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Journal of Clinical Oncology, Vol 24, No 12 (April 20), 2006: pp. 1898-1903 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.9130 Phase II Study of Gemcitabine and Oxaliplatin in Combination With Bevacizumab in Patients With Advanced Hepatocellular Carcinoma
From the Massachusetts General Hospital; Dana-Farber Cancer Institute; and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Address reprint requests to Andrew X. Zhu, MD, PhD, Tucker Gosnell Center for Gastrointestinal Cancers, Massachusetts General Hospital Cancer Center, 100 Blossom St, Cox 640, Boston, MA 02114; e-mail: azhu{at}partners.org
PURPOSE: Hepatocellular carcinoma (HCC) is a vascular tumor with poor prognosis. Given the reported activity of gemcitabine and oxaliplatin (GEMOX) in HCC and the potential benefits of targeting the vascular endothelial growth factor pathway with bevacizumab (B), a phase II study of GEMOX-B was undertaken to define efficacy and toxicity profiles in HCC patients. PATIENTS AND METHODS: Eligible patients had pathologically proven measurable unresectable or metastatic HCC. For cycle 1 (14 days), bevacizumab 10 mg/kg was administered alone intravenously on day 1. For cycle 2 and beyond (28 days/cycle), bevacizumab 10 mg/kg was administered on days 1 and 15, gemcitabine 1,000 mg/m2 was administered as a dose rate infusion at 10 mg/m2/min followed by oxaliplatin at 85 mg/m2 on days 2 and 16. RESULTS: Thirty-three patients were enrolled and 30 patients were assessable for efficacy. The objective response rate was 20%, and 27% of patients had stable disease. Median overall survival was 9.6 months (95% CI, 8.0 months to not available) and median progression-free survival (PFS) was 5.3 months (95% CI, 3.7 to 8.7 months); the PFS rate at 3 and 6 months was 70% (95% CI, 54% to 85%) and 48% (95% CI, 31% to 65%), respectively. The most common treatment-related grade 3 to 4 toxicities included leukopenia/neutropenia, transient elevation of aminotransferases, hypertension, and fatigue. CONCLUSION: GEMOX-B could be safely administered with close monitoring and had moderate antitumor activity for patients with advanced HCC. The high 6-month PFS rate is encouraging, and this regimen is worthy of further investigation.
Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death.1 In the United States, 17,550 new cancers of the liver and intrahepatic bile duct are expected in 2005, with an estimated 15,420 deaths.2 The incidence rates for HCC in the United States continued to increase steadily through 1998 and have doubled during the period of 1975 to 1995.3,4 Unresectable or metastatic HCC carries a poor prognosis and systemic therapy with cytotoxic agents provides little benefit.5 Improving survival for patients with metastatic HCC requires development of effective systemic therapy. Doxorubicin is considered the most active single agent. However, neither doxorubicin nor any other chemotherapeutic agent or combination has produced an improvement in patient survival rates.6,7 Despite initial impressive results of combination chemotherapy using cisplatin, interferon alfa, doxorubicin, and fluorouracil,8 the recently reported randomized phase III study failed to demonstrate that this combination improved overall survival when compared with single-agent doxorubicin.9 An effective systemic therapy with demonstrable palliative or survival benefit for patients with unresectable HCC has not been identified. The combination of gemcitabine and oxaliplatin (GEMOX) is a well-established regimen that initially demonstrated encouraging antitumor activity in pancreaticobiliary cancers in phase II studies.10,11 In a phase III study in pancreatic cancer, GEMOX was shown to be more active than gemcitabine alone, with improved response rate, progression-free survival (PFS) and clinical benefit; however, it failed to demonstrate a statistically significant advantage in overall survival.12 This regimen was tolerable with predictable toxicity and safety profiles. Taieb et al13 examined the GEMOX regimen in advanced HCC and demonstrated antitumor activity with a 19% clinical response rate and an acceptable toxicity profile. HCCs are vascular tumors and increased levels of vascular endothelial growth factor (VEGF) and microvessel density have been observed.14-16 High VEGF expression has been associated with inferior survival.17-19 Therefore, inhibition of angiogenesis represents a potential therapeutic target in HCC. Thalidomide, an agent with antiangiogenic activity,20 either alone or in combination with other agents, has had disappointing results in advanced HCC.21-23 This prompted us to examine other antiangiogenic agents with potentially enhanced efficacy. Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA), a recombinant, humanized monoclonal antibody that targets VEGF, has emerged as an important therapeutic agent in colorectal cancer.24 In addition to its direct antiangiogenic effects, bevacizumab may enhance chemotherapy administration by normalizing tumor vasculature and decreasing the elevated interstitial pressure in tumors.25,26 Given the reported activity of GEMOX and potential benefits of targeting the VEGF pathway with bevacizumab, a phase II study was undertaken to examine the efficacy and safety profiles of combining bevacizumab with GEMOX (GEMOX-B) in patients with unresectable or metastatic HCC.
Patient Selection The clinical trial was reviewed and approved by the Institutional Review Board at Dana-Farber/Harvard Cancer Center (Boston, MA). All patients were required to provide written informed consent before study participation according to institutional and federal guidelines. Eligibility criteria included the following: histologically proven measurable locally advanced, recurrent, or metastatic HCC; no more than two prior systemic chemotherapy regimens; age at least 18 years; Eastern Cooperative Oncology Group performance status of 0 to 1; Cancer of the Liver Italian Program score  327; and adequate hepatic, renal, and bone marrow functions (serum bilirubin 3.0 mg/dL, AST 7x the institutional upper limit of normal; serum creatinine 2.0 mg/dL; absolute neutrophil count  1.0 x 109/L, and a platelet count of 75 x 109/L). In addition, prior chemoembolization therapy was permitted if performed more than 4 weeks before study entry and measurable disease was present outside of the prior chemoembolization field, and patients who had received prior treatments should have had documented progressive disease before study entry. Exclusion criteria included a concurrent malignancy; significant medical comorbidities; clinically significant cardiovascular disease including uncontrolled hypertension, myocardial infarction, and unstable angina; New York Heart Association grade 2 or greater congestive heart failure; history of active bleeding; proteinuria at baseline (> 2 g protein/d); major surgery within 28 days before the initiation of study treatment; serious, nonhealing wound, ulcer, or bone fracture; pregnancy or lactation; known CNS metastases; or an inability to give written informed consent. Patients with radiographic findings of esophageal varices on computed tomography (CT) scans were allowed to participate in the study as long as they did not have active bleeding. Patients receiving anticoagulation for deep vein thrombosis were allowed to participate in the study with careful monitoring of prothrombin time.
Treatment Protocol Before study entry, patients underwent a physical examination, including an assessment of performance status, weight, and concurrent nonmalignant disease and therapy. Laboratory studies included a CBC; differential count; platelet count; biochemical (sodium, potassium, chloride, bicarbonate, glucose, uric acid, lactate dehydrogenase, albumin, and calcium), hepatic, and renal function tests; and measurement of alpha-fetoprotein (AFP) level. Required radiologic studies included a chest and abdominal-pelvic CT scan or magnetic resonance imaging scan. Serum hepatitis B and C serology were determined before treatment. A pregnancy test was obtained from all women of childbearing potential within 24 hours before initiation of therapy. Urinalysis was performed and if positive for urine protein (reading of 1+ or greater), patients underwent a 24-hour urine collection for protein. During treatment, patients were monitored weekly during the first and second cycles and once every 2 weeks for the subsequent cycles. Analysis of AFP level was performed before the beginning of each cycle. CT or magnetic resonance imaging scans were performed at the end of cycle 3 and every two cycles thereafter. Response and progression were evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors Committee.28 Treatment was continued until one of the following criteria was met: disease progression per Response Evaluation Criteria in Solid Tumors criteria, unacceptable toxicity, patient refusal, or need to delay chemotherapy more than 3 weeks.
Toxicity Evaluation and Dose Modification
Statistical Considerations
Patient Characteristics Between May 2004 and February 2005, 33 patients with unresectable or metastatic HCC were entered onto this trial. Of these, 16 patients (49%) had metastatic disease. Eleven patients (33%) had single extrahepatic sites; 10 patients had lung metastases and one patient had bone metastasis. Five patients had two or more sites of metastases including lung, lymph nodes, abdomen, adrenal glands, bone, pancreas, and soft tissue in the pelvis. All were eligible for assessment of toxicity and 30 patients were eligible for assessment of response. Baseline patient characteristics are summarized in Table 1. There were 22 men (67%) and 11 women (33%), with a median age of 64 years (range, 26 to 82 years). Thirty patients (91%) had an elevated AFP level at the time of entry. Five (15%) patients had radiographic evidence of portal vein thrombosis at baseline. One patient had esophageal varices by CT scan but had no active bleeding at the time of study entry.
Clinical Efficacy Among all patients, 162 cycles of treatments were administered. A median of three cycles were administered to each patient (range, one to 15 cycles). Twelve patients completed more than five cycles of therapy. The median dosage of gemcitabine and oxaliplatin received per patient was 750 and 66 mg/m2, respectively. All patients received bevacizumab 10 mg/kg throughout the therapy. Nine patients (27%) withdrew from therapy because of disease progression and 12 patients (36%) withdrew as a result of treatment-related toxicity. At the time of analysis, nine patients remained on study and 19 patients had died. Median follow-up time was 8.8 months (range, 1.6 to 14.7 months). Of the 14 patients who are still alive, the median duration of follow-up is 10.5 months (range, 5.4 to 14.7 months). Clinical efficacy results are shown in Table 2. Of the 33 patients enrolled, three patients were determined not assessable for response because they only received one dose of bevacizumab. One developed grade 3 vasovagal syncope and was removed from study. Another patient with underlying arrhythmia developed grade 3 bradycardia due to concurrent cardiac medications and was removed from study. The third patient developed grade 3 upper GI bleeding due to esophageal varices.
No patient achieved a complete response. Six patients had confirmed partial response with a response rate of 20%. Of these six patients, one had hepatitis C virus, one had hepatitis B virus, and four had no clear etiology for the liver disease. None of these six patients had portal vein thrombosis. Eight patients (27%) had stable disease as their best response, with a median duration of 9 months (range, 4.5 to 13.7 months). Of 30 patients who had an elevated AFP level at baseline, a greater than 50% decrease was observed in 12 patients (40%). The median overall survival time was 9.6 months (95% CI, 8.0 months to not available), and the median PFS time was 5.3 months (95% CI, 3.7 to 8.7 months; Figs 1 and 2). The PFS at 3 and 6 months was 70% (95% CI, 54% to 85%) and 48% (95% CI, 31% to 65%), respectively.
Toxicity Toxicity data for all 33 patients are provided in Table 3. The combination of GEMOX-B regimen was generally well tolerated. One patient died as a result of respiratory failure while receiving therapy, which was possibly related to gemcitabine and/or oxaliplatin. Treatment-related discontinuations occurred in 12 patients: four patients developed elevated aminotransferases, two had upper GI bleeding, and one patient each developed grade 3 epistaxis, GI perforation, grade 3 fatigue, respiratory distress, oxaliplatin-induced allergic reaction, and uncontrolled hypertension.
The most common grade 3 to 4 nonhematologic toxicities were fatigue and transient elevation of aminotransferases, with 11 patients (33%) experiencing grade 3 AST and five patients (15%) experiencing grade 3 ALT. Other GI side effects were mild; only two patients had grade 3 nausea/vomiting and one patient grade 3 diarrhea. Peripheral neuropathy was generally mild and only one patient developed grade 3 neuropathy after being on study for more than 12 months. Fourteen (42%) patients experienced grade 3 to 4 neutropenia without neutropenic fever. Three patients received granulocyte colony-stimulating factor support. Three patients (9%) had grade 3 thrombocytopenia. Nine patients (27%) developed grade 3 hypertension. One patient was removed from the study because of uncontrolled hypertension. Two patients developed upper GI bleeding and were found to have esophageal varices on endoscopy. Grade 3 epistaxis was seen in one patient and hematochezia was seen in another. One patient had small bowel perforation and was also found to have evidence of metastatic disease in the small bowel.
The prognosis for patients with locally advanced and metastatic HCC is dismal, with a median survival of less than 9 months. Development of effective systemic therapy for HCC remains a major challenge. Increasing evidence has suggested the importance of angiogenesis in hepatocarcinogenesis. In an attempt to develop an active systemic regimen for HCC, we postulated that an agent with antiangiogenic activity such as bevacizumab might have direct anti-HCC effect as well as augmenting the efficacy of GEMOX chemotherapy. We selected the GEMOX-based chemotherapy regimen because of its reasonable efficacy data from a phase II study and the predictable safety profiles.13 Our results demonstrate that GEMOX-B has moderate antitumor activity in this population. The overall response rate was 20% and an additional 27% of patients had stable disease. The median overall survival was 9.6 months and the median PFS was 5.3 months, with the PFS rate at 3 and 6 months approaching 70% and 48%, respectively. This regimen compares comparably with other regimens reported in recent phase I/II HCC studies including sorafenib (Table 4). However, HCC is a heterogeneous disease in etiology as well as biologic and clinical behavior, and direct comparison of phase II study results is subject to patient selection bias. Whether this regimen will eventually prove to be efficacious in HCC will require a prospectively conducted randomized phase III study. However, based on our own institutional experience with prior phase II studies with similarly selected HCC patients, this GEMOX-B regimen is more active than the two most recent prior regimens studied: one with the combination of epirubicin and thalidomide and the other with gemcitabine.21,34 In those studies, no responses were seen and PFS was only 2 months. Our data are similar to the previously published GEMOX regimen results with similar response rate and PFS, although our study had a larger sample size. Whether the addition of bevacizumab enhances the activity of the GEMOX regimen cannot be delineated from this study. However, two lines of evidence appear to suggest that bevacizumab may have anti-HCC activity alone. First, Schwartz et al35 reported their preliminary experience of single-agent bevacizumab in HCC in a phase I study. Of the first 13 patients treated, partial responses were seen in two patients and stable disease of more than 4 months was seen in seven patients. Second, we have seen a more than 50% decrease in AFP in 40% of patients who had an elevated baseline level after treatment with bevacizumab alone in our study.
The GEMOX-B regimen could be safely administered with close monitoring in the majority of patients. The gemcitabine- and oxaliplatin-related toxicities were predictable, dose dependent, and manageable. With monitoring and dose modification, responding patients continued treatment for a prolonged period of time. The most common grade 3 to 4 toxicities included myelosuppression, transient elevation of aminotransferases, and fatigue. Although up to 42% of patients developed grade 3 to 4 neutropenia, most patients were able to continue treatment after dose reductions. No neutropenic fever was encountered. Compared with the previously reported toxicities of GEMOX, we encountered a higher percentage of patients with grade 3 transient elevations of aminotransferases. In our study, both gemcitabine and oxaliplatin were administered on the same day instead of on two consecutive days as previously reported. Patients were eligible for the study if they had up to 7x the upper normal limit of AST. Whether the schedule difference of GEMOX, different eligibility criteria, or addition of bevacizumab contributed to the higher incidence of transient elevation of transaminases needs to be elucidated in future studies. The elevated aminotransferases were reversible on withholding or dose reduction of GEMOX. Although there was significant concern about potential bevacizumab-related toxicity in this population, only two patients developed grade 3 upper GI bleeding due to varices and one patient developed grade 3 epistaxis. We observed a relatively high incidence (27%) of patients developing grade 3 hypertension. Most of these were well controlled with medications and only one patient was removed from the study because of uncontrolled hypertension. One patient with metastatic disease to the small bowel developed a small bowel perforation consistent with what has been seen with bevacizumab therapy for other malignancies. Selecting the appropriate primary end points for HCC studies remains an area of significant debate. Although overall survival should be considered the primary end point in phase III studies, it may be less informative in small phase II studies because of the heterogeneity of the disease and patient selection bias. Using response criteria suffers from the inherent difficulty of imaging HCC lesions consistently and the variable pattern of HCC growth. In addition, newer molecularly targeted agents may be cytostatic instead of cytotoxic. PFS has the advantage of assessing overall tumor modifying effects of a particular agent/regimen and may be most informative in HCC phase II studies. Ideally, the natural history of the study cohort should be well known and patients should have documented disease progression before study entry, although the latter is not possible for newly diagnosed patients. Future trial designs should include stratification of patients according to one of the many staging or prognostic scoring systems to better identify those who truly may benefit from systemic therapy. In conclusion, we have demonstrated moderate antitumor activity of the combination of GEMOX-B in patients with advanced HCC. This regimen could be safely administered with close monitoring and is worthy of additional investigation, in particular, in HCC patients with good performance status and preserved hepatic function.
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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank the patients who participated in this study, their families, and the referring physicians. A.X.Z. thanks Christopher Willett, MD, Robert Mayer, MD, Charles Fuchs, MD, and Bruce Chabner, MD, for their guidance and encouragement.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
