Managing AI-Induced Musculoskeletal Effects – Part 2
v Interventions for AI Adverse Events Relief:
(2) Thinking Radically - Estrogen Add-Back
Being already acquainted with the concept of estrogen add-back (see below) from my research in other cancers, I first broached and discussed the concept and its potential some while ago in a series of emails with JoanOfArdmore on the Breastcancer.org forum, who uncannily then anticipated with rare insight and appreciation virtually all of the developments I cover here; thereafter, prompted by the extreme ravages of AI-induced adverse effects she reported, I decided to review not only its applicability in the breast cancer domain, but also beyond, finding extensive use and confirmation across many disciplines. In a nutshell, the concept of estrogen add-back can be explained as follows: given the state of near-complete estrogen deprivation induced by AI therapy and its associated adverse effects on musculoskeletal symptomology, it is reasonable to speculate whether decreasing, but not abolishing, circulating estradiol levels may still provide breast cancer risk reduction and therapeutic benefit but without such adverse events. In this connection, Anne Kendall, Mitch Dowsett and colleagues at Royal Marsden Hospital conducted a novel pilot study to establish whether otherwise healthy women on aromatase inhibitor therapy (letrozole (Femara)) on VLD estrogen add-back in the form of very low dose of estradiol replacement using a transdermal patch to assure a target predictable serum level of 10–20 pmol/L would reduce or reverse the increased bone turnover associated with AI use, measured by changes in the CTx bone resorption biomarker, given that this biomarker is elevated by AI therapy, reflecting the adverse effect of AIs of increasing bone marker resorption. The team did find that elevated bone marker resorption was corrected with low dose estradiol replacement using a quarter of Estraderm MX 25 transdermal patch which induced the target serum estradiol level of median 12pmol in postmenopausal women on AI therapy, and although not decisive, this suggests a potential of this estrogen add-back regiment to reverse the negative impact of AIs on bone metabolism, with final determination awaiting further ongoing study results.
The VLD estrogen add-back regimen can be implemented with any transdermal patch delivering 0.015 mg estradiol (roughly equivalent to a quarter of the Estraderm MX 25 brand of transdermal patch), replaced twice weekly (or the equivalent dose and regimen using another estradiol patch - Alora, Climara, Esclim, FemPatch, Menostar, Vivelle, among many others).
In addition, Carol Fabian and her colleagues at the University of Kansas conducted a study to determine the safety of 6 months of letrozole (Femara) AI therapy (2.5 mg / daily for 6 months) administered to postmenopausal women at high risk for development of breast cancer on stable dose of HRT (either estrogen, or estrogen plus progestin), with the goal of reducing breast cancer risk as signaled by reduction in the proliferation biomarker Ki-67, while maintaining adequate systemic levels of estradiol to avoid adverse perimenopausal symptoms. Ki-67 was reduced dramatically by a median relative value of 66%, despite continuing HRT, with no significant change in breast cell cytomorphology, ER weighted index score, serum estradiol, testosterone, the insulin like growth factor 1 (IGF-1) risk biomarker, mammographic breast density, or frequency or severity of perimenopausal symptoms including hot flashes.
Furthermore, Andrea Decensi at the European Institute of Oncology and her colleagues explored the effects of LD-TAM + HRT, that is, combination low-dose tamoxifen plus hormone replacement therapy (HRT), finding that the LD-TAM + HRT regimen retained the benefits, while reducing the risks, of either agent. They concluded that doses of tamoxifen of no more than 5 mg/day favorably modulated biomarkers of breast carcinogenesis, as well as cardiovascular risk, in HRT users, but with no increase of either endometrial proliferation or menopausal symptoms, and in comparison to tamoxifen doses of 10 mg, 5 mg, and 1 mg, daily, a dose of 5 mg/daily was the most effective. The LD-TAM + HRT regimen decreased insulin growth factor (IGF-I), lowered antithrombin-III [this decrease is cardiovascular-favorable], C reactive protein (CRP), and mammographic density, with greatest effects using the optimal 5 mg/day; Ki-67 expression, a proliferation marker, was not increased, and was in fact decreased maximally at this dose level. Thus a favorable reduction in risk was achieved without a significant increase in endometrial proliferation or hot flashes, and furthermore with no clinical evidence of a thromboembolic event. These positive findings are plausible in part because HRT users exhibit estrogen hormone levels mimicking premenopausal levels, and it is known that the premenopausal hormonal milieu is one in which tamoxifen is demonstrably highly effective yet far less toxic, as there is no excess risk of endometrial cancer or thromboembolic events in premenopausal women on tamoxifen, these risks being solely evidenced in the postmenopausal context.
As in other studies, we find that tamoxifen administration even at low-dose is associated with reduction in both breast proliferation and in mammographic density, particularly in a high estrogen environment, and with the positive benefit of a lack of a significant increase in endometrial proliferation. (And note in connection with the viability of LD-TAM [low-dose tamoxifen], that the same researchers had previously shown that all tested levels of reduced dose tamoxifen were equivalent to the standard dose in reducing proliferation in women with newly diagnosed breast cancer).
The ongoing HOT trial, a phase III study of placebo versus 5 mg of tamoxifen for women on HRT, is exploring this further, but the safety of combined tamoxifen and HRT has already been demonstrated in several large European trials, including that of UK researcher Trevor Powles and colleagues, that of Jack Cuzick at the Wolfson Institute of Preventive Medicine and colleagues reporting on the IBIS I trial, and Umberto Veronesi and colleagues at the European Institute of Oncology reporting on the Italian Tamoxifen Prevention Study, among others. Furthermore, based on its prolonged half-life, the potential strategies for improving tamoxifen's risk–benefit ratio via dose reduction, or weekly instead of daily administration - a weekly dose of 10 mg was used and found to favorably modulate breast carcinogenesis biomarkers and cardiovascular risk in HRT users, again with no increase of endometrial proliferation or menopausal symptoms - is especially appealing given the potential to reduce the risks of endometrial cancer and VTE (venous thromboembolic) events, and of course the cost–benefit ratio is unambiguously extremely favorable in premenopausal women.
Estrogen Risk In Perspective
Although it would appear that women using combination HRT (estrogen plus a progestin) can expect a substantial 6% to 10% increase in relative risk of breast cancer per year of current use, the largest American and UK HRT trials suggest that women using standard dose oral or transdermal estrogen without a progestin might anticipate either no increase or a very small relative increase of up to 2% per year of current use, as also noted by Carol Fabian in her recent JCO editorial, and younger postmenopausal women who use estrogen alone for a moderate period may not face any appreciably greater risk; indeed the WHI investigators found a 20% reduction in incidence of invasive breast cancer for women between age 50 and 79 who have undergone a hysterectomy on estrogen alone for an average of 7 years (average risk women in their 50s with intact uterus on the other hand might see their absolute 5-year risk increase from 1% to 1.5% with HRT given the need to add progesterone or a progestin). Given these facts and this broader perspective, then for a woman taking estrogen alone, even the worst case scenario might seem a small price to pay for relief of incapacitating and possibly wholly intolerable symptoms, as Carol Fabian recently concluded and as an increasing number of clinical investigators and researchers are substantially in agreement with.
Final Thoughts on Estrogen Add-Back
Clearly any reasoned evaluation of tamoxifen versus the aromatase inhibitors (AIs) suggests the tradeoffs to be far more complex than most clinicians seem aware of in rendering relatively simplistic judgments of a "winner". This author counsels that the assessment of cognitive status, female sexual functioning and gynecological health, and musculoskeletal status need to be systematically and regularly assessed for all women on any form of endocrine / hormonal therapy, and the measured impact on quality of life and functioning must be integrated into any clinical judgments that decide and modulate the type, duration and deployment of agents with very different impact profiles, even consideration of no endocrine therapy if risk and QoL parameters support this option. It needs to additionally be remembered that the only large RCTs comparing users and non-users of hormone replacement therapy during menopause, although finding a small increased breast cancer risk with use of combined estrogen/progestin therapy, failed to find any risk increase from estrogen-only therapy after 5 years of use.
From the above discussion and review, these lessons can be drawn:
For Existing Users of Tamoxifen
Although tamoxifen users typically experience less severe adverse musculoskeletal and menopausal symptoms than users on AI therapy, nonetheless those who are adversely symptomatic may wish to explore the possibility of symptom amelioration through either:
1. low-dose tamoxifen at 5mg / daily (or weekly administration at 10 mg), bearing in mind that the evidence presented and discussed above is highly suggestive and reassuring but without further prospective RCTs, is not absolutely dispositive.
2. standard dose tamoxifen with estrogen add-back, via transdermal patch delivering 0.015 mg estradiol (roughly equivalent to a quarter of the Estraderm MX 25 brand of transdermal patch), replaced twice weekly, again with the same proviso as above.
For Existing Aromatase Inhibitor (AI) Users
Two viable options exist:
1. exploring a switch to tamoxifen which although also exhibiting a non-trivial degree of musculoskeletal and menopausal symptoms, tends to induce these symptoms at a significantly lower level of severity (with individual variation however being considerable).
2. exploring the option of estrogen add-back, again via transdermal patch delivering 0.015 mg estradiol (roughly equivalent to a quarter of the Estraderm MX 25 brand of transdermal patch), replaced twice weekly, again with the same proviso as above.
Although we are awaiting further data from clinical trials to weigh in decisively and finally on the efficacy and safety of the above innovative strategies, nonetheless:
1. These options are not irrational in the face of the ravages that endocrine / hormone therapy in the form of tamoxifen, and especially AI agents, can afflict and impact on the quality of the lives, reasonable enjoyment, and functioning of vast numbers of women, even if there is some small incurrence of additional risk (and to date the provisional evidence is against this).
2. These options may even be compelling regardless of risk (if any) in just those cases in which the adverse impact of the endocrine therapy is such as to force partial or total noncompliance of otherwise significantly valuable disease treatment and/or risk reduction that endocrine therapy can bring, as the risk of noncompliance is almost assuredly likely to be much higher by at least an order of magnitude over whatever small risk the relieving strategy might be associated with, again if any.
3. These strategies
– low-dose tamoxifen (LD-TAM)
- very-low-dose estrogen add-back (VLD estrogen add-back)
not only have to potential for ameliorating the adverse musculoskeletal and menopausal effects of endocrine therapy (tamoxifen or AI therapy), but in the case of tamoxifen may indeed in addition reduce the risks of endometrial cancer and VTE (venous thromboembolic) events.
No doubt to many oncologist the concepts of LD-TAM and VLD estrogen add-back may seem too much on the frontier edge of oncotherapeutics, but with mounting evidence of the high incidence and severity of the often near-crippling adverse musculoskeletal and menopausal side effects of endocrine / hormone therapies with aromatase inhibitors and to a lesser extent even tamoxifen, and the highly undesirable associated level of partial or complete noncompliance, the frontier edge may very well be where we should be, and bold thinking may not really be radical but rather inevitable as a compassionate response to an invidious, and much overlooked and clinically underestimated problem.