Jennie Smith

Changes to the menstrual cycle remain the most important clinical indicators of women’s reproductive aging, according to new standardized staging criteria.

The changes identified by the most recent Stages of Reproductive Aging Workshop are now defined in 10 stages, whereas the 2001 STRAW criteria had 7. The new criteria, called STRAW-10 and published Feb. 16 in Menopause, offer more detail on the characteristics of flow and cycle length at each stage, along with corresponding endocrine changes. The article was published simultaneously in Climacteric, Fertility and Sterility, and the Journal of Clinical Endocrinology and Metabolism.

For example, the late reproductive stage is now subdivided into two stages, –3b and –3a, instead of only stage –3 as before (Menopause 2012 Feb. 16 [doi:10.1097/gme0b013c31824d8f40]). In stage –3b, flow remains regular, whereas in stage –3a there are subtle changes in flow and length of cycle.

The postmenopausal stage +1, identified in the earlier STRAW criteria, also has been subdivided into three lettered stages, with the endocrine changes and duration of each stage described.

Unlike the previous STRAW criteria, the menstrual changes identified in STRAW-10 are relevant to any healthy woman, regardless of ethnicity, age, body mass index, or lifestyle, researchers said, noting that although factors such as smoking status and BMI may affect the timing of menopause, the bleeding patterns remain reliable indicators of the reproductive stage.

"Despite the availability of blood tests and sonograms, the menstrual cycle remains the single best way to estimate where a woman is along the reproductive path," commented Dr. Margery Gass, one of the coauthors of the new criteria, the executive director of the North American Menopause Society, and the editor of Menopause.

"According to STRAW-10, most women (and their clinicians) can use the changes in their menstrual pattern to determine how close they are to menopause: late reproductive phase (subtle changes in cycle length and blood flow), early menopause transition (menstrual period 7 or more days early or late), and late menopause transition (the occurrence of more than 60 days between cycles)," Dr. Gass said in an interview.

STRAW-10 incorporates three biomarkers – anti-Müllerian hormone (AMH), inhibin B, and antral follicle count – that are not mentioned in the original STRAW criteria, along with follicle-stimulating hormone (FSH), which was included in the original criteria.

In developing the new criteria, an international group of 41 researchers, led by epidemiologist Siobán D. Harlow, Ph.D., of the University of Michigan, Ann Arbor, evaluated data from cohort studies of midlife women with the aim to incorporate the scientific findings of the past decade on ovarian aging and its endocrine and clinical indicators.

Although much has been learned since 2001 with regard to biomarkers, Dr. Harlow and colleagues emphasized that the biomarker criteria outlined in STRAW-10 must still be considered "supportive," in part because more research is needed and in part because of the invasiveness and expense of testing.

Dr. Gass commented that for clinicians, checking hormone levels should not be considered necessary "except in women who have undergone endometrial ablation or hysterectomy, or who have unusual health circumstances."

Women for whom the STRAW-10 criteria are not applicable include those with polycystic ovarian syndrome or hypothalamic amenorrhea. Women with chronic illnesses such as HIV-AIDS, or those who are undergoing certain types of cancer treatments, also are difficult to assess under STRAW-10, as cycles and hormone levels can change in response to medication.

Although the new criteria do not use age in determining reproductive staging, women younger than 40 years who have premature ovarian insufficiency or premature ovarian failure do not fit well under STRAW-10, the researchers noted, as their course of reproductive aging is more variable.

The STRAW-10 meetings received funding from the National Institutes of Health and the Department of Health and Human Services through the National Institute on Aging (NIA) and the Office of Research on Women’s Health, as well as the North American Menopause Society (NAMS), the American Society for Reproductive Medicine (ASRM), the International Menopause Society in Cape Town, South Africa, and the Endocrine Society.

Dr. Gass receives support from NAMS. Dr. Harlow disclosed support from the NIA and NAMS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Coauthor Dr. Janet E. Hall disclosed support from NIA and the Endocrine Society. Dr. Roger Lobo is a past president of the ASRM, and Dr. Robert W. Rebar disclosed salary support from ASRM. Pauline Maki, Ph.D., disclosed support from the NIA and other public sources along with board membership on NAMS, a consultant relationship with Noven Pharmaceuticals, and lecture fees from Pfizer and others. Dr. Tobie J. de Villiers disclosed past support from Adcock Ingram, Servier, Pfizer, Bayer, and Amgen without direct bearing on the STRAW-10 work. The remaining two coauthors said they had no relevant financial disclosures.

Changes to the menstrual cycle remain the most important clinical indicators of women’s reproductive aging, according to new standardized staging criteria.

The changes identified by the most recent Stages of Reproductive Aging Workshop are now defined in 10 stages, whereas the 2001 STRAW criteria had 7. The new criteria, called STRAW-10 and published Feb. 16 in Menopause, offer more detail on the characteristics of flow and cycle length at each stage, along with corresponding endocrine changes. The article was published simultaneously in Climacteric, Fertility and Sterility, and the Journal of Clinical Endocrinology and Metabolism.

For example, the late reproductive stage is now subdivided into two stages, –3b and –3a, instead of only stage –3 as before (Menopause 2012 Feb. 16 [doi:10.1097/gme0b013c31824d8f40]). In stage –3b, flow remains regular, whereas in stage –3a there are subtle changes in flow and length of cycle.

The postmenopausal stage +1, identified in the earlier STRAW criteria, also has been subdivided into three lettered stages, with the endocrine changes and duration of each stage described.

Unlike the previous STRAW criteria, the menstrual changes identified in STRAW-10 are relevant to any healthy woman, regardless of ethnicity, age, body mass index, or lifestyle, researchers said, noting that although factors such as smoking status and BMI may affect the timing of menopause, the bleeding patterns remain reliable indicators of the reproductive stage.

"Despite the availability of blood tests and sonograms, the menstrual cycle remains the single best way to estimate where a woman is along the reproductive path," commented Dr. Margery Gass, one of the coauthors of the new criteria, the executive director of the North American Menopause Society, and the editor of Menopause.

"According to STRAW-10, most women (and their clinicians) can use the changes in their menstrual pattern to determine how close they are to menopause: late reproductive phase (subtle changes in cycle length and blood flow), early menopause transition (menstrual period 7 or more days early or late), and late menopause transition (the occurrence of more than 60 days between cycles)," Dr. Gass said in an interview.

STRAW-10 incorporates three biomarkers – anti-Müllerian hormone (AMH), inhibin B, and antral follicle count – that are not mentioned in the original STRAW criteria, along with follicle-stimulating hormone (FSH), which was included in the original criteria.

In developing the new criteria, an international group of 41 researchers, led by epidemiologist Siobán D. Harlow, Ph.D., of the University of Michigan, Ann Arbor, evaluated data from cohort studies of midlife women with the aim to incorporate the scientific findings of the past decade on ovarian aging and its endocrine and clinical indicators.

Although much has been learned since 2001 with regard to biomarkers, Dr. Harlow and colleagues emphasized that the biomarker criteria outlined in STRAW-10 must still be considered "supportive," in part because more research is needed and in part because of the invasiveness and expense of testing.

Dr. Gass commented that for clinicians, checking hormone levels should not be considered necessary "except in women who have undergone endometrial ablation or hysterectomy, or who have unusual health circumstances."

Women for whom the STRAW-10 criteria are not applicable include those with polycystic ovarian syndrome or hypothalamic amenorrhea. Women with chronic illnesses such as HIV-AIDS, or those who are undergoing certain types of cancer treatments, also are difficult to assess under STRAW-10, as cycles and hormone levels can change in response to medication.

Although the new criteria do not use age in determining reproductive staging, women younger than 40 years who have premature ovarian insufficiency or premature ovarian failure do not fit well under STRAW-10, the researchers noted, as their course of reproductive aging is more variable.

The STRAW-10 meetings received funding from the National Institutes of Health and the Department of Health and Human Services through the National Institute on Aging (NIA) and the Office of Research on Women’s Health, as well as the North American Menopause Society (NAMS), the American Society for Reproductive Medicine (ASRM), the International Menopause Society in Cape Town, South Africa, and the Endocrine Society.

Dr. Gass receives support from NAMS. Dr. Harlow disclosed support from the NIA and NAMS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Coauthor Dr. Janet E. Hall disclosed support from NIA and the Endocrine Society. Dr. Roger Lobo is a past president of the ASRM, and Dr. Robert W. Rebar disclosed salary support from ASRM. Pauline Maki, Ph.D., disclosed support from the NIA and other public sources along with board membership on NAMS, a consultant relationship with Noven Pharmaceuticals, and lecture fees from Pfizer and others. Dr. Tobie J. de Villiers disclosed past support from Adcock Ingram, Servier, Pfizer, Bayer, and Amgen without direct bearing on the STRAW-10 work. The remaining two coauthors said they had no relevant financial disclosures.

Changes to the menstrual cycle remain the most important clinical indicators of women’s reproductive aging, according to new standardized staging criteria.

The changes identified by the most recent Stages of Reproductive Aging Workshop are now defined in 10 stages, whereas the 2001 STRAW criteria had 7. The new criteria, called STRAW-10 and published Feb. 16 in Menopause, offer more detail on the characteristics of flow and cycle length at each stage, along with corresponding endocrine changes. The article was published simultaneously in Climacteric, Fertility and Sterility, and the Journal of Clinical Endocrinology and Metabolism.

For example, the late reproductive stage is now subdivided into two stages, –3b and –3a, instead of only stage –3 as before (Menopause 2012 Feb. 16 [doi:10.1097/gme0b013c31824d8f40]). In stage –3b, flow remains regular, whereas in stage –3a there are subtle changes in flow and length of cycle.

The postmenopausal stage +1, identified in the earlier STRAW criteria, also has been subdivided into three lettered stages, with the endocrine changes and duration of each stage described.

Unlike the previous STRAW criteria, the menstrual changes identified in STRAW-10 are relevant to any healthy woman, regardless of ethnicity, age, body mass index, or lifestyle, researchers said, noting that although factors such as smoking status and BMI may affect the timing of menopause, the bleeding patterns remain reliable indicators of the reproductive stage.

"Despite the availability of blood tests and sonograms, the menstrual cycle remains the single best way to estimate where a woman is along the reproductive path," commented Dr. Margery Gass, one of the coauthors of the new criteria, the executive director of the North American Menopause Society, and the editor of Menopause.

"According to STRAW-10, most women (and their clinicians) can use the changes in their menstrual pattern to determine how close they are to menopause: late reproductive phase (subtle changes in cycle length and blood flow), early menopause transition (menstrual period 7 or more days early or late), and late menopause transition (the occurrence of more than 60 days between cycles)," Dr. Gass said in an interview.

STRAW-10 incorporates three biomarkers – anti-Müllerian hormone (AMH), inhibin B, and antral follicle count – that are not mentioned in the original STRAW criteria, along with follicle-stimulating hormone (FSH), which was included in the original criteria.

In developing the new criteria, an international group of 41 researchers, led by epidemiologist Siobán D. Harlow, Ph.D., of the University of Michigan, Ann Arbor, evaluated data from cohort studies of midlife women with the aim to incorporate the scientific findings of the past decade on ovarian aging and its endocrine and clinical indicators.

Although much has been learned since 2001 with regard to biomarkers, Dr. Harlow and colleagues emphasized that the biomarker criteria outlined in STRAW-10 must still be considered "supportive," in part because more research is needed and in part because of the invasiveness and expense of testing.

Dr. Gass commented that for clinicians, checking hormone levels should not be considered necessary "except in women who have undergone endometrial ablation or hysterectomy, or who have unusual health circumstances."

Women for whom the STRAW-10 criteria are not applicable include those with polycystic ovarian syndrome or hypothalamic amenorrhea. Women with chronic illnesses such as HIV-AIDS, or those who are undergoing certain types of cancer treatments, also are difficult to assess under STRAW-10, as cycles and hormone levels can change in response to medication.

Although the new criteria do not use age in determining reproductive staging, women younger than 40 years who have premature ovarian insufficiency or premature ovarian failure do not fit well under STRAW-10, the researchers noted, as their course of reproductive aging is more variable.

The STRAW-10 meetings received funding from the National Institutes of Health and the Department of Health and Human Services through the National Institute on Aging (NIA) and the Office of Research on Women’s Health, as well as the North American Menopause Society (NAMS), the American Society for Reproductive Medicine (ASRM), the International Menopause Society in Cape Town, South Africa, and the Endocrine Society.

Dr. Gass receives support from NAMS. Dr. Harlow disclosed support from the NIA and NAMS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Coauthor Dr. Janet E. Hall disclosed support from NIA and the Endocrine Society. Dr. Roger Lobo is a past president of the ASRM, and Dr. Robert W. Rebar disclosed salary support from ASRM. Pauline Maki, Ph.D., disclosed support from the NIA and other public sources along with board membership on NAMS, a consultant relationship with Noven Pharmaceuticals, and lecture fees from Pfizer and others. Dr. Tobie J. de Villiers disclosed past support from Adcock Ingram, Servier, Pfizer, Bayer, and Amgen without direct bearing on the STRAW-10 work. The remaining two coauthors said they had no relevant financial disclosures.

England’s clinical and cost-effectiveness agency has said that it would not recommend lapatinib or trastuzumab with aromatase inhibitors as first-line treatments for postmenopausal women with HER2 positive metastatic breast cancer.

The new negative draft guidance follows previous negative guidance, issued in July 2011, and a subsequent appeal by Roche, the manufacturer of trastuzumab (Herceptin). While an independent panel upheld parts of Roche’s appeal in November, the National Institute for Health and Clinical Excellence nonetheless rejected both treatments once more, citing cost concerns and unclear overall survival evidence for this patient group.

In clinical trial results evaluated by NICE, lapatinib plus an aromatase inhibitor was associated with progression-free survival of 5.2 months, and trastuzumab plus an aromatase inhibitor with 2.4 months; however, NICE said that there was insufficient evidence of an overall survival gain with either treatment.

While NICE has never before issued guidance on lapatinib (Tyverb and Tykerb, GlaxoSmithKline) for any indication, trastuzumab is currently recommended by NICE for the treatment of HER2 positive gastric cancer and for two groups of women with breast cancer: those whose tumors overexpress HER2 at levels of 3+ who have not had chemotherapy for metastatic breast cancer and for whom anthracycline is inappropriate (for this group, trastuzumab is recommended in combination with paclitaxel); and those who have early-stage HER2 positive breast cancer following surgery and chemotherapy.

Lapatinib and trastuzumab combined with aromatase inhibitors are being assessed as treatments for women only when chemotherapy is deemed unsuitable.

Trastuzumab, a humanized monoclonal antibody directed against HER2, is administered as an intravenous infusion of 4 mg/kg, followed by a weekly maintenance dose of 2 mg/kg until disease progression (or an alternative schedule of 8 mg/kg followed by 3-weekly doses of 6 mg/kg). NICE estimates the cost of treatment with trastuzumab plus the aromatase inhibitor anastrozole to be between £26,000 and £27,000, depending on the dosing schedule.

Lapatinib, an oral medication, is administered in six tablets totaling 1,500 mg/day. Treatment with lapatinib plus the aromatase inhibitor letrozole is estimated at about £28,000.

NICE said that the estimated incremental cost effectiveness ratio for lapatinib plus letrozole, compared with letrozole alone, is about £74,400 per quality-adjusted life year gained. Trastuzumab plus anastrozole, compared with anastrozole alone, is estimated at £51,000 per QALY gained. Both estimates surpass NICE’s cost-effectiveness caps.

England’s clinical and cost-effectiveness agency has said that it would not recommend lapatinib or trastuzumab with aromatase inhibitors as first-line treatments for postmenopausal women with HER2 positive metastatic breast cancer.

The new negative draft guidance follows previous negative guidance, issued in July 2011, and a subsequent appeal by Roche, the manufacturer of trastuzumab (Herceptin). While an independent panel upheld parts of Roche’s appeal in November, the National Institute for Health and Clinical Excellence nonetheless rejected both treatments once more, citing cost concerns and unclear overall survival evidence for this patient group.

In clinical trial results evaluated by NICE, lapatinib plus an aromatase inhibitor was associated with progression-free survival of 5.2 months, and trastuzumab plus an aromatase inhibitor with 2.4 months; however, NICE said that there was insufficient evidence of an overall survival gain with either treatment.

While NICE has never before issued guidance on lapatinib (Tyverb and Tykerb, GlaxoSmithKline) for any indication, trastuzumab is currently recommended by NICE for the treatment of HER2 positive gastric cancer and for two groups of women with breast cancer: those whose tumors overexpress HER2 at levels of 3+ who have not had chemotherapy for metastatic breast cancer and for whom anthracycline is inappropriate (for this group, trastuzumab is recommended in combination with paclitaxel); and those who have early-stage HER2 positive breast cancer following surgery and chemotherapy.

Lapatinib and trastuzumab combined with aromatase inhibitors are being assessed as treatments for women only when chemotherapy is deemed unsuitable.

Trastuzumab, a humanized monoclonal antibody directed against HER2, is administered as an intravenous infusion of 4 mg/kg, followed by a weekly maintenance dose of 2 mg/kg until disease progression (or an alternative schedule of 8 mg/kg followed by 3-weekly doses of 6 mg/kg). NICE estimates the cost of treatment with trastuzumab plus the aromatase inhibitor anastrozole to be between £26,000 and £27,000, depending on the dosing schedule.

Lapatinib, an oral medication, is administered in six tablets totaling 1,500 mg/day. Treatment with lapatinib plus the aromatase inhibitor letrozole is estimated at about £28,000.

NICE said that the estimated incremental cost effectiveness ratio for lapatinib plus letrozole, compared with letrozole alone, is about £74,400 per quality-adjusted life year gained. Trastuzumab plus anastrozole, compared with anastrozole alone, is estimated at £51,000 per QALY gained. Both estimates surpass NICE’s cost-effectiveness caps.

England’s clinical and cost-effectiveness agency has said that it would not recommend lapatinib or trastuzumab with aromatase inhibitors as first-line treatments for postmenopausal women with HER2 positive metastatic breast cancer.

The new negative draft guidance follows previous negative guidance, issued in July 2011, and a subsequent appeal by Roche, the manufacturer of trastuzumab (Herceptin). While an independent panel upheld parts of Roche’s appeal in November, the National Institute for Health and Clinical Excellence nonetheless rejected both treatments once more, citing cost concerns and unclear overall survival evidence for this patient group.

In clinical trial results evaluated by NICE, lapatinib plus an aromatase inhibitor was associated with progression-free survival of 5.2 months, and trastuzumab plus an aromatase inhibitor with 2.4 months; however, NICE said that there was insufficient evidence of an overall survival gain with either treatment.

While NICE has never before issued guidance on lapatinib (Tyverb and Tykerb, GlaxoSmithKline) for any indication, trastuzumab is currently recommended by NICE for the treatment of HER2 positive gastric cancer and for two groups of women with breast cancer: those whose tumors overexpress HER2 at levels of 3+ who have not had chemotherapy for metastatic breast cancer and for whom anthracycline is inappropriate (for this group, trastuzumab is recommended in combination with paclitaxel); and those who have early-stage HER2 positive breast cancer following surgery and chemotherapy.

Lapatinib and trastuzumab combined with aromatase inhibitors are being assessed as treatments for women only when chemotherapy is deemed unsuitable.

Trastuzumab, a humanized monoclonal antibody directed against HER2, is administered as an intravenous infusion of 4 mg/kg, followed by a weekly maintenance dose of 2 mg/kg until disease progression (or an alternative schedule of 8 mg/kg followed by 3-weekly doses of 6 mg/kg). NICE estimates the cost of treatment with trastuzumab plus the aromatase inhibitor anastrozole to be between £26,000 and £27,000, depending on the dosing schedule.

Lapatinib, an oral medication, is administered in six tablets totaling 1,500 mg/day. Treatment with lapatinib plus the aromatase inhibitor letrozole is estimated at about £28,000.

NICE said that the estimated incremental cost effectiveness ratio for lapatinib plus letrozole, compared with letrozole alone, is about £74,400 per quality-adjusted life year gained. Trastuzumab plus anastrozole, compared with anastrozole alone, is estimated at £51,000 per QALY gained. Both estimates surpass NICE’s cost-effectiveness caps.

The cost effectiveness agency for England and Wales said that it would not recommend abiraterone, a drug considered to be a breakthrough second-line treatment for men with castration-resistant metastatic prostate cancer.

The National Institute for Health and Clinical Excellence said that abiterone’s cost was the main factor bearing on its negative draft guidance, which is now subject to public and manufacturer consultation. NICE indicated that it would be open to considering the drug if its manufacturer were to revise its discounting scheme to make it more affordable to the National Health Service.

Abiraterone (Zytiga, Janssen), which received fast-track approval from the Food and Drug Administration in April 2011 and was recommended by the European Medicines Agency in July 2011, is an oral drug that inhibits the production of androgens. It is administered along with prednisone or prednisolone for men whose disease has resisted surgical or medical castration and progressed following initiation of docetaxel-based chemotherapy.

In a double-blinded, manufacturer-sponsored, randomized controlled trial enrolling 1,195 men with previously treated late-stage castration-resistant prostate cancer, patients in the treatment arm (n = 797) saw overall survival of 14.8 months compared with 10.9 months for those in the placebo arm. The trial had to be unblinded early on the strength of the results (N. Engl. J. Med. 2011;364:1995-2005).

In announcing its negative decision, NICE acknowledged that there was sufficient clinical trial evidence to suggest that abiraterone could extend overall survival by more than 3 months compared with placebo. The agency also said that 4,300 people with castration-resistant metastatic prostate cancer were receiving docetaxel in England and Wales in 2011, with the number expected to rise to 5,500 this year, and that approximately 75% of these would be eligible for abiraterone treatment according to its licensed indication.

Abiraterone costs £2,930 in the United Kingdom for a 30-day supply. It is taken as a single dose of 1 g per day, in four tablets containing 250 mg each.

While abiraterone’s manufacturer agreed to discount the drug to the National Health Service by an undisclosed amount, NICE said that the incremental cost-effectiveness ratio for was £63,200 cost per quality-adjusted life year even with that discount, while the highest ICER for a NICE-recommended drug is currently £50,200 per QALY.

Current NICE recommendations for men whose disease has progressed after first-line docetaxel are mitoxantrone and best supportive care.

The cost effectiveness agency for England and Wales said that it would not recommend abiraterone, a drug considered to be a breakthrough second-line treatment for men with castration-resistant metastatic prostate cancer.

The National Institute for Health and Clinical Excellence said that abiterone’s cost was the main factor bearing on its negative draft guidance, which is now subject to public and manufacturer consultation. NICE indicated that it would be open to considering the drug if its manufacturer were to revise its discounting scheme to make it more affordable to the National Health Service.

Abiraterone (Zytiga, Janssen), which received fast-track approval from the Food and Drug Administration in April 2011 and was recommended by the European Medicines Agency in July 2011, is an oral drug that inhibits the production of androgens. It is administered along with prednisone or prednisolone for men whose disease has resisted surgical or medical castration and progressed following initiation of docetaxel-based chemotherapy.

In a double-blinded, manufacturer-sponsored, randomized controlled trial enrolling 1,195 men with previously treated late-stage castration-resistant prostate cancer, patients in the treatment arm (n = 797) saw overall survival of 14.8 months compared with 10.9 months for those in the placebo arm. The trial had to be unblinded early on the strength of the results (N. Engl. J. Med. 2011;364:1995-2005).

In announcing its negative decision, NICE acknowledged that there was sufficient clinical trial evidence to suggest that abiraterone could extend overall survival by more than 3 months compared with placebo. The agency also said that 4,300 people with castration-resistant metastatic prostate cancer were receiving docetaxel in England and Wales in 2011, with the number expected to rise to 5,500 this year, and that approximately 75% of these would be eligible for abiraterone treatment according to its licensed indication.

Abiraterone costs £2,930 in the United Kingdom for a 30-day supply. It is taken as a single dose of 1 g per day, in four tablets containing 250 mg each.

While abiraterone’s manufacturer agreed to discount the drug to the National Health Service by an undisclosed amount, NICE said that the incremental cost-effectiveness ratio for was £63,200 cost per quality-adjusted life year even with that discount, while the highest ICER for a NICE-recommended drug is currently £50,200 per QALY.

Current NICE recommendations for men whose disease has progressed after first-line docetaxel are mitoxantrone and best supportive care.

The cost effectiveness agency for England and Wales said that it would not recommend abiraterone, a drug considered to be a breakthrough second-line treatment for men with castration-resistant metastatic prostate cancer.

The National Institute for Health and Clinical Excellence said that abiterone’s cost was the main factor bearing on its negative draft guidance, which is now subject to public and manufacturer consultation. NICE indicated that it would be open to considering the drug if its manufacturer were to revise its discounting scheme to make it more affordable to the National Health Service.

Abiraterone (Zytiga, Janssen), which received fast-track approval from the Food and Drug Administration in April 2011 and was recommended by the European Medicines Agency in July 2011, is an oral drug that inhibits the production of androgens. It is administered along with prednisone or prednisolone for men whose disease has resisted surgical or medical castration and progressed following initiation of docetaxel-based chemotherapy.

In a double-blinded, manufacturer-sponsored, randomized controlled trial enrolling 1,195 men with previously treated late-stage castration-resistant prostate cancer, patients in the treatment arm (n = 797) saw overall survival of 14.8 months compared with 10.9 months for those in the placebo arm. The trial had to be unblinded early on the strength of the results (N. Engl. J. Med. 2011;364:1995-2005).

In announcing its negative decision, NICE acknowledged that there was sufficient clinical trial evidence to suggest that abiraterone could extend overall survival by more than 3 months compared with placebo. The agency also said that 4,300 people with castration-resistant metastatic prostate cancer were receiving docetaxel in England and Wales in 2011, with the number expected to rise to 5,500 this year, and that approximately 75% of these would be eligible for abiraterone treatment according to its licensed indication.

Abiraterone costs £2,930 in the United Kingdom for a 30-day supply. It is taken as a single dose of 1 g per day, in four tablets containing 250 mg each.

While abiraterone’s manufacturer agreed to discount the drug to the National Health Service by an undisclosed amount, NICE said that the incremental cost-effectiveness ratio for was £63,200 cost per quality-adjusted life year even with that discount, while the highest ICER for a NICE-recommended drug is currently £50,200 per QALY.

Current NICE recommendations for men whose disease has progressed after first-line docetaxel are mitoxantrone and best supportive care.

The cost-effectiveness institute for England and Wales has rejected three biological treatments for metastatic colorectal cancer that has progressed after initial or second-line treatment.

The National Institute for Health and Clinical Excellence said Jan. 24 that cetuximab (Erbitux, Merck Serono), bevacizumab (Avastin, Roche) and panitumumab (Vectibix, Amgen) had all failed to reach the agency’s cost-effectiveness criteria for the treatment of metastatic colorectal cancer that has progressed following initial combination chemotherapy.

All the treatments are monoclonal antibodies licensed for the second- or third-line treatment of metastasized colorectal cancer. Cetuximab was evaluated by NICE as monotherapy or combination therapy, bevacizumab in combination with nonoxaliplatin (Eloxatin) chemotherapy, and panitumumab as monotherapy.

NICE published its final guidance on these drugs Jan 25 in the Lancet Oncology. The negative guidance was widely anticipated after NICE issued draft guidance in September 2011 and again in November against the treatments.

In a news release about its decision, the agency singled out the clinical evidence for bevacizumab as especially wanting. NICE said that evidence from three clinical trials (two observational studies and one randomized, controlled trial) evaluating bevacizumab’s effectiveness as a second- or third-line treatment could not be used to establish overall survival benefit. Because of this, the NICE reviewers did not attempt to quantify bevacizumab’s cost-effectiveness in terms of incremental cost-effectiveness rations (ICERs) or Quality Adjusted Life Years (QALYs).

Despite the negative guidance, NICE has not closed the book on bevacizumab for advanced metastatic bowel cancer, having noted in its draft guidance in November that a phase II clinical trial comparing bevacizumab plus 5-fluorouracil plus folinic acid and irinotecan (FOLFIRI) with panitumumab plus FOLFIRI after first-line treatment was underway, with an expected completion date of August 2012, and said that it would take those results into consideration.

With cetuximab, NICE reviewed evidence from a randomized controlled trial (n = 230) enrolling patients with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. (NICE estimates that 30%-50% of people with colorectal cancer have the KRAS wild-type gene.) Subjects had been previously treated with oxaliplatin-based and irinotecan (Camptosar)-based therapies. Median overall survival was 9.5 months for cetuximab plus best supportive care, compared with 4.8 months for best supportive care alone (hazard ratio, 0.55; 95% confidence interval, 0.41-0.74; P less than .001).

However, the NICE reviewers noted that there were no head-to-head trials of cetuximab plus irinotecan compared with best supportive care in KRAS wild-type colorectal cancer, forcing cetuximab’s manufacturer to submit an indirect comparison combining evidence from multiple clinical trials, including nonrandomized trials. This mixed analysis cast doubt on the robustness of the overall survival estimates, NICE said.

NICE estimated an ICER of £98,000 per QALY gained for cetuximab plus best supportive care, compared with best supportive care alone. For cetuximab plus irinotecan plus best supportive care compared with best supportive care alone, NICE estimated an ICER of £88,000 per QALY gained.

The case for panitumumab monotherapy was derived from a randomized, controlled trial that had a subgroup of 243 patients with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. Patients had been previously treated with oxaliplatin and irinotecan therapies, meaning that panitumumab was given as third- or fourth-line therapy. Panitumumab was associated with a progression-free survival benefit of about 5 weeks, compared with best supportive care; however, this did not reach statistical significance.

The NICE reviewers concluded that absent additional evidence, the true magnitude of panitumumab’s survival benefit was uncertain. Further, panitumumab’s expense – NICE estimated its ICER at between £110,000 and £150,000 per QALY gained – would have meant that NICE could not recommend it even if a survival benefit had been established.

All three medications – cetuximab, bevacizumab, and panitumumab – are administered by intravenous infusion.

The recommended dosage of cetuximab is an initial dose of 400 mg/m² of body surface area followed by 250 mg/m² once a week. The U.K. list price of a 100-mg vial of cetuximab is £178.10, and a 500-mg vial is £890.50.

Bevacizumab’s dosage is 5 or 10 mg/kg of body weight once every 2 weeks or 7.5 or 15 mg/kg of body weight once every 3 weeks. The list price of a 100-mg vial is £242.66, and a 400-mg vial is £924.40. Panitumumab’s dosage is 6 mg/kg every 14 days. It costs £379.29 for 100 mg and £1,517 for 400 mg.

In announcing its decisions on bevacizumab, cetuximab, and panitumumab, NICE emphasized that it had six other recommended treatments for various stages of colorectal cancer, metastatic and nonmetastatic.

NICE recommends only two treatments for metastatic cancer that has progressed after first-line treatment: monotherapy with irinotecan for people who previously received FOLFIRI (irinotecan in combination with 5-fluorouracil plus folinic acid), and FOLFOX (oxaliplatin in combination with 5-fluorouracil plus folinic acid) for people who previously received FOLFIRI.

The cost-effectiveness institute for England and Wales has rejected three biological treatments for metastatic colorectal cancer that has progressed after initial or second-line treatment.

The National Institute for Health and Clinical Excellence said Jan. 24 that cetuximab (Erbitux, Merck Serono), bevacizumab (Avastin, Roche) and panitumumab (Vectibix, Amgen) had all failed to reach the agency’s cost-effectiveness criteria for the treatment of metastatic colorectal cancer that has progressed following initial combination chemotherapy.

All the treatments are monoclonal antibodies licensed for the second- or third-line treatment of metastasized colorectal cancer. Cetuximab was evaluated by NICE as monotherapy or combination therapy, bevacizumab in combination with nonoxaliplatin (Eloxatin) chemotherapy, and panitumumab as monotherapy.

NICE published its final guidance on these drugs Jan 25 in the Lancet Oncology. The negative guidance was widely anticipated after NICE issued draft guidance in September 2011 and again in November against the treatments.

In a news release about its decision, the agency singled out the clinical evidence for bevacizumab as especially wanting. NICE said that evidence from three clinical trials (two observational studies and one randomized, controlled trial) evaluating bevacizumab’s effectiveness as a second- or third-line treatment could not be used to establish overall survival benefit. Because of this, the NICE reviewers did not attempt to quantify bevacizumab’s cost-effectiveness in terms of incremental cost-effectiveness rations (ICERs) or Quality Adjusted Life Years (QALYs).

Despite the negative guidance, NICE has not closed the book on bevacizumab for advanced metastatic bowel cancer, having noted in its draft guidance in November that a phase II clinical trial comparing bevacizumab plus 5-fluorouracil plus folinic acid and irinotecan (FOLFIRI) with panitumumab plus FOLFIRI after first-line treatment was underway, with an expected completion date of August 2012, and said that it would take those results into consideration.

With cetuximab, NICE reviewed evidence from a randomized controlled trial (n = 230) enrolling patients with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. (NICE estimates that 30%-50% of people with colorectal cancer have the KRAS wild-type gene.) Subjects had been previously treated with oxaliplatin-based and irinotecan (Camptosar)-based therapies. Median overall survival was 9.5 months for cetuximab plus best supportive care, compared with 4.8 months for best supportive care alone (hazard ratio, 0.55; 95% confidence interval, 0.41-0.74; P less than .001).

However, the NICE reviewers noted that there were no head-to-head trials of cetuximab plus irinotecan compared with best supportive care in KRAS wild-type colorectal cancer, forcing cetuximab’s manufacturer to submit an indirect comparison combining evidence from multiple clinical trials, including nonrandomized trials. This mixed analysis cast doubt on the robustness of the overall survival estimates, NICE said.

NICE estimated an ICER of £98,000 per QALY gained for cetuximab plus best supportive care, compared with best supportive care alone. For cetuximab plus irinotecan plus best supportive care compared with best supportive care alone, NICE estimated an ICER of £88,000 per QALY gained.

The case for panitumumab monotherapy was derived from a randomized, controlled trial that had a subgroup of 243 patients with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. Patients had been previously treated with oxaliplatin and irinotecan therapies, meaning that panitumumab was given as third- or fourth-line therapy. Panitumumab was associated with a progression-free survival benefit of about 5 weeks, compared with best supportive care; however, this did not reach statistical significance.

The NICE reviewers concluded that absent additional evidence, the true magnitude of panitumumab’s survival benefit was uncertain. Further, panitumumab’s expense – NICE estimated its ICER at between £110,000 and £150,000 per QALY gained – would have meant that NICE could not recommend it even if a survival benefit had been established.

All three medications – cetuximab, bevacizumab, and panitumumab – are administered by intravenous infusion.

The recommended dosage of cetuximab is an initial dose of 400 mg/m² of body surface area followed by 250 mg/m² once a week. The U.K. list price of a 100-mg vial of cetuximab is £178.10, and a 500-mg vial is £890.50.

Bevacizumab’s dosage is 5 or 10 mg/kg of body weight once every 2 weeks or 7.5 or 15 mg/kg of body weight once every 3 weeks. The list price of a 100-mg vial is £242.66, and a 400-mg vial is £924.40. Panitumumab’s dosage is 6 mg/kg every 14 days. It costs £379.29 for 100 mg and £1,517 for 400 mg.

In announcing its decisions on bevacizumab, cetuximab, and panitumumab, NICE emphasized that it had six other recommended treatments for various stages of colorectal cancer, metastatic and nonmetastatic.

NICE recommends only two treatments for metastatic cancer that has progressed after first-line treatment: monotherapy with irinotecan for people who previously received FOLFIRI (irinotecan in combination with 5-fluorouracil plus folinic acid), and FOLFOX (oxaliplatin in combination with 5-fluorouracil plus folinic acid) for people who previously received FOLFIRI.

The cost-effectiveness institute for England and Wales has rejected three biological treatments for metastatic colorectal cancer that has progressed after initial or second-line treatment.

The National Institute for Health and Clinical Excellence said Jan. 24 that cetuximab (Erbitux, Merck Serono), bevacizumab (Avastin, Roche) and panitumumab (Vectibix, Amgen) had all failed to reach the agency’s cost-effectiveness criteria for the treatment of metastatic colorectal cancer that has progressed following initial combination chemotherapy.

All the treatments are monoclonal antibodies licensed for the second- or third-line treatment of metastasized colorectal cancer. Cetuximab was evaluated by NICE as monotherapy or combination therapy, bevacizumab in combination with nonoxaliplatin (Eloxatin) chemotherapy, and panitumumab as monotherapy.

NICE published its final guidance on these drugs Jan 25 in the Lancet Oncology. The negative guidance was widely anticipated after NICE issued draft guidance in September 2011 and again in November against the treatments.

In a news release about its decision, the agency singled out the clinical evidence for bevacizumab as especially wanting. NICE said that evidence from three clinical trials (two observational studies and one randomized, controlled trial) evaluating bevacizumab’s effectiveness as a second- or third-line treatment could not be used to establish overall survival benefit. Because of this, the NICE reviewers did not attempt to quantify bevacizumab’s cost-effectiveness in terms of incremental cost-effectiveness rations (ICERs) or Quality Adjusted Life Years (QALYs).

Despite the negative guidance, NICE has not closed the book on bevacizumab for advanced metastatic bowel cancer, having noted in its draft guidance in November that a phase II clinical trial comparing bevacizumab plus 5-fluorouracil plus folinic acid and irinotecan (FOLFIRI) with panitumumab plus FOLFIRI after first-line treatment was underway, with an expected completion date of August 2012, and said that it would take those results into consideration.

With cetuximab, NICE reviewed evidence from a randomized controlled trial (n = 230) enrolling patients with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. (NICE estimates that 30%-50% of people with colorectal cancer have the KRAS wild-type gene.) Subjects had been previously treated with oxaliplatin-based and irinotecan (Camptosar)-based therapies. Median overall survival was 9.5 months for cetuximab plus best supportive care, compared with 4.8 months for best supportive care alone (hazard ratio, 0.55; 95% confidence interval, 0.41-0.74; P less than .001).

However, the NICE reviewers noted that there were no head-to-head trials of cetuximab plus irinotecan compared with best supportive care in KRAS wild-type colorectal cancer, forcing cetuximab’s manufacturer to submit an indirect comparison combining evidence from multiple clinical trials, including nonrandomized trials. This mixed analysis cast doubt on the robustness of the overall survival estimates, NICE said.

NICE estimated an ICER of £98,000 per QALY gained for cetuximab plus best supportive care, compared with best supportive care alone. For cetuximab plus irinotecan plus best supportive care compared with best supportive care alone, NICE estimated an ICER of £88,000 per QALY gained.

The case for panitumumab monotherapy was derived from a randomized, controlled trial that had a subgroup of 243 patients with KRAS wild-type metastatic colorectal cancer that had progressed after first-line chemotherapy. Patients had been previously treated with oxaliplatin and irinotecan therapies, meaning that panitumumab was given as third- or fourth-line therapy. Panitumumab was associated with a progression-free survival benefit of about 5 weeks, compared with best supportive care; however, this did not reach statistical significance.

The NICE reviewers concluded that absent additional evidence, the true magnitude of panitumumab’s survival benefit was uncertain. Further, panitumumab’s expense – NICE estimated its ICER at between £110,000 and £150,000 per QALY gained – would have meant that NICE could not recommend it even if a survival benefit had been established.

All three medications – cetuximab, bevacizumab, and panitumumab – are administered by intravenous infusion.

The recommended dosage of cetuximab is an initial dose of 400 mg/m² of body surface area followed by 250 mg/m² once a week. The U.K. list price of a 100-mg vial of cetuximab is £178.10, and a 500-mg vial is £890.50.

Bevacizumab’s dosage is 5 or 10 mg/kg of body weight once every 2 weeks or 7.5 or 15 mg/kg of body weight once every 3 weeks. The list price of a 100-mg vial is £242.66, and a 400-mg vial is £924.40. Panitumumab’s dosage is 6 mg/kg every 14 days. It costs £379.29 for 100 mg and £1,517 for 400 mg.

In announcing its decisions on bevacizumab, cetuximab, and panitumumab, NICE emphasized that it had six other recommended treatments for various stages of colorectal cancer, metastatic and nonmetastatic.

NICE recommends only two treatments for metastatic cancer that has progressed after first-line treatment: monotherapy with irinotecan for people who previously received FOLFIRI (irinotecan in combination with 5-fluorouracil plus folinic acid), and FOLFOX (oxaliplatin in combination with 5-fluorouracil plus folinic acid) for people who previously received FOLFIRI.

The Food and Drug Administration has identified a new risk factor for progressive multifocal leukoencephalopathy, a life-threatening brain infection associated with the use of natalizumab, an immunomodulatory agent used to treat multiple sclerosis and Crohn’s disease.

Testing positive for anti–John Cunningham virus (JCV) antibodies raises the risk of developing progressive multifocal leukoencephalopathy (PML), particularly when patients have been on natalizumab treatment for more than 2 years and have previously taken immunosuppressant medicines such as mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil. When all three risk factors are present – 2 or more years of natalizumab therapy, anti-JCV, and prior immunosuppressant use – the incidence of PML is estimated to be 11 in 1,000 patients, FDA said in a drug safety communication Jan. 20.

When patients have anti-JCV antibodies but have been on natalizumab less than 2 years and have no prior immunosuppressant use, PML incidence is less than 1 in 1,000, the FDA said. PML incidence is estimated at 2 of every 1,000 anti–JCV positive patients with less than 2 years on natalizumab and with prior immunosuppressant use. For those with anti-JCV antibodies and more than 2 years treatment but no prior immunosuppressants, incidence is about 4 in 1,000, the FDA communication said. The FDA, which already had a black box warning on natalizumab (Tysabri, Biogen Idec, and Elan) describing increased PML risk, said Jan. 20 that it had changed the product labeling to reflect the newly stratified risk information, and also announced in a news release that it had approved a new test, called the Stratify JCV Antibody ELISA test (Focus Diagnostics), to detect anti-JCV antibodies in people deemed at risk of developing PML.

In most people, JCV is harmless; however, those on immunomodulatory agents like natalizumab are at risk of death or serious disability from PML caused by JCV exposure.

The agency stressed that patients on natalizumab may be at risk for developing PML even without a positive test for JCV antibodies, because the infection can occur at any time, or because false negative results can occur. Patients should be monitored carefully and natalizumab treatment should be stopped at the first sign of PML. While there is no treatment for PML, stopping treatment early may allow the immune system to recover and fight JCV infection.

Natalizumab, a monoclonal antibody administered by intravenous infusion, works by blocking a protein that is found on the surface of leukocytes, preventing their movement from the blood into the brain and reducing the inflammation and nerve damage caused by MS. In Crohn’s disease, it works by blocking adhesion and migration of leukocytes into the gut. For both indications it is administered by intravenous infusion of 300 mg every 4 weeks.

In 2004, the FDA approved natalizumab as a treatment for MS in patients who had failed other therapies; however, it was withdrawn the following year by its manufacturer due to safety concerns related to PML. In 2006, it was returned to market under a restricted prescribing program to treat relapsing forms of MS and was granted marketing authorization by the European Medicines Agency (EMA) to treat highly active relapsing MS. In 2008, it was approved in the United States for the treatment of Crohn’s disease, also under a restricted prescribing program, in patients failing other therapies.

The EMA in 2007 refused to grant marketing authorization to natalizumab for Crohn’s, citing an unfavorable risk-benefit profile. In 2010 the EMA concluded a review of the risks of natalizumab for relapsing MS following increasing reports of PML cases. The EMA retained natalizumab’s marketing authorization for relapsing MS but strengthened its warnings about PML risk.

To listen to a podcast concerning the natalizumab warning, click on the "Listen" button below. Podcast courstesy of the FDA.

The Food and Drug Administration has identified a new risk factor for progressive multifocal leukoencephalopathy, a life-threatening brain infection associated with the use of natalizumab, an immunomodulatory agent used to treat multiple sclerosis and Crohn’s disease.

Testing positive for anti–John Cunningham virus (JCV) antibodies raises the risk of developing progressive multifocal leukoencephalopathy (PML), particularly when patients have been on natalizumab treatment for more than 2 years and have previously taken immunosuppressant medicines such as mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil. When all three risk factors are present – 2 or more years of natalizumab therapy, anti-JCV, and prior immunosuppressant use – the incidence of PML is estimated to be 11 in 1,000 patients, FDA said in a drug safety communication Jan. 20.

When patients have anti-JCV antibodies but have been on natalizumab less than 2 years and have no prior immunosuppressant use, PML incidence is less than 1 in 1,000, the FDA said. PML incidence is estimated at 2 of every 1,000 anti–JCV positive patients with less than 2 years on natalizumab and with prior immunosuppressant use. For those with anti-JCV antibodies and more than 2 years treatment but no prior immunosuppressants, incidence is about 4 in 1,000, the FDA communication said. The FDA, which already had a black box warning on natalizumab (Tysabri, Biogen Idec, and Elan) describing increased PML risk, said Jan. 20 that it had changed the product labeling to reflect the newly stratified risk information, and also announced in a news release that it had approved a new test, called the Stratify JCV Antibody ELISA test (Focus Diagnostics), to detect anti-JCV antibodies in people deemed at risk of developing PML.

In most people, JCV is harmless; however, those on immunomodulatory agents like natalizumab are at risk of death or serious disability from PML caused by JCV exposure.

The agency stressed that patients on natalizumab may be at risk for developing PML even without a positive test for JCV antibodies, because the infection can occur at any time, or because false negative results can occur. Patients should be monitored carefully and natalizumab treatment should be stopped at the first sign of PML. While there is no treatment for PML, stopping treatment early may allow the immune system to recover and fight JCV infection.

Natalizumab, a monoclonal antibody administered by intravenous infusion, works by blocking a protein that is found on the surface of leukocytes, preventing their movement from the blood into the brain and reducing the inflammation and nerve damage caused by MS. In Crohn’s disease, it works by blocking adhesion and migration of leukocytes into the gut. For both indications it is administered by intravenous infusion of 300 mg every 4 weeks.

In 2004, the FDA approved natalizumab as a treatment for MS in patients who had failed other therapies; however, it was withdrawn the following year by its manufacturer due to safety concerns related to PML. In 2006, it was returned to market under a restricted prescribing program to treat relapsing forms of MS and was granted marketing authorization by the European Medicines Agency (EMA) to treat highly active relapsing MS. In 2008, it was approved in the United States for the treatment of Crohn’s disease, also under a restricted prescribing program, in patients failing other therapies.

The EMA in 2007 refused to grant marketing authorization to natalizumab for Crohn’s, citing an unfavorable risk-benefit profile. In 2010 the EMA concluded a review of the risks of natalizumab for relapsing MS following increasing reports of PML cases. The EMA retained natalizumab’s marketing authorization for relapsing MS but strengthened its warnings about PML risk.

To listen to a podcast concerning the natalizumab warning, click on the "Listen" button below. Podcast courstesy of the FDA.

The Food and Drug Administration has identified a new risk factor for progressive multifocal leukoencephalopathy, a life-threatening brain infection associated with the use of natalizumab, an immunomodulatory agent used to treat multiple sclerosis and Crohn’s disease.

Testing positive for anti–John Cunningham virus (JCV) antibodies raises the risk of developing progressive multifocal leukoencephalopathy (PML), particularly when patients have been on natalizumab treatment for more than 2 years and have previously taken immunosuppressant medicines such as mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil. When all three risk factors are present – 2 or more years of natalizumab therapy, anti-JCV, and prior immunosuppressant use – the incidence of PML is estimated to be 11 in 1,000 patients, FDA said in a drug safety communication Jan. 20.

When patients have anti-JCV antibodies but have been on natalizumab less than 2 years and have no prior immunosuppressant use, PML incidence is less than 1 in 1,000, the FDA said. PML incidence is estimated at 2 of every 1,000 anti–JCV positive patients with less than 2 years on natalizumab and with prior immunosuppressant use. For those with anti-JCV antibodies and more than 2 years treatment but no prior immunosuppressants, incidence is about 4 in 1,000, the FDA communication said. The FDA, which already had a black box warning on natalizumab (Tysabri, Biogen Idec, and Elan) describing increased PML risk, said Jan. 20 that it had changed the product labeling to reflect the newly stratified risk information, and also announced in a news release that it had approved a new test, called the Stratify JCV Antibody ELISA test (Focus Diagnostics), to detect anti-JCV antibodies in people deemed at risk of developing PML.

In most people, JCV is harmless; however, those on immunomodulatory agents like natalizumab are at risk of death or serious disability from PML caused by JCV exposure.

The agency stressed that patients on natalizumab may be at risk for developing PML even without a positive test for JCV antibodies, because the infection can occur at any time, or because false negative results can occur. Patients should be monitored carefully and natalizumab treatment should be stopped at the first sign of PML. While there is no treatment for PML, stopping treatment early may allow the immune system to recover and fight JCV infection.

Natalizumab, a monoclonal antibody administered by intravenous infusion, works by blocking a protein that is found on the surface of leukocytes, preventing their movement from the blood into the brain and reducing the inflammation and nerve damage caused by MS. In Crohn’s disease, it works by blocking adhesion and migration of leukocytes into the gut. For both indications it is administered by intravenous infusion of 300 mg every 4 weeks.

In 2004, the FDA approved natalizumab as a treatment for MS in patients who had failed other therapies; however, it was withdrawn the following year by its manufacturer due to safety concerns related to PML. In 2006, it was returned to market under a restricted prescribing program to treat relapsing forms of MS and was granted marketing authorization by the European Medicines Agency (EMA) to treat highly active relapsing MS. In 2008, it was approved in the United States for the treatment of Crohn’s disease, also under a restricted prescribing program, in patients failing other therapies.

The EMA in 2007 refused to grant marketing authorization to natalizumab for Crohn’s, citing an unfavorable risk-benefit profile. In 2010 the EMA concluded a review of the risks of natalizumab for relapsing MS following increasing reports of PML cases. The EMA retained natalizumab’s marketing authorization for relapsing MS but strengthened its warnings about PML risk.

To listen to a podcast concerning the natalizumab warning, click on the "Listen" button below. Podcast courstesy of the FDA.

Less than half of U.S. teenagers were vaccinated against hepatitis A in 2009 – a rate that may leave a large portion of young people susceptible to hepatitis A infection in adulthood, a study has shown.

Nationally, the vaccination rate in 2009 was only 42% among 13- to 17-year-olds nationwide, although 70% of vaccinated teens had received the second dose necessary for durable immunity against hepatitis A. Just over half of vaccinated teens had received the vaccine before age 10 years, and 48% had been vaccinated at age 11 years or older.

(c)Micah Young/iStock.com

In contrast, coverage rates in 2009 among teens for the tetanus toxoid–acellular pertussis vaccine and meningococcal conjugate vaccine were 55.6% and 53.6%, respectively.

The findings are from the first study to use provider-reported data to evaluate hepatitis A vaccination coverage.

Hepatitis A morbidity and mortality are more severe among adolescents and adults than children, noted Dr. Christina G. Dorell of the Centers for Disease Control and Prevention and her colleagues (Pediatrics 2012;129:213-21[doi: 10.1542/peds.2011-2197]).

Although hepatitis A infections are not common in the United States, 1,987 cases were reported nationally in 2009, with the highest rates of disease among young adults between 20 and 29 years of age. When unreported and asymptomatic cases are considered, the actual incidence of hepatitis A infections in 2009 was more than 10 times greater than the reported number, according to CDC estimates.

Dr. Dorell and her colleagues likened the potential threat of low hepatitis A coverage to that presented by measles outbreaks in undervaccinated population pockets.

To determine hepatitis A vaccination coverage rates, the researchers used data from the 2009 National Immunization Survey–Teen, a randomized telephone survey of parents that then sought additional data from vaccine providers identified by the parents. Nearly 35,000 parents completed telephone surveys, 20,066 of which could be matched with adequate provider information and entered into analysis.

Vaccine coverage varied widely depending on the adolescents’ state of residence. The 33 states (and the District of Columbia) that were the latest to adopt universal childhood hepatitis A vaccination recommendations (in 2006) saw the lowest rates of coverage as of 2009 – collectively, only 27.8%. However, those states also had the highest proportion of adolescents vaccinated at 11 years of age or older, likely because of recent adoption of the universal-vaccination recommendations.

In contrast, the 11 states that had adopted hepatitis requirements earlier (in 1999) saw nearly three-quarters (74.3%) of adolescents covered by one or more doses in 2009. The six states that in 1999 adopted a weaker recommendation to "consider" early childhood hepatitis A vaccination saw an overall vaccination rate of 54% in 2009.

Adjusted prevalence ratios of vaccination initiation were highest for states with a vaccination requirement and for adolescents whose providers recommended vaccination, the researchers found.

In some states, adolescents of American Indian, Hispanic, black, or Asian ethnicity were more likely to have hepatitis A coverage, possibly related to outreach in those groups. In other states, adolescents in rural areas were less likely to be vaccinated than those living in urban areas, where pediatrician-to-children ratios are higher. Poverty was not generally seen as bearing on vaccination rates, possibly because of a federal program providing free vaccines to lower-income families.

Study limitations included the fact that the parent telephone surveys were conducted exclusively on landlines, while a quarter of U.S. adolescents live in homes without landlines. Other limitations included potential recall bias in parent reports, as well as incomplete provider data or vaccination histories.

The study authors also noted that adolescents with inadequate provider data were excluded from the analysis – teens who may have had less access to primary health care and therefore were less likely to have received vaccine.

"Excluding this group may have resulted in elevated vaccination coverage estimates," the researchers cautioned. Thus, overall coverage in fact could be even less than the already low 42% reported.

Dr. Dorell and her colleagues said they had no relevant financial disclosures.

Less than half of U.S. teenagers were vaccinated against hepatitis A in 2009 – a rate that may leave a large portion of young people susceptible to hepatitis A infection in adulthood, a study has shown.

Nationally, the vaccination rate in 2009 was only 42% among 13- to 17-year-olds nationwide, although 70% of vaccinated teens had received the second dose necessary for durable immunity against hepatitis A. Just over half of vaccinated teens had received the vaccine before age 10 years, and 48% had been vaccinated at age 11 years or older.

(c)Micah Young/iStock.com

In contrast, coverage rates in 2009 among teens for the tetanus toxoid–acellular pertussis vaccine and meningococcal conjugate vaccine were 55.6% and 53.6%, respectively.

The findings are from the first study to use provider-reported data to evaluate hepatitis A vaccination coverage.

Hepatitis A morbidity and mortality are more severe among adolescents and adults than children, noted Dr. Christina G. Dorell of the Centers for Disease Control and Prevention and her colleagues (Pediatrics 2012;129:213-21[doi: 10.1542/peds.2011-2197]).

Although hepatitis A infections are not common in the United States, 1,987 cases were reported nationally in 2009, with the highest rates of disease among young adults between 20 and 29 years of age. When unreported and asymptomatic cases are considered, the actual incidence of hepatitis A infections in 2009 was more than 10 times greater than the reported number, according to CDC estimates.

Dr. Dorell and her colleagues likened the potential threat of low hepatitis A coverage to that presented by measles outbreaks in undervaccinated population pockets.

To determine hepatitis A vaccination coverage rates, the researchers used data from the 2009 National Immunization Survey–Teen, a randomized telephone survey of parents that then sought additional data from vaccine providers identified by the parents. Nearly 35,000 parents completed telephone surveys, 20,066 of which could be matched with adequate provider information and entered into analysis.

Vaccine coverage varied widely depending on the adolescents’ state of residence. The 33 states (and the District of Columbia) that were the latest to adopt universal childhood hepatitis A vaccination recommendations (in 2006) saw the lowest rates of coverage as of 2009 – collectively, only 27.8%. However, those states also had the highest proportion of adolescents vaccinated at 11 years of age or older, likely because of recent adoption of the universal-vaccination recommendations.

In contrast, the 11 states that had adopted hepatitis requirements earlier (in 1999) saw nearly three-quarters (74.3%) of adolescents covered by one or more doses in 2009. The six states that in 1999 adopted a weaker recommendation to "consider" early childhood hepatitis A vaccination saw an overall vaccination rate of 54% in 2009.

Adjusted prevalence ratios of vaccination initiation were highest for states with a vaccination requirement and for adolescents whose providers recommended vaccination, the researchers found.

In some states, adolescents of American Indian, Hispanic, black, or Asian ethnicity were more likely to have hepatitis A coverage, possibly related to outreach in those groups. In other states, adolescents in rural areas were less likely to be vaccinated than those living in urban areas, where pediatrician-to-children ratios are higher. Poverty was not generally seen as bearing on vaccination rates, possibly because of a federal program providing free vaccines to lower-income families.

Study limitations included the fact that the parent telephone surveys were conducted exclusively on landlines, while a quarter of U.S. adolescents live in homes without landlines. Other limitations included potential recall bias in parent reports, as well as incomplete provider data or vaccination histories.

The study authors also noted that adolescents with inadequate provider data were excluded from the analysis – teens who may have had less access to primary health care and therefore were less likely to have received vaccine.

"Excluding this group may have resulted in elevated vaccination coverage estimates," the researchers cautioned. Thus, overall coverage in fact could be even less than the already low 42% reported.

Dr. Dorell and her colleagues said they had no relevant financial disclosures.

Less than half of U.S. teenagers were vaccinated against hepatitis A in 2009 – a rate that may leave a large portion of young people susceptible to hepatitis A infection in adulthood, a study has shown.

Nationally, the vaccination rate in 2009 was only 42% among 13- to 17-year-olds nationwide, although 70% of vaccinated teens had received the second dose necessary for durable immunity against hepatitis A. Just over half of vaccinated teens had received the vaccine before age 10 years, and 48% had been vaccinated at age 11 years or older.

(c)Micah Young/iStock.com

In contrast, coverage rates in 2009 among teens for the tetanus toxoid–acellular pertussis vaccine and meningococcal conjugate vaccine were 55.6% and 53.6%, respectively.

The findings are from the first study to use provider-reported data to evaluate hepatitis A vaccination coverage.

Hepatitis A morbidity and mortality are more severe among adolescents and adults than children, noted Dr. Christina G. Dorell of the Centers for Disease Control and Prevention and her colleagues (Pediatrics 2012;129:213-21[doi: 10.1542/peds.2011-2197]).

Although hepatitis A infections are not common in the United States, 1,987 cases were reported nationally in 2009, with the highest rates of disease among young adults between 20 and 29 years of age. When unreported and asymptomatic cases are considered, the actual incidence of hepatitis A infections in 2009 was more than 10 times greater than the reported number, according to CDC estimates.

Dr. Dorell and her colleagues likened the potential threat of low hepatitis A coverage to that presented by measles outbreaks in undervaccinated population pockets.

To determine hepatitis A vaccination coverage rates, the researchers used data from the 2009 National Immunization Survey–Teen, a randomized telephone survey of parents that then sought additional data from vaccine providers identified by the parents. Nearly 35,000 parents completed telephone surveys, 20,066 of which could be matched with adequate provider information and entered into analysis.

Vaccine coverage varied widely depending on the adolescents’ state of residence. The 33 states (and the District of Columbia) that were the latest to adopt universal childhood hepatitis A vaccination recommendations (in 2006) saw the lowest rates of coverage as of 2009 – collectively, only 27.8%. However, those states also had the highest proportion of adolescents vaccinated at 11 years of age or older, likely because of recent adoption of the universal-vaccination recommendations.

In contrast, the 11 states that had adopted hepatitis requirements earlier (in 1999) saw nearly three-quarters (74.3%) of adolescents covered by one or more doses in 2009. The six states that in 1999 adopted a weaker recommendation to "consider" early childhood hepatitis A vaccination saw an overall vaccination rate of 54% in 2009.

Adjusted prevalence ratios of vaccination initiation were highest for states with a vaccination requirement and for adolescents whose providers recommended vaccination, the researchers found.

In some states, adolescents of American Indian, Hispanic, black, or Asian ethnicity were more likely to have hepatitis A coverage, possibly related to outreach in those groups. In other states, adolescents in rural areas were less likely to be vaccinated than those living in urban areas, where pediatrician-to-children ratios are higher. Poverty was not generally seen as bearing on vaccination rates, possibly because of a federal program providing free vaccines to lower-income families.

Study limitations included the fact that the parent telephone surveys were conducted exclusively on landlines, while a quarter of U.S. adolescents live in homes without landlines. Other limitations included potential recall bias in parent reports, as well as incomplete provider data or vaccination histories.

The study authors also noted that adolescents with inadequate provider data were excluded from the analysis – teens who may have had less access to primary health care and therefore were less likely to have received vaccine.

"Excluding this group may have resulted in elevated vaccination coverage estimates," the researchers cautioned. Thus, overall coverage in fact could be even less than the already low 42% reported.

Dr. Dorell and her colleagues said they had no relevant financial disclosures.

Attitudes toward sun exposure – and behaviors – change between childhood and adolescence, researchers have found, suggesting that children in this age bracket may be critical targets for physicians to advise.

Among children who were interviewed at age 10 years and again at 13, those in the elder group were only half as consistent in their sunscreen use as they had previously been, and were significantly more likely to report liking the appearance of a tan or seeking to become tan. Actual incidence of sunburn and tanning, meanwhile, remained high and largely unchanged between ages 10 and 13 years, with recent sunburns reported by more than half of children at both ages.

© Vesna Andjic/iStockphoto.com

The findings, published online Jan. 23 in Pediatrics, were the first to examine sunburn and sun behaviors prospectively in this age group.

Stephen W. Dusza, Dr.P.H., of Memorial Sloan-Kettering Cancer Center in New York, led SONIC (Study of Nevi in Children), which used self-reported data from 360 students who were enrolled as fifth graders in Framingham, Mass., schools in 2004 and had complete data upon follow-up in 2007. High-resolution photography of the back was conducted for all subjects at both points. Almost three-fourths (74%) of the subjects analyzed were white, and males accounted for more than half the sample (62%).

At baseline in 2004, 53% of subjects reported having had a sunburn (defined as "pink or red skin") at least once the previous summer, and this proportion remained similar (55%) at follow-up, a nonsignificant difference. Actual incidence of tanning also changed little. At both baseline and follow-up, about 85% of students reported having gotten a tan the previous summer (Pediatrics 2012;129:309-17).

Sunscreen use, meanwhile, dropped sharply. In 2004, 50% of students reported that they used sunscreen "often or always" when outside for 6 or more hours in the summer. By 2007, only 25% reported the same, a significant difference.

The children in the study with the highest risk of developing skin cancer – those with pale skin – experienced the sharpest increase in reported sunburns, Dr. Dusza and his colleagues found. In 2007, fair-skinned children were 40% more likely to report two or more recent sunburns than in 2004. By contrast, children with light olive to black skin were 70% less likely to report two or more recent burns at follow-up, compared with baseline.

Some 53% of students reported "liking a tan" at age 10, but 66% did by age 13, a significant difference. And although 22% of 10-year-olds reported deliberately spending time in the sun to get a tan, a full 40% did so at follow up, also a significant difference. Girls were twice as likely to report liking a tan in 2007, compared with 2004 (odds ratio, 2.4). Boys also were more likely to report liking a tan when they reached age 13 (OR, 1.5).

The researchers acknowledged as weaknesses their study’s reliance on self-reported sun behaviors by children, noting that these reports have been shown to have "fair to moderate agreement" with direct observation.

Moreover, they said, nearly one-fourth of the children recruited in 2004 dropped out of the study because of relocation, and could not be included in the analysis. Among these were a disproportionate number of children with darker skins, an understudied group as far as sun behaviors are concerned. And finally, because the study did not seek reasons for sunscreen use or nonuse, "it was beyond the scope of this study to ascribe reasons for the drop in sunscreen use during these 3 years."

Despite these limitations, the findings strongly underscore the necessity of "new and creative messages" in both schools and physicians’ offices, with an aim to promote consistent sunscreen use and to deter tanning in this important age bracket, Dr. Dusza and his colleagues wrote in their analysis. In the United States, melanoma is reported to be one of the two most common cancers of young people, so it is important to encourage strong sun protection practices at young ages, the researchers noted.

In addition, "further studies are required to learn how to interweave enhanced sun-protection policies in settings such as beaches, after-school sites, and sporting events frequented by preadolescents and adolescents," the researchers wrote. Particular effort is needed to reach this group, they added, because adolescence "is a period of flexing independence, coupled with feelings of invincibility."

It also is important because the use of tanning beds, particularly for girls, is reported to begin at age 14, Dr. Dusza and his colleagues said.

Dr. Dusza and colleagues’ study was funded by the National Institutes of Health, as part of an ongoing study of nevi in children. Dr. Dusza and colleagues reported that they had no relevant financial disclosures.

Attitudes toward sun exposure – and behaviors – change between childhood and adolescence, researchers have found, suggesting that children in this age bracket may be critical targets for physicians to advise.

Among children who were interviewed at age 10 years and again at 13, those in the elder group were only half as consistent in their sunscreen use as they had previously been, and were significantly more likely to report liking the appearance of a tan or seeking to become tan. Actual incidence of sunburn and tanning, meanwhile, remained high and largely unchanged between ages 10 and 13 years, with recent sunburns reported by more than half of children at both ages.

© Vesna Andjic/iStockphoto.com

The findings, published online Jan. 23 in Pediatrics, were the first to examine sunburn and sun behaviors prospectively in this age group.

Stephen W. Dusza, Dr.P.H., of Memorial Sloan-Kettering Cancer Center in New York, led SONIC (Study of Nevi in Children), which used self-reported data from 360 students who were enrolled as fifth graders in Framingham, Mass., schools in 2004 and had complete data upon follow-up in 2007. High-resolution photography of the back was conducted for all subjects at both points. Almost three-fourths (74%) of the subjects analyzed were white, and males accounted for more than half the sample (62%).

At baseline in 2004, 53% of subjects reported having had a sunburn (defined as "pink or red skin") at least once the previous summer, and this proportion remained similar (55%) at follow-up, a nonsignificant difference. Actual incidence of tanning also changed little. At both baseline and follow-up, about 85% of students reported having gotten a tan the previous summer (Pediatrics 2012;129:309-17).

Sunscreen use, meanwhile, dropped sharply. In 2004, 50% of students reported that they used sunscreen "often or always" when outside for 6 or more hours in the summer. By 2007, only 25% reported the same, a significant difference.

The children in the study with the highest risk of developing skin cancer – those with pale skin – experienced the sharpest increase in reported sunburns, Dr. Dusza and his colleagues found. In 2007, fair-skinned children were 40% more likely to report two or more recent sunburns than in 2004. By contrast, children with light olive to black skin were 70% less likely to report two or more recent burns at follow-up, compared with baseline.

Some 53% of students reported "liking a tan" at age 10, but 66% did by age 13, a significant difference. And although 22% of 10-year-olds reported deliberately spending time in the sun to get a tan, a full 40% did so at follow up, also a significant difference. Girls were twice as likely to report liking a tan in 2007, compared with 2004 (odds ratio, 2.4). Boys also were more likely to report liking a tan when they reached age 13 (OR, 1.5).

The researchers acknowledged as weaknesses their study’s reliance on self-reported sun behaviors by children, noting that these reports have been shown to have "fair to moderate agreement" with direct observation.

Moreover, they said, nearly one-fourth of the children recruited in 2004 dropped out of the study because of relocation, and could not be included in the analysis. Among these were a disproportionate number of children with darker skins, an understudied group as far as sun behaviors are concerned. And finally, because the study did not seek reasons for sunscreen use or nonuse, "it was beyond the scope of this study to ascribe reasons for the drop in sunscreen use during these 3 years."

Despite these limitations, the findings strongly underscore the necessity of "new and creative messages" in both schools and physicians’ offices, with an aim to promote consistent sunscreen use and to deter tanning in this important age bracket, Dr. Dusza and his colleagues wrote in their analysis. In the United States, melanoma is reported to be one of the two most common cancers of young people, so it is important to encourage strong sun protection practices at young ages, the researchers noted.

In addition, "further studies are required to learn how to interweave enhanced sun-protection policies in settings such as beaches, after-school sites, and sporting events frequented by preadolescents and adolescents," the researchers wrote. Particular effort is needed to reach this group, they added, because adolescence "is a period of flexing independence, coupled with feelings of invincibility."

It also is important because the use of tanning beds, particularly for girls, is reported to begin at age 14, Dr. Dusza and his colleagues said.

Dr. Dusza and colleagues’ study was funded by the National Institutes of Health, as part of an ongoing study of nevi in children. Dr. Dusza and colleagues reported that they had no relevant financial disclosures.

Attitudes toward sun exposure – and behaviors – change between childhood and adolescence, researchers have found, suggesting that children in this age bracket may be critical targets for physicians to advise.

Among children who were interviewed at age 10 years and again at 13, those in the elder group were only half as consistent in their sunscreen use as they had previously been, and were significantly more likely to report liking the appearance of a tan or seeking to become tan. Actual incidence of sunburn and tanning, meanwhile, remained high and largely unchanged between ages 10 and 13 years, with recent sunburns reported by more than half of children at both ages.

© Vesna Andjic/iStockphoto.com

The findings, published online Jan. 23 in Pediatrics, were the first to examine sunburn and sun behaviors prospectively in this age group.

Stephen W. Dusza, Dr.P.H., of Memorial Sloan-Kettering Cancer Center in New York, led SONIC (Study of Nevi in Children), which used self-reported data from 360 students who were enrolled as fifth graders in Framingham, Mass., schools in 2004 and had complete data upon follow-up in 2007. High-resolution photography of the back was conducted for all subjects at both points. Almost three-fourths (74%) of the subjects analyzed were white, and males accounted for more than half the sample (62%).

At baseline in 2004, 53% of subjects reported having had a sunburn (defined as "pink or red skin") at least once the previous summer, and this proportion remained similar (55%) at follow-up, a nonsignificant difference. Actual incidence of tanning also changed little. At both baseline and follow-up, about 85% of students reported having gotten a tan the previous summer (Pediatrics 2012;129:309-17).

Sunscreen use, meanwhile, dropped sharply. In 2004, 50% of students reported that they used sunscreen "often or always" when outside for 6 or more hours in the summer. By 2007, only 25% reported the same, a significant difference.

The children in the study with the highest risk of developing skin cancer – those with pale skin – experienced the sharpest increase in reported sunburns, Dr. Dusza and his colleagues found. In 2007, fair-skinned children were 40% more likely to report two or more recent sunburns than in 2004. By contrast, children with light olive to black skin were 70% less likely to report two or more recent burns at follow-up, compared with baseline.

Some 53% of students reported "liking a tan" at age 10, but 66% did by age 13, a significant difference. And although 22% of 10-year-olds reported deliberately spending time in the sun to get a tan, a full 40% did so at follow up, also a significant difference. Girls were twice as likely to report liking a tan in 2007, compared with 2004 (odds ratio, 2.4). Boys also were more likely to report liking a tan when they reached age 13 (OR, 1.5).

The researchers acknowledged as weaknesses their study’s reliance on self-reported sun behaviors by children, noting that these reports have been shown to have "fair to moderate agreement" with direct observation.

Moreover, they said, nearly one-fourth of the children recruited in 2004 dropped out of the study because of relocation, and could not be included in the analysis. Among these were a disproportionate number of children with darker skins, an understudied group as far as sun behaviors are concerned. And finally, because the study did not seek reasons for sunscreen use or nonuse, "it was beyond the scope of this study to ascribe reasons for the drop in sunscreen use during these 3 years."

Despite these limitations, the findings strongly underscore the necessity of "new and creative messages" in both schools and physicians’ offices, with an aim to promote consistent sunscreen use and to deter tanning in this important age bracket, Dr. Dusza and his colleagues wrote in their analysis. In the United States, melanoma is reported to be one of the two most common cancers of young people, so it is important to encourage strong sun protection practices at young ages, the researchers noted.

In addition, "further studies are required to learn how to interweave enhanced sun-protection policies in settings such as beaches, after-school sites, and sporting events frequented by preadolescents and adolescents," the researchers wrote. Particular effort is needed to reach this group, they added, because adolescence "is a period of flexing independence, coupled with feelings of invincibility."

It also is important because the use of tanning beds, particularly for girls, is reported to begin at age 14, Dr. Dusza and his colleagues said.

Dr. Dusza and colleagues’ study was funded by the National Institutes of Health, as part of an ongoing study of nevi in children. Dr. Dusza and colleagues reported that they had no relevant financial disclosures.

Women with raised but falling human chorionic gonadotropin concentrations 6 months after a molar pregnancy do not need chemotherapy, as almost all of them will spontaneously remit, the results of a large retrospective cohort study have shown.

The findings, published online in the Lancet (Lancet 2011 [doi:10.1016/S0140-6736(11)61265-8]), challenge current international clinical guidelines (Int. J. Gynecol. Obstet. 2002;77:285-7) that consider chemotherapy to be indicated when hCG concentrations are high for 6 months or more following evacuation of a hydatidiform mole.

The new findings argue that an elevated hCG level at 6 months is not an indicator of malignancy when values are falling, and that instead of initiating chemotherapy, women with raised but falling hCG can undergo surveillance of their hCG levels, with testing until they return to normal.

Chemotherapy is needed only if hCG levels are still rising at 6 months, have plateaued, or are greater than 345 IU/L, or if there is radiologic evidence of neoplasia.

If the surveillance approach were to become standard, more women could avoid exposure to toxic chemotherapy drugs and could safely conceive sooner after evacuation of a molar pregnancy, said the authors of the study led by Dr. Roshan Agarwal of Imperial College London.

Current U.K. guidelines advise women not to become pregnant until 12 months following chemotherapy, whereas they would have to wait only 6 months after a spontaneous return to normal hCG.

For their research, Dr. Agarwal and colleagues retrospectively identified 13,960 women registered at London's Charing Cross Hospital between January 1993 and May 2008 who had undergone evacuation of a complete or partial hydatidiform mole. Of these, 974 (7%) required chemotherapy within 6 months, and hCG normalized spontaneously in 12,910 (92%) within 6 months.

The remaining 76 women still had high hCG concentrations (more than 5 IU/L) 6 months after evacuation of the molar pregnancy. Sixty-six patients underwent surveillance, in which blood and urine samples were collected and evaluated every 2 weeks until normal hCG was achieved, followed by monthly urine samples for 6 months. Ten patients underwent chemotherapy.

In the surveillance group, 98% of patients (n = 65) saw hCG values return to normal without chemotherapy (in all but 6 of them within a year), and the remaining patient, who had chronic renal failure, remained healthy despite having elevated hCG, Dr. Agarwal and colleagues reported.

Among the 10 patients who received chemotherapy, 6 had complete responses, and 4 had partial or no responses but remained well, even though hCG concentrations in 2 patients continued to be elevated. There was no significant difference in time to normalization between the groups and no deaths had occurred in either group after a median 2 years' follow-up.

The investigators acknowledged that a weakness of their study is retrospective design, the use of a single study site, and the small number of patients with raised hCG at 6 months.

However, they said, the findings “directly challenge the present clinical dogma” to show that the surveillance model is clinically acceptable. The results “will change international practice and spare women unnecessary exposure to chemotherapy,” they wrote in their analysis.

In a case study linked to Dr. Agarwal and colleagues' article, Rosemary A. Fisher, also of Imperial College London, described a woman who had a miscarriage and three consecutive molar pregnancies, yet was able to achieve a normal pregnancy with use of a donor egg.

“To the best of our knowledge, this report establishes for the first time that oocyte donation can enable women with familial recurrent hydatidiform moles due to NLRP7 mutations to achieve a normal pregnancy,” Ms. Fisher and colleagues wrote, adding that this finding offered “hope to other women with this condition.”

The study also shows “that the major role of NLRP7 in pregnancy is in the developing oocyte,” they said.

Women with raised but falling human chorionic gonadotropin concentrations 6 months after a molar pregnancy do not need chemotherapy, as almost all of them will spontaneously remit, the results of a large retrospective cohort study have shown.

The findings, published online in the Lancet (Lancet 2011 [doi:10.1016/S0140-6736(11)61265-8]), challenge current international clinical guidelines (Int. J. Gynecol. Obstet. 2002;77:285-7) that consider chemotherapy to be indicated when hCG concentrations are high for 6 months or more following evacuation of a hydatidiform mole.

The new findings argue that an elevated hCG level at 6 months is not an indicator of malignancy when values are falling, and that instead of initiating chemotherapy, women with raised but falling hCG can undergo surveillance of their hCG levels, with testing until they return to normal.

Chemotherapy is needed only if hCG levels are still rising at 6 months, have plateaued, or are greater than 345 IU/L, or if there is radiologic evidence of neoplasia.

If the surveillance approach were to become standard, more women could avoid exposure to toxic chemotherapy drugs and could safely conceive sooner after evacuation of a molar pregnancy, said the authors of the study led by Dr. Roshan Agarwal of Imperial College London.

Current U.K. guidelines advise women not to become pregnant until 12 months following chemotherapy, whereas they would have to wait only 6 months after a spontaneous return to normal hCG.

For their research, Dr. Agarwal and colleagues retrospectively identified 13,960 women registered at London's Charing Cross Hospital between January 1993 and May 2008 who had undergone evacuation of a complete or partial hydatidiform mole. Of these, 974 (7%) required chemotherapy within 6 months, and hCG normalized spontaneously in 12,910 (92%) within 6 months.

The remaining 76 women still had high hCG concentrations (more than 5 IU/L) 6 months after evacuation of the molar pregnancy. Sixty-six patients underwent surveillance, in which blood and urine samples were collected and evaluated every 2 weeks until normal hCG was achieved, followed by monthly urine samples for 6 months. Ten patients underwent chemotherapy.

In the surveillance group, 98% of patients (n = 65) saw hCG values return to normal without chemotherapy (in all but 6 of them within a year), and the remaining patient, who had chronic renal failure, remained healthy despite having elevated hCG, Dr. Agarwal and colleagues reported.

Among the 10 patients who received chemotherapy, 6 had complete responses, and 4 had partial or no responses but remained well, even though hCG concentrations in 2 patients continued to be elevated. There was no significant difference in time to normalization between the groups and no deaths had occurred in either group after a median 2 years' follow-up.

The investigators acknowledged that a weakness of their study is retrospective design, the use of a single study site, and the small number of patients with raised hCG at 6 months.

However, they said, the findings “directly challenge the present clinical dogma” to show that the surveillance model is clinically acceptable. The results “will change international practice and spare women unnecessary exposure to chemotherapy,” they wrote in their analysis.

In a case study linked to Dr. Agarwal and colleagues' article, Rosemary A. Fisher, also of Imperial College London, described a woman who had a miscarriage and three consecutive molar pregnancies, yet was able to achieve a normal pregnancy with use of a donor egg.

“To the best of our knowledge, this report establishes for the first time that oocyte donation can enable women with familial recurrent hydatidiform moles due to NLRP7 mutations to achieve a normal pregnancy,” Ms. Fisher and colleagues wrote, adding that this finding offered “hope to other women with this condition.”

The study also shows “that the major role of NLRP7 in pregnancy is in the developing oocyte,” they said.

Women with raised but falling human chorionic gonadotropin concentrations 6 months after a molar pregnancy do not need chemotherapy, as almost all of them will spontaneously remit, the results of a large retrospective cohort study have shown.

The findings, published online in the Lancet (Lancet 2011 [doi:10.1016/S0140-6736(11)61265-8]), challenge current international clinical guidelines (Int. J. Gynecol. Obstet. 2002;77:285-7) that consider chemotherapy to be indicated when hCG concentrations are high for 6 months or more following evacuation of a hydatidiform mole.

The new findings argue that an elevated hCG level at 6 months is not an indicator of malignancy when values are falling, and that instead of initiating chemotherapy, women with raised but falling hCG can undergo surveillance of their hCG levels, with testing until they return to normal.

Chemotherapy is needed only if hCG levels are still rising at 6 months, have plateaued, or are greater than 345 IU/L, or if there is radiologic evidence of neoplasia.

If the surveillance approach were to become standard, more women could avoid exposure to toxic chemotherapy drugs and could safely conceive sooner after evacuation of a molar pregnancy, said the authors of the study led by Dr. Roshan Agarwal of Imperial College London.

Current U.K. guidelines advise women not to become pregnant until 12 months following chemotherapy, whereas they would have to wait only 6 months after a spontaneous return to normal hCG.

For their research, Dr. Agarwal and colleagues retrospectively identified 13,960 women registered at London's Charing Cross Hospital between January 1993 and May 2008 who had undergone evacuation of a complete or partial hydatidiform mole. Of these, 974 (7%) required chemotherapy within 6 months, and hCG normalized spontaneously in 12,910 (92%) within 6 months.

The remaining 76 women still had high hCG concentrations (more than 5 IU/L) 6 months after evacuation of the molar pregnancy. Sixty-six patients underwent surveillance, in which blood and urine samples were collected and evaluated every 2 weeks until normal hCG was achieved, followed by monthly urine samples for 6 months. Ten patients underwent chemotherapy.

In the surveillance group, 98% of patients (n = 65) saw hCG values return to normal without chemotherapy (in all but 6 of them within a year), and the remaining patient, who had chronic renal failure, remained healthy despite having elevated hCG, Dr. Agarwal and colleagues reported.

Among the 10 patients who received chemotherapy, 6 had complete responses, and 4 had partial or no responses but remained well, even though hCG concentrations in 2 patients continued to be elevated. There was no significant difference in time to normalization between the groups and no deaths had occurred in either group after a median 2 years' follow-up.

The investigators acknowledged that a weakness of their study is retrospective design, the use of a single study site, and the small number of patients with raised hCG at 6 months.

However, they said, the findings “directly challenge the present clinical dogma” to show that the surveillance model is clinically acceptable. The results “will change international practice and spare women unnecessary exposure to chemotherapy,” they wrote in their analysis.

In a case study linked to Dr. Agarwal and colleagues' article, Rosemary A. Fisher, also of Imperial College London, described a woman who had a miscarriage and three consecutive molar pregnancies, yet was able to achieve a normal pregnancy with use of a donor egg.

“To the best of our knowledge, this report establishes for the first time that oocyte donation can enable women with familial recurrent hydatidiform moles due to NLRP7 mutations to achieve a normal pregnancy,” Ms. Fisher and colleagues wrote, adding that this finding offered “hope to other women with this condition.”

The study also shows “that the major role of NLRP7 in pregnancy is in the developing oocyte,” they said.

Oral contraceptives containing the newer progestogen types desogestrel, drospirenone, and gestodene have been associated with twice the risk of venous thromboembolism as those containing levonorgestrel, an older agent.

Women taking combination oral contraceptives (OCs) with levonorgestrel were at a threefold increased risk for confirmed venous thromboembolism (VTE), compared with women not taking any contraceptive pills, while users of OCs containing desogestrel, drospirenone, and gestodene saw a sixfold increased risk. The risk for drospirenone was seen as comparable to that of desogestrel and gestodene.

However, a lower dose of estrogen (20 mcg instead of 30 mcg) was not seen to lessen the risk associated with drospirenone-containing pills, the investigators found, while with desogestrel and gestodene, lower-estrogen preparations were associated with lower risk. (The OCs with desogestrel or gestodene and 20 mcg of ethinyl estradiol implied relative risks of VTE that were 23% and 17% lower, respectively, than the risks for the same progestogens with 30 mcg of ethinyl estradiol.)

The results, published in BMJ (2001 [doi: 10.1136/bmj.d6423]), confirm those of a previous study by the same Denmark-based team of investigators, who in 2009 reported a significantly higher risk of VTE for OCs containing these three progestogens than for OCs with levonorgestrel (BMJ 2009;339:b2890 [doi: 10.1136/bmj.b2890]).

Both studies were led by Dr. Øjvind Lidegaard, professor of obstetrics and gynecology at the University of Copenhagen, and his colleagues, who used the same registry-based cohort of all Danish women aged 15-49 years with no history of VTE and who were not pregnant. The new study followed the women from 2001 to 2009, 4 years longer than the previous study (though their prescription information was collected from 1995), and the study collected more detailed information on OC use and VTE events.

During the study period, which comprised more than 8 million woman-years of observation, 4,246 first episodes of VTE occurred. After adjustment for age, calendar year, education, and length of OC use, the relative risk of VTE in women who used pills with desogestrel, drospirenone, or gestodene was found to be twice that of women on levonorgestrel-containing pills.

Dr. Lidegaard and his colleagues found that, compared with women not using hormonal contraception, the relative risk of confirmed VTE in users of OCs containing 30-40 mcg of ethinyl estradiol with levonorgestrel was 2.9 (95% confidence interval, 2.2-3.8), compared with 6.6 in women using OCs containing desogestrel (95% CI, 5.6-7.8), 6.2 in users of gestodene (5.6-7.0), and 6.4 in women taking drospirenone (5.4-7.5).

With users of OCs containing levonorgestrel as a reference, and after adjustment for length of use, the rate ratio of confirmed VTE for users of OCs with desogestrel was 2.2 (95% CI, 1.7-3.0), with gestodene it was 2.1 (95% CI, 1.6-2.8), and with drospirenone it was 2.1 (1.6-2.8).

To prevent one VTE per year, approximately 2,000 women would need to switch from a pill containing desogestrel, gestodene, or drospirenone to one with levonorgestrel, the researchers concluded.

Critics of Dr. Lidegaard and colleagues' previous study, which revealed similar differences in risk between levonorgestrel and the newer progestogens, argued that because no declining risk was seen after the first few months of use for women using levonorgestrel-containing pills, as would be expected, left-censoring bias might have occurred, making the risk of VTE associated with levonorgestrel seem artificially low compared with that seen with drospirenone, which was introduced in 2001.

Dr. Lidegaard and his colleagues described several changes in their new study's design to strengthen it, noting that they had eliminated left-censoring bias by letting the new study period begin in 2001, which marked the introduction of drospirenone-containing OCs in Denmark, but still collected the women's full OC exposure history for the previous 6 years.

In addition, they defined length of OC use more precisely than in the previous study, stratified analyses into confirmed and unconfirmed VTE events, and better excluded women predisposed to VTE, they said.

The investigators acknowledged as a weakness of the study that they could not control for family disposition and body mass index. However, they noted, other studies had not shown a strong confounding effect for those factors even when data were available.

Oral contraceptives containing the newer progestogen types desogestrel, drospirenone, and gestodene have been associated with twice the risk of venous thromboembolism as those containing levonorgestrel, an older agent.

Women taking combination oral contraceptives (OCs) with levonorgestrel were at a threefold increased risk for confirmed venous thromboembolism (VTE), compared with women not taking any contraceptive pills, while users of OCs containing desogestrel, drospirenone, and gestodene saw a sixfold increased risk. The risk for drospirenone was seen as comparable to that of desogestrel and gestodene.

However, a lower dose of estrogen (20 mcg instead of 30 mcg) was not seen to lessen the risk associated with drospirenone-containing pills, the investigators found, while with desogestrel and gestodene, lower-estrogen preparations were associated with lower risk. (The OCs with desogestrel or gestodene and 20 mcg of ethinyl estradiol implied relative risks of VTE that were 23% and 17% lower, respectively, than the risks for the same progestogens with 30 mcg of ethinyl estradiol.)

The results, published in BMJ (2001 [doi: 10.1136/bmj.d6423]), confirm those of a previous study by the same Denmark-based team of investigators, who in 2009 reported a significantly higher risk of VTE for OCs containing these three progestogens than for OCs with levonorgestrel (BMJ 2009;339:b2890 [doi: 10.1136/bmj.b2890]).

Both studies were led by Dr. Øjvind Lidegaard, professor of obstetrics and gynecology at the University of Copenhagen, and his colleagues, who used the same registry-based cohort of all Danish women aged 15-49 years with no history of VTE and who were not pregnant. The new study followed the women from 2001 to 2009, 4 years longer than the previous study (though their prescription information was collected from 1995), and the study collected more detailed information on OC use and VTE events.

During the study period, which comprised more than 8 million woman-years of observation, 4,246 first episodes of VTE occurred. After adjustment for age, calendar year, education, and length of OC use, the relative risk of VTE in women who used pills with desogestrel, drospirenone, or gestodene was found to be twice that of women on levonorgestrel-containing pills.

Dr. Lidegaard and his colleagues found that, compared with women not using hormonal contraception, the relative risk of confirmed VTE in users of OCs containing 30-40 mcg of ethinyl estradiol with levonorgestrel was 2.9 (95% confidence interval, 2.2-3.8), compared with 6.6 in women using OCs containing desogestrel (95% CI, 5.6-7.8), 6.2 in users of gestodene (5.6-7.0), and 6.4 in women taking drospirenone (5.4-7.5).

With users of OCs containing levonorgestrel as a reference, and after adjustment for length of use, the rate ratio of confirmed VTE for users of OCs with desogestrel was 2.2 (95% CI, 1.7-3.0), with gestodene it was 2.1 (95% CI, 1.6-2.8), and with drospirenone it was 2.1 (1.6-2.8).

To prevent one VTE per year, approximately 2,000 women would need to switch from a pill containing desogestrel, gestodene, or drospirenone to one with levonorgestrel, the researchers concluded.

Critics of Dr. Lidegaard and colleagues' previous study, which revealed similar differences in risk between levonorgestrel and the newer progestogens, argued that because no declining risk was seen after the first few months of use for women using levonorgestrel-containing pills, as would be expected, left-censoring bias might have occurred, making the risk of VTE associated with levonorgestrel seem artificially low compared with that seen with drospirenone, which was introduced in 2001.

Dr. Lidegaard and his colleagues described several changes in their new study's design to strengthen it, noting that they had eliminated left-censoring bias by letting the new study period begin in 2001, which marked the introduction of drospirenone-containing OCs in Denmark, but still collected the women's full OC exposure history for the previous 6 years.

In addition, they defined length of OC use more precisely than in the previous study, stratified analyses into confirmed and unconfirmed VTE events, and better excluded women predisposed to VTE, they said.

The investigators acknowledged as a weakness of the study that they could not control for family disposition and body mass index. However, they noted, other studies had not shown a strong confounding effect for those factors even when data were available.

Oral contraceptives containing the newer progestogen types desogestrel, drospirenone, and gestodene have been associated with twice the risk of venous thromboembolism as those containing levonorgestrel, an older agent.

Women taking combination oral contraceptives (OCs) with levonorgestrel were at a threefold increased risk for confirmed venous thromboembolism (VTE), compared with women not taking any contraceptive pills, while users of OCs containing desogestrel, drospirenone, and gestodene saw a sixfold increased risk. The risk for drospirenone was seen as comparable to that of desogestrel and gestodene.

However, a lower dose of estrogen (20 mcg instead of 30 mcg) was not seen to lessen the risk associated with drospirenone-containing pills, the investigators found, while with desogestrel and gestodene, lower-estrogen preparations were associated with lower risk. (The OCs with desogestrel or gestodene and 20 mcg of ethinyl estradiol implied relative risks of VTE that were 23% and 17% lower, respectively, than the risks for the same progestogens with 30 mcg of ethinyl estradiol.)

The results, published in BMJ (2001 [doi: 10.1136/bmj.d6423]), confirm those of a previous study by the same Denmark-based team of investigators, who in 2009 reported a significantly higher risk of VTE for OCs containing these three progestogens than for OCs with levonorgestrel (BMJ 2009;339:b2890 [doi: 10.1136/bmj.b2890]).

Both studies were led by Dr. Øjvind Lidegaard, professor of obstetrics and gynecology at the University of Copenhagen, and his colleagues, who used the same registry-based cohort of all Danish women aged 15-49 years with no history of VTE and who were not pregnant. The new study followed the women from 2001 to 2009, 4 years longer than the previous study (though their prescription information was collected from 1995), and the study collected more detailed information on OC use and VTE events.

During the study period, which comprised more than 8 million woman-years of observation, 4,246 first episodes of VTE occurred. After adjustment for age, calendar year, education, and length of OC use, the relative risk of VTE in women who used pills with desogestrel, drospirenone, or gestodene was found to be twice that of women on levonorgestrel-containing pills.

Dr. Lidegaard and his colleagues found that, compared with women not using hormonal contraception, the relative risk of confirmed VTE in users of OCs containing 30-40 mcg of ethinyl estradiol with levonorgestrel was 2.9 (95% confidence interval, 2.2-3.8), compared with 6.6 in women using OCs containing desogestrel (95% CI, 5.6-7.8), 6.2 in users of gestodene (5.6-7.0), and 6.4 in women taking drospirenone (5.4-7.5).

With users of OCs containing levonorgestrel as a reference, and after adjustment for length of use, the rate ratio of confirmed VTE for users of OCs with desogestrel was 2.2 (95% CI, 1.7-3.0), with gestodene it was 2.1 (95% CI, 1.6-2.8), and with drospirenone it was 2.1 (1.6-2.8).

To prevent one VTE per year, approximately 2,000 women would need to switch from a pill containing desogestrel, gestodene, or drospirenone to one with levonorgestrel, the researchers concluded.

Critics of Dr. Lidegaard and colleagues' previous study, which revealed similar differences in risk between levonorgestrel and the newer progestogens, argued that because no declining risk was seen after the first few months of use for women using levonorgestrel-containing pills, as would be expected, left-censoring bias might have occurred, making the risk of VTE associated with levonorgestrel seem artificially low compared with that seen with drospirenone, which was introduced in 2001.

Dr. Lidegaard and his colleagues described several changes in their new study's design to strengthen it, noting that they had eliminated left-censoring bias by letting the new study period begin in 2001, which marked the introduction of drospirenone-containing OCs in Denmark, but still collected the women's full OC exposure history for the previous 6 years.

In addition, they defined length of OC use more precisely than in the previous study, stratified analyses into confirmed and unconfirmed VTE events, and better excluded women predisposed to VTE, they said.

The investigators acknowledged as a weakness of the study that they could not control for family disposition and body mass index. However, they noted, other studies had not shown a strong confounding effect for those factors even when data were available.