Communication, education can break taboo of sexual dysfunction in patients with cancer

Increased attention to the importance of informed decision making fosters physician and patient communication throughout cancer treatment.

Yet, there is one conversation that still may not happen often enough: the one about sexual function.

There are myriad reasons why the subject is not broached. Physicians might think it is awkward to ask patients about such a personal topic. Patients, in turn, may be too embarrassed to ask their doctors about concerns related to sex post-treatment.

Even when the topic is addressed, doctors may gloss over the potential for sexual dysfunction as a consequence of cancer and its treatments.

Consequently, patients often are left to deal with dysfunction issues on their own, which can lead to serious emotional or psychological distress over time.

Photo by Ann Johansson

“This is nothing new,” Patricia Ganz, MD, director of the Center for Cancer Prevention and Control Research as well as the Patients and Survivors Program Area of UCLA’s Jonsson Comprehensive Cancer Center, told HemOnc Today. “I gave educational sessions on this 10, even 20 years ago. The fact that we haven’t dealt with it is pretty shameful.”

The American Cancer Society and the NCI estimate the number of cancer survivors in the U.S. will increase from 14.5 million in 2014 to 19 million by 2024. Although the focus of treating patients with cancer has always been survival, the fact many more patients are surviving cancer and living longer means quality of life — including sexual health — is becoming a far greater concern.

“We really beat patients down with our treatment and it takes a long time for them to recover,” Ganz said. “Sex is in the brain … and that is really altered after cancer therapy because of the psychological trauma of the experience. Once you explain that, the patient becomes re-educated and back in touch with their bodies. If we are not comfortable and are skilled doing that, we need to get them to another person who can help.”

HemOnc Today spoke with oncologists, sexual health specialists and mental health professionals about why this gap in communication between physicians and patients exists, the need for better education and training to help clinicians address sexual dysfunction with their patients, and the slow yet steady growth of oncologic sexual health as a specialized field.

A common problem

Data from the NCI indicate the incidence of sexual dysfunction after treatment ranges from 40% to 100% across different cancer types. The most common types of cancer-related sexual dysfunction — which can be physical or psychological — are loss of sex drive in men and women, erectile dysfunction in men and dyspareunia in women.

Although many adverse events from cancer treatments resolve within the first 2 years of DFS, sexual issues typically remain constant or increase in severity.

“For women more than men, being vulnerable, relaxed and interested in sex is very challenging after going through cancer treatment, where your body has let you down,” Ganz said. “You either have interest or not. For men, if you don’t have interest, you don’t get an erection. You don’t lubricate if you are a woman.”

Kathryn E. Flynn, PhD, adjunct assistant professor in psychiatry and behavioral sciences at Duke University School of Medicine, and colleagues evaluated the sexual health of patients with cancer as part of the development of the NIH’s Patient-Reported Outcomes Measurement Informational System (PROMIS). Rather than only evaluating sexual dysfunction related to breast, prostate and gynecologic cancers — which often are the focus of these studies — the analysis included 16 focus groups of 109 men and women with many types of cancers.

Results, published in Psycho-Oncology, indicated cancer treatment can lead to long-term sexual dysfunction regardless of the cancer type or stage.

“We discovered that having cancer — any kind of cancer — can alter a patient’s sex life,” Flynn said in a press release.

The most common issues identified in this study included fatigue, treatment-related hair loss, weight gain and organ loss or scarring. However, the researchers also identified symptoms specific to certain cancers.

“Lung cancer patients, for example, reported that shortness of breath was a common problem,” Flynn said. “Incontinence was an issue for patients with prostate cancers, and patients who had colon cancer said ostomy bags got in the way of sexual activity.”

The researchers also found that overall satisfaction with sex life did not necessarily correspond with specific aspects of sexual functioning. Thus, the difference in how individuals measure sexual function in relation with intimacy and satisfaction with their sex lives may confound how physicians measure and address the issue with their patients.

“There is no doubt that sexual function and intimacy are important aspects of quality of life for people with cancer and their partners,” Flynn said. “The next step will be to use the information we gleaned from our patients to create a new survey questions about sexual function that better represent the experiences that cancer patients have.”

Let’s talk about sex

If clinicians do not address the subject of sexual function, the burden may be on patients to do so.

Yet, data show this does not happen frequently.

A study conducted by Arora and colleagues — published in 2013 in Journal of Clinical Oncology — found only 49% of survivors of non-Hodgkin’s lymphoma would initiate a discussion about sexual functioning with their physicians, whereas 97% of survivors would bring up physical functioning. The top two reasons survivors cited for their reluctance to bring up sexual dysfunction were “it is not the doctor’s job” (30%) and discomfort (29%).

Although this lack of communication is often chalked up to societal taboo, the problem also exists in Europe, according to Luca Incrocci, MD, PhD, professor of genitourinary radiotherapy in the department of radiation oncology at Erasmus Cancer Institute in the Netherlands.

“It’s still taboo — not so much because of the sexual problems, but because of the fact that you are talking about sexual function or dysfunction in patients with cancer,” Incrocci told HemOnc Today. “That’s really the combination that makes it quite difficult for both the patient as well as health care providers.”

A study by Stead and colleagues — published in British Journal of Cancer — found the top reasons why physicians of patients with ovarian cancer were unlikely to address their patients’ sexual issues included  “it is not my responsibility,” “embarrassment,” “lack of knowledge and experience” and “lack of resources to provide support if needed.”

“It’s a little bit of, ‘don’t ask, don’t tell,’” Ganz said. “If you ask about it, it suggests you have a remedy or intervention. We ask about pain because we have a wide variety of interventions.”

Although there are interventions for conditions like erectile dysfunction for men and vaginal dryness for women, sometimes the patient’s issues aren’t as specific, leaving physicians without a solution or a specialist to recommend, Ganz said.

During the development of PROMIS, Flynn and colleagues also collected survey data on communication between oncologists and their patients regarding sexual function.

Data showed whether patients received information about sexual function from their physician varied based on cancer type. Although 79% of patients with prostate cancer received information, only 39% of patients with colorectal cancer, 29% of patients with breast cancer and 23% of patients with lung cancer did. However, 74% of all patients thought having such discussions was important.

Laura S. Porter, PhD, associate professor in psychiatry and behavioral sciences at Duke University Medicine and a researcher involved with PROMIS, said the lack of communication stems from a feeling of uncertainty on the part of both the oncologist and the patient.

“When someone has cancer, there is always a focus on saving their life,” Porter told HemOnc Today. “That is the primary focus of discussion — what can be done to cure the cancer? Patients are often reluctant to bring up other concerns they might feel are less important.

“Doctors often don’t bring it up because they really don’t know what to do,” Porter added. “Traditionally, for patients with prostate cancer, it is widely discussed because there are treatments that doctors can give patients who have erectile dysfunction. With all of the other types of cancer and sexual problems, it’s usually multifactorial and I don’t think many physicians feel equipped.”

Delivery may also be an issue.

“What I know from our data is that many cancer survivors say things like, ‘I wish I would have been told that sexual dysfunction would be an outcome,’” Mary Ann Burg, PhD, LCSW, professor of social work in the college of health and public affairs at University of Central Florida, said in an interview about a study she coauthored in Cancer. “That would suggest that the patient believed he or she wasn’t told by the physician. Yet, what you’re told in a health care encounter with a physician is not always what you hear.

“Typically the oncologist will tell a patient [after they have been diagnosed] what extent of cancer he or she has, what stage and what treatments are recommended,” Burg said. “Side effects may or may not be a part of the conversation. Once you hear the word ‘cancer,’ though, sometimes you don’t hear much else.”

Burg said it would be wrong to indict all physicians for not broaching the subject of sexual dysfunction, because there is a possibility that some information was presented.

“Overall, though, it’s clear that the message is not getting across, so more needs to be done to educate people about these potential sexual dysfunction side effects,” Burg said. “It’s not necessarily enough to say it at the encounter when the patient is being diagnosed. It needs to be discussed at other times so the patient has the opportunity to really hear it.”

The impact of treatment

Oncologists should not avoid asking about sexual health if they feel they cannot adequately address issues raised by their patients, according to Don S. Dizon, MD, clinical co-director of gynecologic oncology and director of the oncology sexual health clinic at Massachusetts General Hospital.

“Those of us who publish in this field try to make the point that you don’t need to have all the answers,” Dizon told HemOnc Today. “You do not need to get all the details about what the issue might be; but, at the very least, our patients want to feel that it’s not taboo. Models do exist, but this can be a handoff situation, just like we do with many other things in medicine.”

Medical oncologists are trained to look for heart failure and, although they may not be the ones managing the heart failure, they can call in a cardiologist, Dizon said.

“We cause neuropathy and can get help for that. We cause pulmonary issues, and we can get help for that. We cause hypertension and, yes, we can get help for that, too,” Dizon said. “Patients deserve to be queried so they can get help for sexual dysfunction, too.”

Dizon co-authored a study — published in 2013 in The Journal of Sexual Medicine — that focused on quality of life for patients with breast cancer. Results indicated quality-of-life measures — including sexual functioning — change considerably during the course of diagnosis, treatment and post-treatment.

Thus, physicians should regularly ask their patients about their sexual function, Dizon said.

“We’re going to recognize the issue more, and patients are going to be empowered to realize that they don’t have to choose between survival and sex,” Dizon said. “I don’t think everyone will require sexual health counselling, because some people will make the determination that surviving cancer was worth not having the ability to have an erection or that surviving cancer means intimacy is more important than sexual function. That’s a judgment that people will make. But, if they’re making the opposite judgment that they are too young to be celibate or they want to have sex without any more pain, they need help.”

Ganz — a researcher and speaker at the forefront of this movement in the U.S. — hopes, one day, the sex talk will become standard for physicians and their patients.

A study she co-authored that was published in Breast Cancer Research and Treatment assessed the efficacy of a 6-week psychoeducational group intervention focused on the sexual well-being of survivors of breast cancer.

Data showed that 4 months post intervention, survivors were more likely to report improvement in their sexual relationships, communication and sexual satisfaction when they received the intervention.

“Now in the U.S. we talk about financial toxicity, which had been a taboo for a long time,” Ganz said. “However, the sexual health well-being toxicity is universal. Think about what we do to people who we give 6 to 9 months of therapy and body-altering surgery. Their energy level declines and they lose all of their body hair. It takes months to recover from that, but we don’t always see what our patients are going through.”

Physicians can help address sexual dysfunction by acknowledging the impact of cancer therapies.

“I learned early on that patients didn’t want to talk to me about side effects of chemotherapy because they thought I’d stop their therapy, so they would talk to a nurse, a social worker or a psychologist,” Ganz said. “It is important to sensitize physicians and nurses to the total experience and have more understanding of the impact of our treatments on patients’ lives.”

Sexual health as a specialty

Incrocci identifies himself as one of a small number of oncologists interested in sexual medicine. Dizon said he can name only three oncologists — himself and Ganz included — doing work in sexual health.

Due to the increasing number of cancer survivors, more specialists who deal with the aftereffects of cancer treatment will be necessary.

“I am one of the few radiation oncologists interested in sexual dysfunction for patients with cancer, but fortunately I’m not the only one,” Incrocci said. “Some younger urologists, gynecologists and medical oncologists are getting more interested. What we are trying to do at symposiums and meetings is to teach the new generation how to talk about sexuality and sexual function in patients with cancer.”

Incrocci said the best thing to do would be to introduce the subject at the college level first, then teach sexual medicine at the specialist level.

“All of the specialists should have some hours of education on sexual medicine,” he said. “The most important thing is to learn about how to talk about sexuality.”

Despite this need, progress has been made in recent years.

“If I look back at when I started in 1995, we have made big improvements, but it took 20 years to get to where we are now,” Incrocci said. “We will need at least another 20 years to get to the level where the new medical specialists focusing on sexual functioning after cancer exist and have more solutions for the problem.”

At some institutions, gynecologists lead sexual health counseling for patients, whereas psychologists and social workers lead programs at other institutions, Dizon said. Yet, none of these experts deal directly with cancer. Consequently, oncologists need to expand their specialty to include sexual dysfunction as something they can handle as well as — if not more easily — than non-cancer specialists.

“The issue regarding wider availability of sexual health counseling comes down to people either not feeling they are trained to do it or not really feeling that they are comfortable hearing the responses,” Dizon said.

Survivorship care plans could be a good first step toward educating patients about sexual dysfunction issues if their implementation is standardized, Burg said.

Further, a simple assessment of problems and concerns at the end of treatment using a patient-symptom checklist often uncovers this problem in a non-judgmental way, and can help initiate the conversation during survivorship care planning, Ganz said.

“The hope is a patient receives some kind of discussion and a physical record about their cancer and the potential side effects of their cancer and treatment so they can have that to reflect back on as they transition to their survivorship phase,” Burg said. “There needs to be a mechanism for that to happen, either through a survivorship care plan or a specific encounter for discussion of side effects that is part of the treatment plan.”

Societies can change society

In 2006, ASCO published a clinical practice guideline on fertility preservation for adults and children with cancer.

Although those guidelines have since been updated, it was the initial push that the oncological community needed to address a serious side effect issue from cancer treatment.

“ASCO did a great thing by putting their stakes in the ground when it came to fertility preservation,” Dizon said. “They convened an expert panel, they came out with consensus guidelines and … they said, ‘This is an important part of life for patients who are living after cancer. We need to make sure that we are able to address these issues even before they receive any therapy for cancer.’”

Dizon hopes sexual health will be addressed in the same manner.

“Only a consensus opinion will change people’s minds about asking about sexual dysfunction,” he said.

The American Society for Radiation Oncology (ASTRO) attempted to broach the topic a few years ago.

“ASTRO organized a roundtable to talk about radiotherapy for prostate and gynecological cancer and its relation to sexual dysfunction,” Incrocci said.

Incrocci was invited to talk about the effect of sildenafil citrate (Viagra, Pfizer) on sexual dysfunction after radiotherapy for prostate cancer. Then, the European Cancer Organization (ECCO) organized a similar symposium for nurses.

Incrocci also will speak about sexual functioning in patients with cancer at the World Conference on Lung Cancer in Denver in September.

“Still, I think the big societies, should do more,” Incrocci said. “They are scared to talk about sexual functioning.”

ASCO organized a symposium on the topic a few years ago, but more structured movements are needed, Incrocci said. He suggested there should be an annual activity such as a session or refresher course, as well as roundtable discussions on sexual dysfunction within different specialties.

“It would be great if a big society like ASCO would come up with a guideline on how to deal with sexual dysfunction in cancer patients, using the level of evidence we have from many studies,” he said. “It would be very helpful because it would make the scientific community more open to talk about the problems.”

ASCO has identified sexual dysfunction as an issue it plans to address at some point, but there are a number of currently competing principles, Dizon said.

In the meantime, physicians should feel comfortable and confident enough to broach the subject with their patients, Porter said.

“This taboo makes it worse for everybody,” Porter said. “Some couples may avoid having a sexual relationship during cancer treatment. That avoidance builds and makes the dysfunction persist. They feel like they can’t talk to the doctor and the doctor feels like they can’t talk to the patient and then nobody is talking to one another. Avoidance makes it even harder and causes feelings of shame and guilt. Having the doctors say, ‘You may also experience these sexual side effects. Please let me know if this is a concern of yours and we’ll talk about it,’ and address this with a patient or couple may be important on the psychological side.”

Experts emphasized clinicians’ willingness to have these conversations coincides with their ultimate goal of helping patients.

“Sexual health is not like Pandora’s box,” Dizon said. “You’re not going to hear sordid stories from your patients. They’re really just looking for guidance.”– by Anthony SanFilippo

References:

Arora NK, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2012.47.6705.

Burg MA, et al. Cancer. 2015;doi:10.1002/cncr.28951.

Desantis CE, et al. Ca Cancer J Clin. 2014;doi:10.3322/caac21235.

Flynn KE, et al. Psycho-oncology. 2012;doi:10.1002/pon.1947.

Flynn KE, et al. Psycho-oncology. 2011;doi:10.1002/pon.1738.

Gao J and Dizon DS. J Sex Med. 2013;doi:10.1111/jsm.12029.

Lee SJ, et al. J Clin Oncol. 2006;doi:10.1200/JCO.2006.06.5888.

NCI. Sexuality and reproductive issues–for health professionals (Physician data query). Available at: www.cancer.gov/about-cancer/treatment/side-effects/sexuality-fertility-women/sexuality-hp-pdq#cit/section_1.3. Accessed on June 25, 2015.

Rowland JH, et al. Breast Cancer Res Treat. 2009;doi:10.1007/s10549-009-0398-x.

Stead ML, et al. Br J Cancer. 2003 Mar 10;88(5):666-71.

For more information:

Mary Ann Burg, PhD, LCSW, can be reached at University of Central Florida College of Health and Public Affairs, 4000 Central Florida Blvd., Orlando, FL 32816; email: m.burg@ucf.edu.

Don S. Dizon, MD, can be reached at Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114; email: donstevendizon@me.com.

Patricia Ganz, MD, can be reached at UCLA Jonsson Comprehensive Cancer Center, 650 Charles Young Drive South, Room A2-125 CHS, Los Angeles, CA 90095-6900; email: pganz@mednet.ucla.edu.

Luca Incrocci, MD, PhD, can be reached at Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email: l.incrocci@erasmusmc.nl.

Laura S. Porter, PhD, can be reached at Duke University School of Medicine, DUMC 3159, Durham NC, 27710; email: laura.porter@duke.edu.

Disclosure: Burg, Dizon, Ganz, Incrocci and Porter report no relevant financial disclosures.

 

Is estrogen therapy safe for the management of sexual dysfunction in female cancer survivors of a hormone-responsive cancer?

We consider vaginal estrogen to be a generally safe and effective treatment for dyspareunia in women with a history of hormone-sensitive cancer, although this is a highly individualized decision and confirmatory randomized studies are needed.

The majority of sexually active women who are diagnosed with breast or gynecologic cancers experience short- or long-term decrements in sexual function, often resulting in considerable distress. Although new agents for women’s sexual dysfunctions are in the pipeline, current therapies available in the U.S. include systemic and topical hormone replacement and a new selective ER modulator (ospemifene [Osphena, Shionogi]).

Does systemic estrogen replacement therapy (ERT) increase the risk for recurrence in women who have had estrogen-sensitive disease? The Swedish HABITS and Stockholm trials provide the best evidence to date in breast cancer survivors, but with markedly different results. The HABITS trial — terminated after a median follow-up of 2.1 years — found a more than threefold increased risk for breast cancer events in women using ERT. In contrast, the Stockholm trial — which also closed early due to the HABITS trial — found no increased risk at a median follow-up of 4.1 years. The reasons for this discrepancy between studies remain unknown, although lower overall progestin exposures in the Stockholm trial have been hypothesized as one possible explanation.

Concerns about the safety of ERT come as a disappointment to many of our patients who are eager for relief of their sexual difficulties. On the other hand, while systemic ERT certainly relieves vasomotor symptoms, its effects on sexual function per se are surprisingly modest. Large population-based studies of postmenopausal women indicate use of ERT does not lower the risk for sexual dysfunction. Similar findings have been reported in samples of high-risk women who undergo bilateral salpingo-oophorectomy.

The clearest indication for estrogen therapy is dyspareunia, which is common in survivors who have lost ovarian function due to treatment and is made worse by use of aromatase inhibitors (AIs). Local estrogen therapy in the form of vaginal tablets, rings or creams is more effective than systemic therapy for management of dyspareunia and entails far less exposure to estrogen. Nevertheless, there is no clearly established “safe” level of estrogen exposure in women with hormone-sensitive cancers.

There are no longitudinal randomized trials demonstrating the safety of vaginal estrogen in women with hormone-sensitive cancers. The largest retrospective study to date is a nested case-control study including over 13,000 survivors of breast cancer, of whom 271 used vaginal estrogen with no evidence of increased risk.

Despite these reassuring findings, questions remain about the long-term safety of vaginal estrogen, particularly in women using AIs and with estrogen-sensitive gynecologic cancers. Although a handful of breast cancer survivors participated in phase 3 trials for ospemifene, the risks and benefits of this option relative to vaginal estrogen remain to be understood.

In our institution’s multidisciplinary sexual health program, we take a stepped approach to treating dyspareunia in cancer survivors. Many women benefit from nonhormonal management using a vaginal moisturizer and an appropriate lubricant. We introduce vaginal dilators in graduated sizes for women who are avoidant of sex, who describe or show signs of pelvic floor tension, or who have been sexually inactive for a long time. Counseling the woman and her partner to respond adaptively to discomfort and to approach intimacy more flexibly is essential.

Women who continue to experience pain despite these conservative measures may be candidates for local estrogen therapy if there are no other medical contraindications. Decisions about estrogen therapy are made in collaboration with the oncologist and are preceded by a thorough discussion of known and unknown risks and treatment alternatives.

 

References:

Carter J, et al. J Sex Med. 2011;doi:10.1111/j.1743-6109.2010.01988.x.

Dennerstein L and Lehert P. Menopause. 2004;11:778-785.

Dew JE, et al. Climacteric. 2003;6:45-52.

Fahlen M, et al. Eur J Cancer. 2013;doi:10.1016/j.ejca.2012.07.003.

Holmberg L, et al. Lancet. 2004;363:453-455.

Le Ray I, et al. Breast Cancer Res Treat. 2012;doi:10.1007/s10549-012-2198-y.

Leiblum SR, et al. Menopause. 2006;13:46-56.

Madalinska JB, et al. J Clin Oncol. 2006;24:3576-3582.

von Schoultz E, et al. J Natl Cancer Inst. 2005;97:533-535.

Andrea Bradford, PhD, is assistant professor in the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center. She can be reached at abradford@mdanderson.org. Disclosure: Bradford reports no relevant financial disclosures.

Denise Nebgen, MD, PhD, is associate professor in the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center. She can be reached at dnebgen@mdanderson.org. Disclosure: Nebgen reports no relevant financial disclosures.

If a patient is taking an aromatase inhibitor, I counsel against using this strategy.

Endocrine therapy (ET) — a major cornerstone of treatment of patients with ER-positive breast cancer — has enormous positive effect in the metastatic, adjuvant and even preventive settings. Although not as toxic as chemotherapy, ET is not without side effects, principally related to ER antagonism (by the selective estrogen receptor modulators [SERMs] and down regulators [SERDs]) or reduction in circulating estrogen levels. Atrophic vaginitis with associated sexual dysfunction is one of the most common, problematic complaints of women on ET. Although low libido is multi-factorial, and even in women without breast cancer is often not improved by estrogen replacement therapy (ERT), dyspareunia is almost universally resolved with the latter. In other words, the best treatment for lack of estrogen is, indeed, estrogen therapy.

Is estrogen therapy safe in women with prior history of breast cancer, especially if it was ER positive? This issue is enormously complicated, with no single answer for all patients. However, a series of indirect and direct clinical observations is informative. First, reduction in estrogen levels is clearly effective in treating the cancer. In the late 1890s, Beatson first described a response in two of three premenopausal women with locally advanced breast cancer. We now understand that oophorectomy, or more recently chemical ovarian suppression, substantially reduces estrogen levels. Over the ensuing century, progestational agents (megestrol acetate, medroxyprogesterone), SERMs (tamoxifen, raloxifene), and a SERD (fulvestrant [Faslodex, AstraZeneca]) have all been found to be active against ER-positive breast cancer. However, when compared, the most effective treatment for ER-positive breast cancer is estrogen reduction with selective selective aromatase inhibitors (AIs), alone in postmenopausal women or in conjunction with ovarian suppression in women who continue to have ovarian function.

Nonetheless, there are several arguments for ERT for women with dyspareunia due to ET. Previously, the treatment of choice for women with metastatic breast cancer was pharmacologic doses of estrogen or estrogenic compounds, a strategy that has been reproduced in the modern era. Indeed, in a direct comparison, tamoxifen was not found to be any more effective than high-dose estrogen, albeit it was less toxic. However, the levels of estrogen achieved with this strategy are far greater than physiologic levels. More germane, preclinical studies by Lippman and colleagues demonstrated that the growth response to estradiol concentrations of cultured ER-positive human breast cancer cell lines was biphasic, with no growth in media stripped of estrogen, robust growth at relatively low levels, but suppression of growth at higher concentrations.

It has also been argued that intravaginal estrogen preparations produce only very low levels of systemic estrogen, and perhaps due to cornification of re-invigorated vaginal epithelium, none at all. First, the preclinical data cited above suggest that low circulating levels may be most dangerous. Second, even with longstanding use and cornification, when measured carefully using high-resolution assays, circulating levels of estrogen become elevated in women using intravaginal estrogen, especially when taking AIs. In unaffected women with normal postmenopausal estrogen levels, it has been reported that intravaginal estrogen application does not elevate circulating levels, but has indirect estrogenic effects, such as lowered serum lipid concentrations even without a detectable elevation in estrogen levels.

There are at least two clinical studies that suggest that estrogenic agonism may not be safe. In the HABITS trial, women taking tamoxifen were randomly assigned ERT (systemic) vs. not. This trial was closed early due to a statistically significant higher rate of recurrence in the ERT arm. The ATAC trial demonstrated that although single-agent anastrozole was more effective than tamoxifen, combining the two was equivalent to the latter alone and inferior to AI therapy alone. Although there are other explanations for this outcome, one of the most plausible is that the estrogenic agonism of tamoxifen becomes detrimental in the setting of AI-induced, very low estrogen levels.

Taken together, these data suggest that, especially in women on an AI, estrogen agonism, particularly at low dose, may be detrimental with regard to cancer recurrence and that exogenous estrogen replacement — albeit at higher doses — for any woman on ET is not safe. If the objective of adjuvant ET is prevention of ER-positive breast cancer recurrence, then one must be cautious about the use of any hormonal use, intravaginal or otherwise. Women on ET should be counseled to try non-hormonal vaginal lubricants and consider formal sexual therapy consultation. However, these may be only modestly effective, and many women and their partners will remain anguished over the loss of physical intimacy. In this case, a careful and balanced discussion regarding the quality-of-life benefits and potential risks of exogenous estrogen therapy is warranted.

 

References:

Baum M, et al. Lancet. 2002;359:2131-2139.

Beatson GW. Lancet. 1896;148:104-107.

Dowsett M, et al. J Clin Oncol. 2010; doi:10.1200/JCO.2009.23.1274.

Ellis MJ, et al. JAMA. 2009; doi:10.1001/jama.2009.1204.

Holmberg L, et al. Lancet. 2004;363:453-455.

Ingle JN, et al. N Engl J Med. 1981;304:16-21.

Lippman M, et al. Cancer Res. 1976;36:4595-4601.

Lippman M, et al. Cancer Res. 1977;37:1901-1907.

Lippman ME and Bolan G. Nature. 1975;256:592-593.

MacLennan A, et al. Cochrane Database Syst Rev. 2001;(1):CD002978.

Pagani O, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1404037.

Powles TJ, et al. Lancet. 1993;342:60-61.

Sarkar NN. Eur J Contracept Reprod Health Care. 2003;8:217-224.

Stoll BA. Eur J Cancer Clin Oncol. 1989;25:1909-1913.

Wills S, et al. J Oncol Pract. 2012;doi:10.1200/JOP.2011.000352.

Daniel F. Hayes, MD, is clinical director of the Breast Oncology Program at University of Michigan Comprehensive Cancer Center. He can be reached at hayesdf@umich.edu. Disclosure: Hayes reports research funding from AstraZeneca, Janssen, Pfizer and PUMA and honoraria from Eli Lilly.