Survivorship

Abstract

Advances in the treatment of childhood cancers and supportive care have resulted in marked improvements in survival rates. As of 2009, there were an estimated 363,000 survivors of childhood cancer in the United States; of these approximately 24 % have survived more than 30 years since their diagnosis, contributing to the growing number of long-term survivors of childhood and adult cancer in the United States (Mariotto et al. 2009). However, the use of chemotherapy, radiation, and/or surgery at an early age can contribute to complications that may not become apparent until years after the completion of therapy (Armenian and Robison 2013). A recent article from the Childhood Cancer Survivor Study (CCSS) cohort reported that two out of three survivors will develop a chronic health condition, and more than one-third will develop a condition that is severe or life-threatening (Oeffinger et al. 2006). To address the needs of this growing population, in 2005, the Institute of Medicine (IOM) published From Cancer Patient to Cancer Survivor: Lost in Transition, a report outlining the gaps in survivorship care. The report introduced the concept of survivorship care plans to summarize information critical to the individual’s long-term care, such as the cancer diagnosis, treatment, and potential consequences; the timing and content of follow-up visits; tips on maintaining a healthy lifestyle and preventing recurrent or new cancers; legal rights affecting employment and insurance; and the availability of psychological and support services (Hewitt et al. 2006). This report provided the basis for professional organizations including the Children’s Oncology Group, National Comprehensive Cancer Network and the American Society of Clinical Oncology to publish evidenced-based guidelines for survivorship care for cancer survivors. It is crucial for health-care professionals who care for cancer survivors at all stages of their survivorship to be familiar with actual and potential late effects survivors may experience throughout their lifetime.

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16.1 Introduction

Advances in the treatment of childhood cancers and supportive care have resulted in marked improvements in survival rates. However, the use of chemotherapy, radiation, and/or surgery at an early age can contribute to complications that may not become apparent until years after the completion of therapy (Armenian and Robison 2013). A recent article from the Childhood Cancer Survivor Study (CCSS) cohort reported that two out of three survivors will develop a chronic health condition, and more than one-third will develop a condition that is severe or lifethreatening (Oeffinger et al. 2006). Several groups have published reports outlining gaps in survivorship care. In addition, these reports have introduced guidelines for survivorship care. These guidelines include testing to assess possible long-term affects of chemotherapy, radiation and/or surgery, including heart and renal function, as well as evaluation of hearing, sexual function, and work-up for secondary malignancies.

16.2 Survivorship Guideline Overview

The 2005 IOM report established five essential components of survivorship care that have been adapted and implemented by leading oncology professional organizations into their own individual survivorship guidelines. These include the following:

• 1. Prevention of new and recurrent cancers and other late effects

• 2. Surveillance of cancer spread, recurrence, or second cancers

• 3. Assessment of late psychosocial and physical effects

• 4. Intervention for consequences of cancer and treatment (e.g., medical problems, symptoms, psychological distress, financial and social concerns)

• 5. Coordination of care between primary care providers and specialists to ensure that all of the survivor’s health needs are met (NCCN 2014)

In 2011, the LIVESTRONG foundation convened a meeting of experts and stakeholders in the survivorship field to define essential components of survivorship care. After 2 days of consensus building, the group agreed on the following elements that all medical settings must provide for cancer survivors, either directly or through referral:

• 1. Survivorship care plan, psychosocial care plan, and treatment summary

• 2. Screening for new cancers and surveillance for recurrence

• 3. Care coordination strategy that addresses care coordination with PCPs and primary oncologists

• 4. Health promotion education

• 5. Symptom management and palliative care (https://assets-livestrong-org.s3.amazonaws.com/media/site_proxy/data/7e26de7ddcd2b7ace899e75f842e50c0075c4330.pdf)

In 2012, the Commission on Cancer (CoC) and the American College of Surgeons (ACS) updated their accreditation standards for hospital cancer programs (http://www.facs.org/cancer/coc/programstandards2012.html). Their patient-centered focus now includes the development and dissemination of a survivorship plan for all patients. This requirement is to be phased in by 2015.

16.2.1 Children’s Oncology Group Long-Term Follow-Up Guidelines

The Children’s Oncology Group (COG) is a 238-member National Cancer Institute-supported cooperative clinical trials group whose goals include minimizing the risk of long-term effects that may impact duration and/or quality of life in pediatric cancer survivors (Landier et al. 2006). The first version of the risk-based, exposure-related guidelines (Long-Term Follow-up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer) for use in directing follow-up care for survivors of pediatric malignancies was published in March of 2003. The COG guidelines represent a hybrid of evidence-based and consensus-driven approaches to guideline development and consist of clinically relevant screening recommendations that take into account the specialized health-care needs of pediatric cancer survivors (Landier et al. 2006). The guidelines are designed to standardize and direct follow-up care that facilitates early identification of and intervention for treatment-related complications (Landier et al. 2006). They also provide a platform for research into the efficacy and cost-effectiveness of health screening of this population. Recommendations for follow-up of individuals can be customized from the treatment exposure history including chemotherapy agents, radiation therapy and surgical history. The guideline supplies a patient treatment summary and an extensive list of “health links” offering detailed information on guideline-specific topics for survivors. The guidelines are updated at least every 5 years by a multidisciplinary task force who monitor the literature and report to the COG Long-Term Follow-up Guidelines Core Committee (Landier et al. 2004). Clinicians are advised to check the Children’s Oncology Group website periodically for the latest updates and revisions to the guidelines which are posted at www.survivorshipguidelines.org (Table 16.1).

Table 16.1 Example of a summary of cancer treatment (abbreviated)

16.2.2 National Comprehensive Cancer Network Survivorship Guidelines

On January 31, 1995, this national alliance was created to develop and institute standards of care for the treatment of cancer and perform outcomes research. With 13 original NCCN Member Institutions, the goal was to ensure delivery of high-quality, cost-effective services to people with cancer across the country. NCCN became a developer and promoter of national programs to facilitate the fulfillment of NCCN Member Institution missions in education, research, and patient care. Now an alliance of 25 of the world’s leading cancer centers, NCCN develops and communicates scientific, evaluative information to better inform the decision-making process between patients and physicians, ultimately improving patient outcomes. The NCCN Survivorship guidelines were originally released in 2013 and included eight distinct areas: anxiety and depression, cognitive function, exercise, fatigue, immunizations and infections, pain, sexual function, and sleep disorders. A new updated version was published in 2014. These guidelines, however, are not specifically intended to provide guidance for the care of survivors of childhood cancers and refer providers to the Children’s Oncology group survivorship guidelines, as well as the NCCN guidelines for Adolescent and Young Adults available at www.NCCN.org.

16.2.3 American Society of Clinical Oncology

The American Society of Clinical Oncology published their guide to survivorship care in 2014 entitled Providing High Quality Survivorship Care in Practice: An ASCO guide. It further detailed high-quality survivorship care to include the following:

• 1. Surveillance for recurrence

• 2. Monitoring for and managing psychosocial and medical late effects

• 3. Providing screening recommendations for second cancers

• 4. Providing health education to survivors regarding their diagnoses, treatment exposures, and potential late and long-term effects

• 5. Providing referrals to specialists and resources as indicated

• 6. Familial genetic risk assessment (as appropriate)

• 7. Guidance about diet, exercise, and health promotion activities

• 8. Providing resources to assist with financial and insurance issues

• 9. Empowering survivors to advocate for their own health-care needs (Oeffinger et al. 2014).

This guide discusses how to build a survivorship care program for clinicians including models of care, implementation of a survivorship program, providing care, and measuring the quality of survivorship care. It also includes resources for transitioning care of survivors and working with primary care providers to continue high-quality health care addressing the unique needs of cancer survivors.

16.3 Treatment-Related Late Effects

16.3.1 Cardiac Toxicity

Cardiac toxicity during or following treatment for pediatric bone tumors is largely due to the inclusion of the anthracycline, doxorubicin, given at relatively high doses. Most treatment regimens for bone sarcomas require a minimum cumulative doxorubicin dose of 375 mg/m², with some as high as 600 mg/m². The pathophysiology of doxorubicin-induced cardiac damage is incompletely understood, but one important mechanism is thought to be cardiomyocyte death due to the production of free radicals and oxidative stress (Janeway and Grier 2010). Clinically apparent doxorubicin-associated cardiotoxicity presenting as congestive heart failure has been classified as acute, chronic, and late based on the timing of onset related to the doxorubicin administration (Janeway and Grier 2010). Acute cardiotoxicity, occurring after a single dose or course of doxorubicin is rare, particularly with modern chemotherapy regimens. Chronic doxorubicin-associated cardiotoxicity occurs within weeks to months of completing therapy. There are rare reports of late cardiotoxicity in which clinically apparent doxorubicin-induced heart failure occurs more than 1 year after the completion of therapy, particularly in association with periods of increased cardiac growth and demand such as puberty and pregnancy (Janeway and Grier 2010).

Data from the Childhood Cancer Survivor Study (CCSS) demonstrate that survivors of osteosarcoma have been reported to have a cumulative incidence of 10 % at 20 years for acute congestive heart failure for those patients who received >300 mg/m² (Nagarajan et al. 2011). The Rizzoli Institute has reported the study with the longest follow-up and most complete reporting of adverse events in patients with osteosarcoma. This study reported a 4 % incidence of severe doxorubicin-induced cardiotoxicity (Oeffinger et al. 2006). Cardiotoxicity was noted 1–12 weeks after the completion of therapy, with the exception of one patient who developed cardiac toxicity during the last trimester of pregnancy 8 years after completing treatment (Oeffinger et al. 2006). The Italian Sarcoma Group also reported their experience in patients treated for osteosarcoma from 1983 to 2006 with a reported incidence of cardiomyopathy of 2 % (Longhi et al. 2012). The median interval from the cessation of chemotherapy to the onset of cardiomyopathy was 2 months with a median total dose of doxorubicin of 480 mg/m² (Longhi et al. 2012).

Survivors of Ewing sarcoma reported in the CCSS were more likely than siblings to have arrhythmias (7.4 % vs. 2.9 %) and other serious cardiac conditions (4.5 % vs. 0.5 %) (Ginsberg et al. 2010). After adjusting for age, sex, and race/ethnicity, the relative risk of a survivor having an arrhythmia or serious cardiac event 5 or more years after diagnosis is 2.3 (95 % CI = 1.4–3.9) and 7.5 (95 % CI = 3.1–18.7), respectively (Ginsberg et al. 2010). The Scandinavian Sarcoma Study Group also demonstrated an increased incidence in heart disease and hypertension in Ewing sarcoma survivors compared to age- and gender-matched individuals from the general population, reporting an odds ratio for heart disease of 7.9 (95 % CI = 2.5–25.3; p = 0.001) (Aksnes et al. 2009). They described two patients treated before the age of 4 who developed cardiotoxicity, and concluded that age of exposure along with cumulative dose were independent risk factors (Aksnes et al. 2009). In the Italian Sarcoma Group report, the cardiotoxicity incidence was 1.3 %, with a median interval from the cessation of chemotherapy to the onset of cardiomyopathy of 3 months (Longhi et al. 2012). The median doxorubicin dose was 400 mg/m².

Cumulative dose is the most important factor affecting the risk of doxorubicin-associated cardiotoxicity, with a significant increase in the incidence of heart failure occurring after the administration of 550 mg/m² (Janeway and Grier 2010). Additional risk factors for doxorubicin-induced cardiotoxicity include older (greater than 40) and very young (less than 4 years) age, and female sex (Chrischilles et al. 2014). The number of patients who have doxorubicin-associated heart failure is much lower than the number of patients who develop echocardiographic abnormalities after treatment with doxorubicin.

Dexrazoxane is a topoisomerase 2 inhibitor that scavenges free radicals and chelates heavy metals. It is thought to protect the heart from doxorubicin-induced cardiotoxicity by forming complexes with iron, preventing both tissue damage and the formation of free radicals (Janeway and Grier 2010). Two randomized controlled studies in children show that dexrazoxane decreases the risk of short-term, subclinical cardiac toxicity without increasing infectious complications (Wexler et al. 1996; Moghrabi et al. 2007). Additional studies are required to determine whether dexrazoxane decreases the risk of late cardiotoxicity. A recent study reported an increased incidence of secondary malignancies in patients with Hodgkin’s disease who were randomized to receive dexrazoxane, but concerns have been raised about the methodology of the study (Hellmann 2007; Lipshultz et al. 2007; Tebbi et al. 2007). A trial in which children with leukemia were randomized to receive dexrazoxane did not show an increase in secondary leukemias in patients who received dexrazoxane (Barry et al. 2008). Dexrazoxane has not been systematically assessed in any bone sarcoma studies, so it is not possible at this time to make an evidence-based guideline for or against its use.

The Children’s Oncology Group long-term follow-up guidelines recommend detailed history of shortness of breath, orthopnea, chest pain, palpitations, or if under 25 years abdominal symptoms including nausea or vomiting. Physical exam should include assessment of cardiac murmur, S3, S4, increased P2 sound, pericardial rub, rales, wheezes, jugular venous distension, and peripheral edema. Echocardiogram at entry into long-term follow-up is recommended, and then periodically based on age at treatment, radiation dose, and cumulative anthracycline dose. EKG is recommended at entry into long-term follow-up, repeat as clinically indicated (COG 2013) (Table 16.2).

Table 16.2a Recommended frequency of echocardiogram (or comparable cardiac imaging) following anthracyclines

Table 16.2b Recommended frequency of echocardiogram (or comparable cardiac imaging) following radiation

16.3.2 Renal Toxicity

The treatment-related nephrotoxicity for bone tumor patients is primarily due to the chemotherapeutic agents, namely, cisplatin, methotrexate, and ifosfamide. Cisplatin and methotrexate have been a standard of care in the treatment of osteosarcoma since the 1970s, and remaining two of the three drug combination routinely utilized for localized osteosarcoma. Ifosfamide was introduced in first-line therapy of childhood soft tissue sarcomas and bone sarcomas since the 1980s and continues to be used for bone sarcomas today.

The nephrotoxicity of cisplatin is considered dose-related and includes a variable reduction of glomerular filtration rate (GFR) along with tubular dysfunction. Cisplatin directly damages the tubular epithelial cells, resulting in a pathology resembling acute tubular necrosis that leads to increased magnesium loss in the urine expressed as increased renal magnesium (Mg) excretion and hypomagnesaemia (Janeway and Grier 2010). Cisplatin-induced hypokalemia and hypocalcemia are the result of both altered renal processing in the presence of hypomagnesaemia and increased kidney losses. In 12–20 % of patients, cisplatin-associated hypomagnesaemia persists after the completion of chemotherapy (Stohr et al. 2007). About 60 % of children receiving median cisplatin doses of 500–600 mg/m² have decreased glomerular function at the completion of therapy (Skinner et al. 1998). However, these deficits in glomerular filtration seem to be mild, and improvement is common. In two long-term follow-up studies of osteosarcoma survivors receiving ifosfamide in addition to standard therapy with methotrexate/adriamycin/cisplatin therapy, the incidence of glomerular impairment was low and the extent of dysfunction was minimal (Koch Nogueira et al. 1998; Arndt et al. 1999). The risk of cisplatin-associated nephrotoxicity is associated with higher dose rates and greater dose intensity. Consequently, prolonged infusions and fractionated doses administered over several days have been recommended (Launay-Vacher et al. 2008).

Methotrexate and its metabolites can precipitate in the renal tubules causing acute renal insufficiency and failure (Janeway and Grier 2010). Early studies of high-dose methotrexate done in the 1970 demonstrated that nephrotoxicity was common, and the mortality rate following high-dose methotrexate was as high as 6 % (Von Hoff et al. 1977). The use of aggressive hydration and alkalization of urine as well as the use of leucovorin rescue along with routine monitoring of methotrexate levels has decreased the incidence of nephrotoxicity following high-dose methotrexate to 1–8 % (Janeway and Grier 2010). Unfortunately, severe and fatal cases of high-dose methotrexate-associated nephrotoxcity still occur in patients with osteosarcoma (Widemann et al. 2004). Methotrexate-induced nephrotoxicity is typically an acute treatment side effect and rarely causes long-term renal damage as a single agent. However, it may contribute to the cumulative effects of other nephrotoxic agents.

Many studies have demonstrated that tubular toxicity develops as a result of treatment with ifosfamide. Both glomerular and tubular function may be affected by ifosfamide, and a variety of tubular disorders, such as Fanconi syndrome and hypophosphatemic rickets, have been described. The combination of cisplatin and ifosfamide is particularly hazardous, since evidence suggests that ifosfamide nephrotoxicity is possibly potentiated by cisplatin. Ifosfamide-related proximal tubular damage is typically observed with a reduction in glomerular filtration rate, hypophosphatemia, and glycosuria (Oberlin et al. 2009). In one study by the Children’s Oncology Group, in which the cumulative dose of ifosfamide was 71 g/m², Fanconi syndrome was described in approximately 7 % of patients (Goorin et al. 2002). Fanconi syndrome is a global proximal tubule defect in which resorption of glucose, amino acids, phosphate, and bicarbonate in the proximal tubule is impaired. Excessive urinary losses result in metabolic acidosis, hypophosphatemia, and hypokalemia. Although less prevalent, glomerular dysfunction can also develop, usually in patients who have evidence of tubular toxicity (Janeway and Grier 2010). When measured 6 months after the completion of therapy, 9 % of patients who received a median ifosfamide dose of 62 g/m² had a glomerular filtration rate below 60 ml/min/1.73 m². Although glomerular dysfunction is usually mild, acute renal failure can also occur, particularly at high cumulative doses. In most patients, ifosfamide-associated nephrotoxicity remains stable over time. A small proportion of patients will have significant improvements or worsening of both tubular and glomerular function (Heney et al. 1991). The risk of ifosfamide-associated nephrotoxicity is associated with higher cumulative doses, younger age at the time of administration, preexisting renal dysfunction, exposure to other nephrotoxic drugs, and treatment with cisplatin (Loebstein et al. 1999). Other than aggressive hydration, there are no specific therapies or modifications that are known to protect against the development of ifosfamide-related nephrotoxicity.

The COG long-term follow-up guidelines recommend annual blood pressure monitoring, annual urinalysis, and serum chemistries including BUN, creatinine at baseline and as clinically indicated for patients who received cisplatin and/or ifosfamide to monitor for renal toxicity (COG 2013).

16.3.3 Ototoxicity

Hearing loss as a late effect of therapy can occur after exposure to cancer-therapeutic agents such as platinum compounds and cranial radiation. Platinum agents cisplatin and carboplatin have improved cure rates in many childhood cancers including bone sarcomas, but their use may result in irreversible high-frequency sensorineural hearing loss. The deficit is progressive with increasing cumulative dosing (Grewal et al. 2010). In general, approximately 50 % of children treated with cisplatin-based regimens reportedly develop some degree of permanent hearing loss (Knight et al. 2005). With cumulative doses in excess of 400 mg/m², typical for osteosarcoma treatment, up to 90 % of young children may suffer moderate-to-severe deficits, with severe hearing loss seen in up to 25 % (Knight et al. 2005).

The mechanism of platinum cochlear toxicity is through interference with signal transduction from the Organ of Corti in the cochlea (Grewal et al. 2010). Three sites of damage occur: the outer hair cells (effector cells), the spiral ganglion (main nerve supply to the cochlea), and the stria vascularis (primary blood supply) (Rybak et al. 2007). Chemotherapy-related damage begins in the first row of outer hair cells at the base of the cochlea, where high-frequency sounds are processed. Therefore, the use of platinum compounds can result in bilateral sensorineural hearing loss, which initially involves the higher frequencies (4,000–8,000 Hz) (Schell et al. 1989). With increasing doses of chemotherapy, or when compounded by other ototoxic factors such as radiation or aminoglycoside use, loss of hair cells can progress apically in the cochlea to involve the speech frequencies. High-frequency hearing sensitivity is critical for the understanding of speech. The speech frequencies are considered to be 500–2,000 Hz.

Major risk factors for hearing loss are younger age, higher cumulative dose of chemotherapy, central nervous system tumors, and concomitant CNS radiation. Individual susceptibility to cisplatin is variable. Dolan et al. demonstrated that 38–47 % of human variation in susceptibility to cisplatin-induced ototoxicity is due to genetic variables (Dolan et al. 2004). Children are more susceptible to ototoxicity from platinum agents than adults. For cisplatin, the risk of significant hearing loss involving the speech frequencies (500–2,000 Hz) usually occurs with cumulative doses that exceed 400 mg/m² in pediatric patients, whereas adults may tolerate doses up to 600 mg/m² before significant hearing loss involving the speech frequencies occurs (Schell et al. 1989). For carboplatin, ototoxicity has been reported to occur at similar cumulative doses in excess of 400 mg/m². Other factors that may contribute to hearing loss include medications such as aminoglycoside antibiotics and loop diuretics, impaired renal function, and coexisting ear pathology such as chronic otitis or middle ear effusions (Grewal et al. 2010).

Clinically detectable hearing loss may require more than one cycle of a platinum agent to occur. Knight et al. reported a series of children who were receiving platinum compounds for a variety of oncologic diagnoses found a median time to observation of ototoxicity to be 135 days (Knight et al. 2005). No patient in that series showed improvement in hearing, suggesting that hearing loss is permanent. Progressive hearing loss as long as 136 months from the end of therapy with platinum compounds has been reported in a cohort of survivors of pediatric solid tumors (Bertolini et al. 2004).

Several otoprotectants are in clinical and preclinical trials, although their efficacy is unclear at present. Because cisplatin ototoxicity alters the antioxidant system of the outer hair cells, several agents that reduce oxidative stress in the cochlea have been tested (Rybak and Ramkumar 2007). Sodium thiosulfate is currently being tested by the Children’s Oncology Group in an intervention trial of pediatric patients treated with cisplatin (Hyppolito et al. 2006). Preclinical data indicated that this antioxidant confers otoprotection without affecting cytotoxicity (Neuwelt et al. 2006). After encouraging results in adult patients with ovarian cancer, amifostine as an otoprotectant was studied in children with high-risk germ cell tumors and osteosarcoma who received platinum-based regimens. Amifostine unfortunately did not lessen the risk of unacceptable hearing loss in either group and was limited by emesis in the patients with osteosarcoma (Gallegos-Castorena et al. 2007). In a retrospective review of patients with osteosarcoma, the incidence of ototoxicity was lower in patients who received cisplatin in two divided doses of 60 mg/m²/dose given 24 h apart than those who received a single dose of 120 mg/m² (Lewis et al. 2009). The current standard treatment for osteosarcoma uses divided dosing of 60 mg/m²/dose daily over 2 days.

The Children’s Oncology Group long-term follow-up guidelines recommend a complete audiological evaluation consisting of air conduction, bone conduction, speech audiometry, and tympanometry for all survivors at risk for hearing loss on entry into long-term follow-up and more frequently if any change is noted (COG 2013). The general principles of management of hearing loss include awareness on the part of parents and providers, appropriate referrals to audiologists and otolaryngologists, and implementation of amplification and other adaptive strategies where indicated (Grewal et al. 2010).

16.3.4 Sexual Function and Infertility

When considering late effects in cancer survivors, sexual functioning in adolescent and young adult survivors of childhood cancer has been particularly neglected in the literature, despite increasing reports of the importance of sexual functioning on quality of life. The psychosocial difficulties that cancer survivors experience including significant changes in peer relationships, disturbed body image, worry about the future, difficulties with intimate relationships, diminished quality of life, can influence psychosexual functioning (Ford et al. 2014). Additionally, treatment-related factors that may influence sexual functioning include disruptions in normal pubertal development, premature ovarian failure, and the burden of medical comorbidities (Ford et al. 2014). Zebrack et al. surveyed nearly 600 survivors aged 18–39 regarding their sexual functioning, health-related quality of life, psychological distress, and life satisfaction (Zebrack et al. 2010). Fifty-two percent of female survivors and 32 % of male survivors reported at least “a little problem” in one or more areas of sexual functioning (Zebrack et al. 2010). These findings are consistent with other studies of sexual functioning in childhood cancer survivors which report that females survivors are twice as likely than their male counterparts to report marked sexual impairment (Bober et al. 2013). It has been postulated that young women may perceive changes such as the impact of treatment on body image and psychosexual development as being more traumatic than male peers, and this is one reason why female survivors may be more vulnerable to cancer-related sexual dysfunction (Oeffinger et al. 2006). Moreover, long-term effects of treatment on menopausal status and vaginal health (e.g., vaginal dryness or vaginal atrophy) may additionally be related to the loss of sexual function in this group of young women (Oeffinger et al. 2006).

Although examination of sexual functioning in a mixed group of cancer survivors allows for greater power for analysis, it fails to consider the unique difficulties tumor site specific groups may face. This most certainly is true for survivors of bone tumors, who face a unique gamut of issues related to body image and sexual functioning. Few studies have examined the unique issues of patients who have undergone treatment for bone tumors. Most studies have examined this population related to their local control measures including limb salvage, amputation, and Van Nes rotationplasty. In one recent study, almost half of the young adult survivors of bone cancer in childhood who had undergone a Van Nes rotationplasty expressed some limitation in initiating intimate relationships as a result of the rotationplasty (Veenstra et al. 2000). In another study, adolescent and young adult bone cancer survivors who had undergone amputation reported a significantly more active sex life (88 %) than those who had limb-sparing surgeries (75 %) which has been re-demonstrated in other studies of limb salvage survivors (Refaat et al. 2002). Additionally, fear of infertility, disclosure of cancer history, and concern for health of future offspring also may impact sexual functioning and intimate relationships. Refer to Chap. 5 for a more detailed discussion of fertility issues.

The Children’s Oncology Group long-term follow-up guidelines recommend a detailed reproductive history for patients receiving alkylating agents with annual visits including pubertal onset, sexual functioning, and medication use, as medications can have a substantial impact on sexual functioning (COG 2013). Sexual history includes vaginal dryness and libido for females; and erections, nocturnal emissions, and libido for males. It also recommends annual tanner staging until sexual maturity for all patients, with semen analysis at the request of a sexually mature patient, or serum FSH if unable to obtain semen analysis for males (COG 2013). For females, obtain a baseline of serum FSH, LH, estradiol at age 13 and as clinically indicated in patients with delayed or arrested puberty, irregular menses, primary or secondary amenorrhea, and/or clinical signs of estrogen deficiency (COG 2013). A sexual health assessment should be a part of comprehensive survivorship clinics including attention to functioning and the psychological component of health and well-being, including self-image, subjective attitude toward one’s own sexuality and relationships with intimate partners (Zebrack et al. 2010). Clinicians must be skillful in their approach and informed of the developmental and psychosocial needs unique to young adults with cancer and geared toward making young people feel comfortable discussing personal issues and providing appropriate referrals to reproductive providers and counselors.

16.3.5 Second Malignant Neoplasms (SMNs)

The improved survival of children and young adults with cancer has resulted in one of the most ominous and significant long-term problems associated with therapy, the development of second malignant neoplasms. Childhood cancer survivors are at significant risk for development of malignant neoplasms. This risk is approximately tenfold greater than the general population, and an important health-related concern for the aging childhood cancer survivor population (Armenian and Robison 2013). SMNs are the leading cause of treatment-related mortality in long-term cancer survivors (Armenian and Robison 2013). Commonly reported solid SMNs include breast, thyroid, soft tissue and bone sarcomas, skin and brain cancer, and there is a strong and well-defined association with radiation exposure that is characterized by a latency that exceeds 10 years (Armenian and Robison 2013). Other SMNs such as therapy-associated leukemia (t-MDS/AML) are notable for their shorter latency, typically less than 10 years from primary cancer diagnosis, and association with alkylating agents and topoisomerase II inhibitor chemotherapy (Bhatia and Sklar 2002). Survivors who develop a first SMN are at an especially high risk of multiple occurrences of subsequent neoplasms, such that within 20 years from their original diagnosis the estimated cumulative incidence of another neoplasm is 47 % (Armenian and Robison 2013). Data collection regarding genetic predisposition syndromes and molecular epidemiologic studies are ongoing to address the role of genetics in the development of SMNs.

The Childhood Cancer Survivor Study (CCSS) has collected data on perhaps the largest cohort of relatively long-term survivors and began to analyze the relations between anticancer treatment and SMN development (Meadows et al. 2009). Overall female survivors were at greater risk than male survivors for the occurrence of any SMN (RR = 1.64) (Meadows et al. 2009). Age at the time of original diagnosis was also an important risk factor; children younger at diagnosis are at an increased overall risk of SMNs and specific risk of thyroid and CNS SMNs (Meadows et al. 2009). Exposure to increased doses of alkylating agents, anthracyclines, and epidodophyllotoxins, all components of bone tumor treatment, was also associated with an increased risk of any SMN (Meadows et al. 2009). The cumulative incidence of SMNs in Ewing sarcoma survivors in the study at 25 years from their original diagnosis was 9 %, with a median time from first diagnosis to first SMN of 14.5 years (range 4–32 years) (Ginsberg et al. 2010). SMNS included breast cancer, osteosarcoma, papillary thyroid cancer, acute myelogenous leukemia, and five sarcomas (Ginsberg et al. 2010). In contrast, the cumulative incidence for osteosarcoma survivors at 25 years was 5.4 % with breast cancer as the leading SMN, followed by skin cancer, gastrointestinal cancer, thyroid, and soft-tissue or bone sarcomas (Nagarajan et al. 2011).

The Children’s Oncology Group long-term follow-up guidelines recommend annual detailed history of fatigue, bleeding, or easy bruising as well as dermatologic exam assessing for pallor, petechiae, or purpura. Complete blood count and bone marrow exam should be performed as clinically indicated. Clinicians should counsel patients to report any fatigue, pallor, petechiae, or bone pain. Survivors should be aware of their risk of secondary cancers and maintain a healthy lifestyle including avoiding smoking or excessive alcohol intake, eating healthy well-balanced diet, maintaining regular exercise, and regular use of sunscreen.

It is well recognized that radiation exposure is a considerable risk for solid secondary malignant neoplasms. Excluding 11 nonmelanoma skin cancers, there were 36 SMNs reported among 34 participants in the CCSS analysis of Ewing sarcoma patients (Ginsberg et al. 2010). Of these patients, 86.7 % had received radiation therapy (Ginsberg et al. 2010). Of the 403 Ewing sarcoma survivor participants, the survivors who received radiation had a SMN incidence ratio was 6.6 % (95 % CI = 4.5–9.6), and for those survivors who did not receive radiation the standardized incidence ratio was 3.3 (CI = 1.1–10.2, P = .28) (Ginsberg et al. 2010). As expected, thyroid cancer and secondary sarcomas were found most frequently in or near the radiation field. The standardized incidence ratio for breast cancer among women treated with whole-lung radiation was 36.0 (95 % CI = 15.5–83.5) with an excess absolute risk of 5.6 (Ginsberg et al. 2010). Among women not treated with chest radiation, the standard incidence ratio was 17.0 (95 % CI-7.8–37.2) with an excess absolute risk of 3.2 (Ginsberg et al. 2010).

The Children’s Oncology Group long-term follow-up guidelines recommend annual breast exam beginning at puberty until the age of 25, then every 6 months for all females who have had radiation fields involving the breast. For radiation doses greater than or equal to 20 Gy yearly mammography is recommended beginning 8 years after radiation or at age 25, whichever comes first. Breast MRI is recommended yearly as an adjunct to mammography beginning 8 years after radiation or at age 25, whichever occurs last. In radiation fields that include bone, detailed history should include bone pain and physical exam with palpation of any bones in irradiated field. X-ray or other diagnostic imaging should be considered in patients with clinical symptoms (COG 2013).

16.4 Surgical Late Effects

Amputation and limb-sparing surgery prevent local recurrence of bone tumors by removal of all gross and microscopic disease. If optimally executed, both procedures accomplish an en bloc excision of tumor with a margin of normal uninvolved tissue. The type of surgical procedure, the primary tumor site, and the age of the patient affect the risk of postsurgical complications (Oeffinger et al. 2009). Complications in survivors treated with amputation include prosthetic fit problems, chronic pain in the residual limb, phantom limb pain, and bone overgrowth (Nagarajan et al. 2002; Aulivola et al. 2004). While limb-sparing surgeries may offer a more aesthetically pleasing outcome, complications have been reported more frequently in survivors who underwent these procedures than in those treated with amputation. Complications after limb-sparing surgery include nonunion, pathologic fracture, aseptic loosening, limb-length discrepancy, endoprosthetic fracture, and limited joint range of motion (Nagarajan et al. 2002; Kaste et al. 2001). Occasionally, refractory complications develop after limb-sparing surgery and require amputation (Eiser et al. 2001; Renard et al. 2000).

A number of studies have compared functional outcomes after amputation and limb-sparing surgery, but results have been limited by inconsistent methods of functional assessment and small cohort sizes. Overall, data suggest that limb-sparing surgery results in better function than amputation, but differences are relatively modest (Nagarajan et al. 2002; Renard et al. 2000). Similarly, long-term quality of life outcomes among survivors undergoing amputation and limb-sparing procedures have not differed substantially (Eiser et al. 2001). A longitudinal analysis of health status among extremity sarcoma survivors in the CCSS indicates an association between lower extremity amputation and increasing activity limitations with age, and an association between upper extremity amputation and lower educational attainment (Marina et al. 2013) (Table 16.3).

Table 16.3 Bone and joint late effects

16.5 Conclusion

Survivors of pediatric bone tumors face lifelong challenges related to their treatment. Health-care providers, both adult oncologists and primary care physicians, rate childhood sarcoma survivors as a population of patients that they feel the least comfortable treating (Landier et al. 2006). In comparison to adult oncologists, primary care physicians reported a lower level of knowledge regarding both common childhood cancers and associations of late effects with treatment exposures (Landier et al. 2006). While their reported level of knowledge of these factors was higher than primary care providers, adult oncologists still were substantially less knowledgeable than pediatric oncologists scoring a mean of 2.66, compared to 1.88 for primary care providers, while pediatric oncologists scored a mean of 4.41 (score range 1–5 with 5 representing self-reported highest level of knowledge, comfort, or interest) (Landier et al. 2006). Survivors of pediatric bone tumors experience multiple and sometimes significant health issues related to their treatment that may increase their risk of early mortality and diminish quality of life. Knowledge about risk factors for late effects is essential to provide timely preventative or corrective interventions, since many treatment effects have delayed manifestations related to growth, development, and aging (Landier et al. 2006). Published evidence-based guidelines can provide the optimal surveillance plan and screening evaluations based on a personalized plan that integrates risks related to the previous cancer, cancer therapy, genetic predispositions, lifestyle behaviors, and comorbid health conditions. The full benefits of risk-based health care cannot be realized unless survivors and health-care providers have accurate information about cancer diagnosis, treatment modalities, and potential cancer-related health risks to guide recommendations for screening and risk-reducing interventions, regardless of treatment setting or provider (Landier et al. 2006).