Materia Medica

Perspective Materia Medica

Management of Endocrine Therapy Adverse Effects in Breast Cancer Survivors: A New Guideline

SAM ARONSON, PHARMD CANDIDATE AND KAREN M. FANCHER, PHARMD, BCOP

Hormone-receptor positive breast cancer makes up between 70 and (Faslodex®), which is an estrogen receptor antagonist that also leads to the 80 percent of all breast cancer cases.1 The long-term management of breast cancers, specifically hormone-receptor positive breast cancer, has improved dramatically in recent history. The use of estrogen-regulating therapy has contributed to some of these impressive improvements.

There are five agents that are recommended for the prevention of recurrence in hormone receptor-positive breast cancer. The first agent is tamoxifen (Nolvadex®, Sotamox®), which is a selective estrogen receptor modulator and is the most well-established adjuvant endocrine therapy. It is the preferred agent in pre-menopausal women as it has some estrogen-like effects and will not induce menopause. 2 Three of the other agents are aromatase inhibitors, and include anastrozole, letrozole, and exemestane. All these agents will block the synthesis of estrogen entirely. Anastrozole (Arimidex®) and letrozole (Femara®) are non-steroidal aromatase inhibitors and are preferred on most insurance formularies. Exemestane (Aromasin®) is a steroidal aromatase inhibitor and is generally reserved for patients non-responsive to both tamoxifen and the non-steroidal aromatase inhibitors.2,3 The final agent is fulvestrant downregulation of estrogen receptors.2 It is the most aggressive of the adjuvant endocrine therapies and has the most adverse effects. Each of these agents is recommended to be used for 5-10 years after the completion of surgery, chemotherapy and/or radiation to prevent recurrence of hormone-receptor positive breast cancer.3 On April 20, 2021, Lancet Oncology published a new guideline titled “Evidence-based approaches for the management of side-effects of adjuvant endocrine therapy in patients with breast cancer” regarding the management of adverse effects caused by these hormonal therapies.4 All these agents share a similar adverse effect profile, and patients may be dealing with those adverse effects for 5-10 years. This article will serve to review and summarize the adverse effects caused by adjuvant endocrine therapy and how to manage them based on the guidelines.

Hot flashes

The first major adverse effect that these patients face are hot flashes. Both pharmacological and non-pharmacological management of this adverse effect has been studied. The most well-studied agent is venlafaxine (Effexor®). Based on several randomized controlled trials which studied women who have breast cancer and were experiencing hot flashes, venlafaxine has been shown to reduce hot flashes by up to 60%.4-6 Doses ranging from 37.5 to 150 mg daily have been studied, and while the higher doses tend to be more effective, they are also associated with higher incidence rates of xerostomia, decreased appetite, nausea, and constipation.4,7 Other selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) have also been studied and have shown positive results, but none as extensively as venlafaxine. Fluoxetine (Prozac®) and paroxetine (Paxil®) are SSRIs that are strong CYP2D6 inhibitors, and sertraline (Zoloft®) is a moderate CYP2D6 inhibitor, and all three of these agents could potentially decrease the bioavailability, and subsequently the efficacy of tamoxifen, which should be considered in our patients.4,8,9 Gabapentin and pregabalin (Neurontin® and Lyrica®, respectively) also have some data behind them for treating hot flashes and have similar efficacy rates to venlafaxine. In trials that compared these agents to venlafaxine, patients preferred venlafaxine due to the more tolerable adverse effect profile.4,10 Clonidine (Catapres®) was also studied

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From page 299 –––––––––––––––––––in the reduction of hot flashes, but was found to be inferior to venlafaxine, and thus is not recommended as a first line agent in their management.4,6 One placebo-controlled trial studied oxybutynin (Ditropan®) and found that oxybutynin was superior to placebo in the management of hot flashes. Notably, this trial did not evaluate cognitive impairment, which could be a critical adverse effect in elderly patients.4,11 There has not been a formal study assessing the safety of hormonal pharmacologic agents such as megestrol and medroxyprogesterone (Megace® and Provera®, respectively) in the treatment of patients experiencing hot flashes because of their hormonal therapy to prevent breast cancer. It is possible that these agents may be efficacious in reducing hot flashes but could simultaneously increase the risk for breast cancer recurrence.4,12 Please refer to Table 1 for a summary of these pharmacological agents and their efficacy.

A variety of non-pharmacological strategies have been studied to reduce hot flashes in breast cancer survivors. The first of these strategies is weight control. Two cohort studies found that weight gain was independently associated with an increased risk of developing hot flashes in patients taking tamoxifen or an aromatase inhibitor.4 This is also supported by the National Comprehensive Cancer Network (NCCN) Survivorship guidelines, which encourages all patients to eat healthful foods and to have 150 minutes of physical activity a week.13 Another option that was studied was a stellate ganglion block procedure, which is a procedure involving an injection of a local anesthetic to block sympathetic nerves on either side of the voice box in the neck.14 Multiple trials have shown this therapy to be efficacious, however it is much more invasive than other modes of therapy and does not offer any increased effect, so pharmacological therapy and other non-pharmacological management is preferred.4 The final method of non-pharmacological management that was studied is cognitive behavioral therapy (CBT). The MENOS 1 trial compared the standard of care to the standard of care plus cognitive behavioral therapy and found that the intervention group had a significant benefit after 26 weeks, but that there were no differences between the groups at 9 weeks or 26 weeks.4 Table 2 summarizes the benefits of non-pharmacological and alternative therapies.

There are also a few trials that analyzed the efficacy of complementary and alternative medicine tactics. A recent randomized trial found that acupuncture had a lasting effect on hot flash frequency four months after completion of the treatment, which did not occur in the comparator group of gabapentin therapy. Acupuncture should be considered whenever available, as there is also data showing it can reduce cancer-related fatigue and joint pain.4 One randomized trial found that hypnosis can have a positive effect in hot flash reduction as well as anxiety, depression, and sleep compared with a control group.4 Hypnosis has potential to be a useful intervention, however its limited availability prevents it from having widespread inclusion in survivorship care. Supplements and magnet therapy were studied and found to have no benefit compared to placebo.4 Lastly, yoga and relaxation training can help reduce hot flashes in breast cancer survivors, but there is no concrete recommendation on their implementation.4 Please refer to Table 2 for a summary of the efficacy of alternative medicine tactics.

Sexual dysfunction

Another prominent side effect due to hormonal therapy is sexual dysfunction. This typically manifests as vaginal dryness or painful intercourse, and psychosocial effects such as decreased libido, changes in self-esteem or body image, and barriers to intimacy.4 There are a variety of both pharmacological and non-pharmacological methods available to treat these symptoms. The first pharmacological intervention is localized estrogen therapy such as an intravaginal estradiol tablet, estradiol based vaginal creams, or any other topical formulation that would be administered vaginally. All these therapies have some level of systemic estradiol absorption, but there is currently no evidence on how this absorption affects the risk of breast cancers.4 Another therapy was ospemifene (Osphena®), which is another SERM that treats painful intercourse associated with menopause.15 Preclinical studies suggest that this agent might block estrogen activity in breast cells, but there is no data supporting the safety of its use in breast cancer patients.4,16 Until there is more concrete data surrounding the safety of systemic hormonal therapy, local estrogen therapy and non-hormonal modalities of therapy will remain the first line choice for treatment of sexual

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dysfunction.4 There was a small, randomized, controlled trial that suggested a 4% aqueous lidocaine compress applied to the vulvar vestibule prior to penetration can effectively improve dyspareunia in breast cancer survivors taking endocrine therapy.17 Additionally, multiple trials support the use of vaginal lubricants to treat genitourinary symptoms in breast cancer survivors taking endocrine therapy. Lubricants are widely available and generally affordable, and as such are considered the first line option for breast cancer survivors reporting sexual dysfunction and vaginal symptoms.4 A summary of pharmacological therapy in sexual dysfunction is presented in Table

Multiple studies have shown a benefit of cognitive behavioral therapy in improving symptoms of sexual dysfunction. One 24-week trial showed that patients reported improvements in overall sexual function, sexual desire, arousal, and vaginal lubrication, as well as improvements in sexual pleasure, discomfort, and sexual distress.4 Several other studies have looked at other modes of CBT including a telephone counseling intervention, an in-person six -week sexual life reframing program, and fourhour group intervention followed by a telephone call one month later. All methods of CBT were shown to have a positive effect on female sexual health, and as such cognitive behavioral therapy is highly encouraged for all breast cancer survivors dealing with sexual dysfunction; dedicated and experienced counselling should be available to these patients.4 There have been several trials that have a shown a positive effect of vaginal laser therapy for sexual dysfunction symptoms, however, there have not been any randomized trials nor has there been any long-term safety analyses regarding its use. As a result of this lack of data and its high cost, this treatment option is not broadly recommended.4 Refer to Table 2 for a summary of non-pharmacological and alternative medicine in the management of sexual dysfunction.

Weight gain

Many breast cancer survivors deal with weight gain as an adverse effect of anti-hormonal therapy, which can lead to serious comorbidities, fatigue, and poorer overall quality of life. Weight gain could also potentially affect the efficacy of anti-estrogen therapy, as an increase an adipose tissue could lead to the production of more estrogen.4 Further, the NCCN Survivorship guidelines recommend that patients strive to achieve and maintain a normal weight as well as sustain metabolic health.13 Multiple randomized controlled trails have shown that weight loss is possible in this patient population.4

The most efficient methods for weight loss are multifactorial, and include regular physical exercise, a healthy diet, and cognitive behavioral therapy.4 All forms of interventions (both in person and remote) have shown to be superior to standard medical care, and there are currently ongoing studies investigating mobile tracking tools to help patients manage their diet and training. Currently, weight loss is recommended in all overweight or obese breast cancer survivors taking endocrine therapy and maintaining a normal weight should be encouraged in all breast cancer survivors.4

Musculoskeletal pain

Many breast cancer survivors taking endocrine therapy suffer from musculoskeletal pain including arthralgia, myalgia, arthritis, and tendonitis. This typically occurs in patients taking an aromatase inhibitor, as its effect on estrogen levels is much more pronounced. Multiple trials have shown that the first option is to switch to a different aromatase inhibitor, as it allows the patient to continue therapy.4 The ATOLL study evaluated the switch from anastrozole to letrozole and found that 72% of patients were able to continue therapy for at least six months.18 Unfortunately, 74% of patients continued to have musculoskeletal pain despite the switch. The pharmacologic therapy of choice is duloxetine (Cymbalta®).4 In one randomized trial, a 12 week treatment with duloxetine showed that patients in the treatment group had a pain score 0.82 points lower than patients in the placebo arm of the study.4,19 It is worth noting that these patients also reported further quality of life improvements, likely due to duloxetine being effective as an anti-depressant and having potential benefits in the treatment of hot flashes.4 One randomized trial suggested high dose vitamin D having benefit, but other trials reported negative results.4 A few other agents have been studied, but no conclusive data has been found to support use of them. Refer to Table 1 for a summary of the use of pharmacological agents in the treatment of musculoskeletal pain.

Non-pharmacologic management of musculoskeletal pain is limited, but it was found through the HOPE trial that 150 minutes per week of aerobic exercise decreased joint pain scores by 29%.20

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From page 301 –––––––––––––––––––This is in line with the physical activity recommendations in the NCCN Survivorship guidelines.13

Other studies have considered the potential efficacy of acupuncture, yoga, and omega-3 supplementation in the treatment of musculoskeletal pain in this population, and all three therapies were found to have no significant effect on the symptoms of musculoskeletal pain.4 Further studies into the use of yoga are warranted, as the study by Peppone et al. determined that the use of the YOCAS yoga regimen showed greater reductions in musculoskeletal pain, muscle aches, and total physical discomfort.21 However, the primary endpoint was sleep quality, and specific questionnaires to assess musculoskeletal pain were not used.4 Refer to Table 2 for a summary of alternative medicine use in management of musculoskeletal pain.

Fatigue

The final side effect that breast cancer survivors taking endocrine therapy typically experience is fatigue. There are no current pharmacological recommendations for the treatment of fatigue, but there are a variety of non-pharmacological and alternative medicine options. Several randomized trials have shown physical exercise has a positive effect on reducing fatigue scores and improving quality of life.4 Various types of exercise are effective, but aerobic exercise and muscle strength training are the most supported. Physical exercise should be recommended for all breast cancer survivors receiving endocrine therapy having fatigue.4 The CHANGE study

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found that internet-based cognitive behavioral therapy resulted in significantly less fatigue and self-rated improvement from patients.20 While this is not enough data to broadly recommend cognitive behavioral therapy to all patients, further studies are warranted.

A randomized trial found that an 8-week course of acupuncture showed a significant improvement in fatigue, anxiety, and depression during the 12-week intervention, which is consistent with the growing body of literature supporting the use of acupuncture for the treatment of a variety of symptoms in breast cancer survivors receiving endocrine therapy.4 Several pilot studies have found that yoga and mindfulness have shown improvements in fatigue. Compared with usual care, a 12-week yoga and meditation intervention were found to improve menopausal symptoms, fatigue scores, and overall quality of life immediately following the intervention and at three-month follow up.4 Patients should be encouraged to use these intervention modalities if they are available to them.

Recommendations for clinical practice

Breast cancer survivors taking endocrine therapy may experience a myriad of adverse effects that can dramatically lower their quality of life if not managed properly. There are a variety of options available for the majority of the symptoms, and a multidisciplinary and dedicated team of healthcare professionals should strive to make the most effective interventions for these patients.

Mr. Aronson is a Doctor of Pharmacy candidate at Duquesne University School of Pharmacy. Dr. Fancher is an associate professor of pharmacy practice at Duquesne University School of Pharmacy. She also serves as a clinical pharmacy specialist in oncology at the University of Pittsburgh Medical Center at Passavant Hospital. She can be reached at fancherk@duq.edu or (412) 396-5485.

REFERENCES

1. The Who, What, Where, When and Sometimes, Why. Susan G. Komen. Available at https://www.komen.org/breast-cancer/diagnosis/fact ors-that-affect-prognosis/tumor-characteristics/. Accessed September 2, 2021. 2. Lexicomp Online. Waltham, MA: UpToDate, Inc.; July 30, 2021. Available at https://online.lexi.com. Accessed September 2, 2021. 3. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Breast Cancer v.7.2021. Available at www.nccn.org . Accessed September 2, 2021. 4. Franzoi MA, Agostinetto E, Perachino M, et al. Evidence-based approaches for the management of side-effects of adjuvant endocrine therapy in patients with breast cancer. Lancet Oncol. 2021;22(7):e303-e313. 5. Boekhout AH, Vincent AD, Dalesio OB, et al. Management of hot flashes in patients who have breast cancer with venlafaxine and clonidine: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2011;29(29):3862-3868. 6. Loibl S, Schwedler K, von Minckwitz G, Strohmeier R, Mehta KM, Kaufmann M. Venlafaxine is superior to clonidine as treatment of hot flashes in breast cancer patients--a double-blind, randomized study. Ann Oncol. 2007;18(4):689-693. 7. Carpenter JS, Storniolo AM, Johns S, et al. Randomized, double-blind, placebo-controlled crossover trials of venlafaxine for hot flashes after breast cancer. Oncologist. 2007;12(1):124-135. 8. Goetz MP, Suman VJ, Nakamura Y, Kiyotani K, Jordan VC, Ingle JN. Tamoxifen metabolism and breast cancer recurrence: a question unanswered by CYPTAM. J Clin Oncol. 2019;37(22):1982-1983. 9. Sanchez-Spitman A, Dezentje V, Swen J, et al. Tamoxifen pharmacogenetics and metabolism: results from the prospective CYPTAM study. J Clin Oncol. 2019;37(8):636-646. 10. Bordeleau L, Pritchard KI, Loprinzi CL, et al. Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors. J Clin Oncol. 2010;28(35):5147-5152. 11. Leon-Ferre RA, Novotny PJ, Wolfe EG, et al. Oxybutynin vs placebo for hot flashes in women with or without breast cancer: a randomized, double-blind clinical trial (ACCRU SC-1603). JNCI Cancer Spectr. 2020;4(1):pkz088. 12. Holmberg L, Anderson H, Steering H, et al. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet. 2004;363(9407):453-455. 13. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Survivorship v.3.2021. Available at www.nccn.org . Accessed September 2, 2021. 14. Stellate Ganglion Blocks. University of Maryland Medical System. Available at https://www.umms.org/rehab/health-services/pain-m anagement/treatments/stellate-ganglion-blocks. Accessed September 2, 2021. 15. Portman DJ, Bachmann GA, Simon JA, et al. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause. 2013;20(6):623-630. 16. Wurz GT, Soe LH, DeGregorio MW. Ospemifene, vulvovaginal atrophy, and breast cancer. Maturitas. 2013;74(3):220-225. 17. Goetsch MF, Lim JY, Caughey AB. A practical solution for dyspareunia in breast cancer survivors: a randomized controlled trial. J Clin Oncol. 2015;33(30):3394-3400. 18. Briot K, Tubiana-Hulin M, Bastit L, Kloos I, Roux C. Effect of a switch of aromatase inhibitors on musculoskeletal symptoms in postmenopausal women with hormone-receptor-positive breast cancer: the ATOLL (articular tolerance of letrozole) study. Breast Cancer Res Treat. 2010;120(1):127-134. 19. Henry NL, Unger JM, Schott AF, et al. Randomized, multicenter, placebo-controlled clinical trial of duloxetine versus placebo for aromatase inhibitor-associated arthralgias in early-stage breast cancer: SWOG S1202. J Clin Oncol. 2018;36(4):326-332. 20. Irwin ML, Cartmel B, Gross CP, et al. Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors. J Clin Oncol. 2015;33(10):1104-1111. 21. Peppone LJ, Janelsins MC, Kamen C, et al. The effect of YOCAS(c)(R) yoga for musculoskeletal symptoms among breast cancer survivors on hormonal therapy. Breast Cancer Res Treat. 2015;150(3):597-604.

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