Cancer Treatment

Xeloda and Avastin for colorectal cancer

The European Commission has approved its oral chemotherapy Xeloda (capecitabine) for the treatment of metastatic colorectal cancer in combination with any chemotherapy in all lines of treatment with or without Avastin. While the FDA had nto specifically approved Xeldoa with Avastin, it indicated Avastin with 5 FU containing regimens and expert consensus is that multiple studies have shown that Xeldoa is at  least equivanln to 5FU in coloretal cancer.

nccn.org, breast cancer

Hurwitz H, Kabbinavar F:
Bevacizumab Combined with Standard Fluoropyrimidine-Based Chemotherapy Regimens to Treat Colorectal Cancer.
Oncology 2005;69(Suppl.3):17-24

Enzastaurin for breast cancer

Enzastaurin is an oral, serine threonine kinase inhibitor which selectively targets the PKC-ß and PI3K/AKT signaling pathways. By blocking these key pathways frequently over-expressed in a wide variety of cancers, enzastaurin suppresses tumor cell proliferation, induces tumor cell death and inhibits tumor-induced angiogenesis. Enzastaurin is being evaluated as a maintenance therapy for the treatment of diffuse large B-cell lymphoma (DLBCL), as well as being evaluated in several studies across a variety of more common tumor types including: breast, colon, lung, ovarian and prostate cancers.

For breast cancer, Lily is sponsoring several comparative trials. There is phase II randomized studies: “A Double-Blind, Randomized, Phase 2 Trial of Capecitabine Plus Enzastaurin Versus Capecitabine Plus Placebo in Patients With Metastatic or Recurrent Breast Cancer Previously Treated With an Anthracycline and a Taxane” and NCT00536939, to determine efficacy and safety of paclitaxel, bevacizumab and enzastaurin versus paclitaxel, bevacizumab, and placebo in patients who are diagnosed with locally recurrent or metastatic breast cancer. A Randomized, Double-Blind, Phase II Trial of Fulvestrant Plus Enzastaurin Versus Fulvestrant Plus Placebo in Aromatase Inhibitor-Resistant Metastatic Breast Cancer, NCT00451555, is also recruting.

It is not clear how the NCT00536939 would be affeted by new developments in the Avastin story in breast cancer. Genetech has filed for the FDA approval for the breast cancer indication in May 2006. However, on Dec. 17th or 2007, ODAC has recoemmended that Avastin not be FDA approved. This was based on the newer analysis that revealed excess mortalitya nd no increase in survival in the Avastin arm, although there was a small progression free survival advantage. While the application for aproval of Avastin is in the process of the FDA approval, and the ODAC has recommended against approval, we cannot act based on this fact until the FDA reacts. The data reported to the FDA had not been fully released for analysis and it is not know whether FDA will follow experts' recommendations. FDA had on ooccasion disregarded this nonbinding recommendation. The recommendations was made based on the publicly available and released information that has gone through sufficient peer-review and discussion.

Pearce HL, et al, The evolution of cancer research and drug discovery at Lilly Research Laboratories. Adv Enzyme Regul. 2005;45:229-55. Epub 2005 Sep 6.

Antiangiogenic Therapy for Breast Cancer: One Step Forward, Two Steps Back?. JWatch Oncology and Hematology 2008: 1-1

Abraxane and Avastin for lung cancer

Lay Summary: One phase II study suggests high response rates for Abraxane and Avastin in nonsmall lung cancer.

The combination of Abraxane (albumin bound paclitaxel) and Paraplatin® (carboplatin) and Avastin (bevacizumab) provides responses or disease stabilization in over 75% of patients with chemotherapy-naïve, advanced non-small cell lung cancer (NSCLC). These results were presented at the 2006 annual Chemotherapy Foundation Symposium.

Abraxane consists of the active ingredient paclitaxel, which is found in Taxol® and its generic equivalents. However, in the formulation of Abraxane, paclitaxel is delivered in a suspension of albumin particles, offering several advantages to Taxol and its generic equivalents, in which polyethoxylated castor oil (Cremophor EL) is used as the solvent for paclitaxel.

Results from previous studies have indicated that single-agent Abraxane is well tolerated and produces significant responses in patients with previously un-treated NSCLC. Researchers continue to evaluate Abraxane in combination with other chemotherapy agents, as well as targeted therapies for the treatment of NSCLC.

Results presented at the Chemotherapy Foundation Symposium were from a phase II open-label clinical trial including 50 chemotherapy-naïve advanced NSCLC patients. Treatment included Abraxane (300 mg/m2) and Paraplatin AUC 6 plus Avastin every 3 weeks. Avastin was not continued beyond 4-6 cycles of chemotherapy.

Confirmed responses were achieved in 26% of patients.
Disease stabilization was achieved in an additional 48% of patients.
Hemoptysis occurred in 6% if patients with 1 fatal event.
The researchers concluded that the treatment combination consisting of Abraxane, Paraplatin and Avastin provides responses or disease stabilization in a vast majority of patients with chemotherapy-naïve, advanced NSCLC. These results provide further evidence that Abraxane in combination with other agents is promising in the treatment of NSCLC.

Abraxane is in phase II studies with carboplatin in lung cancer.

Reynolds C, et al. Nab-Paclitaxel/Carboplatin/Bevacizumab in Advanced Non-Squamous NSCLC. Proceedings of the Chemotherapy Foundation Symposium XXIV. New York, New York. November 12, 2006.

nccn.org, lung cancer

Nexavar for melanoma

Lay Summary:Nexavar has not been proven to be effecive for melanoma.

A Phase III trial administering Nexavar®
(sorafenib) or placebo tablets in combination with the chemotherapeutic agents
carboplatin and paclitaxel in patients with advanced melanoma did not meet its
primary endpoint of improving progression-free survival (PFS). The treatment
effect was comparable in each arm. The international Phase III, double-blind, randomized, placebo-controlled  trial evaluated Nexavar when administered in combination with a standard
dosing schedule (21-day cycles) of carboplatin and paclitaxel. Two hundred
seventy patients progressing after one previous systemic chemotherapeutic
treatment (with either dacarbazine (DTIC) or temozolomide) were enrolled into
the study. The study was designed to measure the safety and efficacy of
Nexavar when co-administered with chemotherapy, and had PFS as its primary
endpoint. PFS is defined as the time that a patient lives without meaningful
tumor growth. The safety profile of these agents in combination (Nexavar with
carboplatin/paclitaxel) was comparable to those previously reported for these
agents in combination. Thus, for now, Nexvar remains an experiemental modality for melanoma.

B. Kasper, V. D’Hondt, P. Vereecken, A. Awada Novel treatment strategies for malignant melanoma: A new beginning?.  Critical Reviews in Oncology/Hematology, Volume 62, Issue 1, Pages 16-22 2006

T Eisen et al, Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis British Journal of Cancer (2006) 95, 581-586.

First line chemotherapy for non small cell lung cancer

Lay Summary: First line chemotherapy for non-small cell lung cancer is discussed.

Palliative chemotherapy for metastatic lung cancer is now standard. Platinum-based combinations were the first regimens to convincingly have an impact on survival and have been the standard of care in NSCLC. A European study showed that gemcitabine/cisplatin was essentiall equivalent to paclitaxel and a platin and the former became standard in Europe whereas the latter is most often used in the USA. Docetaxel ahs been shown to be equivalent to paclitaxel in phase III studies. More recently Avastin has been shown to add to the survival benefit. Bevacizumab (Avastin®) is a humanized recombinant antibody to vascular endothelial growth factor-A (VEGF-A). VEGF-A bound to bevacizumab cannot bind to or activate VEGF receptors (VEGF-R) on vascular endothelial and other cells. Biological consequences include inhibition of angiogenesis (growth of new blood vessels) in tumors. Bevacizumab combined with intravenous fluorouracil-based chemotherapy is indicated as first- or second-line therapy for advanced or metastatic colon or rectal cancers.

An Eastern Cooperative Oncology Group (ECOG) multicenter RCT (E2100) on paclitaxel with (n=341) versus without (n=339) bevacizumab as first-line therapy for inoperable metastatic disease found that it was of value. The first interim analysis reported statistically significant improvement in overall response rate (ORR), PFS, and OS. The second interim analysis also found statistically significant improvement in ORR (30% versus 14%, p<0.0001) and PFS (11.4 versus 6.1 months; p<0.0001), but effects on OS were no longer statistically significant (28.4 versus 25.2 months; p=0.12). Avastin has subsequently gained approval for breast cancer in the US and EU, and for first-line NSCLC in the US.

A second large multicenter study, AVAIL,  has shown that adding bevacizumab (Avastin, Genentech) to chemotherapy improves survival in patients with advanced non–small-cell lung cancer (NSCLC).  This latest study was conducted in Europe and used a different chemotherapy regimen, gemcitabine and cisplatin, the European standard,  from that used in the first trial, which was carried out in the United States. But the results from both trials were similar — adding bevacizumab significantly improved progression-free survival (PFS).

However, one can question the true benefit of bevacizumab, pointing out that the improvement in median PFS over control was only 2 weeks. On the other hand,  the drug increases the risk for adverse events and costs thousands of dollars. However, the same is true of the now accepted in the USA paclitaxel and carboplatin + Avastin. In the USA paclitaxel and carboplatin is now standard and Avastin was approved by the FDA in a "a first-line treatment of patients with locally advanced, metastatic or recurrent non-small cell lung cancer in combination with platinum-based chemotherapy" .

M. A. Socinski, D. E. Morris, G. A. Masters, and R. Lilenbaum
Chemotherapeutic Management of Stage IV Non-small Cell Lung Cancer
Chest, January 1, 2003; 123(1_suppl): 226S - 243S.

Paris D. Makrantonakis, Eleni Galani, Peter G. Harper, Non-Small Cell Lung Cancer in the Elderly The Oncologist, Vol. 9, No. 5, 556-560, September 2004;

nccn.org, NSCL Cancer

R. Milroy
New American College of Chest Physicians Lung Cancer Guidelines*: An Important Addition to the Lung Cancer Guidelines Armamentarium
Chest, September 1, 2007; 132(3): 744 - 746.

Lung Cancer Disease Site Group. Chemotherapy in stage IV (metastatic) non-small cell lung cancer. Toronto (ON): Cancer Care Ontario (CCO); 2005 Jan. 22 p. (Practice guideline report; no. 7-2). [28 references]

AVAIL, American Society of Clinical Oncology 43rd Annual Meeting: Abstract LBA7514. Presented June 2, 2007.

Revised: 3/10/08

Taxotere Avastin for salivary gland

Salivary galnd tumors are not common in stage IV and not much is known about how to optimally treat metastatic salivary galnd cancer.  Their cancer may be responsive to aggressive combinations of chemotherapy and radiation. Patients with any metastatic lesions could be considered for clinical trials. Chemotherapy using doxorubicin, cisplatin, cyclophosphamide, and fluorouracil as single agents or in various combinations is associated with modest responses. NCCN recommends trials, supportive care, chemotherapy (without specifying regimen) or radiotherapy with chemotherapy.

Bevacizumab is an anti-VEGF monoclonal antibody that is FDA-approved for use in other malignancies. Savvides and colleagues from Case Comprehensive Cancer Center in Cleveland reported the preliminary results of a phase 2 study examining the efficacy of bevacizumab in combination with docetaxel and radiation in locally advanced HNC. Eight patients with stage IV disease completed therapy and 5 of 8 had a posttreatment neck dissection that demonstrated a pathologic complete response. These patients are now receiving adjuvant bevacizumab. The addition of this agent to curative CRT appears to be feasible. No episodes of severe bleeding were noted, which has been a concern with this agent. Khuntia and colleagues from the University of Wisconsin presented the design of an ongoing phase 1 trial of neoadjuvant bevacizumab followed by concurrent radiation, cisplatin, and bevacizumab for locally advanced HNC. Results of this study were not yet available.Seiwert and colleagues reported the results of a phase 1 study of bevacizumab plus 5-FU and hydroxyurea with concomitant radiotherapy for poor-prognosis HNC. Thirty-four patients completed treatment and, although there were toxicities, the addition of bevacizumab did not appear to be associated with a major synergistic toxic effect.

Speight PM, Barrett AW: Salivary gland tumours. Oral Dis 8 (5): 229-40, 2002.

Seiwert TY, Haraf DJ, Cohen EE, et al. A phase I study of bevacizumab with fluorouracil and hydroxyurea with concomitant radiotherapy for poor prognosis head and neck cancer. Proc Am Soc Clin Oncol. 2006;24:287s. Abstract 5530.

nccn.org, salvary gland

Savvides P, Greskovich J, Bokar J, et al. Phase II study of bevacizumab in combination with docetaxel and radiation in locally advanced squamous cell cancer of the head and neck (SCCHN). Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 122.

Khuntia D, Jeraj R, Kruser TJ, et al. Phase I trial of neoadjuvant bevacizumab followed by concurrent radiation, cisplatin and bevacizumab for locoregionally advanced squamous cell carcinoma of the head and neck. Program and abstracts of the 2007 Multidisciplinary Head and Neck Cancer Symposium; January 18-20, 2007; Rancho Mirage, California. Abstract 63.

Adjuvant therapy (and Avastin) for stage II colon cancer

Lay Summary: Adjuvant chemotherapy for Stage II colon cancer is controversial but the field until recently was moving away from it.  A recent study is reporting again that it may be beneficial.

Recent guidelines make it optional rather than recommended. An ASCO panel collaborating with the Cancer Care Ontario Practice Guideline Initiative reviewed randomized controlled trials and other relevant studies from the literature through May 2003. This meta-analysis found no evidence in stage II patients of statistically significant improvement in survival with adjuvant chemotherapy.

"The routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer is not recommended," the panel writes. "However, there are populations of patients with stage II disease that could be considered for adjuvant therapy, including patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology."

Limitations of the literature reviewed include insufficient number of patients in previously reported trials, the relatively good prognosis of patients with stage II disease, competing noncancer-related deaths in this population, the lack of consistent information provided on the stage II subsets in the trials analyzed, and the relatively small percentage of patients with stage II disease in each trial.

The guidelines acknowledge that the same relative benefit probably results from adjuvant therapy for patients at both stages II and III, but that the number of patients studied in most trials is too small to detect and quantify absolute survival benefits from adjuvant therapy in stage II disease. To detect a survival difference of 2% between treatment and control groups of a trial, a sample size of 9,680 per group would be needed (90% power with a significance level of .05).

"Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease," the authors write. "The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. Patients with stage II disease should be encouraged to participate in randomized trials." This is also the conclusion of the NCCN and other guidelines.

However, the addition of Avastin to adjuvant FOLFOX is experimental.The NSABP recently opened an adjuvant trial for stage II and III colon cancer patients, C-08. That trial will also randomize patients to receive adjuvant therapy with FOLFOX, with or without bevacizumab; however, in that trial, all stage II patients will receive therapy, and prognostic markers will be retrospectively analyzed.

Researchers recently conducted a clinical study to further evaluate adjuvant chemotherapy in the treatment of Stage II colorectal cancer.  The study, referred to as the QUASAR study, included 3,239 patients with Stage II colorectal cancer who were treated with surgery followed by adjuvant chemotherapy (consisting of a 5-fluorouracil-based regimen) or with no further treatment.  Median follow-up was five and a half years.

• The five-year survival was improved by 3.5% among patients who received adjuvant chemotherapy compared with those who did not receive adjuvant therapy.
• The risk of recurrences was reduced by approximately 22% among patients treated with adjuvant chemotherapy.

The researchers concluded that adjuvant chemotherapy in Stage II colorectal cancer is associated with a modest though significant improvement in survival.

Patients diagnosed with Stage II colorectal cancer may wish to speak with their physician regarding their individual risks and benefits of chemotherapy.

Reference: QUASAR Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomized study. Lancet Oncology. 2007;370:2020-2029.

Benson AB 3rd, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, Krzyzanowska MK, Maroun J, McAllister P, Van Cutsem E, Brouwers M, Charette M, Haller DG. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004 Aug 15;22(16):3408-19. [45 references]

Deborah Schrag, Sheryl Rifas-Shiman, Leonard Saltz, Peter B. Bach, Colin B. Begg
Adjuvant Chemotherapy Use for Medicare Beneficiaries With Stage II Colon Cancer Journal of Clinical Oncology, Vol 20, Issue 19 (October), 2002: 3999-4005

NCCN.ORG, Colon Cancer

Lisa Baddi, Al Benson, III Adjuvant Therapy in Stage II Colon Cancer: Current Approaches The Oncologist, Vol. 10, No. 5, 325-331, May 2005;

Avastin for renal cell cancer

Lay Summary: Avastin is an effective treatment for renal cell carcinoma.

Several studies indicate that Avastin is effective for renal cell carcinoma. A randomized, double-blind, Phase II trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks in 166 patients with renal cancer. Subjects were randomized to three groups: 40 to placebo, 37 to low-dose bevacizumab, and 39 to high-dose bevacizumab. The investigators reported that there was a significant prolongation of the time to progression of disease in the high-dose--antibody group as compared with the placebo group (hazard ratio, 2.55; P<0.001). Although there were no significant differences in survival, this study cannot rule out such a benefit due to the fact that the study was too underpowered to detect differences in survival between treatment groups that may be clinically significant. According to updated results from a phase II clinical trial presented at the 23rd annual Chemotherapy Foundation Symposium, treatment with the combination of Tarceva® (erlotinib) and Avastin® (bevacizumab) resulted in good survival among patients with metastatic renal cell carcinoma.
Current NCCN guidelines recommend Avastin as an option for crossover therapy of renal cell carcinoma after first line therapy with IL2, sorafenib or sunitinib.

Coppin C, Porzsolt F, Awa A, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Systematic Rev. 2004;3:CD001425.

Hainsworth J, Spigel D, Greco A. Combination Therapy with Bevacizumab and Erlotinib for Patients with Metastatic Clear Cell Renal Carcinoma. Proceedings from the 23rd annual Chemotherapy Foundation Symposium. New York. 2005; Abstract #22.

Aimery de Gramonta, Eric Van Cutsemb, Investigating the Potential of Bevacizumab in Other Indications: Metastatic Renal Cell, Non-Small Cell Lung, Pancreatic and Breast Cancer, Oncology Suppl. 3, 2005   

Avastin for prostate cancer

Lay Summary: A great deal of clinical investigation of Avastin for prostate cacner is ongoing but little is as of yet securely known.

is ongoing Drugs used in chemotherapy, such as docetaxel and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether docetaxel, prednisone and bevacizumab are more effective than docetaxel and prednisone in treating prostate cancer.

Findings from a recent phase II trial have shown that a combination of provange and avastin may be beneficial for patients with prostate cancer. The study population consisted of 22 patients who had androgen depended prostate cancer and was having increasing levels of PSA. All patients had undergone previous definitive treatment either in the form of radiation therapy or surgery. All patients received a combination of APC8015 (provenge) in combination with avastin. The treatment was continued until patient had either disease progression or intolerable side effects. The FDA is deliberating on this therapy. ODAC's recommendation against Provenge is being widely discussed.

Out of 22 patients 21 were evaluable for end points of the study. The median PSA doubling time in these patients was 6.7 months and median time on treatment was 12.7 months. No patients on the study had objective disease progression (onset of measurable bone or soft tissue metastasis). Four patients could not continue with the study due to toxicities and were removed from the study.

The results of a CALGB trial indicate that Avastin™/Taxotere® and estramustine can be administered safely and effectively in patients with hormone-refractory prostate cancer. The median age of the patients in this trial was 73 years, and the median PSA at study entry was 128 ng/dl. Of the 79 evaluable patients treated, 45% had measurable soft tissue lesions while 85% had a positive bone scan. Thromboembolic events (6%) were reported in 5 patients; one patient succumbed to a pulmonary embolus. Measurable disease responses were observed and 42% of patients, while 79% of patients evidenced a >50 percent PSA decline. The median time to progression has not yet been reached, and the median survival reported was approximately 20 months. The rate of thromboembolic events with this combination appears to be similar to what has been reported for other estramustine/taxane studies. Avastin alone is in a phase II trial.

There is an ongoig randomized phase III trial that is studying docetaxel, prednisone and bevacizumab to see how well they work compared to docetaxel and prednisone in treating patients with prostate cancer that did not respond to hormone therapy. Other combination trials are also being launched.

http://www.slhn-lehighvalley.org/body.cfm?id=700#CTSU90401

http://www.clinicaltrials.gov/ct/gui/show/NCT00089609

Picus J, Halabi S, Rini B, et al. The use of bevacizumab (B) with Taxotere (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): Initial results of CALGB 90006. Proceedings from the 39th annual meeting of the American Society of Clinical Oncology, May 2003.Abstract 1578.

nccn.org, prostate

Avastin for breast cancer

Lay Summary: Avastin has a role on metastatic breast cancer, especially in combinations with taxanes. A recent study has, however, thrown the role of Avastin into question.

Avastin has a definite role for metastatic breast cancer. A previous Phase III study of bevacizumab in metastatic breast cancer found that the addition of bevacizumab to capecitabine produced a significant increase in response rates, but this did not translate into improved progression free survival or overall survival (Miller, et al., 2005). This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab in 462 patients with metastatic breast cancer previously treated with an anthracycline and a taxane. Patients were randomly assigned to receive capecitabine (2,500 mg/m2/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1. Combination therapy significantly increased the response rates (19.8% v 9.1%; P = .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio = 0.98). Overall survival (15.1 v 14.5 months) and time to deterioration in quality of life as measured by the Functional Assessment Of Cancer Treatment-Breast were comparable in both treatment groups. The investigators reported that bevacizumab was well tolerated in this heavily pretreated patient population (Miller, et al., 2005). No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab.

Preliminary results from a large, randomized clinical trial for patients with previously untreated recurrent or metastatic breast cancer -- cancer that has spread from the breast to other parts of the body -- show that those patients who received bevacizumab (Avastin™) in combination with standard chemotherapy had a longer time period before their cancer progressed than patients who received the same chemotherapy without bevacizumab. Preliminary results suggest that patients in the study who received bevacizumab in combination with standard chemotherapy consisting of single-agent paclitaxel had a delay in worsening of their cancer by approximately five months, on average, compared to patients treated with paclitaxel chemotherapy alone. In the E2100 study, the addition of bevacizumab (Avastin) to paclitaxel resulted in an increase in progression-free survival of more than 4 months. In the trial, patients receiving just paclitaxel had about 6.11 months before the cancer progressed. Those who were treated with both the cytotoxic agent and the new targeted therapy had progression-free survival that averaged 10.97 months. The difference in progression-free survival was statistically significant at the P <.001 level. Accodingly, Avastin had been added to the NCCN guidelines. Genetech has filed for the FDA approval for the breast cancer indication in May 2006. However, on Dec. 17th or 2007, ODAC has recommended that Avastin not be FDA approved. This was based on the newer analysis that revealed excess mortality and no increase in survival in the Avastin arm, although there was a small progression free survival advantage. Subsdequently FDA rejected this recommendation and approved Avastin on 2/27/08.

Miller KD. E2100: A phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer. Clin Breast Cancer. 2003;3(6):421-422.

Ramaswamy B, Shapiro CL. Phase II trial of bevacizumab in combination with docetaxel in women with advanced breast cancer. Clin Breast Cancer. 2003;4(4):292-294.

Cobleigh MA, Langmuir VK, Sledge GW, et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol. 2003;30(5 Suppl 16):117-124.

Add: While the application for aproval of Avastin is in the process of the FDA approval, and the ODAC has recommended against approval, we cannot act based on this fact until the FDA reacts. The data reported to the FDA had not been fully released for analysis and it is not know whether FDA will follow experts' recommendations. FDA had on ooccasion disregarded this nonbinding recommendation. The recommendations was made based on the publicly available and released information that has gone through sufficient peer-review and discussion. It wouldbe preliminary to deny based on this report of Dec 27th in the New England Journal of Medicine (here, http://content.nejm.org/cgi/content/short/357/26/26660). See also the discussion at: Antiangiogenic Therapy for Breast Cancer: One Step Forward, Two Steps Back?. JWatch Oncology and Hematology 2008: 1-1

Revised: 2/18/08

Revised: 3/10/08 - Despite a negative recommendation from the Oncologic Drugs Advisory Committee, Genentech Inc.'s Avastin (bevacizumab) gained accelerated approval from the FDA for use in combination with paclitaxel chemotherapy for the first-line treatment of metastatic HER2-negative breast cancer.