Lung SBRT credentialing in the Canadian OCOG-LUSTRE randomized trial.

Purpose: To report on the Stereotactic Body Radiation Therapy (SBRT) credentialing experience during the Phase III Ontario Clinical Oncology Group (OCOG) LUSTRE trial for stage I non-small cell lung cancer. Methods: Three credentialing requirements were required in this process: (a) An institutional technical survey; (b) IROC (Imaging and Radiation Oncology Core) thoracic phantom end-to-end test; and (c) Contouring and completion of standardized test cases using SBRT for one central and one peripheral lung cancer, compared against the host institution as the standard. The main hypotheses were that unacceptable variation would exist particularly in OAR definition across all centres, and that institutions with limited experience in SBRT would be more likely to violate per-protocol guidelines. Results: Fifteen Canadian centres participated of which 8 were new, and 7 were previously established (≥2 years SBRT experience), and all successfully completed surveys and IROC phantom testing. Of 30 SBRT test plans, 10 required replanning due to major deviations, with no differences in violations between new and established centres (p = 0.61). Mean contouring errors were highest for brachial plexus in the central (C) case (12.55 ± 6.62 mm), and vessels in the peripheral (P) case (13.01 ± 12.55 mm), with the proximal bronchial tree (PBT) (2.82 ± 0.78 C, 3.27 ± 1.06 P) as another variable structure. Mean dice coefficients were lowest for plexus (0.37 ± 0.2 C, 0.37 ± 0.14 P), PBT (0.77 ± 0.06 C, 0.75 ± 0.09 P), vessels (0.69 ± 0.29 C, 0.64 ± 0.31 P), and esophagus (0.74 ± 0.04 C, 0.76 ± 0.04 P). All plans passed per-protocol planning target volume (PTV) coverage and maximum/volumetric organs-at-risk constraints, although variations existed in dose gradients within and outside the target. Conclusions: Clear differences exist in both contouring and planning with lung SBRT, regardless of centre experience. Such an exercise is important for studies that rely on high precision radiotherapy, and to ensure that implications on trial quality and outcomes are as optimal as possible.

Frameless Stereotactic Radiosurgery With Linear Accelerator (LINAC)-Based Technology for Brain Metastases: Outcomes Analysis in 141 Patients.

Objectives Brain metastases (BM) are the most common intracranial tumors in adults. Surgery and frame-based stereotactic radiosurgery (SRS) are well-described treatment options. Frameless SRS is an emerging BM treatment option offering fewer side effects. The aim of this study was to describe the therapeutic outcomes and toxicity of frameless SRS with linear accelerator (LINAC)-based technology for BM treatment in our institution. Materials and methods We performed a retrospective study including all adult patients treated with frameless SRS with LINAC-based technology for BM between October 2010 and July 2016. Patients were followed routinely with MRI scans at three-month intervals. Primary endpoints were progression-free survival, local control, overall survival, and toxicity related to the treatment. All survival times were computed with the Kaplan-Meier method. All cumulative incidences were computed using competing risk analyses. Results A total of 194 metastatic lesions in 141 patients were treated in a 69-month interval. At the time of analysis, 33 patients were still alive, with a median follow-up time of 25.1 months. The overall median survival was 8.7 months. The median progression-free survival was 5.3 months. Local recurrence as a first event was 25% and 38% at one and two years, respectively, while distant brain recurrence as a first event was 18% and 21%. Death before any brain event occurred in 31% of patients. The cumulative incidence of radiation necrosis as a first brain event was 2% at one and two years. Conclusions The treatment of BM with LINAC-based frameless SRS in our institution had an overall and progression-free survival comparable with the literature for frameless SRS and for conventional frame-based SRS while being less invasive and more comfortable for the patient. In our study, frameless SRS with LINAC technology seems to be safe for BM treatment with minimal rates of radiation necrosis.

Image Guided Adaptive Endorectal Brachytherapy in the Nonoperative Management of Patients With Rectal Cancer.

PURPOSE: Organ preservation or nonoperative management of rectal cancer is of growing interest. Image guided adaptive endorectal brachytherapy is a radiation dose escalation modality: we explored its role in elderly patients unfit for surgery and patients refusing surgery. METHODS AND MATERIALS: In this registry study, patients with rectal cancer who were ineligible for surgery received 40 Gy in 16 fractions of pelvic external beam radiation therapy. They subsequently received 3 weekly image guided adaptive brachytherapy boosts of 10 Gy to the residual tumor, for a total of 30 Gy in 3 fractions. Complete clinical response (cCR) and local control were the primary endpoints. RESULTS: 94 patients were included; the median age was 81.1 years. With a median follow-up of 1.9 years, the proportion of cCR was 86.2%, the tumor regrowth proportion was 13.6%, and the cumulative incidence of local relapse was 2.7% at 1 year and 16.8% at 2 years. When considering responders and nonresponders, the 2-year local control was 71.5%. The overall survival at 2 years was 63.6%. Acute rectal grade 1 to 2 toxicity included all patients: 12.8% of patients had late bleeding requiring iron replacement, blood transfusions, or argon plasma therapy. CONCLUSIONS: Results of this registry study, evaluating radiation dose escalation for elderly medically unfit patients with unselected tumors, reveal that a high proportion of patients achieved cCR with a manageable toxicity profile. This technology will likely contribute to the challenging nonoperative management paradigm of rectal cancer.

Canadian Phase III Randomized Trial of Stereotactic Body Radiotherapy Versus Conventionally Hypofractionated Radiotherapy for Stage I, Medically Inoperable Non-Small-Cell Lung Cancer - Rationale and Protocol Design for the Ontario Clinical Oncology Group (OCOG)-LUSTRE Trial.

We describe a Canadian phase III randomized controlled trial of stereotactic body radiotherapy (SBRT) versus conventionally hypofractionated radiotherapy (CRT) for the treatment of stage I medically inoperable non-small-cell lung cancer (OCOG-LUSTRE Trial). Eligible patients are randomized in a 2:1 fashion to either SBRT (48 Gy in 4 fractions for peripherally located lesions; 60 Gy in 8 fractions for centrally located lesions) or CRT (60 Gy in 15 fractions). The primary outcome of the study is 3-year local control, which we hypothesize will improve from 75% with CRT to 87.5% with SBRT. With 85% power to detect a difference of this magnitude (hazard ratio = 0.46), a 2-sided α = 0.05 and a 2:1 randomization, we require a sample size of 324 patients (216 SBRT, 108 CRT). Important secondary outcomes include overall survival, disease-free survival, toxicity, radiation-related treatment death, quality of life, and cost-effectiveness. A robust radiation therapy quality assurance program has been established to assure consistent and high quality SBRT and CRT delivery. Despite widespread interest and adoption of SBRT, there still remains a concern regarding long-term control and risks of toxicity (particularly in patients with centrally located lesions). The OCOG-LUSTRE study is the only randomized phase III trial testing SBRT in a medically inoperable population, and the results of this trial will attempt to prove that the benefits of SBRT outweigh the potential risks.

Palliative Radiation Therapy for Advanced Head and Neck Carcinomas: A Phase 2 Study.

PURPOSE: Incurable head and neck cancer is hard to manage with usual palliative care. Radiation therapy (RT) in this setting is sometimes omitted because there is an apprehension that the side effects in the head and neck region might counterbalance the benefits. The objective of this phase 2 study was to evaluate whether highly conformal RT could improve the therapeutic ratio with this comprehensive Quality of Life (QOL) and toxicity evaluation. METHODS AND MATERIALS: Patients from 2 academic centers, deemed unfit for radical treatment because of their poor medical condition or advanced cancer stage by an experienced tumor board, were offered 25 Gy in 5 daily intensity modulated RT fractions over 1 week to the symptomatic tumor volume. QOL was evaluated with the European Organization for Research and Treatment of Cancer QLQ-C15-PAL and QLQ-H&N35 questionnaires, and toxicities with the Common Terminology Criteria for Adverse Events version 4.0. Survival and time to tumor progression were calculated with the Kaplan-Meier method. RESULTS: Thirty-two patients were recruited, of whom 66% had at least T4, N3, or M1 disease. The QOL questionnaires completion rate was 86%. Eighty-eight percent of patients received the planned dose. The median overall survival and progression-free survival times were, respectively, 6.5 and 3.2 months. No grade 4 or 5 toxicity was seen. Only 13% of patients had any grade 3 toxicities, and 17% of patients reported no toxicity at all. The QOL was equal or improved, and head and neck symptoms remained equal to or lower than the baseline values for most patients at up to 6 months. Eighty-five percent of patients would have chosen to receive this RT regimen again when asked. CONCLUSIONS: This palliative RT regimen was highly tolerable and effective in preserving or improving self-reported QOL in most patients for up to 6 months, which corresponds to this population's median overall survival. Given the minimal side effects, intensification could be considered to achieve longer locoregional control.

Stereotactic Body Radiotherapy for Inoperable Liver Tumors: Results of a Single Institutional Experience.

OBJECTIVES: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for liver tumors unsuitable for ablation or surgery. We report our experience with SBRT in the treatment of liver tumors. MATERIALS AND METHODS: Patients with primary or secondary liver cancer were identified in our local SBRT database. Patients were included irrespective of prior liver-directed therapies. The primary endpoint of our review was in-field local control (LC). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: From 2009 to 2015, a total of 71 liver lesions in 68 patients were treated with SBRT (three patients had two liver lesions treated). The median age was 71 years (27-89 years). Hepatocellular carcinoma (HCC) was the diagnosis in 23 patients (34%), with the grade of Child-Pugh A (52%), B (39%), or C (nine percent) cirrhosis. Six patients (nine percent) had intrahepatic cholangiocarcinoma (IHC). The remaining 39 patients (57%) had metastatic liver lesions. Colorectal adenocarcinoma was the most common primary tumor type (81%). The median size for HCC, IHC, and metastatic lesions was 5 cm (2-9 cm), 3.6 cm (2-4.9 cm), and 4 cm (1-8 cm), respectively. The median prescribed dose was 45 Gy (16-50 Gy). Median follow-up was 11.5 months (1-45 months). Actuarial one-year in-field LC for HCC and metastatic lesions was 85% and 64% respectively (p= 0.66). At one year, the actuarial rate of new liver lesions was 40% and 26%, respectively, (p=0.58) for HCC and metastases. Only six patients with IHC were treated with SBRT in this study - in these patients, one-year LC was 78% with new liver lesions in 53%. The SBRT treatments were well tolerated. The side effects included common criteria for adverse events (CTCAE) v4 grade 1 acute gastrointestinal toxicity in three patients, grade 3 nausea in one patient, and grade 3 acute dermatitis in another patient. Two patients had grade 5 toxicity. Radiation pneumonitis was observed in one patient two months post-SBRT treatment, and another patient was suspected to have had radio-induced liver disease (RILD) two months after SBRT. No late toxicity was seen. CONCLUSION: SBRT is a well-tolerated and effective alternative treatment option for selected patients with primary and metastatic liver tumors.

Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma.

PURPOSE: To describe outcomes of prospective trials of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Two trials of SBRT for patients with active HCC unsuitable for standard locoregional therapies were conducted from 2004 to 2010. All patients had Child-Turcotte-Pugh class A disease, with at least 700 mL of non-HCC liver. The SBRT dose range was 24 to 54 Gy in six fractions. Primary end points were toxicity and local control at 1 year (LC1y), defined as no progressive disease (PD) of irradiated HCC by RECIST (Response Evaluation Criteria in Solid Tumors). RESULTS: A total of 102 patients were evaluable (Trial 1, 2004 to 2007: n = 50; Trial 2, 2007 to 2010: n = 52). Underlying liver disease was hepatitis B in 38% of patients, hepatitis C in 38%, alcohol related in 25%, other in 14%, and none in 7%. Fifty-two percent received prior therapies (no prior sorafenib). TNM stage was III in 66%, and 61% had multiple lesions. Median gross tumor volume was 117.0 mL (range, 1.3 to 1,913.4 mL). Tumor vascular thrombosis (TVT) was present in 55%, and extrahepatic disease was present in 12%. LC1y was 87% (95% CI, 78% to 93%). SBRT dose (hazard ratio [HR] = 0.96; P = .02) and being in Trial 2 (HR = 0.38; P = .03) were associated with LC1y on univariate analysis. Toxicity ≥ grade 3 was seen in 30% of patients. In seven patients (two with TVT PD), death was possibly related to treatment (1.1 to 7.7 months after SBRT). Median overall survival was 17.0 months (95% CI, 10.4 to 21.3 months), for which only TVT (HR = 2.47; P = .01) and being in Trial 2 (HR = 0.49; P = .01) were significant on multivariate analysis. CONCLUSION: These results provide strong rationale for studying SBRT for HCC in a randomized trial.

Image-guided radiotherapy: has it influenced patient outcomes?

Cancer control and toxicity outcomes are the mainstay of evidence-based medicine in radiation oncology. However, radiotherapy is an intricate therapy involving numerous processes that need to be executed appropriately in order for the therapy to be delivered successfully. The use of image-guided radiation therapy (IGRT), referring to imaging occurring in the radiation therapy room with per-patient adjustments, can increase the agreement between the planned and the actual dose delivered. However, the absence of direct evidence regarding the clinical benefit of IGRT has been a criticism. Here, we dissect the role of IGRT in the radiotherapy (RT) process and emphasize its role in improving the quality of the intervention. The literature is reviewed to collect evidence that supports that higher-quality dose delivery enabled by IGRT results in higher clinical control rates, reduced toxicity, and new treatment options for patients that previously were without viable options.

Stereotactic body radiation therapy for hepatocellular carcinoma.

Stereotactic body radiotherapy (SBRT), in which highly conformal potent radiation doses are delivered in fewer fractions than traditional radiation therapy (RT), is an increasingly popular treatment for hepatocellular carcinoma (HCC). The great majority of HCCs smaller than 6 cm and with Child-Pugh A liver function are controlled with SBRT with limited toxicity. Long-term local control is reduced in larger tumors, and toxicity is increased in patients with Child-Pugh B or C liver function. SBRT is an effective treatment for tumor vascular thrombi and can lead to sustained vascular recanalization. The first site of recurrence following SBRT is most often within the liver, away from the high dose volume, providing rationale for combining SBRT with regional or systemic therapies. Randomized trials of SBRT are warranted.