December 2, 2010 (Montreal, Quebec) — An investigational glioblastoma treatment that delivers alternating electric fields through scalp electrodes might also have application in other cancers, particularly nonsmall-cell lung cancer (NSCLC), according to an Israeli presenter here at the Society for Neuro-Oncology 15th Annual Scientific Meeting.
Clinical trials of the device, known as NovoTTF, in glioblastoma and NSCLC have shown that it is either comparable or superior to chemotherapy in terms of overall survival, but much less toxic.
The device is also notable for the responses it elicits from professionals, according to Zvi Ram, MD, professor and chair of neurosurgery at Tel-Aviv Sourasky Medical Center in Israel.
To date, reports about the electrical device have elicited both antagonistic and enthusiastic reaction from oncologists, with "neither the enthusiasts nor the antagonists having significant bases for either kind of acute reaction," Dr. Ram told Medscape Medical News after his presentation.
Dr. Ram did not dwell on the antagonism. "It's human nature," he said about such audience reactions.
Traditional approaches to glioblastoma have a lot of room for improvement, explained Dr. Ram. "We're used to hurting the brain all the time. I operate on these patients; I take chunks of the brain out. Oncologists give toxins and irradiate the brain. That's what we're used to. Now somebody is thinking far outside the box with a new modality that's noninvasive."
Another neuro-oncology expert confirmed that NovoTTF is effective.
"There is little doubt that this device has an antitumor effect and the toxicity profile is nonexistent. The next few years will tell us where NovoTTF will fit into the treatment of glioblastoma and a variety of other difficult tumors," said Philip H. Gutin, MD, chair of the Department of Neurosurgery and Fred Lebow Chair in Neuro-Oncology at Memorial Sloan-Kettering Cancer Center in New York City.
The NovoTTF device delivers low-amplitude "tumor treatment fields," ranging from 100 to 300 kHz, which have been shown in vitro to slow and reverse tumor cell proliferation by inhibiting mitosis, according to a press release from NovoCure, the manufacturer of the device and sponsor of the trial.
The press release states that "alternating electric fields within the tumor exert physical forces on electrically charged cellular components, preventing the normal mitotic process and causing cell death prior to division."
The portable device weighs about 2.75 kg, is connected to a battery pack, and is designed to be worn almost constantly, with a target of at least 20 hours each day.
Some Glioblastoma Results Not Seen "Anywhere"
In a randomized phase 3 clinical trial presented earlier this year at the American Society of Clinical Oncology annual meeting, an intent-to-treat analysis comparing NovoTTF with the best available chemotherapy found no statistical difference in 1-year overall survival in 237 recurrent glioblastoma patients between treatments.
However, a per protocol analysis (which included only patients who wore the device for 70% of the recommended time during the first month) showed a statistically significant benefit with NovoTTF in 1-year survival, compared with chemotherapy (29.5% vs 19.1%; hazard ratio, 0.64; P = .01).
Now, a post hoc analysis of several subgroups in the study has found some additional advantages, reported Dr. Ram.
One subgroup of 110 "good prognosis" patients (younger than 60 years and with a Karnofsky Performance Scale score of more than 80) showed a "more robust" survival benefit than was seen in the overall intent-to-treat analysis, he said.
In this subgroup, patients treated with NovoTTF had a median survival of 9.2 months, compared with 6.6 months for those treated with chemotherapy (P < .01). This compares to 6.6 months and 6.0 months in the overall intent-to-treat group, he explained.
Moreover, 1-year overall survival in this subgroup was 35.2% with NovoTTF group, compared with 20.8% with chemotherapy (P < .01), which is an improvement over the nonsignificant difference between the 2 groups (23.6% vs 20.7%) in the larger analysis.
Another subgroup analysis looked at patients who had previously failed treatment with bevacizumab (roughly 20% of the entire cohort). Both an intent-to-treat analysis and a per protocol analysis showed significant overall survival advantages for NovoTTF, said Dr. Ram.
Among 44 patients in the intent-to-treat group, median overall survival with NovoTTF was 4 months and with chemotherapy was 3.1 months (hazard ratio, 0.43; P < .02). Among 29 patients in the per protocol analysis, median overall survival was 6.3 months with NovoTTF and 3.3 months with chemotherapy (hazard ratio, 0.21; P = .02).
"You don't see this anywhere," he told Medscape Medical News. "There's no drug in the world that could produce such a response in patients who had already failed [bevacizumab]."
The investigators also analyzed a surgery-naive group. "You know these are going to be poor responders, almost identical to bevacizumab failure," said Dr. Ram.
In this group of 38 patients, an intent-to-treat analysis showed that overall survival was 9.8 months with NovoTTF and 5.5 months with chemotherapy.
Finally, an analysis using the Quality of Life Symptom Scale, measured prospectively during the study, showed significant differences between the 2 groups, with NovoTTF-treated patients having more favorable constipation scores (–34 vs –35) and diarrhea scores (+77 vs +50) than chemotherapy-treated patients.
Nausea and vomiting scores were –15 for the NovoTTF group and –61 for the chemotherapy group, and pain scores were –1 and +63, respectively.
A quality-of-life analysis using the EORTC QLQ-C30 showed scores of in favor of NovoTTF for cognitive functioning (+14 vs –7) and for emotional functioning (+7 vs +1).
"We do this to all our patients; we intoxicate them," said Dr. Ram about the adverse effects of chemotherapy. "Even if NovoTTF did not extend survival, if it was equivalent to chemotherapy [for survival], then it may still improve quality of life."
Dr. Ram did not know the median length of time that the NovoTTF cohort wore the device, but an earlier phase 2 study followed some of them for 59 months. "Seventy percent are still alive — that's unheard of," he remarked.
"There were concerns that patients might have more headaches or seizures, but there were none," he said.
Dr. Ram reported that the rate of adverse events related to the central nervous system (CNS) was similar for NovoTTF and chemotherapy (66% vs 67%), as were serious CNS adverse events (21% vs 22%), seizures (15% vs 12%), and headaches (18% vs 13%).
"There are no real concerns that this does anything hazardous to the brain," he said.
NSCLC Data
Dr. Ram also presented evidence suggesting that NovoTTF therapy has benefits in other forms of cancer.
A study reported by his colleagues earlier this year at the European Society for Medical Oncology Congress showed that NovoTTF therapy combined with chemotherapy resulted in significant prolongation of survival in patients with NSCLC, compared with historic controls, he said.
"If this kind of therapy acts against brain cancer cells, it should act also against other tumor types," he reasoned.
In the study, which looked at 42 NSLC patients, NovoTTF was delivered with newly designed electrodes placed on the chest and neck of patients with locally advanced metastatic stage IIIb and IV disease, he explained.
Overall survival was better with the combination of NovoTTF plus pemetrexed than with pemetrexed alone (13.8 vs 8.3 months), as was the rate of 1-year survival rate (57% vs 30%).
"We're talking about something that appears to be acting against cancer cells, regardless of origin," said Dr. Ram. "Action in the lung seems similar to what has been seen in [glioblastoma multiforme] — a slow resolution of malignant pleural effusion and masses within the chest over time."
"It's very interesting and exciting, even if we do not yet have enough definitive data," said Alba B. Brandes, MD, moderator of the session and chair of medical oncology at Azienda USL, a group of 9 hospitals in and around Bologna, Italy.
The study investigators have been criticized for repackaging their nonsignificant intent-to-treat results into per protocol results that show significance, she said.
"An intention-to-treat population and per protocol population are 2 different things and, from a statistical point of view, it is sometimes difficult for the oncologic community to accept."
However, she said, the per protocol observations should not be dismissed, because when looked at this way, the results become "not a little significant, but highly significant," she said.
"I was really surprised to see what happened in the lung cancer. I am a medical oncologist and I have never seen that complete a response. It's surprising. We have to wonder if all that we know about the treatment of tumors is correct."
Dr. Ram acknowledged that the per protocol analysis of the findings is unconventional, but that "there is no precedent for this kind of therapy. I think we may need to redesign the way we assess results in the future. We cannot use the same guidelines and definitions that we were traditionally using."
Dr. Ram is a consultant for NovoCure, which sponsored the trial and manufactures the device. Dr. Gutin has disclosed no relevant financial relationships.
Society for Neuro-Oncology (SNO) 15th Annual Scientific Meeting: Abstract NO-55. Presented November 19, 2010.
Σάββατο, 4 Δεκεμβρίου 2010
Παρασκευή, 3 Δεκεμβρίου 2010
R-EVOLUTION
Published Online 2 December 2010
< Science Express Index
Science DOI: 10.1126/science.1197258
* Research Article
A Bacterium That Can Grow by Using Arsenic Instead of Phosphorus
1. Felisa Wolfe-Simon1,2,*,
2. Jodi Switzer Blum2,
3. Thomas R. Kulp2,
4. Gwyneth W. Gordon3,
5. Shelley E. Hoeft2,
6. Jennifer Pett-Ridge4,
7. John F. Stolz5,
8. Samuel M. Webb6,
9. Peter K. Weber4,
10. Paul C. W. Davies1,7,
11. Ariel D. Anbar1,3,8 and
12. Ronald S. Oremland2
+ Author Affiliations
1.
1NASA Astrobiology Institute, USA.
2.
2U.S. Geological Survey, Menlo Park, CA, USA.
3.
3School of Earth and Space Exploration, Arizona State University, Tempe, AZ, USA.
4.
4Lawrence Livermore National Laboratory, Livermore, CA, USA.
5.
5Department of Biological Sciences, Duquesne University, Pittsburgh, PA, USA.
6.
6Stanford Synchrotron Radiation Lightsource, Menlo Park, CA, USA.
7.
7BEYOND: Center for Fundamental Concepts in Science, Arizona State University, Tempe, AZ, USA.
8.
8Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ, USA.
1. *To whom correspondence should be addressed. E-mail: felisawolfesimon@gmail.com
Abstract
Life is mostly composed of the elements carbon, hydrogen, nitrogen, oxygen, sulfur, and phosphorus. Although these six elements make up nucleic acids, proteins, and lipids and thus the bulk of living matter, it is theoretically possible that some other elements in the periodic table could serve the same functions. Here, we describe a bacterium, strain GFAJ-1 of the Halomonadaceae, isolated from Mono Lake, California, which substitutes arsenic for phosphorus to sustain its growth. Our data show evidence for arsenate in macromolecules that normally contain phosphate, most notably nucleic acids and proteins. Exchange of one of the major bioelements may have profound evolutionary and geochemical significance.
http://en.wikipedia.org/wiki/GFAJ-1
< Science Express Index
Science DOI: 10.1126/science.1197258
* Research Article
A Bacterium That Can Grow by Using Arsenic Instead of Phosphorus
1. Felisa Wolfe-Simon1,2,*,
2. Jodi Switzer Blum2,
3. Thomas R. Kulp2,
4. Gwyneth W. Gordon3,
5. Shelley E. Hoeft2,
6. Jennifer Pett-Ridge4,
7. John F. Stolz5,
8. Samuel M. Webb6,
9. Peter K. Weber4,
10. Paul C. W. Davies1,7,
11. Ariel D. Anbar1,3,8 and
12. Ronald S. Oremland2
+ Author Affiliations
1.
1NASA Astrobiology Institute, USA.
2.
2U.S. Geological Survey, Menlo Park, CA, USA.
3.
3School of Earth and Space Exploration, Arizona State University, Tempe, AZ, USA.
4.
4Lawrence Livermore National Laboratory, Livermore, CA, USA.
5.
5Department of Biological Sciences, Duquesne University, Pittsburgh, PA, USA.
6.
6Stanford Synchrotron Radiation Lightsource, Menlo Park, CA, USA.
7.
7BEYOND: Center for Fundamental Concepts in Science, Arizona State University, Tempe, AZ, USA.
8.
8Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ, USA.
1. *To whom correspondence should be addressed. E-mail: felisawolfesimon@gmail.com
Abstract
Life is mostly composed of the elements carbon, hydrogen, nitrogen, oxygen, sulfur, and phosphorus. Although these six elements make up nucleic acids, proteins, and lipids and thus the bulk of living matter, it is theoretically possible that some other elements in the periodic table could serve the same functions. Here, we describe a bacterium, strain GFAJ-1 of the Halomonadaceae, isolated from Mono Lake, California, which substitutes arsenic for phosphorus to sustain its growth. Our data show evidence for arsenate in macromolecules that normally contain phosphate, most notably nucleic acids and proteins. Exchange of one of the major bioelements may have profound evolutionary and geochemical significance.
http://en.wikipedia.org/wiki/GFAJ-1
FDA: CARBOPLATIN DOSING USING CALVERT FORMULA SHOULD NOT EXCEED 900 mg FOR AUC-6 AND 750 mg FOR AUC-5
Carboplatin dosing
This communication is to inform members of the oncology community of recent changes in the measurement of serum creatinine which may have an impact on carboplatin dosing. Based on preliminary communications with the National Cancer Institute/Cancer Therapy Evaluation Program, a potential safety issue with carboplatin dosing has been identified. By the end of 2010, all clinical laboratories in the US will use the new standardized Isotope Dilution Mass Spectrometry (IDMS) method to measure serum creatinine. The IDMS method appears to underestimate serum creatinine values compared to older methods when the serum creatinine values are relatively low (e.g., ~0.7 mg/dL). Measurement of serum creatinine by the IDMS-method could result in an overestimation of the Glomerular Filtration Rate (GFR) in some patients with normal renal function. If the total carboplatin dose is calculated based on IDMS-measured serum creatinine using the Calvert formula, carboplatin dosing couldbe higher than desired and could result in increased drug-related toxicity.
The current label for carboplatin provides safe dosing instructions that are based on actual GFR measurements. Provided that actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the instructions described in the label.
(http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=13328).
If a patient’s GFR is estimated based on serum creatinine measurements by the IDMS method, FDA recommends that physicians consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing. Based on the Calvert formula described in the carboplatin label, the maximum doses can be calculated as:
Total Carboplatin Dose (mg) = (target AUC) x (GFR +25) [Calvert formula]
Maximum Carboplatin Dose (mg) = target AUC (mg·min/mL) x (150 mL/min)
The maximum dose is based on a GFR estimate that is capped at 125 mL/min for patients with normal renal function. No higher estimated GFR values should be used.
For a target AUC = 6, the maximum dose is 6 x 150 = 900 mg
For a target AUC = 5, the maximum dose is 5 x 150 = 750 mg
For a target AUC = 4, the maximum dose is 4 x 150 = 600 mg
Principal investigators of ongoing clinical trials should assess whether carboplatin dosing in those trials should be adjusted according to the above information.
This communication is to inform members of the oncology community of recent changes in the measurement of serum creatinine which may have an impact on carboplatin dosing. Based on preliminary communications with the National Cancer Institute/Cancer Therapy Evaluation Program, a potential safety issue with carboplatin dosing has been identified. By the end of 2010, all clinical laboratories in the US will use the new standardized Isotope Dilution Mass Spectrometry (IDMS) method to measure serum creatinine. The IDMS method appears to underestimate serum creatinine values compared to older methods when the serum creatinine values are relatively low (e.g., ~0.7 mg/dL). Measurement of serum creatinine by the IDMS-method could result in an overestimation of the Glomerular Filtration Rate (GFR) in some patients with normal renal function. If the total carboplatin dose is calculated based on IDMS-measured serum creatinine using the Calvert formula, carboplatin dosing couldbe higher than desired and could result in increased drug-related toxicity.
The current label for carboplatin provides safe dosing instructions that are based on actual GFR measurements. Provided that actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the instructions described in the label.
(http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=13328).
If a patient’s GFR is estimated based on serum creatinine measurements by the IDMS method, FDA recommends that physicians consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing. Based on the Calvert formula described in the carboplatin label, the maximum doses can be calculated as:
Total Carboplatin Dose (mg) = (target AUC) x (GFR +25) [Calvert formula]
Maximum Carboplatin Dose (mg) = target AUC (mg·min/mL) x (150 mL/min)
The maximum dose is based on a GFR estimate that is capped at 125 mL/min for patients with normal renal function. No higher estimated GFR values should be used.
For a target AUC = 6, the maximum dose is 6 x 150 = 900 mg
For a target AUC = 5, the maximum dose is 5 x 150 = 750 mg
For a target AUC = 4, the maximum dose is 4 x 150 = 600 mg
Principal investigators of ongoing clinical trials should assess whether carboplatin dosing in those trials should be adjusted according to the above information.
FINGER LENGTH AND PROSTATE CANCER RISK
December 2, 2010 — Men whose index finger is longer than their ring finger are at a lower risk of prostate cancer than those with a finger pattern the other way round, according to a new study in the British Journal of Cancer.
The relative length of the first and third fingers is set before birth, and it is thought to relate to the levels of sex hormones the baby is exposed to in the womb. Babies exposed to less of the male sex hormone testosterone are more likely to have longer index fingers.
Finger Length and Prostate Cancer
Over a 15-year period, researchers from The University of Warwick and The Institute of Cancer Research (ICR) collected data on finger length in 1,524 patients with prostate cancer as well as 3,044 healthy people. Men were shown pictures of hands with different finger lengths and asked to identify the one most like their own right hand.
The most common finger length pattern, seen in more than half the men in the study, was a shorter index than ring finger. Men whose index and ring fingers were the same length (about 19%) had a similar prostate cancer risk to those with a shorter index than ring finger. However, men whose index fingers were longer than their ring finger were 33% less likely to have prostate cancer.
Risk reduction was even greater in men aged under 60, say the researchers, who found that this younger group were 87% less likely to be in the prostate cancer group.
Testosterone Exposure
The researchers believe that being exposed to less testosterone before birth helps protect against prostate cancer later in life. The phenomenon is thought to occur because the genes HOXA and HOXD control both finger length and development of sex organs.
“Our results show that relative finger length could be used as a simple test for prostate cancer risk, particularly in men aged under 60,” says joint senior author Professor Ros Eeles from the ICR and The Royal Marsden NHS Foundation Trust. “This exciting finding means that finger pattern could potentially be used to select at-risk men for ongoing screening, perhaps in combination with other factors such as family history or genetic testing.”
The study was funded by Prostate Cancer Research Foundation and Cancer Research UK.
Diagnosing Prostate Cancer
Helen Rippon, head of research at The Prostate Cancer Charity in the U.K., says in an emailed statement: “Diagnosis of prostate cancer is not a simple affair and the best blood test we have, known as a PSA test, tells us only that something might be wrong with the prostate, not whether it is cancerous or not. Anything that adds to our knowledge about whether a man is likely to develop prostate cancer or not is to be welcomed, especially when it is something as easy as looking at the length of his fingers.
“This research also adds to the growing body of evidence that the balance of hormones we are exposed to before birth influences our health for the rest of our lives.”
Rippon says men who check their hands and find they have a shorter index finger should not be unduly concerned. “They share this trait with more than half of all men and it does not mean they will definitely develop prostate cancer in later life,” she says.
The relative length of the first and third fingers is set before birth, and it is thought to relate to the levels of sex hormones the baby is exposed to in the womb. Babies exposed to less of the male sex hormone testosterone are more likely to have longer index fingers.
Finger Length and Prostate Cancer
Over a 15-year period, researchers from The University of Warwick and The Institute of Cancer Research (ICR) collected data on finger length in 1,524 patients with prostate cancer as well as 3,044 healthy people. Men were shown pictures of hands with different finger lengths and asked to identify the one most like their own right hand.
The most common finger length pattern, seen in more than half the men in the study, was a shorter index than ring finger. Men whose index and ring fingers were the same length (about 19%) had a similar prostate cancer risk to those with a shorter index than ring finger. However, men whose index fingers were longer than their ring finger were 33% less likely to have prostate cancer.
Risk reduction was even greater in men aged under 60, say the researchers, who found that this younger group were 87% less likely to be in the prostate cancer group.
Testosterone Exposure
The researchers believe that being exposed to less testosterone before birth helps protect against prostate cancer later in life. The phenomenon is thought to occur because the genes HOXA and HOXD control both finger length and development of sex organs.
“Our results show that relative finger length could be used as a simple test for prostate cancer risk, particularly in men aged under 60,” says joint senior author Professor Ros Eeles from the ICR and The Royal Marsden NHS Foundation Trust. “This exciting finding means that finger pattern could potentially be used to select at-risk men for ongoing screening, perhaps in combination with other factors such as family history or genetic testing.”
The study was funded by Prostate Cancer Research Foundation and Cancer Research UK.
Diagnosing Prostate Cancer
Helen Rippon, head of research at The Prostate Cancer Charity in the U.K., says in an emailed statement: “Diagnosis of prostate cancer is not a simple affair and the best blood test we have, known as a PSA test, tells us only that something might be wrong with the prostate, not whether it is cancerous or not. Anything that adds to our knowledge about whether a man is likely to develop prostate cancer or not is to be welcomed, especially when it is something as easy as looking at the length of his fingers.
“This research also adds to the growing body of evidence that the balance of hormones we are exposed to before birth influences our health for the rest of our lives.”
Rippon says men who check their hands and find they have a shorter index finger should not be unduly concerned. “They share this trait with more than half of all men and it does not mean they will definitely develop prostate cancer in later life,” she says.
AN UNRECOGNIZED HERCEPTIN SIDE EFFECT?
Urol Int. 2010 Nov 27. [Epub ahead of print]
Observation of de Novo Bladder Dysfunction under Treatment with Her2-neu Antibodies.
Hinkel A, Strumberg D, Noldus J, Pannek J.
Department of Urology, Marienhospital, Ruhr-Universität Bochum, Bochum, Germany.
Abstract
Purpose: We diagnosed de novo bladder dysfunction in several breast cancer patients under cancer-specific therapy with trastuzumab. The goal of this retrospective analysis was to investigate whether bladder dysfunction is common in a larger population of breast cancer patients receiving trastuzumab therapy. Patients and Methods: We identified 93 patients who received at least two doses of trastuzumab at our institution in the years 2003-2006. 57 of those patients were still alive at the time of this analysis. We mailed a validated global questionnaire for the assessment of incontinence (King's Health Questionnaire, KHQ) to them, additionally asking for bladder dysfunction observed under trastuzumab therapy. Results: 43 (75%) of the patients returned the questionnaire, 11 (25%) of them reporting severe de novo bladder dysfunction under therapy. Significant differences between symptomatic and asymptomatic patients were detected in all KHQ subscales. Previous conditions and surgeries as well as medications, especially hormonal therapy, were excluded as underlying causes. However, there were more patients under taxane-based chemotherapy in the symptomatic group. Conclusions: The epidermal growth factor receptor is involved in the cellular response to mechanical stretch in the urinary bladder. Based on our findings, we hypothesize that interfering with this pathway may well be the cause of symptomatic bladder dysfunction in patients under trastuzumab medication. A prospective study is required to further elucidate this hypothesis.
Observation of de Novo Bladder Dysfunction under Treatment with Her2-neu Antibodies.
Hinkel A, Strumberg D, Noldus J, Pannek J.
Department of Urology, Marienhospital, Ruhr-Universität Bochum, Bochum, Germany.
Abstract
Purpose: We diagnosed de novo bladder dysfunction in several breast cancer patients under cancer-specific therapy with trastuzumab. The goal of this retrospective analysis was to investigate whether bladder dysfunction is common in a larger population of breast cancer patients receiving trastuzumab therapy. Patients and Methods: We identified 93 patients who received at least two doses of trastuzumab at our institution in the years 2003-2006. 57 of those patients were still alive at the time of this analysis. We mailed a validated global questionnaire for the assessment of incontinence (King's Health Questionnaire, KHQ) to them, additionally asking for bladder dysfunction observed under trastuzumab therapy. Results: 43 (75%) of the patients returned the questionnaire, 11 (25%) of them reporting severe de novo bladder dysfunction under therapy. Significant differences between symptomatic and asymptomatic patients were detected in all KHQ subscales. Previous conditions and surgeries as well as medications, especially hormonal therapy, were excluded as underlying causes. However, there were more patients under taxane-based chemotherapy in the symptomatic group. Conclusions: The epidermal growth factor receptor is involved in the cellular response to mechanical stretch in the urinary bladder. Based on our findings, we hypothesize that interfering with this pathway may well be the cause of symptomatic bladder dysfunction in patients under trastuzumab medication. A prospective study is required to further elucidate this hypothesis.
SERRATED POLYPS INCREASE RISK OF COLORECTAL CANCER
NEW YORK (Reuters Health) Nov 25 - Large or proximal serrated polyps are associated with an increased risk of neoplasia and colorectal cancer (CRC), and their presence should trigger more frequent surveillance, according to two studies published online in the November Gastroenterology.
In the first study, researchers in Japan found on multivariate analysis that patients with large serrated polyps (LSPs) were four times more likely to have advanced neoplasia, while their risk of CRC was 3.34-fold greater.
The other study, conducted by researchers from Portland VA Medical Center and Oregon Health and Science University, found that during follow-up colonoscopies of patients who had been initially screened, the 39 who had no neoplasia but did have proximal ND-SP (nondysplastic serrated polyps) were 3.14 times as likely to develop neoplasia compared to those without polyps.
"Based on the best available data, we propose a modification to the current surveillance guidelines that explicitly recognizes the importance of large or proximal serrated polyps," Dr. Jonathan P. Terdiman and Dr. Kenneth R. McQuaid write in an editorial. "Key to our recommendations is recognition that serrated polyps once removed require endoscopic surveillance similar to that recommended in patients with traditional colonic adenomas."
Serrated adenomas were long considered benign, the editorialists note. But despite growing evidence that these lesions may be associated with neoplasia and cancer, they add, the guidelines remain silent on their clinical importance.
To investigate the significance of serrated polyps, Dr. Sakiko Hiraoka of the Okayama University Graduate School of Medicine in Okayama and colleagues looked at 10,199 people who had first-time colonoscopies. Within the cohort, 15.4% of patients had advanced neoplasia, 6.9% had CRC, and 1.4% had large serrated polyps (10 mm or larger).
LSPs were the most important risk factor for CRC, especially proximal disease, with an odds ratio of 4.79. The OR of proximal CRC was 5.36 for proximal LSPs, and 9.00 for protruded LSPs.
In the other study, Dr. Mitchal A. Schreiner and colleagues report on 3,121 asymptomatic patients 50 to 75 years old who had screening colonoscopies, 1,371 of whom were followed for up to 5.5 years. Proximal nondysplastic serrated polyps (ND-SP) were found in 7.9% of patients at initial screening; 17.3% of these patients had advanced neoplasia, compared to 10% of patients without proximal ND-SP. Patients with large ND-SP (10 mm or larger) were 3.37 times as likely to have synchronous advanced neoplasia.
Based on the findings, Dr. Schreiner and his colleagues suggest patients with proximal or large ND-SP undergo a surveillance schedule similar to that used for patients with one to two tubular adenomas smaller than 10 mm.
And in patients with ND-SP along with advanced neoplasia, they add, "strict adherence to guidelines recommending 3-year surveillance should be encouraged."
Gastroenterology. 2011;139:1497-1502, 1503-1510. Abstract, Abstract
In the first study, researchers in Japan found on multivariate analysis that patients with large serrated polyps (LSPs) were four times more likely to have advanced neoplasia, while their risk of CRC was 3.34-fold greater.
The other study, conducted by researchers from Portland VA Medical Center and Oregon Health and Science University, found that during follow-up colonoscopies of patients who had been initially screened, the 39 who had no neoplasia but did have proximal ND-SP (nondysplastic serrated polyps) were 3.14 times as likely to develop neoplasia compared to those without polyps.
"Based on the best available data, we propose a modification to the current surveillance guidelines that explicitly recognizes the importance of large or proximal serrated polyps," Dr. Jonathan P. Terdiman and Dr. Kenneth R. McQuaid write in an editorial. "Key to our recommendations is recognition that serrated polyps once removed require endoscopic surveillance similar to that recommended in patients with traditional colonic adenomas."
Serrated adenomas were long considered benign, the editorialists note. But despite growing evidence that these lesions may be associated with neoplasia and cancer, they add, the guidelines remain silent on their clinical importance.
To investigate the significance of serrated polyps, Dr. Sakiko Hiraoka of the Okayama University Graduate School of Medicine in Okayama and colleagues looked at 10,199 people who had first-time colonoscopies. Within the cohort, 15.4% of patients had advanced neoplasia, 6.9% had CRC, and 1.4% had large serrated polyps (10 mm or larger).
LSPs were the most important risk factor for CRC, especially proximal disease, with an odds ratio of 4.79. The OR of proximal CRC was 5.36 for proximal LSPs, and 9.00 for protruded LSPs.
In the other study, Dr. Mitchal A. Schreiner and colleagues report on 3,121 asymptomatic patients 50 to 75 years old who had screening colonoscopies, 1,371 of whom were followed for up to 5.5 years. Proximal nondysplastic serrated polyps (ND-SP) were found in 7.9% of patients at initial screening; 17.3% of these patients had advanced neoplasia, compared to 10% of patients without proximal ND-SP. Patients with large ND-SP (10 mm or larger) were 3.37 times as likely to have synchronous advanced neoplasia.
Based on the findings, Dr. Schreiner and his colleagues suggest patients with proximal or large ND-SP undergo a surveillance schedule similar to that used for patients with one to two tubular adenomas smaller than 10 mm.
And in patients with ND-SP along with advanced neoplasia, they add, "strict adherence to guidelines recommending 3-year surveillance should be encouraged."
Gastroenterology. 2011;139:1497-1502, 1503-1510. Abstract, Abstract
NO DRUG FOR PROSTATE CANCER CHEMOPREVENTION APPROVED
December 2, 2010 — The Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) recommended against prostate cancer chemoprevention labeling for the 5α-reductase inhibitors finasteride (Proscar) and dutasteride (Avodart), because both agents increase the likelihood of high-grade tumors when given as preventive agents to healthy men.
Panelists and FDA reviewers shared 3 main concerns about the drugs: the risk of exposing currently healthy people to an increased risk for high-grade tumors, the fact that risk reduction was only in low-grade tumors, and the doubt that the supporting clinical studies are generalizable to clinical practice in the American population.
The unusually contentious ODAC meeting — which at one point required the calming intervention of FDA Office of Oncology Drug Products director Richard Pazdur, MD — pitted the ODAC panel, most of whom are oncologists, against researchers and experts from Merck & Company (makers of finasteride) and GlaxoSmithKline (GSK, makers of dutasteride).
The Merck team, led by Ian Thompson, MD, who headed the Prostate Cancer Prevention Trial (PCPT), tried but failed to convince the ODAC that the increase in high-grade prostate cancers in otherwise healthy men treated with finasteride was a statistical artifact. Dr. Thompson is chair of the Department of Urology at the University of Texas Health Sciences Center in San Antonio. The final vote was 18 to 0 against the proposal that the finasteride risk/benefit profile is favorable for reducing prostate cancer risk in men older than 55 years with a normal digital rectal examination and a prostate-specific antigen (PSA) level of 3.0 ng/mL or less.
A feisty GSK team, which included Gerald L. Andriole, Jr., MD, director of the Men's Health Center at Washington University in St. Louis, Missouri, and Christopher J. Logothetis, MD, chair of the Department of Genitourinary Medical Oncology at the University of Texas M.D. Anderson Cancer Center in Houston, did not convince the ODAC that, even in high-risk men, the benefits of dutasteride for the many outweighed the risk for high-grade tumors in the few. The panel also voted 14 to 2 (with 2 abstentions) against the proposal that the dutasteride risk/benefit profile is favorable for reducing prostate cancer risk in men with a previous negative biopsy (due to clinical concern) and an elevated PSA level.
Interestingly, Merck was not asking for a new indication for finasteride, but wanted to have the results of the PCPT tucked into the Clinical Studies section of the product labeling. The FDA reviewers appeared to view this as an attempted end-run around New Drug Application requirements, and the FDA briefing document presented at the meeting stated bluntly that "the proposed changes could be interpreted to suggest that Proscar is safe and effective for the prevention of prostate cancer in healthy men." GSK, which was asking for a new chemoprevention indication for dutasteride, based that request mainly on the phase 3 Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study.
The finasteride and dutasteride studies showed a 23% reduction in the relative risk for prostate cancer in the active-treatment group, compared with placebo, but for both drugs, the reduction was only in low-grade tumors (Gleason score ≤6), and both were associated with an unexpected increase in high-grade tumors (Gleason score, 8 to 10).
In addition to these 2 concerns, ODAC director Dr. Pazdur asked whether the beneficial effects of what would be long-term therapy were generalizable to the American population, because of concerns about the clinical trial design, about the patient populations, and about the relatively brief (4- and 7-year) trials.
One design issue was that study data were based on mandated and scheduled biopsies rather than the "for-cause" biopsies characteristic of clinical practice. The concern was that the scheduled biopsies might have picked up indolent tumors that would not have caused morbidity or mortality for most men, and that conclusions based on those biopsies might not be applicable in "real world" terms. According to the FDA briefing document, autopsy data show latent prostate cancer in 30% to 70% of men 50 to 80 years of age.
Another problem was that neither study included many African American men, despite the high incidence of prostate cancer in this population and a possibly greater susceptibility to high-grade disease.
A major clinical concern was that the 5α-reductase inhibitors, by suppressing tumors with a Gleason score of 6 (the detection of which often triggers more intensive intervention), might be delaying detection of more deadly tumors (Gleason score, 8 to 10), or even contributing to the development of such tumors. ODAC chair Wyndham Wilson, MD, PhD, chief of lymphoma therapeutics at the National Cancer Institute's Center for Cancer Research in Rockville, Maryland, compared this to "hiding our heads in the sand" until prostate cancers become too advanced to treat successfully.
GSK researchers argued that the increased detection of high-grade tumors was the result of treatment-related prostate shrinkage, which might have improved detection sensitivity. Invited speaker Patrick Walsh, MD, professor of urology at the Johns Hopkins University School of Medicine in Baltimore, Maryland, reviewed data on prostate shrinkage, and concluded that "shrinkage does not make it easier to detect high-grade disease. More high-grade disease is found because there is more to find."
The PCPT was a 7-year, placebo-controlled trial that randomized nearly 19,000 men 55 years and older with a normal digital rectal examination and a PSA level of 3.0 ng/mL or less to either finasteride or placebo. At end of the study, prostate cancer was detected by needle biopsy in 18.4% of men in the finasteride group and in 24.4% in the placebo group, for a relative risk of 0.74. The reduced risk was driven by decreases in low-risk tumors (Gleason score ≤6).
REDUCE randomized more than 8000 men at high risk of being diagnosed with prostate cancer to daily dutasteride or placebo for 4 years. The results showed that men in the dutasteride group had a 23% lower risk of being diagnosed with biopsy-detectable prostate cancer than men in the placebo group (P < .0001), but this risk reduction was due to the decrease in low-risk tumors (Gleason score, 5 to 6).
Dr. Thompson, Dr. Wilson, and Dr. Walsh have disclosed no relevant financial relationships. Dr. Andriole and Dr. Logothetis report receiving research support and travel funding from GSK.
Panelists and FDA reviewers shared 3 main concerns about the drugs: the risk of exposing currently healthy people to an increased risk for high-grade tumors, the fact that risk reduction was only in low-grade tumors, and the doubt that the supporting clinical studies are generalizable to clinical practice in the American population.
The unusually contentious ODAC meeting — which at one point required the calming intervention of FDA Office of Oncology Drug Products director Richard Pazdur, MD — pitted the ODAC panel, most of whom are oncologists, against researchers and experts from Merck & Company (makers of finasteride) and GlaxoSmithKline (GSK, makers of dutasteride).
The Merck team, led by Ian Thompson, MD, who headed the Prostate Cancer Prevention Trial (PCPT), tried but failed to convince the ODAC that the increase in high-grade prostate cancers in otherwise healthy men treated with finasteride was a statistical artifact. Dr. Thompson is chair of the Department of Urology at the University of Texas Health Sciences Center in San Antonio. The final vote was 18 to 0 against the proposal that the finasteride risk/benefit profile is favorable for reducing prostate cancer risk in men older than 55 years with a normal digital rectal examination and a prostate-specific antigen (PSA) level of 3.0 ng/mL or less.
A feisty GSK team, which included Gerald L. Andriole, Jr., MD, director of the Men's Health Center at Washington University in St. Louis, Missouri, and Christopher J. Logothetis, MD, chair of the Department of Genitourinary Medical Oncology at the University of Texas M.D. Anderson Cancer Center in Houston, did not convince the ODAC that, even in high-risk men, the benefits of dutasteride for the many outweighed the risk for high-grade tumors in the few. The panel also voted 14 to 2 (with 2 abstentions) against the proposal that the dutasteride risk/benefit profile is favorable for reducing prostate cancer risk in men with a previous negative biopsy (due to clinical concern) and an elevated PSA level.
Interestingly, Merck was not asking for a new indication for finasteride, but wanted to have the results of the PCPT tucked into the Clinical Studies section of the product labeling. The FDA reviewers appeared to view this as an attempted end-run around New Drug Application requirements, and the FDA briefing document presented at the meeting stated bluntly that "the proposed changes could be interpreted to suggest that Proscar is safe and effective for the prevention of prostate cancer in healthy men." GSK, which was asking for a new chemoprevention indication for dutasteride, based that request mainly on the phase 3 Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study.
The finasteride and dutasteride studies showed a 23% reduction in the relative risk for prostate cancer in the active-treatment group, compared with placebo, but for both drugs, the reduction was only in low-grade tumors (Gleason score ≤6), and both were associated with an unexpected increase in high-grade tumors (Gleason score, 8 to 10).
In addition to these 2 concerns, ODAC director Dr. Pazdur asked whether the beneficial effects of what would be long-term therapy were generalizable to the American population, because of concerns about the clinical trial design, about the patient populations, and about the relatively brief (4- and 7-year) trials.
One design issue was that study data were based on mandated and scheduled biopsies rather than the "for-cause" biopsies characteristic of clinical practice. The concern was that the scheduled biopsies might have picked up indolent tumors that would not have caused morbidity or mortality for most men, and that conclusions based on those biopsies might not be applicable in "real world" terms. According to the FDA briefing document, autopsy data show latent prostate cancer in 30% to 70% of men 50 to 80 years of age.
Another problem was that neither study included many African American men, despite the high incidence of prostate cancer in this population and a possibly greater susceptibility to high-grade disease.
A major clinical concern was that the 5α-reductase inhibitors, by suppressing tumors with a Gleason score of 6 (the detection of which often triggers more intensive intervention), might be delaying detection of more deadly tumors (Gleason score, 8 to 10), or even contributing to the development of such tumors. ODAC chair Wyndham Wilson, MD, PhD, chief of lymphoma therapeutics at the National Cancer Institute's Center for Cancer Research in Rockville, Maryland, compared this to "hiding our heads in the sand" until prostate cancers become too advanced to treat successfully.
GSK researchers argued that the increased detection of high-grade tumors was the result of treatment-related prostate shrinkage, which might have improved detection sensitivity. Invited speaker Patrick Walsh, MD, professor of urology at the Johns Hopkins University School of Medicine in Baltimore, Maryland, reviewed data on prostate shrinkage, and concluded that "shrinkage does not make it easier to detect high-grade disease. More high-grade disease is found because there is more to find."
The PCPT was a 7-year, placebo-controlled trial that randomized nearly 19,000 men 55 years and older with a normal digital rectal examination and a PSA level of 3.0 ng/mL or less to either finasteride or placebo. At end of the study, prostate cancer was detected by needle biopsy in 18.4% of men in the finasteride group and in 24.4% in the placebo group, for a relative risk of 0.74. The reduced risk was driven by decreases in low-risk tumors (Gleason score ≤6).
REDUCE randomized more than 8000 men at high risk of being diagnosed with prostate cancer to daily dutasteride or placebo for 4 years. The results showed that men in the dutasteride group had a 23% lower risk of being diagnosed with biopsy-detectable prostate cancer than men in the placebo group (P < .0001), but this risk reduction was due to the decrease in low-risk tumors (Gleason score, 5 to 6).
Dr. Thompson, Dr. Wilson, and Dr. Walsh have disclosed no relevant financial relationships. Dr. Andriole and Dr. Logothetis report receiving research support and travel funding from GSK.
ANOTHER FAILURE OF HIGH DOSE CHEMOTHERAPY FOR GERM CELL TUMORS
A randomized phase III study comparing standard dose BEP with sequential high-dose VIP plus stem-cell support in patients with poor-prognosis germ-cell cancer
02.12.10
Category: Scientific News
An intergroup European study did not demonstrate improved outcome of first-line high-dose chemotherapy
The development of effective chemotherapy such as cisplatin, etoposid, and bleomycin (BEP) has dramatically improved the prognosis of patients with metastatic non-seminomatous germ-cell cancer (GCC). However, patients with poor prognosis according to the International Germ Cell Cancer Collaborative Group criteria (IGCCCG) only achieve long-term survival rates of 50%–60%. In order to improve these results, the German Testicular Cancer Study Group (GTCSG) developed a dose intensification approach, consisting of one cycle of cisplatin, etoposide, and ifosfamide (VIP) with stem-cell mobilization followed by three to four sequential high-dose cisplatin, etoposide, and ifosfamide (HD-VIP) cycles each with granulocyte colony-stimulating factor (G-CSF) and peripheral blood stem-cell transfusion at 21-day intervals, in order to achieve an early dose intensification.
The aim of the study conducted by the European Organization for Research and Treatment of Cancer (EORTC) in collaboration with the GTCSG and the Spanish Grupo Germinal was to compare the efficacy of one cycle of standard dose VIP plus three cycles of HD-VIP followed by stem-cell infusion to four cycles of standard BEP in previously untreated patients with poor-prognosis GCC and to compare the toxicity of these two treatments. Results are published online on 17 November 2010 in the Annals of Oncology.
To show a 15% improvement in a 1-year failure-free survival (FFS), the study aimed to recruit 222 patients but was closed prematurely due to slow accrual. Between April 1999 and June 2007, 137 patients from 27 European oncology centers were included. Two sites were excluded due to poor data documentation. Of 131 patients included in the analysis, 11 were considered ineligible. The median follow-up of 4.4 years overall is similar in the two arms.
All 66 patients who were randomly assigned to BEP started the treatment. Of 65 patients allocated to HD-CT, 62 (95.4%) received the treatment. In the BEP arm, 93.8% of patients received four cycles of scheduled treatment compared with 75.4% in the HD-CT arm and as expected the main reason for this was toxicity. Toxicity was more severe in patients treated by HD-CT. Seven (5%) of 131 patients died during treatment. Three died of toxicity: two who were assigned to the HD-CT arm died of sepsis (one after the first cycle of standard dose VIP) and one on the BEP arm who died of cardiac failure. The other patients died of lung embolus (one) or malignant disease (three).
The dose intensity in the BEP arm was 97.7%, while the dose intensity in the HD-CT arm was 89.3%. One or more cycles were postponed in 25% of the patients in the BEP arm compared with 66% in the HD-CT arm. This was mainly due to patient wish or infrastructure problems and not toxicity.
There was no improvement in complete response rate for patients treated in the HD-CT arm compared with patients treated on the BEP arm (intention to treat 44.6% versus 33.3%). Overall, there was no difference in FFS between the two treatment arms. The 1-year FFS rate was 48% after BEP and 66.1% after HD-CT with a difference of 18.1% (P = 0.035). The 2-year FFS rate was 44.8% after BEP and 58.2% after HD-CT but this 16.3% (standard deviation 7.5%) difference was not statistically significant. Overall survival did not differ between the two groups. On BEP, 83% of patients survived 1 year 65.5% survived 2 years. For the HD-CT arm, the 1- and 2-year survival rates were 86.1% and 72.9%, respectively.
The assessment of the prognostic value of marker half-life was conducted in the subset of 116 patients with at least two treatment cycles for whom the marker half-life could be calculated (62 BEP and 54 HD-CT). Marker decline was not prognostic for FFS or overall survival. However, there was a borderline significant interaction between treatment and marker decline for FFS (P = 0.05) and a suggestion for a greater benefit from VIP in patients with satisfactory marker decline.
The authors concluded that there is no clear evidence that high-dose chemotherapy plus autologous hematopoietic stem-cell support given as part of first-line therapy increase survival in patients with poor-prognosis GCC. Although this randomized trial indicates about 10% absolute improvement at 2 years with HD-VIP, it was not possible to demonstrate a statistical significance of the difference due to early study closure.
The authors also noticed if not used in the first-line therapy, HD-CT will still remain important at relapse. An international collaborative group is working on a definition of favorable or unfavorable prognostic criteria for relapsing patients and this could have a significant impact on the success of choosing patients for conventional or high-dose salvage chemotherapy in the future. To maintain the highest chance of cure, patients with a poor prognosis or relapsed disease should be transferred to a specialized center without any delay to benefit from optimal interdisciplinary management and supportive care. In order to improve on the poor outcome for poor-risk GCC, further clarification of the role of HD-CT as well as new combinations of drugs should be investigated in well-designed clinical trials and this can only be achieved by close international collaboration.
02.12.10
Category: Scientific News
An intergroup European study did not demonstrate improved outcome of first-line high-dose chemotherapy
The development of effective chemotherapy such as cisplatin, etoposid, and bleomycin (BEP) has dramatically improved the prognosis of patients with metastatic non-seminomatous germ-cell cancer (GCC). However, patients with poor prognosis according to the International Germ Cell Cancer Collaborative Group criteria (IGCCCG) only achieve long-term survival rates of 50%–60%. In order to improve these results, the German Testicular Cancer Study Group (GTCSG) developed a dose intensification approach, consisting of one cycle of cisplatin, etoposide, and ifosfamide (VIP) with stem-cell mobilization followed by three to four sequential high-dose cisplatin, etoposide, and ifosfamide (HD-VIP) cycles each with granulocyte colony-stimulating factor (G-CSF) and peripheral blood stem-cell transfusion at 21-day intervals, in order to achieve an early dose intensification.
The aim of the study conducted by the European Organization for Research and Treatment of Cancer (EORTC) in collaboration with the GTCSG and the Spanish Grupo Germinal was to compare the efficacy of one cycle of standard dose VIP plus three cycles of HD-VIP followed by stem-cell infusion to four cycles of standard BEP in previously untreated patients with poor-prognosis GCC and to compare the toxicity of these two treatments. Results are published online on 17 November 2010 in the Annals of Oncology.
To show a 15% improvement in a 1-year failure-free survival (FFS), the study aimed to recruit 222 patients but was closed prematurely due to slow accrual. Between April 1999 and June 2007, 137 patients from 27 European oncology centers were included. Two sites were excluded due to poor data documentation. Of 131 patients included in the analysis, 11 were considered ineligible. The median follow-up of 4.4 years overall is similar in the two arms.
All 66 patients who were randomly assigned to BEP started the treatment. Of 65 patients allocated to HD-CT, 62 (95.4%) received the treatment. In the BEP arm, 93.8% of patients received four cycles of scheduled treatment compared with 75.4% in the HD-CT arm and as expected the main reason for this was toxicity. Toxicity was more severe in patients treated by HD-CT. Seven (5%) of 131 patients died during treatment. Three died of toxicity: two who were assigned to the HD-CT arm died of sepsis (one after the first cycle of standard dose VIP) and one on the BEP arm who died of cardiac failure. The other patients died of lung embolus (one) or malignant disease (three).
The dose intensity in the BEP arm was 97.7%, while the dose intensity in the HD-CT arm was 89.3%. One or more cycles were postponed in 25% of the patients in the BEP arm compared with 66% in the HD-CT arm. This was mainly due to patient wish or infrastructure problems and not toxicity.
There was no improvement in complete response rate for patients treated in the HD-CT arm compared with patients treated on the BEP arm (intention to treat 44.6% versus 33.3%). Overall, there was no difference in FFS between the two treatment arms. The 1-year FFS rate was 48% after BEP and 66.1% after HD-CT with a difference of 18.1% (P = 0.035). The 2-year FFS rate was 44.8% after BEP and 58.2% after HD-CT but this 16.3% (standard deviation 7.5%) difference was not statistically significant. Overall survival did not differ between the two groups. On BEP, 83% of patients survived 1 year 65.5% survived 2 years. For the HD-CT arm, the 1- and 2-year survival rates were 86.1% and 72.9%, respectively.
The assessment of the prognostic value of marker half-life was conducted in the subset of 116 patients with at least two treatment cycles for whom the marker half-life could be calculated (62 BEP and 54 HD-CT). Marker decline was not prognostic for FFS or overall survival. However, there was a borderline significant interaction between treatment and marker decline for FFS (P = 0.05) and a suggestion for a greater benefit from VIP in patients with satisfactory marker decline.
The authors concluded that there is no clear evidence that high-dose chemotherapy plus autologous hematopoietic stem-cell support given as part of first-line therapy increase survival in patients with poor-prognosis GCC. Although this randomized trial indicates about 10% absolute improvement at 2 years with HD-VIP, it was not possible to demonstrate a statistical significance of the difference due to early study closure.
The authors also noticed if not used in the first-line therapy, HD-CT will still remain important at relapse. An international collaborative group is working on a definition of favorable or unfavorable prognostic criteria for relapsing patients and this could have a significant impact on the success of choosing patients for conventional or high-dose salvage chemotherapy in the future. To maintain the highest chance of cure, patients with a poor prognosis or relapsed disease should be transferred to a specialized center without any delay to benefit from optimal interdisciplinary management and supportive care. In order to improve on the poor outcome for poor-risk GCC, further clarification of the role of HD-CT as well as new combinations of drugs should be investigated in well-designed clinical trials and this can only be achieved by close international collaboration.
BEVACIZUMAB FOR NEWLY DIAGNOSED GLIOBLASTOMA?
December 1, 2010 (Montreal, Quebec) — A large study of patients with newly diagnosed glioblastoma multiforme suggests that the addition of 2 agents — bevacizumab and irinotecan — to standard chemoradiation can extend survival, compared with historic controls.
The addition of bevacizumab, an inhibitor of vascular endothelial growth factor, and irinotecan, a topoisomerase inhibitor that prevents DNA replication, appears to boost progression-free survival and overall survival by about 6 months, compared with rates reported for patients receiving temozolomide-based chemotherapy and radiation alone, reported Annick Desjardins, MD, from Duke University Medical Center in Durham, North Carolina.
But the study design was harshly criticized by Martin van den Bent, MD, PhD, who chaired the session in which it was presented here at the Society for Neuro-Oncology 15th Annual Scientific Meeting.
"It's flatly outrageous. It should not have been done," he said in an interview with Medscape Medical News after the session. Dr. van den Bent is past chair of the European Organization of Research and Treatment Brain Tumor Group, and professor of neuro-oncology at the Daniel den Hoed Cancer Center, Erasmus University, in Rotterdam, the Netherlands.
"What I find very disturbing is that they did a very big study of 120 patients — which is a lot; it's really a big study — but by doing it in an uncontrolled fashion they ended up with an impossible interpretation of whether the irinotecan added to the bevacizumab made any difference."
The study, which was supported by Genentech, began with 125 patients (mean age, 56 years; 59% male) with newly diagnosed grade 4 malignant glioblastoma multiforme. The majority of patients (70%) had Karnofsky Performance Status scores above 90.
Two to 4 weeks after surgical resection, patients received the standard of care — 6 weeks of radiation and daily temozolomide 75 mg/m2. Added to this regimen, starting a minimum of 28 days after craniotomy, bevacizumab 10 mg/kg was administered once every 2 weeks.
In the second phase of treatment, patients received 6 to 12 more weeks of bevacizumab at the same dose, combined with temozolomide at 200 mg/m2 on days 1 to 5 of each month, plus irinotecan, dosed according to whether patients were or were not taking enzyme-inducing antiepileptic drugs (340 mg/m2 or 125 mg/m2, respectively, on days 1 and 15 of each month).
The first phase of treatment was associated with minimal toxicity, the authors report in their study published online October 30 in the International Journal of Radiation Oncology, Biology, Physics.
At the meeting, Dr. Desjardins reported that grade 4 thrombocytopenia occurred in 2.4% of patients, neutropenia in 0.8%, central nervous system (CNS) hemorrhage in 0.8%, and deep vein thrombosis and pulmonary embolism in 1.6%. Five patients did not complete the first phase of the treatment (1 with grade 2 CNS hemorrhage, 2 with pulmonary emboli, 1 with grade 4 pancytopenia, and 1 with wound dehiscence), and 7 others did not go on to the second phase (3 had tumor progression, 2 withdrew because of fatigue, 1 had a bowel perforation, and 1 had a rectal abscess).
A total of 113 patients went on to the second phase of treatment and have been followed for a median of 28 months, said Dr. Desjardins.
Better Results Than Historic Controls
A final analysis of the original cohort of 125 shows a median progression-free survival of 14.2 months and a median overall survival of 21.3 months, she reported. A median progression-free survival of 6.9 months and a median overall survival of 15.9 months have been reported in the literature, she noted.
Additionally, progression-free survival at 6 months, 1 year, and 2 years in her cohort was 88%, 64%, and 16%, respectively, and overall survival at was 94%, 82%, and 44%, respectively.
There were 4 toxic deaths in the entire cohort: 1 from pulmonary embolism, 1 from sepsis, 1 from myocardial infarction, and 1 from Pneumocystis jiroveci.
For all 125 patients, overall serious toxicities included 1 CNS hemorrhage, 9 venous thromboembolisms, 2 wound dehiscences, 1 bowel perforation, 17 grade 4 hematologic toxicities, 1 secondary malignancy, and 2 pneumocystis pneumonias.
The regimen appears safe and tolerable, and appears to improve survival, compared with historic controls, concluded Dr. Desjardins.
But historic controls are not a valid comparison, said the moderator, Dr. van den Bent.
In addition, he challenged Dr. Desjardins on the podium about the design of the study, pointing out that exposing all patients to the bevacizumab/irinotecan regimen rather than randomizing them to one or the other makes it impossible to know which drug is preferable.
Wasting Resources and Opportunities
Asked in an interview about his public criticisms, Dr. van den Bent was adamant.
"Duke has been accused repeatedly of not doing the right studies, doing studies that don't make reasonable interpretation possible. By doing that, they are wasting resources, wasting progress, and wasting opportunities to carry the field forward. This is a very serious thing," he said.
Doing studies in this way is not the way to go. . . . If you have an uncontrolled study, you basically have no way of telling if the addition of a novel compound makes any difference or not. So all the patients were exposed to the toxicity of the combination regimen and we don't know if it works or not."
Dr. van den Bent was also critical of the field's eagerness to embrace bevacizumab on the basis of questionable science. "The use of bevacizumab at present is based on uncontrolled studies, it's been [approved by the US Food and Drug Administration] on a scientifically nonvalid end point. There are ongoing, properly controlled, randomized studies looking at adding bevacizumab to radiation and temozolomide, but . . . Duke takes the next step and adds another compound before we even know if there is benefit to adding bevacizumab. They're taking 2 steps at a time and we can't evaluate. We haven't learned anything."
Medscape Medical News has previously reported on the widely different viewpoints in Europe and the United States about the use of bevacizumab in glioblastoma. This is an indication that has been approved in the United States but not in Europe — decisions that were made on the basis of the same data.
The study was supported by Genentech. Dr. Desjardins has disclosed no relevant financial relationships. Dr. van den Bent is a consultant for MSD, Hoffman-La Roche, BMS, Ark Therapeutics, Siena Biotech, Novartis, Merck, and Eli Lilly.
Int J Radiat Oncol Biol Phys. Published online October 30, 2010. Abstract
Society for Neuro-Oncology 15th Annual Scientific Meeting: Abstract OT-34. Presented November 21, 2010.
The addition of bevacizumab, an inhibitor of vascular endothelial growth factor, and irinotecan, a topoisomerase inhibitor that prevents DNA replication, appears to boost progression-free survival and overall survival by about 6 months, compared with rates reported for patients receiving temozolomide-based chemotherapy and radiation alone, reported Annick Desjardins, MD, from Duke University Medical Center in Durham, North Carolina.
But the study design was harshly criticized by Martin van den Bent, MD, PhD, who chaired the session in which it was presented here at the Society for Neuro-Oncology 15th Annual Scientific Meeting.
"It's flatly outrageous. It should not have been done," he said in an interview with Medscape Medical News after the session. Dr. van den Bent is past chair of the European Organization of Research and Treatment Brain Tumor Group, and professor of neuro-oncology at the Daniel den Hoed Cancer Center, Erasmus University, in Rotterdam, the Netherlands.
"What I find very disturbing is that they did a very big study of 120 patients — which is a lot; it's really a big study — but by doing it in an uncontrolled fashion they ended up with an impossible interpretation of whether the irinotecan added to the bevacizumab made any difference."
The study, which was supported by Genentech, began with 125 patients (mean age, 56 years; 59% male) with newly diagnosed grade 4 malignant glioblastoma multiforme. The majority of patients (70%) had Karnofsky Performance Status scores above 90.
Two to 4 weeks after surgical resection, patients received the standard of care — 6 weeks of radiation and daily temozolomide 75 mg/m2. Added to this regimen, starting a minimum of 28 days after craniotomy, bevacizumab 10 mg/kg was administered once every 2 weeks.
In the second phase of treatment, patients received 6 to 12 more weeks of bevacizumab at the same dose, combined with temozolomide at 200 mg/m2 on days 1 to 5 of each month, plus irinotecan, dosed according to whether patients were or were not taking enzyme-inducing antiepileptic drugs (340 mg/m2 or 125 mg/m2, respectively, on days 1 and 15 of each month).
The first phase of treatment was associated with minimal toxicity, the authors report in their study published online October 30 in the International Journal of Radiation Oncology, Biology, Physics.
At the meeting, Dr. Desjardins reported that grade 4 thrombocytopenia occurred in 2.4% of patients, neutropenia in 0.8%, central nervous system (CNS) hemorrhage in 0.8%, and deep vein thrombosis and pulmonary embolism in 1.6%. Five patients did not complete the first phase of the treatment (1 with grade 2 CNS hemorrhage, 2 with pulmonary emboli, 1 with grade 4 pancytopenia, and 1 with wound dehiscence), and 7 others did not go on to the second phase (3 had tumor progression, 2 withdrew because of fatigue, 1 had a bowel perforation, and 1 had a rectal abscess).
A total of 113 patients went on to the second phase of treatment and have been followed for a median of 28 months, said Dr. Desjardins.
Better Results Than Historic Controls
A final analysis of the original cohort of 125 shows a median progression-free survival of 14.2 months and a median overall survival of 21.3 months, she reported. A median progression-free survival of 6.9 months and a median overall survival of 15.9 months have been reported in the literature, she noted.
Additionally, progression-free survival at 6 months, 1 year, and 2 years in her cohort was 88%, 64%, and 16%, respectively, and overall survival at was 94%, 82%, and 44%, respectively.
There were 4 toxic deaths in the entire cohort: 1 from pulmonary embolism, 1 from sepsis, 1 from myocardial infarction, and 1 from Pneumocystis jiroveci.
For all 125 patients, overall serious toxicities included 1 CNS hemorrhage, 9 venous thromboembolisms, 2 wound dehiscences, 1 bowel perforation, 17 grade 4 hematologic toxicities, 1 secondary malignancy, and 2 pneumocystis pneumonias.
The regimen appears safe and tolerable, and appears to improve survival, compared with historic controls, concluded Dr. Desjardins.
But historic controls are not a valid comparison, said the moderator, Dr. van den Bent.
In addition, he challenged Dr. Desjardins on the podium about the design of the study, pointing out that exposing all patients to the bevacizumab/irinotecan regimen rather than randomizing them to one or the other makes it impossible to know which drug is preferable.
Wasting Resources and Opportunities
Asked in an interview about his public criticisms, Dr. van den Bent was adamant.
"Duke has been accused repeatedly of not doing the right studies, doing studies that don't make reasonable interpretation possible. By doing that, they are wasting resources, wasting progress, and wasting opportunities to carry the field forward. This is a very serious thing," he said.
Doing studies in this way is not the way to go. . . . If you have an uncontrolled study, you basically have no way of telling if the addition of a novel compound makes any difference or not. So all the patients were exposed to the toxicity of the combination regimen and we don't know if it works or not."
Dr. van den Bent was also critical of the field's eagerness to embrace bevacizumab on the basis of questionable science. "The use of bevacizumab at present is based on uncontrolled studies, it's been [approved by the US Food and Drug Administration] on a scientifically nonvalid end point. There are ongoing, properly controlled, randomized studies looking at adding bevacizumab to radiation and temozolomide, but . . . Duke takes the next step and adds another compound before we even know if there is benefit to adding bevacizumab. They're taking 2 steps at a time and we can't evaluate. We haven't learned anything."
Medscape Medical News has previously reported on the widely different viewpoints in Europe and the United States about the use of bevacizumab in glioblastoma. This is an indication that has been approved in the United States but not in Europe — decisions that were made on the basis of the same data.
The study was supported by Genentech. Dr. Desjardins has disclosed no relevant financial relationships. Dr. van den Bent is a consultant for MSD, Hoffman-La Roche, BMS, Ark Therapeutics, Siena Biotech, Novartis, Merck, and Eli Lilly.
Int J Radiat Oncol Biol Phys. Published online October 30, 2010. Abstract
Society for Neuro-Oncology 15th Annual Scientific Meeting: Abstract OT-34. Presented November 21, 2010.
TAC-A NEW STANDARD OF CARE
N Engl J Med. 2005 Jun 2;352(22):2302-13.
Adjuvant docetaxel for node-positive breast cancer.
Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group 001 Investigators.
Hospital Universitario San Carlos, Madrid, Spain. mmartin@geicam.org
Comment in:
* Ann Oncol. 2006 Feb;17(2):352.
* N Engl J Med. 2005 Jun 2;352(22):2346-8.
* N Engl J Med. 2005 Sep 1;353(9):954-5; author reply 954-5.
* N Engl J Med. 2005 Sep 1;353(9):954-5; author reply 954-5.
Abstract
BACKGROUND: We compared docetaxel plus doxorubicin and cyclophosphamide (TAC) with fluorouracil plus doxorubicin and cyclophosphamide (FAC) as adjuvant chemotherapy for operable node-positive breast cancer.
METHODS: We randomly assigned 1491 women with axillary node-positive breast cancer to six cycles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery. The primary end point was disease-free survival.
RESULTS: At a median follow-up of 55 months, the estimated rates of disease-free survival at five years were 75 percent among the 745 patients randomly assigned to receive TAC and 68 percent among the 746 randomly assigned to receive FAC, representing a 28 percent reduction in the risk of relapse (P=0.001) in the TAC group. The estimated rates of overall survival at five years were 87 percent and 81 percent, respectively. Treatment with TAC resulted in a 30 percent reduction in the risk of death (P=0.008). The incidence of grade 3 or 4 neutropenia was 65.5 percent in the TAC group and 49.3 percent in the FAC group (P<0.001); rates of febrile neutropenia were 24.7 percent and 2.5 percent, respectively (P<0.001). Grade 3 or 4 infections occurred in 3.9 percent of the patients who received TAC and 2.2 percent of those who received FAC (P=0.05); no deaths occurred as a result of infection. Two patients in each group died during treatment. Congestive heart failure and acute myeloid leukemia occurred in less than 2 percent of the patients in each group. Quality-of-life scores decreased during chemotherapy but returned to baseline levels after treatment.
CONCLUSIONS: Adjuvant chemotherapy with TAC, as compared with FAC, significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer.
Adjuvant docetaxel for node-positive breast cancer.
Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group 001 Investigators.
Hospital Universitario San Carlos, Madrid, Spain. mmartin@geicam.org
Comment in:
* Ann Oncol. 2006 Feb;17(2):352.
* N Engl J Med. 2005 Jun 2;352(22):2346-8.
* N Engl J Med. 2005 Sep 1;353(9):954-5; author reply 954-5.
* N Engl J Med. 2005 Sep 1;353(9):954-5; author reply 954-5.
Abstract
BACKGROUND: We compared docetaxel plus doxorubicin and cyclophosphamide (TAC) with fluorouracil plus doxorubicin and cyclophosphamide (FAC) as adjuvant chemotherapy for operable node-positive breast cancer.
METHODS: We randomly assigned 1491 women with axillary node-positive breast cancer to six cycles of treatment with either TAC or FAC as adjuvant chemotherapy after surgery. The primary end point was disease-free survival.
RESULTS: At a median follow-up of 55 months, the estimated rates of disease-free survival at five years were 75 percent among the 745 patients randomly assigned to receive TAC and 68 percent among the 746 randomly assigned to receive FAC, representing a 28 percent reduction in the risk of relapse (P=0.001) in the TAC group. The estimated rates of overall survival at five years were 87 percent and 81 percent, respectively. Treatment with TAC resulted in a 30 percent reduction in the risk of death (P=0.008). The incidence of grade 3 or 4 neutropenia was 65.5 percent in the TAC group and 49.3 percent in the FAC group (P<0.001); rates of febrile neutropenia were 24.7 percent and 2.5 percent, respectively (P<0.001). Grade 3 or 4 infections occurred in 3.9 percent of the patients who received TAC and 2.2 percent of those who received FAC (P=0.05); no deaths occurred as a result of infection. Two patients in each group died during treatment. Congestive heart failure and acute myeloid leukemia occurred in less than 2 percent of the patients in each group. Quality-of-life scores decreased during chemotherapy but returned to baseline levels after treatment.
CONCLUSIONS: Adjuvant chemotherapy with TAC, as compared with FAC, significantly improves the rates of disease-free and overall survival among women with operable node-positive breast cancer.
LOWER BP IS NOT ALWAYS BETTER
November 22, 2010 — Diastolic blood pressure (BP) of less than 70 mm Hg in patients with type 2 diabetes is linked to increased cardiovascular risk, even when systolic BP is in guideline-recommended target ranges, according to the results of a study reported online ahead of print November 8 in Diabetes Care.
"Blood pressure ranges associated with cardiovascular disease (CVD) events in advanced type 2 diabetes are not clear," write Robert J. Anderson, MD, from the VA Medical Center in Omaha, Nebraska, and colleagues. "Our objective was to determine whether baseline and follow-up (On-Study) systolic BP (SBP), diastolic DBP, and SBP combined with DBP predict CVD events in the Veterans Affairs Diabetes Trial (VADT)."
In the Veterans Affairs Diabetes Trial, 1791 participants with hypertension in a standard glycemic treatment group and an intensive glycemic treatment group were assigned to stepped treatment with the goal of maintaining BP below 130/80 mm Hg. The investigators determined associations of BP levels of all participants at baseline and On-Study with cardiovascular risk, using a main study endpoint of the time from randomization to the first event of myocardial infarction, stroke, congestive heart failure, surgery for vascular disease, inoperable coronary disease, amputation for ischemic gangrene, or death from cardiovascular disease.
Isolated systolic BP of at least 140 mm Hg was associated with cardiovascular risk both at baseline (hazard ratio [HR], 1.508; P < .001) and On-Study (HR, 1.469; P = .002). Diastolic BP of less than 70 mm Hg was also associated with increased cardiovascular risk at baseline (HR, 1.482; P < .001) and On-Study (HR, 1.491; P < .001).
When combined BP categories were analyzed, the risk for cardiovascular events was increased for a systolic BP of 140 mm Hg or more with a diastolic BP of less than 70 mm Hg at baseline (HR, 1.785; P = .03) as well as On-Study (HR, 2.042; P = .003), and for nearly all systolic BP readings with diastolic BP of less than 70 mm Hg.
"Increased risk of CVD events with SBP≥140 mmHg emphasizes the urgency for treatment of systolic hypertension," the study authors write. "Increased risk with DBP<70 mmHg, even when combined with SBP in guideline-recommended target ranges, supports a new finding in patients with type 2 diabetes. The results emphasize that DBP<70 mmHg in these patients was associated with elevated CVD risk and may best be avoided."
Limitations of this study include lack of randomization to BP control groups or BP treatment, lack of generalizability to younger individuals and women, low statistical power in the higher BP categories, and the confounding treatment effect of BP control during the study. In addition, this analysis did not examine the effects of lowering BP.
"A possible negative effect of antihypertensive treatments that excessively lower DBP must be considered," the study authors write. "Future research questions include whether BP control changed outcomes for individual patients in higher risk SBP or DBP categories. We also plan to investigate the potential associations of these high risk BP categories with microvascular events."
This study was supported by the VA Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, with additional support from the American Diabetes Association and the National Eye Institute of the National Institutes of Health. GlaxoSmithKline, Novo Nordisk, Roche Diagnostics, Sanofi-Aventis, Amylin, and Kos Pharmaceuticals provided pharmaceutical and other supplies and financial assistance.
Some of the study authors have disclosed various financial relationships with Roche Pharmaceuticals, the American Diabetes Association, Aventis, and/or Novo Nordisk.
Diabetes Care. Published online November 8, 2010.
"Blood pressure ranges associated with cardiovascular disease (CVD) events in advanced type 2 diabetes are not clear," write Robert J. Anderson, MD, from the VA Medical Center in Omaha, Nebraska, and colleagues. "Our objective was to determine whether baseline and follow-up (On-Study) systolic BP (SBP), diastolic DBP, and SBP combined with DBP predict CVD events in the Veterans Affairs Diabetes Trial (VADT)."
In the Veterans Affairs Diabetes Trial, 1791 participants with hypertension in a standard glycemic treatment group and an intensive glycemic treatment group were assigned to stepped treatment with the goal of maintaining BP below 130/80 mm Hg. The investigators determined associations of BP levels of all participants at baseline and On-Study with cardiovascular risk, using a main study endpoint of the time from randomization to the first event of myocardial infarction, stroke, congestive heart failure, surgery for vascular disease, inoperable coronary disease, amputation for ischemic gangrene, or death from cardiovascular disease.
Isolated systolic BP of at least 140 mm Hg was associated with cardiovascular risk both at baseline (hazard ratio [HR], 1.508; P < .001) and On-Study (HR, 1.469; P = .002). Diastolic BP of less than 70 mm Hg was also associated with increased cardiovascular risk at baseline (HR, 1.482; P < .001) and On-Study (HR, 1.491; P < .001).
When combined BP categories were analyzed, the risk for cardiovascular events was increased for a systolic BP of 140 mm Hg or more with a diastolic BP of less than 70 mm Hg at baseline (HR, 1.785; P = .03) as well as On-Study (HR, 2.042; P = .003), and for nearly all systolic BP readings with diastolic BP of less than 70 mm Hg.
"Increased risk of CVD events with SBP≥140 mmHg emphasizes the urgency for treatment of systolic hypertension," the study authors write. "Increased risk with DBP<70 mmHg, even when combined with SBP in guideline-recommended target ranges, supports a new finding in patients with type 2 diabetes. The results emphasize that DBP<70 mmHg in these patients was associated with elevated CVD risk and may best be avoided."
Limitations of this study include lack of randomization to BP control groups or BP treatment, lack of generalizability to younger individuals and women, low statistical power in the higher BP categories, and the confounding treatment effect of BP control during the study. In addition, this analysis did not examine the effects of lowering BP.
"A possible negative effect of antihypertensive treatments that excessively lower DBP must be considered," the study authors write. "Future research questions include whether BP control changed outcomes for individual patients in higher risk SBP or DBP categories. We also plan to investigate the potential associations of these high risk BP categories with microvascular events."
This study was supported by the VA Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, with additional support from the American Diabetes Association and the National Eye Institute of the National Institutes of Health. GlaxoSmithKline, Novo Nordisk, Roche Diagnostics, Sanofi-Aventis, Amylin, and Kos Pharmaceuticals provided pharmaceutical and other supplies and financial assistance.
Some of the study authors have disclosed various financial relationships with Roche Pharmaceuticals, the American Diabetes Association, Aventis, and/or Novo Nordisk.
Diabetes Care. Published online November 8, 2010.
URINE TEST TO DETECT PREECLAMPSIA
December 1, 2010 (Denver, Colorado) — A simple measurement of key proteins in spot urine samples can detect preeclampsia in women during the early stages of pregnancy, according to research presented here at Renal Week 2010: American Society of Nephrology 43rd Annual Meeting.
Researchers in the United Kingdom report that an analysis of urine samples obtained before 20 weeks of gestation from 145 pregnant women who either did or did not develop preeclampsia allowed them to identify 5 protein peaks that predicted preeclampsia with 92% accuracy.
The clinical signs of preeclampsia typically do not appear until later in pregnancy, but the researchers theorized that because abnormal placentation or placental insufficiency is central to the pathogenesis of preeclampsia, and placentation is complete by 18 weeks of gestation, changes in the urinary protein profile early in pregnancy might predict the development of the disease.
"Given that proteinuria is a key diagnostic and prognostic factor in preeclampsia, the renal morphological changes occur early in the disease, and the initiation of this process begins 4 to 5 months before the clinical manifestations," explained Matt Hall, MBChB, from the Leicester General Hospital and the University of Leicester, in the United Kingdom, who was lead author of the study.
"We hypothesized that there could be a unique fingerprint early in pregnancy that would be predictive of disease development."
The prospective longitudinal study involved pregnant women who were recruited before 20 weeks of gestation from a high-risk obstetric outpatient clinic. Urine samples were taken and analyzed the same day with surface enhanced laser desorption/ionization time-of-flight mass spectrometry.
After delivery, patients were categorized as having had preeclampsia or a normal pregnancy, defined by International Society for the Study of Hypertension in Pregnancy 2001 criteria.
A spectral analysis of the urine samples of preeclampsia and nonpreeclampsia pregnancies taken before 20 weeks of gestation was performed with an artificial neural network algorithm and multivariate nonlinear regression. A random sampling of 50 test datasets validated the model.
The results identified a panel of 5 peaks that predicted preeclampsia with 92% accuracy; the test datasets showed a sensitivity of 87% and a specificity of 82%.
"We've identified the urine protein fingerprint of pregnancy that is capable of predicting the subsequent development of preeclampsia with high accuracy," Dr. Hall said. "Validation of this model and characterization of this peptide peak are believed to assemble an accurate predictive model for preeclampsia."
Preeclampsia is a leading cause of maternal and fetal morbidity and mortality, affecting up to 5% of pregnancies worldwide.
Numerous biomarkers have been investigated to try to detect the condition early, most notably soluble FMS-like tyrosine kinase and soluble endoglin — peptides that are produced by the placenta. The identification of a urinary proteomic fingerprint could help with diagnosis, said Arlene Chapman, MD, professor of medicine at Emory School of Medicine in Atlanta, Georgia.
"Preeclampsia can be sort of a diagnostic dilemma that really results from the placenta not growing properly at different stages in the pregnancy," she said. "There are different compounds released into the maternal circulation that may end up being an early footprint for detecting the condition."
"There are several biomarkers that have had some success in validation to identify the clinical scenario before it occurs, so it's interesting to see a unique proteomic footprint that might provide an early detector for this condition as well."
Earlier detection could allow for improved care for the mother and child, she added.
"Women typically don't go to their doctor more than once a month in early pregnancy, and sometimes less than that if they're doing well, so this could allow for closer monitoring of their blood pressure, for instance, and patients could be placed on blood pressure medication sooner rather than later, if necessary.
"Clinicians could also monitor [women] to identify proteinuria earlier. All of those things suggest better protection for the mom and the baby," Dr. Chapman said. "They will need to spend some time validating this in prospective populations to see if it can actually detect the development of preeclampsia, but I think this is exciting."
The study was supported by an unrestricted grant from Baxter Healthcare and University Hospitals Leicester National Health Service Trust Charitable Funds. Dr. Hall and Dr. Chapman have disclosed no relevant financial relationships.
Renal Week 2010: American Society of Nephrology 43rd Annual Meeting. Abstract FC223. Presented November 19, 2010.
Researchers in the United Kingdom report that an analysis of urine samples obtained before 20 weeks of gestation from 145 pregnant women who either did or did not develop preeclampsia allowed them to identify 5 protein peaks that predicted preeclampsia with 92% accuracy.
The clinical signs of preeclampsia typically do not appear until later in pregnancy, but the researchers theorized that because abnormal placentation or placental insufficiency is central to the pathogenesis of preeclampsia, and placentation is complete by 18 weeks of gestation, changes in the urinary protein profile early in pregnancy might predict the development of the disease.
"Given that proteinuria is a key diagnostic and prognostic factor in preeclampsia, the renal morphological changes occur early in the disease, and the initiation of this process begins 4 to 5 months before the clinical manifestations," explained Matt Hall, MBChB, from the Leicester General Hospital and the University of Leicester, in the United Kingdom, who was lead author of the study.
"We hypothesized that there could be a unique fingerprint early in pregnancy that would be predictive of disease development."
The prospective longitudinal study involved pregnant women who were recruited before 20 weeks of gestation from a high-risk obstetric outpatient clinic. Urine samples were taken and analyzed the same day with surface enhanced laser desorption/ionization time-of-flight mass spectrometry.
After delivery, patients were categorized as having had preeclampsia or a normal pregnancy, defined by International Society for the Study of Hypertension in Pregnancy 2001 criteria.
A spectral analysis of the urine samples of preeclampsia and nonpreeclampsia pregnancies taken before 20 weeks of gestation was performed with an artificial neural network algorithm and multivariate nonlinear regression. A random sampling of 50 test datasets validated the model.
The results identified a panel of 5 peaks that predicted preeclampsia with 92% accuracy; the test datasets showed a sensitivity of 87% and a specificity of 82%.
"We've identified the urine protein fingerprint of pregnancy that is capable of predicting the subsequent development of preeclampsia with high accuracy," Dr. Hall said. "Validation of this model and characterization of this peptide peak are believed to assemble an accurate predictive model for preeclampsia."
Preeclampsia is a leading cause of maternal and fetal morbidity and mortality, affecting up to 5% of pregnancies worldwide.
Numerous biomarkers have been investigated to try to detect the condition early, most notably soluble FMS-like tyrosine kinase and soluble endoglin — peptides that are produced by the placenta. The identification of a urinary proteomic fingerprint could help with diagnosis, said Arlene Chapman, MD, professor of medicine at Emory School of Medicine in Atlanta, Georgia.
"Preeclampsia can be sort of a diagnostic dilemma that really results from the placenta not growing properly at different stages in the pregnancy," she said. "There are different compounds released into the maternal circulation that may end up being an early footprint for detecting the condition."
"There are several biomarkers that have had some success in validation to identify the clinical scenario before it occurs, so it's interesting to see a unique proteomic footprint that might provide an early detector for this condition as well."
Earlier detection could allow for improved care for the mother and child, she added.
"Women typically don't go to their doctor more than once a month in early pregnancy, and sometimes less than that if they're doing well, so this could allow for closer monitoring of their blood pressure, for instance, and patients could be placed on blood pressure medication sooner rather than later, if necessary.
"Clinicians could also monitor [women] to identify proteinuria earlier. All of those things suggest better protection for the mom and the baby," Dr. Chapman said. "They will need to spend some time validating this in prospective populations to see if it can actually detect the development of preeclampsia, but I think this is exciting."
The study was supported by an unrestricted grant from Baxter Healthcare and University Hospitals Leicester National Health Service Trust Charitable Funds. Dr. Hall and Dr. Chapman have disclosed no relevant financial relationships.
Renal Week 2010: American Society of Nephrology 43rd Annual Meeting. Abstract FC223. Presented November 19, 2010.
ROCK STARS OF SCIENCE
December 1, 2010 — Stephen Baylin, MD, is not a rock star. But he seems to be something along those lines — at least to a clerk at his neighborhood 7-Eleven convenience store.
Dr. Baylin, who is a cancer biologist and researcher in epigenetic therapy at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland, is one of the 2010 Rock Stars of Science, a public-service campaign that is now in its second year and is featured in a 6-page photo spread in the December issue of GQ magazine.
He is one of 6 oncologists/cancer researchers in the promotional campaign, which includes celebrity rock stars such as Bret Michaels, Debbie Harry, and Timbaland.
The Rock Stars of Science campaign aims, in an unconventional way, to communicate the importance of biomedical research and scientists in the United States.
The December issue of GQ is now on newsstands, which Dr. Baylin found out inadvertently.
"I was at the 7-Eleven and noticed a picture of Jeff Bridges on the cover of a magazine. I've really enjoyed him in movies, so I looked at the magazine — which turned out be GQ," he told Medscape Medical News.
Dr. Baylin proceeded to the cash register, looking at the magazine. The young male clerk looked too and recognized Dr. Baylin in the photos.
As Dr. Baylin left the store, where he regularly buys a morning cup of coffee, the clerk shouted hopefully after him, "I've always wanted to meet Sandra Bullock!"
The sponsor of the Rock Star campaign, the menswear designer Geoffrey Beene and his charity organization Geoffrey Beene Gives Back, hopes Dr. Baylin's shopping experience will be repeated many times over — but with scientists and their work being accurately recognized as vitally connected to American life.
"Scientists must venture outside their comfort zones to show the public how cool — and how important — their work really is," said Francis Collins, MD, director of the National Institutes of Health in a press statement from the campaign. Dr. Collins was one of the 2009 Rock Stars of Science.
"I urge every scientist to get into the act by telling friends, neighbors, community leaders, and elected officials about his or her research and what it means for our nation's health. Imagine how powerful that would be," he said.
Anonymous Profession?
Scientists might be the most anonymous professionals in the United States, suggests the Rock Star of Science campaign.
Nearly half of Americans polled in Harris Interactive and Research!America surveys could not name a single living scientist, according to the campaign.
In effort to "bridge" what the Rock Star campaign calls "a serious recognition gap for science," 17 of the nation's top medical researchers, including 2 Nobel laureates, dressed up in outfits reminiscent of 1940s hardboiled detectives and posed for pictures with prominent musicians.
In addition to Dr. Baylin, who is deputy director of the Sidney Kimmel Comprehensive Cancer Center and a Stand Up to Cancer Dream Team leader, the other oncologists/cancer researchers on the 2010 roster are:
* Catriona Jamieson, MD, PhD, assistant professor of medicine and hematologic malignancies, University of California, San Diego (UCSD), and director of Stem Cell Research, Moores UCSD Cancer Center
* Joan Massaguė, PhD, chair of the cancer biology and genetics program, Memorial Sloan-Kettering Cancer Center, New York City, and executive committee member, Geoffrey Beene Cancer Research Center
* Phillip A. Sharp, PhD, Nobel laureate; professor at the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, Cambridge; and chair, Stand Up To Cancer Scientific Advisory Committee
* Charles L. Sawyers, MD, chair of the human oncology and pathogenesis program at Memorial Sloan-Kettering Cancer Center, and executive committee member, Geoffrey Beene Cancer Research Center
* Craig B. Thompson, MD, president/CEO of Memorial Sloan-Kettering Cancer Center, and chair of the executive committee of the Geoffrey Beene Cancer Research Center
Each of the Rock Stars of Science is profiled on the campaign's Web site. The profile touches on both the gravity of their work and personal tidbits that could be considered of lesser import.
For instance, Dr. Sawyers, who has been part of teams that discovered the groundbreaking chronic myeloid leukemia drug Gleevec (Novartis) and the potentially groundbreaking advanced prostate cancer drug MDV 3100 (Medivation), reveals that his "worst part-time job ever" was delivering yellow pages door to door.
Dr. Baylin said his participation in the Rock Stars of Science campaign has raised his profile in other areas of his life, not just in convenience stores.
Dr. Baylin's photo shoot for the Rock Stars of Science pictorial took place in Los Angeles when he participated in the filming of the annual Stand Up To Cancer television program, a creation of the Entertainment Industry Foundation, which also sponsors the Rock Stars, and the American Association for Cancer Research.
In the photos, he was teamed with Mehmet Toner, PhD, from Harvard University in Boston, Massachusetts, and the rapper B.o.B., who has a number of hit songs and is only 19 years of age.
During the photo shoot, a friend in the audience took some digital pictures with a camera phone and emailed them to Dr. Baylin, who in turn emailed them to his grandchildren.
"My 2 eldest grandchildren swooned. B.o.B. is a favorite of theirs. I am now validated as a cool grandfather!"
Dr. Baylin, who is a cancer biologist and researcher in epigenetic therapy at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland, is one of the 2010 Rock Stars of Science, a public-service campaign that is now in its second year and is featured in a 6-page photo spread in the December issue of GQ magazine.
He is one of 6 oncologists/cancer researchers in the promotional campaign, which includes celebrity rock stars such as Bret Michaels, Debbie Harry, and Timbaland.
The Rock Stars of Science campaign aims, in an unconventional way, to communicate the importance of biomedical research and scientists in the United States.
The December issue of GQ is now on newsstands, which Dr. Baylin found out inadvertently.
"I was at the 7-Eleven and noticed a picture of Jeff Bridges on the cover of a magazine. I've really enjoyed him in movies, so I looked at the magazine — which turned out be GQ," he told Medscape Medical News.
Dr. Baylin proceeded to the cash register, looking at the magazine. The young male clerk looked too and recognized Dr. Baylin in the photos.
As Dr. Baylin left the store, where he regularly buys a morning cup of coffee, the clerk shouted hopefully after him, "I've always wanted to meet Sandra Bullock!"
The sponsor of the Rock Star campaign, the menswear designer Geoffrey Beene and his charity organization Geoffrey Beene Gives Back, hopes Dr. Baylin's shopping experience will be repeated many times over — but with scientists and their work being accurately recognized as vitally connected to American life.
"Scientists must venture outside their comfort zones to show the public how cool — and how important — their work really is," said Francis Collins, MD, director of the National Institutes of Health in a press statement from the campaign. Dr. Collins was one of the 2009 Rock Stars of Science.
"I urge every scientist to get into the act by telling friends, neighbors, community leaders, and elected officials about his or her research and what it means for our nation's health. Imagine how powerful that would be," he said.
Anonymous Profession?
Scientists might be the most anonymous professionals in the United States, suggests the Rock Star of Science campaign.
Nearly half of Americans polled in Harris Interactive and Research!America surveys could not name a single living scientist, according to the campaign.
In effort to "bridge" what the Rock Star campaign calls "a serious recognition gap for science," 17 of the nation's top medical researchers, including 2 Nobel laureates, dressed up in outfits reminiscent of 1940s hardboiled detectives and posed for pictures with prominent musicians.
In addition to Dr. Baylin, who is deputy director of the Sidney Kimmel Comprehensive Cancer Center and a Stand Up to Cancer Dream Team leader, the other oncologists/cancer researchers on the 2010 roster are:
* Catriona Jamieson, MD, PhD, assistant professor of medicine and hematologic malignancies, University of California, San Diego (UCSD), and director of Stem Cell Research, Moores UCSD Cancer Center
* Joan Massaguė, PhD, chair of the cancer biology and genetics program, Memorial Sloan-Kettering Cancer Center, New York City, and executive committee member, Geoffrey Beene Cancer Research Center
* Phillip A. Sharp, PhD, Nobel laureate; professor at the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, Cambridge; and chair, Stand Up To Cancer Scientific Advisory Committee
* Charles L. Sawyers, MD, chair of the human oncology and pathogenesis program at Memorial Sloan-Kettering Cancer Center, and executive committee member, Geoffrey Beene Cancer Research Center
* Craig B. Thompson, MD, president/CEO of Memorial Sloan-Kettering Cancer Center, and chair of the executive committee of the Geoffrey Beene Cancer Research Center
Each of the Rock Stars of Science is profiled on the campaign's Web site. The profile touches on both the gravity of their work and personal tidbits that could be considered of lesser import.
For instance, Dr. Sawyers, who has been part of teams that discovered the groundbreaking chronic myeloid leukemia drug Gleevec (Novartis) and the potentially groundbreaking advanced prostate cancer drug MDV 3100 (Medivation), reveals that his "worst part-time job ever" was delivering yellow pages door to door.
Dr. Baylin said his participation in the Rock Stars of Science campaign has raised his profile in other areas of his life, not just in convenience stores.
Dr. Baylin's photo shoot for the Rock Stars of Science pictorial took place in Los Angeles when he participated in the filming of the annual Stand Up To Cancer television program, a creation of the Entertainment Industry Foundation, which also sponsors the Rock Stars, and the American Association for Cancer Research.
In the photos, he was teamed with Mehmet Toner, PhD, from Harvard University in Boston, Massachusetts, and the rapper B.o.B., who has a number of hit songs and is only 19 years of age.
During the photo shoot, a friend in the audience took some digital pictures with a camera phone and emailed them to Dr. Baylin, who in turn emailed them to his grandchildren.
"My 2 eldest grandchildren swooned. B.o.B. is a favorite of theirs. I am now validated as a cool grandfather!"
ANNUAL MRI MAMMOGRAPHY BENEFITS HIGH RISK WOMEN
November 30, 2010 (Chicago, Illinois) — Women with a personal history of breast cancer should be screened annually with magnetic resonance imaging (MRI), according to a new study presented here at Radiological Society of North America 96th Scientific Assembly and Annual Meeting.
"Annual screening MRI is recommended by the American Cancer Society as an adjunct to mammographic screening for individuals who have sufficient genetic or family history, defined by a greater than 20% lifetime risk of developing cancer," according to Wendy B. DeMartini, MD, from the University of Washington Medical Center and Seattle Cancer Care Alliance. However, "there is currently insufficient evidence to support screening MRI for women with a personal history of treated breast cancer."
Dr. DeMartini and her colleagues compared the diagnostic performance of screening MRI in women at high risk for breast cancer with that of women who have already had breast cancer.
They performed a retrospective review of initial breast MRI screening exams of 1025 women from January 2004 to June 2009. Of these women, 327 had a genetic or family history of breast cancer and 646 had a personal history of treated breast cancer.
Overall, MRI testing identified 25 of 27 cancers, for a sensitivity rate of 92.6%.
However, cancer yield was significantly greater in women with a personal history of breast cancer than in those with a genetic or family history (3.1% vs 1.5%; P < .0001); the same was true for specificity (93.6% vs 86.3%; P = .0003).
The researchers also found that biopsy was recommended in fewer women with a personal history than in those with genetic risk factors or a family history (9.3% vs 15.0%), and that the positive predictive value of biopsy was greater in the personal history group than in the genetic or family history group (35.7% vs 12.2%; P = .009).
"The diagnostic performance of screening MRI in patients with a personal history of treated breast cancer supports consideration of this tool as an adjunct to screening mammography," Dr. DeMartini concluded.
In an interview after her talk, Dr. DeMartini told Medscape Medical News that these data add to other data that have recently been published in this area. "We think that women with a personal history of breast cancer should consider breast MRI screening, and we hope that the American Cancer Society will consider this in the future," she said.
She cautioned that her study results are from a single institution, and she would like to see them replicated at other centers. "Studies from other institutions would be important. In addition, although our study is the largest study to date in this patient population, there are a total of only 27 breast cancers in the study, so we do have this small numbers phenomenon, and that is going to be the case even in a larger study."
Commenting on this study for Medscape Medical News, Stamatia Destounis, MD, from the University of Rochester School of Medicine and Dentistry in New York, said: "This study is very important and reinforces many of the findings that breast imagers see in their daily practice. Women with a personal history of breast cancer are at risk of developing a recurrence or a new cancer in either breast, and breast MRI can be very useful in detecting occult cancer that may otherwise not be found with standard screening techniques."
Dr. Destounis, who was not part of the study, added that mammography "is a great screening tool. But for women postsurgery and postradiation, . . . the breast tissue becomes more difficult to interpret, and it also becomes more difficult to detect a new cancer. Breast MRI gives us anatomical and functional information, allowing us to detect subtle small cancers that could be missed otherwise."
This study is a good starting point for open discussions with current policy makers about the utility of MRI screening in this group of women, she said.
Dr. DeMartini and Dr. Destounis have disclosed no relevant financial relationships.
Radiological Society of North America (RSNA) 96th Scientific Assembly and Annual Meeting: Abstract SSAO1-01. Presented November 28, 2010.
"Annual screening MRI is recommended by the American Cancer Society as an adjunct to mammographic screening for individuals who have sufficient genetic or family history, defined by a greater than 20% lifetime risk of developing cancer," according to Wendy B. DeMartini, MD, from the University of Washington Medical Center and Seattle Cancer Care Alliance. However, "there is currently insufficient evidence to support screening MRI for women with a personal history of treated breast cancer."
Dr. DeMartini and her colleagues compared the diagnostic performance of screening MRI in women at high risk for breast cancer with that of women who have already had breast cancer.
They performed a retrospective review of initial breast MRI screening exams of 1025 women from January 2004 to June 2009. Of these women, 327 had a genetic or family history of breast cancer and 646 had a personal history of treated breast cancer.
Overall, MRI testing identified 25 of 27 cancers, for a sensitivity rate of 92.6%.
However, cancer yield was significantly greater in women with a personal history of breast cancer than in those with a genetic or family history (3.1% vs 1.5%; P < .0001); the same was true for specificity (93.6% vs 86.3%; P = .0003).
The researchers also found that biopsy was recommended in fewer women with a personal history than in those with genetic risk factors or a family history (9.3% vs 15.0%), and that the positive predictive value of biopsy was greater in the personal history group than in the genetic or family history group (35.7% vs 12.2%; P = .009).
"The diagnostic performance of screening MRI in patients with a personal history of treated breast cancer supports consideration of this tool as an adjunct to screening mammography," Dr. DeMartini concluded.
In an interview after her talk, Dr. DeMartini told Medscape Medical News that these data add to other data that have recently been published in this area. "We think that women with a personal history of breast cancer should consider breast MRI screening, and we hope that the American Cancer Society will consider this in the future," she said.
She cautioned that her study results are from a single institution, and she would like to see them replicated at other centers. "Studies from other institutions would be important. In addition, although our study is the largest study to date in this patient population, there are a total of only 27 breast cancers in the study, so we do have this small numbers phenomenon, and that is going to be the case even in a larger study."
Commenting on this study for Medscape Medical News, Stamatia Destounis, MD, from the University of Rochester School of Medicine and Dentistry in New York, said: "This study is very important and reinforces many of the findings that breast imagers see in their daily practice. Women with a personal history of breast cancer are at risk of developing a recurrence or a new cancer in either breast, and breast MRI can be very useful in detecting occult cancer that may otherwise not be found with standard screening techniques."
Dr. Destounis, who was not part of the study, added that mammography "is a great screening tool. But for women postsurgery and postradiation, . . . the breast tissue becomes more difficult to interpret, and it also becomes more difficult to detect a new cancer. Breast MRI gives us anatomical and functional information, allowing us to detect subtle small cancers that could be missed otherwise."
This study is a good starting point for open discussions with current policy makers about the utility of MRI screening in this group of women, she said.
Dr. DeMartini and Dr. Destounis have disclosed no relevant financial relationships.
Radiological Society of North America (RSNA) 96th Scientific Assembly and Annual Meeting: Abstract SSAO1-01. Presented November 28, 2010.
A RARE COMPLICATION OF BEVACIZUMAB
Acta Oncol. 2010 Nov 26. [Epub ahead of print]
Bevacizumab-induced nasal septal perforation: Incidence of symptomatic, confirmed event(s) in colorectal cancer patients.
Ramiscal JA, Jatoi A.
Mayo Clinic Medical School, Rochester, Minnesota 55905, USA.
Abstract
Abstract Purpose. In breast cancer patients, Mailliez and others described that 5 of 70 patients (7%) developed a bevacizumab-induced nasal septal perforation. However, to date, no studies have reported such rates in colorectal cancer patients, who derive a survival advantage with this drug. Methods. This study examined the incidence of bevacizumab-induced, clinically symptomatic, otolaryngology specialist-confirmed nasal septal perforation among 100 patients who had been consecutively-treated for metastatic colorectal cancer. Results. The incidence of nasal septal perforation was 1% (95% confidence intervals: -0.95% to 2.95%). This single adverse event was successfully managed conservatively. Within the whole group, 94 had been treated with bevacizumab at 5 mg/kg every two weeks, except for four patients treated at higher doses. The median number of bevacizumab doses (range) was seven (1-96). Concomitant chemotherapy had been prescribed to all patients, consisting of oxaliplatin, 5-fluorouracil, leucovorin, as per one of the FOLFOX regimens (44 patients); irinotecan, 5-fluorouracil, leucovorin, as per the FOLFIRI regimen (13 patients); both these regimens and no other (five patients); or a different regimen (38 patients). Conclusion. Nasal septal perforation from bevacizumab occurs infrequently among colorectal cancer patients.
Bevacizumab-induced nasal septal perforation: Incidence of symptomatic, confirmed event(s) in colorectal cancer patients.
Ramiscal JA, Jatoi A.
Mayo Clinic Medical School, Rochester, Minnesota 55905, USA.
Abstract
Abstract Purpose. In breast cancer patients, Mailliez and others described that 5 of 70 patients (7%) developed a bevacizumab-induced nasal septal perforation. However, to date, no studies have reported such rates in colorectal cancer patients, who derive a survival advantage with this drug. Methods. This study examined the incidence of bevacizumab-induced, clinically symptomatic, otolaryngology specialist-confirmed nasal septal perforation among 100 patients who had been consecutively-treated for metastatic colorectal cancer. Results. The incidence of nasal septal perforation was 1% (95% confidence intervals: -0.95% to 2.95%). This single adverse event was successfully managed conservatively. Within the whole group, 94 had been treated with bevacizumab at 5 mg/kg every two weeks, except for four patients treated at higher doses. The median number of bevacizumab doses (range) was seven (1-96). Concomitant chemotherapy had been prescribed to all patients, consisting of oxaliplatin, 5-fluorouracil, leucovorin, as per one of the FOLFOX regimens (44 patients); irinotecan, 5-fluorouracil, leucovorin, as per the FOLFIRI regimen (13 patients); both these regimens and no other (five patients); or a different regimen (38 patients). Conclusion. Nasal septal perforation from bevacizumab occurs infrequently among colorectal cancer patients.
6.2 MONTHS PFS FOR PLEXXICON IN MELANOMA STUDIES DESPITE AMAZING RESPONSE RATES
November 25, 2010 — The experimental drug PLX4032 (Plexxicon/Roche) for melanoma was hailed as a "major breakthrough" earlier this year after showing unprecedented response rates in a phase 1 study.
Those high response rates have now been confirmed in a phase 2 study, which also suggests that there is a progression-free-survival advantage.
A phase 3 study is now in progress.
However, excitement over this drug has been tempered somewhat by the emergence of resistance, seen after only several months of treatment. But new research into the mechanism behind this resistance has yielded a rather surprising finding, and points the way forward for further drug development.
First Targeted Therapy in Melanoma
PLX4032 is the first targeted agent for melanoma. It homes in on the BRAF mutation, which drives the disease in about 50% of melanoma patients.
This BRAF mutation is also found in other cancers, including lung and colon, and is thought to occur in 8% of solid tumors.
Early results in melanoma — from a phase 1 study of 32 melanoma patients with a BRAF mutation — showed responses in a "remarkable 81% of patients," which "represent a major breakthrough," enthused the authors of an editorial that accompanied the publication of the study in the New England Journal of Medicine (2010;363;809-819, 876-879).
The latest clinical results, presented recently at the International Melanoma Research Congress of the Society for Melanoma Research in Sydney, Australia, confirm the high response rates.
They come from an open-label phase 2 trial of 132 patients with previously treated advanced melanoma positive for the BRAF mutation. Researchers report that 82% of patients had a response (52%) or stable disease (30%), and 52% had a decrease in their tumor size of 30% or more.
The median progression-free survival was 6.2 months in these patients; typically progression-free survival for such patients is only about 2 months, according to the researchers. Overall survival is typically around 6 to 9 months, they add, but the median overall survival has not yet been reached in the trial.
The safety profile is similar to that already reported for the experimental agent, and includes the development again of the grade 3 cutaneous squamous cell carcinoma, this time in 26% (34 of 132) patients. In these cases, the cutaneous squamous cell carcinoma lesions were excised and the patients continued with the experimental therapy. In addition, abnormal liver function was reported in 14% of patients, joint pain/arthritis in 11%, and gastrointestinal symptoms (including gastritis and pancreatitis) in 10%. Rash, photosensitivity, and hair loss were also reported.
These response rates are amazing," said Antoni Ribas MD, from the Jonsson Comprehensive Cancer Center at the University of California in Los Angeles, who was involved in both the phase 1 and phase 2 clinical trials.
"So far in advanced melanoma, we have seen responses to drug therapy in only about 10% of patients, yet here we are seeing some sort of response in nearly every patient," he told Medscape Medical News in an interview.
"This is a huge step forward; in fact, it's a paradigm shift," he said.
The responses are not durable; they last for an average of about 7 months before the disease progresses, Dr. Ribas noted. Even so, he speculates that the response to the drug might lead to an improvement in survival by shifting the first part of the survival curve over by a few months.
Studying Resistance to the Drug
The decline in response indicates resistance to the drug, which means that these patients will need to be treated with other drugs.
New studies on the mechanisms involved in the emergence of this resistance has been reported in 2 letters published online November 24 in Nature.
In one of these studies, a team from the Jonsson Comprehensive Cancer Center, which included Dr. Ribas, looked at tissue from patients participating in the trials, and came up with a surprising finding.
Initially, the team presumed that the resistance to the BRAF inhibitor developed because BRAF had mutated further, but this was not the case.
This is an important finding, which will save both time and effort, the team believes, because it means that second-generation drugs targeting BRAF will not work, and therefore should not be developed.
"We were surprised that we couldn't find a single case [in which] a secondary mutation in BRAF was driving the resistance," Roger Lo, MD, assistant professor of dermatology at the Jonsson Comprehensive Cancer Center and corresponding author of the letter, said in a statement.
"In a big portion of known cases [in which] certain cancers acquire resistance to targeted drugs, the oncogene being targeted by the drug finds a way to get around the drug by developing other mutations," he said. It's almost like "you hit it with an axe, but the cancer soon finds a way to mitigate the effects of the axe," he explained.
But in the case of PLX4032 and BRAF inhibition, other mechanisms are involved. Dr. Lo and colleagues found 2 mutually exclusive mechanisms that explain the acquired resistance in about 40% of patients. One mechanism involves a cell-surface protein that the cancer cell begins to overexpress, creating an alternate survival pathway for the cancer when BRAF is blocked by PLX4032. The other mechanism involves a second oncogene, NRAS, which becomes mutated and allows the cancer to short circuit the PLX4032-inhibited BRAF mutation and reactivate the BRAF survival pathway.
"We've found 2 mechanisms in 2 subsets of melanoma, and we'll need different drugs to treat those 2 subsets," Dr. Lo said.
There are certainly other mechanisms of acquired resistance, he added, in the remaining 60% of patients.
In the second study, another mechanism of resistance was reported by a team from the Dana-Farber Cancer Institute in Boston, Massachusetts. They identified a novel cancer gene encoding COT (known as MAP3K8), and found that it became elevated during BRAF inhibitor treatment or the development of drug resistance. In some cases, high levels of the COT protein were evident in tissue from patients whose tumors returned or relapsed after drug treatment.
"Although we need to extend these results to larger numbers of samples, this is tantalizing clinical evidence that COT plays a role in at least some relapsing melanomas," said senior author of the letter Levi Garraway, MD, medical oncologist and assistant professor at Dana-Farber and Harvard Medical School.
This research suggests that one way forward in the development of new drugs is to focus on a combination of therapies directed against the MAP kinase pathway — a pathway in which both BRAF and COT are known to act. Such agents could be effective in overcoming the resistance that develops to PLX4032, they speculate.
"In melanoma, as well as in several other cancers, there is a critical need to understand the resistance mechanism, which will enable us to be smarter up front in designing drugs that can yield more lasting clinical responses," Dr. Garraway said in a statement.
"Biology is showing us where to hit in order to develop new drugs," Dr. Ribas concluded.
Nature. Published online November 24, 2010.
Those high response rates have now been confirmed in a phase 2 study, which also suggests that there is a progression-free-survival advantage.
A phase 3 study is now in progress.
However, excitement over this drug has been tempered somewhat by the emergence of resistance, seen after only several months of treatment. But new research into the mechanism behind this resistance has yielded a rather surprising finding, and points the way forward for further drug development.
First Targeted Therapy in Melanoma
PLX4032 is the first targeted agent for melanoma. It homes in on the BRAF mutation, which drives the disease in about 50% of melanoma patients.
This BRAF mutation is also found in other cancers, including lung and colon, and is thought to occur in 8% of solid tumors.
Early results in melanoma — from a phase 1 study of 32 melanoma patients with a BRAF mutation — showed responses in a "remarkable 81% of patients," which "represent a major breakthrough," enthused the authors of an editorial that accompanied the publication of the study in the New England Journal of Medicine (2010;363;809-819, 876-879).
The latest clinical results, presented recently at the International Melanoma Research Congress of the Society for Melanoma Research in Sydney, Australia, confirm the high response rates.
They come from an open-label phase 2 trial of 132 patients with previously treated advanced melanoma positive for the BRAF mutation. Researchers report that 82% of patients had a response (52%) or stable disease (30%), and 52% had a decrease in their tumor size of 30% or more.
The median progression-free survival was 6.2 months in these patients; typically progression-free survival for such patients is only about 2 months, according to the researchers. Overall survival is typically around 6 to 9 months, they add, but the median overall survival has not yet been reached in the trial.
The safety profile is similar to that already reported for the experimental agent, and includes the development again of the grade 3 cutaneous squamous cell carcinoma, this time in 26% (34 of 132) patients. In these cases, the cutaneous squamous cell carcinoma lesions were excised and the patients continued with the experimental therapy. In addition, abnormal liver function was reported in 14% of patients, joint pain/arthritis in 11%, and gastrointestinal symptoms (including gastritis and pancreatitis) in 10%. Rash, photosensitivity, and hair loss were also reported.
These response rates are amazing," said Antoni Ribas MD, from the Jonsson Comprehensive Cancer Center at the University of California in Los Angeles, who was involved in both the phase 1 and phase 2 clinical trials.
"So far in advanced melanoma, we have seen responses to drug therapy in only about 10% of patients, yet here we are seeing some sort of response in nearly every patient," he told Medscape Medical News in an interview.
"This is a huge step forward; in fact, it's a paradigm shift," he said.
The responses are not durable; they last for an average of about 7 months before the disease progresses, Dr. Ribas noted. Even so, he speculates that the response to the drug might lead to an improvement in survival by shifting the first part of the survival curve over by a few months.
Studying Resistance to the Drug
The decline in response indicates resistance to the drug, which means that these patients will need to be treated with other drugs.
New studies on the mechanisms involved in the emergence of this resistance has been reported in 2 letters published online November 24 in Nature.
In one of these studies, a team from the Jonsson Comprehensive Cancer Center, which included Dr. Ribas, looked at tissue from patients participating in the trials, and came up with a surprising finding.
Initially, the team presumed that the resistance to the BRAF inhibitor developed because BRAF had mutated further, but this was not the case.
This is an important finding, which will save both time and effort, the team believes, because it means that second-generation drugs targeting BRAF will not work, and therefore should not be developed.
"We were surprised that we couldn't find a single case [in which] a secondary mutation in BRAF was driving the resistance," Roger Lo, MD, assistant professor of dermatology at the Jonsson Comprehensive Cancer Center and corresponding author of the letter, said in a statement.
"In a big portion of known cases [in which] certain cancers acquire resistance to targeted drugs, the oncogene being targeted by the drug finds a way to get around the drug by developing other mutations," he said. It's almost like "you hit it with an axe, but the cancer soon finds a way to mitigate the effects of the axe," he explained.
But in the case of PLX4032 and BRAF inhibition, other mechanisms are involved. Dr. Lo and colleagues found 2 mutually exclusive mechanisms that explain the acquired resistance in about 40% of patients. One mechanism involves a cell-surface protein that the cancer cell begins to overexpress, creating an alternate survival pathway for the cancer when BRAF is blocked by PLX4032. The other mechanism involves a second oncogene, NRAS, which becomes mutated and allows the cancer to short circuit the PLX4032-inhibited BRAF mutation and reactivate the BRAF survival pathway.
"We've found 2 mechanisms in 2 subsets of melanoma, and we'll need different drugs to treat those 2 subsets," Dr. Lo said.
There are certainly other mechanisms of acquired resistance, he added, in the remaining 60% of patients.
In the second study, another mechanism of resistance was reported by a team from the Dana-Farber Cancer Institute in Boston, Massachusetts. They identified a novel cancer gene encoding COT (known as MAP3K8), and found that it became elevated during BRAF inhibitor treatment or the development of drug resistance. In some cases, high levels of the COT protein were evident in tissue from patients whose tumors returned or relapsed after drug treatment.
"Although we need to extend these results to larger numbers of samples, this is tantalizing clinical evidence that COT plays a role in at least some relapsing melanomas," said senior author of the letter Levi Garraway, MD, medical oncologist and assistant professor at Dana-Farber and Harvard Medical School.
This research suggests that one way forward in the development of new drugs is to focus on a combination of therapies directed against the MAP kinase pathway — a pathway in which both BRAF and COT are known to act. Such agents could be effective in overcoming the resistance that develops to PLX4032, they speculate.
"In melanoma, as well as in several other cancers, there is a critical need to understand the resistance mechanism, which will enable us to be smarter up front in designing drugs that can yield more lasting clinical responses," Dr. Garraway said in a statement.
"Biology is showing us where to hit in order to develop new drugs," Dr. Ribas concluded.
Nature. Published online November 24, 2010.
TRASTUZUMAB EFFECTIVE FOR T1b TUMORS
December 1, 2010 — The addition of trastuzumab (Herceptin) to chemotherapy is now the standard of care for many patients with early HER2-positive breast cancer, but not all; those will very small tumors are often not treated.
Women with small T1a (≤0.5 cm) and T1b (from 0.5 to 1 cm) node-negative (N0) cancers usually have an excellent prognosis and are not believed to derive a benefit from adjuvant therapy.
However, a review paper published in the December issue of the Lancet Oncology points out that there is "strong circumstantial evidence to justify some form of trastuzumab-based adjuvant therapy in most women with T1b, N0, HER2-positive breast cancers."
According to retrospective data, note authors Susana Banerjee, PhD, and Ian E. Smith, MD, from the Royal Marsden Hospital, London, United Kingdom, some small HER2-positive cancers might have a worse clinical outcome than others.
"Retrospective studies of . . . T1a,bN0 breast cancer, treated with local therapy and usually without adjuvant therapy, have consistently reported a 10-year relapse-free survival of more than 90%," the authors write. "However, many of these studies have limitations, including small sample size, short follow-up, and some patients receiving adjuvant systemic therapy."
The risk of recurrence in this subgroup of breast cancer patients and the true benefit of any adjuvant treatment remain unclear, they note. In addition, HER2-positive breast cancer, which accounts for approximately 15% to 20% of cases, is a distinct biologic subgroup and is associated with an aggressive clinical course.
Not Considered Low Risk
Drs. Smith and Banerjee note that retrospective data from several studies suggest that HER2 is a marker of poor prognosis in patients with small node-negative cancers. In fact, they point out, these tumors have a substantially increased risk for recurrence and should not be considered low risk.
As previously reported by Medscape Medical News, some researchers believe that all low-grade HER2-positive tumors should be treated with adjuvant systemic therapy, no matter what their size. Two studies that were presented at the 2008 San Antonio Breast Cancer Symposium (SABCS) found that patients with this tumor subtype have a poorer prognosis and a higher risk for recurrence.
"The biology of the tumor, and not the size or grade, matters most in these patients," Sian Tovey, MD, from the Glasgow Royal Infirmary, Scotland, who presented the results from one of the studies at the SABCS, told Medscape Medical News at the time. "Any patient who is HER2 positive should be categorized as high risk and should receive adjuvant trastuzumab therapy."
In their review, Drs. Smith and Banerjee point out that the number of women being diagnosed with T1a,bN0 primary tumors is rising because of improved breast cancer awareness and screening programs. Thus, there is a need for clarification of the optimal treatment.
Benefit Suggested, Inconsistent Guidelines
The pivotal adjuvant trastuzumab trials, which involved more than 14,000 patients, excluded women with tumors smaller than 1 cm. But there is indirect evidence that trastuzumab might benefit patients with these smaller tumors, they write. For example, a subset analysis of the Herceptin Adjuvant (HERA) trial showed that those with tumors 1 to 2 cm in size derived at least as much clinical benefit from 1 year of adjuvant trastuzumab as did the overall cohort (Lancet. 2007;369:29-36).
In another subanalysis from the Breast Cancer International Research Group 006 trial, results suggested that node-negative patients gained at least as much benefit from trastuzumab as did the overall group, both for disease-free and overall survival (SABCS 2006. Abstract 52). These results supported those from the HERA study, the authors note.
The lack of supportive evidence, however, places clinicians in a dilemma when they are trying to select appropriate therapy for this group of breast cancer patients. "Present guidelines for the systemic treatment of small, HER2-positive breast cancers are uncertain and inconsistent," Drs. Smith and Banerjee write.
Future Directions
Ideally, prospective randomized trials of trastuzumab-based treatment are needed for this population, but they are not likely to ever be conducted for a number of reasons, the authors write. Because of the low incidence of small HER2-positive breast cancers and the relatively low event rate, a large number of patients would be needed, which would be expensive. The design of trials has already proven difficult to agree upon, and successful recruitment to a randomized trial with a no-treatment group would be challenging. Finally, the choice of treatment for the investigational group is controversial.
Taking this into consideration, they suggest that the "next best approach would be a nonrandomized prospective study." Additional supportive evidence could be garnered from ongoing trials that include patients with small HER2-positive tumors.
The authors offer 2 more recommendations. One is to create prospective databases on the management of patients with HER2-positive cancers, which would provide retrospective analyses of outcomes associated with different treatments. The second is to incorporate molecular markers and multigene assays into clinical datasets, which might help identify and stratify relative risk within this subgroup.
"As in other areas of breast cancer management, this type of approach will eventually lead to a much more accurate prediction of which systemic therapies, if any, will most benefit each individual patient with these difficult, small, HER2-positive cancers," they conclude.
Dr. Smith reports receiving occasional honoraria for lecturing from Roche. Dr. Banerjee has disclosed no relevant financial relationships.
Lancet Oncol. 2010;11:1193-1199.
Women with small T1a (≤0.5 cm) and T1b (from 0.5 to 1 cm) node-negative (N0) cancers usually have an excellent prognosis and are not believed to derive a benefit from adjuvant therapy.
However, a review paper published in the December issue of the Lancet Oncology points out that there is "strong circumstantial evidence to justify some form of trastuzumab-based adjuvant therapy in most women with T1b, N0, HER2-positive breast cancers."
According to retrospective data, note authors Susana Banerjee, PhD, and Ian E. Smith, MD, from the Royal Marsden Hospital, London, United Kingdom, some small HER2-positive cancers might have a worse clinical outcome than others.
"Retrospective studies of . . . T1a,bN0 breast cancer, treated with local therapy and usually without adjuvant therapy, have consistently reported a 10-year relapse-free survival of more than 90%," the authors write. "However, many of these studies have limitations, including small sample size, short follow-up, and some patients receiving adjuvant systemic therapy."
The risk of recurrence in this subgroup of breast cancer patients and the true benefit of any adjuvant treatment remain unclear, they note. In addition, HER2-positive breast cancer, which accounts for approximately 15% to 20% of cases, is a distinct biologic subgroup and is associated with an aggressive clinical course.
Not Considered Low Risk
Drs. Smith and Banerjee note that retrospective data from several studies suggest that HER2 is a marker of poor prognosis in patients with small node-negative cancers. In fact, they point out, these tumors have a substantially increased risk for recurrence and should not be considered low risk.
As previously reported by Medscape Medical News, some researchers believe that all low-grade HER2-positive tumors should be treated with adjuvant systemic therapy, no matter what their size. Two studies that were presented at the 2008 San Antonio Breast Cancer Symposium (SABCS) found that patients with this tumor subtype have a poorer prognosis and a higher risk for recurrence.
"The biology of the tumor, and not the size or grade, matters most in these patients," Sian Tovey, MD, from the Glasgow Royal Infirmary, Scotland, who presented the results from one of the studies at the SABCS, told Medscape Medical News at the time. "Any patient who is HER2 positive should be categorized as high risk and should receive adjuvant trastuzumab therapy."
In their review, Drs. Smith and Banerjee point out that the number of women being diagnosed with T1a,bN0 primary tumors is rising because of improved breast cancer awareness and screening programs. Thus, there is a need for clarification of the optimal treatment.
Benefit Suggested, Inconsistent Guidelines
The pivotal adjuvant trastuzumab trials, which involved more than 14,000 patients, excluded women with tumors smaller than 1 cm. But there is indirect evidence that trastuzumab might benefit patients with these smaller tumors, they write. For example, a subset analysis of the Herceptin Adjuvant (HERA) trial showed that those with tumors 1 to 2 cm in size derived at least as much clinical benefit from 1 year of adjuvant trastuzumab as did the overall cohort (Lancet. 2007;369:29-36).
In another subanalysis from the Breast Cancer International Research Group 006 trial, results suggested that node-negative patients gained at least as much benefit from trastuzumab as did the overall group, both for disease-free and overall survival (SABCS 2006. Abstract 52). These results supported those from the HERA study, the authors note.
The lack of supportive evidence, however, places clinicians in a dilemma when they are trying to select appropriate therapy for this group of breast cancer patients. "Present guidelines for the systemic treatment of small, HER2-positive breast cancers are uncertain and inconsistent," Drs. Smith and Banerjee write.
Future Directions
Ideally, prospective randomized trials of trastuzumab-based treatment are needed for this population, but they are not likely to ever be conducted for a number of reasons, the authors write. Because of the low incidence of small HER2-positive breast cancers and the relatively low event rate, a large number of patients would be needed, which would be expensive. The design of trials has already proven difficult to agree upon, and successful recruitment to a randomized trial with a no-treatment group would be challenging. Finally, the choice of treatment for the investigational group is controversial.
Taking this into consideration, they suggest that the "next best approach would be a nonrandomized prospective study." Additional supportive evidence could be garnered from ongoing trials that include patients with small HER2-positive tumors.
The authors offer 2 more recommendations. One is to create prospective databases on the management of patients with HER2-positive cancers, which would provide retrospective analyses of outcomes associated with different treatments. The second is to incorporate molecular markers and multigene assays into clinical datasets, which might help identify and stratify relative risk within this subgroup.
"As in other areas of breast cancer management, this type of approach will eventually lead to a much more accurate prediction of which systemic therapies, if any, will most benefit each individual patient with these difficult, small, HER2-positive cancers," they conclude.
Dr. Smith reports receiving occasional honoraria for lecturing from Roche. Dr. Banerjee has disclosed no relevant financial relationships.
Lancet Oncol. 2010;11:1193-1199.
ANTIDEPRESSANTS INCREASE CARDIOVASCULAR RISK
November 30, 2010 — Findings from a prospective cohort study released today suggest tricyclic antidepressants (TCAs) are associated with a 35% increased risk for cardiovascular disease (CVD), which is not explained by existing psychiatric illness.
However, researchers found no increased cardiac risk associated with selective serotonin reuptake inhibitors (SSRIs).
"This suggests that there may be some characteristic of tricyclics that is raising the risk," Mark Hamer, PhD, of University College London, United Kingdom, said in a release. "Tricyclics are known to have a number of side effects; they are linked to increased blood pressure, weight gain, and diabetes, and these are all risk factor for CVD," he adds.
Dr. Hamer told Medscape Medical News that clinicians need to "be cautious about prescribing TCAs, especially in people with other risk factors."
In the study, published online December 1 in the European Heart Journal, Dr. Hamer and colleagues assessed the association between antidepressant medication use and future risk for CVD in 14,784 Scottish adults with no known history of CVD.
All were participants in the Scottish Health Survey, which collects information from the general population every 3 to 5 years. Data from separate surveys in 1995, 1998, and 2003 were combined and linked with records on hospital admissions and deaths, with follow-up until 2007. Individuals with a history of clinically confirmed CVD were excluded.
According to the investigators, 729 (4.9%) of the 14,784 study subjects reported using antidepressant medication: 2.2% reported TCA use, 2% reported SSRI use, and 0.7% reported taking other antidepressants.
Findings Support Previous Research
During an average of 8 years of follow-up, there were 1434 CVD events, of which 26.2% were fatal. After adjusting for various confounding factors, including indicators of mental illness, there was a 35% increased risk for CVD associated with TCA use (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.03 – 1.77).
There was also a nonsignificant association between TCA use and coronary heart disease events (969 events; multivariate HR, 1.24; 95% CI, 0.87 – 1.75).
In contrast, SSRI use was not associated with increased CVD risk (HR, 1.11; 95% CI, 0.77 – 1.60) and neither class of drug was associated with all-cause mortality.
"Our study is the first to contain a representative sample of the whole community, including elderly and unemployed participants, men and women, [and] our data are largely consistent with the few previous studies in healthy people," Dr. Hamer said.
In 1 such study, use of TCAs was associated with about a 2-fold increased relative risk for myocardial infarction during 4.5 years of follow-up, compared with subjects who did not use antidepressants. There was no increased risk with SSRIs in this study (Cohen et al. Am J Med. 2000).
The absence of information on medication compliance and dosage is a limitation of the current study, Dr. Hamer and colleagues note. However, because this was an observational study, it is not possible to infer causation, they add, and it is "plausible that the results could be explained by residual confounding due to unmeasured or unknown risk factors."
Consider CVD in Depressed Patients
Reached for outside comment, Andrew H. Kemp, PhD, MAPS, of the University of Sydney, Australia, who was not involved in the study, called the findings "interesting and important," and he said the findings are "consistent with the well-known, increased anticholinergic effects of TCAs."
"These effects," Dr. Kemp explained, "are likely to be due to the effects on the heart and involve blockade of the muscarinic acetylcholine receptors at the sinoatrial node of the heart, the generator of the sinus rhythm. Blockade of these receptors leads to inhibition of parasympathetic activity and tachycardia.
"While TCAs are associated with greater affinity to muscarinic receptors, SSRIs are more benign, with the exception of paroxetine, which has considerable antimuscarinic potency," Dr. Kemp continued. "Decreased parasympathetic activity leads to increased heart rate and a decrease in heart rate variability, the latter of which may predict sudden cardiac death, even in relatively healthy individuals without a prior history of CVD."
In a study published in Biological Psychiatry in October 2010, Dr. Kemp and colleagues showed that major depressive disorder without CVD is associated with reductions in heart rate variability and that antidepressants do not reverse the observed reductions. This, they say, highlights the need to consider the cardiovascular system in patients presenting with and being treated for depression (Kemp et al. Biol Psychiatry. 2010).
Dr. Hamer and colleagues and Dr. Kemp have disclosed no relevant financial relationships.
Eur Heart J. Published online December 1, 2010.
However, researchers found no increased cardiac risk associated with selective serotonin reuptake inhibitors (SSRIs).
"This suggests that there may be some characteristic of tricyclics that is raising the risk," Mark Hamer, PhD, of University College London, United Kingdom, said in a release. "Tricyclics are known to have a number of side effects; they are linked to increased blood pressure, weight gain, and diabetes, and these are all risk factor for CVD," he adds.
Dr. Hamer told Medscape Medical News that clinicians need to "be cautious about prescribing TCAs, especially in people with other risk factors."
In the study, published online December 1 in the European Heart Journal, Dr. Hamer and colleagues assessed the association between antidepressant medication use and future risk for CVD in 14,784 Scottish adults with no known history of CVD.
All were participants in the Scottish Health Survey, which collects information from the general population every 3 to 5 years. Data from separate surveys in 1995, 1998, and 2003 were combined and linked with records on hospital admissions and deaths, with follow-up until 2007. Individuals with a history of clinically confirmed CVD were excluded.
According to the investigators, 729 (4.9%) of the 14,784 study subjects reported using antidepressant medication: 2.2% reported TCA use, 2% reported SSRI use, and 0.7% reported taking other antidepressants.
Findings Support Previous Research
During an average of 8 years of follow-up, there were 1434 CVD events, of which 26.2% were fatal. After adjusting for various confounding factors, including indicators of mental illness, there was a 35% increased risk for CVD associated with TCA use (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.03 – 1.77).
There was also a nonsignificant association between TCA use and coronary heart disease events (969 events; multivariate HR, 1.24; 95% CI, 0.87 – 1.75).
In contrast, SSRI use was not associated with increased CVD risk (HR, 1.11; 95% CI, 0.77 – 1.60) and neither class of drug was associated with all-cause mortality.
"Our study is the first to contain a representative sample of the whole community, including elderly and unemployed participants, men and women, [and] our data are largely consistent with the few previous studies in healthy people," Dr. Hamer said.
In 1 such study, use of TCAs was associated with about a 2-fold increased relative risk for myocardial infarction during 4.5 years of follow-up, compared with subjects who did not use antidepressants. There was no increased risk with SSRIs in this study (Cohen et al. Am J Med. 2000).
The absence of information on medication compliance and dosage is a limitation of the current study, Dr. Hamer and colleagues note. However, because this was an observational study, it is not possible to infer causation, they add, and it is "plausible that the results could be explained by residual confounding due to unmeasured or unknown risk factors."
Consider CVD in Depressed Patients
Reached for outside comment, Andrew H. Kemp, PhD, MAPS, of the University of Sydney, Australia, who was not involved in the study, called the findings "interesting and important," and he said the findings are "consistent with the well-known, increased anticholinergic effects of TCAs."
"These effects," Dr. Kemp explained, "are likely to be due to the effects on the heart and involve blockade of the muscarinic acetylcholine receptors at the sinoatrial node of the heart, the generator of the sinus rhythm. Blockade of these receptors leads to inhibition of parasympathetic activity and tachycardia.
"While TCAs are associated with greater affinity to muscarinic receptors, SSRIs are more benign, with the exception of paroxetine, which has considerable antimuscarinic potency," Dr. Kemp continued. "Decreased parasympathetic activity leads to increased heart rate and a decrease in heart rate variability, the latter of which may predict sudden cardiac death, even in relatively healthy individuals without a prior history of CVD."
In a study published in Biological Psychiatry in October 2010, Dr. Kemp and colleagues showed that major depressive disorder without CVD is associated with reductions in heart rate variability and that antidepressants do not reverse the observed reductions. This, they say, highlights the need to consider the cardiovascular system in patients presenting with and being treated for depression (Kemp et al. Biol Psychiatry. 2010).
Dr. Hamer and colleagues and Dr. Kemp have disclosed no relevant financial relationships.
Eur Heart J. Published online December 1, 2010.
Εγγραφή σε:
Αναρτήσεις (Atom)