Whole Brain Irradiation or Stereotactic RadioSurgery for five or more brain metastases (WHOBI-STER): A prospective comparative study of neurocognitive outcomes, level of autonomy in daily activities and quality of life.

AIMS: To evaluate neurocognitive performance, daily activity and quality of life (QoL), other than usual oncologic outcomes, among patients with brain metastasis ≥5 (MBM) from solid tumors treated with Stereotactic Brain Irradiation (SBI) or Whole Brain Irradiation (WBI). METHODS: This multicentric randomized controlled trial will involve the enrollment of 100 patients (50 for each arm) with MBM ≥ 5, age ≥ 18 years, Karnofsky Performance Status (KPS) ≥ 70, life expectancy > 3 months, known primary tumor, with controlled or controllable extracranial disease, baseline Montreal Cognitive Assessment (MoCA) score ≥ 20/30, Barthel Activities of Daily Living score ≥ 90/100, to be submitted to SBI by LINAC with monoisocentric technique and non-coplanar arcs (experimental arm) or to WBI (control arm). The primary endpoints are neurocognitive performance, QoL and autonomy in daily-life activities variations, the first one assessed by MoCa Score and Hopkins Verbal Learning Test-Revised, the second one through the EORTC QLQ-C15-PAL and QLQ-BN-20 questionnaires, the third one through the Barthel Index, respectively. The secondary endpoints are time to intracranial failure, overall survival, retreatment rate, acute and late toxicities, changing of KPS. It will be considered significant a statistical difference of at least 30% between the two arms (statistical power of 80% with a significance level of 95%). DISCUSSION: Several studies debate what is the decisive factor accountable for the development of neurocognitive decay among patients undergoing brain irradiation for MBM: radiation effect on clinically healthy brain tissue or intracranial tumor burden? The answer to this question may come from the recent technological advancement that allows, in a context of a significant time saving, improved patient comfort and minimizing radiation dose to off-target brain, a selective treatment of MBM simultaneously, otherwise attackable only by WBI. The achievement of a local control rate comparable to that obtained with WBI remains the fundamental prerequisite. TRIAL REGISTRATION: NCT number: NCT04891471.

Lattice or Oxygen-Guided Radiotherapy: What If They Converge? Possible Future Directions in the Era of Immunotherapy.

Palliative radiotherapy has a great role in the treatment of large tumor masses. However, treating a bulky disease could be difficult, especially in critical anatomical areas. In daily clinical practice, short course hypofractionated radiotherapy is delivered in order to control the symptomatic disease. Radiation fields generally encompass the entire tumor mass, which is homogeneously irradiated. Recent technological advances enable delivering a higher radiation dose in small areas within a large mass. This goal, previously achieved thanks to the GRID approach, is now achievable using the newest concept of LATTICE radiotherapy (LT-RT). This kind of treatment allows exploiting various radiation effects, such as bystander and abscopal effects. These events may be enhanced by the concomitant use of immunotherapy, with the latter being ever more successfully delivered in cancer patients. Moreover, a critical issue in the treatment of large masses is the inhomogeneous intratumoral distribution of well-oxygenated and hypo-oxygenated areas. It is well known that hypoxic areas are more resistant to the killing effect of radiation, hence the need to target them with higher aggressive doses. This concept introduces the "oxygen-guided radiation therapy" (OGRT), which means looking for suitable hypoxic markers to implement in PET/CT and Magnetic Resonance Imaging. Future treatment strategies are likely to involve combinations of LT-RT, OGRT, and immunotherapy. In this paper, we review the radiobiological rationale behind a potential benefit of LT-RT and OGRT, and we summarize the results reported in the few clinical trials published so far regarding these issues. Lastly, we suggest what future perspectives may emerge by combining immunotherapy with LT-RT/OGRT.

How Much Daily Image-guided Volumetric Modulated Arc Therapy Is Useful for Proctitis Prevention With Respect to Static Intensity Modulated Radiotherapy Supported by Topical Medications Among Localized Prostate Cancer Patients?

BACKGROUND/AIM: To evaluate if topical support therapy during static-intensity modulated radiotherapy (sIMRT) course is able to equal the characteristic minimum risk for radiation proctitis of Image-guided volumetric modulated arc therapy (IG-VMAT) treatment among localized prostate cancer patients. PATIENTS AND METHODS: Rectal toxicity data of the above patients were retrospectively collected throughout three different clinical periods at our Radiotherapy Deparment: from October 2011 to December 2012, prostate cancer patients were treated with sIMRT and in advance supported by means of daily topical corticosteroids; from January 2013 to November 2016, topical corticosteroids were replaced by daily hyaluronic acid enemas; from December 2016 to May 2018 eligible patients were treated with newly introduced IG-VMAT supported by only on-demand topical corticosteroids. RESULTS: Among 359 eligible patients, IG-VMAT was proven generally more effective than sIMRT supported by topical medications in terms of proctitis reduction, although without clinical and practical relevance. CONCLUSION: Topical medications might have a role in radiation proctitis prevention.

Anatomical Predictors of Dosimetric Advantages for Deep-inspiration-breath-hold 3D-conformal Radiotherapy Among Women With Left Breast Cancer.

BACKGROUND/AIM: This study aimed to analyze the dosimetric gain of the deep-inspiration-breath-hold (DIBH) technique over the free-breathing (FB) one in left breast cancer (LBC) 3D-conformal-radiotherapy (3D-CRT), and simultaneously investigate the anatomical parameters related to heart RT-exposure. PATIENTS AND METHODS: Treatment plans were generated in both DIBH and FB scenarios for 116 LBC patients monitored by the Varian RPM™ respiratory gating system for delivery of conventional or moderately hypofractionated schedules (±sequential boost). For comparison, we considered cardiac and ipsilateral lung doses and volumes. RESULTS: A significant reduction of cardiac and pulmonary doses using DIBH technique was achieved compared to FB plans. Larger clinical target volumes generally need longer distance between medial and lateral entrances of tangent fields at body surface, thus conditioning a worse heart RT-exposure. CONCLUSION: The DIBH technique reduces cardiac and pulmonary doses for LBC patients. Through easily detectable anatomical parameters, it is possible to predict which patients benefit most from DIBH-RT.

Phase II trial of high dose stereotactic body radiation therapy for lymph node oligometastases.

Lymph nodes are common sites of oligometastases for several primaries. Stereotactic body radiation therapy (SBRT) represents an effective treatment but no consensus exists regarding dose and fractionation. Aim of this trial was to evaluate safety and efficacy of high-dose SBRT. We included patients with 1 to 3 lymph node metastases. Primary end-point was safety, while secondary end-points were in-field local control (LC), out-field lymph nodal progression free survival (LPFS), distant metastasis free survival (DMFS), progression free survival (PFS) and overall survival (OS). 64 lesions in 52 patients were treated from 2015 to 2019. Most common primary tumor was genitourinary cancer (75%), in particular prostate cancer (65.4%). With a median follow-up of 24.4 months (range 3-49), treatment was very well tolerated, with only 4 (7.7%) patients reporting acute side effects, all classified as grade 1, in the form of pain, fatigue, nocturia and dysuria. No toxicity ≥ grade 2 were reported. Rates of LC at 1, 2 and 3 years were 97.9%, 82.1% and 82.1%. Male sex (HR 0.12, p value 0.014) was associated with improved LC. LPFS at 1, 2 and 3 years were 69.6%, 49.6% and 46.1%, respectively, and DMFS was 81.74%, 67.5% and 58.5%, respectively. Presence of lesions in other organs was correlated with inferior DMFS (HR 3.82, p = 0.042). PFS at 1, 2 and 3 years were 67.4%, 42.4% and 31.86%, respectively. OS at 1, 2 and 3 years were 97.3%, 94.2%, 84%, respectively and significantly correlated with in-field recurrence (HR 8.72, p = 0.000). Our prospective trial confirms safety and efficacy of SBRT in the management of lymph node metastases. Registered Clinical trial NCT02570399.

Prognostic value of two geriatric screening tools in a cohort of older patients with early stage Non-Small Cell Lung Cancer treated with hypofractionated stereotactic radiotherapy.

OBJECTIVES: To investigate whether assessment with two geriatric screening tools shows a correlation with clinical outcomes of patients aged 65 years or more, with early-stage Non-Small Cell Lung Cancer (es-NSCLC) treated with hypofractionated stereotactic radiotherapy. METHODS: From March 2014 to June 2018 we retrospectively evaluated 42 patients with stage I and II lung tumors. Patients were assessed with Charlson Comorbidity Index (CCI) and G8 screening tool. Median age was 74 years (range, 65-91). Stereotactic radiotherapy was performed with Helical Tomotherapy delivering 50-70 Gray (Gy) in 8-10 fractions. Toxicity was evaluated using Common Terminology Criteria for Adverse Events v4.0 criteria. RESULTS: Median CCI and G8 scores were 6 (4-11) and 14 (12-17), respectively. With a median follow-up of 14 months (3-37), we observed: 3 cases of acute Grade 2 (G2) radiation pneumonitis, 1 late G2 non-cardiac chest pain, 1 late G2 dysphagia and 1 case of late G2 radiation pneumonitis. At statistical analysis, G8 scores ≤14 were significantly associated with late toxicity rates (p = .0073). Local failure was predictive of disease free survival and Overall Survival (p < .001 and p = .001). Death occurred in 12 patients, 6 for non-cancer related causes, with 1- and 2-yrs cancer specific survival rates of 94.8% and 90%, 1- and 2-yrs OS rates of 93% and 80%, respectively. CONCLUSIONS: Our experience shows a correlation between G8 scores and late toxicity in older patients treated with stereotactic radiotherapy for lung cancer, suggesting the need for prospective studies evaluating its use for the identification of patients at higher risk of adverse events.

Acute and late toxicity and preliminary outcomes report of moderately hypofractionated helical tomotherapy for localized prostate cancer: a mono-institutional analysis.

AIMS: To assess toxicity and clinical outcomes of moderately hypofractionated helical tomotherapy (HT) for the curative treatment of localized prostate cancer (PC). METHODS: From December 2012 to May 2018, 170 patients were treated with definitive intent for PC. Thirty-four percent were low risk, 30% intermediate risk (IR) and 36% high risk (HR). All patients received 70 Gy in 28 fractions to the prostate; 61.6 Gy were delivered to the seminal vesicles for IR; pelvic lymph nodes irradiation for a total dose of 50.4 Gy was added in the HR subgroup. Toxicity was assessed using CTCAE V4.0, and biochemical failure was defined following Phoenix criteria. Time-to-event data were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: The median follow-up was 36 months (range 12-78); acute toxicity was as follows: G1 and G2 in 27.6% and 19.4% for GI; 53% and 24% for GU. No G ≥ 3 event was observed. For late toxicity, G ≥ 3 GI and GU rates were, respectively, 3% and 2.4% at 3 years and 3% and 4.8% at 4 years; no G4 occurred. A statistical correlation between acute or late G3 incidence and clinical or dosimetric parameters was not found. At the time of analysis, 2- and 3-year biochemical relapse-free survival rates were 90% and 87.5% and 2- and 3-year overall survival rates were 96.4% and 90%, respectively. The log-rank test revealed no difference between the risk groups in terms of biochemical control (p = 0.16). CONCLUSIONS: Moderately hypofractionated RT with HT for localized prostate cancer reported excellent outcomes with mild acute and late toxicity incidence, with promising biochemical control rates.

Trends in combined radio-chemotherapy for locally advanced rectal cancer: a survey among radiation oncology centers of Sicily region on behalf of AIRO.

AIM: To conduct a survey among Sicilian centers of radiation oncology belonging to Associazione Italiana di Radioterapia ed Oncologia Clinica (AIRO), to record the different methods of integration of radio-chemotherapy both in neoadjuvant and adjuvant settings, to evaluate surgical procedures in relation to the sphincter preservation and to report the different toxicity profiles of the treatment strategies. METHODS: A questionnaire was sent at the end of 2017 to all the radiation oncology centers of Sicily region in order to collect the data from individual centers and the treatment characteristics retrospectively over the previous 5 years, from 2012 to 2016. The required data were collected from 13 centers out of 17 which, in relation to the single catchment areas, correspond to approximately 85% of the Sicilian population. The requested data concerned the type of integrated treatment (neoadjuvant vs adjuvant vs radical), combination with chemotherapy (induction, concomitant, adjuvant), type of surgical intervention (sphincter-saving vs abdomino-perineal resection), disease stage, schedule and radiotherapy technique adopted, as well as toxicity detected over the treatment period. RESULTS: A total of 784 pts (M/F: 509/275) were treated between 2012 and 2016, with a median age of 67 years (range 25-92). The majority of patients was treated in the neoadjuvant phase (62% of the total) compared to the adjuvant phase (31%) and to those treated radically (7%). Twenty-five percent of patients did not receive combination chemotherapy mainly for cardiovascular problems. Chemotherapy used concomitantly to radiotherapy was single-agent capecitabine (73% of patients) or 5-fluorouracil (27%). The use of chemotherapy alone before concomitant treatment is more common for patients treated in the adjuvant phase (64% of this subgroup), while 14% of patients treated in the neoadjuvant phase received induction chemotherapy before the concomitant phase; in both cases of chemotherapy alone, the majority of patients (91%) received oxaliplatin-based protocols (FOLFOX/XELOX/CAPOX). Few patients (3%) received chemotherapy alone after the concomitant phase. Information on the surgical treatment received is available for 88% of the sample. Of these, 93% received a surgical treatment. The overall rate of sphincter-saving surgery (anterior resection) was 72%, but the contribution of neoadjuvant treatment allowed to reach a rate of 83% in this subgroup (against 65% found in the subgroup of patients treated in adjuvant phase). Traditional radiotherapy schedule (45-50 Gy in 25-28 fractions) was used in 90% of patients, of which an intensified treatment in neoadjuvant phase (45 Gy + boost of 9-10 Gy) was used in 11% of patients. A short-course regimen (25 Gy in 5 fraction) in neoadjuvant setting was opted rarely (7%). Three-dimensional conformal technique was preferred over intensity-modulated ones (73% vs 27%). Toxicity was mainly of grade I-II CTCAE (skin 23%, gastrointestinal 39%, genitourinary 14%) compared to grade III (gastrointestinal 4%, genitourinary and hematological < 1%). Interestingly, the toxicity rates were significantly higher in the adjuvant group compared to the neoadjuvant (GI: 58% vs 31%, GU: 21% vs 10%). CONCLUSION: The present survey shows that in the Sicily region integrated therapies for rectal cancer have allowed a neoadjuvant approach in the majority of patients, thus resulting in a greater use of sphincter conservative surgery. The toxicity has also been reported to be significantly less in this treatment setting.

Hypofractionated postoperative helical tomotherapy in prostate cancer: a mono-institutional report of toxicity and clinical outcomes.

Purpose: This is a mono-institutional study of acute and late toxicities and early biochemical control of a retrospective series of 75 prostate cancer patients treated with moderate postoperative hypofractionation delivered by helical tomotherapy (HT). Patients and methods: From April 2013 to June 2017, 75 patients received adjuvant (n=37) or salvage (n=38) treatment, delivering to prostate bed a total dose of 63.8 Gy (equivalent dose in 2-Gy fractions=67.4 Gy) using 2.2 Gy fractions. Whole-pelvis irradiation was performed in 63% of cases (median dose, 49.3 Gy; range, 48-55.1 Gy). Concurrent hormonal therapy was administered in 46% of cases. Common Terminology Criteria for Adverse Events (version 4.0) was adopted for acute and late genitourinary (GU) and gastrointestinal (GI) toxicity evaluations. Biochemical progression was defined as PSA level increase of ≥0.2 or more above the postoperative radiotherapy (RT) nadir. Results: Acute GU toxicities were as follows: G1 in 46% and G2 in 4%, detecting no G≥3 events. For GI toxicity, we recorded G1 in 36% and G2 in 18%. With a median follow-up of 30 months (range, 12-58 months), we found late toxicity G2 GI in 6.6% and G≥2 GU in 5.3%, including two patients who underwent surgical incontinence correction. Acute GI≥2 toxicity and diabetes were found to be predictive of late GI≥2 toxicity (P=0.04 and P=0.0019). Actuarial 2- and 3-year biochemical recurrence-free survivals were 88% and 73%, respectively, for the entire population. Conclusion: In our experience, moderate hypofractionated postoperative RT with HT was feasible and safe, with reports of low incidence of toxicity and promising biochemical control rates.