Outcomes and toxicity in re-irradiation of gynecologic cancer: Systematic review of the Italian association of radiation and clinical oncology (AIRO).

AIMS: The aim of this study was to provide a literature review on the efficacy and safety of reirradiation(re-I) of locoregional recurrences in gynecological malignancies. METHODS: A computerized literature search was performed in 4 electronic databases (1993-2020). Random-effects models and a tendency towards high heterogeneity (Cochran Q chi-square test and the I2 statistic) were used. A meta-analysis technique over single and multi-arm studies was performed to determine the pooled acute and late toxicity rate ≥ G3, locoregional control (LC), and overall survival (OS). RESULTS: Out of 178 articles, only 18 articles accounting for 820 patients (pts) met the inclusion criteria. Outcomes were evaluable for 522 patients. Subgroup analyses highlighted moderate to high heterogeneity among studies. BT (Brachytherapy) showed a 2y OS of 63% (95% CI, 55 to 71 p = 0,36) and 5y OS of 42% (95% CI, 35 to 50, p = 0,43) with 1y-2y-3y LC of 74 (95% CI, 62 to 75, p = 0.04)49% (95% CI, 40 to 58, p = 0.38) and 48% (95% CI, 39 to 58, p = 0,45) respectively. Chemotherapy does not improve SBRT outcomes: BT showed a G3- G4 toxicities rate was of26% (95% CI: 8-49%); studies on SBRT re-I showed a G3-G4 toxicity around of 20% if combined with CHT, and <10 when alone. CONCLUSION: A large heterogeneity among studies was revealed, but showing promising results in terms of safety and feasibility. BT resulted the best kind of radiation therapy delivery in terms of clinical outcome and comparable to the SBRT technique in terms of toxicities.

Pattern of care for re-irradiation in locally recurrent rectal cancer: a national survey on behalf of the AIRO gastrointestinal tumors study group.

PURPOSE: Radical resection (R0) represents the best curative treatment for local recurrence (LR) rectal cancer. Re-irradiation (re-RT) can increase the rate of R0 resection. Currently, there is a lack of guidelines on Re-RT for LR rectal cancer. The Italian Association of Radiation and clinical oncology for gastrointestinal tumors (AIRO-GI) study group released a national survey to investigate the current clinical practice of external beam radiation therapy in these patients. MATERIAL AND METHODS: In February 2021, the survey was designed and distributed to members of the GI working group. The questionnaire consisted of 40 questions regarding center characteristics, clinical indications, doses, and treatment techniques of re-RT for LR rectal cancer. RESULTS: A total of 37 questionnaires were collected. Re-RT was reported as an option for neoadjuvant treatment in resectable and unresectable disease by 55% and 75% of respondents, respectively. Long-course treatment with 30-40 Gy (1.8-2 Gy/die, 1.2 Gy bid) and hypofractionated regimen of 30-35 Gy in 5 fractions were used in most centers. A total dose of 90-100 Gy as EqD2 dose (α/ß = 5 Gy) was delivered by 46% of the respondents considering the previous treatment. Modern conformal techniques and daily image-guided radiation therapy protocols were used in 94% of centers. CONCLUSION: Our survey showed that re-RT treatment is performed with advanced technology that allow a good management of LR rectal cancer. Significant variations were observed in terms of dose and fractionation, highlighting the need for a consensus on a common treatment strategy that could be validated in prospective studies.

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.

Complete pathological response in locally advanced non-small-cell lung cancer patient: A case report.

BACKGROUND: Chemotherapy and radiotherapy followed by durvalumab is currently the standard treatment for locally advanced node-positive non-small-cell lung cancer (NSCLC). We describe the case of a patient with locally advanced node-positive NSCLC (LA-NSCLC) treated in a phase II prospective protocol with chemotherapy, accelerated hypofractionated radiotherapy (AHRT) and surgery in the pre-immunotherapy era. CASE SUMMARY: A 69-year-old male, ex-smoker (20 PY), with a Karnofsky performance status of 90, was diagnosed with locally advanced squamous cell lung carcinoma. He was staged by total body computed tomography (CT) scanning, and integrated 18F-fluorodeoxyglucose positron emission tomography/CT scan [cT4 cN3 cM0, stage IIIC according to TNM (tumor-node-metastasis) 8th edition] and received AHRT between chemotherapy cycles, in accordance with the study protocol (EudractCT registration 2008-006525-14). At the end of the study the patient underwent surgery, which was not part of the protocol, and showed a complete pathological response. CONCLUSION: This case report confirms that AHRT can be used successfully to treat primary LA-NSCLC with bilateral mediastinal lymph node involvement. Our case is of particular interest because of the pathological response after AHRT and the lack of surgical complications. We hypothesize that this radiotherapeutic approach, with its proven efficacy, could be delivered as a short course reducing treatment costs, increasing patient compliance and reducing toxicity. We are currently investigating the possibility of combining hypofractionation, chemotherapy and immunotherapy for patients with LA-NSCLC.

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.

High-pressure oxygen rewires glucose metabolism of patient-derived glioblastoma cells and fuels inflammasome response.

Human glioblastoma (GBM) is one of the most feared primary malignant brain tumors. We investigated the effect of hyperbaric oxygen (HBO) on GBM patient-derived cells and on microglia cell biology (CHME-5). HBO administered to GBM cells inhibited cell proliferation, downregulated hypoxia-inducible factor 1 α (HIF-1α) expression, and induced glucose metabolism reprogramming (glucose rewiring). It also affected the ability of a cell to perpetuate its lineage, give rise to differentiated cells and interact with its environment to maintain a balance between quiescence, proliferation and regeneration (stemness features). Such an effect may be ascribable to an increase in intracellular ROS levels and to the triggering of inflammasome signaling by HBO itself through caspase1 activation. Moreover, the results obtained from the combination of HBO and radiotherapy (RT) clearly showed a radiosensitising effect of HBO on GBM cells grown in both 2D and 3D, and a radioprotective effect of HBO in CHME-5. In addition, the exposure of M0 microglia cells to exhausted medium or extracellular vesicles (EVs) of HBO-treated GBM cells upregulated the expression of pro-inflammatory cytokines IL1ß, IL6 and STAT1, whilst also downregulating the anti-inflammatory cytokine PPARγ. Collectively, these data provide a scientific rationale for the use of HBO in combination with RT for the treatment of patients with GBM.

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.

Effects of radiotherapy and short-term starvation combination on metastatic and non-tumor cell lines.

BACKGROUND: Since its discovery in the late 19th century, radiotherapy has been one of the most important medical treatments in oncology. Recently, fasting or short-term starvation (STS) in cancer patients undergoing chemotherapy has been studied to determine its potential for enhancing the therapeutic index and for preventing side- effects, but no data are available in the radiotherapy setting. We thus decided to investigate the effects in vitro of STS in combination with radiotherapy in metastatic cancer cells and non-cancer cells. METHODS: Cells were incubated in short-term starvation medium (STS medium, 0·5 g/L glucose + 1% FBS) or in control medium (CM medium, 1 g/L glucose + 10 % FBS) for 24 h and then treated with single high-dose radiation. A plexiglass custom-built phantom was used to irradiate cells. DNA damage was evaluated using alkaline comet assay and theCometAnalyser software. The cell surviving fraction was assessed by clonogenic assay. FINDING: STS followed by single high-dose radiation significantly increased DNA damage in metastatic cancer cell lines but not in normal cells. Furthermore, STS reduced the surviving fraction of irradiated tumor cells, indicating a good radio-sensitizing effect on metastatic cell lines. This effect was not observed in non-tumor cells. INTERPRETATION: Our results suggest that STS may alter cellular processes, enhancing the efficacy of radiotherapy in metastatic cancer cellsin vitro. Interestingly, STS has radioprotective effect on the survival of healthy cells.

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.

Efficacy and toxicity of CyberKnife re-irradiation and "dose dense" temozolomide for recurrent gliomas.

BACKGROUND: Stereotactic radiosurgery (SRS) can be a useful adjunct to the treatment of recurrent glioblastoma multiforme (GBM). Its combination with chemotherapy is attractive for the possible radiosensitization effect and cytotoxicity on tumor cells in distant areas. The aim of this study was to evaluate the efficacy and toxicity of CyberKnife SRS alone and combined with a "dose-dense" administration of temozolomide (TMZ) for recurrent GBM. METHODS: Between July 2007 and July 2010, 23 patients underwent CyberKnife SRS. In 12 patients irradiation was combined with TMZ at 75 mg/m(2)/day for 21 days every 28 days. The median prescription dose in this group was 20 Gy (mean 20.7 ± 4 Gy) with a median number of fractions of 2. The median dose for the 11 patients who underwent SRS alone was 20 Gy (mean 19.9 ± 4.4 Gy; p = NS). RESULTS: The median survival was 12 months for patients who underwent SRS/TMZ and 7 months for those who received SRS alone (p < 0.01). The 6-month progression-free survival (PFS) of the SRS/TMZ group was 66.7% vs. 18% for those who underwent SRS alone (p = 0.03). The median time to progression (TTP) was 7 months for patients who underwent SRS/TMZ and 4 months for those who underwent SRS alone (p = 0.01). Corticosteroid dependency was developed by most patients; radionecrosis was evident in one patient (4.3%) receiving TMZ. Grade 3 hematological toxicity was recorded in >40% of patients receiving chemotherapy. CONCLUSIONS: The results suggest that Cyberknife re-treatments are relatively safe using selected dose/fraction schemes. The combination with TMZ improved patients' outcomes with OS and 6-month PFS that favorably compares with alternative treatments, but the incidence of major adverse effects was >40%. Further studies are warranted.