Annals of Surgical Oncology Sign the Guestbook
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
10.1245/s10434-006-9074-0
Annals of Surgical Oncology 14:759-765 (2007)
© 2007 Society of Surgical Oncology
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by D’Angelica, M.
Right arrow Articles by Saltz, L. B
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by D’Angelica, M.
Right arrow Articles by Saltz, L. B

Original Article

Lack of Evidence for Increased Operative Morbidity After Hepatectomy with Perioperative Use of Bevacizumab: A Matched Case-Control Study

Michael D’Angelica, MD1, Peter Kornprat, MD1, Mithat Gonen, PhD2, Ki-Young Chung, MD3, William R. Jarnagin, MD, FACS1, Ronald P. DeMatteo, MD, FACS1, Yuman Fong, MD, FACS1, Nancy Kemeny, MD3, Leslie H. Blumgart, MD, FACS, FRCS1 and Leonard B Saltz, MD3

1 Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
2 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
3 Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA

Correspondence: Address correspondence and reprint requests to: Michael D’Angelica, MD; E-mail: dangelim{at}mskcc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Bevacizumab (bev) is a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF). Perioperative bev is now commonly used in patients undergoing hepatic resection. Little is known, however, about the safety of perioperative bev use in the setting of hepatic resection.

Methods: Computerized pharmacy records were used to identify all patients who received bev between January 2004 and June 2005. Patients who underwent hepatectomy for colorectal metastases and received bev within 12 weeks of surgery were identified and compared with a group of matched historical controls.

Results: Thirty-two patients underwent hepatic resection of colorectal cancer metastases and received bev within the specified perioperative period. Sixteen patients received bev before surgery and 24 received bev after surgery. A subset of eight patients received bev both before and after surgery. The median time between bev administration and surgery was 6.9 weeks before (range, 3–15 weeks) and 7.4 weeks after (range, 5–15 weeks). Perioperative complications occurred in 13 patients (40.6%), two of which were considered major complications. There was no statistically significant difference in perioperative morbidity and severity of complications when compared with a set of matched controls.

Conclusions: Clinical experience thus far does not indicate a statistically significantly increased risk of perioperative complications with the incorporation of bev into pre- and/or postoperative treatment paradigms. Given the long half-life of bev and the potential for anti-VEGF therapy to impede wound healing and/or liver regeneration, we continue to favor a window of 6 to 8 weeks between bev administration and surgery.

Key Words: Colorectal metastases • Hepatectomy • Bevacizumab • Bev • Perioperative morbidity


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Partial hepatectomy for selected patients with hepatic metastases from colorectal cancer has become a safe and accepted treatment modality. In fact, hepatic resection is the only potentially curative therapy for metastatic colorectal cancer, with well-documented 5-year survival rates up to 40% and 10-year survival of 20%.1,2 Over the past decade, substantial improvements in systemic chemotherapy for colorectal cancer have been made. After decades of only modest activity with 5-fluorouracil (5-FU) and leucovorin (LV), response rates exceeding 50% are now obtained with irinotecan and oxaliplatin combinations.3–5 Furthermore, the addition of the anti–vascular endothelial growth factor (VEGF) agent bevacizumab (bev) has markedly improved survival in phase 3 randomized trials and is now approved for first-line therapy in metastatic colorectal cancer.6,7 Despite a lack of specific prospective data confirming a benefit, chemotherapy is commonly used in the adjuvant setting for patients undergoing hepatic resection for colorectal metastases. More recently, the neoadjuvant use of chemotherapy to "down-stage" unresectable hepatic tumors or to help assess patients best suited for partial hepatectomy has gained popularity. However, the safety of chemotherapy that includes bev in the perioperative setting of hepatectomy has not been evaluated.

Bev is a humanized anti-VEGF monoclonal antibody (rhuMAb VEGF; Avastin; Genentech Inc., South San Francisco, CA). VEGF is a glycoprotein that is overexpressed in many solid tumors and is a key regulator of the angiogenesis process. VEGF, through binding its receptors on tumor-related endothelium and tumor cells, acts as a direct mitogen and also increases vascular permeability.8 In addition to inhibiting VEGF activity, bev has both anti-angiogenic effects and direct effects on tumor cells. It may also act by improving blood flow through tumors, thereby increasing exposure to other cytotoxic agents.

Bev-associated adverse events such as bleeding, thrombotic events, hypertension, proteinuria, and gastrointestinal perforations have been reported.6,9,10 Because VEGF is also critically involved in wound healing and liver regeneration, there are important unanswered questions about the safety of the use of bev around the time of liver resection.11 One study has addressed the relative incidence of wound healing and bleeding complications after colorectal surgery in patients who were provided bev 28 to 60 days after surgery. The study found no marked increase in postoperative complications in patients receiving bev.12 To our knowledge, there are no published studies analyzing the safety of perioperative bev in the setting of hepatic surgery. Therefore, we reviewed our perioperative experience with bev in patients undergoing hepatic resection and compared these patients with matched historical controls not receiving bev.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A waiver of authorization was obtained from the Institutional Review Board of Memorial Sloan-Kettering Cancer Center, New York, to conduct this study. Computerized pharmacy records were used to identify all patients treated with bev between January 2004 and June 2005. A total of 456 such patients were identified. This list was then cross-referenced with a prospective hepatobiliary surgical database to identify patients who underwent hepatic resection. Of these 456 patients, 32 (7%) underwent hepatic resection within 3 months of receiving bev. Eight patients received bev preoperatively, 16 postoperatively, and 8 both pre- and postoperatively.

Patients were considered for partial hepatectomy if all detected tumors could be removed completely with grossly negative surgical margins and a safe liver remnant volume. All patients were evaluated for major comorbid conditions preoperatively that might preclude a safe hepatic resection. Every patient underwent routine preoperative abdominal and pelvic computed tomographic (CT) scans, chest roentgenograms or chest CT, and colonoscopy. Other imaging studies, such as ultrasonography, magnetic resonance imaging, and positron emissions tomographic scans, were obtained at the discretion of the treating surgeon.

As previously published, resections were generally performed with inflow vascular control before parenchymal dissection. Parenchymal division was generally performed with a clamp-crushing technique under intermittent Pringle maneuver. For major resections, hepatic venous outflow control was typically achieved extrahepatically before dividing the liver parenchyma. Anesthetic management included placement of a central venous catheter and performance of the procedure with a low central venous pressure (<5 mm Hg pressure) whenever possible.13 Intraoperative ultrasound was performed in all patients, and abdominal drains were not used routinely. After surgery, patients were monitored overnight in the postanesthesia care unit and then transferred to the ward if stable. Preoperative antibiotics were provided to all patients, and postoperative antibiotics were not administered. Although deep venous prophylaxis with subcutaneous heparin was not routinely used, all patients wore compression stockings until they could ambulate.

The liver resections were defined according to the Couinaud classification.14 Major liver resections were defined as a resection of three or more segments. Bilobar tumor involvement was defined as tumor involving any segments of the left and right hemiliver. Operative morbidity was defined as any complication resulting from the procedure, whenever it occurred. Postoperative complications were graded on a 1-to-5 scale according to a previously published grading system (Table 1Go).15 The number of perioperative blood product transfusions was also recorded.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Summary of postoperative complication grading scale15
 
Patients receiving bev (cases) were individually matched to 32 patients who also underwent hepatectomy for removal of metastatic colorectal tumors, but with no perioperative exposure to bev (controls), on the basis of age decade, sex, and extent of hepatectomy (less than three segments resected vs. three or more segments resected). When several controls were available, the one with the most recent operation date was selected. The control patients were culled from a prospectively maintained hepatobiliary surgical database in which operative, pathologic, and morbidity data are prospectively recorded.13 Statistical analysis was performed with SPSS software (SPSS Inc., version 12, Chicago, IL) and StatXact (Cytel Co., version 6, Cambridge, MA). Cases and controls were compared by a signed rank test for continuous variables (such as blood loss) and McNemar’s test for dichotomous variables (such as morbidity). Exact reference distributions were used to assure that type I errors were controlled at the nominal level.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Demographics
Between January 2004 and June 2005, a total of 32 patients underwent partial hepatectomy for colorectal metastases and received perioperative chemotherapy that included bev. Twenty-three patients (71.9%) were men, and most (29, 90.6%) were white/ non-Hispanic. The median age was 51 years (range, 33–78 years), and four patients (12.5%) were 70 years of age or older. The median body-mass index was 28 (range, 19–44). Fourteen patients (43.7%) had comorbidity as a result of various diseases. Comorbid conditions included cardiac disease (three patients), diabetes (two patients), hypertension (two patients), hypercholesterolemia (four patients), other concurrent cancers (two patients), and psychosis (one patient).

Chemotherapy
All patients received chemotherapy regimens containing bev within 3 months of hepatic resection. Sixteen patients received bev before surgery and 24 patients received bev after surgery. A subset of eight patients received bev both before and after surgery. In addition to bev, 18 patients (56.2%) received a combination with 5-FU, LV, and oxaliplatin (FOLFOX), and 12 (37.5%) were provided 5-FU, LV, and irinotecan (FOLFIRI). One patient (3.1%) received both regimens because of progression of disease while receiving first-line therapy. One patient (3.1%) was provided five doses of FU-LV alone in combination with bev. The median number of doses of bev provided preoperatively was nine (range, 4–15) and eight (range, 1–16) postoperatively. The median time interval between administration of bev and the date of surgery date was 6.9 weeks (range, 3–15 weeks) before and 7.4 weeks (range, 5–15 weeks) after surgery.

Intraoperative Results
The median number of hepatic tumors was two (range, 1–7), and eight patients (25%) had four or more lesions. The median size of the largest tumor was 2.3 cm (range, 1–15 cm). Tumors were bilobar in distribution in 17 patients (53.1%). Seventeen of the hepatectomies (53.1%) were major resections (three or more segments). No patient in this series had thermoablative therapy performed as a primary procedure; however, one patient (3.1%) underwent radiofrequency ablation, and two (6.2%) underwent cryoablation combined with partial hepatectomy. One patient (3.1%) required a biliary resection and hepaticojejunostomy to remove the tumors. Nine patients (28.1%) underwent simultaneous hepatic and colorectal resections. The median operative time was 235 minutes (range, 85–500 minutes), and the median Pringle time was 30 minutes (range, 0–50 minutes).

Perioperative Morbidity
The median intraoperative estimated blood loss was 300 mL (range, 0–1500 mL), and the median number of units of packed red blood cells transfused per patient during their perioperative hospital stay was 0 (range, 0–3 units). Overall, 11 patients (34.3%) required a postoperative red blood cell transfusion. Three patients (9.4%) required a transfusion of fresh frozen plasma. There were no intraoperative complications. The median postoperative hospital stay was 7 days (range, 4–20 days).

There was no postoperative mortality. The median follow-up after operation was 6 months and ranged from 6 weeks to 17 months. Postoperative complications occurred in 13 patients (40.6%), two of which (6.3% of all patients, 15.3% of patients with complications) were considered major (grade 3). The types of postoperative complications are listed in Table 2Go. The two major complications included a single subphrenic abscess requiring radiologic-guided percutaneous drainage and one groin abscess treated by incision and drainage. Both of these major complications resolved appropriately; the drain for the subphrenic abscess was removed in 1 month and the groin abscess cavity healed in 3 weeks. One urinary tract infection, one deep venous thrombosis, one pulmonary embolus, one ventricular arrhythmia, and one superficial thrombophlebitis all resolved with appropriate medical therapy, and none resulted in recurring or prolonged morbidity. The five open wounds all healed within 2 months of surgery.


View this table:
[in this window]
[in a new window]

  		TABLE 2. Summary of 13 postoperative complications stratified by grade and type of complication
 
Table 3Go lists the complications as related to the timing of bev administration. Of the eight patients who received only preoperative bev, three experienced complications (pulmonary embolus, deep venous thrombosis, and subphrenic abscess). These patients received bev 7, 6, and 3 weeks preoperatively. Eight patients received bev both before and after surgery. Of these eight patients, four experienced postoperative complications (three wound infections and one urinary tract infection). The three wound infections in this group occurred in patients receiving bev at 8, 7, and 6 weeks preoperatively. Of the 16 patients who received only postoperative bev, there were six perioperative complications (three wound infections, one groin abscess, one superficial thrombophlebitis, and one arrhythmia) that occurred immediately after surgery and could not be directly attributed to bev use.


View this table:
[in this window]
[in a new window]

  		TABLE 3. Summary of perioperative complications stratified by timing of bevacizumab administration
 
There were no severe intraoperative or postoperative bleeding episodes. No patient developed marked postoperative liver dysfunction. In the patients who received bev postoperatively, there were no delayed complications such as bleeding, wound breakdown, intestinal perforation, anastomotic breakdown, or hepatic dysfunction.

Control Patients and Matched-Pair Analysis
Controls matched for age, sex, and extent of hepatectomy were compared with the 32 patients who received perioperative bev. The characteristics of these two groups are listed in Table 4Go. The control group had a higher rate of extrahepatic procedures, but this did not reach statistical significance. The extrahepatic resections in the bev group included nine colorectal resections for a primary tumor and one resection of the biliary tree for local extension of a hepatic tumor. The extrahepatic resections in the control group included one colorectal resection for a primary tumor, one lung resection for an additional metastasis, and four patients with locally advanced liver tumors requiring resection of the diaphragm in two, the biliary tree in one, and the abdominal wall in one. The median blood loss was higher in the control group (500 mL vs. 300 mL, P = .04).


View this table:
[in this window]
[in a new window]

  		TABLE 4. Comparison of cases and matched pairs
 
There was no statistically significant difference in postoperative morbidity between the two groups (Table 5Go). Overall and major postoperative morbidity were nearly identical. There was a higher incidence of wound infections in the patients receiving bev, but this did not reach statistical significance. The three major complications in the control group were perihepatic fluid collections requiring radiologic drainage. Two of these collections were infected. Minor complications in the control group included two wound infections, three symptomatic pleural effusions, and four patients with mildly prolonged ileus.


View this table:
[in this window]
[in a new window]

  		TABLE 5. Comparison of postoperative complications
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Hepatic resection has become the standard of care for selected patients with limited hepatic metastases from colorectal cancer.1 In recent years, systemic chemotherapy for colorectal cancer has greatly improved. 5-FU–based chemotherapy combined with oxaliplatin or irinotecan has improved survival in patients with advanced disease.3–5 More recently, the addition of bev to these combinations has further improved survival for patients with metastatic colorectal cancer in randomized trials, and bev is now approved for first-line use in conjunction with chemotherapy.6,9,10,16 Given the improved efficacy of chemotherapy, combining hepatic resection with pre-or postoperative chemotherapy that includes bev is rational and is now common practice.

The safety of hepatic resection in the setting of pre-and/or postoperative chemotherapy is important and particularly critical when considering the use of bev. The depletion of VEGF has a number of potential mechanisms of action. It presumably has anti-angiogenic effects, as well as possibly some anti-mitogenic effects, and may improve blood flow through tumors through a normalization of pathologic blood vessels, thereby assisting in the delivery of other administered cytotoxic agents.17–19 When considering hepatic resection, one must realize that VEGF plays a central role in liver regeneration and wound healing.20–23 VEGF inhibition might also decrease endothelial cell repair capacity, causing defects in the interior vascular lining and exposing the subendothelial collagen, theoretically increasing the risk of bleeding and/or thromboembolic events.23,24

In published clinical trials, a number of adverse events seemed to be specifically associated with bev, including arterial thromboembolic events, bleeding (usually in the form of mild epistaxis), hypertension, proteinuria, and bowel perforation.6,9,25 However, little is known about the perioperative safety of bev use. The half-life of bev in humans is variable and ranges between 11 and 50 days, with a median of approximately 21 days.26 Furthermore, at two half-lives after giving the standard dose of 5 mg/kg, approximately 1.25 mg/kg would exist in the circulation, and this is enough to clear the circulation of free VEGF. It is unknown, however, whether clearance of circulating VEGF is an appropriate measure of the biologic activity of bev.11 The optimal time interval between discontinuance of bev and operation is unclear, although it has generally been recommended to defer surgery for 6 to 8 weeks, which represents two half-lives of bev. There is even less information to guide the timing of bev administration in the postoperative setting. We are only aware of one report on the postoperative use of bev in 187 patients who had undergone primary colon or rectal surgery between 28 and 60 days before bev therapy. This study compared these patients to 155 patients who received chemotherapy without bev and found no statistically significant difference in wound healing or bleeding complications.12

To our knowledge, there have been no reports on the safety of perioperative use of bev in the setting of partial hepatectomy. The safe performance of a partial hepatectomy mandates meticulous hemostasis and the ability of a liver remnant to regenerate. Because VEGF plays a critical role in wound healing, liver regeneration, and endothelial integrity, the assessment of perioperative bev use in the setting of partial hepatectomy is critically important. This report describes the perioperative outcome of 32 patients who received perioperative bev. The complications of the surgery were typical, and we did not identify any obvious trend toward bevspecific adverse events. Furthermore, when compared with matched controls, there was no difference in the postoperative morbidity. After matching for age, sex, and extent of resection, there were some differences between the study group and matched controls. There were more extrahepatic resections in the study group, largely composed of colorectal resections. There was also a slightly lower blood loss (200-mL difference) and smaller tumors in the study group. The higher rate of extrahepatic organ resections in the control group should, if anything, bias the results toward a higher complication rate. Furthermore, the small difference in blood loss, although statistically significant, is unlikely to be clinically relevant. This complication rate is also consistent with prior publications from our group on large numbers of patients with perioperative morbidities ranging from 31% to 45%.1,13,27

Although there seemed to be a nonsignificant trend toward slightly more wound infections than expected (based on previous data), bev was only provided postoperatively after complete healing in three of the five major wound infections. Therefore, we cannot ascribe these infections to bev use. In fact, no complications were clearly attributable to postoperative bev, which was initiated 5 to 15 weeks after the operation in this series. Importantly, there were no cases of bleeding, perforation, or major hepatic dysfunction in any patient during follow-up. Two thrombotic events did occur in the bev group, although this is within the expected range and not much different than the control group (in which none occurred). In the patients who received preoperative bev, the complications seemed to cluster in patients receiving bev within 8 weeks of the operation. Only two patients received preoperative bev within 4 weeks of surgery, one of whom developed a postoperative abscess. However, these were small numbers of patients with a complication rate no different than the controls, making definitive conclusions impossible.

These results serve as an initial and early report and must be interpreted with caution. This is a small group of patients, and finding marked differences would require a dramatic increase in complications. The cases were also heterogenous in their timing of bev administration before or after surgery. On the other hand, the perioperative complication profile was within the limits expected in any group of patients who underwent hepatic resection. This suggests that liver resection can generally be practiced safely with perioperative bev use. The more important issue is the timing of bev use around hepatic surgery. The results of this study, with a few exceptions, generally reflect a policy of waiting 6 to 8 weeks between surgery and the use of bev. Therefore, on the basis of these results and the published data on the half-life of bev, we recommend an interval of 6 to 8 weeks between bev administration and partial hepatectomy until further data addresses the issue of bev use closer to the time of surgery.

In summary, initial data indicate that partial hepatectomy is safe with the perioperative use of bev if it is provided at an appropriate interval before or after surgery. It is critical that ongoing assessments of perioperative morbidity be analyzed and published to continue to address this extremely important issue.


   FOOTNOTES
 
M. D and P. K. contributed equally to this work.

Received for publication February 27, 2006. Accepted for publication May 5, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Fong Y, Fortner J, Sun R, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230:309–30.[CrossRef][Medline]
  2. Scheele J, Stang R, Altendorf-Hofmann A, et al. Resection of colorectal liver metastases. World J Surg 1995; 19:59–71.[CrossRef][Medline]
  3. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000; 343:905–14.[Abstract/Free Full Text]
  4. Kemeny N, Jarnagin W, Paty P, et al. Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. J Clin Oncol 2005; 23:4888–96.[Abstract/Free Full Text]
  5. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22:229–37.[Abstract/Free Full Text]
  6. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335–42.[Abstract/Free Full Text]
  7. Giantonio BJ, Catalano PJ, Meropol NJ, et al. High-dose bevacizumab improves survival when combined with FOL-FOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) Study E3200 (abstract 2). Proc Am Soc Clin Oncol 2005; 23:16S.
  8. Jain RK. Molecular regulation of vessel maturation. Nat Med 2003; 9:685–93.[CrossRef][Medline]
  9. Kabbinavar F, Hurwitz HI, 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 2003; 21:60–5.[Abstract/Free Full Text]
  10. Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 2005; 23:3706–12.[Abstract/Free Full Text]
  11. Ellis LM, Curley SA, Grothey A. Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol 2005; 23:4853–5.[Free Full Text]
  12. Scappaticci F, Fehrenbacher L, Cartwright J, et al. Lack of effect of bevacizumab on wound healing/bleeding complications when given 28–60 days following primary cancer surgery (abstract 3530). Proc Am Soc Clin Oncol 2004; 22:14S.
  13. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic resection. Ann Surg 2002; 236:397–407.[CrossRef][Medline]
  14. Couinaud C. Bases anatomiques des hepatectomies gauche et droite reglees. J Chir 1954; 70:933–66.
  15. Martin RC, Brennan MF, Jaques DP. Quality of complication reporting in the surgical literature. Ann Surg 2002; 235:803–13.[CrossRef][Medline]
  16. Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol 2005; 23:3502–8.[Abstract/Free Full Text]
  17. Winkler F, Kozin SV, Tong RT, et al. Kinetics of vascular normalization by VEGFR-2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004; 6:553–63.[Medline]
  18. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005; 7:58–62.[Medline]
  19. Fernando NH, Hurwitz HI. Inhibition of vascular endothelial growth factor in the treatment of colorectal cancer. Semin Oncol 2003; 30:39–50.[Medline]
  20. Furnus CC, Inda AM, Andrini LB, et al. Chronobiology of the proliferative events related to angiogenesis in mice live regeneration after partial hepatectomy. Cell Biol Int 2003; 27:383–6.[CrossRef][Medline]
  21. Kraizer Y, Mawasi N, Saegal J, et al. Vascular endothelial growth factor and angiopoetin in liver regeneration. Biochem Biophys Res Commun 2001; 287:209–15.[CrossRef][Medline]
  22. LeCouter J, Moritz DR, Li B, et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 2003; 299:890–3.[Abstract/Free Full Text]
  23. Haroon Z, Amin K, Saito W, et al. SU5416 delays wound healing through inhibition of TGF-beta 1 activation. Cancer Biol Ther 2002; 1:121–6.[Medline]
  24. Kilickap S, Abali H, Celik I. Bevacizumab, bleeding, thrombosis, and warfarin. J Clin Oncol 2003; 21:3542.[Free Full Text]
  25. Shah MA, Ilson D, Kelsen DP. Thromboembolic events in gastric cancer: high incidence in patients receiving irinotecan-and bevacizumab-based therapy. J Clin Oncol 2005; 23:2574–6.[Free Full Text]
  26. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti–vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001; 19:843–50.[Abstract/Free Full Text]
  27. Kooby DA, Stockman J, Ben-Porat L, et al. Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases. Ann Surg 2003; 237:860–70.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Ann OncolHome page
B. Nordlinger, E. Van Cutsem, T. Gruenberger, B. Glimelius, G. Poston, P. Rougier, A. Sobrero, M. Ychou, and on behalf of the European Colorectal Metastases Tr
Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel
Ann. Onc., June 1, 2009; 20(6): 985 - 992.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
M. M. Kemeny
How Many Patients and How Many Complications Does It Take to Decide if a Drug Is Safe to Use Before Surgery?
J. Clin. Oncol., April 10, 2009; 27(11): 1917 - 1918.
[Full Text] [PDF]

Home page
 JCOHome page
S. B. Kesmodel, L. M. Ellis, E. Lin, G. J. Chang, E. K. Abdalla, S. Kopetz, J.-N. Vauthey, M. A. Rodriguez-Bigas, S. A. Curley, and B. W. Feig
Preoperative Bevacizumab Does Not Significantly Increase Postoperative Complication Rates in Patients Undergoing Hepatic Surgery for Colorectal Cancer Liver Metastases
J. Clin. Oncol., November 10, 2008; 26(32): 5254 - 5260.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Surg. Oncol.Home page
D. Zorzi, Y. S. Chun, D. C. Madoff, E. K. Abdalla, and J.-N. Vauthey
Chemotherapy With Bevacizumab Does Not Affect Liver Regeneration After Portal Vein Embolization in the Treatment of Colorectal Liver Metastases
Ann. Surg. Oncol., October 1, 2008; 15(10): 2765 - 2772.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
A. J. Bilchik and J. R. Hecht
Perioperative Risks of Bevacizumab and Other Biologic Agents for Hepatectomy: Theoretical or Evidence Based?
J. Clin. Oncol., April 10, 2008; 26(11): 1786 - 1788.
[Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
C. Brostjan, K. Gebhardt, B. Gruenberger, V. Steinrueck, H. Zommer, H. Freudenthaler, S. Roka, and T. Gruenberger
Neoadjuvant Treatment of Colorectal Cancer with Bevacizumab: The Perioperative Angiogenic Balance Is Sensitive to Systemic Thrombospondin-1 Levels
Clin. Cancer Res., April 1, 2008; 14(7): 2065 - 2074.
[Abstract] [Full Text] [PDF]

Home page
 The OncologistHome page
N. Kemeny
Presurgical Chemotherapy in Patients Being Considered for Liver Resection
Oncologist, July 1, 2007; 12(7): 825 - 839.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
P.-A. Clavien, H. Petrowsky, M. L. DeOliveira, and R. Graf
Strategies for Safer Liver Surgery and Partial Liver Transplantation
N. Engl. J. Med., April 12, 2007; 356(15): 1545 - 1559.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by D’Angelica, M.
Right arrow Articles by Saltz, L. B
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by D’Angelica, M.
Right arrow Articles by Saltz, L. B

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS