New statistics for cancer in Europe show an overall downward trend for cancer deaths, and estimates show that there has been a fall in overall cancer deaths for both men and women from 2011 to 2007.
The downward trend is driven mainly by decreases in breast cancer mortality in women and in lung and colorectal cancer mortality in men.
These 3 cancers are "the top causes of cancer deaths, and these are showing major changes," said Carlo La Vecchia, MD, from the Department of Epidemiology at the Mario Negri Institute and faculty of medicine at the University of Milan, Italy.
Dr. La Vecchia and colleagues used a new mathematical model to predict cancer mortality. Their new estimates were published online February 8 in the Annals of Oncology.
The new model predicts that the total number of cancer deaths in the European Union will reach 1,281,436 in 2011, which works out to a standardized rate of 143 per 100,000 men and 85 per 100,000 women.
This compares with 1,256,001 cancer deaths in 2007, with standardized rates of 153.8 per 100,000 men and 90.7 per 100,000 women, corresponding to a 7% fall in men and a 6% fall in women, the researchers note.
In addition to the 3 cancers highlighted by Dr. La Vecchia, the model predicts declines in mortality for stomach, uterine, and prostate cancers, and for leukemia.
In fact, a downward trend in mortality rates was seen in all cancer types that were examined, with the exception of pancreatic cancer (which is stable in men and shows a slight increase in women) and lung cancer (which is increasing in women).
The rising rates of lung cancer in women are of particular concern, the researchers note. The number of women dying from lung cancer is increasing steadily across all of Europe — with the exception of the United Kingdom, which had the highest rates in women for a decade but is now seeing a leveling off.
"Despite these favorable trends in cancer death rates in Europe, the number of cancer deaths remains approximately stable, due to the ageing of the population," Dr. La Vecchia commented in a statement.
"Further, there is a persisting gap in cancer mortality between central and eastern European countries and western Europe; this is likely to persist for the foreseeable future," he said.
The new model predicts that Germany will see the greatest drop in overall cancer.
In contrast, the highest total cancer mortality rates in both sexes are seen in Poland, where there has been no improvement in recent years, which is "particularly worrying," the researchers note.
France is also singled out for concern; the predicted decline in cancer deaths there is modest because of the recent unfavorable trends in lung cancer among French (and Spanish) women.
Ongoing Downward Trend
The decline in cancer deaths from 2007 to 2011 outlined in this report is a continuation of the downward trend that has occurred in Europe over the past few decades.
"A substantial decline in total cancer mortality rates has been observed since the late 1980s in men, and since even earlier in women in the European Union," the authors write. Between 1990–1994 and 2000–2004, the rates declined by 9% in men and by 8% in women, they note. These declines continued in 2007, and this latest model predicts that they will continue to do so up to 2011.
Senin, 28 Februari 2011
Sabtu, 26 Februari 2011
SHORT TELOMERES AND CANCER RISK
The first prospective population-based study to examine telomere length and subsequent cancer risk has confirmed animal data suggesting that short telomeres are associated with higher cancer risk and worse cancer survival. The study appears in the July 7 issue of JAMA.
"The key message that the aging of cells may contribute to cancer manifestation and dissemination has been postulated before, based on several lines of evidence. Our study provides the first large-scale support of this notion," senior author Stefan Kiechl, MD, from the Department of Neurology at Innsbruck Medical University in Austria, told Medscape Medical News.
The researchers suggest that this might be because some cells that have lost bits of telomere over many cell cycles reactivate telomerase in a bid to recover their lost youth, but wind up with uncontrolled cell division instead.
Telomeres are nucleoprotein complexes at the ends of chromosomes that shorten a bit with each cell division, and thus constitute a sort of internal cell clock. Once telomeres shorten to nubs, their associated chromosomes become unstable, and the cell is headed for senescence and death. Experimental work in animals has suggested that short telomeres might also contribute to malignant cell transformation.
The research team, led by Peter Willeit, MD, from Innsbruck Medical University, report that short telomere length was associated with a 60% increased risk for subsequent cancer, independent of other risk factors, in 787 subjects in the Bruneck Study in Italy. All were cancer-free at baseline in 1995, when leukocyte telomere length was measured by quantitative polymerase chain reaction.
Subjects with the shortest telomeres had more than triple the incident cancer risk of those with the longest telomeres. Hazard ratio for incident cancer was 1.60 for every 1-standard-deviation (1-SD) decrease in telomere length. Compared with subjects in the group with the longest telomeres, incident cancer risk was 3.11 for those in the group with the shortest telomeres and 2.15 for those in the group with mid-length telomeres.
The researchers also found a doubling of cancer mortality with every 1-SD decrease in telomere length, that the association between telomere length and cancer risk applied to both males and females, and that short telomeres were particularly associated with cancer subtypes with high fatality rates.
Dr. Kiechl said that the study could have implications for clinical trial design. "However, a step to be taken is to prove whether telomere length at the time of cancer diagnosis is a predictor of cancer mortality as well; preliminary unpublished data form our group indicate that this is the case. In the current JAMA publication, we have measured telomere length well in advance of cancer onset," Dr. Kiechl said.
Dr. Kiechl expects telomere length to be useful in cancer screening. "We are confident that telomere length, in addition to other recent advances like microRNA profiling, may become components of future risk scores for cancer manifestation — at least for some types of cancer," he said. "I think that it may also become useful in the estimation of tumor prognosis, which again can influence the choice of therapy."
Dr. Kiechl also said that the researchers were surprised to find that individuals with the shortest telomeres at baseline showed an increase in telomere length over the 10-year follow-up. "This may eventually indicate that aged cells at risk of cell senescence are capable of reactivating telomerase to prolong telomeres," he said.
The researchers have disclosed no relevant financial relationships.
"The key message that the aging of cells may contribute to cancer manifestation and dissemination has been postulated before, based on several lines of evidence. Our study provides the first large-scale support of this notion," senior author Stefan Kiechl, MD, from the Department of Neurology at Innsbruck Medical University in Austria, told Medscape Medical News.
The researchers suggest that this might be because some cells that have lost bits of telomere over many cell cycles reactivate telomerase in a bid to recover their lost youth, but wind up with uncontrolled cell division instead.
Telomeres are nucleoprotein complexes at the ends of chromosomes that shorten a bit with each cell division, and thus constitute a sort of internal cell clock. Once telomeres shorten to nubs, their associated chromosomes become unstable, and the cell is headed for senescence and death. Experimental work in animals has suggested that short telomeres might also contribute to malignant cell transformation.
The research team, led by Peter Willeit, MD, from Innsbruck Medical University, report that short telomere length was associated with a 60% increased risk for subsequent cancer, independent of other risk factors, in 787 subjects in the Bruneck Study in Italy. All were cancer-free at baseline in 1995, when leukocyte telomere length was measured by quantitative polymerase chain reaction.
Subjects with the shortest telomeres had more than triple the incident cancer risk of those with the longest telomeres. Hazard ratio for incident cancer was 1.60 for every 1-standard-deviation (1-SD) decrease in telomere length. Compared with subjects in the group with the longest telomeres, incident cancer risk was 3.11 for those in the group with the shortest telomeres and 2.15 for those in the group with mid-length telomeres.
The researchers also found a doubling of cancer mortality with every 1-SD decrease in telomere length, that the association between telomere length and cancer risk applied to both males and females, and that short telomeres were particularly associated with cancer subtypes with high fatality rates.
Dr. Kiechl said that the study could have implications for clinical trial design. "However, a step to be taken is to prove whether telomere length at the time of cancer diagnosis is a predictor of cancer mortality as well; preliminary unpublished data form our group indicate that this is the case. In the current JAMA publication, we have measured telomere length well in advance of cancer onset," Dr. Kiechl said.
Dr. Kiechl expects telomere length to be useful in cancer screening. "We are confident that telomere length, in addition to other recent advances like microRNA profiling, may become components of future risk scores for cancer manifestation — at least for some types of cancer," he said. "I think that it may also become useful in the estimation of tumor prognosis, which again can influence the choice of therapy."
Dr. Kiechl also said that the researchers were surprised to find that individuals with the shortest telomeres at baseline showed an increase in telomere length over the 10-year follow-up. "This may eventually indicate that aged cells at risk of cell senescence are capable of reactivating telomerase to prolong telomeres," he said.
The researchers have disclosed no relevant financial relationships.
Kamis, 24 Februari 2011
Polyphenols, Hormesis and Disease: Part II
In the last post, I explained that the body treats polyphenols as potentially harmful foreign chemicals, or "xenobiotics". How can we reconcile this with the growing evidence that at least a subset of polyphenols have health benefits?
Clues from Ionizing Radiation
One of the more curious things that has been reported in the scientific literature is that although high-dose ionizing radiation (such as X-rays) is clearly harmful, leading to cancer, premature aging and other problems, under some conditions low-dose ionizing radiation can actually decrease cancer risk and increase resistance to other stressors (1, 2, 3, 4, 5). It does so by triggering a protective cellular response, increasing cellular defenses out of proportion to the minor threat posed by the radiation itself. The ability of mild stressors to increase stress resistance is called "hormesis." Exercise is a common example. I've written about this phenomenon in the past (6).
The Case of Resveratrol
Resveratrol is perhaps the most widely known polyphenol, available in supplement stores nationwide. It's seen a lot of hype, being hailed as a "calorie restriction mimetic" and the reason for the "French paradox."* But there is quite a large body of evidence suggesting that resveratrol functions in the same manner as low-dose ionizing radiation and other bioactive polyphenols: by acting as a mild toxin that triggers a hormetic response (7). Just as in the case of radiation, high doses of resveratrol are harmful rather than helpful. This has obvious implications for the supplementation of resveratrol and other polyphenols. A recent review article on polyphenols stated that while dietary polyphenols may be protective, "high-dose fortified foods or dietary supplements are of unproven efficacy and possibly harmful" (8).
The Cellular Response to Oxidants
Although it may not be obvious, radiation and polyphenols activate a cellular response that is similar in many ways. Both activate the transcription factor Nrf2, which activates genes that are involved in detoxification of chemicals and antioxidant defense**(9, 10, 11, 12). This is thought to be due to the fact that polyphenols, just like radiation, may temporarily increase the level of oxidative stress inside cells. Here's a quote from the polyphenol review article quoted above (13):
Nrf2 is one of the main pathways by which polyphenols increase stress resistance and antioxidant defenses, including the key cellular antioxidant glutathione (14). Nrf2 activity is correlated with longevity across species (15). Inducing Nrf2 activity via polyphenols or by other means substantially reduces the risk of common lifestyle disorders in animal models, including cardiovascular disease, diabetes and cancer (16, 17, 18), although Nrf2 isn't necessarily the only mechanism. The human evidence is broadly consistent with the studies in animals, although not as well developed.
One of the most interesting effects of hormesis is that exposure to one stressor can increase resistance to other stressors. For example, long-term consumption of high-polyphenol chocolate increases sunburn resistance in humans, implying that it induces a hormetic response in skin (19). Polyphenol-rich foods such as green tea reduce sunburn and skin cancer development in animals (20, 21).
Chris Masterjohn first introduced me to Nrf2 and the idea that polyphenols act through hormesis. Chris studies the effects of green tea on health, which seem to be mediated by polyphenols.
A Second Mechanism
There is a place in the body where polyphenols are concentrated enough to be direct antioxidants: in the digestive tract after consuming polyphenol-rich foods. Digestion is a chemically harsh process that readily oxidizes ingested substances such as polyunsaturated fats (22). Oxidized fat is neither healthy when it's formed in the deep fryer, nor when it's formed in the digestive tract (23, 24). Eating polyphenol-rich foods effectively prevents these fats from being oxidized during digestion (25). One consequence of this appears to be better absorption and assimilation of the exceptionally fragile omega-3 polyunsaturated fatty acids (26).
What does it all Mean?
I think that overall, the evidence suggests that polyphenol-rich foods are healthy in moderation, and eating them on a regular basis is generally a good idea. Certain other plant chemicals, such as suforaphane found in cruciferous vegetables, and allicin found in garlic, exhibit similar effects and may also act by hormesis (27). Some of the best-studied polyphenol-rich foods are tea (particularly green tea), blueberries, extra-virgin olive oil, red wine, citrus fruits, hibiscus tea, soy, dark chocolate, coffee, turmeric and other herbs and spices, and a number of traditional medicinal herbs. A good rule of thumb is to "eat the rainbow", choosing foods with a variety of colors.
Supplementing with polyphenols and other plant chemicals in amounts that would not be achievable by eating food is probably not a good idea.
* The "paradox" whereby the French eat a diet rich in saturated fat, yet have a low heart attack risk compared to other affluent Western nations.
** Genes containing an antioxidant response element (ARE) in the promoter region. ARE is also sometimes called the electrophile response element (EpRE).
Clues from Ionizing Radiation
One of the more curious things that has been reported in the scientific literature is that although high-dose ionizing radiation (such as X-rays) is clearly harmful, leading to cancer, premature aging and other problems, under some conditions low-dose ionizing radiation can actually decrease cancer risk and increase resistance to other stressors (1, 2, 3, 4, 5). It does so by triggering a protective cellular response, increasing cellular defenses out of proportion to the minor threat posed by the radiation itself. The ability of mild stressors to increase stress resistance is called "hormesis." Exercise is a common example. I've written about this phenomenon in the past (6).
The Case of Resveratrol
Resveratrol is perhaps the most widely known polyphenol, available in supplement stores nationwide. It's seen a lot of hype, being hailed as a "calorie restriction mimetic" and the reason for the "French paradox."* But there is quite a large body of evidence suggesting that resveratrol functions in the same manner as low-dose ionizing radiation and other bioactive polyphenols: by acting as a mild toxin that triggers a hormetic response (7). Just as in the case of radiation, high doses of resveratrol are harmful rather than helpful. This has obvious implications for the supplementation of resveratrol and other polyphenols. A recent review article on polyphenols stated that while dietary polyphenols may be protective, "high-dose fortified foods or dietary supplements are of unproven efficacy and possibly harmful" (8).
The Cellular Response to Oxidants
Although it may not be obvious, radiation and polyphenols activate a cellular response that is similar in many ways. Both activate the transcription factor Nrf2, which activates genes that are involved in detoxification of chemicals and antioxidant defense**(9, 10, 11, 12). This is thought to be due to the fact that polyphenols, just like radiation, may temporarily increase the level of oxidative stress inside cells. Here's a quote from the polyphenol review article quoted above (13):
We have found that [polyphenols] are potentially far more than 'just antioxidants', but that they are probably insignificant players as 'conventional' antioxidants. They appear, under most circumstances, to be just the opposite, i.e. prooxidants, that nevertheless appear to contribute strongly to protection from oxidative stress by inducing cellular endogenous enzymic protective mechanisms. They appear to be able to regulate not only antioxidant gene transcription but also numerous aspects of intracellular signaling cascades involved in the regulation of cell growth, inflammation and many other processes.It's worth noting that this is essentially the opposite of what you'll hear on the evening news, that polyphenols are direct antioxidants. The scientific cutting edge has largely discarded that hypothesis, but the mainstream has not yet caught on.
Nrf2 is one of the main pathways by which polyphenols increase stress resistance and antioxidant defenses, including the key cellular antioxidant glutathione (14). Nrf2 activity is correlated with longevity across species (15). Inducing Nrf2 activity via polyphenols or by other means substantially reduces the risk of common lifestyle disorders in animal models, including cardiovascular disease, diabetes and cancer (16, 17, 18), although Nrf2 isn't necessarily the only mechanism. The human evidence is broadly consistent with the studies in animals, although not as well developed.
One of the most interesting effects of hormesis is that exposure to one stressor can increase resistance to other stressors. For example, long-term consumption of high-polyphenol chocolate increases sunburn resistance in humans, implying that it induces a hormetic response in skin (19). Polyphenol-rich foods such as green tea reduce sunburn and skin cancer development in animals (20, 21).
Chris Masterjohn first introduced me to Nrf2 and the idea that polyphenols act through hormesis. Chris studies the effects of green tea on health, which seem to be mediated by polyphenols.
A Second Mechanism
There is a place in the body where polyphenols are concentrated enough to be direct antioxidants: in the digestive tract after consuming polyphenol-rich foods. Digestion is a chemically harsh process that readily oxidizes ingested substances such as polyunsaturated fats (22). Oxidized fat is neither healthy when it's formed in the deep fryer, nor when it's formed in the digestive tract (23, 24). Eating polyphenol-rich foods effectively prevents these fats from being oxidized during digestion (25). One consequence of this appears to be better absorption and assimilation of the exceptionally fragile omega-3 polyunsaturated fatty acids (26).
What does it all Mean?
I think that overall, the evidence suggests that polyphenol-rich foods are healthy in moderation, and eating them on a regular basis is generally a good idea. Certain other plant chemicals, such as suforaphane found in cruciferous vegetables, and allicin found in garlic, exhibit similar effects and may also act by hormesis (27). Some of the best-studied polyphenol-rich foods are tea (particularly green tea), blueberries, extra-virgin olive oil, red wine, citrus fruits, hibiscus tea, soy, dark chocolate, coffee, turmeric and other herbs and spices, and a number of traditional medicinal herbs. A good rule of thumb is to "eat the rainbow", choosing foods with a variety of colors.
Supplementing with polyphenols and other plant chemicals in amounts that would not be achievable by eating food is probably not a good idea.
* The "paradox" whereby the French eat a diet rich in saturated fat, yet have a low heart attack risk compared to other affluent Western nations.
** Genes containing an antioxidant response element (ARE) in the promoter region. ARE is also sometimes called the electrophile response element (EpRE).
Rabu, 23 Februari 2011
ANTI-MET TREATMENT FOR BONE METASTASES FROM PROSTATE CANCER
Dramatic resolution of bone metastases occurred in 85% of patients with castration-resistant prostate cancer treated with a wide-spectrum tyrosine kinase inhibitor, according to preliminary study data.
The data, from the open label Lead-in Stage of an ongoing adaptive design phase II randomized discontinuation trial, showed that only one of 62 patients had less than stable disease in bone and soft tissue as best response to cabozantinib (XL184), said David C. Smith, MD, of the University of Michigan in Ann Arbor, and colleagues.
Bone pain and use of narcotic drugs declined, as did markers of bone turnover, investigators in the multicenter trial reported during a poster presentation at the Genitourinary Cancers Symposium here.
And, at 12 weeks of follow-up, three-fourths of the study patients had disease control, Smith and colleagues added.
As a result of the observed activity, the randomized-discontinuation phase of the trial was stopped, and data were unblinded.
Among patients randomized to placebo or to continue treatment with cabozantinib, discontinuation of active therapy was associated with rapid disease progression, Smith and colleagues reported.
Despite their preliminary nature, the team's findings created a stir at the GU cancers meeting.
"The bone scan changes are unprecedented," remarked Oliver Sartor, MD, of Tulane University in New Orleans, who was not involved in the study.
"The scans show that something quite remarkable is going on. This honestly appears to be a whole new mechanism of action," he said.
Added Celestia Higano, MD, of the University of Washington in Seattle, "I have never seen those kind of [bone] changes with any agent."
According to other investigators at the symposium, the bone effects of cabozantinib are not limited to castration-resistant prostate cancer. Benefits have also been observed in breast cancer, melanoma, thyroid cancer, and renal cell cancer.
Bone metastases in castration-resistant prostate cancer are associated with increased expression of MET, which has a key role in tumor cell survival, proliferation, invasion, and metastasis. Studies have shown that osteoblasts and osteoclasts express MET and vascular endothelial growth factor (VEGF) receptors.
Moreover, VEGF type 2 receptor (R2) acts synergistically with MET to stimulate angiogenesis.
Cabozantinib inhibits both MET and VEGFR2, which might block progression of osteolytic and osteoblastic bone lesions, Smith and colleagues noted.
Preclinical studies demonstrated that cabozantinib inhibits progression of prostate cancer xenografts in bone.
Smith's group reported findings from a trial to evaluate the effect of 12 weeks of treatment with cabozantinib, followed by randomized discontinuation, conducted among men with bone and visceral metastases from castration-resistant prostate cancer.
CT/MRI bone scans were performed at baseline and then every six weeks.
The primary endpoint was objective response at 12 weeks. Of 168 patients enrolled to date, 100 had completed 12 weeks of follow-up. Additionally, investigators examined data for 62 patients with known bone metastases and at least one bone scan after baseline.
Of the 100 evaluable patients, about half had progressed on docetaxel. Additionally, about half had visceral disease, 88% had lymph node involvement, 78% had bone metastases, 50% had significant bone pain, and 37% required narcotics for bone pain.
The investigators reported that 26 of the 100 patients dropped out before completing 12 weeks of treatment, primarily because of disease progression (10 patients) and adverse events (nine).
Smith reported that 53 of 62 (85%) patients evaluable by bone scan had complete or partial resolution of bone lesions, and eight others had stable disease. Of 43 evaluable patients with bone metastases and bone pain, 26 (60%) had improvement in pain as early as six weeks after starting cabozantinib.
Among 33 evaluation patients who required narcotics for bone pain, 21 (64%) had improvement in pain at six or 12 weeks, and 13 (46%) decreased the dosage or discontinued narcotics.
Adverse events were common, but severe events were not. The most common adverse events were fatigue (71% of patients), decreased appetite (52%), diarrhea (46%), nausea (40%), constipation (34%), dysphonia (33%), vomiting (29%), hypertension (25%), and dysgeusia (24%).
The most common grade 3+ adverse events were fatigue (15%) and hypertension (8%). Additionally, 5% of patients had severe hand-foot syndrome (19% all grades).
The substantial activity against bone metastases did not translate into similar activity against the primary tumor. Smith reported that only six of 100 patients had objective responses. However, 82 had stable disease. At 12 weeks, 74 of 100 had disease control.
Additionally, a minority of patients had a PSA response to cabozantinib.
The researchers also reported that markers of bone turnover decreased by as much as 80% at 12 weeks.
According to investigators, a nonrandomized expansion-cohort study of cabozantinib in castration-resistant prostate cancer has begun patient accrual.
The data, from the open label Lead-in Stage of an ongoing adaptive design phase II randomized discontinuation trial, showed that only one of 62 patients had less than stable disease in bone and soft tissue as best response to cabozantinib (XL184), said David C. Smith, MD, of the University of Michigan in Ann Arbor, and colleagues.
Bone pain and use of narcotic drugs declined, as did markers of bone turnover, investigators in the multicenter trial reported during a poster presentation at the Genitourinary Cancers Symposium here.
And, at 12 weeks of follow-up, three-fourths of the study patients had disease control, Smith and colleagues added.
As a result of the observed activity, the randomized-discontinuation phase of the trial was stopped, and data were unblinded.
Among patients randomized to placebo or to continue treatment with cabozantinib, discontinuation of active therapy was associated with rapid disease progression, Smith and colleagues reported.
Despite their preliminary nature, the team's findings created a stir at the GU cancers meeting.
"The bone scan changes are unprecedented," remarked Oliver Sartor, MD, of Tulane University in New Orleans, who was not involved in the study.
"The scans show that something quite remarkable is going on. This honestly appears to be a whole new mechanism of action," he said.
Added Celestia Higano, MD, of the University of Washington in Seattle, "I have never seen those kind of [bone] changes with any agent."
According to other investigators at the symposium, the bone effects of cabozantinib are not limited to castration-resistant prostate cancer. Benefits have also been observed in breast cancer, melanoma, thyroid cancer, and renal cell cancer.
Bone metastases in castration-resistant prostate cancer are associated with increased expression of MET, which has a key role in tumor cell survival, proliferation, invasion, and metastasis. Studies have shown that osteoblasts and osteoclasts express MET and vascular endothelial growth factor (VEGF) receptors.
Moreover, VEGF type 2 receptor (R2) acts synergistically with MET to stimulate angiogenesis.
Cabozantinib inhibits both MET and VEGFR2, which might block progression of osteolytic and osteoblastic bone lesions, Smith and colleagues noted.
Preclinical studies demonstrated that cabozantinib inhibits progression of prostate cancer xenografts in bone.
Smith's group reported findings from a trial to evaluate the effect of 12 weeks of treatment with cabozantinib, followed by randomized discontinuation, conducted among men with bone and visceral metastases from castration-resistant prostate cancer.
CT/MRI bone scans were performed at baseline and then every six weeks.
The primary endpoint was objective response at 12 weeks. Of 168 patients enrolled to date, 100 had completed 12 weeks of follow-up. Additionally, investigators examined data for 62 patients with known bone metastases and at least one bone scan after baseline.
Of the 100 evaluable patients, about half had progressed on docetaxel. Additionally, about half had visceral disease, 88% had lymph node involvement, 78% had bone metastases, 50% had significant bone pain, and 37% required narcotics for bone pain.
The investigators reported that 26 of the 100 patients dropped out before completing 12 weeks of treatment, primarily because of disease progression (10 patients) and adverse events (nine).
Smith reported that 53 of 62 (85%) patients evaluable by bone scan had complete or partial resolution of bone lesions, and eight others had stable disease. Of 43 evaluable patients with bone metastases and bone pain, 26 (60%) had improvement in pain as early as six weeks after starting cabozantinib.
Among 33 evaluation patients who required narcotics for bone pain, 21 (64%) had improvement in pain at six or 12 weeks, and 13 (46%) decreased the dosage or discontinued narcotics.
Adverse events were common, but severe events were not. The most common adverse events were fatigue (71% of patients), decreased appetite (52%), diarrhea (46%), nausea (40%), constipation (34%), dysphonia (33%), vomiting (29%), hypertension (25%), and dysgeusia (24%).
The most common grade 3+ adverse events were fatigue (15%) and hypertension (8%). Additionally, 5% of patients had severe hand-foot syndrome (19% all grades).
The substantial activity against bone metastases did not translate into similar activity against the primary tumor. Smith reported that only six of 100 patients had objective responses. However, 82 had stable disease. At 12 weeks, 74 of 100 had disease control.
Additionally, a minority of patients had a PSA response to cabozantinib.
The researchers also reported that markers of bone turnover decreased by as much as 80% at 12 weeks.
According to investigators, a nonrandomized expansion-cohort study of cabozantinib in castration-resistant prostate cancer has begun patient accrual.
Selasa, 22 Februari 2011
KYPHOPLASTY FOR CANCER VERTEBRAL COMPRESSION FRACTURE
Kyphoplasty should be considered an early treatment option for patients with cancer who have symptomatic vertebral compression fractures (VCFs), conclude researchers reporting the first randomized trial in such a patient population.
The results come from the Cancer Patient Fracture Evaluation (CAFE) study, published online February 17 in the Lancet Oncology.
However, an accompanying editorial points out that there are a lot of unanswered questions, and raises the possibility that the benefit seen could be largely a placebo effect.
The trial was funded by Medtronic Spine, which acquired Kyphon, the company that developed the kyphoplasty procedure to improve upon vertebroplasty. Both involve injecting bone cement between cracked vertebrae, but with kyphoplasty, a balloon is first inserted and inflated to increase the space inside the collapsed bone.
The study found that cancer patients with VCFs who underwent kyphoplasty had significantly less pain and disability and significantly better function and quality of life than patients who were treated nonsurgically with standard therapy, including analgesics and bed rest.
"With the results of this new randomized study, there is now clinical evidence of a treatment option for spinal factures in cancer patients," principal investigator James Berenson, MD, from the Institute for Myeloma and Bone Cancer Research in West Hollywood, California, said in a statement.
Previous studies have found that VCFs occur in about 24% of patients with multiple myeloma, 14% with breast cancer, 8% with lung cancer, and 6% with prostate cancer, the authors note.
Could it Be a Placebo Effect?
There are several limitations of the study, including the fact that the randomization was only for 1 month, according to the editorialists.
"This trial leaves unanswered important questions regarding vertebral augmentation in patients with cancer," write David Schiff, MD, and Mary Jensen, MD, from the University of Virginia Health Sciences Center in Charlottesville.
They wonder if vertebroplasty would provide similar benefits in this group of patients, and point out that it costs about a third of what kyphoplasty costs.
"There are no good comparative data of vertebroplasty vs kyphoplasty in malignant VCF," Dr. Schiff told Medscape Medical News.
The editorialists also note that the trial was not blinded, and wonder if the benefit of kyphoplasty could be "primarily a placebo effect."
"I find it hard to believe that it could be a placebo effect," Dr. Berenson responded. "The effects are pretty dramatic," he toldMedscape Medical News. Many of these cancer patients were bed-ridden, yet after the kyphoplasty they were walking and moving around, he said.
There was a significant improvement in function and quality of life, and a significant reduction in disability and in the use of analgesic medications, he pointed out.
Dr. Berenson also explained that he believes it would be unethical to conduct a blinded trial in cancer patients. It was for these reasons that the trial was designed to offer cancer patients who were randomized to the control group a chance to crossover after a month of standard nonsurgical treatment.
Editorialist Dr. Schiff, who is the Harrison Distinguished Professor at the Neuro-Oncology Center at the University of Virginia, toldMedscape Medical News that he agrees with Dr. Berenson "that the benefit of kyphoplasty in CAFE is a large effect."
"However, it would be remiss not to point out that in osteoporotic VCFs, vertebroplasty beats best medical care (unblinded) but does not beat injection with anesthetic but no bone cement," he continued.
Dr. Schiff was referring to 2 trials published in 2009 (N Engl J Med. 2009;361:557-568 and 569-579) that showed a similar benefit from vertebroplasty and sham procedures in patients with osteoporotic spinal fractures. At the time, an accompanying editorial (N Engl J Med. 2009;361:619-621) predicted that those results "may change vertebroplasty from a procedure that is virtually always considered to be successful to one that is considered no better than placebo."
With that in mind, Dr. Schiff commented on the CAFE study: "Thus, without a control arm of injection without bone cement, it is not impossible that the beneficial effect of kyphoplasty in cancer-related VCF could be due in large part to placebo effect."
"One could design a placebo-controlled study that at some defined time point allowed individual patients to be unblended and to crossover to kyphoplasty if originally randomized to the placebo control arm and not experiencing symptom improvement," Dr. Schiff suggested, adding that "this would circumvent ethical concerns."
Benefits From Kyphoplasty
CAFE was an international study conducted in 134 cancer patients who had 1 to 3 painful VCFs. Most of the patients had multiple myeloma or breast cancer, but a few had lung, prostate, or other cancers.
All participants could receive various nonsurgical treatments, including analgesics, bed rest, bracing, physiotherapy, rehabilitation, walking aids, radiation, and other antitumor therapy, at the discretion of the treating physician. Patients with concurrent osteoporosis or bone metastasis could also receive treatment with calcium and vitamin D supplements and antiresorptive or anabolic agents, as necessary.
Approximately half of the patients (n = 68) underwent kyphoplasty; the remainder (n = 60) acted as the control group.
A month later, there were significant differences on several measures between the patients who underwent kyphoplasty and those who did not.
The primary end point was change after 1 month in the Roland-Morris Disability Questionnaire (RDQ) score, which is validated for back-specific physical functioning. Patients who underwent kyphoplasty had a significantly greater change in RDQ score from baseline to 1 month (mean of 17.6 to 9.1; P < .0001) than those who did not (mean of 18.2 to 18.0; P = .83).
There was also a "marked reduction in back pain" and a significant reduction in the use of analgesics (P = .001). Of the patients who were randomized to kyphoplasty, 94% reported using analgesics at baseline, but only 52% were still using them a month after the procedure; there was little change in the control group (85% vs 82%).
Crossover After 1 Month
After a month in the trial, patients in the control group were given a chance to crossover and undergo kyphoplasty; 34 of 52 patients chose to do so. The remaining 18 patients continued with nonsurgical management.
Assessment at 6 months showed that the original kyphoplasty group and the crossover group both had significantly improved RDQ scores, whereas the patients who remained in the control group did not.
For both groups of patients who underwent kyphoplasty, the improvements seen were generally maintained until the final assessment at 12 months, the researchers note.
"Because of the limited improvement in the control group, the results of this study suggest that balloon kyphoplasty should be considered as an early treatment option for patients with cancer who have symptomatic VCFs," they conclude.
Reducing the use of pain medications decreases the risk for drug-related adverse effects and potential for interactions, and improving function reduces the risk for complications related to being bed-ridden, such as deep vein thrombosis, pneumonia, and decubitus ulcers, the researchers point out.
"Thus, a procedure that effectively treats VCFs for patients with cancer might confer clinical and quality-of-life benefits beyond treatment of the fracture itself," they add.
The CAFE study was funded by Medtronic Spine. Dr. Berenson and several coauthors report receiving consulting fees and research funding from Medtronic, and 2 coauthors are employees of the company. Dr. Schiff reports receiving consultancy fees and acting on the advisory board for Genentech. Dr. Jensen reports receiving consultancy fees from Kuros Biotechnology.
Lancet Oncol. Published online February 17, 2011.
The results come from the Cancer Patient Fracture Evaluation (CAFE) study, published online February 17 in the Lancet Oncology.
However, an accompanying editorial points out that there are a lot of unanswered questions, and raises the possibility that the benefit seen could be largely a placebo effect.
The trial was funded by Medtronic Spine, which acquired Kyphon, the company that developed the kyphoplasty procedure to improve upon vertebroplasty. Both involve injecting bone cement between cracked vertebrae, but with kyphoplasty, a balloon is first inserted and inflated to increase the space inside the collapsed bone.
The study found that cancer patients with VCFs who underwent kyphoplasty had significantly less pain and disability and significantly better function and quality of life than patients who were treated nonsurgically with standard therapy, including analgesics and bed rest.
"With the results of this new randomized study, there is now clinical evidence of a treatment option for spinal factures in cancer patients," principal investigator James Berenson, MD, from the Institute for Myeloma and Bone Cancer Research in West Hollywood, California, said in a statement.
Previous studies have found that VCFs occur in about 24% of patients with multiple myeloma, 14% with breast cancer, 8% with lung cancer, and 6% with prostate cancer, the authors note.
Could it Be a Placebo Effect?
There are several limitations of the study, including the fact that the randomization was only for 1 month, according to the editorialists.
"This trial leaves unanswered important questions regarding vertebral augmentation in patients with cancer," write David Schiff, MD, and Mary Jensen, MD, from the University of Virginia Health Sciences Center in Charlottesville.
They wonder if vertebroplasty would provide similar benefits in this group of patients, and point out that it costs about a third of what kyphoplasty costs.
"There are no good comparative data of vertebroplasty vs kyphoplasty in malignant VCF," Dr. Schiff told Medscape Medical News.
The editorialists also note that the trial was not blinded, and wonder if the benefit of kyphoplasty could be "primarily a placebo effect."
"I find it hard to believe that it could be a placebo effect," Dr. Berenson responded. "The effects are pretty dramatic," he toldMedscape Medical News. Many of these cancer patients were bed-ridden, yet after the kyphoplasty they were walking and moving around, he said.
There was a significant improvement in function and quality of life, and a significant reduction in disability and in the use of analgesic medications, he pointed out.
Dr. Berenson also explained that he believes it would be unethical to conduct a blinded trial in cancer patients. It was for these reasons that the trial was designed to offer cancer patients who were randomized to the control group a chance to crossover after a month of standard nonsurgical treatment.
Editorialist Dr. Schiff, who is the Harrison Distinguished Professor at the Neuro-Oncology Center at the University of Virginia, toldMedscape Medical News that he agrees with Dr. Berenson "that the benefit of kyphoplasty in CAFE is a large effect."
"However, it would be remiss not to point out that in osteoporotic VCFs, vertebroplasty beats best medical care (unblinded) but does not beat injection with anesthetic but no bone cement," he continued.
Dr. Schiff was referring to 2 trials published in 2009 (N Engl J Med. 2009;361:557-568 and 569-579) that showed a similar benefit from vertebroplasty and sham procedures in patients with osteoporotic spinal fractures. At the time, an accompanying editorial (N Engl J Med. 2009;361:619-621) predicted that those results "may change vertebroplasty from a procedure that is virtually always considered to be successful to one that is considered no better than placebo."
With that in mind, Dr. Schiff commented on the CAFE study: "Thus, without a control arm of injection without bone cement, it is not impossible that the beneficial effect of kyphoplasty in cancer-related VCF could be due in large part to placebo effect."
"One could design a placebo-controlled study that at some defined time point allowed individual patients to be unblended and to crossover to kyphoplasty if originally randomized to the placebo control arm and not experiencing symptom improvement," Dr. Schiff suggested, adding that "this would circumvent ethical concerns."
Benefits From Kyphoplasty
CAFE was an international study conducted in 134 cancer patients who had 1 to 3 painful VCFs. Most of the patients had multiple myeloma or breast cancer, but a few had lung, prostate, or other cancers.
All participants could receive various nonsurgical treatments, including analgesics, bed rest, bracing, physiotherapy, rehabilitation, walking aids, radiation, and other antitumor therapy, at the discretion of the treating physician. Patients with concurrent osteoporosis or bone metastasis could also receive treatment with calcium and vitamin D supplements and antiresorptive or anabolic agents, as necessary.
Approximately half of the patients (n = 68) underwent kyphoplasty; the remainder (n = 60) acted as the control group.
A month later, there were significant differences on several measures between the patients who underwent kyphoplasty and those who did not.
The primary end point was change after 1 month in the Roland-Morris Disability Questionnaire (RDQ) score, which is validated for back-specific physical functioning. Patients who underwent kyphoplasty had a significantly greater change in RDQ score from baseline to 1 month (mean of 17.6 to 9.1; P < .0001) than those who did not (mean of 18.2 to 18.0; P = .83).
There was also a "marked reduction in back pain" and a significant reduction in the use of analgesics (P = .001). Of the patients who were randomized to kyphoplasty, 94% reported using analgesics at baseline, but only 52% were still using them a month after the procedure; there was little change in the control group (85% vs 82%).
Crossover After 1 Month
After a month in the trial, patients in the control group were given a chance to crossover and undergo kyphoplasty; 34 of 52 patients chose to do so. The remaining 18 patients continued with nonsurgical management.
Assessment at 6 months showed that the original kyphoplasty group and the crossover group both had significantly improved RDQ scores, whereas the patients who remained in the control group did not.
For both groups of patients who underwent kyphoplasty, the improvements seen were generally maintained until the final assessment at 12 months, the researchers note.
"Because of the limited improvement in the control group, the results of this study suggest that balloon kyphoplasty should be considered as an early treatment option for patients with cancer who have symptomatic VCFs," they conclude.
Reducing the use of pain medications decreases the risk for drug-related adverse effects and potential for interactions, and improving function reduces the risk for complications related to being bed-ridden, such as deep vein thrombosis, pneumonia, and decubitus ulcers, the researchers point out.
"Thus, a procedure that effectively treats VCFs for patients with cancer might confer clinical and quality-of-life benefits beyond treatment of the fracture itself," they add.
The CAFE study was funded by Medtronic Spine. Dr. Berenson and several coauthors report receiving consulting fees and research funding from Medtronic, and 2 coauthors are employees of the company. Dr. Schiff reports receiving consultancy fees and acting on the advisory board for Genentech. Dr. Jensen reports receiving consultancy fees from Kuros Biotechnology.
Lancet Oncol. Published online February 17, 2011.
Senin, 21 Februari 2011
EARLY HAIR LOSS INCREASE PROSTATE CANCER RISK
Men in their 60s with prostate cancer are twice as likely as their cancer-free peers to have had androgenic alopecia (or male pattern baldness) begin in their 20s, French investigators report in the Annals of Oncology.
In a retrospective case–control study, men in their late 60s with prostate cancer had an odds ratio of 2.01 for androgenic alopecia at age 20 (95% confidence interval, 1.07 to 3.70; P = .0285), compared with age-matched controls.
However, although early hair loss might be a risk marker for prostate cancer later in life, there was no association between premature balding and advanced tumor stage, high Gleason score (7 or greater), or high prostate-specific antigen (PSA) level (>20 ng/mL), the researchers report.
Receding hairlines did not correlate with an early prostate cancer diagnosis, and the pattern of hair loss was not predictive of tumor aggressiveness, the authors found.
Nonetheless, alopecia's early assault on male vanity could help identify young men at risk for prostate cancer, the authors contend.
"An improved knowledge of risk factors, especially those that are easily identifiable in the patient, may allow us to target a population at high risk of developing prostate cancer and that may benefit from screening or chemoprevention," they write.
Lead researcher Michael Yassa, MD, currently assistant professor of medicine at the University of Montreal in Quebec, Canada, told Medscape Medical News that the findings suggest an avenue of investigation into the origins of prostate cancer.
"I think that further research should [focus] on finding the exact link between hair loss, androgens, and prostate cancer — what exactly links those 3 together. Maybe that will give us more information about what to do with these people," he said.
A better understanding of that interplay could answer questions about whether men with a history of early balding could benefit from earlier screening or chemoprophylaxis with a 5-alpha reductase inhibitor (finasteride, dutasteride) or other agents, he and his coauthors suggest.
But a prostate cancer expert who was not involved in the study told Medscape Medical News that an early risk marker, even if it is validated in further studies, might do more harm than good.
"Most of the diagnoses that are made in younger people are not important to make; they alter a person's life and I really don't want people thinking about the specter of prostate cancer when they're very young," said Donald S. Kaufman, MD, director of the Claire and John Bertucci Center for Genitourinary Cancers at Massachusetts General Hospital in Boston.
In addition, the authors' assertion that prostate cancer could be prevented with finasteride or dutasteride is controversial, Dr. Kaufman said.
"I don't think that's something we all would agree with," he said.
Pattern Recall
The investigators recruited 388 prostate cancer patients from databases from radiation oncology follow-up clinics in Paris and Toulouse, France, and 281 age-matched controls with no history of prostate cancer or hormonal disorders from the same hospital databases.
The participants (mean age, 67.2 years for cases; 66.4 years for controls) were mailed a questionnaire asking about their prostate cancer history, paternal prostate cancer, and balding history. They were also asked to recall and score their balding patterns at ages 20, 30, and 40, using a modified Hamilton-Norwood scale.
In addition, physicians of the respondents were sent a questionnaire confirming or ruling out prostate cancer history. Physicians of cases were asked the patient's age at diagnosis, disease stage at presentation (including TNM stage, Gleason score, and initial PSA level), primary therapy, treatment failures, time between treatment and failure, and their most recent medical impression of the disease (remission, failure, or metastasis).
The authors found that any balding at 20 years, but not at 30 or 40 years, was associated with an increased prostate cancer incidence later. There were no significant associations between the pattern of hair loss (frontal, vertex, or both) and the later development of prostate cancer, and early-onset alopecia was not associated with early-onset prostate cancer. There was also no association between early-onset disease and more aggressive tumors, defined as stage T3–T4, a Gleason score of 7 or higher, or a PSA greater than 20 ng/mL.
The study's funding source was not disclosed. Dr. Yassa, his coauthors, and Dr. Kaufman have disclosed no relevant financial relationships.
In a retrospective case–control study, men in their late 60s with prostate cancer had an odds ratio of 2.01 for androgenic alopecia at age 20 (95% confidence interval, 1.07 to 3.70; P = .0285), compared with age-matched controls.
However, although early hair loss might be a risk marker for prostate cancer later in life, there was no association between premature balding and advanced tumor stage, high Gleason score (7 or greater), or high prostate-specific antigen (PSA) level (>20 ng/mL), the researchers report.
Receding hairlines did not correlate with an early prostate cancer diagnosis, and the pattern of hair loss was not predictive of tumor aggressiveness, the authors found.
Nonetheless, alopecia's early assault on male vanity could help identify young men at risk for prostate cancer, the authors contend.
"An improved knowledge of risk factors, especially those that are easily identifiable in the patient, may allow us to target a population at high risk of developing prostate cancer and that may benefit from screening or chemoprevention," they write.
Lead researcher Michael Yassa, MD, currently assistant professor of medicine at the University of Montreal in Quebec, Canada, told Medscape Medical News that the findings suggest an avenue of investigation into the origins of prostate cancer.
"I think that further research should [focus] on finding the exact link between hair loss, androgens, and prostate cancer — what exactly links those 3 together. Maybe that will give us more information about what to do with these people," he said.
A better understanding of that interplay could answer questions about whether men with a history of early balding could benefit from earlier screening or chemoprophylaxis with a 5-alpha reductase inhibitor (finasteride, dutasteride) or other agents, he and his coauthors suggest.
But a prostate cancer expert who was not involved in the study told Medscape Medical News that an early risk marker, even if it is validated in further studies, might do more harm than good.
"Most of the diagnoses that are made in younger people are not important to make; they alter a person's life and I really don't want people thinking about the specter of prostate cancer when they're very young," said Donald S. Kaufman, MD, director of the Claire and John Bertucci Center for Genitourinary Cancers at Massachusetts General Hospital in Boston.
In addition, the authors' assertion that prostate cancer could be prevented with finasteride or dutasteride is controversial, Dr. Kaufman said.
"I don't think that's something we all would agree with," he said.
Pattern Recall
The investigators recruited 388 prostate cancer patients from databases from radiation oncology follow-up clinics in Paris and Toulouse, France, and 281 age-matched controls with no history of prostate cancer or hormonal disorders from the same hospital databases.
The participants (mean age, 67.2 years for cases; 66.4 years for controls) were mailed a questionnaire asking about their prostate cancer history, paternal prostate cancer, and balding history. They were also asked to recall and score their balding patterns at ages 20, 30, and 40, using a modified Hamilton-Norwood scale.
In addition, physicians of the respondents were sent a questionnaire confirming or ruling out prostate cancer history. Physicians of cases were asked the patient's age at diagnosis, disease stage at presentation (including TNM stage, Gleason score, and initial PSA level), primary therapy, treatment failures, time between treatment and failure, and their most recent medical impression of the disease (remission, failure, or metastasis).
The authors found that any balding at 20 years, but not at 30 or 40 years, was associated with an increased prostate cancer incidence later. There were no significant associations between the pattern of hair loss (frontal, vertex, or both) and the later development of prostate cancer, and early-onset alopecia was not associated with early-onset prostate cancer. There was also no association between early-onset disease and more aggressive tumors, defined as stage T3–T4, a Gleason score of 7 or higher, or a PSA greater than 20 ng/mL.
The study's funding source was not disclosed. Dr. Yassa, his coauthors, and Dr. Kaufman have disclosed no relevant financial relationships.
Jumat, 18 Februari 2011
HEDGEHOG INHIBITORS FOR BASAL CELL CARCINOMA
(New Orleans, Louisiana) — The investigational hedgehog pathway inhibitor GDC-0449 (Genentech) has shown "dramatic" efficacy in reducing the number of new and existing basal cell skin cancers in patients with basal cell nevus syndrome (BCNS), according to research presented here at a late-breaking study session at the American Academy of Dermatology 69th Annual Meeting.
"Currently, surgery is the standard treatment for basal cell carcinoma [BCC]. However, surgery is not an option for patients with really bad BCCs, locally aggressive or metastatic disease, and certainly not for patients who suffer from this genetic disorder of basal cell nevus syndrome," said Jean Y. Tang, MD, from Stanford University in Palo Alto, California. "There is no treatment to prevent these tumors and these patients [undergo] hundreds of surgeries in their lifetime."
Patients with BCNS, also known as Gorlin syndrome, and BCC tumors have mutations in components of the hedgehog signaling pathway that keep it constantly turned on and lead to tumor cell growth and proliferation.
"Molecularly targeted therapies focus on turning this pathway off, and one way to do that is to antagonize the smoothened receptor, which would inactivate the pathway and stop BCC growth," Dr. Tang explained. "GDC-0449 is a small molecule that does just this. It targets the hedgehog pathway by binding to the smoothened receptor. Therefore, we hypothesized that it would stop BCC development in patients with BCNS."
Accordingly, Dr. Tang and her team initiated a phase 2 randomized double-blind placebo-controlled trial in which they enrolled 41 patients from 3 centers and assigned them in a 2:1 ratio to receive oral GDC-0449 150 mg or placebo once daily for 18 months.
The average age of the patients was 54 to 60 years, and they were balanced in terms of sex and weight. At baseline, both groups had 23 or 24 BCCs; they were followed for an average of 8 months.
The researchers found that subjects who were randomized to GDC-0449 had very few BCCs develop over time — 0.07 BCCs per month — compared with 1.74 BCCs per month for patients on placebo (P < .0001). GDC-0449 also significantly reduced the size of existing BCCs (P = .006).
Dr. Tang reported that some patients achieved a near-complete remission and that no resistance to the drug developed.
Palmar pits, a common feature of BCNS, disappeared among patients on the active drug. "Our patients are just struck by this. They've lived with this all their lives and now they can comfortably shake the hands of strangers," she noted.
Because of the big difference in the results, the data safety and monitoring board voted to end the placebo group. The investigators are currently converting participants in the placebo group to the active drug and testing different regimens.
"We're really excited as dermatologists because we're sick of just chopping up these poor patients' skin and we're excited to offer something better," she said.
In an interview with Medscape Medical News, Dr. Tang admitted she is elated with these results. "It is fantastic to us. It feels like this drug could really change the treatment and management of BCCs in these unfortunate patients. For the first time ever, there's something that works besides surgery."
Adverse Effects a Problem for Some
The adverse effects — most notably loss of taste, muscle cramps, and hair thinning — caused 20% of patients to stop treatment.
"These side effects may limit the drug's usefulness. I would tell a patient with this syndrome that if they have a big burden of disease — we're talking 50 or more BCCs — the side-effect profile is worth it, but if they have less than 10 or 20, I'm not sure the side effects are worth it," she said. "But these kinds of discussions need to be made on an individual patient-by-patient basis."
The researchers want to determine whether GDC-0449 can be given intermittently.
"I think because of the side-effect profile, most patients probably won't tolerate taking it every single day for the rest of their lives. Most likely this medication would be given in low doses, or perhaps patients can be on it for 6 or 12 months every few years just to clean up and reduce the burden of BCC tumors on their skin," she said.
The response from the patients has been extremely positive, Dr. Tang said.
"Basically, all of the BCNS patients are connected to each other on Facebook now. One of the first came back to us in tears and told us 'Doctor, this is the first month I've never had a biopsy in 10 years'. The patients are incredibly grateful for this treatment," she said.
The adverse effects are impossible to hide; as a result, patient advocacy groups have been questioning the ethics of having a placebo group, Dr. Tang added.
"Going forward, we won't have one anymore, but it was important to establish our statistical end points," she said.
"This is the first ever molecularly targeted drug against the hedgehog pathway for basal cells, and it basically opens up a new era for treatments of basal cell cancers," Dr. Tang said. "There are a lot of other tumors that are hedgehog-driven, and we hope that whatever we learn in this trial can help other patients with hedgehog-driven tumors."
Richard L. Gallo, MD, PhD, told Medscape Medical News that he found the results of this study "exciting."
"This is a great example of the benefit of understanding the molecular pharmacology of some of these drugs and the pathophysiology behind the origin of these diseases, so the results are very encouraging," he said after the presentation.
"It appears that the side-effect profile so far is very tolerable in this patient population," noted Dr. Gallo, who moderated the late-breaking abstract session. "Clearly, the comments from the patient advocates support what the investigators are saying. I think there will be only good things to say about this in the future."
This study was supported by Genentech. Dr. Tang has disclosed no relevant financial relationships. Dr. Gallo reports financial relationships with Allergan, Ceregenex, Galderma, Inimex, Intendis, Johnson and Johnson, Novartis, and Skin Epibiotics.
"Currently, surgery is the standard treatment for basal cell carcinoma [BCC]. However, surgery is not an option for patients with really bad BCCs, locally aggressive or metastatic disease, and certainly not for patients who suffer from this genetic disorder of basal cell nevus syndrome," said Jean Y. Tang, MD, from Stanford University in Palo Alto, California. "There is no treatment to prevent these tumors and these patients [undergo] hundreds of surgeries in their lifetime."
Patients with BCNS, also known as Gorlin syndrome, and BCC tumors have mutations in components of the hedgehog signaling pathway that keep it constantly turned on and lead to tumor cell growth and proliferation.
"Molecularly targeted therapies focus on turning this pathway off, and one way to do that is to antagonize the smoothened receptor, which would inactivate the pathway and stop BCC growth," Dr. Tang explained. "GDC-0449 is a small molecule that does just this. It targets the hedgehog pathway by binding to the smoothened receptor. Therefore, we hypothesized that it would stop BCC development in patients with BCNS."
Accordingly, Dr. Tang and her team initiated a phase 2 randomized double-blind placebo-controlled trial in which they enrolled 41 patients from 3 centers and assigned them in a 2:1 ratio to receive oral GDC-0449 150 mg or placebo once daily for 18 months.
The average age of the patients was 54 to 60 years, and they were balanced in terms of sex and weight. At baseline, both groups had 23 or 24 BCCs; they were followed for an average of 8 months.
The researchers found that subjects who were randomized to GDC-0449 had very few BCCs develop over time — 0.07 BCCs per month — compared with 1.74 BCCs per month for patients on placebo (P < .0001). GDC-0449 also significantly reduced the size of existing BCCs (P = .006).
Dr. Tang reported that some patients achieved a near-complete remission and that no resistance to the drug developed.
Palmar pits, a common feature of BCNS, disappeared among patients on the active drug. "Our patients are just struck by this. They've lived with this all their lives and now they can comfortably shake the hands of strangers," she noted.
Because of the big difference in the results, the data safety and monitoring board voted to end the placebo group. The investigators are currently converting participants in the placebo group to the active drug and testing different regimens.
"We're really excited as dermatologists because we're sick of just chopping up these poor patients' skin and we're excited to offer something better," she said.
In an interview with Medscape Medical News, Dr. Tang admitted she is elated with these results. "It is fantastic to us. It feels like this drug could really change the treatment and management of BCCs in these unfortunate patients. For the first time ever, there's something that works besides surgery."
Adverse Effects a Problem for Some
The adverse effects — most notably loss of taste, muscle cramps, and hair thinning — caused 20% of patients to stop treatment.
"These side effects may limit the drug's usefulness. I would tell a patient with this syndrome that if they have a big burden of disease — we're talking 50 or more BCCs — the side-effect profile is worth it, but if they have less than 10 or 20, I'm not sure the side effects are worth it," she said. "But these kinds of discussions need to be made on an individual patient-by-patient basis."
The researchers want to determine whether GDC-0449 can be given intermittently.
"I think because of the side-effect profile, most patients probably won't tolerate taking it every single day for the rest of their lives. Most likely this medication would be given in low doses, or perhaps patients can be on it for 6 or 12 months every few years just to clean up and reduce the burden of BCC tumors on their skin," she said.
The response from the patients has been extremely positive, Dr. Tang said.
"Basically, all of the BCNS patients are connected to each other on Facebook now. One of the first came back to us in tears and told us 'Doctor, this is the first month I've never had a biopsy in 10 years'. The patients are incredibly grateful for this treatment," she said.
The adverse effects are impossible to hide; as a result, patient advocacy groups have been questioning the ethics of having a placebo group, Dr. Tang added.
"Going forward, we won't have one anymore, but it was important to establish our statistical end points," she said.
"This is the first ever molecularly targeted drug against the hedgehog pathway for basal cells, and it basically opens up a new era for treatments of basal cell cancers," Dr. Tang said. "There are a lot of other tumors that are hedgehog-driven, and we hope that whatever we learn in this trial can help other patients with hedgehog-driven tumors."
Richard L. Gallo, MD, PhD, told Medscape Medical News that he found the results of this study "exciting."
"This is a great example of the benefit of understanding the molecular pharmacology of some of these drugs and the pathophysiology behind the origin of these diseases, so the results are very encouraging," he said after the presentation.
"It appears that the side-effect profile so far is very tolerable in this patient population," noted Dr. Gallo, who moderated the late-breaking abstract session. "Clearly, the comments from the patient advocates support what the investigators are saying. I think there will be only good things to say about this in the future."
This study was supported by Genentech. Dr. Tang has disclosed no relevant financial relationships. Dr. Gallo reports financial relationships with Allergan, Ceregenex, Galderma, Inimex, Intendis, Johnson and Johnson, Novartis, and Skin Epibiotics.
Kamis, 17 Februari 2011
INTENSIVE CHEMOTHERAPY INCREASES SURVIVAL OF OLDER TEENAGERS WITH ALL
Historically, older teenagers (those aged 15 - 18 years) with acute lymphoblastic leukemia (ALL) have had a much worse prognosis than younger patients.
Now, however, physicians at St. Jude Children's Research Hospital in Memphis, Tennessee, report that most older adolescents with ALL can be cured with intensive chemotherapy that takes into account their individual risk profile — without stem cell transplantation and without radiation to the brain.
This report was published online December 20 in the Journal of Clinical Oncology.
"The contemporary clinical trials for ALL show 5-year survival rates of 83% to 94% in children and much lower rates — anywhere from 27% to 59% — for older teens and adults," said lead author Ching-Hon Pui, MD, chairman of oncology at St. Jude.
"But with our latest protocol, which uses more effective risk-adjusted chemotherapy and sophisticated patient monitoring, we were able to push the cure rates for older teens to nearly 88%, essentially closing the survival gap between older and younger patients," he told Medscape Medical News.
Older teenagers are difficult to cure because they tend to have more high-risk leukemia, suffer more toxic adverse effects from their treatment, and are less likely to be compliant with their therapy.
"Teens are well known to be less compliant. For example, if they're invited to a party, they won't take their medicine because they don't want to be sick. Or they forget, because they have to take pills 3 times a day," Dr. Pui said. "Teens with chronic illness are notorious for compliance issues. With younger children, it's easier. They are supervised by their parents, who make sure they take their medicine as prescribed."
Study Details
In this report, Dr. Pui and his team compared the long-term survival of 963 pediatric patients, including 89 older adolescents, treated between 1991 and 2007 who were enrolled in 4 consecutive Total Therapy studies — studies XIIA, XIIB, XIV, and XV — that used protocols developed at St. Jude.
In the first 3 studies, treatment selection was based on presenting clinical features and leukemic cell genetics. In study XV, measuring the level of minimal residual disease (MRD) either by flow cytometry or polymerase chain reaction, was used to monitor the patient's response to and compliance with treatment, which featured intensive methotrexate, glucocorticoid, vincristine, and asparaginase, as well as early triple intrathecal therapy for higher-risk ALL.
In the Total XV study, any patient with 1% or more bone marrow MRD on day 19 of remission induction, or 0.1% to 0.99% MRD after completion of induction therapy, was considered to have standard-risk ALL. Patients who were unable to achieve morphologic remission or who had presence of MRD 1% or greater after completion of induction therapy and persistence of MRD 0.1% or greater beyond week 7 of continuation treatment were deemed to have high-risk ALL and became candidates for allogeneic stem cell transplantation.
The Total XV regimen also replaced radiation of the brain with intrathecal chemotherapy. Patients with low-risk disease received 13 to 18 intrathecal treatments, and patients with standard-risk disease received 16 to 25 intrathecal treatments. Prophylactic cranial irradiation was not used, as per the protocol of Total XV.
Survival Rate Increased Significantly With XV Protocol
In the earlier studies, the 5-year event-free survival rate and the 5-year overall survival rate for the 44 older adolescents were both 59.1% (95% confidence interval [CI], 43% - 72%). This was "strikingly" inferior to the event-free survival rate of 82.6% (95% CI, 78.5% - 86%; P < .001) and the overall survival rate of 88.3% (95% CI, 84.7% - 91.1%) achieved in the 403 younger patients, the investigators reported.
In contrast, in study XV, the 5-year event-free survival rates were 86.4% ± 5.2% (standard error) for the 45 older adolescents and 87.4% ± 1.7% for the 453 younger patients. The 5-year overall survival rates were 87.9% ± 5.1% for the older teenagers and 94.1% ± 1.2% for the younger patients.
In addition, patients treated in study XV were less likely to suffer serious late treatment effects, including second cancers and infertility. "Our patients had a good quality of life. We have followed them for over 10 years, and of the 500 patients, only one developed a secondary cancer," Dr. Pui noted. "This is the lowest for any protocol."
Dr. Pui also said that his study highlights the fact that good results in pediatric ALL can be achieved without the use of radiation. It also underlines the importance of personalizing therapy and being aware of compliance.
"We do not give everyone the same dose. Instead, we base the dose on individual pharmacokinetics and pharmacodynamics. We pay close attention to compliance. We monitor patients regularly, and we can tell who is not taking their oral medications. We counsel these patients until they become compliant, and we keep checking to make sure they stay compliant. This is very important, especially for the older teens," Dr. Pui said.
The study also reinforces the growing body of evidence that suggests older teenagers and even young adults with ALL do better on pediatric — as opposed to adult — protocols.
"Pediatric ALL specialists who treat adolescents love to see this kind of data get published," Susan Rheingold, MD, assistant professor of medicine at Children's Hospital of Philadelphia in Pennsylvania, told Medscape Medical News.
Studies have been showing since the early 2000s that older teenagers and young adults do better on pediatric protocols than adult protocols, she said. "In general, the pediatric protocols had a 65% 5-year cure rate, and the adult protocols had a 45% cure rate. When those results began to come out, pediatric oncologists started to say, 'We need to be treating these older adolescents. We need to be treating them like 10-year-olds, and not like 70-year-olds, so we can improve their cure rate. And when it's a 20% higher cure rate — that's significant," she said.
Dr. Rheingold noted that the protocols of the Children's Oncology Group are open to patients up to the age of 30 years.
"You don't stop being a child automatically at the age of 18. Our university hospital [University of Pennsylvania Medical Center] is hearing the message that pediatric oncologists are curing these young adult patients at higher rates with chemo and without transplants, and are sending us patients who are in their 20s," she said.
"The emergency rooms between the adult hospital and the pediatric hospital are probably no further than 100 feet apart. A 21-year-old can walk into either emergency room with a new diagnosis of leukemia, and you would hate to think that what door they chose to walk into could change their cure rate by 10% or 20%."
This research was supported in part by the National Institutes of Health, the American Cancer Society, and the American Lebanese Syrian Associated Charities. Dr. Pui and Dr. Rheingold have disclosed no relevant financial relationships.
Now, however, physicians at St. Jude Children's Research Hospital in Memphis, Tennessee, report that most older adolescents with ALL can be cured with intensive chemotherapy that takes into account their individual risk profile — without stem cell transplantation and without radiation to the brain.
This report was published online December 20 in the Journal of Clinical Oncology.
"The contemporary clinical trials for ALL show 5-year survival rates of 83% to 94% in children and much lower rates — anywhere from 27% to 59% — for older teens and adults," said lead author Ching-Hon Pui, MD, chairman of oncology at St. Jude.
"But with our latest protocol, which uses more effective risk-adjusted chemotherapy and sophisticated patient monitoring, we were able to push the cure rates for older teens to nearly 88%, essentially closing the survival gap between older and younger patients," he told Medscape Medical News.
Older teenagers are difficult to cure because they tend to have more high-risk leukemia, suffer more toxic adverse effects from their treatment, and are less likely to be compliant with their therapy.
"Teens are well known to be less compliant. For example, if they're invited to a party, they won't take their medicine because they don't want to be sick. Or they forget, because they have to take pills 3 times a day," Dr. Pui said. "Teens with chronic illness are notorious for compliance issues. With younger children, it's easier. They are supervised by their parents, who make sure they take their medicine as prescribed."
Study Details
In this report, Dr. Pui and his team compared the long-term survival of 963 pediatric patients, including 89 older adolescents, treated between 1991 and 2007 who were enrolled in 4 consecutive Total Therapy studies — studies XIIA, XIIB, XIV, and XV — that used protocols developed at St. Jude.
In the first 3 studies, treatment selection was based on presenting clinical features and leukemic cell genetics. In study XV, measuring the level of minimal residual disease (MRD) either by flow cytometry or polymerase chain reaction, was used to monitor the patient's response to and compliance with treatment, which featured intensive methotrexate, glucocorticoid, vincristine, and asparaginase, as well as early triple intrathecal therapy for higher-risk ALL.
In the Total XV study, any patient with 1% or more bone marrow MRD on day 19 of remission induction, or 0.1% to 0.99% MRD after completion of induction therapy, was considered to have standard-risk ALL. Patients who were unable to achieve morphologic remission or who had presence of MRD 1% or greater after completion of induction therapy and persistence of MRD 0.1% or greater beyond week 7 of continuation treatment were deemed to have high-risk ALL and became candidates for allogeneic stem cell transplantation.
The Total XV regimen also replaced radiation of the brain with intrathecal chemotherapy. Patients with low-risk disease received 13 to 18 intrathecal treatments, and patients with standard-risk disease received 16 to 25 intrathecal treatments. Prophylactic cranial irradiation was not used, as per the protocol of Total XV.
Survival Rate Increased Significantly With XV Protocol
In the earlier studies, the 5-year event-free survival rate and the 5-year overall survival rate for the 44 older adolescents were both 59.1% (95% confidence interval [CI], 43% - 72%). This was "strikingly" inferior to the event-free survival rate of 82.6% (95% CI, 78.5% - 86%; P < .001) and the overall survival rate of 88.3% (95% CI, 84.7% - 91.1%) achieved in the 403 younger patients, the investigators reported.
In contrast, in study XV, the 5-year event-free survival rates were 86.4% ± 5.2% (standard error) for the 45 older adolescents and 87.4% ± 1.7% for the 453 younger patients. The 5-year overall survival rates were 87.9% ± 5.1% for the older teenagers and 94.1% ± 1.2% for the younger patients.
In addition, patients treated in study XV were less likely to suffer serious late treatment effects, including second cancers and infertility. "Our patients had a good quality of life. We have followed them for over 10 years, and of the 500 patients, only one developed a secondary cancer," Dr. Pui noted. "This is the lowest for any protocol."
Dr. Pui also said that his study highlights the fact that good results in pediatric ALL can be achieved without the use of radiation. It also underlines the importance of personalizing therapy and being aware of compliance.
"We do not give everyone the same dose. Instead, we base the dose on individual pharmacokinetics and pharmacodynamics. We pay close attention to compliance. We monitor patients regularly, and we can tell who is not taking their oral medications. We counsel these patients until they become compliant, and we keep checking to make sure they stay compliant. This is very important, especially for the older teens," Dr. Pui said.
The study also reinforces the growing body of evidence that suggests older teenagers and even young adults with ALL do better on pediatric — as opposed to adult — protocols.
"Pediatric ALL specialists who treat adolescents love to see this kind of data get published," Susan Rheingold, MD, assistant professor of medicine at Children's Hospital of Philadelphia in Pennsylvania, told Medscape Medical News.
Studies have been showing since the early 2000s that older teenagers and young adults do better on pediatric protocols than adult protocols, she said. "In general, the pediatric protocols had a 65% 5-year cure rate, and the adult protocols had a 45% cure rate. When those results began to come out, pediatric oncologists started to say, 'We need to be treating these older adolescents. We need to be treating them like 10-year-olds, and not like 70-year-olds, so we can improve their cure rate. And when it's a 20% higher cure rate — that's significant," she said.
Dr. Rheingold noted that the protocols of the Children's Oncology Group are open to patients up to the age of 30 years.
"You don't stop being a child automatically at the age of 18. Our university hospital [University of Pennsylvania Medical Center] is hearing the message that pediatric oncologists are curing these young adult patients at higher rates with chemo and without transplants, and are sending us patients who are in their 20s," she said.
"The emergency rooms between the adult hospital and the pediatric hospital are probably no further than 100 feet apart. A 21-year-old can walk into either emergency room with a new diagnosis of leukemia, and you would hate to think that what door they chose to walk into could change their cure rate by 10% or 20%."
This research was supported in part by the National Institutes of Health, the American Cancer Society, and the American Lebanese Syrian Associated Charities. Dr. Pui and Dr. Rheingold have disclosed no relevant financial relationships.
Selasa, 15 Februari 2011
RISE IN BREAST CANCER INCIDENCE IN UK
Although breast cancer mortality continues to fall, the incidence of breast cancer is increasing in the United Kingdom; the latest estimate for lifetime risk is now 1 in 8 (up from 1 in 9 ten years ago).
This new estimate, from Cancer Research UK, was widely reported in the media, with headlines emphasizing the frightening statistic of 1 in 8, but few reports explained that risk increases sharply with age.
Breast cancer rates have risen by 3.5% in 10 years, the organization reported. A diagnosis of breast cancer was recorded in 47,700 women in 2008, compared with 42,400 women in 1999.
The biggest rise was among women 50 to 69 years of age, where the increase was more than 6% in that 10-year period. This age group represents almost half (48%) the total number of cases. Another 33% of cases were diagnosed in women older than 70 years of age.
Only 19% of the total cases were diagnosed in younger women (25 to 49 years); in this age group, the rate of breast cancer actually dropped slightly (by 0.5%).
According to Cancer Research UK, "there's no simple answer" to why breast cancer rates are increasing, but more cancers being detected by mammography screening, lifestyle changes such as increased alcohol use and obesity, an aftermath of prolonged use of hormone replacement therapy, women having fewer children and breastfeeding less, and the increasing age of the population are possible explanations.
Age in particular has a major effect. The risk for breast cancer increases sharply from around the time of the menopause and continues to rise with increasing age.
Risk for Breast Cancer by Age
All of these potential explanations, along with several others, are discussed in some detail on a science blog on the Cancer Research UK Web site.
Change in Mammography Policy
These latest figures chart a rise from 1999 to 2008, but about halfway through that period (in 2004), there was a change in national policy in the United Kingdom, when women 65 to 69 years of age started to be included in the national screening breast screening program. Before 2004, invitations for mammograms stopped when women reached 65 years of age (they start at 50 years).
The rise in breast cancer diagnoses in this age group probably coincides with this, according to the organization, because an increase in the number of women being screened would very likely lead to more cancers being detected.
Cancer Research UK acknowledges the controversy that has raged over mammography leading to the overdiagnosis of breast cancer, in particular the fact that it picks up cases of ductal carcinoma in situ (DCIS), which might never develop into a problem. "But our new analysis doesn't include cases of DCIS, so these noninvasive tumors can't explain the rising breast cancer rates in women aged 65 to 69," it reports.
Now for the Good News
"While it's worrying that women are now more likely to develop breast cancer than they were a decade ago, there is good news too," Cancer Research UK explains, pointing out that survival rates have "shot up."
"Almost 2 out of every 3 women with breast cancer now survive the disease beyond 20 years, compared with less than half in the 1990s. And more than three quarters of women diagnosed with breast cancer survive for at least 10 years, or more," it notes.
This new estimate, from Cancer Research UK, was widely reported in the media, with headlines emphasizing the frightening statistic of 1 in 8, but few reports explained that risk increases sharply with age.
Breast cancer rates have risen by 3.5% in 10 years, the organization reported. A diagnosis of breast cancer was recorded in 47,700 women in 2008, compared with 42,400 women in 1999.
The biggest rise was among women 50 to 69 years of age, where the increase was more than 6% in that 10-year period. This age group represents almost half (48%) the total number of cases. Another 33% of cases were diagnosed in women older than 70 years of age.
Only 19% of the total cases were diagnosed in younger women (25 to 49 years); in this age group, the rate of breast cancer actually dropped slightly (by 0.5%).
According to Cancer Research UK, "there's no simple answer" to why breast cancer rates are increasing, but more cancers being detected by mammography screening, lifestyle changes such as increased alcohol use and obesity, an aftermath of prolonged use of hormone replacement therapy, women having fewer children and breastfeeding less, and the increasing age of the population are possible explanations.
Age in particular has a major effect. The risk for breast cancer increases sharply from around the time of the menopause and continues to rise with increasing age.
Risk for Breast Cancer by Age
| Age (Years) | Risk |
| 29 | 1 in 2000 |
| 39 | 1 in 215 |
| 49 | 1 in 50 |
| 59 | 1 in 22 |
| 69 | 1 in 13 |
| Lifetime risk | 1 in 8 |
All of these potential explanations, along with several others, are discussed in some detail on a science blog on the Cancer Research UK Web site.
Change in Mammography Policy
These latest figures chart a rise from 1999 to 2008, but about halfway through that period (in 2004), there was a change in national policy in the United Kingdom, when women 65 to 69 years of age started to be included in the national screening breast screening program. Before 2004, invitations for mammograms stopped when women reached 65 years of age (they start at 50 years).
The rise in breast cancer diagnoses in this age group probably coincides with this, according to the organization, because an increase in the number of women being screened would very likely lead to more cancers being detected.
Cancer Research UK acknowledges the controversy that has raged over mammography leading to the overdiagnosis of breast cancer, in particular the fact that it picks up cases of ductal carcinoma in situ (DCIS), which might never develop into a problem. "But our new analysis doesn't include cases of DCIS, so these noninvasive tumors can't explain the rising breast cancer rates in women aged 65 to 69," it reports.
Now for the Good News
"While it's worrying that women are now more likely to develop breast cancer than they were a decade ago, there is good news too," Cancer Research UK explains, pointing out that survival rates have "shot up."
"Almost 2 out of every 3 women with breast cancer now survive the disease beyond 20 years, compared with less than half in the 1990s. And more than three quarters of women diagnosed with breast cancer survive for at least 10 years, or more," it notes.
Senin, 14 Februari 2011
DIET SODA INCREASES CARDIOVASCULAR RISK?
Diet soda may not be the healthier alternative many had hoped. A new study suggests that the popular drinks may increase the risk for stroke, myocardial infarction, and vascular death.
"People who had diet soda every day experienced a 61% higher risk of vascular events than those who reported drinking no soda," lead investigator Hannah Gardener, ScD, an epidemiologist from the University of Miami Miller School of Medicine in Florida, told reporters attending a news conference here at the International Stroke Conference.
The risk persisted after controlling for metabolic syndrome, peripheral vascular disease, and cardiac disease history (relative risk, 1.48; 95% confidence interval, 1.03 - 2.12).
"This is the first report of this association," said American Stroke Association national spokesperson Larry Goldstein, MD. "I think that it's always good to do things in moderation. People should look at this information and consider it in the context of their other risk factors."
The researchers looked at more than 2500 people from the multiethnic Northern Manhattan Study. Participants were asked to report how much and what kind of soda they drank.
During an average follow-up of 9.3 years, 559 vascular events occurred, including ischemic and hemorrhagic stroke.
The researchers also observed a marginally significant increased risk for vascular events among those who consumed diet soda daily and regular soda once or more a month (adjusted relative risk, 1.74; 95% confidence interval, 0.96 - 3.16).
As reported by Medscape Medical News, previous studies have suggested a link between diet soda consumption and the risk for metabolic syndrome and diabetes. But this is the first time diet drinks have been associated with vascular events.
"This is an observational study and not a prospective randomized trial," Dr. Goldstein, from the Duke Stroke Center, in Durham, North Carolina, pointed out. "This is an association and not yet a proven causal relationship."
The investigators acknowledge that additional studies are needed. The potential mechanisms for the association between diet soda and vascular events remain unknown.
What should clinicians advise patients on the basis of the information we have today? Steven Greenberg, MD, from Harvard Medical School in Boston, Massachusetts, suggests that patients start by concentrating on a healthy diet and regular exercise. "Once the metabolic syndrome is under control and any risk of diabetes, then we can consider cutting back on soda consumption." Dr. Greenberg is the vice chair of the International Stroke Conference Committee, and during an interview he suggested that patients shouldn't rush to eliminate diet drinks.
"I do think this is a wake-up call, though," he said, "and we need to start paying closer attention."
This study was funded by the Javits award from the National Institute of Neurological Disorders and Stroke and the Evelyn McKnight Brain Institute. The researchers have disclosed no relevant financial relationships.
American Stroke Association International Stroke Conference. Abstract # P55. News conference February 9, 2011.
"People who had diet soda every day experienced a 61% higher risk of vascular events than those who reported drinking no soda," lead investigator Hannah Gardener, ScD, an epidemiologist from the University of Miami Miller School of Medicine in Florida, told reporters attending a news conference here at the International Stroke Conference.
The risk persisted after controlling for metabolic syndrome, peripheral vascular disease, and cardiac disease history (relative risk, 1.48; 95% confidence interval, 1.03 - 2.12).
"This is the first report of this association," said American Stroke Association national spokesperson Larry Goldstein, MD. "I think that it's always good to do things in moderation. People should look at this information and consider it in the context of their other risk factors."
The researchers looked at more than 2500 people from the multiethnic Northern Manhattan Study. Participants were asked to report how much and what kind of soda they drank.
During an average follow-up of 9.3 years, 559 vascular events occurred, including ischemic and hemorrhagic stroke.
The researchers also observed a marginally significant increased risk for vascular events among those who consumed diet soda daily and regular soda once or more a month (adjusted relative risk, 1.74; 95% confidence interval, 0.96 - 3.16).
As reported by Medscape Medical News, previous studies have suggested a link between diet soda consumption and the risk for metabolic syndrome and diabetes. But this is the first time diet drinks have been associated with vascular events.
"This is an observational study and not a prospective randomized trial," Dr. Goldstein, from the Duke Stroke Center, in Durham, North Carolina, pointed out. "This is an association and not yet a proven causal relationship."
The investigators acknowledge that additional studies are needed. The potential mechanisms for the association between diet soda and vascular events remain unknown.
What should clinicians advise patients on the basis of the information we have today? Steven Greenberg, MD, from Harvard Medical School in Boston, Massachusetts, suggests that patients start by concentrating on a healthy diet and regular exercise. "Once the metabolic syndrome is under control and any risk of diabetes, then we can consider cutting back on soda consumption." Dr. Greenberg is the vice chair of the International Stroke Conference Committee, and during an interview he suggested that patients shouldn't rush to eliminate diet drinks.
"I do think this is a wake-up call, though," he said, "and we need to start paying closer attention."
This study was funded by the Javits award from the National Institute of Neurological Disorders and Stroke and the Evelyn McKnight Brain Institute. The researchers have disclosed no relevant financial relationships.
American Stroke Association International Stroke Conference. Abstract # P55. News conference February 9, 2011.
Minggu, 13 Februari 2011
Polyphenols, Hormesis and Disease: Part I
What are Polyphenols?
Polyphenols are a diverse class of molecules containing multiple phenol rings. They are synthesized in large amounts by plants, certain fungi and a few animals, and serve many purposes, including defense against predators/infections, defense against sunlight damage and chemical oxidation, and coloration. The color of many fruits and vegetables, such as blueberries, eggplants, red potatoes and apples comes from polyphenols. Some familiar classes of polyphenols in the diet-health literature are flavonoids, isoflavonoids, anthocyanidins, and lignins.
The Case Against Polyphenols
Mainstream diet-health authorities seem pretty well convinced that dietary polyphenols are an important part of good health, due to their supposed antioxidant properties. In the past, I've been critical of the hypothesis. There are several reasons for it:
A Reappraisal
After reading more about polyphenols, and coming to understand that the prevailing hypothesis of why they work makes no sense, I decided that the whole thing is probably bunk: at best, specific polyphenols are protective in rodents at unnaturally high doses due to some drug-like effect. But-- I kept my finger on the pulse of the field just in case, and I began to notice that more sophisticated studies were emerging almost weekly that seemed to confirm that realistic amounts of certain polyphenol-rich foods (not just massive quantities of polyphenol extract) have protective effects against a variety of health problems. There are many such studies, and I won't attempt to review them comprehensively, but here are a few I've come across:
In the face of this accumulating evidence, I've had to reconsider my position on polyphenols. In the process, and through conversations with knowledgeable researchers in the polyphenol field, I encountered a different hypothesis that puts the puzzle pieces together nicely.
* Serum levels briefly enter the mid nM to low uM range, depending on the food (2). Compare that with the main serum antioxidants: ~200 uM for uric acid, ~100 uM for vitamin C, ~30 uM for vitamin E.
Polyphenols are a diverse class of molecules containing multiple phenol rings. They are synthesized in large amounts by plants, certain fungi and a few animals, and serve many purposes, including defense against predators/infections, defense against sunlight damage and chemical oxidation, and coloration. The color of many fruits and vegetables, such as blueberries, eggplants, red potatoes and apples comes from polyphenols. Some familiar classes of polyphenols in the diet-health literature are flavonoids, isoflavonoids, anthocyanidins, and lignins.
The Case Against Polyphenols
Mainstream diet-health authorities seem pretty well convinced that dietary polyphenols are an important part of good health, due to their supposed antioxidant properties. In the past, I've been critical of the hypothesis. There are several reasons for it:
- Polyphenols are often, but not always, defensive compounds that interfere with digestive processes, which is why they often taste bitter and/or astringent. Plant-eating animals including humans have evolved defensive strategies against polyphenol-rich foods, such as polyphenol-binding proteins in saliva (1).
- Ingested polyphenols are poorly absorbed (2). The concentration in blood is low, and the concentration inside cells is probably considerably lower*. In contrast, essential antioxidant nutrients such as vitamins E and C are efficiently absorbed rather than excluded from the circulation.
- Polyphenols that manage to cross the gut barrier are rapidly degraded by the liver, just like a variety of other foreign molecules, again suggesting that the body doesn't want them hanging around (2).
- The most visible hypothesis of how polyphenols influence health is the idea that they are antioxidants, protecting against the ravages of reactive oxygen species. While many polyphenols are effective antioxidants at high concentrations in a test tube, I don't find it very plausible that the low and transient blood concentration of polyphenols achieved by eating polyphenol-rich foods makes a meaningful contribution to that person's overall antioxidant status, when compared to the relatively high concentrations of other antioxidants in blood (uric acid; vitamins C, E; ubiquinone) and particularly inside cells (SOD1/2, catalase, glutathione reductase, thioredoxin reductase, paraoxonase 1, etc.).
- There are a number of studies showing that the antioxidant capacity of the blood increases after eating polyphenol-rich foods. These are often confounded by the fact that fructose (in fruit and some vegetables) and caffeine (in tea and coffee) can increase the blood level of uric acid, the blood's main water-soluble antioxidant. Drinking sugar water has the same effect (2).
- Rodent studies showing that polyphenols improve health typically use massive doses that exceed what a person could consume eating food, and do not account for the possibility that the rodents may have been calorie restricted because their food tastes horrible.
A Reappraisal
After reading more about polyphenols, and coming to understand that the prevailing hypothesis of why they work makes no sense, I decided that the whole thing is probably bunk: at best, specific polyphenols are protective in rodents at unnaturally high doses due to some drug-like effect. But-- I kept my finger on the pulse of the field just in case, and I began to notice that more sophisticated studies were emerging almost weekly that seemed to confirm that realistic amounts of certain polyphenol-rich foods (not just massive quantities of polyphenol extract) have protective effects against a variety of health problems. There are many such studies, and I won't attempt to review them comprehensively, but here are a few I've come across:
- Dr. David Grassi and colleagues showed that polyphenol-rich chocolate lowers blood pressure, improves insulin sensitivity and lowers LDL cholesterol in hypertensive and insulin resistant volunteers when compared with white chocolate (3). Although dark chocolate is also probably richer in magnesium, copper and other nutrients than white chocolate, the study is still intriguing.
- Dr. Christine Morand and colleagues showed that drinking orange juice every day lowers blood pressure and increases vascular reactivity in overweight volunteers, an effect that they were able to specifically attribute to the polyphenol hesperidin (4).
- Dr. F. Natella and colleagues showed that red wine prevents the increase in oxidized blood lipids (fats) that occurs after consuming a meal high in oxidized and potentially oxidizable fats (5).
- Several studies have shown that hibiscus tea lowers blood pressure in people with hypertension when consumed regularly (6, 7, 8). It also happens to be delicious.
- Dr. Arpita Basu and colleagues showed that blueberries lower blood pressure and oxidized LDL in men and women with metabolic syndrome (9).
- Animal studies have generally shown similar results. Dr. Xianli Wu and colleagues showed the blueberries potently inhibit atherosclerosis (hardening and thickening of the arteries that can lead to a heart attack) in a susceptible strain of mice (10). This effect was associated with a higher expression level of antioxidant enzymes in the vessel walls and other tissues.
In the face of this accumulating evidence, I've had to reconsider my position on polyphenols. In the process, and through conversations with knowledgeable researchers in the polyphenol field, I encountered a different hypothesis that puts the puzzle pieces together nicely.
* Serum levels briefly enter the mid nM to low uM range, depending on the food (2). Compare that with the main serum antioxidants: ~200 uM for uric acid, ~100 uM for vitamin C, ~30 uM for vitamin E.
Kamis, 10 Februari 2011
My Gluten-Free January
I've been avoiding most gluten, particularly wheat, for over a year now. I never had obvious symptoms that I could clearly link to eating wheat, although I had my suspicions. I've made many changes to my diet over the last decade, and I feel much better than I did ten years ago, but it's hard to disentangle all the factors. I don't think I ever went an entire month without eating any gluten at all before this January. After posting Matt Lentzner's challenge to go gluten-free this January, I felt obligated to do it myself, so I signed up!
I succeeded in avoiding all gluten for the month of January, even though it was a pain at times. I felt good before January, and didn't start with any health or body weight problems, so there wasn't much to improve. I also felt good while strictly avoiding gluten this January, perhaps a little better than usual but it's hard to say.
At the end of the month, I did a blinded wheat challenge using the method I described in a previous post, which uses gluten-free bread as the placebo (1). I recorded my blood sugar at 30 minute intervals after eating the bread, and recorded how I felt physically and emotionally for three days after each challenge.
The result? I think the bread gave me gas, but that's about it. I'm not even positive that was due to the wheat. My energy level was good, and I didn't experience any digestive pain or changes in transit time. There was no significant difference in my blood glucose response between the bread and the gluten-free bread.
I decided that I didn't have any symptoms, so I celebrated by having a porter (1) with friends a few nights later. I slept poorly and woke up with mild digestive discomfort and gas. Then I ate wheat later in the week and slept poorly and got gas again. Hmmm...
Some people might say that the body adapts to any food, and wheat is no different. Go without it for a while, and the body has a tough time digesting it. But I can go for weeks without eating a potato, a chicken thigh or broccoli, and all will digest just fine when I eat them again.
I'm pretty sure I don't have a severe reaction to gluten. I think I'm going to stick with my mostly gluten-free habits, and eat it occasionally when I'm offered food in social situations.
Did anyone else do a blinded wheat challenge? Describe it in the comments!
I succeeded in avoiding all gluten for the month of January, even though it was a pain at times. I felt good before January, and didn't start with any health or body weight problems, so there wasn't much to improve. I also felt good while strictly avoiding gluten this January, perhaps a little better than usual but it's hard to say.
At the end of the month, I did a blinded wheat challenge using the method I described in a previous post, which uses gluten-free bread as the placebo (1). I recorded my blood sugar at 30 minute intervals after eating the bread, and recorded how I felt physically and emotionally for three days after each challenge.
The result? I think the bread gave me gas, but that's about it. I'm not even positive that was due to the wheat. My energy level was good, and I didn't experience any digestive pain or changes in transit time. There was no significant difference in my blood glucose response between the bread and the gluten-free bread.
I decided that I didn't have any symptoms, so I celebrated by having a porter (1) with friends a few nights later. I slept poorly and woke up with mild digestive discomfort and gas. Then I ate wheat later in the week and slept poorly and got gas again. Hmmm...
Some people might say that the body adapts to any food, and wheat is no different. Go without it for a while, and the body has a tough time digesting it. But I can go for weeks without eating a potato, a chicken thigh or broccoli, and all will digest just fine when I eat them again.
I'm pretty sure I don't have a severe reaction to gluten. I think I'm going to stick with my mostly gluten-free habits, and eat it occasionally when I'm offered food in social situations.
Did anyone else do a blinded wheat challenge? Describe it in the comments!
Building brawn may also boost brain power
It has long been a cliche that muscle bulk doesn't equate with intelligence. Most of the science about activity and brain health has focused on the role of endurance exercise in improving brain functioning.Aerobic exercise causes a steep spike in blood movement to the brain, an action some researchers speculated might be necessary to create new brain cells, or neurogenesis.Running and other forms
CALCIUM CHANNEL BLOCKERS-MAKROLIDE INTERACTION
Doctors need to be careful when prescribing macrolide antibiotics to patients on calcium-channel blockers (CCBs) because of an underappreciated drug-drug interaction that can lead to hypotension and shock, new research shows [1]. The findings are important because millions of people take CCBs and many are prescribed antibiotics every year, say Dr Alissa J Wright (University of Toronto, ON) and colleagues in a study published online January 17, 2011 in CMAJ.Although the interaction "is perfectly predictable based upon the pharmacology of the drugs, it has been previously documented in only about five case reports," senior author Dr David Juurlink(University of Toronto, ON) explained to heartwire . He says that this study is the first rigorous attempt to describe the clinical consequences of this interaction: "In a sense, this paper attaches a risk estimate to how dangerous this drug combination is."
The research also shows that there is a safe choice if doctors do need to use a macrolidelike antibiotic, he adds. The study found that macrolides such as erythromycin orclarithromycin increase the risk of hypotension if used in combination with a CCB, but a related antibiotic, azithromycin, does not.
Juurlink observes that "it's not wrong to use a macrolide [in a patient taking a CCB], but it's probably more sensible if you are going to use one to use azithromycin. If, for some reason, you had to use clarithromycin or erythromycin, it might be reasonable just to edge back a little bit on the dose of the CCB."
Biggest Risk With Erythromycin
In their population-based, nested, case-crossover study, Wright and colleagues analyzed the healthcare records of around a million individuals over the age of 65 who were receiving a single CCB between 1994 and 2009. Of these patients, 7100 were admitted to hospital for hypotension or shock, and 176 had received a macrolide antibiotic (36 received erythromycin, 100 received clarithromycin, and 40 received azithromycin) in a seven-day interval immediately before admission to the hospital or in a seven-day control interval one month earlier. For each antibiotic, the researchers estimated the risk of hypotension or shock associated with the use of a CCB.
They found a strong association between erythromycin use and hospital admission for hypotension, with an almost sixfold increased risk of low BP (odds ratio 5.8), and a lower but still significant risk associated with the use of clarithromycin (OR 3.7). In contrast, there was no such link with azithromycin use (OR 1.5).
Juurlink explains that, pharmacologically, macrolide antibiotics inhibit a cytochrome P450 enzyme, which metabolizes all CCBs, so their use can lead to the accumulation of the CCB and potential toxicity. But azithromycin does not inhibit this cytochrome P450 enzyme. The use of combination CCBs and macrolide antibiotics "isn't exactly uncommon, but no one has actually ever attached a measure of how dangerous the combination is, and that's what this study does," he notes.
The findings, says Juurlink, apply to all CCBs, because they are all metabolized by the same pathway, although it may be a bigger problem with some than others, he says, adding that his team could not examine the risks for separate CCBs because of a lack of statistical power.
Nevertheless, the results "have considerable clinical relevance, highlighting the consequences of an underappreciated yet avoidable drug interaction involving medications used by millions of people every year. Clinicians should be aware of the potential interaction between these drugs," he and his colleagues state.
Juurlink adds that although the use of erythromycin is declining, clarithromycin is still used frequently. "But I don't think clarithromycin and azithromycin are that different in price, quite frankly, so the latter represents a good choice if macrolide antibiotic therapy is required."
The research also shows that there is a safe choice if doctors do need to use a macrolidelike antibiotic, he adds. The study found that macrolides such as erythromycin orclarithromycin increase the risk of hypotension if used in combination with a CCB, but a related antibiotic, azithromycin, does not.
Juurlink observes that "it's not wrong to use a macrolide [in a patient taking a CCB], but it's probably more sensible if you are going to use one to use azithromycin. If, for some reason, you had to use clarithromycin or erythromycin, it might be reasonable just to edge back a little bit on the dose of the CCB."
Biggest Risk With Erythromycin
In their population-based, nested, case-crossover study, Wright and colleagues analyzed the healthcare records of around a million individuals over the age of 65 who were receiving a single CCB between 1994 and 2009. Of these patients, 7100 were admitted to hospital for hypotension or shock, and 176 had received a macrolide antibiotic (36 received erythromycin, 100 received clarithromycin, and 40 received azithromycin) in a seven-day interval immediately before admission to the hospital or in a seven-day control interval one month earlier. For each antibiotic, the researchers estimated the risk of hypotension or shock associated with the use of a CCB.
They found a strong association between erythromycin use and hospital admission for hypotension, with an almost sixfold increased risk of low BP (odds ratio 5.8), and a lower but still significant risk associated with the use of clarithromycin (OR 3.7). In contrast, there was no such link with azithromycin use (OR 1.5).
Juurlink explains that, pharmacologically, macrolide antibiotics inhibit a cytochrome P450 enzyme, which metabolizes all CCBs, so their use can lead to the accumulation of the CCB and potential toxicity. But azithromycin does not inhibit this cytochrome P450 enzyme. The use of combination CCBs and macrolide antibiotics "isn't exactly uncommon, but no one has actually ever attached a measure of how dangerous the combination is, and that's what this study does," he notes.
The findings, says Juurlink, apply to all CCBs, because they are all metabolized by the same pathway, although it may be a bigger problem with some than others, he says, adding that his team could not examine the risks for separate CCBs because of a lack of statistical power.
Nevertheless, the results "have considerable clinical relevance, highlighting the consequences of an underappreciated yet avoidable drug interaction involving medications used by millions of people every year. Clinicians should be aware of the potential interaction between these drugs," he and his colleagues state.
Juurlink adds that although the use of erythromycin is declining, clarithromycin is still used frequently. "But I don't think clarithromycin and azithromycin are that different in price, quite frankly, so the latter represents a good choice if macrolide antibiotic therapy is required."
Rabu, 09 Februari 2011
Gluten-Free January Raffle!
Hi, Gluten-Free January participants. Matt, Janine and I have collected about 200 survey responses at this point. So far, the results are very interesting! But we want to get as many responses as possible, because the more responses we get, the more informative the data will be for all of us. So please fill out the survey Matt sent you by e-mail, no matter what your results were, and no matter whether you stuck with the diet or not! The survey is strictly about your GFJ experience, not investment opportunities, timeshares, ShamWows or anything else. It will take you less than 5 minutes, and it's totally anonymous. The deadline is Feb 15th. Big thanks to everyone who has taken it so far.
To encourage participants to complete the survey, we're organizing a raffle. Matt and I have five Gluten-Free January T-shirts we're ready to give out for free. These shirts were designed by Matt and they're really cool. I have one myself, and the print and fabric quality are top notch. Here's what the logo looks like:
If you've completed the survey and want to be included in the raffle, please e-mail Matt to let him know you've completed it. Anyone who has already e-mailed Matt to let him know they completed the survey will automatically be entered, so no need for a second e-mail. So far, very few people have written Matt, so your probability of winning a shirt is high!
To encourage participants to complete the survey, we're organizing a raffle. Matt and I have five Gluten-Free January T-shirts we're ready to give out for free. These shirts were designed by Matt and they're really cool. I have one myself, and the print and fabric quality are top notch. Here's what the logo looks like:
If you've completed the survey and want to be included in the raffle, please e-mail Matt to let him know you've completed it. Anyone who has already e-mailed Matt to let him know they completed the survey will automatically be entered, so no need for a second e-mail. So far, very few people have written Matt, so your probability of winning a shirt is high!Guidelines to offer kids a healthy smile
February is National Children’s Dental Health Month, and the New Jersey Department of Health and Senior Services is urging parents to ensure their children are polishing up on their tooth brushing skills, and maintaining good oral hygiene in order to have a lifelong healthy smile.“Over 50 percent of children ages 5-9 have at least one cavity or filling,” said Dr. Poonam Alaigh, Commissioner of
SURVIVAL BENEFIT WITH MITOXANTRONE IN RELAPSED ALL
The survival rate for children with acute lymphoblastic leukemia (ALL) has dramatically increased over the past few decades, from about 50% to more than 80%. Despite these advances, patients who relapse often do poorly, and ALL remains a leading cause of death in children.
However, a new study has found that in patients in first relapse, mitoxantrone confers a significant benefit in progression-free and overall survival, compared with idarubicin. In fact, randomization was halted early by the Data and Safety Monitoring Committee because of differences in progression-free and overall survival between the 2 treatment groups.
The study was presented here at the American Society of Hematology 52nd Annual Meeting, and was published in the December 11 issue of the Lancet.
Vaskar Saha, MBBS, PhD, professor of pediatric oncology at the University of Manchester, United Kingdom, and colleagues found that the estimated 3-year progression-free survival was 35.9% (95% confidence interval [CI], 25.9 - 45.9) in children who received idarubicin, compared with 64.6% (95% CI, 54.2 - 73.2) in those who received mitoxantrone (P = .0004).
Similarly, 3-year overall survival was 45.2% (95% CI, 34.5 - 55.3) for idarubicin and 69.0% (95% CI, 58.5 - 77.3; P = .004) for mitoxantrone. "Mitoxantrone almost halved the hazard of an event at any given timepoint for both progression-free and overall survival," the authors note.
Suitable End Points for Drug Assessment
In an accompanying editorial, Martin Schrappe, MD, PhD, from the University Medical Center Schleswig-Holstein, Kiel, Germany, points out that the difference between the 2 regimens "translated into a clear survival advantage of more than 20%, which is one of the largest improvements ever achieved by a single modification of treatment."
Dr. Schrappe notes that another finding of this study concerns end points for drug assessment. The quantitative detection of minimal residual disease has major prognostic importance in both adult and pediatric leukemia, he explains. In the current study, however, minimal residual disease was measured in intermediate-risk patients at the completion of treatment, but no difference could be detected between the 2 study groups.
"On the basis of minimal residual disease as a surrogate end point, this highly efficacious combination of drugs would not have been considered for further assessment," he writes. This finding is relevant "for ongoing discussions on suitable end points for drug assessment."
Lower Toxicity With Mitoxantrone
In the trial, Dr. Saha and colleagues randomized 216 patients from 1 to 18 years of age with first relapse of ALL to receive either idarubicin or mitoxantrone during induction. The trial was undertaken in 22 centers in the United Kingdom and Ireland and 9 in Australia and New Zealand; neither the patients nor the healthcare workers were masked.
All high-risk patients and intermediate-risk patients with postinduction high minimal residual disease underwent allogenic stem cell transplantation after 3 blocks of therapy. Standard-risk patients and the remaining intermediate-risk patients continued with chemotherapy.
Median follow-up was 41 months in both groups, and the estimated 3-year progression-free survival of the entire cohort was 50.3% (95% CI, 42.9 - 57.3); overall survival was 57.1% (49.5 - 63.9). The adjusted hazard ratio for progression-free survival was 0.54 (95% CI, 0.36 - 0.82; P = .003), and for overall survival was 0.56 (95% CI, 0.36 - 0.87, P = .01).
Of 212 evaluable patients, 108 (51%) remain in second complete remission (45 of 109 [41%] in the idarubicin group and 63 of 103 [61%] in the mitoxantrone group).
A third complete remission was achieved in 6 of 38 patients in the idarubicin group and in 3 of 18 in the mitoxantrone group. A total of 49 patients underwent transplantation in each study group, after which 16 (33%) in the idarubicin group and 2 (4%) in the mitoxantrone group relapsed.
The authors note that throughout the trial, grade 3 or higher toxic effects were significantly lower with mitoxantrone than with idarubicin (incidence rate ratio mitoxantrone/idarubicin, 0.86; 95% CI, 0.75 - 0.98; P = .02). The toxic effects during the first 2 phases of the study were significantly higher with idarubicin than with mitoxantrone. These events were primarily hepatic and gastrointestinal.
Cytotoxics Still Have Role
Mitoxantrone has only been infrequently used in therapeutic trials in pediatric ALL, the researchers write. "A perception that optimization has been reached with available drugs has shifted focus towards newer drugs and targeted therapy."
They note that these newer agents will be prohibitively expensive for many patients (whereas mitoxantrone is a cheap and readily available), and clearly need further clinical assessment in this population.
"Our results suggest that, while we wait for targeted therapies to become a reality, conventional cytotoxics still have a role in treatment of acute lymphoblastic leukemia," they conclude.
The study was funded by Cancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation. Dr. Saha reports participating in speaker bureaus and advisory boards for EUSA Pharma, Genzyme, Medac, Kyowa-Hakko, and Novartis. Coauthor Philip Ancliff, MA, MRCP, MRCPath, from Great Ormond Street Hospital, London, United Kingdom, reports receiving travel support from Genzyme and Gilead. Coauthor Nicholas Goulden, MB, ChB, MRCP, FRCPath, PhD, also from Great Ormond Street Hospital, reports participating in advisory boards for Enzon. Dr. Schrappe has disclosed no relevant financial relationships
However, a new study has found that in patients in first relapse, mitoxantrone confers a significant benefit in progression-free and overall survival, compared with idarubicin. In fact, randomization was halted early by the Data and Safety Monitoring Committee because of differences in progression-free and overall survival between the 2 treatment groups.
The study was presented here at the American Society of Hematology 52nd Annual Meeting, and was published in the December 11 issue of the Lancet.
Vaskar Saha, MBBS, PhD, professor of pediatric oncology at the University of Manchester, United Kingdom, and colleagues found that the estimated 3-year progression-free survival was 35.9% (95% confidence interval [CI], 25.9 - 45.9) in children who received idarubicin, compared with 64.6% (95% CI, 54.2 - 73.2) in those who received mitoxantrone (P = .0004).
Similarly, 3-year overall survival was 45.2% (95% CI, 34.5 - 55.3) for idarubicin and 69.0% (95% CI, 58.5 - 77.3; P = .004) for mitoxantrone. "Mitoxantrone almost halved the hazard of an event at any given timepoint for both progression-free and overall survival," the authors note.
Suitable End Points for Drug Assessment
In an accompanying editorial, Martin Schrappe, MD, PhD, from the University Medical Center Schleswig-Holstein, Kiel, Germany, points out that the difference between the 2 regimens "translated into a clear survival advantage of more than 20%, which is one of the largest improvements ever achieved by a single modification of treatment."
Dr. Schrappe notes that another finding of this study concerns end points for drug assessment. The quantitative detection of minimal residual disease has major prognostic importance in both adult and pediatric leukemia, he explains. In the current study, however, minimal residual disease was measured in intermediate-risk patients at the completion of treatment, but no difference could be detected between the 2 study groups.
"On the basis of minimal residual disease as a surrogate end point, this highly efficacious combination of drugs would not have been considered for further assessment," he writes. This finding is relevant "for ongoing discussions on suitable end points for drug assessment."
Lower Toxicity With Mitoxantrone
In the trial, Dr. Saha and colleagues randomized 216 patients from 1 to 18 years of age with first relapse of ALL to receive either idarubicin or mitoxantrone during induction. The trial was undertaken in 22 centers in the United Kingdom and Ireland and 9 in Australia and New Zealand; neither the patients nor the healthcare workers were masked.
All high-risk patients and intermediate-risk patients with postinduction high minimal residual disease underwent allogenic stem cell transplantation after 3 blocks of therapy. Standard-risk patients and the remaining intermediate-risk patients continued with chemotherapy.
Median follow-up was 41 months in both groups, and the estimated 3-year progression-free survival of the entire cohort was 50.3% (95% CI, 42.9 - 57.3); overall survival was 57.1% (49.5 - 63.9). The adjusted hazard ratio for progression-free survival was 0.54 (95% CI, 0.36 - 0.82; P = .003), and for overall survival was 0.56 (95% CI, 0.36 - 0.87, P = .01).
Of 212 evaluable patients, 108 (51%) remain in second complete remission (45 of 109 [41%] in the idarubicin group and 63 of 103 [61%] in the mitoxantrone group).
A third complete remission was achieved in 6 of 38 patients in the idarubicin group and in 3 of 18 in the mitoxantrone group. A total of 49 patients underwent transplantation in each study group, after which 16 (33%) in the idarubicin group and 2 (4%) in the mitoxantrone group relapsed.
The authors note that throughout the trial, grade 3 or higher toxic effects were significantly lower with mitoxantrone than with idarubicin (incidence rate ratio mitoxantrone/idarubicin, 0.86; 95% CI, 0.75 - 0.98; P = .02). The toxic effects during the first 2 phases of the study were significantly higher with idarubicin than with mitoxantrone. These events were primarily hepatic and gastrointestinal.
Cytotoxics Still Have Role
Mitoxantrone has only been infrequently used in therapeutic trials in pediatric ALL, the researchers write. "A perception that optimization has been reached with available drugs has shifted focus towards newer drugs and targeted therapy."
They note that these newer agents will be prohibitively expensive for many patients (whereas mitoxantrone is a cheap and readily available), and clearly need further clinical assessment in this population.
"Our results suggest that, while we wait for targeted therapies to become a reality, conventional cytotoxics still have a role in treatment of acute lymphoblastic leukemia," they conclude.
The study was funded by Cancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation. Dr. Saha reports participating in speaker bureaus and advisory boards for EUSA Pharma, Genzyme, Medac, Kyowa-Hakko, and Novartis. Coauthor Philip Ancliff, MA, MRCP, MRCPath, from Great Ormond Street Hospital, London, United Kingdom, reports receiving travel support from Genzyme and Gilead. Coauthor Nicholas Goulden, MB, ChB, MRCP, FRCPath, PhD, also from Great Ormond Street Hospital, reports participating in advisory boards for Enzon. Dr. Schrappe has disclosed no relevant financial relationships
Selasa, 08 Februari 2011
BSE, Mad Cow, Creutzfeldt-Jakob disease - Fellow Veterans
Good evening. This particular blog is not really so much about health insurance as about a health issue I only recently discovered. It is directed to my fellow military veterans who served in the UK and/or Europe as well as any of my readers who lived in Europe for an extended period between 1980 and 1996 (between three and six months or more). I was stationed in Berlin, Germany from 1983-1986
California's Hidden Non-Dependent Tax On Health Premiums
A part of the PPACA (ObamaCare) provides that parents may add children to their employer-sponsored coverage plan up to age 26, whether a dependent student or not.Turns out California's tax law requires the state to levy taxes on any amount of premium paid by the employer for non-dependent children of employees.Many California workers added non-dependent children under age 26 to their group health
Walking, Nutrition for a Healthy Mind
Women can take simple steps to bolster their brain power now and keep mentally agile as they age, according to an article in The Sun by fitness expert Nicki Waterman and nutritionist Amanda Ursell.First up is the importance of nutrition, which starts during pregnancy, as the fetus is hungry for solid nutrients to improve brain development. Ursell encouraged pregnant women to consume good sources
8 HPV TYPES CAUSE 90% OF CERVICAL CANCER
A massive multinational cervical cancer study described as "the benchmark for all time" has confirmed that 8 human papillomavirus (HPV) types cause more than 90% of all cervical cancers worldwide, and that HPV 16, 18, and 45 cause 94% of cervical adenocarcinomas.
The study was published online October 15 in the Lancet Oncology.
The research team, led by Silvia de Sanjose, MD, from Institut Català d'Oncologia-Catalan Institute of Oncology in Barcelona, Spain, concludes that "HPV types 16, 18, 31, 33, 34, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines."
Maurie Markman, MD, vice president of patient oncology services and national director for medical oncology at Cancer Treatment Centers of America, in Philadelphia, Pennsylvania, told Medscape Medical News: " I suspect the next generation of cervix cancer vaccines will specifically include each of the 8 HPV types noted in this paper, since this will cover 90% of the cases of cervix cancer."
Currently, the 2 HPV vaccines on the market — Gardasil (Merck & Co) and Cervarix (GlaxoSmithKline) — protect against subtypes 16 and 18; together, these cause 70% of cervical cancer. In addition, Gardasil offers protection against 2 other subtypes (HPV 6 and 11) that cause genital warts.
However, there has been some evidence that the current vacciness might offer at least some cross-protection against other cervical cancer subtypes. A Merck research team, led by Janine Bryan, PhD, reported that Gardasil immunization induces antibodies capable of neutralizing HPV 45 in vitro (Hum Vaccin. 2007;3:109-115). The cross-reactive, cross-neutralizing antibodies were generated at reduced titers, compared with vaccine-specific types, and the researchers emphasized that antibody titers required for cross-protection against nonvaccine types were not known at that time.
The mechanism behind the cross-neutralization is that a single HPV species can contain several types. The HPV A9 species that contains type 18 also contains type 45. The HPV A7 species that contains type 16 also contains type 58, which was linked to cervical cancer in the de Sanjose multinational study.
There are also conclusions from the latest study on HPV screening. The researchers note that "our results also suggest that type-specific, high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45."
HPV 16, 18, and 45 are the most common types, and occur at a much younger age than other high-risk HPV genotypes. As such, these 3 HPV types should be the focus of future type-specific HPV screening, say the authors.
Massive Multinational Study
The researchers in this retrospective cross-sectional study collected samples from 10,575 cases of invasive cervical cancer diagnosed between 1949 and 2009 from 38 countries in Europe, North America, central South America, Africa, Asia, and Oceania. Polymerase chain reaction and DNA testing were used to identify the HPV genotype present in these tissue samples. They found that 8977 (85%) were positive for HPV DNA.
Over the 60-year study period, the 8 most common HPV types identified were (in descending order of frequency) 16, 18, 45, 33, 31, 52, 58, and 35. Together, they account for 91% of all cases of cervical cancer. HPV 16, 18, and 45 were found in 75% of the most common type of cervical cancer (squamous cell) and in 94% of adenocarcinomas (the second most common form).
Across 5 continents and despite a wide variety of screening programs, women infected with HPV types 16, 18, and 45 were diagnosed with cervical cancers an average of 4 years earlier than women with other high-risk HPV types. The researchers also found that HPV 16, 18, and 45 were more likely to be integrated into the human genome than other HPV types.
The authors recommend that, in light of the early presentation of cases of invasive cervical cancer that were positive for HPV 45, this genotype should be considered in type-specific screening protocols, and women who are positive should be offered closer surveillance.
Future Directions
The authors conclude that "this international effort . . . reinforces the rationale for prevention of cervical cancer through use of existing vaccines."
In an editorial comment that accompanied the study, Cosette Wheeler, MD, from the University of New Mexico Health Sciences Center, in Albuquerque, suggests that the HPV-negative cases were likely due to artifacts such as tissue inadequacy, nucleic-acid degradation in formalin-fixed tissues, low viral loads, and potential misdiagnosis, in part due to the absence of staging data and of stains to exclude samples of endometrial origin.
"Although a minor fraction of invasive cervical cancer might still arise, independent of HPV, studies of fresh-frozen cancer tissues suggest that this is only a small percentage of all invasive cancers," Dr. Wheeler writes.
Dr. Wheeler concludes that "the overall HPV prevalence data confirm the inclusion of specific pools of high-risk HPV in routine cervical screening and in the next generation of HPV vaccines."
Dr. de Sanjose reports receiving consultancy fees from Qiagen, Sanofi, and GlaxoSmithKline. Dr. Wheeler reports receiving research funding from Roche Molecular Systems, Merck & Co., and GlaxoSmithKline, and travel support from GlaxoSmithKline.
The study was published online October 15 in the Lancet Oncology.
The research team, led by Silvia de Sanjose, MD, from Institut Català d'Oncologia-Catalan Institute of Oncology in Barcelona, Spain, concludes that "HPV types 16, 18, 31, 33, 34, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines."
Maurie Markman, MD, vice president of patient oncology services and national director for medical oncology at Cancer Treatment Centers of America, in Philadelphia, Pennsylvania, told Medscape Medical News: " I suspect the next generation of cervix cancer vaccines will specifically include each of the 8 HPV types noted in this paper, since this will cover 90% of the cases of cervix cancer."
Currently, the 2 HPV vaccines on the market — Gardasil (Merck & Co) and Cervarix (GlaxoSmithKline) — protect against subtypes 16 and 18; together, these cause 70% of cervical cancer. In addition, Gardasil offers protection against 2 other subtypes (HPV 6 and 11) that cause genital warts.
However, there has been some evidence that the current vacciness might offer at least some cross-protection against other cervical cancer subtypes. A Merck research team, led by Janine Bryan, PhD, reported that Gardasil immunization induces antibodies capable of neutralizing HPV 45 in vitro (Hum Vaccin. 2007;3:109-115). The cross-reactive, cross-neutralizing antibodies were generated at reduced titers, compared with vaccine-specific types, and the researchers emphasized that antibody titers required for cross-protection against nonvaccine types were not known at that time.
The mechanism behind the cross-neutralization is that a single HPV species can contain several types. The HPV A9 species that contains type 18 also contains type 45. The HPV A7 species that contains type 16 also contains type 58, which was linked to cervical cancer in the de Sanjose multinational study.
There are also conclusions from the latest study on HPV screening. The researchers note that "our results also suggest that type-specific, high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45."
HPV 16, 18, and 45 are the most common types, and occur at a much younger age than other high-risk HPV genotypes. As such, these 3 HPV types should be the focus of future type-specific HPV screening, say the authors.
Massive Multinational Study
The researchers in this retrospective cross-sectional study collected samples from 10,575 cases of invasive cervical cancer diagnosed between 1949 and 2009 from 38 countries in Europe, North America, central South America, Africa, Asia, and Oceania. Polymerase chain reaction and DNA testing were used to identify the HPV genotype present in these tissue samples. They found that 8977 (85%) were positive for HPV DNA.
Over the 60-year study period, the 8 most common HPV types identified were (in descending order of frequency) 16, 18, 45, 33, 31, 52, 58, and 35. Together, they account for 91% of all cases of cervical cancer. HPV 16, 18, and 45 were found in 75% of the most common type of cervical cancer (squamous cell) and in 94% of adenocarcinomas (the second most common form).
Across 5 continents and despite a wide variety of screening programs, women infected with HPV types 16, 18, and 45 were diagnosed with cervical cancers an average of 4 years earlier than women with other high-risk HPV types. The researchers also found that HPV 16, 18, and 45 were more likely to be integrated into the human genome than other HPV types.
The authors recommend that, in light of the early presentation of cases of invasive cervical cancer that were positive for HPV 45, this genotype should be considered in type-specific screening protocols, and women who are positive should be offered closer surveillance.
Future Directions
The authors conclude that "this international effort . . . reinforces the rationale for prevention of cervical cancer through use of existing vaccines."
In an editorial comment that accompanied the study, Cosette Wheeler, MD, from the University of New Mexico Health Sciences Center, in Albuquerque, suggests that the HPV-negative cases were likely due to artifacts such as tissue inadequacy, nucleic-acid degradation in formalin-fixed tissues, low viral loads, and potential misdiagnosis, in part due to the absence of staging data and of stains to exclude samples of endometrial origin.
"Although a minor fraction of invasive cervical cancer might still arise, independent of HPV, studies of fresh-frozen cancer tissues suggest that this is only a small percentage of all invasive cancers," Dr. Wheeler writes.
Dr. Wheeler concludes that "the overall HPV prevalence data confirm the inclusion of specific pools of high-risk HPV in routine cervical screening and in the next generation of HPV vaccines."
Dr. de Sanjose reports receiving consultancy fees from Qiagen, Sanofi, and GlaxoSmithKline. Dr. Wheeler reports receiving research funding from Roche Molecular Systems, Merck & Co., and GlaxoSmithKline, and travel support from GlaxoSmithKline.
Minggu, 06 Februari 2011
3 DRUG INDUCTION CHEMOTHERAPY BEST FOR LOCALLY ADVANCED HEAD AND NECK CANCER?
The addition of docetaxel to standard induction chemotherapy with cisplatin and fluorouracil (PF) significantly improves the long-term survival of patients with locally advanced squamous cell head and neck cancer, reducing their likelihood of dying by 26% over 6 years.
These long-term results from the TAX 324 trial, published online January 12 in the Lancet Oncology, confirm that the 3-drug regimen — docetaxel, cisplatin, and fluorouracil (TPF) — should become the standard of care for all patients with locally advanced squamous cell cancer of the head and neck who are candidates for induction chemotherapy, say the authors.
"This is the longest follow-up with this regimen, and it is the longest follow-up of any regimen in head and neck cancer," said lead author Jochen Lorch, MD, from Harvard Medical School in Boston, Massachusetts. "The results from our study will definitely lay the concerns as to whether TPF is truly superior to PF to rest."
This study with 6-year results confirms earlier data showing the superiority of the 3-drug regimen; the 2-year results were published in 2007 (N Engl J Med. 2007; 357:1705-1715).
Comparing 3- and 2-Drug Regimens
The TAX 324 trial involved 501 patients with stage 3 or 4 disease randomized to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin and radiotherapy for 5 days per week for 7 weeks.
The TPF regimen consisted of docetaxel 75 mg/m2, followed by intravenous cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2 per day, administered as a continuous 24-hour infusion for 4 days. The PF regimen consisted of intravenous cisplatin 100 mg/m2, followed by fluorouracil 1000 mg/m2 per day as a continuous 24-hour infusion for 5 days.
Most patients (69%) had 3 or more years of follow-up. Significantly more patients survived in the TPF group than in the PF group (hazard ratio, 0.70; P = .006). Median overall survival was 71 months in the TPF group and 30 months in the PF group (P = .006).
The study also found that patients treated with TPF had better locoregional control (P = .04), but the incidence of distant metastases did not differ significantly.
Benefits Endure With Time
To see whether these benefits endured with time, Dr. Lorch and his colleagues performed an analysis of data gathered retrospectively from the TAX 324 patients' medical records as of December 1, 2008.
With a median follow-up of 72.2 months (95% confidence interval [CI], 68.8 to 75.5), they found that the original survival advantage was sustained.
The median overall survival in the TPF group was 70.6 months (95% CI, 49.0 to 89.0); in the PF group, it was 34.8 months (95% CI, 22.6 to 48.0; P = .014).
The estimated survival at 5 years was 52% in the TPF group and 42% in the PF group. Progression-free survival was significantly longer for patients receiving TPF than for those receiving PF (median, 38.1 vs 13.2 months).
In a subgroup analysis, patients with hypopharyngeal and laryngeal tumors had significantly longer progression-free survival with TPF than with PF (median, 20.9 vs 10.1 months). They also had a significantly lower risk for disease progression than PF-treated patients.
Patients with larynx and hypopharynx disease also fared better if they received TPF. Their median overall survival was 51.9 months, compared with 23.5 months for those treated with PF.
Surrogates for Toxicity
In addition, the researchers looked at tracheostomy and dependence on a gastric feeding tube as surrogates for treatment-related long-term toxicity. They report that no significant differences in these measures were detected between the treatment groups.
In the TPF group, 3 of 91 patients (3%) remained feeding-tube dependent, compared with 8 of 71 patients (11%) in the PF group. Six (7%) of 92 patients had tracheostomies in the TPF group, compared with 8 of 71 patients (11%) in the PF group.
"The data suggest that TPF is at least not any worse, and if anything may be a little better in terms of the long-term toxicities of feeding tubes and tracheostomies, but those data were somewhat limited," Dr. Lorch said.
"It was a little difficult to get reliable data because often there was no mention of whether they had tracheostomies or feeding tubes. When patients are being followed for years, it may not always be mentioned in physicians' notes, so this was one limitation of our study," he told Medscape Medical News.
Nevertheless, Dr. Lorch said that the take-home message for oncologists is that TPF should be considered the regimen of choice in squamous cell head and neck cancer patients with large primary tumors or extensive lymphadenopathy.
In an accompanying editorial, June Corry, MD, and Danny Rischin, MD, from the Peter MacCallum Cancer Centre, East Melbourne, Australia, agree that the continued superior results with TPF over PF definitively answer the question of which regimen is better.
But Role of Induction Is Unclear
However, the editorialists point out that the role of induction chemotherapy in the overall treatment of locally advanced head and neck cancer is still unclear.
"Use of TPF requires a subsequent compromise in dose intensity of the chemotherapy that can be given concomitantly with radiation," they write. "Weekly low-dose carboplatin (as used in TAX 324) is not a recognized standard concomitant regimen, and no data are available showing it to be better than radiation alone."
The lack of comparative data raises concerns that subjecting patients to a protracted course of treatment "might compromise the delivery of the concomitant component, which has been shown to have the largest effect on locoregional control and overall survival in locally advanced head and neck cancer," they write.
Some trials comparing sequential regimens with induction TPF and concomitant chemoradiation have closed early. "Hopefully, other completed or ongoing trials will provide the answers we need to determine whether there is a role for TPF-induction chemotherapy," they write.
Drs. Corry and Rischin also note that oropharyngeal cancers that are associated with human papillomavirus (HPV) have better outcomes than HPV-negative cancers. They warn that not stratifying patients according to their HPV status might confound the interpretation of such trials.
The study was supported by Sanofi-Aventis. Dr. Lorch, Dr. Corry, and Dr. Rischin have have disclosed no relevant financial relationships.
These long-term results from the TAX 324 trial, published online January 12 in the Lancet Oncology, confirm that the 3-drug regimen — docetaxel, cisplatin, and fluorouracil (TPF) — should become the standard of care for all patients with locally advanced squamous cell cancer of the head and neck who are candidates for induction chemotherapy, say the authors.
"This is the longest follow-up with this regimen, and it is the longest follow-up of any regimen in head and neck cancer," said lead author Jochen Lorch, MD, from Harvard Medical School in Boston, Massachusetts. "The results from our study will definitely lay the concerns as to whether TPF is truly superior to PF to rest."
This study with 6-year results confirms earlier data showing the superiority of the 3-drug regimen; the 2-year results were published in 2007 (N Engl J Med. 2007; 357:1705-1715).
Comparing 3- and 2-Drug Regimens
The TAX 324 trial involved 501 patients with stage 3 or 4 disease randomized to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy with weekly carboplatin and radiotherapy for 5 days per week for 7 weeks.
The TPF regimen consisted of docetaxel 75 mg/m2, followed by intravenous cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2 per day, administered as a continuous 24-hour infusion for 4 days. The PF regimen consisted of intravenous cisplatin 100 mg/m2, followed by fluorouracil 1000 mg/m2 per day as a continuous 24-hour infusion for 5 days.
Most patients (69%) had 3 or more years of follow-up. Significantly more patients survived in the TPF group than in the PF group (hazard ratio, 0.70; P = .006). Median overall survival was 71 months in the TPF group and 30 months in the PF group (P = .006).
The study also found that patients treated with TPF had better locoregional control (P = .04), but the incidence of distant metastases did not differ significantly.
Benefits Endure With Time
To see whether these benefits endured with time, Dr. Lorch and his colleagues performed an analysis of data gathered retrospectively from the TAX 324 patients' medical records as of December 1, 2008.
With a median follow-up of 72.2 months (95% confidence interval [CI], 68.8 to 75.5), they found that the original survival advantage was sustained.
The median overall survival in the TPF group was 70.6 months (95% CI, 49.0 to 89.0); in the PF group, it was 34.8 months (95% CI, 22.6 to 48.0; P = .014).
The estimated survival at 5 years was 52% in the TPF group and 42% in the PF group. Progression-free survival was significantly longer for patients receiving TPF than for those receiving PF (median, 38.1 vs 13.2 months).
In a subgroup analysis, patients with hypopharyngeal and laryngeal tumors had significantly longer progression-free survival with TPF than with PF (median, 20.9 vs 10.1 months). They also had a significantly lower risk for disease progression than PF-treated patients.
Patients with larynx and hypopharynx disease also fared better if they received TPF. Their median overall survival was 51.9 months, compared with 23.5 months for those treated with PF.
Surrogates for Toxicity
In addition, the researchers looked at tracheostomy and dependence on a gastric feeding tube as surrogates for treatment-related long-term toxicity. They report that no significant differences in these measures were detected between the treatment groups.
In the TPF group, 3 of 91 patients (3%) remained feeding-tube dependent, compared with 8 of 71 patients (11%) in the PF group. Six (7%) of 92 patients had tracheostomies in the TPF group, compared with 8 of 71 patients (11%) in the PF group.
"The data suggest that TPF is at least not any worse, and if anything may be a little better in terms of the long-term toxicities of feeding tubes and tracheostomies, but those data were somewhat limited," Dr. Lorch said.
"It was a little difficult to get reliable data because often there was no mention of whether they had tracheostomies or feeding tubes. When patients are being followed for years, it may not always be mentioned in physicians' notes, so this was one limitation of our study," he told Medscape Medical News.
Nevertheless, Dr. Lorch said that the take-home message for oncologists is that TPF should be considered the regimen of choice in squamous cell head and neck cancer patients with large primary tumors or extensive lymphadenopathy.
In an accompanying editorial, June Corry, MD, and Danny Rischin, MD, from the Peter MacCallum Cancer Centre, East Melbourne, Australia, agree that the continued superior results with TPF over PF definitively answer the question of which regimen is better.
But Role of Induction Is Unclear
However, the editorialists point out that the role of induction chemotherapy in the overall treatment of locally advanced head and neck cancer is still unclear.
"Use of TPF requires a subsequent compromise in dose intensity of the chemotherapy that can be given concomitantly with radiation," they write. "Weekly low-dose carboplatin (as used in TAX 324) is not a recognized standard concomitant regimen, and no data are available showing it to be better than radiation alone."
The lack of comparative data raises concerns that subjecting patients to a protracted course of treatment "might compromise the delivery of the concomitant component, which has been shown to have the largest effect on locoregional control and overall survival in locally advanced head and neck cancer," they write.
Some trials comparing sequential regimens with induction TPF and concomitant chemoradiation have closed early. "Hopefully, other completed or ongoing trials will provide the answers we need to determine whether there is a role for TPF-induction chemotherapy," they write.
Drs. Corry and Rischin also note that oropharyngeal cancers that are associated with human papillomavirus (HPV) have better outcomes than HPV-negative cancers. They warn that not stratifying patients according to their HPV status might confound the interpretation of such trials.
The study was supported by Sanofi-Aventis. Dr. Lorch, Dr. Corry, and Dr. Rischin have have disclosed no relevant financial relationships.
More Kids Have Health Coverage
If you are a parent, you know that your children’s health and wellbeing is your number one concern. According to a new report, an increasing number of parents in America are resting easy, knowing that their kids have health coverage.The report shows that last year, Medicaid or the Children’s Health Insurance Program (CHIP) provided health coverage to two million additional children. All
FALLOPIAN TUBE CANCER STAGING
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis:Carcinoma in situ (limited to tubal mucosa)
T1: Tumor limited to the fallopian tube(s)
T1A: Tumor limited to one tube, without penetrating the serosal surface; no ascites
T1B: Tumor limited to both tubes, without penetrating the serosal surface; no ascites
T1C: Tumor limited to one or both tubes with extension onto or through the tubal
serosa, or with malignant cells in ascites or peritoneal washings
T2: Tumor involves one or both fallopian tubes with pelvic extension
T2A: Extension and/or metastasis to the uterus and/or ovaries
T2B: Extension to other pelvic structures
T2C: Pelvic extension with malignant cells in ascites or peritoneal washings
T3: Tumor involves one or both fallopian tubes, with peritoneal implants outside the
pelvis
T3A: Microscopic peritoneal metastasis outside the pelvis
T3B: Macroscopic peritoneal metastasis outside the pelvis 2 cm or less in greatest
dimension
T3C: Peritoneal metastasis outside the pelvis and more than 2 cm in diameter
* FIGO no longer includes Stage 0 (Tis)
Note: Liver capsule metastasis is T3/Stage III; liver parenchymal metastasis
M1/Stage IV. Pleural effusion must have positive cytology for M1/Stage IV.
REGIONAL LYMPH NODES (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
DISTANT METASTASIS (M)
M0: No distant metastasis (no pathologic M0; use clinical M to complete stage group)
M1: Distant metastasis (excludes metastasis within the peritoneal cavity)
PATHOLOGIC STAGE GROUPING
GROUP T N M
0* Tis N0 M0
I T1 N0 M0
IA T1a N0 M0
IB T1b N0 M0
IC T1c N0 M0
II T2 N0 M0
IIA T2a N0 M0
IIB T2b N0 M0
IIC T2c N0 M0
III T3 N0 M0
IIIA T3a N0 M0
IIIB T3b N0 M0
IIIC T3c N0 M0-Any T N1 M0
IV Any T Any N M1
*FIGO no longer includes Stage 0 (Tis)
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