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Originally published as JCO Early Release 10.1200/JCO.2005.81.908 on March 28 2005 © 2005 American Society of Clinical Oncology.
Thromboembolic Events in Gastric Cancer: High Incidence in Patients Receiving Irinotecan- and Bevacizumab-Based TherapyMemorial Sloan-Kettering Cancer Center, New York, NY To the Editor: Thromboembolic events occur commonly in gastric cancer, but are infrequently reported in phase II and III clinical trials. We are performing two parallel clinical trials containing irinotecan-based therapy and have noted a high incidence of venous and arterial thromboembolic events. These events may be related to the therapy administered. However, the high incidence may also reflect the hypercoaguable state of the disease. Investigators and practicing oncologists should be aware of these potential toxicities in the treatment of gastric cancer. Irinotecan is a relatively new drug in the treatment of gastric cancer.1 Although irinotecan-based therapy may be associated with fatal vascular thromboembolic events in the treatment of colorectal cancer,2 a similar association has not been reported in the treatment of gastric cancer.3-7 Bevacizumab is another drug that may be associated with thromboembolic events,8 although this was not substantiated in phase III evaluation.9
We are performing a phase II clinical trial of bevacizumab, irinotecan, and cisplatin in metastatic or unresectable gastric cancer (National Cancer Institute [NCI] protocol 6447), as well as a phase II study of preoperative chemotherapy with irinotecan and cisplatin (without bevacizumab) for locally advanced gastric cancer (NCI protocol 5917). Each protocol was reviewed and approved by the institutional review board of Memorial Sloan-Kettering Cancer Center (New York, NY) and by the NCI. Written, informed consent was obtained from each patient. Routine inclusion and exclusion criteria were used for both studies, with additional exclusion criteria for protocol 6447 including uncontrolled hypertension (> 160/90 mmHg on medication), major surgical procedure or trauma within 28 days of starting therapy, chronic daily use of aspirin (> 325 mg/d), Patients included in this analysis have either had a thromboembolic event or have completed at least two cycles of therapy as of December 10, 2004. Because virtually identical eligibility criteria were used for both studies, patients were well matched and there were no significant differences in the comorbidity spectrum of patients enrolled on both studies. We have observed thromboembolic events in six (25%) of 24 patients (95% CI, 11% to 45%) enrolled on protocol 6447 as detailed in Table 1. Patients 1 and 2 had a deep venous thrombosis (DVT) and remain on study, having demonstrated response to therapy. Patients 3 through 6 had incidental pulmonary emboli (PEs) identified at the time of routine computed tomography (CT) scans at the end of cycle 2 (patients 3 and 5), cycle 4 (patient 4), and cycle 6 (patient 6), and were removed from the study as per protocol. Patient 3 and 4 had DVTs identified before their CT scan, whereas patients 5 and 6 did not. Patients 3 and 4 remain on therapy with irinotecan and cisplatin, but without bevacizumab, and patient 6 proceeded with salvage therapy due to disease progression. Except for patient 3, who had recently been on a cross-Atlantic air flight, none of the patients had a risk factor for thrombosis other than gastric cancer. There was no evidence of thrombus progression once anticoagulation began.
We have noted thromboembolic events in eight (30%) of 26 enrolled patients (95% CI, 15% to 51%) on protocol 5917, as shown in Table 2. Patients 1 and 4 developed thromboses in the immediate postoperative period, unrelated to chemotherapy. Patients 2 and 6 were found to have a PE incidentally on preoperative staging CT following completion of four cycles of chemotherapy, both of whom also had a lower extremity DVT. Patient 3 developed a DVT at the onset of cycle 3. Each patient proceeded to gastric resection without consequence. Patients 5, 7, and 8 each had an arterial thrombotic event. Patient 5 had a transient renal artery thrombosis with a complete right kidney infarct that was identified at the time of a gastric perforation. This patient recovered well and received additional cisplatin-based chemotherapy without consequence. Patients 7 and 8 both developed cerebrovascular accidents (CVA) within their first cycle of therapy. Both patients had other risk factors for the development of a CVA. Neither patient received further chemotherapy nor proceeded with resection due to their poor performance status following the CVA.
Altogether, we have observed 14 (28%) venous or arterial thromboembolic events in 50 patients enrolled on both studies (95% CI, 16% to 41%). Excluding the patients who developed a thrombus following surgery, and patient 5 on protocol 5917 who developed a transient renal artery blood clot in the setting of a gastric perforation, the incidence of thromboembolic events that are possibly attributable to chemotherapy is 11 (22%) of 50 (95% CI, 12% to 34%). The incidence of thromboembolic events with and without bevacizumab is not significantly different, and there was no difference in the pattern of venous thromboses. All patients who received anticoagulation have not subsequently experienced significant gastrointestinal bleeding events, including six patients who had their primary tumor in place, or further complications from their thrombus. All six patients with a PE were identified incidentally on CT scanning without antecedent symptoms of sudden onset shortness of breath, palpitations, or chest discomfort. Four of these patients had evidence of a DVT identified at the time of the PE or previously. There were a total of seven DVTs in this group as well, only one of which was asymptomatic. We are reporting a high incidence of thromboembolic events in patients with gastric cancer being treated with irinotecan- and bevacizumab-based chemotherapy. The sample size of these studies do not allow for definitive conclusions regarding the relation of bevacizumab to the occurrence of thromboembolic events. The reported incidence of venous thromboembolic phenomenon in gastric cancer is 10% to 15%.10,11 However, on our review of recent large clinical trials, these events are unlisted as observed events,12-15 except as complications of central venous catheters.16 It is therefore possible that this toxicity is under-reported in the literature. Conversely, we note that irinotecan-based therapy in the treatment of colorectal cancer has been associated with fatal venous and arterial vascular events. We similarly observed both venous and arterial thromboembolic events in our parallel studies. This raises the question of whether the incidence of thrombotic events that we have observed is related to irinotecan therapy in this disease. Our high rate of incidental PE may also reflect improvements in the resolution of routine CT scans. Random assignment studies comparing irinotecan-based therapy to non–irinotecan-based therapy and bevacizumab-based therapy to non–bevacizumab-based therapy may provide some insight as to the relative contribution of each drug in the development of thromboembolic events during the treatment of gastric cancer. Notably, one recent randomized phase II study comparing irinotecan-based therapy to non–irinotecan-based therapy in gastric cancer did not report the occurrence of any thromboembolic events in either arm of the study.5 A second phase III study comparing irinotecan and fluorouracil infusion to cisplatin and fluorouracil infusion has recently completed accrual, and these data are eagerly awaited. We remain uncertain as to whether our observations represent a clustering of events related to the hypercoaguable state of this disease or to the therapy administered. Investigators and practicing oncologists should be aware of these potential toxicities in the treatment of gastric cancer. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant: David Ilson, Pfizer Pharmaceutical, Sanofi; David P. Kelsen, Pfizer Pharmaceutical. Honoraria: David Ilson, Pfizer Pharmaceutical. Research Funding: Manish A. Shah, Pfizer Pharmaceutical; David Ilson, Pfizer Pharmaceutical, Aventis. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue. Acknowledgment Supported by American Society of Clinical Oncology Career Development Award 2001 (M.S.) and the National Cancer Institute Phase II Contract (D.K.). REFERENCES 1. Shah MA, Schwartz GK: Treatment of metastatic esophagus and gastric cancer. Semin Oncol 31:574-587, 2004[CrossRef][Medline]
2. Rothenberg ML, Meropol NJ, Poplin EA, et al: Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: Summary findings of an independent panel. J Clin Oncol 19:3801-3807, 2001
3. Souglakos J, Syrigos KN, Potamianou A, et al: Combination of irinotecan (CPT-11) plus oxaliplatin (L-OHP) as first-line treatment in locally advanced or metastatic gastric cancer: A multicenter phase II trial. Ann Oncol 15:1204-1209, 2004
4. Pozzo C, Barone C, Szanto J, et al: Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: Results of a randomized phase II study. Ann Oncol 15:1773-1781, 2004
5. Bouche O, Raoul JL, Bonnetain F, et al: Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LF5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: A Federation Francophone de Cancerologie Digestive Group Study - FCCD 9803. J Clin Oncol 22:4319-4328, 2004
6. Boku N, Ohtsu A, Shimada Y, et al: Phase II study of a combination of irinotecan and cisplatin against metastatic gastric cancer. J Clin Oncol 17:319-323, 1999 7. Ajani JA, Baker J, Pisters P, et al: CPT-11 plus cisplatin in patients with advanced, untreated gastric or gastroesophageal junction carcinoma. Cancer 94:641-646, 2002[CrossRef][Medline]
8. Kabbinavar F, Hurwitz H, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003
9. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 10. Caine GJ, Stonelake PS, Lip GYH, et al: The hypercoagulable state of malignancy: Pathogenesis and current debate. Neoplasia 4:465-473, 2002[CrossRef][Medline] 11. Levitan N, Dowlati A, Remick SC, et al: Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore) 78:285-291, 1999[CrossRef][Medline]
12. Vanhoefer U, Rougier P, Wilke H, et al: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18:2648-2657, 2000
13. Ohtsu A, Shimada Y, Shirao K, et al: Randomized phase III trial of fluorouracil versus flourouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol 21:54-59, 2003 14. Icli F, Celik I, Aykan F, et al: A randomized phase III trial of etoposide, epirubicin, and cisplatin versus 5-fluorouracil, epirubicin, and cisplatin in the treatment of patients with advanced gastric carcinoma. Cancer 83:2475-2480, 1998[CrossRef][Medline]
15. Tebbutt NC, Norman A, Cunningham D, et al: A multicentre, randomised phase III trial comparing protracted venous infusion (PVI) 5-fluorouracil with PVI plus mitomycin C in patients with inoperable oesophago-gastric cancer. Ann Oncol 13:1568-1575, 2002
16. Ross P, Nicolson M, Cunningham D, et al: Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20:1996-2004, 2002
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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1+ protienuria, or evidence of bleeding diathesis or coagulopathy. In both studies, patients received cisplatin 30 mg/m
