Comparing simultaneous integrated boost vs sequential boost in anal cancer patients: results of a retrospective observational study.

BACKGROUND: To evaluate clinical outcomes of simultaneous integrated boost (SIB) - intensity modulated radiotherapy (RT) in patients with non metastatic anal cancer compared to those of a set of patients treated with 3-dimensional conformal RT and sequential boost (SeqB). METHODS: A retrospective cohort of 190 anal cancer patients treated at 3 academic centers with concurrent chemo-RT employing either SIB or SeqB was analysed. The SIB-group consisted of 87 patients, treated with 2 cycles of Mitomycin (MMC) and 5-Fluorouracil (5FU) using SIB-IMRT delivering 42-45Gy/28-30 fractions to the elective pelvic lymph nodes and 50.4-54Gy/28-30fractions to the primary tumor and involved nodes, based on pre-treatment staging. The SeqB group comprised 103 patients, treated with MMC associated to either 5FU or Capecitabine concurrent to RT with 36 Gy/20 fractions to a single volume including gross tumor, clinical nodes and elective nodal volumes and a SeqB to primary tumor and involved nodes of 23.4 Gy/13 fractions. We compared colostomy-free survival (CFS), overall survival (OS) and the cumulative incidence of colostomy for each radiation modality. Cox proportional-hazards model addressed factors influencing OS and CFS. RESULTS: Median follow up was 34 (range 9-102) and 31 months (range 2-101) in the SIB and SeqB groups. The 1- and 2-year cumulative incidences of colostomy were 8.2% (95%CI:3.6-15.2) and 15.0% (95%CI:8.1-23.9) in the SIB group and 13.9% (95%CI: 7.8-21.8) and 18.1% (95%CI:10.8-27.0) in the SeqB group. Two-year CFS and OS were 78.1% (95%CI:67.0-85.8) and 87.5% (95%CI:77.3-93.3) in the SIB group and 73.5% (95%CI:62.6-81.7) and 85.4% (95%CI:75.5-91.6) in the SeqB, respectively. A Cox proportional hazards regression model highlighted an adjusted hazard ratio (AdjHR) of 1.18 (95%CI: 0.67-2.09;p = 0.560), although AdjHR for the first 24 months was 0.95 (95%CI: 0.49-1.84;p = 0.877) for the SIB approach. CONCLUSIONS: SIB-based RT provides similar clinical outcomes compared to SeqB-based in the treatment of patients affected with non metastatic anal cancer.

Variability of clinical target volume delineation for rectal cancer patients planned for neoadjuvant radiotherapy with the aid of the platform Anatom-e.

OBJECTIVE: Delineation of treatment volumes is a major source of uncertainties in radiotherapy (RT). This is also true for rectal cancer patients undergoing neoadjuvant RT, with a potential impact on treatment quality. We investigated the role of the digital platform Anatom-e (Anatom-e Information Sytems Ltd., Houston, Texas) in increasing the compliance to follow a specific treatment protocol in a multicentric setting. MATERIALS AND METHODS: Two clinical cases of locally advanced rectal cancer were chosen. Participants were instructed to follow the 2009 Radiation Therapy Oncology Group consensus atlas and asked to manually segment clinical target volumes (CTVs), for both patient 1 and 2, on day 1 with and without the use of Anatom-e. After one week (day 2), the same radiation oncologist contoured again, with and without Anatom-e, the same CT series. Intraobserver (Intra-OV) and interobserver (Inter-OV) variability were evaluated with the Dice similarity coefficient (DSC), the Hausdorff distance (HD) and mean distance to agreement (MDA). RESULTS: For clinical case 1, no significant difference was found for Intra-OV and Inter-OV. For clinical case 2, no significant difference was found for Intra-OV but a statistically significant difference was found for Inter-OV in DSC when using or not the platform. Mean DCS was 0.65 (SD: ±0.64; range: 0.58-0.79) for day 1 vs reference volume without Anatom-e and 0.72 (SD: ±0.39; range: 0.67-0.77) (p = 0.03) with it. Mean MDA was lower with Anatom-e (3.61; SD: ±1.33; range: 2.85-4.78) than without (4.14; SD: ±2.97; range: 2.18-5.21), with no statistical significance (p = 0.21) The use of Anatom-e decreased the SD from 2.97 to 1.33. Mean HD was lower with Anatom-e (26.06; SD: ±2.05; range: 24.08-32.62), with no statistical significance (p = 0.14) compared to that without (31.39; SD: ±1.31; range: 26.14-48.72). CONCLUSIONS: The use of Anatom-e decreased the Inter-OV in the CTV delineation process for locally advanced rectal cancer with complex disease presentation planned for neoadjuvant RT. This system may be potentially helpful in increasing the compliance to follow shared guidelines and protocols.

Dose to Pelvic Bone Marrow Defined with FDG-PET Predicts for Hematologic Nadirs in Anal Cancer Patients Treated with Concurrent Chemo-radiation.

PURPOSE: To investigate whether irradiated volume of pelvic active bone marrow (ACTBM) may predict decreased blood cells nadirs in anal cancer patients undergoing concurrent chemo-radiation. METHODS: Forty-four patients were analyzed and pelvic active bone marrow (ACTBM) was characterized employing 18FDG-PET. Dosimetric parameters on dose-volume histograms were correlated to nadirs with generalized linear modeling. RESULTS: ACTBM mean dose was significantly correlated to white blood cell (ß = -1.338; 95%CI: -2.455/-0.221; p = 0.020), absolute neutrophil count (ß = -1.651; 95%CI: -3.284/-0.183; p = 0.048), and platelets (ß = -0.031; 95%CI: -0.057/-0.004; p = 0.024) nadirs. Other dosimetric parameters were found to be correlated (ACTBM-V10,-V20,-V30and-V40). CONCLUSIONS: 18FDG-PET is able to define active bone marrow and may predict for decreased blood cells count nadirs.

Image-guided IMRT with simultaneous integrated boost as per RTOG 0529 for the treatment of anal cancer.

AIM: To report on clinical outcomes of simultaneous integrated boost intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy as per Radiation Therapy Oncology Group (RTOG) 0529 protocol in anal cancer patients. METHODS: Clinical stage T1-T4 N0-N3 anal cancer patients were submitted to concomitant chemoradiation. Patients with cT2N0 disease were prescribed 50.4 Gy/28 fractions to the gross tumor planning target volume (PTV) and 42 Gy/28 fractions to the elective nodal PTV. Patients staged as cT3-T4/N0-N3 were given 54 Gy/30 fractions to the macroscopic anal PTV, while clinical nodes were prescribed 50.4 Gy/30 fractions if <3 cm or 54 Gy/30 fractions if ≥3 cm; elective nodal PTV was prescribed 45 Gy/30 fractions. Two cycles of concomitant 5-fluorouracil and mitomycin C were planned for all patients. Oncological outcomes, acute and late toxicity profiles and pattern of failure were reported. RESULTS: The 3-year colostomy-free survival rate was 64% (95% CI 0.52-0.75). The 3-year local control, disease-free and overall survival rates were 69% (95% CI 0.57-0.79), 71% (95% CI 0.59-0.80) and 79% (95% CI 0.66-0.87), respectively. The cumulative incidence of colostomies was 15.1% (95% CI 8.15-23.88) at 24 months. The cumulative incidence of cancer-specific deaths was 16.4% (95% CI 8.60-26.47) at 36 months. Major acute toxicity consisted of hematological (G3-G4: 26%) and cutaneous (G3-G4: 16%) events. Only one case of ≥G3 late toxicity was documented. CONCLUSIONS: Simultaneous integrated boost IMRT and concurrent chemotherapy as per RTOG 0529 protocol seems to be safe and feasible with consistent oncological outcomes and a mild acute and late toxicity profile in anal cancer patients.

Incorporating 18FDG-PET-defined pelvic active bone marrow in the automatic treatment planning process of anal cancer patients undergoing chemo-radiation.

BACKGROUND: To investigate whether the incorporation of 18FDG-PET into the automatic treatment planning process may be able to decrease the dose to active bone marrow (BM) for locally advanced anal cancer patients undergoing concurrent chemo-radiation (CHT-RT). METHODS: Ten patients with locally advanced anal cancer were selected. Bone marrow within the pelvis was outlined as the whole outer contour of pelvic bones or employing 18FDG-PET to identify active BM within osseous structures. Four treatment planning solutions were employed with different automatic optimization approaches toward bone marrow. Plan A used iliac crests for optimization as per RTOG 05-29 trial; plan B accounted for all pelvic BM as outlined by the outer surface of external osseous structures; plan C took into account both active and inactive BM as defined using 18FDG-PET; plan D accounted only for the active BM subregions outlined with 18FDG-PET. Dose received by active bone marrow within the pelvic (ACTPBM) and in different subregions such as lumbar-sacral (ACTLSBM), iliac (ACTIBM) and lower pelvis (ACTLPBM) bone marrow was analyzed. RESULTS: A significant difference was found for ACTPBM in terms of Dmean (p = 0.014) V20 (p = 0.015), V25 (p = 0.030), V30 (p = 0.020), V35 (p = 0.010) between Plan A and other plans. With respect to specific subsites, a significant difference was found for ACTLSBM in terms of V30 (p = 0.020)), V35 (p = 0.010), V40 (p = 0.050) between Plan A and other solutions. No significant difference was found with respect to the investigated parameters between Plan B,C and D. No significant dosimetric differences were found for ACTLSPBM and ACTIBM and inactive BM subregions within the pelvis between any plan solution. CONCLUSIONS: Accounting for pelvic BM as a whole compared to iliac crests is able to decrease the dose to active bone marrow during the planning process of anal cancer patients treated with intensity-modulated radiotherapy. The same degree of reduction may be achieved optimizing on bone marrow either defined using the outer bone contour or through 18FDG-PET imaging. The subset of patients with a benefit in terms of dose reduction to active BM through the inclusion of 18FDG-PET in the planning process needs further investigation.

No differences in radiological changes after 3D conformal vs VMAT-based stereotactic radiotherapy for early stage non-small cell lung cancer.

OBJECTIVE: To compare patterns of acute and late radiological lung injury following either 3D conformal or image-guided volumetric modulated arc therapy stereotactic radiotherapy for Stage I non-small-cell lung cancer. METHODS: We included 148 patients from a prospective mono-institutional stereotactic body radiation therapy (SBRT) series (time interval 2004-2014), treated with prescription BED10 Gy (at 80%) in the range 100-120 Gy. The first 95 patients (2004-2010) were planned with 3D-CRT, with a stereotactic body frame. The second cohort (2010-2014) included 53 patients, planned with volumetric IMRT on a smaller planning target volume generated from a patient's specific internal target volume, with a frameless approach through cone-beam CT guidance. Acute and late radiological modifications were scored based on modified Kimura's and Koenig's classifications, respectively. RESULTS: Median follow-up time was 20.5 months. The incidence of acute radiological changes was superimposable between the groups: increased density was observed in 68.4 and 64.2% of patients for 3D-CRT and VMAT, respectively, and patchy ground glass opacity in 23.7 and 24.5%, respectively; diffuse ground glass opacity was 2.6 vs 9.4%, respectively, and patchy consolidation 2.6 vs 1.9%, respectively. Late changes occurred in approximately 60% of patients: modified conventional pattern was the most frequent modification (25 vs 32.6%, respectively); other patterns were less common (mass-like 19.6 vs 17.4%, and scar-like 13 vs 10.9%, respectively). CONCLUSION: Results of the present study indicate that the pattern of radiological lung changes following SBRT for peripheral early stage non-small-cell lung cancer is not influenced by the different techniques used for planning and delivery. Advances in knowledge: This comparative observational study shows that smaller margins, image guidance and most importantly dose distribution do not change the pattern of radiological injury after lung SBRT; the same scoring system can be used, and expected incidence is similar.

Radiosurgery/stereotactic radiotherapy in combination with immunotherapy and targeted agents for melanoma brain metastases.

INTRODUCTION: The clinical landscape of advanced melanoma drastically changed after the introduction of both targeted therapies and immunotherapy. This rapid development in systemic therapies led to a change in the management of patients with brain metastases, with the subsequent need to re-assess the role of local therapies, in particular stereotactic radiosurgery (SRS). Areas covered: In this non-systematic review, we report on the current knowledge on the use of SRS in combination with immunotherapy and BRAF/MEK inhibitors for patients with melanoma brain metastases, as well as ongoing trials in this field. Expert commentary: It is now more common to observe patients with melanoma brain metastases with better performance status and prolonged life expectancy. A combination of targeted therapy and immunotherapy, in different sequences, has been shown to be feasible and well tolerable, on the basis of retrospective reports. Additional data from ongoing prospective trials are however needed to confirm or not these findings and better explore the efficacy of the combination.

Pre-operative treatments for adenocarcinoma of the lower oesophagus and gastro-oesophageal junction: a review of the current evidence from randomized trials.

Adenocarcinomas of the lower oesophagus and gastro-oesophageal junction are a complex clinico-pathological setting. Multimodality therapy is considered mandatory in most disease presentations. Nevertheless, the most appropriate treatment package has yet to be established. We herein summarize the evidence derived from randomized phase III trials on pre-operative treatments in this oncological scenario.

Stereotactic ablative radiotherapy in the treatment of hepatocellular carcinoma >3 cm.

Stereotactic ablative radiotherapy (SABR) is a safe treatment approach for hepatocellular carcinoma (HCC) with comparable results to other local therapies. For lesions larger than 3 cm, no definitive standard treatment is present and several options are available. We retrospectively review local control (LC) and survival results of SABR in patients with HCC lesions >3 cm. Between 2012 and 2015, we treated 29 patients (39 lesions) having histological or radiological diagnosis of HCC and at least one lesion sized >3 cm. Patients were prescribed 36-48 Gy in 3-5 fractions (mainly 16 Gy × 3 fractions or 8 Gy × 5 fractions), in 3-5 consecutive days. A total of 15 lesions (52 %) had complete, while 10 (34 %) had partial remission; 3 (11 %) had a stable disease. Mean time for CR achievement was 5.8 months (range 1-17). One- and two-year actuarial LC was 100 %. Moreover, 1- and 2-year progression-free (PFS), cancer-specific and overall survival were 57.9 % [standard error (SE) 0.09; 95 % CI 36.9-74.2] and 41.2 % (SE 0.12; 95 % CI 17.7-63.5), 80.7 % (SE 0.08; 95 % CI 59.6-91.5) and 63.3 % (SE 0.11; 95 % CI 38.4-80.3), 71.7 % (SE 0.08; 95 % CI 51.2-84.7) and 56.2 % (SE 0.10; 95 % CI 33.8-73.6). On multivariate analysis, achieving a CR within the target lesion had a borderline significance with respect to PFS (HR 0.83; SE = 0.014; z -1.15; p = 0.095; 95 % CI 0.71-7.45). Time between HCC diagnosis and SABR delivery (< vs >12 months) was significantly correlated with OS (HR 16.5; SE 21.5; z = 2.14; p = 0.032; 95 % CI 1.27-213.3) as CLIP score (score: 0-1 vs 2) (HR 5.6; SE 4.6; z = 2.10; p = 0.036; 95 % CI 1.11-27.8). A total of 6 major toxic events (G3-G4) were recorded (20 %). In 2 patients (6 %), a radiation-induced liver disease was seen. In conclusion, SABR provided LC and survival rates comparable to other local therapies for patients with HCC lesion sized >3 cm, with acceptable toxicity profile.

Stereotactic ablative radiation therapy prior to liver transplantation in hepatocellular carcinoma.

OBJECTIVE: Stereotactic ablative radiotherapy (SABR) is a safe treatment approach for hepatocellular carcinoma (HCC) with comparable effectiveness to other local therapies. Only scant information is available concerning the role of SABR prior to liver transplantation (LT) for HCC. We present a consecutive case series investigating the role of SABR as a bridge or downstaging option in HCC patients subsequently submitted to LT. MATERIALS AND METHODS: Between September 2012 and May 2014, 8 patients for a total of 13 lesions underwent SABR prior to LT. Inclusion criteria were a pathological or radiological diagnosis of HCC, lesion size ≤6 cm or lesion number ≤3 with a total diameter ≤6 cm, no extrahepatic metastases, Child-Pugh class A-B, ECOG performance status ≤1. Patients were prescribed 36-48 Gy in 3-5 fractions (8 Gy × 5 fractions or 16 Gy × 3 fractions), in 3-5 consecutive days according to clinical and dosimetric decision making. Radiological response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Pathological response was assessed through the rate of tumor necrosis relative to the total tumor volume. Acute and late toxicities were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 (CTCAE v 4.0). RESULTS: Among the 13 pathologically evaluated lesions, 8 (61.5 %) lesions had a complete response 2 (15.3 %) had a minimal pathological response and other 2 (15.3 %) showed stable disease. The remaining lesion had a significant pathological response. Maximum detected toxicity included a G2 GGT increase in two patients (at 1 and 3 months respectively). One patient developed a non-classic RILD with a fivefold increase in transaminase enzymes level and a shift in Child-Pugh category from B7 to C10 due to bilirubin increase. Only one modification in the surgical strategy was needed during LT. CONCLUSIONS: SABR proved to be a safe and effective local therapy prior to LT in HCC patients. Prospective controlled clinical trials are needed to evaluate its efficacy compared to other local therapies in this setting.

Risk stratification system and pattern of relapse in patients treated with adjuvant radiotherapy after radical prostatectomy.

PURPOSE: To retrospectively evaluate the role of adjuvant radiotherapy (ART) as monotherapy in a cohort of prostate cancer patients with undetectable prostate-specific antigen (PSA) after surgery and to propose a risk stratification system. METHODS: Between 2003 and 2010, 174 consecutive patients were treated with ART (median dose 71 Gy) at a single institution. Subsequently, we assigned a score of 1 to the following risk factors (RF): T stage ≥3b, presurgical PSA ≥10 ng/mL, pathologic Gleason score (GS) ≥4 + 3, and positive surgical margin (R1). The scores were then summed to stratify the population into low risk (LR), intermediate risk (IR), and high risk (HR). RESULTS: Median follow-up was 61 months (range 4-105). Five-year biochemical relapse-free survival (bRFS), clinical relapse-free survival (cRFS), and overall survival (OS) were respectively 93%, 97.1%, and 98.6%. On univariate analyses, GS was the only variable related to bRFS (p = 0.04) and to cRFS (p = 0.05). Any variable was related to OS. Kaplan-Meier analysis showed that HR patients (3-4 RF) had a worse bRFS (p = 0.02) compared to LR patients (0 RF or R1 as single RF); IR patients (1-2 RF) had a lower bRFS compared to LR patients (p = 0.06). Patients with R1 as single RF have the same bRFS as patients with 0 RF (p = 0.6) and are considered as LR patients. CONCLUSIONS: Adjuvant radiotherapy leads to excellent bRFS and cRFS rates at 5 years (93.3% and 97.1%, respectively) in our population. Patients with multiple RF are at higher risk of bRFS. Patients with R1 as single RF have bRFS rates comparable to patients without any RF.

Three-dimensional ultrasound-based target volume delineation and consequent dose calculation in prostate cancer patients with bilateral hip replacement: a report of 4 cases.

AIM: To investigate the role of 3D ultrasound (3D-US) in target volume delineation in prostate cancer radiotherapy. METHODS: Four patients with intermediate risk prostate cancer and metal artifacts on planning computed tomography (CT) due to previous bilateral hip replacement underwent 3D-US with the Clarity platform (Clarity System, Elekta, Stockholm, Sweden) to allow for image-guided procedures. Ultrasound and CT images were coregistered to allow for better delineation of the prostate gland and organs at risk (OAR). Electron density override (EDO) and standard electron density (EDS) methods were compared for appropriate dose calculation. RESULTS: 3D-US and planning CT minimized image artifacts, providing better evidence of patient anatomy, particularly regarding soft tissue visualization. Prostate gland and seminal vesicles were better delineated, particularly in the posterior aspect. Anterior rectal wall and bladder neck were more visible. No difference was found in terms of average planning target volume dose, D15%, or D25% for rectum or D15%, D25%, or D35% of bladder between EDO and EDS. CONCLUSIONS: 3D-US proved to be a viable tool for target volume and OAR visualization in patients with prostate cancer with hip prostheses.

Three-dimensional ultrasound-based image-guided hypofractionated radiotherapy for intermediate-risk prostate cancer: results of a consecutive case series.

External beam radiotherapy (EBRT) is a standard of care in the treatment of prostate cancer. Hypofractionation is a valid option either radiobiologically and logistically in this context. Image-guidance procedures are strongly needed to provide ballistic precision to radiation delivery. The Clarity platform allows for the acquisition of three-dimensional ultrasound scans (3D-US) to perform image-guided radiotherapy. We treated a consecutive series of intermediate-risk prostate cancer patients (according to NCCN stratification) with a hypofractionated schedule (70.2 Gy/26 fractions at 2.7 Gy/daily to the prostate gland excluding the seminal vesicles at 62.1 Gy) under 3D-US guidance with the Clarity platform. The 3-year biochemical-relapse-free survival, distant-metastases-free, cancer-specific and overall survival were 98.6% (CI: 91.1-99.6%), 98.6% (CI: 91.1-99.6%), 97.5% (CI: 94.5-99.1%), and 94.3% (CI: 90.4-96.7%), respectively. Maximum detected acute GU toxicity was G0 in 22 patients (29.7%), G1 in 30 (22.7%), G2 in 19 (25.6%), G3 in 3 (4%). Maximum detected acute GI toxicity at the end of EBRT was G0 in 42 patients (56.8%), G1 in 22 (29.7%), G2 in 9 (12.1%), G3 in 1 (1.4%). The 3-year actuarial rates of ≥ G2 late toxicities were 6.1% for genito-urinary and 8.9% for gastrointestinal. The whole image-guidance workflow resulted in being robust and reliable. EBRT delivered employing a hypofractionated schedule under 3D-US-based image guidance proved to be a safe and effective treatment approach with consistent biochemical control and a mild toxicity profile. Hence, it has been transferred into daily clinical practice in our Department.