Endocrine Complications
Summary of Key Points
Introduction
• Endocrine dysfunction may occur as a direct result of cancer or may be a consequence of cancer therapy (e.g., surgery, radiation, chemotherapy, biological agents, and hormone therapy). Endocrine dysfunction may be an intentional consequence or an adverse effect of antineoplastic therapy.
• Hypopituitarism with clinically significant deficiencies of growth hormone, thyrotropin, gonadotropin, and corticotrophin may result from radiation (cranial or total body irradiation), surgery, or chemotherapy.
• Thyroid dysfunction from neck irradiation, immune therapy (interleukin-2), and small molecule tyrosine kinase inhibitors such as sunitinib may result in either hyperthyroidism or hypothyroidism.
• Gonadal dysfunction after surgery, radiotherapy, or chemotherapy results in disruption of puberty, infertility, and premature menopause.
• Adrenal dysfunction from agents such as ketoconazole or aminoglutethimide may result in glucocorticoid or mineralocorticoid deficiency.
• Pancreatitis and, occasionally, pancreatic exocrine or endocrine deficiencies may result from chemotherapy (l-asparaginase and streptozotocin).
Diagnostic Considerations
• A detailed history along with a complete physical examination is critical for diagnosis. Locations of primary and metastatic tumors along with past and current therapies are necessary elements of evaluation.
• Signs and symptoms such as delayed or precocious puberty, fatigue, weight loss or gain, amenorrhea, orthostatic hypotension, hyperpigmentation, or electrolyte abnormalities should prompt consideration of unrecognized endocrine dysfunction.
• When one hormonal deficiency is identified, others should be sought.
Evaluation and Treatment
Thyroid
• Primary hypothyroidism is characterized by a low free thyroxine (T4) level and an elevated thyroid-stimulating hormone (TSH) level, whereas central hypothyroidism is associated with a low free T4 level and inappropriately normal or low TSH levels. Replacement with levothyroxine is indicated and is highly effective.
• Hyperthyroidism is caused by increased T4 and/or T3 (triiodothyronine) levels with a low serum TSH level. Treatment options include surgery, radioiodine ablation, or antithyroid medications (e.g., propylthiouracil). Rarely, hyperthyroidism may be associated with production of TSH-like substances by germ cell or choriocarcinoma. Management in these instances involves thyroid suppression and treatment of the primary tumor.
Adrenal
• Low- or high-dose corticotrophin testing can distinguish between central and primary causes of adrenal insufficiency. Acute adrenal insufficiency is a medical emergency and should be treated by immediate parenteral glucocorticoid replacement and supportive care. Chronic insufficiency is treated by oral glucocorticoid supplement with or without mineralocorticoid.
Syndrome of Inappropriate Antidiuretic Hormone Secretion
• Hyponatremia is classically associated with high-dose cyclophosphamide and vinca alkaloid administration. Measurement of serum and urine osmolality, renal function tests, and assessment of volume status of a patient are the key to diagnosis. Treatment involves fluid restriction and increased salt intake. Patients with refractory cases might need loop diuretics, doxycycline, or newer vasopressin receptor blockers.
1. A 57-year-old patient with metastatic renal cell cancer is being treated with sunitinib, 50 mg, on a schedule of 4 weeks on and 2 weeks off. After 2 months, she noticed fatigue, anorexia, edema, fluid retention, and cold intolerance. What would be next appropriate step in management of this patient?
2. Radiographic imaging shows ongoing response to treatment. Two-dimensional echocardiography shows a normal ejection fraction. Thyroid functions were noted to be abnormal, with an elevated TSH level of 55. What would be the next step in management of this patient?
A Stop sunitinib and switch to sorafenib.
B Discontinue sunitinib until the TSH level returns to normal, and then resume sunitinib at a lower dose.
C Reduce the dose of sunitinib and initiate levothyroxine therapy.
D Continue the current dose of sunitinib and initiate levothyroxine therapy.
3. A 68-year-old man is found to have metastatic malignant melanoma to the bilateral lungs. The tumor is B-raf negative. You offer treatment with ipilimumab, 3 mg/kg intravenously every 3 weeks. The patient is clinically asymptomatic. Which of the following is not true about the possible endocrine adverse effects?
1. Answer: B. This patient has classic symptoms of hypothyroidism. Sunitinib-induced hypothyroidism is well documented. One or more thyroid function test abnormalities developed in as many as 85% of patients with metastatic renal cell cancer. Hypothyroidism has been reported in patients receiving sunitinib as early as 1 to 2 weeks after initiation of therapy. Thyroid-stimulating hormone (TSH) tends to improve during the 2-week-off treatment period. The incidence of hypothyroidism increases with the duration of sunitinib therapy. Thyroid dysfunction can appear as TSH elevation with normal T4 levels (subclinical hypothyroidism) or aas TSH elevation with low T4 levels (overt hypothyroidism). The latter is more likely to be associated with clinical features of hypothyroidism.
2. Answer: D. Patients experiencing overt hypothyroidism should be treated with thyroid hormone replacement therapy. Typical levothyroxine doses should allow normalization of TSH concentrations and resolution of symptoms. Patients with asymptomatic subclinical hypothyroidism may be monitored and treated when overt hypothyroidism develops. Treatment interruptions of sunitinib (~5% of patients in clinical trials), discontinuation (<1% of patients in clinical trials), or dose modifications for thyroid dysfunction are generally not necessary. Interestingly, a positive correlation between hypothyroidism and improved clinical outcome has also been observed in persons with renal, breast, brain, and head and neck cancers who were treated with sunitinib. Switching to sorafenib is not indicated with ongoing response to present treatment in this patient.
3. Answer: D. Ipilimumab (anti–CTLA-4 antibody) has been shown to induce hypophysitis and result in hypopituitarism by an immune-mediated phenomenon. In the phase 3 trial, nine patients treated with ipilimumab (1.8%) had severe or life-threatening hypopituitarism. Several other endocrine adverse effects including hypothyroidism, adrenal insufficiency, or hypogonadism were also noted. Primary thyroid disease may be seen as hyperthyroidism with Graves disease or as hypothyroidism as a result of destructive thyroiditis. Secondary hypothyroidism may result from decreased production of TSH resulting from hypophysitis and panhypopituitarism. Immune-mediated pancreatitis was also noted in the study. The median time to onset of endocrine symptoms was 11 weeks; delayed symptoms were observed in some patients even after completion of intended four courses. Some of the endocrine dysfunction is thought to be reversible with cessation of therapy with ipilimumab. Limited data are available on long-term sequelae of the therapy.
