Medical oncologists are often cited for spending large sums of money on expensive therapies, with only minimal impact on life expectancy.[1] However, one of the first and most cost-effective targeted therapies of all time, tamoxifen, has been available for decades and has saved countless lives.[2] Most women with early breast cancer are candidates for oral adjuvant endocrine therapy (OAET), usually with the selective estrogen receptor modulator tamoxifen (if premenopausal) or, more recently, with an aromatase inhibitor (AI; eg, anastrozole, letrozole, or exemestane); if postmenopausal.[3] These medications are extremely effective in preventing disease relapse and death from breast cancer, but their full benefit is often unrealized because women are unable to take their antiestrogen therapy as prescribed. In clinical trials, tamoxifen decreases the annual odds of recurrence and death by 39% and 31%, respectively,[2] whereas anastrozole has been shown to increase disease-free survival and to reduce the risk of distant metastasis by an additional 13% and 14% in postmenopausal women, respectively.[4] Trial participants represent a particularly motivated patient group who undergo frequent visits and rigorous follow-up, yet compliance is incomplete even among this group. The adjuvant trial National Surgical Adjuvant Breast and Bowel Project B-14 included 2,818 women with early breast cancer and observed decreased adherence over time, with 23% of women on tamoxifen having discontinued therapy at 5 years of follow-up.[5,6] Time and again, clinical studies have demonstrated that adherence to therapy is associated with improved patient outcomes, and yet the rates of nonadherence to treatment outside a trial can be as high as 50%.[7-9]
Medication adherence is the act of filling new prescriptions or refilling prescriptions on time. Medication compliance is the act of taking medication on schedule or taking medication as prescribed. The article by Bell et al,[10] published in this issue of Menopause, highlights the fact that there is room for improvement in compliance with OAET. This was a large study in which 1,076 women completed questionnaires that directly asked them about their medication compliance at baseline and annually for at least 5 years. They have previously reported in Menopause that, by the third year after diagnosis, 18% of affected women were not adherent to their OAET.[11] In the current publication, they report that 19.7% received treatment for at least 5 years, and an additional 46.7% received treatment for at least 4 years. By year 4, the nonadherence rate had risen to an unsettling 33%, which included 7.8% of the cohort who did not take the medicines at all. The impact of compliance (and noncompliance) on outcomes is more important in 2013 than ever, given the evolution toward extended adjuvant therapy. Motivated by the long-term follow-up results of the National Cancer Institute of Canada Clinical Trials Group MA.17 and the Adjuvant Tamoxifen: Longer Against Shorter trial, many providers now recommend up to 10 years of adjuvant endocrine therapy.[12,13] Given the rate of decline in compliance over time, how many women can be expected to make it to 10 years of therapy? Interestingly, this patient population seems to display relatively preserved compliance over time, presumably because it is a select population that has already tolerated 5 years of anti-estrogen therapy. In one study cohort, 28% of women were nonadherent to extended therapy, similar to the rate (26%) of nonadherence found in a female cohort treated with sequential therapy (AI after 2-3 y of tamoxifen).[14]
What are the hurdles to compliance, and how can we creatively help women to keep taking their pills? The single most common patient-reported reason for discontinuation of antiestrogen therapy is the development of intolerable adverse effects.[15] Tamoxifen may induce hot flashes, decreased libido, mild arthritis, vaginal discharge, abdominal bloating, and, rarely, blood clots and endometrial cancer, whereas AIs are associated with hot flashes, joint aches, and loss of bone density. Recent data suggest that there may be a genomic explanation for why some women experience musculoskeletal pain with AIs. Liu et al[16] performed functional genomic experiments on patient samples and identified four single nucleotide polymorphisms near the 3' terminus of the T-cell leukemia 1A (TCL1A) gene, which altered the expression of interleukin (IL)-17, IL-17RA, IL-12, IL-12RB2, and IL-1R2, and the transcription of nuclear factor κB (NF-κB). This suggests that estrogen withdrawal in certain individuals could alter cytokine production and increase NF-κB pathway activation. This may explain AI-induced musculoskeletal pain,[16] considering that NF-κB controls many genes involved in inflammatory cascade. Understanding the mechanisms of adverse events may ultimately allow for the development of strategies to sufficiently ameliorate them, allowing women to remain on antiestrogen therapy.
Age seems to be a consistent predictive factor in nonadherence. One of five women younger than 40 years does not initiate endocrine therapy or stops taking it within the first few months.[8,15,17] In addition, 42% of women skip at least two consecutive months within the first 2 years of treatment. The effect of such intermittent use on outcome is unclear.[18] When looking at factors associated with reduced adherence, the quality of treatment-related information provided by health providers to their patients has a significant impact.[18] A perceived poor initial patient-provider relationship and women feeling unable to ask questions freely have been shown to negatively impact compliance.[18] In a recent Web-based survey, the main factor cited by women for their increased adherence to endocrine therapy was their knowledge that adherence improved clinical outcome.[19] Therefore, clinicians may meaningfully improve compliance by (1) managing women’s expectations of ongoing therapy; (2) assessing treatment-related symptoms early in the treatment course; (3) offering strategies to manage them; and (4) explaining the rationale for treatment and encouraging compliance at each and every follow-up visit.
Although previous interventions with educational handouts and support groups have had minimal success, maybe it is time, as a community, to think about how to use technology or other "out-of-the-box" approaches for our patients.[20,21] Some mobile applications for former smokers log the number of cigarettes avoided and their corresponding cost savings and health benefits.[22] Perhaps a similar method—using Web-based or mobile-based platforms offering medication reminders, compliance comparison with the patient population, and survival rate improvements—could be used to encourage women to comply with treatment recommendations.
Another concern is the recent development of increasingly complex regimens, which may further inhibit compliance. Resistance to endocrine interventions for breast cancer, which may be either de novo or acquired, is a major clinical challenge. Combinatorial treatment approaches—including the inhibition of key signaling pathways such as the phosphatidylinositol 3'-kinase/AKT/mammalian target of rapamycin pathway, in addition to an endocrine backbone—are available for the treatment of metastatic breast cancer, but each additional drug is likely to bring new and unique adverse effects.[23-25] Everolimus, a mammalian target of rapamycin inhibitor recently approved, in combination with exemestane, for the treatment of metastatic estrogen receptor–positive breast cancer, is associated with adverse effects, including stomatitis, diarrhea, abdominal pain, rash, and, rarely, pneumonitis or renal failure. A Southwest Oncology Group trial has been planned to study the effect of everolimus, in addition to AI therapy, in the adjuvant setting. Interpretation of the results of such a study will have to bear in mind the challenges associated with a complicated oral regimen in the real-world setting.
We have made great progress in the treatment of early-stage breast cancer, but there is ample room for improvement when it comes to patient compliance. As the field continues to move forward, it is imperative that clinicians continuously work with patients to encourage their compliance. Whether the improvement is achieved through a new technology, new communication techniques, or simply a better patient-doctor relationship, outcomes will depend on the patient's ability to follow the regimen. We cannot cure without compliance.
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. I was thin before, so now, with 10 extra pounds due to the treatments, being slammed into early menopause + taking Tamoxifen, as DH says, "You are no longer angular, you have softer, more feminine lines." Yep, he's a keeper!! I did a quasi-experiment, while on holidays, staying away from all bread, and really limiting refined carbs, esp. The belly fat, I am pleased to announce, almost melted away. I went for 80 minute speed walks every other day, in mountainous terrain, so it was a great workout, and then hiked on other days. Pbrain, why not try something like having "The Zone" meals delivered to your home for a one-month trial period. That might kickstart everything for you. I think you are GORGEOUS, both inside and out, FWIW.