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.
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SHORT TELOMERES AND CANCER RISK
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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.
ANTI-MET TREATMENT FOR BONE METASTASES FROM PROSTATE CANCER
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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.
KYPHOPLASTY FOR CANCER VERTEBRAL COMPRESSION FRACTURE
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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.
EARLY HAIR LOSS INCREASE PROSTATE CANCER RISK
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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.
HEDGEHOG INHIBITORS FOR BASAL CELL CARCINOMA
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(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.
INTENSIVE CHEMOTHERAPY INCREASES SURVIVAL OF OLDER TEENAGERS WITH ALL
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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.
RISE IN BREAST CANCER INCIDENCE IN UK
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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.
DIET SODA INCREASES CARDIOVASCULAR RISK?
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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.
CALCIUM CHANNEL BLOCKERS-MAKROLIDE INTERACTION
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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."
SURVIVAL BENEFIT WITH MITOXANTRONE IN RELAPSED ALL
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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
8 HPV TYPES CAUSE 90% OF CERVICAL CANCER
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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.
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.
FALLOPIAN TUBE CANCER STAGING
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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)
MAMMOGRAMS BETTER TO BEGIN AT AGE 40
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A new analysis is poised to reignite the debate that has been raging over the value of mammography in women younger than 50 years of age.
There was a furor when the revised US Preventative Service Task Force (USPSTF) recommendations for breast cancer screening were released in November 2009. The most notable changes were to advise against routine screening mammograms for women 40 to 49 years of age, to change the screening interval from 1 to 2 years in women 50 years and older, and to end screening at 74 years.
The updated guidelines became mired in controversy as soon as they were published, as previously reported by Medscape Medical News. A number of organizations, including the American Cancer Society (ACS), the American College of Radiology, and the American College of Obstetricians and Gynecologists, recommended that physicians and patients continue to follow earlier guidelines.
Now, a study published in the February issue of the American Journal of Radiology that analyzed the same data as the USPSTF has come up with very different results.
R. Edward Hendrick, PhD, clinical professor of radiology at the University of Colorado School of Medicine in Denver, and Mark Helvie, MD, director of breast imaging at the University of Michigan Comprehensive Cancer Center in Ann Arbor, found that beginning screening at a younger age and at more frequent intervals can save more lives.
What is most important is to save the most lives," Dr. Hendrick told Medscape Medical News, "not to do the fewest mammograms. If you want to save the most lives, then doing annual mammograms from age 40 to 84 years clearly is superior."
According to the analysis, women who receive annual mammograms starting at age 40 can significantly reduce the risk of dying from breast cancer by 71%. This is in contrast to women who follow the USPSTF recommendations, who had a 23.2% reduction in mortality.
Lower Mortality With Earlier Screening
Dr. Hendrick and Dr. Helvie used 6 model scenarios of screening mammography that were created by the Cancer Intervention and Surveillance Modeling Network, which is the same modeling data used by the USPSTF. They compared mortality reduction for women who followed the 2009 USPSTF recommendations with that for women who followed the ACS recommendations (annual screening beginning at age 40).
"In their summary paper, the USPSTF did not do any averaging over the 6 models," explained Dr. Hendrick. In our analyses, we selected a model that was "somewhere in the middle, but it wasn't an average over the 6."
When the USPSTF looked at any of these modeling data, they chose the point on the graph when it first begins to turn over in terms of mortality reduction per mammogram done. "That was biennial screening beginning at age 50," he said.
In contrast, the authors of new analysis averaged the 6 models and found that for women 40 to 84 years, annual screening conveyed an estimated 39.6% reduction in mortality (range over the 6 models, 29.4% to 54%). This was compared with biennial screening at 50 to 74 years, which showed an estimated mortality reduction of 23.2% (range, 20% to 28%).
They found that approximately 12 lives per 1000 women screened would be saved with annual screening beginning at age 40, whereas with the USPSTF-recommended screening regimen, an estimated 7 lives per 1000 women screened would be saved. Overall, the ACS screening guidelines would result in 5 more lives per 1000 women saved than the USPSTF screening guidelines.
Overemphasis of Harms
The USPSTF also overemphasized the potential harms of screening mammography, explained Dr. Hendrick.
You can't really compare having a call back for additional testing to dying of breast cancer," he said. "They were comparing something with mild implications to something with huge implications. They looked at the potential harms of screening without looking at lives saved from a proper perspective."
The actual number of false-positive tests is also actually quite low, Dr. Hendrick noted. For a woman 40 to 49 years who receives annual screening, a false-positive test will occur once every 10 years on average. She will be recalled for additional imaging once every 12 years and undergo a false-positive biopsy once every 149 years. A missed malignancy will happen once every 1000 years.
In the USPSTF report, the harms of unnecessary recall for additional imaging were emphasized, the authors note. However, "this harm can be mitigated if women elect real-time screening interpretation with same-visit diagnostic imaging offered at many [American] facilities, . . . but this option was not mentioned by the USPSTF report."
May Dissuade Payors
Because the new recommendations were made by a federal panel, they do have an effect on healthcare decisions, Dr. Hendrick said.
In fact, the guidelines could have dissuaded some women from having a screening mammography, and could influence reimbursement from Medicare, Medicaid, and private payors, he added.
The USPSTF recommendations have done potential damage to women's health by failing to seize the singular opportunity to both improve mammography in the United States and to increase screening mammography compliance," say the authors.
Dr. Hendrick reports being a consultant to GE Healthcare and serving on the medical advisory boards of the Koning Corporation and Bracco, both of which develop and manufacture diagnostic imaging systems. Dr. Helvie reports receiving grant support from GE Healthcare.
There was a furor when the revised US Preventative Service Task Force (USPSTF) recommendations for breast cancer screening were released in November 2009. The most notable changes were to advise against routine screening mammograms for women 40 to 49 years of age, to change the screening interval from 1 to 2 years in women 50 years and older, and to end screening at 74 years.
The updated guidelines became mired in controversy as soon as they were published, as previously reported by Medscape Medical News. A number of organizations, including the American Cancer Society (ACS), the American College of Radiology, and the American College of Obstetricians and Gynecologists, recommended that physicians and patients continue to follow earlier guidelines.
Now, a study published in the February issue of the American Journal of Radiology that analyzed the same data as the USPSTF has come up with very different results.
R. Edward Hendrick, PhD, clinical professor of radiology at the University of Colorado School of Medicine in Denver, and Mark Helvie, MD, director of breast imaging at the University of Michigan Comprehensive Cancer Center in Ann Arbor, found that beginning screening at a younger age and at more frequent intervals can save more lives.
What is most important is to save the most lives," Dr. Hendrick told Medscape Medical News, "not to do the fewest mammograms. If you want to save the most lives, then doing annual mammograms from age 40 to 84 years clearly is superior."
According to the analysis, women who receive annual mammograms starting at age 40 can significantly reduce the risk of dying from breast cancer by 71%. This is in contrast to women who follow the USPSTF recommendations, who had a 23.2% reduction in mortality.
Lower Mortality With Earlier Screening
Dr. Hendrick and Dr. Helvie used 6 model scenarios of screening mammography that were created by the Cancer Intervention and Surveillance Modeling Network, which is the same modeling data used by the USPSTF. They compared mortality reduction for women who followed the 2009 USPSTF recommendations with that for women who followed the ACS recommendations (annual screening beginning at age 40).
"In their summary paper, the USPSTF did not do any averaging over the 6 models," explained Dr. Hendrick. In our analyses, we selected a model that was "somewhere in the middle, but it wasn't an average over the 6."
When the USPSTF looked at any of these modeling data, they chose the point on the graph when it first begins to turn over in terms of mortality reduction per mammogram done. "That was biennial screening beginning at age 50," he said.
In contrast, the authors of new analysis averaged the 6 models and found that for women 40 to 84 years, annual screening conveyed an estimated 39.6% reduction in mortality (range over the 6 models, 29.4% to 54%). This was compared with biennial screening at 50 to 74 years, which showed an estimated mortality reduction of 23.2% (range, 20% to 28%).
They found that approximately 12 lives per 1000 women screened would be saved with annual screening beginning at age 40, whereas with the USPSTF-recommended screening regimen, an estimated 7 lives per 1000 women screened would be saved. Overall, the ACS screening guidelines would result in 5 more lives per 1000 women saved than the USPSTF screening guidelines.
Overemphasis of Harms
The USPSTF also overemphasized the potential harms of screening mammography, explained Dr. Hendrick.
You can't really compare having a call back for additional testing to dying of breast cancer," he said. "They were comparing something with mild implications to something with huge implications. They looked at the potential harms of screening without looking at lives saved from a proper perspective."
The actual number of false-positive tests is also actually quite low, Dr. Hendrick noted. For a woman 40 to 49 years who receives annual screening, a false-positive test will occur once every 10 years on average. She will be recalled for additional imaging once every 12 years and undergo a false-positive biopsy once every 149 years. A missed malignancy will happen once every 1000 years.
In the USPSTF report, the harms of unnecessary recall for additional imaging were emphasized, the authors note. However, "this harm can be mitigated if women elect real-time screening interpretation with same-visit diagnostic imaging offered at many [American] facilities, . . . but this option was not mentioned by the USPSTF report."
May Dissuade Payors
Because the new recommendations were made by a federal panel, they do have an effect on healthcare decisions, Dr. Hendrick said.
In fact, the guidelines could have dissuaded some women from having a screening mammography, and could influence reimbursement from Medicare, Medicaid, and private payors, he added.
The USPSTF recommendations have done potential damage to women's health by failing to seize the singular opportunity to both improve mammography in the United States and to increase screening mammography compliance," say the authors.
Dr. Hendrick reports being a consultant to GE Healthcare and serving on the medical advisory boards of the Koning Corporation and Bracco, both of which develop and manufacture diagnostic imaging systems. Dr. Helvie reports receiving grant support from GE Healthcare.
BONE TURNOVER MARKERS AS PROGNOSTIC FACTORS IN PROSTATE CANCER
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Bone Turnover Markers as Predictors of Mortality Risk in Prostate Cancer Patients with Bone Metastases Following Treatment with Zoledronic Acid.
Jung K, Miller K, Wirth M, Albrecht M, Lein M.
Department of Urology, University Hospital Charité, Berlin, Germany; Berlin Institute for Urologic Research, Berlin, Germany.
Abstract
BACKGROUND: Clinical data have limited validity for predicting the survival of prostate cancer (PCa) patients with bone metastases. There is a need to improve the predictive evidence both for clinicians and patients.
OBJECTIVE: To evaluate the predictive ability of serum bone markers for mortality risk in PCa patients with bone metastases.
DESIGN, SETTING, AND PARTICIPANTS: We conducted a survival analysis in relation to bone markers in a subgroup of 52 patients treated with zoledronic acid (4mg every 4 wk for 15 mo) in a prospective, multicentre trial during 2002-2005, about 4 yr after the end of the trial.
MEASUREMENTS: Serum levels of total and bone-specific alkaline phosphatase, amino-terminal procollagen propeptides of type I collagen (PINP), cross-linked N-terminal (NTx) and cross-linked C-terminal telopeptides of type I collagen (ICTP), C-terminal telopeptides of type I collagen, prostate-specific antigen from the last visit of the treatment study, and clinical data were related to the overall survival (OS) status of patients in the follow-up. Univariate and multivariate Cox regression analyses with internal bootstrapping validation and concordance index calculations were performed.
RESULTS AND LIMITATIONS: Out of the 52 patients followed, 34 died within a median follow-up of 13.8 mo, and 18 patients were alive at a median follow-up of 43.8 mo. The patients who died within the follow-up period had significantly higher concentrations of ICTP, NTx, and PINP than the surviving patients. Cox regression models with clinical data and bone markers showed that ICTP and PINP were most predictive for mortality risk in addition to the occurrence of skeletal-related complications and the continuation of treatment with zoledronic acid. Internal validation confirmed the reliability of the results, although the sample size was small.
Jung K, Miller K, Wirth M, Albrecht M, Lein M.
Department of Urology, University Hospital Charité, Berlin, Germany; Berlin Institute for Urologic Research, Berlin, Germany.
Abstract
BACKGROUND: Clinical data have limited validity for predicting the survival of prostate cancer (PCa) patients with bone metastases. There is a need to improve the predictive evidence both for clinicians and patients.
OBJECTIVE: To evaluate the predictive ability of serum bone markers for mortality risk in PCa patients with bone metastases.
DESIGN, SETTING, AND PARTICIPANTS: We conducted a survival analysis in relation to bone markers in a subgroup of 52 patients treated with zoledronic acid (4mg every 4 wk for 15 mo) in a prospective, multicentre trial during 2002-2005, about 4 yr after the end of the trial.
MEASUREMENTS: Serum levels of total and bone-specific alkaline phosphatase, amino-terminal procollagen propeptides of type I collagen (PINP), cross-linked N-terminal (NTx) and cross-linked C-terminal telopeptides of type I collagen (ICTP), C-terminal telopeptides of type I collagen, prostate-specific antigen from the last visit of the treatment study, and clinical data were related to the overall survival (OS) status of patients in the follow-up. Univariate and multivariate Cox regression analyses with internal bootstrapping validation and concordance index calculations were performed.
RESULTS AND LIMITATIONS: Out of the 52 patients followed, 34 died within a median follow-up of 13.8 mo, and 18 patients were alive at a median follow-up of 43.8 mo. The patients who died within the follow-up period had significantly higher concentrations of ICTP, NTx, and PINP than the surviving patients. Cox regression models with clinical data and bone markers showed that ICTP and PINP were most predictive for mortality risk in addition to the occurrence of skeletal-related complications and the continuation of treatment with zoledronic acid. Internal validation confirmed the reliability of the results, although the sample size was small.
FINGER LENGTH AND PROSTATE CANCER RISK
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Men whose index finger is longer than their ring finger are at a lower risk of prostate cancer than those with a finger pattern the other way round, according to a new study in the British Journal of Cancer.
The relative length of the first and third fingers is set before birth, and it is thought to relate to the levels of sex hormones the baby is exposed to in the womb. Babies exposed to less of the male sex hormone testosterone are more likely to have longer index fingers.
Finger Length and Prostate Cancer
Over a 15-year period, researchers from The University of Warwick and The Institute of Cancer Research (ICR) collected data on finger length in 1,524 patients with prostate cancer as well as 3,044 healthy people. Men were shown pictures of hands with different finger lengths and asked to identify the one most like their own right hand.
The most common finger length pattern, seen in more than half the men in the study, was a shorter index than ring finger. Men whose index and ring fingers were the same length (about 19%) had a similar prostate cancer risk to those with a shorter index than ring finger. However, men whose index fingers were longer than their ring finger were 33% less likely to have prostate cancer.
Risk reduction was even greater in men aged under 60, say the researchers, who found that this younger group were 87% less likely to be in the prostate cancer group.
Testosterone Exposure
The researchers believe that being exposed to less testosterone before birth helps protect against prostate cancer later in life. The phenomenon is thought to occur because the genes HOXA and HOXD control both finger length and development of sex organs.
“Our results show that relative finger length could be used as a simple test for prostate cancer risk, particularly in men aged under 60,” says joint senior author Professor Ros Eeles from the ICR and The Royal Marsden NHS Foundation Trust. “This exciting finding means that finger pattern could potentially be used to select at-risk men for ongoing screening, perhaps in combination with other factors such as family history or genetic testing.”
The study was funded by Prostate Cancer Research Foundation and Cancer Research UK.
Diagnosing Prostate Cancer
Helen Rippon, head of research at The Prostate Cancer Charity in the U.K., says in an emailed statement: “Diagnosis of prostate cancer is not a simple affair and the best blood test we have, known as a PSA test, tells us only that something might be wrong with the prostate, not whether it is cancerous or not. Anything that adds to our knowledge about whether a man is likely to develop prostate cancer or not is to be welcomed, especially when it is something as easy as looking at the length of his fingers.
“This research also adds to the growing body of evidence that the balance of hormones we are exposed to before birth influences our health for the rest of our lives.”
Rippon says men who check their hands and find they have a shorter index finger should not be unduly concerned. “They share this trait with more than half of all men and it does not mean they will definitely develop prostate cancer in later life,” she says.
The relative length of the first and third fingers is set before birth, and it is thought to relate to the levels of sex hormones the baby is exposed to in the womb. Babies exposed to less of the male sex hormone testosterone are more likely to have longer index fingers.
Finger Length and Prostate Cancer
Over a 15-year period, researchers from The University of Warwick and The Institute of Cancer Research (ICR) collected data on finger length in 1,524 patients with prostate cancer as well as 3,044 healthy people. Men were shown pictures of hands with different finger lengths and asked to identify the one most like their own right hand.
The most common finger length pattern, seen in more than half the men in the study, was a shorter index than ring finger. Men whose index and ring fingers were the same length (about 19%) had a similar prostate cancer risk to those with a shorter index than ring finger. However, men whose index fingers were longer than their ring finger were 33% less likely to have prostate cancer.
Risk reduction was even greater in men aged under 60, say the researchers, who found that this younger group were 87% less likely to be in the prostate cancer group.
Testosterone Exposure
The researchers believe that being exposed to less testosterone before birth helps protect against prostate cancer later in life. The phenomenon is thought to occur because the genes HOXA and HOXD control both finger length and development of sex organs.
“Our results show that relative finger length could be used as a simple test for prostate cancer risk, particularly in men aged under 60,” says joint senior author Professor Ros Eeles from the ICR and The Royal Marsden NHS Foundation Trust. “This exciting finding means that finger pattern could potentially be used to select at-risk men for ongoing screening, perhaps in combination with other factors such as family history or genetic testing.”
The study was funded by Prostate Cancer Research Foundation and Cancer Research UK.
Diagnosing Prostate Cancer
Helen Rippon, head of research at The Prostate Cancer Charity in the U.K., says in an emailed statement: “Diagnosis of prostate cancer is not a simple affair and the best blood test we have, known as a PSA test, tells us only that something might be wrong with the prostate, not whether it is cancerous or not. Anything that adds to our knowledge about whether a man is likely to develop prostate cancer or not is to be welcomed, especially when it is something as easy as looking at the length of his fingers.
“This research also adds to the growing body of evidence that the balance of hormones we are exposed to before birth influences our health for the rest of our lives.”
Rippon says men who check their hands and find they have a shorter index finger should not be unduly concerned. “They share this trait with more than half of all men and it does not mean they will definitely develop prostate cancer in later life,” she says.
ESTROGEN MODIFIES LUNG CANCER OUTCOME
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More evidence that estrogen modifies the outcome of lung cancer comes from a huge study of women with breast cancer, about half of whom were taking antiestrogens such as tamoxifen.
Among the women who subsequently developed lung cancer, the use of antiestrogens was associated with a significantly reduced risk for death from lung cancer, compared with the general population.
The finding comes from a study published online January 24 in Cancer.
"Our results support the hypothesis that there is a hormonal influence on lung cancer, which has been suggested by findings such as the presence of estrogen and progesterone receptors in a substantial proportion of lung cancers," senior author Elisabetta Rapiti, MD, from the Geneva Cancer Registry, said in a statement.
"If prospective studies confirm our results and find that antiestrogen agents improve lung cancer outcomes, this could have substantial implications for clinical practice," she added.
Approached by Medscape Medical News for independent comment, Howard West, MD, from the Swedish Cancer Institute in Seattle, Washington, said: "These results are very provocative, especially since they are compatible with the findings from the Women's Health Initiative [WHI], which demonstrated a higher mortality rate from lung cancer in women who received estrogen and progestins, compared with the placebo arm."
"I completely agree that these results warrant prospective testing of antiestrogens," Dr. West continued. "Until we have results from such trials, I would be inclined to discuss these results with women who are taking hormone replacement therapy, as I already do, which may lead to their stopping hormone replacement therapy after considering the balance of benefit vs risk. I wouldn't, however, go so far as to say that these results justify giving antiestrogen therapy as a treatment for lung cancer."
Study Prompted by WHI Findings
The current study was, in fact, prompted by those findings on lung cancer from the WHI study, the authors explain.
When that finding was published, the WHI researchers noted that "treatment with estrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, [but] it increased the number of deaths from lung cancer, in particular deaths from nonsmall-cell lung cancer."
Dr. Rapiti and colleagues, including first author Christine Bouchardy, MD, hypothesized that if it is true that hormone therapy increases the risk for lung cancer death, then the use of antiestrogens should be associated with a decreased risk for lung cancer death.
This was, indeed, what they found.
The team analyzed data from 6655 women with breast cancer from the Geneva Cancer Registry, nearly half of whom (46%) had taken antiestrogens.
Over a median follow-up of 7.3 years, the researchers found that 40 of these women developed lung cancer. The incidence of lung cancer was similar in the group taking and the group not taking antiestrogens (P = .39).
The team then compared outcomes for this small group of women with population results from standardized mortality ratios.
They found that the incidence of lung cancer was similar among women who had and had not taken antiestrogens and the general population.
However, the risk for death from lung cancer was significantly lower in women who had taken the drugs than in those who had not, and than in the general population. Specifically, there were 87% fewer cases of death from lung cancer in the antiestrogen group than in the general population.
Lung cancer mortality rates were 9.2 per 100,000 for women taking antiestrogens and 45.0 per 100,000 for women not taking these drugs (P = .026).
The finding is unlikely to be due to differences in smoking, the authors note, because patterns of tobacco exposure were similar in the 2 groups. However, they also note that they obtained this information for only about half of the entire cohort.
New Evidence for the Role of Estrogen
The team concludes: "In analyses comparing tumor registry to population results from standardized mortality ratios, we found that antiestrogen treatment for breast cancer was associated with a reduced risk of death from lung cancer, providing new evidence on the role of estrogen in lung cancer progression."
"From a biological perspective, the observation that estrogen intake is associated with increased lung cancer mortality, and that antiestrogen treatment is associated with a decreased lung cancer mortality, as demonstrated in this study, strongly suggests that estrogens are involved in lung cancer progression," they add.
When approached for independent comment by Medscape Medical News, Dr. West noted that the finding showed a significant reduction in the rate of lung cancer mortality among women who were taking antiestrogens, compared with age-adjusted mortality rates in the general population.
"In fact, the rate was only 13% of the calculated result that would be expected, a statistically significant difference," he said.
"However, these results are predicated on a very small number of patients, compared with a prediction based on a model," Dr. West pointed out.
Among the women who subsequently developed lung cancer, the use of antiestrogens was associated with a significantly reduced risk for death from lung cancer, compared with the general population.
The finding comes from a study published online January 24 in Cancer.
"Our results support the hypothesis that there is a hormonal influence on lung cancer, which has been suggested by findings such as the presence of estrogen and progesterone receptors in a substantial proportion of lung cancers," senior author Elisabetta Rapiti, MD, from the Geneva Cancer Registry, said in a statement.
"If prospective studies confirm our results and find that antiestrogen agents improve lung cancer outcomes, this could have substantial implications for clinical practice," she added.
Approached by Medscape Medical News for independent comment, Howard West, MD, from the Swedish Cancer Institute in Seattle, Washington, said: "These results are very provocative, especially since they are compatible with the findings from the Women's Health Initiative [WHI], which demonstrated a higher mortality rate from lung cancer in women who received estrogen and progestins, compared with the placebo arm."
"I completely agree that these results warrant prospective testing of antiestrogens," Dr. West continued. "Until we have results from such trials, I would be inclined to discuss these results with women who are taking hormone replacement therapy, as I already do, which may lead to their stopping hormone replacement therapy after considering the balance of benefit vs risk. I wouldn't, however, go so far as to say that these results justify giving antiestrogen therapy as a treatment for lung cancer."
Study Prompted by WHI Findings
The current study was, in fact, prompted by those findings on lung cancer from the WHI study, the authors explain.
When that finding was published, the WHI researchers noted that "treatment with estrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, [but] it increased the number of deaths from lung cancer, in particular deaths from nonsmall-cell lung cancer."
Dr. Rapiti and colleagues, including first author Christine Bouchardy, MD, hypothesized that if it is true that hormone therapy increases the risk for lung cancer death, then the use of antiestrogens should be associated with a decreased risk for lung cancer death.
This was, indeed, what they found.
The team analyzed data from 6655 women with breast cancer from the Geneva Cancer Registry, nearly half of whom (46%) had taken antiestrogens.
Over a median follow-up of 7.3 years, the researchers found that 40 of these women developed lung cancer. The incidence of lung cancer was similar in the group taking and the group not taking antiestrogens (P = .39).
The team then compared outcomes for this small group of women with population results from standardized mortality ratios.
They found that the incidence of lung cancer was similar among women who had and had not taken antiestrogens and the general population.
However, the risk for death from lung cancer was significantly lower in women who had taken the drugs than in those who had not, and than in the general population. Specifically, there were 87% fewer cases of death from lung cancer in the antiestrogen group than in the general population.
Lung cancer mortality rates were 9.2 per 100,000 for women taking antiestrogens and 45.0 per 100,000 for women not taking these drugs (P = .026).
The finding is unlikely to be due to differences in smoking, the authors note, because patterns of tobacco exposure were similar in the 2 groups. However, they also note that they obtained this information for only about half of the entire cohort.
New Evidence for the Role of Estrogen
The team concludes: "In analyses comparing tumor registry to population results from standardized mortality ratios, we found that antiestrogen treatment for breast cancer was associated with a reduced risk of death from lung cancer, providing new evidence on the role of estrogen in lung cancer progression."
"From a biological perspective, the observation that estrogen intake is associated with increased lung cancer mortality, and that antiestrogen treatment is associated with a decreased lung cancer mortality, as demonstrated in this study, strongly suggests that estrogens are involved in lung cancer progression," they add.
When approached for independent comment by Medscape Medical News, Dr. West noted that the finding showed a significant reduction in the rate of lung cancer mortality among women who were taking antiestrogens, compared with age-adjusted mortality rates in the general population.
"In fact, the rate was only 13% of the calculated result that would be expected, a statistically significant difference," he said.
"However, these results are predicated on a very small number of patients, compared with a prediction based on a model," Dr. West pointed out.
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