Hospital Medicine

Malignancy-associated hypercalcemia

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I. What every physician needs to know.

Malignancy-associated hypercalcemia results from increased bone resorption and release of calcium from bone secondary to four different mechanisms present in underlying malignant processes.

1. Local osteolytic hypercalcemia results from boney metastasis. These cells cause a local release of cytokines, such as TNF and IL-1, which then stimulate the differentiation of osteoclast precursors into mature osteoclasts and increase bone resorption; it is mostly seen in breast cancer and non-small cell lung cancer. Other osteoclast activating factors such as IL-1 beta, lymphotoxin, TNF and IL-6 stimulate osteoclastogenesis in multiple myeloma and some cases of lymphoma.

2. Tumor secretion of parathyroid hormone-related protein (PTHrP) also known as "humoral hypercalcemia of malignancy". PTHrP has some homology with PTH and binds to the same receptors as PTH thus increasing bone resorption as well as reabsorption of calcium in the distal tubules of the kidney along with inhibition of phosphate transport in the proximal tubules. This results in hypercalcemia and hypophosphatemia similar to hyperparathyroidism. It is the most common cause of hypercalcemia in patients with non-metastatic solid tumors and in some patients with non-Hodgkin’s lymphoma.

3. Tumor production of calcitriol or 1,25-hydroxy vitamin D is present in almost all cases of hypercalcemia associated with Hodgkin's disease and about 1/3 cases of non-Hodgkin's lymphoma. Interestingly, increased calcitriol production is also responsible for hypercalcemia related to granulomatous diseases such as sarcoidosis and tuberculosis where the liver enzyme 25-hydroxylase responsible for activating Vitamin D is upregulated.

4. Finally, in rare instances, tumors such as ovarian carcinoma, lung carcinoma, or primitive neuroectodermal tumors can secrete ectopic PTH and cause hypercalcemia also known as "ectopic hyperparathyroidism".

II. Diagnostic Confirmation: Are you sure your patient has Malignancy-Associated Hypercalcemia?

Total and sometimes ionized calcium levels should be ordered to confirm presence of hypercalcemia and estimate severity of the disease. If obtaining total calcium level only, the clinician should ensure to make corrections for patient's albumin level as needed.

A. History Part I: Pattern Recognition:

The mnemonic "moans, groans, stones, and bones with psychic overtones" describes the clinical manifestations of hypercalcemia. Abdominal pain and constipation, muscle or joint pains, boney pain, polyuria, nephrolithiasis, neuropsychiatric symptoms such as depression, headache, fatigue, confusion, cognitive dysfunction are a few of the clinical manifestations that can be present in patients with hypercalcemia depending on the severity and acuity of the disease.

B. History Part 2: Prevalence:

Malignancy-associated hypercalcemia is relatively common and presents in 20-30% of cancer patients. It occurs in both solid tumors and leukemias but is mostly associated with breast cancer, lung cancer, and multiple myeloma.

C. History Part 3: Competing diagnoses that can mimic Malignancy-Associated Hypercalcemia.

Hypercalcemia resulting from hyperparathyroidism, granulomatous disease, or excessive intake of vitamin D or calcium are other competing diagnoses which need to be ruled out. These tend to be more chronic than malignancy-associated hypercalcemia, which carries a poor prognosis with approximately a 50% 30-day mortality.

D. Physical Examination Findings.

Generally, physical exam findings of hypercalcemia are few and depend on the underlying disease process, the acuity of disease progression, and patient's other comorbidities. Mild elevations in calcium levels are usually asymptomatic. With moderate to severe hypercalcemia, especially if the calcium level rises rapidly, patients can present with altered mental status, confusion or even coma. Nonspecific abdominal pain or flank pain with radiation to groins concerning for kidney stones may be present. Proximal muscle weakness and pain on palpation or joint pain are other physical exam findings.

Hyperreflexia and tongue fasciculation can also be present in hypercalcemia. Additionally, findings related to the underlying malignancy such as cachexia, lymphadenopathy, hepatomegaly, splenomegaly, and masses can be present.

E. What diagnostic tests should be performed?

Malignancy work up should be initiated on new diagnosis of malignancy-associated hypercalcemia including but not necessarily limited to chest radiographs, mammogram, bone scan, bone survey, SPEP/UPEP, and computed tomography (CT) of chest, abdomen, pelvis. Many patients presenting with malignancy-associated hypercalcemia have known underlying malignancy in which case further diagnostic testing is not always necessary.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

After hypercalcemia is confirmed with elevated total and/or ionized calcium levels, then further tests should be obtained to rule out diagnoses other than malignancy-associated hypercalcemia and determine mechanism of hypercalcemia.

1. Intact PTH is very helpful in diagnosing malignancy-associated hypercalcemia if inappropriately low.

2. PTHrP can be obtained if malignancy is suspected. However, PTH is elevated or normal which in the majority of cases and is related to concomitant primary hyperparathyroidism, although ectopic PTH secretion is possible.

3. If lymphoma or granulomatous diseases are suspected, then plasma 1,25-hydroxy vitamin D level can be obtained to establish the diagnosis of tumor production of calcitriol.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Imaging studies are not diagnostic for hypercalcemia and are only useful in diagnosing any underlying malignancy associated with hypercalcemia.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

PTHrP is an over-utilized laboratory value which is usually obtained on presentation for further workup. Usually, the mechanism of hypercalcemia can be elucidated with obtaining PTH alone and PTHrP is useful only in the minority of cases where the mechanism remains unknown after initial testing.

ECG is often obtained with acute hypercalcemia in the inpatient setting and can be associated with some abnormalities such as QTc shortening and fist degree AV block. Occasionally, the ST segment can be depressed. Life-threatening cardiac arrhythmias secondary to hypercalcemia are unusual.

III. Default Management.

Management of malignancy-associated hypercalcemia is usually guided by the severity of the hypercalcemia determined by the calcium level as well as presenting symptoms and laboratory findings. Generally, neurologic and renal complications of hypercalcemia increase with increasing severity of hypercalcemia.

Mild hypercalcemia with calcium levels 10.5-11.9 mg/dL usually is asymptomatic and does not require any specific treatment other than addressing the underlying malignant process and following general measures including removal of excess calcium intake from enteral feeds and supplements. Medications associated with hypercalcemia such as lithium, thiazide diuretics, vitamin D and calcitriol if present should also be withheld.

Treatment of moderate hypercalcemia with calcium levels 12.0-13.9 mg/dL largely depends on patient's symptoms and renal function. Generally, intravascular volume repletion is sufficient in these patients to increase calciuresis and decrease calcium levels by increasing glomerular filtration rate and the filtered load of calcium as well as inhibiting reabsorption of calcium in the proximal tubules.

Severe hypercalcemia with calcium levels > 14.0 mg/dL can be associated with kidney injury and other symptoms including mental status changes. If more severe symptoms are present, calcitonin can be used along with intravascular volume repletion to decrease calcium levels more rapidly. Loop-diuretics can be used in certain instances after complete intravascular volume repletion in order to increase calciuresis or when saline infusion is limited by renal failure or heart failure; however, their use has fallen out of favor given potential for intravascular volume depletion and worsening of renal dysfunction and hypercalcemia.

Bisphosphonate therapy which blocks osteoclastic bone resorption is the main and most effective long-term treatment of malignancy-associated hypercalcemia and is usually initiated in patients with mild to severe hypercalcemia on presentation.

Glucocorticoids can be used in cases of hypercalcemia associated with calcitriol production.

A. Immediate management.

In severe and symptomatic hypercalcemia also known as "hypercalcemic crisis", immediate intravascular volume repletion with normal saline at a rate of 200-500 ml per hour should be initiated and continued until patient is adequately volume resuscitated and has good urine output of 100-150 ml per hour. Furosemide therapy can be used thereafter to increase calciuresis but is generally discouraged if patient can tolerate volume repletion.

Immediate but short-acting Calcitonin 4 units/kg SC or IM every 12 hours can be used for a short period of time while awaiting the response to bisphosphonate therapy which can take 2-4 days. Often tachyphylaxis to the effects of calcitonin develops within 48 hours of initiation of therapy.

B. Physical Examination Tips to Guide Management.

Monitoring volume status is essential in guiding management of hypercalcemia with aggressive intravascular volume repletion. Jugular venous distention, lung exam, oxygen saturation, and urine output should be followed closely while administering IV saline to avoid volume excess.

Patient's mental status should also be closely monitored to insure improvement with therapy. If patient fails to improve with successful treatment of hypercalcemia, brain imaging should be considered to rule out other intracranial process such as metastatic disease, CVA or intracranial bleed.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Typically, calcium and phosphate levels as well renal function are followed to monitor response to therapy.

D. Long-term management.

Malignancy-associated hypercalcemia carries a very poor prognosis with 30-day mortality approaching 50%. Potential survival benefits had been reported with bisphosphonate use in breast cancer and multiple myeloma in the past but more recently evidence is developing for prolonged survival and symptom relief independent of type of malignancy or calcium levels prior to treatment. Management should focus on anti-neoplastic therapy when indicated or comfort care in patients with advanced disease. In the palliative care population, it seems reasonable to offer antihypercalcemic therapy with bisphosphonates if consistent with goals of palliative and comfort care. There appears to be a larger survival benefit with greater reduction of calcium levels after bisphosphonate treatment. Older patient age and history of recurrent episodes of hypercalcemia seem to be associated with less response and worse outcome.

E. Common Pitfalls and Side-Effects of Management.

Inadequate intravascular volume repletion.

Administration of loop diuretics such as furosemide before adequate volume repletion can lead to worsening renal function and hypercalcemia.

Volume overload with aggressive IV saline administration especially with patients with renal dysfunction or cardiovascular disease.

A. Renal Insufficiency.

Intravascular volume repletion may be limited in setting of renal insufficiency depending on degree of CKD or AKI. Generally, bisphosphonate therapy is discouraged in patients with creatinine > 4.5, a dose reduction is not recommended but infusion over a longer time can decrease renal toxicity. If indicated and consistent with goals of care, dialysis to remove calcium should be entertained in patients with a glomerular filtration rate of less than 10-20 ml per minute.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure.

Again, rate and volume of intravascular saline infusion may be limited by volume overload. In these cases, consider concomitant administration of loop diuretics if necessary. In severe cases, dialysis may be necessary to remove calcium if patient is hemodynamically stable.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

Monitor closely for hypoglycemia or hyperglycemia in patients with decreased oral intake in setting of mental status changes resulting from hypercalcemia. Antihyperglycemic agents will likely need to be held, especially metformin and sulfonylureas in setting of renal insufficiency possibly resulting from hypercalcemia. Insulin doses will need to be decreased as well to avoid prolonged hypoglycemia with decreased renal clearance of insulin. Hyperglycemic side effects should be anticipated and managed accordingly if use of glucocorticoids is considered for the treatment of hypercalcemia.

F. Malignancy.

Consider use of glucocorticoids in certain malignancies such as lymphomas associated with tumor production of calcitriol. Otherwise, no change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management unless patient has cor pulmonale secondary to severe pulmonary hypertension resulting from pulmonary fibrosis. In this case, again aggressive and complete intravascular volume repletion may be challenging in setting of heart failure.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

Patients may be more prone to developing neuropsychiatric symptoms of hypercalcemia and may require treatment with lower calcium levels. Also, potential use of concomitant medications such as lithium which can exacerbate hypercalcemia and sedating medications which can alter mental status may complicate the clinical picture.

A. Sign-out considerations While Hospitalized.

Aspiration and fall precautions in setting of altered mental status, continue NPO status until improved.

Monitor volume status closely while on IV fluids, consider furosemide or discontinuation of saline infusion if patient develops shortness of breath, orthopnea, or hypoxia.

Clear sign-out of CODE status and resuscitation orders in case of cardiopulmonary arrest.

B. Anticipated Length of Stay.

Anticipate 1-4 days of hospitalization depending on severity of hyperglycemia and symptoms. With new malignancy diagnosis, the length of stay may be longer for staging, oncology consultation, and initiation of anti-neoplastic therapy.

C. When is the Patient Ready for Discharge.

Resolution of symptoms and decrease in calcium level with trend towards improved renal function are goals of hospitalization. Patient should be ready for discharge after discontinuation of IV saline with decreasing calcium levels and normalization of mental status.

D. Arranging for Clinic Follow-up.

Depending on goals of therapy, patient should either have oncology or primary care clinic follow up. If not enrolled in hospice prior to admission, consider hospice referral on discharge.

1. When should clinic follow up be arranged and with whom.

In patients already receiving treatment for their malignancy, an oncology clinic follow up should be arranged for calcium and renal function testing within 2-3 weeks of discharge, which is how long the response to bisphosphonates usually lasts.

Patients with new diagnosis of malignancy and without an oncologist, should ideally have their initial oncology consult while in the hospital and follow up with a new oncology clinic appointment within 1-2 weeks of discharge to discuss any potential treatment options.

Otherwise, patients should follow up with their primary care provider in 2-3 weeks of discharge for calcium and renal function testing.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

If new malignancy diagnosis, patients should ideally undergo an expedited inpatient malignancy workup including tissue biopsy for diagnosis and staging imaging.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Chemistry panel including BUN and creatinine as well as calcium levels should be obtained prior to clinic visit.

E. Placement Considerations.

Given the poor prognosis associated with malignancy-associated hypercalcemia, discussions regarding goals of care should be initiated while hospitalized with patient and/or representative if patient is unable to participate in the discussion. Palliative care and Hospice referrals should be obtained prior to discharge from the hospital. In most cases, given the advanced nature of the underlying malignancy, discharge to home hospice or inpatient hospice is reasonable depending on the patient's preferences.

Physical therapy and occupational therapy consults may be appropriate to determine the level of care the patient would need after discharge while keeping in mind the likelihood of rapid deterioration of his or her condition.

F. Prognosis and Patient Counseling.

Malignancy-associated hypercalcemia carries a very poor prognosis with a 30-day mortality approaching 50%. Patients achieving normocalcemia or a greater reduction of calcium levels with bisphosphonate therapy have a slightly better but still short survival of 53 days versus 25 days on average.

A. Core Indicator Standards and Documentation.

Currently, there are no JCAHO core indicators or measures for malignancy-associated hypercalcemia.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Fall and aspiration precautions are necessary with altered mental status in setting of hypercalcemia.

DVT prophylaxis is required in setting of underlying malignancy and anticipated immobilization with altered mental status or deconditioning related to malignancy unless contraindicated in setting of life-threatening bleed such known brain metastases with high risk for hemorrhagic conversion.

PUD prophylaxis should be used if patient is NPO because of altered mental status or other indication.

One of the main focuses of hospitalization should be clarification of goals of care given the poor prognosis of the diagnosis of malignancy-associated hypercalcemia. Code status should be clarified and if applicable a POLST form clarifying acceptable therapies to patient should be completed prior to discharge. Careful consideration of disposition after hospital discharge such as discharge to inpatient hospice or home hospice can prevent readmission for hypercalcemia especially with orders for comfort care.

VII. What's the Evidence?

Mallik, S,, Mallik, G,, Macabulos, ST,, Dorigo, A. "Malignancy Associated Hypercalcaemia-Responsiveness to IV Bisphosphonates and Prognosis in a Palliative Population.". Support Care Cancer 2015. 2015.

(This article suggests possible change in practice in the palliative care population with regards to treatment of malignancy-associated hypercalcemia with bisphosphonates.)
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