Advances in the care of breast cancer survivors
BMJ 2023; 382 doi: https://doi.org/10.1136/bmj-2022-071565 (Published 18 September 2023) Cite this as: BMJ 2023;382:e071565Linked editorial
Understanding inequalities in breast cancer screening uptake
Linked research
Effect of invitation letter in language of origin on screening attendance
- Elizabeth J Cathcart-Rake, medical oncologist,
- Amye J Tevaarwerk, medical oncologist,
- Tufia C Haddad, medical oncologist,
- Stacy D D’Andre, medical oncologist,
- Kathryn J Ruddy, medical oncologist
- Correspondence to: E J Cathcart-Rake Cathcart-rake.elizabeth{at}mayo.edu
Abstract
Breast cancer survivors may experience significant after effects from diagnoses of breast cancer and cancer directed therapies. This review synthesizes the evidence about optimal management of the sequelae of a diagnosis of breast cancer. It describes the side effects of chemotherapy and endocrine therapy and evidence based strategies for management of such effects, with particular attention to effects of therapies with curative intent. It includes strategies to promote health and wellness among breast cancer survivors, along with data to support the use of integrative oncology strategies. In addition, this review examines models of survivorship care and ways in which digital tools may facilitate communication between clinicians and patients. The strategies outlined in this review are paramount to supporting breast cancer survivors’ quality of life.
Introduction
Breast cancer is the most common cancer in the world, with 2.26 million diagnoses in 2020.1 People with breast cancer are living longer as a result of improvements in screening and treatment, such that in the US alone the number of survivors of breast cancer is expected to grow by more than 2 million in the next decade.23 Unfortunately, survivors may experience significant after effects from breast cancer diagnoses and cancer directed therapies. Symptoms related to surgery, radiation, and systemic therapies may persist lifelong and limit quality of life.
This review synthesizes the evidence base on optimal management of treatment sequelae in survivors of breast cancer. We describe the side effects of chemotherapy and endocrine therapy and evidence based strategies for management of such effects, with particular attention to effects of therapies with curative intent. We include strategies to promote health and wellness among breast cancer survivors, along with data to support the use of integrative oncology strategies. In addition, we examine models of survivorship care and ways in which digital tools may facilitate communication between clinicians and patients.
Sources and selection criteria
We searched PubMed for the term “breast cancer survivorship” (without restricting the date range) on 17 August 2022 and limited our search to papers designated as randomized controlled trials (RCTs) or meta-analyses. This identified 245 peer reviewed publications, some of which we excluded because they were focused more on disease outcomes than on management of toxicity and models of survivorship care. We supplemented this search strategy by a hand search of the references of key articles. We achieved inclusion of identified articles by assessing a study’s impact and its methods, with preference given to RCTs. When RCT evidence was not available for certain topics, we included other study types, focusing on the highest level of evidence available and excluding lower level evidence. To ensure that we covered all critical data relevant to management of endocrine therapy toxicity, management of long term effects of chemotherapy, new models of care and digital tools to facilitate communication and symptom management, integrative oncology for breast cancer survivors, general health maintenance (including screening for second cancers), genetic testing, and surveillance for recurrence, we also added select additional studies for inclusion on the basis of consensus among our author group (medical oncologists with specific expertise in symptom control (ECR, KR), survivorship (KR, AT), integrative medicine (SD), and digital oncologic tools (TH, AT)).
Epidemiology
Breast cancer is the most commonly diagnosed cancer, accounting for nearly a quarter of all cancer cases globally.4 More than 2.3 million people worldwide are given a diagnosis of breast cancer annually, and more than 7.8 million women are breast cancer survivors with diagnoses over the past five years, according to 2020 statistics.4 Although the incidence of and mortality from breast cancer vary from region to region, these numbers are steadily growing, such that more than 3 million new cases of breast cancer are projected to be diagnosed by 2040.4
Burden and management of long term effects of systemic therapies
Despite recent advances that help us to tailor and de-escalate treatment on the basis of estimates of clinical benefit to limit toxicity,56 many curatively treated breast cancer patients still receive chemotherapy. This is particularly true among patients with triple negative breast cancer, who may receive up to four chemotherapies (anthracycline, cyclophosphamide, taxane, platinum) and an immunotherapy (pembrolizumab) (known as the KEYNOTE-522 regimen), with a fifth chemotherapy agent added if residual disease is present at the time of surgery.7 The persistent (chronic) and future (late) side effects of these systemic therapies are mediated by a variety of host factors, including age, menopausal status, and existing comorbidities such as diabetes and hypertension.8910111213 Moreover, some toxicities, such as cancer related cognitive impairment (also known as “chemo brain”), are broadly linked to the use of cancer therapy but not tied to a particular agent.14 The robustness of evidence based screening and prevention strategies varies between different treatment sequelae.15
“Traditional” chemotherapeutic agents
Three chemotherapeutic classes (that is, anthracyclines, alkylating agents, and taxanes) have relatively well understood toxicity profiles in the curative setting based on decades of use in breast cancer (table 1). For instance, anthracyclines increase the risk of cardiovascular events in the short term (for example, arrhythmias) and can cause long term irreversible left ventricular dysfunction.2324 Anthracyclines and cyclophosphamide carry a risk of secondary leukemia, although this may be less true for cyclophosphamide at the doses used in breast cancer.252627 Likewise, anthracyclines and cyclophosphamide are gonadotoxic,2829 affecting reproduction, menopausal symptom burden, and potentially bone and cardiac health. Taxanes contribute to chemotherapy induced peripheral neuropathy (CIPN), a primarily sensory peripheral neuropathy involving the feet and hands in a sock and glove-like distribution, which may persist lifelong in a small subset of patients. Although duloxetine can assuage CIPN related burning pain, more information is needed to inform strategies used to prevent CIPN and methods to treat numbness/tingling.1330
Chronic and late effects after treatment with common chemotherapeutics, immunotherapeutics, and associated targeted therapeutics used in (neo)adjuvant breast cancer setting
Capecitabine and platinums—Despite longer track records in other disease settings, capecitabine and platinums (namely, carboplatin) are relatively new additions to the adjuvant breast cancer armamentarium. The persistent and future toxicity profiles, particularly when used in younger patients, are less well characterized. For instance, platinums can cause gonadal failure,31 although the effect on ovarian function is poorly studied for carboplatin in the breast cancer setting.16323334 This is despite routine use of carboplatin in combination with docetaxel and trastuzumab (with or witout pertuzumab) in the TCH(+/−P) regimens for human epidermal growth factor receptor 2 (HER2) positive disease for more than a decade.35 The effect of platinum dosing (for example, weekly versus every three weeks) on ovarian reserve remains unassessed.27 Platinums have been shown to increase the risk of secondary leukemia in ovarian cancer33; the additive risk when used with anthracyclines and cyclophosphamide as in the Keynote-522 regimen remains understudied.33
Targeted therapy and immunotherapy agents
HER2 targeted agents—Trastuzumab has been joined by pertuzumab, ado-trastuzumab emtansine, and neratinib in the adjuvant setting. Studies of these newer agents report lower incidences of cardiotoxicity compared with trastuzumab, but ado-trastuzumab emtansine is more hepatotoxic and carries a risk of persistent neuropathy.2236 The degree to which the cardiac effects of HER2 targeted agents are confined to the treatment period is not well studied for the newer agents but is presumably similar to that for trastuzumab.3738 Patients who do experience cardiotoxicity during HER2 directed therapy do not seem to develop this later, in the absence of other risk factors such as receipt of anthracycline.
Immunotherapy, PARP inhibitors, and abemaciclib—Routine use of pembrolizumab in higher risk triple negative breast cancer has followed the Keynote-522 results. Most of the available data on chronic and late toxicity profiles come from other disease settings, in which long term immune related side effects occurred in 43.2% of patients and ranged from mild disease, such as hypothyroidism (14.0%), to severely debilitating diagnoses, such as hypophysitis (2.1%), which may necessitate lifelong hydrocortisone treatment.39 Similarly, the poly ADP ribose polymerase (PARP) inhibitor olaparib has recently emerged as a tool for BRCA carriers with high risk disease or residual disease after neoadjuvant chemotherapy.40 Most of what is known about the chronic and late toxicity profile comes from patients with ovarian cancer and short term follow-up.41 Finally, abemaciclib is a recent adjuvant therapy for estrogen sensitive breast cancers with a high risk of recurrence; knowledge of toxicities is largely based on that seen in patients with metastatic breast cancer.
Although many targeted agents have fewer listed side effects than do traditional chemotherapeutic agents, their acute toxicities become subacute and longer lasting problems owing to a longer duration of therapy (for example, two years for abemaciclib in the adjuvant setting).4042 Certain toxicities, such as interstitial lung disease from abemaciclib, may even be fatal (albeit rarely).43 Furthermore, owing to short term follow-up of studies with relatively small numbers supporting the efficacy of these agents, long term toxicities in the adjuvant setting have not yet been fully described.
Endocrine therapy
Endocrine therapies improve survival for people with hormone receptor positive breast cancer.444546 Endocrine therapy encompasses a range of therapeutics, including oral drugs, such as tamoxifen and the aromatase inhibitors (letrozole, anastrozole, and exemestane), as well as gonadotropin releasing hormone (GNRH) agonists, such as goserelin and leuprolide. Endocrine therapies may be recommended for up to 10 years in people with early stage disease.47
Whereas some patients report manageable or no side effects from endocrine therapy, other patients experience debilitating prolonged symptoms.4849 Because of the duration of endocrine therapy, both on-therapy and long term effects of endocrine therapy are within the scope of this survivorship review. Side effects of endocrine therapy are particularly predominant among premenopausal patients taking GNRH agonists for ovarian suppression.50 These may worsen quality of life, and severe symptoms may also contribute to non-adherence to and/or early discontinuation of endocrine therapy, in turn worsening breast cancer survival.5152535455 Therefore, control of side effects related to endocrine therapy is essential in people with estrogen receptor positive breast cancer.
Vasomotor symptoms
Vasomotor symptoms have been seen in up to 80% of patients receiving endocrine therapy in population based studies.56 Patients may experience relief from vasomotor symptoms through use of a variety of strategies, as delineated in table 2.
Side effects of endocrine therapy
As the efficacies of therapeutic strategies have not been directly compared, individualized evaluations of potential benefits and side effects should be completed on a patient-by-patient basis. For instance, although paroxetine is an effective agent for hot flashes, it has the potential to interact with tamoxifen metabolism contributing to a potential decrease in the efficacy of tamoxifen.86 Patients treated with gabapentinoids for alternative diagnoses, such as diabetic neuropathy, might see improvements in their hot flashes, but in one randomized, crossover trial of 66 patients assigned to gabapentin or venlafaxine, 68% reported an overall preference for venlafaxine (P=0.01) over gabapentin. In this study, patients randomized to venlafaxine and to gabapentin both had a 66% reduction in hot flash scores, but patients receiving venlfaxine reported greated reduction in severity and frequency of hot flashes and fewer adverse effects.87 Furthermore, patients who do not experience benefit from one drug may glean benefit from another, so trialing a second drug is worthwhile if the first is ineffective.88
Finally, although estrogen based hormone replacement therapy should be avoided in this setting, data on the benefit-to-risk ratio of progestin monotherapy are limited.89 Megestrol acetate was compared with placebo in an RCT including 97 women with breast cancer; 74% of the megestrol acetate group, compared with 20% of the placebo group, had a decrease of 50% or more in the frequency of hot flashes (P<0.001).90 Medroxyprogesterone seems to be particularly effective; an RCT of 218 women found that a depot injection of medroxyprogesterone versus venlafaxine significantly increased the number of women with >50% reduction in hot flashes (74% v 46%; P<0.001).91
Genitourinary symptoms
Genitourinary symptoms are related to low estrogenic states and are pervasive among patients receiving aromatase inhibitors and ovarian suppression.6667 However, although many patients wish to discuss such problems with clinicians, such symptoms are infrequently discussed in oncology clinics, which exacerbates non-use of safe and evidence based treatments.929394 Vaginal dryness is commonly experienced, and efficacious treatment options are available; however, dyspareunia, poor libido, and other sexual health concerns are frequently distressing to breast cancer survivors and lack data driven management options (table 2).
Vaginal estrogen is commonly recommended for vaginal dryness and its sequelae in patients with no history of breast cancer, but this approach may carry some risks in patients with a history of estrogen sensitive breast cancers. Systemic estrogen concentrations may be very mildly increased after vaginal estrogen in a dose dependent fashion, but this may or may not be clinically significant.95 One recent cohort study of 8461 breast cancer survivors in Denmark reported a 39% higher risk of recurrence of breast cancer at a median follow-up of 9.8 years after diagnosis, but no difference in mortality, among patients who received concurrent vaginal estrogen therapy and aromatase inhibitors.96 This study was non-randomized and therefore different doses of vaginal estrogen may have been used; however, the risk-to-benefit ratio of vaginal estrogen remains controversial. Of note, a topical vaginal androgen, dehydroepiandrosterone, does not seem to raise estrogen concentrations in patients taking aromatase inhibitors.70
Musculoskeletal symptoms
Approximately half of breast cancer survivors taking aromatase inhibitors experience “aromatase inhibitor associated musculoskeletal symptoms” or AIMSS.76 Various plausible pathogenic explanations have been proposed as to why AIMSS occurs: aromatase inhibitors have pro-inflammatory properties, estrogen helps to maintain synovial fluid health, and pain sensitivity may be altered by aromatase inhibitors.979899 Of note, tamoxifen may also contribute to musculoskeletal symptoms, more commonly muscle cramping, but insufficient evidence exists about effective treatments.100
Both duloxetine and acupuncture have been shown to reduce AIMSS in placebo controlled clinical trials (table 2),101 but one common first approach to AIMSS is a brief hiatus in treatment to ensure symptom improvement or resolution, followed by a switch from one aromatase inhibitor to another (or to tamoxifen).7780102 One prospective, multicenter, non-randomized study of 179 patients reported that 74% had less severe AIMSS after switching from anastrozole to letrozole. Another open label randomized trial of exemestane versus letrozole in 503 women reported that 39% of patients were able to stay on aromatase inhibitor after switching to a second aromatase inhibitor, whereas all patients who did not switch chose to discontinue therapy; however, complete resolution of AIMSS after such a switch is uncommon.80102 This approach is safe and low risk, and it typically does not require additional time or cost.103
Alopecia
More than a third of breast cancer survivors taking endocrine therapy report hair thinning and loss, described as frontal and parietal hairline recession.104105 Prospective investigations into the clinical characteristics and incidence of endocrine therapy related alopecia are ongoing. Minoxidil, a vasodilative agent that causes hair follicles to transition into growth phase and increases the size of hair follicles, offers a promising potential therapy for endocrine therapy related alopecia; the use of topical and low dose oral minoxidil has been supported by early studies. Although this may be offered as an off-label treatment, RCT results are eagerly awaited.106107
Osteoporosis
Aromatase inhibitors increase risks for bone thinning, osteoporosis, and fractures, which are major drivers of cost, morbidity, and mortality, particularly in breast cancer survivors.108109 Bisphosphonates and receptor activator of nuclear factor-κB ligand (RANKL) inhibitors lessen the risks for bone loss and fractures among both postmenopausal patients and premenopausal patients taking ovarian function suppression or with chemotherapy related ovarian failure.110111112113114115116117118119 Additionally, these agents decrease risk for bone recurrence and improve breast cancer-free survival.120 The most recently published double blinded RCT of 3425 postmenoapusal patients compared denosumab with placebo; denosumab improved disease-free survival with a hazard ratio of 0.83 (95% confidence interval 0.71 to 0.97; P=0.016) and reduced fractures with a hazard ratio of 0.76 (0.63 to 0.92; P=0.004) at a median follow-up of eight years.121
Other important components of survivorship care
Screening for recurrence
Screening for recurrence relies on regular (usually at least annual) visits with a cancer specialist or primary care provider for physical examination and assessment of symptoms that might indicate that cancer has returned.122123124 Female survivors who have residual breast tissue (because they have not undergone bilateral mastectomy) and no evidence of distant metastases are generally recommended to undergo annual mammography at least until age 75 (unless medical comorbidities substantially limit the projected benefit of early detection of local recurrences and new primaries).125 Supplemental screening imaging (for example, magnetic resonance imaging of the breast, ultrasonography, or molecular breast imaging) may also be considered for female survivors with dense breast tissue (for whom mammography is less sensitive) or for those with an elevated risk of new primary cancer.126127 Male survivors should also consider unilateral surveillance mammography if they had breast conserving therapy (to detect local recurrences).128
Routine imaging or blood tests to assess for distant recurrence is not recommended by current guidelines.122124 If a survivor develops a sign or symptom of possible recurrence on physical examination or history, distant imaging (for example, positron emission tomography, computed tomography, or bone scan) may be warranted.
Genetic testing
For patients who do not meet criteria for genetic testing at the time of the initial cancer diagnosis (or who undergo only limited genetic testing at that time), periodically asking about new cancers diagnosed in family members that might affect the projected yield of genetic testing is important. Survivors who are found to carry pathogenic variants predisposing to cancer may warrant additional screening or risk reducing surgeries.
Financial toxicity
Advances in breast cancer management have enabled more cures; however, they have also contributed to the unsustainable rise in the cost of care,129 with the overall financial burden disproportionately affecting patients. Financial toxicity has been described as a combination of objective financial burden and subjective financial distress, and this adverse event has a spectrum of severity with 79% of patients with cancer reporting moderate to catastrophic financial burden.130131 High costs of cancer care, particularly out-of-pocket costs, are associated with worse patient reported outcomes, lower quality of life, and poor adherence to treatment.131132 Several factors have been associated with risk of financial toxicity, including younger age, female sex, non-white race, employment changes, low average household income, increasing distance from treatment centers, and increasing out-of-pocket costs.133 Furthermore, significant geographic disparities exist in financial burden across the world. Large out-of-pocket costs may be required in some parts of the world (for example, the US, Africa, and Central and South America), whereas other healthcare systems (for example, Canada, the EU, and the UK) protect patients against out-of-pocket costs.134 Defined risk factors for financial toxicity now exist, along with a validated assessment tool.135 Globally, cancer practices need to systematically screen patients for financial toxicity or proactively discuss finances associated with care during or after cancer care, notably when options with variable costs are available.
Fear of recurrence
Fear of recurrence is experienced by up to 80% of women with breast cancer.136 This can lead to worsened quality of life, depression, anxiety, and lack of proper follow-up surveillance.137138139 Assessing patient safety is important, as is consideration of referral to mental health professionals.140 Cognitive behavioral therapy (CBT), discussed further below, has been shown in multiple trials (and a recent systematic review to decrease fear of recurrence, which assessed the quality of the 17 RCTs).121 One included study ranodmized 56 patients to a form of CBT, termed cognitively based compassion training, over eight weeks and found reduced fear of cancer recurrence and psychologic stress (significant time × group interaction of 3.521; P<0.05).141 Cognitive behavioral therapy can be delivered via individual therapy, group therapy, or digitally.140 An RCT of mindfulness based stress reduction (MBSR; also discussed further, below) included 322 patients with breast cancer who were given a six week MBSR course versus usual care. Patients assigned to the MBSR group had significantly reduced fear of recurrence and anxiety scores (P<0.01), as assessed at baseline/six weeks and 12 weeks.142
Survivorship care plans
Survivorship care plans were proposed in the 2005 Institute of Medicine report “From Cancer Patient to Cancer Survivor: Lost in Transition” as a potential way to support primary care providers in the provision of survivorship care (in part to control costs and in part to assure that survivors receive all of the non-cancer related care that they need).143 However, subsequent clinical trials assessing the impact of survivorship care plans have shown mixed effects on a variety of survivorship outcomes.144145 A persistent need remains for novel approaches to facilitate dynamic transmission of knowledge between survivors and clinicians. As noted below, digital tools are showing potential in this arena and allow for a shared tool for primary care physicians and sub-specialists to communicate and improve care coordination. However, scaling and disseminating interventions into the “real world” is challenging. When asked about survivorship care plans, breast cancer survivors surveyed in one qualitative study recommended better education and personalization with regard to nutrition, exercise, managing side effects, comorbidities, and provision of resources, such as health coaches.146 Breast cancer support groups can also help patients to cope with their diagnosis and treatment related side effects.
General health maintenance
Screening for and treating new non-breast cancers and managing other medical conditions are critical components of breast cancer survivorship care. Cardiovascular disease is common, especially in this population, in part as a result of the toxicities of breast cancer therapy.147148
Screening for second cancers
Breast cancer survivors face elevated risks of colorectal, ovarian, lung, endometrial, and thyroid carcinomas, as well as sarcoma and non-lymphocytic leukemia.149150151 In addition, they face standard age related risks of many other cancers. For people who are not known carriers of genetic mutations predisposing them to cancer or otherwise at high risk of a second malignancy, guidelines recommend continuing with age appropriate cancer screening as recommended for the general population.122152 The primary differences between recommendations in the US and Europe pertain to the age range for screening for colorectal cancer and to the fact that screening for Helicobacter pylori is recommended in some EU countries.153
Cholesterol, diabetes, and blood pressure monitoring and management
Hypertension, diabetes, coronary artery disease, and cerebrovascular disease share the following risk factors with breast cancer: obesity, metabolic syndrome, age, and lack of physical activity. In addition, certain breast cancer therapies, such as anthracycline based chemotherapies and anti-HER2 therapies, are associated with various cardiovascular toxicities, including heart failure.154155 Interestingly, a recent case-control Kaiser Permanente study, including 3642 women with breast cancer and 68 202 matched controls, found that breast cancer survivors were more likely to develop diabetes (subdistribution hazard ratio 1.16, 1.07 to 1.26) but less likely to develop dyslipidemia (0.90, 0.86 to 0.95) than matched women without cancer.156 Although some early studies suggested that aromatase inhibitors might lead to more cardiovascular disease than tamoxifen, a recent cross sectional evaluation of 569 breast cancer survivors, 40% of whom had used aromatase inhibitors, found no difference in carotid intima media thickness (median 0.63 (interquartile range 0.56-0.71) mm with low exposure to aromatase inhibitors, 0.66 (0.59-0.75) mm with intermediate exposure, 0.64 (0.59-0.73) mm with high exposure), advanced glycation end products (median 2.13 (1.90-2.40) arbitrary units with low exposure to aromatase inhibitors, 2.20 (1.90-2.51) with intermediate exposure, 2.11 (1.90-2.43) with high exposure), or hyperlipidemia (data not provided) by exposure to aromatase inhibitors.157
Thus, for most breast cancer survivors, a reasonable approach is to follow the United States Preventive Service Task Force (USPSTF) guidelines, which include office blood pressure and weight measurement for all patients aged ≥18; fasting plasma glucose, glycated hemaglobin, or oral glucose tolerance test to screen for diabetes in those aged 35-70; lipid panel to screen for dyslipidemia for those aged 40-70 (plus those aged 21-39 on the basis of clinical judgment); and counseling about smoking cessation for all adults who smoke. Optimal screening intervals for these assessments are unknown, but the USPSTF suggests annual screening for hypertension and weight, screening every three years for diabetes, and screening every five years for dyslipidemia.158 Guidelines from the European Society of Cardiology are similar.
A meta-analysis that included data from 10 RCTs and 1095 breast cancer survivors found that diet and exercise interventions improved anthropomorphic measurements, systolic blood pressure, and C reactive protein but did not affect cholesterol, glucose, insulin, or leptin.159 Drugs are often needed to optimize cardiovascular health in survivors with abnormal cholesterol, blood pressure, and/or glucose. Unfortunately, evidence that screening and aggressive management of cardiovascular risk factors improve long term cardiac outcomes in breast cancer survivors is limited.
Integrative oncology approaches to breast cancer survivorship
Exercise
Exercise is one of the most important lifestyle interventions patients can engage in to prevent recurrence and decrease symptoms associated with breast cancer treatments. Research has shown that exercise reduces both recurrence of and death from breast cancer; one meta-analysis reported that meeting recommended physical activity guidelines (at least eight hours of moderate intesnity aerobic exercise a week) after diagnosis was associated with lower risk of breast cancer related death (hazard ratio 0.67, 95% confidence interval 0.50 to 0.90) during average follow-up periods ranging from 4.3 to 12.7 years.160161162163164 Exercise has also been shown to improve fatigue, anxiety, depression, quality of life, physical function, strength, sleep, and bone health.165166167168169170171172173 Resistance training is safe in patients with lymphedema and should be encouraged.174 Unfortunately, most breast cancer survivors do not meet the recommended goals of 150 minutes of moderate aerobic exercise a week and twice weekly strength training.175 The American Cancer Society also recognizes that people should move about during the day: “move more and sit less.”176
The American Society of Clinical Oncology (ASCO) recommends aerobic and strength exercises during active treatment to reduce the side effects of therapy.177 Exercise in patients undergoing chemotherapy has been shown to improve fatigue and cognition,168169177178179 quality of life, depression/anxiety, and sleep quality.165180 In people taking aromatase inhibitors, exercise, including aerobic and strength training for a 12 month program, reduced pain scores by 30%.181 This is important given that many people will stop aromatase inhibitors because of side effects.
Patients with no comorbidities do not need medical clearance before starting an exercise program. However, patients with neuropathy, bone/arthritis problems, or lymphedema should be referred for evaluation by a rehabilitation specialist and can consider medical clearance. Those with serious comorbidities, such as coronary artery disease, chronic obstructive pulmonary disease, recent surgeries, severe nutritional deficiencies, fatigue, or bone metastasis, should undergo medical clearance and rehabilitation evaluation before starting a program.182
Yoga has additional benefits and is recommended by the Society for Integrative Oncology (SIO)/ASCO.183 Yoga has been shown to improve quality of life (grade B) and may improve depression/anxiety (grade C) and fatigue (grade C).183 Gentle yoga can be considered to help with sleep problems (grade C). SIO/ASCO also recommends consideration of yoga for aromatase inhibitor induced joint pain and pain after breast cancer therapy (both low level evidence). Yoga can be adapted for patients with functional limitations and is available in person or online. Patients with limited mobility or serious comorbidities should be evaluated and work with a certified instructor to avoid injury.184
Dietary factors
No one specific diet is known to improve prognosis or quality of life during or after cancer treatment. However, some general recommendations can be made. The Women’s Health Initiative trial was a dietary prevention trial that randomized 41 835 women to low fat (20%) plus increased fruits/vegetables and whole grains versus a standard diet. Women in the intervention arm who developed breast cancer had improved overall survival compared with the usual diet group (10 year overall survival 82% v 78%; hazard ratio 0.78, 0.65 to 0.94; P=0.01).185 Whether the observed benefits were due to decreased fat intake or the increase in other healthy foods is unclear. In another trial, 2437 women with early stage breast cancer were randomized to a low fat (20%) diet versus a standard diet. The primary endpoint, relapse-free survival, was improved in those in the low fat diet group (9.8% v 12.4% with events; hazard ratio 0.78, 0.60 to 0.98; P=0.03). This was more pronounced in women with hormone receptor negative tumors. However, the low fat group lost weight, and the benefits may have been just due to weight loss.186 Other studies have shown increased all cause mortality in breast cancer survivors consuming the highest amounts of saturated/trans fats.187188 Therefore, a plant heavy diet (which includes the Mediterranean diet and some Asian diets), incorporating healthy fats and whole grains while avoiding processed meats and carbohydrates, sugar sweetened drinks, and artificial sweeteners, is recommended.176 A Mediterranean diet containing nuts and extra virgin olive oil has cardiovascular benefits,189190191 and incorporating high fiber foods may also be beneficial.192
The effects of meal timing has also been studied. For example, data collected from 2413 women from the Women’s Healthy Eating and Living study showed that women who fasted <13 hours per night had increased recurrences of breast cancer compared with those who extended overnight fasting periods (hazard ratio 1.36, 1.05 to 1.76).193 Longer fasting was also associated with improvement in glycated hemoglobin. Further evidence is needed to know the effect of extended overnight fasting on risk for recurrence.
Recommendations for limiting alcohol consumption for primary and secondary breast cancer prevention vary; however, most evidence suggests that alcohol increases the risk of recurrence, especially after the menopause. A recent review suggests limiting alcohol to less than three drinks a week,194 whereas the National Comprehensive Cancer Network’s survivorship guidelines take a more stringent view on alcohol and state that women with breast cancer should abstain.
Dietary soy is safe for people with a history of breast cancer and may be beneficial.195 However, soy supplements are not recommended.196
Acupuncture
Acupuncture is an ancient Chinese medicine practice of placing fine needles into various points in the body. Heat (moxibustion) or electrostimulation can be added to standard needling.197 The mechanism of action is not well understood. Traditional Chinese medicine explains acupuncture as a technique for balancing the flow of energy or life force that flows through meridians in the body.198 Acupuncture may also stimulate nerves, fascia, or muscles to affect its action.199200 Sessions are generally weekly and often include other evaluations of the patient’s constitution, lifestyle advice, and herbal therapies. These components of traditional acupuncture are not often included in clinical trials in which only the acupuncture needle part of the treatment is assessed.201 Studies of acupuncture are challenging to perform and evaluate owing to heterogeneity of providers, difficulty in choosing a control group (waitlist versus sham versus standard of care), not including other components of acupuncture treatment (pragmatic study), and difficulty in double blinding. The placebo effect is well established as playing a significant role in these studies.202 However, evidence has been mounting, and SIO/ASCO recommends electro-acupuncture for consideration for chemotherapy induced nausea on the basis of RCTs and a consensus conference (in addition to standard drug therapies) (grade B, SIO).197203204 SIO/ASCO guidelines for managing pain recommend acupuncture for aromatase inhibitor related joint pain and general pain/musculoskeletal pain from cancer (both with intermediate level evidence quality) and consideration of acupuncture for CIPN and procedural or surgical pain (both with low quality level evidence).205 Acupuncture is generally safe but should be avoided in patients with severe cytopenias, and needles should not be inserted into areas of tumors or infections.206207208
Acupressure is another technique in which manual pressure is applied to different body parts to achieve an effect, using pressure from fingers, bands, or beads. This has been most well studied for nausea/vomiting, using a pressure point called Neiguan located on the inner arm near the wrist.209210211212 This treatment is a grade B recommendation from SIO/ASCO.183 It may also be useful for other cancer related symptoms, including pain and fatigue.205213214
Cognitive behavioral therapy
CBT is a psychological treatment that treats anxiety/depression and insomnia and improves relaxation and quality of life.215216 It may also help people with the fear of recurrence.121 The techniques included in this form of talking therapy involve trying to change thinking patterns to improve a particular condition; for instance, a therapist treating a patient with anxiety will often identify a patient’s anxious/nervous thought patterns and help to reframe these thoughts so that they are less detrimental. CBT has been shown to improve sleep and anxiety/depressive symptoms and increase quality of life in cancer patients. For instance, among 11 RCTs of patients with breast cancer, the overall effect size of CBT on quality of life of breast cancer survivors was 0.39 (95% confidence interval 0.12 to 0.66; P<0.001, I2=83%).215216217218219220221222223224225
Insomnia is a common problem for patients with breast cancer, both during and after treatment, owing to direct treatment effects (including tamoxifen or steroids prescribed with chemotherapy), stress of diagnosis and treatment, or other causes. Insomnia often coexists with other symptoms such as pain, anxiety/depression, and fatigue, leading to reduced quality of life.226 CBT-insomnia is a form of CBT that has been shown to improve insomnia in breast cancer patients for up to 12 months post-intervention217223; in one systematic review and meta-analysis of 22 studies, CBT-insomnia significantly reduced severity of insomnia (g=0.78).217 CBT-insomnia involves stimulus control, sleep hygiene, cognitive therapy, and relaxation therapy.219227
Mindfulness
Mindfulness practice is a technique used to train attention and awareness to focus on the present moment in a non-judgmental way.228 Mindfulness practice is recommended by SIO/ASCO for anxiety, depression, and quality of life (grade A).183 Patients may practice mindfulness in different ways, including meditation, yoga, Tai Chi, breathing techniques, and body scans. Mindfulness practices improve anxiety, depression, sleep, and quality of life in cancer patients.229230231232233234235236 MBSR is a more formal program that teaches a variety of meditation practices either in person or online, weekly over six to eight weeks,228 and may also improve mood, sleep, fatigue, and quality of life.226234235237 Studies have been mixed regarding the effects of MBSR on cognitive function.238 The duration of beneficial effects of MBSR may not be long lasting, and more studies are needed to determine whether ongoing practice or repeat courses are needed to maintain benefits.237239
Supplements
Guidelines state that dietary supplements are not recommended for the treatment of cancer or prevention of recurrence and are not recommended for cancer survivors in the absence of a documented nutritional deficiency, poor diet, or other medical indication.183240241 However, some dietary supplements may be useful in symptom management. For example, Wisconsin ginseng has been shown to reduce fatigue in breast cancer patients undergoing chemotherapy,242 and ginger may help with nausea.243244245 Treating vitamin D deficiency may be associated with improved breast cancer outcomes and bone health.246247 Dietary soy is safe, but supplements are not recommended or useful for hot flashes.248249250 Some supplements, however, can be harmful and should be avoided. For example, acetyl-L carnitine was shown to worsen taxane induced neuropathy.251 Vitamin B12 before/during chemotherapy and iron during chemotherapy were associated with increased recurrence of and death from breast cancer.252 Patients should also avoid supplemental antioxidants during chemotherapy, as some studies suggest worse cancer outcomes.253 Supplements/herbal medicines can interfere with cancer treatments, generally, through cytochrome P450/P-glycoprotein interactions, which may increase the toxicity of therapy or decrease its effectiveness.254255 Many patients are taking dietary supplements and do not inform their care teams.256257 Asking whether patients are taking dietary supplements and assessing for potential interactions are important.
Digital tools to enhance survivorship care
With the burgeoning population of breast cancer survivors, transformation of delivery models for cancer care has become a necessity. Telehealth and virtual care have been adopted globally, and they may offer solutions to enable the transition of some aspects of survivorship care from the clinic into the home or community environment. Communication with care team members, symptom management, and disease surveillance can be facilitated by digital products and platforms, as summarized in this section.
Electronic/mobile health services
Digital technologies leveraged for electronic health (eHealth) interventions are most commonly mediated through the web or internet, whereas mobile health (mHealth) interventions are mediated through smartphone or tablet devices, most commonly via applications. Digital delivery of educational content for patients and online peer support groups accessible through a web browser or mobile device are a few examples of eHealth/mHealth tools that foster self-management.
A systematic review with meta-analyses (random effects model) of RCTs evaluated the effectiveness of eHealth delivered interventions in patients during and after breast cancer treatment.258 Most interventions were web based and included videos, forums, and electronic reminder systems. The 32 unique studies (4790 participants) included were conducted within health systems globally, showing the broad reach of these interventions and diversity within the populations represented. A significant effect of eHealth interventions on quality of life (standardized mean difference 0.20, 95% confidence interval 0.03 to 0.36), self-efficacy (0.45, 0.24 to 0.65), distress (–0.41, –0.63 to –0.20), and fatigue (–0.37, –0.61 to –0.13) was seen. They had no effect on anxiety or depression. Studies (78.1%) measuring patient reported experience measures (n=25) found that acceptability (n=9) was high, with high ratings for satisfaction (range 71-100%), usefulness (71-95%), and ease of use (73-92%).
A systematic review of mHealth applications used across the breast cancer continuum was conducted by searching four databases with an objective of providing an overview of available, research tested interventions. Ten of the 29 identified studies targeted breast cancer survivorship (846 patients).259 All aimed to assess lifestyle changes, and nearly all interventions were mobile applications, some of which included email or SMS text messaging features, as well as video enabled sessions with a healthcare professional. Several of the included studies showed a significant association for weight loss and increased physical activity with the mHealth intervention.260261 More high quality research is needed to better understand the effect of mHealth applications on these and other clinical outcomes.
Telehealth services
The electronic health record (EHR) has become the standard for storing and viewing patients’ health data and clinical documentation. A shift has taken place from passively viewing health information to an interactive EHR, and patients report that this facilitates better communication, enables a more effective partnership with providers, and helps to track their health information more proactively.262
Asynchronous telehealth services are a form of eHealth/mHealth, often mediated respectively through the web or application based EHR patient portals. They can facilitate secure messaging between survivors and their care teams, as well as store-and-forward transmission of data.263 The latter can be used for electronic patient reported outcomes, such as self-reported symptom assessments, or for patients to send images. The submitted data can be reviewed by a healthcare provider and care recommendations can be returned to patients at a convenient time outside of an in-person assessment,.
Synchronous telehealth services require an interactive audio and/or video telecommunication system to permit real time communication between providers at the distant site and the patient at the originating site.263 Emerging literature suggests that patients’ acceptance of and satisfaction with video telemedicine visits in the breast surgical oncology practice have been high.264265 High patient satisfaction scores were also observed in a multisite, multiregional medical oncology practice. In that study, rates of use of telehealth visits were lower for patients ≥65 years of age and those residing in rural communities than for younger patients and those in urban areas.266 Breast cancer clinicians have also expressed satisfaction with telemedicine and recognize it as a valuable option to enhance outpatient care and routine follow-up.267 When appropriate, moving some follow-up care to the home via telehealth visits may improve access to facility based care while still serving the needs of breast cancer survivors.
Remotely delivered rehabilitation, weight loss, and physical activity programs
Beyond episodic visits, entire programs supporting cancer survivors have been transformed for virtual care delivery. As an example, telerehabilitation has been developed and implemented in several cancer practices to facilitate physical therapy for complications of breast cancer treatments, including lymphedema, limited shoulder range of motion, pain, fatigue, and loss of muscle strength.268 Although remotely delivered physical therapy is a viable model of care delivery for survivors, research is needed to understand patients’ acceptance of and compliance with the telerehabilitation program, as well as its efficacy compared with traditional in-person physical therapy.
Additionally, the feasibility and effectiveness of a remotely delivered weight loss program has been compared with usual care in an RCT of patients who have completed treatment for early stage breast cancer.269 Compared with usual care, the virtual weight loss program, including telephone calls and optional text messaging, was associated with significantly greater improvements in weight, metabolic syndrome risk score, physical quality of life, musculoskeletal pain, and other variables. Notably, the effects on weight, adiposity, and metabolic syndrome risk scores were sustained at 18 months. Bringing these weight loss programs into the home environment with a goal of improving overall health and wellness may improve patients’ access and adherence to them.
Remotely delivered physical activity programs for breast cancer survivors have also emerged separately or in concert with weight loss programs, and early results have shown their feasibility and acceptance in both older rural and young breast cancer survivors.270271 Interventions supporting these programs include the use of video enabled exercise sessions, web based education, wearable devices/accelerometers, and certified instruction or peer coaching. In an RCT of a remotely delivered exercise program versus a waitlist wellness control group of breast cancer survivors, those receiving the intervention had significantly greater reductions in sedentary behavior, and the increase in moderate to vigorous physical activity was inversely proportional to sedentary behavior. As shown in a separate study, remotely delivered programs for cancer survivors, when combined with telecoaching, can improve program retention and adherence enabling improved outcomes for patients.272
This growing body of evidence supports continued investment in the development and study of remotely delivered programs for breast cancer survivors that foster rehabilitation, weight loss, and increased physical activity. They have the potential to improve health related quality of life and clinical outcomes, and they can furthermore break down barriers to access and adherence to these services that traditionally have been offered at limited institutions through traditional in-person care models.
Cancer treatment delivery at home
Home hospital programs can provide supportive care to patients with cancer in the home environment, and studies have shown the feasibility, safety, and effectiveness of oncology specific home hospital programs.273274 Initially developed and adopted several decades ago in single payer health systems globally,275276 the programs have expanded to include delivery of systemic cancer treatment in the home. Studies have shown that this is safe, improves patient and care giver experience, and reduces treatment costs.277 Many breast cancer drugs administered to breast cancer survivors have a low risk for reactions and would be amenable to administration in the home, such as GNRH analogs, biologics, and bone supportive care. This could be transformative for care of breast cancer survivors and warrants investigation.
Emerging treatments
Many emerging treatments for long term toxicities of systemic therapies exist. Two upcoming clinical trials will focus on therapies that might prevent the development of long term peripheral neuropathy, one testing a compound called GM-1 and another a device that provides both cryotherapy and compression therapy (NCT number not yet assigned). For therapy related alopecia, a clinical trial is under way to study the benefits of minoxidil in a randomized controlled fashion (NCT05417308).
Guidelines
Various national and international organizations have issued breast cancer survivorship guidelines, as well as guidelines for the management of specific symptoms facing breast cancer survivors, for integrative medicine approaches, and for surveillance strategies. General survivorship guidelines from the American Cancer Society, American Society of Clinical Oncology, European Society of Clinical Oncology, and National Comprehensive Cancer Network guidelines were reviewed in detail to inform this review.
Conclusions
In general, the complexity of after effects from breast cancer are likely to increase as new therapies are added to our armamentarium and treatment becomes increasingly tailored. As the sections above highlight, survivors and clinicians face challenges in monitoring persistent and late after effects from cancer and its treatment. Following up for multiple aftereffects in trials of cancer directed therapy over the long term can be costly, and many clinical trials may be too small to capture rare side effects. Digital tools may help to engage survivors in long term tracking, but reporting bias will be a potential confounder and care must be exercised to prevent under-representation of populations with lower digital literacy.
Questions for future research
How can we prevent and/or treat many of the challenging long term side effects of systemic therapy, including peripheral neuropathy, therapy related alopecia, and vaginal dryness?
What is the optimal way to help patients to differentiate between evidence based integrative oncology approaches and approaches that may not help and may actually harm patients?
How can digital tools enhance the benefit of survivorship care plans?
How patients were involved in the creation of this article
All of the authors of this manuscript are clinicians who interact with breast cancer survivors regularly. All also engage with patient advocates as part of their research efforts. A team of breast cancer survivors and patient advocates provided feedback on the long term side effects and integrative oncology strategies that are covered in this manuscript; we would personally like to acknowledge the following breast cancer survivors and advocates: Lisa Halverson, Anne Mehnke, Tracee Cole, and Jody Koubsky.
Footnotes
Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors
Contributors: KJ was responsible for the original conception and design of the article, with input from all co-authors; all authors were responsible for the acquisition and interpretation of data for the work, drafting the work, revising it critically, and final approval of the version to be published. All authors agreed to be accountable for all aspects of the work and will assure that questions related to the accuracy or integrity of any part of the work will be appropriately investigated and resolved.
Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: none.
Provenance and peer review: Commissioned; externally peer reviewed.