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Advances and Remaining Challenges in the Treatment for Borderline Resectable and Locally Advanced Pancreatic Ductal Adenocarcinoma. J Clin Med 2022; 11:jcm11164866. [PMID: 36013111 PMCID: PMC9410260 DOI: 10.3390/jcm11164866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/10/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies in the United States. Improvements in imaging have permitted the categorization of patients according to radiologic involvement of surrounding vasculature, i.e., upfront resectable, borderline resectable, and locally advanced disease, and this, in turn, has influenced the sequence of chemotherapy, surgery, and radiation therapy. Though surgical resection remains the only curative treatment option, recent studies have shown improved overall survival with neoadjuvant chemotherapy, especially among patients with borderline resectable/locally advanced disease. The role of radiologic imaging after neoadjuvant therapy and the potential benefit of adjuvant therapy for borderline resectable and locally advanced disease remain areas of ongoing investigation. The advances made in the treatment of patients with borderline resectable/locally advanced disease are promising, yet disparities in access to cancer care persist. This review highlights the significant advances that have been made in the treatment of borderline resectable and locally advanced PDAC, while also calling attention to the remaining challenges.
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Cho Y, Kim JW, Kim HS, Park JS, Lee IJ. Intraoperative Radiotherapy for Resectable Pancreatic Cancer Using a Low-Energy X-Ray Source: Postoperative Complications and Early Outcomes. Yonsei Med J 2022; 63:405-412. [PMID: 35512742 PMCID: PMC9086690 DOI: 10.3349/ymj.2022.63.5.405] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/29/2021] [Accepted: 02/01/2022] [Indexed: 12/03/2022] Open
Abstract
PURPOSE We evaluated the safety, feasibility, and early treatment outcomes of intraoperative radiotherapy (IORT) using a low-energy X-ray source. MATERIALS AND METHODS Patients with resectable pancreatic cancer were enrolled in this single-institution, prospective, single-arm, phase II trial. Patients underwent surgery and IORT with 10 Gy prescribed at a 5-mm depth from the tumor bed using a 50 kV X-ray source (Intrabeam, Carl Zeiss). Six cycles of adjuvant gemcitabine-based chemotherapy were administered 8-12 weeks after surgery. RESULTS A total of 41 patients were included. Thirty-one patients (75.6%) underwent wide R0 resection, while 5 (12.2%) underwent R1 resection and 5 (12.2%) underwent narrow R0 resection (retroperitoneal margin <1 mm). Grade 3 postoperative complications were reported in only one patient (4.9%) who needed additional surgery due to ulcer perforation. At a median follow-up of 9 months, four patients showed local-only recurrence, nine had distant metastases, and two showed both local and distant recurrence. The 1-year local control rate was 76.4%. CONCLUSION Our preliminary report suggests that IORT is well-tolerated and feasible in patients with resectable pancreatic cancer. Further follow-up is needed to confirm the clinical benefits of IORT in terms of local control and overall survival. TRIAL REGISTRATION Trial Registration: Clinical trial registration No. (NCT03273374).
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Affiliation(s)
- Yeona Cho
- Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Won Kim
- Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyung Sun Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Joon Seong Park
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
| | - Ik Jae Lee
- Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
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Lee YS, Kim HS, Cho Y, Lee IJ, Kim HJ, Lee DE, Kang HW, Park JS. Intraoperative radiation therapy induces immune response activity after pancreatic surgery. BMC Cancer 2021; 21:1097. [PMID: 34641806 PMCID: PMC8507125 DOI: 10.1186/s12885-021-08807-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 09/23/2021] [Indexed: 11/10/2022] Open
Abstract
Background Pancreatic cancer has highly aggressive features, such as local recurrence that leads to significantly high morbidity and mortality and recurrence after successful tumour resection. Intraoperative radiation therapy (IORT), which delivers targeted radiation to a tumour bed, is known to reduce local recurrence by directly killing tumour cells and modifying the tumour microenvironment. Methods Among 30 patients diagnosed with pancreatic cancer, 17 patients received IORT immediately after surgical resection. We investigated changes in the immune response induced by IORT by analysing the peritoneal fluid (PF) and blood of patients with and without IORT treatment after pancreatic cancer surgery. Further, we treated three pancreatic cell lines with PF to observe proliferation and activity changes. Results Levels of cytokines involved in the PI3K/SMAD pathway were increased in the PF of IORT-treated patients. Moreover, IORT-treated PF inhibited the growth, migration, and invasiveness of pancreatic cancer cells. Changes in lymphocyte populations in the blood of IORT-treated patients indicated an increased immune response. Conclusions Based on the characterisation and quantification of immune cells in the blood and cytokine levels in the PF, we conclude that IORT induced an anti-tumour effect by activating the immune response, which may prevent pancreatic cancer recurrence. Clinical trial registration NCT03273374. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08807-3.
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Affiliation(s)
- Yun Sun Lee
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63 gil, Gangnam-gu, Seoul, 06229, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University, Seoul, South Korea
| | - Hyung Sun Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63 gil, Gangnam-gu, Seoul, 06229, South Korea
| | - Yeona Cho
- Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, South Korea
| | - Ik Jae Lee
- Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyo Jung Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63 gil, Gangnam-gu, Seoul, 06229, South Korea
| | - Da Eun Lee
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63 gil, Gangnam-gu, Seoul, 06229, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University, Seoul, South Korea
| | - Hyeon Woong Kang
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63 gil, Gangnam-gu, Seoul, 06229, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University, Seoul, South Korea
| | - Joon Seong Park
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63 gil, Gangnam-gu, Seoul, 06229, South Korea.
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4
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Sekigami Y, Michelakos T, Fernandez-Del Castillo C, Kontos F, Qadan M, Wo JY, Harrison J, Deshpande V, Catalano O, Lillemoe KD, Hong TS, Ferrone CR. Intraoperative Radiation Mitigates the Effect of Microscopically Positive Tumor Margins on Survival Among Pancreatic Adenocarcinoma Patients Treated with Neoadjuvant FOLFIRINOX and Chemoradiation. Ann Surg Oncol 2021; 28:4592-4601. [PMID: 33393047 DOI: 10.1245/s10434-020-09444-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/14/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Microscopically positive margins (R1) negatively impact survival in pancreatic ductal adenocarcinoma (PDAC). For patients with close/positive margins, intraoperative radiotherapy (IORT) can improve local control. The prognostic impact of an R1 resection in patients who receive total neoadjuvant therapy (TNT; FOLFIRINOX with chemoradiation) and IORT is unknown. METHODS Clinicopathologic data were retrospectively collected for borderline/locally advanced (BR/LA) PDAC patients who received TNT and underwent resection between 2011 and 2019. Disease-free (DFS) and overall survival (OS) measured from time of diagnosis were compared between groups. RESULTS Two hundred one patients received TNT and were resected, with a median DFS and OS of 24 months and 47 months, respectively. Eighty-eight patients (44%) received IORT; of these, 69 (78%) underwent an R0 and 19 (22%) an R1 resection. There was no significant difference in clinicopathologic factors between the IORT and no-IORT groups, except for resectability status (LA: IORT 69%, no-IORT 53%, p = 0.021) and surgeons' concern for a positive/close margin. R1 resection was associated with worse DFS and OS in the no-IORT population. However, among patients who received IORT, there was no difference in DFS (R0: 29 months, IQR 14-47 vs R1: 20 months, IQR 15-28; p = 0.114) or OS (R0: 48 months, IQR 25-not reached vs R1: 37 months, IQR 30-47; p = 0.307) between patients who underwent R0 vs R1 resection. In multivariate analysis, within the IORT group, R1 resection was not associated with DFS or OS. CONCLUSION IORT may mitigate the adverse effect of an R1 resection on DFS and OS in BR/LA PDAC patients receiving TNT.
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Affiliation(s)
- Yurie Sekigami
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Wang 460, 15 Parkman Street, Boston, MA, 02114, USA
| | - Theodoros Michelakos
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Wang 460, 15 Parkman Street, Boston, MA, 02114, USA
| | - Carlos Fernandez-Del Castillo
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Wang 460, 15 Parkman Street, Boston, MA, 02114, USA
| | - Filippos Kontos
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Wang 460, 15 Parkman Street, Boston, MA, 02114, USA
| | - Motaz Qadan
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Wang 460, 15 Parkman Street, Boston, MA, 02114, USA
| | - Jennifer Y Wo
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Jon Harrison
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Wang 460, 15 Parkman Street, Boston, MA, 02114, USA
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Onofrio Catalano
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Wang 460, 15 Parkman Street, Boston, MA, 02114, USA.,Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Keith D Lillemoe
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Wang 460, 15 Parkman Street, Boston, MA, 02114, USA
| | - Theodore S Hong
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Wang 460, 15 Parkman Street, Boston, MA, 02114, USA.
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First report on the feasibility of a permanently implantable uni-directional planar low dose rate brachytherapy sheet for patients with resectable or borderline resectable pancreatic cancer. Brachytherapy 2020; 20:207-217. [PMID: 32978081 DOI: 10.1016/j.brachy.2020.08.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 08/17/2020] [Accepted: 08/18/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Margin negative resection in pancreatic cancer remains the only curative option but is challenging, especially with the retroperitoneal margin. Intraoperative radiation therapy (IORT) can improve rates of local control but requires specially designed facilities and equipment. This retrospective review describes initial results of a novel implantable mesh of uni-directional low dose rate (LDR) Pd-103 sources (sheet) used to deliver a focal margin-directed high-dose boost in patients with concern for close or positive margins. METHODS Eleven consecutive patients from a single institution with resectable or borderline resectable pancreatic cancer with concern for positive margins were selected for sheet placement and retrospectively reviewed. Procedural outcomes, including the time to implant the device and complications, and clinical outcomes, including survival and patterns of failure, are reported. A dosimetric comparison of the LDR sheet with hypothetical stereotactic body radiotherapy (SBRT) boost is reported. RESULTS One patient had a resectable disease, and 10 patients had a borderline resectable disease and underwent neoadjuvant treatment. Sheet placement added 15 min to procedural time with no procedural or sheet-related complications. At a median follow up of 13 months, 64% (n = 7) of patients are alive and 55% (n = 6) are disease-free. Compared to a hypothetical SBRT boost, the LDR sheet delivered a negligible dose to kidneys, liver, and spinal cord with a 50% reduction in max dose to the small bowel. CONCLUSION This is the first report of the use of an implantable uni-directional LDR brachytherapy sheet in patients with resected pancreatic cancer with concern for margin clearance, with no associated toxicity and favorable clinical outcomes.
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Calvo FA, Asencio JM, Roeder F, Krempien R, Poortmans P, Hensley FW, Krengli M. ESTRO IORT Task Force/ACROP recommendations for intraoperative radiation therapy in borderline-resected pancreatic cancer. Clin Transl Radiat Oncol 2020; 23:91-99. [PMID: 32529056 PMCID: PMC7280753 DOI: 10.1016/j.ctro.2020.05.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 05/10/2020] [Indexed: 12/20/2022] Open
Abstract
Radiation dose-escalation with intraoperative electron beam radiation therapy to the posterior resection margin and/or to residual disease is feasible with limited toxicity. Preoperative therapy prolongs the interval to surgery and IOERT, allowing an improved selection of patients who are candidates for local treatment intensification. Primary systemic therapy combined with chemoradiation allows to boost with IOERT in over 70% of patients with R0 surgical tumour beds. Median survival time ranges from 19 to 35 months in electron boosted patients. Overall survival at 5 years of over 30% is reported by contemporary expert IOERT institutions. Radiation therapy (RT) is a valuable component of multimodal treatment for localized pancreatic cancer. Intraoperative radiation therapy (IORT) is a very precise RT modality to intensify the irradiation effect for cancer involving upper abdominal structures and organs, generally delivered with electrons (IOERT). Unresectable, borderline and resectable disease categories benefit from dose-escalated chemoradiation strategies in the context of active systemic therapy and potential radical surgery. Prolonged preoperative treatment may act as a filter for selecting patients with occult resistant metastatic disease. Encouraging survival rates have been documented in patients treated with preoperative chemoradiation followed by radical surgery and IOERT (>20 months median survival, >35% survival at 3 years). Intensive preoperative treatment, including induction chemotherapy followed by chemoradiation and an IOERT boost, appears to prolong long-term survival within the subset of patients who remain relapse-free for>2 years (>30 months median survival; >40% survival at 3 years). Improvement of local control through higher RT doses has an impact on the survival of patients with a lower tendency towards disease spread. IOERT is a well-accepted approach in the clinical scenario (maturity and reproducibility of results), and extremely accurate in terms of dose-deposition characteristics and normal tissue sparing. The technique can be adapted to systemic therapy and surgical progress. International guidelines (National Comprehensive Cancer Network or NCCN guidelines) currently recommend use of IOERT in cases of close surgical margins and residual disease. We hereby report the ESTRO/ACROP recommendations for performing IOERT in borderline-resectable pancreatic cancer.
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Affiliation(s)
- Felipe A Calvo
- Department of Oncology, Clínica Universidad de Navarra, Madrid, Spain.,School of Medicine, Complutense University, Madrid, Spain
| | - Jose M Asencio
- Department of General Surgery, Hospital General Universitario Gregorio Marañón, Institute for Sanitary Research Gregorio Marañón (IiSGM), Madrid, Spain, Complutense University of Madrid, Madrid, Spain
| | - Falk Roeder
- Department of Radiotherapy and Radio-Oncology, Paracelsus Medical University Hospital Salzburg, Landeskrankenhaus, Salzburg, Austria.,CCU Molecular Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Robert Krempien
- Department of Radiotherapy, Helios Hospital Berlin-Buch, Berlin, Germany
| | | | - Frank W Hensley
- Department of Radiation Oncology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Marco Krengli
- Radiotherapy Unit, Department of Translation Medicine, University of Piemonte Orientale, Novara, Italy
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7
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Joechle K, Gkika E, Grosu AL, Lang SA, Fichtner-Feigl S. Intraoperative Strahlentherapie – Indikationen und Optionen in der Viszeralchirurgie. Chirurg 2020; 91:743-754. [DOI: 10.1007/s00104-020-01179-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Zusammenfassung
Hintergrund
Die intraoperative Strahlentherapie (IORT) ermöglicht durch die chirurgische Exposition des Tumors und des Tumorbetts eine hohe Präzision, welche eine hohe Strahlendosis im Bereich des Tumors zulässt und gleichzeitig gesundes Gewebe als den dosislimitierenden Faktor vor Strahlung schützt. Aus diesem Grund bietet die IORT besonders dann einen Vorteil, wenn die lokale Tumorkontrolle das Langzeitüberleben entscheidend beeinflusst und Funktionserhalt ermöglicht.
Ziel der Arbeit
Die in dieser Übersichtsarbeit aufgearbeiteten Erkenntnisse aus der Literaturrecherche erlauben einen evidenzbasierten Umgang hinsichtlich Indikationen und Therapieoptionen der IORT für intraabdominelle Tumoren.
Ergebnisse und Schlussfolgerung
Die Effektivität der IORT kann anhand der vorhandenen Evidenzlage nicht abschließend beurteilt werden, jedoch ist die IORT als Ergänzung der multimodalen Therapie bei (Rezidiv‑)Rektumkarzinomen und Sarkomen aktiv im klinischen Alltag etabliert. Magen- und Pankreaskarzinome stellen weitere Indikationen dar; ergänzende Studien sind jedoch notwendig, um die Rolle der IORT hier klar zu definieren. Ein wesentlicher Faktor, damit für Patienten mit primärem Karzinom und insbesondere für Patienten mit lokalem Rezidiv verbesserte lokale Rezidiv- und Überlebensraten erreicht werden können, scheint die Patientenselektion zu sein.
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Jin L, Shi N, Ruan S, Hou B, Zou Y, Zou X, Jin H, Jian Z. The role of intraoperative radiation therapy in resectable pancreatic cancer: a systematic review and meta-analysis. Radiat Oncol 2020; 15:76. [PMID: 32272945 PMCID: PMC7147036 DOI: 10.1186/s13014-020-01511-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 03/10/2020] [Indexed: 01/05/2023] Open
Abstract
PURPOSE Several studies investigating the role of intraoperative radiotherapy (IORT) in the treatment of resectable pancreatic cancer (PC) have been published; however, their results remain inconsistent. By conducting a systematic review and meta-analysis, this study aimed to compare clinical outcomes in patients with resectable PC who underwent surgery with or without IORT. METHODS AND MATERIALS The MEDLINE/PubMed, EMBASE, and Cochrane Library databases were searched to identify relevant studies published up to February 28, 2019. The main outcome measures included median survival time (MST), local recurrence (LR), postoperative complications, and operation-related mortality. Pooled effect estimates were obtained by performing a random-effects meta-analysis. RESULTS A total of 1095 studies were screened for inclusion, of which 15 studies with 834 patients were included in the meta-analysis. Overall, 401 patients underwent pancreatic resection with IORT and 433 underwent surgery without IORT. The pooled analysis revealed that IORT group experienced favorable overall survival (median survival rate [MSR], 1.20; 95% confidence interval [CI], 1.06-1.37, P = 0.005), compared with patients who did not receive IORT. Additionally, the pooled data showed a significantly reduced LR rate in the IORT group compared with that in the non-IORT group (relative risk [RR], 0.70; 95% CI, 0.51-0.97, P = 0.03). The incidences of postoperative complications (RR, 0.95; 95% CI, 0.73-1.23) and operation-related mortality (RR, 1.07; 95% CI, 0.44-2.63) were similar between the IORT and non-IORT groups. CONCLUSION IORT significantly improved locoregional control and overall survival in patients with resectable PC, without increasing postoperative complications and operation-related mortality rates.
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Affiliation(s)
- Liang Jin
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080 China
| | - Ning Shi
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080 China
| | - Shiye Ruan
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080 China
| | - Baohua Hou
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080 China
| | - Yiping Zou
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080 China
| | - Xiongfeng Zou
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080 China
| | - Haosheng Jin
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080 China
| | - Zhixiang Jian
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080 China
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Harrison JM, Wo JY, Ferrone CR, Horick NK, Keane FK, Qadan M, Lillemoe KD, Hong TS, Clark JW, Blaszkowsky LS, Allen JN, Castillo CFD. Intraoperative Radiation Therapy (IORT) for Borderline Resectable and Locally Advanced Pancreatic Ductal Adenocarcinoma (BR/LA PDAC) in the Era of Modern Neoadjuvant Treatment: Short-Term and Long-Term Outcomes. Ann Surg Oncol 2019; 27:1400-1406. [DOI: 10.1245/s10434-019-08084-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Indexed: 12/14/2022]
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Kim JW, Cho Y, Kim HS, Choi WH, Park JS, Lee IJ. A phase II study of intraoperative radiotherapy using a low-energy x-ray source for resectable pancreatic cancer: a study protocol. BMC Surg 2019; 19:31. [PMID: 30845939 PMCID: PMC6404292 DOI: 10.1186/s12893-019-0492-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 02/19/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The current standard treatment for resectable pancreatic cancer is surgical resection followed by adjuvant chemotherapy. Local recurrence rates are high even after curative resection; thus, the long-term outcome of locally advanced pancreatic cancer remains poor. Intraoperative radiotherapy (IORT) uses a low-energy x-ray source to deliver a single fraction of high-dose radiation to the tumor bed during a surgical procedure, while effectively sparing the surrounding normal tissues. IORT has the potential to improve the efficacy of radiation therapy for pancreatic cancer. METHODS/DESIGN This prospective, one-armed, phase II study will investigate the role of IORT in improving local control in patients with resectable pancreatic adenocarcinoma. The patients will receive surgery and IORT of 10 Gy prescribed at a 5-mm depth of the tumor bed, followed by adjuvant gemcitabine chemotherapy according to the current standard of care. The aim is to enroll 42 patients. DISCUSSION The primary endpoint of this trial is to evaluate the feasibility of IORT and the local recurrence rate after one year. The secondary endpoints include the acute and late toxicities, and disease-free survival and overall survival rates. TRIAL REGISTRATION The trial was prospectively registered at Clinicaltrials.gov NCT03273374 on September 6, 2017.
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Affiliation(s)
- Jun Won Kim
- Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273 Republic of Korea
| | - Yeona Cho
- Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273 Republic of Korea
| | - Hyung Sun Kim
- Department of Pancreatobiliary Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273 Republic of Korea
| | - Won Hoon Choi
- Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273 Republic of Korea
| | - Joon Seong Park
- Department of Pancreatobiliary Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273 Republic of Korea
| | - Ik Jae Lee
- Department of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273 Republic of Korea
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Yegya-Raman N, Shah MM, Grandhi MS, Poplin E, August DA, Kennedy TJ, Malhotra U, Spencer KR, Carpizo DR, Jabbour SK. Adjuvant therapeutic strategies for resectable pancreatic adenocarcinoma. ACTA ACUST UNITED AC 2018; 1. [PMID: 30687847 DOI: 10.21037/apc.2018.07.05] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Of all patients diagnosed with pancreatic adenocarcinoma, only 15-20% present with resectable disease. Despite curative-intent resection, the prognosis remains poor with the majority of patients recurring, prompting the need for adjuvant therapy. Historical data support the use of adjuvant 5-fluorouracil (5-FU) or gemcitabine, but recent data suggest either gemcitabine plus capecitabine or modified FOLFIRINOX can improve overall survival when compared to gemcitabine alone. The use of adjuvant chemoradiation therapy remains controversial, primarily due to limitations in study design and mixed results of historical trials. The ongoing Radiation Therapy Oncology Group (RTOG)-0848 trial hopes to further define the role of adjuvant chemoradiation therapy. Intraoperative radiation therapy (IORT) and adjuvant immunotherapy represent additional possibilities to improve outcomes, but evidence supporting their use is limited. This article reviews adjuvant therapeutic strategies for resectable pancreatic adenocarcinoma, including chemotherapy, chemoradiation therapy, IORT and immunotherapy.
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Affiliation(s)
- Nikhil Yegya-Raman
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Mihir M Shah
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Miral S Grandhi
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Elizabeth Poplin
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - David A August
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Timothy J Kennedy
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Usha Malhotra
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Kristen R Spencer
- Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Darren R Carpizo
- Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | - Salma K Jabbour
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
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12
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Toesca DAS, Koong AJ, Poultsides GA, Visser BC, Haraldsdottir S, Koong AC, Chang DT. Management of Borderline Resectable Pancreatic Cancer. Int J Radiat Oncol Biol Phys 2018; 100:1155-1174. [PMID: 29722658 DOI: 10.1016/j.ijrobp.2017.12.287] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 11/07/2017] [Accepted: 12/27/2017] [Indexed: 12/13/2022]
Abstract
With the rapid development of imaging modalities and surgical techniques, the clinical entity representing tumors that are intermediate between resectable and unresectable pancreatic adenocarcinoma has been identified has been termed "borderline resectable" (BR). These tumors are generally amenable for resection but portend an increased risk for positive margins after surgery and commonly necessitate vascular resection and reconstruction. Although there is a lack of consensus regarding the appropriate definition of what constitutes a BR pancreatic tumor, it has been demonstrated that this intermediate category carries a particular prognosis that is in between resectable and unresectable disease. In order to downstage the tumor and increase the probability of clear surgical margins, neoadjuvant therapy is being increasingly utilized and studied. There is a lack of high-level evidence to establish the optimal treatment regimen for BR tumors. When resection with negative margins is achieved after neoadjuvant therapy, the prognosis for BR tumors approaches and even exceeds that for resectable disease. This review presents the current definitions, different treatment approaches, and the clinical outcomes of BR pancreatic cancer.
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Affiliation(s)
- Diego A S Toesca
- Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California
| | - Amanda J Koong
- Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California
| | | | - Brendan C Visser
- Department of Surgery, Stanford Cancer Institute, Stanford, California
| | | | - Albert C Koong
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Daniel T Chang
- Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California.
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Macchia G, Valentini V, Mattiucci GC, Mantini G, Alfieri S, Digesù C, Deodato F, Trodella L, Doglietto GB, Cellini N, Morganti AG. Preoperative Chemoradiation and Intra-Operative Radiotherapy for Pancreatic Carcinoma. TUMORI JOURNAL 2018; 93:53-60. [PMID: 17455872 DOI: 10.1177/030089160709300110] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Aims and background In recent years, preoperative chemoradiation has received growing interest for the treatment of locally advanced pancreatic cancer. In an attempt to improve resectability and disease control, we used preoperative radiation therapy and concomitant 5-fluorouracil in a combined modality therapy protocol. The aim of the study was to evaluate definitive results in terms of toxicity, response and clinical outcome. Material and methods Twenty-eight patients with unresectable (cT4,19 patients) or resectable (cT3, 9 patients) nonmetastatic pancreatic tumors received radiotherapy (39.6 Gy) plus 5-fluorouracil (continuous infusion, days 1-4 at 1000 mg/m2/day). After 4 weeks, patients were evaluated for surgical resection. In 9 resected patients, electron-beam intra-operative radiotherapy (10 Gy) was given before reconstruction. Thereafter, in resected patients, adjuvant chemotherapy was prescribed. Results During chemoradiation, 1 patient (3.6%) developed grade 3 acute gastrointestinal toxicity and 2 patients (7.1%) developed grade 3 hematological toxicity. Three of 19 patients with unresectable tumors had tumor downstaging (15.8%). Two patients showed partial response (response rate, 7.1%; 95% CI, 0.2-25.3) and 4 patients (14.3%) had minimal tumor response. Four patients (14.3%) showed progressive disease after chemoradiation. One postoperative death was recorded. The median survival time was 11.3 months (20.5 and 9.0 months in resected and unresected patients, respectively). Only one local failure was recorded in 8 patients resected with negative margins. Conclusions Although the response rate is still low, our preliminary results suggest that preoperative 5-fluorouracil chemoradiation is well tolerated and may result in tumor downstaging. Delivery of intra-operative radiotherapy seems to be associated with a low rate of local recurrences.
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Affiliation(s)
- Gabriella Macchia
- Unità Operativa di Radioterapia, Universitti Cattolica del S. Cuore, Campobasso.
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14
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Pilar A, Gupta M, Ghosh Laskar S, Laskar S. Intraoperative radiotherapy: review of techniques and results. Ecancermedicalscience 2017; 11:750. [PMID: 28717396 PMCID: PMC5493441 DOI: 10.3332/ecancer.2017.750] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Indexed: 12/14/2022] Open
Abstract
Intraoperative radiotherapy (IORT) is a technique that involves precise delivery of a large dose of ionising radiation to the tumour or tumour bed during surgery. Direct visualisation of the tumour bed and ability to space out the normal tissues from the tumour bed allows maximisation of the dose to the tumour while minimising the dose to normal tissues. This results in an improved therapeutic ratio with IORT. Although it was introduced in the 1960s, it has seen a resurgence of popularity with the introduction of self-shielding mobile linear accelerators and low-kV IORT devices, which by eliminating the logistical issues of transport of the patient during surgery for radiotherapy or building a shielded operating room, has enabled its wider use in the community. Electrons, low-kV X-rays and HDR brachytherapy are all different methods of IORT in current clinical use. Each method has its own unique set of advantages and disadvantages, its own set of indications where one may be better suited than the other, and each requires a specific kind of expertise. IORT has demonstrated its efficacy in a wide variety of intra-abdominal tumours, recurrent colorectal cancers, recurrent gynaecological cancers, and soft-tissue tumours. Recently, it has emerged as an attractive treatment option for selected, early-stage breast cancer, owing to the ability to complete the entire course of radiotherapy during surgery. IORT has been used in a multitude of roles across these sites, for dose escalation (retroperitoneal sarcoma), EBRT dose de-escalation (paediatric tumours), as sole radiation modality (early breast cancers) and as a re-irradiation modality (recurrent rectal and gynaecological cancers). This article aims to provide a review of the rationale, techniques, and outcomes for IORT across different sites relevant to current clinical practice.
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Affiliation(s)
- Avinash Pilar
- Department of Radiation Oncology, Tata Memorial Hospital, Dr Ernest Borges' Marg, Parel, Mumbai, MS, India 400012
| | - Meetakshi Gupta
- Department of Radiation Oncology, Tata Memorial Hospital, Dr Ernest Borges' Marg, Parel, Mumbai, MS, India 400012
| | - Sarbani Ghosh Laskar
- Department of Radiation Oncology, Tata Memorial Hospital, Dr Ernest Borges' Marg, Parel, Mumbai, MS, India 400012
| | - Siddhartha Laskar
- Department of Radiation Oncology, Tata Memorial Hospital, Dr Ernest Borges' Marg, Parel, Mumbai, MS, India 400012
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15
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Intraoperative radiation therapy (IORT) in pancreatic cancer. Radiat Oncol 2017; 12:8. [PMID: 28069018 PMCID: PMC5223572 DOI: 10.1186/s13014-016-0753-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 12/21/2016] [Indexed: 01/04/2023] Open
Abstract
Despite the important improvements made in the fields of surgery, chemotherapy and radiation therapy, pancreatic cancer remains one of the most lethal malignancies. Improved outcomes with novel chemotherapy regimes led again to increased attention on the role of localized radiotherapy, since local tumor progression causes significant morbidity and mortality in patients. Even after resection local failure rates are as high as 50-80%. The immediate proximity to critical structures (bone marrow, spinal cord, kidneys, liver, and intestine) limits the dose of radiation that can be administered to the tumor bed with conventional external beam radiation therapy (EBRT). The intraoperative radiotherapy (IORT) appears to be an ideal therapeutic strategy for this disease, having the advantage of enabling the delivery of high doses of radiation to areas that are at risk for microscopic disease, saving critical organs and reducing the possibility of inducing radiotoxicity. This technique allows a theoretical increase in the radiation therapeutic index to tumor compared to the adjacent organs at risk (OAR). The aim of this review is to update and comment on IORT in the multidisciplinary management of pancreatic cancer.
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16
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Pancreatic Cancer: 80 Years of Surgery-Percentage and Repetitions. HPB SURGERY : A WORLD JOURNAL OF HEPATIC, PANCREATIC AND BILIARY SURGERY 2016; 2016:6839687. [PMID: 27847403 PMCID: PMC5099466 DOI: 10.1155/2016/6839687] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 06/01/2016] [Indexed: 12/18/2022]
Abstract
Objective. The incidence of pancreatic cancer is estimated to be 48,960 in 2015 in the US and projected to become the second and third leading causes of cancer-related deaths by 2030. The mean costs in 2015 may be assumed to be $79,800 per patient and for each resection $164,100. Attempt is made to evaluate the results over the last 80 years, the number of survivors, and the overall survival percentage. Methods. Altogether 1230 papers have been found which deal with resections and reveal survival information. Only 621 of these report 5-year survivors. Reservation about surgery was first expressed in 1964 and five-year survival of nonresected survivors is well documented. Results. The survival percentage depends not only on the number of survivors but also on the subset from which it is calculated. Since the 1980s the papers have mainly reported the number of resections and survival as actuarial percentages, with or without the actual number of survivors being reported. The actuarial percentage is on average 2.75 higher. Detailed information on the original group (TN), number of resections, and actual number of survivors is reported in only 10.6% of the papers. Repetition occurs when the patients from a certain year are reported several times from the same institution or include survivors from many institutions or countries. Each 5-year survivor may be reported several times. Conclusion. Assuming a 10% resection rate and correcting for repetitions and the life table percentage the overall actual survival rate is hardly more than 0.3%.
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17
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Loehrer AP, Kinnier CV, Ferrone CR. Treatment of Locally Advanced Pancreatic Ductal Adenocarcinoma. Adv Surg 2016; 50:115-28. [PMID: 27520867 DOI: 10.1016/j.yasu.2016.03.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Andrew P Loehrer
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
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18
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is increasingly common and a leading cause of cancer-related mortality. Surgery remains the only possibility for cure. Upwards of 40% of patients present with locally advanced PDAC (LA-PDAC), where management strategies continue to evolve. In this review, we highlight current trends in neoadjuvant chemotherapy, surgical resection, and other multimodality approaches for patients with LA-PDAC. Despite promising early results, additional work is needed to more accurately and appropriately tailor treatment for patients with LA-PDAC.
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Affiliation(s)
- Andrew P Loehrer
- Department of Surgery, Massachusetts General Hospital, Boston, Mass., USA
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19
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Roeder F. Neoadjuvant radiotherapeutic strategies in pancreatic cancer. World J Gastrointest Oncol 2016; 8:186-197. [PMID: 26909133 PMCID: PMC4753169 DOI: 10.4251/wjgo.v8.i2.186] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 10/12/2015] [Accepted: 12/11/2015] [Indexed: 02/05/2023] Open
Abstract
This review summarizes the current status of neoadjuvant radiation approaches in the treatment of pancreatic cancer, including a description of modern radiation techniques, and an overview on the literature regarding neoadjuvant radio- or radiochemotherapeutic strategies both for resectable and irresectable pancreatic cancer. Neoadjuvant chemoradiation for locally-advanced, primarily non- or borderline resectable pancreas cancer results in secondary resectability in a substantial proportion of patients with consecutively markedly improved overall prognosis and should be considered as possible alternative in pretreatment multidisciplinary evaluations. In resectable pancreatic cancer, outstanding results in terms of response, local control and overall survival have been observed with neoadjuvant radio- or radiochemotherapy in several phase I/II trials, which justify further evaluation of this strategy. Further investigation of neoadjuvant chemoradiation strategies should be performed preferentially in randomized trials in order to improve comparability of the current results with other treatment modalities. This should include the evaluation of optimal sequencing with newer and more potent systemic induction therapy approaches. Advances in patient selection based on new molecular markers might be of crucial interest in this context. Finally modern external beam radiation techniques (intensity-modulated radiation therapy, image-guided radiation therapy and stereotactic body radiation therapy), new radiation qualities (protons, heavy ions) or combinations with alternative boosting techniques widen the therapeutic window and contribute to the reduction of toxicity.
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20
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High-dose-rate intraoperative radiation therapy: the nuts and bolts of starting a program. J Contemp Brachytherapy 2014; 6:99-105. [PMID: 24790628 PMCID: PMC4003434 DOI: 10.5114/jcb.2014.42027] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Revised: 03/01/2014] [Accepted: 03/28/2014] [Indexed: 12/05/2022] Open
Abstract
High-dose-rate intraoperative radiation therapy (HDR-IORT) has historically provided effective local control (LC) for patients with unresectable and recurrent tumors. However, IORT is limited to only a few specialized institutions and it can be difficult to initiate an HDR-IORT program. Herein, we provide a brief overview on how to initiate and implement an HDR-IORT program for a selected group of patients with gastrointestinal and pelvic solid tumors using a multidisciplinary approach. Proper administration of HDR-IORT requires institutional support and a joint effort among physics staff, oncologists, surgeons, anesthesiologists, and nurses. In order to determine the true efficacy of IORT for various malignancies, collaboration among institutions with established IORT programs is needed.
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21
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Palta M, Willett C, Czito B. The Role of Intraoperative Radiation Therapy in Patients With Pancreatic Cancer. Semin Radiat Oncol 2014; 24:126-31. [DOI: 10.1016/j.semradonc.2013.11.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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22
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Jingu K, Tanabe T, Nemoto K, Ariga H, Umezawa R, Ogawa Y, Takeda K, Koto M, Sugawara T, Kubozono M, Shimizu E, Abe K, Yamada S. Intraoperative Radiotherapy for Pancreatic Cancer: 30-Year Experience in a Single Institution in Japan. Int J Radiat Oncol Biol Phys 2012; 83:e507-11. [DOI: 10.1016/j.ijrobp.2012.01.024] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Revised: 01/05/2012] [Accepted: 01/06/2012] [Indexed: 10/28/2022]
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23
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Mornex F, Hatime M, Touch S, Elmorabit B, Pigne G, Enachescu C, Diaz O, Elkhoti Y. Radiotherapy of the pancreas: state of the art in 2012. Recent Results Cancer Res 2012; 196:89-103. [PMID: 23129368 DOI: 10.1007/978-3-642-31629-6_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Affiliation(s)
- F Mornex
- Radiation Oncology Department, Centre Hospitalier Lyon Sud, Université Claude Bernard, Lyon, France.
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24
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Ogawa K, Karasawa K, Ito Y, Ogawa Y, Jingu K, Onishi H, Aoki S, Wada H, Kokubo M, Etoh H, Kazumoto T, Takayama M, Negoro Y, Nemoto K, Nishimura Y. Intraoperative radiotherapy for resected pancreatic cancer: a multi-institutional retrospective analysis of 210 patients. Int J Radiat Oncol Biol Phys 2010; 77:734-42. [PMID: 20207498 DOI: 10.1016/j.ijrobp.2009.09.010] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2009] [Revised: 09/05/2009] [Accepted: 09/16/2009] [Indexed: 12/22/2022]
Abstract
PURPOSE To retrospectively analyze the results of intraoperative radiotherapy (IORT) with or without external beam radiotherapy (EBRT) for resected pancreatic cancer. METHODS AND MATERIALS The records of 210 patients treated with gross complete resection (R0: 147 patients; R1: 63 patients) and IORT with or without EBRT were reviewed. One hundred forty-seven patients (70.0%) were treated without EBRT and 114 patients (54.3%) were treated in conjunction with chemotherapy. The median doses of IORT and EBRT were 25 Gy (range, 20-30 Gy) and 45 Gy (range, 20-60Gy), respectively. The median follow-up of the surviving 62 patients was 26.3 months (range, 2.7-90.5 months). RESULTS At the time of this analysis, 150 of 210 patients (71.4%) had disease recurrences. Local failure was observed in 31 patients (14.8%), and the 2-year local control rate in all patients was 83.7%. The median survival time and the 2-year actuarial overall survival (OS) in all 210 patients were 19.1 months and 42.1%, respectively. Patients treated with IORT and chemotherapy had a significantly more favorable OS than those treated with IORT alone (p = 0.0011). On univariate analysis, chemotherapy use, degree of resection, carbohydrate antigen 19-9, and pathological N stage had a significant impact on OS and on multivariate analysis; these four factors were significant prognostic factors. Late gastrointestinal morbidity of NCI-CTC Grade 4 was observed in 7 patients (3.3%). CONCLUSION IORT yields an excellent local control rate for resected pancreatic cancer with few frequencies of severe late toxicity, and IORT combined with chemotherapy confers a survival benefit compared with that of IORT alone.
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Affiliation(s)
- Kazuhiko Ogawa
- Department of Radiology, University of the Ryukyus, Okinawa, Japan.
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Bergenfeldt M, Albertsson M. Current state of adjuvant therapy in resected pancreatic adenocarcinoma. Acta Oncol 2009; 45:124-35. [PMID: 16546857 DOI: 10.1080/02841860600554238] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Pancreatic carcinoma cannot generally be cured by surgery alone. This review summarizes the development of adjuvant therapy over the past two decades. Four randomized controlled trials compare long-term survival of different treatments. The small GITSG-study supports combined chemoradiation, but the EORTC-study found no significant effect. A Norwegian study of adjuvant chemotherapy found an increased median survival, but no effect beyond two years. The large ESPAC-1 study shows a benefit for 5-FU based chemotherapy, while chemoradiation had a negative effect. Thus, evidence favours adjuvant therapy, but 5-FU may not be the ultimate drug. Support for gemcitabine is given by preliminary data from a German randomized trial, and further American and European studies are upcoming. However, postoperative therapy is problematic, as 20-30% of resected patients never undergo treatment because of slow recovery or other reasons. Preoperative therapy has some theoretical advantages, and moreover, patients with rapidly progressive disease may be spared surgery. Randomized controlled trials are lacking, but published results compare well with postoperative, adjuvant therapy. The value of locally targeted therapy is difficult to assess. Reasonable results have been obtained with regional chemotherapy, whereas intraoperative radiotherapy does not seem to increase survival despite reducing reducing local recurrences.
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Affiliation(s)
- Magnus Bergenfeldt
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgical Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
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26
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Showalter TN, Rao AS, Rani Anne P, Rosato FE, Rosato EL, Andrel J, Hyslop T, Xu X, Berger AC. Does Intraoperative Radiation Therapy Improve Local Tumor Control in Patients Undergoing Pancreaticoduodenectomy for Pancreatic Adenocarcinoma? A Propensity Score Analysis. Ann Surg Oncol 2009; 16:2116-22. [DOI: 10.1245/s10434-009-0498-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Accepted: 04/12/2009] [Indexed: 11/18/2022]
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Matsumoto K, Yamao K, Okubo K, Hara K, Sawaki A, Mizuno N, Tajika M, Kawai H, Ashida R. Endoscopic ultrasound-guided ethanol injection in the pancreas in a porcine model: a preliminary study. J Gastroenterol Hepatol 2008; 23:e1-6. [PMID: 18702683 DOI: 10.1111/j.1440-1746.2007.04918.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM Despite aggressive multimodal treatments, survival rates for patients with pancreatic cancer remain disappointing. Local progression is problematic, and minimally invasive procedures allowing locoregional control are needed. In this study, we attempted endoscopic ultrasound (EUS)-guided injection of ethanol into the pancreas. METHODS Under EUS guidance, pure ethanol (2 mL) was injected into normal tissue of the pancreatic body in two anesthetized domestic pigs. Serum concentrations of amylase, aspartame aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase were measured before treatment and at 2 h, 48 h and 2 weeks after injection. Body weight and clinical signs were also observed. After the animals were euthanized, the pancreases were analyzed histologically. RESULTS EUS imaging allows real-time surveillance of the injection procedure. Mild diarrhea was noted in one animal, but no other adverse effects were observed. No marked changes in laboratory tests were noted. Histologically, parenchymal necrosis extending over a wide area was seen without severe inflammation. CONCLUSION EUS-guided ethanol injection in the pancreas seems to be technically simple. More detailed assessments of the safety and dose-effect relationship issues associated with this procedure are required.
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Affiliation(s)
- Kakuya Matsumoto
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan.
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28
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Valentini V, Morganti AG, Macchia G, Mantini G, Mattiucci GC, Brizi MG, Alfieri S, Bossola M, Pacelli F, Sofo L, Doglietto G, Cellini N. Intraoperative radiation therapy in resected pancreatic carcinoma: long-term analysis. Int J Radiat Oncol Biol Phys 2008; 70:1094-9. [PMID: 18313525 DOI: 10.1016/j.ijrobp.2007.07.2346] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2007] [Revised: 07/16/2007] [Accepted: 07/16/2007] [Indexed: 12/30/2022]
Abstract
PURPOSE The combination of external radiotherapy (RT) plus intraoperative radiotherapy (IORT) in patients with pancreatic cancer is still debated. This study presents long-term results (minimum follow-up, 102 months) for 26 patients undergoing integrated adjuvant RT (external RT+IORT). METHODS AND MATERIALS From 1990 to 1995, a total of 17 patients with pancreatic cancer underwent IORT (10 Gy) and postoperative external RT (50.4 Gy). Preoperative "flash" RT was included for the last 9 patients. The liver and pancreatic head received 5 Gy (two 2.5-Gy fractions) the day before surgery. In the subsequent period (1996-1998), 9 patients underwent preoperative concomitant chemoradiation (39.6 Gy) with 5-fluorouracil, IORT (10 Gy), and adjuvant chemotherapy. RESULTS Preoperative chemoradiation was completed in all patients, whereas postoperative therapy was completed in 13 of 17 patients. All 26 patients underwent pancreatectomy (25 R0 and one R1 resections). One patient died of postoperative complications (3.8%) not related to IORT. The 9 patients undergoing concomitant chemoradiation were candidates for adjuvant chemotherapy; however, only 4 of 9 underwent adjuvant chemotherapy. At last follow-up, 4 patients (15.4%) were alive and disease free. Disease recurrence was documented in 20 patients (76.9%). Sixteen patients (61.5%) showed distant metastasis, and 5 patients (19.2%) showed local recurrence. The incidence of local recurrence in R0 patients was 4 of 25 (16.0%). The overall 5-year survival rate was 15.4%. There was significant correlation with overall survival of tumor diameter (p=0.019). CONCLUSIONS The incidence of local recurrence in this long follow-up series (19.2%) was definitely less than that reported in other studies of adjuvant RT (approximately 50%), suggesting a positive impact on local control of integrated adjuvant RT (IORT+external RT).
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Affiliation(s)
- Vincenzo Valentini
- Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome, Italy
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Messick C, Hardacre JM, McGee MF, Siegel CT, Stellato TA, Sanabria JR, Kinsella TJ, Schulak JA. Early experience with intraoperative radiotherapy in patients with resected pancreatic adenocarcinoma. Am J Surg 2008; 195:308-11; discussion 312. [PMID: 18207129 DOI: 10.1016/j.amjsurg.2007.12.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2007] [Revised: 12/13/2007] [Accepted: 12/13/2007] [Indexed: 01/12/2023]
Abstract
BACKGROUND The use of intraoperative radiotherapy (IORT) in patients with resected pancreatic adenocarcinoma has not been clearly defined. METHODS The medical records of our first 22 patients receiving IORT for resected pancreatic adenocarcinoma (2001 to 2006) were reviewed and compared with the records of 27 consecutive patients not receiving IORT for resected pancreatic adenocarcinoma (2004 to 2006). RESULTS There were no 30-day mortalities in either group, and complication rates were similar. Local recurrence occurred in 18% in the IORT group (median 14 months) and 12% in the no-IORT group (median 7 months). Distant recurrence occurred in 47% in the IORT group (median 11 months) and 32% in the no-IORT group (median 6.5 months). Median overall, stage-specific, and location-specific survival did not differ between the groups. CONCLUSIONS Although limited in size and follow-up, our experience showed that complications, recurrence, and survival were not affected by IORT, but time to recurrence may be longer with IORT.
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Affiliation(s)
- Craig Messick
- Department of Surgery, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH 44106-5047, USA
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Abstract
Adenocarcinoma of the pancreas carries a grim prognosis. Surgery is currently the only curative option, but even the few patients undergoing complete resection of early localised disease run a high risk for relapse and death. Although numerous clinical trials have been conducted during the past 20 years to find an effective adjuvant treatment, thus far no general consensus on the most appropriate regimen has been reached. In a small randomised study performed in the 1980s by the GITSG (Gastrointestinal Tumor Study Group), encouraging results were obtained with fluorouracil (5-FU)-based split-course chemoradiotherapy, but these findings were not confirmed in a randomised study initiated some years later by the EORTC (European Organisation for Research and Treatment of Cancer). More recently, the ESPAC (European Study Group for Pancreatic Cancer)-1 trial even indicated a detrimental effect of chemoradiotherapy, while chemotherapy with 5-FU was shown to have a significant positive impact on long-term survival. However, this latter finding is in contrast to earlier studies of adjuvant chemotherapy with 5-FU combinations from Norway and Japan that did not suggest a prolonged beneficial effect of 5-FU on survival. Thus, the results for adjuvant regimens based on systemic 5-FU with or without external radiotherapy are conflicting. Clinical experience with intraoperative radiotherapy or regionally targeted chemotherapy to prevent local relapse, though encouraging, is still preliminary. More recently, gemcitabine, which is the most effective single agent in advanced pancreatic cancer, has also been evaluated in the adjuvant setting. The RTOG (Radiation Therapy Oncology Group)-9704 trial demonstrated that gemcitabine is superior to 5-FU as an addition to chemoradiotherapy, but the results did not allow conclusions about the value of radiation in the combined modality approach. The Charité Onkologie CONKO-001 is a randomised trial from Germany and Austria that compared adjuvant gemcitabine with observation alone. Gemcitabine was very well tolerated and almost doubled median disease-free survival and overall survival rate at 5 years, although the advantage in overall survival failed to reach statistical significance. In summary, the available data from randomised clinical trials of adjuvant therapy suggest that (i) chemoradiotherapy has no obvious advantage compared with chemotherapy alone; and (ii) chemotherapy with gemcitabine is effective and probably offers the best benefit-risk ratio of all currently available adjuvant treatment options.
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Affiliation(s)
- Helmut Oettle
- Department of Medical Hematology and Oncology, Charité - Berlin University School of Medicine, Campus Virchow-Klinikum, Berlin, Germany
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31
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Abstract
Ductal adenocarcinoma of the pancreas is one of the leading causes of cancer death in the UK, Europe and US, with incidence closely paralleling mortality. Until recently, enthusiasm for treating these patients was limited for a number of reasons: the majority of patients undergoing surgery would relapse early, adjuvant treatment was of unproven value and systemic therapy in advanced disease had only a small chance of a short-term benefit. More recently, however, it has become recognised that specialist surgery can improve results and there is evidence that adjuvant chemotherapy has a significant advantage in terms of 5-year survival. In particular adjuvant systemic 5-fluorouracil with folinic acid can result in 5-year survival of < or = 29% (compared with 11% for controls) and adjuvant gemcitabine can improve disease-free survival to 13.4 months from a median of 6.9 months in controls, but not overall survival. In contrast the role of adjuvant chemoradiation in addition to chemotherapy remains unproven and the survival results appear to be inferior to systemic chemotherapy alone. New agents, such as capecitabine and erlotinib, are emerging with some activity in this dismal disease signalling hope for the future.
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Affiliation(s)
- Kyaw L Aung
- Clatterbridge Centre for Oncology, Bebington, Wirral, Merseyside, CH63 4JY, UK.
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32
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Ducreux M, Boige V, Goéré D, Deutsch E, Ezra P, Elias D, Malka D. The multidisciplinary management of gastrointestinal cancer. Pancreatic cancer: from pathogenesis to cure. Best Pract Res Clin Gastroenterol 2007; 21:997-1014. [PMID: 18070700 DOI: 10.1016/j.bpg.2007.10.025] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Pancreatic cancer is the fourth leading cause of cancer-related death in the USA. The disease has a high mortality rate and the 5-year survival rate is estimated to be 4%. Currently, surgical resection is only possible in 20% of patients; even then, the overall 5-year survival rate is only 25%. As such, surgical therapy alone is not sufficient for pancreatic carcinoma, and prospective investigation of additional modalities is crucial. Numerous negative trials have shown that chemotherapy alone is the standard of care after resection of pancreatic carcinoma. However, results remain poor and progress with new drugs is needed in this setting. For locally advanced disease, the situation is more complicated; the ideal chemoradiation schedule has not been clearly defined, and improvements could come in the near future from the use of new radiotherapy tools and targeted therapies. For advanced disease, chemotherapy alone has given very disappointing results. A multidisciplinary approach combining biological assessment of targets with clinical trials to evaluate new targeted drugs should be considered.
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Affiliation(s)
- Michel Ducreux
- Unité de Gastroentérologie, Département de Médecine, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif cedex, France.
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33
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Di Giorgio A, Alfieri S, Rotondi F, Prete F, Di Miceli D, Ridolfini MP, Rosa F, Covino M, Doglietto GB. Pancreatoduodenectomy for tumors of Vater's ampulla: report on 94 consecutive patients. World J Surg 2005; 29:513-8. [PMID: 15776300 DOI: 10.1007/s00268-004-7498-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Evaluation of prognostic factors of adenocarcinoma of Vater's ampulla is still a matter of debate. The aim of this study was to evaluate retrospectively factors that influence early and long-term outcomes in a 20-year single-institution experience on ampullary carcinoma. A total of 94 consecutive patients with ampullary carcinoma or adenoma with severe dysplasia were managed from 1981 to 2002. Among them, 64 underwent pancreatoduodenectomy, and the remaining 30 submitted to surgical (n = 5) or endoscopic (n = 25) palliative treatment. Demographic, clinical, and pathologic data were collected, and a comparison was made between patients who did or did not undergo resection. Standard statistical analyses were carried out in an attempt to establish a correlation between clinical variables, intraoperative and pathologic factors, and survival in patients with resection. A total of 85 (90.4%) patients had potentially resectable lesions due to the extent of the tumor, but only 64 (68%) underwent curative resection. The surgical morbidity rate was 34.3%. Postoperative mortality was 9.3%, with no deaths among the 38 more recently treated patients. Median survivals were 9 and 54 months for nonresected and resected patients, respectively. The overall 5-year survival was 64.4% for patients undergoing pancreatoduodenectomy. Survival was found to be significantly affected by resection, tumor size, tumor grade, and tumor infiltration. Patients with negative lymph nodes show a trend toward longer survival. In a multivariate analysis, only the depth of tumor infiltration influenced patient survival. Pancreatoduodenectomy is the treatment of choice for ampullary carcinoma and adenomas with high-grade dysplasia, with a good chance of long-term survival. Surgical resection remains the most important factor influencing outcome.
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Affiliation(s)
- Andrea Di Giorgio
- Department of Surgical Sciences, Digestive Surgery Unit, Catholic University-School of Medicine, Largo F. Vito 8, Rome 00168, Italy
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34
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Abstract
Improving survival in patients with pancreatic cancer remains a formidable challenge. For the few patients with localised stages of the disease, intra-operative radiotherapy, adjuvant chemoradiotherapy and neo-adjuvant therapies remain non-validated and the survival benefit conferred by 5-fluorouracil-folinic acid adjuvant chemotherapy over radical surgery alone is still a matter of debate. Gemcitabine has recently emerged as the standard single agent in advanced stages of the disease and pharmacokinetic refinements such as the use of a fixed-dose infusion rate may further improve still rather modest result figures. At present, most efforts deal with the development of more effective doublet or triplet therapies, combining gemcitabine with either conventional cytotoxic drugs--the most promising being oxaliplatin--or more innovative, targeted therapeutic agents. Among these agents, matrix metalloprotease inhibitors and farnesyltransferase inhibitors have already undergone Phase III trials, alone or in combination with gemcitabine, with rather disappointing results. However, preclinical and Phase I and II studies of cyclooxygenase-2 or lipoxygenase inhibitors, various immunotherapeutic approaches and several tyrosine kinase inhibitors or monoclonal antibodies against growth factors or their receptors are encouraging and may provide some hope for patients with pancreatic cancer.
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Affiliation(s)
- Michel Ducreux
- Unité de Gastroentérologie, Institut Gustave Roussy, Villejuif, France.
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35
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Reni M, Passoni P, Bonetto E, Balzano G, Panucci MG, Zerbi A, Ronzoni M, Staudacher C, Villa E, Di Carlo V. Final results of a prospective trial of a PEFG (Cisplatin, Epirubicin, 5-Fluorouracil, Gemcitabine) regimen followed by radiotherapy after curative surgery for pancreatic adenocarcinoma. Oncology 2005; 68:239-45. [PMID: 16015040 DOI: 10.1159/000086780] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2004] [Accepted: 08/02/2004] [Indexed: 01/24/2023]
Abstract
BACKGROUND Postoperative management of patients with pancreatic adenocarcinoma (PA) is controversial. METHODS The aim of this pilot study was to assess the feasibility of postoperative combination chemotherapy followed by radiotherapy in patients aged 18-70 years with a histological diagnosis of PA, and Karnofsky performance status (KPS) > or =70. Cisplatin and epirubicin 40 mg/m2 on day 1, gemcitabine 600 mg/m2 on day 1 and 8, and 5-fluorouracil 200 mg/m2/day as protracted infusion (PEFG regimen) were delivered every 28 days for 4 cycles. Assuming a minimum one-year disease-free survival (DFS) of interest of 65% and a maximum of low interest of 45% (alpha 0.05; beta 0.10), the target enrollment was 51 patients, and the strategy would be considered to deserve further analysis if more than 29 patients were DF at one-year from surgery. RESULTS Fifty-one patients, KPS >80: 29, median tumor size 3.5 cm, stage II/III/IVA: 2/34/13, grade 3-4: 22, positive resection margins: 26, node positive: 46, received 179 cycles of chemotherapy. Main grade 3/4 toxicity consisted of neutropenia (51%), thrombocytopenia (18%), and anemia (4%). One-year DFS was 67 +/- 7%. Two-year overall survival was 53 +/- 7%. CONCLUSION Postoperative management of PA with this multimodality strategy was well tolerated and yielded a promising outcome.
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Affiliation(s)
- Michele Reni
- Department of Radiochemotherapy, S. Raffaele H. Scientific Institute, Milan, Italy.
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36
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Hishinuma S, Ogata Y, Tomikawa M, Ozawa I, Inoue K, Katano S, Tsukiyama I. Prophylactic hepatic irradiation following curative resection of pancreatic cancer. ACTA ACUST UNITED AC 2005; 12:235-42. [PMID: 15995813 DOI: 10.1007/s00534-004-0958-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2004] [Accepted: 11/15/2004] [Indexed: 01/12/2023]
Abstract
BACKGROUND/PURPOSE It is unlikely that adjuvant chemoradiotherapy applied to the pancreatic bed alone significantly improves the survival of patients with resectable pancreatic cancer. The aim of the present study was to determine whether prophylactic hepatic irradiation (PHI) improved patient outcome after the curative resection of pancreatic cancer. METHODS The study population was comprised of 34 patients (PHI group) who were administered PHI after curative resection of pancreatic cancer between September 1994 and December 2003. The whole liver was irradiated with a total dose of 19.8-22.0 Gy under continuous infusion of 5-fluorouracil. The cumulative rate of liver metastasis and the survival outcomes of the PHI group were compared with those of 31 patients without PHI (non-PHI group) who underwent curative resection of pancreatic cancer. RESULTS The planned PHI was completed for 32 of the 34 patients. Two patients developed complications that might have been PHI-related. One developed liver abscesses which were successfully managed by percutaneous drainage. The other died of liver failure without recurrence 11 months after the operation. The cumulative incidence of liver metastasis was significantly lower for the PHI group than the non-PHI group (P=0.0455). Patients in the PHI group also survived significantly longer compared to those in the non-PHI group (P=0.0002). CONCLUSIONS The present findings suggest that PHI is well tolerated and is a potentially effective treatment strategy after curative resection of pancreatic cancer, thereby providing the basis for a randomized controlled trial.
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Affiliation(s)
- Shoichi Hishinuma
- Department of Surgery, Tochigi Cancer Center, 4-9-13 Yohnan, Utsunomiya, Tochigi, 320-0834, Japan
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37
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O'Connor JK, Sause WT, Hazard LJ, Belnap LP, Noyes RD. Survival after attempted surgical resection and intraoperative radiation therapy for pancreatic and periampullary adenocarcinoma. Int J Radiat Oncol Biol Phys 2005; 63:1060-6. [PMID: 15978737 DOI: 10.1016/j.ijrobp.2005.03.036] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2005] [Revised: 03/21/2005] [Accepted: 03/21/2005] [Indexed: 01/15/2023]
Abstract
PURPOSE To evaluate a single institution's experience with intraoperative radiation therapy (IORT) in combination with attempted surgical resection for pancreatic and periampullary adenocarcinoma. METHODS AND MATERIALS From May 1986 until June 2001, 77 patients at LDS Hospital underwent attempted surgical resection and IORT for pancreatic or periampullary adenocarcinoma. A potentially curative resection was defined as surgery with negative or microscopic positive margins. No patients had metastatic disease at the time of surgery and IORT. Forty-four patients with tumors located in the pancreas and 9 patients with periampullary tumors underwent potentially curative surgical resection and IORT. Twenty-four patients had pancreatic tumors deemed unresectable and underwent surgical bypass and IORT. Actuarial survival was calculated from the date of IORT until last follow-up or death by use of the Kaplan-Meier method. RESULTS Patients undergoing a potentially curative resection and IORT for periampullary adenocarcinoma had a median survival of 167 months and a 56% 5-year actuarial survival, compared with a median survival of 16 months and a 19% 5-year actuarial survival for patients undergoing the same treatment for pancreatic adenocarcinoma (p = 0.03). Patients with unresectable disease who underwent bypass and IORT had a median survival of 11 months and a 0% 3-year survival, significantly worse than patients able to undergo surgical resection and IORT (p = 0.0002). The operative mortality for all patients undergoing potentially curative resection and IORT was 3.7%. CONCLUSIONS Intraoperative radiation therapy is well tolerated and does not increase the morbidity or mortality of potentially curative surgical resection for pancreatic or periampullary adenocarcinoma. Patients with periampullary adenocarcinoma have a better prognosis than those with pancreatic adenocarcinoma, and patients with unresectable pancreatic disease fared worse.
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Affiliation(s)
- John K O'Connor
- Department of Radiation Oncology, Tulane Cancer Center, New Orleans, LA, USA
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38
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Ghaneh P, Neoptolemos JP. Conclusions from the European Study Group for Pancreatic Cancer adjuvant trial of chemoradiotherapy and chemotherapy for pancreatic cancer. Surg Oncol Clin N Am 2004; 13:567-87, vii-viii. [PMID: 15350935 DOI: 10.1016/j.soc.2004.06.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Pancreatic ductal adenocarcinoma remains one of the most difficult cancers to treat. It is a tumor that tends to present late, and surgical resection is only possible in a minority of patients. After successful surgery, the prognosis is still relatively poor. Attempts at more radical pancreatic resections and extended lymphadenectomy, although feasible without excessive morbidity and mortality, have failed to produce any convincing improvement in survival. During the last few years, therefore, efforts have been directed toward the development of adjuvant therapies in an attempt to improve outcome. This article describes the main trials of adjuvant chemotherapy, chemoradiotherapy, and chemoradiotherapy with follow-on chemotherapy and presents the results of the European Study Group for Pancreatic Cancer (ESPAC) 1 trial and the status of the ESPAC 2 and 3 trials.
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Affiliation(s)
- Paula Ghaneh
- Department of Surgery, University of Liverpool, 5th Floor, UCD Building,Daulby Street, Liverpool L69 3GA, UK
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39
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Shibata SI, Pezner R, Chu D, Doroshow JH, Chow WA, Leong LA, Margolin KA, McNamara MV, Morgan RJ, Raschko JW, Somlo G, Tetef ML, Yen Y, Synold TW, Wagman L, Vora N, Carroll M, Lin S, Longmate J. A study of radiotherapy modalities combined with continuous 5-FU infusion for locally advanced gastrointestinal malignancies. Eur J Surg Oncol 2004; 30:650-7. [PMID: 15256240 DOI: 10.1016/j.ejso.2003.11.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2003] [Indexed: 11/26/2022] Open
Abstract
AIM We describe the feasibility of combining infusional 5-fluorouracil (5-FU) with intraoperative radiation therapy (IORT). METHODS Patients with surgically resectable locally advanced gastrointestinal cancers were treated concurrently during surgery with IORT and a 72 h infusion of 5-FU. Patients without previous external beam radiation therapy (EBRT) were subsequently treated with EBRT (40-50Gy) concurrent with a 21-day continuous infusion of 5-FU. Pancreatic, gastric, duodenal, ampullary, recurrent colorectal, and recurrent anal cancer were included. RESULTS During IORT/5-FU, no chemotherapy-related grade III or IV hematologic or gastrointestinal toxicity was noted. Post-surgical recovery or wound healing was not affected. One of nine patients who received post-operative radiation required a treatment break. During follow-up, there were more complications in patients with pelvic tumours, especially those with previous radiation. Nine patients have had local and/or local regional recurrences, two of these in the IORT field. CONCLUSIONS Treatment with a combination of IORT and 5-FU followed by EBRT and 5-FU is feasible. However, long-term complications may be increased in previously irradiated recurrent pelvic tumours.
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Affiliation(s)
- S I Shibata
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
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40
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Okamoto A, Matsumoto G, Tsuruta K, Baba H, Karasawa K, Kamisawa T, Egawa N. Intraoperative radiation therapy for pancreatic adenocarcinoma: the Komagome hospital experience. Pancreas 2004; 28:296-300. [PMID: 15084975 DOI: 10.1097/00006676-200404000-00016] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
We analyzed 144 patients with pancreatic adenocarcinoma who had received intraoperative radiation therapy (IORT) in combination with external beam radiation therapy (EBRT) within the past 20 years. The patients were divided into 2 groups: group 1 contained 65 patients with locally unresectable tumors who underwent bypass operations and group 2 contained 68 patients with resectable tumors who underwent pancreatic resection. As a pilot study, we performed additional arterial infusion chemotherapy after changing peripancreatic hemodynamics during EBRT in the remaining 11 patients. The 30 patients who received R0 resection had the best survival rates (3-year survival rate of 35.4%), while 3 patients with stage III disease survived more than 5 years. The survival of group 1 patients nearly equaled that of group 2 patients who underwent R1 or R2 resection (median survival, 10.9 vs. 11.1 months, respectively; P = 0.43). The 1-year survival rate for the 11 patients receiving arterial infusion chemotherapy was 45.4%, and 5 patients survived over 1 year without developing hepatic metastasis or regrowth of primary tumors. The survival benefits obtained using this form of radiotherapy are apparently limited. On the other hand, additional arterial infusion chemotherapy employing a new drug delivery system using hemodynamic change does appear promising.
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Affiliation(s)
- Atsutake Okamoto
- Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.
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41
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Mu DQ, Peng SY, Wang GF. Risk factors influencing recurrence following resection of pancreatic head cancer. World J Gastroenterol 2004; 10:906-909. [PMID: 15040043 PMCID: PMC4727020 DOI: 10.3748/wjg.v10.i6.906] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2003] [Revised: 06/23/2003] [Accepted: 09/01/2003] [Indexed: 12/15/2022] Open
Abstract
AIM Whether operative procedure is a risk factor influencing recurrence following resection of carcinoma in the head of pancreas or not remains controversies. In this text we compared the recurrence rate of two operative procedure: the Whipple procedure and extended radical operation, and inquired into the factors influencing recurrence after radical resection. METHODS From January 1995 to December 1998, 35 cases of carcinoma of pancreas underwent the Whipple operadure, 21 patients received the Extended radical operation. All patients were followed up for more than 3 years. Prognostic factors included operative procedure, size of tumor, lymph node, interstitial invasion. RESULTS Deaths duo to recurrence within 3 years after operation were studied. The death rate was 51.4% in the Whipple procedure and 42.9% in the Extended radical operative procedure. There was a significant difference between the two groups. Recurrence occurred in 75% patients with tumor large than 4 cm, in 87.5% patients with lymph node involvement, and in 50% patients with the presence of interstitial invasion. CONCLUSION Tumor exceeding 4 cm, lymph node involvement, and presence of interstitial invasion are high risk factors of recurrence after Whipple's procedure and extended radical operation.
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Affiliation(s)
- De-Qing Mu
- Department of Surgery, the Second Affiliated Hospital, Medical College of Zhejiang University, Hangzhou 310009 Zhejiang Province, China.
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42
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Delaney G, Barton M, Jacob S. Estimation of an optimal radiotherapy utilization rate for gastrointestinal carcinoma. Cancer 2004; 101:657-70. [PMID: 15305395 DOI: 10.1002/cncr.20443] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Radiotherapy utilization rates for cancer vary widely, both within and between countries. The optimal proportion of patients with gastrointestinal malignancies who should receive at least one course of radiotherapy at some time during their illness is an important benchmark. METHODS The authors studied treatment guidelines and treatment reviews to identify the indications for radiotherapy for patients with gastrointestinal malignancies. Optimal radiotherapy utilization trees were constructed to show the clinical attributes of patients with gastrointestinal carcinomas who will benefit from radiotherapy. Epidemiologic incidence data for each of these clinical attributes were obtained to calculate the optimal proportion of all patients with gastrointestinal malignancies for whom radiotherapy was considered appropriate. Optimal rates of radiotherapy use were compared with actual rates in population-based studies to assess any discrepancies between actual and optimal radiotherapy utilization rates. RESULTS Radiotherapy was indicated in 80% of patients with esophageal carcinoma, 68% of patients with gastric carcinoma, 57% of patients with pancreatic carcinoma, 13% of patients with carcinoma of the gallbladder, 0% of patients with hepatic carcinoma, 14% of patients with colon carcinoma, and 61% of patients with rectal carcinoma. The actual radiotherapy utilization rates for most of these gastrointestinal malignancies fell well short of optimal rates, which were derived from evidence-based treatment guidelines. CONCLUSIONS It is possible to model optimal radiotherapy utilization using published treatment guidelines and existing incidence data. There was a discrepancy between the optimal and actual rates of radiotherapy utilization for patients with carcinomas of the esophagus, stomach, pancreas, and rectum. Strategies to implement evidence-based clinical guidelines are recommended.
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Affiliation(s)
- Geoff Delaney
- Collaboration for Cancer Outcomes Research and Evaluation, Liverpool Hospital, Sydney, Australia.
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43
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Neoptolemos JP, Cunningham D, Friess H, Bassi C, Stocken DD, Tait DM, Dunn JA, Dervenis C, Lacaine F, Hickey H, Raraty MGT, Ghaneh P, Büchler MW. Adjuvant therapy in pancreatic cancer: historical and current perspectives. Ann Oncol 2003; 14:675-92. [PMID: 12702520 DOI: 10.1093/annonc/mdg207] [Citation(s) in RCA: 95] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The results from pancreatic ductal adenocarcinoma appear to be improving with increased resection rates and reduced postoperative mortality reported by specialist pancreatic cancer teams. Developments with medical oncological treatments have been difficult, however, due to the fundamentally aggressive biological nature of pancreatic cancer and its resistance to chemotherapy coupled with a relative dearth of randomised controlled trials. The European Study Group for Pancreatic Cancer (ESPAC)-1 trial recruited nearly 600 patients and is the largest trial in pancreatic cancer. The results demonstrated that the current best adjuvant treatment is chemotherapy using bolus 5-fluorouracil with folinic acid. The median survival of patients randomly assigned to chemoradiotherapy was 15.5 months and is comparable with many other studies, but the median survival in the chemotherapy arm was 19.7 months and is as good or superior to multimodality treatments including intra-operative radiotherapy, adjuvant chemoradiotherapy and neo-adjuvant therapies. The use of adjuvant 5-fluorouracil with folinic acid may be supplanted by gemcitabine but requires confirmation by ongoing clinical trials, notably ESPAC-3, which plans to recruit 990 patients from Europe, Canada and Australasia. Major trials such as ESPAC-1 and ESPAC-3 have set new standards for the development of adjuvant treatment and it is now clear that such treatment in this field has the potential to significantly improve both patient survival and quality of life after curative resection.
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Affiliation(s)
- J P Neoptolemos
- Department of Surgery, University of Liverpool, Liverpool, UK.
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Schwarz RE, Smith DD, Keny H, Iklé DN, Shibata SI, Chu DZJ, Pezner RD. Impact of intraoperative radiation on postoperative and disease-specific outcome after pancreatoduodenectomy for adenocarcinoma: a propensity score analysis. Am J Clin Oncol 2003; 26:16-21. [PMID: 12576918 DOI: 10.1097/00000421-200302000-00004] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
For periampullary cancer,intraoperative radiation therapy (IORT) administered to the site with the highest locoregional recurrence risk carries the rationale to improve tumor control. An IORT effect on survival remains unclear. IORT impact on postoperative outcomes after pancreatectomy for adenocarcinoma was analyzed, with a specific attempt to correct for the nonrandom IORT treatment assignment, and to account for treatment group imbalances in the interpretation of outcome differences. A propensity-score-adjusted analysis, based on variable selection by logistic regression, was used to rebalance treatments. Between 1989 and 1999, 61 patients underwent partial or total pancreatectomy for a primary periampullary adenocarcinoma at the City of Hope National Medical Center. Diagnoses included pancreatic (n = 36), duodenal (n = 11), ampullary (n = 10), and bile duct cancer (n = 4). Thirty patients received IORT to the resection area, with a median dose of 15 Gy (range: 10-20), followed by postoperative external beam radiation (n = 24). Mortality was 0%, the complication rate 61%. Of 33 patients with a documented recurrence, 6 had an isolated locoregional recurrence only (1 IORT versus 5 no IORT, = 0.05); the systemic recurrence pattern differed as well (IORT 94%, no IORT 67%; = 0.04). IORT had no significant impact on hospital stay (overall median: 17 days), disease-free survival (16 months), and overall survival (23 months) when adjusted for those most relevant variables reflecting IORT treatment group assignment propensity. After adjustment for relevant propensity factors, IORT was not linked to a significantly increased risk for complications, hospital stay, or survival hazard. The recurrence pattern may be affected in some patients, but systemic recurrences predominate. We continue to explore IORT in combination with systemic chemotherapy.
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Affiliation(s)
- Roderich E Schwarz
- City of Hope National Medical Center, Department of General Oncologic Surgery, Duarte, California, USA
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Niedergethmann M, Hildenbrand R, Wostbrock B, Hartel M, Sturm JW, Richter A, Post S. High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas. Pancreas 2002; 25:122-9. [PMID: 12142733 DOI: 10.1097/00006676-200208000-00002] [Citation(s) in RCA: 155] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION AND AIMS Only curative resection for pancreatic adenocarcinoma is related to a favorable prognosis, but the overall survival after surgery still remains poor, and early recurrence is frequently observed. Because recurrence is the limiting factor and the main cause of death after curative resection, the identification of markers that predict early postoperative recurrence is of paramount importance. Angiogenesis is essential for tumor growth and metastases; therefore, we set out to clarify whether vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) correlate with early recurrence and poor prognosis after curative resection. A second goal was to characterize the VEGF-producing cells and the subcellular distribution. METHODOLOGY Seventy patients with ductal adenocarcinoma of the pancreas were studied after curative resection with a follow-up of at least 2 years. The MVD quantification was performed immunohistochemically with use of a monoclonal antibody to CD34. The VEGF expression was studied with use of polyclonal antibody. To detect the intracellular localization of specific VEGF mRNA sequences, nonisotopic in situ hybridization was performed. The correlations among VEGF expression and MVD, clinicopathologic parameters, and clinical outcome were then statistically analyzed. RESULTS The VEGF immunoreactivity was 88.6%, and positive mRNA signals were obtained in the cytoplasm of carcinoma and endothelial cells in 81.4%. Furthermore, we observed tumor-associated macrophages close to infiltrating carcinoma cells. All endothelial cells showed positive immunoreactivity to the anti-CD34 antibody, and a median distribution of 85 vessels/x200 field was observed. A significant correlation (p < 0.05) was found between the MVD and the International Union Against Cancer (UICC) stage. Statistical analysis showed a significant correlation between VEGF expression and the height of MVD (p < 0.05). Kaplan-Meier analyses revealed that VEGF expression and MVD had a statistically significant correlation with survival after curative resection (p < 0.05). Furthermore, multivariate analysis indicated that VEGF expression is an independent prognostic marker for cancer recurrence within 8 months after curative surgery (p = 0.003). CONCLUSION In pancreatic adenocarcinoma, the VEGF expression and the height of MVD are closely correlated, and both-rather than UICC stage and TNM classification (tumor size and nodal involvement)-are markers of prognostic relevance after curative resection. Furthermore, VEGF is a predictor of early recurrence after curative resection. The current study indicates that VEGF may promote the distribution of metastases, leading to early cancer recurrence and poor outcome.
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Affiliation(s)
- Marco Niedergethmann
- Department of Surgery, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany. marco.niedergethmann@ chir.ma.uni-heidelberg.de
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