Description
Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor A. Vascular endothelial growth factors, and their receptors contribute to tumor growth and metastasis by promoting angiogenesis. This evidence review examines the off-label use of bevacizumab in patients with advanced adenocarcinoma of the pancreas.

For individuals who have advanced pancreatic cancer who receive bevacizumab, the evidence includes phase 2 and 3 randomized controlled trials and a TEC Assessment. Relevant outcomes are overall survival, disease-specific survival, symptoms, and change in disease status, quality of life, and treatment-related morbidity. Studies have failed to demonstrate that bevacizumab, either alone or in combination with another therapy, improves overall survival; data for progression-free survival have been inconsistent. The evidence is insufficient to determine the effects of the technology on health outcomes.  

Background 
PANCREATIC ADENOCARCINOMA 
In the United States, pancreatic adenocarcinoma is the tenth most common cancer in men and the fourth leading cause of cancer deaths in men and women. Only 7% of cases are detected at an early stage, and more than 90% of patients develop metastases. The 1-year survival rate is 25%; the 5-year survival rate is 6% overall, and 22% for those diagnosed early with only local disease.

Treatment
For patients with advanced, unresectable disease, the standard of care is gemcitabine. Gemcitabine is approved by the U.S. Food and Drug Administration as a single-agent first-line treatment for patients with locally advanced (stage II or III when surgery is not an option) or metastatic (stage IV) adenocarcinoma of the pancreas, including patients previously treated with 5-fluorouracil. Gemcitabine is sometimes given as part of combination therapy with erlotinib, which is approved by the Food and Drug Administration for first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer.

Vascular endothelial growth factors (VEGFs) and their receptors contribute to tumor growth and metastasis by promoting angiogenesis, the growth of new vasculature.^1,2,3,4 Without angiogenesis, nutrients, oxygen, and other essential molecules reach malignant cells only by passive diffusion from preexisting blood vessels, which would limit most tumors to diameters of several millimeters. Certain normal physiologic processes (e.g., embryonic development, menstruation, wound healing) require angiogenesis, and some noncancer pathologic processes are linked to angiogenesis (e.g., macular degeneration, atherosclerosis, psoriasis).⁵

Approximately 89% to 93% of pancreatic cancer patients have a VEGF variant, which is associated with early recurrence after surgery, liver metastases, and poor prognosis. A VEGF variant in tumors also correlates with tumor size.⁶ Bevacizumab, a VEGF-specific angiogenesis inhibitor, is used to treat a variety of cancers. Because VEGF appears to play a role in pancreatic cancer, bevacizumab was considered a promising therapy. The results of 2 older phase 2 trials seemed to indicate a potential benefit.^7,8      

Regulatory Status
Bevacizumab for the treatment of advanced pancreatic adenocarcinoma is not a U.S. Food and Drug Administration (FDA)-labeled indication.

Related Policies
None

Policy
Bevacizumab is considered INVESTIGATIONAL for treatment of advanced adenocarcinoma of the pancreas. 

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be MEIDICALLY NECESSARY if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and NOT MEDICALLY NECESSARY. 

Policy Guidelines
The HCPCS code for bevacizumab is:

J9035: Injection, bevacizumab, 10 mg.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all U.S. Food and Drug Administration (FDA)-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

In addition, many states have mandates related to coverage of off-label use of FDA-approved cancer agents.

Rationale 
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms. 

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

PANCREATIC ADENOCARCINOMA
Clinical Context and Therapy Purpose
The purpose of administering bevacizumab to patients who have advanced pancreatic cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the administration of bevacizumab improve the net health outcome in individuals with advanced pancreatic cancer?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is individuals with advanced pancreatic cancer, defined as locally advanced (stage II or III) or metastatic (stage IV) adenocarcinoma.

Interventions
The therapy being considered is bevacizumab, which is a chemotherapeutic agent.

Comparators
The following therapies are currently being used to make treat advanced pancreatic cancer: chemotherapy and tyrosine kinase inhibitor.

Outcomes
The general outcomes of interest for advanced-stage pancreatic cancer are overall survival (OS), symptom reduction, and treatment-related adverse events (e.g., bleeding, stomach pain, nausea, vomiting, stomach or intestine perforation).

Timing
Given the poor outcome prognosis for those with advanced pancreatic cancer, follow-up would be out to 1 year for most patients.

Setting
Bevacizumab would be administered in an outpatient setting, infusion center, or hospital.

Systematic Reviews
This evidence review was informed by a TEC Assessment (2009).⁹ That Assessment evaluated the use of bevacizumab in advanced adenocarcinoma of the pancreas to identify any incremental benefit of using the agent in this population, taking into account potential increases in survival and quality of life, as well as the effects of treatment-related adverse events. Five studies identified for the Assessment tested the use of bevacizumab in patients with advanced adenocarcinoma. These studies consisted of 2 phase 3 trials, 2 phase 2 trials, and 1 phase 1 trial. In all trials, bevacizumab was added to gemcitabine; the latter considered the current standard of care. Some trials also included other agents, including cisplatin and erlotinib. The individual studies included in the Assessment are detailed below.

Randomized Controlled Trials
The 2 phase 3 trials, by Kindler et al. (2010)¹⁰ and by Van Cutsem et al. (2009),¹¹ provided the strongest evidence because of their designs. Neither trial demonstrated that the addition of bevacizumab resulted in a statistically significant difference in the primary outcome of OS. For the secondary outcome of progression-free survival (PFS), the Van Cutsem et al. (2009) study showed benefit, while the Kindler et al. (2010) study did not.

Kindler et al. (2005) randomized 590 patients with advanced pancreatic cancer (local or metastatic) to gemcitabine with or without bevacizumab.¹² This trial demonstrated sufficient activity to proceed to the phase 3 trial reported by Kindler et al. (2010). The latter trial was stopped early when it was determined that combination gemcitabine plus bevacizumab could not achieve longer survival than gemcitabine alone.

Van Cutsem et al. (2009) randomized 607 patients with metastatic adenocarcinoma of the pancreas to gemcitabine plus erlotinib, with or without bevacizumab.¹¹ There was no statistically significant difference between the 2 groups in the primary outcome of OS. Median OS was 7.1 months for the treatment group and 6.0 months for the control group (hazard ratio, 0.89; 95% confidence interval [CI], 0.74 to 1.07; p = 0.21). The trial reported a statistically significant difference in PFS of 4.6 months in the treatment arm and 3.6 months in the control group (hazard ratio, 0.73; 95% CI, 0.61 to 0.86; p < 0.001). Although this secondary outcome was significant, few details were given about the methods used to assess PFS, which might have been subject to greater measurement error than OS.

Phase 2 trials have evaluated bevacizumab alone or in combination with cytotoxic chemotherapy for metastatic pancreatic cancer; they are briefly described.

Fogelman et al. (2011) reported on a phase 2 trial of bevacizumab plus gemcitabine and oxaliplatin as first-line therapy for metastatic or locally advanced pancreatic cancer.¹³ Eligible patients had stage III (n = 14) or IV (n = 36) pancreatic cancer and had received no prior gemcitabine. Treatment cycles were repeated every 2 weeks, and computed tomography was performed every 6 weeks. Fifty patients were enrolled. Median age was 59 years. The overall response rate was 36%; 34% demonstrated stable disease. Median PFS was 4.9 months; median survival was 11.9 months; 1-year survival was 42%. Patients with locally advanced disease lived 12.8 months; patients with metastatic disease lived 10.2 months. The trialists concluded that the regimen did not meet the objective of a 14-month median survival and that the toxicity was significant.

Ko et al. (2012) conducted a phase 2 randomized trial of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for advanced pancreatic adenocarcinoma.¹⁴ Patients with locally advanced or metastatic pancreatic adenocarcinoma, previously untreated, were randomized to bevacizumab plus cetuximab, either with (arm A; n = 30) or without (arm B; n = 31) gemcitabine. Tumor assessments were performed every 8 weeks. The primary study end point was PFS. Median treatment duration was 9 weeks in arm A and 8 weeks in arm B (range, 2.0 – 40.4 weeks). Patients in arm A had median PFS and OS of 3.55 months and 5.41 months, respectively, compared with 1.91 months and 4.17 months in arm B. The trial closed early due to lack of sufficient efficacy in either treatment arm. The authors concluded that the combination of cetuximab and bevacizumab did not result in promising activity with or without gemcitabine and suggested that a strategy of dual epidermal growth factor receptor and vascular endothelial growth factors inhibition in pancreatic cancer did not warrant further development.

Astsaturov et al. (2011) reported on a phase 2 randomized, open-label trial for patients with metastatic pancreatic cancer.¹⁵ Patients were randomized to bevacizumab alone or in combination with docetaxel cytotoxic therapy. The primary end point was PFS. At 4 months, only 2 and 3 patients were stable, respectively, and the trial was discontinued on the study-defined grounds of the futility of less than 25% PFS in the 2 groups.

Section Summary: Randomized Controlled Trials
At least 2 phase 3 and 3 phase 2 randomized controlled trials have evaluated bevacizumab for advanced pancreatic cancer. Three studies were discontinued early due to failure to meet prespecified efficacy criteria, and bevacizumab did not show an incremental benefit in OS.

Noncontrolled Trials
Martin et al. (2012) investigated the safety and efficacy of bevacizumab combined with gemcitabine followed by infusional 5-fluorouracil in patients with advanced pancreatic cancer in a phase 2 trial.¹⁶ The primary end point was the proportion of patients with PFS at 6 months from initiation of therapy. If PFS at 6 months was 41% or more, the regimen would be considered promising. Of the 42 patients enrolled in the study, 39 were evaluable for the primary end point. PFS at 6 months was 49% (95% CI, 34% to 64%). Median PFS was 5.9 months (95% CI, 3.5 to 8.1 months), and median OS was 7.4 months (95% CI, 4.7 to 11.2 months). Partial response and stable disease occurred in 30% and 45% of patients, respectively. Grade 3 and 4 toxicities included fatigue (14%), hypertension (5%), and venous thrombosis (5%). The authors concluded that the study met its primary end point and that further investigation of anti-vascular endothelial growth factor therapy in combination with fluoropyrimidine-based therapy was warranted in advanced pancreatic cancer.

Ko et al. (2010) reported on the partial results of a phase 2, uncontrolled study of gemcitabine-refractory metastatic pancreatic cancer patients treated with bevacizumab and erlotinib.¹⁷ Recruitment stalled after the publication of the relative ineffectiveness of bevacizumab in the phase 3 trials previously described. Of the 36 patients followed in this study, 8 (22%) reached the primary end point of 6-month survival. This survival rate for bevacizumab-treated patients was inferior to published rates of cytotoxic regimens.

Observational Studies
Single-arm case series published both before and after the phase 3 studies reported by Kindler and Van Cutsem and colleagues have reported on outcomes for pancreatic cancer after treatment with bevacizumab. Given the availability of phase 2 and 3 trials, the case series data do not provide significant additional data on efficacy. Examples of single-arm observational studies include: Tai et al. (2016),¹⁸ Phillip et al. (2016),¹⁹ Crane et al. (2009),²⁰ and Javle et al. (2009).²¹

SUMMARY OF EVIDENCE
For individuals who have advanced pancreatic cancer who receive bevacizumab, the evidence includes phase 2 and 3 randomized controlled trials and a TEC Assessment. Relevant outcomes are overall survival, disease-specific survival, symptoms, and change in disease status, quality of life, and treatment-related morbidity. Studies have failed to demonstrate that bevacizumab, either alone or in combination with another therapy, improves overall survival; data for progression-free survival have been inconsistent. The evidence is insufficient to determine the effects of the technology on health outcomes. 

PRACTICE GUIDELINES AND POSITION STATEMENTS
National Comprehensive Cancer Network guidelines for pancreatic adenocarcinoma (v.2.2018)²² state that gemcitabine is recommended for pancreatic cancer patients with locally advanced or metastatic disease. While phase 2 studies have suggested some benefit from adding another chemotherapy agent (e.g., bevacizumab or cetuximab), phase 3 studies have shown that the only new targeted drug for which there is evidence of a statistically significant increase in survival when combined with gemcitabine is erlotinib.  

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable. 

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 1. 

Table 1. Summary of Key Trials

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.  

References 

1. Cebe-Suarez S, Zehnder-Fjallman A, Ballmer-Hofer K. The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci. Mar 2006;63(5):601-615. PMID 16465447
2. Verheul HM, Pinedo HM. Inhibition of angiogenesis in cancer patients. Expert Opin Emerg Drugs. May 2005;10(2):403-412. PMID 15934875
3. Rhee J, Hoff PM. Angiogenesis inhibitors in the treatment of cancer. Expert Opin Pharmacother. Aug 2005;6(10):1701-1711. PMID 16086656
4. Schneider BP, Miller KD. Angiogenesis of breast cancer. J Clin Oncol. Mar 10 2005;23(8):1782-1790. PMID 15755986
5. Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Off-label uses of bevacizumab: breast and lung cancer indications. TEC Assessment. 2006;Volume 21:Tab 8.
6. Borja-Cacho D, Jensen EH, Saluja AK, et al. Molecular targeted therapies for pancreatic cancer. Am J Surg. Sep 2008;196(3):430-441. PMID 18718222
7. Ko AH, Tempero MA. Treatment of metastatic pancreatic cancer. J Natl Compr Canc Netw. Sep 2005;3(5):627-636. PMID 16194454
8. Ducreux M, Boige V, Malka D. Treatment of advanced pancreatic cancer. Semin Oncol. Apr 2007;34(2 Suppl 1):S25-30. PMID 17449349
9. Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Off-label use of bevacizumab: advanced adenocarcinoma of the pancreas. TEC Assessment. 2009;Volume 24:Tab 4.
10. Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303).J Clin Oncol. Aug 1 2010;28(22):3617-3622. PMID 20606091
11. Van Cutsem E, Vervenne WL, Bennouna J, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. May 1 2009;27(13):2231-2237. PMID 19307500
12. Kindler HL, Friberg G, Singh DA, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. Nov 1 2005;23(31):8033-8040. PMID 16258101
13. Fogelman D, Jafari M, Varadhachary GR, et al. Bevacizumab plus gemcitabine and oxaliplatin as first-line therapy for metastatic or locally advanced pancreatic cancer: a phase II trial. Cancer Chemother Pharmacol. Dec 2011;68(6):1431-1438. PMID 21479635
14. Ko AH, Youssoufian H, Gurtler J, et al. A phase II randomized study of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma. Invest New Drugs. Aug 2012;30(4):1597-1606. PMID 21629990
15. Astsaturov IA, Meropol NJ, Alpaugh RK, et al. Phase II and coagulation cascade biomarker study of bevacizumab with or without docetaxel in patients with previously treated metastatic pancreatic adenocarcinoma. Am J Clin Oncol. Feb 2011;34(1):70-75. PMID 20458210
16. Martin LK, Li X, Kleiber B, et al. VEGF remains an interesting target in advanced pancreas cancer (APCA): results of a multi-institutional phase II study of bevacizumab, gemcitabine, and infusional 5-fluorouracil in patients with APCA. Ann Oncol. Jul 5 2012;23(11):2812-2820. PMID 22767582
17. Ko AH, Venook AP, Bergsland EK, et al. A phase II study of bevacizumab plus erlotinib for gemcitabine-refractory metastatic pancreatic cancer. Cancer Chemother Pharmacol. Nov 2010;66(6):1051-1057. PMID 20130876
18. Tai CJ, Huang MT, Wu CH, et al. Two targeted medications (bevacizumab plus cetuximab) improve the therapeutic response of pancreatic carcinoma. Medicine (Baltimore). Apr 2016;95(15):e3259. PMID 27082562
19. Phillip V, Zahel T, Bartl K, et al. Influence of sorafenib and bevacizumab on pancreatic volume - A monocentric CT based analysis. Pancreatology. Jul-Aug 2016;16(4):621-624. PMID 26968257
20. Crane CH, Winter K, Regine WF, et al. Phase II study of bevacizumab with concurrent capecitabine and radiation followed by maintenance gemcitabine and bevacizumab for locally advanced pancreatic cancer: Radiation Therapy Oncology Group RTOG 0411. J Clin Oncol. Sep 1 2009;27(25):4096-4102. PMID 19636002  
21. Javle M, Yu J, Garrett C, et al. Bevacizumab combined with gemcitabine and capecitabine for advanced pancreatic cancer: a phase II study. Br J Cancer. Jun 16 2009;100(12):1842-1845. PMID 19491904
22. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 2.2018 https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed September 18, 2018.

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