Interobserver agreement on definition of the target volume in stereotactic radiotherapy for pancreatic adenocarcinoma using different imaging modalities.

PURPOSE: The aim of this study was to evaluate interobserver agreement (IOA) on target volume definition for pancreatic cancer (PACA) within the Radiosurgery and Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (DEGRO) and to identify the influence of imaging modalities on the definition of the target volumes. METHODS: Two cases of locally advanced PACA and one local recurrence were selected from a large SBRT database. Delineation was based on either a planning 4D CT with or without (w/wo) IV contrast, w/wo PET/CT, and w/wo diagnostic MRI. Novel compared to other studies, a combination of four metrics was used to integrate several aspects of target volume segmentation: the Dice coefficient (DSC), the Hausdorff distance (HD), the probabilistic distance (PBD), and the volumetric similarity (VS). RESULTS: For all three GTVs, the median DSC was 0.75 (range 0.17-0.95), the median HD 15 (range 3.22-67.11) mm, the median PBD 0.33 (range 0.06-4.86), and the median VS was 0.88 (range 0.31-1). For ITVs and PTVs the results were similar. When comparing the imaging modalities for delineation, the best agreement for the GTV was achieved using PET/CT, and for the ITV and PTV using 4D PET/CT, in treatment position with abdominal compression. CONCLUSION: Overall, there was good GTV agreement (DSC). Combined metrics appeared to allow a more valid detection of interobserver variation. For SBRT, either 4D PET/CT or 3D PET/CT in treatment position with abdominal compression leads to better agreement and should be considered as a very useful imaging modality for the definition of treatment volumes in pancreatic SBRT. Contouring does not appear to be the weakest link in the treatment planning chain of SBRT for PACA.

Vestibular Schwannoma Hypofractionated Stereotactic Radiation Therapy in Five Fractions.

AIM: To retrospectively analyse the long-term results of hypofractionated stereotactic radiation therapy (HSRT) applied in five fractions for vestibular schwannomas. MATERIALS AND METHODS: One hundred and thirty-four patients with vestibular schwannomas underwent medical treatment of HSRT. The median follow-up time interval was 54 months (range 6-121 months). All patients had a prescribed dose of 22 Gy in five fractions to D90. Restaging was carried out by thin-slice contrast-enhanced T1 magnetic resonance imaging. Progression was defined as 2 mm post-treatment tumour enlargement. Progression or death for any reason was counted as an event in progression-free survival rates. Acute toxicity was defined as adverse events occurring within 3 months of HSRT; long-term toxicity was defined as such events occurring after 3 months. RESULTS: In 74/128 patients who had >6 months of follow-up (54%), the HSRT resulted in a partial or a complete response. The mean time interval for response in 50% of these was 4 years, whereas in 49 patients (38%) vestibular schwannomas failed to show any response, resulting in stable disease. Five of 128 patients (4%) showed marked progressive vestibular schwannomas after treatment in the first 3 years; two of them received conventionally fractionated radiation therapy. Local control at 3, 5 and 7 years was 96%, 95% and 94%, respectively. Seven were lost to follow-up. The median planning target volume was 2.1 ml (range 0.78-8.66). The 3- and 5-year progression-free survival rates were 95% and 94%, respectively. Seven patients reported a marked deterioration in hearing ability. Post-radiation therapy magnetic resonance imaging showed variability in oedema collection, but no patient suffered from radio-necrosis. Grade 2 temporary facial nerve disorders were observed in 10 patients (8%) 3-6 months after HSRT. CONCLUSION: Delivering HSRT in five fractions for vestibular schwannoma appears safe and efficient, combining both efficiency and short treatment time while optimising neurological function preservation.

Combination of stereotactic radiotherapy and targeted therapy: patterns-of-care survey in German-speaking countries.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) is increasingly used in metastasized patients receiving targeted/immunotherapy. Information on safety and effectivity of concurrent SBRT and targeted/immunotherapy remains limited, resulting in a lack of consensus on treatment strategies. This study aimed to investigate how SBRT-experienced centers in German-speaking countries combine both therapies. MATERIALS AND METHODS: Patterns-of-care of combined treatment with SBRT and targeted/immunotherapy were assessed in 27 radiation oncology centers (19 German, 1 Austrian and 7 Swiss centers). A survey was performed to analyze the details of SBRT, SBRT planning and combined modality treatment. Consensus was defined as ≥75% agreement among participants. RESULTS: Most participants (60%) were university centers. SBRT for oligometastases has been performed since the year 2008 (median, range 1997-2016), since then a median of 140 cases (5-1100) of SBRT have been performed. In all, 67% performed concurrent SBRT and targeted agents. BRAF inhibitors and VEGF/EGFR inhibitors (bevacizumab [90%], erlotinib [11%], sorafenib [19%], lapatinib [4%]) were considered a contraindication. Bevacizumab was never given simultaneously with SBRT; other agents were given concurrently in 7-52% of centers. A majority (59%) paused targeted agents 1 week before/after SBRT. Only 1 center reduced SBRT dose when combined with targeted agents. CONCLUSION: Although evidence for safety and efficacy of concurrent SBRT and targeted agents is limited, it is regularly performed outside of clinical trials. The survey showed consensus not to combine SBRT with antiangiogenic agents, especially bevacizumab. Furthermore, SBRT with concurrent BRAF inhibitors should be practiced with caution and BRAF inhibitors should be paused at least 1 week before SBRT.

[Clinical target volume : Principles and limits]. / Klinisches Zielvolumen : Grundsätze und Grenzen.

BACKGROUND: The clinical target volume (CTV) is regarded fundamental for radiotherapy planning by the International Commission on Radiation Units and Measurements (ICRU). OBJECTIVES: The aim of this article is to give an overview on the basics and problems of defining the CTV for radiotherapy planning. MATERIALS AND METHODS: After briefly defining CTV, a short description of the process to homogenize CTV in intraindividual comparisons is given, where special attention is paid to radiological requirements. This information is summarized in a number of tables. RESULTS: CTV is the most complex volume among the target volumes that have been defined by the ICRU. A survey of the determinants of the definition of CTV is given. CONCLUSIONS: This overview on the basic rules of how to define CTVs can help to increase the understanding of the radiological requirements for optimum imaging to support radiotherapy planning regardless of the specialty of the physician.

Interobserver variability in target volume delineation of hepatocellular carcinoma : An analysis of the working group "Stereotactic Radiotherapy" of the German Society for Radiation Oncology (DEGRO).

BACKGROUND: Definition of gross tumor volume (GTV) in hepatocellular carcinoma (HCC) requires dedicated imaging in multiple contrast medium phases. The aim of this study was to evaluate the interobserver agreement (IOA) in gross tumor delineation of HCC in a multicenter panel. METHODS: The analysis was performed within the "Stereotactic Radiotherapy" working group of the German Society for Radiation Oncology (DEGRO). The GTVs of three anonymized HCC cases were delineated by 16 physicians from nine centers using multiphasic CT scans. In the first case the tumor was well defined. The second patient had multifocal HCC (one conglomerate and one peripheral tumor) and was previously treated with transarterial chemoembolization (TACE). The peripheral lesion was adjacent to the previous TACE site. The last patient had an extensive HCC with a portal vein thrombosis (PVT) and an inhomogeneous liver parenchyma due to cirrhosis. The IOA was evaluated according to Landis and Koch. RESULTS: The IOA for the first case was excellent (kappa: 0.85); for the second case moderate (kappa: 0.48) for the peripheral tumor and substantial (kappa: 0.73) for the conglomerate. In the case of the peripheral tumor the inconsistency is most likely explained by the necrotic tumor cavity after TACE caudal to the viable tumor. In the last case the IOA was fair, with a kappa of 0.34, with significant heterogeneity concerning the borders of the tumor and the PVT. CONCLUSION: The IOA was very good among the cases were the tumor was well defined. In complex cases, where the tumor did not show the typical characteristics, or in cases with Lipiodol (Guerbet, Paris, France) deposits, IOA agreement was compromised.

Pancreatic stellate cells in pancreatic cancer: In focus.

Pancreatic stellate cells are stromal cells that have multiple physiological functions such as the production of extracellular matrix, stimulation of amylase secretion, phagocytosis and immunity. In pancreatic cancer, stellate cells exhibit a different myofibroblastic-like morphology with the expression of alpha-smooth muscle actin, the activated form is engaged in several mechanisms that support tumorigenesis and cancer invasion and progression. In contrast to the aforementioned observations, eliminating the stromal cells that are positive for alpha-smooth muscle actin resulted in immune-evasion of the cancer cells and resulted in worse prognosis in animal models. Understanding the cancer-stromal signaling in pancreatic adenocarcinoma will provide novel strategies for therapy. Here we provide an updated review of studies that handle the topic "pancreatic stellate cells in cancer" and recent experimental approaches that can be the base for future directions in therapy.

Stereotactic body radiotherapy (SBRT) in recurrent or oligometastatic pancreatic cancer : A toxicity review of simultaneous integrated protection (SIP) versus conventional SBRT.

BACKGROUND: Stereotactic body radiotherapy (SBRT) in pancreatic cancer can be limited by its proximity to organs at risk (OAR). In this analysis, we evaluated the toxicity and efficacy of two different treatment approaches in patients with locally recurrent or oligometastatic pancreatic cancer. MATERIALS AND METHODS: According to the prescription method, patients were divided in two cohorts (C1 and C2). The planning target volume (PTV) was created through a 4 mm expansion of the internal target volume. In C2, a subvolume was additionally created, a simultaneous integrated protection (SIP), which is the overlap of the PTV with the planning risk volume of an OAR to which we prescribed a reduced dose. RESULTS: In all, 18 patients were treated (7 with local recurrences, 9 for oligometastases, 2 for both). Twelve of 23 lesions were treated without SIP (C1) and 11 with SIP (C2). The median follow-up was 12.8 months. Median overall survival (OS) was 13.2 (95% confidence interval [CI] 9.8-14.6) months. The OS rates at 6 and 12 months were 87 and 58%, respectively. Freedom from local progression for combined cohorts at 6 and 12 months was 93 and 67% (95% CI 15-36), respectively. Local control was not statistically different between the two groups. One patient in C2 experienced grade ≥3 acute toxicities and 1 patient in C1 experienced a grade ≥3 late toxicity. CONCLUSION: The SIP approach is a useful prescription method for abdominal SBRT with a favorable toxicity profile which does not compromise local control and overall survival despite dose sacrifices in small subvolumes.

Correlation of 18F-Fluorodeoxyglucose Positron Emission Tomography Parameters with Patterns of Disease Progression in Locally Advanced Pancreatic Cancer after Definitive Chemoradiotherapy.

AIMS: A proportion of patients with pancreatic cancer never develop metastatic disease. We evaluated a role for 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in identifying a subset of patients with locally advanced pancreatic cancer (LAPC) who never develop metastatic disease and only experience local disease and may therefore benefit from local treatment intensification. MATERIAL AND METHODS: Patients with histologically confirmed LAPC entered a single-centre phase II study of definitive upfront chemoradiotherapy (CRT). All patients underwent FDG-PET/CT before and 6 weeks after CRT. Tumour volume, standardised uptake values (SUVmax, SUVpeak, SUVmean, SUVmedian) and total lesion glycolysis (TLG) were measured on each scan and the response in each parameter was evaluated. The presence or absence of metastatic disease was noted on contrast-enhanced CT carried out every 3 months for 1 year and then at clinician discretion. RESULTS: Twenty-three patients with LAPC were recruited; 17/23 completed treatment and had interpretable sequential imaging. Twenty-four per cent of patients only ever experienced local disease. Median pre-CRT FDG-PET parameters were significantly lower in patients with local disease only during follow-up compared with those who developed metastatic disease: SUVmax 3.8 versus 8.6 (P=0.006), SUVpeak 2.5 versus 7.5 (P=0.002), SUVmean 1.8 versus 3.3 (P=0.001), SUVmedian 1.7 versus 3.0 (P=0.002), TLG 26.9 versus 115.9 (P=0.006). Tumour volume, post-CRT FDG-PET values and their relative change were not statistically different between local disease and metastatic disease groups. Receiver operating characteristic curves for pre-CRT FDG-PET parameters to predict those who never develop metastatic disease all had areas under the curve (AUCs) ≥ 0.932. Pre-CRT FDG-PET SUVmax < 6.2 predicted patients with local disease only during follow-up with 100.0% sensitivity and 92.3% specificity, 80.0% positive predictive value and 100% negative predictive value. CONCLUSIONS: Our findings suggest that patients with less FDG-avid tumours are less likely to metastasise and may therefore benefit from upfront local treatment intensification.

Comparison of four target volume definitions for pancreatic cancer. Guidelines for treatment of the lymphatics and the primary tumor.

BACKGROUND AND PURPOSE: Target volume definitions for radiotherapy in pancreatic ductal adenocarcinoma (PDAC) vary substantially. Some groups aim to treat the primary tumor only, whereas others include elective lymph nodes (eLNs). eLNs close to the primary tumor are often included unintentionally within the treatment volume, depending on the respective treatment philosophies. We aimed to measure the percentages of anatomical coverage of eLNs by comparing four different contouring guidelines. PATIENTS AND METHODS: Planning target volumes (PTVs) were contoured using planning computed tomography (CT) scans of 11 patients with PDAC based on the Oxford, RTOG (Radiation Therapy Oncology Group), Michigan, and SCALOP (Selective Chemoradiation in Advanced Localised Pancreatic Cancer trial) guidelines. Clinical target volumes (CTVs) included the peripancreatic, para-aortic, paracaval, celiac trunk, superior mesenteric, and portal vein lymph node areas. Volumetric comparisons of the coverage of all eLN regions were conducted to illustrate the differences between the four contouring strategies. RESULTS: The PTV sizes of the RTOG and Oxford guidelines were comparable. The SCALOP and Michigan PTV sizes were similar to each other and significantly smaller than the RTOG and Oxford PTVs. A large variability of eLN coverage was found for the various subregions according to the respective contouring strategies. CONCLUSION: This is the first study to directly compare the percentage of anatomical coverage of eLNs according to four PTVs in the same patient cohort. Potential practical consequences are discussed in detail.

Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation.

Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC.

Human pancreatic tumor cells are sensitized to ionizing radiation by knockdown of caveolin-1.

Caveolin-1 (Cav-1) is an integral transmembrane protein and a critical component in interactions of integrin receptors with cytoskeleton-associated and signaling molecules. Since integrin-mediated cell adhesion generates signals conferring radiation resistance, we examined the effects of small interfering RNA-mediated knockdown of Cav-1 alone or in combination with beta1-integrin or focal adhesion kinase (FAK) on radiation survival and proliferation of pancreatic carcinoma cell lines. Irradiation induced Cav-1 expression in PATU8902, MiaPaCa2 and Panc1 cell lines. The cell lines showed significant radiosensitization after knockdown of Cav-1, beta1-integrin or FAK and cholesterol depletion by beta-cyclodextrin relative to nonspecific controls. Under knockdown conditions, proliferation of non-irradiated and irradiated cells was significantly attenuated relative to controls. These findings correlated with changes in expression or phosphorylation of Akt, glycogen synthase kinase 3beta, Paxillin, Src, c-Jun N-terminal kinase and mitogen-activated protein kinase. Analysis of DNA microarray data revealed a Cav-1 overexpression in a subset of pancreatic ductal adenocarcinoma samples. The data presented show, for the first time, that disruption of interactions of Cav-1 with beta1-integrin or FAK affects radiation survival and proliferation of pancreatic carcinoma cells and suggest that Cav-1 is critical to these processes. These results indicate that strategies targeting Cav-1 may be useful as an approach to improve conventional therapies, including radiotherapy, for pancreatic cancer.

Farnesyltransferase inhibitors as radiation sensitizers.

PURPOSE: The inhibition of activated Ras combined with radiotherapy was identified as a potential method for radiosensitization. MATERIALS AND METHODS: Immunoblotting was used to control for prenylation inhibition of the respective Ras isoforms and for changes in activity of downstream proteins. Clonogenic assays with human and rodent tumour cell lines and transfected cell lines served for the testing of radiosensitivity. Xenograft tumours were treated with farnesyl transferase inhibitors and radiation and assayed for ex vivo plating efficiency, regrowth of tumours and EF5 staining for detection of hypoxia. Concurrent treatment with L-778,123 and radiotherapy was performed in non-small cell lung cancer (NSCLC) and head and neck cancer (HNC) patients. RESULTS: Blocking the prenylation of Ras proteins in cell lines with Ras activated by mutations or receptor signalling resulted in radiation sensitization in in vitro and in vivo. The PI3 kinase downstream pathway was identified as a contributor to Ras-mediated radiation resistance. Additionally, increased oxygenation of xenograft tumours was observed after FTI treatment. Combined treatment in a phase I study was safe and effective in NSCLC and HNC. CONCLUSIONS: Tumour cells with activated Ras were sensitized to radiation. Unravelling the underlying mechanisms promises to lead to even more specific drugs with higher potency and safety.

Adjuvant and neoadjuvant radiochemotherapy in ductal pancreatic carcinoma.

BACKGROUND: Ductal pancreatic carcinoma ranks third among malignancies of the gastrointestinal tract and its incidence is rising. Today, patients with this disease still have fatal prognosis necessitating efforts towards more effective treatment. MATERIAL AND METHODS: This report provides a review of adjuvant and neoadjuvant radiotherapy in pancreatic carcinoma without distant metastasis. Particular respect is given to prospective, randomized trials. They are analyzed according to clinical staging: 1. In resectable tumors adjuvant, neoadjuvant or intraoperative radiotherapy is performed. 2. Radiotherapy in neoadjuvant intention is an approach for downstaging to achieve resectability in initially irresectable tumors. RESULTS: The widespread use of new techniques such as supervoltage irradiation, computer based 3-D-planning, interventional therapy and combination of different therapeutic modalities induced a great number of studies. When concomitant chemotherapy was added to radiotherapy, results became significantly better compared to exclusive radiotherapy. It is shown that patients with operable tumors will have better survival rates and lower risk of relapse, if radiochemotherapy is added to surgery. Patients with irresectable tumors possible can be downstaged and be brought to resection nevertheless. CONCLUSIONS: Simultaneous radiochemotherapy with 5-FU and mitomycin C can be performed without elevated risk of acute side effects of higher degree. This approach may be indicated in the case of adjuvant situations in patients free of distant metastases. Neoadjuvant simultaneous radiochemotherapy should only be performed as a part of a clinical trial.

Preoperative Chemoradiation in Locally Advanced Pancreatic Carcinoma: A Phase II Study.

BACKGROUND: Effectiveness and feasibility of preoperative chemoradiation (CRT) in locally advanced adenocarcinoma of the pancreas are evaluated. MATERIAL AND METHODS: 29 eligible of 37 registered patients were treated. 3d-Conformal external radiotherapy was delivered with a 1.8-Gy single dose and a total dose of 50.4 Gy plus 5.4 Gy boost. Simultaneous chemotherapy consisted of 5-fluorouracil and mitomycin C. RESULTS: Among 27 completely treated patients, 16 (59%) underwent surgery, 6 of them being irresectable intraoperatively. Ten patients (37%) had clear resection margins at Whipple's procedure. Eleven patients were not considered for surgery (7 still irresectable at restaging, 3 distant metastases, 1 refusal of surgery). Toxicity was predominantly hematological (grade 3: 30%, grade 4: 7%); furthermore, there was nausea/vomiting (grade 3: 20%, grade 4: 0%). No patient died perioperatively. The tumor-related overall survival rate was better for resected patients than for nonresected patients (50% vs. 6%, 2-year survival, p = 0.07), median overall survival was 9 months (median follow-up, 28 months). CONCLUSIONS: Neoadjuvant CRT without significant acute toxicity produced a resectability rate of 37% (all R0), which should be confirmed by randomized phase III studies. Copyright 2000 S. Karger GmbH, Freiburg