Chapter 52: Endocrine and Metabolic Complications of Cancer Therapy

In the past two decades, cancer research has rapidly advanced, spurred by the development of high-throughput technology and the maturation of genomic and proteomic research methods. These advances have resulted in treatments that have substantial effects on the outcomes of certain cancers. The continuous development of new antineoplastic agents adds increasing challenges for practicing physicians.

Current cancer treatments include surgery, radiation, cytotoxic chemotherapy, hormonal therapy, bio-immunotherapy, and targeted therapy. Adverse effects of antineoplastic agents on the endocrine system are caused by several different mechanisms and can range from a subtle laboratory abnormality with limited clinical significance to potentially lethal clinical syndromes. Antineoplastic agents in general can be cytotoxic to endocrine cells and result in glandular dysfunction. Antineoplastic agents can also interfere with the synthesis or postsynthesis processing of hormones at different levels (ie, transcription, translation, or posttranslation). An agent may inhibit or induce secretion of a hormone by interacting with receptors, perturbing intracellular second messenger metabolism, or may affect hormone delivery by changing carrier protein levels in serum or by competing for binding on the carrier protein. Finally, antineoplastic agents can interact with signal transduction pathways to inhibit or enhance hormonal action in the end organs.

In this chapter, we summarize the major and common endocrine complications of cancer therapy and discuss screening and surveillance of these complications in cancer patients and survivors.

Glucose Metabolism Disorders

Diabetes Mellitus

Serum glucose is under continuous complex regulation. Many processes can affect glucose levels, including gut absorption, cellular uptake, gluconeogenesis, and glycogenolysis. Multiple hormones also play important roles in overall glucose homeostasis, including insulin, glucagon, growth hormone (GH), cortisol, somatostatin, and incretins.

Glucocorticoids are frequently used with many chemotherapy protocols and can have profound effects on glucose levels by increasing insulin resistance. Glucocorticoids can unmask preexisting prediabetic states by precipitating overt diabetes or make diabetes more difficult to control. The severity may range from asymptomatic hyperglycemia to nonketotic hyperosmolar coma. Most patients taking glucocorticoids with elevated glucose require insulin therapy to achieve blood glucose control, especially when given high-dose steroids. Long-acting and intermediate-acting insulin formulations are often combined with mealtime rapid-acting or short-acting insulins. Currently, there emerging studies about the management of steroid-induced diabetes mellitus in cancer patients by using multiple daily injections including mealtime short-acting insulin to counteract postprandial glucose excursions. Recent concerns about the promotion of malignancy by the mitogenic effect of insulin (¹) and especially insulin analogs (²) that cross-activate insulin-like growth factor 1 (IGF-1) receptors (³), in combination with conflicting clinical study results on insulin glargine and cancer, have brought attention to the gap in knowledge about proper diabetes management for maximization of survival in cancer patients and survivors. A large cohort study showed that insulin analogs including insulin glargine are associated with a lower risk of cancer in general than human insulin (⁴).

Mammalian target of rapamycin (mTOR) inhibitors, L-asparaginase, streptozocin, and interferon-α (IFN-α) have also been associated with impaired glucose homeostasis and frank diabetes mellitus (⁵).

Phosphoinositide-3 (PI3) kinase/Akt/mTOR pathway–targeted therapy can cause hyperglycemia. Inhibition of this pathway results in peripheral insulin resistance, increased gluconeogenesis, and hepatic glycogenolysis (⁵). Everolimus, a tyrosine kinase inhibitor, is used in patients with advanced breast cancer, progressive neuroendocrine tumors of pancreatic origin, and advanced renal cell carcinoma. Fifty percent of patients taking everolimus have hyperglycemia (Table 52-1) (⁶). Temsirolimus is another kinase inhibitor used in patients with advanced renal cell carcinoma. The incidence of hyperglycemia in patients using this drug is 26% (⁷). The mechanism by which temsirolimus leads to diabetes may be similar to that of tacrolimus, which decreases glucose-stimulated insulin release in the pancreatic islets by reducing adenosine triphosphate (ATP) production and glycolysis (⁸).

Idelalisib, a PI3 kinase inhibitor, is indicated in patients with chronic lymphocytic leukemia. One of the idelalisib’s emergent laboratory abnormalities is hyperglycemia, which occurred in 54% of patients taking both idelalisib and rituximab in a phase III study (^9,10). Another study showed that idelalisib alone in different dose regimens increased serum glucose in 40% of patients (¹¹).

L-Asparaginase is used mainly to treat hematologic malignancies. The risk of hyperglycemia associated with pegylated Escherichia coli asparaginase has been reported to be similar to the risk associated with native asparaginase; in one study, the risk was about 20% in children with acute lymphoblastic leukemia treated with either agent. The exact mechanism of L-asparaginase–associated hyperglycemia is not known, although it has been postulated that inhibition of insulin, insulin receptor synthesis, or both may be the cause, leading to a combined insulin deficiency–insulin resistance syndrome (¹²). Pancreatitis, which can occur with L-asparaginase therapy, is another possible mechanism for hyperglycemia. Pancreatitis can cause islet cell destruction, and some patients might require insulin therapy (¹³). One potential complication is hypoglycemia after cessation of L-asparaginase; thus, close monitoring of blood glucose is recommended. Diabetic ketoacidosis has been reported during L-asparaginase therapy. Long-term insulin therapy may not be needed in some cases of L-asparaginase–induced diabetes mellitus (¹²).

Streptozocin, used primarily to treat malignant islet cell tumors and other neuroendocrine tumors, is an N-nitrosourea derivative of glucosamide. Streptozocin’s effect on islet cells is species specific and dose related; rat islet cells appear to be more susceptible to the cytotoxic effects of streptozocin than human islet cells. Most of streptozocin’s effects are reversible upon discontinuation of the drug. Although the reported incidence of glucose intolerance varies from 6% to 60%, most cases are mild to moderate in severity (¹⁴).

Interferon therapy activates immune system cells to fight some cancers and certain infections. According to a survey on IFN therapy in Japan, some patients may experience earlier development of type 1 diabetes, resulting in initiation of insulin therapy (¹⁵). These patients were positive for islet cell antibody and anti-glutamic acid decarboxylase antibodies (¹⁶).

We recommend monitoring of fasting serum glucose levels prior to the start of and during these therapies and possibly determining the levels of anti-islet autoantibodies before IFN therapy in patients with family history of type 1 diabetes mellitus (¹⁵).

Glucosuria

Some antineoplastic drugs (eg, ifosfamide and mercaptopurine) cause a proximal tubular defect and lower the renal threshold for glucosuria without affecting glucose metabolism. Glucosuria has been detected with an increased incidence in 67% of adult and 75% of pediatric patients treated with high-dose ifosfamide, cisplatin, and high-dose methotrexate, compared to the early postchemotherapy assessment (13% adults and 29% children) (¹⁷).

Lipid Disorders

Lipid disorders are seldom evaluated in the process of active anticancer therapy, because patients are often encouraged to maintain a positive metabolic balance via liberal oral intake. Investigation or treatment of mild lipid abnormalities is often overlooked because the focus is on maintaining a positive caloric balance during cancer treatment. Some lipid disorders may be short-lived without clear clinical consequences, but some may be of clinical importance and need to be detected and treated. In general, triglyceride levels higher than 1,000 mg/dL increase the rate of complications, including pancreatitis.

Lipid disorders are among the main side effects of vitamin A derivatives, which are commonly used in dermatologic disorders. One vitamin A derivative, bexarotene, has been used against malignancies like cutaneous T-cell lymphoma, acute promyelocytic leukemia, and head and neck cancer. Bexarotene is an agonist of retinoid X receptors, a family of peroxisome proliferator-activated receptors that are upregulated by the binding of bexarotene to a receptor on the nucleus. This upregulation not only regulates lipid metabolism but also affects thyroid hormone synthesis (¹⁸). Hypothyroidism contributes to lipid disorders in patients receiving bexarotene. Because bexarotene causes hypertriglyceridemia in approximately 40% of patients, lipid levels and thyroid functions should be checked before bexarotene therapy. If triglyceride levels are 200 to 400 mg/dL, dietary modifications are recommended. If triglyceride levels are 400 to 1,000 mg/dL, omega-3 fatty acids with fibrates or nicotinic acid should be started. Lipid levels should be checked after initiation of therapy, because triglyceride levels over 1,000 mg/dL increase the risk of acute pancreatitis (¹⁹).

Hypercholesterolemia is the second most common side effect of bexarotene, having been reported in 48% of treated patients (²⁰). The long-term significance of drug-induced hypercholesterolemia is unclear; however, atorvastatin has been successfully used to treat bexarotene-associated hypercholesterolemia in patients at the University of Texas MD Anderson Cancer Center (MDACC).

Mitotane, an analog of the insecticide dichlorodiphenyltrichloroethane, is used in patients with adrenocortical carcinoma as adjuvant therapy. The potential side effects of this therapy include hypercholesterolemia. Although the exact mechanisms of hypercholesterolemia remain unclear, mitotane stimulates hydroxymethylglutarate–coenzyme A reductase. A study from MDACC showed that mitotane increases high-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels (²¹). Patients with adrenocortical carcinoma usually have a poor prognosis, making the clinical significance of mild to moderate elevation of cholesterol uncertain. However, in long-term survivors on adjuvant mitotane therapy, hyperlipidemia can lead to early development of atherosclerotic disease. The benefits of treating mitotane-induced lipid abnormalities in long-term survivors have not been established.

Mammalian target of rapamycin inhibitors have metabolic side effects that include hypercholesterolemia and hypertriglyceridemia (see Table 52-1). Although the mechanisms of these side effects are unclear, hypercholesterolemia can be caused by dysregulation of sterol regulatory element binding proteins in the mTOR pathway (²²). Another possible mechanism is reduction in lipid clearance from the bloodstream (²³).

Before starting mTOR inhibitor therapy, baseline fasting glucose, LDL cholesterol, and triglyceride levels should be checked. The lipid profile should be monitored for every cycle. The goals of lipid-reducing therapy are to keep fasting LDL cholesterol at or below 190 mg/dL and triglycerides at or below 300 mg/dL, if life expectancy is >1 year. Therapeutic lifestyle changes are the first appropriate approach for patients with hyperlipidemia. If such lifestyle changes fail to reduce LDL cholesterol to ≤190 mg/dL, statin therapy should be started. The goals of LDL cholesterol reduction vary with patients’ cardiovascular risk factors. Patients with triglyceride levels above 1,000 mg/dL have an increased risk for acute pancreatitis. Fibrate, omega-3 acid esters, niacin, and combination therapy are the treatment options for hypertriglyceridemia (⁵).

Water and Electrolyte Disorders

Serum osmolality is tightly regulated, primarily by interaction between the hypothalamic osmoreceptors that regulate secretion of antidiuretic hormone from cells in the paraventricular and supraoptic nuclei, the hypothalamic thirst center, and the kidneys. Disruption of any of these regulators may lead to a disturbance in free water clearance and subsequent abnormalities in serum sodium levels.

Syndrome of Inappropriate Antidiuretic Hormone Secretion and Hyponatremia

Hyponatremia is a relatively common electrolyte abnormality in patients with cancer. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the most common underlying causes for hyponatremia in this patient population. In addition to its association with hyponatremia, SIADH is characterized by low serum osmolality and an inappropriately high urine osmolality with elevated urine sodium. SIADH is a diagnosis of exclusion after ruling out hypovolemia, heart failure, renal insufficiency, cirrhosis, adrenal insufficiency, hypothyroidism, salt-wasting syndrome, and the use of diuretics. In patients with cancer, SIADH may be caused by ectopic antidiuretic hormone production by a variety of tumors. Syndrome of inappropriate antidiuretic hormone secretion is most commonly seen in patients with small cell lung cancer. Other tumors described (less commonly) in association with SIADH include malignant thymoma, oral squamous cell carcinoma, prostate carcinoma, and pancreatic carcinoma. Chemotherapy-induced lysis of antidiuretic hormone–containing cancer cells may lead to severe hyponatremia at the time of chemotherapy induction.

Other factors that may increase antidiuretic hormone secretion include nausea, pain, narcotics, and nicotine. Antineoplastic agents such as high-dose intravenous cyclophosphamide, vincristine, vinblastine, and cisplatin can also increase antidiuretic hormone secretion.

In cases of hyponatremia secondary to SIADH, urine osmolality is higher than plasma osmolality, and urine sodium is determined by sodium intake. In patients with SIADH, urine sodium is usually higher than 40 mEq/L. Fluid restriction (usually 500-1,500 mL of free water a day), an increase in salt intake, and occasionally, loop diuretics are attempted first in most cases of SIADH when the patient is asymptomatic or has mild symptoms. In the presence of severe symptoms (seizures or obtundation), hypertonic saline infusions might be needed with close and frequent monitoring of sodium levels to avoid rapid correction and possible osmotic demyelination syndrome (previously called central pontine myelinolysis). Demeclocycline (600-1,200 mg/d) can be used in cases in which hyponatremia does not respond to more fluid restriction. Vasopressin receptor (V2) antagonists (tolvaptan and conivaptan) have been approved by the US Food and Drug Administration for treatment of clinically significant hypervolemic or euvolemic hyponatremia associated with heart failure or SIADH (²⁴).

Diabetes Insipidus and Hypernatremia

Central diabetes insipidus can occur after surgery for brain tumors and occasionally in cases of tumors near the sella or the hypothalamus that invade the neurohypophysis or disrupt the pituitary stalk. These cases are often recognized by a clinical presentation of polyuria or polydipsia and are usually treated with 1-deamino-8-D-arginine vasopressin (subcutaneously, intranasally, or orally) to control the symptoms and correct the associated hypernatremia.

Nephrogenic diabetes insipidus can also occur in patients with cancer, and multiple antineoplastic agents have been described in association with this syndrome. Ifosfamide is well known to induce damage to the proximal renal tubule and, to a lesser extent, the distal renal tubule, and thereby induce nephrogenic diabetes insipidus. Streptozocin has also been reported to cause nephrogenic diabetes insipidus.

In addition to being associated with diabetes insipidus, hypernatremia in patients with cancer is commonly caused by insufficiency of free water, especially when patients are on parenteral or tube feeding regimens or are too debilitated to obtain water for themselves.

Osteoporosis

Normal bone remodeling requires a delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts. Antineoplastic therapy may affect this balance by increasing the activity of osteoclasts (eg, interleukin-2) and sometimes by having direct toxic effects on osteoblast function. Hormones and cytokines (ie, parathyroid hormone [PTH], PTH-related peptide, and interleukin-1) can also affect the overall bone turnover rate.

Bone mineral loss is one of the side effects of cancer treatment. Hormone-suppressive therapies, chemotherapeutics, and corticosteroids can cause osteoporosis in cancer patients (²⁵). Improved oncologic treatments and patient longevity have increased the importance of skeletal health in cancer patients.

Breast cancer patients are at high risk for osteoporosis after hormone-suppressive therapy (²⁶). Aromatase inhibitors, including anastrozole and letrozole, have been shown to decrease bone density and increase the rate of fractures in postmenopausal women. This is in sharp contrast to the positive effect on bone (both bone mineral density and fracture rates) seen with tamoxifen, a selective estrogen receptor modulator (Fig. 52-1). In the ATAC (Arimidex [anastrozole], Tamoxifen, Alone or in Combination) trial, 9,366 postmenopausal women with invasive operable breast cancer who had completed primary therapy were randomly assigned to receive anastrozole, tamoxifen, or both. More fractures were seen in patients receiving anastrozole compared with patients on tamoxifen (²⁷). According to these findings, patients should undergo bone mineral density testing prior to treatment with aromatase inhibitors, and annual follow-up should be conducted thereafter. Antiresorptive therapy is usually added if a patient’s bone density is within the osteoporotic range (T score ≤ –2.5) before treatment or if a significant decline in bone mineral density was seen during follow-up.

Osteoporosis can also occur in prostate cancer patients treated with androgen deprivation therapy (ADT), which can consist of gonadotropin-releasing hormone (GnRH) agonists, nonsteroidal antiandrogens, bilateral orchiectomy, and/or androgen blockers. These therapies can result in bone mineral loss and fractures (²⁸) due to hypogonadism that increases bone resorption. The risk of fractures is higher in prostate cancer patients undergoing ADT than in those not undergoing ADT (²⁹).

Patients with prostate cancer should be evaluated with dual-energy x-ray absorptiometry before starting ADT. Patients with fragility fractures or osteoporosis should be offered antiosteoporosis treatment. Before such treatment, nonpharmacologic approaches such as lifestyle modifications and calcium and vitamin D supplementation can be helpful (³⁰).

Antineoplastic agents have also been implicated in chemotherapy-associated osteoporosis. Prolonged therapy with oral methotrexate for acute lymphoblastic leukemia has led to distal extremity pain, severe osteoporosis, and associated fractures, with significant improvement after cessation of methotrexate therapy (³¹). Other agents reported to reduce bone density include cisplatin and carboplatin. In addition, many chemotherapy protocols include corticosteroids, which are known to decrease bone density and increase the risk of fractures.

Patients who have undergone bone marrow transplantation have been reported to have low bone mass. The reduced bone density is likely to be secondary to the long-term side effects of bone marrow radiation, chemotherapy, corticosteroids, and hypogonadism.

Osteoblasts and osteoclasts are under the influence of many hormonal and signaling pathways, including tyrosine kinase receptors for platelet-derived growth factor (PDGF receptors α and β) and c-Abl. Activation of the PDGF pathway improves bone mineral density in ovariectomized rats and accelerates fracture healing. The absence of c-Abl is associated with impaired osteoblast maturation, leading to an osteoporosis phenotype (³²).

Multikinase inhibitors such as sorafenib, sunitinib, and imatinib, among others, can inhibit pathways that affect bone remodeling. Not much is known about the clinical effects of tyrosine kinase inhibitors, small molecules with variable receptor affinity and an intracellular signal blocking effect, on bone. Imatinib has been the best studied and will be discussed here.

After 2 to 4 years of treatment with imatinib in patients with chronic myelogenous leukemia, a significant increase in the volume of the trabecular bone in the iliac crest has been observed (³³). Pre-osteoblast cells exposed to imatinib undergo suppression of PDGF-induced PI3 kinase/Akt activation with upregulation of genes associated with osteoblast differentiation and bone formation.

More studies are needed to determine the effects of imatinib and other tyrosine kinase inhibitors on bone and bone mineral metabolism.

Osteomalacia and Rickets

Osteomalacia occurs when normal mineralization of the organic bone matrix fails. In children, abnormal mineralization and maturation of the growth plate at the epiphysis is called rickets. Nutritional deficiency (especially vitamin D deficiency) and renal wasting of phosphorus leading to hypocalcemia or hypophosphatemia are among the common causes of osteomalacia. Other contributing factors include drugs such as anticonvulsants or aluminum and systemic acidosis. Antineoplastic agents can also cause or worsen osteomalacia.

Ifosfamide-induced tubular damage leads to renal phosphate wasting, hypophosphatemia, and rickets. Although renal and skeletal consequences of ifosfamide therapy have been well described in children, only four adult patients with osteomalacia have been reported (³⁴). Another antineoplastic agent, the estrogen derivative estramustine, used in prostate cancer metastatic to bone, can cause hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and osteomalacia with normal vitamin D levels (³⁵).

Hypercalcemia

Calcium homeostasis is normally maintained by the interplay of PTH, calcitonin, phosphorus, and vitamin D metabolites in several target organs, including bones, parathyroid glands, intestines, and kidneys. In patients with cancer, multiple factors can affect this delicate balance, including nutritional status, medications, and tumor secretion of cytokines, hormones, or other humoral factors.

Hypercalcemia occurs in 5% to 10% of all patients with advanced cancer, and severe hypercalcemia (calcium level >12 mg/dL) is seen in about 0.5% of all patients with cancer (³⁶). Squamous carcinoma, renal cell carcinoma, non–small cell lung carcinoma, breast carcinoma, leukemia, non-Hodgkin lymphoma, and multiple myeloma are among the most common malignancies associated with hypercalcemia. Retinoic acid derivatives have been reported to induce hypercalcemia in treatment of acute promyelocytic leukemia (³⁷).

Hyperparathyroidism occurs 2.5 to 3 times more often in patients treated with low-dose (2-7.5 Gy) external radiation to the head and neck area than in the age-matched control population. Hyperparathyroidism after high-dose irradiation is uncommon. Radiation exposure from radioactive iodine treatment has also been reported in association with hyperparathyroidism (³⁸).

Hypocalcemia

Many factors can increase a cancer patient’s risk of hypocalcemia. These factors include the patient’s nutritional status, the antineoplastic agents used, and the type of surgical procedures performed (eg, neck dissection). Cytotoxic chemotherapy can result in tumor lysis syndrome and its resultant hypocalcemia, as commonly seen in treatment of hematologic malignancies. Hyperphosphatemia, hyperkalemia, hypocalcemia, and hyperuricemia can occur after induction chemotherapy; it is of vital importance to prevent the complications of tumor lysis by hydration, alkaline diuresis, inhibition of uric acid synthesis, and administration of oral calcium or aluminum-based compounds to bind intestinal phosphate and enhance calcium absorption. Intravenous calcium administration can potentially cause calcium phosphate precipitation in the presence of severe hyperphosphatemia and should be used with extreme caution. Dialysis may be needed in cases of symptomatic hypocalcemia and serum phosphorus levels higher than 10 mg/dL.

Cisplatin has been associated with hypocalcemia. One proposed mechanism of cisplatin’s ability to induce hypocalcemia is through hypomagnesemia resulting in decreased PTH secretion (³⁹). Other theories include inhibition of 1,25-dihydroxy-vitamin D formation by hypomagnesemia or cisplatin inhibition of mitochondrial function in the proximal renal tubule. Other agents reported to induce hypocalcemia include dactinomycin, carboplatin, doxorubicin, and cytarabine. Hypocalcemia has been seen following administration of bisphosphonates (zoledronic acid and pamidronate) or denosumab (a monoclonal antibody that inhibits receptor activator of nuclear factor-κB ligand [RANKL]), both used to reduce skeletal complications in treatment and prevention of advanced malignancies involving the bone (⁴⁰). Serum calcium levels and 25-hydroxyvitamin D levels should be checked prior to and during therapy with bisphosphonates or denosumab.

Hypomagnesemia

Hypomagnesemia is a well-known side effect in patients receiving platinum-based chemotherapy. Cisplatin has toxic effects on the kidneys, causing morphologic changes and necrosis in the proximal tubule, a major site of magnesium reabsorption. Hypomagnesemia is a frequent complication of cisplatin chemotherapy, affecting up to 90% of patients; 10% of these patients have symptoms of muscle weakness, tremulousness, and dizziness. A recent study showed that premedication with magnesium reduced cisplatin-induced nephrotoxicity in patients with thoracic cancers (⁴¹).

Carboplatin, a second-generation platinum compound, was developed to reduce the side effects of cisplatin. However, hypomagnesemia has been seen with increasing frequency and severity at higher doses of carboplatin.

Oxaliplatin, a third-generation platinum derivative that has become an integral part of various chemotherapy protocols, particularly in advanced colorectal cancer, has dose-limiting cumulative sensory neurotoxicity similar to that of cisplatin. Oxaliplatin chelates to calcium and decreases magnesium levels. Hypomagnesemia was seen in 11% of patients with advanced epithelial ovarian cancer treated with oxaliplatin in a phase II trial (⁴²). Oxaliplatin is considered to carry a lower risk for hypomagnesemia compared with cisplatin and carboplatin.

Cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), is used to treat metastatic colon cancer. Because EGFR is common in the loop of Henle, cetuximab blocks reabsorption of magnesium in the kidneys. Increased renal wasting of magnesium can cause supplement-resistant hypomagnesemia. Magnesium levels should be checked before and during cetuximab therapy. Cetuximab-induced hypomagnesemia is also used as a marker of worse overall survival (⁴³).

Hypothalamic-pituitary damage leading to single or multiple hormonal deficiencies can occur in patients treated with cranial or craniospinal irradiation or intracranial surgery. Cranial radiation therapy is often used to treat leukemia and lymphoma, nonpituitary brain tumors, pituitary tumors, nasopharyngeal carcinoma, and skull base tumors (⁴⁴). The hypothalamus appears to be more radiosensitive than the pituitary gland and may be damaged by low radiation doses (<40 Gy), but high radiation doses are likely to damage both hypothalamic and pituitary functions. Deficiency in one or more pituitary hormones occurs following irradiation (>40 Gy) of the hypothalamic-pituitary area in about 90% of patients 5 years after radiation treatment (Fig. 52-2) (⁴⁵).

Ipilimumab, an immunoglobulin G1 antibody that blocks cytotoxic T lymphocyte-associated antigen 4 (CTLA4), is used to treat melanoma and renal cell carcinoma. Ipilimumab-induced autoimmune hypophysitis was reported in 11% of patients in a retrospective study (Table 52-2) (⁴⁶). The risk factors for ipilimumab-induced hypophysitis are male gender and old age (⁴⁷). The typical clinical presentation includes headache, fatigue, and nausea. Magnetic resonance imaging (MRI) may reveal pituitary gland and stalk enlargement. After cessation of the drug, pituitary morphology returns to normal (Fig. 52-3) (⁴⁸). The earliest and most frequently affected hormone is adrenocorticotropic hormone (ACTH), but other hormones can also be affected; the effects often disappear after drug cessation. Physicians should be aware of hypopituitarism symptoms and test for adrenal insufficiency, hypogonadism, and hypothyroidism.

Growth Hormone Deficiency

Growth hormone deficiency is frequently noted after cranial irradiation. In children, isolated GH deficiency can occur after low radiation doses, but high doses may produce panhypopituitarism. Hypopituitarism appears to be dose dependent. At low doses (20-24 Gy), the only effect may be an altered pulsatile secretory pattern. At doses higher than 30 Gy, deficient GH secretion and growth retardation are observed in more than a third of patients (Fig. 52-4). Children who receive cranial irradiation require long-term follow-up (⁴⁹).

Growth hormone deficiency is also common in adults who have undergone cranial radiation therapy. In those patients, GH deficiency is thought to cause decreased bone and muscle mass, fatigue, impaired sense of well-being, lowered exercise capacity, increased volume of adipose tissue, and altered myocardial function. In addition, patients with GH deficiency may have a higher occurrence of atherosclerotic plaques and an increased risk for cardiovascular diseases. GH replacement in these patients can restore normal adipose tissue composition, bone metabolism, quality of life, sense of well-being, lipid profile, and cardiac function. Despite the apparent benefits, data on the effect of GH replacement in long-term cancer survivors are still lacking. Growth hormone replacement is contraindicated in any patient with an active malignant condition, but it can be initiated in an adult in whom malignant disease has been absent for at least 5 years. Another treatment reported to result in GH deficiency is long-term intrathecal opioids. Patients receiving this treatment have about a 15% elevation in the risk of developing GH deficiency (⁵⁰).

Central Hypothyroidism

Radiation therapy can cause immediate and long-term effects. One such effect, central hypothyroidism, may be a result of the possible effects of brain or head and neck irradiation on hypothalamic and pituitary regulation of thyroid-stimulating hormone (TSH) secretion. Not only cranial irradiation but also craniospinal irradiation can cause central hypothyroidism. In one study, central hypothyroidism was detected a year after the end of radiation treatment in 6% of patients (⁵¹). In that study, 15% to 20% of patients who had undergone cranial irradiation had diminished TSH secretion 5 years after the end of treatment, and approximately 35% of those patients had it after 10 years. Because of the combined effect of irradiation on the thyroid gland and the hypothalamic-pituitary axis, we suggest measuring patients’ levels of both serum free thyroxine and TSH concentrations yearly or if the patients is having symptoms suggestive of hypothyroidism to replace thyroid hormones when necessary.

Chemotherapy may enhance the deleterious effect of radiation. Children with brain tumors (not involving the hypothalamic-pituitary axis) who receive vincristine, carmustine, lomustine, or procarbazine in combination with brain irradiation have a 35% incidence of hypothyroidism, compared with a 10% incidence in children who undergo brain irradiation alone (⁵²).

Bexarotene was found to cause central hypothyroidism in 40% of patients with cutaneous T-cell lymphoma (²⁰). Reversible, retinoid X receptor–mediated suppression of TSH secretion is one explanation for this side effect. Bexarotene patients often require higher levothyroxine dose compared with patients with other causes of hypothyroidism. This observation is related to bexarotene-related increase in thyroid hormone metabolic clearance (⁵³).

Hypogonadotropic Hypogonadism

Brain surgery and irradiation of the skull carry the potential for hypothalamic-pituitary damage, including hypogonadotropic hypogonadism. Hypogonadism occurs within 7 years after cranial irradiation for nonpituitary neoplasia in 25% of patients. Hypogonadism is transient in the presence of hyperprolactinemia and is treated with antidopaminergic therapy (⁵⁴). Hyperprolactinemia is the most commonly reported hormonal abnormality in patients who have undergone head and neck irradiation, occurring in more than 66% of patients (^55,56). Hyperprolactinemia inhibits gonadotropin secretion from the pituitary gland and decreases the responsiveness of the pituitary gland to GnRH, causing secondary hypogonadism. In children, inadequate sexual development, delayed puberty, and absent menarche are significant problems, whereas in adults, gonadotropin deficiency may cause sex steroid hormone deficiency, infertility, and loss of axillary and pubic hair (Fig. 52-5). Sex steroid hormone deficiency lowers libido and may have deleterious effects on bone and lipid metabolism.

Early or even precocious puberty has also been reported in patients with acute lymphoblastic leukemia treated with combined chemotherapy and cranial irradiation and in patients with brain tumors treated with cranial irradiation. This phenomenon is more common in girls. Coexisting GH deficiency is frequently noted. In a recent study of male cancer survivors (excluding those who had undergone treatment that may have otherwise affected gonadal function), chronic opioid therapy, given in morphine-equivalent daily doses of at least 200 mg daily, was associated with secondary hypogonadism (⁵⁷).

Thyroid Neoplasms

Ionizing radiation is implicated in the etiology of thyroid cancer. Irradiation of the thyroid, especially in children and young adults (such as young patients with Hodgkin disease), increases the risk of papillary thyroid carcinoma (⁵⁸).

Hyperthyroidism

Radiation-induced hyperthyroidism has been described but is far less common than radiation-induced hypothyroidism.

Radiation-induced silent thyroiditis with transient thyrotoxicosis has been reported in patients treated with radiation. Thyroiditis-induced thyrotoxicosis occurs within a few months of radiation therapy in most cases; hypothyroidism occurs several months later. The risk of Graves disease increases following radiation therapy. Patients with lymphoma treated with radiation constitute the largest number of patients who have developed Graves disease after radiation therapy; this finding raises the possibility of a relationship between the two clinical entities. Patients treated with radiation for nasopharyngeal, breast, and/or laryngeal carcinomas may also develop Graves disease. Cytokines have also been reported to lead to Graves disease. Interferon is known to induce the production of autoantibodies and can lead to autoimmune thyroid disease, such as autoimmune primary hypothyroidism, transient thyrotoxicosis, or more rarely, Graves disease. Women have a higher risk than men of developing autoimmune thyroid disease upon starting IFN treatment (⁵⁹). It is important to distinguish the cases in which IFN induces transient thyrotoxicosis followed by hypothyroidism from the cases in which IFN induces Graves disease. Thyroid scans showing increased homogeneous uptake in the presence of hyperthyroidism are highly suggestive of Graves disease and warrant treatment with antithyroid medications (eg, methimazole).

Systemic therapies can also be linked to hyperthyroidism. Monoclonal antibodies directed against CTLA4 (ipilimumab and tremelimumab) and anti-CD52 antibody (alemtuzumab) are associated with painful thyroiditis and Graves disease (⁶⁰). Interleukin-2 (denileukin diftitox) treatment alone causes transient hyperthyroidism followed by hypothyroidism in about 50% of patients (⁶¹). The mechanism of interleukin-2–induced autoimmune thyroid dysfunction is unclear, although interleukin-2–induced disruption of self-tolerance has been suggested as a mechanism. Tyrosine kinase inhibitors can cause transient thyrotoxicosis via destructive thyroiditis (⁶⁰). Pembrolizumab treatment caused hyperthyroidism in 1 of 135 patients in a safety study (⁶²).

Hypothyroidism

Head and neck irradiation frequently causes dysfunction of the thyroid gland. Radiation can induce primary hypothyroidism when given in doses higher than 25 Gy to the region near the thyroid gland (Fig. 52-6). Secondary and tertiary hypothyroidism can be seen with doses of 40 Gy or higher to the hypothalamic-pituitary area. Most cases of primary hypothyroidism occur about 5 years after radiation therapy. The probability of hypothyroidism is dose related and increases with duration of follow-up after radiation treatment. In a study of 1,677 patients with Hodgkin disease whose thyroid had been irradiated, the risk of thyroid disease was 52% and 67% after 20 and 26 years, respectively (⁶³). Four hundred eighty-six patients (29%) received thyroxine therapy because of elevated serum TSH concentrations, and 27 (2%) had transient elevations in serum thyrotropin level that were not treated. A recent review estimated the rate of hypothyroidism after thyroid irradiation to be 20% to 30%, with half of the cases occurring within the first 5 years (⁶³).

A significant number of patients develop subclinical hypothyroidism (elevated TSH with normal thyroxine levels), not overt hypothyroidism, when less than 40 Gy of radiation is administered. Subclinical hypothyroidism (20%) is more frequent than overt hypothyroidism (5%) 5 years after chemotherapy and radiation therapy (⁶⁴). Multiple factors increase the risk for hypothyroidism, including high doses of radiation to the head and neck, combined radiation and surgical treatments, time interval since therapy, and failure to shield midline structures. Other risk factors include thyroid resection during a laryngectomy or disruption of the vascular supply of the thyroid gland during surgery.

The use of iodine-131 (¹³¹I) may result in thyroid dysfunction. The use of ¹³¹I-metaiodobenzylguanidine in treatment of metastatic pheochromocytoma carries the possibility of inducing primary hypothyroidism and requires routine use of potassium perchlorate to block the thyroid ¹³¹I uptake.

Interferon therapy is associated with primary hypothyroidism in about 10% of treated patients and was not related to IFN dosage (⁶⁵). The presence of pretreatment serum antithyroid antibodies in patients treated with IFN therapy increases the risk for development of IFN-induced thyroid disease. During 6 years of observation after IFN therapy, the absence of thyroid autoantibodies at the end of IFN treatment was found to be a protective factor against development of thyroiditis, whereas positivity for thyroid antibodies at high titers at the end of IFN treatment was significantly related to chronic subclinical hypothyroidism. Interferon-related thyroid autoimmunity is not a completely reversible phenomenon, because some patients develop chronic thyroiditis, especially in the presence of high autoantibody titers.

Interleukin-2 causes painless thyroiditis with acute onset, with initial hyperthyroxinemia followed by primary hypothyroidism. The hypothyroidism may last months but is occasionally permanent; 9% of patients require replacement thyroid hormone therapy (⁶⁶).

Patients treated with multiple antineoplastic agents (with or without radiation) also have a higher than normal incidence of primary hypothyroidism. Fifteen percent of patients who received a combination of cisplatin, bleomycin, dactinomycin, vinblastine, and etoposide developed elevated TSH levels with normal free triiodothyronine (T₃) and free thyroxine (T₄), compatible with subclinical primary hypothyroidism, in contrast to the control group (⁶⁷).

The targeted therapy has also been linked to development of a variety of thyroid abnormalities. For example, autoimmune thyroid disease has been seen in 23% of patients receiving alemtuzumab (⁶⁸).

Imatinib use was reported to increase levothyroxine requirements in thyroidectomized patients, whereas nonthyroidectomized patients had no significant alterations of their thyroid functions. These data suggest that imatinib and maybe tyrosine kinase inhibitors in general may accelerate the clearance of levothyroxine, leading to clinical hypothyroidism in patients who are dependent on exogenous levothyroxine (⁶⁹).

Thyroid dysfunction was reported in 21% of renal cell carcinoma patients receiving sorafenib (⁷⁰). Prospective studies estimated the risk of thyroid dysfunction to reach 68%; however, only 6% of patients had clinical symptoms requiring thyroid hormone replacement (⁷¹). Sorafenib-related thyroiditis has been suggested as a mechanism of thyroid dysfunction in some of the patients, but it is unclear if thyroid dysfunction represents an autoimmune process or a manifestation of vascular endothelial growth factor blockade affecting the thyroid blood supply.

Sorafenib also affects the thyroid hormone replacement dose requirement in thyroidectomized patients with differentiated or medullary thyroid cancer. In one study, the dose of L-thyroxin had to be changed in 42% of the patients using sorafenib (⁷²). Another study showed that the daily dose of L-thyroxin was increased in 19% of patients and decreased in 16% of patients with anorexia and weight loss (⁷³).

Similarly, thyroid dysfunction was reported in 62% of patients receiving sunitinib, including 36% of patients who had persistent elevation of TSH, which was suggestive of primary hypothyroidism, especially in patients with longer sunitinib use. Destructive thyroiditis has been suggested as an explanation, although some patients became athyrotic on sunitinib after having normal thyroid function at baseline (⁷⁴). Another study showed that thyroid size was reduced to 59% after 12 months of sunitinib use in patients with renal cell carcinoma (⁷⁵). Other prospective studies found that 27% of patients receiving sunitinib had elevated TSH requiring hormone replacement (⁷⁶). Some patients were reported to present with thyrotoxic phase preceding hypothyroidism, which further supports the theory of sunitinib-related destructive thyroiditis leading to hypothyroidism in these patients (⁷⁷). Impaired iodine uptake and inhibition of peroxidase activity were also suggested as potential mechanisms to explain hypothyroidism (^78,79).

Ipilimumab-induced activation of T cells results in not only antitumor activity but also immune infiltration of endocrine glands. The major endocrine glands affected by ipilimumab are the pituitary and thyroid glands. Although hypophysitis causes central hypothyroidism, thyroiditis causes primary hypothyroidism (⁸⁰).

Pembrolizumab is an anti-programmed cell death (PD)-1 antibody that blocks interaction of PD-1 with the PD-L1 or PD-L2 ligand (see Table 52-2). Although PD-1 is expressed by T lymphocytes, PD-L1 or PD-L2 on tumor cells inhibits T-lymphocyte action. Anti-PD-1 antibody reverses this inhibition. The US Food and Drug Administration granted the approval to use pembrolizumab in patients with unresectable or metastatic melanoma. Primary hypothyroidism has been reported to occur in 8.3% of patients receiving pembrolizumab, with median time to onset being 3.5 months (range, 0.7 weeks to 19 months). Because the timing of the onset of thyroid dysfunction varies widely, patients who have received pembrolizumab should be monitored closely for changes in thyroid function (⁶²).

Abnormalities in Thyroid Hormone-Binding Proteins

Thyroid hormones are preferentially bound to thyroid hormone–binding globulin (TBG) (65%-70%), transthyretin (15%-20%), and albumin (10%-15%). Multiple factors can affect the levels of these binding proteins and the subsequent levels of bound thyroid hormones. In patients with malignancies, changes in sex hormone levels, glucocorticoids, narcotics, nutritional status, and some antineoplastic agents are the major factors affecting the protein-binding properties. Overall, the level of total T₃ and T₄ may be affected, but in general, the levels of free (biologically active) hormones are normal. The effect on TBG synthesis or clearance is usually reversible. Not only are estrogens known to increase TBG and total thyroid hormone levels, but tamoxifen also causes elevated plasma concentrations of TBG in postmenopausal women with breast cancer after 6 months of therapy. Nonsteroidal aromatase inhibitors (anastrozole and letrozole) are known to lower estrogen levels, but the effect on TBG has still not been fully documented in the literature; when letrozole was given at 2.5 mg/d, however, there was a statistically significant decrease in total T₄ but not total T₃ levels (⁸¹).

Glucocorticoids are frequently used in combination with chemotherapy and are known to suppress TSH secretion and inhibit TBG synthesis. L-Asparaginase can inhibit the synthesis of albumin and TBG, which affects serum thyroid hormone levels. 5-Fluorouracil increases total T₃ and T₄ levels and maintains a normal free thyroxine index, suggesting that this agent increases serum thyroid hormone–binding proteins, resulting in normal thyroid function (⁸²).

Mitotane increases the levels of hormone-binding globulins, but the increase in TBG is less remarkable than mitotane’s effect on corticosteroid-binding globulin.

Primary Adrenal Insufficiency

Mitotane is an orphan drug mostly used to treat adrenocortical carcinoma. Mitotane has selective toxicity to both normal and malignant adrenocortical cells. It also causes an increase in serum levels of cortisol-binding globulin (⁸³). Glucocorticoid replacement therapy is needed when mitotane is used; high doses are required because of the increased levels of binding globulin and enhanced metabolic clearance of corticosteroids by mitotane.

Animal studies found cases of adrenal necrosis associated with sunitinib use, leading the Food and Drug Administration to recommend monitoring adrenal functions in patients receiving sunitinib. However, there was no evidence of adrenal hemorrhage or clinical evidence of adrenal insufficiency in subsequent clinical safety data (⁸⁴).

Secondary Adrenal Insufficiency

Prolonged glucocorticoid treatment is the most common cause of adrenal dysfunction in patients with cancer. Secondary (central) adrenal insufficiency may develop up to 2 years after discontinuation of glucocorticoids and can persist for months. Irradiation of the hypothalamic-pituitary region causes ACTH deficiency with resultant secondary adrenal insufficiency in 19% to 42% of patients. The median time to development of adrenal insufficiency after radiation therapy is 5 years, but onset can occur in as little as 2 years. The 1-μg cosyntropin stimulation test has been proposed to screen central adrenal insufficiency in cancer survivors who received >30 Gy of radiation to hypothalamic and pituitary areas (⁸⁵).

Prolonged therapy with busulfan was initially reported to cause a reversible clinical syndrome resembling central adrenal insufficiency as evidenced by metyrapone testing. No recent reports have corroborated this finding. Long-term intrathecal opioid therapy for intractable nonmalignant pain resulted in central adrenal insufficiency in 15% of patients tested for insulin-induced hypoglycemia (⁵⁰).

Megestrol acetate is used to stimulate appetite in patients with cancer, but its prolonged use can lead to a Cushing-like syndrome, and sudden withdrawal after prolonged treatment may result in adrenal insufficiency. Megestrol shows glucocorticoid-like effects with an acute suppressive effect on the hypothalamic-pituitary axis and ACTH secretion, leading to central adrenal insufficiency as determined with the 1-μg cosyntropin stimulation test (^86,87). Secondary adrenal insufficiency can be diagnosed by a variety of tests with varying sensitivity and specificity, but in our practice, we frequently use a combination of basal (8:00 AM) serum cortisol and ACTH measurement as well as1-μg cosyntropin stimulation testing. Rarely, insulin-induced hypoglycemia is used to assess the overall cortisol and GH response to hypoglycemia when evaluating patients for panhypopituitarism.

Direct radiation exposure and cytotoxic chemotherapeutic agents are common causes of hypogonadism and infertility in cancer survivors. Because of the considerable differences between female and male gametogeneses, cancer therapy can have a variety of effects on fertility and gonadal functions in the two sexes.

Female Gonadal Disorders

Oogenesis occurs during embryonic life, and oocytes remain quiescent most of their lifespan; it is this property that makes oocytes resistant to the adverse effects of cytotoxic chemotherapy. However, because the number of oocytes is limited, damage to oocytes may in effect shorten a woman’s reproductive period. Granulosa cells are also susceptible to cytotoxic drugs, as evidenced by the results of ovarian biopsies performed after chemotherapy (Fig. 52-7). Infertility may occur as a result of impairment of either granulosa cells or oocytes.

With advances in cancer treatment, an increasing number of women survive malignancies to face reproductive disorders. It is of vital importance to discuss fertility issues before radiation or systemic chemotherapy, because these modalities carry significant risks for ovarian dysfunction and infertility. The effects of radiation treatment on the ovaries differ with patient age, radiation dose, and field of treatment. Radiation treatment that includes the pelvis increases the risk of infertility more than radiation treatment that includes only the abdomen (⁸⁸). Pregnancy rates decrease at doses between 5 and 10 Gy (⁸⁹). Fractionated radiation seems to carry less risk for permanent sterility. When possible, fractionated radiation should be used with shielding of the gonads, and restriction of radiation fields reduces the risk of ovarian failure. Ovarian transposition (oophoropexy) to the paracolic gutters before pelvic irradiation has been suggested to preserve ovarian function in women less than 40 years of age with cervical carcinoma less than 3 cm in diameter (⁹⁰). Ovarian transposition can also be used prior to pelvic irradiation in other diseases, including lymphoma. This procedure can be done by either a laparotomy or a laparoscopy with the intent of preventing radiation-induced (but not chemotherapy-induced) ovarian failure. Assisted fertilization is often needed after this procedure.

Oocyte cryopreservation has been proposed as a means of preserving fertility in women treated for cancer, but it has been less successful in humans than in animal models. Ovarian tissue cryopreservation and transplantation have also been proposed for patients before cancer treatment.

The ethical issues behind these techniques are still being disputed, and there is still the concern of potential disease recurrence from residual disease in autografted ovarian tissues. Obtaining unilaminar follicles from cryopreserved, thawed tissue and growing them in vitro has been proposed to reduce the risk of recurrence. The cytotoxic effects of chemotherapeutic agents are seen more in rapidly dividing cells than in cells at rest, which led to the hypothesis (⁹¹) that GnRH agonists would suppress the hypothalamic-pituitary-ovary axis and make the ovaries less susceptible to the cytotoxic effects of chemotherapy. In animal models, GnRH agonist therapy lowered cyclophosphamide-induced but not radiation-induced ovarian toxicity. Some studies have reported encouraging results of the use of this approach in women with breast cancer, leukemia, and lymphoma (⁹¹). Another study showed that GnRH agonist therapy may protect ovarian reserve but does not decrease the risk of premature ovarian failure in patients treated for lymphoma (⁹²).

In premenopausal women with breast cancer treated with regimens based on anthracyclines (5-fluorouracil, epirubicin, and cyclophosphamide), the rate of chemotherapy-related amenorrhea is 93%. At the end of therapy, menstrual periods resumed in 24% of the patients (⁹³).

Alkylating agents, which are non–cell-cycle specific, are generally highly gonadotoxic. Mechlorethamine is usually used in combination with vincristine, procarbazine, and prednisone. This combination is highly gonadotoxic, but the exact contribution of mechlorethamine to the gonadotoxicity is difficult to evaluate. Chlorambucil, melphalan, busulfan, and cyclophosphamide also carry a high risk of ovarian damage. Ovarian failure with alkylating agents was found to impose the highest risk with an estimated odds ratio (relative to no treatment) of 3.98 (⁹⁴). The extent of cisplatin toxicity in women is less well defined, with an odds ratio (relative to no treatment) of 1.77. Temporary amenorrhea developed in 2 of 12 female patients in whom cisplatin (0.4-0.6 g/m²) was used in combination with bleomycin and vinblastine to treat ovarian germ cell tumors; the amenorrhea lasted from 12 to 15 months after the cessation of chemotherapy (⁹⁴).

Transient and permanent ovarian failure has been reported with etoposide use (⁹⁵).

Antimetabolites, which are cell-cycle specific, may exert few toxic effects on the ovaries. As a single agent, doxorubicin has few, if any, adverse effects on ovarian function, although a synergistic effect of the combination of doxorubicin and cyclophosphamide is a concern.

Vinblastine has been known to cause reversible and dose-related amenorrhea when combined with alkylating agents (⁹⁶).

Male Gonadal Disorders

Spermatogenesis occurs in a continuous cycle of meiosis, mitosis, differentiation, and maturation. Germ cells and spermatogonia, in contrast to Leydig or Sertoli cells, are sensitive to cytotoxic agents. If sufficient germ cells remain after cytotoxic chemotherapy, resumption of spermatogenesis usually occurs; the longer the duration of azoospermia, the lower is the likelihood of spermatogenesis recovery (⁹⁷).

Radiation damage to the gonads is dose dependent. Low-dose testicular irradiation leads to a transient suppression of sperm counts with a recovery time proportional to the radiation dose (⁹⁸). However, permanent infertility was reported in patients who received fractionated radiation doses of more than 2 Gy (Fig. 52-8), whereas clinically significant Leydig cell impairment occurs rarely with doses of less than 20 Gy (⁹⁹).

Therapy with alkylating agents such as cyclophosphamide or chlorambucil administered alone may result in reversible but prolonged azoospermia. Chlorambucil causes azoospermia at cumulative doses of 400 to 800 mg; recovery may take 3 to 4 years after a mean total dose of about 750 mg/m² (¹⁰⁰). Cyclophosphamide affects spermatogenesis more than Leydig cell function, causing reduced sperm count with normal testosterone levels.

Antineoplastic agents causing azoospermia in humans can be classified in four groups. The first group consists of chemotherapeutics that cause prolonged azoospermia: chlorambucil, cyclophosphamide, procarbazine, melphalan, and cisplatin. The chemotherapeutics in the second group, carmustine and lomustine, cause azoospermia in adults who had chemotherapy treatment prior to puberty. The agents in the third group cause prolonged azoospermia when given with other sterilizing agents; this group consists of busulfan, ifosfamide, nitrogen mustard, and dactinomycin. The agents in the fourth group have additive and temporary effects on azoospermia when combined with agents from the other three groups; this group consists of doxorubicin, thiotepa, cytosine arabinoside, and vinblastine (¹⁰¹).

Multiple methods of preventing or reversing infertility in men treated for cancer have been suggested. In rats, fertility can be restored by suppressing testosterone with GnRH agonists or antagonists, either before or after cytotoxic therapy. This approach does not protect survival of stem cells in the testes but enhances the ability of the testes to maintain differentiation of type A spermatogonia (¹⁰²). It would be premature to apply this method to everyday clinical practice, as the limited data from human trials did not show this benefit. Semen cryopreservation before starting gonadotoxic therapy followed by assisted fertilization is another strategy to preserve fertility in men with cancer.

Primary care physicians and oncologists should be aware of the major long-term consequences of cancer therapy for early detection and management of treatment-related side effects. Long-term follow-up is frequently needed because many of the complications occur years after treatment and can have subtle clinical presentations.

For long-term cancer survivors who were treated with streptozocin, L-asparaginase, or partial pancreatectomy, screening for delayed development of diabetes mellitus is recommended.

In children with a history of cranial irradiation or craniospinal irradiation, the growth rate should be assessed at 6-month intervals. A more detailed evaluation, including measurement of the levels of GH and IGF-1, thyroid function tests, and bone age assessments, should be performed when there is evidence of an abnormal growth pattern. The T₄ and TSH measurements should be performed annually for the first 5 years and less frequently thereafter. Careful physical examination should be performed annually to detect thyroid nodules, and if any are detected, a more detailed examination should be performed using ultrasound and, if necessary, fine-needle aspiration biopsy.

In adults who have undergone cranial irradiation with >20 Gy, clinical monitoring with measurement of serum cortisol, ACTH, free T₄, IGF-1 (if the patient is a candidate for GH replacement), prolactin, luteinizing hormone, follicle-stimulating hormone, and serum testosterone and documentation of menstrual history should be undertaken annually for 15 years and then every 2 years for another 15 years (⁵⁴).

In survivors of childhood malignancies, bone mass may be assessed in the early 30s, an age at which peak bone mass has been attained in most people. It is also important to consider the possibility of bone loss in androgen- or estrogen-deficient adults. If bone mass is normal, no further evaluation is needed beyond the usual recommendations for prevention of osteoporosis. In those with low bone mass, an active program of calcium and vitamin D supplementation, exercise, and occasionally, medical therapy (bisphosphonates or recombinant parathyroid hormone) should be combined with assessment of bone mass every 12 to 18 months.

Patients who have been treated with chemotherapeutic agents that cause hypophosphatemia, hypomagnesemia, or hypocalcemia, such as ifosfamide, platinum compounds, fludarabine, or estramustine, are particularly at risk for osteomalacia and should undergo an evaluation of serum calcium, phosphorus, magnesium, alkaline phosphatase, and vitamin D metabolite levels.

Patients who have been treated with aromatase inhibitors should have bone mineral density measurements before and during treatment and should be given calcium and vitamin D. Patients can be given bisphosphonates if deemed necessary. Because multitarget tyrosine kinase inhibitors can cause thyroid dysfunction, thyroid hormone levels should be checked before treatment begins. During treatment, thyroid hormone levels should be checked periodically to adjust thyroxine replacement. Multitarget tyrosine kinase inhibitors can cause new-onset hypothyroidism or increase the levothyroxine requirements in patients on chronic thyroid hormone replacement.