Kerri Wachter

SAN ANTONIO – Adding the HER2-directed monoclonal antibody pertuzumab to trastuzumab and docetaxel therapy improves pathologic complete response in the neoadjuvant setting and appears to eradicate some HER2-positive tumors in patients with early breast cancer, investigators have reported.

Pathologic complete response (pCR) at the time of surgery, the primary end point of the study, was 46% with the per­tuzumab* (Omnitarg)/trastuzumab (Herceptin)/do­cetaxel (Taxotere) combination, compared with 29% for trastuzumab/docetaxel alone among women with early HER2–positive
disease.

"What we have observed is a higher pCR rate with trastuzumab and pertuzumab when combined with docetaxel," Dr. Luca Gianni said during a Dec. 10 press briefing. The results were presented at the San Antonio Breast Cancer Symposium.

Pathologic complete response for neoadjuvant pertuzumab and trastuzumab without chemotherapy was 17%. "Efficacy of the trastuzumab/pertuzumab doublet most importantly shows that a proportion of HER2-positive tumors can be eradicated without the need for chemotherapy," said Dr. Gianni, director of medical oncology at the National Cancer Institute, Milan, Italy.

"The results of ... these patients having eradication of the tumor indicates that there is a subset of women who can do without chemotherapy. We don’t know, as of yet, how to identify those women, but if we were able to do so, we would spare [them] the unnecessary toxicity," he said.

The monoclonal antibody pertuzumab is a novel targeted medicine called a HER2 dimerization inhibitor. HER dimerization, or pairing, is thought to play an important role in the growth and formation of several different cancer types. Pertuzumab is the first investigational agent designed to specifically prevent the HER2 receptor from pairing with other HER receptors and may ultimately inhibit cancer cell growth or lead to cancer cell death.

The NEOSPHERE study (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) is a randomized multicenter phase II study that was conducted in 78 centers and involved 417 women with newly diagnosed HER2-positive early, inflammatory, or locally advanced breast cancer who had never received Herceptin.

Patients with operable or locally-advanced/inflammatory HER2-positive breast cancer were included in the study if they had not previously undergone chemotherapy and if their primary tumors were smaller than 2 cm.

The women were randomized to one of four treatments: docetaxel plus trastuzumab (n = 107), docetaxel plus trastuzumab and pertuzumab (n = 107), trastuzumab plus pertuzumab (n = 107), and docetaxel plus pertuzumab (n = 96).

Each group received four cycles of treatment before surgery. Treatment cycles were administered intravenously every 3 weeks. Pertuzumab was administered at an 840-mg loading dose and a 420-mg maintenance dose. Trastuzumab was given at an 8-mg/kg loading dose and a 6-mg/kg maintenance dose. Docetaxel was given at a 75-mg/m² dose with escalation to a 100-mg/m² dose if the starting dose was well tolerated.

After surgery all patients received trastuzumab for up to 1 year and three cycles (every 3 weeks) of standard therapy with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC).

Patients in the neoadjuvant trastuzumab/pertuzumab group also received docetaxel before receiving FEC.

Pathologic complete response in the intent-to-treat population was 29% for the trastuzumab/docetaxel group, 46% for trastuzumab/pertuzumab/docetaxel group, 17% for the trastuzumab/pertuzumab group, and 24% for the pertuzumab/docetaxel group.

The difference between pCR for the docetaxel/trastuzumab group and the trastuzumab/pertuzumab group was significant (P = .0198), as were the differences between the docetaxel/trastuzumab group and the docetaxel/trastuzumab/pertuzumab group (P = .0141), and between the docetaxel /trastuzumab/ pertuzumab group and the docetaxel/pertuzumab group (P = .003).

"The tolerability of all combinations was very good," said Dr. Gianni. "When we used the doublet of tumor antibodies, we basically did not observe any grade 3 or higher adverse events."

He noted that there was no clinically meaningful incidence of diarrhea or skin rash with the addition of pertuzumab. There was also a "lack of any meaningful increase in cardiac risk with the addition of pertuzumab over a short course of four cycles of neoadjuvant therapy."

Trastuzumab is approved for the treatment of early-stage breast cancer that is HER2 positive and has spread into the lymph nodes, or is HER2 positive and has not spread into the lymph nodes, but has one high-risk feature. The drug is also indicated for use in metastatic HER2-positive breast cancer and is approved, in combination with chemotherapy, for the treatment of HER2-positive metastatic cancer of the stomach or gastroesophageal junction.

The study was sponsored by F. Hoffmann-La Roche Ltd.

Dr. Gianni reported that he is on the advisory boards for F. Hoffmann-La Roche Ltd., Genentech Inc., GlaxoSmithKline, Boehringer Ingelheim GmbH, and Pfizer Inc.

* CORRECTION, 12/16/2010:  The original version of this article misidentified the brand name for pertuzumab. The correct brand name is Omnitarg. This version has been updated.

SAN ANTONIO – Adding the HER2-directed monoclonal antibody pertuzumab to trastuzumab and docetaxel therapy improves pathologic complete response in the neoadjuvant setting and appears to eradicate some HER2-positive tumors in patients with early breast cancer, investigators have reported.

Pathologic complete response (pCR) at the time of surgery, the primary end point of the study, was 46% with the per­tuzumab* (Omnitarg)/trastuzumab (Herceptin)/do­cetaxel (Taxotere) combination, compared with 29% for trastuzumab/docetaxel alone among women with early HER2–positive
disease.

"What we have observed is a higher pCR rate with trastuzumab and pertuzumab when combined with docetaxel," Dr. Luca Gianni said during a Dec. 10 press briefing. The results were presented at the San Antonio Breast Cancer Symposium.

Pathologic complete response for neoadjuvant pertuzumab and trastuzumab without chemotherapy was 17%. "Efficacy of the trastuzumab/pertuzumab doublet most importantly shows that a proportion of HER2-positive tumors can be eradicated without the need for chemotherapy," said Dr. Gianni, director of medical oncology at the National Cancer Institute, Milan, Italy.

"The results of ... these patients having eradication of the tumor indicates that there is a subset of women who can do without chemotherapy. We don’t know, as of yet, how to identify those women, but if we were able to do so, we would spare [them] the unnecessary toxicity," he said.

The monoclonal antibody pertuzumab is a novel targeted medicine called a HER2 dimerization inhibitor. HER dimerization, or pairing, is thought to play an important role in the growth and formation of several different cancer types. Pertuzumab is the first investigational agent designed to specifically prevent the HER2 receptor from pairing with other HER receptors and may ultimately inhibit cancer cell growth or lead to cancer cell death.

The NEOSPHERE study (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) is a randomized multicenter phase II study that was conducted in 78 centers and involved 417 women with newly diagnosed HER2-positive early, inflammatory, or locally advanced breast cancer who had never received Herceptin.

Patients with operable or locally-advanced/inflammatory HER2-positive breast cancer were included in the study if they had not previously undergone chemotherapy and if their primary tumors were smaller than 2 cm.

The women were randomized to one of four treatments: docetaxel plus trastuzumab (n = 107), docetaxel plus trastuzumab and pertuzumab (n = 107), trastuzumab plus pertuzumab (n = 107), and docetaxel plus pertuzumab (n = 96).

Each group received four cycles of treatment before surgery. Treatment cycles were administered intravenously every 3 weeks. Pertuzumab was administered at an 840-mg loading dose and a 420-mg maintenance dose. Trastuzumab was given at an 8-mg/kg loading dose and a 6-mg/kg maintenance dose. Docetaxel was given at a 75-mg/m² dose with escalation to a 100-mg/m² dose if the starting dose was well tolerated.

After surgery all patients received trastuzumab for up to 1 year and three cycles (every 3 weeks) of standard therapy with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC).

Patients in the neoadjuvant trastuzumab/pertuzumab group also received docetaxel before receiving FEC.

Pathologic complete response in the intent-to-treat population was 29% for the trastuzumab/docetaxel group, 46% for trastuzumab/pertuzumab/docetaxel group, 17% for the trastuzumab/pertuzumab group, and 24% for the pertuzumab/docetaxel group.

The difference between pCR for the docetaxel/trastuzumab group and the trastuzumab/pertuzumab group was significant (P = .0198), as were the differences between the docetaxel/trastuzumab group and the docetaxel/trastuzumab/pertuzumab group (P = .0141), and between the docetaxel /trastuzumab/ pertuzumab group and the docetaxel/pertuzumab group (P = .003).

"The tolerability of all combinations was very good," said Dr. Gianni. "When we used the doublet of tumor antibodies, we basically did not observe any grade 3 or higher adverse events."

He noted that there was no clinically meaningful incidence of diarrhea or skin rash with the addition of pertuzumab. There was also a "lack of any meaningful increase in cardiac risk with the addition of pertuzumab over a short course of four cycles of neoadjuvant therapy."

Trastuzumab is approved for the treatment of early-stage breast cancer that is HER2 positive and has spread into the lymph nodes, or is HER2 positive and has not spread into the lymph nodes, but has one high-risk feature. The drug is also indicated for use in metastatic HER2-positive breast cancer and is approved, in combination with chemotherapy, for the treatment of HER2-positive metastatic cancer of the stomach or gastroesophageal junction.

The study was sponsored by F. Hoffmann-La Roche Ltd.

Dr. Gianni reported that he is on the advisory boards for F. Hoffmann-La Roche Ltd., Genentech Inc., GlaxoSmithKline, Boehringer Ingelheim GmbH, and Pfizer Inc.

* CORRECTION, 12/16/2010:  The original version of this article misidentified the brand name for pertuzumab. The correct brand name is Omnitarg. This version has been updated.

SAN ANTONIO – Adding the HER2-directed monoclonal antibody pertuzumab to trastuzumab and docetaxel therapy improves pathologic complete response in the neoadjuvant setting and appears to eradicate some HER2-positive tumors in patients with early breast cancer, investigators have reported.

Pathologic complete response (pCR) at the time of surgery, the primary end point of the study, was 46% with the per­tuzumab* (Omnitarg)/trastuzumab (Herceptin)/do­cetaxel (Taxotere) combination, compared with 29% for trastuzumab/docetaxel alone among women with early HER2–positive
disease.

"What we have observed is a higher pCR rate with trastuzumab and pertuzumab when combined with docetaxel," Dr. Luca Gianni said during a Dec. 10 press briefing. The results were presented at the San Antonio Breast Cancer Symposium.

Pathologic complete response for neoadjuvant pertuzumab and trastuzumab without chemotherapy was 17%. "Efficacy of the trastuzumab/pertuzumab doublet most importantly shows that a proportion of HER2-positive tumors can be eradicated without the need for chemotherapy," said Dr. Gianni, director of medical oncology at the National Cancer Institute, Milan, Italy.

"The results of ... these patients having eradication of the tumor indicates that there is a subset of women who can do without chemotherapy. We don’t know, as of yet, how to identify those women, but if we were able to do so, we would spare [them] the unnecessary toxicity," he said.

The monoclonal antibody pertuzumab is a novel targeted medicine called a HER2 dimerization inhibitor. HER dimerization, or pairing, is thought to play an important role in the growth and formation of several different cancer types. Pertuzumab is the first investigational agent designed to specifically prevent the HER2 receptor from pairing with other HER receptors and may ultimately inhibit cancer cell growth or lead to cancer cell death.

The NEOSPHERE study (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) is a randomized multicenter phase II study that was conducted in 78 centers and involved 417 women with newly diagnosed HER2-positive early, inflammatory, or locally advanced breast cancer who had never received Herceptin.

Patients with operable or locally-advanced/inflammatory HER2-positive breast cancer were included in the study if they had not previously undergone chemotherapy and if their primary tumors were smaller than 2 cm.

The women were randomized to one of four treatments: docetaxel plus trastuzumab (n = 107), docetaxel plus trastuzumab and pertuzumab (n = 107), trastuzumab plus pertuzumab (n = 107), and docetaxel plus pertuzumab (n = 96).

Each group received four cycles of treatment before surgery. Treatment cycles were administered intravenously every 3 weeks. Pertuzumab was administered at an 840-mg loading dose and a 420-mg maintenance dose. Trastuzumab was given at an 8-mg/kg loading dose and a 6-mg/kg maintenance dose. Docetaxel was given at a 75-mg/m² dose with escalation to a 100-mg/m² dose if the starting dose was well tolerated.

After surgery all patients received trastuzumab for up to 1 year and three cycles (every 3 weeks) of standard therapy with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC).

Patients in the neoadjuvant trastuzumab/pertuzumab group also received docetaxel before receiving FEC.

Pathologic complete response in the intent-to-treat population was 29% for the trastuzumab/docetaxel group, 46% for trastuzumab/pertuzumab/docetaxel group, 17% for the trastuzumab/pertuzumab group, and 24% for the pertuzumab/docetaxel group.

The difference between pCR for the docetaxel/trastuzumab group and the trastuzumab/pertuzumab group was significant (P = .0198), as were the differences between the docetaxel/trastuzumab group and the docetaxel/trastuzumab/pertuzumab group (P = .0141), and between the docetaxel /trastuzumab/ pertuzumab group and the docetaxel/pertuzumab group (P = .003).

"The tolerability of all combinations was very good," said Dr. Gianni. "When we used the doublet of tumor antibodies, we basically did not observe any grade 3 or higher adverse events."

He noted that there was no clinically meaningful incidence of diarrhea or skin rash with the addition of pertuzumab. There was also a "lack of any meaningful increase in cardiac risk with the addition of pertuzumab over a short course of four cycles of neoadjuvant therapy."

Trastuzumab is approved for the treatment of early-stage breast cancer that is HER2 positive and has spread into the lymph nodes, or is HER2 positive and has not spread into the lymph nodes, but has one high-risk feature. The drug is also indicated for use in metastatic HER2-positive breast cancer and is approved, in combination with chemotherapy, for the treatment of HER2-positive metastatic cancer of the stomach or gastroesophageal junction.

The study was sponsored by F. Hoffmann-La Roche Ltd.

Dr. Gianni reported that he is on the advisory boards for F. Hoffmann-La Roche Ltd., Genentech Inc., GlaxoSmithKline, Boehringer Ingelheim GmbH, and Pfizer Inc.

* CORRECTION, 12/16/2010:  The original version of this article misidentified the brand name for pertuzumab. The correct brand name is Omnitarg. This version has been updated.

SAN ANTONIO – In sharp contrast with previous findings, zoledronic acid failed to improve disease-free survival when added to adjuvant chemotherapy for women with stage II/III breast cancer in a highly anticipated phase III trial.

"In terms of primary analysis and primary end point, this is a negative trial," Dr. Robert Coleman said during a press briefing on Dec. 8 at the annual San Antonio Breast Cancer Symposium. "It is highly unlikely that this conclusion will change with further follow-up."

The randomized, open-label AZURE (Adjuvant Treatment with Zoledronic Acid in Stage II/III Breast Cancer) trial involved 3,360 women with stage II/III breast cancer at 174 participating centers. Based on the results, Novartis, maker of zoledronic acid (Zometa), announced that it is withdrawing applications for the drug’s approval as an adjuvant breast cancer treatment in the United States and Europe. The company said it will evaluate its plans based on the data, which did include one positive finding.

Older women who had undergone menopause at least 5 years earlier showed a significant 29% improvement in overall survival with the osteoporosis drug added to standard therapy. This was not true for premenopausal or perimenopausal women, however, and no benefit was seen in disease-free survival, the primary end point.

The National Cancer Research Network in the United Kingdom conducted the study, with partial funding by an academic grant from Novartis. Several study authors reported financial relationships with a number of pharmaceutical companies, including Novartis.

Patients were randomized to either a standard adjuvant therapy alone or in combination with the study drug. In the latter arm, a 4-mg dose of zoledronic acid was given every 3-4 weeks for the first 6 months (six doses). For months 6-30, zoledronic acid was given every 3 months (eight doses). After 30 months, zoledronic acid was given every 6 months (five doses). Treatment with zoledronic acid lasted for 5 years.

Patients were included if they had stage II/III breast cancer; the population included node-positive adjuvant patients and T3/T4 or confirmed node-positive neoadjuvant patients. The women could not have any evidence of metastasis. They had to have a complete primary tumor resection and a Karnofsky performance score of at least 80.

Patients were excluded if they had received bisphosphonate treatment in the last year, bone disease (including osteoporosis) at study entry, a serum creatinine level greater than 1.5 upper limit of normal, significant ongoing dental problems or planned dental surgery, or other malignancies.

At a median follow-up of 59 months, there was no difference in disease-free survival overall (adjusted hazard ratio 0.98, P = .79) or invasive disease-free survival (adjusted HR = 0.98, P = .73).

"Clearly our results are very different from those published by the ABCSG [the Austrian Breast & Colorectal Cancer Study Group] investigators [study 12]," said Dr. Coleman, professor of medical oncology at the University of Sheffield (England), referring to an earlier study that suggested the bone drug might also prevent breast cancer recurrence (N. Engl. J. Med. 2009; 360:679-91).

The ABCSG-12 study included more than 1,800 premenopausal women with hormone receptor–positive, early-stage breast cancer. Following complete resection and hormone therapy – including goserelin treatment to suppress ovarian function and induce menopause – women were treated with or without zoledronic acid for 3 years. The researchers demonstrated that the addition of 3 years of zoledronic acid therapy to hormonal therapy following surgery improved disease-free survival by 32% (HR .68, P = .009).

"In AZURE, ER-positive premenopausal women [the same population as in the ABCSG XII trial] are showing no benefit – in fact, there’s almost a disadvantage with zoledronic acid – and that’s clearly different from ABCSG 12," said Dr. Coleman.

The AZURE researchers did extensive planned subgroup analyses. "One clearly stands out from all the others. That is the treatment effect on disease-free survival according to menopausal status," Dr. Coleman noted.

The AZURE trial demonstrated a trend toward longer overall survival for all women on zoledronic acid, but this did not achieve significance (adjusted HR = 0.85, P = .07). However, there was a clear overall survival benefit for women at least 5 years out from menopause on zoledronic acid. These women had a 29% reduction in the risk of death (P = .017). There was no difference between the control and treatment groups among pre- and perimenopausal women (adjusted HR 1.01, P = .93).

Dr. Coleman speculated that lower levels of estrogen had a role in the responses of older women to zoledronic acid. In the earlier Austrian trial, he noted, younger women were forced into early menopause with hormonal therapy, and that may have played a similar role in the responses seen in that trial.

The impact of estrogen on the micro-environment could be a factor, agreed Dr. Rowan T. Chlebowski at the press briefing. "If you have an estrogen-rich environment, in many cases that estrogen is driving tumor growth. "When you get rid of the estrogen and the estrogen is not running the cell, then the things that bisphosphonates change in the microenvironment – the other pathways that it blocks – can have an effect," said Dr. Chlebowski, a medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-University of California.

In terms of safety, "zoledronic acid is a pretty well tolerated drug and it’s difficult to see any major differences between the control group and test group in terms of serious adverse events – certainly in terms of chemotherapy toxicities," Dr. Coleman said.

Notably there were 17 confirmed cases of osteonecrosis of the jaw in the zoledronic acid arm (1.16%) and another 9 possible cases. There were no cases among control patients.

Zometa is approved for the reduction or delay of bone complications (skeletal-related events, or SREs) across a broad range of metastatic cancers (breast, hormone-refractory prostate, lung, and other solid tumors) involving bone and multiple myeloma, as well as for the treatment of hypercalcemia of malignancy (HCM).

SAN ANTONIO – In sharp contrast with previous findings, zoledronic acid failed to improve disease-free survival when added to adjuvant chemotherapy for women with stage II/III breast cancer in a highly anticipated phase III trial.

"In terms of primary analysis and primary end point, this is a negative trial," Dr. Robert Coleman said during a press briefing on Dec. 8 at the annual San Antonio Breast Cancer Symposium. "It is highly unlikely that this conclusion will change with further follow-up."

The randomized, open-label AZURE (Adjuvant Treatment with Zoledronic Acid in Stage II/III Breast Cancer) trial involved 3,360 women with stage II/III breast cancer at 174 participating centers. Based on the results, Novartis, maker of zoledronic acid (Zometa), announced that it is withdrawing applications for the drug’s approval as an adjuvant breast cancer treatment in the United States and Europe. The company said it will evaluate its plans based on the data, which did include one positive finding.

Older women who had undergone menopause at least 5 years earlier showed a significant 29% improvement in overall survival with the osteoporosis drug added to standard therapy. This was not true for premenopausal or perimenopausal women, however, and no benefit was seen in disease-free survival, the primary end point.

The National Cancer Research Network in the United Kingdom conducted the study, with partial funding by an academic grant from Novartis. Several study authors reported financial relationships with a number of pharmaceutical companies, including Novartis.

Patients were randomized to either a standard adjuvant therapy alone or in combination with the study drug. In the latter arm, a 4-mg dose of zoledronic acid was given every 3-4 weeks for the first 6 months (six doses). For months 6-30, zoledronic acid was given every 3 months (eight doses). After 30 months, zoledronic acid was given every 6 months (five doses). Treatment with zoledronic acid lasted for 5 years.

Patients were included if they had stage II/III breast cancer; the population included node-positive adjuvant patients and T3/T4 or confirmed node-positive neoadjuvant patients. The women could not have any evidence of metastasis. They had to have a complete primary tumor resection and a Karnofsky performance score of at least 80.

Patients were excluded if they had received bisphosphonate treatment in the last year, bone disease (including osteoporosis) at study entry, a serum creatinine level greater than 1.5 upper limit of normal, significant ongoing dental problems or planned dental surgery, or other malignancies.

At a median follow-up of 59 months, there was no difference in disease-free survival overall (adjusted hazard ratio 0.98, P = .79) or invasive disease-free survival (adjusted HR = 0.98, P = .73).

"Clearly our results are very different from those published by the ABCSG [the Austrian Breast & Colorectal Cancer Study Group] investigators [study 12]," said Dr. Coleman, professor of medical oncology at the University of Sheffield (England), referring to an earlier study that suggested the bone drug might also prevent breast cancer recurrence (N. Engl. J. Med. 2009; 360:679-91).

The ABCSG-12 study included more than 1,800 premenopausal women with hormone receptor–positive, early-stage breast cancer. Following complete resection and hormone therapy – including goserelin treatment to suppress ovarian function and induce menopause – women were treated with or without zoledronic acid for 3 years. The researchers demonstrated that the addition of 3 years of zoledronic acid therapy to hormonal therapy following surgery improved disease-free survival by 32% (HR .68, P = .009).

"In AZURE, ER-positive premenopausal women [the same population as in the ABCSG XII trial] are showing no benefit – in fact, there’s almost a disadvantage with zoledronic acid – and that’s clearly different from ABCSG 12," said Dr. Coleman.

The AZURE researchers did extensive planned subgroup analyses. "One clearly stands out from all the others. That is the treatment effect on disease-free survival according to menopausal status," Dr. Coleman noted.

The AZURE trial demonstrated a trend toward longer overall survival for all women on zoledronic acid, but this did not achieve significance (adjusted HR = 0.85, P = .07). However, there was a clear overall survival benefit for women at least 5 years out from menopause on zoledronic acid. These women had a 29% reduction in the risk of death (P = .017). There was no difference between the control and treatment groups among pre- and perimenopausal women (adjusted HR 1.01, P = .93).

Dr. Coleman speculated that lower levels of estrogen had a role in the responses of older women to zoledronic acid. In the earlier Austrian trial, he noted, younger women were forced into early menopause with hormonal therapy, and that may have played a similar role in the responses seen in that trial.

The impact of estrogen on the micro-environment could be a factor, agreed Dr. Rowan T. Chlebowski at the press briefing. "If you have an estrogen-rich environment, in many cases that estrogen is driving tumor growth. "When you get rid of the estrogen and the estrogen is not running the cell, then the things that bisphosphonates change in the microenvironment – the other pathways that it blocks – can have an effect," said Dr. Chlebowski, a medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-University of California.

In terms of safety, "zoledronic acid is a pretty well tolerated drug and it’s difficult to see any major differences between the control group and test group in terms of serious adverse events – certainly in terms of chemotherapy toxicities," Dr. Coleman said.

Notably there were 17 confirmed cases of osteonecrosis of the jaw in the zoledronic acid arm (1.16%) and another 9 possible cases. There were no cases among control patients.

Zometa is approved for the reduction or delay of bone complications (skeletal-related events, or SREs) across a broad range of metastatic cancers (breast, hormone-refractory prostate, lung, and other solid tumors) involving bone and multiple myeloma, as well as for the treatment of hypercalcemia of malignancy (HCM).

SAN ANTONIO – In sharp contrast with previous findings, zoledronic acid failed to improve disease-free survival when added to adjuvant chemotherapy for women with stage II/III breast cancer in a highly anticipated phase III trial.

"In terms of primary analysis and primary end point, this is a negative trial," Dr. Robert Coleman said during a press briefing on Dec. 8 at the annual San Antonio Breast Cancer Symposium. "It is highly unlikely that this conclusion will change with further follow-up."

The randomized, open-label AZURE (Adjuvant Treatment with Zoledronic Acid in Stage II/III Breast Cancer) trial involved 3,360 women with stage II/III breast cancer at 174 participating centers. Based on the results, Novartis, maker of zoledronic acid (Zometa), announced that it is withdrawing applications for the drug’s approval as an adjuvant breast cancer treatment in the United States and Europe. The company said it will evaluate its plans based on the data, which did include one positive finding.

Older women who had undergone menopause at least 5 years earlier showed a significant 29% improvement in overall survival with the osteoporosis drug added to standard therapy. This was not true for premenopausal or perimenopausal women, however, and no benefit was seen in disease-free survival, the primary end point.

The National Cancer Research Network in the United Kingdom conducted the study, with partial funding by an academic grant from Novartis. Several study authors reported financial relationships with a number of pharmaceutical companies, including Novartis.

Patients were randomized to either a standard adjuvant therapy alone or in combination with the study drug. In the latter arm, a 4-mg dose of zoledronic acid was given every 3-4 weeks for the first 6 months (six doses). For months 6-30, zoledronic acid was given every 3 months (eight doses). After 30 months, zoledronic acid was given every 6 months (five doses). Treatment with zoledronic acid lasted for 5 years.

Patients were included if they had stage II/III breast cancer; the population included node-positive adjuvant patients and T3/T4 or confirmed node-positive neoadjuvant patients. The women could not have any evidence of metastasis. They had to have a complete primary tumor resection and a Karnofsky performance score of at least 80.

Patients were excluded if they had received bisphosphonate treatment in the last year, bone disease (including osteoporosis) at study entry, a serum creatinine level greater than 1.5 upper limit of normal, significant ongoing dental problems or planned dental surgery, or other malignancies.

At a median follow-up of 59 months, there was no difference in disease-free survival overall (adjusted hazard ratio 0.98, P = .79) or invasive disease-free survival (adjusted HR = 0.98, P = .73).

"Clearly our results are very different from those published by the ABCSG [the Austrian Breast & Colorectal Cancer Study Group] investigators [study 12]," said Dr. Coleman, professor of medical oncology at the University of Sheffield (England), referring to an earlier study that suggested the bone drug might also prevent breast cancer recurrence (N. Engl. J. Med. 2009; 360:679-91).

The ABCSG-12 study included more than 1,800 premenopausal women with hormone receptor–positive, early-stage breast cancer. Following complete resection and hormone therapy – including goserelin treatment to suppress ovarian function and induce menopause – women were treated with or without zoledronic acid for 3 years. The researchers demonstrated that the addition of 3 years of zoledronic acid therapy to hormonal therapy following surgery improved disease-free survival by 32% (HR .68, P = .009).

"In AZURE, ER-positive premenopausal women [the same population as in the ABCSG XII trial] are showing no benefit – in fact, there’s almost a disadvantage with zoledronic acid – and that’s clearly different from ABCSG 12," said Dr. Coleman.

The AZURE researchers did extensive planned subgroup analyses. "One clearly stands out from all the others. That is the treatment effect on disease-free survival according to menopausal status," Dr. Coleman noted.

The AZURE trial demonstrated a trend toward longer overall survival for all women on zoledronic acid, but this did not achieve significance (adjusted HR = 0.85, P = .07). However, there was a clear overall survival benefit for women at least 5 years out from menopause on zoledronic acid. These women had a 29% reduction in the risk of death (P = .017). There was no difference between the control and treatment groups among pre- and perimenopausal women (adjusted HR 1.01, P = .93).

Dr. Coleman speculated that lower levels of estrogen had a role in the responses of older women to zoledronic acid. In the earlier Austrian trial, he noted, younger women were forced into early menopause with hormonal therapy, and that may have played a similar role in the responses seen in that trial.

The impact of estrogen on the micro-environment could be a factor, agreed Dr. Rowan T. Chlebowski at the press briefing. "If you have an estrogen-rich environment, in many cases that estrogen is driving tumor growth. "When you get rid of the estrogen and the estrogen is not running the cell, then the things that bisphosphonates change in the microenvironment – the other pathways that it blocks – can have an effect," said Dr. Chlebowski, a medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-University of California.

In terms of safety, "zoledronic acid is a pretty well tolerated drug and it’s difficult to see any major differences between the control group and test group in terms of serious adverse events – certainly in terms of chemotherapy toxicities," Dr. Coleman said.

Notably there were 17 confirmed cases of osteonecrosis of the jaw in the zoledronic acid arm (1.16%) and another 9 possible cases. There were no cases among control patients.

Zometa is approved for the reduction or delay of bone complications (skeletal-related events, or SREs) across a broad range of metastatic cancers (breast, hormone-refractory prostate, lung, and other solid tumors) involving bone and multiple myeloma, as well as for the treatment of hypercalcemia of malignancy (HCM).

WASHINGTON – A good family history risk assessment is still a better tool for predicting disease risk than is personal genomic screening, despite advances in genomic technology.

Dr. Charis Eng and coauthor Brandie Leach compared the effectiveness of family history risk assessment with direct-to-consumer personal genomic screening for the assessment of prostate, breast, and colorectal cancer. They enrolled 22 patients at their clinic and 22 spouses.

Among colon cancer patients, nine were considered at high risk on the basis of family health history. In fact, validated genetic testing showed that five had mutations that put them at very high risk. "None of them were picked up by personal genome scanning," Dr. Eng noted. "I think what’s alarming is the inability of personal genome scanning to identify the real high-risk patients."

Each participant had a family health history taken, and then provided a sample for the personal genomic screening (Navigenics Inc.). "After the family health history, we assessed them as if they were in clinic ... the 22 patients got counseling and interpretation right away," said Dr. Eng, director of the Genomic Medicine Institute of the Cleveland Clinic Foundation. If the interpretation suggested that a patient was at high risk for a condition, the patient was offered validated genetic testing.

The researchers alerted the spouses if they found something concerning on the family health history and offered them genetic counseling. "If anything looked alarming, it would then follow the same flow as for a patient," Dr. Eng said in an interview.

Next, the investigators used standardized algorithms to classify patients based on their risk for the three cancers using both family health assessment and personal genomic screening – low (same as the general population), intermediate, and high. They also assessed each subject’s hereditary risk based on clinical criteria and/or validated genetic test results.

Overall concordance between family health assessment and personal genomic screening was low for all three cancers (K less than 0.15). Cancer risk using family health assessment and personal genomic screening agreed on participant risk categories only 46% of the time.

For prostate cancer, personal genomic screening predicted a moderate/high risk for eight individuals, while these individuals had the same risk as the general population based on family health assessment. Based on personal genomic screening, 12 individuals were determined to have a moderate colon cancer risk, while these individuals had the same risk as the general population based on family health assessment.

Overall, for the 22 individuals with a hereditary cancer risk, the personal genomic screening identified only 1 at high risk. None of the three individuals with hereditary prostate cancer was assessed as high risk on personal genomic screening. Likewise, the 10 individuals with hereditary breast cancer were assessed as high risk using family health assessment, but only 1 was considered to be at high risk based on personal genomic screening.

Family health risk assessment and personal genomic screening may be complementary tools for cancer risk assessment. However, evaluation of family history is still the preferred method and should be used to clinically evaluate an individual’s risk of developing cancer for now.

It may be that the tests will be used as an additional tool to refine risk assessment for patients who are identified as having a moderate risk of disease by family health history, said Dr. Eng. However, it’s too early to put that into practice.

Dr. Eng and Ms. Leach reported that they had no relevant financial relationships.

WASHINGTON – A good family history risk assessment is still a better tool for predicting disease risk than is personal genomic screening, despite advances in genomic technology.

Dr. Charis Eng and coauthor Brandie Leach compared the effectiveness of family history risk assessment with direct-to-consumer personal genomic screening for the assessment of prostate, breast, and colorectal cancer. They enrolled 22 patients at their clinic and 22 spouses.

Among colon cancer patients, nine were considered at high risk on the basis of family health history. In fact, validated genetic testing showed that five had mutations that put them at very high risk. "None of them were picked up by personal genome scanning," Dr. Eng noted. "I think what’s alarming is the inability of personal genome scanning to identify the real high-risk patients."

Each participant had a family health history taken, and then provided a sample for the personal genomic screening (Navigenics Inc.). "After the family health history, we assessed them as if they were in clinic ... the 22 patients got counseling and interpretation right away," said Dr. Eng, director of the Genomic Medicine Institute of the Cleveland Clinic Foundation. If the interpretation suggested that a patient was at high risk for a condition, the patient was offered validated genetic testing.

The researchers alerted the spouses if they found something concerning on the family health history and offered them genetic counseling. "If anything looked alarming, it would then follow the same flow as for a patient," Dr. Eng said in an interview.

Next, the investigators used standardized algorithms to classify patients based on their risk for the three cancers using both family health assessment and personal genomic screening – low (same as the general population), intermediate, and high. They also assessed each subject’s hereditary risk based on clinical criteria and/or validated genetic test results.

Overall concordance between family health assessment and personal genomic screening was low for all three cancers (K less than 0.15). Cancer risk using family health assessment and personal genomic screening agreed on participant risk categories only 46% of the time.

For prostate cancer, personal genomic screening predicted a moderate/high risk for eight individuals, while these individuals had the same risk as the general population based on family health assessment. Based on personal genomic screening, 12 individuals were determined to have a moderate colon cancer risk, while these individuals had the same risk as the general population based on family health assessment.

Overall, for the 22 individuals with a hereditary cancer risk, the personal genomic screening identified only 1 at high risk. None of the three individuals with hereditary prostate cancer was assessed as high risk on personal genomic screening. Likewise, the 10 individuals with hereditary breast cancer were assessed as high risk using family health assessment, but only 1 was considered to be at high risk based on personal genomic screening.

Family health risk assessment and personal genomic screening may be complementary tools for cancer risk assessment. However, evaluation of family history is still the preferred method and should be used to clinically evaluate an individual’s risk of developing cancer for now.

It may be that the tests will be used as an additional tool to refine risk assessment for patients who are identified as having a moderate risk of disease by family health history, said Dr. Eng. However, it’s too early to put that into practice.

Dr. Eng and Ms. Leach reported that they had no relevant financial relationships.

WASHINGTON – A good family history risk assessment is still a better tool for predicting disease risk than is personal genomic screening, despite advances in genomic technology.

Dr. Charis Eng and coauthor Brandie Leach compared the effectiveness of family history risk assessment with direct-to-consumer personal genomic screening for the assessment of prostate, breast, and colorectal cancer. They enrolled 22 patients at their clinic and 22 spouses.

Among colon cancer patients, nine were considered at high risk on the basis of family health history. In fact, validated genetic testing showed that five had mutations that put them at very high risk. "None of them were picked up by personal genome scanning," Dr. Eng noted. "I think what’s alarming is the inability of personal genome scanning to identify the real high-risk patients."

Each participant had a family health history taken, and then provided a sample for the personal genomic screening (Navigenics Inc.). "After the family health history, we assessed them as if they were in clinic ... the 22 patients got counseling and interpretation right away," said Dr. Eng, director of the Genomic Medicine Institute of the Cleveland Clinic Foundation. If the interpretation suggested that a patient was at high risk for a condition, the patient was offered validated genetic testing.

The researchers alerted the spouses if they found something concerning on the family health history and offered them genetic counseling. "If anything looked alarming, it would then follow the same flow as for a patient," Dr. Eng said in an interview.

Next, the investigators used standardized algorithms to classify patients based on their risk for the three cancers using both family health assessment and personal genomic screening – low (same as the general population), intermediate, and high. They also assessed each subject’s hereditary risk based on clinical criteria and/or validated genetic test results.

Overall concordance between family health assessment and personal genomic screening was low for all three cancers (K less than 0.15). Cancer risk using family health assessment and personal genomic screening agreed on participant risk categories only 46% of the time.

For prostate cancer, personal genomic screening predicted a moderate/high risk for eight individuals, while these individuals had the same risk as the general population based on family health assessment. Based on personal genomic screening, 12 individuals were determined to have a moderate colon cancer risk, while these individuals had the same risk as the general population based on family health assessment.

Overall, for the 22 individuals with a hereditary cancer risk, the personal genomic screening identified only 1 at high risk. None of the three individuals with hereditary prostate cancer was assessed as high risk on personal genomic screening. Likewise, the 10 individuals with hereditary breast cancer were assessed as high risk using family health assessment, but only 1 was considered to be at high risk based on personal genomic screening.

Family health risk assessment and personal genomic screening may be complementary tools for cancer risk assessment. However, evaluation of family history is still the preferred method and should be used to clinically evaluate an individual’s risk of developing cancer for now.

It may be that the tests will be used as an additional tool to refine risk assessment for patients who are identified as having a moderate risk of disease by family health history, said Dr. Eng. However, it’s too early to put that into practice.

Dr. Eng and Ms. Leach reported that they had no relevant financial relationships.

WASHINGTON – A good family history risk assessment is still a better tool for predicting disease risk than is personal genomic screening, despite advances in genomic technology.

Dr. Charis Eng and coauthor Brandie Leach compared the effectiveness of family history risk assessment with direct-to-consumer personal genomic screening for the assessment of prostate, breast, and colorectal cancer. They enrolled 22 patients at their clinic and 22 spouses.

Among colon cancer patients, nine were considered at high risk on the basis of family health history. In fact, validated genetic testing showed that five had mutations that put them at very high risk. "None of them were picked up by personal genome scanning," Dr. Eng noted. "I think what’s alarming is the inability of personal genome scanning to identify the real high-risk patients."

Each participant had a family health history taken, and then provided a sample for the personal genomic screening (Navigenics Inc.). "After the family health history, we assessed them as if they were in clinic ... the 22 patients got counseling and interpretation right away," said Dr. Eng, director of the Genomic Medicine Institute of the Cleveland Clinic Foundation. If the interpretation suggested that a patient was at high risk for a condition, the patient was offered validated genetic testing.

The researchers alerted the spouses if they found something concerning on the family health history and offered them genetic counseling. "If anything looked alarming, it would then follow the same flow as for a patient," Dr. Eng said in an interview.

Next, the investigators used standardized algorithms to classify patients based on their risk for the three cancers using both family health assessment and personal genomic screening – low (same as the general population), intermediate, and high. They also assessed each subject’s hereditary risk based on clinical criteria and/or validated genetic test results.

Overall concordance between family health assessment and personal genomic screening was low for all three cancers (K less than 0.15). Cancer risk using family health assessment and personal genomic screening agreed on participant risk categories only 46% of the time.

For prostate cancer, personal genomic screening predicted a moderate/high risk for eight individuals, while these individuals had the same risk as the general population based on family health assessment. Based on personal genomic screening, 12 individuals were determined to have a moderate colon cancer risk, while these individuals had the same risk as the general population based on family health assessment.

Overall, for the 22 individuals with a hereditary cancer risk, the personal genomic screening identified only 1 at high risk. None of the three individuals with hereditary prostate cancer was assessed as high risk on personal genomic screening. Likewise, the 10 individuals with hereditary breast cancer were assessed as high risk using family health assessment, but only 1 was considered to be at high risk based on personal genomic screening.

Family health risk assessment and personal genomic screening may be complementary tools for cancer risk assessment. However, evaluation of family history is still the preferred method and should be used to clinically evaluate an individual’s risk of developing cancer for now.

It may be that the tests will be used as an additional tool to refine risk assessment for patients who are identified as having a moderate risk of disease by family health history, said Dr. Eng. However, it’s too early to put that into practice.

Dr. Eng and Ms. Leach reported that they had no relevant financial relationships.

WASHINGTON – A good family history risk assessment is still a better tool for predicting disease risk than is personal genomic screening, despite advances in genomic technology.

Dr. Charis Eng and coauthor Brandie Leach compared the effectiveness of family history risk assessment with direct-to-consumer personal genomic screening for the assessment of prostate, breast, and colorectal cancer. They enrolled 22 patients at their clinic and 22 spouses.

Among colon cancer patients, nine were considered at high risk on the basis of family health history. In fact, validated genetic testing showed that five had mutations that put them at very high risk. "None of them were picked up by personal genome scanning," Dr. Eng noted. "I think what’s alarming is the inability of personal genome scanning to identify the real high-risk patients."

Each participant had a family health history taken, and then provided a sample for the personal genomic screening (Navigenics Inc.). "After the family health history, we assessed them as if they were in clinic ... the 22 patients got counseling and interpretation right away," said Dr. Eng, director of the Genomic Medicine Institute of the Cleveland Clinic Foundation. If the interpretation suggested that a patient was at high risk for a condition, the patient was offered validated genetic testing.

The researchers alerted the spouses if they found something concerning on the family health history and offered them genetic counseling. "If anything looked alarming, it would then follow the same flow as for a patient," Dr. Eng said in an interview.

Next, the investigators used standardized algorithms to classify patients based on their risk for the three cancers using both family health assessment and personal genomic screening – low (same as the general population), intermediate, and high. They also assessed each subject’s hereditary risk based on clinical criteria and/or validated genetic test results.

Overall concordance between family health assessment and personal genomic screening was low for all three cancers (K less than 0.15). Cancer risk using family health assessment and personal genomic screening agreed on participant risk categories only 46% of the time.

For prostate cancer, personal genomic screening predicted a moderate/high risk for eight individuals, while these individuals had the same risk as the general population based on family health assessment. Based on personal genomic screening, 12 individuals were determined to have a moderate colon cancer risk, while these individuals had the same risk as the general population based on family health assessment.

Overall, for the 22 individuals with a hereditary cancer risk, the personal genomic screening identified only 1 at high risk. None of the three individuals with hereditary prostate cancer was assessed as high risk on personal genomic screening. Likewise, the 10 individuals with hereditary breast cancer were assessed as high risk using family health assessment, but only 1 was considered to be at high risk based on personal genomic screening.

Family health risk assessment and personal genomic screening may be complementary tools for cancer risk assessment. However, evaluation of family history is still the preferred method and should be used to clinically evaluate an individual’s risk of developing cancer for now.

It may be that the tests will be used as an additional tool to refine risk assessment for patients who are identified as having a moderate risk of disease by family health history, said Dr. Eng. However, it’s too early to put that into practice.

Dr. Eng and Ms. Leach reported that they had no relevant financial relationships.

WASHINGTON – A good family history risk assessment is still a better tool for predicting disease risk than is personal genomic screening, despite advances in genomic technology.

Dr. Charis Eng and coauthor Brandie Leach compared the effectiveness of family history risk assessment with direct-to-consumer personal genomic screening for the assessment of prostate, breast, and colorectal cancer. They enrolled 22 patients at their clinic and 22 spouses.

Among colon cancer patients, nine were considered at high risk on the basis of family health history. In fact, validated genetic testing showed that five had mutations that put them at very high risk. "None of them were picked up by personal genome scanning," Dr. Eng noted. "I think what’s alarming is the inability of personal genome scanning to identify the real high-risk patients."

Each participant had a family health history taken, and then provided a sample for the personal genomic screening (Navigenics Inc.). "After the family health history, we assessed them as if they were in clinic ... the 22 patients got counseling and interpretation right away," said Dr. Eng, director of the Genomic Medicine Institute of the Cleveland Clinic Foundation. If the interpretation suggested that a patient was at high risk for a condition, the patient was offered validated genetic testing.

The researchers alerted the spouses if they found something concerning on the family health history and offered them genetic counseling. "If anything looked alarming, it would then follow the same flow as for a patient," Dr. Eng said in an interview.

Next, the investigators used standardized algorithms to classify patients based on their risk for the three cancers using both family health assessment and personal genomic screening – low (same as the general population), intermediate, and high. They also assessed each subject’s hereditary risk based on clinical criteria and/or validated genetic test results.

Overall concordance between family health assessment and personal genomic screening was low for all three cancers (K less than 0.15). Cancer risk using family health assessment and personal genomic screening agreed on participant risk categories only 46% of the time.

For prostate cancer, personal genomic screening predicted a moderate/high risk for eight individuals, while these individuals had the same risk as the general population based on family health assessment. Based on personal genomic screening, 12 individuals were determined to have a moderate colon cancer risk, while these individuals had the same risk as the general population based on family health assessment.

Overall, for the 22 individuals with a hereditary cancer risk, the personal genomic screening identified only 1 at high risk. None of the three individuals with hereditary prostate cancer was assessed as high risk on personal genomic screening. Likewise, the 10 individuals with hereditary breast cancer were assessed as high risk using family health assessment, but only 1 was considered to be at high risk based on personal genomic screening.

Family health risk assessment and personal genomic screening may be complementary tools for cancer risk assessment. However, evaluation of family history is still the preferred method and should be used to clinically evaluate an individual’s risk of developing cancer for now.

It may be that the tests will be used as an additional tool to refine risk assessment for patients who are identified as having a moderate risk of disease by family health history, said Dr. Eng. However, it’s too early to put that into practice.

Dr. Eng and Ms. Leach reported that they had no relevant financial relationships.

SILVER SPRING, MD – A Food and Drug Administration panel voted Dec. 2 that the risk-benefit profile of vandetanib is acceptable for at least some patients with medullary thyroid cancer, but that postmarketing evaluation of alternative dosing should be required by the agency as part of its approval.

The Oncologic Drugs Advisory Committee also was asked by the FDA to comment on whether the drug’s indication should be limited to patients with progressive, symptomatic medullary thyroid cancer, given concerns about the safety of the drug. The majority of panel members agreed that some restrictive language should be added to the indication in light of toxicity concerns, particularly the possibility of QTc prolongation.

"The risk-benefit profile is acceptable, from my perspective, for this drug to be approved for this indication. ... I think that there is enough of a signal at lower doses, which presumably would lead to less toxicity, that they should be explored," said panel member Dr. Mikkael Sekeres, who is a professor medicine at the Cleveland Clinic.

Dr. Wyndham Wilson of the National Cancer Institute, Rockville, Md., who is the panel chair, agreed. "It’s all about steady state levels, not about dose. ... The pharmacology data would suggest that you could probably get reasonable steady-state levels with a somewhat lower dose rate and still have equal effectiveness."

Vandetanib is an oral, multiple-tyrosine kinase inhibitor that acts on the vascular endothelial growth factor, epidermal growth factor receptor, and rearranged during transfection pathways. Medullary thyroid cancer patients with early-stage disease can be treated surgically with curative intent; for patients with distant metastases, the 5-year survival rate is approximately 40%.

AstraZeneca, the developer of vandetanib, is seeking an indication for patients with locally advanced or metastatic medullary thyroid cancer.

The drug was previously under investigation for the treatment of non–small cell lung cancer. However, the treatment with vandetanib did not improve overall survival benefit and only modestly improved progression-free survival (PFS) in this patient group.

In the phase III study, 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer were randomized 2:1 to once-daily administration of either vandetanib 300 mg (the maximum tolerated dose) or placebo. AstraZeneca’s analysis showed a significant 54% reduction in risk of progression with vandetanib, improving median PFS by 11 months.

Dose reductions and interruptions because of adverse events in the phase III study and in two phase II studies were troubling, however. In the phase III trial, 36% of vandetanib patients required a dose reduction and 47% required a dose interruption.

Grade 3 or greater adverse events occurred in 55% of vandetanib-treated patients in the phase III trial, compared with 24% in the placebo group. The most common adverse events overall were diarrhea, rash, nausea, and hypertension.

The FDA and the panel were both particularly concerned about adverse event signals from the vandetanib safety database relating to QT interval prolongation, cerebrovascular events, interstitial lung disease/pneumonia and serious skin conditions. Of the total of 3,019 patients in safety database, 319 were treated with 300 mg vandetanib for medullary thyroid cancer.

According to the FDA, the incidence of grade 3-4 QTc prolongation in those patients was 8%. When ECGs were reviewed, more than 35% of patients experienced QTc prolongation greater than 60 ms – a grade 4 toxicity.

The panel was also concerned about events that occurred among the 3,019 patients in the overall safety database, which included sudden death (0.4%), torsade de pointes (less than 0.1%), grade 3-5 interstitial lung disease (0.8%), and Stevens-Johnson syndrome (0.7%).

QT prolongation is dose dependent with a mean prolongation of 35 ms in patients receiving 300 mg vandetanib, according to the FDA.

Given these adverse events, many panel members expressed concern about treating asymptomatic patients with medullary thyroid cancer, which has a long natural history that can involve periods of disease indolence, given the toxicity of the drug. Many panel members cited this as reason for the necessity of postmarketing evaluation of other doses.

The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of potential conflicts of interest by the FDA before a meeting, but it occasionally grants a waiver to a panelist with a conflict of interest.

SILVER SPRING, MD – A Food and Drug Administration panel voted Dec. 2 that the risk-benefit profile of vandetanib is acceptable for at least some patients with medullary thyroid cancer, but that postmarketing evaluation of alternative dosing should be required by the agency as part of its approval.

The Oncologic Drugs Advisory Committee also was asked by the FDA to comment on whether the drug’s indication should be limited to patients with progressive, symptomatic medullary thyroid cancer, given concerns about the safety of the drug. The majority of panel members agreed that some restrictive language should be added to the indication in light of toxicity concerns, particularly the possibility of QTc prolongation.

"The risk-benefit profile is acceptable, from my perspective, for this drug to be approved for this indication. ... I think that there is enough of a signal at lower doses, which presumably would lead to less toxicity, that they should be explored," said panel member Dr. Mikkael Sekeres, who is a professor medicine at the Cleveland Clinic.

Dr. Wyndham Wilson of the National Cancer Institute, Rockville, Md., who is the panel chair, agreed. "It’s all about steady state levels, not about dose. ... The pharmacology data would suggest that you could probably get reasonable steady-state levels with a somewhat lower dose rate and still have equal effectiveness."

Vandetanib is an oral, multiple-tyrosine kinase inhibitor that acts on the vascular endothelial growth factor, epidermal growth factor receptor, and rearranged during transfection pathways. Medullary thyroid cancer patients with early-stage disease can be treated surgically with curative intent; for patients with distant metastases, the 5-year survival rate is approximately 40%.

AstraZeneca, the developer of vandetanib, is seeking an indication for patients with locally advanced or metastatic medullary thyroid cancer.

The drug was previously under investigation for the treatment of non–small cell lung cancer. However, the treatment with vandetanib did not improve overall survival benefit and only modestly improved progression-free survival (PFS) in this patient group.

In the phase III study, 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer were randomized 2:1 to once-daily administration of either vandetanib 300 mg (the maximum tolerated dose) or placebo. AstraZeneca’s analysis showed a significant 54% reduction in risk of progression with vandetanib, improving median PFS by 11 months.

Dose reductions and interruptions because of adverse events in the phase III study and in two phase II studies were troubling, however. In the phase III trial, 36% of vandetanib patients required a dose reduction and 47% required a dose interruption.

Grade 3 or greater adverse events occurred in 55% of vandetanib-treated patients in the phase III trial, compared with 24% in the placebo group. The most common adverse events overall were diarrhea, rash, nausea, and hypertension.

The FDA and the panel were both particularly concerned about adverse event signals from the vandetanib safety database relating to QT interval prolongation, cerebrovascular events, interstitial lung disease/pneumonia and serious skin conditions. Of the total of 3,019 patients in safety database, 319 were treated with 300 mg vandetanib for medullary thyroid cancer.

According to the FDA, the incidence of grade 3-4 QTc prolongation in those patients was 8%. When ECGs were reviewed, more than 35% of patients experienced QTc prolongation greater than 60 ms – a grade 4 toxicity.

The panel was also concerned about events that occurred among the 3,019 patients in the overall safety database, which included sudden death (0.4%), torsade de pointes (less than 0.1%), grade 3-5 interstitial lung disease (0.8%), and Stevens-Johnson syndrome (0.7%).

QT prolongation is dose dependent with a mean prolongation of 35 ms in patients receiving 300 mg vandetanib, according to the FDA.

Given these adverse events, many panel members expressed concern about treating asymptomatic patients with medullary thyroid cancer, which has a long natural history that can involve periods of disease indolence, given the toxicity of the drug. Many panel members cited this as reason for the necessity of postmarketing evaluation of other doses.

The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of potential conflicts of interest by the FDA before a meeting, but it occasionally grants a waiver to a panelist with a conflict of interest.

SILVER SPRING, MD – A Food and Drug Administration panel voted Dec. 2 that the risk-benefit profile of vandetanib is acceptable for at least some patients with medullary thyroid cancer, but that postmarketing evaluation of alternative dosing should be required by the agency as part of its approval.

The Oncologic Drugs Advisory Committee also was asked by the FDA to comment on whether the drug’s indication should be limited to patients with progressive, symptomatic medullary thyroid cancer, given concerns about the safety of the drug. The majority of panel members agreed that some restrictive language should be added to the indication in light of toxicity concerns, particularly the possibility of QTc prolongation.

"The risk-benefit profile is acceptable, from my perspective, for this drug to be approved for this indication. ... I think that there is enough of a signal at lower doses, which presumably would lead to less toxicity, that they should be explored," said panel member Dr. Mikkael Sekeres, who is a professor medicine at the Cleveland Clinic.

Dr. Wyndham Wilson of the National Cancer Institute, Rockville, Md., who is the panel chair, agreed. "It’s all about steady state levels, not about dose. ... The pharmacology data would suggest that you could probably get reasonable steady-state levels with a somewhat lower dose rate and still have equal effectiveness."

Vandetanib is an oral, multiple-tyrosine kinase inhibitor that acts on the vascular endothelial growth factor, epidermal growth factor receptor, and rearranged during transfection pathways. Medullary thyroid cancer patients with early-stage disease can be treated surgically with curative intent; for patients with distant metastases, the 5-year survival rate is approximately 40%.

AstraZeneca, the developer of vandetanib, is seeking an indication for patients with locally advanced or metastatic medullary thyroid cancer.

The drug was previously under investigation for the treatment of non–small cell lung cancer. However, the treatment with vandetanib did not improve overall survival benefit and only modestly improved progression-free survival (PFS) in this patient group.

In the phase III study, 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer were randomized 2:1 to once-daily administration of either vandetanib 300 mg (the maximum tolerated dose) or placebo. AstraZeneca’s analysis showed a significant 54% reduction in risk of progression with vandetanib, improving median PFS by 11 months.

Dose reductions and interruptions because of adverse events in the phase III study and in two phase II studies were troubling, however. In the phase III trial, 36% of vandetanib patients required a dose reduction and 47% required a dose interruption.

Grade 3 or greater adverse events occurred in 55% of vandetanib-treated patients in the phase III trial, compared with 24% in the placebo group. The most common adverse events overall were diarrhea, rash, nausea, and hypertension.

The FDA and the panel were both particularly concerned about adverse event signals from the vandetanib safety database relating to QT interval prolongation, cerebrovascular events, interstitial lung disease/pneumonia and serious skin conditions. Of the total of 3,019 patients in safety database, 319 were treated with 300 mg vandetanib for medullary thyroid cancer.

According to the FDA, the incidence of grade 3-4 QTc prolongation in those patients was 8%. When ECGs were reviewed, more than 35% of patients experienced QTc prolongation greater than 60 ms – a grade 4 toxicity.

The panel was also concerned about events that occurred among the 3,019 patients in the overall safety database, which included sudden death (0.4%), torsade de pointes (less than 0.1%), grade 3-5 interstitial lung disease (0.8%), and Stevens-Johnson syndrome (0.7%).

QT prolongation is dose dependent with a mean prolongation of 35 ms in patients receiving 300 mg vandetanib, according to the FDA.

Given these adverse events, many panel members expressed concern about treating asymptomatic patients with medullary thyroid cancer, which has a long natural history that can involve periods of disease indolence, given the toxicity of the drug. Many panel members cited this as reason for the necessity of postmarketing evaluation of other doses.

The FDA usually follows the recommendations of its advisory panels. Panel members are cleared of potential conflicts of interest by the FDA before a meeting, but it occasionally grants a waiver to a panelist with a conflict of interest.

The insulinlike growth factor I receptor may offer a much-needed therapeutic target for triple-negative breast cancer.

High levels of IGF-IR expression appear to confer a survival benefit for a subset of patients with this type of cancer, based on the results of a small study.

“In triple-negative breast cancer patients younger than 55, high expression is associated with longer survival,” Dr. Agneiszka W. Witkiewicz said at a press briefing sponsored by the American Association for Cancer Research.

Unlike hormone receptor–positive or HER2-positive breast cancers, triple-negative breast cancer has lacked a therapeutic drug target. While triple-negative breast cancer accounts for only 15%-20% of breast cancer cases, it results in half of all breast cancer deaths, said Dr. Witkiewicz, a pathologist at Thomas Jefferson University in Philadelphia.

The researchers evaluated tissue from 99 women with triple-negative breast cancer. They stained the samples with anti-IGF-IR antibody (Ventana Medical Systems Inc.), and scored IGF-IR protein expression. Patients were stratified as high expression (a score of 3) or low expression (scores 0-2). More than a quarter of patients (29%) had high IGF-IR expression – and this was significantly correlated with negative lymph nodes. Among patients older than 55 years, there was no survival difference between those with low and high IGF-IR expression.

The study was presented in Denver at the AACR's International Conference on Molecular Diagnostics in Cancer Therapeutic Development. One of the coauthors is employed by Ventana.

The insulinlike growth factor I receptor may offer a much-needed therapeutic target for triple-negative breast cancer.

High levels of IGF-IR expression appear to confer a survival benefit for a subset of patients with this type of cancer, based on the results of a small study.

“In triple-negative breast cancer patients younger than 55, high expression is associated with longer survival,” Dr. Agneiszka W. Witkiewicz said at a press briefing sponsored by the American Association for Cancer Research.

Unlike hormone receptor–positive or HER2-positive breast cancers, triple-negative breast cancer has lacked a therapeutic drug target. While triple-negative breast cancer accounts for only 15%-20% of breast cancer cases, it results in half of all breast cancer deaths, said Dr. Witkiewicz, a pathologist at Thomas Jefferson University in Philadelphia.

The researchers evaluated tissue from 99 women with triple-negative breast cancer. They stained the samples with anti-IGF-IR antibody (Ventana Medical Systems Inc.), and scored IGF-IR protein expression. Patients were stratified as high expression (a score of 3) or low expression (scores 0-2). More than a quarter of patients (29%) had high IGF-IR expression – and this was significantly correlated with negative lymph nodes. Among patients older than 55 years, there was no survival difference between those with low and high IGF-IR expression.

The study was presented in Denver at the AACR's International Conference on Molecular Diagnostics in Cancer Therapeutic Development. One of the coauthors is employed by Ventana.

The insulinlike growth factor I receptor may offer a much-needed therapeutic target for triple-negative breast cancer.

High levels of IGF-IR expression appear to confer a survival benefit for a subset of patients with this type of cancer, based on the results of a small study.

“In triple-negative breast cancer patients younger than 55, high expression is associated with longer survival,” Dr. Agneiszka W. Witkiewicz said at a press briefing sponsored by the American Association for Cancer Research.

Unlike hormone receptor–positive or HER2-positive breast cancers, triple-negative breast cancer has lacked a therapeutic drug target. While triple-negative breast cancer accounts for only 15%-20% of breast cancer cases, it results in half of all breast cancer deaths, said Dr. Witkiewicz, a pathologist at Thomas Jefferson University in Philadelphia.

The researchers evaluated tissue from 99 women with triple-negative breast cancer. They stained the samples with anti-IGF-IR antibody (Ventana Medical Systems Inc.), and scored IGF-IR protein expression. Patients were stratified as high expression (a score of 3) or low expression (scores 0-2). More than a quarter of patients (29%) had high IGF-IR expression – and this was significantly correlated with negative lymph nodes. Among patients older than 55 years, there was no survival difference between those with low and high IGF-IR expression.

The study was presented in Denver at the AACR's International Conference on Molecular Diagnostics in Cancer Therapeutic Development. One of the coauthors is employed by Ventana.

Bone metabolism appears to change before patients show clinical signs of rheumatoid arthritis and could ultimately serve as an early marker of disease, based on a study of 79 patients.

“There appears to be an alteration in bone metabolism parallel to inflammation and autoimmunity in the asymptomatic preclinical phase of RA, which may reflect the beginning of joint destruction,” according to Dr. Dirkjan van Schaardenburg, a rheumatologist at Jan van Breemen Institute in Amsterdam, and his coinvestigators.

They found significantly increased average levels of only P1NP (procollagen type I intact N-terminal propeptide) and osteoprotegerin in the group of preclinical RA patients, compared with a control group of healthy individuals. Specifically, P1NP increased by 5 ng/mL and osteoprotegerin increased by 4 pmol/L (Ann. Rheum. Dis. 2010 Oct. 18 [doi:10.1136/ard.2010.135723]).

Three blood samples taken 1, 2, and 5 years prior to the onset of symptoms were identified for 47 patients with RA; two samples were collected from 18 patients and one sample was collected from 14 patients. The individuals had been blood donors prior to developing the disease.

The study was funded by the Dutch Arthritis Association. The authors reported that they had no competing interests.

Bone metabolism appears to change before patients show clinical signs of rheumatoid arthritis and could ultimately serve as an early marker of disease, based on a study of 79 patients.

“There appears to be an alteration in bone metabolism parallel to inflammation and autoimmunity in the asymptomatic preclinical phase of RA, which may reflect the beginning of joint destruction,” according to Dr. Dirkjan van Schaardenburg, a rheumatologist at Jan van Breemen Institute in Amsterdam, and his coinvestigators.

They found significantly increased average levels of only P1NP (procollagen type I intact N-terminal propeptide) and osteoprotegerin in the group of preclinical RA patients, compared with a control group of healthy individuals. Specifically, P1NP increased by 5 ng/mL and osteoprotegerin increased by 4 pmol/L (Ann. Rheum. Dis. 2010 Oct. 18 [doi:10.1136/ard.2010.135723]).

Three blood samples taken 1, 2, and 5 years prior to the onset of symptoms were identified for 47 patients with RA; two samples were collected from 18 patients and one sample was collected from 14 patients. The individuals had been blood donors prior to developing the disease.

The study was funded by the Dutch Arthritis Association. The authors reported that they had no competing interests.

Bone metabolism appears to change before patients show clinical signs of rheumatoid arthritis and could ultimately serve as an early marker of disease, based on a study of 79 patients.

“There appears to be an alteration in bone metabolism parallel to inflammation and autoimmunity in the asymptomatic preclinical phase of RA, which may reflect the beginning of joint destruction,” according to Dr. Dirkjan van Schaardenburg, a rheumatologist at Jan van Breemen Institute in Amsterdam, and his coinvestigators.

They found significantly increased average levels of only P1NP (procollagen type I intact N-terminal propeptide) and osteoprotegerin in the group of preclinical RA patients, compared with a control group of healthy individuals. Specifically, P1NP increased by 5 ng/mL and osteoprotegerin increased by 4 pmol/L (Ann. Rheum. Dis. 2010 Oct. 18 [doi:10.1136/ard.2010.135723]).

Three blood samples taken 1, 2, and 5 years prior to the onset of symptoms were identified for 47 patients with RA; two samples were collected from 18 patients and one sample was collected from 14 patients. The individuals had been blood donors prior to developing the disease.

The study was funded by the Dutch Arthritis Association. The authors reported that they had no competing interests.

The insulinlike growth factor I receptor may offer a much-needed therapeutic target for triple-negative breast cancer, which can be notoriously hard to treat.

High levels of insulinlike growth factor I receptor (IGF-IR) expression appear to enhance survival or a subset of patients with this type of cancer, based on the results of a small study.

“In triple-negative breast cancer patients younger than 55, high expression is associated with longer survival,” Dr. Agneiszka W. Witkiewicz said during a press briefing sponsored by the American Association for Cancer Research (AACR).

Unlike hormone receptor– positive or HER2-positive breast cancers, triple-negative breast cancer has lacked a drug target and is managed with conventional chemotherapy. While triple-negative breast cancer accounts for only 15%-20% of breast cancer cases, it results in half of all breast cancer deaths, said Dr. Witkiewicz, a pathologist at Thomas Jefferson University in Philadelphia and an investigator on the study.

Tissue was evaluated from 99 women with triple-negative breast cancer. The samples were stained with anti-IGF-IR antibody (Ventana Medical Systems Inc.), and scored for IGF-IR protein expression according to standardized criteria originally developed to assess HER2 expression. Patients were stratified as high expression (a score of 3) or low expression (scores 0-2).

In all, 29%) of patients had high IGF-IR expression – which was significantly correlated with negative lymph nodes. In patients older than 55 years, there was no survival difference between those with low and high IGF-IR expression.

IGF-IR belongs to the large class of tyrosine kinase receptors that appear to control proliferation and apoptosis in tumors, and may play a role in resistance to chemotherapy.

The study was presented in Denver as a poster at the AACR's International Conference on Molecular Diagnostics in Cancer Therapeutic Development.

One of the coauthors is employed by Ventana Medical Systems, which makes an anti-IGF1-R antibody and is developing an IGF-IR probe.

The insulinlike growth factor I receptor may offer a much-needed therapeutic target for triple-negative breast cancer, which can be notoriously hard to treat.

High levels of insulinlike growth factor I receptor (IGF-IR) expression appear to enhance survival or a subset of patients with this type of cancer, based on the results of a small study.

“In triple-negative breast cancer patients younger than 55, high expression is associated with longer survival,” Dr. Agneiszka W. Witkiewicz said during a press briefing sponsored by the American Association for Cancer Research (AACR).

Unlike hormone receptor– positive or HER2-positive breast cancers, triple-negative breast cancer has lacked a drug target and is managed with conventional chemotherapy. While triple-negative breast cancer accounts for only 15%-20% of breast cancer cases, it results in half of all breast cancer deaths, said Dr. Witkiewicz, a pathologist at Thomas Jefferson University in Philadelphia and an investigator on the study.

Tissue was evaluated from 99 women with triple-negative breast cancer. The samples were stained with anti-IGF-IR antibody (Ventana Medical Systems Inc.), and scored for IGF-IR protein expression according to standardized criteria originally developed to assess HER2 expression. Patients were stratified as high expression (a score of 3) or low expression (scores 0-2).

In all, 29%) of patients had high IGF-IR expression – which was significantly correlated with negative lymph nodes. In patients older than 55 years, there was no survival difference between those with low and high IGF-IR expression.

IGF-IR belongs to the large class of tyrosine kinase receptors that appear to control proliferation and apoptosis in tumors, and may play a role in resistance to chemotherapy.

The study was presented in Denver as a poster at the AACR's International Conference on Molecular Diagnostics in Cancer Therapeutic Development.

One of the coauthors is employed by Ventana Medical Systems, which makes an anti-IGF1-R antibody and is developing an IGF-IR probe.

The insulinlike growth factor I receptor may offer a much-needed therapeutic target for triple-negative breast cancer, which can be notoriously hard to treat.

High levels of insulinlike growth factor I receptor (IGF-IR) expression appear to enhance survival or a subset of patients with this type of cancer, based on the results of a small study.

“In triple-negative breast cancer patients younger than 55, high expression is associated with longer survival,” Dr. Agneiszka W. Witkiewicz said during a press briefing sponsored by the American Association for Cancer Research (AACR).

Unlike hormone receptor– positive or HER2-positive breast cancers, triple-negative breast cancer has lacked a drug target and is managed with conventional chemotherapy. While triple-negative breast cancer accounts for only 15%-20% of breast cancer cases, it results in half of all breast cancer deaths, said Dr. Witkiewicz, a pathologist at Thomas Jefferson University in Philadelphia and an investigator on the study.

Tissue was evaluated from 99 women with triple-negative breast cancer. The samples were stained with anti-IGF-IR antibody (Ventana Medical Systems Inc.), and scored for IGF-IR protein expression according to standardized criteria originally developed to assess HER2 expression. Patients were stratified as high expression (a score of 3) or low expression (scores 0-2).

In all, 29%) of patients had high IGF-IR expression – which was significantly correlated with negative lymph nodes. In patients older than 55 years, there was no survival difference between those with low and high IGF-IR expression.

IGF-IR belongs to the large class of tyrosine kinase receptors that appear to control proliferation and apoptosis in tumors, and may play a role in resistance to chemotherapy.

The study was presented in Denver as a poster at the AACR's International Conference on Molecular Diagnostics in Cancer Therapeutic Development.

One of the coauthors is employed by Ventana Medical Systems, which makes an anti-IGF1-R antibody and is developing an IGF-IR probe.

The American Academy of Dermatology Association has updated its position statement on the use of isotretinoin, continuing to support physician-monitored use of the drug for severe acne.

"Isotretinoin continues to be considered a critically important drug for treating patients with severe acne who fail other therapies," Dr. William D. James, president of the AAD, noted in a statement. "Isotretinoin offers our patients with severe acne significant, life-changing benefits. Providing this medicine safely is our top priority."

The update follows the publication of studies that failed to support claims of a link between depression and isotretinoin and a link between inflammatory bowel disease and isotretinoin.

In particular, the group noted that "a correlation between isotretinoin use and depression/anxiety symptoms has been suggested but an evidence-based causal relationship has not been established."

A study published in November suggested that suicide risk is more likely related to the psychological effects associated with severe acne than to isotretinoin use (BMJ 2010;341:c5812).

Likewise, the group stated that "current evidence is insufficient to prove either an association or a causal relationship between isotretinoin use and inflammatory bowel disease (IBD) in the general population."

In two studies published in 2009, researchers found no clear relationship between isotretinoin and IBD (Am. J. Gastroenterol. 2009;104:2774-8 and Am. J. Gastroenterol. 2009;104:2387-93).

Physicians should be aware of these potential concerns and discuss them with their patients. Physicians should also monitor patients for any indication of these symptoms, noted Dr. James.

The AAD also called for continued compliance with the manufacturer-sponsored and FDA-approved risk management program for prescribing isotretinoin (iPLEDGE).

The complete position statement on isotretinoin is available on the AAD’s Web site.

The American Academy of Dermatology Association has updated its position statement on the use of isotretinoin, continuing to support physician-monitored use of the drug for severe acne.

"Isotretinoin continues to be considered a critically important drug for treating patients with severe acne who fail other therapies," Dr. William D. James, president of the AAD, noted in a statement. "Isotretinoin offers our patients with severe acne significant, life-changing benefits. Providing this medicine safely is our top priority."

The update follows the publication of studies that failed to support claims of a link between depression and isotretinoin and a link between inflammatory bowel disease and isotretinoin.

In particular, the group noted that "a correlation between isotretinoin use and depression/anxiety symptoms has been suggested but an evidence-based causal relationship has not been established."

A study published in November suggested that suicide risk is more likely related to the psychological effects associated with severe acne than to isotretinoin use (BMJ 2010;341:c5812).

Likewise, the group stated that "current evidence is insufficient to prove either an association or a causal relationship between isotretinoin use and inflammatory bowel disease (IBD) in the general population."

In two studies published in 2009, researchers found no clear relationship between isotretinoin and IBD (Am. J. Gastroenterol. 2009;104:2774-8 and Am. J. Gastroenterol. 2009;104:2387-93).

Physicians should be aware of these potential concerns and discuss them with their patients. Physicians should also monitor patients for any indication of these symptoms, noted Dr. James.

The AAD also called for continued compliance with the manufacturer-sponsored and FDA-approved risk management program for prescribing isotretinoin (iPLEDGE).

The complete position statement on isotretinoin is available on the AAD’s Web site.

The American Academy of Dermatology Association has updated its position statement on the use of isotretinoin, continuing to support physician-monitored use of the drug for severe acne.

"Isotretinoin continues to be considered a critically important drug for treating patients with severe acne who fail other therapies," Dr. William D. James, president of the AAD, noted in a statement. "Isotretinoin offers our patients with severe acne significant, life-changing benefits. Providing this medicine safely is our top priority."

The update follows the publication of studies that failed to support claims of a link between depression and isotretinoin and a link between inflammatory bowel disease and isotretinoin.

In particular, the group noted that "a correlation between isotretinoin use and depression/anxiety symptoms has been suggested but an evidence-based causal relationship has not been established."

A study published in November suggested that suicide risk is more likely related to the psychological effects associated with severe acne than to isotretinoin use (BMJ 2010;341:c5812).

Likewise, the group stated that "current evidence is insufficient to prove either an association or a causal relationship between isotretinoin use and inflammatory bowel disease (IBD) in the general population."

In two studies published in 2009, researchers found no clear relationship between isotretinoin and IBD (Am. J. Gastroenterol. 2009;104:2774-8 and Am. J. Gastroenterol. 2009;104:2387-93).

Physicians should be aware of these potential concerns and discuss them with their patients. Physicians should also monitor patients for any indication of these symptoms, noted Dr. James.

The AAD also called for continued compliance with the manufacturer-sponsored and FDA-approved risk management program for prescribing isotretinoin (iPLEDGE).

The complete position statement on isotretinoin is available on the AAD’s Web site.

The American Academy of Dermatology Association has updated its position statement on the use of isotretinoin, continuing to support physician-monitored use of the drug for severe acne.

"Isotretinoin continues to be considered a critically important drug for treating patients with severe acne who fail other therapies," Dr. William D. James, president of the AAD, noted in a statement. "Isotretinoin offers our patients with severe acne significant, life-changing benefits. Providing this medicine safely is our top priority."

The update follows the publication of studies that failed to support claims of a link between depression and isotretinoin and a link between inflammatory bowel disease and isotretinoin.

In particular, the group noted that "a correlation between isotretinoin use and depression/anxiety symptoms has been suggested but an evidence-based causal relationship has not been established."

A study published in November suggested that suicide risk is more likely related to the psychological effects associated with severe acne than to isotretinoin use (BMJ 2010;341:c5812).

Likewise, the group stated that "current evidence is insufficient to prove either an association or a causal relationship between isotretinoin use and inflammatory bowel disease (IBD) in the general population."

In two studies published in 2009, researchers found no clear relationship between isotretinoin and IBD (Am. J. Gastroenterol. 2009;104:2774-8 and Am. J. Gastroenterol. 2009;104:2387-93).

Physicians should be aware of these potential concerns and discuss them with their patients. Physicians should also monitor patients for any indication of these symptoms, noted Dr. James.

The AAD also called for continued compliance with the manufacturer-sponsored and FDA-approved risk management program for prescribing isotretinoin (iPLEDGE).

The complete position statement on isotretinoin is available on the AAD’s Web site.

The American Academy of Dermatology Association has updated its position statement on the use of isotretinoin, continuing to support physician-monitored use of the drug for severe acne.

"Isotretinoin continues to be considered a critically important drug for treating patients with severe acne who fail other therapies," Dr. William D. James, president of the AAD, noted in a statement. "Isotretinoin offers our patients with severe acne significant, life-changing benefits. Providing this medicine safely is our top priority."

The update follows the publication of studies that failed to support claims of a link between depression and isotretinoin and a link between inflammatory bowel disease and isotretinoin.

In particular, the group noted that "a correlation between isotretinoin use and depression/anxiety symptoms has been suggested but an evidence-based causal relationship has not been established."

A study published in November suggested that suicide risk is more likely related to the psychological effects associated with severe acne than to isotretinoin use (BMJ 2010;341:c5812).

Likewise, the group stated that "current evidence is insufficient to prove either an association or a causal relationship between isotretinoin use and inflammatory bowel disease (IBD) in the general population."

In two studies published in 2009, researchers found no clear relationship between isotretinoin and IBD (Am. J. Gastroenterol. 2009;104:2774-8 and Am. J. Gastroenterol. 2009;104:2387-93).

Physicians should be aware of these potential concerns and discuss them with their patients. Physicians should also monitor patients for any indication of these symptoms, noted Dr. James.

The AAD also called for continued compliance with the manufacturer-sponsored and FDA-approved risk management program for prescribing isotretinoin (iPLEDGE).

The complete position statement on isotretinoin is available on the AAD’s Web site.

The American Academy of Dermatology Association has updated its position statement on the use of isotretinoin, continuing to support physician-monitored use of the drug for severe acne.

"Isotretinoin continues to be considered a critically important drug for treating patients with severe acne who fail other therapies," Dr. William D. James, president of the AAD, noted in a statement. "Isotretinoin offers our patients with severe acne significant, life-changing benefits. Providing this medicine safely is our top priority."

The update follows the publication of studies that failed to support claims of a link between depression and isotretinoin and a link between inflammatory bowel disease and isotretinoin.

In particular, the group noted that "a correlation between isotretinoin use and depression/anxiety symptoms has been suggested but an evidence-based causal relationship has not been established."

A study published in November suggested that suicide risk is more likely related to the psychological effects associated with severe acne than to isotretinoin use (BMJ 2010;341:c5812).

Likewise, the group stated that "current evidence is insufficient to prove either an association or a causal relationship between isotretinoin use and inflammatory bowel disease (IBD) in the general population."

In two studies published in 2009, researchers found no clear relationship between isotretinoin and IBD (Am. J. Gastroenterol. 2009;104:2774-8 and Am. J. Gastroenterol. 2009;104:2387-93).

Physicians should be aware of these potential concerns and discuss them with their patients. Physicians should also monitor patients for any indication of these symptoms, noted Dr. James.

The AAD also called for continued compliance with the manufacturer-sponsored and FDA-approved risk management program for prescribing isotretinoin (iPLEDGE).

The complete position statement on isotretinoin is available on the AAD’s Web site.