Authors : Marc R. Theoret, M.D., Yang-Min Ning, M.D., Ph.D., Jenny J. Zhang, Ph.D., Robert Justice, M.D., Patricia Keegan, M.D., and Richard Pazdur, M.D.
The use of 5α-reductase inhibitors for prevention of prostate cancer continues to be widely discussed within the scientific and medical communities. Much of this discussion has been fueled by the findings of two large randomized, placebo-controlled trials — the Prostate Cancer Prevention Trial (PCPT) with finasteride and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial . Together, these trials showed an overall relative reduction of 23 to 25% in prostate-cancer diagnoses, a seemingly significant benefit from drugs aimed at preventing one of the most common cancers in men. However, the observed reduction resulted from a decreased incidence of only low-grade prostate cancer (Gleason score, ≤6). In fact, in both trials, there was an absolute increase in the incidence of high-grade prostate cancers in the chemoprevention group.
Evaluating the potential chemopreventive benefits of 5α-reductase inhibitors and assessing the potential increased risk for high-grade prostate cancers have been central issues for the Food and Drug Administration (FDA). There has been much hope for an FDA-approved chemopreventive agent for prostate cancer, and there is clearly ongoing off-label use of 5α-reductase inhibitors for this indication. The FDA has been actively evaluating the relevant data and held a meeting of its Oncologic Drugs Advisory Committee to address this topic in December 2010.
Both chemoprevention trials were conducted in men who were at risk for prostate cancer but did not have diagnosed prostate cancer at study entry. The FDA’s analysis of the trials confirmed that there was a relative reduction of approximately 25% in the overall incidence of prostate cancer and a significantly increased incidence of high-grade prostate cancers. During the FDA review of the REDUCE trial, we requested that biopsy specimens be reassessed, according to the modified Gleason scale, by an independent pathologist who was unaware of the earlier scores. The central pathologist for PCPT performed this reassessment. The use of modified Gleason scores is consistent with current recommendations for prostate-cancer grading and the grading system used in PCPT; modified Gleason scores were not originally reported in the REDUCE trial.
The reassessment revealed no reduction in the incidence of tumors with modified Gleason scores between 7 and 10 — a finding that was consistent with the published data. However, an absolute increase of 0.5% in the incidence of tumors with modified Gleason scores of 8 to 10 (relative risk, 2.06; 95% confidence interval [CI], 1.13 to 3.75) was observed with dutasteride treatment. This increase is similar to the absolute increase of 0.7% in the incidence of such tumors observed with finasteride treatment (relative risk, 1.70; 95% CI, 1.23 to 2.34) .These results suggest that one additional man would receive a diagnosis of high-grade prostate cancer (modified Gleason score, 8 to 10) for every 150 to 200 men treated long-term with a 5α-reductase inhibitor.
It has been suggested that detection bias, attributable to the fact that 5α-reductase inhibitors reduce serum levels of prostate-specific antigen (PSA) and prostate volume, led to an increase in detection of high-grade prostate cancer in the finasteride group of the PCPT. Indeed, the sensitivity of an elevated PSA level (a PSA level above 4 ng per milliliter in the placebo group or, in the finasteride group, above the adjusted value designed to correct for a finasteride-induced PSA reduction of approximately 50%) for the detection of prostate cancer, including high-grade tumors, was increased in the finasteride group of the PCPT. The observation that the increased risk of high-grade tumors (modified Gleason score, 8 to 10) with finasteride or dutasteride persisted in analyses of scheduled biopsies independent of PSA results argues against PSA-related detection bias as the cause of the observed increase in the incidence of high-grade tumors. Approximately 56% of all prostate cancers in the PCPT and 90% of those in the REDUCE trial were diagnosed by means of scheduled biopsies.
As for detection bias due to 5α-reductase inhibitors’ reduction of prostate volume by approximately 20%, it is possible that core needle biopsies may uncover more cancers, including high-grade tumors, in smaller prostates because of increased sampling density. Proponents of this hypothesis accounted for the intergroup difference in prostate volume either by statistically adjusting for prostate volume at the time of biopsy (using logistic-regression analysis or the Peters–Belson method) or by circumventing any potential for sampling bias by extrapolating from the Gleason scores for a subgroup of patients who had had prostatectomies to patients without prostatectomy data (weighted imputation estimation). These analyses resulted in estimates of the relative risk of high-grade prostate cancer (Gleason score, 7 to 10) in the finasteride group ranging from no increase to a relative decrease of 27%. Since conventional criteria define “high-grade” as a Gleason score of 8 to 10 and 75% of the increase in tumors with modified Gleason scores of 7 to 10 observed in the finasteride group involved tumors with a score between 8 and 10, the FDA repeated the same analyses, statistically adjusting for prostate volume and using a modified Gleason score of 8 to 10 as the definition of a high-grade tumor. The results of those analyses do not support the contention that increased sampling density is responsible for the increased incidence of high-grade tumors in the finasteride group (see table for opposing risk estimations for tumors with a modified Gleason score of 7 to 10 and those with a score of 8 to 10). Although questions concerning detection bias remain, none of the post hoc exploratory analyses provide convincing evidence that the increased incidence of high-grade disease observed in both trials can be dismissed.
Analyses of these trials indicate that the reduction in prostate-cancer risk with both drugs was limited to tumors with a modified Gleason score of 6 or lower. Prospectively collected data in REDUCE showed that 80% of such tumors met the Epstein pathological criteria for “very-low-risk” disease, which indicates that a reduction in their incidence is unlikely to be clinically significant. An analysis of biopsies performed in response to an elevated PSA level or an abnormal digital rectal examination, as would be done in clinical practice, revealed a smaller reduction in the relative risk of prostate cancer (14%; 95% CI, 4 to 23%) than that reported for all cancers in men receiving finasteride. Therefore, the trade-off inherent in using a 5α-reductase inhibitor for prostate-cancer prevention is the acceptance of one additional high-grade cancer in order to avert three to four potentially clinically relevant lower-grade cancers.
The conclusion drawn by the advisory committee in December was that finasteride and dutasteride do not have a favorable risk–benefit profile for the proposed use of chemoprevention of prostate cancer in healthy men. The FDA agrees with this assessment. The effects of finasteride or dutasteride on the incidence of metastatic prostate cancer and prostate-cancer–specific morbidity and mortality have not been evaluated.
Strategies for reducing cancer risk expose people who do not have and may never develop cancer to a drug and its potential adverse effects. In these circumstances, a high level of certainty about benefits and risks of intervention is warranted. The labels of approved 5α-reductase inhibitors, which are currently indicated for the treatment of symptomatic benign prostatic hyperplasia and male-pattern hair loss, have been modified to include the observation of high-grade prostate cancers in the relevant trials. In addition, health care professionals prescribing 5α-reductase inhibitors to men who opt for PSA screening should be aware that these agents reduce PSA values and that any increase in the PSA level above the lowest value obtained may signal the presence of prostate cancer, even if the value remains in the normal range for men not taking such an agent.
Showing posts with label FDA. Show all posts
Showing posts with label FDA. Show all posts
Sunday, July 17, 2011
Saturday, May 21, 2011
What Patients Need To Know About Osteoporosis
Osteoporosis is a condition that is sure to become increasingly diagnosed as our population ages.
Osteoporosis is significant because it is associated with an increased risk of bone fracture, including fracture of the hip and vertebra, which are the cause of significant morbidity, mortality, loss of independence and medical expense in the elderly. In current clinical practice, osteoporosis is diagnosed on the basis of either the occurrence of a low-impact or fragility fracture, or on the basis of measured low bone mineral density (BMD). A low-impact fracture is one that occurs after a fall from standing height or less; a fragility fracture occurs spontaneously or with no trauma (cough, sneeze, sudden movement).
Bone strength is determined by bone density, bone “quality,” and bone microarchitecture. Of these features, bone density, or mass, is what we are able to measure. Osteoporosis is defined by World Health Organization criteria based on a person’s bone density by dual energy x-ray absorptiometry (DXA). Osteoporosis occurs when bone density is below 2.5 standard deviations from the mean for non-Hispanic white women between ages 20 and 29 (T score < -2.5). Osteopenia is defined by bone density of between 1 and 2.5 standard deviations below the mean for non-Hispanic white women in their twenties (T score of -1 to -2.5).
In recent years a variety of effective medications have been developed and approved for treatment of low bone density. Nonetheless, there are still significant gaps in our knowledge. Recently, the FDA issued a warning about an increased risk of “atypical fractures” that has been observed amongst women who take bisphosphonates, the most commonly prescribed drugs for osteoporosis. A few years ago these drugs were also linked to another rare problem, osteonecrosis of the jaw. This was primarily described in cancer patients and those on cancer medications, but the finding got patients, dentists, and oral surgeons quite worked up over the potential risks.
In clinical practice there is significant variation in the practice of screening for and treating osteoporosis and its precursor, osteopenia. According to national epidemiological data from NHANES III over 56% of women over age 50 have reduced bone density, of these 16% have osteoporosis. In their 80s 87% of women have reduced bone density and 44% of have osteoporosis. The key to prevention and treatment is trying to figure out who and when to treat aggressively to best prevent fractures. Current guidelines by the US Preventive Services Task Force support screening women at age 65. However, many post-menopausal women under age 65 are also at risk and the conservative evidence-based USPSTF guidelines do not comment on which of these women should also be screened. Other professional guidelines, such as those issued by the National Osteoporosis Foundation, support screening younger women who are post-menopausal and who have risk factors.
A variety of clinical tools exist to help women quantify their osteoporosis risk.
Osteoporosis risk factors include:
• Low body weight (<57 kg)
• Asian or Caucasian ethnicity
• Personal history of fragility fracture
• Family history of osteoporosis
• Smoking
• Drinking > 2 glasses of alcohol per day
• Excessive caffeine intake
• Certain medications (glucocorticoids)
• Sedentary lifestyle
• Amenorrhea (lapses in menstruation prior to menopause)
• Eating disorders
• Marathon running
• Dietary deficiencies of calcium and vitamin D
• Chronic health conditions (chronic liver and kidney disease, rheumatoid arthritis)
Many women fall into these increased risk categories and thus are screened before age 65 leaving them with a diagnosis of osteopenia or osteoporosis and creating the conundrum of what to do for the remainder of a woman’s life.
In general, most women with osteopenia should not receive pharmacologic therapy unless they are higher risk, or have already suffered a fracture. Instead, they should be counseled to institute behavioral measures, such as increased weight-bearing exercise and increases in calcium and vitamin D supplementation. When these women should be rescreened is not clear, but probably no more often than every two years. Tracking the rate of bone density decline may help identify women who subsequently should receive drug therapy.
Effective pharmacologic treatments for osteoporosis are available and are, in general, well tolerated. Medication options include the bisphosphonates: alendronate, residronate, ibandronate and zoledronic acid, hormonal treatments (estrogen and selective estrogen receptor modulators), and recombinant parathyroid hormone (teriparatide). Of these options, the oral bisphosphonates, alendronate (Fosamax) and residronate (Actonel), have the most evidence supporting their efficacy in fracture prevention, and are considered first line. These drugs, however, can be somewhat inconvenient to administer because of their poor bioavailability that requires them to be taken on an empty stomach for best absorption. In addition, they are associated with gastrointestinal side effects—specifically esophagitis, and for this reason are contraindicated in patients with precancerous changes of the espophagus, “Barrett’s Esophagus.” For patients who experience gastrointestinal side effects the intravenous bisphosphonate, zoledronic acid may be administered every one to two years.
Hormonal therapies, such as estrogen, are effective treatment for low bone density. However, as indicated by the results of the Women’s Health Initiate, their use has been associated with an increased risk of breast cancer and cardiovascular disease. Raloxifene, a selective estrogen receptor modulator (SERM), is approved for both prevention and treatment of osteoporosis. Its use, while associated with a reduction in breast cancer risk, is also associated with an increased risk of thomboembolism. Its effect on cardiovascular disease appears to be neutral.
The appropriate duration of therapy and frequency of monitoring patients who are on pharmaceutical treatment are areas that remain ill-defined. Studies have indicated that 5 years of alendronate may be adequate for many average risk women. However, my experience in clinical practice is that many women are left on these drugs for years and years. Some have advocated drug “holidays” after five years of therapy. The largest randomized controlled trial looking at alendronate use and fracture outcomes was 10 years in duration, which in my view calls into question the safety of prolonged use.
Many questions remain about how to approach the treatment of aging bones to prevent the debilitating outcome of bone fracture. Seasoned clinicians have seen the problems that may occur in some cases with treating large populations of well patients for normal life processes (postmenopausal estrogen replacement therapy). Let’s hope that future research will address the question of when to treat with medication and for how long with further precision. Until then let’s use appropriate caution when prescribing medicine for normal senior bones.
by : Juliet K. Mavromatis
Osteoporosis is significant because it is associated with an increased risk of bone fracture, including fracture of the hip and vertebra, which are the cause of significant morbidity, mortality, loss of independence and medical expense in the elderly. In current clinical practice, osteoporosis is diagnosed on the basis of either the occurrence of a low-impact or fragility fracture, or on the basis of measured low bone mineral density (BMD). A low-impact fracture is one that occurs after a fall from standing height or less; a fragility fracture occurs spontaneously or with no trauma (cough, sneeze, sudden movement).
Bone strength is determined by bone density, bone “quality,” and bone microarchitecture. Of these features, bone density, or mass, is what we are able to measure. Osteoporosis is defined by World Health Organization criteria based on a person’s bone density by dual energy x-ray absorptiometry (DXA). Osteoporosis occurs when bone density is below 2.5 standard deviations from the mean for non-Hispanic white women between ages 20 and 29 (T score < -2.5). Osteopenia is defined by bone density of between 1 and 2.5 standard deviations below the mean for non-Hispanic white women in their twenties (T score of -1 to -2.5).
In recent years a variety of effective medications have been developed and approved for treatment of low bone density. Nonetheless, there are still significant gaps in our knowledge. Recently, the FDA issued a warning about an increased risk of “atypical fractures” that has been observed amongst women who take bisphosphonates, the most commonly prescribed drugs for osteoporosis. A few years ago these drugs were also linked to another rare problem, osteonecrosis of the jaw. This was primarily described in cancer patients and those on cancer medications, but the finding got patients, dentists, and oral surgeons quite worked up over the potential risks.
In clinical practice there is significant variation in the practice of screening for and treating osteoporosis and its precursor, osteopenia. According to national epidemiological data from NHANES III over 56% of women over age 50 have reduced bone density, of these 16% have osteoporosis. In their 80s 87% of women have reduced bone density and 44% of have osteoporosis. The key to prevention and treatment is trying to figure out who and when to treat aggressively to best prevent fractures. Current guidelines by the US Preventive Services Task Force support screening women at age 65. However, many post-menopausal women under age 65 are also at risk and the conservative evidence-based USPSTF guidelines do not comment on which of these women should also be screened. Other professional guidelines, such as those issued by the National Osteoporosis Foundation, support screening younger women who are post-menopausal and who have risk factors.
A variety of clinical tools exist to help women quantify their osteoporosis risk.
Osteoporosis risk factors include:
• Low body weight (<57 kg)
• Asian or Caucasian ethnicity
• Personal history of fragility fracture
• Family history of osteoporosis
• Smoking
• Drinking > 2 glasses of alcohol per day
• Excessive caffeine intake
• Certain medications (glucocorticoids)
• Sedentary lifestyle
• Amenorrhea (lapses in menstruation prior to menopause)
• Eating disorders
• Marathon running
• Dietary deficiencies of calcium and vitamin D
• Chronic health conditions (chronic liver and kidney disease, rheumatoid arthritis)
Many women fall into these increased risk categories and thus are screened before age 65 leaving them with a diagnosis of osteopenia or osteoporosis and creating the conundrum of what to do for the remainder of a woman’s life.
In general, most women with osteopenia should not receive pharmacologic therapy unless they are higher risk, or have already suffered a fracture. Instead, they should be counseled to institute behavioral measures, such as increased weight-bearing exercise and increases in calcium and vitamin D supplementation. When these women should be rescreened is not clear, but probably no more often than every two years. Tracking the rate of bone density decline may help identify women who subsequently should receive drug therapy.
Effective pharmacologic treatments for osteoporosis are available and are, in general, well tolerated. Medication options include the bisphosphonates: alendronate, residronate, ibandronate and zoledronic acid, hormonal treatments (estrogen and selective estrogen receptor modulators), and recombinant parathyroid hormone (teriparatide). Of these options, the oral bisphosphonates, alendronate (Fosamax) and residronate (Actonel), have the most evidence supporting their efficacy in fracture prevention, and are considered first line. These drugs, however, can be somewhat inconvenient to administer because of their poor bioavailability that requires them to be taken on an empty stomach for best absorption. In addition, they are associated with gastrointestinal side effects—specifically esophagitis, and for this reason are contraindicated in patients with precancerous changes of the espophagus, “Barrett’s Esophagus.” For patients who experience gastrointestinal side effects the intravenous bisphosphonate, zoledronic acid may be administered every one to two years.
Hormonal therapies, such as estrogen, are effective treatment for low bone density. However, as indicated by the results of the Women’s Health Initiate, their use has been associated with an increased risk of breast cancer and cardiovascular disease. Raloxifene, a selective estrogen receptor modulator (SERM), is approved for both prevention and treatment of osteoporosis. Its use, while associated with a reduction in breast cancer risk, is also associated with an increased risk of thomboembolism. Its effect on cardiovascular disease appears to be neutral.
The appropriate duration of therapy and frequency of monitoring patients who are on pharmaceutical treatment are areas that remain ill-defined. Studies have indicated that 5 years of alendronate may be adequate for many average risk women. However, my experience in clinical practice is that many women are left on these drugs for years and years. Some have advocated drug “holidays” after five years of therapy. The largest randomized controlled trial looking at alendronate use and fracture outcomes was 10 years in duration, which in my view calls into question the safety of prolonged use.
Many questions remain about how to approach the treatment of aging bones to prevent the debilitating outcome of bone fracture. Seasoned clinicians have seen the problems that may occur in some cases with treating large populations of well patients for normal life processes (postmenopausal estrogen replacement therapy). Let’s hope that future research will address the question of when to treat with medication and for how long with further precision. Until then let’s use appropriate caution when prescribing medicine for normal senior bones.
by : Juliet K. Mavromatis
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