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Bevacizumab, Capecitabine, and Oxaliplatin As Neoadjuvant Therapy for Patients With Potentially Curable Metastatic Colorectal Cancer

Brigit Gruenberger, Dietmar Tamandl, Johannes Schueller, Werner Scheithauer, Christoph Zielinski, Friedrich Herbst, Thomas Gruenberger

From the Department of Oncology, Rudolfstiftung Hospital; the Department of Internal Medicine I and Cancer Center, Medical University of Vienna; and the Department of General Surgery, Medical University of Vienna, Vienna, Austria

Corresponding author: Thomas Gruenberger, MD, Department of General Surgery, Waehringer Guertel 18-20, 1090 Vienna, Austria; e-mail: thomas.gruenberger{at}meduniwien.ac.at

	ABSTRACT

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Purpose Patients with colorectal cancer (CRC) and liver metastases have a poor prognosis, but can benefit from perioperative chemotherapy and disease resection. Bevacizumab improves outcomes in patients with metastatic CRC; however, its impact on surgical complications and hepatic regeneration after liver resection remains to be determined.

Patients and Methods Fifty-six patients with metastatic CRC with liver metastases potentially curable by resection were eligible for this single-center, nonrandomized phase II trial. Eligibility criteria defined patients at high risk of early recurrence. Patients received biweekly bevacizumab plus capecitabine and oxaliplatin for six cycles. The sixth cycle of therapy did not include bevacizumab, resulting in 5 weeks between the last administration of bevacizumab and surgery.

Results Objective response to neoadjuvant chemotherapy was achieved in 41 patients (73%). Fifty-two patients underwent liver resection including 11 with synchronous primary tumor resection. No increased intraoperative bleeding events or wound-healing complications were observed and only three patients (6%) required perioperative blood transfusions. Further surgery was necessary in a single patient. Postoperative liver function and regeneration were normal in all but one patient. No postoperative mortality occurred and morbidity was encountered in 11 patients (20%). The mean length of postoperative hospitalization was 9 days (± 4.0).

Conclusion These data suggest that bevacizumab can be safely administered until 5 weeks before liver resection in patients with metastatic CRC without increasing the rate of surgical or wound healing complications or severity of bleeding. To our knowledge, they are also the first to show that neoadjuvant bevacizumab does not affect liver regeneration after resection.

	INTRODUCTION

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Colorectal cancer (CRC) is a leading cause of cancer death, with approximately 350,000 new cases reported annually in Europe and the United States.¹ Median survival of patients with metastatic CRC treated with best supportive care is approximately 6 months.² Palliative chemotherapy considerably improves treatment outcome, with fluorouracil (FU) plus irinotecan and/or oxaliplatin extending median overall survival to approximately 20 months.^3-7 Furthermore, several phase II/III clinical trials in patients with metastatic CRC have demonstrated that the addition of the novel antiangiogenic agent bevacizumab (Avastin; Genentech, San Francisco, CA) to standard first-line FU-based chemotherapy regimens improves overall survival, progression-free survival, and response rates compared with chemotherapy alone.^8-10

The liver is the most common site of metastasis with 25% of patients presenting with liver metastases at diagnosis; an additional 25% to 45% develop liver metastases on disease recurrence. These patients have poor prognosis, despite advances in survival with chemotherapy. Surgical resection of liver metastases is considered the only curative treatment option for patients with resectable liver metastases and no extrahepatic disease^11,12 and is now an accepted practice. The current 5-year survival rates after resection of liver metastases are 25% to 40%.^13,14 Unfortunately, a large proportion of patients (approximately 80%) are considered to be unresectable at presentation due to extrahepatic disease involvement or insufficient remaining healthy liver tissue.¹¹ In addition, approximately 50% of patients experience disease recurrence which is confined to the liver.¹⁵

To address this issue, there has been an increased use of chemotherapy before potentially curative surgery. The theoretical advantages of preoperative chemotherapy in patients who are initially resectable include the treatment of undetected distant microscopic metastases, thus reducing the risk of disease recurrence after resection.^16-18 Neoadjuvant chemotherapy may also be useful to determine chemoresponsiveness of the tumor to help select the optimal adjuvant therapy, as well as identify patients with particularly aggressive disease in whom surgery would be inappropriate. Furthermore, neoadjuvant chemotherapy is being increasingly used to downsize colorectal liver metastases and render 10% to 30% of initially unresectable patients potentially resectable.¹⁹

Perioperative morbidity after neoadjuvant treatment of liver metastases is a major issue, especially in patients with resectable disease. However, in the recently presented final analysis of the European Organisation for the Research and Treatment of Cancer (EORTC) 40983 trial, postoperative morbidity was observed in 25% of patients in the neoadjuvant chemotherapy-treated group,²⁰ which is comparable to the rate of complications seen with liver resection alone.

Bevacizumab combined with FU-based chemotherapy improves all efficacy outcomes, including response rate, in the first-line metastatic setting and therefore would be expected to also allow a higher proportion of patients to become resectable. Furthermore, from its known mechanism of action,²¹ bevacizumab would also be expected to have an effect on dormant micrometastases, promoting tumor shrinkage and inhibition of angiogenesis. However, the effects of bevacizumab therapy in the neoadjuvant setting are relatively unknown.

We report the results of a single-center, nonrandomized, phase II study designed to determine the feasibility, perioperative complication rate (including blood transfusions), and potential impact on postoperative liver regeneration with neoadjuvant capecitabine and oxaliplatin (XELOX) plus bevacizumab in patients with potentially curable metastatic CRC.

	PATIENTS AND METHODS

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Patients
The trial enrolled patients with histologically confirmed resectable CRC liver metastases who were at high risk of early recurrence defined as one or more risk factors according to Fong et al.¹⁵ These risk factors included: synchronous liver metastases; metastatic disease developed within 1 year after primary resection; lymph node–positive primary tumors; more than one liver metastasis; a liver metastasis larger than 5 cm; and a positive carcinoembryonic antigen level. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, adequate bone marrow reserve, and adequate renal and hepatic function.

Exclusion criteria included prior chemotherapy for metastatic disease; prior history of bleeding diathesis or coagulopathy; clinical evidence of CNS metastases; history of thromboembolic or hemorrhagic events within 6 months before treatment; clinically significant cardiovascular disease. All patients provided written informed consent before study entry according to institutional regulations. The study was approved by our institutional review board.

Treatment
Eligible patients received bevacizumab 5 mg/kg administered by intravenous infusion and oxaliplatin was administered at 85 mg/m² over a 2-hour period; both agents were given on day 1 of a 2-week cycle. Capecitabine was administered orally at a dose of 1,750 mg/m² twice per day on days 1 through 7 of a 2-week cycle. Treatment was administered for six cycles, but the sixth cycle of therapy did not include bevacizumab (Fig 1).

View larger version (7K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Treatment and surgery schedule. B, bevacizumab; XELOX, capecitabine and oxaliplatin.

Study Evaluations
Pretreatment evaluation included a complete medical history, physical examination, routine hematology and biochemistry analyses, and computed tomography (CT) scans of the thorax and abdomen to define the extent of disease. A multidisciplinary team of oncologists, liver surgeons, and radiologists confirmed that the patient was eligible for this single-center study. After the initial assessment, CBCs (including platelet and differential) and serum biochemistry analyses were obtained at least once every course of treatment. Carcinoembryonic antigen levels were assessed every 4 weeks. Subjective symptoms, physical examination results, performance status, and all adverse reactions were recorded before each treatment cycle according to the CTC.²² Tumor size was measured before and after the sixth cycle by CT scan or magnetic resonance imaging. Response rate was evaluated according to Response Evaluation Criteria in Solid Tumors by an independent radiologist.

Surgical Technique
Surgery was planned 2 weeks after the last dose of chemotherapy, resulting in a gap of 5 weeks between surgery and the last bevacizumab dose; patients must have recovered from any severe adverse effects of chemotherapy. Curative liver resection was obligatory, which included the resection of all liver metastases with a negative margin. Therapy with bevacizumab plus XELOX was restarted 5 weeks after surgery (after complete wound healing) for another six cycles (Fig 1).

Study End Points
The primary objective of this study was to assess the feasibility of bevacizumab therapy before surgery. Secondary end points included the evaluation of potential curative resection, hepatic regeneration, morbidity, and objective response rate. Efficacy and safety analyses were performed in all patients who received at least one dose of study drug.

Statistical Analysis
According to the design of this proof of concept study, the primary objective was to evaluate if the incidence of perioperative blood transfusions would not exceed an acceptable limit of 40%, based on our experience and the results of published studies.^23,24 For a sample size of 50 patients (the number planned to be included), an incidence of events involving at least 13 patients (26%) would result in a 95% CI between 15% and 40%. A positive proof of concept result was accepted if the number of patients having bleeding events did not exceed 12 (24%), corresponding to a 95% CI of 13% to 38%.

	RESULTS

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From April 2005 to October 2006, 56 patients with CRC liver metastases potentially curable by resection (with or without primary in situ) were enrolled onto the study. Patient characteristics are listed in Table 1. The median age was 61.5 (standard deviation [SD] 10.5) years and the majority (89%) of the patients had ECOG performance status 0. In addition, a large proportion of patients had lymph-node-positive primary tumors (60.7%), synchronous liver metastases (60.7%), and bilobar liver metastases (51.8%).

Safety
The combination of bevacizumab plus XELOX was relatively well tolerated (Table 2). The most common grade 3/4 nonhemtalogic and hematologic adverse events were diarrhea (33%), peripheral neuropathy (10%), and neutropenia (10%). A low incidence of rare, serious adverse events that may be associated with bevacizumab included thromboembolic events (7%), hypertension (3%), and gastrointestinal perforation (2%). No grade 3/4 proteinuria or bleeding were observed and there were no treatment-related deaths.

View larger version (28K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Tumor response (A) before and (B) after neoadjuvant treatment (post-therapy scan shown at a higher level illustrating the largest diameter of the remaining lesion).

Of the remaining four patients, liver resection was suspended in one patient due to extrahepatic disease discovered during laparotomy and three patients did not undergo surgery due to progressive disease. These three patients received an irinotecan-based second-line chemotherapy regimen.

Postoperative Morbidity and Mortality
The median length of postoperative hospitalization was 8.8 days (SD ± 4.0). No patients died during the study or experienced increased bleeding events or wound-healing complications. Only three patients (6%) required blood transfusions (one unit in two patients, two units in a patient undergoing a third liver resection). According to this number of bleeding events (95% CI, 1% to 17%), no increase of bleeding events could be observed. A total of 42 patients (79%) experienced no complications after surgery (Table 4). Complications observed in the remaining 11 patients included sepsis (n = 3; 6%) and hyperbilirubinemia (n = 2; 4%), just one patient required further surgery. To date, peri- and postoperative complications are consistent with previous studies evaluating chemotherapy alone.

Synchronous Resection Subgroup
Peri- and postoperative complications observed in the 11 patients who underwent synchronous resection are consistent with those patients who underwent liver resection only. None of the synchronous resection patients experienced wound-healing or bleeding complications and no patient required perioperative blood transfusion. Only three patients experienced postoperative complications, which were single cases of wound infection, sepsis, and anastomotic leak. Similarly, the median length of hospitalization was 9.4 days (SD ± 3.5), which was consistent with the liver resection only patients.

	DISCUSSION

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Our data demonstrate that with appropriate management, preoperative bevacizumab can be used in combination with chemotherapy, with minimal risk of bleeding/wound-healing complications, in patients with metastatic CRC undergoing potentially curative liver resection. In patients who received bevacizumab until 5 weeks before liver resection, the rate of surgical (21% v 25%), wound healing (0% v 0%), or bleeding complications (0% v 3%) were not increased compared with historical data for chemotherapy alone.²⁰ In addition, a high objective response rate and disease control rate were observed in this study. This high level of efficacy may be due to the fact that only patients with metastatic CRC confined to the liver were included and all patients had a good performance status.

The feasibility and effectiveness of preoperative bevacizumab and chemotherapy are supported by the results of the open-label, community setting trial of bevacizumab plus standard first-line chemotherapy (First BEAT). In this trial, surgery with curative intent was performed in 215 (11.2%) of 1,914 patients (R0 resection rate, 8.9%) who were considered to be unresectable at diagnosis of metastatic disease.²⁵ In addition, in a large subgroup of patients with metastatic disease confined exclusively to the liver and ECOG performance status 0 (n = 484), hepatic metastasectomy with curative intent was performed in 17.4% of patients, including 26.6% of patients receiving bevacizumab plus continuous oxaliplatin and FU (FOLFOX).²⁶

The toxicity profile of biweekly bevacizumab plus XELOX as used in our study indicates that the combination regimen was well tolerated. The incidence of hematologic adverse events was consistent with previous studies of bevacizumab plus XELOX.^27,28 However, due to the reporting of grade 3/4 diarrhea in 33% of the patients, we decided to reduce the dose of capecitabine to 3,000 mg/m²/d in our currently ongoing multicenter study. Most patients (85%) received six cycles of therapy before surgery, including 45% without dose reduction. In addition, the observed low rate of adverse events associated with bevacizumab was effectively managed using standard therapy. Furthermore, a low rate of postsurgical morbidity and mortality was noted, including no perioperative deaths, severe bleeding events, or wound-healing complications. These data support previous neoadjuvant bevacizumab data, including First BEAT, where no increase in wound-healing complications or bleeding events were observed, compared with historical data for chemotherapy alone.²⁰ Moreover, single-institution retrospective data of 125 patients who underwent hepatic surgery showed that neoadjuvant bevacizumab plus chemotherapy did not increase the rate of any (49% v 43%; P = .51), hepatobiliary (5% v 11%; P = .20), or wound-healing complications (28% v 25%; P = .68) compared with neoadjuvant chemotherapy alone.²⁹

Bevacizumab is a potent inhibitor of VEGF activity, and thus it has been suggested that use of bevacizumab in the neoadjuvant setting could potentially impact on postsurgical wound healing and hepatic regeneration.^16,21 Based on early clinical data/experience and the half-life of bevacizumab, it is currently recommended that, to avoid the potential of wound healing/bleeding complications, bevacizumab is suspended for at least 6 weeks before elective surgery; should not be reinitiated for at least 28 days after major surgery; and any surgical incisions should be completely healed.³⁰ Our data show that a gap of 5 weeks between bevacizumab therapy and liver resection does not increase the rate of complications in patients with metastatic CRC and should not prohibit or delay surgery. In addition, we provide the first clinical data to indicate that bevacizumab in combination with chemotherapy does not appear to affect liver regeneration after resection.

Patients with synchronous primary CRC and liver metastases have poor prognosis and may benefit from an aggressive treatment strategy of perioperative chemotherapy and resection of tumor sites.¹⁶ In this study, potentially curable resection was achieved in all patients with synchronous metastases, and similar to those who underwent liver resection only, no bleeding or wound-healing complications were observed in this subgroup. These data indicate that synchronous primary and liver metastases should not preclude potentially curative liver resection, if a response is achieved with neoadjuvant treatment.

The optimal neoadjuvant chemotherapy regimen has not been determined. There are few trials which have evaluated XELOX in the neoadjuvant setting. Recent data from NO16966 showed that bevacizumab in combination with XELOX or FOLFOX allowed surgery with curative intent in 59 (6.1%, intent-to-treat population) of 699 patients and 34 (19.2%, liver metastases only) of 177 patients.¹⁰ Neoadjuvant therapy in this study appeared well tolerated and only one patient experienced pathologic hepatic toxicity, but further randomized trials are required to define the safety and efficacy profile of XELOX in this setting. The most common regimens combine fluoropyrimidines with oxaliplatin or irinotecan. These chemotherapy regimens, particularly FOLFOX, provide higher response rates and are therefore widely accepted as the most effective. However, accumulating data indicate that oxaliplatin- and irinotecan-based regimens are commonly associated with pathological hepatic toxicity, including steatohepatitis, which is characterized by inflammation of the liver with concurrent fat accumulation, which may compromise liver tolerance to resection.^16,31 In addition, data suggest that chemotherapy induced hepatotoxicity increases with dose and/or number of treatment cycles. Therefore, the improved efficacy of bevacizumab combination therapy may result in a reduced dose of chemotherapy and/or number of treatment cycles required to achieve resectability.

Neoadjuvant therapy before potentially curative surgery will soon be recognized as new standard of care for patients with metastatic CRC and potentially resectable metastases, based on the final results of the randomized phase III EORTC 40983 trial that were recently presented by Nordlinger et al²⁰ at the Annual Meeting of the American Society of Clinical Oncology. This trial showed that perioperative chemotherapy followed by surgery and postoperative chemotherapy significantly improved 3-year progression-free survival in all eligible (36.2% v 28.1%; P = .041) and all resected patients (42.4% v 33.2%; P = .025) compared with surgery alone.

Our trial showed that bevacizumab plus XELOX allowed potentially curative resection in approximately 95% of patients and not a single patient experienced increased bleeding events or wound-healing complications. In conclusion, we and others have produced a wealth of data, in approximately 400 patients, which suggest that bevacizumab plus standard chemotherapy is a feasible, safe, and effective neoadjuvant regimen in patients with metastatic CRC and liver metastases undergoing potentially curative liver resection.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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.

Employment or Leadership Position: None Consultant or Advisory Role: Christoph Zielinski, F. Hoffmann-LaRoche Ltd (U) Stock Ownership: None Honoraria: Werner Scheithauer, F. Hoffmann-LaRoche Ltd; Christoph Zielinski, F. Hoffmann-LaRoche Ltd; Thomas Gruenberger, F. Hoffmann-LaRoche Ltd Research Funding: Werner Scheithauer, F. Hoffmann-LaRoche Ltd; Christoph Zielinski, F. Hoffmann-LaRoche Ltd; Thomas Gruenberger, F. Hoffmann-LaRoche Ltd Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Thomas Gruenberger

Administrative support: Johannes Schueller

Provision of study materials or patients: Johannes Schueller, Werner Scheithauer, Friedrich Herbst, Thomas Gruenberger

Collection and assembly of data: Brigit Gruenberger

Data analysis and interpretation: Brigit Gruenberger, Dietmar Tamandl, Thomas Gruenberger

Manuscript writing: Brigit Gruenberger

Final approval of manuscript: Brigit Gruenberger, Dietmar Tamandl, Johannes Schueller, Werner Scheithauer, Christoph Zielinski, Friedrich Herbst, Thomas Gruenberger

	NOTES

 
Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, 2006; the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007; the 8th World Congress on Gastrointestinal Cancer, Barcelona, Spain, June 28 to July 1, 2006; and the 31st European Society of Medical Oncology Conference, Istanbul, Turkey, September 29 to October 2, 2006.

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

	REFERENCES

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Submitted August 14, 2007; accepted December 3, 2007.

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