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The Survivorship Care Gap: Addressing Breast Cancer's Late Effects

DiGiulio, Sarah

doi: 10.1097/01.COT.0000429341.69753.38
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Continuing our series on the shortfalls of cancer survivorship care, this article covers why experts say persisting late side effects from breast cancer and its treatment—changes in sexuality, fertility, and cognitive functioning—need more attention. For care to improve, these topics need more discussion by everyone involved.

“Many women post-breast cancer go on to live long and healthy lives—and that means that a range of other medical problems, that perhaps are related to treatment, may surface,” said Hester Hill Schnipper, LICSW, BCD, OSW-C, Program Manager for Oncology Social Work at Beth Israel Deaconess Medical Center in Boston. The treatments can throw women into early menopause, complicating sexual health and fertility, and there are body image issues—for example, patients' breasts may look different or be absent, she said. “Lots of women are distressed or depressed for a long time about how they look or feel. And, it's real—they do look different.”

A survivor herself of two separate breast cancers (first in 1993 and then again in 2005), Schnipper has counseled breast cancer patients at Beth Israel for more than 30 years and is the author of After Breast Cancer: A Common Sense Guide to Life After Breast Cancer (OT, 9/25/03).

Support groups like the ones Schnipper runs benefit survivors by creating a space to talk about their post-treatment needs, but physicians also need to be informed about those issues. “The doctors who are going to be following the women post-treatment need to be comfortable talking to and asking women about their needs. They need to be educated about what issues survivors face and informed about the resources in their community that they can refer women to.”

The reality is that many women avoid talking with their physicians about their post-treatment needs regarding sexual health, body image issues, and cognitive problems, Schnipper continued. “And, there are also plenty of oncologists who don't feel comfortable talking with their patients about it—it goes both ways.”

HESTER HILL SCHNIPPER, LICSW, BCD, OSW-C: “Many women post-breast cancer go on to live long and healthy lives—and that means that a range of other medical problems may surface.”

‘Breaking the Silence’ on Sexual Health

Some 50 to 90 percent of breast cancer survivors have either immediate or long-lasting sexual complaints after treatment, noted Michael Krychman, MD, Executive Director of the Southern California Center for Sexual Health and Survivorship and Associate Clinical Professor and Director of Anne's Clinic at the University of California, Irvine.

As he noted at an Educational Session (“Navigating the Obstacles and Risks of Survivorship”) at the most recent CTRC-AACR San Antonio Breast Cancer Symposium, aromatase inhibitors and chemotherapy lower estrogen stores, can decrease elasticity and pliability of the vagina, can cause vaginal dryness, and can lower libido—slowing down sexual response overall. “So, if you do not see sexual health issues in your clinical practice, you're certainly not asking the right questions,” he said. “The first and foremost issue is breaking the silence.”

Over-the-counter moisturizers and lubricants without additives can be very effective in addressing many such sexual complaints, Krychman said. Emerging data suggest that such OTC products can be as effective as local estrogen in treating vulvar and vaginal atrophy (VVA)—by increasing elasticity and pliability—if used on a regular, consistent basis—“But many patients do not even use them.”

MICHAEL KRYCHMAN, MD: “Barriers to treatment exist on both the patient and health care provider sides—patients can be hesitant to talk, but providers often do not address the issues.”

The message to patients is not consistent, Krychman continued. “If you ask a medical or surgical oncologist, a patient, a gynecologist, or even a sexual medicine specialist what the exact paradigm should be for management of a sexual complaint in a breast cancer survivor, there will likely be a variety of answers.”

Krychman noted that in addition to OTC products, there are promising new non-hormonal therapies currently in clinical trials:

  • Intravaginal dehydroepiandrosterone (DHEA): Stage III clinical trials have shown that daily doses improve dryness and can minimally increase libido. The product is currently being reviewed by the FDA, but has not been studied specifically in the breast cancer population. Preliminary data also show it can reverse the effects of VVA without an increase in systemic estradiol levels, although the precise mechanism is not yet known, Krychman noted.
  • Ospemifene: The oral medication targets the vaginal epithelium to reduce dryness and pain—and was found to be neutral to the breasts. Stage III clinical trials have been completed, and the product is now under FDA review. “This is exciting, because oncology care professionals are probably more comfortable using selective estrogen receptor modulator-like medications rather than minimally absorbed local estrogens.”

Culture Change for Fertility

Research has shown that fewer than half of all U.S. physicians follow the American Society of Clinical Oncology's guidelines, released in 2006, that recommend that all cancer patients of childbearing age be informed about fertility preservation (JCO 2009;27:5952–5957; OT, 9/25/09).

Still, as Marla L. Clayman, PhD, MPH, Assistant Professor in the Division of General Internal Medicine and a member of the Robert H. Lurie Comprehensive Cancer Center, pointed out, oncologists themselves are not necessarily in the best position to know the state of science on oncofertility because they may not have had specific training in the area and the field is changing so rapidly.

Studies have shown that providers are less likely to discuss fertility preservation with their patients if: the patient's prognosis is poor, the patient already has children, or there is a suspicion that the patient may not be able to afford fertility preservation,” she said. “We have to create a culture change if providers are to communicate that information as consistently and as early as they should.”

Clayman coauthored the recently published report of the Oncofertility Consortium, a group led by Northwestern University researchers to study the biological, psychological, legal, social, and ethical issues related to oncofertility to improve its role in cancer care (Rodriguez et al:Journal of Cancer Survivorship 2013;7:140–145).

The report, funded by a five-year grant from the National Institutes of Health, recommends the creation of a body with representation and support from professional societies (including the American Academy of Pediatrics, the American Society of Clinical Oncology, and the American Society for Reproductive Medicine) as well as a governmental agency, the public, clinicians, and legal, psychological, social, ethical, and theological scholars to be one authoritative voice to evaluate new research and technology to integrate it into current care models (see box).

As Clayman reported at the 2011 ASCO Annual Meeting (Abstract 9123), even in NCI-designated Comprehensive Centers most of those did not have policies and procedures for fertility preservation—of the 30 centers studied, 67 percent reported having education material available to hand out, but there was variability in who received those resources and providers reported not knowing whom should receive the materials. Eight sites (27%) reported having at least one clinical staff member whose job had protected time for fertility preservation; and sites that reported good coordination among the care subspecialties used patient navigators, fertility hotlines, or other such means to ensure timely access to referral.

The sites in Clayman's study that seemed to be most apt to provide fertility preservation care had a mid-level provider or person-to-person model. “It's much easier for patients to have that introductory I-just-want-to-find-out-about-this conversation with somebody who's in the oncology office than to have to schedule a consult with the reproductive endocrinologist just to find out what their options are,” Clayman said.

MARLA L. CLAYMAN, PHD, MPH: “We have to create a culture change if providers are to communicate information about fertility preservation as consistently and as early as they should.”

Her current work, an R25 educational research grant project with principal investigators at Moffitt Cancer Center, is developing a method to train mid-level practitioners who work in the oncology office to be a point-person for fertility preservation.

Cognitive Concerns

As Tim Ahles, PhD, a behavioral psychologist who founded and currently leads Memorial Sloan-Kettering Cancer Center's Neurocognitive Research Laboratory, explained, substantial studies on cancer-related cognitive problems didn't start until the mid-1990s, and the mechanisms at play are still being investigated.

“We know it's likely that chemotherapy is a very important player, but other cancer treatments and factors also impact cognitive functioning,” he said. His review of several longitudinal studies showed consistently that 20 to 25 percent of women had lower-than-expected cognitive functioning, but the characteristics that set that group apart were not apparent (Psycho-Oncology 2012;21:1141–1148).

TIM AHLES, PHD: “We know it's likely that chemotherapy is a very important player, but other cancer treatments and factors also impact cognitive functioning.”

Pre-existing genetic factors, changes in hormonal levels, and inflammation, are likely all involved, said Patricia Ganz, MD, Professor of Health Policy and Management at the Fielding School of Public Health and Professor of Medicine at the David Geffen School of Medicine, both at UCLA, and Director of the Division of Cancer Control Research at the Jonsson Comprehensive Cancer Center.

As she noted at the same SABCS Survivorship Educational Session, her recent research used PET scans to look at how chemotherapy and radiation affect brain metabolism identified an association between pro-inflammatory cytokine levels in the blood and brain metabolism—suggesting that inflammation contributes to cognitive problems (see box) (Brain, Behavior, and Immunity doi:10.1016/j.bbi.2012.07.015).

Another study of hers, currently in press in the Journal of Clinical Oncology, showed that patients at greatest risk for cognitive complaints also had the TNF alpha 308 SNP marker. “We suspect that this SNP may make them more vulnerable to the increased cytokine levels, increased fatigue, and increased cognitive complaints,” Ganz said. “This research gives us a biologically plausible reason why some individuals may have more persistent complaints.”

And, another recent study suggests that the mental demand and stress of a breast cancer diagnosis could themselves play a role in early cognitive problems. That research used functional magnetic resonance imaging (fMRI) to test brain function in women before and after chemotherapy and radiotherapy, while also recording fatigue levels and cognitive functioning scores (OT, 2/10/13 issue).

“Understanding possible sources of cognitive problems over the cancer treatment trajectory is essential if we are to find better ways to help survivors manage any decline in cognitive function over the course of treatment and beyond,” the author, Bernadine Cimprich, PhD, RN, Associate Professor Emerita at the University of Michigan School of Nursing, noted via email in an interview for this article.

PATRICIA GANZ, MD: “Some patients are more vulnerable to long-lasting side effects than others, and we cannot just let them suffer. We can't ignore them.”

The findings show that cognitive problems can begin before any adjuvant treatment and that women awaiting chemotherapy are more vulnerable to cognitive problems related to worry and fatigue, she said. Compounded with any neurotoxic effects of chemotherapy, early cognitive problems and fatigue became worse over time in those patients—“So, it makes sense to initiate early assessment and interventions to help maintain the patients' cognitive capacity as much as possible over the course of treatment.”

SUSAN RAFTE: “To have validation through research that these are real issues—that helps survivors.”

Regardless of the factors behind the complaints, they should not go untreated, Ganz said. “The first step is to treat the pain, anxiety, and fatigue—and get them under control—before assuming the patient has ‘chemobrain.’” And, if patients do not improve, they may need to be referred to a neuropsychologist for further interventions.

Observational studies are ongoing to test whether modafinil, currently prescribed to prevent sleep disturbances for individuals with narcolepsy, may help improve cognitive complaints in breast cancer patients, Ganz said. And, among other individualized cognitive training and rehabilitation methods being tested, a group of Memorial Sloan-Kettering researchers are studying computer-based interventions, which could potentially make treatment available anywhere in the country via the Internet, Ahles noted.

Existing nonpharmacologic interventions such as cognitive behavioral therapy, physical activity and exercise programs, and nature-based methods have shown some effectiveness in reducing fatigue and improving cognitive functioning in some populations—including for breast cancer patients—but can be difficult to administer in some conventional clinical settings, Cimprich said.

“Successful implementation requires patient engagement with the right members of the multidisciplinary care team, and may require coordinated efforts of nurses, social workers, physical therapists, and psychologists.”

How Validation Helps

Breast cancer advocate Susan Rafte, Survivor Founder of the Pink Ribbons Project, said that 17 years ago when she was first diagnosed with breast cancer, none of her doctors explained that there could be biological reasons for feeling forgetful and confused during or after breast cancer treatment. Everybody said, ‘there's no such thing,’ she said in a phone interview. “So to have validation through research that these are real issues—that helps survivors.”

Talking about these too-often ignored issues was the focus of the SABCS Survivorship session, which Rafte moderated and helped plan (OT, 2/10/13 Meeting Reporter suppl). “Physicians need to understand what the needs are for survivors, they need to have the knowledge and the tools to share with patients, and they need to be comfortable communicating that information well.”

Continuing Series

Earlier articles covered other key discussions on survivorship care: delivery models and care plans (9/10/12 issue), the nurse's role on the care team (10/10/12 Nursing Hem/Onc Spotlight), and the persistent psychological effects survivors face (11/10/12 issue).

New NCCN Survivorship Guidelines

The National Comprehensive Cancer Network last month issued its first Clinical Practice Guidelines in Oncology for Survivorship. The guidelines, released at the organization's Annual Conference, cover eight areas: anxiety and depression, cognitive function, exercise, fatigue, immunizations and infections, pain, sexual function, and sleep disorders.

The Oncofertility Consortium

Experts in law, bioethics, and economics from Northwestern University, as well as the University of California-San Diego, the University of Pennsylvania, the University of Missouri-Columbia, and Oregon Health and Sciences University, worked together, funded by a five-year, NIH grant, and recently published guidelines for the clinical practice of oncofertility, and oversight of the emerging technology (Journal of Cancer Survivorship 2013;7:140–145). They called for the creation of one authoritative body that would:

  • Consider measures to protect patients' privacy and confidentiality;
  • Ensure appropriate measures are taken to obtain consent of patients, especially minors;
  • Consider how to address the experimental status of fertility preservation technologies with unknown efficacy, low viability, and safety risks;
  • Maintain a centralized registry of those who preserve tissue, gametes, or embryos, before or during therapy;
  • Be aware of possible conflicts of interests between patients and researchers (in terms of finances and incentives);
  • Consider minimum and maximum ages at which patients may be allowed to preserve fertility;
  • Address limiting the number of children who maybe conceived using frozen tissues, gametes, or embryos; and
  • Provide thoughtful recommendations and oversight for any emerging controversies that arise.

Breast Cancer Treatment and the Brain

These two recent studies help explain how two factors—inflammation and fatigue—play roles in the cognitive problems breast cancer patients may face before, during, and following treatment.

  • Tumor Necrosis Factor-alpha: Patricia Ganz, MD, was the lead author on a study that assessed cognitive complaints, neuropsychological test performance, markers of inflammation, and brain imaging in 93 early-stage breast cancer patients at baseline (after initial treatment of surgery, radiation and/or chemotherapy, but before initiation of any adjuvant endocrine therapy), and at both six and 12 months after enrollment. Use of chemotherapy was associated with increased levels of soluble tumor necrosis factor (TNF) receptor—an inflammatory marker that has been associated with cancer-related fatigue in previous studies—but that those increased TNF receptor levels decline the year after treatment.

The data also showed significant correlations between self-reported cognitive complaints and greater levels of fatigue and depression among the women in the study. The increased cytokine levels traverse through the blood-brain barrier and likely cause local inflammation, which increases the levels of serotonin and dopamine in the brain that can cause depression, fatigue, and social withdrawal, Ganz explained.

  • Fatigue: Bernadine Cimprich, PhD, RN, presented a study at the 2012 San Antonio Breast Cancer Symposium that used fMRI to test brain function in three groups of women—28 who received adjuvant chemotherapy for breast cancer treatment, 37 who received radiotherapy for breast cancer treatment, and 32 healthy controls—as they performed a working memory test before treatment and one month after. The participants also reported their level of fatigue during the test (Abstract S6–3).

The imaging tests showed greater compromise of brain function in the regions needed to perform the memory test in both patient groups awaiting treatment compared with healthy controls, but, the groups did not differ in brain activity levels in these regions at one month post-therapy, she reported. “And, across all groups, greater fatigue was associated with poorer test performance and more reported cognitive problems over time.”

Women who had chemotherapy reported significantly more fatigue before and after treatment, and both patient groups performed less accurately on the cognitive tests before treatment compared with the healthy women. Test scores among those in the chemotherapy group continued to decline, compared with the radiotherapy group and the controls, one month post-treatment.

New ASCO Survivorship Recommendations

In January, the American Society of Clinical Oncology released its first statement establishing an agenda to help improve the quality of care for the 13 million-plus U.S. cancer survivors (JCO 2013;31:631–640).

“We can't let these patients, who are living examples of the progress we have achieved in cancer, fall through the cracks, said ASCO President Sandra Swain, MD. This agenda aims to: provide guidance and education for clinicians overseeing the care of survivors, identify research priorities that address knowledge deficits in late health outcomes and survivorship care, and promote legislation to assure survivor access to care and physician compensation for quality care.

Discussing the guidelines in a telephone interview, corresponding author Melissa M. Hudson, MD, Director of the Cancer Survivorship Division at St. Jude Children's Research Hospital, explained, “We're defining what the next steps are—the action plans to move each of these areas forward. We want to assure that clinicians overseeing the care of survivors have the knowledge and resources to implement quality survivorship care and are fairly compensated for these efforts.”

ASCO established its first Cancer Survivorship Task Force in 2004, but efforts to create comprehensive recommendations for survivorship care stalled because of the lack of high-quality outcomes evidence, she noted. Then, as more time passed and with increasing awareness of survivorship needs, there was another groundswell for this effort—“There was a feeling for many within the organization that we really need to move this beyond a task force and devote the resources of ASCO to back this effort.”

In 2011, ASCO established the Cancer Survivorship Committee to provide long-term leadership and oversight of the organizations survivorship initiatives—and for the following year, that committee worked to develop these recommendations. The new guidelines for clinicians who are managing survivors identify the gaps in knowledge to prioritize the research agenda, Hudson explained. “There's still a lot we can do in symptom control, interventions, and anticipating late health risks that can make a difference in how well as how long cancer patients live.”

The key recommendations are to:

  • Promote patient-centered coordinated care through the use of shared-care models, which allow for collaboration among practitioners of different disciplines or with different skills and knowledge;
  • Increase adoption of quality-improvement programs, such as ASCO's QOPI, which help physicians monitor and improve care for all survivors;
  • Expand research on long-term and late effects to expand the evidence base required to define optimal survivor care;
  • Strengthen the education of health care providers on survivorship care to keep pace with growing evidence on the long-term follow-up care needs for different types of cancers; and
  • Educate and empower cancer survivors and their families to advocate for their unique needs and to ensure optimal long-term health.
© 2013 Lippincott Williams & Wilkins, Inc.
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