BSI-201 misses main goals of Phase III study
* Survival benefit seen in second- and third-line patients
* Did not significantly add to toxicity
NEW YORK, Jan 27 (Reuters) - An experimental drug for a type of advanced breast cancer being developed by Sanofi-Aventis (SASY.PA) failed to extend life or slow disease progression in a late-stage clinical trial, the French drugmaker said on Thursday.
The news was particularly disappointing as the drug, BSI-201, or iniparib, did extend survival by an average of almost five months over chemotherapy alone in an earlier mid-stage study of women with metastatic triple-negative breast cancer.
However, an analysis of subjects in the 519-patient Phase III study who were undergoing their second or third treatment regimens for the disease did show an improvement in both overall survival and progression-free survival that was consistent with results from the earlier trial, Sanofi said.
"While this trial did not meet its primary goal, we believe that the improvement in overall survival and progression-free survival in patients in the second- and third-line setting are important findings," Debasish Roychowdhury, head of Sanofi-Aventis Oncology, said in a statement.
Also of importance, treatment with BSI-201 did not significantly add to the toxicity of the chemotherapy drugs that were administered along with the Sanofi medicine, the company said.
BSI-201, a new anti-tumor agent, is also being studied against lung cancer and other cancers.
Sanofi said it will conduct an in depth analysis of the new data and plans to discuss the results with U.S. and European health regulators as development of the drug for breast cancer continues.
Triple-negative breast cancer refers to a form of the disease in which the tumors are shown to not be over-expressing estrogen, progesterone or the HER2 protein.
Some 15 to 20 percent of breast cancers lack over-expression of all three proteins, and those patients often have poorer outcomes then those with other types of breast cancer.
Σάββατο 29 Ιανουαρίου 2011
VINORELBINE-TRASTUZUMAB BETTER THAN DOCETAXEL-TRASTUZUMAB?
January 26, 2011 — What's the best chemotherapy to use in combination with trastuzumab in women with HER2-positive metastatic and locally advanced breast cancer?
The answer is not found in the efficacy data; instead, it is found in toxicity results, according to the Scandinavian authors of a new study on the subject.
On that score, the investigators found, in a phase 3 trial of first-line therapies, that vinorelbine (Navelbine) had significantly fewer adverse effects than docetaxel (Taxotere) when each was combined with trastuzumab (Herceptin). Efficacy, measured by time to progression, was comparable between the 2 regimens.
Results from the Herceptin Plus Navelbine or Taxotere (HERNATA) trial, which comprised 284 women from Denmark, Sweden, and Norway, were first presented at the European Breast Cancer Conference in 2010 and have now been published in the January 20 issue of the Journal of Clinical Oncology.
The results reflect what medical oncologists have been finding out on their own in clinical practice, suggest the authors of an editorial that accompanies the study.
"Many clinicians choose to partner trastuzumab with vinorelbine or, less frequently, capecitabine" in this first-line setting because the taxane alternatives are generally more toxic, say 2 breast cancer oncologists, Nancy U. Lin, MD, and Eric Winer, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, who wrote the editorial.
"Given the more favorable toxicity profile and the failure to conclude that docetaxel is superior to vinorelbine," they write, "we believe this study firmly establishes the role of trastuzumab plus vinorelbine as an acceptable, and even preferred, option for the first-line treatment of patients with HER2-positive metastatic breast cancer."
The study authors, led by Michael Andersson, MD, from Rigshospitalet in Copenhagen, Denmark, are less definitive. They conclude their paper by saying that "vinorelbine plus trastuzumab should be considered as an alternative first-line option with a favorable risk/benefit balance."
But they also write that "the choice of a first-line chemotherapy drug . . . may not be important . . . regarding treatment efficacy, but it certainly is important in terms of toxicity." In other words, the authors indirectly champion vinorelbine over taxanes, including docetaxel.
According to Dr. Lin and Dr. Winer, only the taxane paclitaxel is currently approved by the US Food and Drug Administration for use in combination with trastuzumab in HER2-positive metastatic breast cancer. Docetaxel is approved for use in combination therapy by the European Medicines Agency. Vinorelbine is approved by neither agency in this setting at this point. However, the National Comprehensive Cancer Network lists vinorelbine — along with paclitaxel (with or without carboplatin), docetaxel, and capecitabine — as preferred first-line agents in this setting.
The editorialists believe that more research studies are not needed to further define which chemotherapy is optimal in this setting. "In our view, little will be gained by playing musical chairs with chemotherapeutic agents," they write.
Trastuzumab is the "great equalizer," they add, "rendering the specific choice of chemotherapy secondary."
What is needed in research is an expansion of investigations into "individualized and targeted" therapies; they need to "claim the limelight," say Dr. Lin and Dr. Winer.
Study Findings
The study, which was supported by Roche and Sanofi-Aventis, enrolled patients with HER2-positive metastatic or locally advanced breast cancer who had not received previous chemotherapy or HER2-targeted therapy for the treatment of their advanced disease.
A total of 284 patients were randomized to treatment with either docetaxel 100 mg/m2 once every 3 weeks (n =1 43) or vinorelbine (30 mg/m2 or 35 mg/m2, according to institutional predefined preference) on days 1 and 8 of a 21-day cycle (n = 141). Trastuzumab was administered to all patients once every 3 weeks.
Treatment was continued until progression, intolerable toxicity, or patient withdrawal.
The primary study end point was time to progression, which was not statistically significantly different: the median for docetaxel was 12.4 months and for vinorelbine was 15.3 months (hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.71 to 1.25; P = .67).
This efficacy outcome favoring vinorelbine was surprising, explain the study authors.
"At the time of conception of the study, it was believed that the vinorelbine plus trastuzumab combination was inferior to docetaxel plus trastuzumab in terms of efficacy," they write.
There was no difference in most of the secondary end points, including overall survival. Median overall survival was 35.7 months for docetaxel and 38.8 months for vinorelbine (HR, 1.01; 95% CI, 0.71 to 1.42; P = .98).
The one exception to this — time to treatment failure — cast docetaxel in a negative light. Median time to treatment was significantly shorter for docetaxel than for vinorelbine (5.6 vs 7.7 months; HR, 0.50; 95% CI, 0.38 to 0.64; P < .0001).
Toxicity is where the 2 agents were most different, say both the authors and the editorialists. More patients in the docetaxel group than in the vinorelbine group discontinued therapy because of toxicity (20.1% vs 6.5%; P < .001).
With docetaxel, compared with vinorelbine, there were also significantly more treatment-related grade 3 to 4 febrile neutropenia (36.0% vs 10.1%), leucopenia (40.3% vs 21.0%), infection (25.1% vs 13.0%), fever (4.3% vs 0.0%), neuropathy (30.9% vs 3.6%), nail changes (7.9% vs 0.7%), and edema (6.5% vs 0.0%).
Dr. Andersson reports receiving honoraria from Roche and Sanofi-Aventis, the 2 companies that sponsored the study. Some of the study coauthors reported financial ties to these companies and others. Dr. Lin reports receiving research funding from Genentech, GlaxoSmithKline, Boehringer Ingelheim, and Infinity Pharmaceuticals. Dr. Winer reports receiving research funding from Genentech.
J Clin Oncol. 2010;29:251-253, 264-271. Abstract, Abstract
The answer is not found in the efficacy data; instead, it is found in toxicity results, according to the Scandinavian authors of a new study on the subject.
On that score, the investigators found, in a phase 3 trial of first-line therapies, that vinorelbine (Navelbine) had significantly fewer adverse effects than docetaxel (Taxotere) when each was combined with trastuzumab (Herceptin). Efficacy, measured by time to progression, was comparable between the 2 regimens.
Results from the Herceptin Plus Navelbine or Taxotere (HERNATA) trial, which comprised 284 women from Denmark, Sweden, and Norway, were first presented at the European Breast Cancer Conference in 2010 and have now been published in the January 20 issue of the Journal of Clinical Oncology.
The results reflect what medical oncologists have been finding out on their own in clinical practice, suggest the authors of an editorial that accompanies the study.
"Many clinicians choose to partner trastuzumab with vinorelbine or, less frequently, capecitabine" in this first-line setting because the taxane alternatives are generally more toxic, say 2 breast cancer oncologists, Nancy U. Lin, MD, and Eric Winer, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, who wrote the editorial.
"Given the more favorable toxicity profile and the failure to conclude that docetaxel is superior to vinorelbine," they write, "we believe this study firmly establishes the role of trastuzumab plus vinorelbine as an acceptable, and even preferred, option for the first-line treatment of patients with HER2-positive metastatic breast cancer."
The study authors, led by Michael Andersson, MD, from Rigshospitalet in Copenhagen, Denmark, are less definitive. They conclude their paper by saying that "vinorelbine plus trastuzumab should be considered as an alternative first-line option with a favorable risk/benefit balance."
But they also write that "the choice of a first-line chemotherapy drug . . . may not be important . . . regarding treatment efficacy, but it certainly is important in terms of toxicity." In other words, the authors indirectly champion vinorelbine over taxanes, including docetaxel.
According to Dr. Lin and Dr. Winer, only the taxane paclitaxel is currently approved by the US Food and Drug Administration for use in combination with trastuzumab in HER2-positive metastatic breast cancer. Docetaxel is approved for use in combination therapy by the European Medicines Agency. Vinorelbine is approved by neither agency in this setting at this point. However, the National Comprehensive Cancer Network lists vinorelbine — along with paclitaxel (with or without carboplatin), docetaxel, and capecitabine — as preferred first-line agents in this setting.
The editorialists believe that more research studies are not needed to further define which chemotherapy is optimal in this setting. "In our view, little will be gained by playing musical chairs with chemotherapeutic agents," they write.
Trastuzumab is the "great equalizer," they add, "rendering the specific choice of chemotherapy secondary."
What is needed in research is an expansion of investigations into "individualized and targeted" therapies; they need to "claim the limelight," say Dr. Lin and Dr. Winer.
Study Findings
The study, which was supported by Roche and Sanofi-Aventis, enrolled patients with HER2-positive metastatic or locally advanced breast cancer who had not received previous chemotherapy or HER2-targeted therapy for the treatment of their advanced disease.
A total of 284 patients were randomized to treatment with either docetaxel 100 mg/m2 once every 3 weeks (n =1 43) or vinorelbine (30 mg/m2 or 35 mg/m2, according to institutional predefined preference) on days 1 and 8 of a 21-day cycle (n = 141). Trastuzumab was administered to all patients once every 3 weeks.
Treatment was continued until progression, intolerable toxicity, or patient withdrawal.
The primary study end point was time to progression, which was not statistically significantly different: the median for docetaxel was 12.4 months and for vinorelbine was 15.3 months (hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.71 to 1.25; P = .67).
This efficacy outcome favoring vinorelbine was surprising, explain the study authors.
"At the time of conception of the study, it was believed that the vinorelbine plus trastuzumab combination was inferior to docetaxel plus trastuzumab in terms of efficacy," they write.
There was no difference in most of the secondary end points, including overall survival. Median overall survival was 35.7 months for docetaxel and 38.8 months for vinorelbine (HR, 1.01; 95% CI, 0.71 to 1.42; P = .98).
The one exception to this — time to treatment failure — cast docetaxel in a negative light. Median time to treatment was significantly shorter for docetaxel than for vinorelbine (5.6 vs 7.7 months; HR, 0.50; 95% CI, 0.38 to 0.64; P < .0001).
Toxicity is where the 2 agents were most different, say both the authors and the editorialists. More patients in the docetaxel group than in the vinorelbine group discontinued therapy because of toxicity (20.1% vs 6.5%; P < .001).
With docetaxel, compared with vinorelbine, there were also significantly more treatment-related grade 3 to 4 febrile neutropenia (36.0% vs 10.1%), leucopenia (40.3% vs 21.0%), infection (25.1% vs 13.0%), fever (4.3% vs 0.0%), neuropathy (30.9% vs 3.6%), nail changes (7.9% vs 0.7%), and edema (6.5% vs 0.0%).
Dr. Andersson reports receiving honoraria from Roche and Sanofi-Aventis, the 2 companies that sponsored the study. Some of the study coauthors reported financial ties to these companies and others. Dr. Lin reports receiving research funding from Genentech, GlaxoSmithKline, Boehringer Ingelheim, and Infinity Pharmaceuticals. Dr. Winer reports receiving research funding from Genentech.
J Clin Oncol. 2010;29:251-253, 264-271. Abstract, Abstract
BREAST IMPLANTS INCREASE RISK OF A RARE LYMPHOMA FORM
January 26, 2011 — Patients with either saline- or silicone gel–filled breast implants may have a very small but significant risk for a rare cancer called anaplastic large-cell lymphoma (ALCL) adjacent to the implant, the US Food and Drug Administration (FDA) announced today.
While the agency continues to investigate the possible association between ALCL and breast implants, it is advising clinicians to consider the possibility of the cancer in patients with breast implants with late onset of fluid build-up called persistent peri-implant seroma. Clinicians also should report any confirmed cases of ALCL in women with breast implants to the FDA.
The agency is advising women with breast implants not to change their routine medical care and follow-up. Because the risk for ALCL appears to be very small, the agency believes the weight of evidence "supports a reasonable assurance that FDA-approved breast implants are safe and effective when used as labeled."
A rare cancer of the immune system that can occur anywhere in the body, ALCL is diagnosed in 1 of every 500,000 women per year in the United States. ALCL in the breast is rarer still, diagnosed annually in roughly 3 of every 100 million women without implants. In women with breast implants, it is usually inside the fibrous scar tissue — called a capsule — surrounding the implant. It is not a cancer of the breast per se.
Treatment options for ALCL are chemotherapy, radiation, and surgery, said William Maisel, MD, MPH, chief scientist and deputy director for science in the FDA's Center for Devices and Radiological Health, at a press conference today. The evidence suggests that the kind of ALCL found in conjunction with breast implants is less aggressive and is sometimes treatable by simply removing the implant, the capsule, and collected fluid, according to Dr. Maisel.
An FDA review of scientific literature published from January 1997 through May 2010 uncovered 34 unique cases of ALCL in women with breast implants throughout the world. The agency is aware of 60 cases in all, some of them identified through other channels. The FDA does not know how many of the 60 may be duplicates of cases found in the literature. An estimated 5 million to 10 million women worldwide have received breast implants, according to the FDA.
Of the 31 published cases of ALCL, 24 involved silicone implants, and 7 saline implants. The median time from implant to ALCL diagnosis was 8 years. For most of the women, the cancer was diagnosed when they sought treatment for implant-related symptoms, such as pain, lumps, swelling, or asymmetry, after their surgical sites had healed. These symptoms result from persistent peri-implant seroma, hardening of the breast area around the implant, or masses surrounding the implant.
Plastic Surgeons and FDA Will Develop Patient Registry
The vast majority of data suggesting a link between ALCL and breast implants emerged only after the FDA approved silicone gel breast implants made by Allergan and Mentor in 2006, said Dr. Maisel. From 1992 to 2006, such silicone gel implants were available only on an investigational basis.
Dr. Maisel noted that silicone from ruptured and even intact implants has been found in nearby breast tissue. According to one theory about the origins of ALCL, this silicone chronically stimulates immune system T cells and induces lymphoma.
"Please understand that is speculative, and a hypothesis," said Dr. Maisel.
To get to firmer scientific ground, the FDA will collaborate with the American Society of Plastic Surgeons and other groups to develop a registry to collect more information that would better characterize ALCL in women with breast implants. The agency also is asking implant manufacturers to report ALCL cases. And for the sake of patient and clinician education, the FDA will work with these manufacturers to update product labeling materials.
More information about today's announcement is available on the FDA Web site. The FDA's preliminary findings and analyses are available here.
While the agency continues to investigate the possible association between ALCL and breast implants, it is advising clinicians to consider the possibility of the cancer in patients with breast implants with late onset of fluid build-up called persistent peri-implant seroma. Clinicians also should report any confirmed cases of ALCL in women with breast implants to the FDA.
The agency is advising women with breast implants not to change their routine medical care and follow-up. Because the risk for ALCL appears to be very small, the agency believes the weight of evidence "supports a reasonable assurance that FDA-approved breast implants are safe and effective when used as labeled."
A rare cancer of the immune system that can occur anywhere in the body, ALCL is diagnosed in 1 of every 500,000 women per year in the United States. ALCL in the breast is rarer still, diagnosed annually in roughly 3 of every 100 million women without implants. In women with breast implants, it is usually inside the fibrous scar tissue — called a capsule — surrounding the implant. It is not a cancer of the breast per se.
Treatment options for ALCL are chemotherapy, radiation, and surgery, said William Maisel, MD, MPH, chief scientist and deputy director for science in the FDA's Center for Devices and Radiological Health, at a press conference today. The evidence suggests that the kind of ALCL found in conjunction with breast implants is less aggressive and is sometimes treatable by simply removing the implant, the capsule, and collected fluid, according to Dr. Maisel.
An FDA review of scientific literature published from January 1997 through May 2010 uncovered 34 unique cases of ALCL in women with breast implants throughout the world. The agency is aware of 60 cases in all, some of them identified through other channels. The FDA does not know how many of the 60 may be duplicates of cases found in the literature. An estimated 5 million to 10 million women worldwide have received breast implants, according to the FDA.
Of the 31 published cases of ALCL, 24 involved silicone implants, and 7 saline implants. The median time from implant to ALCL diagnosis was 8 years. For most of the women, the cancer was diagnosed when they sought treatment for implant-related symptoms, such as pain, lumps, swelling, or asymmetry, after their surgical sites had healed. These symptoms result from persistent peri-implant seroma, hardening of the breast area around the implant, or masses surrounding the implant.
Plastic Surgeons and FDA Will Develop Patient Registry
The vast majority of data suggesting a link between ALCL and breast implants emerged only after the FDA approved silicone gel breast implants made by Allergan and Mentor in 2006, said Dr. Maisel. From 1992 to 2006, such silicone gel implants were available only on an investigational basis.
Dr. Maisel noted that silicone from ruptured and even intact implants has been found in nearby breast tissue. According to one theory about the origins of ALCL, this silicone chronically stimulates immune system T cells and induces lymphoma.
"Please understand that is speculative, and a hypothesis," said Dr. Maisel.
To get to firmer scientific ground, the FDA will collaborate with the American Society of Plastic Surgeons and other groups to develop a registry to collect more information that would better characterize ALCL in women with breast implants. The agency also is asking implant manufacturers to report ALCL cases. And for the sake of patient and clinician education, the FDA will work with these manufacturers to update product labeling materials.
More information about today's announcement is available on the FDA Web site. The FDA's preliminary findings and analyses are available here.
PROGNOSTIC GENE SIGNATURE OF PANCREATIC NEUROENDOCRINE TUMORS
WASHINGTON (Reuters) Jan 20 - Experts in the genetics of cancer said on Thursday they have found out why some people can live for years with the same kind of rare pancreatic cancer that affects Apple CEO Steve Jobs.
They identified new genes that, when mutated in a certain way, appear to cause a relatively less harmful form of pancreatic neuroendocrine tumor.
Patients with these mutations lived twice as long as those whose tumors carried other mutations, the team at Johns Hopkins University in Baltimore report in Science online January 20.
"This is the new molecular view of cancer. The genetic makeup of the cancer will determine what the management (for) this person would be," Dr. Nickolas Papadopoulos, one of the researchers who led the study, said in a telephone interview.
Doctors realize that identifying cancer by the organ where it starts is a very crude tool. Tumors vary in their aggressiveness and makeup, and studies show that particular genetic mutations may be more useful for deciding how to treat a patient and predicting how well he or she will do.
Pancreatic cancer is diagnosed in nearly 37,000 people a year in the United States and kills more than 34,000, according to the American Cancer Society.
But most of these cases are a type of tumor called adenocarcinoma. Neuroendocrine tumors, which account for about 5% of pancreatic cancer cases, are more easily treated and less aggressive. About 40% of these patients are still alive 10 years later.
BAFFLING CASE
Jobs has baffled experts and shareholders. He said in 2004 he had undergone successful surgery for a pancreatic islet cell neuroendocrine tumor but gave no details.
He had a liver transplant in 2009, which could be a treatment for tumor spread, and just announced on Monday he would go on medical leave again but did not say why.
Dr. Papadopoulos and colleagues sequenced all the DNA taken from tumors of 68 patients with pancreatic neuroendocrine tumors.
Patients whose tumors had mutations in three genes called MEN-1, DAXX and ATRX had lived at least 10 years after diagnosis, they report. But more than 60% of patients whose tumors did not have these mutations died within 5 years.
MEN-1 was common, seen in more than 44% of the 68 patients.
"That indicates that mutations in these genes are good prognostic markers for these individuals," Dr. Papadopoulos said.
"What this tells us is that it may be more useful to classify cancers by gene type rather than only by organ or cell type."
The researchers only looked at a subset of pancreatic neuroendocrine tumors -- the silent type that do not cause obvious hormonal symptoms such as weight gain and skin rashes, so their findings do not give much information about the other types.
The researchers found some other potentially good news for patients. Fourteen percent of the tumors carried mutations in a gene family called mTOR.
There are already drugs on the market that affect mTOR genes, including rapamycin, also known as sirolimus, and a similar drug called temsirolimus. Rapamycin is sold under the brand name Rapamune by Pfizer Inc. and is prescribed to suppress the immune system in transplant patients.
Science. Posted January 20, 2011. Abstract
They identified new genes that, when mutated in a certain way, appear to cause a relatively less harmful form of pancreatic neuroendocrine tumor.
Patients with these mutations lived twice as long as those whose tumors carried other mutations, the team at Johns Hopkins University in Baltimore report in Science online January 20.
"This is the new molecular view of cancer. The genetic makeup of the cancer will determine what the management (for) this person would be," Dr. Nickolas Papadopoulos, one of the researchers who led the study, said in a telephone interview.
Doctors realize that identifying cancer by the organ where it starts is a very crude tool. Tumors vary in their aggressiveness and makeup, and studies show that particular genetic mutations may be more useful for deciding how to treat a patient and predicting how well he or she will do.
Pancreatic cancer is diagnosed in nearly 37,000 people a year in the United States and kills more than 34,000, according to the American Cancer Society.
But most of these cases are a type of tumor called adenocarcinoma. Neuroendocrine tumors, which account for about 5% of pancreatic cancer cases, are more easily treated and less aggressive. About 40% of these patients are still alive 10 years later.
BAFFLING CASE
Jobs has baffled experts and shareholders. He said in 2004 he had undergone successful surgery for a pancreatic islet cell neuroendocrine tumor but gave no details.
He had a liver transplant in 2009, which could be a treatment for tumor spread, and just announced on Monday he would go on medical leave again but did not say why.
Dr. Papadopoulos and colleagues sequenced all the DNA taken from tumors of 68 patients with pancreatic neuroendocrine tumors.
Patients whose tumors had mutations in three genes called MEN-1, DAXX and ATRX had lived at least 10 years after diagnosis, they report. But more than 60% of patients whose tumors did not have these mutations died within 5 years.
MEN-1 was common, seen in more than 44% of the 68 patients.
"That indicates that mutations in these genes are good prognostic markers for these individuals," Dr. Papadopoulos said.
"What this tells us is that it may be more useful to classify cancers by gene type rather than only by organ or cell type."
The researchers only looked at a subset of pancreatic neuroendocrine tumors -- the silent type that do not cause obvious hormonal symptoms such as weight gain and skin rashes, so their findings do not give much information about the other types.
The researchers found some other potentially good news for patients. Fourteen percent of the tumors carried mutations in a gene family called mTOR.
There are already drugs on the market that affect mTOR genes, including rapamycin, also known as sirolimus, and a similar drug called temsirolimus. Rapamycin is sold under the brand name Rapamune by Pfizer Inc. and is prescribed to suppress the immune system in transplant patients.
Science. Posted January 20, 2011. Abstract
A POTENTIAL TREATMENT TARGET
LONDON (Reuters) Jan 24 - British scientists have discovered a "rogue gene" that helps cancer spread around the body and say blocking it with the right kind of drugs could stop many types of the disease in their tracks.
Researchers from the University of East Anglia, Norwich, said their findings could lead within a decade to the development of new medicines to halt metastasis.
The culprit gene, called WWP2, is an enzymatic bonding agent found inside cancer cells, the researchers explained in their study, published online in Oncogene on Monday.
It attacks and breaks down transforming growth factor-beta, which normally prevents cancer cells from spreading.
In tests in the laboratory, the UEA team found that by blocking WWP2, levels of the natural inhibitor protein were boosted and the cancer cells remained dormant.
Dr. Surinder Soond, who worked on the study, said it was a "novel and exciting approach to treating cancer and the spread of tumors that holds great potential."
"The challenge now is to identify a potent drug that will get inside cancer cells and destroy the activity of the rogue gene," said Dr. Andrew Chantry, who led the research.
He said this was "a difficult but not impossible task" and one that would be made easier by the better understanding of the biological processes gained in this early research.
Dr. Chantry said in a telephone interview the findings mean drugs could be developed in the next 10 years that could be used to halt the aggressive spread of many forms of cancer, including breast cancer, brain, colon and skin cancer.
If a drug was developed that deactivated WWP2, he said, conventional therapies such as chemotherapy and radiotherapy could be used on primary tumors with no risk of the disease taking hold elsewhere.
He said his team is now working with other scientists to try to design a drug which could interrupt the gene's activity.
Oncogene. Posted online January 24, 2011. Abstract
Researchers from the University of East Anglia, Norwich, said their findings could lead within a decade to the development of new medicines to halt metastasis.
The culprit gene, called WWP2, is an enzymatic bonding agent found inside cancer cells, the researchers explained in their study, published online in Oncogene on Monday.
It attacks and breaks down transforming growth factor-beta, which normally prevents cancer cells from spreading.
In tests in the laboratory, the UEA team found that by blocking WWP2, levels of the natural inhibitor protein were boosted and the cancer cells remained dormant.
Dr. Surinder Soond, who worked on the study, said it was a "novel and exciting approach to treating cancer and the spread of tumors that holds great potential."
"The challenge now is to identify a potent drug that will get inside cancer cells and destroy the activity of the rogue gene," said Dr. Andrew Chantry, who led the research.
He said this was "a difficult but not impossible task" and one that would be made easier by the better understanding of the biological processes gained in this early research.
Dr. Chantry said in a telephone interview the findings mean drugs could be developed in the next 10 years that could be used to halt the aggressive spread of many forms of cancer, including breast cancer, brain, colon and skin cancer.
If a drug was developed that deactivated WWP2, he said, conventional therapies such as chemotherapy and radiotherapy could be used on primary tumors with no risk of the disease taking hold elsewhere.
He said his team is now working with other scientists to try to design a drug which could interrupt the gene's activity.
Oncogene. Posted online January 24, 2011. Abstract
GENE SIGNATURE TO IDENTIFY PRIMARY SITE OF CUP
January 27, 2011 — Real-world data have confirmed the effectiveness of a test designed to help identify the primary tumor site in patients with difficult-to-diagnose cancers. After using the novel gene-expression-profile assay, the determination of the primary diagnosis site and treatment management was altered in more than half of the patients in a new study.
After receiving results from the Tissue of Origin Test (Pathworks Diagnostics), the tumor site diagnosis was changed in 54% of patients (P < .0001). In addition, cancer-specific management changed in 68% of patients, and the recommended chemotherapy regimen was altered in 54% (P < .0001 for both).
"In about 3% to 5% of all new cancer cases, it is difficult to determine the primary tumor site, even after imaging and other pathologic tests," said W. David Henner, MD, PhD, chief medical officer at Pathworks Diagnostics. "Pathologists have been able to give a tentative identification in many of these cases, and that can be useful, but until very recently, there weren't any more definitive ways to identify the primary site."
"Technology now allows the primary site to be more definitively identified," he told Medscape Medical News. "It is becoming more and more important to identify the primary site because therapies have . . . become more targeted."
The study results were presented at the 2011 Gastrointestinal Cancers Symposium recently held in San Francisco, California, which was cosponsored by several organizations, including the American Society of Clinical Oncology.
Difficulty in Diagnosis
The Tissue of Origin Test is a microarray-based gene-expression assay that compares the RNA profile of a formalin-fixed, paraffin-embedded specimen to established RNA profiles of 15 known cancer types representing 58 morphologies. The test has been cleared by the US Food and Drug Administration and measures the gene-expression levels in more than 2000 genes.
Diagnosing a primary tumor site in some cases can involve a large number of various tests, including immunohistochemistry (IHC) panels, serum markers, and imaging studies. However, current histologic and imaging techniques often fail to yield a definitive identification for a significant number of patients. Lead author John Hornberger, MD, CEO and president of Cedar Associates LLC, believes that clinicians are interested in having more reliable methods of determining primary tumor site.
"Going through the literature, we found that there were 147 types of IHCs," he said. "With that many options, there is going to be variability among pathologists — what they order and what they don't order."
However, even with all of the current tests, there are going to be a fair number of patients for whom a diagnosis remains elusive, Dr. Hornberger said in an interview.
Previous studies have demonstrated the reliability and high performance of the test. One validation study, for example, showed that the overall agreement with the reference diagnosis was 89% (95% confidence interval, 85% to 91%), and an average of 12 tissues for each specimen could be ruled out with more than 99% probability. In addition, a multisite reproducibility analysis showed 89.3% concordance between laboratories (J Mol Diagn. 2011;13:48-56).
Real-World Results
In this study, the results changed therapy in more than two thirds of cases, said Dr. Hornberger, and it wasn't just chemotherapy regimens. "Some patients underwent additional surgeries, radiation, and referrals."
He also noted that they asked physicians if they found this test clinically useful, and two thirds of them stated that they did. "This is a test that provides information that these doctors thought was changing their diagnoses and their treatment management decisions."
The objective behind this study was to evaluate the clinical utility of the assay and its real-world effect on diagnosis and patient management. Specifically, Dr. Hornberger and colleagues assessed how the results of the Tissue of Origin Test influenced tumor site diagnosis and subsequent management decisions when used as an adjunct to clinicopathological evaluation.
The retrospective observational registry study comprised 66 physicians who used the test between July and December 2009; completed surveys were available for 111 patients.
Most of the patients had undergone a large number of imaging tests and endoscopic procedures (average, 3.2 tests per patient) prior to the Tissue of Origin Test. Tumor biopsies had also been extensively evaluated with IHC (mean, 9.9 stains per patient).
For this cohort, physicians reported a working diagnosis for 56% of patients prior to using the assay; this rose to 86% after they received the test results. In addition, the number of not-yet-determined diagnoses dropped by 2.5-fold (P = .0001), leaving only 15 patients without a primary site diagnosis.
Outcome Data?
"The use of molecular profiling in cancers of uncertain primary site or origin is potentially very useful," said F. Anthony Greco, MD, but added that outcome data are needed.
"We need more direct data regarding the outcome of patients who receive therapy based on the Tissue of Origin Test or other similar commercially available molecular-profile assays," said Dr. Greco, director of Sarah Cannon Cancer Center in Nashville, Tennessee, who was not involved in the study.
He added that "the real-world setting needs documentation of the accuracy of these tests and improved patient outcomes."
However, another expert pointed out that it might be difficult to conduct an outcomes study.
Conducting an outcomes study would be the ideal scenario, but the practicality of it is unclear, explained Federico A. Monzon, MD, director of Research Pathology and Molecular Diagnostics Cores, The Methodist Hospital Research Institute, Houston, Texas.
"We don't have a homogenous population, which means a lot of confounding variables, such as stage, type of tumor, extent of metastasis, and treatment regimen," he told Medscape Medical News.
There would also be ethical considerations, Dr. Monzon pointed out, if a test that could facilitate diagnosis was withheld from a control group.
I think we are going to be left mainly with retrospective studies, he said, "comparing patients who were treated before the era of molecular identification of tissue of origin and those who were treated afterward."
This study focuses on the clinical impact of this test, he noted. "It shows that physicians are finding the information useful and are making clinical decisions based on it. The test is providing important information to physicians that is otherwise not readily available."
It is important to remember that it has been demonstrated by other researchers that if the tissue of origin can be identified, outcomes can often be improved, he explained. Current treatment guidelines, such as those issued by the National Comprehensive Cancer Network, focus on treating each patient on the basis of the most likely site of the tumor of origin.
"We are pretty much convinced that identifying the tumor of origin will result in determining the most appropriate therapy for each patient," he said. "We should expect that this will lead to better outcomes, although that was not shown in this study."
However, there have been studies that have shown that if the tissue is molecularly identified, outcomes are better. "This has been seen particularly in colon cancer," he said. "It is a rough extrapolation to all the tissue types, but there is literature that supports the idea that better identification of the tissue of origin leads to better outcomes."
The study was funded by Pathworks Diagnostics. Dr. Monzon reports receiving honoraria from Pathworks Diagnostics for speaking engagements related to the Tissue of Origin Test.
2011 Gastrointestinal Cancers Symposium (GICS): Abstract 459. Presented January 22, 2011.
After receiving results from the Tissue of Origin Test (Pathworks Diagnostics), the tumor site diagnosis was changed in 54% of patients (P < .0001). In addition, cancer-specific management changed in 68% of patients, and the recommended chemotherapy regimen was altered in 54% (P < .0001 for both).
"In about 3% to 5% of all new cancer cases, it is difficult to determine the primary tumor site, even after imaging and other pathologic tests," said W. David Henner, MD, PhD, chief medical officer at Pathworks Diagnostics. "Pathologists have been able to give a tentative identification in many of these cases, and that can be useful, but until very recently, there weren't any more definitive ways to identify the primary site."
"Technology now allows the primary site to be more definitively identified," he told Medscape Medical News. "It is becoming more and more important to identify the primary site because therapies have . . . become more targeted."
The study results were presented at the 2011 Gastrointestinal Cancers Symposium recently held in San Francisco, California, which was cosponsored by several organizations, including the American Society of Clinical Oncology.
Difficulty in Diagnosis
The Tissue of Origin Test is a microarray-based gene-expression assay that compares the RNA profile of a formalin-fixed, paraffin-embedded specimen to established RNA profiles of 15 known cancer types representing 58 morphologies. The test has been cleared by the US Food and Drug Administration and measures the gene-expression levels in more than 2000 genes.
Diagnosing a primary tumor site in some cases can involve a large number of various tests, including immunohistochemistry (IHC) panels, serum markers, and imaging studies. However, current histologic and imaging techniques often fail to yield a definitive identification for a significant number of patients. Lead author John Hornberger, MD, CEO and president of Cedar Associates LLC, believes that clinicians are interested in having more reliable methods of determining primary tumor site.
"Going through the literature, we found that there were 147 types of IHCs," he said. "With that many options, there is going to be variability among pathologists — what they order and what they don't order."
However, even with all of the current tests, there are going to be a fair number of patients for whom a diagnosis remains elusive, Dr. Hornberger said in an interview.
Previous studies have demonstrated the reliability and high performance of the test. One validation study, for example, showed that the overall agreement with the reference diagnosis was 89% (95% confidence interval, 85% to 91%), and an average of 12 tissues for each specimen could be ruled out with more than 99% probability. In addition, a multisite reproducibility analysis showed 89.3% concordance between laboratories (J Mol Diagn. 2011;13:48-56).
Real-World Results
In this study, the results changed therapy in more than two thirds of cases, said Dr. Hornberger, and it wasn't just chemotherapy regimens. "Some patients underwent additional surgeries, radiation, and referrals."
He also noted that they asked physicians if they found this test clinically useful, and two thirds of them stated that they did. "This is a test that provides information that these doctors thought was changing their diagnoses and their treatment management decisions."
The objective behind this study was to evaluate the clinical utility of the assay and its real-world effect on diagnosis and patient management. Specifically, Dr. Hornberger and colleagues assessed how the results of the Tissue of Origin Test influenced tumor site diagnosis and subsequent management decisions when used as an adjunct to clinicopathological evaluation.
The retrospective observational registry study comprised 66 physicians who used the test between July and December 2009; completed surveys were available for 111 patients.
Most of the patients had undergone a large number of imaging tests and endoscopic procedures (average, 3.2 tests per patient) prior to the Tissue of Origin Test. Tumor biopsies had also been extensively evaluated with IHC (mean, 9.9 stains per patient).
For this cohort, physicians reported a working diagnosis for 56% of patients prior to using the assay; this rose to 86% after they received the test results. In addition, the number of not-yet-determined diagnoses dropped by 2.5-fold (P = .0001), leaving only 15 patients without a primary site diagnosis.
Outcome Data?
"The use of molecular profiling in cancers of uncertain primary site or origin is potentially very useful," said F. Anthony Greco, MD, but added that outcome data are needed.
"We need more direct data regarding the outcome of patients who receive therapy based on the Tissue of Origin Test or other similar commercially available molecular-profile assays," said Dr. Greco, director of Sarah Cannon Cancer Center in Nashville, Tennessee, who was not involved in the study.
He added that "the real-world setting needs documentation of the accuracy of these tests and improved patient outcomes."
However, another expert pointed out that it might be difficult to conduct an outcomes study.
Conducting an outcomes study would be the ideal scenario, but the practicality of it is unclear, explained Federico A. Monzon, MD, director of Research Pathology and Molecular Diagnostics Cores, The Methodist Hospital Research Institute, Houston, Texas.
"We don't have a homogenous population, which means a lot of confounding variables, such as stage, type of tumor, extent of metastasis, and treatment regimen," he told Medscape Medical News.
There would also be ethical considerations, Dr. Monzon pointed out, if a test that could facilitate diagnosis was withheld from a control group.
I think we are going to be left mainly with retrospective studies, he said, "comparing patients who were treated before the era of molecular identification of tissue of origin and those who were treated afterward."
This study focuses on the clinical impact of this test, he noted. "It shows that physicians are finding the information useful and are making clinical decisions based on it. The test is providing important information to physicians that is otherwise not readily available."
It is important to remember that it has been demonstrated by other researchers that if the tissue of origin can be identified, outcomes can often be improved, he explained. Current treatment guidelines, such as those issued by the National Comprehensive Cancer Network, focus on treating each patient on the basis of the most likely site of the tumor of origin.
"We are pretty much convinced that identifying the tumor of origin will result in determining the most appropriate therapy for each patient," he said. "We should expect that this will lead to better outcomes, although that was not shown in this study."
However, there have been studies that have shown that if the tissue is molecularly identified, outcomes are better. "This has been seen particularly in colon cancer," he said. "It is a rough extrapolation to all the tissue types, but there is literature that supports the idea that better identification of the tissue of origin leads to better outcomes."
The study was funded by Pathworks Diagnostics. Dr. Monzon reports receiving honoraria from Pathworks Diagnostics for speaking engagements related to the Tissue of Origin Test.
2011 Gastrointestinal Cancers Symposium (GICS): Abstract 459. Presented January 22, 2011.
PEMETREXED RETREATMENT FOR MESOTHELIOMA MAY BE HELPFUL
NEW YORK (Reuters Health) Jan 20 - Retreatment with pemetrexed can prolong survival in some patients with malignant pleural mesothelioma (MPM), researchers from Italy report online in Lung Cancer online January 8th.
Pemetrexed (Alimta) is a folate antimetabolite.
"There is a subgroup of patients with advanced MPM who can achieve a prolonged survival advantage from pemetrexed-based chemotherapy," Dr. Giovanni L. Ceresoli from Cliniche Humanitas Gavazenni, Bergamo, told Reuters Health in an email. "In this subgroup of patients (that we can estimate to be about 15-20% of all patients who are candidates for first-line pemetrexed-based chemotherapy), rechallenge with the same regimen is the best available strategy."
Dr. Ceresoli and colleagues investigated the effects of retreatment with pemetrexed-based chemotherapy in 122 MPM patients who progressed after first-line pemetrexed-based chemotherapy. Of these, 68 received a second-line treatment with different regimens, and 36 had best supportive care only.
Of the 31 patients retreated with pemetrexed-based chemotherapy (15 with pemetrexed alone, 16 with a pemetrexed/platinum combination), one experienced a complete response and five achieved a partial response, for an objective response rate of 19%. Nine patients (29%) had stable disease, and the remaining 16 patients (52%) had progressive disease.
Median progression-free survival was 3.8 months, and median overall survival was 10.5 months. One-year estimated progression-free survival was higher for those receiving pemetrexed-based chemotherapy as second-line (13.3%) than for those receiving pemetrexed retreatment later (0%), and 1-year overall survival followed the same pattern (51.6% with second-line retreatment, 16.7% with later retreatment).
Retreatment with pemetrexed was generally well tolerated, and few dose reductions were required.
"Pemetrexed-based chemotherapy is the treatment of choice for patients with malignant pleural mesothelioma (MPM)," Dr. Ceresoli explained. "It should be considered in every patient with this disease who is fit enough to receive chemotherapy. Pemetrexed-based chemotherapy has a role also in multimodality protocols, including surgery and radiotherapy, for the few patients who are diagnosed in an early stage and are candidates for surgical resection. Finally, elderly patients should not be excluded from treatment with pemetrexed, even though they should be carefully evaluated to avoid unnecessary toxicities."
"We have recently concluded a phase II trial of the combination of pemetrexed and carboplatin plus bevacizumab, an anti-angiogenic compound," Dr. Ceresoli said. "The results of this trial, together those of other similar studies, will clarify the role (if any) of anti-angiogenic strategies in MPM. We have also planned a prospective validation of the results of our study on retreatment published on Lung Cancer, and a study on elderly patients including a multi-dimensional geriatric assessment."
Lung Cancer. Posted online January 8, 2011. Abstract
Pemetrexed (Alimta) is a folate antimetabolite.
"There is a subgroup of patients with advanced MPM who can achieve a prolonged survival advantage from pemetrexed-based chemotherapy," Dr. Giovanni L. Ceresoli from Cliniche Humanitas Gavazenni, Bergamo, told Reuters Health in an email. "In this subgroup of patients (that we can estimate to be about 15-20% of all patients who are candidates for first-line pemetrexed-based chemotherapy), rechallenge with the same regimen is the best available strategy."
Dr. Ceresoli and colleagues investigated the effects of retreatment with pemetrexed-based chemotherapy in 122 MPM patients who progressed after first-line pemetrexed-based chemotherapy. Of these, 68 received a second-line treatment with different regimens, and 36 had best supportive care only.
Of the 31 patients retreated with pemetrexed-based chemotherapy (15 with pemetrexed alone, 16 with a pemetrexed/platinum combination), one experienced a complete response and five achieved a partial response, for an objective response rate of 19%. Nine patients (29%) had stable disease, and the remaining 16 patients (52%) had progressive disease.
Median progression-free survival was 3.8 months, and median overall survival was 10.5 months. One-year estimated progression-free survival was higher for those receiving pemetrexed-based chemotherapy as second-line (13.3%) than for those receiving pemetrexed retreatment later (0%), and 1-year overall survival followed the same pattern (51.6% with second-line retreatment, 16.7% with later retreatment).
Retreatment with pemetrexed was generally well tolerated, and few dose reductions were required.
"Pemetrexed-based chemotherapy is the treatment of choice for patients with malignant pleural mesothelioma (MPM)," Dr. Ceresoli explained. "It should be considered in every patient with this disease who is fit enough to receive chemotherapy. Pemetrexed-based chemotherapy has a role also in multimodality protocols, including surgery and radiotherapy, for the few patients who are diagnosed in an early stage and are candidates for surgical resection. Finally, elderly patients should not be excluded from treatment with pemetrexed, even though they should be carefully evaluated to avoid unnecessary toxicities."
"We have recently concluded a phase II trial of the combination of pemetrexed and carboplatin plus bevacizumab, an anti-angiogenic compound," Dr. Ceresoli said. "The results of this trial, together those of other similar studies, will clarify the role (if any) of anti-angiogenic strategies in MPM. We have also planned a prospective validation of the results of our study on retreatment published on Lung Cancer, and a study on elderly patients including a multi-dimensional geriatric assessment."
Lung Cancer. Posted online January 8, 2011. Abstract
CALCIUM CHANNEL BLOCKERS-MAKROLIDE INTERACTION
January 17, 2011 (Toronto, Ontario) — Doctors need to be careful when prescribing macrolide antibiotics to patients on calcium-channel blockers (CCBs) because of an underappreciated drug-drug interaction that can lead to hypotension and shock, new research shows [1]. The findings are important because millions of people take CCBs and many are prescribed antibiotics every year, say Dr Alissa J Wright (University of Toronto, ON) and colleagues in a study published online January 17, 2011 in CMAJ.Although the interaction "is perfectly predictable based upon the pharmacology of the drugs, it has been previously documented in only about five case reports," senior author Dr David Juurlink (University of Toronto, ON) explained to heartwire . He says that this study is the first rigorous attempt to describe the clinical consequences of this interaction: "In a sense, this paper attaches a risk estimate to how dangerous this drug combination is."
The research also shows that there is a safe choice if doctors do need to use a macrolidelike antibiotic, he adds. The study found that macrolides such as erythromycin or clarithromycin increase the risk of hypotension if used in combination with a CCB, but a related antibiotic, azithromycin, does not.
Juurlink observes that "it's not wrong to use a macrolide [in a patient taking a CCB], but it's probably more sensible if you are going to use one to use azithromycin. If, for some reason, you had to use clarithromycin or erythromycin, it might be reasonable just to edge back a little bit on the dose of the CCB."
Biggest Risk With Erythromycin
In their population-based, nested, case-crossover study, Wright and colleagues analyzed the healthcare records of around a million individuals over the age of 65 who were receiving a single CCB between 1994 and 2009. Of these patients, 7100 were admitted to hospital for hypotension or shock, and 176 had received a macrolide antibiotic (36 received erythromycin, 100 received clarithromycin, and 40 received azithromycin) in a seven-day interval immediately before admission to the hospital or in a seven-day control interval one month earlier. For each antibiotic, the researchers estimated the risk of hypotension or shock associated with the use of a CCB.
They found a strong association between erythromycin use and hospital admission for hypotension, with an almost sixfold increased risk of low BP (odds ratio 5.8), and a lower but still significant risk associated with the use of clarithromycin (OR 3.7). In contrast, there was no such link with azithromycin use (OR 1.5).
Juurlink explains that, pharmacologically, macrolide antibiotics inhibit a cytochrome P450 enzyme, which metabolizes all CCBs, so their use can lead to the accumulation of the CCB and potential toxicity. But azithromycin does not inhibit this cytochrome P450 enzyme. The use of combination CCBs and macrolide antibiotics "isn't exactly uncommon, but no one has actually ever attached a measure of how dangerous the combination is, and that's what this study does," he notes.
The findings, says Juurlink, apply to all CCBs, because they are all metabolized by the same pathway, although it may be a bigger problem with some than others, he says, adding that his team could not examine the risks for separate CCBs because of a lack of statistical power.
Nevertheless, the results "have considerable clinical relevance, highlighting the consequences of an underappreciated yet avoidable drug interaction involving medications used by millions of people every year. Clinicians should be aware of the potential interaction between these drugs," he and his colleagues state.
Juurlink adds that although the use of erythromycin is declining, clarithromycin is still used frequently. "But I don't think clarithromycin and azithromycin are that different in price, quite frankly, so the latter represents a good choice if macrolide antibiotic therapy is required."
Juurlink declares no conflicts. Disclosures for the coauthors are listed in the paper
The research also shows that there is a safe choice if doctors do need to use a macrolidelike antibiotic, he adds. The study found that macrolides such as erythromycin or clarithromycin increase the risk of hypotension if used in combination with a CCB, but a related antibiotic, azithromycin, does not.
Juurlink observes that "it's not wrong to use a macrolide [in a patient taking a CCB], but it's probably more sensible if you are going to use one to use azithromycin. If, for some reason, you had to use clarithromycin or erythromycin, it might be reasonable just to edge back a little bit on the dose of the CCB."
Biggest Risk With Erythromycin
In their population-based, nested, case-crossover study, Wright and colleagues analyzed the healthcare records of around a million individuals over the age of 65 who were receiving a single CCB between 1994 and 2009. Of these patients, 7100 were admitted to hospital for hypotension or shock, and 176 had received a macrolide antibiotic (36 received erythromycin, 100 received clarithromycin, and 40 received azithromycin) in a seven-day interval immediately before admission to the hospital or in a seven-day control interval one month earlier. For each antibiotic, the researchers estimated the risk of hypotension or shock associated with the use of a CCB.
They found a strong association between erythromycin use and hospital admission for hypotension, with an almost sixfold increased risk of low BP (odds ratio 5.8), and a lower but still significant risk associated with the use of clarithromycin (OR 3.7). In contrast, there was no such link with azithromycin use (OR 1.5).
Juurlink explains that, pharmacologically, macrolide antibiotics inhibit a cytochrome P450 enzyme, which metabolizes all CCBs, so their use can lead to the accumulation of the CCB and potential toxicity. But azithromycin does not inhibit this cytochrome P450 enzyme. The use of combination CCBs and macrolide antibiotics "isn't exactly uncommon, but no one has actually ever attached a measure of how dangerous the combination is, and that's what this study does," he notes.
The findings, says Juurlink, apply to all CCBs, because they are all metabolized by the same pathway, although it may be a bigger problem with some than others, he says, adding that his team could not examine the risks for separate CCBs because of a lack of statistical power.
Nevertheless, the results "have considerable clinical relevance, highlighting the consequences of an underappreciated yet avoidable drug interaction involving medications used by millions of people every year. Clinicians should be aware of the potential interaction between these drugs," he and his colleagues state.
Juurlink adds that although the use of erythromycin is declining, clarithromycin is still used frequently. "But I don't think clarithromycin and azithromycin are that different in price, quite frankly, so the latter represents a good choice if macrolide antibiotic therapy is required."
Juurlink declares no conflicts. Disclosures for the coauthors are listed in the paper
Πέμπτη 27 Ιανουαρίου 2011
ESTROGEN MODIFIES LUNG CANCER OUTCOME
January 25, 2011— More evidence that estrogen modifies the outcome of lung cancer comes from a huge study of women with breast cancer, about half of whom were taking antiestrogens such as tamoxifen.
Among the women who subsequently developed lung cancer, the use of antiestrogens was associated with a significantly reduced risk for death from lung cancer, compared with the general population.
The finding comes from a study published online January 24 in Cancer.
"Our results support the hypothesis that there is a hormonal influence on lung cancer, which has been suggested by findings such as the presence of estrogen and progesterone receptors in a substantial proportion of lung cancers," senior author Elisabetta Rapiti, MD, from the Geneva Cancer Registry, said in a statement.
"If prospective studies confirm our results and find that antiestrogen agents improve lung cancer outcomes, this could have substantial implications for clinical practice," she added.
Approached by Medscape Medical News for independent comment, Howard West, MD, from the Swedish Cancer Institute in Seattle, Washington, said: "These results are very provocative, especially since they are compatible with the findings from the Women's Health Initiative [WHI], which demonstrated a higher mortality rate from lung cancer in women who received estrogen and progestins, compared with the placebo arm."
"I completely agree that these results warrant prospective testing of antiestrogens," Dr. West continued. "Until we have results from such trials, I would be inclined to discuss these results with women who are taking hormone replacement therapy, as I already do, which may lead to their stopping hormone replacement therapy after considering the balance of benefit vs risk. I wouldn't, however, go so far as to say that these results justify giving antiestrogen therapy as a treatment for lung cancer."
Study Prompted by WHI Findings
The current study was, in fact, prompted by those findings on lung cancer from the WHI study, the authors explain.
When that finding was published, the WHI researchers noted that "treatment with estrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, [but] it increased the number of deaths from lung cancer, in particular deaths from nonsmall-cell lung cancer."
Dr. Rapiti and colleagues, including first author Christine Bouchardy, MD, hypothesized that if it is true that hormone therapy increases the risk for lung cancer death, then the use of antiestrogens should be associated with a decreased risk for lung cancer death.
This was, indeed, what they found.
The team analyzed data from 6655 women with breast cancer from the Geneva Cancer Registry, nearly half of whom (46%) had taken antiestrogens.
Over a median follow-up of 7.3 years, the researchers found that 40 of these women developed lung cancer. The incidence of lung cancer was similar in the group taking and the group not taking antiestrogens (P = .39).
The team then compared outcomes for this small group of women with population results from standardized mortality ratios.
They found that the incidence of lung cancer was similar among women who had and had not taken antiestrogens and the general population.
However, the risk for death from lung cancer was significantly lower in women who had taken the drugs than in those who had not, and than in the general population. Specifically, there were 87% fewer cases of death from lung cancer in the antiestrogen group than in the general population.
Lung cancer mortality rates were 9.2 per 100,000 for women taking antiestrogens and 45.0 per 100,000 for women not taking these drugs (P = .026).
The finding is unlikely to be due to differences in smoking, the authors note, because patterns of tobacco exposure were similar in the 2 groups. However, they also note that they obtained this information for only about half of the entire cohort.
New Evidence for the Role of Estrogen
The team concludes: "In analyses comparing tumor registry to population results from standardized mortality ratios, we found that antiestrogen treatment for breast cancer was associated with a reduced risk of death from lung cancer, providing new evidence on the role of estrogen in lung cancer progression."
"From a biological perspective, the observation that estrogen intake is associated with increased lung cancer mortality, and that antiestrogen treatment is associated with a decreased lung cancer mortality, as demonstrated in this study, strongly suggests that estrogens are involved in lung cancer progression," they add.
When approached for independent comment by Medscape Medical News, Dr. West noted that the finding showed a significant reduction in the rate of lung cancer mortality among women who were taking antiestrogens, compared with age-adjusted mortality rates in the general population.
"In fact, the rate was only 13% of the calculated result that would be expected, a statistically significant difference," he said.
"However, these results are predicated on a very small number of patients, compared with a prediction based on a model," Dr. West pointed out.
The study authors and Dr. West have disclosed no relevant financial relationships.
Cancer. Published online January 24, 2011.
Among the women who subsequently developed lung cancer, the use of antiestrogens was associated with a significantly reduced risk for death from lung cancer, compared with the general population.
The finding comes from a study published online January 24 in Cancer.
"Our results support the hypothesis that there is a hormonal influence on lung cancer, which has been suggested by findings such as the presence of estrogen and progesterone receptors in a substantial proportion of lung cancers," senior author Elisabetta Rapiti, MD, from the Geneva Cancer Registry, said in a statement.
"If prospective studies confirm our results and find that antiestrogen agents improve lung cancer outcomes, this could have substantial implications for clinical practice," she added.
Approached by Medscape Medical News for independent comment, Howard West, MD, from the Swedish Cancer Institute in Seattle, Washington, said: "These results are very provocative, especially since they are compatible with the findings from the Women's Health Initiative [WHI], which demonstrated a higher mortality rate from lung cancer in women who received estrogen and progestins, compared with the placebo arm."
"I completely agree that these results warrant prospective testing of antiestrogens," Dr. West continued. "Until we have results from such trials, I would be inclined to discuss these results with women who are taking hormone replacement therapy, as I already do, which may lead to their stopping hormone replacement therapy after considering the balance of benefit vs risk. I wouldn't, however, go so far as to say that these results justify giving antiestrogen therapy as a treatment for lung cancer."
Study Prompted by WHI Findings
The current study was, in fact, prompted by those findings on lung cancer from the WHI study, the authors explain.
When that finding was published, the WHI researchers noted that "treatment with estrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, [but] it increased the number of deaths from lung cancer, in particular deaths from nonsmall-cell lung cancer."
Dr. Rapiti and colleagues, including first author Christine Bouchardy, MD, hypothesized that if it is true that hormone therapy increases the risk for lung cancer death, then the use of antiestrogens should be associated with a decreased risk for lung cancer death.
This was, indeed, what they found.
The team analyzed data from 6655 women with breast cancer from the Geneva Cancer Registry, nearly half of whom (46%) had taken antiestrogens.
Over a median follow-up of 7.3 years, the researchers found that 40 of these women developed lung cancer. The incidence of lung cancer was similar in the group taking and the group not taking antiestrogens (P = .39).
The team then compared outcomes for this small group of women with population results from standardized mortality ratios.
They found that the incidence of lung cancer was similar among women who had and had not taken antiestrogens and the general population.
However, the risk for death from lung cancer was significantly lower in women who had taken the drugs than in those who had not, and than in the general population. Specifically, there were 87% fewer cases of death from lung cancer in the antiestrogen group than in the general population.
Lung cancer mortality rates were 9.2 per 100,000 for women taking antiestrogens and 45.0 per 100,000 for women not taking these drugs (P = .026).
The finding is unlikely to be due to differences in smoking, the authors note, because patterns of tobacco exposure were similar in the 2 groups. However, they also note that they obtained this information for only about half of the entire cohort.
New Evidence for the Role of Estrogen
The team concludes: "In analyses comparing tumor registry to population results from standardized mortality ratios, we found that antiestrogen treatment for breast cancer was associated with a reduced risk of death from lung cancer, providing new evidence on the role of estrogen in lung cancer progression."
"From a biological perspective, the observation that estrogen intake is associated with increased lung cancer mortality, and that antiestrogen treatment is associated with a decreased lung cancer mortality, as demonstrated in this study, strongly suggests that estrogens are involved in lung cancer progression," they add.
When approached for independent comment by Medscape Medical News, Dr. West noted that the finding showed a significant reduction in the rate of lung cancer mortality among women who were taking antiestrogens, compared with age-adjusted mortality rates in the general population.
"In fact, the rate was only 13% of the calculated result that would be expected, a statistically significant difference," he said.
"However, these results are predicated on a very small number of patients, compared with a prediction based on a model," Dr. West pointed out.
The study authors and Dr. West have disclosed no relevant financial relationships.
Cancer. Published online January 24, 2011.
A POTENTIAL ADAVANTAGE OF BISPHOSPHONATES OVER DENOSUMAB
January 27, 2011 (San Francisco, California) — Taking bisphosphonates for osteoporosis for more than a year is associated with a reduced risk for colorectal cancer, according to a new study from the same Israeli group that reported a reduced risk for breast cancer.
Both sets of results come from an analysis of postmenopausal women who were taking mainly oral bisphosphonates, such as alendronate, for osteoporosis, and were reported by Gad Rennert, MD, PhD, and colleagues from the Clalit Health Services National Cancer Control Center in Haifa, Israel, at the 2011 Gastrointestinal Cancers Symposium, which is cosponsored by the American Society of Clinical Oncology and other societies..
The previous study, showing a reduction in breast cancer risk, was published last year; a similar finding has been reported by 2 independent groups from 2 different populations of postmenopausal women taking bisphosphonates.
These findings stirred great interest in the potential anticancer effects of bisphosphonates, but some experts raised concerns about the breast cancer data. They pointed out that postmenopausal women who were taking bisphosphonates for osteoporosis were likely to have low levels of estrogen, which led to the osteoporosis, and lower levels of estrogen are known to reduce the risk for breast cancer.
Dr. Rennert told Medscape Medical News that his team specifically set out to investigate the effect of bisphosphonates on tumor sites other than the breast to address these concerns. Demonstration of a protective effect at a site other than the breast "would help clear the question" of whether the effect seen with breast cancer is a drug effect or simply a reflection of low estrogen leading to osteoporosis and requiring bisphosphonates, but also reducing the risk for breast cancer in itself.
"Our new data about a similar effect in the colon suggest that it is the drug itself," Dr. Rennert reported.
Further studies are ongoing. "We are working with more tumor sites and seeing a similar effect to what we are seeing with statins," he said. "It definitely looks like a class effect, with a mechanism that possibly involves the mevalonate pathway, which is also involved in the metabolism of statins."
New Data on Colorectal Cancer
"The use of oral bisphosphonates for more than 1 year was associated with a 60% relative reduction in the risk of colorectal cancer, similar to the recently reported association of this drug class with reduction in breast cancer risk," Dr. Rennert and colleagues told the meeting.
The results come from a population-based case–control study of colorectal cancer — the Molecular Epidemiology of Colorectal Cancer — conducted in northern Israel. The data on bisphosphonate use were collected in a subset of 933 pairs of postmenopausal female cases and controls from the Clalit Health Services, using computerized pharmacy controls.
The use of bisphosphonates for more than 1 year prior to the diagnosis of colorectal cancer, but not for less than a year, was associated with a significantly reduced risk for colorectal cancer (odds ratio, 0.50; 95% confidence interval, 0.35 to 0.71).
This association remained statistically significant after adjustment for vegetable consumption, sports activity, family history of colorectal cancer, body mass index, and use of low-dose aspirin, statins, vitamin D, and hormone replacement therapy, the researchers note. Concomitant use of bisphosphonates and statins did not reduce the risk any further.
Intense Interest in Bisphosphonates
There is an intense interest in the potential anticancer effects of bisphosphonates, prompted by several intriguing findings in recent years. In addition to the data suggesting a protective effect against cancer discussed above, there have been several studies suggesting that these drugs have anticancer effects in patients who already have cancer.
The most positive of these results come from an Austrian study, which showed that breast cancer recurrence and death were reduced by a third in women taking bisphosphonates.
However, the most recent study on this was negative overall. The AZURE study found no effect from the potent bisphosphonate zolendronic acid (Zometa, Novartis) on the recurrence of breast cancer or on overall survival. However, a subset analysis showed a significant effect in postmenopausal but not premenopausal women; breast cancer recurrence and deaths were reduced by about a third.
Results from the AZURE study, presented in December 2010 at the San Antonio Breast Cancer Symposium, were described as unexpected and puzzling, and sparked much discussion at the meeting, as reported by Medscape Medical News at the time. This story will continue, because several more studies addressing this issue are underway.
Dr. Rennert and colleagues have disclosed no relevant financial relationships.
2011 Gastrointestinal Cancers Symposium (GICS): Abstract 371. Presented January 22, 2011.
Both sets of results come from an analysis of postmenopausal women who were taking mainly oral bisphosphonates, such as alendronate, for osteoporosis, and were reported by Gad Rennert, MD, PhD, and colleagues from the Clalit Health Services National Cancer Control Center in Haifa, Israel, at the 2011 Gastrointestinal Cancers Symposium, which is cosponsored by the American Society of Clinical Oncology and other societies..
The previous study, showing a reduction in breast cancer risk, was published last year; a similar finding has been reported by 2 independent groups from 2 different populations of postmenopausal women taking bisphosphonates.
These findings stirred great interest in the potential anticancer effects of bisphosphonates, but some experts raised concerns about the breast cancer data. They pointed out that postmenopausal women who were taking bisphosphonates for osteoporosis were likely to have low levels of estrogen, which led to the osteoporosis, and lower levels of estrogen are known to reduce the risk for breast cancer.
Dr. Rennert told Medscape Medical News that his team specifically set out to investigate the effect of bisphosphonates on tumor sites other than the breast to address these concerns. Demonstration of a protective effect at a site other than the breast "would help clear the question" of whether the effect seen with breast cancer is a drug effect or simply a reflection of low estrogen leading to osteoporosis and requiring bisphosphonates, but also reducing the risk for breast cancer in itself.
"Our new data about a similar effect in the colon suggest that it is the drug itself," Dr. Rennert reported.
Further studies are ongoing. "We are working with more tumor sites and seeing a similar effect to what we are seeing with statins," he said. "It definitely looks like a class effect, with a mechanism that possibly involves the mevalonate pathway, which is also involved in the metabolism of statins."
New Data on Colorectal Cancer
"The use of oral bisphosphonates for more than 1 year was associated with a 60% relative reduction in the risk of colorectal cancer, similar to the recently reported association of this drug class with reduction in breast cancer risk," Dr. Rennert and colleagues told the meeting.
The results come from a population-based case–control study of colorectal cancer — the Molecular Epidemiology of Colorectal Cancer — conducted in northern Israel. The data on bisphosphonate use were collected in a subset of 933 pairs of postmenopausal female cases and controls from the Clalit Health Services, using computerized pharmacy controls.
The use of bisphosphonates for more than 1 year prior to the diagnosis of colorectal cancer, but not for less than a year, was associated with a significantly reduced risk for colorectal cancer (odds ratio, 0.50; 95% confidence interval, 0.35 to 0.71).
This association remained statistically significant after adjustment for vegetable consumption, sports activity, family history of colorectal cancer, body mass index, and use of low-dose aspirin, statins, vitamin D, and hormone replacement therapy, the researchers note. Concomitant use of bisphosphonates and statins did not reduce the risk any further.
Intense Interest in Bisphosphonates
There is an intense interest in the potential anticancer effects of bisphosphonates, prompted by several intriguing findings in recent years. In addition to the data suggesting a protective effect against cancer discussed above, there have been several studies suggesting that these drugs have anticancer effects in patients who already have cancer.
The most positive of these results come from an Austrian study, which showed that breast cancer recurrence and death were reduced by a third in women taking bisphosphonates.
However, the most recent study on this was negative overall. The AZURE study found no effect from the potent bisphosphonate zolendronic acid (Zometa, Novartis) on the recurrence of breast cancer or on overall survival. However, a subset analysis showed a significant effect in postmenopausal but not premenopausal women; breast cancer recurrence and deaths were reduced by about a third.
Results from the AZURE study, presented in December 2010 at the San Antonio Breast Cancer Symposium, were described as unexpected and puzzling, and sparked much discussion at the meeting, as reported by Medscape Medical News at the time. This story will continue, because several more studies addressing this issue are underway.
Dr. Rennert and colleagues have disclosed no relevant financial relationships.
2011 Gastrointestinal Cancers Symposium (GICS): Abstract 371. Presented January 22, 2011.
ERIBULIN AND CABAZITAXEL WILL SOON BE APPROVED BY EMEA
European Medicines Agency adopts positive opinions for eribulin and cabazitaxel
21.01.11
Category: Scientific News
Meeting highlights from the Committee for Medicinal Products for Human Use
The European Medicines Agency Committee for Medicinal Products for Human Use at its January 2011 meeting adopted positive opinions recommending the granting of marketing authorizations for the following new medicines:
- Halaven (eribulin), from Eisai Europe Ltd, intended for the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least two chemotherapeutic regimens for advanced disease. The review for Halaven began on 26 May 2010 with an active review time of 180 days.
- Jevtana (cabazitaxel), from Sanofi-aventis, intended in combination with prednisone or prednisolone for the treatment of patients with hormone refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. The review for Jevtana began on 26 May 2010 with an active review time of 208 days.
Δευτέρα 24 Ιανουαρίου 2011
A THEORETICAL DANGER OF DENOSUMAB USE
Interaction between the skeletal and immune systems in cancer: mechanisms and clinical implications.
Department of Clinical Therapeutics, Alexandra General Hospital, University of Athens School of Medicine, 80 Vas. Sofias Avenue, 11528, Athens, Greece, eterpos@med.uoa.gr.
Abstract
The skeletal and immune systems have a complex relationship. Both systems are intimately coupled, with osteoclastogenesis and hematopoiesis occurring in the bone marrow. Bone and immune cells also share common hematopoietic precursors. Furthermore, the skeletal and immune systems share various cytokines, receptors, and transcription factors that regulate signal transduction pathways involved in osteoclastogenesis and immune system activation, including the receptor activator of nuclear factor-κΒ ligand/receptor activator of nuclear factor-κΒ/osteoprotegerin (RANKL-RANK-OPG) pathway. Cancer cells can disrupt both the skeletal and immune systems. Interaction between cancer and bone cells results in a vicious cycle of bone destruction and cancer growth. Bone remodeling generates a growth-factor-rich environment that attracts cancer cells and promotes their proliferation. In turn, cancer cells stimulate osteoclast formation and activity, resulting in additional bone resorption that further stimulates cancer cell growth. Currently available bone-targeted therapies may also modulate the immune system. Bisphosphonates such as zoledronic acid exert stimulating effects on the immune system, resulting in possible anticancer activity against malignant cells. Denosumab, an anti-RANKL monoclonal antibody with proven antiosteoclast activity, may suppress immune responses. This may result in the reported association with an increased risk of neoplasms, as well as serious skin and other infections as reported in some studies, mainly in the postmenopausal setting. When assessing bone-targeted therapies, it is important to consider the shared signaling pathways between bone and the immune system, as well as the clinical risk:benefit ratio.ISOLATED LIMB PERFUSION FOR LIMB SARCOMA
Cancer. 2011 Jan 18. doi: 10.1002/cncr.25850. [Epub ahead of print]
Isolated limb perfusion for unresectable extremity sarcoma: Results of 2 single-institution phase 2 trials.
The University of Texas MD Anderson Cancer Center, Houston, Texas.
Abstract
BACKGROUND: Controversy has surrounded the role of isolated limb perfusion (ILP) for unresectable extremity sarcomas. However, there remains a group of sarcoma patients for whom amputation is the only potential treatment. Because systemic therapies are limited, the authors evaluated ILP in an effort to provide a limb-salvage option.METHODS: Since 1995, patients with unresectable extremity sarcomas were entered in 2 prospective trials using ILP. Study 1 used tumor necrosis factor (TNF) and melphalan in the perfusion circuit at hyperthermic temperatures (39-41°C). Study 2 used doxorubicin at normothermic temperatures. All ILPs were performed using the standard, previously described technique.
RESULTS: Seventeen patients were entered into study 1; there were 10 (58%) partial responses, 1 (6%) near complete response (CR), 1 (6%) CR, and 5 (30%) no response/minor response. Fourteen patients died of their disease, with a median follow-up of 17 months. Seven (41%) patients maintained their limb intact until the time of death. Twelve patients were entered into study 2; there were no partial or CRs and 2 (20%) minor responses. With a median follow-up of 35 months, there are 3 patients alive (2 with their extremity intact and 1 with an amputation). Six patients developed myonecrosis with creatine phosphokinase levels up to 54,000 U/dL.
CONCLUSIONS: Although doxorubicin is active systemically, TNF and melphalan appear to have greater activity and less toxicity during ILP. Future clinical trials are needed to clearly identify the role for ILP in patients with unresectable extremity sarcomas. Cancer 2011. © 2011 American Cancer Society.
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