Sunday, May 20, 2012
Monday, July 26, 2010
Wednesday, July 21, 2010
Avastin: Advisory panel recommends FDA to remove advanced breast cancer indication
GAITHERSBURG, Md. – In a vote of 12 to 1 a recommendation has been issued by the Oncologic Drugs Advisory Committee advisory panel that the FDA remove the advanced breast cancer indication from Avastin (bevacizumab), after two large clinical trials failed to demonstrate a clinically significant benefit of the drug, which is associated with serious side effects. When used in combination with standard chemotherapy, Avastin did not extend progression-free survival (PFS) long enough to be clinically significant in HER2-negative, metastatic breast cancer.
In 2008, the FDA granted special, fast-track approval to Genentech, manufacturer of Avastin, to begin marketing the drug for patients with metastatic breast cancer in combination with the chemotherapy agent paclitaxel. This "accelerated" approval was based on positive early findings from a large Genentech-sponsored clinical trial that found Avastin added 5.5 months PFS vs. paclitaxel alone. However, the data from two new clinical trials (AVADO, RIBBON-1) of almost 2,000 breast cancer patients that Genentech submitted to move from accelerated approval to standard approval failed to demonstrate the PFS to the extent seen in the earlier study.* The PFS in the two trials ranged from a little less than a month, to just under three months. The results failed to demonstrate that the benefits of using Avastin outweigh the potential risks, which include a small risk of death, bleeding, febrile neutropenia and hypertension.
Genentech argued that even small gains in progression-free survival are clinically meaningful and that additional weeks where tumors don't worsen translate to improved quality of life.
The FDA usually follows the advice of its advisory committee, and if they do this time, Avastin would still be approved to treat lung, kidney, and colon cancer. Avastin is also used treat recurrent glioblastoma under accelerated approval. The FDA will make a decision by September 17, 2010.
Source
FDA Panel Nixes Bevacizumab for Breast Cancer. By Emily P. Walker, Washington Correspondent, MedPage Today Published: July 20, 2010. Available at http://www.medpagetoday.com/HematologyOncology/BreastCancer/21276?utm_content=Group_&utm_medium=email&impressionId=&utm_campaign=DailyHeadlines&utm_source=mSpoke&userid= Accessed July 21, 2010.
In 2008, the FDA granted special, fast-track approval to Genentech, manufacturer of Avastin, to begin marketing the drug for patients with metastatic breast cancer in combination with the chemotherapy agent paclitaxel. This "accelerated" approval was based on positive early findings from a large Genentech-sponsored clinical trial that found Avastin added 5.5 months PFS vs. paclitaxel alone. However, the data from two new clinical trials (AVADO, RIBBON-1) of almost 2,000 breast cancer patients that Genentech submitted to move from accelerated approval to standard approval failed to demonstrate the PFS to the extent seen in the earlier study.* The PFS in the two trials ranged from a little less than a month, to just under three months. The results failed to demonstrate that the benefits of using Avastin outweigh the potential risks, which include a small risk of death, bleeding, febrile neutropenia and hypertension.
"Survival trumps everything, and we haven't shown a survival benefit here"
- Ronald Richardson, MD, a medical oncologist at the Mayo Clinic
Genentech argued that even small gains in progression-free survival are clinically meaningful and that additional weeks where tumors don't worsen translate to improved quality of life.
The FDA usually follows the advice of its advisory committee, and if they do this time, Avastin would still be approved to treat lung, kidney, and colon cancer. Avastin is also used treat recurrent glioblastoma under accelerated approval. The FDA will make a decision by September 17, 2010.
*For details of the studies see Avastin did not improve progression-free survival in patients with breast cancer. Available at http://medwritehealthcarecommunications.blogspot.com/2010/07/avastin-did-not-improve-progression.html. Posted July 19, 2010.
Source
FDA Panel Nixes Bevacizumab for Breast Cancer. By Emily P. Walker, Washington Correspondent, MedPage Today Published: July 20, 2010. Available at http://www.medpagetoday.com/HematologyOncology/BreastCancer/21276?utm_content=Group_&utm_medium=email&impressionId=&utm_campaign=DailyHeadlines&utm_source=mSpoke&userid= Accessed July 21, 2010.
Monday, July 19, 2010
Avastin did not improve progression-free survival in patients with breast cancer
Two new studies demonstrated that Avastin (bevacizumab), in combination with chemotherapy did not extend progression free survival (PFS) in patients with advanced breast cancer to the same levels observed in a previous trial used to garner approval of the drug in this indication in 2008. The FDA approved Avastin for treatment of breast cancer was based on results from the E2100 clinical trial, which demonstrated that Avastin in combination with paclitaxel slowed the spread of breast cancer and extended PFS by 5.5 months vs. paclitaxel alone.[1-2]
Data from two post-approval trials told a different story. A first, the AVADO clinical trial involving 736 patients with locally recurrent or metastatic HER2-negative breast cancer who had not previously received chemotherapy for their disease showed that a high dose of Avastin used in combination with docetaxel extended PFS by 0.9 months vs. docetaxel alone. Patients receiving a lower dose of Avastin had PFS extended by 0.8 months.[3]
A second post-approval trial, RIBBON-1 study involving 1237 women with locally recurrent or metastatic HER-2 negative breast cancer who had not received prior treatment for the disease demonstrated that Avastin in combination with taxane or anthracycline-based chemotherapies extended PFS by 1.2 months vs. chemotherapy alone. Patients receiving Avastin in combination with Xeloda (capecitabine) lived 2.9 months longer than patients receiving chemotherapy alone.[4]
Currently, Avastin is indicated for the use in: (1) first-line treatment of a subgroup of women with metastatic breast cancer known as HER2-negative breast cancer, in combination with the chemotherapy drug docetaxel; and (2) first-line treatment of HER2-negative metastatic breast cancer in combination with one of two classes of chemotherapy drugs, known as taxanes and anthracyclines, or with the chemotherapy drug, capecitabine. FDA approval is pending of additional indication for the treatment, in combination with the chemotherapy drug paclitaxel, of patients who have not received chemotherapy for their locally recurrent or metastatic HER2 negative breast cancer. The FDA may ultimately decide to withdraw its approval for Avastin based on results from the post-approval trials.
References:
1. FDA staff release review of Roche's Avastin in breast cancer. First Word. Light Edition. July 16, 2010. Available at http://www.firstwordplus.com/Fws.do?articleid=F731F4EE99584F0FB11A106C99246301 Accessed July 19, 2010.
2. July 20, 2010: Oncologic Drugs Advisory Committee Meeting Announcement. FDA U.S. Food and Drug Administration. Available at http://www.fda.gov/AdvisoryCommittees/Calendar/ucm213724.htm Accessed July 19, 2010.
3. Miles D, Chan A, G. Romieu G, et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. J Clin Oncol 26: 2008 (May 20 suppl; abstr LBA1011). Available at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34482 Accessed July 19, 2010.
4. Robert NJ, Dieras V, J. Glaspy J, et al. RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol 27:15s, 2009 (suppl; abstr 1005). Available at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34532 Accessed July 19, 2010.
Data from two post-approval trials told a different story. A first, the AVADO clinical trial involving 736 patients with locally recurrent or metastatic HER2-negative breast cancer who had not previously received chemotherapy for their disease showed that a high dose of Avastin used in combination with docetaxel extended PFS by 0.9 months vs. docetaxel alone. Patients receiving a lower dose of Avastin had PFS extended by 0.8 months.[3]
A second post-approval trial, RIBBON-1 study involving 1237 women with locally recurrent or metastatic HER-2 negative breast cancer who had not received prior treatment for the disease demonstrated that Avastin in combination with taxane or anthracycline-based chemotherapies extended PFS by 1.2 months vs. chemotherapy alone. Patients receiving Avastin in combination with Xeloda (capecitabine) lived 2.9 months longer than patients receiving chemotherapy alone.[4]
Currently, Avastin is indicated for the use in: (1) first-line treatment of a subgroup of women with metastatic breast cancer known as HER2-negative breast cancer, in combination with the chemotherapy drug docetaxel; and (2) first-line treatment of HER2-negative metastatic breast cancer in combination with one of two classes of chemotherapy drugs, known as taxanes and anthracyclines, or with the chemotherapy drug, capecitabine. FDA approval is pending of additional indication for the treatment, in combination with the chemotherapy drug paclitaxel, of patients who have not received chemotherapy for their locally recurrent or metastatic HER2 negative breast cancer. The FDA may ultimately decide to withdraw its approval for Avastin based on results from the post-approval trials.
References:
1. FDA staff release review of Roche's Avastin in breast cancer. First Word. Light Edition. July 16, 2010. Available at http://www.firstwordplus.com/Fws.do?articleid=F731F4EE99584F0FB11A106C99246301 Accessed July 19, 2010.
2. July 20, 2010: Oncologic Drugs Advisory Committee Meeting Announcement. FDA U.S. Food and Drug Administration. Available at http://www.fda.gov/AdvisoryCommittees/Calendar/ucm213724.htm Accessed July 19, 2010.
3. Miles D, Chan A, G. Romieu G, et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. J Clin Oncol 26: 2008 (May 20 suppl; abstr LBA1011). Available at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=34482 Accessed July 19, 2010.
4. Robert NJ, Dieras V, J. Glaspy J, et al. RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol 27:15s, 2009 (suppl; abstr 1005). Available at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=34532 Accessed July 19, 2010.
Monday, June 14, 2010
Blood pressure drugs, angiotensin-receptor blockers, and risk of cancer: meta-analysis of randomized controlled trials
A recent study by Sipahi et al. published in The Lancet Oncology suggests that angiotensin-receptor blockers (ARBs) may be associated with a "modestly" increased risk of cancer. However, conclusions about the exact risk of cancer associated with each particular drug were not possible to draw due to study limitations.
ARBs are a widely used drug class approved for treatment of hypertension, heart failure, diabetic nephropathy, and, recently, for cardiovascular risk reduction. Experimental studies implicate the renin-angiotensin system, particularly angiotensin II type-1 and type-2 receptors, in the regulation of cell proliferation, angiogenesis, and tumour progression.
*Drugs in this class include:
Sipahi I, Debanne SM, Rowland DY, et al. Blood pressure drugs, angiotensin-receptor blockers and risk of cancer: meta-analysis of randomized controlled trials. Lancet Oncol, Early Online Publication, 14 June 2010, doi:10.1016/S1470-2045(10)70106-6 .
ARBs are a widely used drug class approved for treatment of hypertension, heart failure, diabetic nephropathy, and, recently, for cardiovascular risk reduction. Experimental studies implicate the renin-angiotensin system, particularly angiotensin II type-1 and type-2 receptors, in the regulation of cell proliferation, angiogenesis, and tumour progression.
This study assessed whether ARBs affect cancer occurrence with a meta-analysis of randomized controlled trials of these drugs by searching Medline, Scopus (including Embase), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and the US Food and Drug Administration website for studies published before November, 2009, that included any of the seven currently available ARBs.* Randomized controlled trials with an ARB given in at least one group, with a follow-up of at least 1 year, and that enrolled at least 100 patients were included. The following information was available:
- New-cancer data for 61, 590 patients from five trials
- Data on common types of solid organ cancers for 68, 402 patients from five trials
- Data on cancer deaths for 93, 515 patients from eight trials.
This meta-analysis of randomized controlled trials suggested that ARBs were associated with a modestly increased risk of new cancer diagnosis. The researchers concluded that due to the limited data, it was not possible to draw conclusions about the exact risk of cancer associated with each particular drug, and these findings warranted further investigation.
*Drugs in this class include:
- Atacand (candesartan) (AstraZeneca)
- Avapro (irbesartan) (sanofi-aventis and Bristol Myers Squibb)
- Benicar (omesartan) (Daiichi Sankyo)
- Cozaar (losartan) (Merck & Co.)
- Diovan (valsartan) (Novartis)
- Mycardis (telmisartan) (Boehringer Ingelheim and Astellas)
- Teveten (eprosartan) (Solvay)
Sipahi I, Debanne SM, Rowland DY, et al. Blood pressure drugs, angiotensin-receptor blockers and risk of cancer: meta-analysis of randomized controlled trials. Lancet Oncol, Early Online Publication, 14 June 2010, doi:10.1016/S1470-2045(10)70106-6 .
Friday, May 28, 2010
Stem-cell-like properties of normal and malignant epithelial cells contribute to cell-death resistance
It is not well understood why carcinomas reemerge after chemotherapy and/or radiation treatments. Cancer recurrence and treatment failure seems to be associated with stem-cell-like properties and resistance to apoptosis (programmed cell death) in a subset of cells that have been previously isolated from human epithelial cancers.
One study investigated the mechanisms of apoptosis resistance of cells with stem-cell-like properties in both normal and malignant human epithelia, and whether altered cell cycle regulation played a role.
To address these questions, the following methodology was employed:
Abbreviations
PCR = polymerase chain reaction; RNA = ribonucleic acid
Free full-text article available at: http://www.biomedcentral.com/1471-2407/10/166
One study investigated the mechanisms of apoptosis resistance of cells with stem-cell-like properties in both normal and malignant human epithelia, and whether altered cell cycle regulation played a role.
To address these questions, the following methodology was employed:
- Cells were isolated from fresh human head and neck carcinomas (n = 11), cell lines derived from head and neck, prostate and breast human carcinomas (n = 7), and from normal human oral mucosa (n = 5)
- All cells were exposed to various apoptosis-inducing stimuli (UV, tumour necrosis factor, cisplatin, etoposide, and neocarzinostatin)
- The subset of cells with stem-cell-like properties were identified by flow cytometry for CD44 and epithelial-specific antigen (ESA) expression, colony morphology, tumour sphere formation and rapid adherence assays
- Apoptosis, cell cycle and expression of various cell cycle checkpoint proteins were assessed by Western Blot and quantitative PCR (qPCR)
- Debromohymenialdisine (DBH) and small interfering RNA (siRNA) were used to investigate the role of G2-checkpoint regulators Chk1 and Chk2
- A subset of CD44high cells were found in both cancer biopsies and carcinoma cell lines that showed increased clonogenicity, a significantly lower rate of apoptosis, and a significantly higher proportion of cells in the G2-phase of the cell cycle. An inverse correlation between the Percentage of cells in G2-phase and the rate of apoptosis revealed an inverse correlation.
- It appeared that CD44high carcinoma cells spent longer time in G2, even in untreated controls as shown by pulse-chase with iododeoxyuridine (IdU). These cells expressed higher levels of G2 checkpoint proteins, and their release from G2 with BDH or Chk1 siRNA increased their rate of apoptosis.
- Interestingly, low passage cultures of normal keratinocytes were found to contain a subset of CD44high cells which also showed increased clonogenicity, and a similar pattern of G2-block associated with apoptotic resistance.
Conclusions
The results of this study suggested that not only malignant, but also normal human epithelial cells with stem-cell-like properties have extended G2 cell cycle phase which is associated with greater resistance to apoptosis, and that this property is not a consequence of neoplastic (cancerous) transformation (i.e. not unique to cancer cells). This knowledge provides an opportunity for novel therapeutic approaches targeting G2 checkpoint proteins to release these cells from the G2-block and make them more prone to apoptosis.Abbreviations
PCR = polymerase chain reaction; RNA = ribonucleic acid
Reference
Harper LJ, Costea DE, Gammon L, et al. Normal and malignant epithelial cells with stem-like properties have an extended G2 cell cycle phase that is associated with apoptotic resistance. BMC Cancer 2010, 10:166doi:10.1186/1471-2407-10-166.Free full-text article available at: http://www.biomedcentral.com/1471-2407/10/166
Monday, May 24, 2010
Exercise and its effects on perceived symptoms and physical function in adults with fibromyalgia: results from a randomized trial
Adults with fibromyalgia (FM) have been shown to benefit from exercise and its therapeutic effects on their condition. However, FM symptoms often limit the ability to exercise and create obstacles that discourage an active lifestyle and physical activity.
One study evaluated the effects of accumulating at least 30 minutes of self-selected lifestyle physical activity (LPA) on perceived physical function, pain, fatigue, body mass index, depression, tenderness, and the six-minute walk test in adults with FM.
Eighty-four minimally active adults with FM were randomized to either LPA or a FM education control (FME) group. Participants in the LPA group worked toward accumulating 30 minutes of self-selected moderate-intensity LPA, 5–7 days per week, while the FME participants received only information and support.
Of the 84 participants, 73 (87%) completed the 12-week trial. The LPA group increased their average daily steps by 54%. As well, the LPA group reported significantly less perceived functional deficits (P = 0.032) and less pain (P = 0.006) compared to the FME group. No differences between the groups were seen on the six-minute walk test (P = 0.067), fatigue, depression, body mass index, or tenderness.
This study demonstrated that accumulating as little as 30 minutes of LPA throughout the day can produce clinically relevant changes in how previously minimally active adults with FM perceive physical function and pain.
Reference
Fontaine KR, Conn L, and Clauw DJ. Effects of lifestyle physical activity on perceived symptoms and physical function in adults with fibromyalgia: results of a randomized trial. Arthr ResTher 2010; 12:R55doi:10.1186/ar2967
Article URL: http://arthritis-research.com/content/12/2/R55
One study evaluated the effects of accumulating at least 30 minutes of self-selected lifestyle physical activity (LPA) on perceived physical function, pain, fatigue, body mass index, depression, tenderness, and the six-minute walk test in adults with FM.
Eighty-four minimally active adults with FM were randomized to either LPA or a FM education control (FME) group. Participants in the LPA group worked toward accumulating 30 minutes of self-selected moderate-intensity LPA, 5–7 days per week, while the FME participants received only information and support.
Of the 84 participants, 73 (87%) completed the 12-week trial. The LPA group increased their average daily steps by 54%. As well, the LPA group reported significantly less perceived functional deficits (P = 0.032) and less pain (P = 0.006) compared to the FME group. No differences between the groups were seen on the six-minute walk test (P = 0.067), fatigue, depression, body mass index, or tenderness.
This study demonstrated that accumulating as little as 30 minutes of LPA throughout the day can produce clinically relevant changes in how previously minimally active adults with FM perceive physical function and pain.
Reference
Fontaine KR, Conn L, and Clauw DJ. Effects of lifestyle physical activity on perceived symptoms and physical function in adults with fibromyalgia: results of a randomized trial. Arthr ResTher 2010; 12:R55doi:10.1186/ar2967
Article URL: http://arthritis-research.com/content/12/2/R55
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