Stereotactic Ablative Radiotherapy Dose Research Articles

P2.05-015 Long-Term Outcomes of Prospective Phase П Clinical Trial for Stereotactic Ablation Radiotherapy in Recurrent NSCLC: Topic: Clinical Outcome

To evaluate the long-term efficacy, pattern of failure, and toxicity of stereotactic ablative radiotherapy (SABR) for recurrent or multiple primary non-small-cell lung cancer (NSCLC). Patients with histologically confirmed, 18F-fluorodeoxyglucose (18F-FDG)-PET staged, recurrent or multiple primary NSCLC, suitable for SABR (<5 cm, not abutting critical structures, met with SABR dose volume constraints), were prospectively enrolled and treated with volumetric image-guided SABR to 50 Gy in 4 fractions (prescribed to planning target volume). Lobar recurrent disease was defined as recurrence in the same lobe with the same histology after definitive therapy from prior NSCLC (n=9); recurrent or oligo-metastatic disease (<3 lesions) was defined as recurrence with same histology within four years in different lobe (n=35). Multiple primary NSCLC was defined as secondary NSCLC with either different histology, or same histology but located in the different lobe with more than 4 years after initial definitive treatment of prior NSCLC (n=16); synchronous tumors was defined as with two early stage NSCLC in the different side (n=3). Four-dimensional computed tomography (4DCT) was used for simulation and planning. Patients were followed with CT or PET/CT every three months for two years, then every 6 months for three years and then annually. From February 2006 to April 2013, 63 patients were enrolled and eligible for evaluation. The median age was 70 years (range 45-86) and median follow-up was 4.2 years (the interquartile range 3.0-7.3 years). A total of 5 (7.9%) patients developed cumulative actual local recurrence within PTV and 18 patients (28.6%) developed any cumulative actual recurrence (local, regional and distant) after SABR. Estimated total local failure rates in the same lobe at 3-, 5-year were both 11.2% (95% CI 6.8-15.6). Estimated 3-, 5-year PFS rates were 60.2% (95% CI 53.7-66.7) and 52.6% (95% CI 43.5-61.7), respectively; corresponding overall survival rates were 64.1% (95% CI 58.0-70.2) and 52.9% (95% CI 45.5-60.3). Three (4.8%) patients developed grade 3 treatment-related adverse events (one [1.6%] dermatitis, one [1.6%] chest wall pain, and one [1.6%] radiation pneumonitis). No patient had grade 4 or 5 event. This exploratory prospective study showed excellent 5 years local control, minimal toxicity and outstanding 5 years OS and PFS for recurrent or multiple primary NSCLC treated with SABR, indicating a potential cure for some patients. Close follow up and surveillance after initial definitive treatment should be considered to detect early recurrence in NSCLC.

Estimation of Toxicities Following Stereotactic Ablative Radiation Therapy Treatment of Locally Recurrent and Previously Irradiated Head and Neck Squamous Cell Carcinoma Based on a Normal Tissue Complication Probability Model

Objectives: Locoregional recurrence rate in squamous cell carcinoma of head and neck (SCCHN) following chemoradiation is high. The objective of this study is to determine dosevolume relationship to toxicities of normal tissues in previously-irradiated, locally-recurrent SCCHN (rSCCHN) treated with stereotactic ablative radiotherapy (SABR). Methods: A retrospective review of 20 patients with previously-irradiated, locally rSCCHN from 2008-2011 was conducted. Tumors with a GTV less than 25 cm3 received 8.0 Gy per fraction for 5 fractions (total dose of 40 Gy); tumors with a GTV more than 25 cm3 received 8.8 Gy per fraction for 5 fractions (total dose of 44 Gy). Toxicity was graded based on Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Physical dose was converted into 2Gyper-fraction equivalent dose (EQD2) to correct for different fractionation schemes and allow for summation of SABR and previous IMRT plans. Logistic regression of composite dose volume histogram (DVH) data was performed in the DVH Evaluator software. Maximum likelihood parameter fitting was applied to solve TD50 (v) and normalized slope v50 of the exponential form of the logistic dose response model. Results: Median age was 64 y/o (range: 45-87 y/o) with 14 (70%) males and 6 (30%) females. Thirteen (65%) patients received surgery and 12 (60%) patients received chemotherapy. The median previous radiation dose was 70 Gy (range: 63-118.2 Gy). The median time from prior radiation therapy to SABR was 12.5 months (range: 3-39 months). The median maximum SABR dose was 50 Gy (range: 47.3-55 Gy). The median prescribed SABR EQD2 was 88 Gy (range: 88103.8 Gy) for a/b =3 Gy and was 60 Gy (range: 60-68.9 Gy) for a/b = 10 Gy, respectively. The median tumor volume was 27.3 cc (range: 4.4-75.7 cc). No Grade 4 or greater toxicity was observed. 1 (5%) patient had Grade 3 mucositis. 5 (25%) patients had Grade 2 mucositis and 6 (30%) patients had Grade 1 mucositis. Grade 2-3 mucositis correlated with median composite EQD2 to oral mucosa (TD50 (v) =190.8 Gy, v50 =0.3876). Outcomes were better correlated with median composite EQD2 to structures than to doses for small volumes, possibly due to tight Open Access Abstract

Increasing the Therapeutic Ratio of Stereotactic Ablative Radiotherapy by Individualized Isotoxic Dose Prescription.

To obtain a favorable tradeoff between treatment benefits and morbidity ("therapeutic ratio"), radiotherapy (RT) dose is prescribed according to the tumor volume, with the goal of controlling the disease while respecting normal tissue tolerance levels. We propose a new paradigm for tumor dose prescription in stereotactic ablative radiotherapy (SABR) based on organ-at-risk (OAR) tolerance levels called isotoxic dose prescription (IDP), which is derived from experiences and limitations of conventionally fractionated radiotherapy. With IDP, the radiation dose is prescribed based on the predefined level of normal tissue complication probability of a nearby dose-limiting OAR at a prespecified dose-volume constraint. Simultaneously, the prescribed total tumor dose (TTD) is maximized to the technically highest achievable level in order to increase the local tumor control probability (TCP). IDP is especially relevant for tumors located at eloquent locations or for large tumors in which severe toxicity has been described. IDP will result in a lower RT dose or a treatment scheduled with more fractions if the OAR tolerance level is exceeded, and potential dose escalation occurs when the OAR tolerance level allows it and when it is expected to be beneficial (if TCP < 90%). For patients with small tumors at noneloquent sites, the current SABR dose prescription already results in high rates of local control at low toxicity rates. In this review, the concept of IDP is described in the context of SABR.

Stereotactic Ablative Body Radiotherapy for Lung Cancer

Lung stereotactic ablative radiotherapy (SABR) is a method of delivering high ‘ablative’ doses of radiotherapy to tumours in the lung. It was developed at the Karolinska Institute in the early 1990s using the methods established in cranial radiosurgery with multiple beams prescribed to an isodose and using a custom designed stereotactic body frame for immobilisation. Since then, aligned with the advances in radiotherapy technology and techniques (e.g. four-dimensional computed tomography simulation and image-guided radiotherapy), there has been a rapid increase in the use of lung SABR for both early stage lung cancer and lung metastases. For peripheral primary lung cancers less than 5 cm in diameter, high rates of local control and low levels of acute and late toxicity are consistently reported in the published literature. Compared with historical control rates of stage I lung cancers treated with conventionally fractionated radiotherapy, SABR seems to offer higher rates of local control, lower levels of acute toxicity and a better quality of life after treatment. However, the full results of randomised controlled trials of SABR versus conventionally fractionated are awaited and will provide higher-level evidence. For central lung tumours, very high SABR doses can be associated with significant toxicity. Dose-adapted fractionation schedules seem to have much lower rates of toxicity and prospective trials, including the completed RTOG 0813 study and the on-going EORTC LUNGTEC study, should provide further evidence of safety and establish organ at risk tolerances. SABR can also be used for tumours metastatic to the lung with high rates of local control and is a reasonable alternative to surgery in selected patients. Going forward, prospective trials are underway to establish the safety and efficacy of SABR in oligometastatic disease. Population-based outcomes will be crucial in supporting/establishing SABR as the treatment of choice in medically inoperable patients with peripheral stage I lung cancers. Randomised phase III trials will hopefully extend the evidence base and show the safety and the utility of SABR in early central tumours and oligometastatic disease.

Repeated stereotactic ablative radiotherapy using CyberKnife for patients with hepatocellular carcinoma.

This study aimed to evaluate the outcomes and toxicities of repeated stereotactic ablative radiotherapy (SABR) in hepatocellular carcinoma (HCC). Fourteen HCC patients with local recurrence (18 lesions) after liver SABR received repeated radiotherapy with SABR using CyberKnife. No patients experienced radiation-induced liver disease after the first SABR course. The median first SABR dose was 41 Gy (range, 34-60 Gy); the median second SABR dose, 40 Gy (range, 25-50 Gy); and the median interval, 12.9 months. Local recurrence was divided into in-field recurrence and out-field recurrence. Objective responses were observed in 11 tumors (61.1%), including five tumors (27.8%) with complete responses. Intrahepatic out-field failure was the main cause of treatment failure (7 of 14 patients). In-field failure had developed in 1 of 18 tumors (5.6%), resulting in a 2-year in-field failure-free rate of 88.2%. The median time to progression was 14.0 months, with 1- and 2-year progression-free survival rates of 68.6% and 42.9%, respectively. One- and two-year overall survival rates were 76% and 59.1%, respectively. Of the 14 patients, one developed radiation-induced liver disease and three showed progression of the Child-Turcotte-Pugh class after the second SABR course. Other toxicities were generally mild and tolerable. Repeated SABR in selected HCC patients is feasible with acceptable toxicity.

Feasibility and Efficacy of Stereotactic Ablative Radiotherapy for Barcelona Clinic Liver Cancer-C Stage Hepatocellular Carcinoma

The purpose of this study was to assess the feasibility and efficacy of stereotactic ablative radiotherapy (SABR) for liver tumor in patients with Barcelona Clinic Liver Cancer (BCLC)-C stage hepatocellular carcinoma (HCC). We retrospectively reviewed the medical records of 35 patients between 2003 and 2011. Vascular invasion was diagnosed in 32 patients, extrahepatic metastases in 11 and both in 8. Thirty-two patients were categorized under Child-Pugh (CP) class A and 3 patients with CP class B. The median SABR dose was 45 Gy (range, 30-60 Gy) in 3-5 fractions. The median survival time was 14 months. The 1- and 3-yr overall survival (OS) rate was 52% and 21%, respectively. On univariate analysis, CP class A and biologically equivalent dose ≥ 80 Gy10 were significant determinants of better OS. Severe toxicity above grade 3, requiring prompt therapeutic intervention, was observed in 5 patients. In conclusion, SABR for BCLC-C stage HCC showed 1-yr OS rate of 52% but treatment related toxicity was moderate. We suggest that patients with CP class A are the best candidate and at least SABR dose of 80 Gy10 is required for BCLC-C stage.

Patient-Reported Quality of Life After Stereotactic Ablative Radiotherapy for Early-Stage Lung Cancer

Deterioration in health-related quality of life (HRQOL) is frequently observed after surgery for stage I non-small-cell lung cancer. As stereotactic ablative radiotherapy (SABR) can result in local control percentages exceeding 90%, we studied baseline and post-treatment HRQOL in SABR patients. HRQOL data were collected prospectively using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire in 382 consecutive patients treated with SABR. Patients were referred from 68 Dutch centers, with 86% judged unfit for surgery, and 14% declining surgery. An SABR dose of 60 Gy was delivered in three-, five-, or eight treatment fractions, depending on tumor diameter and location. HRQOL data were available for 382 patients at baseline (pre-SABR), and for 282, 212, 144, 56, and 43 patients at 3, 6, 12, 18, and 24 months post-SABR, respectively. Median survival was 40 months, with a 2-year survival of 66%. Local, regional, and distant failure percentages at 2 years were 6%, 13%, and 22%, respectively. Mean baseline global HRQOL and physical functioning scores were 62.9 ± 1.1 and 61.7 ± 1.1, respectively. Baseline symptom scores were highest for dyspnea (47.1 ± 1.7) and fatigue (37.4 ± 1.3). Except for a nonsignificant decrease in 2 to 3 points per year in physical functioning, no statistically or clinically significant worsening of any of the HRQOL functioning or symptom scores at any follow-up time point was observed. Patients referred for SABR have substantially worse baseline HRQOL scores than those reported in the surgical literature. Clinically relevant deteriorations in HRQOL subscale scores were not observed after SABR.

Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis

Stereotactic ablative radiotherapy (SABR) is increasingly used in the treatment of medically inoperable early stage non-small-cell lung cancer (NSCLC). Because patterns of late disease recurrence after SABR are not well characterised, we aimed to assess these outcomes in a cohort of patients with NSCLC. Patients with (18)F-fluorodeoxyglucose ((18)F-FDG)-PET confirmed stage 1-2 NSCLC who were treated with SABR at the VU University Medical Center (Amsterdam, Netherlands) were identified from an institutional database. SABR doses were 54-60 Gy, delivered in three to eight once-daily fractions, depending on tumour size and location. Clinical follow-up and CT scans were done at 3, 6, and 12 months, then yearly thereafter. (18)F-FDG-PET restaging was only done when clinically indicated. Initial sites of recurrence were classified as local, regional, and distant, and were differentiated from second primary tumours in the lung at multidisciplinary tumour board review. Between April 4, 2003, and Dec 5, 2011, 676 patients were treated with SABR and were eligible for assessment of recurrence. The median follow-up was 32·9 months (IQR 14·9-50·9 months). 124 (18%) of 676 patients had disease recurrence. Actuarial 2-year rates of local, regional, and distant recurrence were 4·9% (95% CI 2·7-7·1), 7·8% (5·3-10·3), and 14·7% (11·4-18·0), respectively. Corresponding 5-year rates were 10·5% (95% CI 6·4-14·6), 12·7% (8·4-17·0), and 19·9% (14·9-24·6), respectively. Of the 124 recurrences, 82 (66%) were distant recurrences and 57 (46%) were isolated distant recurrences. Isolated locoregional recurrences occurred in the remaining 42 patients with disease recurrence (34%), 35 (83%) of whom did not develop subsequent distant recurrence. The median times to local, regional, and distant recurrence were 14·9 months (95% CI 11·4-18·4), 13·1 months (7·9-18·3), and 9·6 months (6·8-12·4), respectively. New pulmonary lesions characterised as second primary tumours in the lung developed in 42 (6%) of 676 patients at a median of 18·0 months (95% CI 12·5-23·5) after SABR. Late recurrences after SABR are infrequent and two distinct patterns account for most cases. The predominant pattern is out-of-field, isolated distant recurrence presenting early, despite initial PET staging. A third of patients develop isolated locoregional recurrence; for these patients standardised follow-up is important to ensure that appropriate salvage treatments are considered. None.

Outcomes of Stereotactic Ablative Radiotherapy in Patients With Potentially Operable Stage I Non-Small Cell Lung Cancer

Approximately two-thirds of patients with early-stage non-small-cell lung cancer (NSCLC) in The Netherlands currently undergo surgical resection. As an increasing number of fit patients have elected to undergo stereotactic ablative radiotherapy (SABR) in recent years, we studied outcomes after SABR in patients with potentially operable stage I NSCLC. In an institutional prospective database collected since 2003, 25% of lung SABR cases (n = 177 patients) were found to be potentially operable when the following patients were excluded: those with (1) synchronous lung tumors or other malignancy, (2) prior high-dose radiotherapy/pneumonectomy, (3) chronic obstructive pulmonary disease with a severity score of 3-4 according to the Global initiative for Obstructive Lung Disease classification. (4) a performance score of ≥3, and (5) other comorbidity precluding surgery. Study patients included 101 males and 76 females, with a median age of 76 years old, 60% of whom were staged as T1 and 40% of whom were T2. Median Charlson comorbidity score was 2 (range, 0-5). ASABR dose of 60 Gy was delivered using a risk-adapted scheme in 3, 5, or 8 fractions, depending on tumor size and location. Follow-up chest computed tomography scans were obtained at 3, 6, and 12 months and yearly thereafter. Median follow-up was 31.5 months; and median overall survival (OS) was 61.5 months, with 1- and 3-year survival rates of 94.7% and 84.7%, respectively. OS rates at 3 years in patients with (n = 59) and without (n = 118) histological diagnosis did not differ significantly (96% versus 81%, respectively, p = 0.39). Post-SABR 30-day mortality was 0%, while predicted 30-day mortality for a lobectomy, derived using the Thoracoscore predictive model (Falcoz PE etal. J Thorac Cardiovasc Surg 2007;133:325-332), would have been 2.6%. Local control rates at 1 and 3 years were 98% and 93%, respectively. Regional and distant failure rates at 3 years were each 9.7%. Toxicity was mild, with grade ≥3 radiation pneumonitis and rib fractures in 2% and 3%, respectively. Patients with potentially operable disease who underwent primary SABR had a median OS that exceeded 5 years. This finding supports ongoing randomized clinical trials comparing surgery and SABR in cases of operable stage I NSCLC.