Malignant Pleural Mesothelioma: Preliminary Toxicity Results of Adjuvant Radiotherapy Hypofractionation in a Prospective Trial (MESO-RT).

Malignant Pleural Mesothelioma (MPM) is a rare malignancy with an overall poor prognosis. The standard therapeutic strategy in early-stage disease is trimodality therapy. In this publication, we report the preliminary toxicity results of the first 20 patients treated with accelerated hypofractionated radiotherapy. Between July 2017 to June 2019, 20 MPM patients were enrolled and treated with accelerated hypofractionated radiotherapy using helical tomotherapy and intensity-modulated arc therapy. The prescription dose was 30 Gy in five daily fractions, while an inhomogeneous dose escalation to 40 Gy was prescribed based solely upon the presence of gross residual tumor. Only one case of G3 toxicity was reported, which was a bilateral pneumonitis that occurred two years after treatment probably due to superinfection. Median Time to Progression reached 18.2 months while one- and three-year Overall Survival rates were 85% (95% CI:60.4-94.9) and 49.5% (95% CI:26.5-68.9), respectively. Treatment of the intact lung with pleural intensity-modulated arc irradiation is a novel treatment strategy that appears to be safe, feasible, and without a high grade of lung toxicity. Survival rates and Time to Progression are encouraging.

Diagnostic and Prognostic Potential of 18F-FET PET in the Differential Diagnosis of Glioma Recurrence and Treatment-Induced Changes After Chemoradiation Therapy.

BACKGROUND: MRI-based differential diagnosis of glioma recurrence (GR) and treatment-induced changes (TICs) remain elusive in up to 30% of treated glioma patients. We aimed to determine 18F-FET PET diagnostic performance in this clinical scenario, its outcome dependency on established prognostic factors, optimal 18F-FET semi-quantitative thresholds, and whether 18F-FET parameters may instantly predict progression-free survival (PFS) and overall survival (OS). METHODS: We retrospectively analyzed 45 glioma patients treated with chemoradiation therapy (32 males; mean age: 51 years, glioma grade: n=26 WHO4; n=15 WHO3; n=4 WHO2) who underwent 18F-FET PET to resolve differential diagnosis of GR and TICs raised by MRI performed in the preceding 2 weeks and depicting any of the following changes in their radiation field: volumetric increase of contrast-enhancing lesions; new contrast-enhancing lesion; significant increase in T2/FLAIR non-enhancing lesion without reducing corticosteroids. 18F-FET PET outcome relied on evaluation of maximum tumor-to-brain ratio (TBRmax), time-to-peak (TTP), and time-activity curve pattern (TAC). Metabolic tumor volume (MTV) and total tumor metabolism (TTM) were calculated for prognostic purposes. Standard of reference was repeat MRI performed 4-6 weeks after the previous MRI. Non-parametric statistics tested 18F-FET-based parameters for dependency on established prognostic markers. ROC curve analysis determined optimal cutoff values for 18F-FET semi-quantitative parameters. 18F-FET parameters and prognostic factors were evaluated for PFS and OS by Kaplan-Meier, univariate, and multivariate analyses. RESULTS: 18F-FET PET sensitivity, specificity, positive predictive value, negative predictive value were 86.2, 81.3, 89.3, 76.5%, respectively; higher diagnostic accuracy was yielded in IDH-wild-type glioma patients compared to IDH-mutant glioma patients (sensitivity: 81.8 versus 88.9%; specificity: 80.8 versus 81.8%). KPS was the only prognostic factor differing according to 18F-FET PET outcome (negative versus positive). Optimal 18F-FET cutoff values for GR were TBRmax ≥ 2.1, SUVmax ≥ 3.5, and TTP ≤ 29 min. PFS differed based on 18F-FET outcome and related metrics and according to KPS; a different OS was observed according to KPS only. On multivariate analysis, 18F-FET PET outcome was the only significant PFS factor; KPS and age the only significant OS factors. CONCLUSION: 18F-FET PET demonstrated good diagnostic performance. 18F-FET PET outcome and metrics were significantly predictive only for PFS.

Multimodal Treatment with GEMOX Plus Helical Tomotherapy in Unresectable Locally Advanced Pancreatic Cancer: A Pooled Analysis of Two Phase 2 Studies.

In locally advanced pancreatic cancer (LAPC), the combination of chemotherapy and radiotherapy is a widely used treatment option. We performed a pooled analysis, including an exploratory analysis for prognostic and predictive factors, of two phase 2 trials including 73 patients with LAPC, treated with gemcitabine and oxaliplatin (GEMOX) and hypofractionated tomotherapy. With a median follow-up of 36 months (range 1-65), median progression-free (PFS) and overall survival (OS) were 10.2 (95% confidence interval [CI] 7.8-13.2) and 14.3 (95% CI 12.0-18.1) months, respectively. The overall resectability rate was 23.3% (95% CI 13.6-33.0), and the R0 resection rate was 13.7% (95% CI 5.8-21.6). In the multivariate analysis, ECOG performance status (PS) 0 and low levels of CA 19-9 were associated with improved OS and PFS. Concerning OS, log(CA19-9) resulted in a hazard ratio (HR) of 1.20 (95% CI 1.02-1.42), p = 0.027. For ECOG PS 0, HR was 1.00; for PS 1, HR was 2.69 (95% CI 1.46-4.96); for PS 2, HR was 4.18 (95% CI 0.90-19.46); p = 0.003. Low CA19-9 levels were also predictive for resection, with an odds ratio of 0.71 (95% CI 0.52-0.97), p = 0.034. In conclusion, GEMOX and hypofractionated radiotherapy is a treatment option in LAPC. Further studies are needed to identify differences in tumor biology, which may help to predict resectability and prognosis.

The role of radiotherapy in adult soft tissues sarcoma of the extremities.

Local management of adult soft tissue sarcoma of the extremities has evolved over the past decades. Until the 1970s, radical surgery (amputations) was the standard therapeutic procedure resulting in significant physical and psychological morbidity for the patients. In the present era, limb sparing surgery combined with radiotherapy represents the current standard of care for high grade and > 5 cm STSs. This approach guarantees high local control rate and function preservation. The aim of this paper is to summarize the current evidence for RT in STSs of the extremities. Outcomes, technical details (techniques, timing, dose, volumes of treatment) and the emerging role of RT in the management of oligometastatic disease will be analysed. Finally, results of the recent clinical trials testing new scenarios in RT of STSs will be described.

Role of Hyperbaric Oxygenation Plus Hypofractionated Stereotactic Radiotherapy in Recurrent High-Grade Glioma.

BACKGROUND: The presence of hypoxic cells in high-grade glioma (HGG) is one of major reasons for failure of local tumour control with radiotherapy (RT). The use of hyperbaric oxygen therapy (HBO) could help to overcome the problem of oxygen deficiency in poorly oxygenated regions of the tumour. We propose an innovative approach to improve the efficacy of hypofractionated stereotactic radiotherapy (HSRT) after HBO (HBO-RT) for the treatment of recurrent HGG (rHGG) and herein report the results of an ad interim analysis. METHODS: We enrolled a preliminary cohort of 9 adult patients (aged >18 years) with a diagnosis of rHGG. HSRT was administered in daily 5-Gy fractions for 3-5 consecutive days a week. Each fraction was delivered up to maximum of 60 minutes after HBO. RESULTS: Median follow-up from re-irradiation was 11.6 months (range: 3.2-11.6 months). The disease control rate (DCR) 3 months after HBO-RT was 55.5% (5 patients). Median progression-free survival (mPFS) for all patients was 5.2 months (95%CI: 1.34-NE), while 3-month and 6-month PFS was 55.5% (95%CI: 20.4-80.4) and 27.7% (95%CI: 4.4-59.1), respectively. Median overall survival (mOS) of HBO-RT was 10.7 months (95% CI: 7.7-NE). No acute or late neurologic toxicity >grade (G)2 was observed in 88.88% of patients. One patient developed G3 radionecrosis. CONCLUSIONS: HSRT delivered after HBO appears to be effective for the treatment of rHGG, it could represent an alternative, with low toxicity, to systemic therapies for patients who cannot or refuse to undergo such treatments. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT03411408.

Neoadjuvant treatment (FOLFOX4 plus hypofractionated tomotherapy) for patients with locally advanced rectal cancer: a multicenter phase II trial.

AIMS: This study aims to evaluate the safety and efficacy of a new neoadjuvant regimen (FOLFOX4 plus hypofractionated tomotherapy) in patients with locally advanced rectal cancer. METHODS: Patients with stage II-III rectal cancer were treated with the pre-operative chemoradiotherapy regimen comprising FOLFOX4 (two cycles), TomoTherapy (25 Gy in five consecutive fractions, one fraction per day in 5 days on the clinical target volume at the isodose of 95% of the total dose), FOLFOX4 (two cycles), followed by surgery with total mesorectal excision and adjuvant chemotherapy with FOLFOX4 (eight cycles). The primary endpoint was pathological complete response (pCR). RESULTS: Fifty-two patients were enrolled and 50 patients were evaluable. A total of 46 (92%) patients completed chemoradiotherapy according to the study protocol and 49 patients underwent surgery. Overall, 12 patients achieved a pCR (24.5%, 95% CI 12.5-36.5). The most common grade 3 or more adverse events were neutropenia and alteration of the alvus. Adverse reactions due to radiotherapy, mainly grade 1-2 dermatitis, tenesmus, urinary dysfunction and pain, were tolerable and fully reversible. The most important surgical complications included infection, anastomotic leakage and fistula, all resolved with conservative treatment. CONCLUSION: FOLFOX and hypofractionated TomoTherapy is effective and safe in patients with locally advanced rectal cancer. Long-term efficacy needs to be further evaluated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02000050 (registration date: 26 November 2013) https://clinicaltrials.gov/ct2/show/NCT02000050.

68Ga-PSMA-11 PET/CT-Guided Stereotactic Body Radiation Therapy Retreatment in Prostate Cancer Patients with PSA Failure after Salvage Radiotherapy.

(1) Purpose: To investigate the role of 68Ga-PSMA-11 PET/CT in guiding retreatment stereotactic body radiation therapy (SBRT) in prostate cancer (PCa) patients in biochemical recurrence (BCR) after salvage radiotherapy (S-RT). (2) Methods: We retrospectively evaluated PCa patients previously treated with S-RT on the prostate bed and with proven serum prostate antigen (PSA) failure after S-RT. In all patients (pts), 68Ga-PSMA-11 PET/CT was positive in the prostate bed only and guided retreatment SBRT. All retreatments were performed by applying the same radiotherapy protocol (median dose of 18 Gy/3 fractions; IQR 18-21 Gy). The median follow-up was 27 months (range 4-35 months). (3) Results: 38 consecutive patients were considered in this analysis. The overall median PSA level before RT was 1.10 ng/mL (IQR 0.82-2.59). PSA decreased at 3 and 6 months after treatment, with a median value of 0.60 ng/mL (IQR 0.31-0.96; p < 0.001) and 0.51 ng/mL (IQR 0.29-1.17; p < 0.001), respectively. Overall, biochemical recurrence-free survival (b-RFS) was 15.0 months (95% CI 13-23). Grade-1 toxicity was reported in 31.6% of patients (12/38). (4) Conclusion: These results confirm that 68Ga-PSMA-11-PET/CT is able to identify the site of recurrence in patients who have failed S-RT, thus supporting the use of metastases-directed radiotherapy as a safe and effective treatment.

Re-irradiation of recurrent glioblastoma using helical TomoTherapy with simultaneous integrated boost: preliminary considerations of treatment efficacy.

Although there is still no standard treatment for recurrent glioblastoma multiforme (rGBM), re-irradiation could be a therapeutic option. We retrospectively evaluated the efficacy and safety of re-irradiation using helical TomoTherapy (HT) with a simultaneous integrated boost (SIB) technique in patients with rGBM. 24 patients with rGBM underwent HT-SIB. A total dose of 20 Gy was prescribed to the Flair (fluid-attenuated inversion recovery) planning tumor volume (PTV) and 25 Gy to the PTV-boost (T1 MRI contrast enhanced area) in 5 daily fractions to the isodose of 67% (maximum dose within the PTV-boost was 37.5 Gy). Toxicity was evaluated by converting the 3D-dose distribution to the equivalent dose in 2 Gy fractions on a voxel-by-voxel basis. Median follow-up after re-irradiation was 27.8 months (range 1.6-88.5 months). Median progression-free survival (PFS) was 4 months (95% CI 2.0-7.9 months), while 6-month PFS was 41.7% (95% CI 22.2-60.1 months). Median overall survival following re-irradiation was 10.7 months (95% CI 7.4-16.1 months). There were no cases of re-operation due to early or late toxicity. Our preliminary results suggest that helical TomoTherapy with the proposed SIB technique is a safe and feasible treatment option for patients with rGBM, including those large disease volumes, reducing toxicity.

Erratum: Passardi, A. et al. Chemoradiotherapy (Gemox Plus Helical Tomotherapy) for Unresectable Locally Advanced Pancreatic Cancer: A Phase II Study. Cancers 2019, 11, 663.

The authors wish to make the following corrections to this paper [...].

Accelerated hypofractionated radiotherapy plus chemotherapy for inoperable locally advanced non-small-cell lung cancer: final results of a prospective phase-II trial with a long-term follow-up.

BACKGROUND: Concurrent chemotherapy and radiation using conventional fractionation is the standard treatment for inoperable, locally advanced non-small-cell lung cancer (NSCLC). We tested accelerated hypofractionated radiotherapy (AHR) and chemotherapy for the treatment of locally advanced NSCLC. METHODS: Eligible patients with locally advanced NSCLC were treated with induction chemotherapy (cisplatin and docetaxel), followed by AHR using tomotherapy and consolidation chemotherapy. The prescribed doses were 30 Gy/5 daily fractions at the reference isodose (60-70%) to the tumor, and 25 Gy/5 daily fractions to the clinically involved lymph nodes. The primary end-point was response rate (RR); the secondary end-points were acute and late side-effects, local progression-free survival (PFS), metastasis-free survival (MFS) and overall survival (OS). This trial closed before the first planned interim analysis due to poor accrual. RESULTS: From January 2009 to January 2012, 17 of the 23 enrolled patients were evaluable. Treatment yielded an overall RR of 82%. Median follow-up was 87 months (range: 6-87), local PFS was 19.8 months (95% CI 9.7 - not reached), MFS was 9.7 months (95% CI 5.8-46.0) and OS was 23 months (95% CI 8.4-48.4). 70% of patients experienced acute G4 neutropenia, 24% G4 leukopenia, 24% G3 paresthesia, 4% G3 cardiac arrythmia, 4% underwent death after chemotherapy. Late toxicity was represented by 24% dyspnea G3. CONCLUSIONS: AHR combined with chemotherapy is feasible with no severe side-effects, and it appears highly acceptable by patients. TRIAL REGISTRATION: This study is registered with the EudractCT registration 2008-006525-14 . Registered on 9 December 2008.

Chemoradiotherapy (Gemox Plus Helical Tomotherapy) for Unresectable Locally Advanced Pancreatic Cancer: A Phase II Study.

The aim of the study was to evaluate the safety and efficacy of a new chemo-radiotherapy regimen for patients with locally advanced pancreatic cancer (LAPC). Patients were treated as follows: gemcitabine 1000 mg/m2 on day 1, and oxaliplatin 100 mg/m2 on day 2, every two weeks (GEMOX regimen) for 4 cycles, 15 days off, hypofractionated radiotherapy (35 Gy in 7 fractions in 9 consecutive days), 15 days off, 4 additional cycles of GEMOX, restaging. From April 2011 to August 2016, a total of 42 patients with non resectable LAPC were enrolled. Median age was 67 years (range 41-75). Radiotherapy was well tolerated and the most frequently encountered adverse events were mild to moderate nausea and vomiting, abdominal pain and fatigue. In total, 9 patients underwent surgical laparotomy (5 radical pancreatic resection 1 thermoablation and 3 explorative laparotomy), 1 patient became operable but refused surgery. The overall resectability rate was 25%, while the R0 resection rate was 12.5%. At a median follow-up of 50 months, the median progression-free survival and overall survival were 9.3 (95% CI 6.2-14.9) and 15.8 (95% CI 8.2-23.4) months, respectively. The results demonstrate the feasibility of a new chemo-radiotherapy regimen as a potential treatment for unresectable LAPC.

SLUG silencing increases radiosensitivity of melanoma cells in vitro.

BACKGROUND: Melanoma radioresistance has been attributed to the presence of tumor cells with highly efficient DNA damage repair mechanisms. We examined the expression of genes involved in DNA damage repair and DNA damage sensing, and assessed their modulation by SLUG silencing, which is potentially capable of increasing radiosensitivity. METHODS: Two melanoma cell lines (M14 and M79) were used to evaluate in vitro radiation-induced cytotoxicity before and after SLUG silencing. mRNA expression levels of BRCA1, ERCC1, DNA-PK, PARP, MGMT, ATM and TGM2 were determined by real-time RT-PCR, and protein expression levels of SLUG, caspase 3, p21, PUMA and pMAPK by Western blotting. RESULTS: The cytotoxic effect of radiation was high in M14 and low in M79 cells. SLUG silencing increased the interference of radiation on cell cycle distribution and cell killing by 60 % and 80 % in M79 cells after a 2.4 Gy and 5 Gy radiation dose, respectively. It also led to a significant inhibition of expression of genes involved in DNA damage repair and DNA damage sensing in all cell lines maintained after radiation. An almost total inhibition was observed for TGM2, which is expressed at a high basal level in the most radioresistant cell line (M79). Protein expression of PUMA was induced by radiation and was enhanced after SLUG silencing. CONCLUSIONS: Our results reveal a pivotal role of SLUG in regulating a cellular network involved in the response to DNA damage, and highlight the importance of TGM2 in radiosensitivity modulation. SLUG silencing appears to increase radiation sensitivity of the melanoma cells tested.

11C-methionine vs. 18F-FDG PET in soft tissue sarcoma patients treated with neoadjuvant therapy: preliminary results.

OBJECTIVE: In patients with soft tissue sarcoma (STS) the histological response (tumour grade regression: TGR) to neoadjuvant chemoradiotherapy (CRT) may influence the outcome. The main aim of the study was to evaluate the predictive value of 11C-methionine (MET) and 18F-FDG PET/CT in patients with STS treated with neoadjuvant CRT, correlating TGR with SUVmax (standardized uptake value) percentage variation before and after CRT. PATIENTS AND METHODS: Nine patients with STS already scheduled for a neoadjuvant CRT and surgery were enrolled. They underwent MET and FDG PET/CT in a one-day procedure before and after the CRT. Pre-therapy SUVmax and the percentage variation of SUVmax for MET and FDG were correlated with TGR according to the Huvos grade. Grades I-II were considered as partial responders (PR) and grades III-IV as complete responders (CR). RESULTS: FDG pre-treatment mean SUVmax in PR patients was 7.1, while in CR patients it was 13.2. Pre-treatment mean MET SUVmax in PR patients was 75, while in CR patients it was 4.9. The mean percentage variation in FDG SUVmax, was -21.2% in PR patients and -745% in CR patients while that for MET SUVmax was 48% in PR patients and -53.9% in CR patients. CONCLUSION: According to this preliminary study, the percentage variation in FDG before and after CRT seems to discriminate between PR and CR better than MET.