Hello and thank you for joining me today for a refresher on Oncologic Emergencies Reviewing Hypercalcemia of Malignancy. My name is Anne Rayne Brown and I'm a clinical pharmacy specialist in critical care at MD Anderson Cancer Center in Houston, Texas. And I have no relevant disclosures to make. Today I will discuss the pharmacologic management of cancer patients presenting to the ICU with severe hypercalcemia and highlight the management of resistant cases. Let's start off with a patient case. This is a patient I recently managed in our COVID ICU. She is a 78 year old female with newly diagnosed diffuse large B-cell lymphoma with germinal center B-cell like subtype originating from the spleen. She was initially admitted directly to the hospital for initiation of chemotherapy. On admission lab she was noted to have tumor lysis syndrome with hyperuricemia with a uric acid of 9.4 and hypercalcemia with an elevated calcium level at 11.9 corrected to 12.6. She was started on IV hydration and given a dose of rasbura case. Unfortunately she tested positive for COVID which resulted in a delay in the initiation of her chemotherapy. We'll return to this case later in the presentation to discuss her hospital course and the treatment for her hypercalcemia of malignancy. Hypercalcemia of malignancy is an oncologic emergency that causes a high burden of debilitating symptoms and conveys a poor prognosis. Calcium homeostasis is tightly regulated but can be derailed by multiple benign or malignant processes all of which may occur in a patient with cancer. Hypercalcemia can occur in up to 30% of patients at some point during the course of their advanced cancer. While it has been associated with almost all cancer subtypes, the most common cancers associated with hypercalcemia include lung cancer, multiple myeloma, and renal cell carcinoma followed by breast, colorectal, and prostate cancer. The detection of hypercalcemia in patients with cancer signifies very poor prognosis with approximately 50% of patients dying within 30 days though more recent studies have showed a fairly low in-hospital mortality rate for patients with severe hypercalcemia requiring ICU admission. Patients with cancer who have hypercalcemia can be classified into one of four types. Humoral hypercalcemia accounts for the majority of cases and is caused by systemic secretion of parathyroid hormone related peptide by malignant tumors which causes increased bone resorption and enhances renal retention of calcium. This type is commonly associated with lung, renal, breast, and colon cancers. Local osteolytic hypercalcemia accounts for approximately 20% of cases in which hypercalcemia results from the marked increase in osteoclastic bone resorption in areas surrounding the malignant cells within the marrow space, commonly associated with multiple myeloma and metastatic breast cancer. Infrequently, lymphomas may secrete the active form of vitamin D 125 dihydroxy vitamin D causing hypercalcemia as a result of the combination of enhanced osteoclastic bone resorption and enhanced intestinal absorption of calcium. Finally, even more rare is ectopic secretion of authentic PTH of which there have only been a few case reports. Hypercalcemia is a result of abnormalities that occur in the normal bone formation and degradation cycle. The primary mechanisms for hypercalcemia include increased bone resorption, increased GI absorption of calcium, and increased renal tubular reabsorption of calcium. During normal bone turnover, osteoclast activity is regulated by the binding of rank surface receptor on the osteoclast to the receptor activator rank ligand on the osteoblast. This binding of rank and rank L regulates osteoclastogenesis. Calcium homeostasis is tightly regulated by many hormones including parathyroid hormone, 125 dihydroxy vitamin D, calcitonin, serum calcium, and serum phosphorus. With humoral hypercalcemia, tumors secrete parathyroid hormone related peptide into the bloodstream resulting in the downstream activation of osteoblasts. Whereas in osteolytic hypercalcemia, local cytokines released by the tumor stimulate osteoblasts to secrete rank ligand. In both cases, activation of osteoblasts triggers increased production of rank ligand. Overproduction of rank L drives increased formation, function, and survival of osteoclasts leading to bone resorption. Bone resorption leads to calcium mobilization into extracellular fluid. Increased calcium in the extracellular fluid enters the circulation and results in hypercalcemia. Because hypercalcemia of malignancy may lead to life-threatening complications, patients often require ICU admission. Clinical symptoms are nonspecific and depend on both the calcium levels and the rapidity of onset. In general, the neurologic and renal complications of hypercalcemia worsen with increasing severity of hypercalcemia, but other factors also influence response to hypercalcemia. For example, the rate of ascent of serum calcium level is important. Rapid increase frequently results in neurologic dysfunction. Similarly, older patients may become severely abundant in the presence of mild hypercalcemia. In this study by Musso and colleagues, they laid out the clinical manifestations seen in ICU patients with severe hypercalcemia, defined as total calcium levels greater than 12 milligrams per deciliter. Renal complications ranged from polyuria to acute kidney injury, with 19 percent of patients requiring renal replacement therapy during their ICU stay, primarily for tumor lysis syndrome, but also for lone hypercalcemia. Cardiovascular complications included sinus tachycardia, hypertension, and infarct-like STS segment elevation. Digestive events, including abdominal pain, occurred, and neurologic impairment occurred, also in patients experiencing seizures, delirium, and coma. Hypercalcemia is categorized according to the serum total calcium levels. Mild hypercalcemia is classified as calcium levels greater than 10.5 and severe hypercalcemia greater than 14. Symptoms of hypercalcemia are often described as moans, stones, groans, and bones. Moans referring to gastrointestinal conditions, including abdominal pain, constipation, decreased appetite, nausea, and vomiting. Stone symptoms of hypercalcemia refer to the kidney-related conditions, including flank pain, frequent urination, and kidney stones. Groans refer to neurologic side effects, including confusion, and bones refer to the bone pain and fractures that these patients may experience. Extreme elevations in calcium levels may cause coma. Although hypercalcemia of malignancy is generally classified by total serum calcium levels, it is occasionally valuable to measure serum levels of ionized calcium in patients with renal failure or with hypoalbuminemia. Forty percent of calcium is serum-bound to albumin. Therefore, a current serum albumin level is necessary for interpretation of the serum calcium level. Albumin and calcium are also highly sensitive to pH, and changes may alter the fraction of calcium ions that are bound to albumin. After hypercalcemia is confirmed with the measurement of the serum total calcium, further laboratory evaluation should be considered related not only to the mechanisms related to the cancer, but also others. Levels of intact PTH should be measured routinely to determine whether it is PTH or non-PTH mediated, or to detect coexisting primary hyperparathyroidism. Although most patients with typical humoral hypercalcemia of malignancy have increased levels of circulating parathyroid hormone-related peptide, levels should only be measured if the diagnosis is uncertain. Plasma-125 dihydroxyvitamin D should be measured to evaluate for excess vitamin D production or ingestion. The pattern of PTH, PTH-related peptide, and vitamin D values can also be helpful in determining the cause of hypercalcemia. The main treatment for hypercalcemia of malignancy is alleviating the underlying disease with either systemic chemotherapy, surgical resection, or targeted radiation, but additional treatment of hypercalcemia is considered in moderate to severe presentations. Optimal therapy should be tailored to both the degree of hypercalcemia and the underlying cause. The cornerstone of treatment for individuals with acute symptomatic hypercalcemia is aggressive fluid resuscitation with intravenous formal saline. Subsequent treatment can include the use of IV bisphosphonates or denosumab, sometimes in combination with calcitonin. Glucocorticoids are used occasionally but are typically only beneficial in lymphoma-secreting calcitriol. They may also delay the onset of tachyphylaxis in calcitonin therapy. Hemodialysis can also be employed to reduce the overall serum calcium levels in the blood. Here I have included visuals for each of the targeted treatments. Initiating aggressive fluid replacement is essential to manage dehydration and pre-renal azotemia associated with hypercalcemia of malignancy. A recommended goal is to achieve a urine output of greater than 75 milliliters per hour. Loop diuretics are also commonly used to promote urinary excretion of calcium, but routine use is not recommended unless diuresis is needed in patients who develop fluid overload from the fluid resuscitation. Calcitonin interferes with osteoclast function, stimulates osteoblast activity, and increases renal calcium extrusion. It has a rapid onset of action of about two hours and is degraded by the kidney without causing neprotoxicity. While it is useful when combined with IV fluids, its use is limited due to the short duration of efficacy and the potential development of tachyphylaxis through down regulation of calcitonin receptors on osteoclasts. We typically employ its use in the short term for a maximum of 48 to 72 hours until the initial effects of bisphosphonates are seen in severe hypercalcemia. Bisphosphonate therapy with either zoledronic acid or pomegranate are considered first-line pharmacologic therapy after rehydration due to their rapid onset of action and relatively extended duration of serum calcium reducing effects, as evidenced from multiple randomized trials compared with other agents. Bisphosphonates exert their activity by adsorbing the surface of bone, thereby disrupting osteoclast activity. There's also evidence of direct cytotoxicity to osteoclasts. Regarding humeral hypercalcemia, it has been suggested that both parathyroid hormone related peptides effect on renal calcium reabsorption, circumvents the main activity of bisphosphonates and contributes to suboptimal response, sometimes observed with therapy. Patients could be considered resistant to therapy if no response is established or if re-administration is required within two weeks of an initial dose of bisphosphonate. The initial effects of bisphosphonates are seen within 48 to 96 hours with maximal efficacy within one week. Depending on the specific agent used, effects of a single dose have been shown to last from 10 to 35 days or even longer. Dinosumab is a human monoclonal antibody that binds to rank ligand, preventing activation of its receptor rank on osteoclasts. By binding rank ligand, dinosumab inhibits osteoclast formation, function, and survival. It also prevents maturation of osteoclasts, thereby degracing bone resorption and inhibiting calcium release. Recent studies have shown that dinosumab was more efficacious than zoledronic acid in delaying or preventing hypercalcemia of malignancy in patients with advanced cancer, including breast cancer, other solid tumors, and multiple myeloma, or in hypercalcemia refractory to bisphosphonates. In the trial leading to dinosumab's FDA approval for the treatment of refractory hypercalcemia of malignancy, Hu and colleagues studied patients who had calcium levels greater than 12.5 despite bisphosphonate therapy. At day 10, 64% of patients had responded. The patient population consisted of patients with aggressive disease, as indicative of a CTCAE grade 3 hypercalcemia within a median of 17 days from their last IV bisphosphonate therapy. Dinosumab as a primary treatment for hypercalcemia has been limited to case reports and this retrospective chart review by Dietzik and colleagues, where they demonstrated efficacy of dinosumab as primary treatment for hypercalcemia of malignancy, but highlighted the potential for prolonged hypocalcemia. Unlike bisphosphonates, dinosumab is not renally eliminated, providing an additional therapeutic option in patients with renal dysfunction. In a systematic review and meta-analysis of six randomized trials with over 13,000 patients, dinosumab was associated with a significantly lower risk of renal events when compared to zoledronic acid at 26%. Currently, dinosumab is recommended in patients refractory to bisphosphonates or in renal failure where bisphosphonate therapy may be contraindicated. NCCN guidelines for multiple myeloma do incorporate recommendations for the use of dinosumab, particularly in patients with severe renal impairment. I've included a cost comparison of the treatment options and despite being approved for the by the FDA over 30 years ago, calcitonin has seen a dramatic increase in acquisition cost over the last few years. Due to its short-lived efficacy and cost, it should be reserved for severe symptomatic cases of hypercalcemia in those patients requiring rapid reduction and in conjunction with more definitive therapies. Now let's return to our patient who was admitted with findings of both TLS and hypercalcemia of malignancy. If you'll remember, our patient with diffused large B-cell lymphoma was initially admitted directly for chemotherapy, which was unfortunately delayed due to COVID-19 diagnosis and the need for supplemental oxygen. On day one, she was initiated on saline hydration to facilitate calciases and given rasburicase for hyperuricemia. On day two, you can see her corrected serum calcium is coming down nicely, but she was also initiated on remdesivir due to worsening hypoxia. On day three, she was initiated on corticosteroids until her chemotherapy could be initiated. By day five, her calcium had started to trend back up, so we started calcitonin until her chemotherapy could be initiated. Unfortunately, on day seven, after her first dose of chemotherapy, she had worsening respiratory distress and on day eight was transferred to the ICU due to high flow nasal cannula requirements at 50 liters and 70%. She also demonstrated worsening acute kidney injury. She was given a dose of tocilizumab for her COVID-19, and you can see that her hypercalcemia is worsening in the setting of AKI and inability to continue her chemotherapy. On day 10, it was decided to give her denosumab instead of abyssocinate in the setting of acute kidney injury and given her chemotherapy continued to be on hold due to worsening respiratory status. Within 24 to 48 hours of denosumab administration, her acute kidney injury had improved and her calcium levels began to trend down. To sum everything up, it is important to understand the pathogenesis of hypercalcemia of malignancy to determine the underlying cause and treatment targets. The most effective strategy for managing hypercalcemia is treatment of the underlying malignancy. For patients with poor prognosis and no viable treatment options, the most humane course may be no treatment at all. For those requiring intervention, the mainstay of therapy are IV hydration, bisphosphonates, and calcitonin. New therapies such as denosumab have emerged but are limited to specific cancer type, refractory cases, and in renal failure. Unfortunately, no uniform guidelines exist, but you may find disease-specific recommendations within both NCCN and ASCO oncologic guidelines. Thank you for joining me virtually and I'd be happy to address any questions.

hypercalcemia of malignancy

oncologic emergency

cancer patients

mechanisms for hypercalcemia

treatment options