Journal of Surgical Oncology 2015;111:648–655

Survivorship DOUGLAS J. HARRISON, MD*

AND

CINDY SCHWARTZ, MD, MPH

Division of Pediatrics, MD Anderson Cancer Center, Houston, Texas

Significant therapeutic advances for soft tissue sarcomas allow increasing numbers of patients—adult and pediatric—to achieve long term survival. However, the harsh cytotoxic therapies are responsible for adverse physical and psychosocial effects that require long-term follow-up care, specific to survivorship issues. In the adult and pediatric patient population, guidelines for care developed by experts in comprehensive survivorship clinics are evolving to assist the practitioner while on-line supports bring information directly to the survivors.

J. Surg. Oncol. 2015;111:648–655. ß 2014 Wiley Periodicals, Inc.

KEY WORDS: sarcoma; long-term; survival; follow-up; late effects

INTRODUCTION Significant advances have been made in the last several decades in the treatment of soft tissue sarcomas (STS), allowing for increasing numbers of patients—both adult and pediatric—to sustain long term survival. As rates of event free (EFS) and overall survival (OS) improve, adequate and appropriate follow up and clinical care of these survivors becomes more and more vital. The incidence of STS is small when compared to other human cancers. As a whole, they account for slightly more than 12,000 cases diagnosed in the United States each year, making up less than 1% of all human malignancies [1–3]. In pediatrics, STS are slightly more common when compared to other pediatric malignancies. STS are the most common solid tumor outside of the central nervous system in children and account for approximately 7% of all pediatric malignancies, with 500 new diagnoses each year in the United States [4]. Survival rates continue to improve due to more effective administration of chemotherapy, the identification of previously unknown therapeutic targets that can be exploited with novel pharmaceuticals, and the development of enhanced surgical techniques and superior modalities of radiation therapy delivery. With increasing numbers of survivors of STS, effective clinical management and follow up of the long term side effects of therapy is essential. The armamentarium for treating patients with STS includes systemic chemotherapy, radiation, and surgical resection, often delivered in combination. The specific tumor histology, extent of disease present, and risk factors such as tumor size determine the modalities employed. Whether neoadjuvant or adjuvant chemotherapy is used, continues to be a subject of debate in the adult patient population [5]. Pediatric and adolescent patients more often receive multi-modality treatment than adults, a consequence primarily of the prevalent histologies of pediatric tumors. As a result, a large cohort of survivors of STS requires follow up for long term side effects of treatment. The most active conventional chemotherapeutics administered to patients with STS are anthracyclines and alkylators. Neoadjuvant or adjuvant doxorubicin alone or in combination with ifosfamide is included in the majority of chemotherapeutic regimens [6]. The associated short and long term side effects of these agents have been well studied. Cardiac injury is the most frequent adverse late effect of doxorubicin. Anthracycline induced cardiac damage may be enhanced when radiation fields include the heart. Ifosfamide is associated with gonadal and nephrotoxicity, with tubular toxicity (Fanconi’s Syndrome) occurring most often after moderate doses and

ß 2014 Wiley Periodicals, Inc.

glomerular toxicity usually arising only at high cumulative doses. All of these therapies increase risk for secondary malignancy in patients with STS. Radiation therapy increases the risk of secondary solid tumors; ifosfamide and, in rare cases doxorubicin, are associated with risk of developing secondary acute myeloid leukemia and solid tumors. Although advances in the molecular classification of STS are leading to the identification of novel pathways that can be exploited with newly developed therapeutics [7–9], the long term side effects of these targeted agents are not yet well defined. As a result, emerging late effects cannot be covered for the purposes of this review, but treating physicians must remain cognizant that there will be consequences of novel therapies. Radiation and surgery are both associated with long term effects on the musculoskeletal system, particularly in young children. Radiation therapy induced deficits in bone growth and hypoplasia of soft tissues emerge over the course of years, with development. Other musculoskeletal effects of radiation include impaired wound healing, muscular atrophy, osteopenia, and direct bone injury which can increase the risk of pathologic fracture. Side effects of radiation determined by the extent and location of the radiation field encompassed include, but are not limited to, endocrinopathies, fertility complications, bowel obstruction, chronic diarrhea, cataracts, dental complications, sinus complications, hearing loss, chronic lung disease, and others. Long term sequelae of surgical techniques necessary to achieve a full resection are also dependent on the site and extent of disease; these factors influence whether surgery is used at diagnosis or after cytoreductive therapy. Lasting functional deficits are unfortunately common in survivors of STS, especially those who require limb sparing procedures for extremity STS. STS is currently treated with an individual approach based on multiple parameters including disease type/histology, risk features (tumor size, biology, metastasis), patient features (age, frailty, patient or family’s assessment of consequences), and local control considerations

Conflict of interest: The authors have no conflicts of interest to disclose. * Correspondence to: Douglas Harrison, MD, Division of Pediatrics, MD Anderson Cancer Center, Houston, TX. Fax: 713-792-0608. E-mail: [email protected] Received 16 June 2014; Accepted 13 October 2014 DOI 10.1002/jso.23844 Published online 29 December 2014 in Wiley Online Library (wileyonlinelibrary.com).

Survivorship (developmental stage, tumor extent, adjacent organs). Stratification techniques that attempt to allocate treatment for populations must consider histologic diagnosis, age, size of the primary tumor, resectability, tumor grade, and presence of metastatic disease. Without uniformity of treatment protocols for the STS population, therapy is often delivered on a patient by patient basis. Follow-up care of the survivor of STS must therefore be individualized on the basis of the specific treatment exposures received. This chapter will review the long term toxicity of STS treatment in the adult and pediatric patient population. It will also review standard of care management guidelines for adult survivors of STS. Finally, it will briefly discuss the importance of following patients in a comprehensive survivorship clinic and outline supports for STS survivors that are available.

Long Term Cardiovascular Complications of STS Survivors Anthracyclines trigger cardiac damage that becomes increasingly severe with increased cumulative dose. It is thought to be related to free radical induced myocyte injury that results in apoptosis [10–13]. Decreased ventricular wall thickness, increased afterload, and decreased contractility ensue [14]. Cardiovascular disease is a well recognized cause of death in adult survivors of pediatric cancer. A cause specific standardized mortality ratio (SMR) of seven was reported in a large cohort of pediatric cancer survivors [15]. Patients with Ewing sarcoma and STS were found to have a cardiac specific SMR of 12 and 4, respectively [15]. The lower cardiac specific SMR in STS survivors compared to Ewing sarcoma survivors is likely reflective of the substantial proportion of patients with STS who do not receive anthracyclines as a component of therapy. Fewer studies address the incidence of doxorubin-induced cardiotoxicity in adult survivors, but breast cancer survivors are known to experience more cardiac complications if they received anthracyclines [16]. Subclinical cardiomyopathy has also been documented in adult survivors of non-Hodgkin’s lymphoma at cumulative dose thresholds similar to those traditionally used in STS chemotherapy regimens [17]. Based on pediatric and adult data, doxorubicin induced cardiotoxicity is an important consideration when following adults who are survivors of pediatric and adult STS [18]. There are acute cardiac effects of anthracycline administration that are usually reversible, but such patients are at increased risk of chronic cardiac damage [19–21]. Late cardiotoxicity manifests by decreased contractility, increased afterload, and reduced ventricular wall thickness which eventually can lead to congestive heart failure and cardiomyopathy over time [22]. Pediatric patients treated with doxorubicin for acute lymphoblastic leukemia (ALL) have an initial dilated cardiomyopathy in early stages of cardiac dysfunction that evolves over time to a more chronic restrictive cardiomyopathy with decreased left ventricular mass, decreased left ventricular shortening fraction, and increased left ventricular afterload [23]. Survivors of adult cancer more commonly have a purely dilated cardiomyopathy which is often indistinguishable from other non anthracycline mediated causes of congestive heart failure [18,22]. Risk factors for anthracycline induced cardiomyopathy include female gender, younger age of administration, and increased cumulative dose (increased incidence of cardiomyopathy is typically seen at higher cumulative doses). Although 450 mg/m2 was previously considered a threshold dose with augmentation of effect by concomitant radiation exposure, recent data suggest that risk is escalated after 200– 250 mg/m2 [24–27]. The risk of long term damage to the heart induced by anthracyclines is mitigated with the use of the cardioprotectant, dexrazoxane, an iron chelator that limits the number of free radicals generated, lessening the damage to cardiac myocytes and potentially mitigating future long term cardiotoxicity [28,29]. It has recently Journal of Surgical Oncology

649

been included into treatment protocols for pediatric STS in the United States. Long term cardiac damage sustained with anthracycline administration continues to be an important clinical concern in the management of all cancer survivors treated with doxorubicin. While the majority of adult STS survivors will not reach the cumulative dose maximum doxorubicin threshold of 450 mg/m2 traditionally associated with cardiovascular compromise, anthracycine-induced cardiovascular long term effects have been documented at doses far lower. In addition, long-term follow-up data is generally limited for adult patients reaching middle age and beyond, when the general population has increasing cardiac risk factors, but it is likely that such risks are compounded at any anthracycline dose. Many pediatric patients (ewing sarcoma, high risk rhabdomyosarcoma, others) will have received high cumulative doses of anthracyclines. Regardless of dose, all who have received anthracyclines should be carefully monitored (Table I). It is logical to reduce other cardiac risks by promoting healthy lifestyles such as avoiding obesity, following a diet low in saturated and trans fats and limiting salt intake. Regular exercise that may mitigate exogenous cardiac risk factors has been shown to produce long term benefits in cancer survivors [30]. Exercise testing may be recommended prior to initiation of an exercise regimen. Isometric exercises, such as the lifting of heavy weights should generally be avoided in this population [21]. After cardiotoxic therapy, patients should be counseled not to smoke and to limit alcohol consumption. Angiotensin converting enzymes inhibitors, beta-blockers, and other afterload reducers have been used to treat asymptomatic cardiac anomalies with some success in delaying future cardiac failure [31]. Screening programs for cancer survivors for cardiac toxicity remain an area of controversy. Pediatric survivors who have received anthracyclines or radiation to the chest wall that incorporated the heart within the radiation field are typically monitored with serial echocardiograms and electrocardiograms (EKG) to screen for defects in cardiac function [32,33]. Serum markers of cardiac injury continue to be evaluated in cancer survivors as possible predictors of future cardiac complications [34]. There is limited data in the adult STS survivor population to effectively guide cardiac monitoring [15]. American Society of Clinical Oncology (ASCO) guidelines have suggested a role for echocardiographic follow-up. Annual evaluations and physical examinations that focus on a thorough assessment of cardiovascular well-being should be performed. We would recommend that care providers for adult survivors of STS remain cognizant that anthracycline induced cardiomyopathy is most likely to manifest late, at least 10–15 years after therapy; echocardiograms should be considered in this population.

Long Term Urinary Tract Toxicity in STS Survivors The benefits of chemotherapy in adult STS are still a subject of debate. If instituted, older regimens were usually limited to the anthracycline, doxorubicin, but newer protocols are incorporating ifosfamide with doxorubicin. The majority of chemotherapy mediated toxicities in survivors of STS may be attributable to use of ifosfamide as neoadjuvant and/or adjuvant chemotherapy. Superior to cyclophosphamide in the adult STS population, ifosfamide has become standard of care for certain pediatric STS depending on risk status and histologic diagnosis (e.g., Ewing sarcoma and several adult STS diagnoses) [35,36]. Ifosfamide induced nephrotoxic effects (short and long term) are often aggravated by concurrent administration of other nephrotoxic chemotherapeutic agents [37]. The acute nephrotoxic effects of ifosfamide are most frequent in younger children and those who have prior renal illness, although patients who receive high cumulative doses may also be affected.

650

Harrison and Schwartz

TABLE I. Late Effects in the STS Survivor by Exposure

Exposure Chemotherapy

Organ system Doxorubicin

Ifosfamide

Cardiotoxicity

Renal toxicity

Secondary malignancy (SMN)

Specific late effect

Follow up and screening recommendations

Pediatric:Dilated followed by restrictive cardiomyopathy Adult:Dilated cardiomyopathy Arrhytmia

Annual H & P focused on CV system

Fanconi syndrome; growth inhibition; Nephrogenic Rickets

Secondary leukemia at high cumulative dose as well as secondary solid malignancy in rare instances

Fertility complications

Radiation

Renal toxicity

Fertility complications

Secondary malignancies

Journal of Surgical Oncology

Radiation induced Nephropathy (Dose 20–25 Gy)

STS patients unlikely to receive primary gonadal radiation but azospermia is documented at doses above 4 Gy in men and ovarian failure at doses above 8 Gy in women

STS patients are at increased risk for solid tumors in the field of radiation

Serial Echocardiogram and EKG for pediatric STS survivors (consider in adult as well) Counseling on healthy lifestyle (diet and exercise counseling, avoidance of exogenous CV risk factors) Annual H & P with BP evaluation

Consider serum electrolyte panel, urinalysis, and creatinine clearance at baseline, then as clinically indicated Annual H & P with focus on screening for known SMN

Annual CBC and differential Urinalysis to look for hematuria Ovarian Harvesting and sperm banking prior to start of therapy if possible Consider annual evaluation of gonadotropic axis with measurement of FSH and testosterone in men and FSH, and estradiol in women Counseling regarding long term fertility options Annual H & P with BP evaluation Consider serum electrolyte panel, urinalysis, and creatinine clearance at baseline, then as clinically indicated Ovarian harvesting and sperm banking prior to start of therapy if possible

Consider annual evaluation of gonadotropic axis with measurement of LH, FSH, and testosterone in men and LH, FSH, and estradiol in women Counseling regarding long term fertility options Annual H & P with focus on screening for known SMN Skin examinations annually Annual urinalysis if bladder was included in field of radiation Monthly Self breast examinations, annual breast examination by provider until age 25 (every 6 months afterwards), and annual mammography and breast MRI in adult women STS survivors who received

Survivorship

651

TABLE I. (Continued) Exposure

Specific late effect

Organ system

Radiation, continued

Surgery

Musculoskeletal complications

Functional and musculoskeletal complications

Pediatrics:Growth arrest at doses above 10–20 Gy if epiphyseal growth plate is within the radiation field; Spinal deformity, craniofacial defects, slipped capital femoral epiphysis, limb length discrepancy depending on dose, volume, and field of radiation ALL:Osteopenia: Muscle, bone, and soft tissue hypoplasia; Strength deficit, Rarely muscle atrophy and edema which can lead to long term fibrosis and chronic pain

Dependent on area and extent of resection

Follow up and screening recommendations chest irradiation starting at age 25 yrs of age or 8 yrs following treatment (whichever falls last) Thyroid examination if neck was included in field of radiation with imaging (U/S) and/or biopsy of suspicious palpable nodules Annual physical assessment and evaluation of area encompassed in the radiation field

Document full range of motion and limb length assessments if indicated

Annual prosthetic evaluation if indicated Evaluate for scoliosis if indicated Refer to physical therapy if indicated Annual physical assessment and evaluation of area resected Document full range of motion and limb length assessments if indicated Annual prosthetic evaluation if indicated Evaluate for scoliosis if indicated Refer to physical therapy if indicated

Proximal tubular damage leads to hyperphosphaturia, glycosuria, and aminoaciduria with subsequent impairment of the ability to acidify the urine, commonly referred to as Fanconi Syndrome [38]. Persistent hypophostemia and acidosis can over time lead to growth inhibition and nephrogenic rickets in children treated with ifosfamide [39]. Long term nephrotoxic effects of ifosfamide manifested by chronic glomerular and tubular toxicity are associated with higher cumulative dose [40,41]. Radiation also has adverse effects on the genitourinary system. Radiation induced nephropathy occurs at doses over 20–25 Gy, but lower doses of radiation have been found to induce kidney injury if concurrent chemotherapy is delivered [42]. Bladder dysfunction has been reported to occur at an incidence of 27% after a median dose of 40 Gy [43]; this risk may be enhanced with nephrotoxic chemotherapy including ifosfamide and cyclophosphamide. The ureter has been found to be relatively resistant to the effects of radiation [44]. Survivors of STS who received nephrotoxic therapy whether it be from chemotherapy, surgery, or radiation should be monitored at least annually with a detailed history and physical examination with blood pressure evaluation, as well as an annual urinalysis. Patients who have received ifosfamide should have a baseline creatinine as well as a serum and urine glucose and phosphorous on entry to screen for Fanconi’s syndrome [45]. If signs of nephrotoxic injury are noted, a referral to a nephrologist should be considered.

Fertility Considerations in the STS survivor Ifosfamide can lead to long term fertility complications. While cyclophosphamide has been well documented to lead to azoospermia in male patients with well defined thresholds of risk, the long term Journal of Surgical Oncology

side effects of ifosfamide are less clear. Patients with osteosarcoma who received high doses of ifosfamide have had an increased incidence of azoospermia [46]. Ifosfamide induced gonadotoxicity in males who received ifosfamide has been reported at a cumulative threshold of over 60 g/m2 [47]. The majority of STS patients will not reach this target, but the long term risk of infertility from ifosfamide continues to be under investigation and is likely present in some treated with lower doses. In women, the prevalence of premature ovarian failure, amenorrhea, and infertility after ifosfamide is also unknown, but likely to occur based on extrapolations from the evidence that cyclophosphamide leads to amenorrhea and premature ovarian failure [48]. Although most STS patients will not receive primary gonadal radiation, ovarian failure has been documented to occur at doses of 8 Gy and above, while azoospermia occurs at doses above 4 Gy in men [49–51]. Scatter radiation to the testis, however, in doses of 1–2500 Gy has been found to lead to testicular dysfunction as measured by elevations of FSH in a study of males with STS [52]. Patients with STS should be counseled regarding their long term infertility risk and recommended to have sperm banking or ovarian harvest prior to starting therapy if possible. Patients who received potentially gonadotoxic chemotherapy such as ifosfamide or radiation therapy to the testis or ovary had been recommended to undergo routine evaluation of the gonadotropic axis with measurements of LH, FSH, and testosterone in men and LH, FSH, and estradiol in women at their annual physical assessment, although these tests are not ideal [45]. Anti Müllerian hormone in females may provide better information regarding gonadotropic axis health than LH. In male survivors there is controversy as to whether inhibin B or the ratio of inhibin B/FSH provides additional information in comparison to FSH alone [53–61].

652

Harrison and Schwartz

Long Term Risk of Secondary Malignancy in the STS Survivor A large registry of cancer survivors found the standardized incidence ratio of secondary malignancies to be 1.6 in patients with a primary connective tissue malignancy [62]. Another large study of cancer survivors showed the diagnosis of primary STS to be an independent risk factor towards the development of a secondary malignancy via a multivariate regression model that adjusted for prior radiation therapy, suggesting that genetic and environmental risk factors associated with STS predispose towards the development of a secondary malignancy [63]. Radiation therapy has been well documented to predispose towards the development of multiple secondary malignancies including melanoma [64], non melanoma skin cancer [65], thyroid cancer [66], breast cancer [63], and other soft tissue and bone sarcomas [67]. STS survivors are at increased risk of developing these secondary malignancies within the radiation field directed towards their primary malignancy. Radiation induced solid tumors typically occur at a median time interval of 10 years following treatment [49]. The risk of secondary malignancy in STS survivors attributable to adjuvant and neoadjuvant chemotherapy is relatively low. Alkylators, including ifosfamide, can increase both the risk of secondary acute myeloid leukemia as well as secondary solid malignancies in cancer survivors, however, the relative exposure to alkylating agents in this particular patient population is relatively small [68–70]. While the risk of secondary malignancy in the adult STS survivor is difficult to quantify, careful screening for secondary malignancies should be recommended with particular attention to treatment exposures. Skin examinations should be performed at survivors’ yearly examinations with attention to areas included in the radiation field, with referral to a dermatologist for any suspicious lesion. Yearly blood counts and differentials should be performed to screen for secondary leukemia if patients received ifosfamide. Similarly, an annual urinalysis should be performed in patients who received ifosfamide or cyclophosphamide or in patients in whom the bladder was exposed to radiation as these patients can be at risk for bladder malignancy in the future. Thyroid examinations should be performed as part of any survivor’s physical examination who received neck irradiation, and patients should be referred for imaging and biopsy of suspicious nodules if palpated. Adult women survivors who received chest radiation should be instructed to perform monthly self breast examinations, have a breast examination annually until age 25 years (and every 6 months following), and be referred for breast mammography and MRI every 2 years after the age of 25 (or 8 years following treatment, whichever occurs last) [71].

Musculoskeletal and Functional Complications in the STS Survivor STS survivors can suffer from significant morbidity when wide field radiation therapy or surgical resection are needed to achieve negative margins essential for effective local control. Surgical removal of extremity muscle or bone via a limb sparing procedure or amputation can lead to severe long term physical limitations requiring ongoing physical therapy, and in rare cases, to associated psychological deficits. Patients may require long term physical therapy. Functional impairments can be made worse by over-use of the compensating normal limb which must compensate. The functional impairments caused by surgical resection are enhanced by radiotherapy. Drastic long term consequences on the soft tissues and bones may be noted, particularly in the pediatric STS population who may have received radiation therapy doses of 36– 60 Gy. If the epiphyseal growth plate is within the treatment field, linear Journal of Surgical Oncology

growth arrest is seen even at doses of 10–20 Gy. The exact dose threshold necessary to achieve growth plate arrest is controversial, but younger patients are clearly at higher risk of premature growth plate closure at lower doses [72]. Additional risks include long term spinal deformity, craniofacial defects, slipped capital femoral epiphysis, and limb length discrepancy depending on the area radiated and dose and volume of radiation employed [73]. Radiation therapy can also lead to osteopenia in pediatric and adult STS patients with associated risk of pathologic fracture, although the interplay between the risk of pathologic fracture and radiation induced osteopenia remains an area of debate [74]. Radiation therapy induces muscle, bone, and soft tissue hypoplasia which can be disfiguring in contrast to the bulk mass of corresponding non irradiated tissue. Long term deficits in strength may not be profound, however. In the STS population, the degree of muscle hypoplasia has been correlated to the volume and dose of radiation [75]. In certain rare cases, radiation induced muscle atrophy, inflammation and edema can also lead to fibrosis which can compromise range of motion and cause chronic pain [76]. Close follow up of STS survivors for musculoskeletal complications of surgery and radiation is essential. Full evaluation of the field of radiation and area of surgical resection should be performed annually with complete assessment of range of motion and documentation of limb measurements if indicated. Growth of pediatric STS survivors should be followed closely and plotted to monitor for growth failure. Prostheses should be evaluated annually. The bone density is not necessarily indicated unless there are concerns for osteopenia in the setting of pathological fracture. In patients who received radiation to the spine or back, an evaluation for scoliosis should be performed. Patients who develop scoliosis or limb length discrepancy should be referred to an orthopedic specialist in these areas. Any STS survivor with pain or swelling in the site of prior surgery or radiation should have a thorough evaluation for secondary neoplasia. Plain films of the area should be considered, if not a full imaging assessment, to evaluate for recurrence or bone complications. Radiation induced muscle atrophy is often permanent and can worsen with age. Exercises to increase the bulk mass of affected muscles are often not effective.

Long Term Follow Up and Support for the STS Survivor Survivors of STS should be evaluated annually with a full history and physical examination. The long term side effects of oncologic therapy are broad, and many centers have developed follow up programs and sub specialty clinics that specialize in the needs of the cancer survivor. Because pediatric patients are more likely than adults to survive their malignancy and because the effects on the developing child are profound, the survivorship literature is significantly more robust for survivors of pediatric malignancy. With improved radiation, surgery, and chemotherapeutics, the percentage of survivors of all adult malignancies, including STS, rises. Adults often have co-morbidities which aggravate the long term complications of cancer therapy. As this survivor population grows with time, so too will the need for better information on how to manage these patients. All cancer survivors should be encouraged to maintain a healthy lifestyle including maintenance of a healthy diet, and avoidance of smoking and substance abuse. They should be referred to smoking cessation programs and/or to substance abuse counseling as indicated. Maintenance of an exercise program, at the discretion of a physician, is especially important to STS survivors who received cardiotoxic medications such as anthracyclines, although isometric exercises should generally be avoided. Patients who suffer from radiation induced muscle hypoplasia or bony abnormalities may benefit from physical therapy, although STS survivors may have limitations imposed by chronic pain and functional

Survivorship deficits. Some cancer centers have developed complementary medicine programs including massage, yoga, acupuncture, and others that may help reduce chronic pain, anxiety and the long term psychological impact of a cancer diagnosis. While these programs can be helpful on a case by case basis, research still needs to be done to fully understand their overall effectiveness in the STS survivor. Cancer survivors warrant close scrutiny and follow up. All cancer survivors, especially those with STS, should have ongoing extensive familial cancer history performed at every visit to assess for risk of inherited cancer predisposition syndromes—such as Li Fraumeni Syndrome (LFS) for which there is a known association with STS [77]. This assessment should be especially thorough for cancer survivors who sustain secondary malignancies. When an inherited cancer predisposition syndrome is suspected, patients should be referred for genetic testing. Vigorous cancer screening regimens are now recommended for patients and families with genetic predisposition syndromes [77].

CONCLUSION As more and more STS patients survive, the question of how to manage the long term complications of treatment becomes increasingly essential. Multiple organ systems can be injured by the treatments used for STS including chemotherapy induced cardiotoxicity, nephrotoxicity, and gonadotoxicty. Ongoing screening and follow up are essential to mitigate adverse consequences. Radiation can further aggravate these cardiac, renal and fertility issues that STS survivors face, enhancing the need for appropriate evaluation, screening, and medical care. Local control methods including radiation and surgical resection can result in pain, disfigurement, and impairment of function. All survivors of STS should be closely followed on an annual basis with a thorough history and physical examination. An exposure-based evaluation should direct screening for the long term side effects of treatment received. Patients should be referred to specialists on a case by case basis, but lifetime follow up at a survivor clinic that specializes in long term side effects of cancer therapy is recommended. All survivors of both pediatric and adult cancer should be encouraged to maintain a healthy lifestyle to minimize co-morbidities which can aggravate the risks of late treatment effects. Psychosocial support may be helpful as survivors struggle not only with risk of recurrence but also the long term side effects brought on with treatment.

REFERENCES 1. American Cancer Society: Cancer Facts and Figures 2014. Atlanta, GA: American Cancer Society, 2014. Available Online. 2. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975–2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER web site, April 2014. 3. Jemal A,Tiwari RC, Murray T, et al.: Cancer Statistics, 2004. CA Cancer J Clin 2004;54:8–29. 4. Gurney JG, Young JL, Roffers SD, et al.: Soft tissue sarcomas. In: Ries LAG, Smith MA, Gurney JG, editors. Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. Bethesda, MD, 1999. 5. Patrikidou A, Domont J, Cioffi A, et al.: Treating soft tissue sarcomas with adjuvant chemotherapy. Curr Treat Options Oncol 2011;12:21–31. 6. Pervaiz N, Coterjohn N, Farrokhar F, et al.: A systematic metaanalysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 2008;113:573– 581. Journal of Surgical Oncology

653

7. Frith AE, Hirbe AC, Van Tine BA: Novel pathways and molecular targets for the treatment of sarcoma. Curr Oncol Rep 2013;15:378–385. 8. Slejfer S, Ray-Coquard I, Papai Z, et al.: Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: A phase II study from the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC Study 62043). J Clin Oncol 2009;27:3126–3132. 9. Vadakara J, von Mehren M: Gastrointestinal stromal tumors: Management of metastatic disease and emerging therapies. Hematol Oncol Clin North Am 2013;27:905–920. 10. Raj S, Franco VI, Lipshutz SE: Anthacycline-induced cardiotoxicity: A review of pathophysiology, diagnosis, and treatment. Curr Treat Options Cardio Med 2014;16:1–14. 11. Arola OJ, Saraste A, Pulli K, et al.: Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res 2000;60:1789–1792. 12. Tokarska-Schlattner M, Zaugg M, Zuppinger C, et al.: New insights into doxorubicin-induced cardiotoxicity: The critical role of cellular energetics. J Mol Cell Cardiol 2006;41:389– 405. 13. Billingham ME, Mason JW, Bristow MR, et al.: Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep 1978;62:865–872. 14. Lipshultz SE, Colan SD, Gelber RD, et al.: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991;324:808–815. 15. Armstrong GT, Liu Q, Yasui Y, et al.: Late mortality among 5-year survivors of childhood cancer: A summary form the childhood cancer survivor study. J Clin Oncol 2009;27:2328–2338. 16. Doyle JJ, Neuget AI, Jacobson JS, et al.: Chemotherapy and cardiotoxicity in older breast cancer patients: A population-based study. J Clin Oncol 2005;23:8597–8605. 17. Hequet O, Le QH, Moullet I, et al.: Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults. J Clin Oncol 2004;22:1864–1871. 18. Carver JR, Shapiro CL, Ng A, et al.: American society of clinical oncology clinical evidence review of the ongoing care of adult cancer survivors: Cardiac and pulmonary late effects. J Clin Oncol 2007;25:3991–4008. 19. Lipshultz SE: Sallan SE Cardiovascular abnormalities in long-term survivors of childhood malignancy. J Clin Oncol 1993;11: 1199–1203. 20. Krischer JP, Epstein S, Cuthbertson DD, et al.: Clinical cardiotoxicity following anthracycline treatment for childhood cancer: The Pediatric Oncology Group experience. J Clin Oncol 1997;15:1544–1552. 21. Steinherz LJ, Steinherz PG, Tan C: Cardiac failure and dysrhythmias 6–19years after anthracycline therapy: A series of 15 patients. Med Pediatr Oncol 1995;24:352–361. 22. Grenier MA, Lipshultz SE: Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol 1998;25: 72–85. 23. Lipshultz SE, Lipsitz SR, Sallan SE, et al.: Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 2005; 23:2629–2636. 24. Lipshultz SE, Lipsitz SR, Mone SM, et al.: Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 1995;332:1738–1743. 25. Giantris A, Abdurrahman L, Hinkle A, et al.: Anthracyclineinduced cardiotoxicity in children and young adults. Crit Rev Oncol Hematol 1998;27:53–68. 26. Bu’Lock A, Mott MG, Oakhill A, et al.: Left ventricular diastolic function after anthracycline chemotherapy in childhood: Relation with systolic function, symptoms, and pathophysiology. Br Heart J 1995;73:340–355. 27. Wong FL, Bhatia S, Landier W, et al.: Cost-effectiveness of the children’s oncology group long-term follow-up screening guidelines for childhood cancer survivors at risk for treatment-related heart failure. Ann Intern Med 2014;160:672–683.

654

Harrison and Schwartz

28. Wexler LH, Andrich MP, Venzon D, et al.: Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin. J Clinic Oncol 1996;14:362– 372. 29. Swain SM, Whaley FS, Gerber MC, et al.: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 1997;15:1318–1332. 30. Baumann FT, Bloch W, Beulertz J: Clinical exercise interventions in pediatric oncology: A systematic review. Pediatr Res 2013; 74:366–374. 31. Simbre VC, Adams MJ, Deshpande SS, et al.: Cardiomyopathy caused by antineoplastic therapies. Curr Treat Options Cardiovasc Med 2001;3:493–505. 32. Harake D, Franco VI, Henkel JM, et al.: Cardiotoxicity in childhood cancer survivors: Strategies for prevention and management. Future Cardiol 2012;8:647–670. 33. Landier W, Bhatia S, Eshelman DA, et al.: Development of riskbased guidelines for pediatric cancer survivors: The Children’s Oncology Group long-term follow-up guidelines from the Children’s Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol 2004;22:4979–4990. 34. Shankar SM, Marina N, Hudson MM, et al.: Monitoring for cardiovascular disease in survivors of childhood cancer: Report from the Cardiovascular Disease Task Force of the Children’s Oncology Group. Pediatrics 2008;121:e387–e396. 35. Carli M, Passone E, Perilongo G, et al.: Ifosfamide in pediatric solid tumors. Oncology 2003;65:99–104. 36. Bramwell VH, Mouridsen HT, Santoro A, et al.: Cyclophosphamide versus ifosfamide: Preliminary report of a randomized phase II trial in adult soft tissue sarcomas. The European Organiztion for Research and Treatment of Cancer [EORTC], Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol 1993;31:180–184. 37. Goren MP, Wright RK, Pratt CB, et al.: Potentiation of ifosfamide neurotoxicity, hematotoxicity, and tubular nephrotoxicity by prior cis-diamminedichloroplatinum(II) therapy. Cancer Res 1987;47: 1457–1460. 38. Skinner R, Pearson AD, Price L, et al.: Nephrotoxicity after ifosfamide. Arch Dis Child 1990;65:732–738. 39. Stohr W, Patzer L, Paulides M, et al.: Growth impairment after ifosfamide-induced nephrotoxicity in children. Pediatr Blood Cancer 2007;48:571–576. 40. Skinner R, Cotterill SK, Stevens MC: Risk factors for nephrotoxicity after ifosfamide treatment in children: A UKCCSG late effects group study. Br J Cancer 2000;82:1636–1645. 41. Oberlin O, Fawaz O, Rey A, et al.: Long-term evaluation of ifosfamide-related nephrotoxicity in children. J Clin Oncol 2009; 27:5350–5355. 42. Cassady JR: Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys 1995;31:1249–1256. 43. Raney B, Heyn R, Hays DM, et al.: Sequelae of treatment in 109 patients followed for 5 to 15 years after diagnosis of sarcoma of the bladder and prostate. A report from the intergroup Rhabdomyosarcoma study committee. Cancer 1993;71:2387– 2394. 44. Marks LB, Carroll PR, Dugan TC, et al.: The response of the urinary bladder, urethra, and ureter to radiation and chemotherapy. Int J Radiat Oncol Biol Phys 1995;31:1257–1280. 45. Schwartz CL, Hobbie WL, Constine LS: Algorhitms of late effects by disease. In: Schwartz CL, Hobbie WL, Constine LS and Ruccione KS editors. Survivors of childhood and adolescent cancer. Edition 3 in press. 46. Longhi A, Macchiagodena M, Vitali G, et al.: Fertility in male patients treated with neoadjuvant chemotherapy for osteosarcoma. J Pediatr Hematol Oncol 2003;25:292–296. 47. Williams D, Crofton PM, Levitt G: Does ifosfamide affect gonadal function? Pediatr Blood Cancer 2008;50:347–351. 48. Kreuser ED, Xiros N, Hetzel WD, et al.: Reproductive and endocrine gonadal capacity in patients with COPP chemotherapy for Hodgkin’s Disease. J Cancer Res Clin Oncol 1987;113: 260–266. Journal of Surgical Oncology

49. Fossa SD, Vassilopoula-Sellin R, Dahl AA: Long term physical sequelae after adult onset cancer. J Cancer Surviv 2008;2:3–11. 50. Wallace WH, Thomas AB, Saran F, et al.: Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Physics 2005;62:738–744. 51. Magelssen H, Brydoy M, Fossa SD: The effects of cancer and cancer treatments on male reproductive function. Nat Clin Pract Urol 2006;3:312–322. 52. Shapiro E, Kinsella TJ, Makuch RW, et al.: Effects of fractionated irradiation of endocrine aspects of testicular function. J Clin Oncol 1985;3:1232–1239. 53. Schmiegelow M, Lassen S, Poulsen HS, et al.: Gonadal status in male survivors following childhood brain tumors. J Clin Endocrinol Metab 2001;86:2446–2452. 54. van Beek RD, Smit M, van den Heuvel-Eibrink MM, et al.: Inhibin B is superior to fsh as a serum marker for spermatogenesis in men treated for Hodgkin’s Lymphoma with chemotherapy during childhood. Hum Reprod 2007;22:3215–3222. 55. Lunsford AJ, Whelan K, McCormick K, et al.: Antimüllerian hormone as a measure of reproductive function in female childhood cancer survivors. Fertil Steril 2014;101:227–231. 56. Krawczuk-Ryback M, Leszczynska E, Poznanska M, et al.: Antimüllerian hormone as a sensitive marker of ovarian function in young cancer survivors. Int J Endocrinol 2013;epub 1–6. 57. Metzger ML, Meacham LR, Patterson B, et al.: Female reproductive health after childhood, adolescent, and adult cancers: Guidelines for the assessment and management of female reproductive complications. J Clin Oncol 2013;31:1239–1247. 58. Wasilewski-Masker K, Seidel KD, Leisenring W, et al.: Male infertility in long-term survivors of pediatric cancer: A report from the childhood cancer survivor study. J Cancer Surviv 2014;8: 437–447. 59. Green DM, Zhu L, Zhang N, et al.: Lack of specificity of plasma concentrations of inhibin B and follicle-stimulating hormone for identification of azoospermic survivors of childhood cancer: A report from the St Jude lifetime cohort study. J Clin Oncol 2013;31:1324–1328. 60. Rendtorff R, Beyer M, Müller A, et al.: Low inhibin B levels alone are not a reliable marker of dysfunctional spermatogenesis in childhood cancer survivors. Andrologia 2012;44Suppl 1: 219–225. 61. Bordallo MA, Guimarães MM, Pessoa CH, et al.: Decreased serum inhibin B/FSH ratio as a marker of sertoli cell function in male survivors after chemotherapy in childhood and adolescence. J Pediatr Endocrinol Metab 2004;17:879–887. 62. Dong C, Hemminski K: Second primary neoplasms in 633, 964 cancer patients in Sweden, 1958–1996. Int J Cancer 2001;93:155–161. 63. Neglia JP, Friedman DL, Yasui Y, et al.: Second malignant neoplasms in five-year survivors of childhood cancer: Childhood cancer survivor study. J Natl Cancer Inst 2001;93:618–629. 64. Guerin S, Dupuy A, Anderson H, et al.: Radiation dose as a risk factor for malignant melanoma following childhood cancer. Eur J Cancer 2003;39:2379–2386. 65. Karagas MR, Mcdonald JA, Greenberg ER, et al.: Risk of basal cell and squamous cell skin cancers after ionizing radiationtherapy. For the Skin Cancer Prevention Study Group. J Natl Cancer Inst 1996;88:1858–1853. 66. Inskip P: Thyroid cancer after radiotherapy for childhood cancer. Med Pediatr Oncol 2001;36:568–573. 67. Dunst J, Ahrens S, Paulussen M, et al.: Second malignancies after treatment for Ewing’s sarcoma: A report of the CESS-studies. Int J Radiat Oncol Phys 1998;42:379–384. 68. Tichelli A, Socie G: Considerations for adult cancer survivors. Hematology Am Soc Hemtol Educ Program 2005;516–522. 69. Hodgson DC, Gilbert ES, Dores GM, et al.: Long-term solid cancer risk among 5-year survivors of hodgkin’s lymphoma. J Clin Oncol 2007;25:1489–1497. 70. Travis LB, Fossa SD, Schonfeld SJ, et al.: Second cancers among 40576 testicular cancer patients: Focus on long-term survivors. J Natl Cancer Inst 2005;97:1354–1365.

Survivorship 71. Children's Oncology Group. Long-term follow up guidelines for survivors of childhood, adolescent, and young adult cancers. Version 4.0. Monrovia, CA: Children's Oncology Group; October 2013; Available on-line: www.survivorshipguidelines.org 72. Paulino A: Late effects of radiotherapy for pediatric extremity sarcomas. Int J of Radiat Biol Phys 2004;60:265–274. 73. Marcus RB, Cantor A, Hears TC, et al.: Local control and function after twice-a-day radiotherapy for Ewing’s sarcoma of bone. Int J Radiat Biol Phys 1991;21:1509–1515. 74. Hopewell JW: Radiation-therapy effects on bone density. Med Pediatr Oncol 2003;41:208–211.

Journal of Surgical Oncology

655

75. Keus RB, Rutgers EJ, Ho GH, et al.: Limb-sparing therapy of extremity soft tissue sarcomas: Treatment outcome and long-term functional results. Eur J Cancer 1994;30A:1459– 1463. 76. Shapeero LG, De Visschere PJ, Verstraete KL, et al.: Posttreatment complications of soft tissue tumours. Eur J Radiol 2009;69:209–221. 77. Villani A, Tabori U, Schiffman J, et al.: Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: A prospective observational study. Lancet Oncol 2011;12:559–567.