotactic radiotherapy for oligometastatic patients: developing of a response predictive model

ObjectivesTreatment of oligometastatic patients is a current challenge in radiation oncology. Aim of this study is to define a dose–response relationship for hypofractionated radiotherapy of oligometastases.MethodsRetrospective analysis of metastases treated by hypofractionated stereotactic radiotherapy was performed. Delivered dose was calculated both as biological effective dose (BED10), and as ratio between BED10 and the logarithm of metastasis volume (BED10 logVolume Ratio, BVR). Two dose–response models were defined by logistic regression. The fitted outcome was the Metastases Complete Response (MCR). Performances of the models were assessed by area under the receiver operating curve (AUC) and by bootstrap calibration of original data. BED10 and BVR impact on survival outcomes has been evaluated.ResultsFifty-three patients with 79 metastases were analyzed. AUC and calibration of BVR-based logistic model showed better accuracy in predicting MCR with respect to BED10-based model. No significant difference between the two ROCs was observed (De Long test p value > 0.05), but significant discordance in calibration resulted in the BED10 model (p value < 0.05 in Hosmer–Lemeshow Goodness of fit test). BVR returned also better results in multivariate analyses for survival outcomes.ConclusionsThe ratio between BED10 and the logarithm of metastasis volume (BVR), as a corrective factor for fitting the probability of metastases response to stereotactic radiotherapy, could be a tool for evaluating and prescribing treatments for oligometastatic disease. BVR can be useful for producing more reliable survival statistics too.

HG-06RE-IRRADIATION (RE-RT) FOR CHILDREN WITH RELAPSING DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): BETTER SURVIVAL AND BETTER TIME

HG-06. RE-IRRADIATION (RE-RT) FOR CHILDREN WITH RELAPSING DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): BETTER SURVIVAL AND BETTER TIME Maura Massimino1, Emilia Pecori1, Elisabetta Schiavello1, Veronica Biassoni1, Emanuele Pignoli1, Barbara Diletto1, Filippo Spreafico1, Michela Casanova1, Roberto Luksch1, Andrea Ferrari1, Monica Terenziani1, Marta Podda1, Cristina Meazza1, Serena Catania1, Stefano Chiaravalli1, Nadia Puma1, Stefano Bergamaschi1, Loris De Cecco1, Andrea Anichini1, Manila Antonelli3, Piergiorgio Modena2, Francesca Buttarelli3, Felice Giangaspero3, and Lorenza Gandola1; Fond. IRCCS Istituto Nazionale dei Tumori, Milano, Italy; Ospedale S.Anna, Como, Italy; Universita Sapienza, Roma, Italy Since 2009 we launched a strategy for children with centrally reviewed MRI DIPG diagnosis. Vinorelbine with nimotuzumab–an anti-EGFR monoclonal antibody-were weekly administered during the delivery of 54 Gy irradiation, 1.8 Gy/fraction daily, and for a total of 12 weeks, thereafter any other week until tumor progression or for two years duration. Since 7/2011 re-RT was offered both in case of local/disseminated progression: for local it consisted of 19.8 G/11 daysfractions; if needed, craniospinal irradiation (CSI) dose was 36 Gy/20 fractions. Of 40 patients treated, 29 had local (24) or disseminated (5) progression and 19 were given local (16) or CS (3) re-irradiation a median 8 months after first radiotherapy (2.5-19 months). Reasons for not re-irradiating the other 10 children were: progression before 7/2011(4), refusal(4), too poor PS(2); progression site were not different in the two groups. Survival after re-irradiation lasted between two weeks-14 months, median 6; a statistically different median OS between the reirradiated/not-reirradiated children was found, being 16 and 12 months, respectively(P 1⁄4 0.003). Re-irradiation induced, in 17 radiologically evaluated patients: 9 tumor volume reduction, 3 stable volumes, while 5 had progression; 14 had symptom amelioration and 13 steroid suspension. 8/9 volume reductions were obtained after same response at previous irradiation while one had stable disease after first irradiation. No adverse event occurred. Re-irradiation after progression was a concrete benefit for both OS and quality of patients life with symptom amelioration in 14/19. This option is worth to be offered also in case of disseminated progression. Neuro-Oncology 18:iii48–iii77, 2016. doi:10.1093/neuonc/now073.5 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Comparison of two radiation techniques for the breast boost in patients undergoing neoadjuvant treatment for breast cancer.

OBJECTIVE After breast conservative surgery (BCS) and whole-breast radiotherapy (WBRT), the use of boost irradiation is recommended especially in patients at high risk. However, the standard technique and the definition of the boost volume have not been well defined. METHODS We retrospectively compared an anticipated pre-operative photon boost on the tumour, administered with low-dose fractionated radiotherapy, and neoadjuvant chemotherapy with two different sequential boost techniques, administered after BCS and standard adjuvant WBRT: (1) a standard photon beam (2) and an electron beam technique on the tumour bed of the same patients. The plans were analyzed for the dosimetric coverage of the CT-delineated irradiated volume. The minimal dose received by 95% of the target volume (D95), the minimal dose received by 90% of the target volume (D90) and geographic misses were evaluated. RESULTS 15 patients were evaluated. The sequential photon and electron boost techniques resulted in inferior target volume coverage compared with the anticipated boost technique, with a median D95 of 96.3% (range 94.7-99.6%) and 0.8% (range 0-30%) and a median D90 of 99.1% (range 90.2-100%) and 54.7% (range 0-84.8%), respectively. We observed a geographic miss in 26.6% of sequential electron plans. The results of the anticipated boost technique were better: 99.4% (range 96.5-100%) and 97.1% (range 86.2-99%) for median D90 and median D95, respectively, and no geographic miss was observed. We observed a dose reduction to the heart, with left-sided breast irradiation, using the anticipated pre-operative boost technique, when analyzed for all dose-volume parameters. When compared with the sequential electron plans, the pre-operative photon technique showed a higher median ipsilateral lung Dmax. CONCLUSION Our data show that an anticipated pre-operative photon boost results in a better coverage with respect to the standard sequential boost while also saving the organs at risk and consequently fewer side effects. ADVANCES IN KNOWLEDGE This is the first dosimetric study that evaluated the association between an anticipated boost and neoadjuvant chemotherapy treatment.