IMMUNOTHERAPY AND ENDOCRINOPATHIES

Oncologists and endocrinologists have made the most congenial of physician partners, going back a long way in modern medical history.

Since the availability of insulin, thyroid extracts, and glucocorticoids, what were once endocrine disorders with the same short-term demise as malignancies have become chronic disorders—often associated with less longevity than for fully healthy adults but enough for them to survive decades, raise families, and achieve professional stature of the highest levels.

We needed our oncology colleagues from time to time as pheochromocytomas, thyroid tumors, and gonadal tumors became metastatic, metastatic testicular tumors being among the first to demonstrate a predictable response to systemic therapy.

Their patients didn't do as well, requiring toxic treatments to take the aggressiveness out of the tumor or often life-altering surgery when a cure might be feasible.

Planning for oncology patients often focused on acute toxicity and symptoms when long-term survival was not anticipated.

As endocrinologists, we could expect a few phone calls for assistance with glucose levels gone high from glucocorticoids given to enhance the chemotherapy effect, threatening hyponatremia, mind-altering hypercalcemia, or—when things went a little better for a little longer—mitigating the bone loss or cutaneous problems from the glucocorticoid therapy that had helped prolong survival.

Unlike our usual concerns in the endocrinology office, such as future cardiovascular or renal disease in our patients with diabetes over decades, planning for incurable oncology patients took a much shorter view, often focused on acute toxicity and symptoms when long-term survival was not anticipated.

The endocrine consequences of successful treatment continue evolving today as immunotherapy enhances outcomes for a variety of malignancies that were previously refractory to chemotherapy. This success comes at a price, whether it be increasingly recognized thyroiditis from PD-1 inhibitors or the more serious hypophysitis and aggressive immunologic disorders from CTLA-4 inhibitors.

Adverse Effects of Remission

Success in oncology has had its endocrine downside for many decades. During my medical school years in the mid-1970s, 60 Minutes did an exposé on radiation-induced thyroid tumors.

At that time, exposure was primarily from infant thymic radiation thought to avert crib death or from the dermatologist treating cystic acne. A few were military nuclear exposures, but the tone of the newscast was that this was a problem we should not have had.

That form of medical radiation exposure for non–life-threatening conditions largely disappeared, only to reemerge in my professional lifetime in another, more justifiable setting.

As treatment of previously lethal disorders increasingly enable children to reach adulthood, clinicians need to seek out the adverse consequences of cancer remission.

Long-term survivorship of Hodgkin disease treated with radiotherapy became increasingly common. Because the thyroid often sits in the treatment field, avoiding exogenous radiation is not possible. After a lag time, the thyroid tumors appeared, this time as an acceptable byproduct of prolonged survival that was not previously possibleAs treatment of previously lethal disorders increasingly enabled children with a variety of tumors to reach adulthood, there has been growing recognition that clinicians who see these long-term survivors need to seek out some of the insidious adverse consequences of cancer remission.

Because brain radiotherapy is often part of the protocol, the Endocrine Society recently established evidence-based guidelines^[1] for the detection and reversal of mostly pituitary and hypothalamic exposure.

What We Might See

Disorders of maturation and linear growth need to be addressed in the pediatric years. They tend to occur fairly early and are easier to detect than in adults.

In adults, we more commonly encounter patients who underperform, do not feel well, have constitutional complaints, and may experience some intellectual deterioration, though without the specificity of maturation or growth impairment.

As endocrinologists, we are familiar with people who develop hypopituitarism after treatment of a pituitary tumor, either with surgery or radiotherapy. We are conditioned to test these people periodically. It goes under the radar sometimes if the treatment took place a long time ago, was not directed to the pituitary specifically, or if follow-up was bundled into either primary or oncology care.

The people who make it to the endocrinologist invariably pass through a few other medical offices first before somebody runs some tests and gets a lowish cortisol, a lowish free T4 without the expected rise in TSH, and sometimes a disproportionately high prolactin in the setting of hypomenorrhea in women or lowish testosterone in men.

The guideline outlines a variety of mostly straightforward testing to establish pituitary underfunction and recommends replacement therapy not much different from that for other causes.

Evolving From Lethal to Chronic

Long-term survivors of pediatric cancer have been common for a long time if the tumor was of endocrine origin. People with thyroid cancer in childhood usually make it to adulthood, with decisions to be made on long-term consequences of sometimes chronically supraphysiologic levothyroxine dosing.

Multiple endocrine neoplasia syndromes and some pheochromocytomas develop in children and become chronic conditions that transition from the pediatrician to the adult internist.

And we are familiar with a number of high-profile athletes who developed testicular carcinoma in their younger years and need ongoing long-term management if they were not cured with unilateral surgery.

In retrospect, this may not be very different from other diseases that have evolved from lethal to chronic. It took the availability of insulin to expect and manage end-organ disease from diabetes.

As cancers make that desirable transition to chronic disorders with long-term medical expectations, physicians will undoubtedly do their best to adapt. Let us applaud the Endocrine Society, who may have recognized this new reality and acted upon it first.