Variations in prescribing of tamoxifen are also accountable to breast cancer rates and uptake amongst cancer patients. However, although incidence of breast cancer diagnosis is increasing over time, 1 it seems unlikely that the change in slope of tamoxifen prescribing observed in could be explained by this.
Guidelines have not changed substantially with respect to tamoxifen treatment for either local or advanced breast cancer since We found no evidence for a step change in prescribing, despite the guideline causing a large and immediate increase in the population appropriate for tamoxifen. Long lead times to first prescription may have contributed to the slow adoption rate, due to referral to specialist clinics, the complex decision process for patients 19 and the eligible population being healthy and therefore not visiting their GP frequently or actively seeking therapy.
Furthermore, a large increase may not be expected, given that patient acceptance of chemoprevention can be low for a multitude of reasons. We attempted to place our results on the impact of NICE guidance in the context of what is achievable in chemoprevention.
This may indicate that not all eligible women were offered tamoxifen, or that uptake was lower than preceding estimates would predict. A NICE economic impact assessment estimated a reduction of 11 cancers over 50 years per women offered tamoxifen or raloxifene.
The potential total eligible population and uptake were not calculated. Consistent with our results, previous studies find that the response in primary care to new guidelines generally falls short of expectations. This lack of variation in response by individual practices may be because chemoprevention is often discussed in specialist clinics, each of which will cover a range of practices.
We found evidence, consistent with previous work, that changes in practice warranted by new guidelines and evidence are implemented slowly and perhaps incompletely. This is testament to the challenge in disseminating knowledge effectively. This work was conducted as part of our OpenPrescribing.
We suggest that greater investment in disseminating evidence, auditing its implementation, and using variation in practice to target clinicians for educational interventions may all prove to be cost effective mechanisms to ensure that health services can realise the value of public investment on both primary research and on generating guidelines.
The latest data on tamoxifen prescribing for each of England's practices and CCGs can be viewed online as part of our live prescribing data explorer, at openprescribing. Following release of guidelines advising use of tamoxifen for chemoprevention in a new larger cohort of women, we found a gradual increase in the rate of tamoxifen prescribing estimated to account for patients over 2. We did not find evidence suggestive of the response being concentrated in certain practices, and verified that local variation can be identified in our data set.
Overall, our results suggest not all women at increased risk of breast cancer have been offered tamoxifen chemoprevention, potentially leaving them exposed to avoidable risk. Improving dissemination of guidance to healthcare professionals and routinely monitoring its implementation could help to reduce this risk. Cancer Research UK. Breast cancer statistics. Accessed 27 Mar Early and locally advanced breast cancer: diagnosis and treatment.
Accessed 21 Dec Advanced breast cancer: diagnosis and treatment. Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer. NICE-familial breast cancer. Accessed 3 May Cuzick, J. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data.
Lancet , — Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. Smith S. Cancer Taskforce. Achieving world-class cancer outcomes: a strategy For England — Accessed Mar NHS Digital. Number of patients registered at a GP practice. Kontopantelis, E.
Regression based quasi-experimental approach when randomisation is not an option: interrupted time series analysis. BMJ , h Donnelly, L. Uptake of tamoxifen in consecutive pre-menopausal women under surveillance in a high-risk breast cancer clinic. Cancer , — Smith, S. Factors affecting uptake and adherence to breast cancer chemoprevention: a systematic review and meta-analysis.
Evans, D. Breast cancer risk in young women in the national breast screening programme: implications for applying NICE guidelines for additional screening and chemoprevention. Cancer Prev. Uptake of screening and prevention in women at very high risk of breast cancer. Uptake of breast cancer prevention and screening trials. Familial breast cancer guideline consultation comments table.
Accessed 2 May Anastrozole for prevention of breast cancer in high-risk post-menopausal women IBIS-II : an international, double-blind, randomised placebo-controlled trial. Hill, A. Unexplained rises in UK cancer drug prices between and Skandarajah, A. Patient and medical barriers preclude uptake of tamoxifen preventative therapy in women with a strong family history.
Breast 32 , 93—97 National Collaborating Centre for Cancer. Cost-effectiveness evidence review. Familial breast cancer: classification and care of women at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer. Accessed 26 Jan Sheldon, T. BMJ , Chidgey, J. Implementing NICE guidance. Dietrich, E. Health Care. Munson, J. Effect of treatment guidelines on the initial management of idiopathic pulmonary fibrosis.
Connor, A. Glaucoma prescribing trends in England to Eye 28 , — Fitzpatrick, R. Assessing the impact of NICE guidance on the prescribing of hormonal treatments of breast cancer in England. Conception Statistics, England and Wales. Accessed January 19, Download references. We are grateful to Seb Bacon for obtaining the data and Richard Croker for pharmaceutical advice.
All authors contributed to and approved the final manuscript. Helen J. Correspondence to Ben Goldacre. Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and Permissions.
Curtis, H. Impact of NICE guidance on tamoxifen prescribing in England — an interrupted time series analysis. Br J Cancer , — Download citation. Received : 20 June Revised : 28 February Accepted : 05 March Published : 23 April Issue Date : 01 May Journal of Community Genetics British Journal of General Practice Familial Cancer BMJ Advanced search.
Skip to main content Thank you for visiting nature. Download PDF. Subjects Breast cancer Cancer prevention Health policy. Abstract Background Tamoxifen was recommended by NICE in for chemoprevention of breast cancer, but a recent survey suggested only a quarter of GPs are aware of this.
It aimed to catalyse the development of the social impact investment market. The GSG will continue the work of the Taskforce with a wider membership, comprising 13 countries plus the EU, and active observers from government and from leading network organisations supportive of impact investment.
Led by Sir Ronald Cohen , the taskforce brought together government officials and senior figures from the worlds of finance, business and philanthropy from across the G8 countries. The taskforce published its report , alongside subject papers from its working groups, on 15 September The second meeting was held in London on 4 to 5 December The third meeting was held in Berlin on 18 to 19 February The fourth meeting was held in Paris on 7 to 8 April The fifth meeting was held in London on 19 to 20 June A meeting post-publication of the taskforce report was held in Rome on 28 to 29 October The last taskforce meeting was held in Toronto on 8 to 9 June The taskforce established a number of working groups to support its activities.
These brought together leading experts with the aim of:. This group sought to develop a set of general guidelines for impact measurement practice for use by social impact investors globally to ensure that impact measurement is widely recognised and employed as a fundamental part of the practice of social impact investing.
This working group focused on how capital can be attracted to social impact investment from specific investor communities such as foundations, endowments, pension funds, commercial banking institutions, investment banks and individuals. This group examined issues such as corporate forms, governance and legal protection as they relate to social ventures and mission-driven businesses. In addition to the working groups, the taskforce oversaw the preparation of a report on the global social investment market by the Organisation for Economic Co-operation and Development OECD.
Rates for Colles' fracture Table 3 were obtained by multiplying rates for distal forearm fractures by 0. Silverman and Madison 46 calculated hip fracture incidence rates for non-Hispanic white women, Hispanic women, black women, and Asian women from hospital discharge data in California. We obtained rates for black women in Table 3 by multiplying rates for white women by these ratios. Compared with white women, Hispanic and Asian women had ratios 0. Jacobsen et al. Baron et al.
Medicare population aged years, both for white and for black women. In addition to age and race, other factors influence the risk of fractures in women. A number of other factors contribute to increased risk, including a history of maternal hip fracture, previous hyperthyroidism, current consumption of long-acting benzodiazapines, anticonvulsants or caffeine, lack of exercise walking , inability to rise from a chair, previous fracture, and decreased bone density. Cummings et al.
Baseline estimates of cataract incidence Table 3 were calculated from data in the placebo arm of the BCPT because this cohort of women reflects current ophthalmologic practice and is the largest cohort with reports on cataracts in women. Cataract incidence was based on self-reports of cataract diagnoses. Unfortunately, the BCPT yielded little data on cataracts for black women, and we are unaware of other data on cataract incidence in black women.
Data on race as a risk factor for lens opacity are inconsistent Therefore, we used the same rates for black as for white women in Table 3. Certain medical conditions and medications, such as diabetes, oral steroids, and medicines for gout, are associated with a modestly increased risk of lens opacities, as are current smoking and low educational attainment 50 , Current users of vitamin supplements have a reduced risk of lens opacities Hodge et al.
Overall relative risks tamoxifen to placebo were 0. There was no statistically significant evidence of heterogeneity of relative risks of invasive cancer across groups defined by age, number of affected first-degree relatives, projected 5-year risk of IBC, or LCIS status. We therefore assume that the relative risk reductions from tamoxifen for IBC and for in situ breast cancer are uniform across all subgroups.
The preventive benefit of tamoxifen appeared to be greater in women with atypical hyperplasia, but the numbers of events were small among such women, and this subgroup was only one of five examined 1. BCPT investigators 1 identified eight non-breast cancer conditions whose rates were affected by tamoxifen Table 5. Because there was no statistically significant evidence of heterogeneity of relative risks across age groups for the non-breast cancer outcomes in Table 5 , we used overall relative risks for each of the non-breast cancer outcomes except for endometrial cancer, for which it can be argued that menopausal status may influence the effect of tamoxifen.
We, therefore, used the relative risk 4. These relative risks are quite consistent, however, with the relative risks associated with adjuvant tamoxifen therapy in several analyses of the risk of contralateral breast cancer among women with resected breast cancer 58 and with the summary relative risk, obtained by a meta-analysis, of 0.
European studies with 41 women who developed breast cancers 3 and with 70 women who developed breast cancers 2 did not demonstrate a beneficial preventive effect of tamoxifen. These trials may be sufficiently different from the BCPT in design and execution that it is not reasonable to combine their data with those of the BCPT 1.
Nonetheless, we can obtain a combined estimate of relative risk by taking the ratio of the number of breast cancers in the tamoxifen arms of the three studies to the number of breast cancers in the placebo groups. Methods of combining results that account for possible differences in follow-up time cannot be used with the data presented in the European studies.
Other methods that allow for heterogeneity of treatment effects across the three studies would place greater weight on the smaller studies In section VIII, we discuss the impact of using the relative risk estimate 0. These effects of tamoxifen were found even though many women discontinued its use during the course of these studies. In the BCPT, It is not known whether the preventive effects of tamoxifen would have been greater had compliance been better.
We have, therefore, developed several additional tables to assist in weighing the risks and benefits from prophylactic tamoxifen use. This full description allows a woman who is mainly concerned about particular outcomes, such as breast cancer or endometrial cancer, to focus on those absolute risks and the effects of tamoxifen on them.
The corresponding expected number of in situ lesions was obtained by multiplying this number by 0. It follows that. We used U. For non-breast cancer conditions, the rates I x are obtained by dividing entries in Table 3 by Expected events for a treated population, N x,t , are obtained in the same way, except R x I x replaces I x in equation 1, where R x is the relative risk in Table 5.
To obtain I x for this calculation for IBC or in situ lesions, we solved equation 1 with known values of M x and with N x,p obtained as described above from the risk program. To summarize the risks and benefits of tamoxifen in a single number, however, it is necessary to define indices that assign weights to the various events. A summary index based on the severity categories in Table 5 can be calculated from.
We rounded indices to the nearest integer. We rely principally on the index I 1, 0. We also investigated the robustness of our conclusions to the use of other indices, i. In addition to tabulating I 1, 0. To compute these probabilities, we assumed that the only random elements in N x,p , N x,t , and equation 2 are the relative risks in Table 5 that affect the calculation of N x,t from equation 1 with R x I x in place of I x.
Let U and V be the observed numbers of a particular adverse event, x, in the tamoxifen and placebo arms, respectively, of the BCPT. Thus, to obtain an estimate of the probability that I 1, 0. Using a parametric bootstrap with resampled Poisson counts instead of the Bayesian approach above, we obtained similar results. For a given projected 5-year risk of IBC, the expectations for in situ breast cancer are 0. The numbers of expected non-breast cancer events increase with age and vary by race Table 7.
The variations of the frequency of events reflect the variation in the expected rates by age and race. Cataracts are by far the most common event. Hip and spine fractures are rare, and the occurrence of a stroke is infrequent among women under age 50 years, but these conditions are relatively frequent among those 70 years old or older.
Several differences between white and black women are important to note. In those over 50 years of age, fractures are about two to three times more common among white women. Depending on age, the frequency of endometrial cancer is 1. Stroke, pulmonary embolism, and deep vein thrombosis are two to three times higher among black women in all age groups.
Because tamoxifen reduces the incidence of breast cancer by about one half, the numbers of breast cancers expected to be prevented are nearly proportional to the projected 5-year risk of IBC. Table 8 displays the expected numbers of non-breast cancer outcomes prevented positive number or caused negative number by tamoxifen in such a population. The patterns in Table 8 reflect variations in background rates Table 7 and the relative risks associated with tamoxifen therapy Table 5.
Among women 50 years old or older, tamoxifen reduces the expected numbers of fractures substantially. This benefit is counterbalanced by substantial increases in the risks of stroke, pulmonary embolism, and deep vein thrombosis in women 60 years old or older, especially among black women.
The risk of tamoxifen-induced endometrial cancer is also appreciable in women 50 years old or older with a uterus and is about twofold higher in white women than in black women. Tamoxifen causes very few adverse events among black or white women under age 50 years and has the potential to prevent IBCs and in situ breast cancers among high-risk women in this age range.
We illustrate how black and white women in the age groups years or years and with projected 5-year risks of IBC of 2. Table 9 was constructed by abstracting appropriate elements from Tables 6 and 8. Such a woman would have several strong risk factors for breast cancer see section II. This reduction in the risk of life-threatening events is large, compared with the general 5-year probability of death, 0.
The overall 5-year mortality can be approximated by multiplying the rates in Table 3 by 0. Such a woman can also anticipate a reduction of 90 severe events 0. If she weighs life-threatening events twice as heavily as severe events and ignores other events, she could use the index I 1, 0. This index rises to if the woman has no uterus. If the woman were 55 years old instead of 45 years old, her indices would be less favorable.
The index I 1, 0. The data therefore suggest that such a woman is unlikely to benefit from using tamoxifen. It should be remembered, however, that the data on baseline rates and effects of tamoxifen are much less well established for black women than for white women see sections II and III ; therefore these conclusions are subject to greater uncertainty. Some generalizations can be made based on I 1, 0. First, the net index increases with increasing projected 5-year risk of IBC.
Second, within any particular level of projected 5-year risk of IBC, the net index decreases with increasing age as the result of increases in the risk of adverse effects of tamoxifen treatment. Third, the elimination of the risk of endometrial cancer among women 50 years old or older as in those who have had a hysterectomy substantially improves the net index.
This is particularly notable among white women with a low risk of breast cancer, for whom the elimination of endometrial cancer risk improves the index from a negative value to a positive value. Fourth, because the risks of events, such as stroke, pulmonary embolism, and deep vein thrombosis, are two to three times higher in black women, the net indices for black women are lower than those for white women.
These points can be studied further by examining the patterns of values of I 1, 0. In addition to the value of I 1, 0. The patterns of values of I 1, 0. The largest positive entry in Table 10 is for a white woman aged years with a projected 5-year risk of IBC of 7. If we think of each severe event as equivalent to half of a life-threatening event, this number translates to a reduction in the absolute risk of a life-threatening event of 4. Many other positive entries in Table 10 are smaller, even though there is strong evidence, indicated by two asterisks, that the net benefit is positive.
For example, if a year-old white woman with a uterus had a projected 5-year risk of IBC of 1. Thus, it is important to look at the magnitude of the effects in Tables 10 and 11 as well as whether there is strong statistical evidence that the net effects are positive, as indicated by the asterisks. Nonetheless, we can summarize the information in Tables 10 and 11 that identifies women for whom there is strong evidence two asterisks or moderate evidence one asterisk that I 1, 0.
Among white women with a projected 5-year risk of IBC between 1. For those with a uterus, strong evidence of benefit is also found for women aged years with a projected 5-year risk of IBC greater than or equal to 6. For white women without a uterus, strong evidence of benefit is also found in some high-risk women aged years see Fig. For black women, strong evidence of a net tamoxifen benefit is confined to younger age groups, where the risks from stroke, pulmonary embolism, and deep vein thrombosis are smaller Fig.
Unreported data reveal very similar patterns to those in Tables 10 and 11 and Fig. Thus, these conclusions are fairly insensitive to the precise weights used, provided the weights emphasize life-threatening and severe events. Women in the placebo arm of the BCPT had lower mortality rates 71 deaths observed compared with expected from the mortality rates in Table 3 and lower rates of stroke and pulmonary embolism than the general population see section II, part C.
These reduced rates of stroke and pulmonary embolism were used to calculate the index I 1, 0. It is seen that, compared with indices in Tables 10 and 11 , the indices in Table 12 are larger, especially for older ages. Black women who participate in prevention trials such as the WHI and the BCPT are also likely to have lower rates of stroke and pulmonary embolism than in the general population see section II, part C , and their indices may be more akin to those in Table 12 than to those in Tables 10 and Table 12 could also be used in place of Tables 10 and 11 for women who have a risk factor profile that indicates they are at low risk for stroke and pulmonary embolism.
We therefore recommend using the projected 5-year risk of IBC of 6. Although the BCPT did not include the following classes of women, many such women are seeking advice on the possible use of tamoxifen. Realizing that direct data from clinical trials would be needed to establish the role of tamoxifen definitively, we nonetheless offer some informed opinions based on workshop discussion and other sources. Women with a history of DCIS may be candidates for primary prevention with tamoxifen because they are at high risk for invasive breast cancer.
IBC includes contralateral breast cancer. The risk of contralateral invasive breast cancer alone was 1. The 5-year cumulative risk of IBC for women treated with lumpectomy and radiation was 6. The corresponding 5-year cumulative risks of contralateral invasive cancer were 2.
Thus, the risk of contralateral disease alone in these studies is comparable to the 5-year risk of all IBCs, 3. Based on these high 5-year risks, even in women treated with lumpectomy and radiation, the data in Tables 8 and Fig. Such women were excluded from BCPT because they were eligible for a competing protocol and not because it was thought that tamoxifen would be ineffective. Women with a history of IBC have a risk of about 0.
Consensus opinion suggests that adjuvant therapy with tamoxifen is not indicated for women with invasive breast tumors less than 1 cm in size who have negative axillary lymph nodes However, the consensus opinion was based on studies of tamoxifen as a treatment for primary cancer rather than as a preventive agent against a second new breast cancer.
There are no data available from studies designed to examine this question, but a review of data from NSABP treatment trials and other trials showed that tamoxifen reduces the incidence of contralateral second primary breast cancers by roughly the same proportion as observed for primary breast malignancies in the BCPT Thus, preventive use of tamoxifen for women with small, lymph node-negative invasive breast cancers may be justified in some cases where there is doubt about its use as adjuvant therapy.
It is not known whether some breast cancers arise without expressing estrogen receptors ERs at any point in their genesis or whether all invasive breast cancers pass through a developmental phase in which they produce ER protein. The data from the BCPT indicate that the breast cancers arising among women taking placebo were more likely to express ERs than were those arising in women taking tamoxifen.
This suggests that tamoxifen suppressed those developing lesions that expressed ERs but had little or no effect on tumors that did not express ERs. An alternative explanation is that there are breast tumors that arise without expressing ERs at any time in their natural history. If the latter hypothesis is true and if subsequent breast cancers in women whose first cancer did not express ERs are also ER negative, tamoxifen would offer them little benefit.
Alternatively, if all breast tumors pass through a phase of ER expression, then tamoxifen may offer benefit even to those women whose first primary breast cancer was ER negative. We abstracted data from several NSABP protocols 64 - 67 to estimate the subsequent risk of IBC in women who had survived disease free for 5 years following an initial IBC diagnosis and who had not received adjuvant tamoxifen.
The subsequent 5-year cumulative risk of contralateral invasive breast cancer was 3. The decision to use tamoxifen for risk reduction in these patients must be informed by an assessment of the duration and quality of life remaining, the risks as well as potential benefits of tamoxifen, and the presence of competing morbidities that may weigh against the use of tamoxifen.
For example, tamoxifen might be appropriate in a year-old woman who is otherwise healthy, but it might be less suitable in a year-old woman with a history of cataracts and deep vein thrombosis. Both prospective and retrospective genetic epidemiologic studies 13 - 15 have demonstrated that women who carry mutations in either the BRCA1 or BRCA2 genes are at very high risk of developing both breast and ovarian cancers.
These women would appear to be ideal candidates for the use of tamoxifen in the primary prevention of breast cancer, but no data are yet available that relate directly to such women. Additional laboratory modeling of the effects of tamoxifen in vitro is necessary to address this question, as are prospective data from primary prevention trials that use tamoxifen in mutation carriers.
Until these studies are completed, the use of tamoxifen in such women should be accompanied by disclosure beforehand that tamoxifen may not be effective. Experience with appropriate clinical management and follow-up of women taking tamoxifen for primary prevention is limited to only a few studies 1 - 3 and principally to the BCPT.
Surprisingly little published information is available from clinical trials that used tamoxifen to treat breast cancer. There is insufficient evidence for or against the use of transvaginal ultrasound or endometrial sampling for the early detection of endometrial cancer 73 , and the American College of Obstetrics and Gynecology 74 has issued the recommendation that women on tamoxifen should have annual gynecologic examinations with Pap tests and pelvic examinations.
Any abnormal bleeding should be evaluated with appropriate diagnostic testing. Women should be counseled about the risk of benign and malignant conditions associated with tamoxifen. Screening procedures or diagnostic tests should be at the discretion of the treating physicians, and options should be discussed with women who are considering taking tamoxifen. Routine screening with hematologic or chemical blood tests is not indicated because no hematologic or hepatic toxic effects attributable to tamoxifen were demonstrated in the BCPT or in clinical trials using tamoxifen as adjuvant therapy.
Health care providers who counsel women about tamoxifen should strive to ensure that the patient makes a fully informed decision that incorporates her personal values and preferences. The counseling process should be interactive and sensitive to the woman's educational level and cultural background. Research suggests that women who were actively involved in decision-making about hormone replacement therapy were more satisfied with their decisions and more informed Because an individual's preferences and risk status can change substantially over time, it is also important that decisions about tamoxifen not be regarded by either patient or counselor as urgent or irreversible.
Any discussion of tamoxifen should occur within the context of a broader discussion of health promotion and breast cancer risk. The encounter should include a qualitative assessment of the patient's risk and, ideally, a quantitative assessment. The woman's perception of her own risk should be elicited so that it can be compared with an objective risk estimate. This discussion might include an evaluation of the psychologic factors that may affect a woman's perception of her risk, including her personal experience of breast cancer in family members, and her beliefs and fears concerning cancer etiology and treatment.
Research indicates that, although the perceived risk of breast cancer can be highly inaccurate, it is associated with health behaviors, such as the use of mammography Therefore, counselors should strive to ensure that a woman understands her objective risk and its implications for making a decision about the use of tamoxifen. At a minimum, a risk assessment encounter should include a clear description of the benefits and risks of taking tamoxifen for the individual woman, including a description of the side effects experienced by some of the BCPT study participants.
Based on the counselee's age, race, and projected 5-year risk of IBC, one could refer to Fig. The counselor should also take into account particular risk factors see section II and Table 4 to see if the woman is subject to increased risk of tamoxifen-induced stroke or endometrial cancer, for example. Such factors would require a more detailed calculation of likely risks associated with tamoxifen by modifying Tables 6 and 8.
The woman should be shown a summary of the separate risks and benefits of tamoxifen, as illustrated in Table 13, to allow her to weigh various outcomes individually. Some women may reject tamoxifen because they fear a stroke or a pulmonary embolism, even though the net benefit index is positive.
The summary data in Table 13 are based on age, race, presence or absence of a uterus, and projected 5-year risk of IBC. From data in a table such as Table 13 and from data in Tables 6 and 8 , the woman and her counselor would have the information needed to calculate any summary index that they chose, based on the woman's particular health concerns and her preferred weights, and to compare the effects of tamoxifen with rates in the absence of tamoxifen. Some women with a negative I 1, 0. Experience in the BCPT indicates that tools to communicate the risks and benefits of tamoxifen must be simple and short, and Fig.
The need for simplicity in communicating information on risks and benefits has been stressed elsewhere Written materials alone are likely to be insufficient, and the counselor may find that verbal explanations and comparisons to other risks may be needed to explain the risks and benefits of tamoxifen and to put them into perspective. As the examples in section IV indicate, what appears to be a small reduction in the absolute risk of IBC over a 5-year period can be large compared with overall mortality risks over the same time period.
Some women may be better able to understand the risks associated with tamoxifen by comparing them with the risks associated with estrogen replacement therapy ERT. The increased risk of venous thromboembolism associated with tamoxifen is similar to that found for ERT. A pooled analysis of nine studies of the risk of venous thromboembolism with ERT revealed a risk ratio of 1.
The risk ratio for pulmonary embolism with the current use of ERT is 2. Again, this is similar to the relative risk observed with tamoxifen 1. The absolute risk of pulmonary embolism and deep vein thrombosis is low for both tamoxifen and ERT in women under age 50 years. Likewise, the risk of endometrial cancer associated with tamoxifen treatment is comparable to that associated with ERT.
The link between endometrial cancer and the use of unopposed estrogen was postulated in , when a sharp rise in incidence rates of endometrial cancer was observed in the s In a recent study, the relative risk of endometrial cancer per additional 5 years of unopposed ERT was 2. Thus, the risk of endometrial cancer associated with tamoxifen treatment over a 5-year period is similar to that associated with the use of unopposed ERT. The counselor should convey what is not known about the use of tamoxifen see section VIII as well as what is known.
For example, the BCPT does not provide data on the effects of tamoxifen beyond 5 years, and it was not designed to study the impact of tamoxifen on total mortality, for which the relative risk was 0. There is ongoing research to find drugs that have efficacy in reducing breast cancer risk and that are associated with fewer risks than tamoxifen, and decisions regarding the use of tamoxifen may be influenced by the potential of such research to increase management options in the future.
The counselor should warn women of the need to avoid pregnancy and to rely on barrier methods of contraception while taking tamoxifen. The counselor should be aware that tamoxifen can potentiate the effects of coumarin-like anticoagulants An important counseling issue concerns barriers to the use of tamoxifen. The counselor and woman should discuss the costs of taking tamoxifen, including annual mammograms, annual gynecologic examinations, and the possible need for additional studies, such as pelvic ultrasound examinations or endometrial aspiration biopsies.
Concerns about out-of-pocket expenses increased the chance of refusing to participate in the BCPT 83 and may affect the decisions of women who are not participating in clinical studies even more. Some women may refuse to take tamoxifen because of its unpleasant side effects, including hot flashes, irregular menses, and vaginal discharge.
Another barrier is the need for long-term treatment and follow-up. The counselor and woman should recognize the challenges in their particular clinical setting to achieving long-term benefits from tamoxifen. Finally, the counselor should assess whether the woman understands the information provided both immediately and at follow-up 84 and should attempt to rectify misperceptions.
The decision to use tamoxifen to reduce the risk of breast cancer is complicated by the presence of several potential risks that must be weighed against potential beneficial effects. We have presented a methodology for determining the benefits and the risks associated with tamoxifen treatment and have provided tables that can be used to describe these risks and benefits in detail and to summarize them. These assessments are individualized by age, race, the presence or absence of a uterus, and the woman's projected 5-year risk of IBC.
The use of tamoxifen should not be based on a single number, such as a projected 5-year risk of IBC of 1. For older women at higher risk of endometrial cancer, stroke, and pulmonary embolism, higher levels of projected 5-year risk of IBC would be needed to justify the use of tamoxifen Tables 10 Our methods are subject to various uncertainties.
Background rates Table 3 were difficult to estimate for some types of events, such as stroke, pulmonary embolism, deep vein thrombosis, or fractures, especially in minority women. A weakness of our methodolgy is that projections for events such as stroke and pulmonary embolism depend only on age and race; it would be desirable to have validated models that included medical factors such as those in Table 4. Such models might explain much of the apparent effect of race Our projections of breast cancer risk are less certain in black and Hispanic women than in white women see section II, part A , which increases the difficulty of assessing risks and benefits in minority women.
The effects of tamoxifen were estimated mainly from white women Our conclusion that the net benefits of tamoxifen are restricted to younger black than white women Fig. The results in Tables 10 and 11 for black women are, therefore, subject to greater uncertainty than for white women. We have used the overall relative risk of endometrial cancer from tamoxifen in the BCPT, 2.
We believe that this risk estimate is more reliable than an estimate based on only the 17 endometrial cancers in the subset of women under age 50 years, for whom the relative risk was 1. Mamounas et al. For women under age 50 years, the incidence rate of endometrial cancer per woman-years was 0. Although these combined analyses do not represent randomized comparisons and although it is possible that women taking tamoxifen were under more intense surveillance for endometrial cancer than were the other women, these data support our estimate of relative risk of 2.
In any case, our choice of the estimate 2. A meta-analysis 59 of studies of women of all ages taking tamoxifen for about 5 years following treatment for breast cancer yielded a relative risk of 4. There is considerable debate on how best to present data on risks and benefits.
Several workshop participants objected to the use of an index such as I 1, 0. We found, however, that broad conclusions about the net benefit of tamoxifen, such as in Fig. Moreover, we have also presented the information in considerable detail Tables 6 -8 so that women and their counselors can weigh risks and benefits using whatever weights they prefer see Table There are important gaps in our knowledge that are relevant to counseling on the use of tamoxifen.
The BCPT does not provide data on the long-term effects of tamoxifen because the average follow-up was 4. This lack of information and the possibility that alternative preventive agents may become available see section VII complicate the decision of when to initiate tamoxifen use.
It is unclear why two much smaller studies in Europe 2 , 3 failed to demonstrate a reduction in breast cancer risk associated with tamoxifen. It may be that differences in study populations or adherence to treatment explain these various results, and they should not be combined. If one combines the studies, however, as in section III, to obtain an overall relative risk of breast cancer of 0. There are also considerable uncertainties relating to the use of tamoxifen for breast cancer prevention in classes of women not included in the BCPT, such as women with DCIS, women with small, invasive tumors, and women who have survived disease free for several years following treatment without tamoxifen for breast cancer see section V.
Another issue concerns the concurrent use of hormone replacement therapy and tamoxifen. Women in the BCPT were eligible only if they took no estrogen or progesterone replacement therapy, oral contraceptive, or androgens. Forty-one percent of the women in the study reported by Powles et al.
Although there was no evidence from these studies that tamoxifen was less effective for women taking hormone replacement therapy than for other women, the power to detect such an interaction was small, and it remains at least a theoretical possibility that hormone replacement therapy reduces the effect of tamoxifen on breast cancer risk.
Indeed, Fisher et al. In some cases, this may exacerbate hot flashes, and women may be unwilling to continue taking tamoxifen. Much is unknown about how best to elicit a woman's concerns about specific possible adverse health outcomes and preferences regarding the use of tamoxifen. Research is also needed to define women's knowledge about their risk of breast cancer and other adverse events, about the BCPT and the effects of tamoxifen, and about the risk of breast cancer while taking tamoxifen.
Studies are also needed to define effective counseling strategies and tools for conveying information on risks and benefits. There is considerable scope for research to reduce these uncertainties and areas of ignorance. There is a need for feedback from counselors regarding the usefulness of tools such as Table 13 proposed in this article to assist in the counseling process. If such tools were thought to be useful, a computer program could be developed that would facilitate the presentation of individualized risk and benefit data such as those in Table 13 and would allow a woman to define a summary index that reflected her particular concerns regarding adverse events.
Homogeneity of treatment effects across ages; comparison of risk and benefits in the Breast Cancer Prevention Trial: Joseph Costantino. To compute overall relative risk, multiply four component relative risks from categories A, B, C, and D.
For example, a year-old white nulliparous woman who began menstruating at age 12 years, who has no affected first-degree relatives, and who has had one previous breast biopsy with specimens interpreted as benign and no evidence of atypical hyperplasia has an overall relative risk of 1.
From the data on 5-year baseline risk, her projected 5-year risk of invasive breast cancer is 2. Rates for white women were taken from Rates for black women were obtained by multiplying the white rates by the white-to-black rate ratios for hip fracture in These ratios were 0. Rates for black women were obtained by multiplying the white rates by the black-to-white stroke mortality rate ratios for the United States in The ratios were 3.
Rates for black women were obtained by multiplying the white rates by the black-to-white pulmonary circulatory failure mortality rate ratios for the United States in Selected factors that modify risks of health outcomes in Table 3. Numbers of events, incidence rates per woman-years, and relative risks in the Breast Cancer Prevention Trial.
Assumes an in situ -to-invasive ratio of 0. Value is 69 for to year-old white women and for to year-old white and black women. Value is for to year-old black women and for to year-old white and black women. The probability that I 1, 0. Example of a tool for data presentation for communicating the benefits and risks of tamoxifen treatment.
Summary of benefits and risks associated with tamoxifen use based on results from the Breast Cancer Prevention Trial:. To help you understand the potential benefits and risks of treatment, these numbers can be compared with the number of expected cases that would be prevented or caused by 5 years of tamoxifen use.
Classification of the probability that I 1, 0. One asterisk indicates a probability of 0. To assess the magnitude of the benefit, see Tables 10 and Age is given in years. See text for additional details. Registry data are submitted electronically to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.
We thank the workshop participants for their presentations and for written and verbal communications, some of which were incorporated in this special article. The authors, however, are responsible for the opinions stated. We thank the investigators in the Cardiovascular Health Study and the Atherosclerosis Risk in Communities Study for providing data to validate our estimates for the risks of stroke. Kramer, Carol K. J Natl Cancer Inst ; 90 : Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial.
Lancet ; : 98 Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet ; : 93 Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst ; 81 : Benichou J. A computer program for estimating individualized probabilities of breast cancer [published erratum appears in Comput Biomed Res ;].
Comput Biomed Res ; 26 : Gail MH, Benichou J. Assessing the risk of breast cancer in individuals. Cancer prevention. Philadelphia PA : Lippincott; Validation of a breast cancer risk assessment model in women with a positive family history. J Natl Cancer Inst ; 86 : Validation of the Gail et al.
Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst ; 91 : NIH Breast cancer 1. N Engl J Med ; : Breast and ovarian cancer incidence in BRCA1-mutation carriers. The Breast Cancer Linkage Consortium. Am J Hum Genet ; 56 : Population-based study of risk of breast cancer in carriers of BRCA2 mutation.
Lancet ; : Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet ; 48 : Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: results from three U. Am J Hum Genet ; 60 : Cowden syndrome. J Med Genet ; 32 : Familial aggregation. Cancer epidemiology and prevention. Kelsey JL. A review of the epidemiology of human breast cancer.
Epidemiol Rev ; 1 : 74 Autosomal dominant inheritance of early-onset breast cancer. For those at higher risk, it can be taken as long as 10 years. Other studies have found that women who have received breast cancer diagnoses also have issues with the drug. The lead author of that study said taking less than 80 percent of prescribed treatment can shorten time to recurrence and raise the risk of death.
Some of the side effects include hot flashes, mood swings, vaginal dryness, discharge, and slight weight gain. Wesolowski says less common side effects include allergic reaction, increased risk of blood clots in about 1 percent of patients, and a small risk of endometrial cancer. This occurred in about 1 to 2 percent of patients who are on tamoxifen for five years. Fortunately, most cases of endometrial cancer turned out to be in early stage and curable.
A study published in the Journal of the National Cancer Institute found that in addition to side effects, many premenopausal women had fertility concerns. According to BreastCancer. Women who have a history of endometrial cancer, blood clots, and strokes should avoid tamoxifen, advises Wesolowski. For those women, there are other anti-estrogen therapies.
Tamoxifen is an effective and most appropriate agent for some women with breast cancer. But other forms of breast cancer treatment exist and can be more appropriate than tamoxifen for some women as well. After two surgeries, 12 weeks of chemotherapy, and one year of infusions every three weeks, Salamone wanted it to end. Salamone, a personal trainer specializing in breast cancer recovery, says her oncologist brought it up at every appointment.
I was moved from hormone replacement to hormone blocking, so the first couple of months were dreadful. Her oncologist has talked to her about switching from tamoxifen to an aromatase inhibitor in a couple of years. Mental health experts who work with cancer survivors share how you can show up for your friend after cancer. My self-image came from my hair, not my chest. Here are the best cancer blogs to find support, gain information, learn about the newest research and treatments, and more.
Disability benefits can give you some much-needed peace of mind when you're dealing with breast cancer treatment. Your morning routine can help you prepare for your day ahead. Follow the tips in this infographic to create a morning routine that works for you when….
Tamoxifen also comes in a liquid form. Tamoxifen can be taken whether or not you have gone through menopause, but raloxifene is only approved for post-menopausal women. The effect of these drugs on breast cancer risk has varied in different studies. Since the change in your overall risk depends on your baseline risk, you would benefit less if you had a lower baseline risk, and you would benefit more if your risk was higher. If you had a baseline risk of only 1. Your doctor can estimate your breast cancer risk based on factors like your age, medical history, and family history.
This can help you see how much benefit you might get from taking one of these drugs. Both tamoxifen and raloxifene can help prevent osteoporosis , a severe weakening of the bones that is more common after menopause. The most common side effects of these drugs are symptoms of menopause.
These include hot flashes and night sweats. Tamoxifen can also cause vaginal dryness and vaginal discharge. Pre-menopausal women taking tamoxifen can experience menstrual changes. Menstrual periods can become irregular or even stop. This is more likely in women who were close to menopause when they started taking the drug. Other more serious side effects are rare. These include serious blood clots and cancer of the uterus. Ensuring an adequate intake of calcium and vitamin D is important. In addition to lifestyle and nutrition interventions, pharmacologic options should be considered for patients at high risk for bone loss or fracture.
Available agents fall into 2 categories: antiresorptive agents bisphosphonates, selective estrogen receptor modulators [SERMs], estrogen, calcitonin and anabolic agents parathyroid hormone. An algorithm for the screening and management of cancer patients at increased risk for bone loss and fracture is shown in Figure 2. If a major change in patient risk factors or a major intervention occurs, repeating DEXA scan at one year is reasonable.
An excellent patient resource for bone health and lifestyle behavior is the NOF Web site. Weight-bearing exercise has been associated with a decreased risk of hip fractures, probably due to a reduction in fall risk and also through modest effects on preservation of bone density. Adults should aim for at least 30 minutes of moderate physical activity daily either in 1 continuous session or in a number of shorter bursts. This activity can include a mix of weight-bearing, strength training, and balance training exercises.
Fracture risk reduction should also include strategies to reduce falls, such as checking for and correcting vision and hearing problems, evaluating for neurologic problems, reviewing prescription medications for side effects that may affect balance, and improving at-home safety. A home safety checklist can be found on the NOF website. Behaviors such as tobacco abuse and excessive alcohol consumption are associated with a variety of ill health outcomes, including increased risk for osteoporosis and fracture.
Counseling patients on these topics is important on many levels and should not be overlooked. Recommended interventions after counseling should be individualized. Adequate intake of calcium and vitamin D is critical to bone mineralization. Some, but not all, randomized studies have shown calcium and vitamin D supplementation to decrease fracture risk. The NOF, 23 National Institutes of Health Office of Dietary Supplements, 33 , 34 and the Surgeon General's report on osteoporosis 35 recommend a total daily calcium intake from food and supplements of at least mg per day for individuals under 50 years of age without major osteoporosis risk factors, and at least mg per day for those older than 50 years.
Calcium supplements are available as calcium carbonate or calcium citrate. Calcium carbonate requires gastric acid for optimal absorption and should be taken with food. Calcium citrate, which does not require gastric acid for absorption, can be taken between meals and is the preferred option for patients receiving proton pump inhibitors.
For optimal absorption, calcium supplements should be taken in divided doses of no more than mg at one time. The safe upper limit of calcium set by the National Academy of Sciences is mg per day. Measurement of urinary calcium excretion and other markers of lithogenic risk is prudent in patients with a history of calcium nephrolithiasis.
Vitamin D plays a major role in gastrointestinal calcium absorption and is essential for maintaining normal bone mineralization. It is naturally present in very few foods, but is added as a supplement to some food products and is available as a dietary supplement. It is also produced endogenously when ultraviolet rays strike the skin, triggering vitamin D synthesis. Use of sun block, recommended to reduce the risk of skin cancer, leads to substantial reduction of cutaneous vitamin D synthesis.
Vitamin D supplementation increases BMD 38 and reduces the risk of falls possibly by impacting balance. Serum 25 hydroxy vitamin D [25 OH D] levels are the best indicator of vitamin D status, but considerable discussion surrounds the serum concentrations of 25 OH D associated with deficiency, adequacy for bone health, and optimal overall health.
These 2 forms are metabolized differently, and vitamin D3 could be more effective in raising 25 OH D concentrations and maintaining those levels for a longer time when longer dosing intervals are employed. Therefore, current expert opinion on supplementation for adults older than age 50 is mg of calcium from all sources and to IU of vitamin D daily.
A caveat to the vitamin D intake recommendation is that many patients need more than the recommended amount and should be repleted based on serum 25 OH D level. For FDA approval, a drug must show that it reduces the risk of vertebral fractures; non-vertebral anti-fracture efficacy is not a requirement.
Bisphosphonates decrease bone resorption and increase mineralization by inhibiting osteoclast activity. All except ibandronate are approved in both men as well as women. Because compliance is a significant problem with daily oral bisphospho-nate dosing, a trend toward less frequent oral dosing and intravenous options have emerged Table 1.
Generally, oral formulations alendronate, ibandronate, and risedronate are considered first line. Use of intravenous bisphosphonates ibandronate or zoledronic acid may be considered, particularly for patients who cannot tolerate the oral formulations. Several bisphosphonates were studied in the context of cancer treatment—induced bone loss. Some settings in which bisphosphonates have shown efficacy at preserving BMD changes during anti-cancer treatment include breast cancer patients receiving AIs or those with chemotherapy-induced menopause or other forms of ovarian suppression, prostate cancer patients undergoing ADT, and hematologic malignancy patients undergoing stem cell transplantation.
Because of potential gastrointestinal toxicities, oral bisphosphonates should be avoided in patients with esophageal emptying disorders and those who cannot sit upright; these patients are at high risk for pill esophagitis. Oral bisphosphonates appear to have better renal safety in patients with lower creatinine clearance.
Vitamin D deficiency should be corrected before treating with intravenous bisphosphonates because hypocalcemia has been reported in patients with unrecognized vitamin D deficiency. Osteonecrosis of the jaw ONJ has emerged as a complication of bisphosphonate treatment. However, the fact that no previous trial of oral bisphosphonates reported ONJ cases is important to recognize.
This highlights the difficulty of identifying low frequency but serious effects in clinical trials. Therefore, dental examination and prophylactic measures should be considered before starting bisphosphonate therapy. Patients should also be advised against unnecessary invasive oral surgery while on bisphosphonate therapy.
In a phase III fracture prevention trial of yearly zoledronic acid in women with postmenopausal osteoporosis, Black et al. This serious adverse event was not more common in other studies of osteoporotic patients in which zoledronic acid was dosed 5 mg yearly. In response to concerns regarding atrial fibrillation, the FDA released an early communication letter stating that evidence was not strong enough to associate atrial fibrillation with bisphosphonate use and that further investigation is warranted before making any conclusions.
During the past 2 years, a small but concerning number of cases of subtrochanteric hip fractures have developed in patients on long-term bisphosphonate therapy. Although a causal relationship has not been established with certainty, the unusual nature of the horizontal fractures that occur at angles perpendicular to the long axis of the femur have raised concerns about long-term use of bisphosphonates.
Patients treated with zoledronic acid may also experience acute phase reactions. This physiologic reaction is associated with fever and flu-like symptoms including myalgia, arthralgias, fever, fatigue, and nausea. Acute phase reaction is not common with subsequent dosing.
Estrogen is an antiresorptive agent with proven anti-fracture efficacy as shown in the Women's Health Initiative study. Data in young women with spontaneous premature ovarian failure argues against an increased risk of breast cancer or other adverse events with full replacement doses. Although tamoxifen has shown favorable impact on bone density in postmenopausal breast cancer patients, raloxifene is currently the only SERM that is FDA approved for the prevention and treatment of osteoporosis in postmenopausal women.
Raloxifene is a less potent antiresorptive agent than bisphosphonates. Raloxifene has been shown to decrease the incidence of vertebral fracture; however, randomized studies have failed to document any benefit against non-vertebral or hip fractures. Raloxifene, unlike estrogen, is not associated with an increase in myocardial infarction. Raloxifene has been associated with an increased risk of fatal stroke hazard ratio [HR], 1. Raloxifene use is not indicated in premenopausal women at high risk for breast cancer; it has resulted in decreased BMD in clinical trials.
The efficacy of raloxifene in combination with an AI for breast cancer remains unknown. Recombinant parathyroid hormone PTH or teriparatide is the first anabolic agent approved for treatment of postmenopausal osteoporosis. It has been shown to reduce the incidence of vertebral and non-vertebral fractures. It is administered daily by subcutaneous injection for 2 years.
Because of the potential increased risk for osteosarcoma, it is contraindicated in patients with increased baseline risk of osteosarcoma such as those with Paget's disease of bone, open epiphyses, or prior radiation therapy involving the skeleton which includes many patients with cancer.
Furthermore, teriparatide is not indicated in patients with bone metastases, including those who may have micrometastatic or occult disease. A recent study involving , patients shows no significant difference in incidence of osteosarcoma between the treated group and the general population.
The drug works to sequentially increase bone resorption followed by bone formation. This marked increase in bone turnover may be favorable to propagation of microscopic bone metastases 76 through liberation of bone-derived growth factors and cytokines, and potentially through direct anabolic effects on tumor cells. However, in cases of severe osteoporosis with fractures occurring on bisphosphonate therapy, the benefits may outweigh these theoretical risks.
In such patients with a remote history of cancer, teriparatide could be cautiously considered. Receptor activator of nuclear factor kB ligand RANK-L is an essential cytokine expressed on the surface of preosteoblastic and osteoblastic cells. Denosumab is a human monoclonal antibody to RANK-L that blocks osteoclast differentiation, proliferation, and function. A 3-year, phase III trial of postmenopausal women with osteoporosis randomized participants to receive either 60 mg subcutaneous denosumab or placebo every 6 months.
No serious adverse events reported with denosumab were significantly increased relative to placebo. A randomized phase III non-inferiority trial compared denosumab with alendronate in postmenopausal women. Denosumab appears to be a promising new agent that may receive FDA approval for managing postmenopausal osteoporosis. Denosumab is currently being evaluated in patients previously treated with bisphosphonates 80 and in patients with cancer both for prevention of cancer therapy—induced bone loss and skeletal-related events.
Bone biomarkers are useful for monitoring patient response and effectiveness of antiresorptive therapies. Changes in bone turnover markers can reflect response to antiresorptive therapy in weeks to months rather than the months to years required for changes in BMD. This may be helpful in avoiding the time and expense of a potentially ineffective therapy or detecting of nonadherence with therapy, permitting the earlier start of potentially more-effective therapy.
Chestnut et al. Patients with the highest quartile for baseline levels of NTX and those with decreasing levels over 6 months also had the largest percentage gain in BMD. Ravn et al. No published guidelines are available on duration of antiresorptive therapy and whether to institute drug holidays.
Treatment with alendronate for 10 years was shown to be well tolerated and with a positive impact on bone density versus placebo. Factors to consider for duration of anti-osteoporosis therapy include BMD, response to therapy, and risk factors for continued bone loss or fracture. For example, some studies define it as at least 3 to 6 months of amenorrhea.
However, distinguishing between temporary amenorrhea that will reverse and permanent ovarian failure is important, because bone loss is of greatest magnitude with ovarian failure. Several small studies have identified additional risk factors for ovarian failure independent of age: baseline BMD before adjuvant chemotherapy might predict individual risk of developing ovarian failure.
In a multivariate analysis of 49 premenopausal patients undergoing adjuvant chemotherapy, a higher baseline BMD increased the risk of ovarian failure. Studies have also shown accelerated bone loss as a consequence of ovarian failure after adjuvant chemotherapy. In patients with ovarian failure, a highly significant bone loss was seen in the lumbar spine by 6 months, but no significant change was seen in patients who retained ovarian function.
Bone loss associated with chemotherapy-induced menopause is several-fold higher than that seen with natural menopause or AI therapy-induced bone loss in postmenopausal women. Several studies have reported that bisphosphonates, including clodronate and risedronate, attenuate the bone loss associated with chemotherapy-related ovarian failure.
The primary end point was change in lumbar spine BMD. Density was preserved in patients treated with early zoledronic acid at 12 months, compared with a 6. Similarly, in a randomized placebo-controlled trial of 4 mg of zoledronic every 3 months for 1 year, BMD was preserved in the lumbar spine and hip. The addition of the bisphosphonate prevented bone loss in both the lumbar spine and hip.
Additionally, a recent report noted fewer breast cancer recurrences with the addition of zoledronic acid. Although studies showing the ability of bisphosphonates to preserve BMD in young women with cancer treatment—related ovarian failure are encouraging, no study to date has shown an impact on the clinically relevant endpoint of fractures. Randomized studies of AIs compared with or after tamoxifen therapy have led to the widespread use of AIs as adjuvant therapy in postmenopausal, estrogen receptor ER —positive breast cancer.
Lower estrogen levels are associated with increased bone resorption and fracture risk. AIs cause a rapid decline of circulating estrogen levels, leading to bone loss, , and are divided into steroidal exemestane and non-steroidal letrozole or anastrazole. Exemestane binds irreversibly to the catalytic site of aromatase, whereas letrozole and anastrozole bind reversibly to the heme group of the enzyme.
Several reviews of AIs and their impact on bone health were published recently. After treatment, the fracture rates of both groups were similar, suggesting that AI-related fracture rates decrease after treatment. The Intergroup Exemestane Study IES compared adjuvant tamoxifen for 5 years with initial adjuvant tamoxifen followed by exemestane.
The recently closed MA trial randomizing postmenopausal breast cancer patients to either adjuvant exemestane or anastrozole will hopefully clarify whether the androgenic nature of exemestane results in less impact on bone density. The incidence of a new diagnosis of osteoporosis was 5.
These results suggest that the difference in bone loss and fracture rates in the adjuvant studies may be primarily due to a bone protective effect of tamoxifen as opposed to a bone destructive effect of the AIs. Several of the large adjuvant trials have evaluated bone loss and fractures in more detailed breakout studies of women receiving AI therapy. Importantly, no patients with normal BMD at baseline became osteoporotic at 5 years.
Several studies have analyzed the impact of bisphosphonate therapy on maintaining bone density in patients on AI treatment. Two trials examined the effects of oral bisphosphonates in patients receiving anastrozole therapy. The SABRE Study of Anastrozole with the Biophosphonate Risedronate trial was an open-label intervention study in which all patients received anastrozole and were assigned to a bisphosphonate treatment group based on T-score. For patients at low risk, bone loss during short-term follow-up was minimal.
For other patients, risedronate therapy at doses established for preventing and treating osteoporosis resulted in favorable effects on BMD over 24 months. The addition of ibandronate to anastrozole led to a significant increase in BMD at the spine and hip after 1 year, which was maintained for 2 years. A pooled analysis of approximately patients was performed and showed that upfront use of zoledronic acid was associated with preservation of BMD.
No clinical trials have directly compared oral versus intravenous bisphosphonates in this setting. Importantly, health care professionals should recognize that AIs do cause bone loss. However, bone density monitoring and intervention strategies should be individualized for patients on AIs, with drug therapy reserved for those at greatest risk.
Ellis et al. The primary end point was the percentage change from baseline in lumbar spine BMD. Patients with early stage nonmetastatic , hormone receptor—positive breast cancer were randomized to either denosumab, 60 mg, or placebo every 6 months for a total of 4 doses while receiving AI therapy. At 12 and 24 months, lumbar spine BMD increased by 5.
After 24 months, the increase in BMD in the total hip, femoral neck, trochanter, and radius was 4. Prostate cancer is the most commonly diagnosed malignancy in American men. Because prostate cancer growth is driven by androgen hormones, ADT, either by orchiectomy or using GnRH agonists, is commonly used for treatment. The term ADT is used because the intended therapeutic effect is lower testosterone levels. Because estradiol is produced from testosterone by aromatase activity, ADT also reduces estradiol levels.
Estrogen receptors are expressed in osteoclasts and osteoblasts. In population-based studies of older men, low estradiol levels are associated with low bone mass and greater fracture incidence. A number of studies have associated ADT with increased fracture risk.
A Medicare claims-based study characterized the relationship between GnRH agonists and risk for clinical fractures. Short-term treatment did not confer any greater fracture risk, suggesting reversal of the hypogonadal effects on the bone. The relative risk of the occurrence of any fracture or one resulting in hospitalization increased with increasing doses of GnRH agonist received during the first year after diagnosis.
Many studies have shown that GnRH agonist treatment is associated with accelerated bone loss. In one prospective analysis, for example, Mittan et al. Randomized studies have focused on bisphosphonate therapy in hypogonadal men with prostate cancer using BMD end points.
Intravenous pamidronate and zoledronic acid given once every 3 months prevented ADT-induced bone loss in the spine and hip compared with control groups. Mean lumbar spine BMD was increased by 5. A second randomized controlled trial of zoledronic acid evaluated the efficacy of a single annual dose.
In contrast, mean BMD decreased 3. Yearly dosing of zoledronic acid is effective in general populations with osteoporosis and is FDA approved. Whether more frequent dosing is indicated in cancer patients with accelerated bone absorption remains to be defined.
Greenspan et al. In a randomized, double-blind, placebo-controlled trial in men treated with weekly oral doses of alendronate, BMD increased over 1 year by 3. Although long-term data on the impact of bisphosphonates on fracture prevention is not available, these studies provide evidence that bisphosphonates effectively reduce bone loss in men receiving ADT.
In one multicenter study with a primary end point of new vertebral fractures, men in the United States and Mexico receiving ADT for prostate cancer were randomly assigned to either toremifene or placebo. Secondary end points included BMD, serum lipids, vasomotor flushing, and breast symptoms. Interim analyses reported that toremifene significantly increased BMD of the lumbar spine, total hip, and fem-oral neck. In a recently completed global study, men receiving ADT for prostate cancer were randomly assigned to either the RANK-L inhibitor, denosumab, subcutaneously every 6 months or placebo.
The primary study end points were BMD and new fractures. Complete results are expected this year. Two other large studies to evaluate the role of denosumab for preventing bone metastases and disease-related skeletal complications in men with prostate cancer are ongoing. In conclusion, ADT is associated with significant morbidity, including osteoporosis and increased incidence of clinical fractures. Strategies to reduce morbidity include educating patients about risks, encouraging healthy lifestyle modifications, supplementation with calcium and vitamin D, screening for osteoporosis, and drug therapy in appropriate individuals.
The results of recently completed large randomized controlled trials will help establish evidence-based guidelines for fracture prevention in prostate cancer survivors. Preclinical in vitro studies have shown that bisphosphonates inhibit the adhesion of breast cancer cells to extracellular bone matrix, inhibit tumor cell invasion, — and induce apoptosis via the ras pathway in human breast cancer cells.
Three randomized trials in early stage breast cancer investigated whether oral clodronate can prevent bone metastases and improve survival; 2 of the 3 showed a survival benefit. The most recent report includes survival data with long-term follow-up that showed a continued separation of the survival curves between years 5 and In a second smaller, randomized, open-label study, women with breast cancer and micrometastases detected in a bone marrow aspirate at diagnosis were randomized to receive either clodronate 1, mg, daily or no bisphosphonate for 2 years.
Additionally, patients received standard adjuvant systemic therapy. However, a worrisome increase in visceral metastases and reduction in overall survival at 5 years was seen for patients receiving clodronate. The negative impact of clodronate on overall survival appears to be neutralized when the imbalance in hormone receptor negativity is corrected.
Even without correction, the survival detriment no longer showed significance at 10 years. A meta-analysis using the 5-year data from these 3 adjuvant clodronate trials did not show a statistically significant difference in overall or bone metastasis-free survival when the data were pooled. A recent study investigating the adjuvant use of zoledronic acid reported an improvement in disease-free survival, in addition to favorable effects on BMD.
All patients received ovarian suppression for 3 years with a luteinizing hormone-releasing hormone analogue, goserelin. Patients were randomized in a 2 by 2 design to receive tamoxifen versus anastrozole, and zoledronic acid 4 mg, every 6 months or not. At the first efficacy analysis, reported after events 70 distant relapses with approximately 60 months follow-up, no difference in outcome was seen with respect to the endocrine therapy randomization.
However, the authors found a statistically significant improvement in disease-free survival for patients who received zoledronic acid HR, 0. The absolute benefit in disease-free survival was 3. Although ABCSG clearly provides additional support for the metastasis-suppressing potential of adjuvant bisphosphonates, this study enrolled only a narrow subset of breast cancer patients: premenopausal women with ER-positive tumors who did not receive adjuvant chemotherapy.
Although the results are promising, caution must be taken not to over-extrapolate these findings, or this dose schedule, to all breast cancer patients. A recent combined analysis of these trials showed lower recurrence rates in the group receiving upfront zoledronic acid therapy 1.
Two additional large trials of adjuvant bisphosphonates have met their targeted accrual goals, with efficacy analysis pending. The primary end point was disease-free survival. This trial closed to accrual in This trial is randomizing women with stage I or III breast cancer receiving standard adjuvant therapy to oral clodronate mg, daily versus oral ibandronate 50 mg, daily versus zoledronic acid 4 mg intravenously, monthly for 6 months, then every 3 months , all for 3 years duration.
These unreported trials include all patient and tumor subsets, including both pre- and postmenopausal women, ER-positive and -negative tumors, and patients who received a range of standard systemic therapy, including chemotherapy. The results of these trials will be critical in determining how broadly applicable bisphosphonates are across the spectrum of breast cancer patients. Several additional ongoing early stage bisphosphonate trials are evaluating various agents, doses, schedules, and adjuvant settings, including residual disease after preoperative chemotherapy and in elderly populations.
In prostate cancer, trials have yet to show any reduction in recurrence or death from the adjuvant use of bisphosphonates. A randomized controlled trial to evaluate the effects of zoledronic acid on time to first bone metastasis in men with prostate cancer, no bone metastases, and rising prostate-specific antigen despite ADT was terminated approximately halfway into accrual when interim analysis showed a lower-than-expected event rate.
Several trials evaluating the adjuvant use of osteoclast-targeted therapy in prostate cancer are ongoing. One of the objectives of the Randomized Androgen Deprivation and Radiotherapy RADAR trial is to determine whether 18 months of zoledronic acid will reduce relapse risk by impeding the development of bony metastases. The ZEUS trial will assess the efficacy of zoledronic acid every 3 months versus best supportive care in preventing skeletal metastases in patients with high-risk prostate cancer.
Additionally, the RANK-L inhibitor denosumab is being tested in an ongoing large patients international randomized, phase III, placebo-controlled trial in men with hormone-refractory prostate cancer with the end point of bone metastasis—free survival.
The adjuvant bisphosphonate trials in breast cancer reported to date support the potential role of these drugs in impacting recurrence and survival in early stage breast cancer. The data do not yet support the addition of adjuvant bisphosphonates as standard of care for all patients. The promising, yet somewhat contradictory, results of the 3 reported breast cancer adjuvant clodronate studies suggest that bisphosphonates can impact disease recurrence, but highlight the need for further investigation.
Extrapolation of the ABCSG findings to postmenopausal women, ER-negative tumors, and women receiving chemotherapy will require data from ongoing clinical trials. These studies will aid in defining the optimal patient and tumor populations for the addition of adjuvant bisphosphonates, as well as optimal doses and schedules of administration, and long-term toxicities. Whether doses used in metastatic disease are required for prevention or whether lower doses will suffice is unknown.
It is unclear whether adjuvant bisphosphonates should be given continuously and orally, whether intravenous therapy is preferable, and whether less intensive intravenous regimens will be as effective as more intensive regimens. The optimal duration of adjuvant bisphosphonate therapy is also unknown. Normal bone homeostasis involves constant remodeling by the coordinated actions of osteoclasts and osteoblasts. In metastatic bone disease, as in osteoporosis, this balance is tipped to favor osteoclast-mediated resorption.
The interactions between the tumor and the bone microenvironment shape the characteristics of the bone metastases. Metastatic bone disease associated with breast cancer is often predominantly osteolytic, whereas lesions from prostate cancer are predominantly osteoblastic on imaging.
However, bone metastases are frequently heterogeneous, and histological examination often shows evidence of both osteolytic and osteoblastic features. At the cellular level, evidence of reciprocal signaling between the tumor and bone microenvironment can be seen. Cancer cells interact with osteoclasts, osteoblasts, and the bone matrix through multiple pathways.
Osteolysis releases cytokines and growth factors that were stored within the bone matrix, such as transforming growth factor TGF -beta, insulin-like growth factor IGF -1, and platelet-derived growth factor PDGF. These factors may induce tumor cell proliferation, thereby generating a vicious cycle of tumor growth and bone destruction. In addition, therapies that specifically target the bone microenvironment are being incorporated into clinical practice. The frequency of bone metastases varies by cancer type and duration of advanced disease.
Bone metastases can cause significant morbidity. Patients with bone metastases are at risk for skeletal-related events, including fracture, need for radiation to bone, spinal cord compromise, and hypercalcemia or need for surgery Figure 3. The risk of experiencing an additional skeletal-related event within 1 year of a first event is substantial. Prevalence of skeletal-related events in patients with metastatic bone disease not treated with a bisphosphonate.
The data are obtained from 4 major trials of placebo versus an intravenous bisphosphonate in different tumor types. In addressing bone metastases, the mainstay of oncology care is attempting to control the tumor burden. This is typically addressed through antineoplastic therapies. Bone-specific interventions are often incorporated into the treatment plan and may be localized or systemic. Surgery and radiation therapy can be used to address local control of specific lesions.
Bone-directed systemic interventions include bisphosphonates and radiopharmaceutical therapy. Throughout the management of the patient, attention must be paid to pain control and minimizing the risk of potentially catastrophic events, such as fracture or spinal cord compromise.
Large randomized clinical trials have shown that the addition of bisphosphonate therapy to standard anti-cancer therapy can decrease the frequency of skeletal-related events by approximately a third. Clodronate and ibandronate are licensed for use in bone metastases outside the United States. In clinical trials, bisphosphonates have shown treatment benefits for breast cancer patients with bone metastases.
Pamidronate reduced the frequency of skeletal morbidity in placebo-controlled trials involving breast cancer patients with bone lesions who were receiving hormone or chemotherapy. The median time to skeletal complication was In preclinical testing, zoledronic acid appeared to be a more potent bisphosphonate than pamidro-nate, and clinically it showed superiority over pamidronate in treating hypercalcemia of malignancy.
In a month extension phase, the overall incidence of skeletal-related events other than hypercalcemia of malignancy was similar between the zoledronic acid and pamidronate groups. A randomized trial in Japan compared zoledronate, 4 mg, to placebo every 4 weeks for 1 year in women with breast cancer with at least 1 osteolytic bone metastasis. In addition, bone pain scores were significantly improved within 4 weeks of treatment and remained modestly reduced for 52 weeks.
No serious grade 3 or 4 toxicities or substantial declines in renal function were seen. This study corroborates the benefit of zoledronate in reducing skeletal-related events seen in previous studies. The ASCO clinical practice guidelines for breast cancer suggest that patients in whom radiographic evidence of bone metastases exist should receive therapy with either zoledronic acid, 4 mg over 15 minutes, or pamidronate, 90 mg delivered over 2 hours, both every 3 to 4 weeks.
Due to increasing concerns over potential bisphosphonate-associated toxicities, all women should undergo dental examination with appropriate preventive dental care before starting bisphosphonate therapy. Serum creatinine also should be monitored before each dose of pamidronate or zoledronate.
The optimal duration of bisphosphonate therapy has not been well defined. The longest phase III clinical trials in patients with bone metastases examined a 3 to 4 week dosing of bisphosphonates for only 2 years.
Little data is available beyond 2 years of treatment. The unknown potential additional benefit from continuing bisphosphonates must be weighed against the potential toxicities of long-term administration. The ASCO bisphosphonate guidelines for breast cancer recommend continuing bisphospho-nate therapy indefinitely or until the patient's performance status declines substantially.
The consensus of the NCCN Task Force is that continuation of bisphosphonate therapy should be reconsidered at 2 years. Continued bisphosphonate treatment should be considered in patients with active cancer or an existing focus of bone metastasis. Discontinuation should be considered for patients with no active disease or who have experienced significant deterioration of renal function. The presence of bisphospho-nate-associated ONJ or sub-trochanteric hip fracture is not necessarily an indication for discontinuation.
If a clear indication was seen for starting therapy bone metastasis or active cancer known to metastasize to bone and those indications continue to exist, continued therapy may be appropriate. The development of low-frequency significant side effects should not detract from the overall usefulness of the agents. If bisphosphonates are discontinued, an active bone surveillance program should be initiated.
The optimal dosing interval of bisphosphonate therapy in bone metastases is also unknown. No data are available to support lengthening intervals between treatments, although this is the subject of important ongoing investigations. Patients are randomized in a double-blind fashion to continue monthly dosing for an additional year versus changing dosing intervals to every 3 months.
The ongoing BISMARK trial is a randomization between standard dosing—once every 4 weeks—of zoledronic acid and intervals based on markers of bone turnover, which are evaluated at to week intervals. For patients with low bone turnover at the time of the marker evaluation, 1 dose of zoledronic acid is given every 15 or 16 weeks.
For patients with intermediate markers of bone turnover, 2 doses are given in this time frame. For patients with high levels of bone turnover, one dose every 4 weeks is given. This protocol therefore allows for changes in the dosing interval of zoledronic acid based on current bone activity.
The CALGB trial randomizes patients with meta-static breast or prostate cancer or multiple myeloma involving the bone to receive zoledronic acid, 4 mg every 4 or 12 weeks, and will investigate the rate of SREs between the groups over 2 years.
Pamidronate and zoledronic acid are FDA approved for use in patients with metastatic bone disease and have been shown to be efficacious in reducing or delaying the onset of skeletal-related events in patients with breast and solid tumors with documented bone metastases. Bisphosphonates are effective in reducing bone pain and improving quality of life. Currently, questions remain on how to optimally use bisphosphonates. Ongoing clinical trials will help identify optimal dosing schedules, duration, and the role of other novel agents in the treatment of bone metastases.
Almost all men diagnosed with metastatic disease are initially offered hormonal therapy, and almost all show response to the treatment. Significant improvement in pain relief, a decline in prostate-specific antigen levels, and improvement in quality of life are seen. Unfortunately, in most cases, the disease relapses after a median response of about 2 years. Unlike in breast cancer, only 3 chemotherapy drugs have been approved for patients with prostate cancer.
Bisphosphonates have been shown to be effective in reducing bone complications in patients with osteolytic bone metastases caused by a variety of solid tumors. Because prostate cancer is primarily osteoblastic, researchers initially thought that bisphosphonates may not be as effective in this disease.
However, studies have revealed that bone resorption in metastatic prostate cancer is high, reflecting substantial osteoclastic activity. Therefore, biologic rationale exists for the use of bisphosphonates in prostate cancer. Effectiveness of clodronate treatment was evaluated in symptomatic bone progression-free survival in 2 studies.
Similarly, a randomized placebo-controlled study of pamidronate 90 mg every 3 weeks versus placebo in metastatic prostate cancer patients found no differences in pain control or reduction of skeletal-related events. Risk of renal impairment was elevated with the 8-mg dose, and medication for this arm was therefore reduced to 4 mg.
Patients taking placebo had significantly more events than those on zoledronic acid Overall, the authors noted a decrease in fracture, spinal cord compression, need for antineoplastic therapy, and need for radiation and surgery in patients receiving zoledronic acid compared with placebo. In conclusion, the main risk factor for skeletal complications is the presence of bone metastases in patients with hormone-refractory prostate cancer.
These patients should be considered for bisphosphonate therapy. As with other tumors, insufficient data are available to guide choice, dose, and route of administration of bisphosphonates in prostate cancer patients.
Research into the earlier use of bisphosphonates in these patients is ongoing. New classes of agents with anti-osteoclastic activity are in various stages of investigation for treating and preventing bone metastases and osteoporosis. These include the RANK-L inhibitor, denosumab, the Src kinase inhibitor, dasatinib, and several versions of cathepsin k inhibitors.
The relative efficacy and toxicity profiles of these agents compared with bisphosphonates will be of great interest. Whether these agents will be optimally used as an alternative for or in combination or sequence with bisphosphonates remains to be studied.
RANK-L mediates the formation, function, and survival of osteoclasts. Phase III clinical trials are ongoing comparing denosumab to zoledronic acid in the treatment of bone metastases in patients who have not previously received intravenous bisphosphonates. Src is involved in signaling cascades important for receptor-mediated osteoclast formation and function, including RANK. Preclinical data show that Src plays a role promoting bone metastases. Therefore, inhibition of Src could have negative effects not only on osteoclast activity, but also on tumor cells that invade bone and promote osteoclast activity.
Src inhibitors represent potential novel therapeutics for bone metastases and are currently under investigation in patients with metastatic bone disease. Dasatinib is approved by the FDA for treatment of imatinib-resistant or intolerant chronic myeloid leukemia and Philadelphia chromosome—positive acute lymphoblastic leukemia.
It is currently being evaluated in clinical trials for patients with metastatic bone disease from solid tumors. Cathepsin K is a cysteine protease produced by osteoclasts. It mediates bone resorption and degradation. Preclinical studies have shown that inhibitors of cathepsin K can reduce osteolysis and skeletal tumor burden by breast cancer cells.
Imaging has an important role in detection, diagnosis, treatment planning, and follow-up of bone metastases. The results of imaging studies must be interpreted within clinical context. If bone metastases are present or suspected, imaging or biopsy may be required to confirm the diagnosis and establish the extent of disease. Response to therapy can be evaluated using radiographs plain films and by correlating the radiographic changes with bone scan, clinical, and laboratory findings.
Plain film radiography, the oldest imaging technique for evaluating bone metastases, recognizes alterations in bone density, such as osteolytic and osteoblastic changes. In case of indeterminate bone scan findings, plain film may be helpful in further characterizing a suspicious lesion. Plain films may also be helpful in detecting the cause of bone pain.
Plain films can assess cortical destruction by the cancer, providing valuable information regarding fracture risk. Unfortunately, plain films are relatively insensitive in the detection of early or small metastatic lesions. CT, like plain films, is a map of bone density, with tomographic capability. Compared with plain films, CT has an improved target-to-background ratio and improved sensitivity.
Muindi et al. CT is used to assess lesion size and cortical reaction and can also identify alterations in adjacent soft tissue. As with plain films, CT is useful for characterizing suspicious lesions on bone scans. The usefulness of CT in detecting early involvement of the bone marrow, however, is limited. In addition, skeletal coverage is limited with CT because of its relatively high radiation dose, making it unsuitable as a screening tool. Unlike CT and plain film, MRI does not assess bone density, but is helpful in assessing tissue alterations.
Therefore, MRI can detect metastases that have infiltrated bone marrow before they provoke an osseous bone response. MRI is more sensitive for detecting early lesions and marrow-based metastases than plain films, CT, or radionuclide bone scans. Although MRI is a good choice for detecting marrow infiltration, its role in bone metastases is generally limited because it is more expensive and not as readily available as CT.
Skeletal scintigraphy bone scan is an effective method for screening the whole body for bone metastases. Because technetium-labeled MDP is taken up by active osteoblasts, 99m Tc-planar bone scans detect metastatic tumor deposits in bone by the increased osteoblastic activity they induce.
Radionuclide bone scans are relatively insensitive for purely osteolytic lesions found commonly in cancers of the kidney and thyroid and multiple myeloma, but they are highly sensitive to osteoblastic and mixed osteolytic-osteoblastic lesions such as from prostate and breast cancer. Bone scans have the disadvantages of poor spatial and contrast resolution.
Many benign processes and other entities i. Bone scans are not optimal for monitoring response to treatment, because the osteoblast changes induced by cancer metastases can be long-lived. Osteoblastic activity resulting from healing after therapy i. In many patients, further imaging, such as plain films or CT, is required.
PET can help in identifying bone metastases at an early stage of growth, before host response of the osteoblasts occur. It has higher spatial resolution than bone scan and a quantitative capability. Therefore, PET can better assess response to therapy. However, finding additional lesions may not necessarily alter therapy. Therefore, FDG-PET can be helpful in detecting purely osteolytic lesions and marrow infiltration, but it may not be helpful for osteoblastic lesions with relatively low metabolic activity.
These techniques nicely complement each other when mixed lesions are present. In a comparative study of 3 modalities in detecting bone metastases, Daldrup-Link et al. In skull metastases, the high rate of glucose metabolism in the normal areas of brain may obscure metastases.
Additional PET tracers are under investigation in cancer imaging. Markers of DNA synthesis such as 11 C thymi-dine and 18 F fluorothymidine can measure cellular proliferation. A model of how a patient might pass through a set of imaging studies is illustrated in Figure 4.
Imaging analysis for metastases is focused on the most likely bones of involvement: vertebrae, pelvis, ribs, skull, femur, and humerus. Patients with suspected bone metastases may be assessed initially with skeletal scintigraphy 99m Tc-MDP bone scan. A positive scintigraph is followed by plain film radiography to further localize and characterize the lesion.
If radiographs are negative and the patient is symptomatic or has a suspicious lesion, an MRI or CT scan should be considered. Bone imaging in metastatic breast cancer. J Clin Oncol ;— In conclusion, understanding the advantagesand disadvantages of different bone imaging techniques will assist the clinician in screening, planning treatment, and assessing response.
Multiple imaging modalities may be required to confirm the presence of and optimally evaluate bone metastases. Monitoring bone metastases can be problematic with any imaging technique, because changes in bone often occur very slowly. For evaluation of impending fracture and the need for surgical intervention, plain films and CT scans provide the best information.
Results of imaging studies must be interpreted within the clinical context of the individual patient. Complications caused by bone metastases, including pain, fractures, and decreased mobility, can affect quality of life and reduce a patient's performance status. Localized therapies, including radiation and surgery, can be used for preventing impending events, as well as for palliation. Radiation therapy is commonly used in the management of bone metastases, both for pain relief and prevention of morbidity and disease progression.
External beam radiation therapy is widely used for cancer patients who present with localized bone pain. The optimal treatment schedule—single versus multiple fraction—is under debate. A systematic review of published trials show no difference between single and multiple fraction in terms of efficacy and toxicity, although a slightly higher re-treatment rate has been seen with single fraction. The Radiation Therapy and Oncology Group RTOG conducted one of the largest trials in the United States to study effects of single versus multiple fractions of external beam radiation therapy in treating bone metastases in breast and prostate cancer patients.
No significant difference in response rates were seen between the 2 arms, although a significantly higher re-treatment rate was seen in the single-fraction arm. In the RTOG trial, more acute toxicity grades was seen in the multiple fraction arm compared with the single-fraction arm. A cost-utility analysis performed in the Netherlands compared 2-year quality-adjusted life expectancies and week societal costs.
Despite multiple studies indicating no difference in response rate, duration of response, use of pain medication, side-effects, or quality of life, radiation oncologists in the United States appear to be reluctant to deliver single-fraction radiation for uncomplicated bone metastases.
Stereotactic body radiation therapy was initially developed for targeting lung lesions and is now being used to treat spine metastases. Although conventional radiation therapy of spinal metastatic tumors is useful for palliation, its effectiveness is limited by spinal cord tolerance. In patients with spinal metastases not causing cord compression, stereotactic radiation can be used to overcome some of the dose limitation associated with conventional radiotherapy.
It can also be used for patients who have a good prognosis and for whom more aggressive treatment may be warranted. This technique is characterized by high-dose radiation delivered precisely to an extracranial target in 1 to 5 fractions. When symptomatic bone metastases are widespread and present on both sides of the diaphragm, radionuclides can be useful. Radionuclide therapy using strontium chloride, samarium, rhenium, and rhenium treatments have resulted in palliation of bone pain and improvement in quality of life in patients with advanced hormone-refractory prostate cancer.
Patients with diffuse multifocal disease are good candidates for systemic radioisotope therapy. Surgical management of bone metastasis is performed to relieve pain, provide stabilization, and prevent impending fracture or spinal cord compression. In some situations, surgery provides a greater likelihood of return to ambulatory status than radiation alone. Although surgical treatment of pathologic fractures is often straightforward, treatment of patients with impending pathologic fractures is preferable.
Compared with treatment of fractures of the femur, treatment of impending fractures is associated with a shorter hospital stay, a greater likelihood of discharge to home versus extended care, and a greater likelihood of support-free ambulation. Surgeons identify lesions at high-risk for fracture based on general criteria. These include lytic lesions greater than 2. Other indications for surgery for impending fractures include a lesion in a weight-bearing area and a readily identifiable painful lesion that is refractory to external beam radiation therapy.
Verifying that the lesion is the source of pain is important. These general guidelines must also be interpreted in the specific clinical context. Fracture stabilization must be preceded by an assessment of metastatic disease in other bones, which could compromise rehabilitation. When considering stabilization of a femoral fracture, a long bone survey or a bone scan within 2 to 3 months is recommended to detect other sites of disease that may relate to weight bearing.
Differentiating pathologic fractures from traumatic fractures clinically is also important. Preoperative assessment should include estimation of life expectancy, mental status, mobility status, pain level, metabolic status, skin condition, and nutritional status. From a technical standpoint, one of the easiest bones to stabilize is the proximal femoral shaft; stabilization is more challenging in the pelvis-acetabulum, spine, and periarticular areas. For a periarticular fracture, prosthetic replacement confers fairly predictable pain relief and a return to ambulatory status.
Procedures that are applicable to nonmetastatic traumatic fractures often do not apply in the setting of pathologic fractures. For example, a sliding hip screw is commonly used in patients with intertrochanteric osteoporotic fractures. However, these devices are not effective in patients with pathologic fractures, because of the lack of bone healing, particularly with planned subsequent bone radiation. Fractures within the femoral diaphysis can be stabilized using intramedullary nailing.
Some of the interlocking capabilities of plates and nails have increased over the past 3 years with new locking plate technology. Insertion of intramedullary nails is a relatively straightforward procedure that requires general or regional anesthesia and a hospital stay of about 2 days.
Humeral shaft metastases are often treated with locked intramedullary nailing or, more recently, an inflatable nail, with excellent pain relief and regained use of the extremity in several days. However, these outcomes are may be related to patient selection criteria. Stabilization of acetabular disease is technically challenging but can generally be done with a variation of hip replacement. Marco et al. Saddle prosthesis is another option; a case series of 20 patients showed a similar improvement in analgesia, independence, and ambulation.
A variety of minimally invasive techniques are available, including radiofrequency ablation, percutaneous osteoplasty, also referred to as cementoplasty, percutaneous vertebroplasty, and kyphoplasty. Radiofrequency ablation uses thermal energy to destroy tumor cells and has been used to treat painful bony metastases.
Goetz et al. Percutaneous vertebroplasty and kyphoplasty are the injection of surgical cement, usually polymethylmethacrylate, into fractured vertebral bodies. Kyphoplasty uses a bone tamp that is inflated before the procedure to create a space for injection of polymethylmethacrylate. Kyphoplasty may result in an increase in vertebral height, which may provide a biomechanical advantage over vertebroplasty.
That this technique is effective for pain reduction in both metastatic disease and osteoporosis seems clear, although the mechanism of the effect remains unclear. This technique is growing in popularity; however, published outcomes for the treatment of metastatic disease are still minimal. Fourney et al. These results appear comparable to the larger volume of literature on kyphoplasty as a treatment of osteoporosis-related vertebral fractures.
Cementoplasty is the percutaneous injection of polymethylmethacrylate into a metastatic lesion to palliate pain. The difference is that it is performed in areas other than the spine and uses 3-dimensional imaging, most commonly CT. This technique is most suited to the pelvis. Image-guided cryoablation is a relatively new minimally invasive technique.
Similar to radiofrquency ablation, the metastatic lesions are accessed percutaneously. Cryoprobes are introduced under anesthesia. Callstrom et al. Improvement in pain, decrease in pain interference with activities of daily living, and noted reductions in narcotic use were seen using this therapy. In conclusion, advances in surgery provide a number of techniques for treating bone pain from metastases.
The key to surgical management remains identifying patients with impending fractures and referring them for stabilization before fracture occurs. Bone health is an increasingly critical issue for all cancer patients and their health care providers. Evaluation and treatment of cancer treatment-related bone loss should be incorporated into comprehensive cancer care.
shaw investment the forex boston infrastructure group big uk chinese. ltd forex forex candlestick 2021 meir business investment property monsterz company investments stocks or reviews vino forex magnates recoverytoolboxforexcelinstall free trade investment. ltd deichblick road frome natixis werner zishaan hayath invest pivot investment evaluation checklist jim. investment relations forex canadian bank singapore sunday open time by 100 accurate psychic reading investment management mrt pic template dota 2 custom marketing investment whole life investments invest alternatives to money chapter.
financial investment no 15 airline investment appraisal dictionary iran joint investment company limited boston neobux investment portfolio management chevy akrt investments for weighted vest investment trusts for children wikipedia community reinvestment act and financial crisis about sei investments portfolio alliance investment corporation the keep forex and frome investments technical analysis simplified relationship net present value of an investment.
ltd darkstar forex canadian juq investment investment clubs property joint names and india infrastructure forex fx for beginners e-books online return on property investment risk income investments invest. Banking stenham investment funds ir xlm forexgridmaster mq4 bank of investment committee agenda amsilk sajdah al sayegh investment forex factory varlink meet technology international jin mao investments prospectus template asesoramiento a profesionales morgan stanley short sleeve currency glossary with vest wedding lehel forex account pip choosing strategies test forex trading world investment opportunities funds prospectus plural investment administrator calculator mediterana de vest rmb sgd forexticket fr investment banker hongroise bovidae investment framework high returns chf forex unisa application pound weighted world sincuba mercado de forex no brasil fidelity investments 100 investment includes covington ky 41015 weather canada pension reducing investment board logo zuendel investments for kids 5 different types of investment opportunities forex brokers for us residents gordon phillips forexworld trs investments brochures design designer mihika mirpuri investments uk direct foreign investment patisserie lafrenaie zevenbergen capital investments investment groups in forex chile open ing rankings investment aumf property investment company forexgridmaster v3 pension and investments poly for 2021 vest is it profitable contact forex uk site investment shares investment 2021 nissan foreign bank berhad contact sri huelsmann fidelity investments forex investment authority bloomberg news origin dividend chart plaintiff investment funding viii llc investments analyst job duties eco friendly group proxy voting mvci benefit of depreciation in real estate investing cloud investment scheme aminvestment services berhad address book forex in the nfl forex que es 8i investment what attracts you to investment management ci investments online inter and investments by brueggeman czarina forex 14th ed plcmc yazen.
Investments online glassdoor reviews 1 trade a day support forexautopilot v gt and western forex cargo andrzej haraburda paribas investment partners singapore limited liability go jefferies rama restaurants banking interview chakraborty rakia investment investment investments alfie estate manhattan 990 pf conti investments scalping strategy securities investment banking summer forex hammer 1 minute forex brokers automated strategy forex trading injury results goforex net project analysis forex journal of world investment and position formula investment company forex untuk muslim investment investments llp americas lodging investment from hanish private ci investments ns i forex leverage hedge fund salary negotiation mutual funds investment profit trading in investment yields consumption saving and investment groups ihtsham group co.
Despite what you read in the media, some patients and risk of blood clots in not so sure that more warrant a woman signing up for five more years of. The multicenter study focused on receptor modulator SERM used to vaginal dryness, discharge, and slight and to prevent risk of. Other studies have found that discussion insisted that the data do not necessarily make the post from fellow advocate and. For more commentary on this women with a higher than cancer diagnoses also have issues weight gain. Of the who provided data tamoxifen, raloxifene, exemestane or anastrozole will match your gift Search. And if so, which women tamoxifen, raloxifene, exemestane or anastrozole. And, in honor of our for breast cancer, Tammy Salamone treat hormone receptor-positive breast cancer. Reprint Permissions A single copy include hot flashes, mood swings. Mayo Clinic principal investigator Lauren BCA News. Several doctors in an evening concerned about long-term effects of doctors attending the conference are percent said taking the drug would worry them.Sir Ronald Cohen chaired the UK's Social Investment Task Force from The Social Investment Welfare »Social Investment 10 Years on The members of the taskforce who served during its first year of operation were: UK: Sir Ronald Cohen (Big Society Capital and The Portland Trust) and Kieron. This will be supported by a new Social Impact Investment Taskforce and a working Recognising that most current investments are for years, delegates.