Long-term treatment outcomes of temozolomide-based chemoradiation in patients with adult-type diffuse IDH-mutant grade 2 astrocytoma.

PURPOSE: To report the long-term outcomes in adult patients with grade 2 IDH-mutant astrocytoma treated with temozolomide (TMZ)-based chemoradiation. METHODS: One hundred and three patients with histologically proven grade 2 astrocytoma received radiation therapy (RT), 50.4-54 Gy in 1.8 Gy fractions, and adjuvant TMZ up to 12 cycles. Fifty-two patients received RT at the time of tumor progression and 51 in the early postoperative period for the presence of at least one high-risk feature (age > 40 years, preoperative tumor size > 5 cm, large postoperative residual tumor, tumor crossing the midline, or presence of neurological symptoms). Overall survival (OS) and progression-free survival (PFS) were calculated from the time of diagnosis. RESULTS: With a median follow-up time of 9.0 years (range, 1.3-15 years), median PFS and OS times were 9 years (95%CI, 6.6-10.3) and 11.8 years (95%CI, 9.3-13.4), respectively. Median PFS was 10.6 years in the early treatment group and 6 years in delayed treatment group (hazard ratio (HR) 0.30; 95%CI 0.16-0.59; p = 0.0005); however, OS was not significantly different between groups (12.8 vs. 10.4 years; HR 0.64; 95%CI 0.33-1.25; p = 0.23). Extent of resection, KPS, and small residual disease were associated with OS, with postoperative tumor ≤ 1 cc that emerged as the strongest independent predictor (HR: 0.27; 95%CI 0.08-0.87; p = 0.01). CONCLUSIONS: TMZ-based chemoradiation is associated with survival benefit in patients with grade 2 IDH-mutant astrocytoma. For this group of patients, chemoradiation can be deferred until time of progression in younger patients receiving extensive resection, while early treatment should be recommended in high-risk patients.

Radiation therapy for atypical and anaplastic meningiomas: an overview of current results and controversial issues.

Meningiomas are the most common intracranial tumors. Most meningiomas are WHO grade 1 tumors whereas less than one-quarter of all meningiomas are classified as atypical (WHO grade 2) and anaplastic (WHO grade 3) tumors, based on local invasiveness and cellular features of atypia. Surgical resection remains the cornerstone of meningioma therapy and represents the definitive treatment for the majority of patients; however, grade 2 and grade 3 meningiomas display more aggressive behavior and are difficult to treat. Several retrospective series have shown the efficacy and safety of postoperative adjuvant external beam radiation therapy (RT) for patients with atypical and anaplastic meningiomas. More recently, two phase II prospective trials by the Radiation Therapy Oncology Group (RTOG 0539) and the European Organisation for Research and Treatment of Cancer (EORTC 2042) have confirmed the potential benefits of fractionated RT for patients with intermediate and high-risk meningiomas; however, several issues remain a matter of debate. Controversial topics include the timing of radiation treatment in patients with totally resected atypical meningiomas, the optimal radiation technique, dose and fractionation, and treatment planning/target delineation. Ongoing randomized trials are evaluating the efficacy of early adjuvant RT over observation in patients undergoing gross total resection.

Does restaging MRI radiomics analysis improve pathological complete response prediction in rectal cancer patients? A prognostic model development.

PURPOSE: Our study investigated the contribution that the application of radiomics analysis on post-treatment magnetic resonance imaging can add to the assessments performed by an experienced disease-specific multidisciplinary tumor board (MTB) for the prediction of pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). MATERIALS AND METHODS: This analysis included consecutively retrospective LARC patients who obtained a complete or near-complete response after nCRT and/or a pCR after surgery between January 2010 and September 2019. A three-step radiomics features selection was performed and three models were generated: a radiomics model (rRM), a multidisciplinary tumor board model (yMTB) and a combined model (CM). The predictive performance of models was quantified using the receiver operating characteristic (ROC) curve, evaluating the area under curve (AUC). RESULTS: The analysis involved 144 LARC patients; a total of 232 radiomics features were extracted from the MR images acquired post-nCRT. The yMTB, rRM and CM predicted pCR with an AUC of 0.82, 0.73 and 0.84, respectively. ROC comparison was not significant (p = 0.6) between yMTB and CM. CONCLUSION: Radiomics analysis showed good performance in identifying complete responders, which increased when combined with standard clinical evaluation; this increase was not statistically significant but did improve the prediction of clinical response.

Current status and perspectives of interventional clinical trials for brain metastases: analysis of ClinicalTrials.gov.

BACKGROUND: The management of brain metastases (BM), the major cause of cancer morbidity and mortality, is becoming an emerging area of interest. Surgery, whole brain radiation therapy (WBRT), or stereotactic radiosurgery (SRS), have historically been the main focal treatments for BM. However, the introduction of innovative targeted- and immune-based therapies is progressively changing the paradigm of BM treatment, resulting in an increase in clinical trials investigating new therapeutic strategies. METHODS: Using ClinicalTrials.gov, the largest clinical trial registry with over 400,000 registered trials, we performed an analysis of phase II and phase III ongoing trials evaluating different systemic therapies, radiotherapy (RT), and surgery given alone or in combination in patients with BM. RESULTS: One hundred sixty-eight trials, 133 phase II and 35 phase III; the largest part having primarily the curative treatment of patients with BM from lung cancer, breast cancer and melanoma, were selected. One hundred sixty-three trials used systemic therapies. One hundred thirteen used tyrosine kinase inhibitors, more frequently Osimertinib, Icotinib and Pyrotinib, 50 used monoclonal antibodies, more frequently Trastuzumab, Pembrolizumab, Nivolumab, 20 used conventional chemotherapies whilst no oncological active drugs were used in 6 trials. Ninety-six trials include RT; 54 as exclusive treatment and 42 in combination with systemic therapies. CONCLUSION: Systemic targeted- and/or immune-based therapies, combined or not with RT, are increasingly used in the routine of BM treatment. SRS is progressively replacing WBRT. All these trials intend to address multiple questions on the management of patients with BMs, including the recommended upfront treatment for different cancer histologies and the optimal timing between systemic therapies and radiation regarding brain control and neurocognitive outcome and quality of life.

Feasibility of clinical target volume reduction for glioblastoma treated with standard chemoradiation based on patterns of failure analysis.

PURPOSE: To analyze recurrence patterns in patients with glioblastoma (GBM) after standard chemoradiation according to different target volume delineation strategies. METHODS AND MATERIALS: Two hundred seven patients with GBM who recurred after standard chemoradiation were evaluated. According to ESTRO target volume delineation guideline, the CTV was generated by adding a 2-cm margin to the GTV, defined as the resection cavity plus residual tumor. Patterns of failure were analyzed using dose-volume histogram. Recurrent lesions were defined as in-field, marginal, or distant if > 80 %, 20-80 %, or < 20 % of the intersecting volume was included in the 95 % isodose line.For each patient, a theoretical plan consisting of reduced 1-cm GTV-to-CTV margin was created to compare patterns of failure and radiation doses to normal brain. RESULTS: Median overall survival and progression-free survival times were 15.3 months and 7.8 months, respectively, from the date of surgery. Recurrences were in-field in 180, marginal in 5, and distant in 22 patients. According to MGMT promoter methylation, distant recurrences occurred in 18.6 % of methylated and 6 % of unmethylated tumors (p = 0.0046). Following replanning with 1-cm reduced margin, dosimetric analysis showed similar patterns of failure. Recurrences were in-field, marginal, and distant in 177, 3, and 27 plans, respectively, although radiation doses to the healthy brain and hippocampi were significantly lower compared with standard target delineation (p = 0.0001). CONCLUSION: Current provide the rationale for evaluating GTV-to-CTV margin reduction in future clinical trials with the aim of limiting the cognitive sequelae of GBM irradiation while maintaining survival benefits of standard chemoradiation.

Single-isocenter multiple-target stereotactic radiosurgery for multiple brain metastases: dosimetric evaluation of two automated treatment planning systems.

PURPOSE: Automated treatment planning systems are available for linear accelerator (linac)-based single-isocenter multi-target (SIMT) stereotactic radiosurgery (SRS) of brain metastases. In this study, we compared plan quality between Brainlab Elements Multiple Brain Metastases (Elements MBM) software which utilizes dynamic conformal arc therapy (DCAT) and Varian HyperArc (HA) software using a volumetric modulated arc therapy (VMAT) technique. PATIENTS AND METHODS: Between July 2018 and April 2021, 36 consecutive patients ≥ 18 years old with 367 metastases who received SIMT SRS at UPMC Hillman Cancer San Pietro Hospital, Rome, were retrospectively evaluated. SRS plans were created using the commercial software Elements MBM SRS (Version 1.5 and 2.0). Median cumulative gross tumor volume (GTV) and planning tumor volume (PTV) were 1.33 cm3 and 3.42 cm3, respectively. All patients were replanned using HA automated software. Extracted dosimetric parameters included mean dose (Dmean) to the healthy brain, volumes of the healthy brain receiving more than 5, 8,10, and 12 Gy (V5Gy, V8Gy, V10Gy and V12Gy), and doses to hippocampi. RESULTS: Both techniques resulted in high-quality treatment plans, although Element MBM DCAT plans performed significantly better than HA VMAT plans, especially in cases of more than 10 lesions). Median V12Gy was 13.6 (range, 1.87-45.9) cm3 for DCAT plans and 18.5 (2.2-62,3) cm3 for VMAT plans (p < 0.0001), respectively. Similarly, V10Gy, V8Gy, V5Gy (p < 0.0001) and median dose to the normal brain (p = 0.0001) were favorable for DCAT plans. CONCLUSIONS: Both Elements MBM and HA systems were able to generate high-quality plans in patients with up to 25 brain metastases. DCAT plans performed better in terms of normal brain sparing, especially in patients with more than ten lesions and limited total tumor volume.

Stereotactic radiosurgery for the treatment of brainstem metastases: a multicenter retrospective study.

BACKGROUND: Brainstem metastases (BSM) are associated with a poor prognosis and their management represents a therapeutic challenge. BSM are often inoperable and, in absence of randomized trials, the optimal radiation treatment of BSM remains to be defined. We evaluated the efficacy and toxicity of linear accelerator (linac)-based stereotactic radiosurgery (SRS) and hypofractionated steretotactic radiotherapy (HSRT) in the treatment of BSM in a series of patients treated in different clinical centers. METHODS: We conducted a multicentric retrospective study of patients affected by 1-2 BSM from different histologies who underwent SRS/HSRT. Freedom from local progression (FLP), cancer-specific survival (CSS), overall survival (OS), and treatment-related toxicity were evaluated. In addition, predictors of treatment response and survivals were evaluated. RESULTS: Between 2008 and 2021, 105 consecutive patients with 111 BMS who received SRS or HSRT for 1-2 BSM were evaluated. Median follow-up time was 10 months (range 3-130). One-year FLP rate was 90.4%. At the univariate analysis, tumor volume ≤ 0.4 cc, and concurrent targeted therapy were associated with longer FLP, with combined treatment that remained a significant independent predictor [0.058, HR 0.139 (95% CI 0.0182-1.064]. Median OS and CSS were 11 months and 14.6 months, respectively. At multivariate analysis, concurrent targeted therapy administration was significantly associated with longer OS [HR 0.514 (95%CI 0.302-0.875); p = 0.01]. Neurological death occurred in 30.4% of patients, although this was due to local progression in only 3 (2.8%) patients. CONCLUSION: Linac-based SRS/HSRT offers excellent local control to patients with BSM, with low treatment-related toxicity and no apparent detrimental effects on OS. When treated with ablative intent, BSM are an uncommon cause of neurological death. The present results indicates that patients with BSM should not be excluded a priori from clinical trials.

Leptomeningeal disease and brain control after postoperative stereotactic radiosurgery with or without immunotherapy for resected brain metastases.

PURPOSE: Immunotherapy has shown activity in patients with brain metastases (BM) and leptomeningeal disease (LMD). We have evaluated LMD and intraparenchymal control rates for patients with resected BM receiving postoperative stereotactic radiosurgery (SRS) and immunotherapy or postoperative SRS alone. We hypothesize that postoperative SRS and immunotherapy will result in a lower rate of LMD with acceptable toxicity compared with postoperative SRS. PATIENTS AND METHODS: One hundred and twenty-nine patients with non-small-cell lung cancer (NSCLC) and melanoma BM who received postoperative fractionated SRS (fSRS; 3×9 Gy) in combination with immunotherapy or postoperative fSRS alone for completely resected BM were retrospectively evaluated. The primary endpoint of the study was the rate of LMD after treatments. The secondary endpoints were local failure, distant brain parenchymal failure (DBF), overall survival (OS), and treatment-related toxicity. RESULTS: Sixty-three patients received postoperative SRS and immunotherapy, either nivolumab or pembrolizumab, and 66 patients received postoperative SRS alone to the resection cavity. With a median follow-up of 15 months, LMD occurred in 19 patients: fSRS group, 14; fSRS and immunotherapy, 5. The 12-month LMD cumulative rates were 22% (95% CI 14% to 37%) in the fSRS group and 6% (95% CI 2% to 17%) in the combined treatment group (p=0.007). Resection cavity control was similar between the groups, whereas DBF and OS were significantly different; the 1-year DBF rates were 31% (95% CI 20% to 46%) in the fSRS and immunotherapy group and 52% (95% CI 39% to 68%) in the fSRS group; respective OS rates were 78% (95% CI 67% to 88%) and 58.7% (95% CI 47% to 70%). Twenty-two patients undergoing postoperative fSRS and immunotherapy and nine subjected to postoperative fSRS experienced treatment-related imaging changes suggestive of radiation-induced brain necrosis (p=0.02). CONCLUSIONS: Postoperative fSRS in combination with immunotherapy decreases the incidence of LMD and DBF in patients with resected BM from NSCLC and melanoma as compared with fSRS alone, reducing the rate of neurological death and prolonging survival.

Could the conservative approach be considered safe in the treatment of locally advanced rectal cancer in case of a clinical near-complete or complete response? A retrospective analysis.

BACKGROUND: Conservative approach has emerged as an option for the management of rectal cancer (RC) patients with a near or complete clinical response after neoadjuvant chemoradiotherapy (nCRT). The aim of this study is to assess the impact of the conservative approach by comparing patients' survival outcomes and quality of life with those who had surgical resection. METHODS: A single-institution and retrospective study including RC patients who reached a near complete or complete clinical response after nCRT from January 2010 to September 2019. Conservative approaches included local excision or watch and wait strategy; surgery approaches included anterior resection or abdominal-perineal resection.Local regrowth (LR), overall survival, disease free survival, metastasis free survival and colostomy free survival were evaluated through Kaplan-Meier curves and compared trough log-rank tests. Quality of life was measured by the following validated questionnaires: EORTC QLC30, EORTC QLQ - CR29 and Fecal Incontinence Quality of Life scale. RESULTS: Overall 157 patients were analyzed: 105 (66,9%) underwent radical surgery and 52 (33,1%) had a conservative approach. With a median follow-up of 51 months, 2 patients in the surgical group had a local recurrence and 8 in the conservative group had a LR, respectively. Distance metastasis occurred in 7 and 1 patients of surgical and conservative group, respectively. No differences were detected in terms of survival outcomes except for colostomy free survival (p: 0,01). The conservative group showed better intestinal (p < 0.01) and sexual (p: 0,04) function and emotional status (p: 0,02). CONCLUSIONS: Conservative approach seems to be safe in terms of survival outcomes with a significant advantage on quality of life in RC patients who achieved clinical complete response after nCRT.