Cytotoxic Drugs
Chemo, Tamoxifen May Increase VTE Risk Among Patients With Breast Cancer
Women receiving chemotherapy for breast cancer have a clinical important risk for developing venous thromboemboli (VTE), while women receiving tamoxifen have an increased risk of VTE immediately following endocrine therapy, a new study published online ahead of print in the journal Bloodhas shown.1
Although previous research have demonstrated that patients with breast cancer are at an increased risk for developing VTE, especially in the peridiagnosis period, the effect of breast cancer treatment on VTE risk is unknown. Therefore, researchers sought to evaluate the impact of breast cancer stage, biology, and treatment on the risk of VTE.
For the study, researchers analyzed data from 13 202 patients with breast cancer from the Clinical Practice Research Datalink in England. Patients' breast cancer was diagnosed between 1997 and 2006 and had follow-up continuing to the end of 2010.
Results showed that patients with breast cancer had an annual VTE incidence of 6% while undergoing chemotherapy and in the month following treatment, which was 10.8-fold higher than women who did not receive chemotherapy.
Researchers also found that patients receiving tamoxifen had a 4-times higher risk for developing VTE immediately following endocrine therapy than the risk before initiating therapy.
The risk of VTE following surgery was also significantly increased during the first month after surgery, but it was not raised after the first month.
REFERENCE
1. Walker AJ, West J, Card TR, et al. When are breast cancer patients at highest risk of venous thromboembolism: a cohort study using English healthcare data [published online ahead of print November 16, 2015]. Blood. doi:10.1182/blood-2015-01-625582.
Source : Oncology Nurse Advisor (Nov 2015)
Docetaxel: Drug Safety Communication - May Cause Symptoms of Alcohol Intoxication
AUDIENCE: Oncology
ISSUE: FDA is warning that the intravenous chemotherapy drug docetaxel contains ethanol, also known as alcohol, which may cause patients to experience intoxication or feel drunk during and after treatment. FDA is revising the labels of all docetaxel drug products to warn about this risk.
BACKGROUND: Docetaxel is a prescription chemotherapy drug used to treat different kinds of cancer, including cancers of the breast, prostate, stomach, head and neck cancers, and non-small-cell lung cancer.
RECOMMENDATION: Health care professionals should consider the alcohol content of docetaxel when prescribing or administering the drug to patients, particularly in those whom alcohol intake should be avoided or minimized and when using it in conjunction with other medications.
Source : FDA (June 2014)
Link to Source
FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran)
Safety Announcement [06-29-2012] The U.S. Food and Drug Administration (FDA) is informing healthcare professionals and the public that preliminary results from a recently completed clinical study suggest that a 32 mg single intravenous dose of ondansetron (Zofran, ondansetron hydrochloride, and generics) may affect the electrical activity of the heart (QT interval prolongation), which could pre-dispose patients to develop an abnormal and potentially fatal heart rhythm known as Torsades de Pointes.
GlaxoSmithKline (GSK) has announced changes to the Zofran drug label to remove the 32 mg single intravenous dose. The updated label will state that ondansetron can continue to be used in adults and children with chemotherapy-induced nausea and vomiting at the lower intravenous dose recommended in the drug label, a dose of 0.15 mg/kg administered every 4 hours for three doses; however, no single intravenous dose should exceed 16 mg. Information from the new clinical study will be included in the updated drug label.
FDA 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 new information on QT prolongation does not change any of the recommended oral dosing regimens for ondansetron. It also does not change the recommended lower dose intravenous dosing of ondansetron to prevent post-operative nausea and vomiting.
As part of the ongoing safety review of ondansetron, FDA continues to assess data about the risk of QT prolongation and will update the public when more information becomes available. FDA previously issued a DSC about the ongoing safety review of ondansetron in September 2011.
Additional Information for Patients (updated from 9/15/2011)
GlaxoSmithKline (GSK), the manufacturer of Zofran, was required by FDA to conduct a thorough QT study to assess the potential for the drug to prolong the QT interval. Preliminary review of the study results shows that QT prolongation occurs in a dose-dependent manner. Specifically, at the highest tested single intravenous dose of 32 mg, the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower tested single intravenous dose of 8 mg, the maximum mean difference in QTcF from placebo after baseline-correction was 6 msec.
Source : FDA
Link to Source
Herceptin Tied to Heart Issues in Breast Cancer
Treatment with trastuzumab prolonged survival among women with HER2-positive early breast cancer, but the benefits were accompanied by significant risks of cardiotoxicity, a systematic review found.
In eight clinical trials included in a meta-analysis, regimens containing trastuzumab (Herceptin) were associated with greater overall survival (HR 0.66, 95% CI 0.57 to 0.77) and disease-free survival (HR 0.60, 95% CI 0.50 to 0.71, P<0.00001 for both), according to Lorenzo Moja, MD, DPH, of the University of Milan in Italy, and colleagues.
However, the treatment significantly raised the risk of congestive heart failure (RR 5.11, 90% CI 3 to 8.72, P<0.00001), the researchers reported in the Cochrane Database of Systematic Reviews.
Women with human epidermal growth factor 2-positive breast cancer tend to have worse outcomes than do those with HER2-negative tumors, and the antibody trastuzumab can block the HER2 receptor.
And despite being found beneficial in large clinical trials, the effects of trastuzumab on mortality have remained uncertain, and the optimal treatment schedule has not been clarified.
Accordingly, Moja and colleagues analyzed data from eight randomized trials that included 11,991 women with early and locally advanced breast cancer, as well as normal cardiac function.
Various chemotherapy regimens were used in the trials, with agents such as docetaxel (Taxotere) and carboplatin.
In six of the studies, trastuzumab was given for 1 year, while in two the duration was shorter, at 6 months or 9 weeks.
The analysis of overall survival involved 9,935 women and 655 deaths, and no heterogeneity was found among the eight trials.
In the two trials in which trastuzumab was given for less than a year, a significant overall survival benefit was not seen.
In six of the trials, trastuzumab was given concurrently with chemotherapy, and significant overall survival benefits were found (HR 0.64, 95% CI 0.53 to 0.76, P<0.00001), but when the antibody was given after chemotherapy, the benefit was lost.
For disease-free survival, significance was maintained in the two shorter duration trials (HR 0.31, 95% CI 0.10 to 0.96, P=0.04), and also when given sequentially or concurrently with chemotherapy.
In the safety analysis, cardiotoxicity also was evident in that trastuzumab treatment was associated with a decline in left ventricular ejection fraction (LVEF, RR 1.83, 90% CI 1.36 to 2.47, P=0.0008).
Longer treatment also was associated with an increased risk of decline in LVEF (RR 2.14, 90% CI 1.58 to 2.89, P<0.0001).
Hematologic toxicities, including neutropenic fever, anemia, and neutropenia were not increased with the use of trastuzumab.
The authors concluded that "in view of the large effect, the large number of meta-analyzed studies and patients, and the relative absence of substantial differences between studies," trastuzumab can be considered beneficial for women with HER2-positive tumors and who are at risk for recurrences.
"However, cardiac toxicities pose an appreciable clinical problem," they stated.
They summed up their findings by explaining that not treating 1,000 low-risk women could result in five developing cardiac toxicities and 900 remaining alive at 3 years, but if treatment were given, the corresponding figures would be 26 and 933.
"Therefore, careful attention is needed in patient selection, as the benefit of trastuzumab could be eroded by cardiac toxicity, particularly in low-risk patients or those at increased cardiovascular risk," they cautioned.
They did note, however, that the cardiac toxicities might be reversible upon withdrawal of treatment.
A limitation of their meta-analysis was its possible lack of generalizability, because the women in these studies tended to be younger, with a median age of 49, and otherwise healthier than those seen in clinical practice, having no cardiovascular problems at baseline.
In addition, the inclusion of trials that were stopped early because interim analyses showed positive effects, with controls then being allowed to cross over to the treatment arm, could introduce bias.
They recommended that all data from randomized trials of trastuzumab be published to help clarify the risks and benefits of the treatment and suggested that a meta-analysis be done for individual patient data.
Source : Medpage Today
Link to Source
Increased Incidence of Myelodysplastic Syndrome and Acute Myeloid Leukemia Following Breast Cancer Treatment with Radiation Alone or Combined with Chemotherapy: a registry cohort analysis 1990-2005
Judith A Malmgren and Mary K Atwood
Abstract
Background
Our objective was to measure myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) risk associated with radiation and/or chemotherapy breast cancer (BC) treatment.
Methods
Our study cohort was composed of BC patients diagnosed from 1990 to 2005 and was followed up for blood disorders, mean length of follow up = 7.17 years, range 2-18 years. 5790 TNM stage 0-III patients treated with surgery alone, radiation and/or chemotherapy were included. Patients without surgery (n=111), with stem cell transplantation (n=98), unknown or non-standard chemotherapy regimens (n=94), lost to follow up (n=66) or 'cancer status known' (n=67) were excluded. Rates observed at our community based cancer care institution were compared to SEER incidence data for rate ratio (RR) calculations.
Results
17 cases of MDS/AML (10 MDS/7 AML) occurred during the follow up period, crude rate .29% (95% CI = .17, .47), SEER comparison RR= 3.94 (95% CI = 2.34, 6.15). The RR of MDS in patients age <65 comparing our cohort incidence to SEER incidence data was 10.88 (95% CI = 3.84, 24.03) and the RR of AML in patients age <65 was 5.32 (95% CI = 1.31, 14.04). No significant increased risk of MDS or AML was observed in women > 65 or the surgery/chemotherapy-only group. A RR of 3.32 (95% CI = 1.42, 6.45) was observed in the surgery/radiation-only group and a RR of 6.32 (95% CI = 3.03, 11.45) in the surgery/radiation/chemotherapy group. 3 out of 10 MDS cases died of disease at an average 3.8 months post diagnosis and five of seven AML cases died at an average 9 months post diagnosis.
Conclusions
An elevated rate of MDS and AML was observed among breast cancer patients <65, those treated with radiation and those treated with radiation and chemotherapy compared to available population incidence data. Although a small number of patients are affected, leukemia risk associated with treatment and younger age is significant.
Source: BMC Cancer 2011, 11:260doi:10.1186/1471-2407-11-260
Link to Full Article
Exposure risks with cytotoxic drugs
Chromosomal abnormalities characteristic of chemotherapy-related myelodysplastic syndrome have been detected in healthcare workers who handle cytotoxic drugs
Christine Clark BSc MSc PhD FRPharmS FCPP(Hon)
Delegates at the American Society of Health- System Pharmacists (ASHP) Midyear Clinical Meeting in Las Vegas in December 2009 heard that patients who have been treated with anticancer drugs are at risk of developing secondary malignancies-often myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML)- and these are associated with specific abnormalities on chromosomes 5, 7 and 11. A recent study showed that similar patterns of chromosomal changes occur in health-care workers who have been handling antineoplastic agents.
A comprehensive exposure assessment study of oncology, pharmacy and nursing personnel funded by the US National Institute for Occupational Safety and Health (NIOSH) provides more evidence for the risks posed by the handling of cytotoxic drugs, according to the principal investigators, Melissa McDiarmid(professor of medicine, epidemiology and preventive medicine, University of Maryland, Baltimore) and Thomas Connor (research biologist, division of applied research and technology, National Institute for Occupational Safety and Health, Cincinnati, Ohio). The study was conducted in three University hospital cancer centres in the USA, all of which claimed to be operating the recommended "safe handling" practices. It included environmental sampling, prospective recording of every drug handling event over a six-week period, biological monitoring for specific anticancer drugs in urine and measures of genotoxic effects. A total of 109 healthcare workers participated in the study, 63 of whom were exposed to cytotoxic drugs in the course of their work and 46 who were not and acted as controls.
"We should have respect for and concern about the use of antineoplastic agents because most of these drugs bind to DNA and act like oncogenes," said Dr McDiarmid. Developmental genotoxicity is a feature of many common anticancer drugs and genotoxicity has been recorded for all classes of these drugs including alkylating agents, antimetabolites and mitotic
inhibitors.
Historically these drugs emerged from the chemical warfare agents that were developed in the First World War. They were introduced into cancer treatment during the 1960s and secondary malignancies were first reported during the 1970s. In 1979 mutagenicity was noted in healthcare workers. The hazardous drugs in question are the 12 defined by the International Agency for Research on Cancer (IARC; see Resources) as group 1 human carcinogens along with 19 other drugs classified as "probable" and "possible" carcinogens.
Turning to evidence of chromosomal damage, Dr McDiarmid pointed out that there is now clear evidence of the types of specific chromosomal changes that lead to the development of MDS or AML. Damage to chromosomes 5 and 7 is known to occur with alkylating agents and damage to chromosome 11 is
linked to treatment with topoisomerase inhibitors.
One arm of this study looked for specific chromosome changes in healthcare workers while the other arm involved a detailed assessment of the extent and level of exposure. Fluorescent in-situ hybridisation was used to look for changes in chromosomes 5, 7 and 11. This is a technique that detects deletions, explained Dr McDiarmid. Abnormalities in chromosomes 5 and 7 were expected from the outset because of the high use of alkylating agents, she added.
Pharmacy staff had twice as many handling events as nursing staff and alkylating agents were the most common products. The results showed that for every handling event there was an increase in the risk of a change to chromosome 5 or 7. When the handling events involving alkylating agents only were analysed there was a five-fold increase in the effect estimate. Dr McDiarmid concluded that the study had demonstrated the presence of the signature lesions of therapy-related MDS and AML in the healthcare workers who handled cytotoxic agents. Moreover, she added, biological exposure to genotoxic agents was clearly occurring despite the adoption of protection
measures.
Dr McDiarmid commented that people often claim to be operating safe handling procedures but they are not evident on "walkthroughs".
She acknowledged that the current guidelines need to be revisited. "We must get everybody on the same page with correct guidelines," she said. She also noted that there was a tendency to assume that this issue had been addressed because guidelines had been published- "we need to demythologise this", she said.
Dr Connor described how the level of exposure to cytotoxic drugs was determined. The healthcare workers included were pharmacists, pharmacy technicians, nurses and nurse aides, along with matched controls. Exposure was assessed by means of a six week handling diary, surface wipe samples, area air samples, personal air samples, urine drug levels and the comet assay for DNA damage. Handling events for pharmacy personnel included preparation of doses, checking, priming tubing and spills and splashes. Handling events for nurses also included drug administration. Surface wipe samples were tested for five drugs-cyclophosphamide, ifosfamide, paclitaxel, 5- fluorouracil and cytarabine- using a highly sensitive liquid chromatography-mass spectroscopy-mass spectroscopy (LC-MS-MS) technique. Wipe samples were collected from multiple sites in the pharmacy and nursing areas. Area air samples were collected from the working areas and personal air samples were collected from the breathing zones of workers. Urine was collected from workers for paclitaxel and cyclophosphamide determination during the last four hours of each shift and during the four-hour period afterwards. Finally, comet assays were performed to assess DNA damage. This relies on single cell gel electrophoresis; the result looks like a comet and broken DNA forms a visible tail to the comet, explained Dr Connor. The comet assay provides evidence of non-specific chromosome damage.
A total of 9491 handling events were recorded and 145 wipe samples were collected. Sixty per cent of the wipe samples demonstrated at least one of the five drugs at concentrations above the limit of detection. As a rule of thumb, wipe sample results of less than 1ng/cm2 are acceptable, but some "quite substantial" values were detected during this study, said Dr Connor. For example at one site, where the drug preparation area was open to adjoining office space (without a pass-through facility or ante-room), contamination was found in the office area and two members of staff had cyclophosphamide in their urine. A total of 108 spills were recorded during more than 4000 handling events at two of the pharmacies. At the third pharmacy, where a closed system transfer device (CSTD) was routinely used, no spills were recorded during more than 5000 handling events. In general, there was less contamination in the nursing areas although heavy contamination with fluorouracil (910ng/cm2) was found on the lid of a waste container in one ward. This was probably due to a breakdown in work practice, such as dripping tubing, commented Dr Connor. No drugs were detected in the air samples collected and this suggests that dermal exposure is the main route of occupational contamination.
Overall, the results showed that surface contamination continues to occur in pharmacy and nursing areas and that levels tend to be higher in pharmacies. Proper clean room facilities with ante-rooms, pass-through hatches and air handling arrangements should be in place where hazardous drugs are handled to minimise contamination risks, Dr Connor said. He also emphasised that there were no spillages in the high-use, highvolume facility that routinely used a CSTD.
Source : Hospital Pharmacy Europe Issue 49 March/April 2010
Link to Source
Women receiving chemotherapy for breast cancer have a clinical important risk for developing venous thromboemboli (VTE), while women receiving tamoxifen have an increased risk of VTE immediately following endocrine therapy, a new study published online ahead of print in the journal Bloodhas shown.1
Although previous research have demonstrated that patients with breast cancer are at an increased risk for developing VTE, especially in the peridiagnosis period, the effect of breast cancer treatment on VTE risk is unknown. Therefore, researchers sought to evaluate the impact of breast cancer stage, biology, and treatment on the risk of VTE.
For the study, researchers analyzed data from 13 202 patients with breast cancer from the Clinical Practice Research Datalink in England. Patients' breast cancer was diagnosed between 1997 and 2006 and had follow-up continuing to the end of 2010.
Results showed that patients with breast cancer had an annual VTE incidence of 6% while undergoing chemotherapy and in the month following treatment, which was 10.8-fold higher than women who did not receive chemotherapy.
Researchers also found that patients receiving tamoxifen had a 4-times higher risk for developing VTE immediately following endocrine therapy than the risk before initiating therapy.
The risk of VTE following surgery was also significantly increased during the first month after surgery, but it was not raised after the first month.
REFERENCE
1. Walker AJ, West J, Card TR, et al. When are breast cancer patients at highest risk of venous thromboembolism: a cohort study using English healthcare data [published online ahead of print November 16, 2015]. Blood. doi:10.1182/blood-2015-01-625582.
Source : Oncology Nurse Advisor (Nov 2015)
Docetaxel: Drug Safety Communication - May Cause Symptoms of Alcohol Intoxication
AUDIENCE: Oncology
ISSUE: FDA is warning that the intravenous chemotherapy drug docetaxel contains ethanol, also known as alcohol, which may cause patients to experience intoxication or feel drunk during and after treatment. FDA is revising the labels of all docetaxel drug products to warn about this risk.
BACKGROUND: Docetaxel is a prescription chemotherapy drug used to treat different kinds of cancer, including cancers of the breast, prostate, stomach, head and neck cancers, and non-small-cell lung cancer.
RECOMMENDATION: Health care professionals should consider the alcohol content of docetaxel when prescribing or administering the drug to patients, particularly in those whom alcohol intake should be avoided or minimized and when using it in conjunction with other medications.
Source : FDA (June 2014)
Link to Source
FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran)
Safety Announcement [06-29-2012] The U.S. Food and Drug Administration (FDA) is informing healthcare professionals and the public that preliminary results from a recently completed clinical study suggest that a 32 mg single intravenous dose of ondansetron (Zofran, ondansetron hydrochloride, and generics) may affect the electrical activity of the heart (QT interval prolongation), which could pre-dispose patients to develop an abnormal and potentially fatal heart rhythm known as Torsades de Pointes.
GlaxoSmithKline (GSK) has announced changes to the Zofran drug label to remove the 32 mg single intravenous dose. The updated label will state that ondansetron can continue to be used in adults and children with chemotherapy-induced nausea and vomiting at the lower intravenous dose recommended in the drug label, a dose of 0.15 mg/kg administered every 4 hours for three doses; however, no single intravenous dose should exceed 16 mg. Information from the new clinical study will be included in the updated drug label.
FDA 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 new information on QT prolongation does not change any of the recommended oral dosing regimens for ondansetron. It also does not change the recommended lower dose intravenous dosing of ondansetron to prevent post-operative nausea and vomiting.
As part of the ongoing safety review of ondansetron, FDA continues to assess data about the risk of QT prolongation and will update the public when more information becomes available. FDA previously issued a DSC about the ongoing safety review of ondansetron in September 2011.
Additional Information for Patients (updated from 9/15/2011)
- Discuss any questions or concerns about ondansetron with your healthcare professional.
- While taking ondansetron, your healthcare professional may order an electrocardiogram (ECG, EKG) to monitor your heart rate and rhythm.
- Seek immediate care if you experience an irregular heartbeat, shortness of breath, dizziness, or fainting while taking ondansetron.
- Report any side effects you experience to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.
- ECG changes including QT interval prolongation have been observed in patients receiving ondansetron. In addition, Torsade de Pointes, an abnormal, potentially fatal, heart rhythm, has been reported in some patients receiving ondansetron.
- The use of a single 32 mg intravenous dose of ondansetron should be avoided. New information indicates that QT prolongation occurs in a dose-dependent manner, and specifically at a single intravenous dose of 32 mg.
- Patients who may be at particular risk for QT prolongation with ondansentron are those with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or patients taking concomitant medications that prolong the QT interval
- Electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia) should be corrected prior to the infusion of ondansetron.
- The lower dose intravenous regimen of 0.15 mg/kg every 4 hours for three doses may be used in adults with chemotherapy-induced nausea and vomiting. However, no single intravenous dose of ondansetron should exceed 16 mg due to the risk of QT prolongation.
- The new information does not change any of the recommended oral dosing regimens for ondansetron, including the single oral dose of 24 mg for chemotherapy induced nausea and vomiting.
- The new information also does not change the recommended lower dose intravenous dosing to prevent post-operative nausea and vomiting.
- Report adverse events involving ondansetron to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.
GlaxoSmithKline (GSK), the manufacturer of Zofran, was required by FDA to conduct a thorough QT study to assess the potential for the drug to prolong the QT interval. Preliminary review of the study results shows that QT prolongation occurs in a dose-dependent manner. Specifically, at the highest tested single intravenous dose of 32 mg, the maximum mean difference in QTcF from placebo after baseline-correction was 20 msec. At the lower tested single intravenous dose of 8 mg, the maximum mean difference in QTcF from placebo after baseline-correction was 6 msec.
Source : FDA
Link to Source
Herceptin Tied to Heart Issues in Breast Cancer
Treatment with trastuzumab prolonged survival among women with HER2-positive early breast cancer, but the benefits were accompanied by significant risks of cardiotoxicity, a systematic review found.
In eight clinical trials included in a meta-analysis, regimens containing trastuzumab (Herceptin) were associated with greater overall survival (HR 0.66, 95% CI 0.57 to 0.77) and disease-free survival (HR 0.60, 95% CI 0.50 to 0.71, P<0.00001 for both), according to Lorenzo Moja, MD, DPH, of the University of Milan in Italy, and colleagues.
However, the treatment significantly raised the risk of congestive heart failure (RR 5.11, 90% CI 3 to 8.72, P<0.00001), the researchers reported in the Cochrane Database of Systematic Reviews.
Women with human epidermal growth factor 2-positive breast cancer tend to have worse outcomes than do those with HER2-negative tumors, and the antibody trastuzumab can block the HER2 receptor.
And despite being found beneficial in large clinical trials, the effects of trastuzumab on mortality have remained uncertain, and the optimal treatment schedule has not been clarified.
Accordingly, Moja and colleagues analyzed data from eight randomized trials that included 11,991 women with early and locally advanced breast cancer, as well as normal cardiac function.
Various chemotherapy regimens were used in the trials, with agents such as docetaxel (Taxotere) and carboplatin.
In six of the studies, trastuzumab was given for 1 year, while in two the duration was shorter, at 6 months or 9 weeks.
The analysis of overall survival involved 9,935 women and 655 deaths, and no heterogeneity was found among the eight trials.
In the two trials in which trastuzumab was given for less than a year, a significant overall survival benefit was not seen.
In six of the trials, trastuzumab was given concurrently with chemotherapy, and significant overall survival benefits were found (HR 0.64, 95% CI 0.53 to 0.76, P<0.00001), but when the antibody was given after chemotherapy, the benefit was lost.
For disease-free survival, significance was maintained in the two shorter duration trials (HR 0.31, 95% CI 0.10 to 0.96, P=0.04), and also when given sequentially or concurrently with chemotherapy.
In the safety analysis, cardiotoxicity also was evident in that trastuzumab treatment was associated with a decline in left ventricular ejection fraction (LVEF, RR 1.83, 90% CI 1.36 to 2.47, P=0.0008).
Longer treatment also was associated with an increased risk of decline in LVEF (RR 2.14, 90% CI 1.58 to 2.89, P<0.0001).
Hematologic toxicities, including neutropenic fever, anemia, and neutropenia were not increased with the use of trastuzumab.
The authors concluded that "in view of the large effect, the large number of meta-analyzed studies and patients, and the relative absence of substantial differences between studies," trastuzumab can be considered beneficial for women with HER2-positive tumors and who are at risk for recurrences.
"However, cardiac toxicities pose an appreciable clinical problem," they stated.
They summed up their findings by explaining that not treating 1,000 low-risk women could result in five developing cardiac toxicities and 900 remaining alive at 3 years, but if treatment were given, the corresponding figures would be 26 and 933.
"Therefore, careful attention is needed in patient selection, as the benefit of trastuzumab could be eroded by cardiac toxicity, particularly in low-risk patients or those at increased cardiovascular risk," they cautioned.
They did note, however, that the cardiac toxicities might be reversible upon withdrawal of treatment.
A limitation of their meta-analysis was its possible lack of generalizability, because the women in these studies tended to be younger, with a median age of 49, and otherwise healthier than those seen in clinical practice, having no cardiovascular problems at baseline.
In addition, the inclusion of trials that were stopped early because interim analyses showed positive effects, with controls then being allowed to cross over to the treatment arm, could introduce bias.
They recommended that all data from randomized trials of trastuzumab be published to help clarify the risks and benefits of the treatment and suggested that a meta-analysis be done for individual patient data.
Source : Medpage Today
Link to Source
Increased Incidence of Myelodysplastic Syndrome and Acute Myeloid Leukemia Following Breast Cancer Treatment with Radiation Alone or Combined with Chemotherapy: a registry cohort analysis 1990-2005
Judith A Malmgren and Mary K Atwood
Abstract
Background
Our objective was to measure myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) risk associated with radiation and/or chemotherapy breast cancer (BC) treatment.
Methods
Our study cohort was composed of BC patients diagnosed from 1990 to 2005 and was followed up for blood disorders, mean length of follow up = 7.17 years, range 2-18 years. 5790 TNM stage 0-III patients treated with surgery alone, radiation and/or chemotherapy were included. Patients without surgery (n=111), with stem cell transplantation (n=98), unknown or non-standard chemotherapy regimens (n=94), lost to follow up (n=66) or 'cancer status known' (n=67) were excluded. Rates observed at our community based cancer care institution were compared to SEER incidence data for rate ratio (RR) calculations.
Results
17 cases of MDS/AML (10 MDS/7 AML) occurred during the follow up period, crude rate .29% (95% CI = .17, .47), SEER comparison RR= 3.94 (95% CI = 2.34, 6.15). The RR of MDS in patients age <65 comparing our cohort incidence to SEER incidence data was 10.88 (95% CI = 3.84, 24.03) and the RR of AML in patients age <65 was 5.32 (95% CI = 1.31, 14.04). No significant increased risk of MDS or AML was observed in women > 65 or the surgery/chemotherapy-only group. A RR of 3.32 (95% CI = 1.42, 6.45) was observed in the surgery/radiation-only group and a RR of 6.32 (95% CI = 3.03, 11.45) in the surgery/radiation/chemotherapy group. 3 out of 10 MDS cases died of disease at an average 3.8 months post diagnosis and five of seven AML cases died at an average 9 months post diagnosis.
Conclusions
An elevated rate of MDS and AML was observed among breast cancer patients <65, those treated with radiation and those treated with radiation and chemotherapy compared to available population incidence data. Although a small number of patients are affected, leukemia risk associated with treatment and younger age is significant.
Source: BMC Cancer 2011, 11:260doi:10.1186/1471-2407-11-260
Link to Full Article
Exposure risks with cytotoxic drugs
Chromosomal abnormalities characteristic of chemotherapy-related myelodysplastic syndrome have been detected in healthcare workers who handle cytotoxic drugs
Christine Clark BSc MSc PhD FRPharmS FCPP(Hon)
Delegates at the American Society of Health- System Pharmacists (ASHP) Midyear Clinical Meeting in Las Vegas in December 2009 heard that patients who have been treated with anticancer drugs are at risk of developing secondary malignancies-often myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML)- and these are associated with specific abnormalities on chromosomes 5, 7 and 11. A recent study showed that similar patterns of chromosomal changes occur in health-care workers who have been handling antineoplastic agents.
A comprehensive exposure assessment study of oncology, pharmacy and nursing personnel funded by the US National Institute for Occupational Safety and Health (NIOSH) provides more evidence for the risks posed by the handling of cytotoxic drugs, according to the principal investigators, Melissa McDiarmid(professor of medicine, epidemiology and preventive medicine, University of Maryland, Baltimore) and Thomas Connor (research biologist, division of applied research and technology, National Institute for Occupational Safety and Health, Cincinnati, Ohio). The study was conducted in three University hospital cancer centres in the USA, all of which claimed to be operating the recommended "safe handling" practices. It included environmental sampling, prospective recording of every drug handling event over a six-week period, biological monitoring for specific anticancer drugs in urine and measures of genotoxic effects. A total of 109 healthcare workers participated in the study, 63 of whom were exposed to cytotoxic drugs in the course of their work and 46 who were not and acted as controls.
"We should have respect for and concern about the use of antineoplastic agents because most of these drugs bind to DNA and act like oncogenes," said Dr McDiarmid. Developmental genotoxicity is a feature of many common anticancer drugs and genotoxicity has been recorded for all classes of these drugs including alkylating agents, antimetabolites and mitotic
inhibitors.
Historically these drugs emerged from the chemical warfare agents that were developed in the First World War. They were introduced into cancer treatment during the 1960s and secondary malignancies were first reported during the 1970s. In 1979 mutagenicity was noted in healthcare workers. The hazardous drugs in question are the 12 defined by the International Agency for Research on Cancer (IARC; see Resources) as group 1 human carcinogens along with 19 other drugs classified as "probable" and "possible" carcinogens.
Turning to evidence of chromosomal damage, Dr McDiarmid pointed out that there is now clear evidence of the types of specific chromosomal changes that lead to the development of MDS or AML. Damage to chromosomes 5 and 7 is known to occur with alkylating agents and damage to chromosome 11 is
linked to treatment with topoisomerase inhibitors.
One arm of this study looked for specific chromosome changes in healthcare workers while the other arm involved a detailed assessment of the extent and level of exposure. Fluorescent in-situ hybridisation was used to look for changes in chromosomes 5, 7 and 11. This is a technique that detects deletions, explained Dr McDiarmid. Abnormalities in chromosomes 5 and 7 were expected from the outset because of the high use of alkylating agents, she added.
Pharmacy staff had twice as many handling events as nursing staff and alkylating agents were the most common products. The results showed that for every handling event there was an increase in the risk of a change to chromosome 5 or 7. When the handling events involving alkylating agents only were analysed there was a five-fold increase in the effect estimate. Dr McDiarmid concluded that the study had demonstrated the presence of the signature lesions of therapy-related MDS and AML in the healthcare workers who handled cytotoxic agents. Moreover, she added, biological exposure to genotoxic agents was clearly occurring despite the adoption of protection
measures.
Dr McDiarmid commented that people often claim to be operating safe handling procedures but they are not evident on "walkthroughs".
She acknowledged that the current guidelines need to be revisited. "We must get everybody on the same page with correct guidelines," she said. She also noted that there was a tendency to assume that this issue had been addressed because guidelines had been published- "we need to demythologise this", she said.
Dr Connor described how the level of exposure to cytotoxic drugs was determined. The healthcare workers included were pharmacists, pharmacy technicians, nurses and nurse aides, along with matched controls. Exposure was assessed by means of a six week handling diary, surface wipe samples, area air samples, personal air samples, urine drug levels and the comet assay for DNA damage. Handling events for pharmacy personnel included preparation of doses, checking, priming tubing and spills and splashes. Handling events for nurses also included drug administration. Surface wipe samples were tested for five drugs-cyclophosphamide, ifosfamide, paclitaxel, 5- fluorouracil and cytarabine- using a highly sensitive liquid chromatography-mass spectroscopy-mass spectroscopy (LC-MS-MS) technique. Wipe samples were collected from multiple sites in the pharmacy and nursing areas. Area air samples were collected from the working areas and personal air samples were collected from the breathing zones of workers. Urine was collected from workers for paclitaxel and cyclophosphamide determination during the last four hours of each shift and during the four-hour period afterwards. Finally, comet assays were performed to assess DNA damage. This relies on single cell gel electrophoresis; the result looks like a comet and broken DNA forms a visible tail to the comet, explained Dr Connor. The comet assay provides evidence of non-specific chromosome damage.
A total of 9491 handling events were recorded and 145 wipe samples were collected. Sixty per cent of the wipe samples demonstrated at least one of the five drugs at concentrations above the limit of detection. As a rule of thumb, wipe sample results of less than 1ng/cm2 are acceptable, but some "quite substantial" values were detected during this study, said Dr Connor. For example at one site, where the drug preparation area was open to adjoining office space (without a pass-through facility or ante-room), contamination was found in the office area and two members of staff had cyclophosphamide in their urine. A total of 108 spills were recorded during more than 4000 handling events at two of the pharmacies. At the third pharmacy, where a closed system transfer device (CSTD) was routinely used, no spills were recorded during more than 5000 handling events. In general, there was less contamination in the nursing areas although heavy contamination with fluorouracil (910ng/cm2) was found on the lid of a waste container in one ward. This was probably due to a breakdown in work practice, such as dripping tubing, commented Dr Connor. No drugs were detected in the air samples collected and this suggests that dermal exposure is the main route of occupational contamination.
Overall, the results showed that surface contamination continues to occur in pharmacy and nursing areas and that levels tend to be higher in pharmacies. Proper clean room facilities with ante-rooms, pass-through hatches and air handling arrangements should be in place where hazardous drugs are handled to minimise contamination risks, Dr Connor said. He also emphasised that there were no spillages in the high-use, highvolume facility that routinely used a CSTD.
Source : Hospital Pharmacy Europe Issue 49 March/April 2010
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