Cognitive Impairment in Long-Term Survivors of Testicular Cancer More Than 20 Years after Treatment.

BACKGROUND: Impaired cognition can be a late effect after treatment in long-term testicular cancer (TC) survivors, negatively affecting their daily life. However, little data is available beyond 20 years post-treatment. We assessed cognitive impairment in very long-term TC survivors after CT or RT and compared the results with stage I TC survivors and controls. METHODS: In this cross-sectional multicenter cohort study, we enrolled TC survivors (treated with orchiectomy followed by CT or RT or orchiectomy only)-with a follow-up duration ≥ 20 years-and age-matched healthy controls. Cognitive testing included the Auditory Verbal Learning Test, Letter Fluency Test, Category Fluency Test, and Trail Making Test. We used fasting blood samples to assess the presence of hypogonadism and measured cardiovascular aging parameters, including carotid pulse wave velocity (c-PWV) and advanced glycation end products (AGEs). RESULTS: We included 184 TC survivors (66 CT patients, 53 RT patients, and 65 orchiectomy-only patients) and 70 healthy controls. The median follow-up was 26 years (range: 20-42). TC survivors had a lower combined score of the cognitive tests (mean cumulative Z-score -0.85; 95% CI -1.39 to -0.33) compared to controls (mean 0.67; 95% CI -0.21 to 1.57, p < 0.01). In univariate analysis, the presence of hypogonadism (ß -1.50, p < 0.01), high c-PWV (ß -0.35, p = 0.09), and high AGEs (ß -1.27, p = 0.02) were associated with lower cognitive scores, while only AGEs (ß -1.17, p = 0.03) remained a significant predictor in multivariate analysis (Model R2 0.31, p < 0.01). CONCLUSIONS: Long-term TC survivors performed worse on cognitive tests compared to controls. Physicians and patients should be informed about timely cardiovascular risk management and testosterone supplementation therapy during follow-up to reduce the risk of cognitive impairment. TRIAL REGISTRATION: NCT02572934.

Intensified Neoadjuvant Chemoradiotherapy for Patients with Potentially Resectable Esophageal Cancer: A Retrospective Cohort Study.

BACKGROUND: Neoadjuvant treatment consisting of five cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy), followed by esophagectomy, is the standard treatment for resectable esophageal cancer in The Netherlands. It remains unclear whether intensification of neoadjuvant therapy leads to better outcomes. This study analyzed the outcomes of intensified chemoradiotherapy. METHODS: We included patients who were deemed eligible for esophagectomy between January 2008 and December 2014. Neoadjuvant therapy consisted of six cycles of carboplatin (area under the curve = 2 mg/mL/min) and paclitaxel (50 mg/m2 of body surface area) and concurrent radiotherapy (50.4 Gy administered in 28 fractions of 1.8 Gy each, 5 days per week), followed by esophagectomy. RESULTS: Of the 176 patients included in this study, 73% underwent a resection. At a median follow-up of 29.3 months for the total cohort, median disease-free survival (DFS) was 22.5 months. DFS at 3 and 5 years was 42% and 36%, respectively, while the overall survival (OS) rates were 47% and 38%, respectively. In addition, the 5-year DFS and OS rates of our resection group were 44% and 48%, respectively. In 102 patients (58%), grade 3 or higher adverse events were observed, mainly hematological. The postoperative mortality rate within 30 days was 4%, and pathological complete response was achieved in 35% of patients. CONCLUSIONS: Intensification of neoadjuvant chemoradiotherapy for patients with potentially resectable esophageal cancer is well tolerated, yielding high pathological complete response rates, but adverse events occurred frequently, and survival compared with conventional neoadjuvant chemoradiotherapy seems similar. Therefore, intensification of neoadjuvant chemoradiotherapy should not be routinely used.

Lessons learned from the Dutch Institute for Clinical Auditing: the Dutch model for quality assurance in lung cancer treatment.

BACKGROUND: Quality registries play an important role in the professional quality system for cancer treatment in The Netherlands. This article provides insight into the Dutch Lung Cancer Audit (DLCA); its core principles, initiation and development, first results and what lessons can be learned from the Dutch experience. METHODS: Cornerstones of the DLCA are discussed in detail, including: audit aims; the leading role for clinicians; web-based registration and feedback; data handling; multidisciplinary evaluation of quality indicators; close collaborations with all stakeholders in healthcare and transparency of results. RESULTS: In 2012 the first Dutch lung cancer specific sub-registry, focusing on surgical treatment was started. Since 2016 all major treating specialisms (lung oncologists, radiation-oncologists, general- and cardiothoracic surgeons-represented in the DLCA-L, -R and -S sub-registries respectively) have joined. Over time, the number of participating hospitals and included patients has increased. In 2016, the numbers of included patients with a non-small cell lung cancer (NSCLC) were 3,502 (DLCA-L), 2,427 (DLCA-R) and 1,979 (DLCA-S). Between sub-registries mean age varied from 66 to 70 years, occurrence of Eastern Cooperative Oncology Group (ECOG) performance score 2+ varied from 3.3% to 20.8% and occurrence of clinical stage I-II from 27.6% to 81.3%. Of all patients receiving chemoradiotherapy 64.2% was delivered concurrently. Of the surgical procedures 71.2% was started with a minimally invasive technique, with a conversion rate of 18.7%. In 2016 there were 17 publicly available quality indicators-consisting of structure, process and outcome indicators- calculated from the DLCA. CONCLUSIONS: the DLCA is a unique registry to evaluate the quality of multidisciplinary lung cancer care. It is accepted and implemented on a nationwide level, enabling participating healthcare providers to get insight in their performance, and providing other stakeholders with a transparent evaluation of this performance, all aiming for continuous healthcare improvement.

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.

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.

Concurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer.

BACKGROUND: Stage III unresectable non-small cell lung cancer (NSCLC) is preferably treated with concurrent schedules of chemoradiotherapy, but none is clearly superior Gemcitabine is a radiosensitizing cytotoxic drug that has been studied in phase 1 and 2 studies in this setting. The aim of this study was to describe outcome and toxicity of low-dose weekly gemcitabine combined with concurrent 3-dimensional conformal radiotherapy (3D-CRT). PATIENTS & METHODS: Treatment consisted of two cycles of a cisplatin and gemcitabine followed by weekly gemcitabine 300 mg/m2 during 5 weeks of 3D-CRT, 60 Gy in 5 weeks (hypofractionated-accelerated). Overall survival (OS), progression-free survival (PFS), and treatment related toxicity according to Common Toxicity Criteria of Adverse Events (CTCAE) version 3.0 were assessed. RESULTS: Between February 2002 and August 2008, 318 patients were treated. Median age was 64 years (range 36-86); 72% were male, WHO PS 0/1/2 was 44/53/3%. Median PFS was 15.5 months (95% confidence interval [CI], 12.9-18.1) and median OS was 24.6 months (95% CI., 21.0-28.1). Main toxicity (CTCAE grade ≥3) was dysphagia (12.6%), esophagitis (9.6%), followed by radiation pneumonitis (3.0%). There were five treatment related deaths (1.6%), two due to esophagitis and three due to radiation pneumonitis. CONCLUSION: Concurrent low-dose gemcitabine and 3D-CRT provides a comparable survival and toxicity profile to other available treatment schemes for unresectable stage III.

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.

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.

UNLABELLED: 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 (18)F-fluoroazomycin arabinoside ((18)F-FAZA) over commonly used (18)F-FDG in the treatment of advanced-stage non-small cell lung cancer (NSCLC). METHODS: Eleven patients with stage III or stage IV NSCLC underwent (18)F-FDG and (18)F-FAZA PET before chemoradiotherapy. The maximum standardized uptake value (SUVmax) was used to depict (18)F-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 (18)F-FDG and (18)F-FAZA uptake values was investigated using voxel-based analysis. Partial-volume correction was applied. RESULTS: All 11 patients showed clear uptake of (18)F-FAZA in the primary tumor. However, different patterns of (18)F-FDG and (18)F-FAZA uptake distributions were observed and varied widely among different tumors. No significant correlation was observed between (18)F-FDG SUVmax and (18)F-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 (18)F-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 (18)F-FDG SUVmax and FHV. The pattern of tumoral (18)F-FDG uptake was rather homogeneous, whereas (18)F-FAZA uptake was more heterogeneous, suggesting that (18)F-FAZA identifies hypoxic areas within metabolically active areas of tumor. A significant correlation between (18)F-FDG SUVmax and lesion size (P = 0.002) was observed. CONCLUSION: (18)F-FAZA PET imaging is able to detect heterogeneous distributions of hypoxic subvolumes out of homogeneous (18)F-FDG background in a clinical setting. Therefore, (18)F-FAZA might be considered a tool for guiding dose escalation to the hypoxic fraction of the tumor.

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.

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.

18F-FDG PET during stereotactic body radiotherapy for stage I lung tumours cannot predict outcome: a pilot study.

PURPOSE: (18)F-Fluorodeoxyglucose positron emission tomography (FDG PET) has been used to assess metabolic response several months after stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer. However, whether a metabolic response can be observed already during treatment and thus can be used to predict treatment outcome is undetermined. METHODS: Ten medically inoperable patients with FDG PET-positive lung tumours were included. SBRT consisted of three fractions of 20 Gy delivered at the 80% isodose at days 1, 6 and 11. FDG PET was performed before, on day 6 immediately prior to administration of the second fraction of SBRT and 12 weeks after completion of SBRT. Tumour metabolism was assessed semi-quantitatively using the maximum standardized uptake value (SUV(max)) and SUV(70%). RESULTS: After the first fraction, median SUV(max) increased from 6.7 to 8.1 (p = 0.07) and median SUV(70%) increased from 5.7 to 7.1 (p = 0.05). At 12 weeks, both median SUV(max) and median SUV(70%) decreased by 63% to 3.1 (p = 0.008) and to 2.5 (p = 0.008), respectively. CONCLUSION: SUV increased during treatment, possibly due to radiation-induced inflammation. Therefore, it is unlikely that (18)F-FDG PET during SBRT will predict treatment success.

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 patient's 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.

TGFbeta-1 dependent fast stimulation of ATM and p53 phosphorylation following exposure to ionizing radiation does not involve TGFbeta-receptor I signalling.

BACKGROUND AND PURPOSE: It has been proposed that radiation induced stimulation of ATM and downstream components involves activation of TGFbeta-1 and that this may be due to TGFbeta-1-receptor I-Smad signalling. Therefore, the aim of this study was to clarify the distinct role of TGFbeta-1-receptor I-Smad signalling in mediating ATM activity following radiation exposure. MATERIALS AND METHODS: A549 cells were stably transfected with a conditionally regulatable TGFbeta-1 antisense construct (Tet-on-system) to test clonogenic activity following irradiation. Phosphorylation profile of ATM, p53, and chk2 was determined in non-cycling, serum-starved cells by immunoblotting. Likewise, A549 wild type cells were used to identify cell cycle distribution as a function of irradiation with or without pretreatment with CMK, a specific inhibitor of furin protease involved in activation of latent TGFbeta-1. Furthermore Western and immunoblot analyses were performed on serum-starved cells to investigate the dependence of ATM- and p53-stimulation on TGFbeta-1-receptor I-Smad signalling by applying a specific TGFbeta-1-receptor I inhibitor. RESULTS: Knock down of TGFbeta-1 by an antisense construct significantly increased clonogenic cell survival following exposure to ionizing radiation. Likewise, CMK treatment diminished the radiation induced G1 arrest of A549 cells. Moreover, both TGFbeta-1-knock down as well as CMK treatment inhibited the fast post-radiation phosphorylation of ATM, p53, and chk2. However, as shown by the use of a specific inhibitor TGFbeta-1-receptor I-Smad signalling was not involved in this fast activation of ATM and p53. CONCLUSIONS: We confirm that TGFbeta-1 plays a critical role in the stimulation of ATM- and p53 signalling in irradiated cells. However, this fast stimulation seems not to be dependent on activation of TGFbeta-1-receptor I-Smad signalling as recently proposed.

Post-irradiation dietary vitamin E does not affect the development of radiation-induced lung damage in rats.

The purpose of this study was to investigate whether application of post-irradiation vitamin E, an anti-oxidant, could prevent the development of radiation induced lung damage. Wistar rats were given vitamin E enriched or vitamin E deprived food starting from 4 weeks after 18Gy single dose irradiation of the right thorax. Neither breathing frequencies nor CT density measurements revealed differences between the groups. It is concluded that post-irradiation vitamin E does not influence radiation-induced fibrosis to the lung.