Joachim Widder

Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials

BACKGROUND The standard of care for operable, stage I, non-small-cell lung cancer (NSCLC) is lobectomy with mediastinal lymph node dissection or sampling. Stereotactic ablative radiotherapy (SABR) for inoperable stage I NSCLC has shown promising results, but two independent, randomised, phase 3 trials of SABR in patients with operable stage I NSCLC (STARS and ROSEL) closed early due to slow accrual. We aimed to assess overall survival for SABR versus surgery by pooling data from these trials. METHODS Eligible patients in the STARS and ROSEL studies were those with clinical T1-2a (<4 cm), N0M0, operable NSCLC. Patients were randomly assigned in a 1:1 ratio to SABR or lobectomy with mediastinal lymph node dissection or sampling. We did a pooled analysis in the intention-to-treat population using overall survival as the primary endpoint. Both trials are registered with ClinicalTrials.gov (STARS: NCT00840749; ROSEL: NCT00687986). FINDINGS 58 patients were enrolled and randomly assigned (31 to SABR and 27 to surgery). Median follow-up was 40·2 months (IQR 23·0-47·3) for the SABR group and 35·4 months (18·9-40·7) for the surgery group. Six patients in the surgery group died compared with one patient in the SABR group. Estimated overall survival at 3 years was 95% (95% CI 85-100) in the SABR group compared with 79% (64-97) in the surgery group (hazard ratio [HR] 0·14 [95% CI 0·017-1·190], log-rank p=0·037). Recurrence-free survival at 3 years was 86% (95% CI 74-100) in the SABR group and 80% (65-97) in the surgery group (HR 0·69 [95% CI 0·21-2·29], log-rank p=0·54). In the surgery group, one patient had regional nodal recurrence and two had distant metastases; in the SABR group, one patient had local recurrence, four had regional nodal recurrence, and one had distant metastases. Three (10%) patients in the SABR group had grade 3 treatment-related adverse events (three [10%] chest wall pain, two [6%] dyspnoea or cough, and one [3%] fatigue and rib fracture). No patients given SABR had grade 4 events or treatment-related death. In the surgery group, one (4%) patient died of surgical complications and 12 (44%) patients had grade 3-4 treatment-related adverse events. Grade 3 events occurring in more than one patient in the surgery group were dyspnoea (four [15%] patients), chest pain (four [15%] patients), and lung infections (two [7%]). INTERPRETATION SABR could be an option for treating operable stage I NSCLC. Because of the small patient sample size and short follow-up, additional randomised studies comparing SABR with surgery in operable patients are warranted. FUNDING Accuray Inc, Netherlands Organisation for Health Research and Development, NCI Cancer Center Support, NCI Clinical and Translational Science Award.

Recommendations for implementing stereotactic radiotherapy in peripheral stage IA non-small cell lung cancer: report from the Quality Assurance Working Party of the randomised phase III ROSEL study

BackgroundA phase III multi-centre randomised trial (ROSEL) has been initiated to establish the role of stereotactic radiotherapy in patients with operable stage IA lung cancer. Due to rapid changes in radiotherapy technology and evolving techniques for image-guided delivery, guidelines had to be developed in order to ensure uniformity in implementation of stereotactic radiotherapy in this multi-centre study.Methods/DesignA Quality Assurance Working Party was formed by radiation oncologists and clinical physicists from both academic as well as non-academic hospitals that had already implemented stereotactic radiotherapy for lung cancer. A literature survey was conducted and consensus meetings were held in which both the knowledge from the literature and clinical experience were pooled. In addition, a planning study was performed in 26 stage I patients, of which 22 were stage 1A, in order to develop and evaluate the planning guidelines. Plans were optimised according to parameters adopted from RTOG trials using both an algorithm with a simple homogeneity correction (Type A) and a more advanced algorithm (Type B). Dose conformity requirements were then formulated based on these results.ConclusionBased on current literature and expert experience, guidelines were formulated for this phase III study of stereotactic radiotherapy versus surgery. These guidelines can serve to facilitate the design of future multi-centre clinical trials of stereotactic radiotherapy in other patient groups and aid a more uniform implementation of this technique outside clinical trials.

Selection of patients for radiotherapy with protons aiming at reduction of side effects: The model-based approach

Most new radiation techniques, have been introduced primarily to reduce the dose to normal tissues in order to prevent radiation-induced side effects. Radiotherapy with protons is such a radiation technique that due to its superior beam properties compared to photons enables better sparing of normal tissues. This paper describes a stepwise methodology to select patients for proton therapy when the primary aim is to reduce side effects. This method has been accepted by the Dutch health authorities to select patients for proton therapy. In addition, an alternative method is described in case randomised controlled trials are considered not appropriate.

Intensified Adjuvant IFADIC Chemotherapy for Adult Soft Tissue Sarcoma: A Prospective Randomized Feasibility Trial

Purpose. The present prospective randomized adjuvant trial was carried out to compare the toxicity, feasibility and efficacy of augmented chemotherapy added to hyperfractionated accelerated radiotherapy after wide or marginal resection of grade 2 and grade 3 soft tissue sarcoma (STS).Patients and methods. Fifty-nine patients underwent primary surgery by wide or marginal excision and were subsequently randomized to receive radiotherapy alone or under the addition of six courses of ifosfamide (1500 mg/m(2) , days 1-4), dacarbazine (DTIC) (200 mg/m(2) , days 1-4) and doxorubicin (25 mg/m(2) , days 1-2) administered in 14-day-intervals supported by granulocyte-colony stimulating factor (30 x 10(6) IU/day, s.c.) on days 5-13. According to the randomization protocol, 28 patients received radiotherapy only, whereas 31 patients were treated with additional chemotherapy.Results. The relative ifosfamide-doxorubicin-DTIC (IFADIC) dose intensity achieved was 93%. After a mean observation period of 41+/-19.7 months (range, 8.1-84 months), 16 patients (57%) in the control group versus 24 patients (77%) in the chemotherapy group were free of disease (p>0.05).Within the control group, tumor relapses occurred in 12 patients (43%;six patients with distant metastases, two with local relapse, four with both) versus seven patients (23%; five patients with distant metastases, one with local recurrence, one with both) from the chemotherapy group. Relapse-free survival (RFS) (p=0.1), time to local failure (TLF) (p=0.09), time to distant failure (TDF) (p=0.17) as well as overall survival (OS) (p=0.4) did not differ significantly between the two treatment groups. Treatment-related toxicity was generally mild in both treatment arms.Conclusion. We conclude that the safety profile of intensified IFADIC added to radiotherapy was manageable and tolerable in the current setting. Inclusion of intensified IFADIC was not translated into a significant benefit concerning OS, RFS, TLF andTDF as compared with radiotherapy only, although a potential benefit of chemotherapy for grade 3 STS patients needs to be validated in prospective randomized trials including larger patient numbers.

Pulmonary oligometastases: Metastasectomy or stereotactic ablative radiotherapy?

BACKGROUND AND PURPOSE Stereotactic ablative radiotherapy (SABR; or stereotactic body radiotherapy, SBRT) emerges as treatment option for pulmonary oligometastatic disease (OMD), but there are no studies comparing SABR with pulmonary metastasectomy (PME). We analysed consecutive patients referred via a university-hospital based multidisciplinary team. MATERIAL AND METHODS Patients were offered PME as first choice and SABR in case they were considered to be less suitable surgical candidates. Overall survival was the primary endpoint. Secondary endpoints were progression-free-survival, local control of treated metastases, and freedom-from-failure of a local-only treatment strategy without systemic therapy. RESULTS From 2007 until 2010, 110 patients were treated and analysed (PME, n=68; SABR, n=42). Median follow-up time was 43 months (minimally, 25). Estimated overall survival rates at one, three, and five years were 87%, 62%, and 41% for PME, and 98%, 60%, and 49% for SABR, respectively (logrank-test, p=0.43). Local control at two years was 94% for SABR and 90% for PME. Progression-free survival was 17% at three years, but 43% of the patients still had not failed a local-only treatment strategy. CONCLUSIONS Although SABR was second choice after PME, survival after PME was not better than after SABR. Prospective comparative studies are clearly required to define the role of both, SABR and PME in OMD.

PET Imaging of Tumor Hypoxia Using 18F-Fluoroazomycin Arabinoside in Stage III–IV Non–Small Cell Lung Cancer Patients

Tumor hypoxia hampers the efficacy of radiotherapy because of its increased resistance to ionizing radiation. The aim of the present study was to estimate the potential added clinical value of the specific hypoxia tracer 18F-fluoroazomycin arabinoside (18F-FAZA) over commonly used 18F-FDG in the treatment of advanced-stage non–small cell lung cancer (NSCLC). Methods: Eleven patients with stage III or stage IV NSCLC underwent 18F-FDG and 18F-FAZA PET before chemoradiotherapy. The maximum standardized uptake value (SUVmax) was used to depict 18F-FDG uptake, and the tumor-to-background (T/B) ratio and tumor fractional hypoxic volume (FHV) were used to quantify hypoxia. The spatial correlation between 18F-FDG and 18F-FAZA uptake values was investigated using voxel-based analysis. Partial-volume correction was applied. Results: All 11 patients showed clear uptake of 18F-FAZA in the primary tumor. However, different patterns of 18F-FDG and 18F-FAZA uptake distributions were observed and varied widely among different tumors. No significant correlation was observed between 18F-FDG SUVmax and 18F-FAZA T/B ratio (P = 0.055). The median FHV of 1.4 was 48.4% (range, 5.0–91.5). A significant positive correlation was found between the 18F-FAZA T/B ratio and FHV of 1.4 (P < 0.001). There was no correlation between the lesion size and FHV or between the 18F-FDG SUVmax and FHV. The pattern of tumoral 18F-FDG uptake was rather homogeneous, whereas 18F-FAZA uptake was more heterogeneous, suggesting that 18F-FAZA identifies hypoxic areas within metabolically active areas of tumor. A significant correlation between 18F-FDG SUVmax and lesion size (P = 0.002) was observed. Conclusion: 18F-FAZA PET imaging is able to detect heterogeneous distributions of hypoxic subvolumes out of homogeneous 18F-FDG background in a clinical setting. Therefore, 18F-FAZA might be considered a tool for guiding dose escalation to the hypoxic fraction of the tumor.

Residual 18F-FDG-PET Uptake 12 Weeks After Stereotactic Ablative Radiotherapy for Stage I Non-Small-Cell Lung Cancer Predicts Local Control

PURPOSE To investigate the prognostic value of [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) uptake at 12 weeks after stereotactic ablative radiotherapy (SABR) for stage I non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS From November 2006 to February 2010, 132 medically inoperable patients with proven Stage I NSCLC or FDG-PET-positive primary lung tumors were analyzed retrospectively. SABR consisted of 60 Gy delivered in 3 to 8 fractions. Maximum standardized uptake value (SUV(max)) of the treated lesion was assessed 12 weeks after SABR, using FDG-PET. Patients were subsequently followed at regular intervals using computed tomography (CT) scans. Association between post-SABR SUV(max) and local control (LC), mediastinal failure, distant failure, overall survival (OS), and disease-specific survival (DSS) was examined. RESULTS Median follow-up time was 17 months (range, 3-40 months). Median lesion size was 25 mm (range, 9-70 mm). There were 6 local failures: 15 mediastinal failures, 15 distant failures, 13 disease-related deaths, and 16 deaths from intercurrent diseases. Glucose corrected post-SABR median SUV(max) was 3.0 (range, 0.55-14.50). Using SUV(max) 5.0 as a cutoff, the 2-year LC was 80% versus 97.7% for high versus low SUV(max), yielding an adjusted subhazard ratio (SHR) for high post-SABR SUV(max) of 7.3 (95% confidence interval [CI], 1.4-38.5; p = 0.019). Two-year DSS rates were 74% versus 91%, respectively, for high and low SUV(max) values (SHR, 2.2; 95% CI, 0.8-6.3; p = 0.113). Two-year OS was 62% versus 81% (hazard ratio [HR], 1.6; 95% CI, 0.7-3.7; p = 0.268). CONCLUSIONS Residual FDG uptake (SUV(max) ≥5.0) 12 weeks after SABR signifies increased risk of local failure. A single FDG-PET scan at 12 weeks could be used to tailor further follow-up according to the risk of failure, especially in patients potentially eligible for salvage surgery.

Survival and Quality of Life After Stereotactic or 3D-Conformal Radiotherapy for Inoperable Early-Stage Lung Cancer

PURPOSE To investigate survival and local recurrence after stereotactic ablative radiotherapy (SABR) or three-dimensional conformal radiotherapy (3D-CRT) administered for early-stage primary lung cancer and to investigate longitudinal changes of health-related quality of life (HRQOL) parameters after either treatment. METHODS AND MATERIALS Two prospective cohorts of inoperable patients with T1-2N0M0 primary lung tumors were analyzed. Patients received 70 Gy in 35 fractions with 3D-CRT or 60 Gy in three to eight fractions with SABR. Global quality of life (GQOL), physical functioning (PF), and patient-rated dyspnea were assessed using the respective dimensions of European Organization for Research and Treatment of Cancer Core Questionnaire-C30 and LC13. HRQOL was analyzed using multivariate linear mixed-effects modeling, survival and local control (LC) using the Kaplan-Meier method, Cox proportional hazards analysis, and Fine and Gray multivariate competing risk analysis as appropriate. RESULTS Overall survival (OS) was better after SABR compared with 3D-CRT with a HR of 2.6 (95% confidence interval [CI]: 1.5-4.8; p < 0.01). 3D-CRT conferred a subhazard ratio for LC of 5.0 (95% CI: 1.7-14.7; p < 0.01) compared with SABR. GQOL and PF were stable after SABR (p = 0.21 and p = 0.62, respectively). Dyspnea increased after SABR by 3.2 out of 100 points (95% CI: 1.0-5.3; p < 0.01), which is clinically insignificant. At 1 year, PF decreased by an excess of 8.7 out of 100 points (95% CI: 2.8-14.7; p < 0.01) after 3D-CRT compared with SABR. CONCLUSION In this nonrandomized comparison of two prospective cohorts of medically inoperable patients with Stage I lung cancer, OS and LC were better after SABR. GQOL, PF, and patient-rated dyspnea were stable after SABR, whereas PF decreased after 3D-CRT approaching clinical significance already at 1 year.

QUALITY ASSURANCE OF 4D-CT SCAN TECHNIQUES IN MULTICENTER PHASE III TRIAL OF SURGERY VERSUS STEREOTACTIC RADIOTHERAPY (RADIOSURGERY OR SURGERY FOR OPERABLE EARLY STAGE (STAGE 1A) NON-SMALL-CELL LUNG CANCER [ROSEL] STUDY)

PURPOSE To determine the accuracy of four-dimensional computed tomography (4D-CT) scanning techniques in institutions participating in a Phase III trial of surgery vs. stereotactic radiotherapy (SBRT) for lung cancer. METHODS AND MATERIALS All 9 centers performed a 4D-CT scan of a motion phantom (Quasar, Modus Medical Devices) in accordance with their in-house imaging protocol for SBRT. A cylindrical cedar wood insert with plastic spheres of 15 mm (ø15) and 30 mm (ø30) diameter was moved in a cosine-based pattern, with an extended period in the exhale position to mimic the actual breathing motion. A range of motion of R = 15 and R = 25 mm and breathing period of T = 3 and T = 6 s were used. Positional and volumetric imaging accuracy was analyzed using Pinnacle version 8.1× at various breathing phases, including the mid-ventilation phase and maximal intensity projections of the spheres. RESULTS Imaging using eight CT scanners (Philips, Siemens, GE) and one positron emission tomography-CT scanner (Institution 3, Siemens) was investigated. The imaging protocols varied widely among the institutions. No strong correlation was found between the specific scan protocol parameters and the observed results. Deviations in the maximal intensity projection volumes averaged 1.9% (starting phase of the breathing cycle [ø]15, R = 15), 12.3% (ø15, R = 25), and -0.9% (ø30, R = 15). The end-expiration volume deviations (13.4%, ø15 and 2.5%, ø30), were, on average, smaller than the end-inspiration deviations (20.7%, ø15 and 4.5%, ø30), which, in turn, were smaller than the mid-ventilation deviations (32.6%, ø15 and 8.0%, ø30). A slightly larger variation in the mid-ventilation origin position was observed (mean, -0.2 mm; range, -3.6-4.2) than in the maximal intensity projection origin position (mean, -0.1 mm; range, -2.5-2.5). The range of motion was generally underestimated (mean, -1.5 mm; range, -5.5-1). CONCLUSIONS Notable differences were seen in the 4D-CT imaging protocols for SBRT among centers. However, the observed deviations in target volumes were generally small. They were slightly larger for the mid-ventilation phases and smallest for the end-expiration phases. Steps to optimize and standardize the 4D-CT scanning protocols for SBRT are desirable.

Dynamics of tumor hypoxia assessed by 18F-FAZA PET/CT in head and neck and lung cancer patients during chemoradiation: Possible implications for radiotherapy treatment planning strategies

INTRODUCTION To define the optimal time point for the integration of hypoxia (18)F-FAZA-PET/CT information into radiotherapy treatment planning to benefit from hypoxia modification or dose escalation treatment. Therefore, we performed a prospective cohort study, using serial hypoxic imaging ((18)F-FAZA-PET/CT) prior to and at several time-points during (chemo)radiotherapy (CHRT) in six head and neck squamous cell (HNSCC) and six non-small cell lung cancer (NSCLC) patients. METHODS The spatio-temporal dynamics of tumor hypoxia and fractional hypoxic volumes (FHV) were evaluated using a voxel-by-voxel analysis based on a (18)F-FAZA-T/B ratio of 1.4 at four time points in HNSCC patients, at baseline (FAZA-BL), at week one (FAZA-W1), two (FAZA-W2), and four (FAZA-W4) during CHRT and at three time points in NSCLC patients (baseline; W2, W4). RESULTS Ten out of twelve patients showed a substantial pre-treatment tumor hypoxia representing a FHV⩾1.4 assessed by (18)F-FAZA-PET/CT. The median FHV was 38% (FAZA-BL), 15% (FAZA-W1), 17% (FAZA-W2) and 1.5% (FAZA-W4) in HNSCC patients, and 34% (FAZA-BL), 26% (FAZA-W2) and 26% (FAZA-W4) in NSCLC patients, respectively. Stable tumor hypoxia was observed in three HNSCC patients and two NSCLC patients at FAZA-W2. In three HNSCC patients and two NSCLC patients FHVs declined to non-detectable hypoxia levels at FAZA-W4 during CHRT, while two NSCLC patients, showed increasing FHVs. CONCLUSION Our results indicate that, instead of using the FAZA-BL scan as the basis for the dose escalation, FAZA-W2 of CHRT is most suitable and might provide a more reliable basis for the integration of (18)F-FAZA-PET/CT information into radiotherapy treatment planning for hypoxia-directed dose escalation strategies.