Avastin (Bevacizumab) Therapy in Oncology

Bevacizumab (Genentech brand name Avastin) is a targeted drug therapy with a growing number of indications in oncology. It is a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF). Increased VEGF serum levels correlate with lower survival rates. The drug inhibits new blood vessel growth (neovascularization), which tumors require to grow and metastasize.”

Single-drug therapy with bevacizumab has shown limited benefit in most studies. However, studies have seen significant benefit for a variety of tumors when bevacizumab is given in combination with chemotherapy. The FDA has approved bevacizumab for the management of colon cancer, lung cancer and breast cancer.

Although oncologists do not know exactly how bevacizumab works or its optimal dose, more than 400 clinical trials of bevacizumab are underway because of its promise in treating many cancers. As oncologists strive to provide optimal therapy for patients, a thorough understanding of what currently is known about the benefits of this drug is critical – particularly in light of its potential medical risks and significant financial cost (roughly $100,000 for an average woman with metastatic breast cancer during one year of therapy). Due to the vast uncertainties regarding this drug, questions are likely to be debated among oncologists for some time.

This article reviews bevacizumab’s current FDA approved uses, commonly accepted off-label uses, and current areas for research and treatment risks. This discussion will be limited to bevacizumab’s oncology uses, but it is also used in non-oncologic conditions, such as macular degeneration.

FDA approved indications

Bevacizumab is currently indicated for the treatment of metastatic colorectal cancer, metastatic non-squamous non-small cell lung cancer, and, most recently, first-line metastatic therapy in combination with paclitaxel for her-2 negative breast cancer.

For metastatic colorectal cancer, there is considerable clinical trial data supporting bevacizumab given with multiple different regimens, including fluoropyrimidines with or without oxaliplatin or irinotecan. Additionally, combination antibody therapy with cetuximab (directed against the epidermal growth factor receptor, EGFR) has also demonstrated efficacy, though the combination of bevacizumab with cetuximab is currently the subject of CALGB 80405 when given in combination with chemotherapy (a strategy that was not effective with the EGFR inhibitor panitumumab in the PACCE trial). While most of the data with bevacizumab has been in the first line setting, ECOG 3200 demonstrated a significant benefit for the addition of bevacizumab in a second-line regimen containing oxaliplatin. In addition to using a higher dose (10 mg/kg every two weeks instead of the more standard 5mg/kg every two weeks in first-line colorectal cancer), patients in this study did not receive prior bevacizumab. Continuation of bevacizumab following progression on a bevacizumab containing regimen is a separate question (See “research questions” below.).

Palliative therapy for non-squamous, non-small cell lung cancer has been significantly improved by adding bevacizumab in combination with carboplatin and paclitaxel (ECOG 4599) or cisplatin and gemcitabine (the AVAiL trial). The dose of bevacizumab was similar to that for first-line colorectal cancer trials at 15 mg/kg every three weeks (averaging 5 mg/kg/week), but the AVAiL trial included an arm with a reduced bevacizumab dose (7.5 mg/kg/three weeks) which also appears efficacious. However, at present most oncologists favor the higher dose.

ECOG 2100 demonstrated a dramatic progression free survival (PFS) advantage for the addition of bevacizumab chemotherapy in the first-line therapy of breast cancer when combined with weekly paclitaxel. Though the PFS lengthened from roughly six months to 12 months, overall survival was not improved. This was probably due to the multiple lines of palliative therapy available for the management of metastatic breast cancer. Nonetheless, bevacizumab recently received FDA approval for this indication.

In the above trials, bevacizumab was continued as a single agent until there was disease progression in cases where the chemotherapy was planned to discontinue (as in the ECOG 4599 and AVAiL). Currently, the benefit of bevacizumab alone is unknown. The drug is also commonly continued with fluoropyrimidine therapy if oxaliplatin or irinotecan is discontinued to minimize toxicity in colorectal cancer management (such as with the OPTIMOX strategy, De Gramont, 2005).

Common standard off-label uses for bevacizumab

There are several ongoing clinical trials including bevacizumab for different tumor types and chemotherapy or radiation therapy combinations. Given the uniformly grave prognosis for cancer patients, oncologists have a long tradition of providing palliative off-label treatments and using a sensible amount of safety and efficacy data. While enrollment in a clinical trial is always preferred, it is not always appropriate, available or desired for a patient. Additionally, given the relatively slow and expensive progress of FDA approval for new indications, oncologists often offer treatments prior to FDA endorsement.

Gray areas exist between what is experimental and what is a reasonable off-label use for a medication. Often this is resolved with consensus expert opinion. But specific insurance plan language is sometimes critical in making this distinction. Current off-label indications for bevacizumab include renal cell cancer, ovarian cancer and glioblastoma mulitforme.

Renal cell cancer (clear cell) has seen a recent explosion of effective targeted therapies. These tumors are commonly characterized as having a loss of heterozygosity in the von Hippel-Lindau gene resulting in a significant up-regulation of VEGF in these vascular tumors. A Phase II study has demonstrated a prolongation of PFS with single-agent bevacizumab versus placebo (Yang JC, et al 2003). Preliminary results of a recent phase III study of alpha interferon therapy with or without bevacizumab (the AVOREN trial) reported that with a median follow-up of 13 months there was a significant improvement in response rates and PFS with the addition of bevacizumab.

While the optimal combination and sequencing of these agents is debated and researched, many experts will now integrate bevacizumab at some point in cancer treatment. Similar issues have been raised by positive reports using bevacizumab in the management of advanced or refractory ovarian cancer and glioblastoma multiforme (GBM). Although the use of bevacizumab to treat these tumors has not received FDA approval, they have become sufficiently supported by the oncology community for inclusion in the National Comprehensive Cancer Network (NCCN) clinical practice guidelines.

Risks and warnings

Although there are no “contraindications” listed for bevacizumab, there are several concerns regarding its use that require great care regarding patient selection and continued treatment. While common side effects include hypertension, headache, nosebleeds, and proteinuria, most of these are mild and manageable with anti-hypertensives. However, the long-term effects of these are not known and are an important consideration as oncologists move toward using these therapies to prevent cancer from recurring. As with other antibody therapies, infusion reaction can occur (in less three percent of cases) and may require premedication or drug discontinuation. Also, other serious adverse reactions have been seen and can limit the appropriateness of bevacizumab therapy.

Early lung cancer trials reported significant and sometimes fatal pulmonary hemorrhaging. Hemorrhaging occurred with greater frequency in patients having squamous cell histology. Such patients were subsequently excluded from clinical trials and excluded from the FDA indication. This safety concern should not be overlooked. While oncologists still do not know the mechanism with certainty, the reason appears to be related to tumor histology rather than the common central location of these tumors. For this reason, there is a “black box” warning for bevacizumab use in patients who have recently coughed up more than half a teaspoon of blood or in whom hemoptysis develops.

Clinical trials also have excluded patients with recent arterial thromboembolic events (heart attack and stroke) as well as patients with brain metastasis. Although there are ongoing trials including bevacizumab usage in patients with brain tumors (including NCCN guidelines supporting its use in the treatment of GBM), patients with irradiated brain metastasis, and patients on chronic anticoagulation, these are situations in which the managing physician must discuss carefully the risks and benefits with the patient. Additionally, operative complications have been seen with bevacizumab, including wound complications. Clinical trials have excluded patients with incomplete wound healing due to bevacizumab's half-life of nearly three weeks. The trials have also required patients to have completed major surgery four to six weeks before receiving bevacizumab and to withhold bevacizumab for a similar period before elective surgery.

Other “black box” warnings include concerns for gastrointestinal perforation (less than four percent) and wound dehiscence (one percent). The significance of these known and additional unknown side-effects, are underscored by the continued reporting of rare but unanticipated complications in ongoing trials, such as reversible posterior leukoencephelopathy syndrome (less than one percent) that can occur anywhere from less than a day to one year after therapy. Recent studies of patients with lung cancer and esophageal cancer have noted tracheoesophageal fistula formation when the drug was provided in combination with chemotherapy and radiation therapy.

Research questions

There are several unanswered questions for which additional research may provide future direction. For instance, can bevacizumab provide similar benefits in the management of the tumors noted, but with different chemotherapeutic agents or with radiation therapy? Will it add to therapy in the adjuvant or neoadjuvant setting? What is the most appropriate dose, schedule and treatment duration? Researchers argue that targeted therapies may not be optimally dosed by the standard phase I trial design and the expense may be significantly modified if trials such as the AVAiL study have evidence supporting the benefit of lower dosages. At present, continuation of bevacizumab into second-line therapy is not supported by the NCCN guidelines.

Still, many oncologists feel that the drug’s efficacy is in making chemotherapy more effective (perhaps by “normalizing” blood flow to tumors and improving chemotherapy delivery). If this were true, oncologists would want to continue bevacizumab even after progression with one chemotherapeutic to combine it with another. The BRiTE registry data demonstrating a survival advantage for metastatic colon cancer patients with continued bevacizumab treatment supports this view. Unfortunately, observational studies can have significant bias and most experts would still strongly favor enrollment onto the SWOG 0600 iBET trial for patients who received first line bevacizumab with a regimen containing oxaliplatin, and who are interested in randomization to continuation with irinotecan and cetuximab.

A separate area of off-label and research use includes changing the treatment line use or combining bevacizumab with alternative chemotherapies which are already approved. For example, first-line therapy for breast cancer has a significant PFS when bevacizumab is combined with paclitaxel, but many physicians might favor capecitabine as first-line chemotherapy for its oral administration and side effect profile. This presents three questions: (1) Would paclitaxel and bevacizumab be as effective if provided in second-line therapy after capecitabine? (2) Could bevacizumab be provided with capecitabine? (3) Would the substitution of nabpaclitaxel (Abraxane, Abraxis; a proprietary “nanoparticle albumin-bound” formulation of paclitaxel that requires no premedications, allows higher paclitaxel doses, and may be more efficacious) be acceptable if infusional therapy is pursued during first line?

Although some of these questions may be answered in ongoing trials, many oncologists do not feel that research resources (including a limited number of eligible patients) should be devoted to answer some of these questions for practical reasons. Instead, they favor empiric treatment. Others may utilize sub-set analysis as in a recent trial of first-line bevacizumab and capecitabine (Sledge, et al, 2007) which showed improvement in response rate but no PFS or OS improvement. They feel that this combination is reasonable in the hormone receptor positive subset that did appeared to have some incremental benefit. At present, the NCCN guidelines only provide paclitaxel as a “preferred” agent to combine with bevacizumab.

In the interest of patient safety and benefit, as well as controlling health care costs, physicians need to be mindful of the limits of their knowledge regarding bevacizumab therapy. This will become a greater issue as this fascinating therapy continues to find more uses.

References

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