Angiogenesis is a critical factor in the propagation and metastasis of many tumor types, including colorectal cancer. Bevacizumab, which targets vascular endothelial growth factor (VEGF)-A, has an established role in the therapy of metastatic colorectal cancer, in first-line and in second-line treatment when used in combination with chemotherapy. Recent data also support an ongoing benefit when antiangiogenic therapy is continued across lines of chemotherapy. After the initial approvals of irinotecan, oxaliplatin, bevacizumab, and the anti-EGFR antibodies, cetuximab and panitumumab, multiple agents failed to improve outcomes in colorectal cancer. In the last 2 years, aflibercept (Zaltrap), a soluble VEGF receptor, and regorafenib (Stivarga) gained approval based upon survival improvements when used in the second-line and refractory settings, respectively. These 2 drugs remain the focus of intense research, with hope that further investigation will uncover methods to optimize benefit through optimal patient selection, improved dosing strategies, and better toxicity management. Herein is a summary of the pivotal trials that resulted in the approval of these drugs, as background to their place in the treatment of advanced colorectal cancer.

Angiogenesis is necessary for normal development and cellular growth, as well as for the promotion and spread of malignant neoplasms. The concept of targeting angiogenic signaling in cancer dates back decades, at least to the initial prescient hypotheses of Folkman concerning the presence of a tumor-angiogenesis factor (TAF), which duly influences endothelial cells, stimulates angiogenesis, and ultimately promotes the growth and spread of malignancies. Folkman also observed that tumor cells seemed to likewise stimulate endothelial cell proliferation.

While the initially identified candidate did not itself prove to be all that was hoped, a great amount of research was later pursued addressing this concept. Further work established the presence of a vascular permeability factor (VPF), later identified as VEGF.

Presently, it is recognized that there are 5 structurally related molecules that constitute the VEGF family of growth factors: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PIGF).

It is believed that these are crucial in the process of angiogenesis, with VEGFA and its cognate receptor VEGFR-2 representing the principal angiogenic signaling locus in vivo. However, the processes of angiogenesis and vasculogenesis remain incompletely understood and the true role of additional VEGF receptors, such as VEGFR-1, is unclear. In addition, multiple additional growth factors and cytokines clearly contribute to the process, many of which may be produced by hypoxic tumor cells and appear capable of replacing VEGF. These include but are not limited to FGF, PDGF-B, HGF, EGF, IL-8, SDF-1&alpha;, and Ang-2. Initial efforts to target neoplastic lesions by affecting the process of angiogenesis have yielded success, though modest, potentially owing to the complexity of the process and the multiple compensatory pathways.

Bevacizumab (Avastin), a recombinant humanized monoclonal antibody that targets VEGF-A, was among the first antiangiogenic agents developed and represents the first clinically approved anticancer agent specifically targeting angiogenesis.

Approval was based upon the AVF2107g study, in which patients with untreated metastatic colorectal cancer were administered either IFL (irinotecan + bolus 5-fuorouracil [5-FU]) plus bevacizumab or IFL alone. A significant survival benefit was seen: 20.3 months versus 15.6 months, P <.001.

Progression-free survival (PFS) was similarly extended, accompanied by an increase in the overall response rate (ORR), 44.8% versus 34.8%. Adverse events (AEs) were similar between the 2 arms, with an increase in overall grade 3/4 AEs, driven by hypertension. The Eastern Cooperative Oncology Group (ECOG) 3200 study evaluated bevacizumab when administered as a component of second-line therapy, after progression on 5-FU and irinotecan. Randomization was to one of 3 arms: FOLFOX-4 (5-FU + leucovorin + oxaliplatin) plus bevacizumab; FOLFOX-4 alone; or bevacizumab alone.

The median overall survival (OS) was significantly improved in the combined chemotherapy plus bevacizumab arm compared with the other 2 arms, at 12.9 months, 10.8 months, and 10.2 months, respectively (hazard ratio [HR] = 075; P = .0011). Median PFS was 7.3 months, 4.7 months, and 2.7 months, respectively. The lack of difference in OS in the latter 2 arms is presumably secondary to differences in postprogression therapy.

Following the approval of bevacizumab, the BRiTE registry was initiated in 2004 and collected data on the treatment and outcomes of patients who received first-line bevacizumab-based therapy, drawing from a less frequently selected community-based population. Upon analysis, the data suggested a marked benefit when bevacizumab was continued with subsequent therapy (ie, beyond progression). The median OS of patients who received postprogression chemotherapy with bevacizumab versus without bevacizumab was 31.8 months and 19.9 months, respectively, supporting the hypothesis that antiangiogenic therapy provided continued benefit across lines of chemotherapy.

Notably, hypertension was the only AE reported more frequently in the bevacizumabtreated group. The somewhat disappointing part of this story came when this hypothesis was actually tested, in the TML study (ML18147).

Here, patients who received first-line bevacizumab containing chemotherapy were treated with the alternate cytotoxic backbone, irinotecan or oxaliplatin, depending upon prior exposure, and were randomized to receive bevacizumab plus chemotherapy or chemotherapy alone. Median OS was improved when bevacizumab was continued with a changing chemotherapy backbone, at 11.2 months versus 9.8 months (HR = 0.81; P = .0062). Median PFS improved from 4.1 months to 5.7 months with bevacizumab (HR = 0.68; P <.0001), although responses were low in both arms, namely 5% with bevacizumab and 4% without. Thus, the hypothesis was confirmed: continued VEGF-A blockage through use of bevacizumab across chemotherapies prolongs survival. Of note, the primary benefit appears to be a modest prolongation in disease stability, which translates to several weeks of prolonged survival on averagea step forward, but a small one.

In the refractory setting, bevacizumab has been evaluated as a single agent and in combination with 5-FU. Of relevance, in the National Cancer Institute Treatment Referral Centre trial (TRC-0301), patients who were refractory to 5-FU, oxaliplatin, and irinotecan were treated with bolus or infusional 5-FU and bevacizumab. Stable disease or response was obtained in 33% of patients and a median PFS of 3.5 months was achieved (95% CI: 2-4.3 months).

However, the primary endpoint of the trial was objective response rate, the classic litmus test to gauge treatment efficacy, which stood at just 1%. An additional reported trial evaluated the combination of infusional 5-FU and bevacizumab in treatment of 48 refractory patients, all of whom had progressed on prior oxaliplatin-, irinotecan-, and cetuximab-based regimens. The median time to treatment progression (TTP) was 3.5 months, with a median OS of 7.7 months (95% CI: 3.9-11.9 mo.)

Nevertheless, objective response was again quite uncommon, at 6.25%. This regimen has not been further pursued in this setting.

Ziv-aflibercept, otherwise known as aflibercept (Zaltrap), is a fusion protein, referred to as a soluble VEGF receptor or VEGF-trap, which contains the key domains of hVEGFR-1 and hVEGFR-2 fused to the Fc portion of IgG1.

In mouse models, the VEGFtrap demonstrated near-complete blockade of tumorassociated angiogenesis and significant decrease in microvessel density.

In addition, aflibercept was demonstrated to bind VEGF-A with a much greater affinity (50-fold to 100-fold higher), with a faster association rate, further blocking the signaling of PIGF and VEGF-B through VEGFR-1.

Recent investigation has compared the activity of aflibercept with bevacizumab in patient-derived xenograft models. Complete tumor stasis was observed in the majority of xenografts through aflibercept treatment and, in a distinct minority, bevacizumab treatment.

This suggests that aflibercept has potential for a broader range of activity than does bevacizumab, a differential effect with as of yet unclear translation to the clinical setting.

Table. Comparison of Key Features in Bevacizumab and Aflibercept Trials [CLICK TO ENLARGE]

AEs indicates adverse events; NR, not reported; OS, overall survival; PFS, progression-free survival.

In initial clinical investigation, aflibercept was shown to be tolerable across a range of doses, with the most common AEs being fatigue (63.8%), nausea (36.2%), and vomiting (27.7%). These were predominantly mild (grade 1) and resolved with discontinuation of therapy.

Toxicities associated with other antiangiogenic agents were also seen: dysphonia (46.8%), hypertension (38.3%), and proteinuria (10.6%). A sharp uptick in the incidence of hypertension, particularly grade 3/4 hypertension, was seen at doses of 4 mg/kg and greater, with maximal VEGF-bound VEGF Trap complex levels at doses of &ge;2 mg/kg. Activity was witnessed in several patients, with responses in ovarian cancer and evidence of prolonged (>1 year) stable disease in renal cell carcinoma. Further studies included a phase I investigation of aflibercept combined with FOLFIRI.

Dose-limiting toxicities at the recommended phase II dose included grade 3 proteinuria as well as nephrotic syndrome. However, 6 of the 23 patients with colorectal cancer demonstrated objective response, some of whom had received prior treatment with both oxaliplatin and irinotecan. An expansion cohort was evaluated, at the 4-mg/kg dose, confirming the initial hints of activity, including a handful of responses and numerous patients attaining stable disease.

The VELOUR study evaluated the benefit of adding aflibercept to FOLFIRI after progression during or shortly following first-line oxaliplatin-based chemotherapy in the metastatic setting.

Patients with relapse within 6 months following oxaliplatin-based adjuvant therapy were allowed. Prior bevacizumab use was permitted, but not required, and was noted in approximately 30% of patients. A statistically significant improvement in median OS was demonstrated, increasing from 12.06 months to 13.5 months (HR 0.817; P = .0032). Two-year OS rates were 28% in the aflibercept arm and 18.7% in the control arm. In addition, median PFS improved from 4.67 to 6.9 months, with RR rising from 11.1% to 19.8%. In subset analysis, there was no clear negative interaction stemming from prior bevacizumab treatment.

Increased rates of grade 3/4 AEs were observed in the experimental arm, including grade 3/4 hypertension and, to a much lesser extent, hemorrhage, arterial thrombotic events, and thromboembolic events. Unexpectedly, AEs typically associated with chemotherapy, not antiangiogenic antibodies, were also witnessed at an increased rate: diarrhea (19.3% vs 7.8%), asthenia (16.9% vs 10.6%), stomatitis and ulceration (13.7% vs 5%), infections (12.3% vs 6.9%), and palmarplantar erythrodysesthesia (2.8% vs 0.5%). As chance would have it, these results were first publicly presented at the same ASCO Annual Meeting as the results from the TML study, which similarly noted an improvement in survival from 9.8 months to 11.2 months, a difference of approximately 1.4 months. Given the near-identical difference in median survival and the suggestion of a slightly worsened AE profile, the approval of aflibercept was not greeted with open arms in the same manner as was the approval of bevacizumab.

The persistent divergence of the OS curves from the VELOUR study suggests a subset of patients who are afforded a more substantial benefit, though it is unclear whether these are patients who would have similarly benefitted from second-line therapy with chemotherapy plus bevacizumab. Post hoc subset analyses were recently conducted, examining clinical criteria that might predict for benefit or lack thereof conferred by aflibercept use in VELOUR. Patients recurring within 6 months following adjuvant oxaliplatin- based chemotherapy (n=124; approximately 10% of the study population) have been previously established to have a poorer prognosis.

On review, these patients appeared to derive no benefit from the addition of aflibercept (HR 1.12; 95% CI: 0.72-1.74). On further analysis, excluding this poor prognosis subset of patients, 2 larger subgroups were identified, including a better efficacy subgroup (ECOG PS 0 or ECOG PS 1 with <2 metastatic sites), wherein the median OS improved from 13.1 months to 16.2 months (HR = 0.73; 95% CI: 0.61-0.86) and 6-month PFS improved from 38% to 63% with the addition of aflibercept to chemotherapy. Additional analysis suggested that patients with liver only metastases were afforded particular benefit compared with the remainder of patients.

Alternatively, in the poor prognosis subgroup, the median OS was unchanged with aflibercept; in fact, there was a trend toward decreased survival, 10.4 months versus 9.6 months, which did not reach significance.

The optimal clinical application of these data is less clear. As the TML study excluded patients who progressed within 3 months following the initiation of first-line chemotherapy (also a poor prognosis subgroup), this subgroup has been cited by some as a population where aflibercept might be preferred over bevacizumab. This has not been directly examined in these subset analyses. The suggestion of limited or absent benefit in poor prognosis subgroups is potential cause to doubt aflibercept as being substantially more efficacious in said setting. For patients with rapid progression or bulky disease, inclusion of an anti-EGFR antibody in the second-line setting may be preferable, when eligible. The therapeutic combination selected in second-line therapy will ultimately depend greatly on the AE profile of therapy, the tumor&rsquo;s mutational status, and the previous treatment history. Desperately needed and glaringly absent in the 10 years since the approval of bevacizumab is the identification of a reproducible biomarker for efficacy of antiangiogenic therapy. As therapeutic options expand, such an identifier has the potential to provide far more power than the clinical factors described. Given the ongoing studies testing aflibercept, it is critical that the scientific community continue to search for this biomarker.

Finally, it is important to note that the approval of aflibercept and the completed randomized studies provide concrete evidence of benefit only with the combination of FOLFIRI (leucovorin calcium, fluorouracil, irinotecan hydrochloride) in patients not previously exposed to this regimen. Thus, for patients treated with a FOLFIRI-based regimen as first-line therapy or who progress on FOLFIRI, there is no robust data to support the addition of aflibercept as a means to overcome therapeutic resistance. There are also no data to support combination with FOLFOX. Aflibercept has been studied as a single agent in refractory colorectal cancer, demonstrating limited activity: a median PFS of 2 months to 2.4 months; OS of 8.5 months to 10.4 months; and a response rate of 1%.

In summary, until further studies demonstrate a benefit outside of the currently approved setting, the utilization of aflibercept in other manners for colorectal cancer is not recommended.

Regorafenib (Stivarga) is a small molecule tyrosine kinase inhibitor (TKI) with a wide range of targets, including but not limited to VEGFR-1, VEGFR-2, PDGFR&beta;, TIE2, RET, FGFR1, RAF-1, and BRAF. It was initially developed as a RAF1 inhibitor, and it differs structurally from sorafenib only by the placement of one fluorine. However, regorafenib demonstrates increased pharmacologic potency compared with sorafenib, with a broader spectrum of biochemical activity.

Preclinical data have demonstrated both its ability to interfere with angiogenesis as well as to inhibit tumor growth in a wide spectrum of models, including colorectal cancer. Regorafenib is primarily metabolized in the liver by CYP3A4 and UGT1A9, with 2 active metabolites, M-2 and M-5, which exhibit similar concentrations to regorafenib at steady state. The mean elimination half-life of regorafenib is 28 hours (range 14-58), although that of its metabolite M-5 is significantly longer, at 51 hours (range 32-70). Initial phase I studies examined multiple schedules of delivery, though ultimately the 28-day cycle of 21 days on followed by 7 days off was selected as the schedule to move forward in investigation, at a dose of 160 mg daily.

A continuous regimen of 100 mg daily has also demonstrated safety, though data on efficacy are lacking.

The CORRECT study evaluated the utility of regorafenib in refractory metastatic colorectal cancer. Patients who had previously received standard available chemotherapies and progressed on or within 2 months of the most recent regimen were randomized in a 2:1 fashion to receive regorafenib or best supportive care (BSC) alone.

The primary endpoint of the trial was OS. One hundred percent of patients had previously received therapy with bevacizumab, with >80% of patients having previously progressed while receiving chemotherapy, which included bevacizumab. Median OS improved with regorafenib from 5 months to 6.4 months (HR = 0.77; P = .0052) and median PFS was improved as well, from 1.7 months to 1.9 months (HR = 0.49; P <.0001). Five patients exhibited a partial response in the experimental arm (1%) versus 1 with placebo (0.4%). Disease control (partial response plus disease stabilization) at least 6 weeks after study initiation was observed in 41% of patients on regorafenib versus 15% on BSC.

Grade 3/4 treatment-related AEs were witnessed in 54% of patients assigned to regorafenib versus 14% in the placebo arm. The most frequent of these were hand-foot skin reaction, fatigue, diarrhea, hypertension, and rash or desquamation. Hyperbilirubinemia was observed in 9% of patients in the experimental arm versus 2% with placebo. There was one fatal case compatible with regorafenib-related drug-induced liver injury. Despite these AEs, quality of life as assessed by EORTC QLQ-C30 and EQ-5D was no different between the 2 groups at baseline or the conclusion of therapy. Similar to other agents that target angiogenic signaling, the incidence of hypertension, nose bleeds, and proteinuria were elevated with regorafenib use, though reassuringly, there was no witnessed increase in thrombotic events, bowel perforation was not observed, and significant bleeding was uncommon.

Adverse events tend to present early in the course of therapy at a median of 2 weeks; thus, it has been recommended that patients be seen at least biweekly during the first 2 cycles of therapy and within a week of initiating treatment. For common hand-foot skin reactions, it has been recommended that pre-existing areas of skin damage (calluses) be addressed via exfoliation pretreatment or use of a keratolytic agent, such as a urea-based ointment, coupled with ongoing use of comfortable, cushioned footwear, moisturizing, and close monitoring. A well-written recent review has gone through specific AE management in greater detail.

In reviewing these data, it is evident that >50% of patients will demonstrate progressive disease within 2 months of initiating regorafenib, suggesting limited overall efficacy. In practice, the attendant toxicities are readily evident upon initiation of therapy. However, a significant yet unidentified subset of patients maintains disease control at 4 months and 6 months, uncommonly witnessed with supportive care alone. Thus, it is clear that regorafenib provides significant clinical benefit and represents an advance in the treatment of patients with refractory disease; however, much work remains to be done to optimize its implementation. Many treated patients derive limited or no benefit and still incur substantial toxicities. As with other therapies, a means to select patients who are more likely to benefit would markedly increase the efficacy/toxicity ratio and thus, the clinical impact and embrace of this drug. Again, a biomarker remains elusive, though hope remains for identification. The proactive as well as reactive management of anticipated AEs may aid to lessen toxicity. Personalized dosing strategies will be the subject of future study, with the aim of improving utilization of regorafenib. At this time, the approved dose is 160 mg, without data to support a maintained benefit with lesser doses of administration. In any case, regorafenib represents a new standard, but will also serve as a benchmark upon which to improve.

Additional Antiangiogenic Agents of Interest

Ramucirumab (Cyramza) is a fully humanized IgG1 monoclonal antibody antagonist of VEGFR-2.26 Recently, ramucirumab has been evaluated in advanced gastric and gastroesophageal cancers, as a component of second-line therapy. While bevacizumab previously failed to demonstrably improve OS in the first-line treatment of gastroesophageal cancers when added to chemotherapy, ramucirumab increased OS as a single agent in the REGARD study, from 3.8 months to 5.2 months (HR 0.776; P = .047).

Hypertension was increased in the ramucirumab group (16% vs 8%) compared with placebo, although other AEs were similar. Shortly after this was reported, the RAINBOW study demonstrated a similar survival improvement when ramucirumab was added to paclitaxel compared with paclitaxel alone. Median OS increased from 9.6 months to 7.4 months (HR 0.807; P = 0.017).

Grade 3 or greater neutropenia, leukopenia, hypertension, and fatigue were all increased in the experimental arm, though febrile neutropenia was low in both groups (3% vs 2%).

Antiangiogenic therapy is of proven benefit across lines of therapy in colorectal cancer.

Aflibercept offers a new treatment option with second-line FOLFIRI-based chemotherapy, with head-to-head comparisons against bevacizumab lacking. Ongoing studies with included biomarker analysis may allow for optimal patient selection.

Regorafenib demonstrates improved survival in the refractory setting, with a subset of patients deriving treatment benefit for several months. Aggressive side effect management and appropriate dose modification is paramount to effective utilization.

The ramucirumab data are of particular interest as Eli Lilly and Company recently published press releases announcing that the RAISE study reached its primary endpoint of OS.

RAISE (NCT01183780) is a phase III, randomized second-line study in metastatic colorectal cancer, with features common to both the TML and VELOUR trials. Patients who had progressed on first-line therapy with fluoropyrimidine, oxaliplatin, and bevacizumab were randomized to FOLFIRI plus ramucirumab or FOLFIRI plus placebo. Patients must have experienced progression during first-line therapy or within 6 months after conclusion of firstline therapy. Results are to be presented at the 2015 GI Cancers Symposium. These results will be of great interest to establish what role, if any, ramucirumab might play in the treatment of metastatic colorectal cancer.

In summary, in metastatic colorectal cancer, the continued inhibition of angiogenic signaling clearly improves patient outcomes, suggesting that there is a role to continue treatment beyond progression, across lines of chemotherapy. The choice to administer bevacizumab as opposed to aflibercept in concert with second-line irinotecan-based chemotherapy remains one of debate, as no head-to-head comparisons exist to establish the optimal treatment paradigm (see Table). Regorafenib represents the first TKI with proven benefit in colorectal cancer. Future studies of both may identify means to improve patient selection and limit toxicity, thus enhancing outcomes. Multiple additional agents are in development that target angiogenesis and may be capable of circumventing current mechanisms of tumor/host resistance relevant to antiangiogenic therapy. This should remain a time of great optimism in the treatment of colorectal cancer.

Folkman J, Merler E, Abernathy C, et al. Isolation of a tumor factor responsible for angiogenesis. 1971;133(2):275-288.

Folkman J. Tumor angiogenesis: therapeutic implications. 1971;285(21):1182-1186.

Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. 1983;219(4587):983-985.

Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. 1989;246(4935):1306-1309.

Kerbel RS. Tumor angiogenesis. 2008;358(19):2039-2049.

Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from antiangiogenesis therapy: Clinical implications and future strategies. 2012;30(32):4026-4034.

Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. 2004;350(23):2335-2342.

Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. 2007;25(12):1539- 1544.

Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). 2008;26(33):5326-5334.

Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. 2013;14(1):29-37.

Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. 2006;24(21):3354-3360.

Vincenzi B, Santini D, Russo A, et al. Bevacizumab in association with de Gramont 5-fluorouracil/folinic acid in patients with oxaliplatin-, irinotecan-, and cetuximab-refractory colorectal cancer: a singlecenter phase 2 trial. 2009;115(20):4849-4856.

Lockhart AC, Rothenberg ML, Dupont J, et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. 2010;28(2):207-214.

Macarulla T, Sauri T, Tabernero J. Evaluation of aflibercept in the treatment of metastatic colorectal cancer. 2014;14(10):1493-1505.

Chiron M, Bagley RG, Pollard J, et al. Differential antitumor activity of aflibercept and bevacizumab in patient-derived xenograft models of colorectal cancer. 2014;13(6):1636-1644.

Van Cutsem E, Khayat D, Verslype C, et al. Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours. 2013;49(1):17-24.

Khayat D, Tejpar S, Spano JP, et al. Intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours: results from the expansion cohort of a phase I study. 2013;49(4):790-797.

Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. 2012;30(28):3499-3506.

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Tabernero J, Van Cutsem E, Lakomy R, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. 2014;50(2):320- 331.

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Articles

Clinical Articles

Angiogenesis is a critical factor in the propagation and metastasis of many tumor types, including colorectal cancer.

The Role of Antiangiogenic Therapy in Previously Treated CRC

Biliary cancer includes gallbladder carcinoma, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. Each of these rare malignancies can be rapidly fatal due to the aggressive progression of disease and late stage at diagnosis. The various types of biliary cancer all have a different staging system, but they share common poor prognostic factors. Currently, effective treatment options are limited, but expanding. Surgery remains the only potential treatment for cure, but it is often not an option for advanced disease or in the setting of serious patient comorbidities. Chemotherapy with fluoropyrimidine-based or gemcitabine-based agents offers modest survival for patients with advanced disease. In recent years, molecular pathways have been increasingly identified to play a role in the carcinogenesis of biliary cancers. These include cell signaling pathways involving EGFR, VEGF, and MEK in the RAS/RAF/MEK/ERK cascade, as well as more recently characterized signals. Novel agents developed against key targets in these pathways have been investigated and show some promise in improving outcomes. In this review, we summarize the current treatment options for biliary cancer and highlight the studies involving novel targeted agents in early stages of clinical investigation.

Cancers of the biliary tract include gallbladder carcinoma, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. Of these, gallbladder cancer is the most common, accounting for 80% to 95% of biliary cancers.

Nearly 90% of gallbladder cancer is adenocarcinoma, with an incidence of 1.5 per 100,000 in the United States.

Aggressive biology, late stage at diagnosis, comorbidities, biliary obstruction, and chemorefractoriness make treatment of biliary cancer challenging. This is reflected in poor outcomes, with an overall median survival of 6 to 10 months.

Similarly, cholangiocarcinoma is an aggressive cancer with poor outcomes. The most common type of cholangiocarcinoma is also adenocarcinoma.

Intrahepatic cholangiocarcinoma has an incidence of 0.7 per 100,000,

with a mortality rate of 0.66 per 100,000.

Interestingly, intrahepatic cholangiocarcinoma has been increasing in incidence, whereas extrahepatic cholangiocarcinoma has been declining.

There are demographic and environmental risk factors for gallbladder cancer and cholangiocarcinoma, including age, obesity, calculi within the gallbladder or common bile duct, and the presence of chronic inflammation.

Factors specific to gallbladder cancer include gallbladder polyps larger than 1 cm,10 whereas factors specific to cholangiocarcinoma include primary sclerosing cholangitis,

Within the last few years, investigators have characterized novel signaling pathways with the potential to be targets for innovative drug development. Cellular signaling proteins, including FGFR, PI3K/ mTor, HER-2, and BRAF, have all been the focus of intense investigation as targets for directed antitumor therapy in biliary cancer. Some of these targets are also being investigated in the treatment of hepatocellular cancer, which we discussed in a prior review.

Clearly, innovative treatments for these highly fatal diseases are needed. This review summarizes the current treatments of biliary cancer and their limitations, presents the emerging studies for targeted treatment, and highlights future directions in this exciting field of research.

Unlike prior versions of the American Joint Commission on Cancer (AJCC) staging system, the 7th Edition has individual classifications specific for gallbladder carcinoma, intrahepatic and extrahepatic cholangiocarcinomas.

Poor prognostic factors for gallbladder cancer include advanced liver extension, nodal involvement, and incomplete resection.

This is reflected in the decreasing survival rate observed with increasing stage. Specifically, 5-year overall survival (OS) rates have been found to be 60%, 39%, and 15% for patients with stage 0, stage 1, and stage 3 disease, respectively.

Poor prognostic factors for intrahepatic cholangiocarcinoma include lymph node involvement, number of tumor foci, vascular involvement, and incomplete resection,

although tumor size has not been consistently shown to be associated with worse outcome. An analysis from the French Association Francophone de ChirurgieIntrahepatic Cholangiocarcinoma (AFC-IHCC) study group showed worse outcomes with advanced stage, specifically a median survival of 53 months for stage 2 and 16 months for stage 3 disease.

Tumor invasion, lymph node involvement, and incomplete resection after pancreaticoduodenectomy (Whipple procedure) are associated with worse outcomes in extrahepatic cholangiocarcinoma.

There are unique anatomically based classification systems for hilar cholangiocarcinomas (also known as Klatskin tumors, which occur at the junction of the right and left hepatic ducts), which include the Bismuth- Corlette and the Blumgart staging systems. Unlike the staging systems for gallbladder cancer and intrahepatic cholangiocarcinoma, outcomes have not been as well correlated with stage for extrahepatic cholangiocarcinoma.

Current Management by Type of Biliary Cancer

The different options for biliary cancer include surgery, adjuvant chemoradiation, transplant, and liverdirected therapies. Studies investigating systemic chemotherapy for advanced disease often include patients with each type of biliary cancer. Table 1 summarizes the key points for treatment for each type of biliary cancer. Table 2 summarizes the major clinical trials reporting on the systemic treatment for advanced biliary cancer. Palliative options are also important in the management of these cancers; these are discussed at the end of this section.

The effectiveness of surgery correlates with intervention at an earlier stage, but is often difficult to obtain, given the frequently vague presentation of gallbladder cancer and delayed diagnosis, resulting in advanced stage. Surgical cure with cholecystectomy alone can be obtained for T1a gallbladder adenocarcinoma (limited to the inner layer lamina propria).

This is often an incidental finding after cholecystectomy performed for other indications, such as symptomatic cholelithiasis. Re-operation with extended cholecystectomy by resecting liver segments 4b and 5 can improve outcomes in patients with T2 tumors.

More radical liver surgery has not been shown to improve survival, and it is associated with increased morbidity.

Local recurrence rates following resection of advanced gallbladder tumors have been shown to be 15% and 20% for R0 and R1 margin status, respectively.

Recurrence rates in the form of distant disease were much worse, with 85% and 80% for R0 and R1 margin status, respectively.

Table 2. Clinical Trials for Systemic Treatment of Biliary Cancer

Adjuvant therapy to minimize local recurrence after resection includes fluoropyrimidine-based or gemcitabine-based chemotherapy (CT) with or without radiation therapy (RT). It should be noted that the evidence for adjuvant treatment is derived largely from retrospective studies, many of which have small sample sizes. In a meta-analysis of 22 studies by Horgan et al investigating adjuvant CT or chemoradiation (CRT), 6 of which investigated gallbladder cancer, adjuvant treatment in general was associated with improved outcomes compared with surgery alone, particularly for patients with lymph node involvement (test for overall effect: Z = 1.50,

A phase III trial by Takada et al showed improved 5-year disease-free survival (DFS) for patients with gallbladder cancer treated with fluorouracil and mitomycin C compared with controls (20.3% vs 11.5%,

Similar to gallbladder cancer, complete surgical resection offers the only potential cure for patients with intrahepatic cholangiocarcinoma. This is often difficult to achieve given advanced disease at presentation and potential limitations in patient comorbidities specific to liver dysfunction. When possible, R0 resection is sought as the surgical goal although the impact of margin width on OS is controversial, particularly in patients with nodal disease.

Recurrence rates can be as high as 53% after R0 resection, and 5-year OS is reported to be 33%.

Similar to hepatocellular carcinoma, local regional therapies are options for patients with unresectable disease or for patients who are too frail to undergo surgery. These include radiofrequency ablation (RFA), transarterial chemoembolization (TACE), and transarterial radioembolization (TARE) with yttrium-90 spheres or selective internal radiation (SIR-spheres). These approaches are generally used on a case-by-case basis when chemotherapy is not an option.

Adjuvant treatments following surgery are similar to those for gallbladder carcinoma and include fluoropyrimidine- based and gemcitabine-based CT with or without RT. In the previously discussed meta-analysis by Horgan et al, 16 studies investigated the effects of CRT on cholangiocarcinoma. As was the case for gallbladder adenocarcinoma, the meta-analysis showed an overall improved effect with CRT compared with surgery alone (test for overall effect: Z = 1.91,

Conversely, whereas the prospective study by Takada et al showed a survival benefit for gallbladder adenocarcinoma, this was not the case for cholangiocarcinoma (26.7% in the group treated with surgery followed by adjuvant mitomycin C and 5-FU vs 24.1% in patients treated with surgery alone).

This may be a consequence of chemorefractoriness or limited sample size.

Surgical strategies for extrahepatic cholangiocarcinoma are dependent on tumor location. Proximal lesions, such as Klatskin tumors, may require partial hepatectomy with hepaticojejunostomy, whereas distal common bile duct tumors often require pancreatico- duodenctomy for R0 resection. Cancers of the middle common bile duct become more challenging in surgical approach, but require major bile duct resection with some sort of reconstruction such as choledochojejunostomy or hepaticojejunostomy. Following radical surgery, the 5-year OS for proximal and distal tumors has been found to be up to 42% and 52%, respectively.

Recommended adjuvant therapy also consists of fluoropyrimidine and gemcitabine-based CRT in an attempt to decrease the rate of recurrence, which has been shown to be as high as 59% for locoregional recurrence and 41% for distant-disease recurrence.

Table 3. Genetic Mutations Associated With Biliary Cancer

Orthotopic liver transplantation (OLT) may be appropriate for select patients with hilar cholangiocarcinoma. The 5-year OS has been shown to be from 25% to 40%, and favorable prognostic factors include diagnosis prior to OLT and the implementation of perioperative chemoradiation around the time transplant.

DFS rates have been reported to be as high as 50%.

In a small series of patients undergoing a protocol developed at the Mayo Clinic involving neoadjuvant 5-FU, XRT, and brachytherapy with iridium, patients who were able to complete the Mayo regimen followed by OLT showed improved DFS (7/8 patients) albeit with a short follow-up time of 1 year.

In a larger multi-institutional study, patients who were able to tolerate neoadjuvant CRT followed by OLT experienced lower rates of disease recurrence of 20% and 5-year DFS of 65%.

However, the toxicity of this treatment regimen was high, resulting in some level of cholangitis and long-term structural complications such as biliary strictures (17%) and arterial compromise (7%).

There have been several phase II and III trials supporting the use of CT in patients with advanced biliary disease. The phase II study ABC-01 conducted in the UK demonstrated that the combination of gemcitabine with cisplatin was superior to gemcitabine alone. The median time to progression (TTP) and 6-month PFS were 4 and 8 months and 45.5% and 57.1%, respectively in the gemcitabine alone and gemcitabine plus cisplatin groups.

The larger phase III study ABC-02 randomized 410 patients with biliary cancer to similar treatment arms in ABC-01 with the primary endpoint of OS. The investigators found an improved median OS of 11.7 months in the gemcitabine plus cisplatin group compared with the group that received gemcitabine alone (median OS of 8.1 months; HR = 0.64; 95% confidence interval [CI], 0.52-0.80; P <.001).

A phase II study from Japan showed similar results for gemcitabine and cisplatin (1-year OS 39.0% for gemcitabine/cisplatin compared with 31.0% gemcitabine alone; HR = 0.69; 95% CI, 0.42-1.13).

Based on this body of evidence, gemcitabine plus cisplatin is recognized as the current standard of care in patients with advanced biliary cancers.

Patients with advanced gallbladder cancer who were treated with gemcitabine and oxaliplatin (GEMOX) in a phase II trial experienced better OS compared with best supportive care (median OS of 9.5 months vs 4.5 months, respectively, P =.039).

A large meta-analysis of over 100 trials concluded that gemcitabine combined with oxaliplatin or cisplatin had an average response rate (RR) of 22.6% (85% CI, 21.0-24.2%).

Gemcitabine plus capecitabine is also a valid and well-tolerated first-line regimen for patients with advanced biliary cancer. In 2 separate studies, the median OS was 14 months, with stable disease and partial response seen in 58% to 72% of patients with improved quality of life.

There are no evidencebased guidelines to support any one second-line therapy and, given an OS of 10 to 14 months, it is reasonable to infer that better treatments are urgently needed to further improve outcomes for patients with metastatic disease.

Jaundice and pruritus are typical clinical manifestations of biliary obstruction, and biliary stents or percutaneous drainage can alleviate these symptoms and improve quality of life.

Palliative options are important for patients with advanced biliary cancer complicated by biliary obstruction. These options include minimally invasive procedures as well as open surgery. Patients with biliary obstruction are considered for endoscopic or percutaneous drainage procedures (ERCP and PTC) or surgical bypass. In patients with very advanced cancers, the percutaneous approach may be the most successful compared with ERCP (92% vs 77%, P =.049).

Elevated bilirubin levels can be a relative contraindication to chemotherapy or require dose adjustment, and these palliative procedures can increase the ability to deliver systemic CT. Lastly, photodynamic therapy (PDT) is a new palliative treatment, which uses intravenous injections of photosensitizing agents that are selectively activated when exposed to external light radiation.

When used with biliary stenting, PDT has shown improved outcomes in the median OS in patients with advanced disease, specifically 21 months for the stented group compared with 7 months in the supportive care group (P = .0109).

Current targeted molecular therapies for biliary cancer can be categorized into agents against EGFR, VEGF, and MEK.

Table 3 outlines the different genetic mutations that are targeted with existing and developing agents. Table 4 summarizes the key points and outcomes of these targeted agents. In general, these agents have not yet been proven in large-scale trials to have clinically significant benefits. Challenges to the development and investigation of targeted therapies include the rarity of biliary cancers in general and the molecular heterogeneity across the different types. Other challenges include the presence of mutations within the targeted pathways, such as KRAS mutations, which may have various degrees of expression across different patient populations and further confound study results.

Nonetheless, there are several promising studies investigating the use these agents in the advanced setting.

EGFR is overexpressed in all types of biliary cancers, with studies showing rates of increased expression in gallbladder carcinoma (12%),

intrahepatic cholangiocarcinoma (10%-32%),

and extrahepatic cholangiocarcinoma (5%-20%).

Targeted agents for advanced biliary cancer in this class include erlotinib, cetuximab, and panitumumab. As a group of agents, EGFR inhibitors have shown little benefit and do not have an established role in the treatment of biliary cancer.

Erlotinib is an oral small-molecule EGFR inhibitor that has been tested alone and in combination with CT. A single-arm study of erlotinib monotherapy showed a partial response rate of 8% with TTP of 2.6 months and OS of 7.5 months.

The addition of GEMOX to erlotinib has been shown to have improved outcomes. A multicenter phase III trial of GEMOX with or without erlotinib showed a trend toward improved progression-free survival (PFS), but no differences in OS. The median PFS was 4.2 months in the GEMOX group compared with 5.8 months in the GEMOX plus erlotinib group (HR 0.80; 95% CI, 0.61-1.03; P = .087), while OS was 9.5 months in each group (HR 0.93; 95% CI, 0.69-1.25; P = .611).

In contrast, a small phase II study of erlotinib plus docetaxel did not show any added benefit of docetaxel to erlotinib alone in terms of OS (only 6.7 months).58 Skin rash constituted the major grade 3-4 toxicity (7%).

Cetuximab is a chimeric monoclonal antibody with activity against EGFR. A single-arm phase II study of GEMOX with cetuximab showed a CR of 10%, with median PFS and OS (8.8 months and 15.2 months, respectively) that were greater compared with the erlotinib studies.

In contrast, the phase II study BINGO very recently published less promising results on GEMOX plus cetuximab compared with GEMOX alone. The median PFS and OS were 6.1 months and 11.0 months in the GEMOX plus cetuximab group compared with 5.5 months and 12.4 in the GEMOX alone group.60 The authors concluded that there was no added benefit of cetuximab to standard CT. Grade 3-4 toxicities were low and included peripheral neuropathy (24%), neutropenia or thrombocytopenia (up to 22%), and increased liver function tests (LFTs) (22%).

Lastly, panitumumab is a humanized monoclonal antibody against EGFR. This agent is being investigated in several active phase II trials testing panitumumab in combination with GEMOX, gemcitabine/ irinotecan, and gemcitabine/cisplatin. A previous single-arm phase II study showed that panitumumab in combination with GEMOX and capecitabine had a median PFS of 8.3 months and OS of 9.8 months.

In a second phase II trial of panitumumab in combination with gemcitabine and irinotecan, outcomes were improved, with a median PFS of 9.7 months and OS of 12.9 months.

VEGF is expressed in up to 50% to 60% of biliary cancers and has been associated with poor prognosis.

Among the targeted agents for advanced biliary cancer in this class are bevacizumab, sorafenib, and sunitinib. These agents are also being investigated in advanced hepatocellular cancer.

Bevacizumab is a humanized monoclonal antibody against all isoforms of VEGF. A small single-arm phase II study investigated bevacizumab in combination with GEMOX. Results showed a RR of 40%, median PFS of 7.0 months and OS of 12.7 months.65 Treatment was well tolerated overall. Grade 3-4 toxicities included neutropenia, elevated LFT&rsquo;s, peripheral neuropathy and hypertension.

Another phase II study investigated bevacizumab in combination with erlotinib.

While the treatment was well tolerated, with the most common grade 3-4 toxicity being rash, the median TTP was 4.4 months and OS was 9.9 months,

which are similar results to GEMOX with erlotinib. A current trial testing bevacizumab with gemcitabine/capecitabine has finished accrual of patients and results are awaited.

Sorafenib is an oral multitargeted tyrosine kinase inhibitor with activity against VEGFR-2 and VEGFR-3. As a single agent, sorafenib has not shown activity against advanced biliary cancer.

Despite a phase II study of sorafenib and gemcitabine showing a RR of 7% and stable disease of 63% in patients with advanced biliary cancers,

a more recent published study did not show any significantly increased benefit compared with the ABC-02 trial.

This single-arm phase II study of sorafenib plus gemcitabine/cisplatin showed a median PFS of 6.5 months (95% CI, 3.5-8.3) and median OS of 14 months (95% CI, 11.6-19.2).

The major grade 3-4 toxicities included hematologic disturbances, elevations in LFT&rsquo;s and pancreatic enzymes, and fatigue.

Sunitinib is a newer oral multitargeted tyrosine kinase inhibitor. In a single-arm phase II study of sunitinib monotherapy, marginal benefit was observed with a median TTP of 1.7 months (95% CI, 1.0-2.4).

Similar to sorafenib, major toxicities included hematologic disturbances, most commonly neutropenia and thrombocytopenia.

Table 4. Targeted Therapies for Advanced Biliary Cancer

Lastly, cediranib is another multitargeted tyrosine kinase inhibitor with activity against VEGFR-1, VEGFR- 2, and VEGFR-3. In the phase II ABC-03 study presented at the 2014 ASCO meeting, cediranib in combination with gemcitabine/cisplatin showed improved RECIST response rates compared with placebo (43% vs 19%, P = .01).72 However, with a median follow-up of 11.9 months, there were no statistically significant differences in PFS between the cediranib and placebo groups (7.7 months vs 7.4 months; HR 0.99; 80% CI, 0.78-1.26) or OS (14.1 months vs 11.9 months; HR 0.76; 95% CI, 0.50-1.14).

Thus, more studies will be needed to determine the effects of cediranib on longterm outcome.

Selumetinib is an oral small molecule inhibitor of MEK1/2. MEK plays a role in cellular proliferation through the RAS/RAF/MEK/ERK signaling pathway, which has been targeted in many cancers including biliary tract malignancies. In a small single-arm phase II study, patients treated with selumetinib showed no clinically significant improved outcomes compared with ABC-2 with a median PFS of 3.7 months (95% CI, 3.5-4.9) and OS of 9.8 months (95% CI, 5.97 to not yet available).

The most common grade 3-4 toxicities included gastrointestinal symptoms and fatigue.

Advances in translational research have identified other potential targets in advanced biliary cancer in addition to those discussed for EGFR, VEGF, and MEK. Among these more novel targets are FGFR, PIK- 3CA (phosphatidylinsositol-3-kinase pathway), BRAF, c-MET, BAP1, and IDH 1/2. Additionally, further trials are actively investigating different combinations of newer agents targeted against the more established molecular pathways. Finally, patient-specific targeted immunotherapies are also being developed and tested for the treatment of biliary cancer.

Through genomic sequencing of patients with advanced cholangiocarcinoma, mutations have been characterized in

, which is a direct negative regulator of EGFR activation.

BGJ398 is an oral pan-inhibitor of FGFR kinase and results in inhibition of tumor angiogenesis and proliferation.

It is currently being tested in a single-arm phase II trial in patients with advanced cholangiocarcinoma with

gene fusions or other mutations who have failed platinum-based CT.

Neratinib is an orally available, irreversible inhibitor of the HER-2/ERRB2 receptor tyrosine kinase. This drug is currently being tested in a phase II study in patients with solid tumors with EGFR gene amplification or mutations in

PIK3CA is involved in the AKT/mTOR pathway and has been identified in patients with both gallbladder cancer and cholangiocarcinoma.

The agent BKM120 is an orally available PI3K inhibitor of all 4 class I PI3K isoforms.

A current multi-institutional phase II trial by Piha-Paul et al is investigating the effects of BKM120 on patients with PI3K-activated solid tumors with the primary endpoint of response rates based on RECIST criteria.

The trial is presently enrolling patients.

BRAF is involved in the RAS/RAF/MEK/ERK molecular signaling pathway. The

mutation is most known in its role in malignant melanoma, but it has been identified in gallbladder carcinoma and cholangiocarcinoma.

There are currently no phase II or III trials in biliary cancer investigating BRAF-targeted therapies. However, vemurafenib is a kinase inhibitor against mutated

and is being investigated in combination with cetuximab and irinotecan in a phase I study for patients with advanced solid malignancies.

Most of the patients enrolled to date have advanced colorectal carcinoma, though the study is open to patients with advanced solid malignancies with the

mutation. The estimated completion date projected for February 2016. Results from this study may have applications to biliary tract cancers.

Biliary cancer comprises of 3 heterogeneously distinct, aggressive carcinomas with limited treatment options. Surgery offers the potential for cure if diagnosed at an early stage. Systemic chemotherapy with gemcitabine and cisplatin is the current standard as shown by the ABC-02 trial.

Differences exist in response and outcomes between gallbladder, extra and intrahepatic cholangiocarcinoma with better response, but worse survival in gallbladder, lesser response but improving survival in extra and the least response and higher survival in intrahepatic cholangiocarcinomas that may be explained by biological differences that may allow inclusion of enriched populations to biomarker-driven targeted agent trials in the future.

Optimal adjuvant therapies still need to be defined for patients with resectable biliary cancers.

Pathways characterized in biliary carcinoma include EGFR, VEGF, and MEK. Agents targeted against EGFR include erlotinib, cetuximab, and panitumumab. Agents against VEGF include bevacizumab, sorafenib, sunitinib, and cediranib. Selumetinib is a small molecule inhibitor with activity against MEK, which plays a key role in the RAS/RAF/MEK/ERK signaling pathway. Although these drugs are well tolerated, several phase II clinical trials have not shown significantly improved benefit in outcomes compared with standard systemic chemotherapy

Other pathways have been identified as having potential roles in the carcinogenesis of biliary cancer. These include FGFR, BRAF, PIK3CA (phosphatidylinsositol-3-kinase pathway), c-MET (hepatocyte growth factor receptor), BAP 1 (BRCA associated protein 1), and IDH 1/2 (isocitrate dehydrogenase). Novel agents include BGJ398, neratinib, BKM120, cabozantinib, vemurafenib, and AG-120. Early-phase investigations are ongoing to determine the tolerability and potential efficacy of targeted therapies against these signals

c-MET is a proto-oncogene encoding HGFR (hepatocyte growth factor receptor) and is involved in multiple signal transduction pathways including MAPK and PIK3.

It has been identified in biliary cancers, mostly in cholangiocarcinoma compared with gallbladder carcinoma.

Cabozantinib is a small molecule inhibitor that blocks the activity of c-Met tyrosine kinase. In mouse xenograft models of hepatocellular carcinoma, cabozantinib was shown to block the MET pathway and result in decreased number of HCC metastases.

Although there are no clinical trials investigating c- MET inhibitors, this remains a potential target for biliary cancer.

(BRCA-associated protein 1) is a chromatin remodeling gene encoding a nuclear deubiquitinase.

While associated with many types of cancers, it has been recently found to be expressed in intrahepatic cholangiocarinomas.

may be integral to a cancer predisposition syndrome, resulting in melanoma, mesothelioma, and other cancers including biliary tumors.

There are currently no clinical trials investigating agents targeting

Biliary cancer includes gallbladder carcinoma, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma.

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