Geertjan van Tienhoven

For radiotherapy of abdominal cancer, four-dimensional magnetic resonance imaging (4DMRI) is desirable for tumor definition and the assessment of tumor and organ motion. However, irregular breathing gives rise to image artifacts. We developed a outlier rejection strategy resulting in a 4DMRI with reduced image artifacts in the presence of irregular breathing. We obtained 2D T2-weighted single-shot turbo spin echo images, with an interleaved 1D navigator acquisition to obtain the respiratory signal during free breathing imaging in 2 patients and 12 healthy volunteers. Prior to binning, upper and lower inclusion thresholds were chosen such that 95% of the acquired images were included, while minimizing the distance between the thresholds (inclusion range (IR)). We compared our strategy (Min95) with three commonly applied strategies: phase binning with all images included (Phase), amplitude binning with all images included (MaxIE), and amplitude binning with the thresholds set as the mean end-inhale and mean end-exhale diaphragm positions (MeanIE). We compared 4DMRI quality based on: Data included (DI); percentage of images remaining after outlier rejection. Reconstruction completeness (RC); percentage of bin-slice combinations containing at least one image after binning. Intra-bin variation (IBV); interquartile range of the diaphragm position within the bin-slice combination, averaged over three central slices and ten respiratory bins. IR. Image smoothness (S); quantified by fitting a parabola to the diaphragm profile in a sagittal plane of the reconstructed 4DMRI. Data included (DI); percentage of images remaining after outlier rejection. Reconstruction completeness (RC); percentage of bin-slice combinations containing at least one image after binning. Intra-bin variation (IBV); interquartile range of the diaphragm position within the bin-slice combination, averaged over three central slices and ten respiratory bins. IR. Image smoothness (S); quantified by fitting a parabola to the diaphragm profile in a sagittal plane of the reconstructed 4DMRI. A two-sided Wilcoxon’s signed-rank test was used to test for significance in differences between the Min95 strategy and the Phase, MaxIE, and MeanIE strategies. Based on the fourteen subjects, the Min95 binning strategy outperformed the other strategies with a mean RC of 95.5%, mean IBV of 1.6 mm, mean IR of 15.1 mm and a mean S of 0.90. The Phase strategy showed a poor mean IBV of 6.2 mm and the MaxIE strategy showed a poor mean RC of 85.6%, resulting in image artifacts (mean S of 0.76). The MeanIE strategy demonstrated a mean DI of 85.6%. Our Min95 reconstruction strategy resulted in a 4DMRI with less artifacts and more precise diaphragm position reconstruction compared to the other strategies. Volunteers: protocol W15_373#16.007; patients: protocol NL47713.018.14

The Dutch Pancreatic Cancer Group initiated the national, multicentre, controlled PREOPANC trial, randomising between preoperative radiochemotherapy and direct explorative laparotomy for patients with (borderline) resectable pancreatic cancer. The aim of this dummy run is to evaluate compliance with the radiotherapy protocol of this trial, and the quality of delineation and radiation plans.

The delineation of pancreatic tumors on CT is challenging. In this study, we quantified the interobserver variation for pancreatic tumor delineation on 3DCT as well as on 4DCT. Eight observers (radiation oncologists) from six institutions delineated pancreatic tumors of four patients with (borderline) resectable pancreatic cancer. The study consisted of two stages. In the 3DCT-stage, the gross tumor volume (GTV) was delineated on a contrast-enhanced scan. In the 4DCT-stage, the internal GTV (iGTV) was delineated, accounting for the respiratory motion. We calculated the volumes of the (i)GTV, the overlap of the delineated volumes (expressed as generalized conformity index: CIgen), the local observer variation (local standard deviation: SD) and the overall observer variation (overall SD). We compared these results between GTVs and iGTVs. Additionally, observers were asked to fill out a questionnaire concerning the difficulty of the delineation and their experience in delineating pancreatic tumors. The ratios of the largest to the smallest delineated GTV and iGTV within the same patient were 6.8 and 16.5, respectively. As the iGTV incorporates the GTV during all respiratory phases, the mean volumes of the iGTV (40.07 cm3) were larger than those of the GTV (29.91 cm3). For all patients, CIgen was larger for the iGTV than for the GTV. The mean overall observer variation (root-mean-square of all local SDs over four patients) was 0.63 cm and 0.80 cm for GTV and iGTV, respectively. The largest local observer variations were seen close to biliary stents and suspicious pathological enlarged lymph nodes, as some observers included them and some did not. This variation was more pronounced for the iGTV than for the GTV. The observers rated the 3DCT-stage and 4DCT-stage equally difficult and treated on average three to four pancreatic cancer patients per year. A considerable interobserver variation in delineation of pancreatic tumors was observed. This variation was larger for 4D than for 3D delineation. The largest local observer variation was found around biliary stents and suspicious pathological enlarged lymph nodes.

Introduction SUPREMO is a phase 3 randomised trial evaluating radiotherapy post-mastectomy for intermediate-risk breast cancer. 1688 patients were enrolled from 16 countries between 2006 and 2013. We report the results of central pathology review carried out for quality assurance. Patients and methods A single recut haematoxylin and eosin (H&E) tumour section was assessed by one of two reviewing pathologists, blinded to the originally reported pathology and patient data. Tumour type, grade and lymphovascular invasion were reviewed to assess if they met the inclusion criteria. Slides from potentially ineligible patients on central review were scanned and reviewed online together by the two pathologists and a consensus reached. A subset of 25 of these cases was double-reported independently by the pathologists prior to the online assessment. Results The major contributors to the trial were the UK (75%) and the Netherlands (10%). There is a striking difference in lymphovascular invasion (LVi) rates (41.6 vs. 15.1% (UK); p = p = p = 0.40) but a significant difference in the reviewed frequency (16.9 vs. 9.9%; p = 0.004). Of the N− cases, 104 (25.1%) would have been ineligible by initial central review by virtue of grade and/or lymphovascular invasion status. Following online consensus review, this fell to 70 cases (16.3% of N− cases, 4.1% of all cases). Conclusions These data have important implications for the design, powering and interpretation of outcomes from this and future clinical trials. If critical pathology criteria are determinants for trial entry, serious consideration should be given to up-front central pathology review.

Pancreatic cancer is the fourth largest cause of cancer death in the United States and Europe with over 100,000 deaths per year in Europe alone. The overall 5-year survival ranges from 2–7 % and has hardly improved over the last two decades. Approximately 15 % of all patients have resectable disease at diagnosis, and of those, only a subgroup has a resectable tumour at surgical exploration. Data from cohort studies have suggested that outcome can be improved by preoperative radiochemotherapy, but data from well-designed randomized studies are lacking. Our PREOPANC phase III trial aims to test the hypothesis that median overall survival of patients with resectable or borderline resectable pancreatic cancer can be improved with preoperative radiochemotherapy. The PREOPANC trial is a randomized, controlled, multicentric superiority trial, initiated by the Dutch Pancreatic Cancer Group. Patients with (borderline) resectable pancreatic cancer are randomized to A: direct explorative laparotomy or B: after negative diagnostic laparoscopy, preoperative radiochemotherapy, followed by explorative laparotomy. A hypofractionated radiation scheme of 15 fractions of 2.4 gray (Gy) is combined with a course of gemcitabine, 1,000 mg/m2/dose on days 1, 8 and 15, preceded and followed by a modified course of gemcitabine. The target volumes of radiation are delineated on a 4D CT scan, where at least 95 % of the prescribed dose of 36 Gy in 15 fractions should cover 98 % of the planning target volume. Standard adjuvant chemotherapy is administered in both treatment arms after resection (six cycles in arm A and four in arm B). In total, 244 patients will be randomized in 17 hospitals in the Netherlands. The primary endpoint is overall survival by intention to treat. Secondary endpoints are (R0) resection rate, disease-free survival, time to locoregional recurrence or distant metastases and perioperative complications. Secondary endpoints for the experimental arm are toxicity and radiologic and pathologic response. The PREOPANC trial is designed to investigate whether preoperative radiochemotherapy improves overall survival by means of increased (R0) resection rates in patients with resectable or borderline resectable pancreatic cancer. Trial open for accrual: 3 April 2013 The Netherlands National Trial Register – NTR3709 (8 November 2012) EU Clinical Trials Register – 2012-003181-40 (11 December 2012)

BACKGROUND: The objective of this study was to evaluate the role of reirradiation and hyperthermia in the treatment of radiation‐associated sarcoma (RAS) in the thoracic region, which is an increasing, yet extremely rare condition with a poor prognosis.METHODS: Between 1979 and 2009, 16 patients with RAS in the thoracic region were treated in the Academic Medical Center and the Institute Verbeeten with reirradiation and hyperthermia. In 13 patients, this treatment was given for unresectable disease and 3 times after resection as adjuvant treatment. The median latency period between the original malignancy diagnosis and the RAS diagnosis was 86 months (range 19‐212 months). Histology was angiosarcoma in 11 patients (69%). The literature on reirradiation with or without hyperthermia for RAS was reviewed.RESULTS: The median survival was 15.5 months (range, 3‐204 months). Four patients were not evaluable for response. The response rate for the remaining 12 patients was 75% (7 complete responses and 2 partial responses). Six patients remained free of local failure until death (5 months and 7 months) or last follow‐up (8 months, 11 months, 39 months, and 68 months).CONCLUSIONS: The current study indicates that combined reirradiation and hyperthermia for RAS in the thoracic region is feasible. The high response rate and the possibility of durable local control suggest that this treatment is promising. Cancer 2012;. © 2011 American Cancer Society.

A 60-year-old Ghanese woman was treated with radiotherapy and capecitabine for metastatic breast cancer. 6 weeks after starting capecitabine she developed palmar and plantar hyperpigmentation, which preceded symptoms of hand-foot syndrome, a known adverse effect of capecitabine. After a dose reduction, the hand-foot syndrome diminished but the hyperpigmentation remained. 8 months later the patient was well and stable.

Pancreatic cancer has an extremely poor prognosis, only a small minority of patients undergo a resection with curative intent. Chemotherapy and/or radiochemotherapy may improve this by prolonging survival or disease-free interval and improving resectability and the proportion of microscopically complete (R0) resections. With regard to prolonging survival, both in the postoperative adjuvant setting and in locally advanced disease, chemotherapy has a positive but limited effect on survival and may be considered standard. The role of postoperative adjuvant radiochemotherapy remains debatable. For improving resectability/proportion of R0 resections, many studies suggest that the proportion of patients undergoing a resection during exploration and the proportion of R0 resections increase after neoadjuvant radiochemotherapy. This may improve the prognosis of patients with a resectable or borderline resectable pancreatic carcinoma. The effect of neoadjuvant radiochemotherapy, if any, is modest. The search for better combinations, including targeted therapy, must continue. The interpretation of single-arm studies is hampered by (selection) biases. The reporting of pathology and study endpoints should be internationally standardized. To avoid biases in studies of patients with (borderline) resectable tumours, prospective parallel registration of all patients referred for surgery would help. Ultimately, randomized controlled phase III trials should establish the role of neoadjuvant radiochemotherapy. Thus, neoadjuvant radiochemotherapy has a potential benefit in resectable and borderline resectable pancreatic cancer, but better combinations are warranted.

To determine the result of surgical treatment of patients with hilar cholangiocarcinoma (HCCA) before and after the transition from predominantly local bile duct resections to more extensive resections including partial liver resection in order to achieve complete tumour resection in the Academic Medical Center, Amsterdam (The Netherlands). Retrospective and descriptive. In the period 1988-2003, 117 consecutive patients underwent resection due to suspected HCCA. Preoperative work-up included staging laparoscopy, preoperative biliary drainage and short-course radiation therapy (3 x 3.5 Gy) to prevent seeding metastases. A more extended multidisciplinary surgical approach combining bile duct resection with partial liver resection was applied as of 1998. Outcomes of resection including 5-year survival were assessed in patients who had undergone resection before (1988-1997; period 1) and after (1998-2003; period 2) this change in surgical approach. In 18 patients (15.3%) a benign lesion was found in the resection specimen. Among the other 99 patients with microscopically confirmed HCCA, 21 (72%) of 29 patients had undergone bile duct resection in combination with partial liver resection in period 2 as compared to 17 (24%) of 70 patients in period 1. The margin tumour free resection rate increased from 20% in period 1 to 59% in period 2. Five-year survival increased from 20% (SE: 5) in period 1, to 33% (SE: 9) in period 2. Morbidity and mortality in period 2 were 69% and 10%, respectively, as compared to 64% and 17% in period 1. More extensive resection of HCCA in combination with partial liver resection in the setting of a multidisciplinary approach led to a higher rate of margin free resections and improved 5-year survival.