Importance and outcome relevance of central pathology review in prostatectomy specimens: data from the SAKK 09/10 randomized trial on prostate cancer.

OBJECTIVE: To conduct a central pathology review within a randomized clinical trial on salvage radiation therapy (RT) in the presence of biochemical recurrence after prostatectomy to assess whether this results in changes in histopathological prognostic factors, such as Gleason score. PATIENTS AND METHODS: A total of 350 patients were randomized and specimens from 279 patients (80%) were centrally reviewed by a dedicated genitourinary pathologist. Gleason score, tumour classification and resection margin status were reassessed and compared with the results of local pathology review. Agreement was assessed using contingency tables and Cohen's kappa coefficient. The association between other histopathological features (e.g. largest diameter of carcinoma) and rapid biochemical progression (up to 6 months after salvage RT) was also investigated. RESULTS: There was good concordance between central and local pathology review for seminal vesicle invasion (pT3b: 91%; κ = 0.95 [95% confidence interval {CI} 0.89, 1.00]), extraprostatic extension (pT3a/b: 94%; κ = 0.82 [95% CI 0.75, 0.89]) and positive surgical margin (PSM) status (87%; κ = 0.7 [95% CI 0.62, 0.79]). The rate of agreement was lower for Gleason score (78%; κ = 0.61 [95% CI 0.52, 0.70]). The median (range) largest diameter of carcinoma was 16 (3-38) mm. A total of 49 patients (18%) experienced rapid biochemical progression after salvage RT. Largest diameter of carcinoma (odds ratio [OR] 2.04 [95% CI 1.30, 3.20]; P = 0.002), resection margin status (OR 0.36 [95% CI 0.18, 0.72]; P = 0.004) and Gleason score (OR 1.55 [95% CI 1.00, 2.42]; P = 0.05) remained associated with rapid progression after salvage RT after backward selection. CONCLUSION: The results of the central pathology analyses showed concordance between central and local pathology review with regard to seminal vesicle invasion, extraprostatic extension and PSM status, but a lower rate of agreement for Gleason score. Largest diameter of carcinoma was found to be a potential prognostic factor for rapid biochemical progression after salvage RT.

The effect of endorectal balloon on anorectal dose during postoperative volumetric arc radiotherapy of prostate cancer.

PURPOSE: To evaluate the impact of endorectal balloon (ERB) on anorectal dose during postoperative VMAT of prostate cancer. METHODS: In ten patients referred for salvage radiotherapy CTs were obtained without ERB and with air-filled ERB of 50ml and 100ml. CTs were repeated weekly (4-6 control CTs) and registered to the respective planning CT. For each planning CT, a VMAT plan was made with defined anorectal dose constraints and propagated on the respective control CTs. The dose volumes V40Gy, V60Gy and V65Gy of the rectal and anal wall (Rwall and Awall, respectively) and the ERB position were obtained from each plan. RESULTS: In plans with ERB, the mean Rwall dose volumes V40Gy, V60Gy and V65Gy were higher by 8%, 5% and 2% (ERB 50ml) and 2%, 3% and 3% (ERB 100ml) in comparison to plans without ERB. The respective Awall dose volume differences were 2%, 0%, -1% (ERB 50ml), and -3%, -2%, -2% (ERB 100ml). The dose volume variability of the Rwall was comparable with and without ERB, but was slightly reduced by ERB for the Awall. The mean ERB position variability was >2mm in anterior-posterior and inferior-superior directions. CONCLUSION: The use of ERB during post-operative VMAT has no advantages for anorectal dose.

The updated Swiss guidelines 2016 for the treatment and follow-up of cutaneous melanoma.

Cutaneous melanoma is the most deadly cutaneous neoplasm. In order to guide treatment decisions and follow-up of melanoma patients, guidelines for the management of melanoma in Switzerland were inaugurated in 2001 and revised in 2006 and 2016. Recent data on surgical and medical treatments from randomised trials necessitated modification of the treatment and follow-up recommendations.

Acute Toxicity and Quality of Life After Dose-Intensified Salvage Radiation Therapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: First Results of the Randomized Trial SAKK 09/10.

PURPOSE: Patients with biochemical failure (BF) after radical prostatectomy may benefit from dose-intensified salvage radiation therapy (SRT) of the prostate bed. We performed a randomized phase III trial assessing dose intensification. PATIENTS AND METHODS: Patients with BF but without evidence of macroscopic disease were randomly assigned to either 64 or 70 Gy. Three-dimensional conformal radiation therapy or intensity-modulated radiation therapy/rotational techniques were used. The primary end point was freedom from BF. Secondary end points were acute toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) and quality of life (QoL) according to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and PR25. RESULTS: Three hundred fifty patients were enrolled between February 2011 and April 2014. Three patients withdrew informed consent, and three patients were not eligible, resulting in 344 patients age 48 to 75 years in the safety population. Thirty patients (8.7%) had grade 2 and two patients (0.6%) had grade 3 genitourinary (GU) baseline symptoms. Acute grade 2 and 3 GU toxicity was observed in 22 patients (13.0%) and one patient (0.6%), respectively, with 64 Gy and in 29 patients (16.6%) and three patients (1.7%), respectively, with 70 Gy (P = .2). Baseline grade 2 GI toxicity was observed in one patient (0.6%). Acute grade 2 and 3 GI toxicity was observed in 27 patients (16.0%) and one patient (0.6%), respectively, with 64 Gy, and in 27 patients (15.4%) and four patients (2.3%), respectively, with 70 Gy (P = .8). Changes in early QoL were minor. Patients receiving 70 Gy reported a more pronounced and clinically relevant worsening in urinary symptoms (mean difference in change score between arms, 3.6; P = .02). CONCLUSION: Dose-intensified SRT was associated with low rates of acute grade 2 and 3 GU and GI toxicity. The impact of dose-intensified SRT on QoL was minor, except for a significantly greater worsening in urinary symptoms.

PTV margin definition in hypofractionated IGRT of localized prostate cancer using cone beam CT and orthogonal image pairs with fiducial markers.

PURPOSE: To evaluate PTV margins for hypofractionated IGRT of prostate comparing kV/kV imaging or CBCT. PATIENTS AND METHODS: Between 2009 and 2012, 20 patients with low- (LR), intermediate- (IR) and high-risk (HR) prostate cancer were treated with VMAT in supine position with fiducial markers (FM), endorectal balloon (ERB) and full bladder. CBCT's and kV/kV imaging were performed before and additional CBCT's after treatment assessing intra-fraction motion. CTVP for 5 patients with LR and CTVPSV for 5 patients with IR/HR prostate cancer were contoured independently by 3 radiation oncologists using MRI. The van Hark formula (PTV margin =2.5Σ +0.7σ) was applied to calculate PTV margins of prostate/seminal vesicles (P/PSV) using CBCT or FM. RESULTS: 172 and 52 CBCTs before and after RT and 507 kV/kV images before RT were analysed. Differences between FM in CBCT or in planar kV image pairs were below 1 mm. Accounting for both random and systematic uncertainties anisotropic PTV margins were 5-8 mm for P (LR) and 6-11 mm for PSV (IR/HR). Random uncertainties like intra-fraction and inter-fraction (setup) uncertainties were of similar magnitude (0.9-1.4 mm). Largest uncertainty was introduced by CTV delineation (LR: 1-2 mm, IR/HR: 1.6-3.5 mm). Patient positioning using bone matching or ERB-matching resulted in larger PTV margins. CONCLUSIONS: For IGRT CBCT or kV/kV-image pairs with FM are interchangeable in respect of accuracy. Especially for hypofractionated RT, PTV margins can be kept in the range of 5 mm or below if stringent daily IGRT, ideally including prostate tracking, is applied. MR-based CTV delineation optimization is recommended.

Late term tolerance in head neck cancer patients irradiated in the IMRT era.

BACKGROUND: The aim was to quantify severe transient and persisting late term effects in our single institution head neck cancer (HNC) cohort treated with curatively intended intensity modulated radiation therapy (IMRT). Hypothesis was if a 2-year follow up (FU) is sufficient to estimate the long term tolerance in HNC irradiated in the IMRT era. METHODS: Between 01/2002-8/2012, 707/1211 (58%) consecutively treated IMRT patients met the inclusion criteria of a FU time >12 months and loco-regional disease control (LRC). 45% presented with loco-regionally advanced disease; 55% were referred for curative definitive IMRT (66 Gy-72 Gy in 30-35 fractions), 45% underwent postoperative IMRT (60-66 Gy in 30-33 fractions). Systemic concomitant therapy was administered in 85%. Highly consistent treatment procedures were performed with respect to contouring processes, dose constraints, radiation schedules, and the use of systemic therapy. Grade 3/4 late term effects were prospectively assessed and analyzed with respect to subgroups at particular risk for specific late effects. RESULTS: Mean/median FU of the cohort was 41/35 months (15-124). 13% of the patients (92/707) experienced any grade 3/4 late effects (101 events in 92/707 patients), 81% in the first 12 months after radiation. 4% of all developed persisting late grade 3/4 effects (25 events in 25/707 patients). CONCLUSIONS: IMRT led to a high late term tolerance in loco-regionally disease free HNC patients. The onset of any G3/4 effects showed a plateau at 2 years. The question of the cervical vessel tolerance in disease free long time survivors is still open and currently under evaluation at our institution.

Use of EORTC target definition guidelines for dose-intensified salvage radiation therapy for recurrent prostate cancer: results of the quality assurance program of the randomized trial SAKK 09/10.

PURPOSE: Different international target volume delineation guidelines exist and different treatment techniques are available for salvage radiation therapy (RT) for recurrent prostate cancer, but less is known regarding their respective applicability in clinical practice. METHODS AND MATERIALS: A randomized phase III trial testing 64 Gy vs 70 Gy salvage RT was accompanied by an intense quality assurance program including a site-specific and study-specific questionnaire and a dummy run (DR). Target volume delineation was performed according to the European Organisation for the Research and Treatment of Cancer guidelines, and a DR-based treatment plan was established for 70 Gy. Major and minor protocol deviations were noted, interobserver agreement of delineated target contours was assessed, and dose-volume histogram (DVH) parameters of different treatment techniques were compared. RESULTS: Thirty European centers participated, 43% of which were using 3-dimensional conformal RT (3D-CRT), with the remaining centers using intensity modulated RT (IMRT) or volumetric modulated arc technique (VMAT). The first submitted version of the DR contained major deviations in 21 of 30 (70%) centers, mostly caused by inappropriately defined or lack of prostate bed (PB). All but 5 centers completed the DR successfully with their second submitted version. The interobserver agreement of the PB was moderate and was improved by the DR review, as indicated by an increased κ value (0.59 vs 0.55), mean sensitivity (0.64 vs 0.58), volume of total agreement (3.9 vs 3.3 cm(3)), and decrease in the union volume (79.3 vs 84.2 cm(3)). Rectal and bladder wall DVH parameters of IMRT and VMAT vs 3D-CRT plans were not significantly different. CONCLUSIONS: The interobserver agreement of PB delineation was moderate but was improved by the DR. Major deviations could be identified for the majority of centers. The DR has improved the acquaintance of the participating centers with the trial protocol.

Chronic cervical spinal cord injury: DTI correlates with clinical and electrophysiological measures.

Diffusion tensor imaging (DTI) is rarely applied in spinal cord injury (SCI). The aim of this study was to correlate diffusion properties after SCI with electrophysiological and neurological measures. Nineteen traumatic cervical SCI subjects and 28 age-matched healthy subjects participated in this study. DTI data of the spinal cord were acquired with a Philips Achieva 3 T MR scanner using an outer volume suppressed, reduced field of view (FOV) acquisition with oblique slice excitation and a single-shot EPI readout. Neurological and electrophysiological measures, American Spinal Injury Association (ASIA) impairment scale scores, and motor (MEP) and somatosensory evoked potentials (SSEP) were assessed in SCI subjects. Fractional anisotropy (FA) values were decreased in the SCI subjects compared to the healthy subjects. In upper cervical segments, the decrease in FA was significant for the evaluation of the entire cross-sectional area of the spinal cord, and for corticospinal and sensory tracts. A decreasing trend was also found at the thoracic level for the corticospinal tracts. The decrease of DTI values correlated with the clinical completeness of SCI, and with SSEP amplitudes. The reduced DTI values seen in the SCI subjects are likely due to demyelination and axonal degeneration of spinal tracts, which are related to clinical and electrophysiological measures. A reduction in DTI values in regions remote from the injury site suggests their involvement with wallerian axonal degeneration. DTI can be used for the quantitative evaluation of the extent of spinal cord damage, and eventually to monitor the effects of future regeneration-inducing treatments.

The use of photon beams of a flattening filter-free linear accelerator for hypofractionated volumetric modulated arc therapy in localized prostate cancer.

PURPOSE: To evaluate the potential usage of flattening filter-free (FFF) photon beams in the treatment of prostate cancer. METHODS AND MATERIALS: Volumetric-modulated arc therapy (VMAT) treatment planning was performed for 7 patients using TrueBeam(®) linear accelerator and photon beams with (X6, X10) and without (X6FFF, X10FFF) flattening filter. Prescribed dose was 19 × 3 Gy = 57 Gy. One or two 360° arcs with dose rate of 600 MU/min for flattened beams, and 1,200 MU/min for FFF beams were used. RESULTS: No difference was detected between the four beams in PTV coverage, conformity, and homogeneity. Mean body dose and body volume receiving 50% of the prescribed dose decreased with increasing mean energy (r(2) = 0.8275, p < 0.01). X6FFF delivered 3.6% more dose compared with the X6 (p < 0.01). X10FFF delivered 3.0% (p < 0.01), and the X10 5.8% (p < 0.01) less mean body dose compared with X6. There was a significant increase in the mean dose to the rectum for the X10 compared with X6 (2.6%, p < 0.01). Mean dose to the bladder increased by 1.3% for X6FFF and decreased by 2.3% for X10FFF. Using a single arc and FFF, treatment time was reduced by 35% (2 SD = 10%). CONCLUSION: FFF beams resulted in dose distributions similar to flattened beams. X10FFF beam provided the best solution, sparing rectum and bladder and minimizing whole-body dose. FFF beams lead to a time efficient treatment delivery, particularly when combined with hypofractionated VMAT.

Follow up after IMRT in oral cavity cancer: update.

PURPOSE: Except for early stages (T1/2 N0), the prognosis for patients with oral cavity cancer (OCC) is known to be worse than for those with pharyngeal carcinoma. While definitive intensity modulated radiation therapy (IMRT)-chemotherapy affords loco-regional control rates (LRC) of approximately 80% in advanced pharyngeal cancer, corresponding rates are reported to be much lower for OCC. The aim of this work was to evaluate loco-regional disease control and overall survival (OAS) in a relatively large OCC patient cohort treated in the IMRT era. METHODS AND MATERIALS: Between October 2002 and June 2011, 160 OCC patients were treated with curative intention IMRT at our department. 122 patients (76%) were referred with primary disease and 38 patients (24%) with a recurrent OCC at least 3 months after surgery alone. Definitive IMRT was performed in 44/160 patients (28%), whilst 116 patients underwent previous surgery. Simultaneous systemic therapy was administered in 72%. RESULTS: Patients with postoperative IMRT (+/-systemic therapy) with R0-1 status (n = 99) reached significantly higher LRC/OAS rates than patients following IMRT for macroscopic disease (n = 61), with 84%/80% versus 38%/33% at 3 years, respectively (p < 0.0001). This was found in patients treated for initial, as well as recurrent, disease. Less than 2% persisting grade 3/4 late effects were observed. CONCLUSIONS: IMRT for R0-1 situations translated into a highly significant superior LRC and OAS compared to the IMRT cohort treated for macroscopic disease. Treatment was well tolerated.