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.
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