Cancer-Associated Hypercalcemia - An Overview

Introduction:

The condition is referred to as hypercalcemia when the serum calcium levels are elevated (more than 10 mg/dL-milligram per deciliter). The primary cause of hypercalcemia in an individual are hyperparathyroidism (a condition with excess parathyroid hormone in the blood) and cancer. Depending on serum calcium levels, cancer-associated hypercalcemia can be mild, moderate, or severe. Treatment of hypercalcemia associated with cancer is considered palliative care or symptomatic relief. However, treatment of underlying cancer should be the primary method of treating cancer-associated hypercalcemia.

What Is Hypercalcemia?

Calcium is a common mineral found in different body parts, including blood. Calcium is vital for the body for multiple reasons, including bone and teeth formation, blood clotting, muscle contraction, regulation of heartbeat, and nerve functions. However, when this calcium level exceeds the normal range due to any disease, the condition is referred to as hypercalcemia. As already known, excess of anything can be bad for the body; therefore, this increase in blood calcium levels can cause multiple harmful effects on the body. The two most common causes of hypercalcemia are hyperparathyroidism, overactivity of the parathyroid glands, and cancer. Depending upon the serum calcium levels, hypercalcemia is classified as mild, moderate, or severe hypercalcemia. The ranges are:

• Normal calcium levels: 8.6 to 10 mg/dL.

• Mild hypercalcemia levels: 10 to 12 mg/dL.

• Moderate hypercalcemia: 12 to 14 mg/dL.

• Severe hypercalcemia: above 14 mg/dL.

What Is Cancer-Associated Hypercalcemia?

Hypercalcemia has been a very common finding in several people with cancer. Increased serum calcium levels have been reported in about 30 % of the people affected by cancers, and cancer-associated hypercalcemia is the most common cause of hypercalcemia in hospitalized patients. Hypercalcemia is often associated with stage IV or late-stage cancer, with a poor prognosis. If an individual has serum calcium levels of more than 13 mg/dL initially when presented, then cancer can cause hypercalcemia in that individual. However, severe and long-standing hypercalcemia, along with symptoms, suggests an advanced stage of cancer. The most common cancers that cause hypercalcemia are multiple myeloma (cancer of the plasma cell, a type of white blood cell), lung cancer, and renal cell cancer. Followed by breast cancer, colorectal cancer, cancers of the head and neck region, and blood cancer. The least common type of cancer associated with hypercalcemia is prostate cancer.

What Causes Cancer-Associated Hypercalcemia?

The primary cause of hypercalcemia in cancer patients is primary hyperparathyroidism (PHPT). Hypercalcemia in cancer mainly occurs through three mechanisms:

• Excessive Secretion of Parathyroid Hormone-Releasing Protein: Excess secretion of the parathyroid hormone-releasing protein (PTHrP) is the most prevalent cause of hypercalcemia in cancer. It accounts for over 80 % of all cases. Excess release of PTHrP leading to hypercalcemia in cancer is commonly seen in solid tumors, including; squamous cell carcinoma of the head and neck, cancer of the lungs, breast cancer, ovarian cancer, and renal cancer. It may also occur in leukemia (blood cancer).

• Spread of Cancer to the Bones With the Release of Osteoclasts Activating Factors: Bony spread of cancer leading to hypercalcemia is seen in about 20 % of cases. It is common in solid organ tumors that spread to the bones, multiple myeloma, and breast cancer.

• Production of Calcitriol (Vitamin D): Increased vitamin D production can also cause hypercalcemia in people with cancer. It is commonly seen in Hodgkin’s lymphoma (cancer affecting the lymphatic system) and a few cases of non-Hodgkin’s lymphoma (cancer in the lymphatic system).

Is Cancer-Associated Hypercalcemia Common?

• Cancer-associated hypercalcemia is common and seen in a large number of people with cancer, more so in people with advanced cancer.

• After primary hyperparathyroidism, cancer is the most common cause of hypercalcemia.

• Cancer-associated hypercalcemia is reported in about 10 % to 30 % of people with cancer.

• It is the most common cause of hypercalcemia in hospitalized patients.

• A report in 2013 stated that the number of people with cancer-associated hypercalcemia was about 71,744 in the United States of America. However, the number has been decreasing since then.

What Are the Symptoms of Cancer-Associated Hypercalcemia?

The symptoms of cancer-associated hypercalcemia can range from mild to severe depending upon the severity of cancer. The patient may be asymptomatic (present with no symptoms) or involve multiple organ systems and have associated symptoms. The symptoms include:

• Loss of appetite.

• Nausea and vomiting.

• Constipation.

• Pain in the abdomen.

• Excessive thirst (polydipsia) and frequent urination (polyuria).

• Weakness, fatigue, and lethargy.

• Muscular pain.

• Headaches.

• Depression.

• Confusion, disorientation, and inability to think properly.

• Pain in the bone.

• Stomach ulcers.

• Heart pounding or palpitations.

• Seizures.

• Comatose (prolonged period of unconsciousness) may occur in elderly patients with neurological involvement of advanced cancer.

How Is Cancer-Associated Hypercalcemia Diagnosed?

The diagnosis of hypercalcemia associated with cancer is made with the help of detailed medical history, family history, and thorough physical examination to determine the underlying cause of the disease. In addition, the following tests are done:

• Serum Calcium Levels: Blood samples are collected, serum calcium levels are checked, and the severity of hypercalcemia is evaluated. Ionized or free calcium levels should also be tested in case of suspected hypercalcemia.

• Parathyroid Hormone: Parathyroid hormone levels in the blood are checked to determine the cause of hypercalcemia. If the parathyroid hormone levels are elevated, the cause is more likely to be primary hyperparathyroidism or familial hyper parathyroid-syndrome. At the same time, non-parathyroid hormone-related hypercalcemia is seen in cancer.

• Parathyroid Hormone Releasing Protein: The levels of PTHrP should also be measured, and an elevated level of PTHrP suggests humoral hypercalcemia of malignancy.

• Vitamin D levels: An elevated vitamin D level can be due to several diseases and conditions. Increased calcitriol levels suggest vitamin D intoxication, whereas elevated calcitriol levels suggest conditions like lymphoma and granulomas (type of cancer).

How Is Cancer-Associated Hypercalcemia Treated?

Treatment of cancer-associated hypercalcemia is considered a supportive or palliative treatment of cancer. The treatment also depends on the severity of the hypercalcemia.

• Mild Hypercalcemia: People with mild hypercalcemia usually do not present with any symptoms; therefore, they do not require immediate treatment. Patients should be educated about proper diet and medicines, avoiding physical activity that may cause dehydration, etc.

• Moderate to Severe Hypercalcemia: Individuals with moderate to severe hypercalcemia will present with several symptoms. They will require immediate therapy and management. Administration of intravenous normal saline along with calcitonin and bisphosphonates is recommended initially. Hydration with normal saline helps in maintaining a normal urine output, thus restoring intravascular volume and increasing the excretion of calcium through urine. Calcitonin is given along with normal saline to reduce bone resorption. Bisphosphonates block the activity of the osteoclasts (bone-resorbing cells) and decrease bone resorption.

• Glucocorticoids: Glucocorticoids (corticosteroids) are recommended for patients with increased vitamin D production. Apart from supportive treatment for controlling hypercalcemia, the underlying cause of cancer should be treated.

Conclusion:

Hypercalcemia or increased serum calcium levels is associated with late-stage cancers. About eighty percent of the people diagnosed with cancer-associated hypercalcemia die within a year. However, it is important to understand the condition's cause, symptoms, and diagnosis to provide better treatment and improve prognosis. Cancer-associated hypercalcemia should be treated by a group of expert interprofessional teams consisting of an oncologist, internist, endocrinologist, and surgeon.