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Multicenter Phase II Study of Irinotecan, Cisplatin, and Bevacizumab in Patients With Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

Manish A. Shah, Ramesh K. Ramanathan, David H. Ilson, Alissa Levnor, David D'Adamo, Eileen O'Reilly, Archie Tse, Robin Trocola, Lawrence Schwartz, Marinela Capanu, Gary K. Schwartz, David P. Kelsen

From the Memorial Sloan-Kettering Cancer Center, New York, NY; and the University of Pittsburgh Cancer Institute, Pittsburgh, PA

Address reprint requests to Manish A. Shah, MD, 1275 York Ave, Howard 910, New York NY 10021; e-mail: shah1{at}mskcc.org

	ABSTRACT

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Purpose Bevacizumab improves survival in several solid tumor malignancies when combined with chemotherapy. We evaluated the efficacy and safety of the addition of bevacizumab to chemotherapy in the treatment of gastric and gastroesophageal junction (GEJ) adenocarcinoma.

Patients and Methods Forty-seven patients with metastatic or unresectable gastric/GEJ adenocarcinoma were treated with bevacizumab 15 mg/kg on day 1, irinotecan 65 mg/m², and cisplatin 30 mg/m² on days 1 and 8, every 21 days. The primary end point was to demonstrate a 50% improvement in time to progression over historical values. Secondary end points included safety, response, and survival.

Results Patient characteristics were as follows: median age 59 years (range, 25 to 75); Karnofsky performance status 90% (70% to 100%); male:female, 34:13; and gastric/GEJ, 24:23. With a median follow-up of 12.2 months, median time to progression was 8.3 months (95% CI, 5.5 to 9.9 months). In 34 patients with measurable disease, the overall response rate was 65% (95% CI, 46% to 80%). Median survival was 12.3 months (95% CI, 11.3 to 17.2 months). We observed no increase in chemotherapy related toxicity. Possible bevacizumab-related toxicity included a 28% incidence of grade 3 hypertension, two patients with a gastric perforation and one patient with a near perforation (6%), and one patient with a myocardial infarction (2%). Grade 3 to 4 thromboembolic events occurred in 25% of patients. Although the primary tumor was unresected in 40 patients, we observed only one patient with a significant upper gastrointestinal bleed.

Conclusion Bevacizumab can be safely given with chemotherapy even with primary gastric and GEJ tumors in place. The response rate, time to disease progression (TTP), and overall survival are encouraging, with TTP improved over historical controls by 75%. Further development of bevacizumab in gastric and GEJ cancers is warranted.

	INTRODUCTION

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Gastric cancer is an aggressive malignancy with median survival for metastatic or unresectable disease of approximately 7 to 10 months. On a global basis, gastric cancer is the third most prevalent malignancy, with an estimated 933,293 new patients in 2002, and the second leading cancer cause of death (nearly 700,000 deaths annually).¹ In the United States, an estimated 22,280 cases of gastric cancer will be diagnosed and 11,260 patients will die from this disease in 2006.² Furthermore, the incidence of gastroesophageal junction (GEJ) adenocarcinoma has risen faster than any other malignancy in the last quarter century in the United States and other Western countries.^3,4

Conventional chemotherapy for metastatic gastric cancer remains palliative with 2-year survival between 10% and 15% and few patients demonstrating long-term survival. The combination of irinotecan and cisplatin has been examined in several phase II studies.^5-8 Weekly^5,7 and bimonthly⁶ schedules were well-tolerated, with primary dose-limiting toxicity being myelosuppression. Response rates ranged from 42% to 58%, with occasional complete responses. However, the median time to progression (TTP) in these studies ranged from 4.2 to 5.8 months and median survival remains approximately 9 months.^5,6

Inhibition of tumor angiogenesis represents a new therapeutic strategy in the treatment of solid tumors. Vascular endothelial growth factor (VEGF) functions as a potent mitogen for vascular endothelial cells, promoting their migration and organization for the neovascularization of micrometastases. VEGF is expressed in gastric cancer, and its expression increases with increasing stage and tumor burden.^9,10 VEGF expression is a negative prognostic factor for survival in patients with gastric cancer.^11,12 Inhibition of VEGF activity by an immunoneutralizing antibody was effective in a gastric cancer xenograft model.¹³ These data suggest that VEGF and angiogenesis appear to play an important role in the pathogenesis and progression of this disease and its inhibition may be of therapeutic value.

Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) is a recombinant, humanized monoclonal antibody that targets VEGF. When administered in combination with chemotherapy, significant improvements in antitumor efficacy were observed in colorectal,¹⁴ lung,¹⁵ and breast cancers.¹⁶ Herein, we report the efficacy and safety of the combination of weekly irinotecan and cisplatin administered with bevacizumab in a multicenter phase II clinical trial for patients with metastatic or unresectable gastric and GEJ adenocarcinoma.

	PATIENTS AND METHODS

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Patient Eligibility
The study was conducted under a protocol reviewed and approved by the National Cancer Institute/Cancer Therapy Evaluation Program (National Cancer Institute protocol #6447) and the institutional review boards at the Memorial Sloan-Kettering (New York, NY) and University of Pittsburgh (Pittsburgh, PA) cancer centers. All patients provided written informed consent. Patients were eligible if they were 18 years of age or older with a pathologically confirmed diagnosis of gastric or GEJ adenocarcinoma. Patients were required to have previously untreated metastatic or unresectable disease. Patients may have received prior adjuvant or neoadjuvant treatment for locoregional resectable disease, but any prior therapy could not have included irinotecan or cisplatin and must have been completed at least 3 weeks before study initiation (6 weeks for mitomycin-c). Patients were required to have a Karnofsky performance status of at least 60%, and adequate organ function as defined as: total neutrophil count (absolute neutrophil count) 1,500/mm³, platelet count 75,000/mm³, serum creatinine 1.5 mg/dL, proteinuria 500 mg/d, total serum bilirubin 1.5 mg/dL, and serum AST and ALT three times the upper limit of normal or five times the upper limit of normal in the case of known liver metastases. Full- or partial-dose anticoagulation was allowed, although patients not on anticoagulation were required to have a prothrombin time (international normalized ratio) 1.5 and a partial thromboplastin time 3 seconds above the upper limits of normal. Patients were required to have radiographically assessable, nonmeasurable disease or measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria.¹⁷

Patients with another neoplastic malignancy within the past 3 years (excluding basal cell carcinoma of the skin, cervical carcinoma in situ, or nonmetastatic prostate cancer adequately treated), a history of or active brain metastases, uncontrolled intercurrent illness including uncontrolled blood pressure (for example, 160/90 mmHg on medication), arterial thrombotic events such as myocardial infarction, unstable angina, cerebrovascular event, or transient ischemic attack within 6 months, or peripheral vascular disease requiring surgical management were excluded. Patients were also not allowed to concurrently use aspirin 325 mg or greater daily, have evidence of bleeding diathesis or coagulopathy, or hypersensitivity to Chinese hamster ovary products.

Pretreatment Evaluation and Treatment Plan
At baseline, patients underwent a full medical history and physical examination. Laboratory assessments at baseline included CBC with differential, prothrombin time, partial prothromboplastin time, electrolytes, blood urea nitrogen, creatinine, liver function tests, lactate dehydrogenase, glucose, and urinalysis. For females of childbearing potential, a negative serum pregnancy test was also required. Patients underwent a baseline ECG and computed tomography (CT) scan of chest, abdomen, and pelvis.

Patients received cisplatin 30 mg/m² infused over 30 minutes followed by irinotecan 65 mg/m² over 30 minutes on days 1 and 8, and bevacizumab 15 mg/kg was administered on day 1 of every 21 day cycle. Patients received 1 L of normal saline hydration and standard delayed emesis prophylaxis (for example, decadron + 5-HT3 inhibition, with aprepitant when this drug became available as well). Therapy was administered in an outpatient setting under medical supervision.

Evaluation on Study and Dose Attenuation
All toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 3.0.¹⁸ Patients were seen before treatment on days 1 and 8 of cycle 1 and before the initiation of each subsequent cycle. Cisplatin was dose reduced to 20 mg/m² for creatinine 1.8 to 2.0 mg/dL. Cisplatin was held for creatinine 2.1 mg/dL. Irinotecan was dose reduced sequentially to 50 mg/m² and to 40 mg/m² for grade 3 to 4 toxicity or for a treatment-related toxicity causing delay in treatment. A cycle was started if the absolute neutrophil count 1,500/mm³ and platelet count 75,000/mm³, and no grade 3 to 4 toxicity was observed. Irinotecan was held for grade 2 diarrhea and both irinotecan and cisplatin were held for grade 3 to 4 ototoxocity or neuropathy. Bevacizumab was held for grade 3 to 4 AST, ALT or bilirubin elevations, for proteinuria more than 2 g/24 hour, and for grade 4 hypertension or uncontrolled grade 3 hypertension. Patients who had a grade 2 to 3 hemorrhage and also required anticoagulation or patients with a grade 4 hemorrhage were removed from study. If irinotecan or cisplatin was held at the start of a cycle, bevacizumab was allowed to be administered, and the treatment was then realigned with the next treatment cycle.

Patients with a grade 4 thromboembolic event (TE) were initially discontinued from study. After our observation of a high rate of TE in gastric cancer independent of bevacizumab,¹⁹ the protocol was amended to allow patients with asymptomatic grade 4 TE to remain on study, provided they had no evidence of bleeding on full-dose anticoagulation. Due to cumulative cisplatin nephrotoxicity, the protocol was amended to allow stable and responding patients to discontinue cisplatin and/or irinotecan and continue bevacizumab after the development of cumulative toxicity.

Tumor assessments were performed every 6 weeks for the first 10 cycles, and every 9 weeks thereafter. For patients with assessable, nonmeasurable disease, RECIST response definitions included complete response (resolution of assessable disease), stable disease (presence of assessable disease), or progression (new sites of disease or clinical progression). The primary tumor within the stomach or GEJ was considered assessable, but nonmeasurable. Confirmatory scans were obtained at least 4 weeks after initial documentation of objective complete or partial response or stable disease. Radiographs were reviewed by a protocol specified radiologist (L.S.).

Biostatistics
The primary aim of this study was to test the hypothesis that TTP will improve by 50% (for example, from 5 months historical estimate to 7.5 months). As per RECIST criteria, any evidence of progression in assessable lesions, measurable lesions, or the development of new lesions, would qualify as disease progression. TTP was defined as the time from initiation of therapy to disease progression or death, removal from study due to excessive treatment related toxicity with the exception of asymptomatic pulmonary embolism, or other unrelated comorbidity. The study was designed to have a 90% power to show an improvement in median TTP from 5 months to 7.5 months with a 10% type I error, two sided, assuming exponential progression-free survival times. A sample size of 47 patients was required to meet these requirements. We also evaluated the median time to study removal, censoring only those patients who remained on study at the time of this analysis. Our secondary aim was to establish other measures of efficacy, including response rate in patients with measurable disease and survival. Progression-free survival and overall survival curves were generated using the Kaplan-Meier method and compared by the log-rank test. Exact 95% CIs were provided for proportions.

Study Monitoring
The Memorial Sloan-Kettering data and safety monitoring board reviewed this study quarterly for safety and toxicity. The Memorial Sloan-Kettering response assessment review committee independently reviewed the radiographic response assessment annually. The study also underwent an independent external National Cancer Institute-directed audit of 33% of enrolled patients on May 18, 2005 to May 19, 2005. No significant protocol discrepancies or deviations were noted.

	RESULTS

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Patient Characteristics
Between May 4, 2004, and July 29, 2005, 80 patients were screened to enroll 47 patients (37 Memorial Sloan-Kettering Cancer Center, 10 University of Pittsburgh Cancer Center) on protocol. Enrolled patient characteristics are provided in Table 1. There was an approximate equal distribution of GEJ and gastric cancers. The majority of patients had their primary malignancy unresected and were previously untreated (85% each). Sites of metastases commonly included the liver (49%), lymph nodes (40%), and peritoneum (34%).

View larger version (7K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier curve for time to disease progression (TTP; n = 47). Median TTP was 8.3 months (95% CI, 5.5 to 9.9 months).

Median overall survival was 12.3 months (95%CI, 11.3 to 17.2 months; Fig 2). Response to therapy was assessable in all 47 enrolled patients. Of 34 patients with measurable disease, 20 patients achieved a partial response and two patients achieved a complete response for an overall response rate of 65% (exact 95%CI, 46% to 80%). For patients with assessable, nonmeasurable disease, 12 patients had stable disease, and one patient had disease progression. Including these nonmeasurable patients, the overall response rate was 46.8% (exact 95% CI, 38% to 68%). Patients with measurable disease demonstrated a significant improvement in survival when compared with patients with nonmeasurable disease (median survival of 15.4 v 8.4 months; log-rank P = .04; Figure 3).

View larger version (6K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier curve for overall survival (n = 47). Median overall survival was 12.3 months (95% CI, 11.3 to 17.2 months).

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Kaplan-Meier curve for overall survival in patients with measurable and nonmeasurable disease.

Bevacizumab-related toxicity included grade 3 hypertension in 13 patients (28%). Grade 3 hypertension developed a median of 6 months after initiation of therapy (range, 4 to 12 months). One patient with a history of coronary artery disease developed a myocardial infarction. Two patients developed a gastric perforation, both at the time of disease progression. One event occurred 1 week after initiation of therapy and was emergently surgically repaired. The second event occurred 3 weeks after study removal for disease progression, 4.9 months after study initiation. This patient died 3 days after the event without an operation. One patient developed a near perforation identified radiographically in the setting of a significant response to therapy after cycle 2. This patient was removed from study, treated conservatively with antiulcer therapy, and then resumed irinotecan and cisplatin without bevacizumab 1 month later without consequence. Including this near perforation, the overall incidence of perforation was three of 47 patients, or 6% (exact 95% CI, 1% to 18%). Two patients developed a grade 3 hemorrhage (4%), one in the setting of anticoagulation for a TE with the primary tumor unresected.

We noted cumulative grade 2 to 3 neurotoxicity and nephrotoxicity with increasing treatment durations. Seven patients (15%) developed neuropathy (two patients with grade 3), and nine patients (19%) developed grade 2 renal insufficiency. The incidence of these toxicities progressively increased beyond 6 months of therapy. Twenty-two patients (47%) received second-line or greater chemotherapy.

	DISCUSSION

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Systemic chemotherapy for metastatic or unresectable gastric/GEJ cancer improves survival and quality of life over best supportive care. Standard cisplatin-based treatments yield response rates ranging from 20% to 40% and median survival of 7 to10 months.²⁰ Despite recent chemotherapeutic advances, median survival for advanced disease remains less than 10 months.^21-23 Based on preclinical evaluation and clinical studies in other malignancies, we examined the addition of bevacizumab to chemotherapy in this disease.

We chose the weekly combination of irinotecan and cisplatin based on early reports of efficacy and safety of this chemotherapy regimen. In three pooled studies, the approximate response rate to irinotecan and cisplatin was 50%, approximate median TTP was 5 months, and survival remains 8 to 9 months.^5-7 More recently, Pozzo and colleagues⁸ administered irinotecan 200 mg/m² and cisplatin 60 mg/m² every 3 weeks and observed considerable toxicity with apparent reduced efficacy with a response rate of 32%, median TTP of 4.2 months, and survival of 6.9 months. In this study, with the addition of bevacizumab, median TTP was 8.3 months and median overall survival was 12.3 months. This study included patients with assessable, but nonmeasurable disease. These patients had a reduced TTP and significantly reduced survival than measurable patients who are more commonly enrolled in phase II studies, suggesting this parameter may be an important stratification variable in future random assignment studies.

We did not observe an increase in chemotherapy-related toxicity. Bevacizumab specific toxicity included grade 3 hypertension in 28% of enrolled patients. Grade 3 hypertension occurred a median of 6 months after study initiation and may be related to cisplatin induced renal insufficiency or cumulative bevacizumab exposure. Further, the 5-mg/m²/wk dose of bevacizumab may be associated with a higher rate of grade 3 to 4 hypertension,²⁴ thus providing the rationale for evaluating a reduced dose of bevacizumab in future studies.

Patients with metastatic gastric and GEJ malignancies often have their primary tumor unresected, thus heightening our awareness of potential rare but significant complications from bevacizumab including GI perforation or major GI hemorrhage. The incidence of perforation in gastric cancer is not well-defined and not commonly reported in therapeutic studies. In two surgical series, the incidence of gastric perforation is estimated to be 0.5% to 4%.^25,26 In these series, perforation was found more often in patients with advanced cancer with serosal invasion and lymph node metastases. Thus, the reported incidence may underestimate the perforation rate in patients with metastatic or unresectable disease. Our incidence of perforation is similar to these reports. A random assignment study with careful safety monitoring will be required to determine the relative impact of the addition of bevacizumab on the risk of perforation.

The occurrence of GI hemorrhage in advanced gastric cancer is also not well established, and was also not reported in several recent large advanced phase studies.^23,27,28 In a cohort study of 97 patients with metastatic gastric cancer to the peritoneum in which the primary tumor was left unresected, 33% of patients required blood transfusions and grade 3 to 4 bleeding from the tumor occurred in 8% of patients.²⁹ Our rate of grade 3 to 4 hemorrhage was similar at 4%.

The development of thromboembolic disease is another adverse event we noted not commonly reported in large therapeutic studies. We previously reported a 30% rate of TE in patients with locally advanced gastric cancer receiving irinotecan and cisplatin with or without bevacizumab.¹⁹ Based on our early experience, we amended our study to allow patients with grade 3 or asymptomatic grade 4 events to remain on study. These patients were able to remain on therapy after the TE for a median of 7.5 months, demonstrating a significant benefit of continuing therapy without significant toxicity. Our observations have led us to perform a closer examination of TE in solid tumors.³⁰ In a retrospective evaluation of TE in patients with solid tumors enrolled on clinical trials at the Memorial Sloan-Kettering Cancer Center (561 patients over 12 months), we found the incidence of a TE in GI malignancies to be 16% whereas in non–GI malignancies, the incidence was 3% (P < .0001). A larger study of the incidence and significance of TE in GI malignancies is now underway.

We conclude that bevacizumab can be added to chemotherapy safely and is active in the treatment of advanced gastric/GEJ adenocarcinoma; a phase III study is warranted both to document efficacy and to better evaluate potential bevacizumab specific toxicity. Bevacizumab can be given to patients with upper GI malignancies whose cancer is unresected without an increased risk of bleeding, even when therapeutic anticoagulation is necessary. These observations coupled with the high response to therapy may make this regimen attractive for preoperative evaluation in upper GI malignancies. Plans for advanced phase studies for resectable and metastatic disease are underway.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure 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 in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Ramesh K. Ramanathan Genentech Eileen O'Reilly Genentech Genentech David P. Kelsen Pfizer Inc

	Author Contributions

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Conception and design: Manish A. Shah, David H. Ilson, Lawrence Schwartz, Gary K. Schwartz, David P. Kelsen Financial support: Ramesh K. Ramanathan, David P. Kelsen Administrative support: Manish A. Shah, Alissa Levnor, Robin Trocola, David P. Kelsen Provision of study materials or patients: Manish A. Shah, Ramesh K. Ramanathan, David H. Ilson, David D'Adamo, Eileen O'Reilly, Archie Tse, Gary K. Schwartz Collection and assembly of data: Manish A. Shah, Alissa Levnor, David D'Adamo, Eileen O'Reilly, Archie Tse, Robin Trocola, Lawrence Schwartz, Marinela Capanu Data analysis and interpretation: Manish A. Shah, David H. Ilson, Lawrence Schwartz, Marinela Capanu, Gary K. Schwartz, David P. Kelsen Manuscript writing: Manish A. Shah, David P. Kelsen Final approval of manuscript: Manish A. Shah, Ramesh K. Ramanathan, David H. Ilson, Eileen O'Reilly, Marinela Capanu, Gary K. Schwartz, David P. Kelsen

 

	NOTES

 
Supported by Grant No. N01 CM62206 to the Memorial Sloan-Kettering Cancer Center and Grant No. U01 CA099168-01 to the University of Pittsburgh Medical Center and Cancer Institute.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005, and the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted June 30, 2006; accepted September 18, 2006.

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