Francesco Pasqualetti

Perioperative High-Dose-Rate Brachytherapy in the Treatment of Recurrent Malignant Gliomas

Purpose:To assess the feasibility and effectiveness of perioperative high-dose-rate brachytherapy for recurrent malignant gliomas.Patients and Methods:Between 2005 and 2008, 21 patients (14 males and seven females) with relapsed malignant glioma underwent a second surgery followed by a brachytherapy implant in the surgical cavity. Median age was 60 years, and median Karnofsky performance status 80. A single fraction of 18 Gy specified at 5 mm depth was administered perioperatively. Then, the applicator was removed nonsurgically. Mean postoperative hospitalization time was 3 days.Results:At the time of analysis, 15 patients (71%) had died and six (29%) were alive. Median follow-up was 32.3 months. Median overall survival from diagnosis amounted to 21.7 months. Median survival after recurrence was 8.0 months, and 6-month progression-free survival 42%. Patients were stratified into classes according to the prognostic recursive partitioning analysis.Conclusion:Perioperative brachytherapy has proven to be safe and well tolerated in patients with recurrent malignant glioma. No severe toxicity was reported, and the treatment has proven to be effective in symptomatic recurrences of malignant gliomas.Hintergrund und Ziel:Beurteilung der Durchführbarkeit und Wirksamkeit einer perioperativen High-Dose-Rate-(HDR-)Brachytherapie bei rezidivierenden malignen Gliomen.Patienten und Methodik:Zwischen 2005 und 2008 wurden 21 Patienten (14 Männer und sieben Frauen) mit rezidivierenden malignen Gliomen einer zweiten Operation zugeführt, gefolgt von einer HDR-Brachytherapie des Rezidivtumorbetts. Das durchschnittliche Alter der Patienten betrug 60 Jahre, der durchschnittliche Karnofsky-Performance-Status 80. Perioperativ wurde eine Einzeldosis von 18 Gy appliziert, dosiert auf 5 mm Gewebetiefe. Anschließend wurde der Applikator entfernt. Die mittlere Dauer des postoperativen Krankenhausaufenthalts lag bei 3 Tagen.Ergebnisse:Zum Zeitpunkt der Analyse waren 15 Patienten (71%) gestorben. Die mediane Nachbeobachtungszeit betrug 32,3 Monate. Die mediane Gesamtüberlebenszeit lag bei 21,7 Monaten. Das mediane Überleben nach Rezidivdiagnose betrug 8,0 Monate, das progressionsfreie 6-Monats-Überleben 42%. Die Patienten wurden gemäß der prognostischen RPA („recursive partitioning analysis“) in Klassen eingeteilt.Schlussfolgerung:Diese Untersuchung hat gezeigt, dass die perioperative HDR-Brachytherapie bei Patienten mit rezidivierten malignen Gliomen sicher und gut verträglich ist. Es wurde keine schwere Toxizität beobachtet. Die Ergebnisse bestätigen die Gültigkeit und Wirksamkeit einer solchen Behandlung bei symptomatischem Auftreten eines malignen Glioms.

Optimal Detection of Sentinel Lymph Node Metastases by Intraoperative Radioactive Threshold and Molecular Analysis in Patients with Melanoma

The aim of this study was to optimize a protocol for radioguided biopsy of the sentinel lymph node (SLN) in patients with melanoma. The protocol was based on a combination of ex vivo counting of the nodes detected intraoperatively and analysis of the harvested nodes by hematoxylin and eosin staining plus immunohistochemistry (conventional histopathology [PATH]) and by molecular biology (reverse-transcriptase polymerase chain reaction [RT-PCR]). Methods: A total of 124 patients with primary clinical stage I–II (according to the American Joint Committee on Cancer) cutaneous melanoma underwent successful radioguided SLN biopsy. SLNs harvested for analysis included any additional nodes whose ex vivo counting rate exceeded 20% of the hottest node. All removed SLNs were examined by conventional PATH and with RT-PCR analysis for the expression of messenger RNA for tyrosinase and the melanoma antigens recognized by T cells. Complete lymph node dissection (CLND) was performed only in the case of SLN metastasis detected by PATH. Different combinations of the intraoperative parameters (only the hottest node and all nodes harvested) and of analysis (PATH and RT-PCR) were tested as predictors of clinical outcome on the basis of long-term follow-up (12–81 mo; median, 55 mo). Results: A total of 197 SLNs were harvested, 41 of which harbored metastasis as detected by RT-PCR analysis; PATH detected metastasis in only 24 of 41 metastatic SLNs. In 5 of 41 instances, metastasis was not in the hottest SLN. The main factor determining correct classification of the SLN status was RT-PCR, which significantly improved detection of metastasis, even if applied only to the hottest node (P < 0.0001 vs. PATH analysis of either the hottest SLN or all nodes above the 20% threshold). Metastatic disease recurred locally in 5 patients who had not undergone CLND; RT-PCR analysis showed metastasis in 4 of these patients. The false-negative rate of SLN biopsy progressively decreased when applying PATH only to the hottest node (32.1%), additional RT-PCR to the hottest node (21.4%), PATH to all nodes (17.9%), and RT-PCR to all nodes (3.6%, P = 0.015 vs. PATH analysis of only the hottest SLN). Conclusion: On the basis of long-term follow-up (the gold standard for final clinical outcome of SLN biopsy), both 20% threshold and RT-PCR analysis should be applied for optimal detection of nodal metastases in patients with melanoma.

Non-melanoma skin cancer treated with high-dose-rate brachytherapy and Valencia applicator in elderly patients: a retrospective case series

Purpose The incidence of non-melanoma skin cancer (NMSC) has been increasing over the past 30 years. Basal cell carcinoma and squamous cell carcinoma are the two most common subtypes of NMSC. The aim of this study was to estimate tumour control, toxicity, and aesthetic events in elderly patients treated with high-dose-rate (HDR) brachytherapy (BT) using Valencia applicator. Material and methods From January 2012 to May 2015, 57 lesions in 39 elderly eligible patients were enrolled. All the lesions had a diameter ≤ 25 mm (median: 12.5 mm) and a depth ≤ 4 mm. The appropriate Valencia applicator, 2 or 3 cm in diameter was used. The prescribed dose was 40 Gy in 8 fractions (5 Gy/fraction) in 48 lesions (group A), and 50 Gy in 10 fractions (5 Gy/fraction) in 9 lesions (group B), delivered 2/3 times a week. The biological effective dose (BED) was 60 Gy and 75 Gy, respectively. Results After median follow-up of 12 months, 96.25% lesions showed a complete response and only two cases presented partial remission. Radiation Therapy Oncology Group – European Organization for Research and Treatment of Cancer (RTOG/EORTC) G 1-2 acute toxicities were observed in 63.2% of the lesions: 56.3% in group A and 77.7% in group B. Late G1-G2 toxicities was observed in 19.3% of the lesions: 18.8% in group A and 22.2% in group B, respectively. No G3 or higher acute or late toxicities occurred. In 86% of the lesions, an excellent cosmetic result was observed (87.5% in group A and 77.8% in group B). Six lesions had a good cosmetic outcome and only 2.3% presented a fair cosmetic impact. Conclusions The treatment of NMSC with HDR-BT using Valencia surface applicator is effective with excellent and good cosmetics results in elderly patients. The hypofractionated course appears effective and no statistical differences were observed between the two groups analysed.

A new nomogram for estimating survival in patients with brain metastases secondary to colorectal cancer

BACKGROUND The prognosis of brain metastases (BM) in colorectal cancer (CRC) is extremely poor, but the incidence is increasing. The performance of existing prognostic classifications such as recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) has never been evaluated in this specific setting. Moreover, the development of nomograms for estimating survival in such patients could be extremely helpful for treating physicians. PATIENTS AND METHODS Between 2000 and 2013, data from 227 patients with BM from CRC were collected at 8 Italian institutions. Overall survival (OS) was estimated with the Kaplan-Meier method and statistical comparison between curves was performed using the log-rank test. The discriminative ability for OS of RPA and GPA was assessed by the Harrell C-index from univariable Cox models. Putative prognostic factors for OS were also studied by multivariable Cox analysis, using the Harrell C index to evaluate the model discriminative ability. After a backward variable selection, a nomogram was developed to predict median survival time from individual patient- and tumor-related characteristics. The nomogram was externally validated on an independent series. RESULTS After a median follow-up of 59 months, fifty percent of patients were still at risk at 5 months. The C index was 0.594 and 0.607 for the RPA and GPA classifications, respectively. The C-index associated with the final multivariable Cox model used for developing the nomogram was 0.643; the favorable prognostic factors for survival were lower age (p=0.061), better Karnofsky performance status (p<0.001), supratentorial site of BM (p<0.001), and lower number of BM (p=0.035). The C index evaluated on the validation series was 0.733, even better than in the development series; also, the calibration of nomogram predictions was good. CONCLUSION The C-index associated to the nomogram model was slightly higher than that obtained for the RPA and GPA classifications. Most importantly, the very satisfactory results of nomogram validation on the external series, make us confident that our instrument may assist in prognostic assessment, treatment decision making, and enrollment into clinical trials.

Non-melanoma skin cancer treated with high-dose-rate brachytherapy: a review of literature

Purpose The incidence of non-melanoma skin cancer (NMSC) has been increasing over the past 30 years. There are different treatment options and surgical excision is the most frequent treatment due to its low rates of recurrence. Radiotherapy is an effective alternative of surgery, and brachytherapy (BT) might be a better therapeutic option due to high radiation dose concentration to the tumor with rapid dose fall-off resulting in normal tissues sparing. The aim of this review was to evaluate the local control, toxicity, and cosmetic outcomes in NMSC treated with high-dose-rate BT (HDR-BT). Material and methods In May 2016, a systematic search of bibliographic database of PubMed, Web of Science, Scopus, and Cochrane Library with a combination of key words of “skin cancer”, “high dose rate brachytherapy”, “squamous cell carcinoma”, “basal cell carcinoma”, and “non melanoma skin cancer“ was performed. In this systematic review, we included randomized trials, non-randomized trials, prospective and retrospective studies in patients affected by NMSC treated with HDR-BT. Results Our searches generated a total of 85 results, and through a process of screening, 10 publications were selected for the review. Brachytherapy was well tolerated with acceptable toxicity and high local control rates (median: 97%). Cosmetic outcome was reported in seven study and consisted in an excellent and good cosmetic results in 94.8% of cases. Conclusions Based on the review data, we can conclude that the treatment of NMSC with HDR-BT is effective with excellent and good cosmetics results, even in elderly patients. The hypofractionated course appears effective with very good local disease control. More data with large-scale randomized controlled trials are needed to assess the efficacy and safety of brachytherapy.

Survival outcomes following repeat surgery for recurrent glioblastoma: a single-center retrospective analysis.

The aim of the present study is to evaluate the impact of extent of resection at initial and repeat craniotomy on overall survival of patients with recurrent glioblastoma. The authors retrospectively reviewed the records of all adults patients who underwent repeat resection of recurrent glioblastoma following radiation and chemotherapy at an academic tertiary-care institution between 2011 and 2015. We evaluated the survival outcomes with regard to extent of resection considering both the initial and repeat resections. The role of possible prognostic factors that may affect survival after repeat resection, including age, preoperative performance status, tumor location and adjuvant treatment, was evaluated using Cox regression analyses. Forty-eight patients were included in this study. The overall median survival of 14 patients who had subtotal resection at recurrence after initial subtotal resection did not statistically differ from seven patients who had gross-total resection at recurrence after initial subtotal resection (18 months vs. 22 months, p = 0.583). The overall median survival of 13 patients who had gross-total resection at recurrence after initial gross-total resection was significantly increased compared with survival of 13 patients who had subtotal resection at recurrence after initial gross-total resection (47 months vs. 14 months, p = 0.009). A Cox proportional hazards model was created demonstrating that preoperative performance status at recurrence (HR 0.418, p = 0.035) and the extent of repeat resection (HR 0.513, p = 0.043) were independent predictors of survival. Gross-total resection at repeat craniotomy is associated with longer overall survival and should be performed whenever possible in patients with recurrent glioblastoma and in good performance status.

Molecular portrait of a rare case of metastatic glioblastoma: somatic and germline mutations using whole-exome sequencing

Despite the latest advances in surgery, radiological assessment, and radiotherapy treatment, the incidence of glioblastoma (GBM) is roughly comparable to that of mortality, and the prognosis is almost always related to intracranial progression after surgery or radio-chemotherapy. The incidence of extracranial metastases of GBM are rarely reported in the literature, –4 and there is still no explanation for this hematological dissemination. A 70-year-old man was referred to the Radiotherapy Department of Pisa University Hospital after partial excision of a WHO grade IV GBM. Microscopic examination showed pleomorphic astrocytic tumor cells with marked nuclear atypia, mitotic activity, microvascular proliferation, necrosis, and positive glial fibrillary acidic protein (GFAP) immunostaining. Shortly after the first visit, the patient reported lumbar spine pain. Radiological investigation revealed the presence of a lytic lumbar lesion. The total-body CT showed bone, lung, and liver tumor masses. In order to obtain a pathological diagnosis of extracranial disease, we decided to perform a biopsy of the sternal lesion (Fig. 1A). Histological examination showed pleomorphic cells, necrosis, and mitotic activity. Positive immunohistochemistry for GFAP and CD56 indicated a glial origin, while negative PanCk, LCA, and TTF1 results excluded epithelial, lymphoid, pulmonary, and thyroid origins. Cytological examination revealed GFAP-positive cells with hyperchromatic nuclei and poor cytoplasm (Fig. 1B). Whole-exome sequencing was performed on paired GBM primary tumor and blood germinal DNA using the Ion Proton System (Life Tech). Filtering the data by high quality score, read depth, absence in dbSNP, mammalian conservation, and allele frequency ,1%, we found that synonymous and missense gene mutations represented the most common types of variations in both GBM tumor and blood DNA. Mutations found in blood DNA were further filtered, looking for disease-associated mutations (OMIM database). We recovered 11 gene variations: FAM161A-R213C, TRMT10A-R61C, OTOG-V2191A, GALC-A349S, TRIP11-S1968G, PRPF8-I1662T, FECH-Y197C, LZTR1-R630Q, ARID1A-Q1142fs, LAMA4-E276Dfs, and HYDIN-D2570T. Additional filtering was performed to remove the entire mutational germinal load from the dataset to identify 70 GBM tumor-exclusive somatic mutations. We selected 8 of the most predominant mutations (higher allele count and read quality) that we assumed had emerged in an early stage of tumor progression: C8A-R30W, CRISP1-R162H, CTBP2-H788L, CTSK-V95L, DOCK9-M1635I, HSD17B7-S173N, PRSS1-Q209E, and TRIM29-V532I. All of these variations were confirmed in the GBM by Sanger sequencing. In order to confirm the metastatic origin of the sternal lesions, we looked for at least one shared mutation within the 8 selected somatic mutations between GBM and sternal biopsy because the amount of starting material was not sufficient for a whole-exome analysis. We microdissected 100 GFAP-positive cells, taken after cytological preparation of the sternal lesion, and extracted DNA. The tumor-somatic C8A-R30W mutation was confirmed in DNA from the sternal biopsy while being absent in blood DNA (Fig. 1C). Sharing of the C8A-R30W mutation between the primary tumor and the sternal lesion confirms the latter as having a GBM metastatic origin. The primary tumor data were also filtered for driver mutations. We found 4 variations in genes identified as tumor suppressors: RB1 deletion of 5 bases (Gln257fs), CREBBP stop mutation (Gln1027*), ARID1A1 one-base deletion (p.Val1867Alafs), and BRCA2 stop mutation (Gln2164*). We finally performed a copy number variation (CNV) analysis, obtaining a prevalence of deletions in TP53, PTEN, ERBB2, TERT, RTEL1, CDKN2A, and PHLDB1 as well as amplifications in BRCA2 using a log2 cutoff of 0.8. The only variation with significant variance, however, was the RTEL1 deletion. Although the reported incidence of extracranial GBM is 0.2%, this phenomenon may not be as rare as believed. The hypoxic and proliferative zone of the GBM has an angiogenesisrelated breakdown of the blood-brain barrier, and GBM cells could have direct communication with the circulatory system. Thus, low levels of circulating GBM cells may be present in the early disease process of susceptible patients and ultimately lead to metastases in extracranial organs. The aggressive

Single-fraction flattening filter–free volumetric modulated arc therapy for lung cancer: Dosimetric results and comparison with flattened beams technique

PURPOSE To report on single-fraction stereotactic body radiotherapy (RT) (SBRT) with flattening filter (FF)-free (FFF) volumetric modulated arc therapy (VMAT) for lung cancer and to compare dosimetric results with VMAT with FF. METHODS AND MATERIALS Overall, 25 patients were treated with 6-MV FFF VMAT (Varian TrueBeam STx LINAC) to a prescribed dose of 24Gy in a single fraction. Treatment plans were recreated using FF VMAT. Dose-volume indices, monitor units (MU), and treatment times were compared between FFF and FF VMAT techniques. RESULTS Dose constraints to PTV, spinal cord, and lungs were reached in FFF and FF plans. In FFF plans, average conformity index was 1.13 (95% CI: 1.07 to1.38). Maximum doses to spinal cord, heart, esophagus, and trachea were 2.9Gy (95% CI: 0.4 to 6.7Gy), 0.8Gy (95% CI: 0 to 3.6Gy), 3.3Gy (95% CI: 0.02 to 13.9Gy), and 1.5Gy (95% CI: 0 to 4.9Gy), respectively. Average V7Gy, V7.4Gy, and mean dose to the healthy lung were 126.5cc (95% CI: 41.3 to 248.9cc), 107.3cc (95% CI: 18.7 to 232.8cc), and 1.1Gy (95% CI: 0.3 to 2.2Gy), respectively. No statistically significant differences were found in dosimetric results and MU between FF and FFF treatments. Treatment time was reduced by an average factor of 2.31 (95% CI: 2.15 to 2.43) from FF treatments to FFF, and the difference was statistically significant. CONCLUSIONS FFF VMAT for lung SBRT provides equivalent dosimetric results to the target and organs at risk as FF VMAT while significantly reducing treatment time.

The effectiveness of bevacizumab in radionecrosis after radiosurgery of a single brain metastasis

Radionecrosis (RN) of brain tissue is a serious late complication of brain irradiation and historically has been treated with corticos-teroid therapy and alternatively surgical decompression. Recently, bevacizumab has been suggested for treatment of cerebral radiation necrosis. We present a case of a 73-years-old women affected by a primary non-small cell lung cancer with a single brain metastasis treated with radiosurgery. Two years after radiosurgery the patient referred neurological symptoms and a brain magnetic resonance confirmed the presence of RN. The patient refused surgical decompression so underwent at the treatment with bevacizumab 7.5 mg/kg/2 weeks for a total of 4 cycles. After two months of treatment the patient reported strumental and clinical improvement. Ten months after bevacizumab discontinuation the patient experienced a recurrence of RN with evident clinical manifestation and confirmed by radiological imaging. A new treatment with bevacizumab was not performed due to the systemic progression disease and the worsening of clinical status. Despite limited to only one clinical case, our study suggests the efficacy of bevacizumab to treat RN. Future studies are needed to confirm its mechanism and to properly define the optimal scheduling, dosage and duration of therapy.

Policies for reirradiation of recurrent high-grade gliomas: a survey among Italian radiation oncologists

Purpose: To assess the contribution of Italian radiation oncologists in the current management of recurrent high-grade gliomas (HGG), focusing on a reirradiation (reRT) approach. Methods: In 2015, the Reirradiation and the Central Nervous System Study Groups on behalf of the Italian Association of Radiation Oncology (AIRO) proposed a survey. All Italian radiation oncologists were individually invited to complete an online questionnaire regarding their clinical management of recurrent HGG, focusing on a reRT approach. Results: A total of 37 of 210 questionnaires were returned (18% of all centers): 16 (43%) from nonacademic hospitals, 14 (38%) from academic hospitals, 5 (13%) from private institutions, and 2 (6%) from hadron therapy centers. The majority of responding centers (59%) treated ≤5 cases per year. Performance status at the time of recurrence, along with a target diameter <5 cm and an interval from primary radiation ≥6 months, were the prevalent predictive factors considered for reRT. Sixty percent of reirradiated patients had already received a salvage therapy, either chemotherapy (40%) or reoperation (20%). The most common approach for reRT was fractionated stereotactic radiotherapy to a mean (photon) dose of 41.6 Gy. Conclusions: Although there were wide variations in the clinical practice of reRT across the 37 centers, the core activities were reasonably consistent. These findings provide a basis for encouraging a national collaborative study to develop, implement, and monitor the use of reRT in this challenging clinical setting.