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Wang X, Wang WH, Wang SL, Song YW, Liu YP, Tang Y, Li N, Liu WY, Fang H, Li YX, Zhao DB, Chi Y, Yang L, Jin J. Efficacy and toxicity of capecitabine combined with intensity-modulated radiotherapy after D1/D2 lymph node dissection in patients with gastric cancer. World J Gastrointest Oncol 2021; 13:1532-1543. [PMID: 34721783 PMCID: PMC8529930 DOI: 10.4251/wjgo.v13.i10.1532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/14/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Adjuvant chemoradiotherapy (ACRT) with oral capecitabine and intensity-modulated radiotherapy (IMRT) were well tolerated in a phase I study in patients who had undergone partial or total gastrectomy for locally advanced gastric cancer (GC). This phase II study aimed to further determine the efficacy and toxicity of this combination after radical resection and D1/D2 lymph node dissection (LND) for patients with locally advanced GC.
AIM To further determine the efficacy and toxicity of this combination after radical resection and D1/D2 LND for patients with locally advanced GC.
METHODS Forty patients (median age, 53 years; range, 24-71 years) with pathologically confirmed adenocarcinoma who underwent D1/D2 LND were included in this study. The patients received ACRT comprising IMRT (total irradiation dose: 45 Gy delivered in daily 1.8-Gy fractions on 5 d a week over 5 wk) and capecitabine chemotherapy (dose: 800 mg/m² twice daily throughout the duration of radiotherapy). The primary study endpoint was disease-free survival (DFS), and the secondary endpoints were overall survival (OS), toxic effects, and treatment compliance.
RESULTS The 3-year DFS and OS were 66.2% and 75%, respectively. The median time to recurrence was 19.5 mo (range, 6.1-68 mo). Peritoneal implantation (n = 10) was the most common recurrence pattern, and the lung was the most common site of extra-abdominal metastases (n = 5). Nine patients developed grade 3 or 4 toxicities during ACRT. Two patients discontinued ACRT, while eleven underwent ACRT without receiving the entire course of capecitabine. There were no treatment-related deaths.
CONCLUSION The ACRT protocol described herein showed acceptable safety and efficacy for patients with locally advanced GC who received radical gastrectomy and D1/2 LND.
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Affiliation(s)
- Xin Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wei-Hu Wang
- Department of Radiation Oncology, Peking University Cancer Hospital and Institute, Beijing 100001, China
| | - Shu-Lian Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Wen Song
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yue-Ping Liu
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yuan Tang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ning Li
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
| | - Wen-Yang Liu
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hui Fang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ye-Xiong Li
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Dong-Bing Zhao
- Department of Pancreatic and Gastric Surgery, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yihebali Chi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lin Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jing Jin
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
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Slagter AE, Vollebergh MA, Jansen EPM, van Sandick JW, Cats A, van Grieken NCT, Verheij M. Towards Personalization in the Curative Treatment of Gastric Cancer. Front Oncol 2020; 10:614907. [PMID: 33330111 PMCID: PMC7734340 DOI: 10.3389/fonc.2020.614907] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 11/02/2020] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is the fifth most common cancer worldwide and has a high mortality rate. In the last decades, treatment strategy has shifted from an exclusive surgical approach to a multidisciplinary strategy. Treatment options for patients with resectable gastric cancer as recommended by different worldwide guidelines, include perioperative chemotherapy, pre- or postoperative chemoradiotherapy and postoperative chemotherapy. Although gastric cancer is a heterogeneous disease with respect to patient-, tumor-, and molecular characteristics, the current standard of care is still according to a one-size-fits-all approach. In this review, we discuss the background of the different treatment strategies in resectable gastric cancer including the current standard, the specific role of radiotherapy, and describe the current areas of research and potential strategies for personalization of therapy.
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Affiliation(s)
- Astrid E Slagter
- Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Marieke A Vollebergh
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Edwin P M Jansen
- Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | | | - Annemieke Cats
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | | | - Marcel Verheij
- Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.,Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands
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Jacobs BAW, Deenen MJ, Joerger M, Rosing H, de Vries N, Meulendijks D, Cats A, Beijnen JH, Schellens JHM, Huitema ADR. Pharmacokinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2019; 8:940-950. [PMID: 31652031 PMCID: PMC6930859 DOI: 10.1002/psp4.12474] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 09/06/2019] [Indexed: 12/19/2022]
Abstract
Capecitabine is an oral prodrug of the anticancer drug 5‐fluorouracil (5‐FU). The primary aim of this study was to develop a pharmacokinetic model for capecitabine and its metabolites, 5′‐deoxy‐5‐fluorocytidine (dFCR), 5′‐deoxy‐5‐fluorouridine (dFUR), 5‐FU, and fluoro‐β‐alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four‐transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL pharmacokinetics were well described by two‐compartment models, and dFUR and 5‐FU were subject to flip‐flop pharmacokinetics. Partial and total gastrectomy were associated with a significantly faster capecitabine absorption resulting in higher capecitabine and metabolite peak concentrations. Patients who were heterozygous polymorphic for a genetic mutation encoding dihydropyrimidine dehydrogenase, the DPYD*2A mutation, demonstrated a 21.5% (relative standard error 11.2%) reduction in 5‐FU elimination. This comprehensive population model gives an extensive overview of capecitabine and metabolite pharmacokinetics in a large and heterogeneous population of cancer patients.
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Affiliation(s)
- Bart A W Jacobs
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Maarten J Deenen
- Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, The Netherlands.,Department of Clinical Pharmacology and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Markus Joerger
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Hilde Rosing
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Niels de Vries
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Didier Meulendijks
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Dutch Medicines Evaluation Board, Utrecht, The Netherlands
| | - Annemieke Cats
- Department of Gastrointestinal Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jos H Beijnen
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Division of Pharmaco-epidemiology & Clinical Pharmacology, Science Faculty, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jan H M Schellens
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Division of Pharmaco-epidemiology & Clinical Pharmacology, Science Faculty, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Alwin D R Huitema
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands
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Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol 2018; 19:616-628. [PMID: 29650363 DOI: 10.1016/s1470-2045(18)30132-3] [Citation(s) in RCA: 375] [Impact Index Per Article: 53.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 01/18/2018] [Accepted: 01/24/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Both perioperative chemotherapy and postoperative chemoradiotherapy improve survival in patients with resectable gastric cancer from Europe and North America. To our knowledge, these treatment strategies have not been investigated in a head to head comparison. We aimed to compare perioperative chemotherapy with preoperative chemotherapy and postoperative chemoradiotherapy in patients with resectable gastric adenocarcinoma. METHODS In this investigator-initiated, open-label, randomised phase 3 trial, we enrolled patients aged 18 years or older who had stage IB- IVA resectable gastric or gastro-oesophageal adenocarcinoma (as defined by the American Joint Committee on Cancer, sixth edition), with a WHO performance status of 0 or 1, and adequate cardiac, bone marrow, liver, and kidney function. Patients were enrolled from 56 hospitals in the Netherlands, Sweden, and Denmark, and were randomly assigned (1:1) with a computerised minimisation programme with a random element to either perioperative chemotherapy (chemotherapy group) or preoperative chemotherapy with postoperative chemoradiotherapy (chemoradiotherapy group). Randomisation was done before patients were given any preoperative chemotherapy treatment and was stratified by histological subtype, tumour localisation, and hospital. Patients and investigators were not masked to treatment allocation. Surgery consisted of a radical resection of the primary tumour and at least a D1+ lymph node dissection. Postoperative treatment started within 4-12 weeks after surgery. Chemotherapy consisted of three preoperative 21-day cycles and three postoperative cycles of intravenous epirubicin (50 mg/m2 on day 1), cisplatin (60 mg/m2 on day 1) or oxaliplatin (130 mg/m2 on day 1), and capecitabine (1000 mg/m2 orally as tablets twice daily for 14 days in combination with epirubicin and cisplatin, or 625 mg/m2 orally as tablets twice daily for 21 days in combination with epirubicin and oxaliplatin), received once every three weeks. Chemoradiotherapy consisted of 45 Gy in 25 fractions of 1·8 Gy, for 5 weeks, five daily fractions per week, combined with capecitabine (575 mg/m2 orally twice daily on radiotherapy days) and cisplatin (20 mg/m2 intravenously on day 1 of each 5 weeks of radiation treatment). The primary endpoint was overall survival, analysed by intention-to-treat. The CRITICS trial is registered at ClinicalTrials.gov, number NCT00407186; EudraCT, number 2006-004130-32; and CKTO, 2006-02. FINDINGS Between Jan 11, 2007, and April 17, 2015, 788 patients were enrolled and randomly assigned to chemotherapy (n=393) or chemoradiotherapy (n=395). After preoperative chemotherapy, 372 (95%) of 393 patients in the chemotherapy group and 369 (93%) of 395 patients in the chemoradiotherapy group proceeded to surgery, with a potentially curative resection done in 310 (79%) of 393 patients in the chemotherapy group and 326 (83%) of 395 in the chemoradiotherapy group. Postoperatively, 233 (59%) of 393 patients started chemotherapy and 245 (62%) of 395 started chemoradiotherapy. At a median follow-up of 61·4 months (IQR 43·3-82·8), median overall survival was 43 months (95% CI 31-57) in the chemotherapy group and 37 months (30-48) in the chemoradiotherapy group (hazard ratio from stratified analysis 1·01 (95% CI 0·84-1·22; p=0·90). After preoperative chemotherapy, in the total safety population of 781 patients (assessed together), there were 368 (47%) grade 3 adverse events; 130 (17%) grade 4 adverse events, and 13 (2%) deaths. Causes of death during preoperative treatment were diarrhoea (n=2), dihydropyrimidine deficiency (n=1), sudden death (n=1), cardiovascular events (n=8), and functional bowel obstruction (n=1). During postoperative treatment, grade 3 and 4 adverse events occurred in 113 (48%) and 22 (9%) of 233 patients in the chemotherapy group, respectively, and in 101 (41%) and ten (4%) of 245 patients in the chemoradiotherapy group, respectively. Non-febrile neutropenia occurred more frequently during postoperative chemotherapy (79 [34%] of 233) than during postoperative chemoradiotherapy (11 [4%] of 245). No deaths were observed during postoperative treatment. INTERPRETATION Postoperative chemoradiotherapy did not improve overall survival compared with postoperative chemotherapy in patients with resectable gastric cancer treated with adequate preoperative chemotherapy and surgery. In view of the poor postoperative patient compliance in both treatment groups, future studies should focus on optimising preoperative treatment strategies. FUNDING Dutch Cancer Society, Dutch Colorectal Cancer Group, and Hoffmann-La Roche.
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Ikoma N, Chen HC, Wang X, Blum M, Estrella JS, Fournier K, Mansfield P, Ajani J, Badgwell BD. Patterns of Initial Recurrence in Gastric Adenocarcinoma in the Era of Preoperative Therapy. Ann Surg Oncol 2017; 24:2679-2687. [PMID: 28332034 DOI: 10.1245/s10434-017-5838-y] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Indexed: 01/28/2023]
Abstract
BACKGROUND We sought to determine the sites of recurrence and identify predicting factors for recurrence and survival in patients who underwent gastrectomy for adenocarcinoma at an institution where preoperative therapy is commonly used for advanced gastric cancer. METHODS We collected clinicopathologic data and sites of recurrence from a prospectively maintained database of patients who underwent potentially curative resection of gastric or gastroesophageal adenocarcinoma at our institution in 1995-2014, and we assessed associations between these characteristics and recurrence patterns and survival. RESULTS We identified 488 patients who underwent R0 resection of localized gastric cancer. The median age was 63 years (interquartile range 53-71 years), and 60% were male. The most common T and N categories, per endoscopic ultrasonography, were T3 (58%) and N0 (61%). Preoperative treatment was used in 61% of patients. A total of 125 (26%) patients experienced recurrence during follow-up. Recurrences were locoregional in 19 patients (15%), peritoneal in 61 (49%), and nonperitoneal distant in 67 (54%). The peritoneum also was the most common organ of recurrence (49%), followed by the liver (21%). The median time from primary resection to recurrence was 2.7 years for locoregional, 1.3 years for peritoneal, and 0.6 years for nonperitoneal distant recurrence (p = 0.01). Median overall survival was markedly shorter after peritoneal and nonperitoneal distant recurrences than after locoregional recurrences. CONCLUSIONS The peritoneum was a common site of recurrence after curative resection of gastric cancer and was associated with poor survival. Prophylactic treatment targeting the peritoneal cavity might improve survival of advanced gastric cancer.
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Affiliation(s)
- Naruhiko Ikoma
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hsiang-Chun Chen
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xuemei Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mariela Blum
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeannelyn S Estrella
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Keith Fournier
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Paul Mansfield
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaffer Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Brian D Badgwell
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Goody RB, MacKay H, Pitcher B, Oza A, Siu LL, Kim J, Wong RKS, Chen E, Swallow C, Knox J, Kassam Z, Cummings B, Feld R, Hedley D, Liu G, Krzyzanowska MK, Dinniwell R, Brade AM, Dawson LA, Pintilie M, Ringash J. Phase 1/2 Study of the Addition of Cisplatin to Adjuvant Chemotherapy With Image Guided High-Precision Radiation Therapy for Completely Resected Gastric Cancer. Int J Radiat Oncol Biol Phys 2016; 96:994-1002. [PMID: 27745984 DOI: 10.1016/j.ijrobp.2016.08.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 08/16/2016] [Accepted: 08/23/2016] [Indexed: 01/07/2023]
Abstract
PURPOSE Locoregional recurrence is common after surgery for gastric cancer. Adjuvant therapy improves outcomes but with toxicity. This phase 1/2 study investigated infusional 5-fluorouracil (5-FU) in combination with biweekly cisplatin delivered concurrently with image guided high-precision radiation therapy. METHODS AND MATERIALS Eligible patients had completely resected stage IB to IV (Union for International Cancer Control TNM 6th edition) nonmetastatic gastric adenocarcinoma. Treatment constituted 12 weeks of infusional 5-FU (200 mg/m2/day) with cisplatin added in a standard 3 + 3 dose escalation protocol (0, 20, 30, and 40 mg/m2) during weeks 1, 3, 5, and 7, and an additional week 9 dose in the final cohort. Radiation therapy (45 Gy in 25 fractions) was delivered during weeks 3 to 7. Maximum tolerated dose (MTD) was determined in phase 1 and confirmed in phase 2. RESULTS Among the 55 patients (median age, 54 years; range 28-77 years; 55% male), the median follow-up time was 3.0 years (range, 0.3-5.3 years). Five patients in phase 1 experienced dose-limiting toxicity, and MTD was determined as 4 cycles of 40 mg/m2 cisplatin. Twenty-seven patients were treated at MTD. Acute grade 3 to 4 toxicity rate was 37.0% at MTD and 29.1% across all dose levels. No treatment-related deaths occurred. Fourteen patients experienced recurrent disease. The 2-year overall survival (OS) and relapse-free survival were 85% and 74%, respectively. Median OS has not been reached. Quality of life (QOL) was impaired during treatment, but most scores recovered by 4 weeks. CONCLUSION Cisplatin can be safely delivered with 5-FU-based chemoradiation therapy. Acute toxicity was acceptable, and patient-reported QOL showed the regimen was tolerable. Outcomes are encouraging and justify further study of this regimen.
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Affiliation(s)
- Rebecca B Goody
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Helen MacKay
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Bethany Pitcher
- Department of Biostatistics, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Amit Oza
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Lillian L Siu
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - John Kim
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Rebecca K S Wong
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Eric Chen
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Carol Swallow
- Department of Surgical Oncology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Jennifer Knox
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Zahra Kassam
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada; Department of Radiation Oncology, Stronach Regional Cancer Centre, Newmarket, Ontario, Canada
| | - Bernard Cummings
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Ron Feld
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - David Hedley
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Geoffrey Liu
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Monika K Krzyzanowska
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Robert Dinniwell
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Anthony M Brade
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Laura A Dawson
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Melania Pintilie
- Department of Biostatistics, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Jolie Ringash
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
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Trip AK, Nijkamp J, van Tinteren H, Cats A, Boot H, Jansen EPM, Verheij M. IMRT limits nephrotoxicity after chemoradiotherapy for gastric cancer. Radiother Oncol 2015. [DOI: 10.1016/j.radonc.2015.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Trip AK, Nijkamp J, van Tinteren H, Cats A, Boot H, Jansen EPM, Verheij M. IMRT limits nephrotoxicity after chemoradiotherapy for gastric cancer. Radiother Oncol 2014; 112:289-94. [PMID: 25241995 DOI: 10.1016/j.radonc.2014.08.039] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 07/30/2014] [Accepted: 08/03/2014] [Indexed: 12/14/2022]
Abstract
OBJECTIVE This observational study compares the effect of different radiotherapy techniques on late nephrotoxicity after postoperative chemoradiotherapy for gastric cancer. PATIENTS AND METHODS Dosimetric parameters were compared between AP-PA, 3D-conformal and IMRT techniques. Renal function was measured by (99m)Tc-MAG-3 renography, glomerular filtration rate (GFR) and the development of hypertension. Mixed effects models were used to compare renal function over time. RESULTS Eighty-seven patients treated between 2002 and 2010 were included, AP-PA (n=31), 3D-conformal (n=25) and IMRT (n=31), all 45 Gy in 25 fractions. Concurrent chemotherapy: 5FU/leucovorin (n=4), capecitabine (n=37), and capecitabine/cisplatin (n=46). Median follow-up time was 4.7 years (range 0.2-8). With IMRT, the mean dose to the left kidney was significantly lower. Left kidney function decreased progressively in the total study population, however with IMRT this occurred at a lower rate. A dose-effect relationship was present between mean dose to the left kidney and the left kidney function. GFR decreased only moderately in time, which was not different between techniques. Six patients developed hypertension, of whom none in the IMRT group. CONCLUSIONS This study confirms progressive late nephrotoxicity in patients treated with postoperative chemoradiotherapy by different techniques for gastric cancer. Nephrotoxicity was less severe with IMRT and should be considered the preferred technique.
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Affiliation(s)
- Anouk Kirsten Trip
- Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jasper Nijkamp
- Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Harm van Tinteren
- Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Annemieke Cats
- Department of Gastroenterology and Hepatology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Henk Boot
- Department of Gastroenterology and Hepatology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | - Marcel Verheij
- Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Stiekema J, Trip AK, Jansen EPM, Aarts MJ, Boot H, Cats A, Ponz OB, Gradowska PL, Verheij M, van Sandick JW. Does adjuvant chemoradiotherapy improve the prognosis of gastric cancer after an r1 resection? Results from a dutch cohort study. Ann Surg Oncol 2014; 22:581-8. [PMID: 25164039 DOI: 10.1245/s10434-014-4032-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the impact of adjuvant chemoradiotherapy (CRT) on survival of non-metastatic gastric cancer patients who had undergone an R1 resection. METHODS We compared the survival of patients after an R1 gastric cancer resection from the population-based Netherlands Cancer Registry who did not receive adjuvant CRT (no-CRT group) with the survival of resected patients who had been treated with adjuvant CRT (CRT group) at our institute. Patients who had a resection between 2002 and 2011 were included. CRT consisted of radiotherapy (45 Gy) combined with concurrent cisplatin- or 5-fluorouracil-based chemotherapy. The impact of CRT treatment on overall survival was assessed using multivariable Cox regression and stratified propensity score analysis. RESULTS A series of 409 gastric cancer patients who had undergone an R1 resection were studied (no-CRT, N = 369; CRT, N = 40). In the no-CRT group, median age was higher (70 vs. 57 years; p < 0.001) and the percentage of patients with diffuse-type tumors was lower (43 vs. 80 %; p < 0.001). There were no significant differences in pathological T- and N-classification. There was a significant difference in median overall survival between the no-CRT and CRT group (13 vs. 24 months; p = 0.003). In a multivariable analysis, adjuvant CRT was an independent prognostic factor for improved overall survival (hazard ratio 0.54; 95 % confidence interval 0.35-0.84). This effect of CRT was further supported by propensity score analysis. CONCLUSIONS Adjuvant CRT was associated with an improved survival in patients who had undergone an R1 resection for gastric cancer.
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Affiliation(s)
- Jurriën Stiekema
- Department of Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Wang X, Jin J, Li YX, Ren H, Fang H, Wang SL, Liu YP, Wang WH, Yu ZH, Song YW, Liu XF. Phase I study of postoperative radiotherapy combined with capecitabine for gastric cancer. World J Gastroenterol 2014; 20:1067-1073. [PMID: 24574780 PMCID: PMC3921531 DOI: 10.3748/wjg.v20.i4.1067] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/14/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of capecitabine combined with postoperative radiotherapy for gastric cancer.
METHODS: We enrolled patients with any T stage and node-positive gastroesophageal or gastric adenocarcinoma after complete resection with negative margins (R0) or microscopic (R1) or macroscopic (R2) resection. Intensity modulated radiotherapy (IMRT) using a five-to-seven-field, coplanar, sliding window technique was delivered to the tumor bed (T4b), anastomosis site, duodenal stump and regional lymph nodes (LNs) to a total dose of 45 Gy (1.8 Gy/fraction, 5 d/wk). Patients with R1 or R2 resection received 10.8 Gy as a boost. Capecitabine was administered twice daily on every radiotherapy treatment day in a dose-escalation schedule (mg/m2) of 625 (level I, n = 6), 700 (level II, n = 6), 800 (level III, n = 6), 900 (level IV, n = 0) and 1000 (level V, n = 0). DLT was defined as grade 4 leukopenia or neutropenia, grade 3-4 thrombocytopenia or anemia and grade 3-4 non-hematological toxicity.
RESULTS: Between October 2007 and August 2009, 18 patients (12 men, 6 women; median age, 54 years) were enrolled in the study. The median number of positive LNs was 6, and total number of resected LNs was 19. Twelve patients underwent R0 resection (66.7%). Fifteen patients received adjuvant chemotherapy under the leucovorin, fluorouracil and oxaliplatin (FOLFOX4) regimen. Six patients each were enrolled at dose levels I, II and III. Grade 1-3 leukopenia (16 patients, 88.9%), anorexia (15, 83.3%) and nausea (15, 83.3%) were the most common toxicities. Grade 3 anorexia/nausea and grade 4 vomiting occurred in one level-I patient. Grade 3 anorexia and nausea occurred in one level-II patient. One level-III patient developed grade 4 neutropenia, while another developed grade 3 radiation esophagitis. No abnormal liver or renal function examinations were observed. Three patients did not finish chemoradiotherapy because of DLTs and two without DLTs received sequential boosts (total dose, 55.8 Gy).
CONCLUSION: The MTD of capecitabine was 800 mg/m2 twice daily concurrent with IMRT for gastric cancer after surgery. The DLTs were anorexia/nausea, vomiting, neutropenia and radiation esophagitis.
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Dikken JL, Coit DG, Baser RE, Gönen M, Goodman KA, Brennan MF, Jansen EPM, Boot H, van de Velde CJH, Cats A, Verheij M. Performance of a nomogram predicting disease-specific survival after an R0 resection for gastric cancer in patients receiving postoperative chemoradiation therapy. Int J Radiat Oncol Biol Phys 2014; 88:624-9. [PMID: 24411620 DOI: 10.1016/j.ijrobp.2013.11.213] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Revised: 10/20/2013] [Accepted: 11/09/2013] [Indexed: 01/07/2023]
Abstract
PURPOSE The internationally validated Memorial Sloan-Kettering Cancer Center (MSKCC) gastric carcinoma nomogram was based on patients who underwent curative (R0) gastrectomy, without any other therapy. The purpose of the current study was to assess the performance of this gastric cancer nomogram in patients who received chemoradiation therapy after an R0 resection for gastric cancer. METHODS AND MATERIALS In a combined dataset of 76 patients from the Netherlands Cancer Institute (NKI), and 63 patients from MSKCC, who received postoperative chemoradiation therapy (CRT) after an R0 gastrectomy, the nomogram was validated by means of the concordance index (CI) and a calibration plot. RESULTS The concordance index for the nomogram was 0.64, which was lower than the CI of the nomogram for patients who received no adjuvant therapy (0.80). In the calibration plot, observed survival was approximately 20% higher than the nomogram-predicted survival for patients receiving postoperative CRT. CONCLUSIONS The MSKCC gastric carcinoma nomogram significantly underpredicted survival for patients in the current study, suggesting an impact of postoperative CRT on survival in patients who underwent an R0 resection for gastric cancer, which has been demonstrated by randomized controlled trials. This analysis stresses the need for updating nomograms with the incorporation of multimodal strategies.
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Affiliation(s)
- Johan L Dikken
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands
| | - Daniel G Coit
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Raymond E Baser
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Mithat Gönen
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Karyn A Goodman
- Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Murray F Brennan
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Edwin P M Jansen
- Department of Radiotherapy, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Henk Boot
- Department of Gastroenterology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | | | - Annemieke Cats
- Department of Gastroenterology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
| | - Marcel Verheij
- Department of Radiotherapy, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
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Stiekema J, Trip AK, Jansen EPM, Boot H, Cats A, Ponz OB, Verheij M, van Sandick JW. The Prognostic Significance of an R1 Resection in Gastric Cancer Patients Treated with Adjuvant Chemoradiotherapy. Ann Surg Oncol 2013; 21:1107-14. [DOI: 10.1245/s10434-013-3397-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Indexed: 12/19/2022]
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Jansen EPM, Boot H, van de Velde CJH, van Sandick J, Cats A, Verheij M. Can adjuvant chemoradiotherapy replace extended lymph node dissection in gastric cancer? Recent Results Cancer Res 2013; 196:229-40. [PMID: 23129378 DOI: 10.1007/978-3-642-31629-6_16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Surgical resection remains the essential part in the curative treatment of gastric cancer. However, with surgery only, long-term survival is poor (5-year survival <25 % in Europe). Randomized studies, which compared limited (D1) lymph node dissection with more extended (D2) resections in the Western world, failed to show a survival benefit for more extensive surgery. A substantial increase in survival was found with perioperative chemotherapy in the MAGIC study. In addition, the SWOG/Intergroup 0116 study showed that postoperative chemoradiotherapy (CRT) prolonged 5-year overall survival compared to surgery only. However, it has been argued that surgical undertreatment undermined survival in this trial. In a randomized Korean study, patients with advanced stage gastric cancer who received postoperative CRT had better outcome after a D2 dissection. At our institute phase I-II studies with adjuvant cisplatin and capecitabine-based CRT have been performed in over 120 patients with resected gastric cancer. Retrospective comparison of patients treated in these studies with those that had surgery only in the D1D2 study, demonstrated that postoperative CRT was associated with better outcome, especially after D1 or a R1 resection. For daily practice, it remains unclear whether patients after optimal (D2) gastric surgery will benefit from postoperative CRT. This is currently being tested in prospective randomized phase III trials (CRITICS; TOPGEAR).
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Affiliation(s)
- Edwin P M Jansen
- Department of Radiotherapy, Antoni van Leeuwenhoek Hospital, The Netherlands.
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Dikken JL, van de Velde CJ, Coit DG, Shah MA, Verheij M, Cats A. Treatment of resectable gastric cancer. Therap Adv Gastroenterol 2012; 5:49-69. [PMID: 22282708 PMCID: PMC3263979 DOI: 10.1177/1756283x11410771] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Stomach cancer is one of the most common cancers worldwide, despite its declining overall incidence. Although there are differences in incidence, etiology and pathological factors, most studies do not separately analyze cardia and noncardia gastric cancer. Surgery is the only potentially curative treatment for advanced, resectable gastric cancer, but locoregional relapse rate is high with a consequently poor prognosis. To improve survival, several preoperative and postoperative treatment strategies have been investigated. Whereas perioperative chemotherapy and postoperative chemoradiation (CRT) are considered standard therapy in the Western world, in Asia postoperative monochemotherapy with S-1 is often used. Several other therapeutic options, although generally not accepted as standard treatment, are postoperative combination chemotherapy, hyperthermic intraperitoneal chemotherapy and preoperative radiotherapy and CRT. Postoperative combination chemotherapy does show a statistically significant but clinically equivocal survival advantage in several meta-analyses. Hyperthermic intraperitoneal chemotherapy is mainly performed in Asia and is associated with a higher postoperative complication rate. Based on the currently available data, the use of postoperative radiotherapy alone and the use of intraoperative radiotherapy should not be advised in the treatment of resectable gastric cancer. Western randomized trials on gastric cancer are often hampered by slow or incomplete accrual. Reduction of toxicity for preoperative and especially postoperative treatment is essential for the ongoing improvement of gastric cancer care.
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Affiliation(s)
- Johan L. Dikken
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands and Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, USA
| | | | - Daniel G. Coit
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, USA
| | - Manish A. Shah
- Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, USA
| | - Marcel Verheij
- Department of Radiotherapy, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Annemieke Cats
- Department of Gastroenterology and Hepatology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, P.O. Box 90203, 1006 BE Amsterdam, The Netherlands
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15
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Dikken JL, van Sandick JW, Maurits Swellengrebel HA, Lind PA, Putter H, Jansen EPM, Boot H, van Grieken NCT, van de Velde CJH, Verheij M, Cats A. Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS). BMC Cancer 2011. [PMID: 21810227 DOI: 10.1186/1471-2047.11-329] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Radical surgery is the cornerstone in the treatment of resectable gastric cancer. The Intergroup 0116 and MAGIC trials have shown benefit of postoperative chemoradiation and perioperative chemotherapy, respectively. Since these trials cannot be compared directly, both regimens are evaluated prospectively in the CRITICS trial. This study aims to obtain an improved overall survival for patients treated with preoperative chemotherapy and surgery by incorporating radiotherapy concurrently with chemotherapy postoperatively. METHODS/DESIGN In this phase III multicentre study, patients with resectable gastric cancer are treated with three cycles of preoperative ECC (epirubicin, cisplatin and capecitabine), followed by surgery with adequate lymph node dissection, and then either another three cycles of ECC or concurrent chemoradiation (45 Gy, cisplatin and capecitabine). Surgical, pathological, and radiotherapeutic quality control is performed. The primary endpoint is overall survival, secondary endpoints are disease-free survival (DFS), toxicity, health-related quality of life (HRQL), prediction of response, and recurrence risk assessed by genomic and expression profiling. Accrual for the CRITICS trial is from the Netherlands, Sweden, and Denmark, and more countries are invited to participate. CONCLUSION Results of this study will demonstrate whether the combination of preoperative chemotherapy and postoperative chemoradiotherapy will improve the clinical outcome of the current European standard of perioperative chemotherapy, and will therefore play a key role in the future management of patients with resectable gastric cancer. TRIAL REGISTRATION clinicaltrials.gov NCT00407186.
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Affiliation(s)
- Johan L Dikken
- Department of Surgery, K6-R, Leiden University Medical Center, P.O. Box9600, 2300 RC Leiden, The Netherlands
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16
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Dikken JL, van Sandick JW, Maurits Swellengrebel HA, Lind PA, Putter H, Jansen EPM, Boot H, van Grieken NCT, van de Velde CJH, Verheij M, Cats A. Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS). BMC Cancer 2011; 11:329. [PMID: 21810227 PMCID: PMC3175221 DOI: 10.1186/1471-2407-11-329] [Citation(s) in RCA: 167] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Accepted: 08/02/2011] [Indexed: 12/13/2022] Open
Abstract
Background Radical surgery is the cornerstone in the treatment of resectable gastric cancer. The Intergroup 0116 and MAGIC trials have shown benefit of postoperative chemoradiation and perioperative chemotherapy, respectively. Since these trials cannot be compared directly, both regimens are evaluated prospectively in the CRITICS trial. This study aims to obtain an improved overall survival for patients treated with preoperative chemotherapy and surgery by incorporating radiotherapy concurrently with chemotherapy postoperatively. Methods/design In this phase III multicentre study, patients with resectable gastric cancer are treated with three cycles of preoperative ECC (epirubicin, cisplatin and capecitabine), followed by surgery with adequate lymph node dissection, and then either another three cycles of ECC or concurrent chemoradiation (45 Gy, cisplatin and capecitabine). Surgical, pathological, and radiotherapeutic quality control is performed. The primary endpoint is overall survival, secondary endpoints are disease-free survival (DFS), toxicity, health-related quality of life (HRQL), prediction of response, and recurrence risk assessed by genomic and expression profiling. Accrual for the CRITICS trial is from the Netherlands, Sweden, and Denmark, and more countries are invited to participate. Conclusion Results of this study will demonstrate whether the combination of preoperative chemotherapy and postoperative chemoradiotherapy will improve the clinical outcome of the current European standard of perioperative chemotherapy, and will therefore play a key role in the future management of patients with resectable gastric cancer. Trial registration clinicaltrials.gov NCT00407186
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Affiliation(s)
- Johan L Dikken
- Department of Surgery, K6-R, Leiden University Medical Center, P.O. Box9600, 2300 RC Leiden, The Netherlands
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Kassam Z, Mackay H, Buckley CA, Fung S, Pintile M, Oza A, Brierley J, Swallow C, Cummings B, Knox JJ, Kim J, Wong R, Siu L, Feld R, Ringash J. Adjuvant chemoradiation for gastric cancer with infusional 5-fluorouracil and cisplatin: a phase I study. ACTA ACUST UNITED AC 2011; 17:34-41. [PMID: 20697512 DOI: 10.3747/co.v17i4.521] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE This phase I study aimed to determine the maximal tolerated dose of cisplatin administered every 2 weeks with infusional 5-fluorouracil (5FU) and concurrent radiation therapy (RT) in patients after complete resection of gastric adenocarcinoma. METHODS Patients with resected stage IB to IV (M0) gastric adenocarcinoma were treated with 12 weeks of infusional 5FU (200 mg/m(2) daily) and with RT (45 Gy in 25 fractions starting on day 16). Cisplatin was administered in escalating doses (0, 20, 30, and 40 mg/m(2)) in weeks 1, 3, 5, and 7. In the final cohort, patients received an additional dose of cisplatin (40 mg/m(2)) in week 9. RESULTS Among the 34 patients [median age: 56 years (range: 31-77 years)] who were assessable for toxicity, 5 experienced dose-limiting toxicities: 1 sepsis (cohort 1), 1 fatigue (cohort 2), 3 upper gastrointestinal toxicity (1 in cohort 2, 2 in cohort 5). Cohort 5 exceeded the maximal tolerated dose. Median follow-up was 2.5 years (range: 0.3-5 years). The 3-year overall and relapse-free survival rates were 86% and 71% respectively; median survival was not reached. CONCLUSIONS Cisplatin was well tolerated in combination with infusional 5FU and RT, showing promising activity in the adjuvant treatment of gastric cancer. Infusional 5FU 200 mg/m(2) daily for 12 weeks with cisplatin 40 mg/m(2) in weeks 1, 3, 5, and 7 and with concurrent RT 45 Gy in 25 fractions, starting at day 16, is being explored in a phase II study at our institution.
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Affiliation(s)
- Z Kassam
- Department of Radiation Oncology, Princess Margaret Hospital, Toronto ON.
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Postoperative chemoradiotherapy in gastric cancer: a phase I study of radiotherapy with dose escalation of oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX regimen). Med Oncol 2010; 28 Suppl 1:S274-9. [PMID: 21116880 DOI: 10.1007/s12032-010-9741-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Accepted: 11/04/2010] [Indexed: 02/05/2023]
Abstract
Concurrent chemoradiotherapy begins to be more and more widely accepted as a standard adjuvant treatment in gastric cancer. And oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) also reveals to be a very effective regimen in gastric cancer. But the safety and the dosages of FOLFOX combining with radiotherapy are still unknown. This study was to determine the maximum-tolerated dose and the dose-limiting toxicity of FOLFOX with higher-dose concurrent radiotherapy (RT) as adjuvant treatment in patients with gastric cancer. Patients with Stage II/III gastric cancer after surgery were recruited. They received one cycle of induction chemotherapy (standard FOLFOX4). Then, they received 50.4 Gy in 1.8-Gy fractions in combination with two cycles of concurrent FOLFOX, and oxaliplatin among this regimen was administered with escalating doses. Dose-limiting toxicity including grade 3 or grade 4 hematologic and nonhematologic toxicities was investigated. Fifteen patients were enrolled at the following dose levels: oxaliplatin 55 mg/m(2) (3 patients), 65 mg/m(2) (6 patients), and 75 mg/m(2) (6 patients). Dose-limiting toxicity was observed in 1 patient at 65 mg/m(2) (grade 4 leukopenia) and in 3 patients at 75 mg/m(2) (1 patient had grade 4 leukopenia, 1 had grade 3 thrombocytopenia, and 1 had grade 3 stomatitis). Combination chemotherapy FOLFOX with oxaliplatin 65 mg/m(2), d 1; leucovorin 200 mg/m(2), 2 h, d1-2; 5-fluorouracil 400 mg/m(2), iv, d 1-2 and 600 mg/m(2) civ, 22 h, d 1-2 given concurrently with RT (50.4 Gy) can be recommended as a safer and preferable regimen for the adjuvant treatment of patients with gastric cancer.
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19
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Time-dependent changes in CT of radiation-induced liver injury: A preliminary study in gastric cancer patients. ACTA ACUST UNITED AC 2010; 30:683-6. [DOI: 10.1007/s11596-010-0565-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2010] [Indexed: 10/18/2022]
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Sclafani F, Gullo G, Santoro A. Postoperative Chemoradiotherapy or Surgery Alone for Gastric Cancer: The Plausibility of the Question and Pertinence of the Answer. J Clin Oncol 2010; 28:e615-6; author reply e617-8. [DOI: 10.1200/jco.2010.30.8023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Francesco Sclafani
- Istituto Clinico Humanitas, Istituto Di Ricovero e Cura a Carattere Scientifico, Rozzano, Italy; and St Vincent's University Hospital, Dublin, Ireland
| | | | - Armando Santoro
- Istituto Clinico Humanitas, Istituto Di Ricovero e Cura a Carattere Scientifico, Rozzano, Italy
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Sun Z, Xu HM. Stage and microscopic positive margins in the treatment of patients with gastric cancer. Ann Surg Oncol 2010; 17:943-5. [PMID: 20039214 DOI: 10.1245/s10434-009-0873-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Dikken JL, Jansen EPM, Cats A, Bakker B, Hartgrink HH, Kranenbarg EMK, Boot H, Putter H, Peeters KCMJ, van de Velde CJH, Verheij M. Impact of the extent of surgery and postoperative chemoradiotherapy on recurrence patterns in gastric cancer. J Clin Oncol 2010; 28:2430-6. [PMID: 20368551 DOI: 10.1200/jco.2009.26.9654] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
PURPOSE The Intergroup 0116 trial has demonstrated that postoperative chemoradiotherapy (CRT) improves survival in gastric cancer. We retrospectively compared survival and recurrence patterns in two phase I/II studies evaluating more intensified postoperative CRT with those from the Dutch Gastric Cancer Group Trial (DGCT) that randomly assigned patients between D1 and D2 lymphadenectomy. PATIENTS AND METHODS Survival and recurrence patterns of 91 patients with adenocarcinoma of the stomach who had received surgery followed by radiotherapy combined with fluorouracil and leucovorin (n = 5), capecitabine (n = 39), or capecitabine and cisplatin (n = 47) were analyzed and compared with survival and recurrence patterns of 694 patients from the DGCT (D1, n = 369; D2, n = 325). For both groups, the Maruyama Index of Unresected Disease (MI) was calculated and correlated with survival and recurrence patterns. RESULTS With a median follow-up of 19 months in the CRT group, local recurrence rate after 2 years was significantly higher in the surgery only (DGCT) group (17% v 5%; P = .0015). Separate analysis of CRT patients who underwent a D1 dissection (n = 39) versus DGCT-D1 (n = 369) showed fewer local recurrences after chemoradiotherapy (2% v 8%; P = .001), whereas comparison of CRT-D2 (n = 25) versus DGCT-D2 (n = 325) demonstrated no significant difference. CRT significantly improved survival after a microscopically irradical (R1) resection. The MI was found to be a strong independent predictor of survival. CONCLUSION After D1 surgery, the addition of postoperative CRT had a major impact on local recurrence in resectable gastric cancer.
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Affiliation(s)
- Johan L Dikken
- Leiden University Medical Center, Leiden, the Netherlands
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Jansen EPM, Boot H, Dubbelman R, Verheij M, Cats A. Postoperative chemoradiotherapy in gastric cancer--a phase I-II study of radiotherapy with dose escalation of weekly cisplatin and daily capecitabine chemotherapy. Ann Oncol 2009; 21:530-534. [PMID: 19690058 DOI: 10.1093/annonc/mdp345] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Postoperative chemoradiotherapy with concurrent 5-fluorouracil improves gastric cancer outcome. We previously demonstrated that chemoradiotherapy with a more intensified--and therefore potentially more effective--schedule with daily cisplatin and oral capecitabine is feasible. Because such an intensive schedule requires an extensive logistic infrastructure which is not available in every hospital, we additionally investigated the tolerability of this combined regimen with weekly instead of daily cisplatin in a dose-escalation study. PATIENTS AND METHODS After R0 or R1 resection, treatment initiated with capecitabine 1000 mg/m(2) b.i.d. for 2 weeks and 1-week rest. Subsequently, patients received capecitabine (575-650 mg/m(2) orally b.i.d., 5 days/week) and cisplatin (20-25 mg/m(2) i.v., once weekly) according to a predefined dose-escalation schedule concurrent with radiation. Radiotherapy was given to a fixed total dose of 45 Gy in 25 fractions. RESULTS Thirty-one patients were eligible and started treatment. During chemoradiotherapy, seven patients developed 10 items of grade III and one episode of grade IV (mainly hematological) toxicity (National Cancer Institute-Common Toxicity Criteria version 3.0). The maximum tolerable dose was determined to be for cisplatin 20 mg/m(2) i.v. weekly and for capecitabine 575 mg/m(2) b.i.d. orally. CONCLUSIONS This phase I-II study demonstrated that postoperative chemoradiotherapy with weekly cisplatin and daily capecitabine is feasible in gastric cancer at the defined dose level. This schedule is currently being tested as the experimental arm in a phase III multicenter study (CRITICS: chemoradiotherapy after induction chemotherapy in cancer of the stomach; Clinicaltrials.gov NCT 00407186).
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Affiliation(s)
| | - H Boot
- Department of Gastroenterology and Hepatology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - R Dubbelman
- Department of Gastroenterology and Hepatology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | | | - A Cats
- Department of Gastroenterology and Hepatology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
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Abstract
Gastric cancer is the second most frequent cause of cancer death worldwide, although much geographical variation in incidence exists. Prevention and personalised treatment are regarded as the best options to reduce gastric cancer mortality rates. Prevention strategies should be based on specific risk profiles, including Helicobacter pylori genotype, host gene polymorphisms, presence of precursor lesions, and environmental factors. Although adequate surgery remains the cornerstone of gastric cancer treatment, this single modality treatment seems to have reached its maximum achievable effect for local control and survival. Minimally invasive techniques can be used for treatment of early gastric cancers. Achievement of locoregional control for advanced disease remains very difficult. Extended resections that are standard practice in some Asian countries have not been shown to be as effective in other developed countries. We present an update of the incidence, causes, pathology, and treatment of gastric cancer, consisting of surgery, new strategies with neoadjuvant and adjuvant chemotherapy or radiotherapy, or both, novel treatment strategies using gene signatures, and the effect of caseload on patient outcomes.
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Affiliation(s)
- Henk H Hartgrink
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
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25
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Hartgrink HH, Jansen EPM, van Grieken NCT, van de Velde CJH. Gastric cancer. LANCET (LONDON, ENGLAND) 2009. [PMID: 19625077 DOI: 10.1016/s0140-6736(09)] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Gastric cancer is the second most frequent cause of cancer death worldwide, although much geographical variation in incidence exists. Prevention and personalised treatment are regarded as the best options to reduce gastric cancer mortality rates. Prevention strategies should be based on specific risk profiles, including Helicobacter pylori genotype, host gene polymorphisms, presence of precursor lesions, and environmental factors. Although adequate surgery remains the cornerstone of gastric cancer treatment, this single modality treatment seems to have reached its maximum achievable effect for local control and survival. Minimally invasive techniques can be used for treatment of early gastric cancers. Achievement of locoregional control for advanced disease remains very difficult. Extended resections that are standard practice in some Asian countries have not been shown to be as effective in other developed countries. We present an update of the incidence, causes, pathology, and treatment of gastric cancer, consisting of surgery, new strategies with neoadjuvant and adjuvant chemotherapy or radiotherapy, or both, novel treatment strategies using gene signatures, and the effect of caseload on patient outcomes.
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Affiliation(s)
- Henk H Hartgrink
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
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Hofheinz RD, Wenz F, Lukan N, Mai S, Kripp M, Staiger W, Schwarzbach M, Willeke F, Möhler M, Post S, Hochhaus A. Oxaliplatin and capecitabine-based chemoradiotherapy for gastric cancer--an extended phase I MARGIT and AIO trial. Int J Radiat Oncol Biol Phys 2008; 73:142-7. [PMID: 18539404 DOI: 10.1016/j.ijrobp.2008.04.033] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2008] [Revised: 04/03/2008] [Accepted: 04/07/2008] [Indexed: 11/15/2022]
Abstract
PURPOSE Adjuvant 5-fluorouracil-based chemoradiotherapy has been shown to improve the prognosis of gastric cancer. To optimize these results, in the present study oxaliplatin and capecitabine were used instead of 5-fluorouracil. We sought to determine the maximum tolerated dose and the dose-limiting toxicities (DLT) of these drugs in combination with intensity-modulated radiotherapy. METHODS AND MATERIALS Patients with resected adenocarcinoma of the stomach or the gastroesophageal junction were included. They received two cycles of induction chemotherapy (oxaliplatin and capecitabine [XelOx] regimen). Using standard Phase I methodology, patients received 45 Gy in 1.8-Gy fractions either in combination with capecitabine 825 mg m(-1) twice a day (Dose Level [DL] I) or capecitabine in combination with weekly oxaliplatin 40 or 50 mg m(-1) (DL II and III). After the completion of chemoradiation, two additional cycles of XelOx were scheduled. RESULTS A total of 32 patients were recruited. Only 1 of 6 patients evaluable on DL I had DLT. Of the first 6 patients on DL II, 1 patient experienced DLT, and 3 of the remaining patients had Grade 3 toxicity. Therefore, DL II was defined as the maximum tolerated dose and a total of 20 patients were treated at this DL. The most frequently observed toxicities (Common Toxicity Criteria Grades 1, 2 and 3) were, respectively, leukocytopenia in 5, 5, and 4 patients; nausea in 3, 7, and 3; and diarrhea in 4, 0, and 1. CONCLUSIONS In summary, capecitabine 825 mg m(-1) twice a day (Days 1-33) and weekly oxaliplatin 40 mg m(-1) was safe and tolerable in combination with intensity-modulated radiotherapy. Furthermore, four cycles of XelOx could be applied before and after chemoradiotherapy in two thirds of the patients.
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Affiliation(s)
- Ralf-Dieter Hofheinz
- Onkologisches Zentrum, III. Medizinische Klinik Mannheim, Medizinische Fakultät Mannheim der Universität Heidelberg, Heidelberg, Germany
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