Katrien Vandecasteele

Salvage intensity-modulated radiotherapy for rising PSA after radical prostatectomy

INTRODUCTION The aim was to prospectively evaluate both acute and late toxicity and biochemical non-evidence of disease (bNED) in patients treated with salvage intensity-modulated radiotherapy (IMRT) +/- androgen deprivation (AD) for biochemical relapse after radical prostatectomy (RP). MATERIALS AND METHODS IMRT was prescribed to a mean prescription dose to the planning target volume (PTV) of 75 Gy to be delivered in 37 fractions of 2 Gy. In total, 135 patients were treated with IMRT. Median age was 64 years. Median PSA level was 0.8 ng/ml. AD was initiated in 94 patients. Indications were perineural invasion, seminal vesicle invasion or Gleason score > or = 8 at RP. (1) Acute toxicity (n = 135). All patients were available for this analysis. Acute toxicity was scored using an in-house developed scoring system. (2) Late toxicity (n = 68). Only patients with a follow-up of at least 18 months were considered for late toxicity analysis. The RILIT score was used to register gastro-intestinal (GI) toxicity. An in-house developed scale was used to register genito-urinary (GU) toxicity. (3) bNED (n = 87). For bNED, all AD-naive patients (n = 38) together with the AD-positive patients with a follow-up > or = 18 months (n = 49) were considered. Factors influencing the results of salvage treatment were analyzed. RESULTS (1) Acute toxicity (n = 135). No patient developed grade 3 GI toxicity. We observed grade 2 toxicity in 20 patients. Four patients developed grade 3 GU toxicity. (2) Late toxicity (n = 68). One patient developed grade 3 rectal blood loss. One patient developed grade 3 anal pain (anal fissure). We observed grade 2 GI toxicity in 9 patients. Two patients developed grade 3GU toxicity. Twenty-one patients developed grade 2 GU toxicity. We observed an urethral stricture in 5 patients. (3) bNED (n = 87). The 3- and 5-year bNED was 67%. Gleason score at RP, perineural invasion and capsular perforation were significant predictors for bNED. PSA before IMRT (<1.0 vs. 1.0 ng/ml) showed a trend in predicting bNED (p = 0.08). CONCLUSION IMRT to 75Gy+/-AD can be delivered with low levels of acute and late toxicity. In patients without perineural invasion and capsular invasion and with a Gleason score > or = 7 (3 + 4), IMRT offers very good 5-years bNED.

Delineation of the Postprostatectomy Prostate Bed Using Computed Tomography: Interobserver Variability Following the EORTC Delineation Guidelines

PURPOSE The present study aims to assess the interobserver agreement of prostate bed delineation after radical prostatectomy using CT alone as proposed by the European Organization for Research and Treatment of Cancer (EORTC) guidelines. METHODS AND MATERIALS Six observers delineated the postoperative prostate bed (PB) and the original seminal vesicle position or remnants (SV) of 10 patients according to the EORTC guidelines. Contours were then compared for agreement between observers (the apparent volume overlap and generalized kappa statistics). Standard deviations were also calculated to measure the variability of the position of the outer margins. RESULTS The mean volume of 100% agreement (±1 standard deviation, SD) was only 5.0 (±3.3) ml for the PB and 0.9 (±1.5) ml for the SV, whereas the mean union of all contours (±1 SD) was 41.1 (±11.8) ml and 25.3 (±13.4) ml, respectively. The mean overall agreement corrected for chance was moderate for both the PB (mean kappa, 0.49; range, 0.35-0.62) and SV (mean kappa, 0.42; range, 0.22-0.59). The overall SD of the outer margins of the PB ranged from 4.6 to 7.0 mm CONCLUSION The delineation of the postprostatectomy bed using CT shows only a moderate observer agreement when following the EORTC guidelines.

Cardiac comorbidity is an independent risk factor for radiation-induced lung toxicity in lung cancer patients

PURPOSE To test the hypothesis that cardiac comorbidity before the start of radiotherapy (RT) is associated with an increased risk of radiation-induced lung toxicity (RILT) in lung cancer patients. MATERIAL AND METHODS A retrospective analysis was performed of a prospective cohort of 259 patients with locoregional lung cancer treated with definitive radio(chemo)therapy between 2007 and 2011 (ClinicalTrials.gov Identifiers: NCT00572325 and NCT00573040). We defined RILT as dyspnea CTCv.3.0 grade ≥2 within 6 months after RT, and cardiac comorbidity as a recorded treatment of a cardiac pathology at a cardiology department. Univariate and multivariate analyses, as well as external validation, were performed. The model-performance measure was the area under the receiver operating characteristic curve (AUC). RESULTS Prior to RT, 75/259 (28.9%) patients had cardiac comorbidity, 44% of whom (33/75) developed RILT. The odds ratio of developing RILT for patients with cardiac comorbidity was 2.58 (p<0.01). The cross-validated AUC of a model with cardiac comorbidity, tumor location, forced expiratory volume in 1s, sequential chemotherapy and pretreatment dyspnea score was 0.72 (p<0.001) on the training set, and 0.67 (p<0.001) on the validation set. CONCLUSION Cardiac comorbidity is an important risk factor for developing RILT after definite radio(chemo)therapy of lung cancer patients.

Hypofractionated Intensity-Modulated Arc Therapy for Lymph Node Metastasized Prostate Cancer

PURPOSE To determine the planning results and acute toxicity after hypofractionated intensity-modulated arc radiotherapy and androgen deprivation for lymph node metastasized (Stage N1) prostate cancer. METHODS AND MATERIALS A total of 31 patients with Stage T1-T4N1M0 prostate cancer were treated with intensity-modulated arc radiotherapy and 3 years of androgen deprivation as primary treatment. The clinical target volume (CTV(p)) was the prostate and seminal vesicles. Elective lymph node areas ((e)) were delineated and expanded by 2 mm to create the CTV(e). The planning target volumes (PTV(p) and PTV(e)) were created using a three-dimensional expansion of the CTV(p) and CTV(e), respectively, of 7 mm. A median dose of 69.3 Gy and 50 Gy was prescribed to the PTV(p) and PTV(e) respectively, to be delivered in 25 fractions. Upper and lower gastrointestinal toxicity was scored using the Radiation Therapy Oncology Group toxicity and radiotherapy-induced lower intestinal toxicity scoring system. Genitourinary toxicity was scored using a combined Radiation Therapy Oncology Group, LENT-SOMA (late effects normal tissue-subjective, objective, management, analytic), and Common Toxicity Criteria toxicity scoring system. RESULTS The median follow-up time was 3 months. The mean prescription dose to the CTV(p) and PTV(p) was 70.4 Gy and 68.6 Gy, respectively. The minimal dose to the CTV(e) and PTV(e) was 49.0 Gy and 47.0 Gy, respectively. No acute Grade 2 or greater gastrointestinal toxicity occurred. Fourteen patients developed acute Grade 2 lower gastrointestinal toxicity. Acute Grade 3 and 2 genitourinary toxicity developed in 2 and 14 patients, respectively. CONCLUSION The results of our study have shown that hypofractionated intensity-modulated arc radiotherapy as primary therapy for N1 prostate cancer is feasible with low toxicity.

Immunogenic Apoptotic Cell Death and Anticancer Immunity.

For many years it has been thought that apoptotic cells rapidly cleared by phagocytic cells do not trigger an immune response but rather have anti-inflammatory properties. However, accumulating experimental data indicate that certain anticancer therapies can induce an immunogenic form of apoptosis associated with the emission of damage-associated molecular patterns (DAMPs), which function as adjuvants to activate host antitumor immune responses. In this review, we will first discuss recent advances and the significance of danger signaling pathways involved in the emission of DAMPs, including calreticulin, ATP, and HMGB1. We will also emphasize that switching on a particular signaling pathway depends on the immunogenic cell death stimulus. Further, we address the role of ER stress in danger signaling and the classification of immunogenic cell death inducers in relation to how ER stress is triggered. In the final part, we discuss the role of radiotherapy-induced immunogenic apoptosis and the relationship of its immunogenicity to the fraction dose and concomitant chemotherapy.

Hypofractionated intensity-modulated arc therapy for lymph node metastasized prostate cancer: Early late toxicity and 3-year clinical outcome

BACKGROUND AND PURPOSE For patients with N1 prostate cancer (PCa) aggressive local therapies can be advocated. We evaluated clinical outcome, gastro-intestinal (GI) and genito-urinary (GU) toxicity after intensity modulated arc radiotherapy (IMAT)+androgen deprivation (AD) for N1 PCa. MATERIAL AND METHODS Eighty patients with T1-4N1M0 PCa were treated with IMAT and 2-3years of AD. A median dose of 69.3Gy (normalized isoeffective dose at 2Gy per fraction: 80Gy [α/β=3]) was prescribed in 25 fractions to the prostate. The pelvic lymph nodes received a minimal dose of 45Gy. A simultaneous integrated boost to 72Gy and 65Gy was delivered to the intraprostatic lesion and/or pathologically enlarged lymph nodes, respectively. GI and GU toxicity was scored using the RTOG/RILIT and RTOG-SOMA/LENT-CTC toxicity scoring system respectively. Three-year actuarial risk of grade 2 and 3/4 GI-GU toxicity and biochemical and clinical relapse free survival (bRFS and cRFS) were calculated with Kaplan-Meier statistics. RESULTS Median follow-up was 36months. Three-year actuarial risk for late grade 3 and 2 GI toxicity is 8% and 20%, respectively. Three-year actuarial risk for late grade 3-4 and 2 GU toxicity was 6% and 34%, respectively. Actuarial 3-year bRFS and cRFS was 81% and 89%, respectively. Actuarial 3-year bRFS and cRFS was, respectively 26% and 32% lower for patients with cN1 disease when compared to patients with cN0 disease. CONCLUSION IMAT for N1 PCa offers good clinical outcome with moderate toxicity. Patients with cN1 disease have poorer outcome.

No association between TGF-β1 polymorphisms and radiation-induced lung toxicity in a European cohort of lung cancer patients

This study aimed at validating the previously published association between TGF-β1 single nucleotide polymorphisms and a reduced risk for radiation-induced lung toxicity. We were not able to confirm the reported association, neither using maximum dyspnea score nor after correction for baseline dyspnea score.

Adaptive radiotherapy for locally advanced non-small cell lung cancer, can we predict when and for whom?

ABSTRACT Background. Adaptive radiotherapy (ART) could be a tool to reduce toxicity and to facilitate dose escalation in stage III NSCLC. Our aim was to identify the most appropriate time and potential benefit of ART. Material and methods. We analyzed volume reduction and dosimetric consequences of 41 patients who were treated with concurrent (cCRT) (n = 21) or sequential (sCRT) chemoradiotherapy to a median dose of 70 Gy, 2 Gy/F. At every treatment fraction a cone-beam CT (CBCT) was performed. The gross tumor volume (GTV-T) was adapted (exclusion of lymph nodes) to create the GTV-T-F1. Every fifth fraction (F5–F30), the GTV-T-F1 was adapted on the CBCT to create a GTV-T-Fx. Dose volume histograms were recalculated for every GTV-T-Fx, enabling to create lookup tables to predict the theoretical dosimetric advantage on common lung dose constraints. Results. The average GTV reduction was 42.1% (range 4.0–69.3%); 50.1% and 33.7% for the cCRT and sCRT patients, respectively. A linear relationship between GTV-T-F1 volume and absolute volume decrease was found for both groups. The mean V5, V20, V30 and mean lung dose increased by 0.8, 3.1, 5.2 and 3.4%, respectively. A larger increase (p < 0.05) was observed for peripheral tumors and cCRT. Lookup tables were generated. Conclusion. ART offers the most beneficial dosimetric effects when performed around fraction 15, especially for patients with a large initial GTV-T treated by cCRT.

TILs in Head and Neck Cancer: Ready for Clinical Implementation and Why (Not)?

The assessment of tumor infiltrating lymphocytes (TILs) has recently emerged as a prognostic biomarker in several solid tumors. Quantification and subtyping of TILs reflects the immune response in the tumor microenvironment, contributing to either tumoral immune attack or escape and thereby affecting outcome. Despite the growing evidence of its value as prognosticator, TILs analysis has not yet found its way to daily clinical practice. The aim of this review is to evaluate whether the current knowledge on TILs in head and neck cancer justifies its clinical implementation. Therefore, we summarize the data on TILs in squamous cell cancer of the head and neck with focus on the most important subsets (T lymphocytes and more specifically CD8+ cytotoxic T cells and FoxP3+ regulatory T cells) and site-specific characteristics such as Human Papilloma Virus infection. In addition, we discuss methodological problems and pitfalls that can account for discordant findings and that may hamper inclusion of TILs assessment in routine practice of pathologists and oncologists.

Advanced Ovarian Cancer: Primary or Interval Debulking? Five Categories of Patients in View of the Results of Randomized Trials and Tumor Biology: Primary Debulking Surgery and Interval Debulking Surgery for Advanced Ovarian Cancer

BACKGROUND Standard treatment of stage III and IV advanced ovarian cancer (AOC) consists of primary debulking surgery (PDS) followed by chemotherapy. Since the publication of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial, clinical practice has changed and many AOC patients are now treated with neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). The best option remains unclear. Ovarian cancer is a heterogenic disease. Should we use the diversity in biology of the tumor and patterns of tumor localization to better stratify patients between both approaches? METHODS This analysis was based on results of five phase III randomized controlled trials on PDS and IDS in AOC patients, three Cochrane reviews, and four meta-analyses. RESULTS There is still no evidence that NACT-IDS is superior to PDS. Clinical status, tumor biology, and chemosensitivity should be taken into account to individualize surgical approach. Nonserous (type 1) tumors with favorable prognosis are less chemosensitive, and omitting optimal PDS will lead to less favorable outcome. For patients with advanced serous ovarian cancer (type 2) associated with severe comorbidity or low performance status, NACT-IDS is the preferred option. CONCLUSION We propose stratifying AOC patients into five categories according to patterns of tumor spread (reflecting the biologic behavior), response to chemotherapy, and prognosis to make a more rational decision between PDS and NACT-IDS. IMPLICATIONS FOR PRACTICE Trial results regarding effect and timing of debulking surgery on survival of patients with advanced ovarian cancer have been inconsistent and hence difficult to interpret. This review examines all randomized trials on primary and interval debulking surgery in advanced ovarian cancer, including the results of the newly published CHORUS (chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer) trial. On the basis of findings presented in this review and in view of recent molecular data on the heterogeneity of ovarian tumors, we propose prognostic categorization for patients with advanced ovarian cancer to better distinguish those who would optimally benefit from primary debulking from those who would better benefit from interval debulking following neoadjuvant chemotherapy.