Impact of Short-Course Palliative Radiation Therapy on Pancreatic Cancer-Related Pain: Prospective Phase 2 Nonrandomized PAINPANC Trial.

PURPOSE: Clinical evidence is limited regarding palliative radiation therapy for relieving pancreatic cancer-related pain. We prospectively investigated pain response after short-course palliative radiation therapy in patients with moderate-to-severe pancreatic cancer-related pain. METHODS AND MATERIALS: In this prospective phase 2 single center nonrandomized trial, 30 patients with moderate-to-severe pain (5-10, on a 0-10 scale) of pancreatic cancer refractory to pain medication, were treated with a short-course palliative radiation therapy; 24 Gy in 3 weekly fractions (2015-2018). Primary endpoint was defined as a clinically relevant average decrease of ≥2 points in pain severity, compared with baseline, within 7 weeks after the start of treatment. Secondary endpoint was global quality of life (QoL), with a clinically relevant increase of 5 to 10 points (0-100 scale). Pain severity reduction and QoL were assessed 9 times using the Brief Pain Inventory and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C15-PAL, respectively. Both outcomes were analyzed using joint modeling. In addition, acute toxicity based on clinician reporting and overall survival (OS) were assessed. RESULTS: Overall, 29 of 30 patients (96.7%) received palliative radiation therapy. At baseline, the median oral morphine equivalent daily dose was 129.5 mg (range, 20.0-540.0 mg), which decreased to 75.0 mg (range, 15.0-360.0 mg) after radiation (P = .021). Pain decreased on average 3.15 points from baseline to 7 weeks (one-sided P = .045). Patients reported a clinically relevant mean pain severity reduction from 5.9 to 3.8 points (P = .011) during the first 3 weeks, which further decreased to 3.2 until week 11, ending at 3.4 (P = .006) in week 21 after the first radiation therapy fraction. Global QoL significantly improved from 50.5 to 60.8 during the follow-up period (P = .001). Grade 3 acute toxicity occurred in 3 patients and no grade 4 to 5 toxicity was observed. Median OS was 11.8 weeks, with a 13.3% 1-year actuarial OS rate. CONCLUSIONS: Short-course palliative radiation therapy for pancreatic cancer-related pain was associated with rapid, clinically relevant reduction in pain severity, and clinically relevant improvement in global QoL, with mostly mild toxicity.

The immune microenvironment after neoadjuvant therapy compared to upfront surgery in patients with pancreatic cancer.

BACKGROUND: Patients with resectable and borderline resectable pancreatic ductal adenocarcinoma increasingly receive neoadjuvant therapy prior to surgery. However, the effect of neoadjuvant therapy on the immune microenvironment remains largely unknown. We analyzed the immune microenvironment in pancreatic cancer tumor tissue samples from patients treated with neoadjuvant therapy compared to patients after upfront surgery to gain knowledge about the immunological environment after therapy. METHODS: Multispectral imaging was performed on tissue from resected specimens from patients with PDAC who underwent upfront surgery (n = 10), neoadjuvant FOLFIRINOX (n = 10) or gemcitabine + radiotherapy (gem-RT) (n = 9) followed by surgery. The samples were selected by a dedicated pancreas pathologist from both the central part and the invasive front of the tumor (by the resected vein or venous surface) and subsequently analyzed using the Vectra Polaris. RESULTS: Patients receiving neoadjuvant FOLFIRINOX display a more pro-inflammatory immune profile, with less regulatory T cells and more CD8 T cells in the tumor tissue compared to patients receiving neoadjuvant gem-RTgem-RT or undergoing upfront surgery. Furthermore, CD163+ macrophages were decreased, and a higher CD163- macrophages versus CD163+ macrophages ratio was found in patients with neoadjuvant FOLFIRINOX. In all treatment groups, percentage of FoxP3+ B cells was significantly higher in tumor tissue compared to adjacent tissue. Furthermore, an increase in regulatory T cells in the tumor tissue was found in patients undergoing upfront surgery or receiving neoadjuvant gem-RT. In the gem-RT group, less CD8 T cells and a higher CD163+ macrophages to CD8 ratio were noted in the tumor tissue, suggesting a more immune suppressive profile in the tumor tissue. CONCLUSION: Patients receiving neoadjuvant FOLFIRINOX display a more pro-inflammatory immune profile compared to patients receiving neoadjuvant gem-RT or undergoing upfront surgery. Furthermore, in all treatment groups, a more immune suppressive microenvironment was found in the tumor tissue compared to the adjacent non-tumorous tissue.

Predictive value of baseline serum carbohydrate antigen 19-9 level on treatment effect of neoadjuvant chemoradiotherapy in patients with resectable and borderline resectable pancreatic cancer in two randomized trials.

BACKGROUND: Guidelines suggest that the serum carbohydrate antigen (CA19-9) level should be used when deciding on neoadjuvant treatment in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer). In patients with resectable pancreatic cancer, neoadjuvant therapy is advised when the CA19-9 level is 'markedly elevated'. This study investigated the impact of baseline CA19-9 concentration on the treatment effect of neoadjuvant chemoradiotherapy (CRT) in patients with resectable and borderline resectable pancreatic cancers. METHODS: In this post hoc analysis, data were obtained from two RCTs that compared neoadjuvant CRT with upfront surgery in patients with resectable and borderline resectable pancreatic cancers. The effect of neoadjuvant treatment on overall survival was compared between patients with a serum CA19-9 level above or below 500 units/ml using the interaction test. RESULTS: Of 296 patients, 179 were eligible for analysis, 90 in the neoadjuvant CRT group and 89 in the upfront surgery group. Neoadjuvant CRT was associated with superior overall survival (HR 0.67, 95 per cent c.i. 0.48 to 0.94; P = 0.019). Among 127 patients (70, 9 per cent) with a low CA19-9 level, median overall survival was 23.5 months with neoadjuvant CRT and 16.3 months with upfront surgery (HR 0.63, 0.42 to 0.93). For 52 patients (29 per cent) with a high CA19-9 level, median overall survival was 15.5 months with neoadjuvant CRT and 12.9 months with upfront surgery (HR 0.82, 0.45 to 1.49). The interaction test for CA19-9 level exceeding 500 units/ml on the treatment effect of neoadjuvant CRT was not significant (P = 0.501). CONCLUSION: Baseline serum CA19-9 level defined as either high or low has prognostic value, but was not associated with the treatment effect of neoadjuvant CRT in patients with resectable and borderline resectable pancreatic cancers, in contrast with current guideline advice.

Same-day adaptive palliative radiotherapy without prior CT simulation: Early outcomes in the FAST-METS study.

BACKGROUND AND PURPOSE: Standard palliative radiotherapy workflows involve waiting times or multiple clinic visits. We developed and implemented a rapid palliative workflow using diagnostic imaging (dCT) for pre-planning, with subsequent on-couch target and plan adaptation based on a synthetic computed tomography (CT) obtained from cone-beam CT imaging (CBCT). MATERIALS AND METHODS: Patients with painful bone metastases and recent diagnostic imaging were eligible for inclusion in this prospective, ethics-approved study. The workflow consisted of 1) telephone consultation with a radiation oncologist (RO); 2) pre-planning on the dCT using planning templates and mostly intensity-modulated radiotherapy; 3) RO consultation on the day of treatment; 4) CBCT scan with on-couch adaptation of the target and treatment plan; 5) delivery of either scheduled or adapted treatment plan. Primary outcomes were dosimetric data and treatment times; secondary outcome was patient satisfaction. RESULTS: 47 patients were enrolled between December 2021 and October 2022. In all treatments, adapted treatment plans were chosen due to significant improvements in target coverage (PTV/CTV V95%, p-value < 0.005) compared to the original treatment plan calculated on daily anatomy. Most patients were satisfied with the workflow. The average treatment time, including consultation and on-couch adaptive treatment, was 85 minutes. On-couch adaptation took on average 30 min. but was longer in cases where the automated deformable image registration failed to correctly propagate the targets. CONCLUSION: A fast treatment workflow for patients referred for painful bone metastases was implemented successfully using online adaptive radiotherapy, without a dedicated CT simulation. Patients were generally satisfied with the palliative radiotherapy workflow.

Evaluation of a workflow for cone-beam CT-guided online adaptive palliative radiotherapy planned using diagnostic CT scans.

PURPOSE: Single-visit radiotherapy (RT) is beneficial for patients requiring pain control and can limit interruptions to systemic treatments. However, the requirement for a dedicated planning CT (pCT)-scan can result in treatment delays. We developed a workflow involving preplanning on available diagnostic CT (dCT) imaging, followed by online plan adaption using a cone-beam CT (CBCT)-scan prior to RT-delivery, in order to account for any changes in anatomy and target position. METHODS: Patients previously treated with palliative RT for bone metastases were selected from our hospital database. Patient dCT-images were deformed to treatment CBCTs in the Ethos platform (Varian Medical Systems) and a synthetic CT (sCT) generated. Treatment quality was analyzed by comparing a coverage of the V95% of the planning/clinical target volume and different organ-at-risk (OAR) doses between adapted and initial clinical treatment plans. Doses were recalculated on the CBCT and sCT in a separate treatment planning system. Adapted plan doses were measured on-couch using an anthropomorphic phantom with a Gafchromic EBT3 dosimetric film and compared to dose calculations. RESULTS: All adapted treatment plans met the clinical goals for target and OARs and outperformed the original treatment plans calculated on the (daily) sCT. Differences in V95% of the target volume coverage between the initial and adapted treatments were <0.2%. Dose recalculations on CBCT and sCT were comparable, and the average gamma pass rate (3%/2 mm) of dosimetric measurements was 98.8%. CONCLUSIONS: Online daily adaptive RT using dCTs instead of a dedicated pCT is feasible using the Ethos platform. This workflow has now been implemented clinically.

The yield of staging laparoscopy for resectable and borderline resectable pancreatic cancer in the PREOPANC randomized controlled trial.

BACKGROUND: The necessity of the staging laparoscopy in patients with pancreatic cancer is still debated. The objective of this study was to assess the yield of staging laparoscopy for detecting occult metastases in patients with resectable or borderline resectable pancreatic cancer. METHOD: This was a post-hoc analysis of the randomized controlled PREOPANC trial in which patients with resectable or borderline resectable pancreatic cancer were randomized between preoperative chemoradiotherapy or immediate surgery. Patients assigned to preoperative treatment underwent a staging laparoscopy prior to preoperative treatment according to protocol, to avoid unnecessary chemoradiotherapy in patients with occult metastatic disease. RESULTS: Of the 246 included patients, 7 did not undergo surgery. A staging laparoscopy was performed in 133 patients (55.6%) and explorative laparotomy in 106 patients (44.4%). At staging laparoscopy, occult metastases were detected in 13 patients (9.8%); 12 liver metastases and 1 peritoneal metastasis. At direct explorative laparotomy, occult metastases were found in 9 patients (8.5%); 6 with liver metastases, 1 with peritoneal metastases, and 2 with metastases at multiple sites. One patient had peritoneal metastases at exploration after a negative staging laparoscopy. Patients with occult metastases were more likely to receive palliative chemotherapy if found with staging laparoscopy compared to laparotomy (76.9% vs. 30.0%, p = 0.040). CONCLUSIONS: Staging laparoscopy detected occult metastases in about 10% of patients with resectable or borderline resectable pancreatic cancer. These patients were more likely to receive palliative systemic chemotherapy compared to patients in whom occult metastases were detected with laparotomy. A staging laparoscopy is recommended before planned resection.

Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial.

PURPOSE: The benefit of neoadjuvant chemoradiotherapy in resectable and borderline resectable pancreatic cancer remains controversial. Initial results of the PREOPANC trial failed to demonstrate a statistically significant overall survival (OS) benefit. The long-term results are reported. METHODS: In this multicenter, phase III trial, patients with resectable and borderline resectable pancreatic cancer were randomly assigned (1:1) to neoadjuvant chemoradiotherapy or upfront surgery in 16 Dutch centers. Neoadjuvant chemoradiotherapy consisted of three cycles of gemcitabine combined with 36 Gy radiotherapy in 15 fractions during the second cycle. After restaging, patients underwent surgery followed by four cycles of adjuvant gemcitabine. Patients in the upfront surgery group underwent surgery followed by six cycles of adjuvant gemcitabine. The primary outcome was OS by intention-to-treat. No safety data were collected beyond the initial report of the trial. RESULTS: Between April 24, 2013, and July 25, 2017, 246 eligible patients were randomly assigned to neoadjuvant chemoradiotherapy (n = 119) and upfront surgery (n = 127). At a median follow-up of 59 months, the OS was better in the neoadjuvant chemoradiotherapy group than in the upfront surgery group (hazard ratio, 0.73; 95% CI, 0.56 to 0.96; P = .025). Although the difference in median survival was only 1.4 months (15.7 months v 14.3 months), the 5-year OS rate was 20.5% (95% CI, 14.2 to 29.8) with neoadjuvant chemoradiotherapy and 6.5% (95% CI, 3.1 to 13.7) with upfront surgery. The effect of neoadjuvant chemoradiotherapy was consistent across the prespecified subgroups, including resectable and borderline resectable pancreatic cancer. CONCLUSION: Neoadjuvant gemcitabine-based chemoradiotherapy followed by surgery and adjuvant gemcitabine improves OS compared with upfront surgery and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer.

Surgical Complications in a Multicenter Randomized Trial Comparing Preoperative Chemoradiotherapy and Immediate Surgery in Patients With Resectable and Borderline Resectable Pancreatic Cancer (PREOPANC Trial).

OBJECTIVES: To investigate the effect of preoperative chemoradiotherapy on surgical complications in patients after pancreatic resection for (borderline-)resectable pancreatic cancer. SUMMARY OF BACKGROUND DATA: Preoperative chemoradiotherapy is increasingly used in patients with (borderline-)resectable pancreatic cancer. concerns have been raised about the potential harmful effect of any preoperative therapy on the surgical complication rate after pancreatic resection. METHODS: An observational analysis was performed within the multicenter randomized controlled PREOPANC trial (April 2013-July 2017). The trial randomly assigned (1:1) patients to preoperative chemoradiotherapy followed by surgery and the remaining adjuvant chemotherapy or to immediate surgery, followed by adjuvant chemotherapy. The main analysis consisted of a per-protocol approach. The endpoints of the present analyses were the rate of postoperative complications. RESULTS: This study included 246 patients from 16 centers, of whom 66 patients underwent resection after preoperative therapy and 98 patients after immediate surgery. No differences were found regarding major complications (37.9% vs 30.6%, P=0.400), postpancreatectomy hemorrhage (9.1% vs 5.1%, P=0.352), delayed gastric emptying (21.2% vs 22.4%, P=0.930), bile leakage (4.5% vs 3.1%, P=0.686), intra-abdominal infections (12.1% vs 10.2%, P=0.800), and mortality (3.0% vs 4.1%, P=1.000). There was a significant lower incidence of postoperative pancreatic fistula in patients who received preoperative chemoradiotherapy (0% vs 9.2%, P=0.011). CONCLUSIONS: Preoperative chemoradiotherapy did not increase the incidence of surgical complications or mortality and reduced the rate of postoperative pancreatic fistula after resection in patients with (borderline-)resectable pancreatic cancer.

External Validity of the Multicenter Randomized PREOPANC Trial on Neoadjuvant Chemoradiotherapy in Pancreatic Cancer: Outcome of Eligible but Nonrandomized Patients.

OBJECTIVES: To investigate the accrual proportion and patients' reasons for not participating in the PREOPANC trial on neoadjuvant chemoradiotherapy versus immediate surgery in resectable and borderline resectable pancreatic cancer, and to compare these patients' outcomes with those of patients who had been randomized in the trial. SUMMARY OF BACKGROUND DATA: The external validity of multicenter randomized trials in cancer treatment has been criticized for suboptimal non-representative inclusion. In trials, it is unclear how outcomes compare between randomized and nonrandomized patients. METHODS: At 8 of 16 participant centers, this multicenter observational study identified validation patients, who had been eligible but not randomized during recruitment for the PREOPANC trial. We assessed the accrual proportion, investigated their most common reasons for not participating in the trial, and compared resection rates, radical (R0) resection rates, and overall survival between the validation patients and PREOPANC patients, who had been randomized in the trial to immediate surgery. RESULTS: In total, 455 patients had been eligible during the recruitment period, 151 of whom (33%) had been randomized. Fifty-five percent of the 304 validation patients had refused to participate. Median overall survival in the validation group was 15.2 months, against 15.5 months in the PREOPANC group (P = 1.00). The respective resection rates (76% vs 73%) and R0 resection rates (51% vs 46%) did not differ between the groups. CONCLUSIONS: The PREOPANC trial included a reasonable percentage of 33% of eligible patients. In terms of the outcomes survival, resection rate, and R0 resection rate, this appeared to be a representative group.

Neoadjuvant Treatment for Resectable and Borderline Resectable Pancreatic Cancer: Chemotherapy or Chemoradiotherapy?

Worldwide, there is a shifting paradigm from immediate surgery with adjuvant treatment to a neoadjuvant approach for patients with resectable or borderline resectable pancreatic cancer (RPC or BRPC). Comparison of neoadjuvant and adjuvant studies is extremely difficult because of a great difference in patient selection. The evidence from randomized studies shows that overall survival by intention-to-treat improves after neoadjuvant gemcitabine-based chemoradiotherapy or chemotherapy (various regimens), as compared to immediate surgery followed by adjuvant chemotherapy. Radiotherapy appears to play an important role in mediating locoregional effects. Yet, since more effective chemotherapy regimens are currently available, in particular FOLFIRINOX and Gemcitabine/Nab-paclitaxel, these chemotherapy regimens should be investigated in future randomized trials combined with (stereotactic) radiotherapy to further improve outcomes of RPC and BRPC.

Gemcitabine-Based Neoadjuvant Treatment in Borderline Resectable Pancreatic Ductal Adenocarcinoma: A Meta-Analysis of Individual Patient Data.

Background: Non-randomized studies have investigated multi-agent gemcitabine-based neo-adjuvant therapies (GEM-NAT) in borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC). Treatment sequencing and specific elements of neoadjuvant treatment are still under investigation. The present meta-analysis aims to assess the effectiveness of GEM-NAT on overall survival (OS) in BR-PDAC. Patients and Methods: A meta-analysis of individual participant data (IPD) on GEM-NAT for BR-PDAC were performed. The primary outcome was OS after treatment with GEM-based chemotherapy. In the Individual Patient Data analysis data were reappraised and confirmed as BR-PDAC on provided radiological data. Results: Six studies investigating GEM-NAT were included in the IPD metanalysis. The IPD metanalysis was conducted on 271 patients who received GEM-NAT. Pooled median patient-level OS was 22.2 months (95%CI 19.1-25.2). R0 rates ranged between 81 and 95% (I 2 = 0%, p = 0.64), respectively. Median OS was 27.8 months (95%CI 23.9-31.6) in the patients who received NAT-GEM followed by resection compared to 15.4 months (95%CI 12.3-18.4) for NAT-GEM without resection and 13.0 months (95%CI 7.4-18.5) in the group of patients who received upfront surgery (p < 0.0001). R0 rates ranged between 81 and 95% (I 2 = 0%, p = 0.64), respectively. Overall survival in the R0 group was 29.3 months (95% CI 24.3-34.2) vs. 16.2 months (95% CI 7·9-24.5) in the R1 group (p = 0·001). Conclusions: The present study is the first meta-analysis combining IPD from a number of international centers with BR-PDAC in a cohort that underwent multi-agent gemcitabine neoadjuvant therapy (GEM-NAT) before surgery. GEM-NAT followed by surgical resection improve survival and R0 resection in BR-PDAC. Also, GEM-NAT may result in a good palliative option in non-resected patients because of progressive disease after neoadjuvant treatment. Results from randomized controlled trials (RCTs) are awaited to validate these findings.

Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial.

PURPOSE: Preoperative chemoradiotherapy may improve the radical resection rate for resectable or borderline resectable pancreatic cancer, but the overall benefit is unproven. PATIENTS AND METHODS: In this randomized phase III trial in 16 centers, patients with resectable or borderline resectable pancreatic cancer were randomly assigned to receive preoperative chemoradiotherapy, which consisted of 3 courses of gemcitabine, the second combined with 15 × 2.4 Gy radiotherapy, followed by surgery and 4 courses of adjuvant gemcitabine or to immediate surgery and 6 courses of adjuvant gemcitabine. The primary end point was overall survival by intention to treat. RESULTS: Between April 2013 and July 2017, 246 eligible patients were randomly assigned; 119 were assigned to preoperative chemoradiotherapy and 127 to immediate surgery. Median overall survival by intention to treat was 16.0 months with preoperative chemoradiotherapy and 14.3 months with immediate surgery (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P = .096). The resection rate was 61% and 72% (P = .058). The R0 resection rate was 71% (51 of 72) in patients who received preoperative chemoradiotherapy and 40% (37 of 92) in patients assigned to immediate surgery (P < .001). Preoperative chemoradiotherapy was associated with significantly better disease-free survival and locoregional failure-free interval as well as with significantly lower rates of pathologic lymph nodes, perineural invasion, and venous invasion. Survival analysis of patients who underwent tumor resection and started adjuvant chemotherapy showed improved survival with preoperative chemoradiotherapy (35.2 v 19.8 months; P = .029). The proportion of patients who suffered serious adverse events was 52% versus 41% (P = .096). CONCLUSION: Preoperative chemoradiotherapy for resectable or borderline resectable pancreatic cancer did not show a significant overall survival benefit. Although the outcomes of the secondary end points and predefined subgroup analyses suggest an advantage of the neoadjuvant approach, additional evidence is required.

The clinical benefit of hyperthermia in pancreatic cancer: a systematic review.

OBJECTIVE: In pancreatic cancer, which is therapy resistant due to its hypoxic microenvironment, hyperthermia may enhance the effect of radio(chemo)therapy. The aim of this systematic review is to investigate the validity of the hypothesis that hyperthermia added to radiotherapy and/or chemotherapy improves treatment outcome for pancreatic cancer patients. METHODS AND MATERIALS: We searched MEDLINE and Embase, supplemented by handsearching, for clinical studies involving hyperthermia in pancreatic cancer patients. The quality of studies was evaluated using the Oxford Centre for Evidence-Based Medicine levels of evidence. Primary outcome was treatment efficacy; we calculated overall response rate and the weighted estimate of the population median overall survival (mp) and compared these between hyperthermia and control cohorts. RESULTS: Overall, 14 studies were included, with 395 patients with locally advanced and/or metastatic pancreatic cancer of whom 248 received hyperthermia. Patients were treated with regional (n = 189), intraoperative (n = 39) or whole-body hyperthermia (n = 20), combined with chemotherapy, radiotherapy or both. Quality of the studies was low, with level of evidence 3 (five studies) and 4. The six studies including a control group showed a longer mp in the hyperthermia groups than in the control groups (11.7 vs. 5.6 months). Overall response rate, reported in three studies with a control group, was also better for the hyperthermia groups (43.9% vs. 35.3%). CONCLUSIONS: Hyperthermia, when added to chemotherapy and/or radiotherapy, may positively affect treatment outcome for patients with pancreatic cancer. However, the quality of the reviewed studies was limited and future randomised controlled trials are needed to establish efficacy.

Quality assurance of the PREOPANC trial (2012-003181-40) for preoperative radiochemotherapy in pancreatic cancer : The dummy run.

BACKGROUND: 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. METHODS: Eleven radiation oncology departments open for accrual of patients in the PREOPANC trial were provided with all necessary information of a selected 'dummy' patient. Each institute was asked to delineate the target volumes, including gross tumour volume, internal gross tumour volume (iGTV), internal clinical target volume, and planning target volume. The institutions were also asked to provide a radiation treatment plan in accordance with the PREOPANC trial protocol. RESULTS: The range of the iGTV was 19.3-77.2 cm3 with a mean iGTV of 41.5 cm3 (standard deviation 14.8 cm3). Nine institutions made a treatment plan using an arc technique for treatment delivery, one an intensity modulated technique and one a 3-field conformal technique. All institutions reached the prescribed target coverage, without exceeding the organs at risk constraints. The institution with the 3­field conformal technique was advised to use a more sophisticated technique (e. g. volumetric modulated arc therapy) to reduce the dose to the spinal cord. CONCLUSION: All institutions showed acceptable deviations from the PREOPANC trial protocol and achieved an acceptable quality of delineation and radiation technique. All institutions were allowed to continue participation in the PREOPANC trial.

Addition of MRI for CT-based pancreatic tumor delineation: a feasibility study.

PURPOSE: To assess the effect of additional magnetic resonance imaging (MRI) alongside the planning computed tomography (CT) scan on target volume delineation in pancreatic cancer patients. MATERIAL AND METHODS: Eight observers (radiation oncologists) from six institutions delineated the gross tumor volume (GTV) on 3DCT, and internal GTV (iGTV) on 4DCT of four pancreatic cancer patients, while MRI was available in a second window (CT + MRI). Variations in volume, generalized conformity index (CIgen), and overall observer variation, expressed as standard deviation (SD) of the distances between delineated surfaces, were analyzed. CIgen is a measure of overlap of the delineated iGTVs (1 = full overlap, 0 = no overlap). Results were compared with those from an earlier study that assessed the interobserver variation by the same observers on the same patients on CT without MRI (CT-only). RESULTS: The maximum ratios between delineated volumes within a patient were 6.1 and 22.4 for the GTV (3DCT) and iGTV (4DCT), respectively. The average (root-mean-square) overall observer variations were SD = 0.41 cm (GTV) and SD = 0.73 cm (iGTV). The mean CIgen was 0.36 for GTV and 0.37 for iGTV. When compared to the iGTV delineated on CT-only, the mean volumes of the iGTV on CT + MRI were significantly smaller (32%, Wilcoxon signed-rank, p < .0005). The median volumes of the iGTV on CT + MRI were included for 97% and 92% in the median volumes of the iGTV on CT. Furthermore, CT + MRI showed smaller overall observer variations (root-mean-square SD = 0.59 cm) in six out of eight delineated structures compared to CT-only (root-mean-square SD = 0.72 cm). However, large local observer variations remained close to biliary stents and pathological lymph nodes, indicating issues with instructions and instruction compliance. CONCLUSIONS: The availability of MRI images during target delineation of pancreatic cancer on 3DCT and 4DCT resulted in smaller target volumes and reduced the interobserver variation in six out of eight delineated structures.

Considerable interobserver variation in delineation of pancreatic cancer on 3DCT and 4DCT: a multi-institutional study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Supraclavicular node disease is not an independent prognostic factor for survival of esophageal cancer patients treated with definitive chemoradiation.

BACKGROUND: The prognostic value of supraclavicular lymph node (SCN) metastases in esophageal cancer is not well established. We analyzed the prognostic value of SCN disease in patients after definitive chemoradiation (dCRT) for esophageal cancer. METHODS: We retrospectively analyzed 207 patients treated between 2003 and 2013 to identify the prognostic value of metastasis in the SCN on treatment failure and survival. All patients were treated with external beam radiotherapy (50.4 Gy in 28 fractions) combined with weekly concurrent paclitaxel 50 mg/m2 and carboplatin AUC2. RESULTS: Median follow-up for patients alive was 43.3 months. The median overall survival (OS) for all patients was 17.5 months. OS at one, three and five years was 67%, 36% and 21%, respectively. For patients with metastasis in a SCN, OS was 23.6 months compared to 17.1 months for patients without metastasis in the SCN (p = .51). In multivariate analyses, higher cT status, cN status and adenocarcinoma were found to be prognostically unfavorable, but a positive SCN was not (p = .67). Median OS and median disease-free survival for tumors with SCN involvement and N0/1 disease was 49.0 months and 51.6 months, respectively, compared to 14.2 months and 8.2 months, respectively, in patients with N2/3 disease. CONCLUSION: In esophageal cancer treated with dCRT, the number of affected lymph nodes is an important independent prognostic factor, whereas involvement of a SCN is not. Supraclavicular lymph nodes should be considered as regional lymph nodes and treated with curative intent if the total number of involved lymph nodes is limited.

Considerable pancreatic tumor motion during breath-holding.

BACKGROUND: Breath-holding (BH) is often used to reduce abdominal organ motion during radiotherapy. However, for inhale BH, abdominal tumor motion during BH has not yet been investigated. The aim of this study was to quantify tumor motion during inhale BH and tumor position variations between consecutive inhale BHs in pancreatic cancer patients. MATERIAL AND METHODS: Twelve patients with intratumoral fiducials were included and asked to perform three consecutive 30-second inhale BHs on each of three measurement days. During BH, lateral fluoroscopic movies were obtained and a two-dimensional (2D) image correlation algorithm was used to track the fiducials and the diaphragm, yielding the tumor and diaphragm motion during each BH. The tumor position variation between consecutive BHs was obtained from the difference in initial tumor position between consecutive BHs on a single measurement day. RESULTS: We observed tumor motion during BH with a mean absolute maximum displacement over all BHs of 4.2 mm (range 1.0-11.0 mm) in inferior-superior (IS) direction and 2.7 mm (range 0.5-8.0 mm) in anterior-posterior (AP) direction. We found only a moderate correlation between tumor and diaphragm motion in the IS direction (Pearson's correlation coefficient |r|>0.6 in 45 of 76 BHs). The mean tumor position variation between consecutive BHs was 0.2 [standard deviation (SD) 1.7] mm in the inferior direction and 0.5 (SD 0.8) mm in the anterior direction. CONCLUSION: We observed substantial pancreatic tumor motion during BH as well as considerable position variation between consecutive BHs on a single day. We recommend further quantifying these uncertainties before introducing breath-hold during radiation treatment of pancreatic cancer patients. Also, the diaphragm cannot be used as a surrogate for pancreatic tumor motion.