Abstract
In the past 10 years, tremendous headway has been made in the fight against colorectal cancer. Advances have included the approval of new cytotoxic agents (oxaliplatin, irinotecan, and capecitabine), as well as biologic agents (cetuximab, bevacizumab, and panitumumab). Studies of bevacizumab, an antibody that targets vascular endothelial growth factor, provided the first proof of principle that addition of antiangiogenic therapy to chemotherapy provided a survival benefit for patients with previously untreated metastatic colorectal cancer. Since then, data have shown that bevacizumab treatment provides this same benefit in the second-line setting. Bevacizumab also appears to be effective when added to various chemotherapy regimens. The mechanisms of action of bevacizumab appear to involve both decreasing the number of abnormal tumor blood vessels that feed the tumor and preventing the growth of future blood vessels; and normalizing the abnormal tumor blood vessels to allow for better delivery of chemotherapy. Future research directions in the setting of metastatic colorectal cancer include continued evaluation of bevacizumab combined with different chemotherapeutic regimens, use of bevacizumab as maintenance therapy, continuation of bevacizumab through multiple lines of treatment, and bevacizumab combined with other biologic agents, such as epidermal growth factor receptor inhibitors.
In 2003, pivotal data showed that antiangiogenic therapy with bevacizumab in combination with first-line chemotherapy for patients with metastatic colorectal cancer yielded significant benefits in response rate and progression-free and overall survivals.1 Since then, bevacizumab has become a standard first-line treatment of metastatic colorectal cancer. Data have also shown clinical benefit when bevacizumab was added to chemotherapy for patients with metastatic non-small cell lung2 and breast3 cancers. A study of bevacizumab combined with second-line chemotherapy for metastatic colorectal cancer patients not previously exposed to bevacizumab also showed a statistically significant increase in response rate, progression-free survival, and overall survival.4 This led the US Food and Drug Administration (FDA) to expand the bevacizumab indication to the first- or second-line setting in combination with 5-fluorouracil (5-FU)– based chemotherapy for patients with metastatic colorectal cancer. This review will discuss the mechanism of action of bevacizumab, use of bevacizumab with different chemotherapy backbones, and future research directions for antiangiogenic therapy in colorectal cancer.
MECHANISM OF ACTION
In 1971, Judah Folkman first proposed that tumor angiogenesis could serve as a potential target for anticancer therapy.5 Tumors grow to a maximum size of 2 to 3 mm3 before they require new blood vessels for nutrient delivery. At some point, an “angiogenic switch” is thrown, and tumors are able to cause the formation of new blood vessels, allowing further tumor growth.6 In normal tissues, there is a constant regulation of proangiogenic and antiangiogenic factors. A change in the balance of these factors towards angiogenesis causes the “angiogenic switch,” or angiogenic phenotype. Vascular endothelial growth factor-A (VEGF-A), most commonly referred to as VEGF, is considered the key regulator of angiogenesis.7 Overexpression of VEGF has been correlated with poor prognosis in several cancers, including colorectal cancer.8 Treatment with bevacizumab, a monoclonal antibody that binds VEGF, has been shown to decrease vascular volume and microvessel density in tumors. However, bevacizumab also seems to potentiate treatment efficacy when given with chemotherapy. One theory from Rakesh Jain suggests that tumor vasculature “normalizes” with antiangiogenic therapy, decreasing the tortuous and leaky vessels and improving delivery of chemotherapy and oxygen to the tumor.9 A study looking at effects of a single bevacizumab dose in rectal cancer patients has shown a decrease in interstitial fluid pressure within tumors, suggesting normalization of tumor blood vasculature.10 The decrease in interstitial fluid pressure allows for easier diffusion of chemotherapy into the tumors. Therefore, the proposed mechanisms of action of bevacizumab, while not completely understood, include both direct antiangiogenic effects and decreased tumor blood supply, and also normalization of tumor blood vasculature resulting in better delivery of chemotherapy to tumors.
BEVACIZUMAB IN THE FIRST-LINE SETTING FOR METASTATIC COLORECTAL CANCER
The first hint of clinical benefit from the addition of bevacizumab to chemotherapy for patients with metastatic colorectal cancer came from a randomized phase II trial conducted by Kabbinavar et al.11 In this three-arm trial, patients were randomly assigned to receive weekly bolus 5-FU and leucovorin (Roswell Park regimen) plus placebo (n = 36), or 5-FU and leucovorin plus bevacizumab at either 5 mg/kg (n = 35) or 10 mg/kg (n = 33) every 2 weeks. The addition of bevacizumab to chemotherapy resulted in an improved response rate (control, 17% [95% confidence interval (CI), 7%–34%]; low-dose bevacizumab, 40% [95% CI, 24%–48%]; high-dose bevacizumab, 24% [95% CI, 12%–43%]), time to progression (control, 5.2 months [95% CI, 3.5–5.6 months]; low-dose bevacizumab, 9.0 months [95% CI, 5.8–10.9 months]; high-dose bevacizumab, 7.2 months [95% CI, 3.8–9.2 months]), and overall survival (control, 13.8 months [95% CI, 9.1–23.0 months]; low-dose bevacizumab, 21.5 months [95% CI, 17.3 months-undetermined]; high-dose bevacizumab, 16.1 months [95% CI, 11.0–20.7 months]). From this study, it appeared that the 5 mg/kg bevacizumab dose yielded better efficacy than 10 mg/kg, and the 5 mg/kg dose was therefore used in the next first-line metastatic colorectal cancer study. It should be noted, however, that there were small patient numbers in each study arm, and a true comparison of the 5mg/kg and 10 mg/kg bevacizumab doses was not done.
The pivotal trial was a randomized phase III trial of bolus irinotecan, 5-FU, and leucovorin (IFL) plus placebo compared with IFL plus bevacizumab 5 mg/kg every 2 weeks, or bolus 5-FU and leucovorin plus bevacizumab 5 mg/kg every 2 weeks.1 Accrual to the 5-FU/leucovorin plus bevacizumab arm was stopped after 110 patients had been enrolled in that arm, when IFL was deemed the standard first-line treatment for metastatic colorectal cancer. A total of 813 patients were randomized to the IFL/placebo or the IFL/bevacizumab arm. Patients in the IFL/bevacizumab arm had a statistically significant improvement in response rate (44.8% vs. 34.8%, P = .004), time to progression (10.4 months vs. 7.1 months, hazard ratio [HR] 0.62, P = .001), and overall survival (20.3 months vs. 15.6 months, HR 0.66, P < .001). The benefit of bevacizumab extended to all prespecified subgroups, including gender, age ≥ 65 years, Eastern Cooperative Oncology Group (ECOG) performance status ≥ 1, rectal tumors, previous adjuvant therapy, and > 1 metastatic disease site.12 Further, subset analysis of patients considered nonresponders by Response Evaluation Criteria in Solid Tumors (RECIST), but who had either stable or progressive disease, confirmed that the addition of bevacizumab to IFL significantly improved progression-free (HR 0.76; 95% CI, 0.60– 0.96) and overall survival (HR 0.63; 95% CI, 0.49–0.80)13 in this group of patients. For patients treated on the discontinued 5-FU/leucovorin plus bevacizumab arm, there was also a suggestion of improved median overall survival over that achieved with IFL/placebo (18.3 months vs. 15.6 months).14
A randomized phase II study evaluated the addition of bevacizumab to bolus 5-FU and leucovorin for patients who were not candidates for irinotecan therapy. Among 209 patients randomized to 5-FU/leucovorin plus placebo or 5-FU/leucovorin plus bevacizumab 5 mg/kg, those in the bevacizumab group had superior response rate (26.0% vs. 15.2%, P = .055), progressionfree survival (9.2 months vs. 5.5 months, P = .0002), and a trend toward improved overall survival (16.6 months vs. 12.9 months, P = .16).15
Once the addition of bevacizumab to IFL and to 5-FU and leucovorin was established, subsequent trials evaluated bevacizumab combined with other chemotherapy backbones in the first-line metastatic colorectal cancer setting. The TREE-2 study was the first to evaluate the addition of bevacizumab to three different oxaliplatincontaining regimens (FOLFOX [infusional 5-FU, leucovorin, and oxaliplatin], bFOL [bolus 5-FU, leucovorin, and oxaliplatin], and CapOx [capecitabine and oxaliplatin]).16 TREE-2 was the second phase of the TREE-1 study, which compared the same three oxaliplatin-containing regimens but without the addition of bevacizumab. Comparison of TREE-1 and TREE-2 results shows that addition of bevacizumab appears to improve response rate, time to progression, and overall survival in all three regimens (Table 1). Results of a phase II study of CapOx plus bevacizumab were similar to those achieved in the TREE-2 CapOx arm, with a 48% response rate and 10.3-month median time to progression.17
Table 1.
TREE trials.16
| TREE-1 RR (%) | TREE-2 RR (%) | TREE-1 TTP (mo) | TREE-2 TTP (mo) | TREE-1 OS (mo) | TREE-2 OS (mo) | |
|---|---|---|---|---|---|---|
| FOLFOX | 41 | 52 | 8.7
95% CI [6.5–9.8] |
9.9
95% CI [7.9–11.7] |
19.2
95% CI [14.2–24.2] |
26.0
95% CI [18.0–NE] |
| bFOL | 20 | 39 | 6.9
95% CI [4.2–8.0] |
8.3
95% CI [6.6–9.9] |
17.9
95% CI [11.5–24.6] |
20.7
95% CI [18.8–25.3] |
| CapOx | 27 | 46 | 5.9
95% CI [5.1–7.4] |
10.3
95% CI [8.6–12.5] |
17.2
95% CI [12.5–22.3] |
27.0
95% CI [21.8–NE] |
Abbreviations: bFOL = bolus 5-fluorouracil (5-FU), leucovorin, oxaliplatin; CapOx = capecitabine, oxaliplatin; FOLFOX = infusional 5-FU, leucovorin, oxaliplatin; NE = not evaluable; CI = confidence interval; OS = overall survival; RR = response rate; TTP = time to disease progression.
Recently, definitive data were presented of a randomized phase III comparison of FOLFOX and CapOx with and without bevacizumab, the XELOX-1/NO16966 study.18 Results confirmed that bevacizumab statistically significantly improves progressionfree survival when added to FOLFOX and CapOx (HR 0.83, P = .0023), and that FOLFOX and CapOx can be used interchangeably as backbone regimens. Survival data showed a trend towards improved survival with the addition of bevacizumab to oxaliplatin-based chemotherapy (HR 0.89, P = .0769). Though this study did show an improvement in progression-free survival and trend towards improvement in overall survival with the addition of bevacizumab to oxaliplatin-based therapy, the improvement was not as large as in previous trials with the addition of bevacizumab to chemotherapy. One reason for this is that patients on this trial stopped therapy prior to disease progression for reasons such as chemotherapy-related toxicity. For patients who were treated on trial therapy until disease progression, the benefit of bevacizumab on progression-free survival when added to chemotherapy was more along the lines of previous trials (HR 0.63, P < .0001). This finding suggests the importance of continuing bevacizumabbased treatment until disease progression, modifying chemotherapy dosing as needed for toxicity.
The BICC-C trial evaluated different irinotecan-based regimens with the addition of bevacizumab. The original design of the BICC-C trial was to compare three different irinotecan-based regimens (FOLFIRI, modified IFL, and Capelri) for patients with previously untreated metastatic colorectal cancer.19 However, with the approval of bevacizumab for the treatment of metastatic colorectal cancer, the trial was changed to evaluate FOLFIRI plus bevacizumab and modified IFL plus bevaciuzmab. Though this study was meant to compare the different irinotecan-based regimens, the addition of bevacizumab to either FOLFIRI or modified IFL showed an improvement in progression-free (11.2 months vs. 7.8 months for FOLFIRI, and 8.3 months vs. 5.9 months for modified IFL) and overall survival (not reached vs. 23.1 months for FOLFIRI, and 19.2 months vs. 17.6 months for modified IFL). This study also showed to superiority of the infusional FOLFIRI over modified IFL.
To summarize the status of bevacizumab in the first-line setting for patients with metastatic colorectal cancer, the dose used is 5 mg/kg given every other week, or 7.5 mg/kg when given every 3 weeks, depending on the schedule of the chemotherapy backbone. In phase III clinical trials, bevacizumab improved efficacy when added to IFL and the oxaliplatin-based regimens FOLFOX and CapOx.1,20 Randomized phase II data showed a benefit of adding bevacizumab to bolus 5-FU and leucovorin and to bolus 5-FU, leucovorin, and oxaliplatin chemotherapy.11,15,16 The BICC-C trial, though not meant to compare regimens with and without bevacizumab, suggests an improvement in progression-free and overall survival with the addition of bevacizumab to either FOLFIRI or modified IFL. In clinical practice and based on the suggested mechanism of action of bevacizumab in improving chemotherapy delivery to the tumor, bevacizumab is used with almost any chemotherapy backbone. Bevacizumab therapy also appears to benefit many patient subsets, including older patients and those with poorer performance status.12 For patients who do not exhibit treatment response based on traditional radiologic criteria, the addition of bevacizumab to chemotherapy may still confer an improvement in progression-free and overall survival, though tumor size may remain stable.13
Future Directions for First-Line Bevacizumab in Metastatic Colorectal Cancer
Future research directions on bevacizumab use in the first-line setting for metastatic colorectal cancer patients include further data on chemotherapy backbones; combining bevacizumab with other targeted agents, such as epidermal growth factor receptor (EGFR) inhibitors; and bevacizumab used as maintenance therapy when cytotoxic agents are held to decrease side effects and promote quality of life.
One major US trial currently accruing patients is the Roche DVS (dense vs. standard) trial (Figure 1), which is evaluating the 3-week vs. a 2-week “dosedense” CapOx regimen plus bevacizumab. Scheithauer et al had previously compared the traditional 3-week CapOx regimen to a “dose-dense” 2-week CapOx regimen. Results showed comparable toxicity in the two arms, while response rate and progression-free survival were better with the 2-week “dose dense” regimen.21
Figure 1.
Design of the DVS (dense vs. standard) trial in patients with chemonaïve, metastatic colorectal cancer (CRC). Abbreviations: Cap = capecitabine; OS = overall survival; Oxali = oxaliplatin; PFS = progression-free survival; RR = response rate; XELOX = capecitabine plus oxaliplatin.
With the success of biologic agents in colorectal cancer, studies have begun to evaluate the combination of bevacizumab and EGFR inhibitors. Mounting experimental evidence suggests that VEGF and EGFR signaling pathways are intimately linked.22,23 Preclinical evidence shows that the combination of the anti-VEGF antibody DC101 and the anti-EGFR antibody cetuximab leads to a marked increase in tumor growth control.24 These observations suggest that, in addition to stimulating cell division, increased EGFR signaling may also increase tumor angiogenesis, and thereby, anti-EGFR agents may interact synergistically with anti-VEGF therapies.
Current studies of combination anti-VEGF and anti-EGFR antibodies as first-line therapy for metastatic colorectal cancer patients include Cancer and Leukemia Group B (CALGB) 80405 (Figure 2) and Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study (Figure 3). In CALGB 80405, patients are treated with either FOLFOX or FOLFIRI and are then randomized to receive bevacizumab, or cetuximab, or both bevacizumab and cetuximab. This study is currently accruing patients. In PACCE, patients are treated with FOLFOX or FOLFIRI and are then randomized to receive bevacizumab alone or bevacizumab plus panitumumab, a fully humanized anti-EGFR monoclonal antibody. Preliminary data from the PACCE study were presented at the World Gastrointestinal Cancer Congress in June 2007.25 This study found that patients who received panitumumab in addition to bevacizumab and oxaliplatin-based chemotherapy had an inferior progression-free (9.0 months vs. 10.5 months, HR 1.29 [1.05–1.58]) and overall survival (18.6 months vs. not reached, HR 1.44 [1.10–1.88]) compared to the patients who received bevacizumab and chemotherapy. There was more dehydration, diarrhea, infection, and skin rash in the panitumumab arms. Whether the increase in toxicity accounted for the survival differences found between the arms remains to be seen.
Figure 2.
Design of Cancer and Leukemia Group B (CALGB) 80405 study in patients with chemonaïve metastatic colorectal cancer (CRC). Patients are treated with FOLFOX (5-fluorouracil [5-FU], leucovorin, oxaliplatin) or FOLFIRI (infusional 5-FU, leucovorin, irinotecan) and are then randomly assigned to receive bevacizumab, cetuximab, or the combination of the two targeted agents. Abbreviations: IHC = immunohistochemistry; ISH = in situ hybridization.
Figure 3.
Design of Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study in patients with chemonaïve metastatic colorectal cancer (CRC). Patients are treated with FOLFOX (5-FU, leucovorin, oxaliplatin) or FOLFIRI (infusional 5-FU, leucovorin, irinotecan) and are then randomly assigned to receive bevacizumab alone or combined with panitumumab. Abbreviations: OS = overall survival; PFS = progression-free survival; RR = response rate.
The OPTIMOX-1 and OPTIMOX-2 studies evaluated the possibility of treating patients with FOLFOX chemotherapy, then stopping the oxaliplatin or all chemotherapy, and then restarting therapy when disease progressed.26,27 The most recently reported results at the 2007 American Society of Clinical Oncology (ASCO) annual meeting suggest that while a treatment break from oxaliplatin is reasonable, complete planned chemotherapy free intervals may result in an inferior overall survival.28 The next study in the OPTIMOX series— the DREAM study—is evaluating maintenance therapy with targeted biologic agents during breaks from oxaliplatin-containing chemotherapy. Metastatic colorectal cancer patients are treated with FOLFOX or CapOX plus bevacizumab, followed by a break from cytotoxic chemotherapy with continuation of either single-agent bevacizumab or bevacizumab plus erlotinib, an oral EGFR tyrosine kinase inhibitor.
BEVACIZUMAB IN THE SECOND-LINE SETTING FOR METASTATIC COLORECTAL CANCER
As in the first-line setting, metastatic colorectal cancer patients who had not previously received bevacizumab were shown to benefit from the addition of bevacizumab to second-line chemotherapy, based on randomized phase III trial data. However, as more patients commonly receive bevacizumab in the first-line setting, an important question is whether bevacizumab therapy should be continued with secondline chemotherapy after having progressive disease with first-line bevacizumab plus chemotherapy.
In the ECOG 3200 study, 829 metastatic colorectal cancer patients previously treated with 5-FU and irinotecan as single agents or combined were randomly assigned to receive FOLFOX, FOLFOX plus bevacizumab 10 mg/kg every other week, or bevacizumab 10 mg/kg alone every other week.4 The addition of bevacizumab to FOLFOX resulted in a statistically significant improvement in response rate (21.8% vs. 9.2%, P < .0001), progression-free survival (7.2 months vs. 4.8 months, P < .0001), and overall survival (12.9 months vs. 10.8 months, P < .002). These data provided the basis for the FDA approval of bevacizumab in combination with 5-FU-based chemotherapy as second-line therapy for metastatic colorectal cancer. Of note, the bevacizumab dose in this trial was 10 mg/kg, whereas in the first-line setting, the dose had previously been defined as 5 mg/kg every other week. This dosing was based on a small, randomized phase II study not powered to evaluate the differences between the 5 mg/kg and 10 mg/kg doses.11 It is not clear if the two doses result in different efficacies. The upcoming Southwest Oncology Group (SWOG) 0600 study is designed to address this issue.
Studies are evaluating combinations of bevacizumab and the EGFR inhibitor cetuximab in the second-line, as in the first-line, setting. Saltz et al reported preliminary results of BOND-2, a randomized phase II trial of bevacizumab, cetuximab, and irinotecan vs. bevacizumab and cetuximab as second- or third-line therapy for patients with irinotecan-refractory metastatic colorectal cancer.29 This trial, like the TREE studies, has a design similar to that of BOND-1, a randomized phase II study of cetuximab plus irinotecan vs. cetuximab alone for patients with irinotecan-refractory metastatic colorectal cancer.30 In BOND-2, the bevacizumab/cetuximab combination resulted in a 20% response rate and 5.6- month median time to progression, and the bevacizumab/cetuximab/irinotecan combination showed a 37% response rate and 7.9-month median time to progression. Based on results from both BOND-1 and BOND-2 (Table 2), the addition of bevacizumab appears to improve outcome in the second-line setting. The follow-up trial to BOND-2 is BOND-2.5, wherein patients with irinotecan-refractory metastatic colorectal cancer who have previously received bevacizumab will be randomly assigned to receive bevacizumab, cetuximab, and irinotecan, or bevacizumab and cetuximab. This trial may shed light on whether bevacizumab should be continued in the second-line setting after disease progression on first-line bevacizumab treatment.
Table 2.
| BOND-1 RR (%) | BOND-2 RR (%) (+bevacizumab) | BOND-1 TTP (mo) | BOND-2 TTP (mo) (+bevacizumab) | |
|---|---|---|---|---|
| Cetuximab + Irinotecan | 23 | 37 | 4.0 | 7.9 |
| Cetuximab | 11 | 20 | 1.5 | 5.6 |
Abbreviations: RR = response rate; TTP = time to disease progression.
The trial designed to clearly evaluate bevacizumab use in the second-line setting after progression on first-line bevacizumab-based therapy is SWOG 0600 (Figure 4). The current trial design calls for accrual of 1,300 metastatic colorectal cancer patients whose disease has progressed on oxaliplatin- and bevacizumab-based firstline therapy. Patients will be treated with irinotecan-based chemotherapy (FOLFIRI or single-agent irinotecan) plus cetuximab, and randomly assigned to receive either placebo, bevacizumab 5 mg/kg every other week, or bevacizumab 10 mg/kg every other week. It is hoped that results of this large study will provide answers regarding continuation of bevacizumab in the second-line setting, and any differences between the two bevacizumab doses.
Figure 4.
Design of Southwest Oncology Group (SWOG) 0600 trial in metastatic colorectal cancer patients who have progressive disease following treatment with oxaliplatin/bevacizumab-based first-line therapy. Patients receive second-line irinotecan-based chemotherapy plus cetuximab and either placebo, bevacizumab 5 mg/kg, or bevacizumab 10 mg/kg every other week. Abbreviations: bev = bevacizumab; HR = hazard ratio; IC = irinotecan, cetuximab; ICB5 = irinotecan, cetuximab, bevacizumab 5 mg/kg; ICB10 = irinotecan, cetuximab, bevacizumab 10 mg/kg; OS = overall survival; oxali = oxaliplatin; RR = response rate; TTF = time to treatment failure; TTP = time to disease progression.
BEVACIZUMAB-RELATED TOXICITIES IN METASTATIC COLORECTAL CANCER PATIENTS
Bevacizumab is generally well tolerated. Toxicities seen in patients receiving bevacizumab have included hypertension, gastrointestinal (GI) perforation, arterial thrombotic events, wound healing complications, and reversible posterior leukoencephalopathy syndrome (RPLS). These toxicities have been evaluated both in the context of bevacizumab clinical trials as well as registry data of almost 2,000 metastatic colorectal cancer patients.
Hypertension occurs in approximately 15% of bevacizumab-treated patients; fewer than 1% have grade 4 hypertension. Hypertension, which appears to be a classeffect of anti-VEGF agents, is well-controlled with antihypertensive agents. Hypertension may be associated with a recently described, rare phenomenon for bevacizumab called RPLS. This is a syndrome of hypertension-associated mental status changes, headache, seizures, and visual disturbance, with associated radiologic findings of posterior cerebral edema. There have been two fatal RPLS cases out of many thousands of bevacizumab-treated patients, resulting in a National Cancer Institute (NCI) action letter in April 2006. Further retrospective investigation into RPLS incidence is ongoing. RPLS is generally reversible through control of blood pressure.
Based on registry data, the GI perforation rate in metastatic colorectal cancer patients treated with bevacizumab is 1.7%.31 Attempts to identify causative factors have investigated peritoneal carcinomatosis, diverticulitis, in situ bowel tumor, obstruction, and radiation therapy, and no clear associated factors have been found.
Bevacizumab treatment has also been associated with an increased incidence of arterial thrombotic events (ATEs), including angina, myocardial infarction, and stroke. Pooled analysis of five randomized trials including 1,745 patients showed a 3.8% overall incidence of ATEs in patients receiving bevacizumab with chemotherapy, compared with 1.7% in those receiving chemotherapy alone.32 Additional risk factors of age ≥ 65 years and history of atherosclerotic disease were identified. Having both risk factors increased the ATE rate to 17.9%, although this patient population also had the same improvement in response rate, progression-free survival, and overall survival with the addition of bevacizumab as the other patients. Therefore, weighing of risk and benefit is important in treating this population of patients. Of note, data have shown the safety of aspirin use,33 as well as full-dose anticoagulation therapy34 in patients treated with bevacizumab.
Because of the requirement of proangiogenic factors in wound healing, risk of postoperative complications increases in patients treated with bevacizumab. In an analysis of two randomized studies, bevacizumab use in patients undergoing surgery 28 to 60 days prior to study enrollment did not significantly increase risk of wound healing complications (1.3% vs. 0.5%).35 Patients who required surgery while receiving bevacizumab had a more substantial increase in risk (13.3% vs. 3.4%). It is recommended that bevacizumab not be started for at least 28 days after a major procedure, and that 6 to 8 weeks elapse from last bevacizumab dose before surgery takes place. A patient requiring emergent surgery would be an exception to the latter recommendation.
CONCLUSIONS
The improvement in patient survival achieved by adding an antiangiogenic agent to chemotherapy for metastatic colorectal cancer patients both in the first- and second-line settings has opened a new door to treatment options. Further research is needed, including how to use these agents optimally—not only combined with chemotherapy but as possible maintenance therapies. Studies are also looking into improving patient survival further by combining targeted therapies that demonstrate preclinical evidence of synergy. Research is needed regarding how to predict and overcome resistance to therapy, and which patients will experience toxicity and how to prevent it; current studies are using biomarkers to aid this process. This is a new and exciting era in the treatment of colorectal cancer, where new agents that are enhancing treatment response without the traditional toxicities of cytotoxic agents are allowing people to live longer, and may increase the proportion of patients who are candidates for surgical cure of metastatic disease.
Footnotes
Disclosures of Potential Conflicts of Interest
Dr. Bendell has received honoraria and research funding from Genentech, research funding from sanofi-aventis, honoraria from Roche, research funding from Bristol-Myers Squibb, and honoraria from Amgen.
References
- 1.Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342. doi: 10.1056/NEJMoa032691. [DOI] [PubMed] [Google Scholar]
- 2.Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial-E4599. ASCO Annual Meeting Proceedings. J Clin Oncol. 2005;23:16S. (abstr 4) [Google Scholar]
- 3.Miller KD, Wang M, Gralow J, et al. E2100: a randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first line therapy for locally recurrent or metastatic breast cancer. Presented at the 41st Annual Meeting of the American Society for Clinical Oncology; Orlando, FL. May 13–17, 2005. [Google Scholar]
- 4.Giantonio B, Catalano PJ, Merepol NJ, et al. High-dose bevacizumab in combination with FOLFOX4 improves survival in patients with previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. ASCO Annual Meeting Proceedings. J Clin Oncol. 2005;23:16S. (abstr 2) [Google Scholar]
- 5.Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–1186. doi: 10.1056/NEJM197111182852108. [DOI] [PubMed] [Google Scholar]
- 6.Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29(suppl 16):15– 18. doi: 10.1053/sonc.2002.37263. [DOI] [PubMed] [Google Scholar]
- 7.Ferrara N. Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol. 2002;29(suppl 16):10–14. doi: 10.1053/sonc.2002.37264. [DOI] [PubMed] [Google Scholar]
- 8.Lee JC, Chow NH, Wang ST, et al. Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients. Eur J Cancer. 2000;36:748–753. doi: 10.1016/s0959-8049(00)00003-4. [DOI] [PubMed] [Google Scholar]
- 9.Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9:685–693. doi: 10.1038/nm0603-685. [DOI] [PubMed] [Google Scholar]
- 10.Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10:145–147. doi: 10.1038/nm988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.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;21:60–65. doi: 10.1200/JCO.2003.10.066. [DOI] [PubMed] [Google Scholar]
- 12.Fyfe GA, Hurwitz H, Fehrenbacher L, et al. Bevacizumab plus irinotecan/5-FU/leucovorin for treatment of metastatic colorectal cancer results in survival benefit in all pre-specified patient subgroups. ASCO Annual Meeting Proceedings. J Clin Oncol. 2004;22:14S. (abstr 3617) [Google Scholar]
- 13.Mass R, Sarkar S, Holden N, et al. Clinical benefit from bevacizumab (BV) in responding (R) and non-responding (NR) patients (pts) with metastatic colorectal cancer (mCRC). ASCO Annual Meeting Proceedings. J Clin Oncol. 2005;23:16S. (abstr 3514) [Google Scholar]
- 14.Hurwitz H, Fehrenbacher L, Hainsworth J, et al. Bevacizumab in combination with 5-fluorouracil and leucovorin: a promising regimen for first-line metastatic colorectal cancer. 2004 ASCO Gastrointestinal Cancers Symposium; San Francisco, CA. January 22–24, 2004; (abstr 286) [Google Scholar]
- 15.Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23:3697–3705. doi: 10.1200/JCO.2005.05.112. [DOI] [PubMed] [Google Scholar]
- 16.Hochster H, Hart LL, Ramanathan RK, et al. Results of the TREE 2 cohort: safety, tolerability, and efficacy of bevacizumab added to three oxaliplatin/fluoropyrimidine regimens as first line treatment of metastatic colorectal cancer. 2006 ASCO Gastrointestinal Cancers Symposium; San Francisco, CA. January 26–28, 2006; (abstr 244) [DOI] [PubMed] [Google Scholar]
- 17.Bendell J, Fernando N, Morse M, et al. A phase II study of oxaliplatin (OX), capecitabine (CAP), and bevacizumab (BV) in the treatment of metastatic colorectal cancer. ASCO Annual Meeting Proceedings. J Clin Oncol. 2006;24:18S. (abstr 3541) [Google Scholar]
- 18.Saltz LB, Clarke S, Diaz Rubio E, et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: updated efficacy results from XELOX-1/NO16966, a randomized phase III trial in first-line metastatic colorectal cancer. 2007 ASCO Annual Meeting Proceedings. J Clin Oncol. 2007;25:18S. (abstr 4028) [Google Scholar]
- 19.Fuchs CS, Marshall J, Mitchell E, et al. Updated results of BICC-C study comparing first-line irinotecan/fluoropyrimadine combinations with or without celecoxib in mCRC: updated efficacy data. 2007 ASCO Annual Meeting Proceedings. J Clin Oncol. 2007;25:18S. (abstr 4027) [Google Scholar]
- 20.Cassidy J, Clarke S, Diaz-Rubio E, et al. First efficacy and safety results from XELOX-1/NO16966, a randomised 2x2 factorial phase III trial of XELOX vs. FOLFOX4 + bevacizumab or placebo in first-line metastatic colorectal cancer (MCRC) Ann Oncol. 2006;17 (abstr LBA3) [Google Scholar]
- 21.Scheithauer W, Komek GV, Raderer M, et al. Randomized multicenter phase II trial of two different schedules of capecitabine plus oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2003;21:1307–1312. doi: 10.1200/JCO.2003.09.016. [DOI] [PubMed] [Google Scholar]
- 22.Petit AM, Rak J, Hung MC, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases downregulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol. 1997;151:1523–1530. [PMC free article] [PubMed] [Google Scholar]
- 23.Clarke K, Smith K, Gullick WJ, et al. Mutant epidermal growth factor receptor enhances induction of vascular endothelial growth factor by hypoxia and insulin-like growth factor-1 via a PI3 kinase dependent pathway. Br J Cancer. 2001;84:1322–1329. doi: 10.1054/bjoc.2001.1805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Jung YD, Mansfield PF, Akagi M, et al. Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer. 2002;38:1133–1140. doi: 10.1016/s0959-8049(02)00013-8. [DOI] [PubMed] [Google Scholar]
- 25.Hecht JR, Chidiac T, Mitchell E, et al. An interim analysis of efficacy and safety from a randomized controlled trial of panitumumab with chemotherapy plus bevacizumab (Bev) for metastatic colorectal cancer (mCRC). Presented at the 9th World Congress on Gastrointestinal Cancer; Barcelona, Spain. June 27–30, 2007. [Google Scholar]
- 26.Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—a GERCOR study. J Clin Oncol. 2006;24:394–400. doi: 10.1200/JCO.2005.03.0106. [DOI] [PubMed] [Google Scholar]
- 27.Maindrault-Goebel F, Lledo G, Chibaudel B, et al. OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study. ASCO Annual Meeting Proceedings. J Clin Oncol. 2006;24:18S. (abstr 3504) [Google Scholar]
- 28.Maindrault-Goebel F, Lledo G, Chibaudel B, et al. Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC): a GERCOR study. 2007 ASCO Annual Meeting Proceedings. J Clin Oncol. 2007;25:18S. (abstr 4013) [Google Scholar]
- 29.Saltz LB, Lenz H, Hochster H, et al. Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. ASCO Annual Meeting Proceedings. J Clin Oncol. 2005;23:16S. (abstr 3508) [Google Scholar]
- 30.Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–345. doi: 10.1056/NEJMoa033025. [DOI] [PubMed] [Google Scholar]
- 31.Kozloff M, Cohn A, Christiansen N, et al. Safety of bevacizumab (BV, Avastin) among patients (pts) receiving first-line chemotherapy (CT) for metastatic colorectal cancer (mCRC)—preliminary results from a larger registry in the US. ASCO Annual Meeting Proceedings. J Clin Oncol. 2005;23:16S. (abstr 3566) [Google Scholar]
- 32.Skillings JR, Johnson DH, Miller K, et al. Arterial thromboembolic events (ATEs) in a pooled analysis of 5 randomized, controlled trials (RCTs) of bevacizumab (BV) with chemotherapy. ASCO Annual Meeting Proceedings. J Clin Oncol. 2005;23:16S. (abstr 3019) [Google Scholar]
- 33.Hambleton J, Skillings J, Kabbinavar F, et al. Safety of low-dose aspirin (ASA) in a pooled analysis of 3 randomized, controlled trials (RCTs) of bevacizumab (BV) with chemotherapy (CT) in patients (pts) with metastatic colorectal cancer (mCRC). ASCO Annual Meeting Proceedings. J Clin Oncol. 2005;23:16S. (abstr 3554) [Google Scholar]
- 34.Hambleton J, Novotny WF, Hurwitz H, et al. Bevacizumab does not increase bleeding in patients with metastatic colorectal cancer receiving concurrent anticoagulation. ASCO Annual Meeting Proceedings. J Clin Oncol. 2004;22:14S. (abstr 3528) [Google Scholar]
- 35.Scappaticci F, Fehrenbacher L, Cartwright T, et al. Lack of effect of bevacizumab on wound healing/bleeding complications when given 28–60 days following primary cancer surgery. ASCO Annual Meeting Proceedings. J Clin Oncol. 2004;22:14S. (abstr 3530) [Google Scholar]