CHICAGO – Tesetaxel, an investigational oral taxane, is highly active when used to treat chemotherapy-naive metastatic breast cancer, a phase II trial suggests. And in contrast to the main intravenously administered taxanes, it does not require steroidal premedication and can cause little-to-no peripheral neuropathy.

A total of 46 women were treated with tesetaxel just once every 3 weeks during an office visit in the trial. The overall response rate was 45% – at least a bit higher than the roughly 20%-35% previously seen with the intravenously administered taxanes paclitaxel (Taxol) and docetaxel (Taxotere), according to presenting author Dr. Loretta M. Itri.

"This compares favorably. This is a phase II open-label study. I’m sure the response rate is going to fall a little bit over time, but ... I think we are going to be nothing less than equivalent to the other taxanes," she said in an interview at the annual meeting of the American Society of Clinical Oncology.

A provision for dose escalation from 27 mg/m² to 35 mg/m² was halted halfway through the trial because there was minimal gain in efficacy but substantially more toxicity. "So this [27 mg/m²] is the dose that we will be taking forward in our clinical trials, and we are abandoning escalation," she said. There were no cases of hypersensitivity reaction regardless of dose used; the rate of grade 3 peripheral neuropathy was 16% with dose escalation but 0% without it.

The majority of the patients having progression on treatment had triple-negative disease, Dr. Itri noted. "Now that we know that it’s the triple-negatives who have recently received a taxane who are the ones who don’t respond, we will probably begin excluding that population ... so that we can further enrich [the study population]. We want to give the drug to people whom we can do something good for," she said.

The next step in breast cancer is an ongoing three-arm phase IIb trial comparing tesetaxel given every 3 weeks vs. weekly, and also comparing it with capecitabine (Xeloda), in about 200 patients.

"What’s interesting about the weekly dose is that we have seen in the phase I study no significant neutropenia. So we feel obligated to evaluate the weekly dose, because if we truly had a taxane regimen with no neutropenia, that could be important," said Dr. Itri, an oncologist and chief medical officer of Genta, the company that is developing tesetaxel.

"I will tell you that I have a real bias here ... The weekly dosing is going to really have to be something special for us to abandon the every-3-week dosing, because the convenience and the compliance are so easy," she continued. "These women have a life to live, and the drug was designed to be as user friendly as possible, and I personally don’t like the idea of sending patients home with cytotoxic chemotherapy."

Discussant Dr. Stacy L. Moulder of the University of Texas M.D. Anderson Cancer Center, Houston, noted the advantages of tesetaxel over intravenous taxanes with respect to factors such as oral administration, no need for premedication, and, possibly, reduced toxicity. "But the question that remains is, is this the best microtubule inhibitor?"

She pointed out that a trial of nab-paclitaxel (Abraxane) found approximately double the median duration of progression-free survival seen with tesetaxel in this trial and a fairly similar rate of higher-grade peripheral neuropathy (J. Clin. Oncol. 2009;27:3611-9). "So I think it remains unanswered whether this drug is as good as some of the currently existing novel taxanes," she maintained.

Unlike the intravenous taxanes, tesetaxel is not a substrate for P-glycoprotein (PGP), a transmembrane pump that is likely the main mechanism of taxane resistance, according to Dr. Itri. Thus, it is highly concentrated in cells that overexpress PGP. In preclinical studies, tesetaxel’s cytotoxic activity has been 3-10 times greater than that of the intravenous taxanes in cells not expressing PGP and 10-100 times greater in multidrug-resistant tumor cells overexpressing PGP.

Women were eligible for the trial if they had HER2-negative, chemotherapy-naive metastatic breast cancer. (Those with hormone receptor–positive disease could have received hormonal therapy for their metastases.) Prior adjuvant taxane therapy given more than a year before enrollment was permitted.

The women received single-agent tesetaxel orally once every 3 weeks and without any antiallergy premedication but with an oral antiemetic as a precaution. "We have completed an effect-of-food study; the drug can be administered with or without food, so there is no need for fasting," Dr. Itri said.

"The patient takes their pill in front of the doctor, so the doctor knows that the patient has gotten a full dose. There is no compliance question," she further noted. "Then they go home and they come back 3 weeks later."

The starting dose was 27 mg/m² every 3 weeks. For the first half of the trial, the dose was escalated up to 35 mg/m² every 3 weeks if tolerated.

Overall, 20% of women had triple-negative disease, according to results reported in a poster session. More than half each had liver metastases (52%) and lung metastases (57%). Fifty-seven percent had received a taxane as part of their adjuvant therapy.

The median number of cycles of tesetaxel received was 4 (range, 1-17). The overall response rate was 45% (49% in women with estrogen receptor–positive disease and 33% in women with triple-negative disease).

The overall response rate was nearly the same among women who received only the nonescalated dose (44%) and among women who received the escalated dose (47%).

An additional 36% of patients achieved stable disease. Median progression-free survival was 5.8 months for all treated patients and 7.3 months for those with estrogen receptor–positive disease.

"Pretty much, the tolerability profile looks really good," Dr. Itri commented. In particular, none of the patients had hypersensitivity reactions.

By far, the most common grade 3/4 adverse event was neutropenia, seen in 33% of patients overall (26% without dose escalation and 43% with it). However, "none of these patients required a colony-stimulating factor or were febrile. So this now becomes a true outpatient regimen," she said.

The rate of grade 3 peripheral neuropathy was 7% overall (0% without dose escalation and 16% with it), and there was no grade 4 peripheral neuropathy. The rate of grade 2 alopecia was 15% regardless of dose.

Genta sponsored the trial. Dr. Itri disclosed employment and stock ownership in Genta. Dr. Moulder disclosed no relevant conflicts of interest.

CHICAGO – Tesetaxel, an investigational oral taxane, is highly active when used to treat chemotherapy-naive metastatic breast cancer, a phase II trial suggests. And in contrast to the main intravenously administered taxanes, it does not require steroidal premedication and can cause little-to-no peripheral neuropathy.

A total of 46 women were treated with tesetaxel just once every 3 weeks during an office visit in the trial. The overall response rate was 45% – at least a bit higher than the roughly 20%-35% previously seen with the intravenously administered taxanes paclitaxel (Taxol) and docetaxel (Taxotere), according to presenting author Dr. Loretta M. Itri.

"This compares favorably. This is a phase II open-label study. I’m sure the response rate is going to fall a little bit over time, but ... I think we are going to be nothing less than equivalent to the other taxanes," she said in an interview at the annual meeting of the American Society of Clinical Oncology.

A provision for dose escalation from 27 mg/m² to 35 mg/m² was halted halfway through the trial because there was minimal gain in efficacy but substantially more toxicity. "So this [27 mg/m²] is the dose that we will be taking forward in our clinical trials, and we are abandoning escalation," she said. There were no cases of hypersensitivity reaction regardless of dose used; the rate of grade 3 peripheral neuropathy was 16% with dose escalation but 0% without it.

The majority of the patients having progression on treatment had triple-negative disease, Dr. Itri noted. "Now that we know that it’s the triple-negatives who have recently received a taxane who are the ones who don’t respond, we will probably begin excluding that population ... so that we can further enrich [the study population]. We want to give the drug to people whom we can do something good for," she said.

The next step in breast cancer is an ongoing three-arm phase IIb trial comparing tesetaxel given every 3 weeks vs. weekly, and also comparing it with capecitabine (Xeloda), in about 200 patients.

"What’s interesting about the weekly dose is that we have seen in the phase I study no significant neutropenia. So we feel obligated to evaluate the weekly dose, because if we truly had a taxane regimen with no neutropenia, that could be important," said Dr. Itri, an oncologist and chief medical officer of Genta, the company that is developing tesetaxel.

"I will tell you that I have a real bias here ... The weekly dosing is going to really have to be something special for us to abandon the every-3-week dosing, because the convenience and the compliance are so easy," she continued. "These women have a life to live, and the drug was designed to be as user friendly as possible, and I personally don’t like the idea of sending patients home with cytotoxic chemotherapy."

Discussant Dr. Stacy L. Moulder of the University of Texas M.D. Anderson Cancer Center, Houston, noted the advantages of tesetaxel over intravenous taxanes with respect to factors such as oral administration, no need for premedication, and, possibly, reduced toxicity. "But the question that remains is, is this the best microtubule inhibitor?"

She pointed out that a trial of nab-paclitaxel (Abraxane) found approximately double the median duration of progression-free survival seen with tesetaxel in this trial and a fairly similar rate of higher-grade peripheral neuropathy (J. Clin. Oncol. 2009;27:3611-9). "So I think it remains unanswered whether this drug is as good as some of the currently existing novel taxanes," she maintained.

Unlike the intravenous taxanes, tesetaxel is not a substrate for P-glycoprotein (PGP), a transmembrane pump that is likely the main mechanism of taxane resistance, according to Dr. Itri. Thus, it is highly concentrated in cells that overexpress PGP. In preclinical studies, tesetaxel’s cytotoxic activity has been 3-10 times greater than that of the intravenous taxanes in cells not expressing PGP and 10-100 times greater in multidrug-resistant tumor cells overexpressing PGP.

Women were eligible for the trial if they had HER2-negative, chemotherapy-naive metastatic breast cancer. (Those with hormone receptor–positive disease could have received hormonal therapy for their metastases.) Prior adjuvant taxane therapy given more than a year before enrollment was permitted.

The women received single-agent tesetaxel orally once every 3 weeks and without any antiallergy premedication but with an oral antiemetic as a precaution. "We have completed an effect-of-food study; the drug can be administered with or without food, so there is no need for fasting," Dr. Itri said.

"The patient takes their pill in front of the doctor, so the doctor knows that the patient has gotten a full dose. There is no compliance question," she further noted. "Then they go home and they come back 3 weeks later."

The starting dose was 27 mg/m² every 3 weeks. For the first half of the trial, the dose was escalated up to 35 mg/m² every 3 weeks if tolerated.

Overall, 20% of women had triple-negative disease, according to results reported in a poster session. More than half each had liver metastases (52%) and lung metastases (57%). Fifty-seven percent had received a taxane as part of their adjuvant therapy.

The median number of cycles of tesetaxel received was 4 (range, 1-17). The overall response rate was 45% (49% in women with estrogen receptor–positive disease and 33% in women with triple-negative disease).

The overall response rate was nearly the same among women who received only the nonescalated dose (44%) and among women who received the escalated dose (47%).

An additional 36% of patients achieved stable disease. Median progression-free survival was 5.8 months for all treated patients and 7.3 months for those with estrogen receptor–positive disease.

"Pretty much, the tolerability profile looks really good," Dr. Itri commented. In particular, none of the patients had hypersensitivity reactions.

By far, the most common grade 3/4 adverse event was neutropenia, seen in 33% of patients overall (26% without dose escalation and 43% with it). However, "none of these patients required a colony-stimulating factor or were febrile. So this now becomes a true outpatient regimen," she said.

The rate of grade 3 peripheral neuropathy was 7% overall (0% without dose escalation and 16% with it), and there was no grade 4 peripheral neuropathy. The rate of grade 2 alopecia was 15% regardless of dose.

Genta sponsored the trial. Dr. Itri disclosed employment and stock ownership in Genta. Dr. Moulder disclosed no relevant conflicts of interest.

CHICAGO – Tesetaxel, an investigational oral taxane, is highly active when used to treat chemotherapy-naive metastatic breast cancer, a phase II trial suggests. And in contrast to the main intravenously administered taxanes, it does not require steroidal premedication and can cause little-to-no peripheral neuropathy.

A total of 46 women were treated with tesetaxel just once every 3 weeks during an office visit in the trial. The overall response rate was 45% – at least a bit higher than the roughly 20%-35% previously seen with the intravenously administered taxanes paclitaxel (Taxol) and docetaxel (Taxotere), according to presenting author Dr. Loretta M. Itri.

"This compares favorably. This is a phase II open-label study. I’m sure the response rate is going to fall a little bit over time, but ... I think we are going to be nothing less than equivalent to the other taxanes," she said in an interview at the annual meeting of the American Society of Clinical Oncology.

A provision for dose escalation from 27 mg/m² to 35 mg/m² was halted halfway through the trial because there was minimal gain in efficacy but substantially more toxicity. "So this [27 mg/m²] is the dose that we will be taking forward in our clinical trials, and we are abandoning escalation," she said. There were no cases of hypersensitivity reaction regardless of dose used; the rate of grade 3 peripheral neuropathy was 16% with dose escalation but 0% without it.

The majority of the patients having progression on treatment had triple-negative disease, Dr. Itri noted. "Now that we know that it’s the triple-negatives who have recently received a taxane who are the ones who don’t respond, we will probably begin excluding that population ... so that we can further enrich [the study population]. We want to give the drug to people whom we can do something good for," she said.

The next step in breast cancer is an ongoing three-arm phase IIb trial comparing tesetaxel given every 3 weeks vs. weekly, and also comparing it with capecitabine (Xeloda), in about 200 patients.

"What’s interesting about the weekly dose is that we have seen in the phase I study no significant neutropenia. So we feel obligated to evaluate the weekly dose, because if we truly had a taxane regimen with no neutropenia, that could be important," said Dr. Itri, an oncologist and chief medical officer of Genta, the company that is developing tesetaxel.

"I will tell you that I have a real bias here ... The weekly dosing is going to really have to be something special for us to abandon the every-3-week dosing, because the convenience and the compliance are so easy," she continued. "These women have a life to live, and the drug was designed to be as user friendly as possible, and I personally don’t like the idea of sending patients home with cytotoxic chemotherapy."

Discussant Dr. Stacy L. Moulder of the University of Texas M.D. Anderson Cancer Center, Houston, noted the advantages of tesetaxel over intravenous taxanes with respect to factors such as oral administration, no need for premedication, and, possibly, reduced toxicity. "But the question that remains is, is this the best microtubule inhibitor?"

She pointed out that a trial of nab-paclitaxel (Abraxane) found approximately double the median duration of progression-free survival seen with tesetaxel in this trial and a fairly similar rate of higher-grade peripheral neuropathy (J. Clin. Oncol. 2009;27:3611-9). "So I think it remains unanswered whether this drug is as good as some of the currently existing novel taxanes," she maintained.

Unlike the intravenous taxanes, tesetaxel is not a substrate for P-glycoprotein (PGP), a transmembrane pump that is likely the main mechanism of taxane resistance, according to Dr. Itri. Thus, it is highly concentrated in cells that overexpress PGP. In preclinical studies, tesetaxel’s cytotoxic activity has been 3-10 times greater than that of the intravenous taxanes in cells not expressing PGP and 10-100 times greater in multidrug-resistant tumor cells overexpressing PGP.

Women were eligible for the trial if they had HER2-negative, chemotherapy-naive metastatic breast cancer. (Those with hormone receptor–positive disease could have received hormonal therapy for their metastases.) Prior adjuvant taxane therapy given more than a year before enrollment was permitted.

The women received single-agent tesetaxel orally once every 3 weeks and without any antiallergy premedication but with an oral antiemetic as a precaution. "We have completed an effect-of-food study; the drug can be administered with or without food, so there is no need for fasting," Dr. Itri said.

"The patient takes their pill in front of the doctor, so the doctor knows that the patient has gotten a full dose. There is no compliance question," she further noted. "Then they go home and they come back 3 weeks later."

The starting dose was 27 mg/m² every 3 weeks. For the first half of the trial, the dose was escalated up to 35 mg/m² every 3 weeks if tolerated.

Overall, 20% of women had triple-negative disease, according to results reported in a poster session. More than half each had liver metastases (52%) and lung metastases (57%). Fifty-seven percent had received a taxane as part of their adjuvant therapy.

The median number of cycles of tesetaxel received was 4 (range, 1-17). The overall response rate was 45% (49% in women with estrogen receptor–positive disease and 33% in women with triple-negative disease).

The overall response rate was nearly the same among women who received only the nonescalated dose (44%) and among women who received the escalated dose (47%).

An additional 36% of patients achieved stable disease. Median progression-free survival was 5.8 months for all treated patients and 7.3 months for those with estrogen receptor–positive disease.

"Pretty much, the tolerability profile looks really good," Dr. Itri commented. In particular, none of the patients had hypersensitivity reactions.

By far, the most common grade 3/4 adverse event was neutropenia, seen in 33% of patients overall (26% without dose escalation and 43% with it). However, "none of these patients required a colony-stimulating factor or were febrile. So this now becomes a true outpatient regimen," she said.

The rate of grade 3 peripheral neuropathy was 7% overall (0% without dose escalation and 16% with it), and there was no grade 4 peripheral neuropathy. The rate of grade 2 alopecia was 15% regardless of dose.

Genta sponsored the trial. Dr. Itri disclosed employment and stock ownership in Genta. Dr. Moulder disclosed no relevant conflicts of interest.

GlaxoSmithKline PLC pulled its application for a new indication for lapatinib less than 2 weeks before a scheduled advisory committee review – a decision that may have stemmed from Food and Drug Administration questions about the breast cancer drug’s efficacy.

GSK announced on July 12 that it had withdrawn the sNDA (supplemental New Drug Application) for lapatinib (Tykerb) in combination with trastuzumab (Herceptin) for use in patients with HER2-positive metastatic breast cancer who received prior trastuzumab therapy.

The application was scheduled for review by the FDA’s Oncologic Drugs Advisory Committee (ODAC) on the morning of July 24. Because GSK would have received the agency’s briefing package for that meeting 2-3 weeks ahead of time, the timing of the withdrawal announcement suggests that the application garnered a negative evaluation by oncology division reviewers and faced a challenging ODAC meeting.

"Our discussions [with the FDA] highlighted questions that could not be addressed with the data currently available," GSK Oncology R&D Head Rafael Amado said in a press release. "We have decided to withdraw our application [in the United States] with the intent to wait for ongoing studies testing the combination of lapatinib with trastuzumab."

Regulatory reviews of the combination use of lapatinib and trastuzumab are ongoing in the European Union and other regions, the company said.

The sNDA was aimed at adding a third indication to the label of lapatinib, which gained initial approval in March 2007. The kinase inhibitor is currently indicated for use with capecitabine (Xeloda) in patients with advanced or metastatic HER2-positive breast cancer who have received prior therapy, including an anthracycline, a taxane, and trastuzumab; and with letrozole (Femara) for the treatment of postmenopausal women with hormone receptor–positive, HER2-positive metastatic breast cancer for whom hormonal therapy is indicated.

The lapatinib-trastuzumab combination would have been the second FDA-approved combination of two targeted agents against HER2-positive breast cancer. In June, the agency approved pertuzumab (Perjeta), in combination with trastuzumab and chemotherapy, for first-line treatment of HER2-positive metastatic breast cancer.

A 4-Week PFS Advantage ...

GSK declined to comment further on the FDA’s observations about the data in the sNDA, saying that its discussions with the agency are proprietary and confidential. Nevertheless, the pivotal trial’s published results suggest the agency may have questioned whether the lapatinib-trastuzumab combination’s efficacy was sufficiently robust and clinically meaningful.

The filing was based on the results of an open-label, phase III study of 296 patients with HER2-positive metastatic breast cancer whose disease had progressed on trastuzumab-containing regimens. The study results were presented at the 2008 American Society of Clinical Oncology (ASCO) annual meeting.

Subjects were randomized 1:1 to receive either lapatinib monotherapy or lapatinib in combination with trastuzumab. Efficacy assessments were performed every 4 weeks through week 16 and every 8 weeks thereafter. Patients with disease progression after receiving at least 4 weeks of study treatment with lapatinib monotherapy were permitted to cross over to the combination treatment, according to published study results (J. Clin. Oncol. 2010;28:1124-30).

The primary end point was progression-free survival based on investigator assessment, with supporting data provided through an independent review. Secondary end points included overall response rate, clinical benefit response rate, overall survival, quality of life, and safety.

According to the published results, the lapatinib-trastuzumab combination was associated with a statistically significant 27% reduced risk of progression or death, compared with lapatinib monotherapy, based upon investigator assessment (hazard ratio, 0.73; 95% confidence interval, 0.57-0.93; P = .008). Median progression-free survival with the combination was 12.0 weeks, compared with 8.1 weeks for lapatinib monotherapy. Independent review verified a statistically significant improvement (HR, 0.71; 95% CI, 0.52-0.98; P = .027).

Median overall survival was 51.6 weeks in the combination group, compared with 39.0 weeks in the lapatinib monotherapy arm. "Although these data are not mature (56% censoring rate), they show a trend in improved overall survival after combination therapy (HR, 0.75; 95% CI, 0.53-1.07; P = .106)," the study’s authors, led by Dr. Kimberly Blackwell of Duke University in Durham, N.C., wrote.

The overall incidence of adverse events was similar between the two groups, although the incidence of diarrhea was significantly higher with combination therapy.

... May Not Have Been Enough for the FDA

The results, as published, appear to raise several red flags from an FDA review perspective. Specifically, oncology review staff may have questioned whether a median progression-free survival advantage of 4 weeks is clinically meaningful.

This was the crux of the issue in the agency’s decision to withdraw the metastatic breast cancer indication from the label of bevacizumab (Avastin). Accelerated approval was originally granted for a bevacizumab breast cancer claim on the basis of the open-label ECOG (Eastern Cooperative Oncology Group) 2100 trial, which demonstrated a median progression-free survival advantage of 5.5 months; however, confirmatory trials showed smaller median improvements ranging from 0.9-2.9 months, and the agency determined these subsequent studies failed to verify the magnitude of benefit seen in ECOG 2100.

The agency also may have had concerns about the lapatinib study’s use of a primary end point based upon investigator assessment.

For open-label trials using progression-free survival as the primary end point, the agency generally requires 100% blinded independent review of progression determinations, although it has indicated a willingness to consider relaxing this requirement. During the afternoon session of ODAC’s July 24 meeting, the committee will discuss the feasibility of conducting independent audits of only a subgroup of patient scans in trials using this end point.

The fact that independent blinded review was not the lapatinib trial’s primary end point might have been a concern for the agency, as might related issues such as missing data or informative censoring. Furthermore, the upper limit of the 95% confidence interval for the independent review results fell just below 1.0, according to the published results, and this statistical result may not have held up under further scrutiny by agency reviewers.

Waiting on Other Studies

Although GSK said that it would await the results from other studies that will provide additional information about the combination of lapatinib with trastuzumab, it declined to highlight any one study in particular.

The ClinicalTrials.gov database lists numerous breast cancer studies, currently in recruitment, for which both lapatinib and trastuzumab are study interventions.

These include a randomized, open-label, phase III trial evaluating the efficacy and safety of lapatinib in combination with trastuzumab vs. trastuzumab alone as maintenance therapy in women with HER2-positive metastatic breast cancer. The 280-patient study, which is being conducted in the United States and Canada, is expected to complete in August 2014.

Another phase III trial is comparing the safety and efficacy of an aromatase inhibitor in combination with lapatinib, trastuzumab or both for the treatment of hormone receptor–positive, HER2-positive metastatic breast cancer. The estimated completion date for the 525-patient study is December 2017.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

GlaxoSmithKline PLC pulled its application for a new indication for lapatinib less than 2 weeks before a scheduled advisory committee review – a decision that may have stemmed from Food and Drug Administration questions about the breast cancer drug’s efficacy.

GSK announced on July 12 that it had withdrawn the sNDA (supplemental New Drug Application) for lapatinib (Tykerb) in combination with trastuzumab (Herceptin) for use in patients with HER2-positive metastatic breast cancer who received prior trastuzumab therapy.

The application was scheduled for review by the FDA’s Oncologic Drugs Advisory Committee (ODAC) on the morning of July 24. Because GSK would have received the agency’s briefing package for that meeting 2-3 weeks ahead of time, the timing of the withdrawal announcement suggests that the application garnered a negative evaluation by oncology division reviewers and faced a challenging ODAC meeting.

"Our discussions [with the FDA] highlighted questions that could not be addressed with the data currently available," GSK Oncology R&D Head Rafael Amado said in a press release. "We have decided to withdraw our application [in the United States] with the intent to wait for ongoing studies testing the combination of lapatinib with trastuzumab."

Regulatory reviews of the combination use of lapatinib and trastuzumab are ongoing in the European Union and other regions, the company said.

The sNDA was aimed at adding a third indication to the label of lapatinib, which gained initial approval in March 2007. The kinase inhibitor is currently indicated for use with capecitabine (Xeloda) in patients with advanced or metastatic HER2-positive breast cancer who have received prior therapy, including an anthracycline, a taxane, and trastuzumab; and with letrozole (Femara) for the treatment of postmenopausal women with hormone receptor–positive, HER2-positive metastatic breast cancer for whom hormonal therapy is indicated.

The lapatinib-trastuzumab combination would have been the second FDA-approved combination of two targeted agents against HER2-positive breast cancer. In June, the agency approved pertuzumab (Perjeta), in combination with trastuzumab and chemotherapy, for first-line treatment of HER2-positive metastatic breast cancer.

A 4-Week PFS Advantage ...

GSK declined to comment further on the FDA’s observations about the data in the sNDA, saying that its discussions with the agency are proprietary and confidential. Nevertheless, the pivotal trial’s published results suggest the agency may have questioned whether the lapatinib-trastuzumab combination’s efficacy was sufficiently robust and clinically meaningful.

The filing was based on the results of an open-label, phase III study of 296 patients with HER2-positive metastatic breast cancer whose disease had progressed on trastuzumab-containing regimens. The study results were presented at the 2008 American Society of Clinical Oncology (ASCO) annual meeting.

Subjects were randomized 1:1 to receive either lapatinib monotherapy or lapatinib in combination with trastuzumab. Efficacy assessments were performed every 4 weeks through week 16 and every 8 weeks thereafter. Patients with disease progression after receiving at least 4 weeks of study treatment with lapatinib monotherapy were permitted to cross over to the combination treatment, according to published study results (J. Clin. Oncol. 2010;28:1124-30).

The primary end point was progression-free survival based on investigator assessment, with supporting data provided through an independent review. Secondary end points included overall response rate, clinical benefit response rate, overall survival, quality of life, and safety.

According to the published results, the lapatinib-trastuzumab combination was associated with a statistically significant 27% reduced risk of progression or death, compared with lapatinib monotherapy, based upon investigator assessment (hazard ratio, 0.73; 95% confidence interval, 0.57-0.93; P = .008). Median progression-free survival with the combination was 12.0 weeks, compared with 8.1 weeks for lapatinib monotherapy. Independent review verified a statistically significant improvement (HR, 0.71; 95% CI, 0.52-0.98; P = .027).

Median overall survival was 51.6 weeks in the combination group, compared with 39.0 weeks in the lapatinib monotherapy arm. "Although these data are not mature (56% censoring rate), they show a trend in improved overall survival after combination therapy (HR, 0.75; 95% CI, 0.53-1.07; P = .106)," the study’s authors, led by Dr. Kimberly Blackwell of Duke University in Durham, N.C., wrote.

The overall incidence of adverse events was similar between the two groups, although the incidence of diarrhea was significantly higher with combination therapy.

... May Not Have Been Enough for the FDA

The results, as published, appear to raise several red flags from an FDA review perspective. Specifically, oncology review staff may have questioned whether a median progression-free survival advantage of 4 weeks is clinically meaningful.

This was the crux of the issue in the agency’s decision to withdraw the metastatic breast cancer indication from the label of bevacizumab (Avastin). Accelerated approval was originally granted for a bevacizumab breast cancer claim on the basis of the open-label ECOG (Eastern Cooperative Oncology Group) 2100 trial, which demonstrated a median progression-free survival advantage of 5.5 months; however, confirmatory trials showed smaller median improvements ranging from 0.9-2.9 months, and the agency determined these subsequent studies failed to verify the magnitude of benefit seen in ECOG 2100.

The agency also may have had concerns about the lapatinib study’s use of a primary end point based upon investigator assessment.

For open-label trials using progression-free survival as the primary end point, the agency generally requires 100% blinded independent review of progression determinations, although it has indicated a willingness to consider relaxing this requirement. During the afternoon session of ODAC’s July 24 meeting, the committee will discuss the feasibility of conducting independent audits of only a subgroup of patient scans in trials using this end point.

The fact that independent blinded review was not the lapatinib trial’s primary end point might have been a concern for the agency, as might related issues such as missing data or informative censoring. Furthermore, the upper limit of the 95% confidence interval for the independent review results fell just below 1.0, according to the published results, and this statistical result may not have held up under further scrutiny by agency reviewers.

Waiting on Other Studies

Although GSK said that it would await the results from other studies that will provide additional information about the combination of lapatinib with trastuzumab, it declined to highlight any one study in particular.

The ClinicalTrials.gov database lists numerous breast cancer studies, currently in recruitment, for which both lapatinib and trastuzumab are study interventions.

These include a randomized, open-label, phase III trial evaluating the efficacy and safety of lapatinib in combination with trastuzumab vs. trastuzumab alone as maintenance therapy in women with HER2-positive metastatic breast cancer. The 280-patient study, which is being conducted in the United States and Canada, is expected to complete in August 2014.

Another phase III trial is comparing the safety and efficacy of an aromatase inhibitor in combination with lapatinib, trastuzumab or both for the treatment of hormone receptor–positive, HER2-positive metastatic breast cancer. The estimated completion date for the 525-patient study is December 2017.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

GlaxoSmithKline PLC pulled its application for a new indication for lapatinib less than 2 weeks before a scheduled advisory committee review – a decision that may have stemmed from Food and Drug Administration questions about the breast cancer drug’s efficacy.

GSK announced on July 12 that it had withdrawn the sNDA (supplemental New Drug Application) for lapatinib (Tykerb) in combination with trastuzumab (Herceptin) for use in patients with HER2-positive metastatic breast cancer who received prior trastuzumab therapy.

The application was scheduled for review by the FDA’s Oncologic Drugs Advisory Committee (ODAC) on the morning of July 24. Because GSK would have received the agency’s briefing package for that meeting 2-3 weeks ahead of time, the timing of the withdrawal announcement suggests that the application garnered a negative evaluation by oncology division reviewers and faced a challenging ODAC meeting.

"Our discussions [with the FDA] highlighted questions that could not be addressed with the data currently available," GSK Oncology R&D Head Rafael Amado said in a press release. "We have decided to withdraw our application [in the United States] with the intent to wait for ongoing studies testing the combination of lapatinib with trastuzumab."

Regulatory reviews of the combination use of lapatinib and trastuzumab are ongoing in the European Union and other regions, the company said.

The sNDA was aimed at adding a third indication to the label of lapatinib, which gained initial approval in March 2007. The kinase inhibitor is currently indicated for use with capecitabine (Xeloda) in patients with advanced or metastatic HER2-positive breast cancer who have received prior therapy, including an anthracycline, a taxane, and trastuzumab; and with letrozole (Femara) for the treatment of postmenopausal women with hormone receptor–positive, HER2-positive metastatic breast cancer for whom hormonal therapy is indicated.

The lapatinib-trastuzumab combination would have been the second FDA-approved combination of two targeted agents against HER2-positive breast cancer. In June, the agency approved pertuzumab (Perjeta), in combination with trastuzumab and chemotherapy, for first-line treatment of HER2-positive metastatic breast cancer.

A 4-Week PFS Advantage ...

GSK declined to comment further on the FDA’s observations about the data in the sNDA, saying that its discussions with the agency are proprietary and confidential. Nevertheless, the pivotal trial’s published results suggest the agency may have questioned whether the lapatinib-trastuzumab combination’s efficacy was sufficiently robust and clinically meaningful.

The filing was based on the results of an open-label, phase III study of 296 patients with HER2-positive metastatic breast cancer whose disease had progressed on trastuzumab-containing regimens. The study results were presented at the 2008 American Society of Clinical Oncology (ASCO) annual meeting.

Subjects were randomized 1:1 to receive either lapatinib monotherapy or lapatinib in combination with trastuzumab. Efficacy assessments were performed every 4 weeks through week 16 and every 8 weeks thereafter. Patients with disease progression after receiving at least 4 weeks of study treatment with lapatinib monotherapy were permitted to cross over to the combination treatment, according to published study results (J. Clin. Oncol. 2010;28:1124-30).

The primary end point was progression-free survival based on investigator assessment, with supporting data provided through an independent review. Secondary end points included overall response rate, clinical benefit response rate, overall survival, quality of life, and safety.

According to the published results, the lapatinib-trastuzumab combination was associated with a statistically significant 27% reduced risk of progression or death, compared with lapatinib monotherapy, based upon investigator assessment (hazard ratio, 0.73; 95% confidence interval, 0.57-0.93; P = .008). Median progression-free survival with the combination was 12.0 weeks, compared with 8.1 weeks for lapatinib monotherapy. Independent review verified a statistically significant improvement (HR, 0.71; 95% CI, 0.52-0.98; P = .027).

Median overall survival was 51.6 weeks in the combination group, compared with 39.0 weeks in the lapatinib monotherapy arm. "Although these data are not mature (56% censoring rate), they show a trend in improved overall survival after combination therapy (HR, 0.75; 95% CI, 0.53-1.07; P = .106)," the study’s authors, led by Dr. Kimberly Blackwell of Duke University in Durham, N.C., wrote.

The overall incidence of adverse events was similar between the two groups, although the incidence of diarrhea was significantly higher with combination therapy.

... May Not Have Been Enough for the FDA

The results, as published, appear to raise several red flags from an FDA review perspective. Specifically, oncology review staff may have questioned whether a median progression-free survival advantage of 4 weeks is clinically meaningful.

This was the crux of the issue in the agency’s decision to withdraw the metastatic breast cancer indication from the label of bevacizumab (Avastin). Accelerated approval was originally granted for a bevacizumab breast cancer claim on the basis of the open-label ECOG (Eastern Cooperative Oncology Group) 2100 trial, which demonstrated a median progression-free survival advantage of 5.5 months; however, confirmatory trials showed smaller median improvements ranging from 0.9-2.9 months, and the agency determined these subsequent studies failed to verify the magnitude of benefit seen in ECOG 2100.

The agency also may have had concerns about the lapatinib study’s use of a primary end point based upon investigator assessment.

For open-label trials using progression-free survival as the primary end point, the agency generally requires 100% blinded independent review of progression determinations, although it has indicated a willingness to consider relaxing this requirement. During the afternoon session of ODAC’s July 24 meeting, the committee will discuss the feasibility of conducting independent audits of only a subgroup of patient scans in trials using this end point.

The fact that independent blinded review was not the lapatinib trial’s primary end point might have been a concern for the agency, as might related issues such as missing data or informative censoring. Furthermore, the upper limit of the 95% confidence interval for the independent review results fell just below 1.0, according to the published results, and this statistical result may not have held up under further scrutiny by agency reviewers.

Waiting on Other Studies

Although GSK said that it would await the results from other studies that will provide additional information about the combination of lapatinib with trastuzumab, it declined to highlight any one study in particular.

The ClinicalTrials.gov database lists numerous breast cancer studies, currently in recruitment, for which both lapatinib and trastuzumab are study interventions.

These include a randomized, open-label, phase III trial evaluating the efficacy and safety of lapatinib in combination with trastuzumab vs. trastuzumab alone as maintenance therapy in women with HER2-positive metastatic breast cancer. The 280-patient study, which is being conducted in the United States and Canada, is expected to complete in August 2014.

Another phase III trial is comparing the safety and efficacy of an aromatase inhibitor in combination with lapatinib, trastuzumab or both for the treatment of hormone receptor–positive, HER2-positive metastatic breast cancer. The estimated completion date for the 525-patient study is December 2017.

Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.

A Cochrane Review of bevacizumab in metastatic breast cancer has found the medication helpful in prolonging progression-free survival and boosting response rates in both first and second-line treatment with certain types of chemotherapy.

However, the same review, published July 10 (doi:10.1002/14651858.CD008941.pub2) found no evidence of improvement in overall survival or quality of life associated with bevacizumab (Avastin), a vascular endothelial growth factor inhibitor whose use in metastatic breast cancer remains controversial.

The findings of improved progression-free survival without gains in overall are consistent with previous published systematic reviews and meta-analyses. The Cochrane Review, led by Dr. Anna Dorothea Wagner of the Centre Hospitalier Universitaire Vaudois in Lausanne (Switzerland) incorporates more trials, more individual patient data, and evidence from the most recent published trial of bevacizumab in breast cancer (Lancet Oncology 2011;12,4:369-76).

"Overall, the clinical value of bevacizumab in metastatic breast cancer can at best be considered as modest," the authors concluded.

In an interview about the Cochrane Review, oncologist Robert W. Carlson of Stanford (Calif.) University called the findings "very reassuring." Dr. Carlson, chair of the National Comprehensive Cancer Network (NCCN) panel that has maintained its endorsement of a bevacizumab and paclitaxel combination despite the Food and Drug Administration’s removal of bevacizumab’s breast cancer indication in November 2011, said that the "objective, independent, thorough look at the data comes up with the same conclusions that I think we already knew."

While the FDA revoked bevacizumab’s breast cancer indication in part because of a lack of evidence for an overall survival gain, the European Medicines Agency continues to recommend bevacizumab in combination with paclitaxel for first-line treatment or with capecitabine for the first-line treatment in patients for whom treatment with taxanes or anthracyclines are inappropriate.

"The question remains whether ... bevacizumab should be available for women with breast cancer. It’s interesting how different people can look at the same conclusions and make different inferences. And that’s really what this study highlights," Dr. Carlson said.

For their research, Dr. Wagner and her colleagues looked at published results from seven randomized controlled trials using bevacizumab and various chemotherapy regimen plus data from one registry and five ongoing studies. For some trials, investigators supplied Dr. Wagner and her colleagues with individual patient data. In all, 4,032 women were included in the analysis of progression-free survival (the trials’ primary end point), and 3,841 in analysis of overall survival.

In first-line chemotherapy progression-free survival was seen as significantly better in the bevacizumab trial arms than in the chemotherapy-only arms (hazard ratio, 0.67; 95% confidence interval, 0.61-0.73). For second-line treatment, a smaller but significant benefit was seen associated with bevacizumab (HR, 0.85; 95% CI, 0.73-0.98). Overall survival did not differ significantly in either first-line (HR, 0.93; 95% CI, 0.84-1.04) or second-line treatment (HR, 0.98; 95% CI, 0.83-1.16).

Patients with previous taxane chemotherapy and with hormone receptor–negative status saw significantly greater progression-free survival benefit, the study found. Quality of life data were available for only two trials and did not show a benefit for bevacizumab. Treatment deaths were lower among patients treated with bevacizumab (odds ratio, 0.60; 95% CI, 0.36-0.99), although serious adverse events were higher (OR, 1.41; 95% CI, 1.13-1.75).

Dr. Wagner and her colleagues wrote in their analysis that their findings had more implications for research priorities than for clinical practice, except to say that, in theory, "patients with a large tumor burden, at risk for local complications but without risk factors for thromboembolic or bleeding complications" should be likelier to benefit.

"If the administration of bevacizumab is considered, the combination with paclitaxel weekly, administered as first-line treatment, should be preferred," the authors said.

"Validated clinical or laboratory markers, which permit a selection of patients most likely to benefit from bevacizumab, are highly warranted," the paper concludes.

Dr. Carlson said that in the decision to use bevacizumab, in the absence of validated clinical markers predicting benefit, "relates to how important you think it is to get a response sooner rather than later, and what kind of risk do you place on the very bad but rare serious side effects – bowel perforation or thrombosis. The challenge is can you identify who those people are prospectively. I wish I could."

Although the NCCN breast cancer guideline still states that bevacizumab should remain an option, "it's not necessarily preferred," Dr Carlson said, adding that he has not prescribed bevacizumab outside a clinical trial for at least 2 years. "While my panel believes it should be available, most of us are not using it."

Dr. Wagner and her colleagues’ study was funded by the Martin Luther University Halle-Wittenberg (Germany) and the German government. One of Dr. Wagner’s coauthors, Dr. Christoph Thomssen, reported an advisory role with and funding from Roche, the parent company of Genentech. Dr. Carlson has received research funding in the past from Genentech but is not doing so currently.

A Cochrane Review of bevacizumab in metastatic breast cancer has found the medication helpful in prolonging progression-free survival and boosting response rates in both first and second-line treatment with certain types of chemotherapy.

However, the same review, published July 10 (doi:10.1002/14651858.CD008941.pub2) found no evidence of improvement in overall survival or quality of life associated with bevacizumab (Avastin), a vascular endothelial growth factor inhibitor whose use in metastatic breast cancer remains controversial.

The findings of improved progression-free survival without gains in overall are consistent with previous published systematic reviews and meta-analyses. The Cochrane Review, led by Dr. Anna Dorothea Wagner of the Centre Hospitalier Universitaire Vaudois in Lausanne (Switzerland) incorporates more trials, more individual patient data, and evidence from the most recent published trial of bevacizumab in breast cancer (Lancet Oncology 2011;12,4:369-76).

"Overall, the clinical value of bevacizumab in metastatic breast cancer can at best be considered as modest," the authors concluded.

In an interview about the Cochrane Review, oncologist Robert W. Carlson of Stanford (Calif.) University called the findings "very reassuring." Dr. Carlson, chair of the National Comprehensive Cancer Network (NCCN) panel that has maintained its endorsement of a bevacizumab and paclitaxel combination despite the Food and Drug Administration’s removal of bevacizumab’s breast cancer indication in November 2011, said that the "objective, independent, thorough look at the data comes up with the same conclusions that I think we already knew."

While the FDA revoked bevacizumab’s breast cancer indication in part because of a lack of evidence for an overall survival gain, the European Medicines Agency continues to recommend bevacizumab in combination with paclitaxel for first-line treatment or with capecitabine for the first-line treatment in patients for whom treatment with taxanes or anthracyclines are inappropriate.

"The question remains whether ... bevacizumab should be available for women with breast cancer. It’s interesting how different people can look at the same conclusions and make different inferences. And that’s really what this study highlights," Dr. Carlson said.

For their research, Dr. Wagner and her colleagues looked at published results from seven randomized controlled trials using bevacizumab and various chemotherapy regimen plus data from one registry and five ongoing studies. For some trials, investigators supplied Dr. Wagner and her colleagues with individual patient data. In all, 4,032 women were included in the analysis of progression-free survival (the trials’ primary end point), and 3,841 in analysis of overall survival.

In first-line chemotherapy progression-free survival was seen as significantly better in the bevacizumab trial arms than in the chemotherapy-only arms (hazard ratio, 0.67; 95% confidence interval, 0.61-0.73). For second-line treatment, a smaller but significant benefit was seen associated with bevacizumab (HR, 0.85; 95% CI, 0.73-0.98). Overall survival did not differ significantly in either first-line (HR, 0.93; 95% CI, 0.84-1.04) or second-line treatment (HR, 0.98; 95% CI, 0.83-1.16).

Patients with previous taxane chemotherapy and with hormone receptor–negative status saw significantly greater progression-free survival benefit, the study found. Quality of life data were available for only two trials and did not show a benefit for bevacizumab. Treatment deaths were lower among patients treated with bevacizumab (odds ratio, 0.60; 95% CI, 0.36-0.99), although serious adverse events were higher (OR, 1.41; 95% CI, 1.13-1.75).

Dr. Wagner and her colleagues wrote in their analysis that their findings had more implications for research priorities than for clinical practice, except to say that, in theory, "patients with a large tumor burden, at risk for local complications but without risk factors for thromboembolic or bleeding complications" should be likelier to benefit.

"If the administration of bevacizumab is considered, the combination with paclitaxel weekly, administered as first-line treatment, should be preferred," the authors said.

"Validated clinical or laboratory markers, which permit a selection of patients most likely to benefit from bevacizumab, are highly warranted," the paper concludes.

Dr. Carlson said that in the decision to use bevacizumab, in the absence of validated clinical markers predicting benefit, "relates to how important you think it is to get a response sooner rather than later, and what kind of risk do you place on the very bad but rare serious side effects – bowel perforation or thrombosis. The challenge is can you identify who those people are prospectively. I wish I could."

Although the NCCN breast cancer guideline still states that bevacizumab should remain an option, "it's not necessarily preferred," Dr Carlson said, adding that he has not prescribed bevacizumab outside a clinical trial for at least 2 years. "While my panel believes it should be available, most of us are not using it."

Dr. Wagner and her colleagues’ study was funded by the Martin Luther University Halle-Wittenberg (Germany) and the German government. One of Dr. Wagner’s coauthors, Dr. Christoph Thomssen, reported an advisory role with and funding from Roche, the parent company of Genentech. Dr. Carlson has received research funding in the past from Genentech but is not doing so currently.

A Cochrane Review of bevacizumab in metastatic breast cancer has found the medication helpful in prolonging progression-free survival and boosting response rates in both first and second-line treatment with certain types of chemotherapy.

However, the same review, published July 10 (doi:10.1002/14651858.CD008941.pub2) found no evidence of improvement in overall survival or quality of life associated with bevacizumab (Avastin), a vascular endothelial growth factor inhibitor whose use in metastatic breast cancer remains controversial.

The findings of improved progression-free survival without gains in overall are consistent with previous published systematic reviews and meta-analyses. The Cochrane Review, led by Dr. Anna Dorothea Wagner of the Centre Hospitalier Universitaire Vaudois in Lausanne (Switzerland) incorporates more trials, more individual patient data, and evidence from the most recent published trial of bevacizumab in breast cancer (Lancet Oncology 2011;12,4:369-76).

"Overall, the clinical value of bevacizumab in metastatic breast cancer can at best be considered as modest," the authors concluded.

In an interview about the Cochrane Review, oncologist Robert W. Carlson of Stanford (Calif.) University called the findings "very reassuring." Dr. Carlson, chair of the National Comprehensive Cancer Network (NCCN) panel that has maintained its endorsement of a bevacizumab and paclitaxel combination despite the Food and Drug Administration’s removal of bevacizumab’s breast cancer indication in November 2011, said that the "objective, independent, thorough look at the data comes up with the same conclusions that I think we already knew."

While the FDA revoked bevacizumab’s breast cancer indication in part because of a lack of evidence for an overall survival gain, the European Medicines Agency continues to recommend bevacizumab in combination with paclitaxel for first-line treatment or with capecitabine for the first-line treatment in patients for whom treatment with taxanes or anthracyclines are inappropriate.

"The question remains whether ... bevacizumab should be available for women with breast cancer. It’s interesting how different people can look at the same conclusions and make different inferences. And that’s really what this study highlights," Dr. Carlson said.

For their research, Dr. Wagner and her colleagues looked at published results from seven randomized controlled trials using bevacizumab and various chemotherapy regimen plus data from one registry and five ongoing studies. For some trials, investigators supplied Dr. Wagner and her colleagues with individual patient data. In all, 4,032 women were included in the analysis of progression-free survival (the trials’ primary end point), and 3,841 in analysis of overall survival.

In first-line chemotherapy progression-free survival was seen as significantly better in the bevacizumab trial arms than in the chemotherapy-only arms (hazard ratio, 0.67; 95% confidence interval, 0.61-0.73). For second-line treatment, a smaller but significant benefit was seen associated with bevacizumab (HR, 0.85; 95% CI, 0.73-0.98). Overall survival did not differ significantly in either first-line (HR, 0.93; 95% CI, 0.84-1.04) or second-line treatment (HR, 0.98; 95% CI, 0.83-1.16).

Patients with previous taxane chemotherapy and with hormone receptor–negative status saw significantly greater progression-free survival benefit, the study found. Quality of life data were available for only two trials and did not show a benefit for bevacizumab. Treatment deaths were lower among patients treated with bevacizumab (odds ratio, 0.60; 95% CI, 0.36-0.99), although serious adverse events were higher (OR, 1.41; 95% CI, 1.13-1.75).

Dr. Wagner and her colleagues wrote in their analysis that their findings had more implications for research priorities than for clinical practice, except to say that, in theory, "patients with a large tumor burden, at risk for local complications but without risk factors for thromboembolic or bleeding complications" should be likelier to benefit.

"If the administration of bevacizumab is considered, the combination with paclitaxel weekly, administered as first-line treatment, should be preferred," the authors said.

"Validated clinical or laboratory markers, which permit a selection of patients most likely to benefit from bevacizumab, are highly warranted," the paper concludes.

Dr. Carlson said that in the decision to use bevacizumab, in the absence of validated clinical markers predicting benefit, "relates to how important you think it is to get a response sooner rather than later, and what kind of risk do you place on the very bad but rare serious side effects – bowel perforation or thrombosis. The challenge is can you identify who those people are prospectively. I wish I could."

Although the NCCN breast cancer guideline still states that bevacizumab should remain an option, "it's not necessarily preferred," Dr Carlson said, adding that he has not prescribed bevacizumab outside a clinical trial for at least 2 years. "While my panel believes it should be available, most of us are not using it."

Dr. Wagner and her colleagues’ study was funded by the Martin Luther University Halle-Wittenberg (Germany) and the German government. One of Dr. Wagner’s coauthors, Dr. Christoph Thomssen, reported an advisory role with and funding from Roche, the parent company of Genentech. Dr. Carlson has received research funding in the past from Genentech but is not doing so currently.

A risk evaluation and mitigation strategy for extended-release and long-acting opioid medications has received Food and Drug Administration approval.

The move has been anticipated as an important element in an attempt to stem the swelling tide of abuse, misuse, and overdose of these prescription drugs while assuring continued access to the highly potent analgesics for patients with moderate to severe persistent pain, Dr. Margaret A. Hamburg said in a media briefing.

The new safety measures, which pertain to approximately 30 currently available medications, will require the manufacturers of the drugs to make FDA-approved education materials available to prescribers no later than March 1, 2013, via development grants to continuing education providers who will develop and deliver the training, said Dr. Hamburg, commissioner of the FDA. In addition, the risk evaluation and mitigation strategy (REMS) will include the distribution of a patient counseling leaflet to prescribers regarding the safe and effective use of the drugs; an updated, single-page medication guide for consumers, an implementation plan, and periodic assessments to evaluate the impact of the program on the safe use of these products, which the FDA will review and use to tweak the program as needed, she said.

"It is important to note that we are focusing on extended-release and long-acting opioid medications ... because these have very specific safety problems that have to be addressed very carefully," according to Dr. John Jenkins, director of the Office of New Drugs within the FDA’s Center for Drug Evaluation and Research. These drugs, including hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine, "can cause problems even when prescribed appropriately."

The prescriber education component of the REMS will include information regarding the risks and benefits of opioid therapy for individual patients, choosing patients appropriately, patient management and monitoring, and patient counseling, Dr. Jenkins explained. It will also include guidance on the potential for misuse, abuse, and addition, as well as recognizing evidence for these outcomes. The updated medication guide and patient counseling document will include information on how to safely use, store, and dispose of these analgesics, specific instructions for recognizing the signs of potential overdose and advice for preventing accidental exposure to family and household visitors, he said.

With respect to the assessment and auditing component of the program, the FDA has established goals, which the manufacturers are expected to achieve, for the percentage of prescribers who complete the training and for assessing prescribers’ understanding of the risk information. Participation in the educational programs is not mandatory for prescribers, Dr. Hamburg stated. The assessments are also required to evaluate whether the [REMS] adversely affect patient access to these drugs, she said. "Patients in pain must have continued assess to medications they need," she added.

The new REMS program is one component of a multiagency, national strategy unveiled by the White House in 2011 to address prescription drug abuse, "which is this country’s fastest-growing drug problem," said Dr. Hamburg, noting that opioid overdoses in particular were the cause of approximately 15,000 deaths among Americans in 2008 and nearly 16,000 in 2009. Called Epidemic: Responding to America's Prescription Drug Abuse Crisis, the national plan suggests expansion of state-based prescription drug-monitoring programs; seeks creation of recommendations for convenient and environmentally responsible ways to dispose of unused medications; and calls for legislative action to reduce "doctor shopping" and "pill mills."

In the absence of the legislative changes needed to fulfill the comprehensive White House plan, the REMS "is an important and timely step by FDA to supplement prescriber training and consumer information," R. Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said during the telebriefing.

A risk evaluation and mitigation strategy for extended-release and long-acting opioid medications has received Food and Drug Administration approval.

The move has been anticipated as an important element in an attempt to stem the swelling tide of abuse, misuse, and overdose of these prescription drugs while assuring continued access to the highly potent analgesics for patients with moderate to severe persistent pain, Dr. Margaret A. Hamburg said in a media briefing.

The new safety measures, which pertain to approximately 30 currently available medications, will require the manufacturers of the drugs to make FDA-approved education materials available to prescribers no later than March 1, 2013, via development grants to continuing education providers who will develop and deliver the training, said Dr. Hamburg, commissioner of the FDA. In addition, the risk evaluation and mitigation strategy (REMS) will include the distribution of a patient counseling leaflet to prescribers regarding the safe and effective use of the drugs; an updated, single-page medication guide for consumers, an implementation plan, and periodic assessments to evaluate the impact of the program on the safe use of these products, which the FDA will review and use to tweak the program as needed, she said.

"It is important to note that we are focusing on extended-release and long-acting opioid medications ... because these have very specific safety problems that have to be addressed very carefully," according to Dr. John Jenkins, director of the Office of New Drugs within the FDA’s Center for Drug Evaluation and Research. These drugs, including hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine, "can cause problems even when prescribed appropriately."

The prescriber education component of the REMS will include information regarding the risks and benefits of opioid therapy for individual patients, choosing patients appropriately, patient management and monitoring, and patient counseling, Dr. Jenkins explained. It will also include guidance on the potential for misuse, abuse, and addition, as well as recognizing evidence for these outcomes. The updated medication guide and patient counseling document will include information on how to safely use, store, and dispose of these analgesics, specific instructions for recognizing the signs of potential overdose and advice for preventing accidental exposure to family and household visitors, he said.

With respect to the assessment and auditing component of the program, the FDA has established goals, which the manufacturers are expected to achieve, for the percentage of prescribers who complete the training and for assessing prescribers’ understanding of the risk information. Participation in the educational programs is not mandatory for prescribers, Dr. Hamburg stated. The assessments are also required to evaluate whether the [REMS] adversely affect patient access to these drugs, she said. "Patients in pain must have continued assess to medications they need," she added.

The new REMS program is one component of a multiagency, national strategy unveiled by the White House in 2011 to address prescription drug abuse, "which is this country’s fastest-growing drug problem," said Dr. Hamburg, noting that opioid overdoses in particular were the cause of approximately 15,000 deaths among Americans in 2008 and nearly 16,000 in 2009. Called Epidemic: Responding to America's Prescription Drug Abuse Crisis, the national plan suggests expansion of state-based prescription drug-monitoring programs; seeks creation of recommendations for convenient and environmentally responsible ways to dispose of unused medications; and calls for legislative action to reduce "doctor shopping" and "pill mills."

In the absence of the legislative changes needed to fulfill the comprehensive White House plan, the REMS "is an important and timely step by FDA to supplement prescriber training and consumer information," R. Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said during the telebriefing.

A risk evaluation and mitigation strategy for extended-release and long-acting opioid medications has received Food and Drug Administration approval.

The move has been anticipated as an important element in an attempt to stem the swelling tide of abuse, misuse, and overdose of these prescription drugs while assuring continued access to the highly potent analgesics for patients with moderate to severe persistent pain, Dr. Margaret A. Hamburg said in a media briefing.

The new safety measures, which pertain to approximately 30 currently available medications, will require the manufacturers of the drugs to make FDA-approved education materials available to prescribers no later than March 1, 2013, via development grants to continuing education providers who will develop and deliver the training, said Dr. Hamburg, commissioner of the FDA. In addition, the risk evaluation and mitigation strategy (REMS) will include the distribution of a patient counseling leaflet to prescribers regarding the safe and effective use of the drugs; an updated, single-page medication guide for consumers, an implementation plan, and periodic assessments to evaluate the impact of the program on the safe use of these products, which the FDA will review and use to tweak the program as needed, she said.

"It is important to note that we are focusing on extended-release and long-acting opioid medications ... because these have very specific safety problems that have to be addressed very carefully," according to Dr. John Jenkins, director of the Office of New Drugs within the FDA’s Center for Drug Evaluation and Research. These drugs, including hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine, "can cause problems even when prescribed appropriately."

The prescriber education component of the REMS will include information regarding the risks and benefits of opioid therapy for individual patients, choosing patients appropriately, patient management and monitoring, and patient counseling, Dr. Jenkins explained. It will also include guidance on the potential for misuse, abuse, and addition, as well as recognizing evidence for these outcomes. The updated medication guide and patient counseling document will include information on how to safely use, store, and dispose of these analgesics, specific instructions for recognizing the signs of potential overdose and advice for preventing accidental exposure to family and household visitors, he said.

With respect to the assessment and auditing component of the program, the FDA has established goals, which the manufacturers are expected to achieve, for the percentage of prescribers who complete the training and for assessing prescribers’ understanding of the risk information. Participation in the educational programs is not mandatory for prescribers, Dr. Hamburg stated. The assessments are also required to evaluate whether the [REMS] adversely affect patient access to these drugs, she said. "Patients in pain must have continued assess to medications they need," she added.

The new REMS program is one component of a multiagency, national strategy unveiled by the White House in 2011 to address prescription drug abuse, "which is this country’s fastest-growing drug problem," said Dr. Hamburg, noting that opioid overdoses in particular were the cause of approximately 15,000 deaths among Americans in 2008 and nearly 16,000 in 2009. Called Epidemic: Responding to America's Prescription Drug Abuse Crisis, the national plan suggests expansion of state-based prescription drug-monitoring programs; seeks creation of recommendations for convenient and environmentally responsible ways to dispose of unused medications; and calls for legislative action to reduce "doctor shopping" and "pill mills."

In the absence of the legislative changes needed to fulfill the comprehensive White House plan, the REMS "is an important and timely step by FDA to supplement prescriber training and consumer information," R. Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said during the telebriefing.

Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.

GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.

The updated label will say that ondansetron, a 5-HT₃ receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.

The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.

Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.

The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.

It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.

Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.

The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.

Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.

GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.

The updated label will say that ondansetron, a 5-HT₃ receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.

The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.

Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.

The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.

It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.

Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.

The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.

Preliminary data indicate that a single 32-mg intravenous dose of ondansetron should be avoided because it may increase the risk of QT prolongation, along with the potentially fatal arrhythmia torsades de pointes, the Food and Drug Administration has announced.

GlaxoSmithKline, which manufactures ondansetron (Zofran), is removing the 32-mg single IV dose from the antinausea and vomiting drug’s label, according to an FDA statement.

The updated label will say that ondansetron, a 5-HT₃ receptor antagonist, can continue to be used to treat adults and children with chemotherapy-induced nausea and vomiting at the dose of 0.15 mg/kg administered every 4 hours for three doses. "However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation," the FDA said.

The new data do not affect recommendations for oral doses of ondansetron (including the single 24-mg oral dose) used for chemotherapy-induced nausea and vomiting, the FDA noted. Recommendations on lower IV doses that are used to prevent postoperative nausea and vomiting (the other approved indication for ondansetron) also are unaffected.

Preliminary results of a study conducted by GlaxoSmithKline showed that QT prolongation "occurs in a dose-dependent manner," the FDA said. At the highest dose tested (the single 32-mg IV dose), the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower single dose tested (8 mg), the maximum mean difference in QTcF from placebo after baseline correction was 6 msec.

The FDA, which required GlaxoSmithKline to conduct the study, "will evaluate the final study results when available, and will work with GSK to explore an alternative single dose regimen that is both safe and effective for the prevention of chemotherapy-induced nausea and vomiting in adults," the FDA said.

It pointed out that ECG changes, including QT interval prolongation and torsades de pointes, have been reported in patients treated with ondansetron. In September 2011, the agency announced that it was reviewing the potential for QT prolongation with ondansetron.

Patients who have congenital long QT syndrome, heart failure, or bradyarrhythmias, or who are taking other medications that prolong the QT interval "may be at particular risk for QT prolongation" with ondansetron, the FDA warned.

The statement is available at www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Serious adverse events associated with ondansetron should be reported to the FDA at 800-332-1088 or www.fda.gov/medwatch.

Prospective Validation of a Prediction Tool for Identifying Patients at High Risk for Chemotherapy-Induced Nausea and Vomiting

• George Dranitsaris, BPharm, PhD,

  

  Nathaniel Bouganim, MD,Carolyn Milano, Lisa Vandermeer, MSc, Susan Dent, MD, Paul Wheatley-Price, MD, Jenny Laporte, RN, Karen-Ann Oxborough, RN, Mark Clemons, MD

  Abstract

  Background

  Even with modern antiemetic regimens, up to 20% of cancer patients suffer from moderate to severe chemotherapy-induced nausea and vomiting (CINV) (≥ grade 2). We previously developed chemotherapy cycle–based risk predictive models for ≥ grade 2 acute and delayed CINV. In this study, the prospective validation of the prediction models and associated scoring systems is described.

  Objective

  Our objective was to prospectively validate prediction models designed to identify patients at high risk for moderate to severe CINV.

  Methods

  Patients receiving chemotherapy were provided with CINV symptom diaries. Prior to each cycle of chemotherapy, the acute and delayed CINV scoring systems were used to stratify patients into low- and high-risk groups. Logistic regression was used to compare the occurrence of ≥ grade 2 CINV between patients considered by the model to be at high vs low risk. The external validity of each system was assessed via an area under the receiver operating characteristic (AUROC) curve analysis.

  Results

  Outcome data were collected from 97 patients following 401 cycles of chemotherapy. The incidence of ≥ grade 2 acute and delayed CINV was 13.5% and 21.4%, respectively. There was a significant correlation between the risk score and the probability of developing acute and delayed CINV following chemotherapy. Both the acute and delayed scoring systems had good predictive accuracy when applied to the validation sample (acute, AUROC = 0.70, 95% CI, 0.62–0.77; delayed, AUROC = 0.75, 95% CI, 0.69–0.80). Patients who were identified as high risk were 3.1 (P = .006) and 4.2 (P < .001) times more likely to develop ≥ grade 2 acute and delayed CINV than were those identified as low risk.

  Conclusion

  This study demonstrates that the scoring systems are able to accurately identify patients at high risk for acute and delayed CINV.

  
  

  *For a PDF of the full article click in the link to the left of this introduction.

Prospective Validation of a Prediction Tool for Identifying Patients at High Risk for Chemotherapy-Induced Nausea and Vomiting

• George Dranitsaris, BPharm, PhD,

  

  Nathaniel Bouganim, MD,Carolyn Milano, Lisa Vandermeer, MSc, Susan Dent, MD, Paul Wheatley-Price, MD, Jenny Laporte, RN, Karen-Ann Oxborough, RN, Mark Clemons, MD

  Abstract

  Background

  Even with modern antiemetic regimens, up to 20% of cancer patients suffer from moderate to severe chemotherapy-induced nausea and vomiting (CINV) (≥ grade 2). We previously developed chemotherapy cycle–based risk predictive models for ≥ grade 2 acute and delayed CINV. In this study, the prospective validation of the prediction models and associated scoring systems is described.

  Objective

  Our objective was to prospectively validate prediction models designed to identify patients at high risk for moderate to severe CINV.

  Methods

  Patients receiving chemotherapy were provided with CINV symptom diaries. Prior to each cycle of chemotherapy, the acute and delayed CINV scoring systems were used to stratify patients into low- and high-risk groups. Logistic regression was used to compare the occurrence of ≥ grade 2 CINV between patients considered by the model to be at high vs low risk. The external validity of each system was assessed via an area under the receiver operating characteristic (AUROC) curve analysis.

  Results

  Outcome data were collected from 97 patients following 401 cycles of chemotherapy. The incidence of ≥ grade 2 acute and delayed CINV was 13.5% and 21.4%, respectively. There was a significant correlation between the risk score and the probability of developing acute and delayed CINV following chemotherapy. Both the acute and delayed scoring systems had good predictive accuracy when applied to the validation sample (acute, AUROC = 0.70, 95% CI, 0.62–0.77; delayed, AUROC = 0.75, 95% CI, 0.69–0.80). Patients who were identified as high risk were 3.1 (P = .006) and 4.2 (P < .001) times more likely to develop ≥ grade 2 acute and delayed CINV than were those identified as low risk.

  Conclusion

  This study demonstrates that the scoring systems are able to accurately identify patients at high risk for acute and delayed CINV.

  
  

  *For a PDF of the full article click in the link to the left of this introduction.

Prospective Validation of a Prediction Tool for Identifying Patients at High Risk for Chemotherapy-Induced Nausea and Vomiting

• George Dranitsaris, BPharm, PhD,

  

  Nathaniel Bouganim, MD,Carolyn Milano, Lisa Vandermeer, MSc, Susan Dent, MD, Paul Wheatley-Price, MD, Jenny Laporte, RN, Karen-Ann Oxborough, RN, Mark Clemons, MD

  Abstract

  Background

  Even with modern antiemetic regimens, up to 20% of cancer patients suffer from moderate to severe chemotherapy-induced nausea and vomiting (CINV) (≥ grade 2). We previously developed chemotherapy cycle–based risk predictive models for ≥ grade 2 acute and delayed CINV. In this study, the prospective validation of the prediction models and associated scoring systems is described.

  Objective

  Our objective was to prospectively validate prediction models designed to identify patients at high risk for moderate to severe CINV.

  Methods

  Patients receiving chemotherapy were provided with CINV symptom diaries. Prior to each cycle of chemotherapy, the acute and delayed CINV scoring systems were used to stratify patients into low- and high-risk groups. Logistic regression was used to compare the occurrence of ≥ grade 2 CINV between patients considered by the model to be at high vs low risk. The external validity of each system was assessed via an area under the receiver operating characteristic (AUROC) curve analysis.

  Results

  Outcome data were collected from 97 patients following 401 cycles of chemotherapy. The incidence of ≥ grade 2 acute and delayed CINV was 13.5% and 21.4%, respectively. There was a significant correlation between the risk score and the probability of developing acute and delayed CINV following chemotherapy. Both the acute and delayed scoring systems had good predictive accuracy when applied to the validation sample (acute, AUROC = 0.70, 95% CI, 0.62–0.77; delayed, AUROC = 0.75, 95% CI, 0.69–0.80). Patients who were identified as high risk were 3.1 (P = .006) and 4.2 (P < .001) times more likely to develop ≥ grade 2 acute and delayed CINV than were those identified as low risk.

  Conclusion

  This study demonstrates that the scoring systems are able to accurately identify patients at high risk for acute and delayed CINV.

  
  

  *For a PDF of the full article click in the link to the left of this introduction.

CHICAGO – Wearing a scalp-cooling cap can reduce hair loss in women receiving chemotherapy for breast cancer, the results of a small prospective cohort study suggest.

Among women who used the cooling headgear starting 20 minutes before chemotherapy and continuing for 60-90 minutes after the infusion, 24% did not wear a wig or headband upon completion of chemotherapy, compared with 4% of a control group that did not have access to the device, investigators reported.

Courtesy Dr. Julie Lemieux

Further, patient satisfaction scores were higher than these numbers in a blinded assessment, according to Dr. Julie Lemieux of Laval University in Quebec City and her coinvestigators.

To grade the results with and without the cooling device, a hairdresser looked at before and after photos of women in the study, and was not told which women were in the scalp-cooling group. The criteria for successful hair preservation was characterization of hair loss as "not at all," "a little," or "moderate" from the beginning to the end of chemotherapy. The procedure was deemed a failure if the reviewer rated hair loss as "a lot," or "all," or "hair shaved."

The hairdresser graded the hair loss intervention as successful in 34% of the scalp-cooling group – as did 49% of the women who wore the caps. Only 9% of the control group received a successful grade from the hairdresser; even fewer, 4%, agreed they had not had substantial hair loss.

In all, 69% of women who tried scalp cooling said the advantages outweighed the disadvantages, and 78% said they would recommend it to other women receiving the same chemotherapy for breast cancer.

"When you look at patient evaluations, they are ... more optimistic than the hairdresser evaluations. They were more satisfied," Dr. Lemieux said in a poster-side interview at the annual meeting of the American Society of Clinical Oncology, where she displayed the results.

Scalp-cooling systems are approved for the reduction of alopecia in Canada, she said, but controversy persists among oncologists over safety and impact, if any, on the effectiveness of chemotherapy.

"If you cool the scalp there is vasoconstriction, so there is less blood that goes in the scalp ... that is the main mechanism," Dr. Lemieux explained. One concern is that scalp metastases could increase; another is that patients might receive less chemotherapy as a result.

Dr. Lemieux and her colleagues reviewed seven randomized trials of hair-cooling studies and found no safety signals. In all, 260 women were enrolled, and the studies covered a variety of chemotherapy regimens, including at least one that is not known to cause alopecia.

They also did a retrospective cohort study, and found that the incidence of scalp metastases was about 1% whether women used scalp cooling or not (Breast Cancer Res. Treat. 2009;118:547-52). Subsequently, they reported on two cases where the scalp was the first metastatic site, with metastases occurring 7 and 9 years after cooling (Breast Cancer Res. Treat. 2011;128:563-6).

At the San Antonio Breast Cancer Symposium, Dr. Lemieux and her associates reported on a retrospective study that found no difference in survival between patients who used scalp cooling and those who did not.

For the current study, the researchers compared outcomes in 110 patients at Centre des Maladies du Sein Deschênes-Fabia in Quebec City, which uses scalp cooling routinely, with those in 26 patients at the Centre Hospitalier Universitaire de Montréal, where scalp cooling is not available. The median patient age was in the early 50s, and most of the women had stage I or II, hormone receptor–positive breast cancer. A variety of neoadjuvant and adjuvant regimens were used.

The system tested in the study used a cap that is placed in a freezer and changed every 20-30 minutes, starting 20 minutes before chemotherapy and continuing for 60-90 minutes afterward. A new generation of scalp-cooling systems uses a compressor that circulates cold fluid in the cap, and it does not have to be changed.

Dr. Lemieux said the researchers conceived the study as a pilot for a larger randomized controlled trial that will address efficacy, cost, and quality of life issues. They are seeking to raise funds, as the companies that make the systems are too small to sponsor a large trial.

Cost is a concern, she noted, because of the additional time the women spend in the infusion room. "So you have to have that time available in the chemotherapy room," she said. "We also want to look at the cost of the system, of the extra time that women are in hospital, and at quality of life, too."

The trial was funded by the Fondations des Hôpitaux Enfant-Jésus et Saint-Sacrement, the Canadian Breast Cancer Research Alliance, and Sanofi-Aventis. Dr. Lemieux received a research grant from the Fonds de la Recherche en Santé du Québec.

CHICAGO – Wearing a scalp-cooling cap can reduce hair loss in women receiving chemotherapy for breast cancer, the results of a small prospective cohort study suggest.

Among women who used the cooling headgear starting 20 minutes before chemotherapy and continuing for 60-90 minutes after the infusion, 24% did not wear a wig or headband upon completion of chemotherapy, compared with 4% of a control group that did not have access to the device, investigators reported.

Courtesy Dr. Julie Lemieux

Further, patient satisfaction scores were higher than these numbers in a blinded assessment, according to Dr. Julie Lemieux of Laval University in Quebec City and her coinvestigators.

To grade the results with and without the cooling device, a hairdresser looked at before and after photos of women in the study, and was not told which women were in the scalp-cooling group. The criteria for successful hair preservation was characterization of hair loss as "not at all," "a little," or "moderate" from the beginning to the end of chemotherapy. The procedure was deemed a failure if the reviewer rated hair loss as "a lot," or "all," or "hair shaved."

The hairdresser graded the hair loss intervention as successful in 34% of the scalp-cooling group – as did 49% of the women who wore the caps. Only 9% of the control group received a successful grade from the hairdresser; even fewer, 4%, agreed they had not had substantial hair loss.

In all, 69% of women who tried scalp cooling said the advantages outweighed the disadvantages, and 78% said they would recommend it to other women receiving the same chemotherapy for breast cancer.

"When you look at patient evaluations, they are ... more optimistic than the hairdresser evaluations. They were more satisfied," Dr. Lemieux said in a poster-side interview at the annual meeting of the American Society of Clinical Oncology, where she displayed the results.

Scalp-cooling systems are approved for the reduction of alopecia in Canada, she said, but controversy persists among oncologists over safety and impact, if any, on the effectiveness of chemotherapy.

"If you cool the scalp there is vasoconstriction, so there is less blood that goes in the scalp ... that is the main mechanism," Dr. Lemieux explained. One concern is that scalp metastases could increase; another is that patients might receive less chemotherapy as a result.

Dr. Lemieux and her colleagues reviewed seven randomized trials of hair-cooling studies and found no safety signals. In all, 260 women were enrolled, and the studies covered a variety of chemotherapy regimens, including at least one that is not known to cause alopecia.

They also did a retrospective cohort study, and found that the incidence of scalp metastases was about 1% whether women used scalp cooling or not (Breast Cancer Res. Treat. 2009;118:547-52). Subsequently, they reported on two cases where the scalp was the first metastatic site, with metastases occurring 7 and 9 years after cooling (Breast Cancer Res. Treat. 2011;128:563-6).

At the San Antonio Breast Cancer Symposium, Dr. Lemieux and her associates reported on a retrospective study that found no difference in survival between patients who used scalp cooling and those who did not.

For the current study, the researchers compared outcomes in 110 patients at Centre des Maladies du Sein Deschênes-Fabia in Quebec City, which uses scalp cooling routinely, with those in 26 patients at the Centre Hospitalier Universitaire de Montréal, where scalp cooling is not available. The median patient age was in the early 50s, and most of the women had stage I or II, hormone receptor–positive breast cancer. A variety of neoadjuvant and adjuvant regimens were used.

The system tested in the study used a cap that is placed in a freezer and changed every 20-30 minutes, starting 20 minutes before chemotherapy and continuing for 60-90 minutes afterward. A new generation of scalp-cooling systems uses a compressor that circulates cold fluid in the cap, and it does not have to be changed.

Dr. Lemieux said the researchers conceived the study as a pilot for a larger randomized controlled trial that will address efficacy, cost, and quality of life issues. They are seeking to raise funds, as the companies that make the systems are too small to sponsor a large trial.

Cost is a concern, she noted, because of the additional time the women spend in the infusion room. "So you have to have that time available in the chemotherapy room," she said. "We also want to look at the cost of the system, of the extra time that women are in hospital, and at quality of life, too."

The trial was funded by the Fondations des Hôpitaux Enfant-Jésus et Saint-Sacrement, the Canadian Breast Cancer Research Alliance, and Sanofi-Aventis. Dr. Lemieux received a research grant from the Fonds de la Recherche en Santé du Québec.

CHICAGO – Wearing a scalp-cooling cap can reduce hair loss in women receiving chemotherapy for breast cancer, the results of a small prospective cohort study suggest.

Among women who used the cooling headgear starting 20 minutes before chemotherapy and continuing for 60-90 minutes after the infusion, 24% did not wear a wig or headband upon completion of chemotherapy, compared with 4% of a control group that did not have access to the device, investigators reported.

Courtesy Dr. Julie Lemieux

Further, patient satisfaction scores were higher than these numbers in a blinded assessment, according to Dr. Julie Lemieux of Laval University in Quebec City and her coinvestigators.

To grade the results with and without the cooling device, a hairdresser looked at before and after photos of women in the study, and was not told which women were in the scalp-cooling group. The criteria for successful hair preservation was characterization of hair loss as "not at all," "a little," or "moderate" from the beginning to the end of chemotherapy. The procedure was deemed a failure if the reviewer rated hair loss as "a lot," or "all," or "hair shaved."

The hairdresser graded the hair loss intervention as successful in 34% of the scalp-cooling group – as did 49% of the women who wore the caps. Only 9% of the control group received a successful grade from the hairdresser; even fewer, 4%, agreed they had not had substantial hair loss.

In all, 69% of women who tried scalp cooling said the advantages outweighed the disadvantages, and 78% said they would recommend it to other women receiving the same chemotherapy for breast cancer.

"When you look at patient evaluations, they are ... more optimistic than the hairdresser evaluations. They were more satisfied," Dr. Lemieux said in a poster-side interview at the annual meeting of the American Society of Clinical Oncology, where she displayed the results.

Scalp-cooling systems are approved for the reduction of alopecia in Canada, she said, but controversy persists among oncologists over safety and impact, if any, on the effectiveness of chemotherapy.

"If you cool the scalp there is vasoconstriction, so there is less blood that goes in the scalp ... that is the main mechanism," Dr. Lemieux explained. One concern is that scalp metastases could increase; another is that patients might receive less chemotherapy as a result.

Dr. Lemieux and her colleagues reviewed seven randomized trials of hair-cooling studies and found no safety signals. In all, 260 women were enrolled, and the studies covered a variety of chemotherapy regimens, including at least one that is not known to cause alopecia.

They also did a retrospective cohort study, and found that the incidence of scalp metastases was about 1% whether women used scalp cooling or not (Breast Cancer Res. Treat. 2009;118:547-52). Subsequently, they reported on two cases where the scalp was the first metastatic site, with metastases occurring 7 and 9 years after cooling (Breast Cancer Res. Treat. 2011;128:563-6).

At the San Antonio Breast Cancer Symposium, Dr. Lemieux and her associates reported on a retrospective study that found no difference in survival between patients who used scalp cooling and those who did not.

For the current study, the researchers compared outcomes in 110 patients at Centre des Maladies du Sein Deschênes-Fabia in Quebec City, which uses scalp cooling routinely, with those in 26 patients at the Centre Hospitalier Universitaire de Montréal, where scalp cooling is not available. The median patient age was in the early 50s, and most of the women had stage I or II, hormone receptor–positive breast cancer. A variety of neoadjuvant and adjuvant regimens were used.

The system tested in the study used a cap that is placed in a freezer and changed every 20-30 minutes, starting 20 minutes before chemotherapy and continuing for 60-90 minutes afterward. A new generation of scalp-cooling systems uses a compressor that circulates cold fluid in the cap, and it does not have to be changed.

Dr. Lemieux said the researchers conceived the study as a pilot for a larger randomized controlled trial that will address efficacy, cost, and quality of life issues. They are seeking to raise funds, as the companies that make the systems are too small to sponsor a large trial.

Cost is a concern, she noted, because of the additional time the women spend in the infusion room. "So you have to have that time available in the chemotherapy room," she said. "We also want to look at the cost of the system, of the extra time that women are in hospital, and at quality of life, too."

The trial was funded by the Fondations des Hôpitaux Enfant-Jésus et Saint-Sacrement, the Canadian Breast Cancer Research Alliance, and Sanofi-Aventis. Dr. Lemieux received a research grant from the Fonds de la Recherche en Santé du Québec.

The clinical effectiveness agency for England and Wales has rejected a second bevacizumab combination for metastatic breast cancer, citing the treatment’s high cost, uncertain effect on quality of life, and lack of robust evidence for overall survival improvements.

Roche’s bevacizumab (Avastin) is a monoclonal antibody that works by inhibiting vascular endothelial growth factor (VEGF). It is licensed in the European Union in combination with Roche’s capecitabine (Xeloda) for metastatic breast cancer; however, the National Institute for Health and Clinical Excellence found that the treatment did not meet its cost-effectiveness criteria. NICE’s decision was widely expected after the agency issued negative draft guidance in April.

In 2010, NICE turned down bevacizumab in combination with a taxane for first-line treatment of metastatic breast cancer, its licensed indication at the time; the European Medicines Agency late that year limited the breast cancer indication to a combination with paclitaxel.

In April 2011, EMA said bevacizumab could also be used with capecitabine if other chemotherapy treatments are inappropriate, citing evidence from RIBBON-1, a randomized, placebo-controlled trial that showed average progression-free survival of 8.6 months in patients receiving the combination, compared with 5.7 months in those receiving capecitabine alone.

In a final appraisal published July 6, NICE acknowledged the statistically significant, 2.9-month gain in progression-free survival seen with bevacizumab in the trial. However, the agency said that quality-of-life data were not captured, and while median overall survival also improved by 2.9 months, this result was not statistically significant due in part to crossover.

The manufacturer’s submission to NICE included clinical trial evidence only for a subgroup of people who had been previously treated with a taxane, while the full indication includes both previously treated and treatment-naive patients.

The NICE reviewers said they found "no biologically plausible reason why bevacizumab plus capecitabine would be more effective" in the previously treated subgroup than in the broader population for which the combination is licensed. They also concluded that the incremental cost-effectiveness ratio for the treatment would be at least £82,000 (U.S.$127,000) per quality-adjusted life year (QALY).

Bevacizumab is administered by intravenous infusion at a recommended dose of 10 mg/kg of body weight once every 2 weeks or 15 mg/kg of body weight once every 3 weeks. The average price of bevacizumab treatment for breast cancer in the United Kingdom is £3,689 (U.S.$5,727) per month, according to NICE.

The clinical effectiveness agency for England and Wales has rejected a second bevacizumab combination for metastatic breast cancer, citing the treatment’s high cost, uncertain effect on quality of life, and lack of robust evidence for overall survival improvements.

Roche’s bevacizumab (Avastin) is a monoclonal antibody that works by inhibiting vascular endothelial growth factor (VEGF). It is licensed in the European Union in combination with Roche’s capecitabine (Xeloda) for metastatic breast cancer; however, the National Institute for Health and Clinical Excellence found that the treatment did not meet its cost-effectiveness criteria. NICE’s decision was widely expected after the agency issued negative draft guidance in April.

In 2010, NICE turned down bevacizumab in combination with a taxane for first-line treatment of metastatic breast cancer, its licensed indication at the time; the European Medicines Agency late that year limited the breast cancer indication to a combination with paclitaxel.

In April 2011, EMA said bevacizumab could also be used with capecitabine if other chemotherapy treatments are inappropriate, citing evidence from RIBBON-1, a randomized, placebo-controlled trial that showed average progression-free survival of 8.6 months in patients receiving the combination, compared with 5.7 months in those receiving capecitabine alone.

In a final appraisal published July 6, NICE acknowledged the statistically significant, 2.9-month gain in progression-free survival seen with bevacizumab in the trial. However, the agency said that quality-of-life data were not captured, and while median overall survival also improved by 2.9 months, this result was not statistically significant due in part to crossover.

The manufacturer’s submission to NICE included clinical trial evidence only for a subgroup of people who had been previously treated with a taxane, while the full indication includes both previously treated and treatment-naive patients.

The NICE reviewers said they found "no biologically plausible reason why bevacizumab plus capecitabine would be more effective" in the previously treated subgroup than in the broader population for which the combination is licensed. They also concluded that the incremental cost-effectiveness ratio for the treatment would be at least £82,000 (U.S.$127,000) per quality-adjusted life year (QALY).

Bevacizumab is administered by intravenous infusion at a recommended dose of 10 mg/kg of body weight once every 2 weeks or 15 mg/kg of body weight once every 3 weeks. The average price of bevacizumab treatment for breast cancer in the United Kingdom is £3,689 (U.S.$5,727) per month, according to NICE.

The clinical effectiveness agency for England and Wales has rejected a second bevacizumab combination for metastatic breast cancer, citing the treatment’s high cost, uncertain effect on quality of life, and lack of robust evidence for overall survival improvements.

Roche’s bevacizumab (Avastin) is a monoclonal antibody that works by inhibiting vascular endothelial growth factor (VEGF). It is licensed in the European Union in combination with Roche’s capecitabine (Xeloda) for metastatic breast cancer; however, the National Institute for Health and Clinical Excellence found that the treatment did not meet its cost-effectiveness criteria. NICE’s decision was widely expected after the agency issued negative draft guidance in April.

In 2010, NICE turned down bevacizumab in combination with a taxane for first-line treatment of metastatic breast cancer, its licensed indication at the time; the European Medicines Agency late that year limited the breast cancer indication to a combination with paclitaxel.

In April 2011, EMA said bevacizumab could also be used with capecitabine if other chemotherapy treatments are inappropriate, citing evidence from RIBBON-1, a randomized, placebo-controlled trial that showed average progression-free survival of 8.6 months in patients receiving the combination, compared with 5.7 months in those receiving capecitabine alone.

In a final appraisal published July 6, NICE acknowledged the statistically significant, 2.9-month gain in progression-free survival seen with bevacizumab in the trial. However, the agency said that quality-of-life data were not captured, and while median overall survival also improved by 2.9 months, this result was not statistically significant due in part to crossover.

The manufacturer’s submission to NICE included clinical trial evidence only for a subgroup of people who had been previously treated with a taxane, while the full indication includes both previously treated and treatment-naive patients.

The NICE reviewers said they found "no biologically plausible reason why bevacizumab plus capecitabine would be more effective" in the previously treated subgroup than in the broader population for which the combination is licensed. They also concluded that the incremental cost-effectiveness ratio for the treatment would be at least £82,000 (U.S.$127,000) per quality-adjusted life year (QALY).

Bevacizumab is administered by intravenous infusion at a recommended dose of 10 mg/kg of body weight once every 2 weeks or 15 mg/kg of body weight once every 3 weeks. The average price of bevacizumab treatment for breast cancer in the United Kingdom is £3,689 (U.S.$5,727) per month, according to NICE.

A 43-year-old woman who was BRCA1 and -2 negative presented initially in 2002, when she was 35 years old, with inflammatory breast carcinoma on the right side. She was 9 months post partum. A biopsy revealed that the tumor was estrogen-receptor (ER)/progesterone- receptor (PR) negative and HER2 (human epidermal growth factor receptor–2) positive. She received neoadjuvant chemotherapy with adriamycin plus docetaxel for 6 cycles, followed by right mastectomy and prophylactic left mastectomy. There was no residual disease in the breast. After mastectomy, the patient underwent CMF (cyclophosphamide, methotrexate, and fluorouracil) chemotherapy for 3 months, as well as radiation therapy to the chest wall. Adjuvant trastuzumab was started concurrently with the CMF chemotherapy, and was continued for 1 year.

*For a PDF of the full article, click on the link to the left of this introduction.

A 43-year-old woman who was BRCA1 and -2 negative presented initially in 2002, when she was 35 years old, with inflammatory breast carcinoma on the right side. She was 9 months post partum. A biopsy revealed that the tumor was estrogen-receptor (ER)/progesterone- receptor (PR) negative and HER2 (human epidermal growth factor receptor–2) positive. She received neoadjuvant chemotherapy with adriamycin plus docetaxel for 6 cycles, followed by right mastectomy and prophylactic left mastectomy. There was no residual disease in the breast. After mastectomy, the patient underwent CMF (cyclophosphamide, methotrexate, and fluorouracil) chemotherapy for 3 months, as well as radiation therapy to the chest wall. Adjuvant trastuzumab was started concurrently with the CMF chemotherapy, and was continued for 1 year.

*For a PDF of the full article, click on the link to the left of this introduction.

A 43-year-old woman who was BRCA1 and -2 negative presented initially in 2002, when she was 35 years old, with inflammatory breast carcinoma on the right side. She was 9 months post partum. A biopsy revealed that the tumor was estrogen-receptor (ER)/progesterone- receptor (PR) negative and HER2 (human epidermal growth factor receptor–2) positive. She received neoadjuvant chemotherapy with adriamycin plus docetaxel for 6 cycles, followed by right mastectomy and prophylactic left mastectomy. There was no residual disease in the breast. After mastectomy, the patient underwent CMF (cyclophosphamide, methotrexate, and fluorouracil) chemotherapy for 3 months, as well as radiation therapy to the chest wall. Adjuvant trastuzumab was started concurrently with the CMF chemotherapy, and was continued for 1 year.

*For a PDF of the full article, click on the link to the left of this introduction.