Fatigue, weakness during melanoma treatment

Issue: October 25, 2015

ByNadine E. Palermo, DO

ByStephanie L. Lee, MD, PhD, ECNU

A 78-year-old woman was referred to the endocrine clinic for evaluation of fatigue and weakness. Her medical history was significant for stage IV melanoma, osteoporosis previously treated with bisphosphonates and vitamin D deficiency.

Approximately 2 months earlier, she began treatment for metastatic melanoma with Yervoy (ipilimumab, Bristol-Myers Squibb), a monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Since initiation of ipilimumab, she described insomnia, tinnitus, headaches and dizziness. She reported that during the past 10 days, she experienced extreme fatigue so severe that she could barely get out of bed. Additionally, she noticed dizziness and lightheadedness with minimal movements. She was seen in the ED for a fall and, subsequently, by her oncologist for evaluation of progressively worsening weakness.

Brain MRI was ordered, and she was urgently seen in endocrine clinic.

Laboratory tests and imaging

On presentation, the patient was hemodynamically stable without orthostatic hypotension, and she had no deficits on neurologic exam, including confrontation visual field testing. She appeared extremely anxious with a fine tremor and had tenderness on palpation of her enlarged thyroid gland. She has no known history of head or neck radiation or family history for autoimmune disease, thyroid disease or thyroid cancer.

Figure 1: MRI of the brain. (A) T1 post-contrast coronal image. (B) Sagittal pre-contrast image. The pituitary is normal without evidence of mass or enlargement, thickened stalk or dural tail associated with a hypophysitis.

Biochemical evaluation was notable for suppressed thyroid-stimulating hormone with elevated peripheral hormones and otherwise normal pituitary (see Table 1).

Imaging was ordered to evaluate the pituitary and thyroid glands because of the known endocrine complications of ipilimumab. The brain MRI with and without contrast revealed a normal-appearing pituitary without suggestion of hypophysitis (enlargement, thickened stalk or dural tail; Figure 1).

Figure 2: Iodine-23 nuclear thyroid scan and uptake. Homogenous radiotracer uptake in an overall enlarged thyroid gland shown in three views: anterior-posterior view (AP), right anterior oblique (RAO) and left anterior oblique view (LAO). The thyroid uptake was 27.6% at 4 hours (expected 5% to 15%) and 74% at 24 hours (expected 15% to 30%). The enlarged thyroid with an elevated uptake is consistent with Graves’ hyperthyroidism. This scan excluded both subacute thyroiditis or autonomous nodules as the etiology of her thyrotoxicosis.

Nuclear thyroid scan performed with iodine-123 revealed an elevated uptake at 4 and 24 hours of 27.6% and 74.5%, respectively (Figure 2). This result is consistent with Graves’ disease and not subacute thyroiditis. Thyroid-stimulating immunoglobulin and thyroid peroxidase antibody titers were elevated at 257% (normal range < 140%) and 787.1 IU/mL (normal range < 5 IU/mL), respectively.

The patient was started on methimazole with improvement in symptoms. During the next 4 months, methimazole was tapered, and she became clinically and biochemically euthyroid (see Table 2). Ipilimumab was later discontinued due to her melanoma response to CTLA-4 therapy. After stopping ipilimumab, she became hypothyroid and was started on levothyroxine therapy.

Endocrine effects of ipilimumab

Ipilimumab has an immune-modulatory effect on tumor cells. It is not surprising that endocrinopathies have been associated with ipilimumab. However, the exact mechanism remains unclear. Dose-independent immune-related adverse events may occur within the first 3 months of CTLA-4 therapy. Although hypophysitis is most common, a spectrum of thyroid abnormalities have been reported, including thyroiditis, hypothyroidism, hyperthyroidism, euthyroid Graves’ ophthalmopathy and, rarely, thyroid storm.

With emerging biologic treatments and increased use of CTLA-4 therapy in patients with melanoma, clinicians should maintain a heightend awareness for potential endocrine-related adverse effects. Interestingly, there has been some suggestion that the development of immune-related adverse events has a positive correlation with favorable clinical response to CTLA-4 therapy. Most experts agree that baseline and follow-up thyroid testing should be completed for all patients receiving ipilimumab therapy. Biochemical endocrine evaluation is equally important when discontinuing therapy.

The role of pituitary imaging is controversial. Case reports have associated ipilimumab-induced hypophysitis with variable MRI scan results ranging from normal, to heterogeneous with homogenous gadolinium enhancement, to enlargement of the pituitary gland (reported to be 60%-100% of baseline size) with a thickened stalk.

References:
Blansfield JA, et al. J Immunother. 2005;28:593-598.
Corsello SM, et al. Cancer Chemotherapy Pharmacol. 2013;doi:10.1007/s00280-013-2213-y.
Hamnvik OP, et al. J Natl Cancer Inst. 2011;doi:10.1093/jnci/djr373.
Hodi FS, et al. N Engl J Med. 2010;doi:10.1056/NEJMoa1003466.

For more information:
Stephanie L. Lee, MD, PhD, ECNU, is an Endocrine Today Editorial Board member. She is Associate Professor of Medicine and Associate Chief, in the Section of Endocrinology, Diabetes and Nutrition at Boston Medical Center. Lee can be reached at Boston Medical Center, 88 E. Newton St., Endocrinology Evans 201, Boston, MA 02118; email: stephanie.lee@bmc.org. Lee reports no relevant financial disclosures.
Nadine E. Palermo, DO, is an endocrinology fellow in the Section of Endocrinology, Diabetes and Nutrition at Boston Medical Center. Palermo can be reached at Boston Medical Center, 88 E. Newton St., Endocrinology Evans 201, Boston, MA 02118. She reports no relevant financial disclosures.