Prospective Evaluation of the Relationship Between Mechanical Stability and Response to Palliative Radiotherapy for Symptomatic Spinal Metastases.

BACKGROUND: A substantial number of patients with spinal metastases experience no treatment effect from palliative radiotherapy. Mechanical spinal instability, due to metastatic disease, could be associated with failed pain control following radiotherapy. This study investigates the relationship between the degree of spinal instability, as defined by the Spinal Instability Neoplastic Score (SINS), and response to radiotherapy in patients with symptomatic spinal metastases in a multi-institutional cohort. METHODS AND MATERIALS: The SINS of 155 patients with painful thoracic, lumbar, or lumbosacral metastases from two tertiary hospitals was calculated using images from radiotherapy planning CT scans. Patient-reported pain response, available for 124 patients, was prospectively assessed. Pain response was categorized, according to international guidelines, as complete, partial, indeterminate, or progression of pain. The association between SINS and pain response was estimated by multivariable logistic regression analysis, correcting for predetermined clinical variables. RESULTS: Of the 124 patients, 16 patients experienced a complete response and 65 patients experienced a partial response. Spinal Instability Neoplastic Score was associated with a complete pain response (adjusted odds-radio [ORadj] 0.78; 95% confidence interval [CI] 0.62-0.98), but not with an overall pain response (ORadj 0.94; 95% CI 0.81-1.10). CONCLUSIONS: A lower SINS, indicating spinal stability, is associated with a complete pain response to radiotherapy. This supports the hypothesis that pain resulting from mechanical spinal instability responds less well to radiotherapy compared with pain from local tumor activity. No association could be determined between SINS and an overall pain response, which might indicate that this referral tool is not yet optimal for prediction of treatment outcome. IMPLICATIONS FOR PRACTICE: Patients with stable painful spinal metastases, as indicated by a Spinal Instability Neoplastic Score (SINS) of 6 or lower, can effectively be treated with palliative external beam radiotherapy. The majority of patients with (impending) spinal instability, as indicated by a SINS score of 7 or higher, will achieve a (partial) response after palliative radiotherapy; however, some patients might require surgical intervention. Therefore, it is recommended to refer patients with a SINS score of 7 or higher to a spine surgeon to evaluate the need for surgical intervention.

Focal salvage high-intensity focused ultrasound in radiorecurrent prostate cancer.

OBJECTIVE: To assess short- to medium-term cancer control rates and side effects of focal salvage high- intensity focused ultrasound (HIFU). MATERIALS AND METHODS: A retrospective registry analysis identified 150 men who underwent focal salvage HIFU (FS-HIFU) (Sonablate 500) between November 2006 and August 2015. Metastatic disease was excluded by nodal assessment on the pelvic MRI, a radioisotope bone scan and positron-emission tomography (PET) imaging (choline-18F-fluorodeoxyglucose PET or choline PET-CT). In our current clinical practice, metastatic disease must be excluded by both choline PET and bone scan. Localization of cancer was carried out using multiparametric MRI of the prostate (T2-weighted, diffusion-weighted and dynamic contrast-enhanced imaging) with systematic or template prostate mapping biopsies. The primary outcome was a composite failure incorporating biochemical failure (BCF) and/or positive localized or distant imaging results and/or positive biopsy and/or systemic therapy and/or metastases/prostate cancer-specific death. The secondary outcome was BCF using the Phoenix-ASTRO definition (prostate-specific antigen [PSA] nadir + 2 ng/mL). We used Kaplan-Meier analysis and Cox proportional hazards regression to quantify the effect of the determinants on the endpoints. RESULTS: The mean (standard deviation [sd]) patient age at focal salvage HIFU was 69.8 (6.1) years and the median (interquartile range [IQR]) PSA pre-focal salvage HIFU was 5.5 (3.6-7.9) ng/mL. The median (IQR) follow-up was 35 (22-52) months. Patients were classified as having low- 2.7% (4/150), intermediate- 39.3% (59/150) and high-risk disease 41.3% (62/150) according to D'Amico classification, prior to focal salvage HIFU. Composite failure occurred in 61% of patients (91/150) and BCF occurred in 51.3% (77/150). The Kaplan-Meier composite endpoint-free survival (CEFS) rate at 3 years was 40% (95% confidence interval [CI] 31-50) for the entire group. Kaplan-Meier estimates of CEFS were 100%, 49% and 24% at 3 years in the low-, intermediate- and high-risk groups pre-salvage HIFU, respectively. The Kaplan-Meier biochemical disease-free survival (BDFS) rate at 3 years was 48% (95% CI 39-59) for the entire group. Kaplan-Meier estimates of BDFS were 100%, 61% and 32% at 3 years in the low-, intermediate- and high-risk groups pre-salvage HIFU, respectively. Complications included urinary tract infection (11.3%; 17/150), bladder neck stricture (8%; 12/150), recto-urethral fistula after one HIFU procedure (2%; 3/150) and osteitis pubis (0.7%; 1/150). CONCLUSION: Focal salvage HIFU conferred a relatively low complication and side effect rate. CEFS and biochemical control in the short to medium term were reasonable, especially in this relatively high-risk cohort, but still low compared with current whole-gland salvage therapies. Focal salvage therapy may offer disease control in men at high risk whilst minimizing additional treatment morbidities.

Perioperative chemotherapy versus neoadjuvant chemoradiotherapy for esophageal or GEJ adenocarcinoma: A propensity score-matched analysis comparing toxicity, pathologic outcome, and survival.

OBJECTIVES: To evaluate toxicity, pathologic outcome, and survival after perioperative chemotherapy (pCT) compared to neoadjuvant chemoradiotherapy (nCRT) followed by surgery for patients with resectable esophageal or gastroesophageal junction (GEJ) adenocarcinoma. METHODS: Consecutive patients with resectable esophageal or GEJ adenocarcinoma who underwent pCT (epirubicin, cisplatin, and capecitabine) or nCRT (paclitaxel, carboplatin, and 41.4 Gy) followed by surgery in a tertiary referral center in the Netherlands were compared. Propensity score matching was applied to create comparable groups. RESULTS: Of 193 eligible patients, 21 were discarded after propensity score matching; 86 and 86 patients who underwent pCT and nCRT, respectively, remained. Grade ≥3 thromboembolic events occurred only in the pCT group (19% vs. 0%, P < 0.001), whereas grade ≥3 leukopenia occurred more frequently in the nCRT group (14% vs. 4%, P = 0.015). No significant differences regarding postoperative morbidity and mortality were found. Pathologic complete response was more frequently observed with nCRT (18% vs. 11%, P < 0.001), without significantly improving radicality rates (95% vs. 89%, P = 0.149). Both strategies resulted in comparable 3-year progression-free survival (pCT vs. nCRT: 46% vs. 55%, P = 0.344) and overall survival rates (49% vs. 50%, P = 0.934). At 3-year follow-up, fewer locoregional disease progression occurred in the nCRT group (19% vs. 37%, P = 0.024). CONCLUSIONS: Compared to perioperative chemotherapy, neoadjuvant chemoradiotherapy achieves higher pathologic response rates and a lower risk of locoregional disease progression, without improving survival.

Screening for psychological distress before radiotherapy for painful bone metastases may be useful to identify patients with high levels of distress.

BACKGROUND: Psychological distress (PD) has a major impact on quality of life. We studied the incidence of PD before and after radiotherapy for painful bone metastases. Furthermore, we aimed to identify factors predictive for PD. METHODS: Between 1996 and 1998, the Dutch Bone Metastasis Study included 1157 patients with painful bone metastases. Patients were randomized between two fractionation schedules. The study showed a pain response of 74% in both groups. Patients filled out weekly questionnaires for 13 weeks, then monthly for two years. The questionnaires included a subscale for PD on the Rotterdam Symptom Checklist. We used generalized estimating equations and multivariable logistic regression analyses. RESULTS: At baseline, 290 patients (27%) had a high level of PD. For the entire group, the level of PD remained constant over time. The majority of patients with a low level of PD at baseline remained at a low level during follow-up. In patients with a high level of PD at baseline, the mean level of PD decreased after treatment and stabilized around the cutoff level. Female patients, higher age, worse performance, lower pain score and worse self-reported QoL were associated with an increased chance of PD, although the model showed moderate discriminative power. CONCLUSIONS: A substantial proportion of patients had a high level of PD before and after radiotherapy for painful bone metastases. Most patients who reported high levels of PD when referred for palliative radiotherapy remained at high levels thereafter. Therefore, screening of PD prior to treatment seems appropriate, in order to select patients requiring intervention.

Systematic review on the treatment of isolated local recurrence of pancreatic cancer after surgery; re-resection, chemoradiotherapy and SBRT.

BACKGROUND: The majority of patients who have undergone a pancreatic resection for pancreatic cancer develop disease recurrence within two years. In around 30% of these patients, isolated local recurrence (ILR) is found. The aim of this study was to systematically review treatment options for this subgroup of patients. METHODS: A systematic search was performed in PubMed, Embase and the Cochrane Library. Studies reporting on the treatment of ILR after initial curative-intent resection of primary pancreatic cancer were included. Primary endpoints were morbidity, mortality and survival after ILR treatment. RESULTS: After screening 1152 studies, 18 studies reporting on 313 patients undergoing treatment for ILR were included. Treatment options for ILR included surgical re-resection (8 studies, 100 patients), chemoradiotherapy (7 studies, 153 patients) and stereotactic body radiation therapy (SBRT) (4 studies, 60 patients). Morbidity and mortality were reported for re-resection (29% and 1%, respectively), chemoradiotherapy (54% and 0%) and SBRT (3% and 1%). Most patients had a prolonged disease-free interval before recurrence. Median survival after treatment of ILR of up to 32, 19 and 16 months was reported for re-resection, chemoradiotherapy and SBRT, respectively. CONCLUSION: In selected patients, treatment of ILR following pancreatic resection for pancreatic cancer seems safe, feasible and associated with relatively good survival.

The Effect of Introducing the Spinal Instability Neoplastic Score in Routine Clinical Practice for Patients With Spinal Metastases.

BACKGROUND: Stable spinal metastases are effectively treated with radiotherapy, whereas unstable spinal metastases often need surgical fixation followed by radiotherapy for local control. The Spinal Instability Neoplastic Score (SINS) was developed as a tool to assess spinal neoplastic related instability with the goal of helping to guide referrals among oncology specialists. We compare the average degree of spinal instability between patients with spinal metastases referred for surgery or for radiotherapy and evaluate whether this difference changed after introduction of the SINS in clinical practice. METHODS: All patients with spinal metastases treated with palliative surgery or radiotherapy in the period 2009-2013 were identified in two spine centers. For all patients, the SINS was scored on pretreatment imaging. The SINS before and after introduction of the SINS in 2011 were compared within the surgical and radiotherapy group. Furthermore, the overall SINS was compared between the two groups. RESULTS: The overall SINS was significantly higher in the surgical group, with a mean SINS of 10.7 (median 11) versus 7.2 (median 8) for the radiotherapy group. The mean SINS decreased significantly for both groups after introduction of the SINS in clinical practice from 11.2 to 10.3 in the surgical group and from 8.4 to 7.2 in the radiotherapy group. CONCLUSION: The SINS differed significantly between patients treated with surgery or radiotherapy. The introduction of SINS led to a decrease in SINS score for both groups, suggesting that using SINS in metastatic spinal disease increases awareness for instability and may subsequently result in earlier referrals for surgical intervention. IMPLICATIONS FOR PRACTICE: Spinal metastases can present with varying degrees of mechanical instability. Because unstable spinal metastases may respond insufficiently to palliative radiotherapy and can lead to loss of ambulation, timely detection and appropriate referral are important. The Spinal Instability Neoplastic Score (SINS) may help physicians caring for patients with metastasized disease to identify spinal instability before the onset of neurological deficits. In this study, it was shown that the introduction of SINS in routine practice led to a decrease in spinal instability in radiotherapy and surgical cohorts. The use of SINS may increase awareness of instability and subsequently result in earlier referrals.

Brief Report: Staged-informed Consent in the Cohort Multiple Randomized Controlled Trial Design.

The "cohort multiple randomized controlled trial," a new design for pragmatic trials, embeds multiple trials within a cohort. The cohort multiple RCT is an attractive alternative to conventional RCTs in fields where recruitment is slow, multiple new (competing) interventions for the same condition have to be tested, new interventions are highly preferred by patients and doctors, and the risk of disappointment bias, cross-over, and contamination is considerable. To prevent these unwanted effects, the cohort multiple RCT provides information on randomization to the intervention group/arm only, and only after randomization (i.e., prerandomization). To some, especially in a clinical setting, this is not ethically acceptable. In this article, we argue that prerandomization in the cohort multiple randomized controlled trial (cmRCT) can be avoided by adopting a staged-informed consent procedure. In the first stage, at entry into the cohort, all potential participants are asked for their informed consent to participate in a cohort study and broad consent to be either randomly selected to be approached for experimental interventions or to serve as control without further notice during participation in the cohort. In a second stage, at the initiation of an RCT within the cohort, informed consent to receive the intervention is then only sought in those randomly selected for the intervention arm. At the third stage, after completion of each RCT, all cohort participants receive aggregate disclosure of trial results. This staged-informed consent procedure avoids prerandomization in cmRCT and aims to keep participants actively engaged in the research process.

Comparing conVEntional RadioTherapy with stereotactIC body radiotherapy in patients with spinAL metastases: study protocol for an randomized controlled trial following the cohort multiple randomized controlled trial design.

BACKGROUND: Standard radiotherapy is the treatment of first choice in patients with symptomatic spinal metastases, but is only moderately effective. Stereotactic body radiation therapy is increasingly used to treat spinal metastases, without randomized evidence of superiority over standard radiotherapy. The VERTICAL study aims to quantify the effect of stereotactic radiation therapy in patients with metastatic spinal disease. METHODS/DESIGN: This study follows the 'cohort multiple Randomized Controlled Trial' design. The VERTICAL study is conducted within the PRESENT cohort. In PRESENT, all patients with bone metastases referred for radiation therapy are enrolled. For each patient, clinical and patient-reported outcomes are captured at baseline and at regular intervals during follow-up. In addition, patients give informed consent to be offered experimental interventions. Within PRESENT, 110 patients are identified as a sub cohort of eligible patients (i.e. patients with unirradiated painful, mechanically stable spinal metastases who are able to undergo stereotactic radiation therapy). After a protocol amendment, also patients with non-spinal bony metastases are eligible. From the sub cohort, a random selection of patients is offered stereotactic radiation therapy (n = 55), which patients may accept or refuse. Only patients accepting stereotactic radiation therapy sign informed consent for the VERTICAL trial. Non-selected patients (n = 55) receive standard radiotherapy, and are not aware of them serving as controls. Primary endpoint is pain response after three months. Data will be analyzed by intention to treat, complemented by instrumental variable analysis in case of substantial refusal of the stereotactic radiation therapy in the intervention arm. DISCUSSION: This study is designed to quantify the treatment response after (stereotactic) radiation therapy in patients with symptomatic spinal metastases. This is the first randomized study in palliative care following the cohort multiple Randomized Controlled Trial design. This design addresses common difficulties associated with classic pragmatic randomized controlled trials, such as disappointment bias in patients allocated to the control arm, slow recruitment, and poor generalizability. TRIAL REGISTRATION: The Netherlands Trials Register number NL49316.041.14. ClinicalTrials.gov registration number NCT02364115 . Date of trial registration February 1, 2015.

Endoscopic biopsy and EUS for the detection of pathologic complete response after neoadjuvant chemoradiotherapy in esophageal cancer: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Accurate determination of residual cancer status after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer could assist in selecting the optimal treatment strategy. The aim of this study was to review the evidence on the diagnostic accuracy of endoscopic biopsy and EUS after nCRT for detecting residual cancer at the primary tumor site (ypT+) and regional lymph nodes (ypN+) as opposed to a pathologic complete response (ypT0 and ypN0). METHODS: PubMed/Medline, Embase, and the Cochrane library were systematically searched. The analysis included diagnostic studies reporting on the accuracy of endoscopic biopsy or EUS in detecting residual cancer versus complete response after nCRT for esophageal cancer with histopathology as the reference standard. Bivariate random-effects models were used to estimate pooled sensitivities and specificities and examine sources of heterogeneity. RESULTS: Twenty-three studies comprising 12 endoscopic biopsy studies (1281 patients), 11 EUS studies reporting on ypT status (593 patients), and 10 EUS studies reporting on ypN status (602 patients), were included. Pooled estimates for sensitivity of endoscopic biopsy after nCRT for predicting ypT+ were 34.5% (95% confidence interval [CI], 26.0%-44.1%) and for specificity 91.0% (95% CI, 85.6%-94.5%). Pooled estimates for sensitivity of EUS after nCRT were 96.4% (95% CI, 91.7%-98.5%) and for specificity were 10.9% (95% CI, 3.5%-29.0%) for detecting ypT+, and 62.0% (95% CI, 46.0%-75.7%) and 56.7% (95% CI, 41.8%-70.5%) for detecting ypN+, respectively. CONCLUSIONS: Endoscopic biopsy after nCRT is a specific but not sensitive method for detecting residual esophageal cancer. Although EUS after nCRT yields a high sensitivity, only a limited number of patients will have negative findings at EUS with still a substantial false-negative rate. Furthermore, EUS provides only moderate accuracy for detecting residual lymph node involvement. Based on these findings, these endoscopic modalities cannot be used to withhold surgical treatment in test-negative patients after nCRT. ( CLINICAL TRIAL REGISTRATION NUMBER: CRD42015016527.).

PREDICT: model for prediction of survival in localized prostate cancer.

PURPOSE: Current models for prediction of prostate cancer-specific survival do not incorporate all present-day interventions. In the present study, a pre-treatment prediction model for patients with localized prostate cancer was developed. METHODS: From 1989 to 2008, 3383 patients were treated with I-125 brachytherapy (n = 1694), external beam radiotherapy (≥74 Gy, n = 336) or radical prostatectomy (n = 1353). Pre-treatment parameters (clinical T-stage, biopsy grade, PSA and age) were related to the hazard of mortality by multivariate Cox proportional hazard analysis. The PRetreatment Estimation of the risk of Death In Cancer of the prosTate (PREDICT) model was developed. The predictive accuracy of the model was assessed by calibration and discrimination and compared to the Ash risk classification system. RESULTS: Of the 3383 patients analyzed, 2755 patients (81 %) were alive at the end of follow-up, 149 patients (4 %) died of prostate cancer and 365 patients (11 %) died of other causes, and for 114 patients (3 %) cause of death was unknown. Median follow-up time was 7.6 years. After correction for overoptimism, the c-statistic of the prediction model for prostate cancer-specific mortality was 0.78 (95 % CI 0.74-0.82), compared to 0.78 (95 % CI 0.75-0.81) for the risk classification system by Ash et al. The PREDICT model showed better calibration than the Ash risk classification system. CONCLUSIONS: The PREDICT model showed a good predictive accuracy and reliability. The PREDICT model might be a promising tool for physicians to predict disease-specific survival prior to any generally accepted intervention in patients with localized prostate cancer.

Biological responses of human solid tumor cells to X-ray irradiation within a 1.5-Tesla magnetic field generated by a magnetic resonance imaging-linear accelerator.

Devices that combine magnetic resonance imaging with linear accelerators (MRL) represent a novel tool for MR-guided radiotherapy. However, whether magnetic fields (MFs) generated by these devices affect the radiosensitivity of tumors is unknown. We investigated the influence of a 1.5-T MF on cell viability and radioresponse of human solid tumors. Human head/neck cancer and lung cancer cells were exposed to single or fractionated 6-MV X-ray radiation; effects of the MF on cell viability were determined by cell plating efficiency and on radioresponsiveness by clonogenic cell survival. Doses needed to reduce the fraction of surviving cells to 37% of the initial value (D0s) were calculated for multiple exposures to MF and radiation. Results were analyzed using Student's t-tests. Cell viability was no different after single or multiple exposures to MRL than after exposure to a conventional linear accelerator (Linac, without MR-generated MF) in 12 of 15 experiments (all P > 0.05). Single or multiple exposures to MF had no influence on cell radioresponse (all P > 0.05). Cells treated up to four times with an MRL or a Linac further showed no changes in D0s with MF versus without MF (all P > 0.05). In conclusion, MF within the MRL does not seem to affect in vitro tumor radioresponsiveness as compared with a conventional Linac. Bioelectromagnetics. 37:471-480, 2016. © 2016 Wiley Periodicals, Inc.

Radiotherapy for renal-cell carcinoma.

Renal-cell carcinoma is considered to be a radioresistant tumour, but this notion might be wrong. If given in a few (even single) fractions, but at a high fraction dose, stereotactic body radiotherapy becomes increasingly important in the management of renal-cell carcinoma, both in primary settings and in treatment of oligometastatic disease. There is an established biological rationale for the radiosensitivity of renal-cell carcinoma to stereotactic body radiotherapy based on the ceramide pathway, which is activated only when a high dose per fraction is given. Apart from the direct effect of stereotactic body radiotherapy on renal-cell carcinoma, stereotactic body radiotherapy can also induce an abscopal effect. This effect, caused by immunological processes, might be enhanced when targeted drugs and stereotactic body radiotherapy are combined. Therefore, rigorous, prospective randomised trials involving a multidisciplinary scientific panel are needed urgently.

(31) P MR spectroscopic imaging combined with (1) H MR spectroscopic imaging in the human prostate using a double tuned endorectal coil at 7T.

PURPOSE: Improved diagnostic sensitivity could be obtained in cancer detection and staging when individual compounds of the choline pool can be detected. Therefore, a novel coil design is proposed, providing the ability to acquire both (1) H and (31) P magnetic resonance spectroscopic imaging (MRSI) in patients with prostate cancer. METHODS: A two-element (1) H/(31) P endorectal coil was designed by adjusting a commercially available 3T endorectal coil. The two-element coil setup was interfaced as a transceiver to a whole body 7T MR scanner. Simulations and phantom measurements were performed to compare the efficiency of the coil. (1) H MRSI and (31) P MRSI were acquired in vivo in prostate cancer patients. RESULTS: The efficiency of the (1) H/(31) P coil is comparable to the dual channel (1) H coil previously published. Individually distinguishable phospholipid metabolites in the in vivo (31) P spectra were: phosphoethanolamine, phosphocholine, phosphate, glycerophosphoethanolamine, glycerophosphocholine, phosphocreatine, and adenosine triposphate. (1) H MRSI was performed within the same scan session, visualizing choline, polyamines, creatine, and citrate. CONCLUSION: (1) H MRSI and (31) P MRSI can be acquired in the human prostate at 7T within the same scan session using an endorectal coil matched and tuned for (1) H (quadrature) and (31) P (linear) without the need of cable traps and with negligible efficiency losses in the (1) H and (31) P channel.

Full-thickness closure in breast-conserving surgery: the impact on radiotherapy target definition for boost and partial breast irradiation. A multimodality image evaluation.

BACKGROUND: During breast-conserving surgery (BCS), surgeons increasingly perform full-thickness closure (FTC) to prevent seroma formation. This could potentially impair precision of target definition for boost and accelerated partial breast irradiation (APBI). The purpose of this study was to investigate the precision of target volume definition following BCS with FTC among radiation oncologists, using various imaging modalities. METHODS: Twenty clinical T1-2N0 patients, scheduled for BCS involving clip placement and FTC, were included in the study. Seven experienced breast radiation oncologists contoured the tumor bed on computed tomography (CT), magnetic resonance imaging (MRI) and fused CT-MRI datasets. A total of 361 observer pairs per image modality were analyzed. A pairwise conformity among the generated contours of the observers and the distance between their centers of mass (dCOM) were calculated. RESULTS: On CT, median conformity was 44 % [interquartile range (IQR) 28-58 %] and median dCOM was 6 mm (IQR 3-9 mm). None of the outcome measures improved when MRI or fused CT-MRI were used. In two patients, superficial closure was performed instead of FTC. In these 14 image sets and 42 observer pairs, median conformity increased to 70 %. CONCLUSIONS: Localization of the radiotherapy target after FTC is imprecise, on both CT and MRI. This could potentially lead to a geographical miss in patients at increased risk of local recurrence receiving a radiation boost, or for those receiving APBI. These findings highlight the importance for breast surgeons to clearly demarcate the tumor bed when performing FTC.

Effect of magnesium oxide on interfraction prostate motion and rectal filling in prostate cancer radiotherapy: analysis of a randomized clinical trial.

PURPOSE: To investigate whether magnesium oxide reduces the interfraction motion of the prostate and the amount of rectal filling and rectal gas, which influences prostate position during radiotherapy for prostate cancer. PATIENTS AND METHODS: From December 2008 to February 2010, 92 prostate cancer patients scheduled for intensity-modulated radiotherapy (77 Gy in 35 fractions) using fiducial marker-based position verification were randomly assigned to receive magnesium oxide (500 mg twice a day) or placebo during radiotherapy. In a previous study, we investigated the effect on intrafraction motion and did not find a difference between the treatment arms. Here, we compared the interfraction prostate motion between the two treatment arms as well as the amount of rectal filling and rectal air pockets using pretreatment planning computed tomography and magnetic resonance imagingscans. RESULTS: There was no statistically significant difference between the treatment arms in translation and rotation of the prostate between treatment fractions, except for the rotation around the cranial caudal axis. However, the difference was less than 1° and therefore considered not clinically relevant. There was no significant difference in the amount of rectal filling and rectal air pockets between the treatment arms. CONCLUSION: Magnesium oxide is not effective in reducing the interfraction prostate motion or the amount of rectal filling and rectal gas during external-beam radiotherapy. Therefore, magnesium oxide is not recommended in clinical practice for these purposes.

Accurate prostate tumour detection with multiparametric magnetic resonance imaging: dependence on histological properties.

BACKGROUND: To benefit most of focal treatment of prostate tumours, detection with high precision of all tumour voxels is needed. Although diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) have good diagnostic performance, perfect tumour detection is challenging. In this study, we investigated the variation in prostate tissue characteristics Gleason score (GS), cell density (CD) and microvessel density (MVD) to explain the limitations in tumour voxel detection with a MRI-based logistic regression model. MATERIAL AND METHODS: Twelve radical prostatectomy patients underwent a pre-operative 3.0T DWI and DCE-MRI exam. The MRI scans were used to calculate voxel-wise tumour probability with a logistic regression model for the peripheral zone (PZ) of the prostate. Tumour probability maps were correlated and validated with whole-mount histology. Additionally, from the whole-mount histological sections CD, MVD and GS were retrieved for every single voxel. GS, CD and MVD of true- and false-positive voxels and of true- and false-negative voxels were compared using Mann-Whitney U-tests. RESULTS: False-negative tumour voxels had significantly lower CD and MVD (p < 0.0001) and were similar to non-tumour PZ. True-positive detected tumour voxels had high CDs and MVDs (p < 0.0001). In addition, tumour voxels with higher GS showed a trend towards more frequent detection (p = 0.06). Tumour voxels with GS ≥ 3 + 4 showed higher CD and MVD compared to tumour voxels with GS 3 + 3 (p < 0.0001). CONCLUSION: Tumour voxels with low CD and MVD resemble healthy tissue and are limiting tumour voxel detection using DWI and DCE-MRI. Nevertheless, the most aggressive tumour voxels, containing high CD, MVD and GS, are more likely to be detected and can therefore be treated with high dose using focal therapy or focal boosting.

Patterns of outcome and toxicity after salvage prostatectomy, salvage cryosurgery and salvage brachytherapy for prostate cancer recurrences after radiation therapy: a multi-center experience and literature review.

PURPOSE: Current salvage treatments for recurrent prostate cancer after primary radiation therapy include radical prostatectomy, cryosurgery and brachytherapy. Because toxicity and failure rates are considerable, salvage treatments are not commonly performed. As most centers perform only one preferred salvage technique, the literature only describes single-center outcomes from a single salvage technique with a limited number of patients. In this overview, five high-volume Dutch centers describe their toxicity and outcome data using different salvage techniques. This provides a view on how salvage is performed in clinical practice in The Netherlands. METHODS: A total of 129 patients from five different centers in the Netherlands were retrospectively analyzed. Biochemical failure (BF) was defined as PSA >0.1 ng/ml for the salvage prostatectomy group (n = 44) and PSA nadir + 2.0 ng/ml (Phoenix definition) for the salvage cryosurgery (n = 54) and salvage brachytherapy group (n = 31). Toxicity was scored according to the Common Toxicity Criteria for Adverse events (CTCAE v3.0). RESULTS: BF occurred in 25 (81%) patients in the brachytherapy group (mean follow-up 29 ± 24 months), 29 (66%) patients in the prostatectomy group (mean follow-up 22 ± 25 months) and 33 (61%) patients in the cryosurgery group (mean follow-up 14 ± 11 months). Severe (grade >3) genitourinary and gastrointestinal toxicity was observed in up to 30% of patients in all three groups. CONCLUSION: This overview shows clinical practice of prostate cancer salvage. Significant failure and toxicity rates are observed, regardless of salvage technique. Patients should be selected with great care before offering these salvage treatment strategies.

Imaging strategies in the management of oesophageal cancer: what's the role of MRI?

OBJECTIVES: To outline the current role and future potential of magnetic resonance imaging (MRI) in the management of oesophageal cancer regarding T-staging, N-staging, tumour delineation for radiotherapy (RT) and treatment response assessment. METHODS: PubMed, Embase and the Cochrane library were searched identifying all articles related to the use of MRI in oesophageal cancer. Data regarding the value of MRI in the areas of interest were extracted in order to calculate sensitivity, specificity, predictive values and accuracy for group-related outcome measures. RESULTS: Although historically poor, recent improvements in MRI protocols and techniques have resulted in better imaging quality and the valuable addition of functional information. In recent studies, similar or even better results have been achieved using optimised MRI compared with other imaging strategies for T- and N-staging. No studies clearly report on the role of MRI in oesophageal tumour delineation and real-time guidance for RT so far. Recent pilot studies showed that functional MRI might be capable of predicting pathological response to treatment and patient prognosis. CONCLUSIONS: In the near future MRI has the potential to bring improvement in staging, tumour delineation and real-time guidance for RT and assessment of treatment response, thereby complementing the limitations of currently used imaging strategies. KEY POINTS: • MRI's role in oesophageal cancer has been somewhat limited to date. • However MRI's ability to depict oesophageal cancer is continuously improving. • Optimising TN-staging, radiotherapy planning and response assessment ultimately improves individualised cancer care. • MRI potentially complements the limitations of other imaging strategies regarding these points.

Why prostate tumour delineation based on apparent diffusion coefficient is challenging: an exploration of the tissue microanatomy.

BACKGROUND: Focal boosting of prostate tumours to improve outcome, requires accurate tumour delineation. For this, the apparent diffusion coefficient (ADC) derived from diffusion-weighted MR imaging (DWI) seems a useful tool. On voxel level, the relationship between ADC and histological presence of tumour is, however, ambiguous. Therefore, in this study the relationship between ADC and histological variables was investigated on voxel level to understand the strengths and limitations of DWI for prostate tumour delineation. MATERIAL AND METHODS: Twelve radical prostatectomy patients underwent a pre-operative 3.0T DWI exam and the ADC was calculated. From whole-mount histological sections cell density and glandular area were retrieved for every voxel. The distribution of all variables was described for tumour, peripheral zone (PZ) and central gland (CG) on regional and voxel level. Correlations between variables and differences between regions were calculated. RESULTS: Large heterogeneity of ADC on voxel level was observed within tumours, between tumours and between patients. This heterogeneity was reflected by the distribution of cell density and glandular area. On regional level, tumour was different from PZ having higher cell density (p = 0.007), less glandular area (p = 0.017) and lower ADCs (p = 0.017). ADC was correlated with glandular area (r = 0.402) and tumour volume (r = -0.608), but not with Gleason score. ADC tended to decrease with increasing cell density (r = -0.327, p = 0.073). On voxel level, correlations between ADC and histological variables varied among patients, for cell density ranging from r = -0.439 to r = 0.261 and for glandular area from r = 0.593 to r = 0.207. CONCLUSIONS: The variation in ADC can to a certain extent be explained by the variation in cell density and glandular area. The ADC is highly heterogeneous, which reflects the heterogeneity of malignant and benign prostate tissue. This heterogeneity might however obscure small tumours or parts of tumours. Therefore, DWI has to be used in the context of multiparametric MRI.

Costs of Newly Funded Proton Therapy Using Time-Driven Activity-Based Costing in The Netherlands.

BACKGROUND: Proton therapy (PT) has characteristics that enable the sparing of healthy, non-cancerous tissue surrounding the radiotherapy target volume better from radiation doses than conventional radiotherapy for patients with cancer. While this innovation entails investment costs, the information about the treatment costs per patient, especially during the start-up phase, is limited. This study aims to calculate the costs of PT at a single center during the start-up phase in the Netherlands. METHODS: The cost of PT per patient was estimated for the treatment indications, head and neck cancer, breast cancer, brain cancer, thorax cancer, chordoma and eye melanoma. A time-driven activity-based costing analysis (TDABC), a methodology that calculates the costs of consumed healthcare resources by a patient, was conducted in a newly established PT center in the Netherlands (HPTC). Both direct (e.g., the human resource costs for medical staff) and indirect costs (e.g., the operating/interest costs, indirect human resource costs and depreciation costs) were included. A scenario analysis was conducted for short-term (2021), middle-term (till 2024) and long-term (after 2024) predicted patient numbers in the PT center. RESULTS: The total cost of PT in 2020 at the center varied between EUR 12,062 for an eye melanoma course and EUR 89,716 for a head and neck course. Overall, indirect costs were the largest cost component. The high indirect costs implied the potential of the scale of economics; according to our estimation, the treatment cost could be reduced to 35% of the current cost when maximum treatment capacity is achieved. CONCLUSION: This study estimated the PT cost delivered in a newly operated treatment center. Scenario analysis for increased patient numbers revealed the potential for cost reductions. Nevertheless, to have an estimation that reflects the matured cost of PT which could be used in cost-effectiveness analysis, a follow-up study assessing the full-fledged situation is recommended.