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Yoshimura M, Hiraoka M, Kokubo M, Sakamoto T, Karasawa K, Matsuo Y, Nakamura M, Mukumoto N, Morita S, Mizowaki T. Multi-Institutional Phase II Study on the Efficacy and Safety of Dynamic Tumor-Tracking, Moderately Hypofractionated Intensity-Modulated Radiotherapy in Patients With Locally Advanced Pancreatic Cancer. Cancer Med 2025; 14:e70648. [PMID: 39907184 PMCID: PMC11795415 DOI: 10.1002/cam4.70648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 09/22/2024] [Accepted: 01/24/2025] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND For delivering high radiation doses to pancreatic tumors, organ motion management is indispensable; however, studies on this are limited. We aimed to evaluate the efficacy and safety of dynamic tumor tracking (DTT) moderately hypofractionated intensity-modulated radiotherapy (IMRT) in patients with locally advanced pancreatic cancer (LAPC). METHODS Patients with histological confirmation for LAPC were included. A linac system, which was mounted with a gimbal function, was used for DTT-IMRT. The prescribed dose was 48 Gy in 15 fractions. The primary endpoint was the 1-year rate of freedom from locoregional progression (FFLP). RESULTS DTT-IMRT was successfully administered in 25 patients enrolled from four institutions. The median range of respiratory motion during DTT-IMRT was 9.8 mm (range: 3.5-27.3 mm), and the median tracking accuracy was 2.6 mm (range: 0.7-5.2 mm). With a median follow-up period of 13.9 months, the 1-year FFLP rate was 75.3% (lower limit of one-sided 80% confidence interval [CI]: 60.2%), which satisfied the predetermined primary endpoint. One-year locoregional progression-free survival, progression-free survival, and overall survival were 56.0% (95% CI: 34.8%-72.7%), 44.0% (95% CI: 24.5%-61.9%), and 60.0% (95% CI: 38.4%-76.1%), respectively. Regarding nonhematologic toxicities, grade 3 acute gastrointestinal (GI) toxicity was observed in two patients (8%), and two patients (8%) each experienced grade 3 late GI and non-GI toxicities. No grade 4 or 5 nonhematologic toxicities were observed. CONCLUSIONS DTT moderately hypofractionated IMRT shows preferable locoregional control without significant toxicity in patients with LAPC. TRIAL REGISTRATION UMIN000017521.
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Affiliation(s)
- Michio Yoshimura
- Department of Radiation Oncology and Image‐Applied Therapy, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Masahiro Hiraoka
- Department of Radiation Oncology and Image‐Applied Therapy, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Masaki Kokubo
- Department of Radiation OncologyKobe City Medical Center General HospitalKobeJapan
| | - Takashi Sakamoto
- Department of Radiation OncologyKyoto Katsura HospitalKyotoJapan
| | - Katsuyuki Karasawa
- Division of Radiation Oncology, Department of RadiologyTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalTokyoJapan
| | - Yukinori Matsuo
- Department of Radiation Oncology and Image‐Applied Therapy, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Mitsuhiro Nakamura
- Department of Advanced Medical Physics, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Nobutaka Mukumoto
- Department of Radiation Oncology and Image‐Applied Therapy, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Takashi Mizowaki
- Department of Radiation Oncology and Image‐Applied Therapy, Graduate School of MedicineKyoto UniversityKyotoJapan
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Waheed A, Murland S, Yip E, Heikal A, Ghosh S, Abraham A, Paulson K, Tankel K, Usmani N, Severin D, Wong C, Joseph K. Sharing Mono-Institutional Experience of Treating Pancreatic Cancer with Stereotactic Body Radiation Therapy (SBRT). Curr Oncol 2024; 31:5974-5986. [PMID: 39451750 PMCID: PMC11506591 DOI: 10.3390/curroncol31100446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 09/14/2024] [Accepted: 09/16/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Stereotactic body radiotherapy (SBRT) is an evolving treatment for the local management of pancreatic cancer (PC). The main purpose of this study is to report our initial experience in terms of local control (LC) and toxicity for PC patients treated with SBRT. METHODS We conducted a retrospective review of patients treated with SBRT using abdominal compression (AC) or an end-expiratory breath-holding (EEBH) technique. The median prescribed dose was 35 Gy, delivered in five fractions. Toxicities were recorded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0, and survival was estimated using the Kaplan-Meier method. RESULTS From 2017 to 2023, 17 PC patients were offered SBRT. Their median age was 69 years. The median follow-up from the date of diagnosis was 22.37 months. The overall survival (OS) was 94% at 1 year and 60.9% at 2 years. The progression-free survival (PFS) was 63.1% at 6 months and 56.1% at 9 months. The median OS was 26.3 months, and the median PFS was 20.6 months. The 6-month and 1-year LC rates were 71% and 50.8%, respectively. CONCLUSION We are successful in implementing the SBRT program at our centre. SBRT appears to be a promising treatment option for achieving LC with limited acute toxicities.
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Affiliation(s)
- Asmara Waheed
- Division of Radiation Oncology, Department of Oncology, University of Alberta & Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada (A.A.); (K.P.); (K.T.); (N.U.); (D.S.)
| | - Shannah Murland
- Department of Radiation Therapy, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada;
| | - Eugene Yip
- Division of Medical Physics, Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada; (E.Y.); (A.H.)
| | - Amr Heikal
- Division of Medical Physics, Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada; (E.Y.); (A.H.)
| | - Sunita Ghosh
- Division of Medical Oncology, Department of Oncology, University of Alberta & Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada;
| | - Aswin Abraham
- Division of Radiation Oncology, Department of Oncology, University of Alberta & Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada (A.A.); (K.P.); (K.T.); (N.U.); (D.S.)
| | - Kim Paulson
- Division of Radiation Oncology, Department of Oncology, University of Alberta & Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada (A.A.); (K.P.); (K.T.); (N.U.); (D.S.)
| | - Keith Tankel
- Division of Radiation Oncology, Department of Oncology, University of Alberta & Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada (A.A.); (K.P.); (K.T.); (N.U.); (D.S.)
| | - Nawaid Usmani
- Division of Radiation Oncology, Department of Oncology, University of Alberta & Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada (A.A.); (K.P.); (K.T.); (N.U.); (D.S.)
| | - Diane Severin
- Division of Radiation Oncology, Department of Oncology, University of Alberta & Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada (A.A.); (K.P.); (K.T.); (N.U.); (D.S.)
| | - Clarence Wong
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB T6G 1Z2, Canada;
| | - Kurian Joseph
- Division of Radiation Oncology, Department of Oncology, University of Alberta & Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada (A.A.); (K.P.); (K.T.); (N.U.); (D.S.)
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Seto I, Yamaguchi H, Takagawa Y, Azami Y, Takayama K, Suzuki M, Machida M, Dai Y, Sulaiman NSB, Kikuchi Y, Kato T, Nishino N, Teranishi Y, Murakami M. Clinical Outcomes of Proton Beam Therapy for Unresectable Locally Advanced Pancreatic Cancer: A Single-Center Retrospective Study. Adv Radiat Oncol 2024; 9:101577. [PMID: 39309704 PMCID: PMC11415529 DOI: 10.1016/j.adro.2024.101577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 06/26/2024] [Indexed: 09/25/2024] Open
Abstract
Purpose We retrospectively researched the treatment outcome of proton beam therapy (PBT) and assessed its efficacy for inoperable locally advanced pancreatic cancer (LAPC) at our institution. Methods and Materials Fifty-four patients (28 men and 26 women, median age 67 years ranging from 40-88 years) were diagnosed with unresectable stage III LAPC and administered PBT from April 2009 to March 2020. Patients who could not complete PBT, had new distant metastases during the treatment, or did not have enough follow-up time were excluded from this study. All patients were clinically staged based on the International Union of Cancer TNM staging system (eighth edition) using computed tomography, magnetic resonance imaging, and positron emission tomography and were diagnosed as stage III (histologic type: 18 patients with adenocarcinoma and 36 clinically diagnosed patients). PBT was performed using the passive method, with a median total dose of 67.5 GyE (range, 50-77 GyE/25-35 fractions).Chemotherapy was used in combination during PBT in 46 patients (85.2%). Overall survival (OS), local progression-free survival (LPFS), progression-free survival, and median OS time were analyzed by Kaplan-Meier and log-rank tests. Univariate and multivariate analyses were performed for the following factors: maximum standardized uptake value (SUVmax), Eastern Cooperative Group performance status (PS), tumor site, total irradiation dose, concurrent chemotherapy, and primary tumor site. Cutoff values for SUVmax and tumor diameter were estimated using receiver operating characteristic curves and the area under the curve based on OS. Multivariate analysis was evaluated using the Cox proportional hazards models. Adverse events were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Results The median observation period was 17.4 months, ranging from 4.0 to 89.7 months. The median tumor diameter was 36.5 mm, ranging from 15 to 90 mm, the median SUVmax was 5.85 (range, 2.1-27.6), and their cutoff values were estimated to be 37 mm and 4.8 mm, respectively. The 1- and 2-year OS was 77.8% and 35.2%, respectively, with a median OS time of 18.2 months, and only one patient survived >5 years. Twelve patients (22.2%) developed local recurrence, and 1- and 2-year LPFS rates were 89.7% and 74.5%, respectively; progression-free survival at 1 year was 58.8%. The PS score, tumor site, and irradiation dose were the prognostic factors related to OS that showed a significant difference. On the other hand, there was a significant difference in factors involved in LPFS, at 96.7%/77.9% in the first year and 86.6%/54.4% in the second year in the groups with tumor dose ≥67.5 GyE and <67.5 GyE, respectively (P = .015). Treatment-related acute toxicities were neutropenia (grade 1/2/3 at 3.7%/11.1%/31.5%, respectively), leukopenia (grade 1/2/3 at 1.8%/7.4%/20.4%, respectively), and thrombocytopenia (grade 1/2 at 1.8%/7.4%, respectively), whereas the late effects including peptic ulcer were captured only grade 2+. The late adverse events of grade 3 or higher were not observed. Conclusions PBT achieving 67.5 Gy combined with standard chemotherapy showed excellent local control for unresectable LAPC. Total irradiation dose, tumor site, and PS score at an initial diagnosis could be important prognostic factors. In this study, the dose-effect relationship was found, so an increase in dose should be considered to improve prognosis.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Yasushi Teranishi
- Department of Surgery, Neuroscience, Southern Tohoku Research Institute for Neuroscience, Southern Tohoku Proton Therapy Center, Southern Tohoku General Hospital, Yatsuyamada, Koriyama, Japan
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Mukherjee S, Qi C, Shaw R, Jones CM, Bridgewater JA, Radhakrishna G, Patel N, Holmes J, Virdee PS, Tranter B, Parsons P, Falk S, Wasan HS, Ajithkumar TV, Holyoake D, Roy R, Scott-Brown M, Hurt CN, O'Neill E, Sebag-Montefiore D, Maughan TS, Hawkins MA, Corrie P. Standard or high dose chemoradiotherapy, with or without the protease inhibitor nelfinavir, in patients with locally advanced pancreatic cancer: The phase 1/randomised phase 2 SCALOP-2 trial. Eur J Cancer 2024; 209:114236. [PMID: 39059185 DOI: 10.1016/j.ejca.2024.114236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 07/08/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024]
Abstract
BACKGROUND The multi-centre two-stage SCALOP-2 trial (ISRCTN50083238) assessed whether dose escalation of consolidative chemoradiotherapy (CRT) or concurrent sensitization using the protease inhibitor nelfinavir improve outcomes in locally advanced pancreatic cancer (LAPC) following four cycles of gemcitabine/nab-paclitaxel. METHODS In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4 Gy in 28 fractions) was identified from a cohort of 27 patients. In stage 2, 159 patients were enrolled in an open-label randomized controlled comparison of standard versus high dose (60 Gy in 30 fractions) CRT, with or without nelfinavir at MTD. Primary outcomes following dose escalation and nelfinavir use were respectively overall survival (OS) and progression free survival (PFS). Secondary endpoints included health-related quality of life (HRQoL). RESULTS High dose CRT did not improve OS (16.9 (60 % confidence interval, CI 16.2-17.7) vs. 15.6 (60 %CI 14.3-18.2) months; adjusted hazard ratio, HR 1.13 (60 %CI 0.91-1.40; p = 0.68)). Similarly, median PFS was not improved by nelfinavir (10.0 (60 %CI 9.9-10.2) vs. 11.1 (60 %CI 10.3-12.8) months; adjusted HR 1.71 (60 %CI 1.38-2.12; p = 0.98)). Local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n = 11/46 (23.9 %) vs. n = 15/45 (33.3 %)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or grade 3/4 adverse event rate. There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment. CONCLUSIONS Dose-escalated CRT may improve local tumour control and is well tolerated when used as consolidative treatment in LAPC but does not impact OS. Nelfinavir use does not improve PFS.
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Affiliation(s)
- Somnath Mukherjee
- Oxford Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
| | - Cathy Qi
- Centre for Statistics in Medicine, University of Oxford, Oxford, UK
| | - Rachel Shaw
- Oncology Clinical Trials Office (OCTO), Department of Oncology, University of Oxford, Oxford, UK
| | - Christopher M Jones
- Department of Oncology, University of Cambridge, Cambridge, UK; Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - John A Bridgewater
- UCL Cancer Institute, University College London Hospitals NHS Foundation Trust, London, UK
| | - Ganesh Radhakrishna
- The Christie Hospital, The Christie Hospitals NHS Foundation Trust, Manchester, UK
| | - Neel Patel
- Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Jane Holmes
- Centre for Statistics in Medicine, University of Oxford, Oxford, UK
| | - Pradeep S Virdee
- Centre for Statistics in Medicine, University of Oxford, Oxford, UK
| | - Bethan Tranter
- Velindre Cancer Centre, Velindre University NHS Trust, Cardiff, UK
| | - Philip Parsons
- Velindre Cancer Centre, Velindre University NHS Trust, Cardiff, UK
| | - Stephen Falk
- Bristol Cancer Centre, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Harpreet S Wasan
- Department of Surgery & Cancer, Imperial College London, London, UK
| | - Thankamma V Ajithkumar
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Daniel Holyoake
- Norfolk & Norwich University Hospital, Norfolk & Norwich University Hospitals NHS Foundation Trust, Norwich, UK
| | - Rajarshi Roy
- Queen's Centre for Oncology, Hull University Teaching Hospitals NHS Trust, Hull, UK
| | - Martin Scott-Brown
- Coventry Cancer Centre, University Hospital Coventry & Warwickshire, Coventry, UK
| | | | - Eric O'Neill
- Department of Oncology, University of Oxford, Oxford, UK
| | | | - Tim S Maughan
- Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK
| | - Maria A Hawkins
- Department of Medical Physics & Biomedical Engineering, University College London, London, UK
| | - Pippa Corrie
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Zaidi F, Calame P, Chevalier C, Henriques J, Vernerey D, Vuitton L, Heyd B, Borg C, Boustani J. A comparison of target volumes drawn on arterial and venous phase scans during radiation therapy planning for patients with pancreatic cancer: the PANCRINJ study. Radiat Oncol 2024; 19:90. [PMID: 39010133 PMCID: PMC11251351 DOI: 10.1186/s13014-024-02477-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 06/18/2024] [Indexed: 07/17/2024] Open
Abstract
BACKGROUND The planification of radiation therapy (RT) for pancreatic cancer (PC) requires a dosimetric computed tomography (CT) scan to define the gross tumor volume (GTV). The main objective of this study was to compare the inter-observer variability in RT planning between the arterial and the venous phases following intravenous contrast. METHODS PANCRINJ was a prospective monocentric study that included twenty patients with non-metastatic PC. Patients underwent a pre-therapeutic CT scan at the arterial and venous phases. The delineation of the GTV was performed by one radiologist (gold standard) and two senior radiation oncologists (operators). The primary objective was to compare the Jaccard conformity index (JCI) for the GTVs computed between the GS (gold standard) and the operators between the arterial and the venous phases with a Wilcoxon signed rank test for paired samples. The secondary endpoints were the geographical miss index (GMI), the kappa index, the intra-operator variability, and the dose-volume histograms between the arterial and venous phases. RESULTS The median JCI for the arterial and venous phases were 0.50 (range, 0.17-0.64) and 0.41 (range, 0.23-0.61) (p = 0.10) respectively. The median GS-GTV was statistically significantly smaller compared to the operators at the arterial (p < 0.0001) and venous phases (p < 0.001), respectively. The GMI were low with few tumors missed for all patients with a median GMI of 0.07 (range, 0-0.79) and 0.05 (range, 0-0.39) at the arterial and venous phases, respectively (p = 0.15). There was a moderate agreement between the radiation oncologists with a median kappa index of 0.52 (range 0.38-0.57) on the arterial phase, and 0.52 (range 0.36-0.57) on the venous phase (p = 0.08). The intra-observer variability for GTV delineation was lower at the venous phase than at the arterial phase for the two operators. There was no significant difference between the arterial and the venous phases regarding the dose-volume histogram for the operators. CONCLUSIONS Our results showed inter- and intra-observer variability in delineating GTV for PC without significant differences between the arterial and the venous phases. The use of both phases should be encouraged. Our findings suggest the need to provide training for radiation oncologists in pancreatic imaging and to collaborate within a multidisciplinary team.
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Affiliation(s)
- Fabien Zaidi
- Department of Radiotherapy, University of Bourgogne Franche-Comté, CHU Besançon, CHRU Besançon, Service de Radiothérapie, Hôpital Jean Minjoz, 3 Boulevard Alexandre Fleming, Besançon, 25030, France
| | - Paul Calame
- Department of Radiology, University of Bourgogne Franche-Comté, CHU Besançon, Besançon, 25030, France
| | - Cédric Chevalier
- Department of Radiotherapy, University of Bourgogne Franche-Comté, CHU Besançon, CHRU Besançon, Service de Radiothérapie, Hôpital Jean Minjoz, 3 Boulevard Alexandre Fleming, Besançon, 25030, France
| | - Julie Henriques
- Methodology and Quality of Life Unit in Oncology, University Hospital of Besançon, Besançon, France
- Université de Franche-Comté, EFS, INSERM, UMR RIGHT, Besançon, F-25000, France
| | - Dewi Vernerey
- Methodology and Quality of Life Unit in Oncology, University Hospital of Besançon, Besançon, France
- Université de Franche-Comté, EFS, INSERM, UMR RIGHT, Besançon, F-25000, France
| | - Lucine Vuitton
- Department of Gastroenteroly, University of Bourgogne Franche-Comté, CHU Besançon, Besançon, 25030, France
| | - Bruno Heyd
- Department of Digestive surgery, University of Bourgogne Franche-Comté, CHU Besançon, Besançon, 25030, France
| | - Christophe Borg
- Department of Oncology, University of Bourgogne Franche-Comté, CHU Besançon, Besançon, 25030, France
| | - Jihane Boustani
- Department of Radiotherapy, University of Bourgogne Franche-Comté, CHU Besançon, CHRU Besançon, Service de Radiothérapie, Hôpital Jean Minjoz, 3 Boulevard Alexandre Fleming, Besançon, 25030, France.
- Université de Franche-Comté, EFS, INSERM, UMR RIGHT, Besançon, F-25000, France.
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Fogaroli RC, Castro DG, Silva ML, Pellizzon ACA, Gondim GR, Chen MJ, Ramos H, Neto ES, Abrahão CH. Involved-Field Radiation Therapy for Patients With Unresectable Pancreatic Adenocarcinomas: Failure Pattern Analysis. Cureus 2023; 15:e48106. [PMID: 37920425 PMCID: PMC10619996 DOI: 10.7759/cureus.48106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2023] [Indexed: 11/04/2023] Open
Abstract
Introduction Unresectable pancreatic tumors are frequently diagnosed. Initial treatment is carried out with chemotherapy. Eventually, in selected cases, radiotherapy may be used to improve local control rates and relieve the symptoms. The volume of radiotherapy treatment fields is the subject of controversy in the literature. The use of involved fields with the gross tumor volume encompassing the primary tumor and lymph nodes considered clinically positive is associated with a lower rate of side effects, but can lead to a higher rate of regional loco failures, especially in regional lymph nodes. The purpose of this article is to analyze the failure pattern of chemotherapy and involved-field radiation therapy (IFRT) for treating patients with unresectable pancreatic adenocarcinomas. Methods Clinical records of thirty consecutive patients treated from March 2016 to June 2020 for unresectable pancreatic adenocarcinoma were analyzed. The patients were treated with initial systemic chemotherapy (median: 6 cycles) with regimens based on gemcitabine or oxaliplatin-irinotecan (folfirinox/folfox) followed by radiotherapy (total dose of 50-54 Gy/with fractionation of 2 Gy/day). The patients were treated with IFRT. Local failure (LF) was defined as an increase in radiographic abnormality within the planning target volume (PTV). Elective nodal failure (ENF) was defined as recurrence in any lymph node region outside the PTV. Any other failure was defined as distant failure (DF). Results The median age of the patients was 68 years (range: 44-80 years); 20 patients (66.7%) were men, and 11 (36.6%) and 19 (63.4%) patients presented with tumors of stage II and III, respectively. Most patients (63.3%) had tumors in the pancreatic head. The median survival was 17.2 months. Tumor recurrences were classified as LF, DF, LF and DF in 7 (23.3%), 17 (56.7%), and 5 (16.7%) patients, respectively. Only one patient (3.3%) had both LF and ENF. No severe side effects related to radiotherapy were reported. Conclusion The use of IFRT did not cause a significant amount of ENF, besides presenting low morbidity, which is of special importance for patients with locally advanced tumors or low performance status. The predominant failure pattern was distant metastases.
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Affiliation(s)
| | | | - Maria L Silva
- Radiation Oncology, A.C. Camargo Cancer Center, São Paulo, BRA
| | | | | | - Michael J Chen
- Radiation Oncology, A.C. Camargo Cancer Center, São Paulo, BRA
| | | | - Elson S Neto
- Radiotherapy, A.C. Camargo Cancer Center, São Paulo, BRA
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Spiers L, Gray M, Lyon P, Sivakumar S, Bekkali N, Scott S, Collins L, Carlisle R, Wu F, Middleton M, Coussios C. Clinical trial protocol for PanDox: a phase I study of targeted chemotherapy delivery to non-resectable primary pancreatic tumours using thermosensitive liposomal doxorubicin (ThermoDox®) and focused ultrasound. BMC Cancer 2023; 23:896. [PMID: 37741968 PMCID: PMC10517508 DOI: 10.1186/s12885-023-11228-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 07/24/2023] [Indexed: 09/25/2023] Open
Abstract
BACKGROUND The dense stroma of pancreatic ductal adenocarcinomas is a major barrier to drug delivery. To increase the local drug diffusion gradient, high doses of chemotherapeutic agent doxorubicin can be released from thermally-sensitive liposomes (ThermoDox®) using ultrasound-mediated hyperthermia at the tumour target. PanDox is designed as a Phase 1 single centre study to investigate enhancing drug delivery to adult patients with non-operable pancreatic ductal adenocarcinomas. The study compares a single cycle of either conventional doxorubicin alone or ThermoDox® with focused ultrasound-induced hyperthermia for targeted drug release. METHODS Adults with non-resectable pancreatic ductal adenocarcinoma are allocated to receive a single cycle of either doxorubicin alone (Arm A) or ThermoDox® with focused ultrasound-induced hyperthermia (Arm B), based on patient- and tumour-specific safety conditions. Participants in Arm B will undergo a general anaesthetic and pre-heating of the tumour by extra-corporal focused ultrasound (FUS). Rather than employing invasive thermometry, ultrasound parameters are derived from a patient-specific treatment planning model to reach the 41 °C target temperature for drug release. ThermoDox® is then concurrently infused with further ultrasound exposure. Tumour biopsies at the targeted site from all patients are analysed post-treatment using high performance liquid chromatography to quantify doxorubicin delivered to the tumour. The primary endpoint is defined as a statistically significant enhancement in concentration of total intra-tumoural doxorubicin, comparing samples from patients receiving liposomal drug with FUS to free drug alone. Participants are followed for 21 days post-treatment to assess secondary endpoints, including radiological assessment to measure changes in tumour activity by Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) criteria, adverse events and patient-reported symptoms. DISCUSSION This early phase study builds on previous work targeting tumours in the liver to investigate whether enhancement of chemotherapy delivery using ultrasound-mediated hyperthermia can be translated to the stroma-dense environment of pancreatic ductal adenocarcinoma. If successful, it could herald a new approach towards managing these difficult-to-treat tumours. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04852367 . Registered 21st April 2022. EudraCT number: 2019-003950-10 (Registered 2019) Iras Project ID: 272253 (Registered 2019) Ethics Number: 20/EE/0284.
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Affiliation(s)
- Laura Spiers
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
- Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK
- NIHR Oxford Biomedical Research Centre, Oxford, UK
| | - Michael Gray
- NIHR Oxford Biomedical Research Centre, Oxford, UK
- Institute of Biomedical Engineering, University of Oxford, Marcella Wing, Botnar Research Centre, Old Rd, Headington, Oxford, OX3 7LD, UK
| | - Paul Lyon
- Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK
| | - Shivan Sivakumar
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
- Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK
| | - Noor Bekkali
- Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK
| | - Shaun Scott
- Nuffield Department of Anaesthetics, John Radcliffe Hospital, Oxford, OX3 7LE, UK
| | - Linda Collins
- Department of Oncology, Oncology Clinical Trials Office (OCTO), University of Oxford, Oxford, UK
| | - Robert Carlisle
- Institute of Biomedical Engineering, University of Oxford, Marcella Wing, Botnar Research Centre, Old Rd, Headington, Oxford, OX3 7LD, UK
| | - Feng Wu
- Nuffield Department of Surgery, Churchill Hospital, Oxford, OX3 7LE, UK
| | - Mark Middleton
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
| | - Constantin Coussios
- Institute of Biomedical Engineering, University of Oxford, Marcella Wing, Botnar Research Centre, Old Rd, Headington, Oxford, OX3 7LD, UK.
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8
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Falco M, Masojć B, Sulikowski T. Radiotherapy in Pancreatic Cancer: To Whom, When, and How? Cancers (Basel) 2023; 15:3382. [PMID: 37444492 DOI: 10.3390/cancers15133382] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/17/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
The diagnosis rate of pancreatic cancer is steadily increasing. The average age of onset is close to 70 years. In most cases, the disease is diagnosed at an advanced stage. The indications for and techniques of radiotherapy are changing over time. The aim of this thesis is to present the role and possibilities of radiotherapy from the perspective of radiation oncologist. The most common cause of treatment failure in pancreatic cancer remains generalisation. The implementation of new systemic treatment regimens contributes to improved treatment outcomes regardless of the stage of the disease. With improved treatment outcomes in terms of the incidence of distant metastases, the impact of local curability on the length and quality of life of patients increases. Modern radiotherapy offers the opportunity to achieve high local cure rates. Postoperative radiotherapy in combination with chemotherapy seems justified in the group of postoperative pancreatic cancer patients with pT3 and pN+ features. In the group of patients with borderline resectable pancreatic cancer, the impact of radiotherapy in combination with the latest chemotherapy regimens is difficult to define clearly. In the setting of a diagnosis of advanced pancreatic cancer, radiotherapy, especially stereotactic radiotherapy, in combination with chemotherapy, contributes to improved local curability and allows to achieve a significantly reduced level of pain.
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Affiliation(s)
- Michał Falco
- Radiation Oncology Department, West Pomeranian Oncology Center, Strzałowska 22, 71-730 Szczecin, Poland
- Hospicjum Św. Jana Ewnagelisty, Pokoju 77, 71-740 Szczecin, Poland
| | - Bartłomiej Masojć
- Radiation Oncology Department, West Pomeranian Oncology Center, Strzałowska 22, 71-730 Szczecin, Poland
| | - Tadeusz Sulikowski
- Department of General, Minimally Invasive, and Gastroenterological Surgery, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland
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9
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Suzuki K, Ikenoyama Y, Hirasawa T, Yoshimizu S, Horiuchi Y, Ishiyama A, Yoshio T, Taguchi S, Yoshioka Y, Fujisaki J. Clinical course and treatment of radiation-induced hemorrhagic gastritis: a case series study. Clin J Gastroenterol 2022; 16:152-158. [PMID: 36586090 DOI: 10.1007/s12328-022-01750-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 12/19/2022] [Indexed: 01/01/2023]
Abstract
Radiation-induced hemorrhagic gastritis is a relatively uncommon complication of irradiation that can be severe. However, appropriate treatment guidelines have not yet been established because of the small number of known cases. At our hospital, we encountered nine cases of radiation-induced hemorrhagic gastritis between July 2005 and July 2018. All patients initially underwent argon plasma coagulation (APC) for hemostasis. The treatment was highly effective, and hemostasis was successfully achieved in eight of the cases. Hemostasis could not be achieved in one case treated with APC; therefore, surgical resection was required. This patient had risk factors, such as liver cirrhosis and a history of abdominal surgery. Our case series suggests that APC is an effective hemostatic method that should be considered as the initial treatment option for radiation-induced hemorrhagic gastritis; however, surgical resection may be considered when the patient is at high risk for rebleeding.
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Affiliation(s)
- Keita Suzuki
- Department of Gastroenterology, Cancer Institute Hospital, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Yohei Ikenoyama
- Department of Gastroenterology, Cancer Institute Hospital, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Toshiaki Hirasawa
- Department of Gastroenterology, Cancer Institute Hospital, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan.
| | - Shoichi Yoshimizu
- Department of Gastroenterology, Cancer Institute Hospital, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Yusuke Horiuchi
- Department of Gastroenterology, Cancer Institute Hospital, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Akiyoshi Ishiyama
- Department of Gastroenterology, Cancer Institute Hospital, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Toshiyuki Yoshio
- Department of Gastroenterology, Cancer Institute Hospital, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
| | - Senzo Taguchi
- Department of Radiation Oncology, Cancer Institute Hospital, Tokyo, Japan
| | - Yasuo Yoshioka
- Department of Radiation Oncology, Cancer Institute Hospital, Tokyo, Japan
| | - Junko Fujisaki
- Department of Gastroenterology, Cancer Institute Hospital, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan
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10
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Increasing Stress to Induce Apoptosis in Pancreatic Cancer via the Unfolded Protein Response (UPR). Int J Mol Sci 2022; 24:ijms24010577. [PMID: 36614019 PMCID: PMC9820188 DOI: 10.3390/ijms24010577] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/23/2022] [Accepted: 12/24/2022] [Indexed: 12/31/2022] Open
Abstract
High rates of cell proliferation and protein synthesis in pancreatic cancer are among many factors leading to endoplasmic reticulum (ER) stress. To restore cellular homeostasis, the unfolded protein response (UPR) activates as an adaptive mechanism through either the IRE1α, PERK, or ATF6 pathways to reduce the translational load and process unfolded proteins, thus enabling tumor cells to proliferate. Under severe and prolonged ER stress, however, the UPR may promote adaptation, senescence, or apoptosis under these same pathways if homeostasis is not restored. In this review, we present evidence that high levels of ER stress and UPR activation are present in pancreatic cancer. We detail the mechanisms by which compounds activate one or many of the three arms of the UPR and effectuate downstream apoptosis and examine available data on the pre-clinical and clinical-phase ER stress inducers with the potential for anti-tumor efficacy in pancreatic cancer. Finally, we hypothesize a potential new approach to targeting pancreatic cancer by increasing levels of ER stress and UPR activation to incite apoptotic cell death.
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11
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Ji T, Feng Z, Sun E, Ng SK, Su L, Zhang Y, Han D, Han-Oh S, Iordachita I, Lee J, Kazanzides P, Bell MAL, Wong J, Ding K. A phantom-based analysis for tracking intra-fraction pancreatic tumor motion by ultrasound imaging during radiation therapy. Front Oncol 2022; 12:996537. [PMID: 36237341 PMCID: PMC9552199 DOI: 10.3389/fonc.2022.996537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 09/07/2022] [Indexed: 11/13/2022] Open
Abstract
PurposeIn this study, we aim to further evaluate the accuracy of ultrasound tracking for intra-fraction pancreatic tumor motion during radiotherapy by a phantom-based study.MethodsTwelve patients with pancreatic cancer who were treated with stereotactic body radiation therapy were enrolled in this study. The displacement points of the respiratory cycle were acquired from 4DCT and transferred to a motion platform to mimic realistic breathing movements in our phantom study. An ultrasound abdominal phantom was placed and fixed in the motion platform. The ground truth of phantom movement was recorded by tracking an optical tracker attached to this phantom. One tumor inside the phantom was the tracking target. In the evaluation of the results, the monitoring results from the ultrasound system were compared with the phantom motion results from the infrared camera. Differences between infrared monitoring motion and ultrasound tracking motion were analyzed by calculating the root-mean-square error.ResultsThe 82.2% ultrasound tracking motion was within a 0.5 mm difference value between ultrasound tracking displacement and infrared monitoring motion. 0.7% ultrasound tracking failed to track accurately (a difference value > 2.5 mm). These differences between ultrasound tracking motion and infrared monitored motion do not correlate with respiratory displacements, respiratory velocity, or respiratory acceleration by linear regression analysis.ConclusionsThe highly accurate monitoring results of this phantom study prove that the ultrasound tracking system may be a potential method for real-time monitoring targets, allowing more accurate delivery of radiation doses.
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Affiliation(s)
- Tianlong Ji
- Department of Radiation Oncology, The First Hospital of China Medical University, Shenyang, China
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Ziwei Feng
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
- Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, MD, United States
| | - Edward Sun
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Sook Kien Ng
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Lin Su
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Yin Zhang
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Dong Han
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Sarah Han-Oh
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Iulian Iordachita
- Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD, United States
| | - Junghoon Lee
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Peter Kazanzides
- Department of Computer Science, Johns Hopkins University, Baltimore, MD, United States
| | - Muyinatu A. Lediju Bell
- Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, MD, United States
| | - John Wong
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Kai Ding
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States
- *Correspondence: Kai Ding,
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12
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McKay MJ, Foster R. Pathobiology, irradiation dosimetric parameters and therapy of radiation-induced gastric damage: a narrative review. J Gastrointest Oncol 2021; 12:3115-3122. [PMID: 35070434 PMCID: PMC8748060 DOI: 10.21037/jgo-21-361] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 10/25/2021] [Indexed: 01/17/2024] Open
Abstract
OBJECTIVE To review the pathobiology, irradiation dosimetric parameters and other risk factors, and therapy of radiation-induced gastric damage (RIGD). BACKGROUND RIGD is a side-effect of upper abdominal radiotherapy. Acute toxicities are usually mild and self-limiting. Late toxicities are potentially life-threatening and include bleeding, perforation or stenosis. The data on RIGD is mainly historical and derived from neoplasms and treatments where the role of radiotherapy is contracting, such as para-aortic nodal irradiation for testis and cervical cancer and Hodgkin's Disease. On the other hand, the role of radiotherapy is expanding, especially with stereotactic body radiotherapy (SBRT) treatments evolving for both primary and secondary upper gastrointestinal neoplasms, which might be expected to increase the frequency of RIGD. Pathoclinical and radiation dosimetric data which might predict the risk of RIGD are evaluated. METHODS English language articles between 1945 and December 2020, using PubMed and Embase, searching titles for keywords including: radiation; ionizing; radiotherapy; gastritis and 65 articles were selected for review. There may have been a risk of bias in the studies evaluated, since the majority of reports were retrospective, largely descriptive and qualitative. CONCLUSIONS A common pathoclinical theme in RIGD is inflammation. Numerous factors predict for a greater likelihood of RIGD, including radiation fraction size and dose, concurrent chemotherapy and previous abdominal surgery. Therapy is pathology-dependent and comprises pharmacological, interventional and in the most severe cases, surgical approaches. It is timely to review the topic of RIGD, discuss the limitations of the data and highlight the need for future research directions.
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Affiliation(s)
- Michael J. McKay
- Northern Cancer Service, North West Cancer Centre, Burnie, Tasmania, Australia
- Rural Clinical School, The University of Tasmania, Northwest Regional Hospital, Burnie, Tasmania, Australia
- Olivia Newton John Cancer Research Institute, Heidelberg, Victoria, Australia
| | - Richard Foster
- Northern Cancer Service, North West Cancer Centre, Burnie, Tasmania, Australia
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13
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Alausa A, Victor UC, Celestine UO, Eweje IA, Balogun TA, Adeyemi R, Olatinwo M, Ogunlana AT, Oladipo O, Olaleke B. Phytochemical based sestrin2 pharmacological modulators in the treatment of adenocarcinomas. PHYTOMEDICINE PLUS 2021; 1:100133. [DOI: 10.1016/j.phyplu.2021.100133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Courtney PT, Paravati AJ, Atwood TF, Raja N, Zimmerman CT, Fanta PT, Lowy AM, Simpson DR, Xu R, Murphy JD. Phase I Trial of Stereotactic Body Radiation Therapy Dose Escalation in Pancreatic Cancer. Int J Radiat Oncol Biol Phys 2021; 110:1003-1012. [PMID: 33571625 DOI: 10.1016/j.ijrobp.2021.02.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 12/22/2020] [Accepted: 02/03/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE Stereotactic body radiation therapy (SBRT) has demonstrated encouraging local tumor control rates in the treatment of pancreatic cancer, yet we lack prospective clinical trials evaluating dose-escalation strategies among patients treated with 5-fraction SBRT. This phase 1 dose-escalation trial was conducted to determine the maximum tolerated dose of SBRT in patients with pancreatic cancer. METHODS AND MATERIALS Thirty patients with pancreatic cancer were enrolled and treated with 40, 45, or 50 Gy SBRT in 5 fractions with doses determined using a time-to-event continual reassessment method trial design. Systemic therapy was permitted before and after SBRT, but not mandated by the study protocol. Toxicity was the primary study endpoint, and any grade ≥3 acute or late toxicity potentially attributable to SBRT was considered a dose-limiting toxicity. Secondary endpoints included local progression, distant progression, and overall survival. RESULTS The median follow up from SBRT was 8.9 months (range, 1.7-62.6 months). Nineteen patients (63%) had locally advanced disease, 3 patients (10%) had metastatic disease, and 8 patients (27%) had medically unresectable disease. Three patients (10%) received 40 Gy, 16 patients (53%) received 45 Gy, and 11 patients (37%) received 50 Gy. Seven patients (23%) experienced grade ≤2 acute toxicity, and 2 patients (6.7%) experienced grade 4 to 5 late toxicity, both of which occurred in the 45 Gy group. Median survival time was 17.1 months from the time of diagnosis and 9.8 months from SBRT. The 1-year cumulative incidence of local progression was 14.2% (95% confidence interval, 4.2%-30%). CONCLUSIONS This dose-escalation trial evaluated high-dose SBRT delivered in 5 fractions, and overall demonstrated favorable local control and survival, but was associated with nontrivial rates of severe late gastrointestinal toxicity potentially attributable to radiation. Further prospective studies are needed to define the safety and efficacy of high-dose SBRT in patients with pancreatic cancer.
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Affiliation(s)
- P Travis Courtney
- University of California San Diego School of Medicine, La Jolla, California; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California
| | - Anthony J Paravati
- Kettering Cancer Care Department of Radiation Oncology, Kettering Health Network, Kettering, Ohio
| | - Todd F Atwood
- Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California
| | - Nandita Raja
- Department of Hematology and Oncology, Kaiser Permanente Southern California, San Diego, California
| | - Collin T Zimmerman
- Department of Hematology and Oncology, Kaiser Permanente Southern California, San Diego, California
| | - Paul T Fanta
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, California
| | - Andrew M Lowy
- Department of Surgery, University of California San Diego Moores Cancer Center, La Jolla, California
| | - Daniel R Simpson
- University of California San Diego School of Medicine, La Jolla, California; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California
| | - Ronghui Xu
- Department of Family Medicine and Public Health and Department of Mathematics, University of California San Diego, La Jolla, California
| | - James D Murphy
- University of California San Diego School of Medicine, La Jolla, California; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.
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15
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Nguyen L, Dobiasch S, Schneider G, Schmid RM, Azimzadeh O, Kanev K, Buschmann D, Pfaffl MW, Bartzsch S, Schmid TE, Schilling D, Combs SE. Impact of DNA repair and reactive oxygen species levels on radioresistance in pancreatic cancer. Radiother Oncol 2021; 159:265-276. [PMID: 33839203 DOI: 10.1016/j.radonc.2021.03.038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 03/29/2021] [Accepted: 03/29/2021] [Indexed: 02/08/2023]
Abstract
PURPOSE Radioresistance in pancreatic cancer patients remains a critical obstacle to overcome. Understanding the molecular mechanisms underlying radioresistance may achieve better response to radiotherapy and thereby improving the poor treatment outcome. The aim of the present study was to elucidate the mechanisms leading to radioresistance by detailed characterization of isogenic radioresistant and radiosensitive cell lines. METHODS The human pancreatic cancer cell lines, Panc-1 and MIA PaCa-2 were repeatedly exposed to radiation to generate radioresistant (RR) isogenic cell lines. The surviving cells were expanded, and their radiosensitivity was measured using colony formation assay. Tumor growth delay after irradiation was determined in a mouse pancreatic cancer xenograft model. Gene and protein expression were analyzed using RNA sequencing and Western blot, respectively. Cell cycle distribution and apoptosis (Caspase 3/7) were measured by FACS analysis. Reactive oxygen species generation and DNA damage were analyzed by detection of CM-H2DCFDA and γH2AX staining, respectively. Transwell chamber assays were used to investigate cell migration and invasion. RESULTS The acquired radioresistance of RR cell lines was demonstrated in vitro and validated in vivo. Ingenuity pathway analysis of RNA sequencing data predicted activation of cell viability in both RR cell lines. RR cancer cell lines demonstrated greater DNA repair efficiency and lower basal and radiation-induced reactive oxygen species levels. Migration and invasion were differentially affected in RR cell lines. CONCLUSIONS Our data indicate that repeated exposure to irradiation increases the expression of genes involved in cell viability and thereby leads to radioresistance. Mechanistically, increased DNA repair capacity and reduced oxidative stress might contribute to the radioresistant phenotype.
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Affiliation(s)
- Lily Nguyen
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Neuherberg, Germany; Department of Radiation Oncology, School of Medicine, Klinikum rechts der Isar, Technical University of Munich (TUM), Germany
| | - Sophie Dobiasch
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Neuherberg, Germany; Department of Radiation Oncology, School of Medicine, Klinikum rechts der Isar, Technical University of Munich (TUM), Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, Munich, Germany
| | - Günter Schneider
- Department of Medicine II, School of Medicine, Klinikum rechts der Isar, Technical University of Munich (TUM), Germany; Deutsches Krebsforschungszentrum (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Roland M Schmid
- Department of Medicine II, School of Medicine, Klinikum rechts der Isar, Technical University of Munich (TUM), Germany
| | - Omid Azimzadeh
- Institute of Radiation Biology (ISB), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Neuherberg, Germany
| | - Kristiyan Kanev
- Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany
| | - Dominik Buschmann
- Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany
| | - Michael W Pfaffl
- Division of Animal Physiology and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich (TUM), Freising, Germany
| | - Stefan Bartzsch
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Neuherberg, Germany; Department of Radiation Oncology, School of Medicine, Klinikum rechts der Isar, Technical University of Munich (TUM), Germany
| | - Thomas E Schmid
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Neuherberg, Germany; Department of Radiation Oncology, School of Medicine, Klinikum rechts der Isar, Technical University of Munich (TUM), Germany
| | - Daniela Schilling
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Neuherberg, Germany; Department of Radiation Oncology, School of Medicine, Klinikum rechts der Isar, Technical University of Munich (TUM), Germany
| | - Stephanie E Combs
- Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Neuherberg, Germany; Department of Radiation Oncology, School of Medicine, Klinikum rechts der Isar, Technical University of Munich (TUM), Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, Munich, Germany.
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16
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Montovano M, Zhang M, Oh P, Thor M, Crane C, Yorke E, Wu AJ, Jackson A. Incidence and Dosimetric Predictors of Radiation-Induced Gastric Bleeding After Chemoradiation for Esophageal and Gastroesophageal Junction Cancer. Adv Radiat Oncol 2021; 6:100648. [PMID: 34195487 PMCID: PMC8233466 DOI: 10.1016/j.adro.2021.100648] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 11/19/2020] [Accepted: 01/05/2021] [Indexed: 02/07/2023] Open
Abstract
Purpose To determine the incidence and predictors of gastric bleeding after chemoradiation for esophageal or gastroesophageal junction cancer. Methods and Materials We reviewed patients receiving chemoradiation to at least 41.4 Gy for localized esophageal cancer whose fields included the stomach and who did not undergo surgical resection. The primary endpoint was grade ≥3 gastric hemorrhage (GB3+). Comprehensive stomach dose-volume parameters were collected, and stomach dose-volume histograms were generated for analysis. Results A total of 145 patients met our inclusion criteria. Median prescribed dose was 50.4 Gy (range, 41.4-56 Gy). Median stomach Dmax was 53.0 Gy (1.0-62.7 Gy), and median stomach V40, V45, and V50 Gy were 112 cm3 (0-667 cm3), 84 cm3 (0-632 cm3), and 50 cm3 (0-565 cm3), respectively. Two patients (1.4%) developed radiation-induced GB3+. The only dosimetric factor that was significantly different for these patients was a higher stomach Dmax (58.1 and 58.3 Gy) than the cohort median (53 Gy). One of these patients also had cirrhosis, and the other had a history of nonsteroidal anti-inflammatory drug use. Five other patients had GB3+ events associated with documented tumor progression. A Cox proportional hazards model based on stomach Dmax with respect to the development of GB3+ was found to be statistically significant. Time-to-event curves and dose-volume atlases were generated, demonstrating an increased risk of GB3+ only when stomach Dmax was >58 Gy (P < .05). Conclusions We observed a low rate of GB3+ events in patients who received chemoradiation to a median dose of 50.4 Gy to volumes that included a significant portion of the stomach. These results suggest that when prescribing 50.4 Gy for esophageal cancer, there is no need to minimize the irradiated gastric volume or dose for the sake of preventing bleeding complications. Limiting stomach maximum doses to <58 Gy may also avoid bleeding, and particular caution should be taken in patients with other risk factors for bleeding, such as cirrhosis.
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Affiliation(s)
- Margaret Montovano
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.,Rutgers New Jersey Medical School, Newark, New Jersey
| | - Minsi Zhang
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Patrick Oh
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Maria Thor
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Christopher Crane
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ellen Yorke
- Rutgers New Jersey Medical School, Newark, New Jersey
| | - Abraham J Wu
- Rutgers New Jersey Medical School, Newark, New Jersey
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17
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Lee D, Komatsu S, Terashima K, Toyama H, Matsuo Y, Takahashi D, Suga M, Nishimura N, Tai K, Kido M, Demizu Y, Tokumaru S, Okimoto T, Sasaki R, Fukumoto T. Surgical spacer placement for proton radiotherapy in locally advanced pancreatic body and tail cancers: initial clinical results. Radiat Oncol 2021; 16:3. [PMID: 33407648 PMCID: PMC7788736 DOI: 10.1186/s13014-020-01731-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 12/17/2020] [Indexed: 11/16/2022] Open
Abstract
Background Particle radiotherapy has increasingly gained acceptance for locally advanced pancreatic cancers owing to superior tumor conformity and dosimetry compared to conventional photon radiotherapy. However, the close proximity of the pancreas to the stomach and duodenum leads to radiation-induced gastrointestinal toxicities, which hinder the delivery of curative doses to the tumor. To overcome this problem, a surgical spacer was placed between the tumor and gastrointestinal tract, and subsequent proton radiotherapy was performed in this study. Methods Data from 9 patients who underwent surgical spacer placement and subsequent proton radiotherapy were analyzed. The safety and feasibility of the spacer placement surgery were evaluated; the impact of the spacer on dosimetry was also assessed using dose volume histogram (DVH) analyses, before and after surgical spacer placement. Results Surgical spacer placement and subsequent proton radiotherapy were successfully completed in all cases. Surgical spacer placement significantly improved the dose intensity covering 95%, mean, and minimum doses for the gross tumor volume, and the clinical and planning target volume based on the DVH, while respecting the dose constraints of the gastrointestinal tract. Based on the Common Terminology Criteria for Adverse Events, two patients (22.2%) developed gastrointestinal ulcer (Grade 2) at 1 and 35 months, and one patient (11.1%) developed gastric perforation (Grade 4) at 4 months after proton radiotherapy. Conclusions Surgical spacer placement in the locally advanced pancreatic body and tail cancers is relatively safe and technically feasible. Comparing radiation plans, surgical spacer placement seems to improve the dose distribution in the locally advanced pancreatic body and tail cancers, which are close to the gastrointestinal tract.
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Affiliation(s)
- Dongha Lee
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Shohei Komatsu
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.
| | - Kazuki Terashima
- Department of Radiology, Hyogo Ion Beam Medical Center, 1-2-1 Kouto, Shingu-cho, Tatsuno, Hyogo, 679-5165, Japan
| | - Hirochika Toyama
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Yoshiro Matsuo
- Department of Radiology, Hyogo Ion Beam Medical Center, 1-2-1 Kouto, Shingu-cho, Tatsuno, Hyogo, 679-5165, Japan
| | - Daiki Takahashi
- Department of Radiology, Hyogo Ion Beam Medical Center, 1-2-1 Kouto, Shingu-cho, Tatsuno, Hyogo, 679-5165, Japan
| | - Masaki Suga
- Department of Radiation Physics, Hyogo Ion Beam Medical Center, 1-2-1 Kouto, Shingu-cho, Tatsuno, Hyogo, 679-5165, Japan
| | - Naoko Nishimura
- Department of Radiation Technology, Hyogo Ion Beam Medical Center, 1-2-1 Kouto, Shingu-cho, Tatsuno, Hyogo, 679-5165, Japan
| | - Kentaro Tai
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Masahiro Kido
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Yusuke Demizu
- Department of Radiology, Hyogo Ion Beam Medical Center, 1-2-1 Kouto, Shingu-cho, Tatsuno, Hyogo, 679-5165, Japan.,Department of Radiation Oncology, Hyogo Ion Beam Medical Center Kobe Proton Center, 1-6-8, Minatojimaminami-machi, chuo-ku, Kobe, Hyogo, 650-0047, Japan
| | - Sunao Tokumaru
- Department of Radiology, Hyogo Ion Beam Medical Center, 1-2-1 Kouto, Shingu-cho, Tatsuno, Hyogo, 679-5165, Japan
| | - Tomoaki Okimoto
- Department of Radiology, Hyogo Ion Beam Medical Center, 1-2-1 Kouto, Shingu-cho, Tatsuno, Hyogo, 679-5165, Japan
| | - Ryohei Sasaki
- Division of Radiation Oncology, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Takumi Fukumoto
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
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18
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Simoni N, Micera R, Paiella S, Guariglia S, Zivelonghi E, Malleo G, Rossi G, Addari L, Giuliani T, Pollini T, Cavedon C, Salvia R, Milella M, Bassi C, Mazzarotto R. Hypofractionated Stereotactic Body Radiation Therapy With Simultaneous Integrated Boost and Simultaneous Integrated Protection in Pancreatic Ductal Adenocarcinoma. Clin Oncol (R Coll Radiol) 2021; 33:e31-e38. [PMID: 32682686 DOI: 10.1016/j.clon.2020.06.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 05/12/2020] [Accepted: 06/29/2020] [Indexed: 12/13/2022]
Abstract
AIMS To evaluate the safety and feasibility of stereotactic body radiation therapy (SBRT) with simultaneous integrated boost (SIB) and simultaneous integrated protection (SIP) in borderline resectable and locally advanced pancreatic ductal adenocarcinoma. MATERIALS AND METHODS Patients receiving SBRT following induction chemotherapy from January 2017 to December 2018 were included in this observational analysis. SBRT was delivered in five consecutive daily fractions by administering 30 Gy to the planning target volume while simultaneously delivering a 50 Gy SIB to the tumour-vessel interface. SIP was created by lowering the dose to 25 Gy on the overlap area between the planning target volume and the planning organ at risk volume. The primary end point was acute and late gastrointestinal grade ≥3 toxicity. Secondary end points were freedom from local progression, overall survival and progression-free survival (PFS). RESULTS Fifty-nine consecutive patients (27 borderline resectable and 32 locally advanced) were included. Fifty-eight patients (98.3%) completed the SBRT planned treatment and 35 patients (59.4%) received surgical resection following SBRT. No acute or late grade ≥3 SBRT-related adverse events were observed. The median follow-up time was 15.1 months in the overall cohort and 18.1 months in censored patients. One- and 2-year freedom from local progression rates were 85% and 80% versus 79.7% and 60.6% in resected and unresected patients, respectively (P = 0.33). The median overall survival and PFS were 30.2 months and 19 months from diagnosis and 19.1 months and 10.7 months from SBRT in the entire cohort. Resected patients had improved 2-year overall survival rates (72.5% versus 49%, P = 0.012) and median PFS (13 months versus 5 months; P < 0.001) relative to unresected patients. There was no survival difference between borderline resectable and locally advanced patients. CONCLUSIONS SBRT with SIB/SIP had an excellent toxicity profile and could be administered safely on pancreatic ductal adenocarcinoma patients, even in a total neoadjuvant setting.
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Affiliation(s)
- N Simoni
- Radiation Oncology Unit, G.B. Rossi University Hospital, Verona, Italy.
| | - R Micera
- Radiation Oncology Unit, G.B. Rossi University Hospital, Verona, Italy
| | - S Paiella
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy.
| | - S Guariglia
- Medical Physics Unit, G.B. Rossi University Hospital, Verona, Italy
| | - E Zivelonghi
- Medical Physics Unit, G.B. Rossi University Hospital, Verona, Italy
| | - G Malleo
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - G Rossi
- Radiation Oncology Unit, G.B. Rossi University Hospital, Verona, Italy
| | - L Addari
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - T Giuliani
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - T Pollini
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - C Cavedon
- Medical Physics Unit, G.B. Rossi University Hospital, Verona, Italy
| | - R Salvia
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - M Milella
- Oncology Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - C Bassi
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - R Mazzarotto
- Radiation Oncology Unit, G.B. Rossi University Hospital, Verona, Italy
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19
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Evans JR, Cuneo KC, Lawrence TS. Drug-Radiotherapy Combination Trial Developments-Letter. Clin Cancer Res 2021; 27:355. [PMID: 33397679 DOI: 10.1158/1078-0432.ccr-20-4003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 11/05/2020] [Accepted: 11/09/2020] [Indexed: 11/16/2022]
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20
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Maximizing Tumor Control and Limiting Complications With Stereotactic Body Radiation Therapy for Pancreatic Cancer. Int J Radiat Oncol Biol Phys 2020; 110:206-216. [PMID: 33358561 DOI: 10.1016/j.ijrobp.2020.11.017] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/04/2020] [Accepted: 11/05/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Stereotactic body radiation therapy (SBRT) and stereotactic ablative body radiation therapy is being increasingly used for pancreatic cancer (PCa), particularly in patients with locally advanced and borderline resectable disease. A wide variety of dose fractionation schemes have been reported in the literature. This HyTEC review uses tumor control probability models to evaluate the comparative effectiveness of the various SBRT treatment regimens used in the treatment of patients with localized PCa. METHODS AND MATERIALS A PubMed search was performed to review the published literature on the use of hypofractionated SBRT (usually in 1-5 fractions) for PCa in various clinical scenarios (eg, preoperative [neoadjuvant], borderline resectable, and locally advanced PCa). The linear quadratic model with α/β= 10 Gy was used to address differences in fractionation. Logistic tumor control probability models were generated using maximum likelihood parameter fitting. RESULTS After converting to 3-fraction equivalent doses, the pooled reported data and associated models suggests that 1-year local control (LC) without surgery is ≈79% to 86% after the equivalent of 30 to 36 Gy in 3 fractions, showing a dose response in the range of 25 to 36 Gy, and decreasing to less than 70% 1-year LC at doses below 24 Gy in 3 fractions. The 33 Gy in 5 fraction regimen (Alliance A021501) corresponds to 28.2 Gy in 3 fractions, for which the HyTEC pooled model had 77% 1-year LC without surgery. Above an equivalent dose of 28 Gy in 3 fractions, with margin-negative resection the 1-year LC exceeded 90%. CONCLUSIONS Pooled analyses of reported tumor control probabilities for commonly used SBRT dose-fractionation schedules for PCa suggests a dose response. These findings should be viewed with caution given the challenges and limitations of this review. Additional data are needed to better understand the dose or fractionation-response of SBRT for PCa.
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21
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Lee JC, Shin DW, Park H, Kim J, Youn Y, Kim JH, Kim J, Hwang JH. Tolerability and safety of EUS-injected adenovirus-mediated double-suicide gene therapy with chemotherapy in locally advanced pancreatic cancer: a phase 1 trial. Gastrointest Endosc 2020; 92:1044-1052.e1. [PMID: 32084409 DOI: 10.1016/j.gie.2020.02.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 02/08/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Locally advanced pancreatic cancer (LAPC) is challenging. Here, we aimed to evaluate the tolerability and safety of Ad5-yCD/mutTK(SR39)rep-ADP (Ad5-DS), a replication-competent adenovirus-mediated double-suicide gene therapy in combination with gemcitabine in patients with LAPC. METHODS Patients with newly diagnosed LAPC were enrolled in this single-center, open-label, 3 + 3 dose-escalation phase 1 trial. Ad5-DS was injected into the pancreatic mass with EUS-guided fine needles combined with oral 5-fluorocytosine and valganciclovir, and a standard dose of intravenous gemcitabine. The doses of Ad5-DS in cohorts 1 to 3 were 1 × 1011, 3 × 1011, and 1 × 1012 viral particles (vp)/mL, respectively. Patients were observed for dose-limiting toxicity (DLT) for 8 weeks after Ad5-DS injection. Toxicity within 12 weeks, tumor response in 12 weeks, disease progression in 6.5 months, and detection of adenoviral DNA particles in 8 weeks were also assessed. RESULTS Among the 11 enrolled patients, 9 completed the evaluation period and 2 withdrew their consent. No DLT was reported; thus, the maximum tolerated dose was not reached. No additional toxicity was reported in 9 to 12 weeks. One patient showed a partial response and 8 showed stable disease at 12 weeks. Two patients showed disease progression at 6.5 months (median progression-free survival, 11.4 months). At 8 weeks, serum adenoviral DNA particles were detected in 4 patients (median, 55 days). CONCLUSION A combination of intratumoral Ad5-DS and gemcitabine is safe and well tolerated in patients with LAPC. This warrants further investigation in a larger clinical trial. (Clinical trial registration number: NCT02894944.).
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Affiliation(s)
- Jong-Chan Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University, Bundang Hospital, Seongnam, Korea
| | - Dong Woo Shin
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University, Bundang Hospital, Seongnam, Korea
| | - Haeseong Park
- Division of Oncology, Alvin J Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Jinkuk Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University, Bundang Hospital, Seongnam, Korea
| | - Yuna Youn
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University, Bundang Hospital, Seongnam, Korea
| | - Jae Hyeong Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University, Bundang Hospital, Seongnam, Korea
| | - Jaihwan Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University, Bundang Hospital, Seongnam, Korea
| | - Jin-Hyeok Hwang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University, Bundang Hospital, Seongnam, Korea
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22
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Raturi VP, Hojo H, Hotta K, Baba H, Takahashi R, Rachi T, Nakamura N, Zenda S, Motegi A, Tachibana H, Ariji T, Motegi K, Nakamura M, Okumura M, Hirano Y, Akimoto T. Radiobiological model-based approach to determine the potential of dose-escalated robust intensity-modulated proton radiotherapy in reducing gastrointestinal toxicity in the treatment of locally advanced unresectable pancreatic cancer of the head. Radiat Oncol 2020; 15:157. [PMID: 32571379 PMCID: PMC7310413 DOI: 10.1186/s13014-020-01592-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/03/2020] [Indexed: 12/31/2022] Open
Abstract
Background The purpose of this study was to determine the potential of escalated dose radiation (EDR) robust intensity-modulated proton radiotherapy (ro-IMPT) in reducing GI toxicity risk in locally advanced unresectable pancreatic cancer (LAUPC) of the head in term of normal tissue complication probability (NTCP) predictive model. Methods For 9 patients, intensity-modulated radiotherapy (IMRT) was compared with ro-IMPT. For all plans, the prescription dose was 59.4GyE (Gray equivalent) in 33 fractions with an equivalent organ at risk (OAR) constraints. Physical dose distribution was evaluated. GI toxicity risk for different endpoints was estimated using published NTCP Lyman Kutcher Burman (LKB) models for stomach, duodenum, small bowel, and combine stomach and duodenum (Stoduo). A Wilcoxon signed-rank test was used for dosimetry parameters and NTCP values comparison. Result The dosimetric results have shown that, with similar target coverage, ro-IMPT achieves a significant dose-volume reduction in the stomach, small bowel, and stoduo in low to high dose range in comparison to IMRT. NTCP evaluation for the endpoint gastric bleeding of stomach (10.55% vs. 13.97%, P = 0.007), duodenum (1.87% vs. 5.02%, P = 0.004), and stoduo (5.67% vs. 7.81%, P = 0.008) suggest reduced toxicity by ro-IMPT compared to IMRT. ∆NTCP IMRT – ro-IMPT (using parameter from Pan et al. for gastric bleed) of ≥5 to < 10% was seen in 3 patients (33%) for stomach and 2 patients (22%) for stoduo. An overall GI toxicity relative risk (NTCPro-IMPT/NTCPIMRT) reduction was noted (0.16–0.81) for all GI-OARs except for duodenum (> 1) with endpoint grade ≥ 3 GI toxicity (using parameters from Holyoake et al.). Conclusion With similar target coverage and better conformity, ro-IMPT has the potential to substantially reduce the risk of GI toxicity compared to IMRT in EDR of LAUPC of the head. This result needs to be further evaluated in future clinical studies.
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Affiliation(s)
- Vijay P Raturi
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan.,Course of Advanced Clinical Research of Cancer, Graduate school of Medicine, Juntendo University, Tokyo, Japan
| | - Hidehiro Hojo
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Kenji Hotta
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Hiromi Baba
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Ryo Takahashi
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Toshiya Rachi
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Naoki Nakamura
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Sadamoto Zenda
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Atsushi Motegi
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Hidenobu Tachibana
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Takaki Ariji
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Kana Motegi
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Masaki Nakamura
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Masayuki Okumura
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Yasuhiro Hirano
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Tetsuo Akimoto
- Division of Radiation Oncology and Particle therapy, National Cancer Center Hospital East, 6-5-1 chome, Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan. .,Course of Advanced Clinical Research of Cancer, Graduate school of Medicine, Juntendo University, Tokyo, Japan.
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23
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Chargari C, Levy A, Paoletti X, Soria JC, Massard C, Weichselbaum RR, Deutsch E. Methodological Development of Combination Drug and Radiotherapy in Basic and Clinical Research. Clin Cancer Res 2020; 26:4723-4736. [PMID: 32409306 DOI: 10.1158/1078-0432.ccr-19-4155] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/14/2020] [Accepted: 05/12/2020] [Indexed: 01/03/2023]
Abstract
Newer technical improvements in radiation oncology have been rapidly implemented in recent decades, allowing an improved therapeutic ratio. The development of strategies using local and systemic treatments concurrently, mainly targeted therapies, has however plateaued. Targeted molecular compounds and immunotherapy are increasingly being incorporated as the new standard of care for a wide array of cancers. A better understanding of possible prior methodology issues is therefore required and should be integrated into upcoming early clinical trials including individualized radiotherapy-drug combinations. The outcome of clinical trials is influenced by the validity of the preclinical proofs of concept, the impact on normal tissue, the robustness of biomarkers and the quality of the delivery of radiation. Herein, key methodological aspects are discussed with the aim of optimizing the design and implementation of future precision drug-radiotherapy trials.
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Affiliation(s)
- Cyrus Chargari
- Department of Radiation Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- Université Paris-Sud, Orsay, France
- INSERM U1030, Molecular Radiotherapy, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- Institut de Recherche Biomédicale des Armées, Brétigny sur Orge, France
| | - Antonin Levy
- Department of Radiation Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
- Université Paris-Sud, Orsay, France
- INSERM U1030, Molecular Radiotherapy, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Xavier Paoletti
- University of Versailles St. Quentin, France
- Institut Curie INSERM U900, Biostatistics for Personalized Medicine Team, St. Cloud, France
| | | | - Christophe Massard
- Université Paris-Sud, Orsay, France
- Drug Development Department (DITEP), Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Ralph R Weichselbaum
- Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois
| | - Eric Deutsch
- Department of Radiation Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
- Université Paris-Sud, Orsay, France
- INSERM U1030, Molecular Radiotherapy, Gustave Roussy, Université Paris-Saclay, Villejuif, France
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24
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Umezawa R, Ito Y, Wakita A, Nakamura S, Okamoto H, Takahashi K, Inaba K, Murakami N, Igaki H, Jingu K, Itami J. How Much Was the Elective Lymph Node Region Covered in Involved-Field Radiation Therapy for Locally Advanced Pancreatic Cancer? Evaluation of Overlap Between Gross Target Volume and Celiac Artery-Superior Mesenteric Artery Lymph Node Regions. Adv Radiat Oncol 2020; 5:377-387. [PMID: 32529131 PMCID: PMC7278027 DOI: 10.1016/j.adro.2019.08.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 08/24/2019] [Accepted: 08/27/2019] [Indexed: 12/26/2022] Open
Abstract
Purpose The purpose of this study was to investigate the overlaps between gross target volume (GTV) and the celiac artery (CA) and superior mesenteric artery (SMA) lymph node regions and to examine the dose incidentally irradiated to the CA and SMA lymph node regions by involved-field radiation therapy (IFRT) for locally advanced pancreatic cancer (LAPC). Methods and Materials Fifty-nine patients who had LAPC without distant metastasis were included. They received IFRT at 50.4 Gy in 28 fractions with 3-dimensional conformal radiation therapy. We calculated the percentages of overlap of GTV in the CA and SMA lymph node regions and examined what cases tend to have an overlap. We also investigated the dose metrics of CA and SMA lymph node regions by IFRT and the frequency of CA or SMA lymph node metastasis after IFRT. Results The median GTV volume was 52.2 mL. Median overlap percentages in the CA and SMA lymph node regions were 39.2% and 28.6%, respectively. There was a significant correlation between GTV volume and SMA overlap percentage (P < .001). Although the SMA overlap percentage was higher in the pancreas head (P = .028), the CA overlap percentage was higher in the pancreas body or tail (P = .002). Median mean dose, D95, and minimum dose in the CA lymph node region were 50.1 Gy, 48.7 Gy, and 45.9 Gy, respectively, and those in the SMA lymph node region 49.9 Gy, 47.3 Gy, and 39.2 Gy, respectively. CA lymph node metastases after IFRT were detected in 4 patients (6.8%). Conclusions An overlap between GTV and CA-SMA lymph node regions was detected in many patients, and the CA and SMA lymph node regions were irradiated incidentally even by IFRT. Prophylactic lymph node regions might not be necessary in radiation therapy planning of LAPC.
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Affiliation(s)
- Rei Umezawa
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan.,Department of Radiation Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshinori Ito
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan.,Department of Radiation Oncology, Showa University School of Medicine, Tokyo, Japan
| | - Akihisa Wakita
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Satoshi Nakamura
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hiroyuki Okamoto
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kana Takahashi
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Koji Inaba
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Naoya Murakami
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hiroshi Igaki
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Keiichi Jingu
- Department of Radiation Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Jun Itami
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
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De Jesus-Acosta A, Narang A, Mauro L, Herman J, Jaffee EM, Laheru DA. Carcinoma of the Pancreas. ABELOFF'S CLINICAL ONCOLOGY 2020:1342-1360.e7. [DOI: 10.1016/b978-0-323-47674-4.00078-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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26
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Cuneo KC, Morgan MA, Sahai V, Schipper MJ, Parsels LA, Parsels JD, Devasia T, Al-Hawaray M, Cho CS, Nathan H, Maybaum J, Zalupski MM, Lawrence TS. Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer. J Clin Oncol 2019; 37:2643-2650. [PMID: 31398082 DOI: 10.1200/jco.19.00730] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
PURPOSE AZD1775 (adavosertib) is an inhibitor of the Wee1 kinase. In this study, we built on our preclinical studies to evaluate the safety and efficacy of AZD1775 in combination with gemcitabine and radiation in patients with newly diagnosed locally advanced pancreatic cancer. PATIENTS AND METHODS Thirty-four patients with locally advanced pancreatic cancer were enrolled with the intention to receive four 21-day cycles of gemcitabine (1,000 mg/m2 days 1 and 8) with AZD1775 (once daily on days 1, 2, 8, and 9). Cycles 2 and 3 were administered concurrently with radiation, and cycles 5 to 8 were optional. AZD1775 was dose escalated using a time-to-event continual reassessment method on the basis of the rate of dose-limiting toxicities within the first 15 weeks of therapy. The primary objective was to determine the maximum tolerated dose of AZD1775 given in conjunction with gemcitabine and radiation. Secondary objectives were to estimate overall and progression-free survival and determine pharmacodynamic activity of AZD1775 in surrogate tissues. RESULTS The recommended phase II dose of AZD1775 was 150 mg/d. Eight patients (24%) experienced a dose-limiting toxicity, most commonly anorexia, nausea, or fatigue. The median overall survival for all patients was 21.7 months (90% CI, 16.7 to 24.8 months), and the median progression-free survival was 9.4 months (90% CI, 8.0 to 9.9 months). Hair follicle biopsy samples demonstrated evidence of Wee1 inhibition with decreased phosphorylation of cyclin-dependent kinase 1 staining by immunohistochemistry after AZD1775 administration at the recommended phase II dose. CONCLUSION AZD1775 in combination with gemcitabine and radiation therapy was well tolerated at a dose that produced target engagement in a surrogate tissue. The overall survival is substantially higher than prior results combining gemcitabine with radiation therapy and warrants additional investigation.
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27
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Pancreatic ductal adenocarcinoma: biological hallmarks, current status, and future perspectives of combined modality treatment approaches. Radiat Oncol 2019; 14:141. [PMID: 31395068 PMCID: PMC6688256 DOI: 10.1186/s13014-019-1345-6] [Citation(s) in RCA: 304] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 07/24/2019] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with poor prognosis and rising incidence. Late detection and a particularly aggressive biology are the major challenges which determine therapeutic failure. In this review, we present the current status and the recent advances in PDAC treatment together with the biological and immunological hallmarks of this cancer entity. On this basis, we discuss new concepts combining distinct treatment modalities in order to improve therapeutic efficacy and clinical outcome - with a specific focus on protocols involving radio(chemo)therapeutic approaches.
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Hallemeier CL, Olsen JR, Murphy JD, Tait D, Apisarnthanarax S, Huguet F, Jabbour SK. Gastrointestinal Cancers: Management of Rectal, Hepatocellular, Pancreatic, and Esophageal Cancers. Int J Radiat Oncol Biol Phys 2019; 104:1-9. [PMID: 30967220 DOI: 10.1016/j.ijrobp.2018.12.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 12/24/2018] [Accepted: 12/28/2018] [Indexed: 10/27/2022]
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Hiroshima Y, Fukumitsu N, Saito T, Numajiri H, Murofushi KN, Ohnishi K, Nonaka T, Ishikawa H, Okumura T, Sakurai H. Concurrent chemoradiotherapy using proton beams for unresectable locally advanced pancreatic cancer. Radiother Oncol 2019; 136:37-43. [PMID: 31015127 DOI: 10.1016/j.radonc.2019.03.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 02/25/2019] [Accepted: 03/11/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND PURPOSE We investigated clinical outcomes of proton beam concurrent chemoradiotherapy (CCRT) for unresectable, locally advanced pancreatic cancer (LAPC) patients. MATERIALS AND METHODS Records from 42 unresectable LAPC patients (21 male and 21 female, 39-83 years old) with IIB/III clinical staging of 1/41 treated by proton beam CCRT were retrospectively reviewed. Twelve patients received a conventional 50 Gray equivalents (GyE) in 25 fractions protocol and 30 others received a higher dose protocol of 54.0-67.5 GyE in 25-33 fractions. Gemcitabine or S-1 (Tegafur, Gimeracil and Oteracil) was used concurrently. Toxicity, overall survival (OS) and local control (LC) were examined. RESULTS Acute adverse events of grades 1, 2, 3 and 4 were found in 4, 15, 17 and 2 patients, respectively. All grade 3 and 4 events were hematologic. Late adverse events of grades 1 and 2 were found in 3 and 2 patients, respectively. No late adverse effects of grade 3 or higher were observed. The 1-year/2-year OS rates from the start of CCRT were 77.8/50.8% with median survival time (MST) of 25.6 months. The 1-year/2-year LC rate from CCRT start was 83.3/78.9% with a median time to local recurrence of more than 36 months. Total irradiation dose was the only significant factor in univariate analyses of OS and LC (p = 0.015 and 0.023, respectively). CONCLUSION Proton beam CCRT lengthened survival periods compared to previous photon CCRT data and higher dose irradiation prolonged LC and OS for unresectable LAPC patients. Proton beam therapy is therefore safe and effective in these cases.
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Affiliation(s)
- Yuichi Hiroshima
- Proton Medical Research Center, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Nobuyoshi Fukumitsu
- Proton Medical Research Center, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Takashi Saito
- Proton Medical Research Center, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Haruko Numajiri
- Proton Medical Research Center, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Keiko Nemoto Murofushi
- Proton Medical Research Center, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Kayoko Ohnishi
- Proton Medical Research Center, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Tetsuo Nonaka
- Proton Medical Research Center, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Hitoshi Ishikawa
- Proton Medical Research Center, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Toshiyuki Okumura
- Proton Medical Research Center, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan
| | - Hideyuki Sakurai
- Proton Medical Research Center, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan
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Kim L, Nguyen N, Singhal N, Phan V, Iankov I, Le H. Application of stereotactic body radiotherapy in advanced pancreatic cancers in Australia. J Med Radiat Sci 2019; 66:54-61. [PMID: 30411540 PMCID: PMC6399188 DOI: 10.1002/jmrs.313] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/04/2018] [Accepted: 10/11/2018] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION The majority of pancreatic cancers present locally advanced and carry a high mortality rate. Treatment is challenging, with mixed data suggesting use of chemotherapy alone or in combination with radiotherapy. The use of radiotherapy has previously been limited due to lack of ability to deliver radiation to the tumour mass without causing significant toxicity to surrounding organs. Stereotactic body radiotherapy (SBRT) allows delivery of higher biologically equivalent dose in a shorter treatment duration. We sought to investigate the safety and application of this technique in our centre. METHOD We enrolled 27 patients from 2015, identified as locally advanced unresectable with histologically confirmed, non-metastatic, pancreatic adenocarcinoma. All patients had endoscopically inserted fiducial markers and where possible concurrent chemotherapy was administered. Dose schedules ranged from 25 to 42 Gy in 5 or 3 fractions. RESULTS With an overall median follow up of 9 months (range, 3-32.7), the median survival was 11.6 months. Of those alive at 1 year, the local control rate was 67%. Six patients had Grade 3 toxicity, and other six had Grade 2 toxicity. None had Grade 4 or above toxicity. The most common symptom recorded was fatigue. CONCLUSION SBRT for locally advanced pancreatic cancer is technically complex but feasible in a high volume centre. SBRT is unique, allowing safe delivery of high radiation dose resulting in good local control and decreases treatment time making it an attractive option for patients with unresectable pancreatic cancer.
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Affiliation(s)
- Laurence Kim
- Department of Radiation OncologyRoyal Adelaide HospitalAdelaideSouth AustraliaAustralia
| | - Nam Nguyen
- Department of GastroenterologyRoyal Adelaide HospitalAdelaideSouth AustraliaAustralia
| | - Nimit Singhal
- Department of Medical OncologyRoyal Adelaide HospitalAdelaideSouth AustraliaAustralia
- School of MedicineUniversity of AdelaideAdelaideSouth AustraliaAustralia
| | - Vinh‐An Phan
- Department of GastroenterologyRoyal Adelaide HospitalAdelaideSouth AustraliaAustralia
| | - Ivan Iankov
- Department of Radiation OncologyRoyal Adelaide HospitalAdelaideSouth AustraliaAustralia
| | - Hien Le
- Department of Radiation OncologyRoyal Adelaide HospitalAdelaideSouth AustraliaAustralia
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Strauss VY, Shaw R, Virdee PS, Hurt CN, Ward E, Tranter B, Patel N, Bridgewater J, Parsons P, Radhakrishna G, O’Neill E, Sebag-Montefiore D, Hawkins M, Corrie PG, Maughan T, Mukherjee S. Study protocol: a multi-centre randomised study of induction chemotherapy followed by capecitabine ± nelfinavir with high- or standard-dose radiotherapy for locally advanced pancreatic cancer (SCALOP-2). BMC Cancer 2019; 19:121. [PMID: 30717707 PMCID: PMC6360784 DOI: 10.1186/s12885-019-5307-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 01/16/2019] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Induction chemotherapy followed by chemoradiation is a treatment option for patients with locally advanced pancreatic cancer (LAPC). However, overall survival is comparable to chemotherapy alone and local progression occurs in nearly half of all patients, suggesting chemoradiation strategies should be optimised. SCALOP-2 is a randomised phase II trial testing the role of radiotherapy dose escalation and/or the addition of the radiosensitiser nelfinavir, following induction chemotherapy of gemcitabine and nab-paclitaxel (GEMABX). A safety run-in phase (stage 1) established the nelfinavir dose to administer with chemoradiation in the randomised phase (stage 2). METHODS Patients with locally advanced, inoperable, non-metastatic pancreatic adenocarcinoma receive three cycles of induction GEMABX chemotherapy prior to radiological assessment. Those with stable/responding disease are eligible for further trial treatment. In Stage 1, participants received one further cycle of GEMABX followed by capecitabine-chemoradiation with escalating doses of nelfinavir in a rolling-six design. Stage 2 aims to register 262 and randomise 170 patients with responding/stable disease to one of five arms: capecitabine with high- (arms C + D) or standard-dose (arms A + B) radiotherapy with (arms A + C) or without (arms B + D) nelfinavir, or three more cycles of GEMABX (arm E). Participants allocated to the chemoradiation arms receive another cycle of GEMABX before chemoradiation begins. Co-primary outcomes are 12-month overall survival (radiotherapy dose-escalation question) and progression-free survival (nelfinavir question). Secondary outcomes include toxicity, quality of life, disease response rate, resection rate, treatment compliance, and CA19-9 response. SCALOP-2 incorporates a detailed radiotherapy quality assurance programme. DISCUSSION SCALOP-2 aims to optimise chemoradiation in LAPC and incorporates a modern induction regimen. TRIAL REGISTRATION Eudract No: 2013-004968-56; ClinicalTrials.gov : NCT02024009.
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Affiliation(s)
| | - Rachel Shaw
- Oncology Clinical Trials Office, University of Oxford, Oxford, UK
| | | | | | - Elizabeth Ward
- Clinical Trials and Evaluation Unit, Bristol Royal Infirmary, Bristol, UK
| | - Bethan Tranter
- Pharmacy Department, Velindre Cancer Centre, Velindre NHS University Trust, Cardiff, UK
| | - Neel Patel
- Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK
| | - John Bridgewater
- Department of Oncology, University College London Hospitals, London, UK
| | - Philip Parsons
- Cardiff NCRI RTTQA group, Department of Medical Physics, Velindre Cancer Centre, Cardiff, UK
| | - Ganesh Radhakrishna
- Oncology Department, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UK
| | - Eric O’Neill
- Department of Oncology, University of Oxford, CRUK MRC Oxford Institute for Radiation Oncology, Oxford, UK
| | | | - Maria Hawkins
- Department of Oncology, University of Oxford, CRUK MRC Oxford Institute for Radiation Oncology, Oxford, UK
| | - Pippa G. Corrie
- Cambridge Cancer Centre, Addenbrooke’s Hospital, Cambridge, UK
| | - Timothy Maughan
- Department of Oncology, University of Oxford, CRUK MRC Oxford Institute for Radiation Oncology, Oxford, UK
| | - Somnath Mukherjee
- Department of Oncology, University of Oxford, CRUK MRC Oxford Institute for Radiation Oncology, Oxford, UK
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Fitzgerald TL, Hunter L, Mosquera C, Jindal C, Biswas T, Zervos E, Efird JT. A simple matrix to predict treatment success and long-term survival among patients undergoing pancreatectomy. HPB (Oxford) 2019; 21:204-211. [PMID: 30087052 DOI: 10.1016/j.hpb.2018.07.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 05/16/2018] [Accepted: 07/09/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND A more accurate measure of long-term survival among patients who have undergone a successful resection for pancreatic adenocarcinoma may be computed by accounting for time already survived during the initial treatment window. METHODS Patients diagnosed with pancreatic adenocarcinoma, from 2004 through 2013, were identified from the American College of Surgeons National Cancer Database (NCDB). A risk-stratification matrix was constructed including age, histopathologic factors and the use of adjuvant therapy, given successful treatment and survival at 3-month following diagnosis. RESULTS A total of 25,897 patients (50% male, 53% >65 years of age) presented with stage I-III pancreatic cancer. The majority of patients had tumors >2 cm size (82%), grade I/II (65%), lymphatic invasion (LI) (66%), and negative margins (76%). A survival advantage for adjuvant therapy was observed among all patients, independent of their risk-profile. For example, a patient ≤65 years of age, with early stage cancer (size ≤2 cm, grade I/II, -ve LI, -ve margins) who received adjuvant therapy had a 62% probability of being alive beyond three years (95%CI = 59%-66%). In contrast, the survival probability decreased to 53% (95%CI = 59%-66%) without adjuvant therapy. CONCLUSIONS These results provide surgeons and patients with more accurate information regarding long-term survival, as well as the benefit of opting for adjuvant therapy after successful pancreatic surgery.
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Affiliation(s)
| | - Lucas Hunter
- Department of Surgical Oncology, Brody School of Medicine, Greenville, NC, USA
| | - Catalina Mosquera
- Department of Surgical Oncology, Brody School of Medicine, Greenville, NC, USA; Vidant Cancer Care, Greenville, NC, USA
| | - Charulata Jindal
- Centre for Clinical Epidemiology and Biostatistics (CCEB), School of Medicine and Public Health, The University of Newcastle (UoN), Newcastle, 2308, Australia
| | - Tithi Biswas
- Department of Radiation Oncology, University Hospitals, Case Western Reserve University, Cleveland, OH, USA
| | | | - Jimmy T Efird
- Centre for Clinical Epidemiology and Biostatistics (CCEB), School of Medicine and Public Health, The University of Newcastle (UoN), Newcastle, 2308, Australia.
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Tuli R, Shiao SL, Nissen N, Tighiouart M, Kim S, Osipov A, Bryant M, Ristow L, Placencio-Hickok V, Hoffman D, Rokhsar S, Scher K, Klempner SJ, Noe P, Davis MJ, Wachsman A, Lo S, Jamil L, Sandler H, Piantadosi S, Hendifar A. A phase 1 study of veliparib, a PARP-1/2 inhibitor, with gemcitabine and radiotherapy in locally advanced pancreatic cancer. EBioMedicine 2019; 40:375-381. [PMID: 30635165 PMCID: PMC6412162 DOI: 10.1016/j.ebiom.2018.12.060] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 12/29/2018] [Accepted: 12/29/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Locally advanced pancreatic cancer (LAPC) has a dismal prognosis with current treatment modalities and one-third of patients die from local progression of disease. Preclinical studies with orthotopic PC demonstrated dramatic synergy between radiotherapy (RT) and the poly(ADP-ribose) polymerase-1/2 inhibitor (PARPi), veliparib. We conducted a phase I trial of gemcitabine, radiotherapy and dose-escalated veliparib in LAPC. METHODS This was a single institution investigator-initiated open-label, single-arm phase 1 clinical trial (NCT01908478). Weekly gemcitabine with daily IMRT and veliparib dose escalated using a Bayesian adaptive design were administered in treatment naïve LA or borderline resectable PC. The primary end point was identification of the MTD. Secondary endpoints included efficacy, characterization of PAR levels using ELISA, DDR alterations with targeted next generation sequencing and transcriptome analysis, tumor mutation burden (TMB) and microsatellite instability (MSI) status. FINDINGS Thirty patients were enrolled. The MTD of veliparib was 40 mg BID with gemcitabine 400 mg/m2 and RT (36 Gy/15 fractions). Sixteen DLTs were identified in 12 patients. Grade ≥ 3 adverse events included lymphopenia (96%) and anemia (36%). Median OS for all patients was 15 months. Median OS for DDR pathway gene altered and intact cases was 19 months (95% CI: 6.2-27.2) and 14 months (95% CI: 10.0-21.8), respectively. There were no significant associations between levels of PAR, TMB, or MSI with outcomes. The DDR transcripts PARP3 and RBX1 significantly correlated with OS. INTERPRETATION This is the first report of a PARPi-chemoradiotherapy combination in PC. The regimen was safe, tolerable at the RP2D, and clinically active as an upfront treatment strategy in patients biologically unselected by upfront chemotherapy. Expression of the DDR transcripts, PARP3 and RBX1, were associated with OS suggesting validation in a follow up phase 2 study. FUND: Phase One Foundation; National Institutes of Health [1R01CA188480-01A1, P01 CA098912]. Veliparib was provided by Abbvie.
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Affiliation(s)
- Richard Tuli
- Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
| | - Stephen L Shiao
- Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Nicholas Nissen
- Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Mourad Tighiouart
- Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Sungjin Kim
- Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Arsen Osipov
- Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Miranda Bryant
- Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Lindsey Ristow
- Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Veronica Placencio-Hickok
- Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA; Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - David Hoffman
- Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Sepehr Rokhsar
- Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Kevin Scher
- Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Samuel J Klempner
- Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Paul Noe
- Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - M J Davis
- Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Ashley Wachsman
- Department of Radiology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Simon Lo
- Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Laith Jamil
- Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Howard Sandler
- Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Steven Piantadosi
- Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
| | - Andrew Hendifar
- Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
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Goldsmith C, Plowman PN, Green MM, Dale RG, Price PM. Stereotactic ablative radiotherapy (SABR) as primary, adjuvant, consolidation and re-treatment option in pancreatic cancer: scope for dose escalation and lessons for toxicity. Radiat Oncol 2018; 13:204. [PMID: 30340643 PMCID: PMC6194644 DOI: 10.1186/s13014-018-1138-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 09/24/2018] [Indexed: 02/14/2023] Open
Abstract
BACKGROUND Stereotactic ablative radiotherapy (SABR) offers an alternative treatment for pancreatic cancer, with the potential for improved tumour control and reduced toxicity compared with conventional therapies. However, optimal dose planning and delivery strategies are unelucidated and gastro-intestinal (GI) toxicity remains a key concern. METHODS Patients with inoperable non-metastatic pancreatic cancer who received CyberKnife® SABR (18-36 Gy) in three fractions as primary, adjuvant, consolidation or re-treatment options were studied. Patient individualised planning and delivery variables were collected and their impact on patient outcome examined. Linear-quadratic (LQ) radiobiology modelling methods were applied to assess SABR parameters against a conventional fractionated radiotherapy schedule. RESULTS In total 42 patients were included, 37 (88%) of whom had stage T4 disease. SABR was used > 6 months post-primary therapy to re-treat residual disease in 11 (26.2%) patients and relapsed disease in nine (21.4%) patients. SABR was an adjuvant to other primary therapy for 14 (33.3%) patients and was the sole primary therapy for eight (19.0%) patients. The mean (95% CI) planning target volume (PTV), prescription isodose, percentage cover, minimum dose to PTV and biological effective dose (BED) were 76.3(63.8-88.7) cc, 67.3(65.2-69.5)%, 96.6(95.5-97.7)%, 22.3(21.0-23.6) Gy and 50.3(47.7-53.0) Gy, respectively. Only 3/37 (8.1%) patients experienced Grade 3 acute toxicities. Two (4.8%) patients converted to resectable status and median freedom-from-local-progression (FFLP) and overall survival (OS) were 9.8 and 8.4 months, respectively. No late toxicity was experienced in 27/32 (84.4%) patients; however, four (12.5%) patients - of whom two had particularly large PTV, two had sub-optimal number of fiducials and three breached organ-at-risk (OAR) constraints-showed Grade 4 duodenal toxicities. Longer delivery time, extended treatment course and reduced percentage coverage additionally associated with late toxicity, likely reflecting parameters typically applied to riskier patients. Larger PTV size and longer treatment course associated with OS. Comparator regimen LQ modelling analysis indicated 50% of patients received minimum PTV doses less potent than a conventional radiotherapy regimen, indicating scope for dose escalation. CONCLUSION The results demonstrate the value of SABR for a range of indications in pancreatic cancer. Dose escalation to increase BED may improve FFLP and OS in inoperable, non-metastatic disease: however concomitant enhanced stringency for duodenal protection is critical, particularly for patients where SABR is more challenging.
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Affiliation(s)
| | - P Nicholas Plowman
- The London CyberKnife Centre, The Harley Street Clinic, 81 Harley Street, London, W1G 8PP, UK.,St. Bartholomew's Hospital, London, UK
| | - Melanie M Green
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Roger G Dale
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Patricia M Price
- The London CyberKnife Centre, The Harley Street Clinic, 81 Harley Street, London, W1G 8PP, UK.,Department of Surgery and Cancer, Imperial College London, London, UK
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Holyoake DLP, Warren DR, Hurt C, Aznar M, Partridge M, Mukherjee S, Hawkins MA. Stomach Dose-Volume Predicts Acute Gastrointestinal Toxicity in Chemoradiotherapy for Locally Advanced Pancreatic Cancer. Clin Oncol (R Coll Radiol) 2018; 30:418-426. [PMID: 29602584 DOI: 10.1016/j.clon.2018.02.067] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 01/05/2018] [Accepted: 02/27/2018] [Indexed: 01/06/2023]
Abstract
AIMS Gastrointestinal toxicity impedes dose escalation in chemoradiotherapy for hepatobiliary malignancies. Toxicity risk depends on clinical and radiotherapy metrics. We aimed to identify predictive factors using data from two prospective phase II clinical trials of locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS Ninety-one patients with available data from the ARCII (59.4 Gy in 33 fractions with gemcitabine, cisplatin and nelfinavir, n = 23) and SCALOP (50.4 Gy in 28 fractions with capecitabine or gemcitabine, n = 74) trials were studied. The independent variables analysed comprised age, sex, performance status, baseline symptoms, tumour size, weight loss, chemotherapy regimen and dose-volume histogram of stomach and duodenum in 5 Gy bins. The outcome measures used were Common Terminology Criteria of Adverse Events (CTCAE) grade and risk of CTCAE grade ≥2 acute upper gastrointestinal toxicity (anorexia, pain, nausea and/or vomiting). The risk of CTCAE grade ≥2 events was modelled using multivariable logistic regression and prediction of severity grade using ordinal regression. RESULTS CTCAE grade ≥2 symptoms occurred in 38 patients (42%). On univariate analysis, stomach V35-45Gy was predictive of risk (odds ratio 1.035, 95% confidence interval 1.007-1.063) and grade (1.023, 1.003-1.044) of toxicity. The area under the curve was 0.632 (0.516-0.747) with toxicity risk 33/66 (50%) above and 5/25 (20%) below the optimal discriminatory threshold (7.1 cm3). Using a threshold of 30 cm3, risk was 13/20 (65%) versus 25/71 (35%). The optimal multivariable logistic regression model incorporated patient sex, chemotherapy regimen and stomach V35-45Gy. Receiving gemcitabine rather than capecitabine (odds ratio 3.965, 95% confidence interval 1.274-12.342) and weight loss during induction chemotherapy (1.216, 1.043-1.419) were significant predictors for the SCALOP cohort, whereas age predicted toxicity risk in ARCII only (1.344, 1.015-1.780). Duodenum dose-volume did not predict toxicity risk or severity in any cohort. CONCLUSIONS In chemoradiotherapy for LAPC the volume of stomach irradiated to a moderately high dose (35-45 Gy) predicts the incidence and severity of acute toxicity. Other predictive factors can include age, sex, recent weight loss and concomitant chemotherapy agents.
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Affiliation(s)
- D L P Holyoake
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - D R Warren
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| | - C Hurt
- Centre for Trials Research, Cardiff University, Cardiff, Wales, UK
| | - M Aznar
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - M Partridge
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| | - S Mukherjee
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - M A Hawkins
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
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Clinical evaluation of intensity-modulated radiotherapy for locally advanced pancreatic cancer. Radiat Oncol 2018; 13:118. [PMID: 29940984 PMCID: PMC6019294 DOI: 10.1186/s13014-018-1063-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 06/14/2018] [Indexed: 01/05/2023] Open
Abstract
Background The purpose was to retrospectively evaluate the effect of intensity-modulated radiotherapy (IMRT) on gastrointestinal (GI) toxicities and outcomes compared to three-dimensional conformal radiotherapy (3DCRT) for locally advanced pancreatic cancer (LAPC). Methods We included 107 consecutive patients who underwent CRT for LAPC from September 2001 to March 2015; 80 patients underwent 3DCRT and 27 patients underwent IMRT. They were compared for GI toxicities, locoregional progression free survival (LRPFS), distant metastasis free survival (DMS), and overall survival (OS). Results Median radiation dose and fractions for 3DCRT and IMRT were 54 Gy/30 fr. and 48 Gy/15 fr. The regimens of CRT consisted of weekly gemcitabine 250 mg/m2 (for 3DCRT) or 1000 mg/m2 (for IMRT). Acute GI toxicity ≥grade 2 occurred in 32 patients (40%) treated with 3DCRT compared with five patients (19%) treated with IMRT. Late GI toxicity of grade 3 occurred in 10 patients (12%) treated with 3DCRT and one patient (4%) treated with IMRT. Patients who underwent IMRT had superior 1-year LRPFS (73.1% vs. 63.2%, p = 0.035) and 1-year OS (92.3% vs. 68.2%, p = 0.037) as compared with those treated with 3DCRT. Multivariate analysis showed that in IMRT patients, higher dose (≥45 Gy) was an independent factor for better LRPFS and OS. Conclusions LAPC patients treated with hypofractionated full-dose gemcitabine IMRT had improved OS and LRPFS without increased GI toxicities when compared to those of patients treated with conventionally fractionated low dose gemcitabine 3DCRT. In IMRT patients, higher dose was an independent favorable prognostic factor for better LRPFS and OS, which suggests that dose escalation with IMRT for LAPC is a promising strategy.
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Chhabra A, Schneider C, Chowdhary M, Diwanji TP, Mohindra P, Mishra MV. How Histopathologic Tumor Extent and Patterns of Recurrence Data Inform the Development of Radiation Therapy Treatment Volumes in Solid Malignancies. Semin Radiat Oncol 2018; 28:218-237. [PMID: 29933882 DOI: 10.1016/j.semradonc.2018.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The ability to deliver highly conformal radiation therapy using intensity-modulated radiation therapy and particle therapy provides for new opportunities to improve patient outcomes by reducing treatment-related morbidities following radiation therapy. By reducing the volume of normal tissue exposed to radiation therapy (RT), while also allowing for the opportunity to escalate the dose of RT delivered to the tumor, use of conformal RT delivery should also provide the possibility of expanding the therapeutic index of radiotherapy. However, the ability to safely and confidently deliver conformal RT is largely dependent on our ability to clearly define the clinical target volume for radiation therapy, which requires an in-depth knowledge of histopathologic extent of different tumor types, as well as patterns of recurrence data. In this article, we provide a comprehensive review of the histopathologic and radiographic data that provide the basis for evidence-based guidelines for clinical tumor volume delineation.
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Affiliation(s)
- Arpit Chhabra
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD
| | - Craig Schneider
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD
| | - Mudit Chowdhary
- Department of Radiation Oncology, Rush University, Chicago, IL
| | - Tejan P Diwanji
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD
| | - Pranshu Mohindra
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD
| | - Mark V Mishra
- Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD.
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Takahashi S, Anada M, Kinoshita T, Shibata T. Respiratory motion of lymph node stations in pancreatic cancer: Analyses using contrast-enhanced four-dimensional computed tomography. Radiother Oncol 2018; 128:569-574. [PMID: 29801722 DOI: 10.1016/j.radonc.2018.05.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 05/03/2018] [Accepted: 05/06/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND PURPOSE Data regarding respiratory motion of lymph node (LN) stations in pancreatic cancer is limited. Therefore, we assessed their respiratory motion using contrast-enhanced four-dimensional-computed tomography (CE-4DCT). MATERIAL AND METHODS We evaluated respiratory motion in 18 pancreatic cancer patients. We selected LN stations around major arteries which were visible on CE-4DCT images. This included the common hepatic, celiac, splenic, and superior mesenteric stations. Two radiation oncologists individually delineated the gross tumor volume (GTV) and the LN stations as observers 1 and 2. RESULTS The respiratory motion of the celiac (median, 3.9 mm each for both observers) and superior mesenteric (median, 4.5 and 5.0 mm for observers 1 and 2, respectively) stations in the craniocaudal (CC) directions was significantly smaller than that of the GTV (median, 8.9 and 7.8 mm for observers 1 and 2, respectively). The respiratory motion of the common hepatic station (median, 3.8 and 3.6 mm for observers 1 and 2, respectively) in the anterior-posterior (AP) direction was significantly larger than that of the GTV (median, 2.8 and 2.2 mm for observers 1 and 2, respectively). CONCLUSIONS We observed significant differences in respiratory motion between the GTV and the LN stations in pancreatic cancer.
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Affiliation(s)
- Shigeo Takahashi
- Department of Radiation Oncology, Kagawa University Hospital, Japan.
| | - Masahide Anada
- Department of Radiation Oncology, Kagawa University Hospital, Japan
| | | | - Toru Shibata
- Department of Radiation Oncology, Kagawa University Hospital, Japan
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Dohopolski MJ, Glaser SM, Vargo JA, Balasubramani GK, Beriwal S. Stereotactic body radiotherapy for locally-advanced unresectable pancreatic cancer-patterns of care and overall survival. J Gastrointest Oncol 2017; 8:766-777. [PMID: 29184680 PMCID: PMC5674248 DOI: 10.21037/jgo.2017.08.04] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 06/19/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Unresectable pancreatic cancer remains a challenging disease to treat. Stereotactic body radiotherapy (SBRT) allows for a higher biologically equivalent dose in an abbreviated course more convenient for patients and the integration of systemic therapy. We sought to investigate utilization trends and survival outcomes for patients treated with pancreatic SBRT versus conventionally fractionated radiotherapy (CFRT). METHODS We engaged the National Cancer Database (NCDB) from 1998-2012 and identified locally-advanced unresectable patients with histologically confirmed, non-metastatic, pancreatic adenocarcinoma who received radiotherapy. Patients who received CFRT (1.5-4.0 Gy per fraction to a dose of ≥45 Gy, n=11,879) were compared to those who received SBRT (6-15 Gy per fraction to a dose of ≥20 Gy, n=474). RESULTS Median follow-up was 11.0 months (18.4 months for survivors). SBRT utilization increased from 0.2% to 7.4% from 1998 to 2012 (P<0.05). On multivariable analysis, factors predictive for preferential utilization of SBRT over CFRT were later year of diagnosis, age ≥75 years, increased facility volume, and no chemotherapy in the initial treatment plan. Unadjusted median survival was 11.2 months for CFRT vs. 12.6 months for SBRT (P=0.002). Results were consistent in the propensity matched model. Variables predictive for improved survival on multivariable analysis were diagnosis after 2010, younger age, lower comorbidity score, tumor size <3 cm, nodal stage zero, and receipt of chemotherapy (P<0.05). CONCLUSIONS SBRT utilization has increased significantly and is associated with a small absolute improvement in overall survival (OS) compared to CFRT. The decreased treatment time, without apparent compromise in survival, makes SBRT an attractive option for patients with unresectable pancreatic cancer warranting further research.
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Affiliation(s)
- Michael J. Dohopolski
- Department of Radiation Oncology, University Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Scott M. Glaser
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - John A. Vargo
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | | | - Sushil Beriwal
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
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Modelling duodenum radiotherapy toxicity using cohort dose-volume-histogram data. Radiother Oncol 2017; 123:431-437. [PMID: 28600084 PMCID: PMC5486774 DOI: 10.1016/j.radonc.2017.04.024] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 04/20/2017] [Accepted: 04/24/2017] [Indexed: 12/25/2022]
Abstract
Background and purpose Gastro-intestinal toxicity is dose-limiting in abdominal radiotherapy and correlated with duodenum dose-volume parameters. We aimed to derive updated NTCP model parameters using published data and prospective radiotherapy quality-assured cohort data. Material and methods A systematic search identified publications providing duodenum dose-volume histogram (DVH) statistics for clinical studies of conventionally-fractionated radiotherapy. Values for the Lyman-Kutcher-Burman (LKB) NTCP model were derived through sum-squared-error minimisation and using leave-one-out cross-validation. Data were corrected for fraction size and weighted according to patient numbers, and the model refined using individual patient DVH data for two further cohorts from prospective clinical trials. Results Six studies with published DVH data were utilised, and with individual patient data included outcomes for 531 patients in total (median follow-up 16 months). Observed gastro-intestinal toxicity rates ranged from 0% to 14% (median 8%). LKB parameter values for unconstrained fit to published data were: n = 0.070, m = 0.46, TD50(1) [Gy] = 183.8, while the values for the model incorporating the individual patient data were n = 0.193, m = 0.51, TD50(1) [Gy] = 299.1. Conclusions LKB parameters derived using published data are shown to be consistent to those previously obtained using individual patient data, supporting a small volume-effect and dependence on exposure to high threshold dose.
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Singh R, Ansinelli H, Sharma S. Clinical outcomes following stereotactic body radiation therapy (SBRT) for non-resectable pancreatic adenocarcinoma. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s13566-017-0313-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Chung SY, Chang JS, Lee BM, Kim KH, Lee KJ, Seong J. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol 2017; 123:438-445. [PMID: 28464997 DOI: 10.1016/j.radonc.2017.04.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Revised: 03/30/2017] [Accepted: 04/05/2017] [Indexed: 12/28/2022]
Abstract
PURPOSE To investigate whether radiotherapy (RT) dose escalation would improve treatment outcomes without increasing severe toxicity in locally advanced pancreatic cancer patients. METHODS From 2005 to 2015, 497 locally advanced pancreatic cancer patients who received neoadjuvant or definitive chemoradiotherapy (CCRT) were included. Patients were divided according to the total dose (TD). Overall survival (OS), progression-free survival (PFS), local failure-free rate (LFFR), distant failure-free rate (DFFR), and toxicity rates were compared between <61Gy (n=345) and ≥61Gy groups (n=152). Additionally, propensity score matching was performed. RESULTS At a median follow-up of 19.3months (range, 4.8-128.5months), the 1-year OS, PFS, LFFR, and DFFR were significantly higher in the ≥61Gy group. After multivariate analysis, a TD of ≥61Gy remained a significant favorable factor for OS (p=0.019), PFS (p=0.001), LFFR (p=0.004), and DFFR (p=0.008). After propensity score matching, the ≥61Gy group still showed higher OS, PFS, and LFFR, but not DFFR (p=0.205). The acute and late toxicity rates showed no significant difference between the two groups. CONCLUSION Patients who received a higher RT dose showed not only improved PFS and LFFR, but also improved OS without an increase in severe toxicity. Dose-escalated CCRT can be a favorable treatment option in locally advanced pancreatic cancer patients.
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Affiliation(s)
- Seung Yeun Chung
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jee Suk Chang
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byung Min Lee
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kyung Hwan Kim
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kyong Joo Lee
- Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jinsil Seong
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Ohira S, Isono M, Ueda Y, Hirata T, Ashida R, Takahashi H, Miyazaki M, Takashina M, Koizumi M, Teshima T. Assessment with cone-beam computed tomography of intrafractional motion and interfractional position changes of resectable and borderline resectable pancreatic tumours with implanted fiducial marker. Br J Radiol 2017; 90:20160815. [PMID: 28256908 DOI: 10.1259/bjr.20160815] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE The volume of targets to which a high radiation dose can be delivered is limited for pancreatic radiotherapy. We assessed changes in movements of pancreatic tumours between simulation and treatment and determined compensatory margins. METHODS For 23 patients, differences in implanted fiducial marker motion magnitude (MMM) and mean marker position (MMP) between four-dimensional CT and cone-beam CT were measured. Subsequently, residual uncertainty was simulated after no action level (NAL) and extended no action level (eNAL) protocols were adopted. RESULTS With no correction, respective 95th percentile of MMM were 4.5 mm, 6.2 mm and 16.0 mm and systematic (random) errors of MMP were 2.8 mm (3.3 mm), 3.2 mm (2.0 mm) and 5.9 mm (4.0 mm) in the left-right (L-R), anteroposterior (A-P) and superoinferior (S-I) directions, so that large margins were required (L-R, 10.5 mm; A-P, 11.7 mm; and S-I, 24.8 mm). NAL reduced systematic errors of MMP, but resultant margins remained large (L-R, 8.0 mm; A-P, 9.6 mm; and S-I, 18.1 mm). eNAL compensated for time trends and obtained minimal margins (L-R, 6.7 mm; A-P, 6.7 mm; and S-I, 15.2 mm). CONCLUSION Motion magnitude and position of pancreatic tumours during simulation are frequently not representative of that during treatment. eNAL compensated for systematic interfractional position change and would be a practical approach for improving targeting accuracy. Advances in knowledge: Considerably large margins, especially in the S-I direction, were required to compensate for intrafractional motion and interfractional position changes of the pancreatic tumour. An application of eNAL was an effective strategy to diminish these margins.
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Affiliation(s)
- Shingo Ohira
- 1 Department of Radiation Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.,2 Department of Medical Physics and Engineering, Osaka University Graduate School of Medicine, Suita, Japan
| | - Masaru Isono
- 1 Department of Radiation Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Yoshihiro Ueda
- 1 Department of Radiation Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.,3 Department of Radiation Oncology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takero Hirata
- 1 Department of Radiation Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Reiko Ashida
- 4 Department of Cancer survey and gastrointestinal oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Hidenori Takahashi
- 5 Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Masayoshi Miyazaki
- 1 Department of Radiation Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Masaaki Takashina
- 2 Department of Medical Physics and Engineering, Osaka University Graduate School of Medicine, Suita, Japan
| | - Masahiko Koizumi
- 2 Department of Medical Physics and Engineering, Osaka University Graduate School of Medicine, Suita, Japan
| | - Teruki Teshima
- 1 Department of Radiation Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
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Neoadjuvant Gemcitabine Chemotherapy followed by Concurrent IMRT Simultaneous Boost Achieves High R0 Resection in Borderline Resectable Pancreatic Cancer Patients. PLoS One 2016; 11:e0166606. [PMID: 27935952 PMCID: PMC5147831 DOI: 10.1371/journal.pone.0166606] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 11/01/2016] [Indexed: 12/17/2022] Open
Abstract
Background To study the feasibility of down stage the borderline resectable pancreatic cancer (BRPC) to resectable disease, we reported our institutional results using an intensity-modulated radiation therapy (IMRT) simultaneous integrated boost (SIB) dose escalation approach to improve R0 resectability. Methods We reviewed our past 7 years of experience of using neoadjuvant induction chemotherapy with Gemcitabine followed by concurrent chemoradiaiton for BRPC. During the concurrent, chemo was 5-FU and radiation were IMRT with SIB technique to target the key areas with dose escalation to 5600 in 28 fractions. The key areas were defined by PET positive area. This was followed by restaging imaging to rule out distant metastases before resection. Results 25 finished dose escalation protocol. 2 of the 25 cases developed distant metastases, 23 (92%) patients without distant metastases underwent pancreatectomy. Among the those received pancreatectomy, 22 (95%) achieved negative margin (R0). The gastrointestinal toxicity > grade 2 was 8% and there was no grade 4 toxicity. Conclusion Neoadjuvant Gemcitabine-based induction chemotherapy followed by 5-FU-based IMRT-SIB is a feasible option in improving the likelihood of R0 resection rate in BRPC without compromising the organs at risk for toxicity.
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Akasaka H, Mizushina Y, Yoshida K, Ejima Y, Mukumoto N, Wang T, Inubushi S, Nakayama M, Wakahara Y, Sasaki R. MGDG extracted from spinach enhances the cytotoxicity of radiation in pancreatic cancer cells. Radiat Oncol 2016; 11:153. [PMID: 27876069 PMCID: PMC5120455 DOI: 10.1186/s13014-016-0729-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 11/15/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND In our previous study, monogalactosyl diacylglycerol (MGDG) purified from spinach was found to have cytotoxic effects in human cancer cell lines. This study further assessed whether MGDG can enhance the cytotoxic effects of radiation in human pancreatic cancer cells in vitro and in vivo. METHODS Glycoglycerolipids from spinach including MGDG were extracted from dried spinach. The cytotoxicity of MGDG were evaluated by the MTT assay using four human pancreatic cancer cell lines (MIAPaCa-2, AsPC-1, BxPC-3 and PANC-1) and normal human dermal fibroblasts (NHDFs). The effects of radiation and MGDG alone or in combination in MIAPaCa-2 cells was analyzed with the colony forming and apoptosis assays, western blotting and cell cycle and DNA damage analyses (γ-H2AX foci staining and comet assay). The inhibitory effects on tumor growth were assessed in a mouse xenograft tumor model. RESULTS MGDG showed dose- and time-dependent cytotoxicity, with half-maximal inhibitory concentrations (IC50) in PANC-1, BxPC-3, MIAPaCa-2 and AsPC-1 cells at 72 h of 25.6 ± 2.5, 26.9 ± 1.3, 18.5 ± 1.7, and 22.7 ± 1.9 μM, respectively. The colony forming assay revealed fewer MIAPaCa-2, BxPC-3 and AsPC-1 cell colonies upon treatment with both MGDG and radiation as compared to irradiation alone (P < 0.05). The combination of MGDG and radiation induced a higher proportion of apoptosis in MIAPaCa-2 cells; this effect was associated with increased mitochondrial release of cytochrome c and activation of cleaved poly (ADP-ribose) polymerase and caspase-3. DNA damage was detected and DNA repair mechanisms were more frequently impaired in cells receiving the combination treatment as compared to either one alone. Tumor growth was inhibited to a greater degree in mice treated by intratumoral injection of MGDG combined with irradiation as compared to either one alone (P < 0.05). CONCLUSIONS This is the first report demonstrating that MGDG enhances the cytotoxicity of radiation to induce apoptosis of cancer cells in vitro and in vivo. Our findings indicate that this therapeutic combination can be an effective strategy for the treatment of pancreatic cancer.
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Affiliation(s)
- Hiroaki Akasaka
- Division of Radiation Oncology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Yoshiyuki Mizushina
- Graduate School of Agriculture, Shinshu University, Minamiminowa-mura, Kamiina-gun, Nagano, 399-4598, Japan
| | - Kenji Yoshida
- Division of Radiation Oncology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Yasuo Ejima
- Division of Radiation Oncology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Naritoshi Mukumoto
- Division of Radiation Oncology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Tianyuan Wang
- Division of Radiation Oncology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Sachiko Inubushi
- Division of Radiation Oncology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Masao Nakayama
- Division of Radiation Oncology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Yuki Wakahara
- Division of Radiation Oncology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Ryohei Sasaki
- Division of Radiation Oncology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.
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Witztum A, George B, Warren S, Partridge M, Hawkins MA. Unwrapping 3D complex hollow organs for spatial dose surface analysis. Med Phys 2016; 43:6009. [PMID: 27806596 DOI: 10.1118/1.4964790] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 08/16/2016] [Accepted: 09/27/2016] [Indexed: 02/11/2024] Open
Abstract
PURPOSE Toxicity dose-response models describe the correlation between dose delivered to an organ and a given toxic endpoint. Duodenal toxicity is a dose limiting factor in the treatment of pancreatic cancer with radiation but the relationship between dose and toxicity in the duodenum is not well understood. While there have been limited studies into duodenal toxicity through investigations of the volume of the organ receiving dose over a specific threshold, both dose-volume and dose-surface histograms lack spatial information about the dose distribution, which may be important in determining normal tissue response. Due to the complex geometry of the duodenum, previous methods for unwrapping tubular organs for spatial modeling of toxicity are insufficient. A geometrically robust method for producing 2D dose surface maps (DSMs), specifically for the duodenum, has been developed and tested in order to characterize the spatial dose distribution. METHODS The organ contour is defined using Delaunay triangulation. The user selects a start and end coordinate in the structure and a path is found by regulating both length and curvature. This path is discretized and rays are cast from each point on the plane normal to the vector between the previous and the next point on the path and the dose at the closest perimeter point recorded. These angular perimeter slices are "unwrapped" from the edge distal to the pancreas to ensure the high dose region (proximal to the tumor) falls in the centre of the dose map. Gamma analysis is used to quantify the robustness of this method and the effect of overlapping planes. RESULTS This method was used to extract DSMs for 15 duodena, with one esophagus case to illustrate the application to simpler geometries. Visual comparison indicates that a 30 × 30 map provides sufficient resolution to view gross spatial features of interest. A lookup table is created to store the area (cm2) represented by each pixel in the DSMs in order to allow spatial descriptors in absolute size. The method described in this paper is robust, requires minimal human interaction, has been shown to be generalizable to simpler geometries, and uses readily available commercial software. The difference seen in DSMs due to overlapping planes is large and justifies the need for a solution that removes such planes. CONCLUSIONS This is the first time 2D dose surface maps have been produced for the duodenum and provide spatial dose distribution information which can be explored to create models that may improve toxicity prediction in treatments for locally advanced pancreatic cancer.
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Affiliation(s)
- A Witztum
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom
| | - B George
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom
| | - S Warren
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom
| | - M Partridge
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom
| | - M A Hawkins
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom
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Panje C, Andratschke N, Brunner TB, Niyazi M, Guckenberger M. Stereotactic body radiotherapy for renal cell cancer and pancreatic cancer : Literature review and practice recommendations of the DEGRO Working Group on Stereotactic Radiotherapy. Strahlenther Onkol 2016; 192:875-885. [PMID: 27778052 DOI: 10.1007/s00066-016-1053-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 09/19/2016] [Indexed: 01/05/2023]
Abstract
PURPOSE This report of the Working Group on Stereotactic Radiotherapy of the German Society of Radiation Oncology (DEGRO) aims to provide a literature review and practice recommendations for stereotactic body radiotherapy (SBRT) of primary renal cell cancer and primary pancreatic cancer. METHODS A literature search on SBRT for both renal cancer and pancreatic cancer was performed with focus on prospective trials and technical aspects for clinical implementation. RESULTS Data on renal and pancreatic SBRT are limited, but show promising rates of local control for both treatment sites. For pancreatic cancer, fractionated SBRT should be preferred to single-dose treatment to reduce the risk of gastrointestinal toxicity. Motion-compensation strategies and image guidance are paramount for safe SBRT delivery in both tumor entities. CONCLUSION SBRT for renal cancer and pancreatic cancer have been successfully evaluated in phase I and phase II trials. Pancreatic SBRT should be practiced carefully and only within prospective protocols due to the risk of severe gastrointestinal toxicity. SBRT for primary renal cell cancer appears a viable option for medically inoperable patients but future research needs to better define patient selection criteria and the detailed practice of SBRT.
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Affiliation(s)
- Cédric Panje
- Department of Radiation Oncology, Zurich University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland
| | - Nikolaus Andratschke
- Department of Radiation Oncology, Zurich University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland
| | - Thomas B Brunner
- Department of Radiation Oncology, Freiburg University Hospital, Freiburg, Germany
| | - Maximilian Niyazi
- Department of Radiation Oncology, University of Munich, Munich, Germany
| | - Matthias Guckenberger
- Department of Radiation Oncology, Zurich University Hospital, Rämistrasse 100, 8091, Zurich, Switzerland.
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Kishi T, Matsuo Y, Nakamura A, Nakamoto Y, Itasaka S, Mizowaki T, Togashi K, Hiraoka M. Comparative evaluation of respiratory-gated and ungated FDG-PET for target volume definition in radiotherapy treatment planning for pancreatic cancer. Radiother Oncol 2016; 120:217-21. [PMID: 27492203 DOI: 10.1016/j.radonc.2016.07.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 07/15/2016] [Accepted: 07/17/2016] [Indexed: 01/08/2023]
Abstract
OBJECTIVE The purpose of this study was to evaluate the usefulness of respiratory-gated positron emission tomography (4D-PET) in pancreatic cancer radiotherapy treatment planning (RTTP). MATERIALS AND METHODS Fourteen patients with 18F-fluorodeoxyglucose (FDG)-avid pancreatic tumours were evaluated between December 2013 and March 2015. Two sets of volumes were contoured for the pancreatic tumour of each patient. The biological target volume in three-dimensional RTTP (BTV3D) was contoured using conventional respiratory un-gated PET. The BTV3D was then expanded using population-based margins to generate a series of internal target volume 3D (ITV3D) values. The ITV 4D (ITV4D) was contoured using 4D-PET. Each of the five phases of 4D-PET was used for 4D contouring, and the ITV4D was constructed by summing the volumes defined on the five individual 4D-PET images. The relative volumes and normalized volumetric overlap were computed between ITV3D and ITV4D. RESULTS On average, the FDG-avid tumour volumes were 1.6 (range: 0.8-2.3) fold greater in the ITV4D than in the BTV3D. On average, the ITV3D values were 2.0 (range: 1.1-3.4) fold larger than the corresponding ITV4D values. CONCLUSION The ITV generated from 4D-PET can be used to improve the accuracy or reduce normal tissue irradiation compared with conventional un-gated PET-based ITV.
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Affiliation(s)
- Takahiro Kishi
- Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Japan
| | - Yukinori Matsuo
- Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Japan
| | - Akira Nakamura
- Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Japan
| | - Yuji Nakamoto
- Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Satoshi Itasaka
- Department of Radiation Oncology, Kurashiki Central Hospital, Japan
| | - Takashi Mizowaki
- Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Japan
| | - Kaori Togashi
- Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Japan
| | - Masahiro Hiraoka
- Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Japan
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Kalbasi A, Komar C, Tooker GM, Liu M, Lee JW, Gladney WL, Ben-Josef E, Beatty GL. Tumor-Derived CCL2 Mediates Resistance to Radiotherapy in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2016; 23:137-148. [PMID: 27354473 DOI: 10.1158/1078-0432.ccr-16-0870] [Citation(s) in RCA: 239] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 06/16/2016] [Accepted: 06/23/2016] [Indexed: 12/13/2022]
Abstract
PURPOSE Local tumor growth is a major cause of morbidity and mortality in nearly 30% of patients with pancreatic ductal adenocarcinoma (PDAC). Radiotherapy is commonly used for local disease control in PDAC, but its efficacy is limited. We studied the impact of selectively intervening on radiotherapy-induced inflammation as an approach to overcome resistance to radiotherapy in PDAC. EXPERIMENTAL DESIGN PDAC cell lines derived from primary pancreatic tumors arising spontaneously in KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx-1 Cre mice were implanted into syngeneic mice and tumors were focally irradiated using the Small Animal Radiation Research Platform (SARRP). We determined the impact of depleting T cells and Ly6C+ monocytes as well as inhibiting the chemokine CCL2 on radiotherapy efficacy. Tumors were analyzed by flow cytometry and IHC to detect changes in leukocyte infiltration, tumor viability, and vascularity. Assays were performed on tumor tissues to detect cytokines and gene expression. RESULTS Ablative radiotherapy alone had minimal impact on PDAC growth but led to a significant increase in CCL2 production by tumor cells and recruitment of Ly6C+CCR2+ monocytes. A neutralizing anti-CCL2 antibody selectively inhibited radiotherapy-dependent recruitment of monocytes/macrophages and delayed tumor growth but only in combination with radiotherapy (P < 0.001). This antitumor effect was associated with decreased tumor proliferation and vascularity. Genetic deletion of CCL2 in PDAC cells also improved radiotherapy efficacy. CONCLUSIONS PDAC responds to radiotherapy by producing CCL2, which recruits Ly6C+CCR2+ monocytes to support tumor proliferation and neovascularization after radiotherapy. Disrupting the CCL2-CCR2 axis in combination with radiotherapy holds promise for improving radiotherapy efficacy in PDAC. Clin Cancer Res; 23(1); 137-48. ©2016 AACR.
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Affiliation(s)
- Anusha Kalbasi
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Chad Komar
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.,Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Graham M Tooker
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.,Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mingen Liu
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.,Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jae W Lee
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.,Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Whitney L Gladney
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.,Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Edgar Ben-Josef
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Gregory L Beatty
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. .,Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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50
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Wilson JM, Fokas E, Dutton SJ, Patel N, Hawkins MA, Eccles C, Chu KY, Durrant L, Abraham AG, Partridge M, Woodward M, O'Neill E, Maughan T, McKenna WG, Mukherjee S, Brunner TB. ARCII: A phase II trial of the HIV protease inhibitor Nelfinavir in combination with chemoradiation for locally advanced inoperable pancreatic cancer. Radiother Oncol 2016; 119:306-11. [PMID: 27117177 PMCID: PMC4917892 DOI: 10.1016/j.radonc.2016.03.021] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Revised: 03/09/2016] [Accepted: 03/20/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND PURPOSE Nelfinavir can enhance intrinsic radiosensitivity, reduce hypoxia and improve vascularity. We conducted a phase II trial combining nelfinavir with chemoradiotherapy (CRT) for locally advanced inoperable pancreatic cancer (LAPC). MATERIALS AND METHODS Radiotherapy (50.4Gy/28 fractions; boost to 59.4Gy/33 fractions) was administered with weekly gemcitabine and cisplatin. Nelfinavir started 3-10days before and was continued during CRT. The primary end-point was 1-year overall survival (OS). Secondary end-points included histological downstaging, radiological response, 1-year progression free survival (PFS), overall survival (OS) and treatment toxicity. An imaging sub-study (n=6) evaluated hypoxia ((18)F-Fluoromisonidazole-PET) and perfusion (perfusion CT) during induction nelfinavir. RESULTS The study closed after recruiting 23 patients, due to non-availability of Nelfinavir in Europe. The 1-year OS was 73.4% (90% CI: 54.5-85.5%) and median OS was 17.4months (90% CI: 12.8-18.8). The 1-year PFS was 21.8% (90% CI: 8.9-38.3%) and median PFS was 5.5months (90% CI: 4.1-8.3). All patients experienced Grade 3/4 toxicity, but many were asymptomatic laboratory abnormalities. Four of 6 patients on the imaging sub-study demonstrated reduced hypoxia and increased perfusion post-nelfinavir. CONCLUSIONS CRT combined with nelfinavir showed acceptable toxicity and promising survival in pancreatic cancer.
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Affiliation(s)
- James M Wilson
- Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK
| | - Emmanouil Fokas
- Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK
| | - Susan J Dutton
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK
| | - Neel Patel
- Department of Radiology, Oxford University Hospitals NHS Foundation Trust, UK
| | - Maria A Hawkins
- Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK
| | - Cynthia Eccles
- Department of Radiotherapy, Oxford University Hospitals NHS Foundation Trust, UK
| | - Kwun-Ye Chu
- Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK; Department of Radiotherapy, Oxford University Hospitals NHS Foundation Trust, UK
| | - Lisa Durrant
- Department of Radiotherapy, Oxford University Hospitals NHS Foundation Trust, UK
| | - Aswin G Abraham
- Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK
| | - Mike Partridge
- Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK
| | - Martha Woodward
- Early Phase Research Hub, Department of Oncology, Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, UK
| | - Eric O'Neill
- Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK
| | - Tim Maughan
- Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK
| | - W Gillies McKenna
- Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK
| | - Somnath Mukherjee
- Department of Oncology, CRUK/MRC Institute for Radiation Oncology, University of Oxford, UK.
| | - Thomas B Brunner
- Department of Radiation Oncology, University of Freiburg, Germany; German Cancer Consortium (DKTK), Heidelberg, Partner Site Freiburg, Germany
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