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Improving quality of life in female cancer survivors: current status and future questions Linda R Duska1 & Don S Dizon*,2

ABSTRACT: Almost 14 million people in the USA alone have been diagnosed with cancer. Given the improvements in diagnosis and treatment, over 60% of patients are expected to survive 5 years or more from the point of diagnosis. Treatments for cancer may result in longterm issues including those that impact the physical, emotional, spiritual or social domains. However, how best to care for issues in survivors remains unclear. Although much attention has been focused on survivorship care plans and survivorship clinics, there are limited data to show they improve outcomes. This article reviews the issues in female cancer survivors that can occur following diagnosis and treatment and suggest strategies that may assist in management. Finally, we review the current views regarding the care of cancer survivors and suggest important issues that must be addressed so that we can reach our goal of improvement in the quality of life of this emerging population. As of January 2012, there are approximately 13.7 million cancer survivors in the USA alone, representing approximately 4% of the population [1] . Among today’s survivors, the most common cancer sites represented include female breast (22%), prostate (20%), colorectal (9%) and gynecologic (8%). Many of these are long-term survivors: 64% have survived 5 years or more; 40% have survived 10 years or more; and 15% have survived 20 years or more after diagnosis [2] . As the US population ages, the number of cancer survivors is projected to increase by 31%, to almost 18 million, by 2022, which represents an increase of more than 4 million survivors in 10 years [2] . For over 50% of women survivors, cancer will arise from one of the ‘traditionally’ female sites of origin including the ovary, uterine corpus, cervix and breast [3] . With the epidemic of obesity in the USA and elsewhere [4] , these figures are likely to increase, especially in women. One study, using National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) data, estimated that in 2007, approximately 50,500 cancers in women (7%) were related to obesity [3] . The percentage of cases attributed to obesity varied widely for different cancer types but is as high as 40% for some cancers, particularly endometrial cancer [5] . In 2005, the US Institute of Medicine (IOM; Washington, DC, USA) released a report called ‘From cancer patient to cancer survivor lost in transition’ to address issues following the diagnosis and treatment for cancer (Box 1) [6] . This report highlighted ten recommendations that spanned issues relevant to cancer survivors, including better education of providers, creation of a survivorship care plan (SCP) and better access to coordinated care. The IOM report was an acknowledgement that despite the strides in screening, diagnosis and treatment, the sequelae of therapy require more attention because after treatment completes, patients are often left with little recourse for managing what comes after as they approach a ‘new normal’, including a lack of information and support for

KEYWORDS 

• cancer survivor • cancer treatment • intimacy • lifestyle • obesity • sexual health • survivorship care plan • survivorship clinic • survivorship medicine

Department of Obstetrics–Gynecology, Division of Gynecologic Oncology, University of Virginia, Charlottesville, VA, USA Department of Medicine, Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA *Author for correspondence: [email protected] 1 2

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Perspective  Duska & Dizon Box 1. Objectives of the Institute of Medicine’s committee on cancer survivorship: improving care and quality of life of the National Cancer Policy Board. ●● Raise awareness of the medical, functional and psychosocial consequences of cancer and its treatment ●● Define quality healthcare for cancer survivors and identify strategies to achieve it ●● Improve the quality of life of cancer survivors through policies to ensure their access to psychosocial services, fair employment practices and health insurance

Data taken from [6].

lingering and long-term toxicities, all of which may be very troubling but difficult to discuss. This article aims to provide the reader with a birds-eye view of a selection of issues faced by female cancer survivors and summarizes some efforts to address them. We also provide our thoughts regarding unanswered questions that we feel should be addressed in future research. However, this is not meant to be a comprehensive review of survivorship, which would go beyond the scope of a single perspective piece. Defining a cancer survivor The broadest definition of a cancer survivor is illustrated by the National Coalition of Cancer Survivors, which defines a survivor as any person living with the diagnosis of cancer, from the time of that diagnosis [7] . However, the needs of a patient likely evolve as they move from diagnosis, treatment, end of therapy and into surveillance. These aspects of the cancer journey may result in changes in both the priorities and issues for cancer survivors. Although there is a lack of a uniform model of cancer survivorship, survivorship has been described by way of ‘seasons’ by Miller and colleagues, and entail acute survivorship (e.g., diagnosis and treatment), extended survivorship (e.g., surveillance) and then permanent survivorship (cure or long-term remission) [8] . For purposes of this discussion, we will speak directly to key issues relevant for patients in extended or permanent survivorship using the domains of suffering described by Cassell and Saunders, since they also mirror the primary domains of quality of life [9] . These include the physical, emotional (psychological), spiritual and social aspects of the self. While we appreciate that quality of life is often characterized in terms of ‘psychosocial’ health, we hope that the framework used in this manuscript illustrates the concepts we have chosen to highlight in a clearer way, emphasizing their individual importance, the data that supports them in women with cancer, and suggested interventions and questions that remain.

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●●Physical domain

The physical domain consists of symptoms that affect the body. For the purposes of this article, we will focus on the areas of the physical domain that are most likely to be issues for female cancer survivors, including cardiovascular effects, gastrointestinal toxicities (e.g., abdominal pain, cramping, chronic constipation or diarrhea, and bowel obstruction), gynecologic issues (e.g., menopausal symptoms and sexual ­dysfunction) and lifestyle-related issues (e.g., obesity). Cardiovascular disease

Women treated for cancer are at an increased risk of cardiovascular complications, which may be a result of comorbidities or a direct result of anticancer treatment. For example, patients treated with radiation therapy (RT) to the chest as a component of breast cancer therapy face a higher risk of cardiac-related mortality compared with those who did not undergo RT. In one study using data from the SEER system, the 15‐year mortality risk was 13 and 10% for patients treated with left- versus right-sided chest RT, respectively, if treatment was rendered in the 1970s; however, for women treated in the 1980s, the risk of RT-related cardiac mortality was similar regardless of side of the chest ­radiated (9 vs 8.7%, respectively) [10] . The increased mortality risk is probably owing due to RT damage to the coronary vessels, which persists far beyond treatment. In one study of almost 4500 women followed for 28 years, RT resulted in an almost twofold higher risk of cardiac death compared with those who did not undergo RT (relative risk: 1.76; 95% CI: 1.34–2.30) [11] . Beyond RT-related cardiovascular damage, chemotherapy can also have an adverse impact on cardiac function. This is most notably demonstrated by the experience with anthracyclines, which remain an important treatment option for women with breast and endometrial cancers. In these patients, the risk of left ventricular dysfunction ranges from 5 to 30% or greater

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Improving quality of life in female cancer survivors: current status & future questions  as the cumulative dose increases from 400 to 500 mg/m2 and higher [12] . Things to consider

These figures for cardiac mortality detailed above highlight the importance of cardiovascular screening in women with cancer. Ideally, this screening begins at the time of initial diagnosis. Given the potentially lingering effects of treatment, however, primary care screening to ensure cardiac risk factors are minimized remains an important aspect of longitudinal care. For women who received chest wall RT or cardiotoxic agents, evaluation for subclinical heart failure (in the otherwise asymptomatic patient) may be considered. If identified, cardiac risk f­actor management becomes even more important. Gastrointestinal symptoms

As noted above, RT is an important treatment modality in women’s cancers, including treatment for breast, cervical and endometrial cancers. While RT is highly effective in treatment and prevention of recurrence for women treated with pelvic RT, it can result in significant long-term gastrointestinal symptoms [13,14] . In fact, estimates are that 90% of patients treated with pelvic RT will develop a permanent change in their bowel function, and 50% of all treated patients have a reduction in their quality of life as a result of these changes [13,15] . In one trial, patients treated with RT had a 21% increase in diarrhea with 8% experiencing fecal incontinence at the end of the treatment [14] . Limitations of daily activities owing to bowel problems, including needing to cancel social activities to stay close to the toilet, were as high as 22%. Despite these figures, symptoms are generally under-reported by patients, which represents a barrier to optimal management [16] . Beyond physical issues, chronic bowel problems related to RT may impact the psychological and social aspects of women’s lives, requiring women to withdraw from normal roles and be virtually house-bound, which can be destructive to their own life, let alone their family life [17,18] . In addition to the likely under-reporting of symptoms by patients, data suggest that clinicians do not do a very good job recognizing that symptoms exist or appreciating their severity of symptoms when present [19] . As an example, one survey of British oncologists revealed that only a minority of patients who develop significant gastrointestinal symptoms after pelvic RT are referred for specialist evaluation [20] . In addition,

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survivors experiencing gastrointestinal symptoms may suffer unnecessarily owing to a lack of access to appropriate diagnostic tests or referral to gastroenterologists with experience in management. Although estimates are that approximately twice as many patients develop substantial bowel problems after pelvic RT as are diagnosed with Crohn’s disease annually, this is not reflected in available gastrointestinal s­pecialists or experience [21] . Things to consider

What can we do better for women who suffer from chronic bowel problems? First, we can make sure to ask, and to ask the right questions in the most appropriate settings. Most women will not admit to fecal leakage or chronic diarrhea owing to embarrassment, as well as fear of judgment from their physician. Second, we must have adequately trained and available expertise to help women manage chronic gastrointestinal problems. Therefore, a multidisciplinary approach to help our patients manage gastrointestinal symptoms is required, which should include nutritionists and gastroenterologists with prerequisite expertise in managing RT-related bowel problems. Other issues to consider in future research may include the prevention of excessive bowel toxicity during treatment, such as new radiation techniques or bowel protection modalities; early intervention to prevent late radiation toxicities; and the development of regional centers with expertise in how best to manage patients with late RT-related symptoms. These regional centers may serve as the primary institutions dedicated to the rapid accrual in clinical trials aimed at patient support and management related to gastrointestinal dysfunction. Sexual dysfunction

While both the social and psychological domains will affect sexual health, there is significant physical impact on sexual function due to treatment and there is no reason to assume that sexuality is not as important to cancer survivors as it is to people without cancer. Investigators report that between 30 and 100% of breast and gynecologic cancer survivors experience some sort of physical sexual dysfunction, characterized by decreased desire, arousal disorder, dyspareunia and ­difficulty or inability to achieve orgasm [22–26] . For premenopausal women, treatment of most women’s cancers can result in amenorrhea resulting in premature menopause. For some women,

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Perspective  Duska & Dizon it will be permanent (e.g., those who have their ovaries removed), while for others it may be temporary (e.g., after chemotherapy). Regardless, premature menopause causes more profound symptoms than natural menopause, probably owing to the abrupt rather than slow decline in hormone levels over time [27] . The symptoms of menopause (e.g., vaginal dryness, hot flashes, lack of libido and dyspareunia) can impact overall sexual health, with impacts on libido, desire, interest and performance. In addition, it can also exacerbate pre-existing sexual dysfunction. Beyond the symptoms associated with amenorrhea, surgery and/or RT can induce physical impacts that can alter one’s body image, such as with breast surgery, or ability to engage sexually, such as reductions in vaginal length owing to radical ­hysterectomy [28–30] . A common complaint is pain owing to penetrative intercourse (dyspareunia), which may or may not be related to involuntary contractions in the vaginal muscles (vaginismus). Since these are often indistinguishable in woman who complain of this, they are now considered together in the latest American Psychiatric Association’s Diagnostic and Statistical Manual for Mental Disorders as the female genital pain/penetration disorder [31] . Physical issues that may result in pain with penetration include reductions in vaginal lubrication, vaginal atrophy and a shortened or restricted vaginal vault. Other physical issues that may occur include postcoital bleeding and other medical issues, including bowel or bladder dysfunction, recurrent bladder infections or urinary/fecal incontinence. All of these may inhibit sexual interest or become a barrier to a woman’s ability to participate in sexual activities. That barriers to discussions about sexual health exist from both practitioner and patient perspective have been well established. For example, patients may wait to bring up issues until asked directly, and if not asked, will routinely not mention them [26] . Despite this, when gynecologic and breast cancer patients are surveyed, more than 40% of them are interested in receiving sexual healthcare but very few of them actually seek such care [32] . Unfortunately, survivors continue to report a lack of information regarding sexuality following cancer treatment. Although numerous reasons are often given, clinicians report a lack of understanding of the breadth of concern, identification of effective means for clinical assessment, and clinical interventions to address concerns [33] . To

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complicate these matters, clinicians are often too busy to devote time to these matters, which may be considered ‘less important’ than detection of recurrent disease or life-threatening toxicities. In one study of gynecologic oncology specialists, Wiggins et al. reported that while nearly all respondents felt comfortable addressing sexual problems in their patients, less than half took a sexual history in new patients and 80% did not feel there was sufficient time to devote to exploring sexual issues [30] . Things to consider

How to better address these issues is an important challenge in survivorship. A crucial step in this process would be for clinicians to acknowledge the importance of sexual health for their patients and adopt screening questions as a routine part of clinical follow-up. We must encourage providers to ask and elicit complaints from their patients, who may be reluctant to bring up problems with sexual dysfunction. One such approach is to use the PLISSIT model (Box 2) , which utilizes both an open- and ­closed-question communication style [34] . These attempts at normalizing symptoms related to sexual function may help reduce the discomfort that may ensue on both patient and provider perspectives. In addition, access to skilled locally available practitioners to aid in a more thorough diagnostic and treatment program if necessary is required. Cancer centers should lead this effort as part of survivorship, which may entail development of programs in sexual health for survivors, networking with reproductive health specialists and the involvement of other health professionals (e.g., rehabilitation medicine specialists, physical therapists, sex therapists and couples counselors). For most women’s cancers, estrogen replacement is an option for symptoms such as hot flashes and vaginal dryness. Hormone replacement has been shown to be safe in cervix cancer, the most common histologic type of ovarian cancer and in all endometrial cancers [35,36] . More caution should be applied in the use of hormone replacement therapy in women with hormone positive cancers (e.g., breast cancer and the endometrioid subtype of ovarian cancer) although limited, retrospective data in breast cancer survivors suggest that use of local estrogen therapy is not associated with a risk of recurrence [37] . Hormonal therapy may be delivered systemically, via oral drugs or cutaneous patches, or vaginally.

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Improving quality of life in female cancer survivors: current status & future questions 

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Box 2. PLISSIT model. Permission ●● Normalize the impact of treatment on sexual health and the importance of sexual health ●● “A lot of patients have issues with sexual function after treatment, I am wondering if this is something you’d like to talk about?” Limited information ●● Characterize impact of treatment on sexual health (in general) or on specific complaints ●● “Vaginal dryness is quite common after the ovaries have been removed.” Specific suggestions ●● Offer advice (if able) or treatment that may aide the patient ●● “For some patients, vaginal estrogen can be very useful to relive dryness and discomfort. Is this something that interests you?” Intensive therapy ●● Refer as appropriate, especially if an issue is uncovered that one is not comfortable or able to fully address ●● “I’m not really the best person to discuss these more fully, but I can refer you to someone who can. Would you be willing to see someone else?

For the treatment of sexual dysfunction, we prefer to administer vaginal estrogen as it results in limited systemic absorption and excellent relief of vaginal dryness. For women who are deemed not to be candidates for vaginal hormonal therapies, nonhormonal treatments can provide relief [38] . These include the use of vaginal moisturizers or vitamin-containing vaginal suppositories (e.g., vitamin A or E) [33,39–41] and treatments aimed at the vasomotor symptoms that accompany menopause, such as bupropion [42] , gabapentin [43] and even hypnotherapy [44] . While herbs such as black kohash and soy products are purported to have a benefit, there are a lack of prospective data to suggest they are effective. Obesity/physical fitness

There is an increased rate of obesity in the USA, in general, and particularly in the female population; this is likely an attributable cause to the increased incidence of cancer. As an example, data from the 2007 National Cancer Institute SEER data showed that approximately 50,500 cancer cases in women (7%) were owing to obesity [3] . If existing trends hold forward, there will be approximately 500,000 additional cases of cancer in the USA by 2030. This analysis also found that if every adult reduced their BMI by 1%, which would be equivalent to a weight loss of approximately 1 kg (or 2.2 lbs) for an adult of average weight, this would prevent the increase in the number of cancer cases and actually result in the avoidance of approximately 100,000 new cases of cancer. While the diagnosis of cancer should be a ‘wake-up call’ to women to improve their weight through better diet and physical ­fitness, this often does not happen [45] .

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Things to consider

Despite these trends, enough data suggest that adoption of a healthy lifestyle (e.g., exercise and a heart-healthy diet) can improve quality of life [46–48] . Therefore, we should encourage a more healthy lifestyle, including adoption of a better diet and regular exercise. In addition, a multidisciplinary approach including physicians (both primary care and oncological specialists), nutritionist, exercise physiology and physical therapy should be involved in the drive to maintain health for survivors. Cognitive dysfunction

Cognitive dysfunction, typically manifest as impairments in short-term memory or a deceased ability to focus on tasks, is a frequent complaint of patients after treatment for cancer. A 2012 meta-analysis summarized the results of 17 studies (n = 807 patients) that evaluated cognitive dysfunction in breast cancer survivors found that chemotherapy was significantly associated with cognitive difficulties, particularly in verbal and visuospatial abilities, which did not appear to be moderated by other factors, such as age, education, time since treatment ended or the use of endocrine therapy [49] . However, a separate data set presented at the 2013 Breast Cancer Symposium reported an association with endocrine therapy and the onset of cognitive decline among women with early-stage breast cancer [50] . Although much of this work has been carried out in breast cancer survivors, reports suggest that patients treated for other cancers also are at risk for cognitive decline, including patients treated for hematologic malignancies and ­ovarian cancer [51] .

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Perspective  Duska & Dizon Second malignancies

Things to consider

The risk of developing a second malignancy ranges from 8 to 12% by 20 years, with leukemia being the most common secondary neoplasm [52] . The risk of a secondary cancer can be related to prior RT treatment and/or to cytotoxic therapy. Types of secondary cancers owing to RT include both hematologic and other solid tumors (e.g., sarcoma) with onset between 5 and 10 years after treatment. Specific classes of chemotherapy (e.g., alkylating agents) increase the risk for a secondary leukemia, and the risk increases with higher drug doses, longer treatment time and higher dose intensity. Other agents that increase the risk of leukemia include cisplatin and the topoisomerase 2 inhibitors. Given the above, all cancer survivors treated with agents that put them at risk for secondary malignancy should be carefully monitored. Physicians should take into account the specific treatment given, the dose, the age of the patient at the time of treatment, and the time interval since treatment completion when designing ­surveillance protocols.

The desires of women to become mothers has motivated clinicians to address the issues of fertility preservation, and to inform the options for women who have lost their ability to have natural offspring [57] . Research is needed to expand the options that will enable the survivor to preserve biologic fertility. These efforts are underway and include the options of ovarian tissue transplantation and in vitro maturation, though both require the use of tissue taken before cancer treatment has begun [57] . Further work is needed to ensure that clinicians are aware of the importance of counseling before treatment, and that opportunities for parenthood do exist after cancer, even if women have lost their ability to become a biologic parent (e.g., gestational surrogacy) [54] .

Reproductive function

The threat of cancer on future parenthood is a significant concern for younger women diagnosed with cancer. It is best that discussions on fertility preservation be conducted prior to cancer treatment, which is consistent with guidelines from the American Society of Clinical Oncology [53] . However, with or without this discussed before cancer treatment, they remain issues of importance after cancer treatment has completed. For some women, particular those who were diagnosed in adolescence or young adulthood, these issues only become relevant after cancer treatment has completed. Even more importantly, there is significant distress associated with the loss of fertility, which includes a loss of self-esteem, control and wellbeing, and the belief in the inherent ‘fairness’ of life [54] . Beyond this, some data suggest that treatment will also impact on a woman’s ability to carry a child to term. For example, in one series of over 100 pregnancies in women treated with a radical trachelectomy for early cervical cancer, the rate of first and second trimester miscarriage was 20 and 3%, respectively [55] . Of those that made it to the third trimester, 25% were delivered prematurely. For women treated with pelvic RT, risks include spontaneous miscarriage, fetal malposition, premature labor and low birth weight offspring [56] .

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●●Emotional/psychologic domain

This domain encompasses emotional and psychological wellbeing of the cancer survivor, including psychological (e.g., depression, anxiety, stress, distress and guilt), body image (including loss of fertility), fear of the future (fear of recurrence), and issues with intimacy. Most patients with cancer experience some level of ongoing psychological distress throughout the course of their disease [58,59] . As an example, as many as 15% of ovarian cancer survivors may meet the criteria for major depression on a screening scale [60] . Addressing the psychological symptoms associated with a cancer diagnosis is crucial to survivorship. However, patients may be unwilling or unable to express their symptoms of depression and anxiety. Therefore, physicians caring for survivors must be especially sensitive to the high prevalence of psychological problems. This requires providers to actively assess for symptoms and offer treatment options. In addition, referral to a therapist and/or psychiatrist may be critical to addressing such issues, including the guilt of surviving. A multidisciplinary approach, including social work and in some cases experts in p ­ alliative care, may also be of assistance. Approximately a third of cancer patients will experience significant distress during the cancer trajectory, which can be related to any of the domains discussed in this article [61] . Cancer distress is frequently under-recognized and for this reason distress has been identified as the ‘sixth vital sign’ [62] . In response, the National Comprehensive Cancer Network recommends

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Improving quality of life in female cancer survivors: current status & future questions  that cancer patients undergo screening for distress in the survivorship period (as well as at the time of transition to end of life care) [63] . Screening should be followed by appropriate intervention for physical symptoms and/or ­referral to psychosocial resources. Fear of recurrence

The stigma of cancer, acute awareness of the possibility of death and fear of metastasis and recurrence, are reported as having a psychological impact on survivors and their families. Fear of cancer recurrence is one of the most commonly reported problems and is the most unmet psychosocial need for help, with 24–40% of cancer survivors reporting moderate to high levels of need for help [64–66] . More than half of survivors report a fear of disease recurrence; in ovarian cancer patients this does not vary between early-stage and advanced-stage survivors [60,67–69] . Surprisingly, routine follow-up examinations may ultimately produce more anxiety than reassurance [70] . In addition, the fear of recurrence seems tied to evaluation of serologic markers of disease, which in women with a history of ovarian cancer refers to CA-125 testing, even among women who are disease free for more than 3 years [71] . Although well described, there is no universal criteria to define or measure pathologic fear of recurrence. Despite this, clinicians should monitor patients for heightened anxiety or sadness related to this fear of recurrence. Psychological and clinical interventions aimed at decreasing the fear of recurrence may be required. Impact on intimacy

Although the high prevalence of sexual dysfunction has been well established the impact of cancer specifically on intimacy has been less established. It is important that sexuality be distinguished from intimacy because although they are very inter-related, they represent very different constructs. Whereas sexuality encompasses the feelings, orientation and capacity to partake and enjoy eroticized experiences, intimacy should be considered a broader state of closeness or ‘belonging’. Unfortunately, much of the literature regarding cancer survivors and sexual health has concentrated on how treatment for cancer impacts penis–vaginal intercourse (sometimes referred to as the ‘coital imperative’). However, this is a limited view of sexual health and ignores both the complexity of sexual practices and

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relationships (e.g., same-sex couples), overemphasizes the impact of sexual performance on sexual health and reduces the importance of intimacy. As an example, Perz and colleagues queried 44 people with cancer, 35 partners, and 37 health professionals and reported that all of these individuals had highly variable views on what defined sexual satisfaction and how it was rated [72] . In addition, it illustrated that while clinicians highlighted the importance of sexual performance, a more nuanced view on sexual health was more important to patients and their partners – one where intimacy was valued by patients, and that alternative means to express intimacy can be highly satisfying, especially for those in whom the physical impact of treatment rendered sexual performance difficult if not impossible. ●●Spiritual & social domains

Spiritual issues

Spiritual wellbeing has been associated with the ability of cancer patients to enjoy life despite symptoms and to experience substantial personal growth via the cancer experience [73–75] . As an example, in one study 47% endorsed high levels of spirituality, 39% in the mid-range and 14% at moderate-to-minimal levels [73] . Spirituality was associated with better overall quality of life and improvement in several quality-of-life domains in survivors with ovarian cancer, including emotional wellbeing. In addition, spirituality had a positive impact on personal growth and the capacity to integrate the cancer experience. Both early- and advanced-stage survivors agree that their illness strengthened their faith and spiritual beliefs, though more advanced-stage survivors felt that their illness had strengthened their faith (58.5%) than felt that it had not (29.27%). Remarkably, spiritual wellbeing also correlates significantly with spiritual change as a result of having had cancer. Social wellbeing

Social wellbeing in survivorship addresses social roles and the impact of cancer on them. Women cancer survivors are mothers, sisters, wives, coworkers and friends; treatment can have a negative impact on these roles, whether by the onset of significant fatigue or owing to physical effects of treatment (e.g., neuropathy). Besides the inability to perform household chores or socialize with friends, the loss of ability to work and financial concerns may be significant [66,76] .

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Perspective  Duska & Dizon Addressing social and spiritual issues may require a multidisciplinary approach. There are often significant provider limitations and discomfort in discussing these issues. Social workers and chaplains can be very helpful in assisting women with these concerns.

Although SCPs have the potential to streamline the transition to primary care providers, more research is needed to how best to utilize and incorporate them for cancer survivors. This represents an area of active investigation in survivorship.

Living beyond cancer Despite a general consensus among clinicians and oncology programs in the USA that an emphasis on cancer survivorship is not only appropriate but necessary, the optimal way to address survivorship needs has yet to be elucidated. For now, survivorship centers are often limited to larger academic centers and out of reach for a large proportion of cancer patients. In addition, the effective transitioning of care from an oncologist to a primary care provider is not clear. Some of the work performed and still required are reviewed below.

Survivorship clinics

Survivorship care plans

One of the recommendations provided in the IOM report was the utilization of SCPs from the oncologist to the primary care provider as a means of summarizing the treatments administered and the follow-up up recommendations for cancer surveillance and toxicity assessments. Despite this, there is little evidence that SCPs benefit patients. As an example, a Canadian study randomly assigned patients whose care was transferred to their primary care doctor to a regularly scheduled visit (called the oncology discharge visit) with or without the provision of a SCP [77] . There was no difference noted in cancer-related distress at 12 months, quality of life, patient satisfaction, coordination of care or utilization of health services. However, patients whose doctors received the SCP were significantly more likely to identify their primary care doctor as responsible for follow-up. However, all patients enrolled in this study had to meet specific eligibility criteria, which may not represent a wider population of cancer survivors. Specifically, patients had to have no complications related to primary treatment and an established primary care provider. In addition, all patients had to agree on the transition to primary care, which may account for selection bias as at least one prior study showed that as many as 30 and 28% of patients in long-term follow-up in oncology either expressed significant anxiety or refused to be discharged, respectively [78] .

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Another unresolved issue faced by clinicians and patients is how best to implement survivorship services. Indeed, a comprehensive model that address how to provide survivorship care has yet to be established. Multiple issues remain unresolved, including who is best to provide services, what services should consist of, and how best to meet the diverse needs identified [79] . More research should be conducted on the role of self-help, internet support and patient-led groups in survivorship. In addition, financial issues regarding the sustainability of services remains an important consideration. Finally, the justification of cancer survivorship programs must be met by objective evidence of improved outcomes, whether they be measured in quality-of-life gains, survival advantages or the increased ­provision of cost-effective services [80] . Relationship between primary & specialty care practices

In the absence of an ideal model for survivorship care, one potential solution is to adopt a shared care model for follow-up [81] . In this model, patients are followed in a coordinated fashion with visits continued through the oncology and primary care clinics. This espouses a clear delineation of responsibilities for each provider and assumes a common pathway to provide appropriate surveillance (for recurrence or secondary primaries) and treatment for any residual toxicities. The shared care model relies on effective communication between providers to ensure that comprehensive follow-up is maintained. In this model, the decision of who may take the primary role for cancer survivorship is also a decision reached by consensus with the patient entrusted to make the decision that she is most comfortable with. Conclusion With improvements in early detection, surgery and adjuvant therapy, women are living longer and better following a diagnosis of cancer. Despite this finding, the literature illustrates that women do have lingering concerns that may persist after

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Improving quality of life in female cancer survivors: current status & future questions  the end of treatment, which span the psychological, physical, sexual and social domains. As we concentrate more efforts to the improvement of quality of life in female cancer survivors, there are significant opportunities for clinicians to assess in different ways to aid cancer survivors. Future research is crucial to understand how we can best assess and serve our growing numbers of cancer survivors. This should include prospective trials aimed at better understanding of the issues in survivorship, trials aimed at the relief of specific symptoms, and ways to ensure the coordination of care among primary care physicians and cancer specialists, including the implementation of SCPs. Future perspective Cancer survivors and clinicians both agree that meeting the needs following diagnosis and

Perspective

treatment of cancer are critical and unmet needs. As a result, it is likely we will see an emergence of more survivorship clinics in the absence of e­vidence that they improve outcomes. At the same time, there is a concerted effort by oncologists, primary care physicians and survivors themselves to collaborate on answering critical questions in healthcare delivery, including issues related to cost–effectiveness. These collaborations are being supported by novel funding mechanisms, including those offered by the Patient-Centered Outcomes Research Institute [82] . These projects have the potential to provide much needed data that may inform best practices in survivorship care, including on whether SCPs meet their intended objectives and how best to coordinate care among providers.

EXECUTIVE SUMMARY Background ●●

Over 13 million people have a history of cancer in the USA alone.

Defining a cancer survivor ●●

A cancer survivor is broadly defined as any person living with a diagnosis of cancer and starts from the time of diagnosis.

●●

Cancer survivors have different needs as they move forward in their cancer journey, which may be represented by

different ‘seasons’ in survivorship. These include acute survivorship, representing the time of diagnosis and treatment; extended survivorship, representing the time of surveillance following treatment; and permanent survivorship, representing cure or long-term remission. Issues in cancer survivors ●●

Treatment can impact the physical domain, long after it has completed. For women, major issues involve

cardiovascular health, gastrointestinal toxicities, gynecologic issues, sexuality and lifestyle-related problems, such as obesity. ●●

Emotional and psychologic health can also be impacted by treatment. These include psychologic issues

(e.g., depression, anxiety, stress and guilt), body-image problems, fear of recurrence and issues with intimacy. ●●

Spiritual wellbeing is associated with better quality of life in cancer survivors. It remains an important coping mechanism for cancer survivors.

●●

Treatment can impact the roles women play in their social lives as mothers, sisters, wives, coworkers and friends. The result can be isolation and may result in other complications, including financial stress.

Living beyond cancer ●●

That the needs of cancer survivors require more attention is widely accepted. However, the optimal approach to cancer survivorship remains unclear.

●●

Although the US Institute of Medicine has endorsed survivorship care plans as a mechanism to improve the quality of care for this population, there is little evidence that they are effective.

●●

The role of survivorship clinics also remains unresolved.

●●

An ideal model of delivery entails shared care between oncology specialists and primary care providers with clear delineation of responsibilities of each provider and relies on effective communication.

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Perspective  Duska & Dizon Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes

References

12 Swain SM, Whaley FS, Ewer MS. Congestive

heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97, 2869–2879 (2003).

Papers of special note have been highlighted as: • of interest; •• of considerable interest 1

2

3

4

5

6

Siegel R, DeSantis C, Virgo K et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J. Clin. 62, 220–241 (2012). de Moor JS, Mariotto AB, Parry C et al. Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol. Biomarkers Prev. 22, 561–570 (2013). Surveillance, Epidemiology, and End Results Cancer Statistics Review 1975-2010. http://seer.cancer.gov/csr/1975_2010/ browse_csr.php?section=2&page=sect_02_ table.21.html Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA 86, 1195–1200 (2001). Obesity and Cancer Risk - National Cancer Institute. http://cancer.gov/cancertopics/factsheet/risk/ obesity From cancer patient to cancer survivor: lost in transition. http://books.nap.edu/openbook.php?record_ id=11468 

•• Seminal paper that outlines the issues faced by cancer survivors who have completed treatment for their malignancies. It served as the wake-up call for oncologists and primary care providers. 7

National Coalition for Cancer Survivorship (NCCS). www.canceradvocacy.org

8

Miller K, Merry B, Miller J. Seasons of survivorship revisited. Cancer J. 14, 369–374 (2008).

9

Cassell EJ. The nature of suffering: physical, psychological, social, and spiritual aspects. NLN Publ. 15-2461, 1–10 (1992).

10 Giordano SH, Kuo YF, Freeman JL, Buchholz

TA, Hortobagyi GN, Goodwin JS. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J. Natl Cancer Inst. 97, 419–424 (2005). 11 Bouillon K, Haddy N, Delaloge S. Long-term

cardiovascular mortality after radiotherapy for breast cancer. J. Am. Coll. Cardiol. 57, 445–452 (2011).

1024

employment, consultancies, honoraria, stock ownership or options, expert t­estimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. a review of the literature. J. Cancer Surviv. 4, 346–360 (2010). 23 Bodurka DC, Sun CC. Sexual function after

gynecologic cancer. Obstet. Gynecol. Clin. North Am. 33, 621–630, ix (2006).

13 Andreyev HJ, Wotherspoon A, Denham JW,

•

Hauer-Jensen M. ‘Pelvic radiation disease’: new understanding and new solutions for a new disease in the era of cancer survivorship. Scand. J. Gastroenterol. 46, 389–397 (2011).

24 Audette C, Waterman J. The sexual health of

Outlines the long-term consequences following pelvic radiation, which was not as well-characterized previously. 

25 Schultz WC, Van De Wiel HB. Sexuality,

14 Nout RA, Putter H, Jürgenliemk-Schulz IM.

Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer: first results of the randomized PORTEC-2 trial. J. Clin. Oncol. 27, 3547–3556 (2009). 15 Andreyev J. Gastrointestinal symptoms after

pelvic radiotherapy: a new understanding to improve management of symptomatic patients. Lancet Oncol. 8, 1007–1017 (2007). 16 Abayomi J, Kirwan J, Hackett A. The

prevalence of chronic radiation enteritis following radiotherapy for cervical or endometrial cancer and its impact on quality of life. Eur. J. Oncol. Nurs. 13, 262–267 (2009). 17 Abayomi J, Kirwan J, Hackett A, Bagnall G.

A study to investigate women’s experiences of radiation enteritis following radiotherapy for cervical cancer. J. Hum. Nutr. Diet. 18, 353–363 (2005). 18 Gillespie C, Goode C, Hackett C, Andreyev

HJ. The clinical needs of patients with chronic gastrointestinal symptoms after pelvic radiotherapy. Aliment. Pharmacol. Ther. 26, 555–563 (2007). 19 Putta S, Andreyev HJ. Faecal incontinence:

a late side-effect of pelvic radiotherapy. Clin. Oncol. (R. Coll. Radiol.) 17, 469–477 (2005). 20 Henson CC, Andreyev HJ, Symonds RP, Peel

D, Swindell R, Davidson SE. Late-onset bowel dysfunction after pelvic radiotherapy: a national survey of current practice and opinions of clinical oncologists. Clin. Oncol. (R. Coll. Radiol.) 23, 552–557 (2011). 21 Andreyev HJ, Wotherspoon A, Denham JW,

Hauer-Jensen M. Defining pelvic-radiation disease for the survivorship era. Lancet Oncol. 11, 310–312 (2010). 22 Brotto LA, Yule M, Breckon E. Psychological

interventions for the sexual sequelae of cancer:

Future Oncol. (2014) 10(6)

women after gynecologic malignancy. J. Midwifery Womens Health 55, 357–362 (2010). intimacy, and gynecological cancer. J. Sex Marital Ther. 29(Suppl. 1), 121–128 (2003). 26 DeSimone M, Spriggs E, Gass JS, Carson SA,

Krychman ML, Dizon DS. Sexual dysfunction in female cancer survivors. Am. J. Clin. Oncol. 37(1), 101–106 (2012). •

Good review of female sexual dysfunction for female cancer survivors.

27 Graziottin A, Basson R. Sexual dysfunction

in women with premature menopause. Menopause 11(6 Pt 2), 766–777 (2004). 28 Flay LD, Matthews JH. The effects of

radiotherapy and surgery on the sexual function of women treated for cervical cancer. Int. J. Radiat. Oncol. Biol. Phys. 31, 399–404 (1995). 29 Quick AM, Seamon LG, Abdel-Rasoul M,

Salani R, Martin D. Sexual function after intracavitary vaginal brachytherapy for early-stage endometrial carcinoma. Int. J. Gynecol. Cancer 22, 703–708 (2012). 30 Wiggins DL, Wood R, Granai CO, Dizon

DS. Sex, intimacy, and the gynecologic oncologists: survey results of the New England Association of Gynecologic Oncologists (NEAGO). J. Psychosoc. Oncol. 25, 61–70 (2007). 31 American Psychiatric Association (Eds).

Diagnostic and Statistical Manual of Mental Disorders (5th Edition). American Psychiatric Association, DC, USA 2013. 32 Hill EK, Sandbo S, Abramsohn E et al.

Assessing gynecologic and breast cancer survivors’ sexual health care needs. Cancer 117, 2643–2651 (2011). 33 Costantino D, Guaraldi C. Effectiveness and

safety of vaginal suppositories for the treatment of the vaginal atrophy in postmenopausal women: an open, noncontrolled clinical trial. Eur. Rev. Med. Pharmacol. Sci. 12, 411–416 (2008).

future science group

Improving quality of life in female cancer survivors: current status & future questions  34 Penson RT, Gallagher J, Gioiella ME et al.

Sexuality and cancer: conversation comfort zone. Oncologist 5, 336–344 (2000). 35 Barakat RR, Bundy BN, Spiritos NM, Bell J,

Mannel RS. Randomized double-blind trial of estrogen replacement therapy versus placebo in stage I or II endometrial cancer: a Gynecologic Oncology Group Study. J. Clin. Oncol. 24, 587–592 (2006). 36 Hopkins ML, Fung MF, Le T, Shorr R.

Ovarian cancer patients and hormone replacement therapy: a systematic review. Gynecol. Oncol. 92, 827–832 (2004). 37 Le Ray I, Dell’Aniello S, Bonnetain F,

Azoulay L, Suissa S. Local estrogen therapy and risk of breast cancer recurrence among hormone-treated patients: a nested case–control study. Breast Cancer Res. Treat. 135, 603–609 (2012). •

Represents some of the low-quality data that informs the risks of endocrine therapy among breast cancer srurvivors taking antiestrogen treatments.

38 Yamaguchi N, Okajima Y, Fujii T, Natori A,

Kobayashi D. The efficacy of nonestrogenic therapy to hot flashes in cancer patients under hormone manipulation therapy: a systematic review and meta-analysis. J. Cancer Res. Clin. Oncol. 139, 1701–1707 (2013). 39 Bygdeman M, Swahn ML. Replens versus

dienoestrol cream in the symptomatic treatment of vaginal atrophy in postmenopausal women. Maturitas 23, 259–263 (1996). •

First to show that Replens can mirror the positive impacts of estrogen for women with vaginal atrophy.

40 Lee Y-K, Chung HH, Kim JW, Park N-H,

Song Y-S, Kang S-B. Vaginal pH-balanced gel for the control of atrophic vaginitis among breast cancer survivors: a randomized controlled trial. Obstet. Gynecol. 117, 922–927 (2011). 41 Loprinzi CL, Sbu-Ghazaleh S, Sloan JA et al.

Phase III randomized double-blind study to evaluate the efficacy of a polycarbophil-based vaginal moisturizer in women with breast cancer. J. Clin. Oncol. 15, 969–973 (1997). 42 Croft H, Settle E Jr, Houser T, Batey SR,

Donahue RM, Ascher JA. A placebocontrolled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline. Clin. Ther. 21, 643–658 (1999). 43 Lavigne JE, Heckler C, Mathews JL et al. A

randomized, controlled, double-blinded clinical trial of gabapentin 300 versus 900 mg versus placebo for anxiety symptoms in breast

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cancer survivors. Breast Cancer Res. Treat. 136, 479–486 (2012).

54 Rosen A. Third-party reproduction and

adoption in cancer patients. J. Natl Cancer Inst. Monogr. 34, 91–93 (2005).

44 Maclaughlan David S, Salzillo S, Bowe P

et al. Randomised controlled trial comparing hypnotherapy versus gabapentin for the treatment of hot flashes in breast cancer survivors: a pilot study. BMJ Open 3, e003138 (2013).

55 Plante M, Gregoire J, Renaud M-C, Roy M.

The vaginal radical trachelectomy: an update of a series of 125 cases and 106 pregnancies. Gynecol. Oncol. 121, 290–297 (2011). 56 Metzger ML, Meacham LR, Patterson B et al.

45 Demark-Wahnefried W, Aziz NM, Rowland

Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications. J. Clin. Oncol. 31, 1239–1247 (2013).

JH, Pinto BM. Riding the crest of the teachable moment: promoting long-term health after the diagnosis of cancer. J. Clin. Oncol. 23, 5814–5830 (2005). 46 Courneya KS, Karvinen KH, Campbell KL

et al. Associations among exercise, body weight, and quality of life in a populationbased sample of endometrial cancer survivors. Gynecol. Oncol. 97, 422–430 (2005). 47 Chlebowski RT, Blackburn GL, Thomson

CA et al. Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study. J. Natl. Cancer Inst. 98, 1767–1776 (2006). 48 Kwan ML, Weltzien E, Kushi LH, Castillo A,

Slattery ML, Caan BJ. Dietary patterns and breast cancer recurrence and survival among women with early-stage breast cancer. J. Clin. Oncol. 27, 919–926 (2009).

•• Important article that assesses reproductive health for the population of women who may have been treated at an early age for cancer. 57 Woodruff TK. The Oncofertility

Consortium – addressing fertility in young people with cancer. Nat. Rev. Clin. Oncol. 7, 466–475 (2010). 58 Norton TR, Manne SL, Rubin S et al.

Prevalence and predictors of psychological distress among women with ovarian cancer. J. Clin. Oncol. 22, 919–926 (2004). 59 Sun CC, Ramirez PT, Bodurka DC. Quality

of life for patients with epithelial ovarian cancer. Nat. Clin. Pract. Oncol. 4, 18–29 (2007).

49 Jim HS, Phillips KM, Chait S et al.

Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J. Clin. Oncol. 30, 3578–3587 (2012). •• Important meta-analysis on cognitive complaints following treatment for breast cancer.

60 Shinn EH, Taylor CL, Kilgore K et al.

Associations with worry about dying and hopelessness in ambulatory ovarian cancer patients. Palliat. Support. Care 7, 299–306 (2009). 61 Carlson LE, Bultz BD. Cancer distress

50 Rugo HS, DeLuca AN, Heflin L, Fang S,

Melisko ME. Prospective study of cognitive function (cog fcn) in women with early-stage breast cancer (ESBC): predictors of cognitive decline. Presented at: 2013 Breast Cancer Symposium. San Francisco, CA, USA, 7–9 September 2013. 51 Ahles TA, Root JC, Ryan EL. Cancer- and

cancer treatment-associated cognitive change: an update on the state of the science. J. Clin. Oncol. 30, 3675–3686 (2012). 52 Leone G, Mele L, Pulsoni A, Equitani F,

Pagano L. The incidence of secondary leukemias. Haematologica 84, 937–945 (1999). 53 Loren AW, Mangu PB, Beck LN et al.

Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J. Clin. Oncol. 31, 2500–2510 (2013). •• Important paper that outlines the clinical guidelines regarding fertility among patients with cancer.

Perspective

screening. Needs, models, and methods. J. Psychosom. Res. 55, 403–409 (2003). 62 Bultz BD, Carlson LE. Emotional distress:

the sixth vital sign – future directions in cancer care. Psychooncology 15, 93–95 (2006). •

Emphasizes the importance of detecting and treating distress in the patient living with or beyond cancer.

63 NCCN Clinical Practice Guidelines in

Oncology. www.nccn.org/professionals/physician_gls/f_ guidelines.asp#supportive  64 Armes J, Crowe M, Colbourne L et al.

Patients’ supportive care needs beyond the end of cancer treatment: a prospective, longitudinal survey. J. Clin. Oncol. 27, 6172–6179 (2009). 65 Hodgkinson K, Butow P, Hunt GE et al. The

development and evaluation of a measure to assess cancer survivors’ unmet supportive care needs: the CaSUN (Cancer Survivors’ Unmet

www.futuremedicine.com

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Perspective  Duska & Dizon Needs measure). Psychooncology 16, 796–804 (2007). 66 Hodgkinson K, Butow P, Hunt GE,

72 Perz J, Ussher JM, Gilbert E. Constructions

Pendlebury S, Hobbs KM, Wain G. Breast cancer survivors’ supportive care needs 2–10 years after diagnosis. Support. Care Cancer Off. J. Multinatl Assoc. Support. Care Cancer 15, 515–523 (2007). 67 Mirabeau-Beale KL, Kornblith AB, Penson

RT et al. Comparison of the quality of life of early and advanced stage ovarian cancer survivors. Gynecol. Oncol. 114, 353–359 (2009). 68 Fitch MI, Steele R. Identifying supportive

care needs of women with ovarian cancer. Can. Oncol. Nurs. 20, 66–74 (2010). 69 Browall M, Carlsson M, Horvath GG.

Information needs of women with recently diagnosed ovarian cancer – a longitudinal study. Eur. J. Oncol. Nurs. 8, 200–207; discussion 208–210 (2004). 70 Gonçalves V, Jayson G, Tarrier N. A

longitudinal investigation of psychological disorders in patients prior and subsequent to a diagnosis of ovarian cancer. J. Clin. Psychol. Med. Settings 17, 167–173 (2010). 71 Abbott-Anderson K, Kwekkeboom KL. A

systematic review of sexual concerns reported

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by gynecological cancer survivors. Gynecol. Oncol. 124, 477–489 (2012). of sex and intimacy after cancer: Q methodology study of people with cancer, their partners, and health professionals. BMC Cancer 13, 270 (2013). •

Important article that discusses intimacy as a primary end point on its own in these patients, beyond that of intercourse.

73 Wenzel LB, Donnelly JP, Fowler JM et al.

Resilience, reflection, and residual stress in ovarian cancer survivorship: a gynecologic oncology group study. Psychooncology 11, 142–153 (2002). 74 Brady MJ, Peterman AH, Fitchett G, Mo M,

Cella D. A case for including spirituality in quality of life measurement in oncology. Psychooncology 8, 417–428 (1999). 75 Carpenter JS, Brockopp DY, Andrykowski

MA. Self-transformation as a factor in the self-esteem and well-being of breast cancer survivors. J. Adv. Nurs. 29, 1402–1411 (1999). 76 Howell D, Fitch MI, Deane KA. Impact of

ovarian cancer perceived by women. Cancer Nurs. 26, 1–9 (2003).

Future Oncol. (2014) 10(6)

77 Grunfeld E, Julian JA, Pond G et al.

Evaluating survivorship care plans: results of a randomized, clinical trial of patients with breast cancer. J. Clin. Oncol. 29, 4755–4762 (2011). 78 Thomas SF, Glynne-Jones R, Chait I, Marks

DF. Anxiety in long-term cancer survivors influences the acceptability of planned discharge from follow-up. Psychooncology 6, 190–196 (1997). 79 MacBride SK, Whyte F. Survivorship and the

cancer follow-up clinic. Eur. J. Cancer Care (Engl.) 7, 47–55 (1998). 80 Aziz NM. Cancer survivorship research: state

of knowledge, challenges and opportunities. Acta Oncol. Stockh. Swed. 46, 417–432 (2007). 81 Ganz PA. A teachable moment for

oncologists: cancer survivors, 10 million strong and growing! J. Clin. Oncol. 23, 5458–5460 (2005). •• Important paper that discusses the growth in cancer survivors in the USA. 82 Patient-Centered Outcomes Research

Institute. www.pcori.org

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