Erwin M. Wiegman

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.

Health-related quality of life in patients surviving non-small cell lung cancer

Background and aims The EuroQol 5D (EQ-5D) is a standardised instrument for measuring health-related quality of life (HRQoL). It provides a utility score for health, and a self-rating of HRQoL (EQ-VAS). In this study, the EQ-5D was used to assess HRQoL in survivors of non-small cell lung cancer (NSCLC). The influence of tumour stage, adverse events, initial treatment and presence of recurrence was examined. Methods Patients treated for NSCLC were sent a questionnaire, consisting of the EQ-5D, EQ-VAS and questions regarding adverse events. Tumour stage, date and type of initial treatment, and presence of recurrence were derived from patient files once patients had completed the questionnaire and informed consent form. Influencing factors were examined by exploring subgroups and using multiple regression analysis. Results Of the 374 patients contacted, 260 (70%) returned a completed questionnaire. The EQ-VAS generated an average self-rated health of 69 (SD 18). The mean utility score was 0.74 (SD 0.27). Respondents with severe adverse events (dyspnoea grade ≥3) had statistically significantly lower utility scores than respondents without severe adverse events (median 0.52 vs 0.81; p <0.001). Subgroups based on a patients initial treatment modality revealed statistically significantly different utility scores (p=0.010). Conclusion The results of the present study provide original data on HRQoL during survival of NSCLC. Adverse events were found to have a considerable impact on HRQoL. This stresses the need to search for treatment modalities that not only improve survival, but also reduce adverse events.

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.

Loco-regional differences in pulmonary function and density after partial rat lung irradiation

PURPOSE The purpose of this study was to explore regional differences in radiosensitivity of rat lung using lung function and computed tomography (CT) density as endpoints. METHODS At first, CT scans were used to determine rat lung volumes. The data obtained enabled the design of accurate collimators to irradiate 50% of the total lung volume for the apex, base, left, right, mediastinal and lateral part of the lung. Male Wistar rats were irradiated with a single dose of 18 Gy of orthovoltage X-rays. Further rat thorax CT scans were made before and 4, 16, 26, and 52 weeks after irradiation to measure in vivo lung density changes indicative of lung damage. To evaluate overall lung function, breathing frequencies were measured biweekly starting 1 week before irradiation. RESULTS Qualitative analysis of the CT scans showed clear density changes for all irradiated lung volumes, with the most prominent changes present in the mediastinal and left group at 26 weeks after radiation. Quantitative analysis using average density changes of whole lungs did not adequately describe the differences in radiation response between the treated groups. However, analysis of the density changes of the irradiated and non-irradiated regions of interest (ROI) more closely matched with the qualitative observations. Breathing frequencies (BF) were only increased after 50% left lung irradiation, indicating that the hypersensitivity of the mediastinal part as assessed by CT analysis, does not result in functional changes. CONCLUSIONS For both BF and CT (best described by ROI analysis), differences in regional lung radiosensitivity were observed. The presentation of lung damage either as function loss or density changes do not necessarily coincide, meaning that for each endpoint the regional sensitivity may be different.

Hypoxia imaging using Positron Emission Tomography in non-small cell lung cancer: Implications for radiotherapy

Tumour hypoxia is an important contributor to radioresistance. Thus, increasing the radiation dose to hypoxic areas may result in improved locoregional tumour control. However, this strategy requires accurate detection of the hypoxic sub-volume using PET imaging. Secondly, hypoxia imaging may also provide prognostic information and may be of help to monitor treatment response. Therefore, a systematic review of the scientific literature was carried out on the use of Positron Emission Tomography (PET) to image Tumour hypoxia in non-small cell lung cancer (NSCLC). More specifically, the purpose of this review was (1) to summarize the different hypoxia tracers used, (2) to investigate whether Tumour hypoxia can be detected in NSCLC and finally (3) whether the presence of hypoxia can be used to predict outcome.

The impact of gastrointestinal and genitourinary toxicity on health related quality of life among irradiated prostate cancer patients

PURPOSE To determine the impact of late radiation-induced toxicity on health-related quality of life (HRQoL) among patients with prostate cancer. PATIENTS AND METHODS The study sample was composed of 227 patients, treated with external beam radiotherapy. Common Terminology Criteria for Adverse Events version 3.0 were used to grade late genitourinary and gastrointestinal toxicity. The European Organization for Research and Treatment of Cancer Quality of life Questionnaire C30 (EORTC QLQ-C30) was used to assess HRQoL at baseline, and 6, 12 and 24 months after completion of radiotherapy. Statistical analysis was performed using a multivariate analysis of variance (MANOVA). RESULTS Urinary incontinence and rectal discomfort significantly affected HRQoL. The impact of urinary incontinence on HRQoL was most pronounced 6 months after radiotherapy and gradually decreased over time. The impact of rectal discomfort on HRQoL was predominant at 6 months after radiotherapy, decreased at 12 months and increased again 2 years after radiotherapy. No significant impact on HRQoL was observed for any of the other toxicity endpoints, or non-toxicity related factors such as hormonal therapy, radiotherapy technique or age. CONCLUSION Urinary incontinence and rectal discomfort have a significant impact on HRQoL. Prevention of these side effects may likely improve quality of life of prostate cancer patients after completion of treatment.

A new CT-based method to quantify radiation-induced lung damage in patients

A new method to assess radiation-induced lung toxicity (RILT) using CT-scans was developed. It is more sensitive in detecting damage and corresponds better to physician-rated radiation pneumonitis than routinely-used methods. Use of this method may improve lung toxicity assessment and thereby facilitate development of more accurate predictive models for RILT.