Parathyroid hormone related peptide–mediated

PTHrP overproduction, humoral hypercalcemia of malignancy (HHM), is the cause of hypercalcemia in about 80% of cancer patients. Eight of the first 13 amino acids of PTHrP are identical to PTH, and PTHrP shares many common actions with PTH, including increased calcium reabsorption in the distal convoluted tubule (DCT), and reduced phosphate reabsorption in the proximal convoluted tubule (PCT) that result in hypercalcemia and hypophosphatemia. However, unlike PTH, which stimulates production of 1,25 (OH) ₂ vitamin D ₃ , PTHrP does not, and as a result, intestinal calcium and phosphorus reabsorption are not increased with PTHrP. It is produced in mammary glands during lactation and by the placenta during pregnancy. It serves several normal regulatory physiologic functions including: uterine blood flow, calcium transport across placenta from mother to fetus, chondrocyte growth and differentiation in long bones, and calcium mobilization from bone into breast milk during lactation. With time, a variety of additional paracrine functions of PTHrP emerged. PTHrP facilitates tooth eruption, promotes branching morphogenesis in mammary glands, and regulates vascular smooth muscle, keratinocyte differentiation, beta cell proliferation, and insulin production.

HHM presents with severe hypercalcemia, serum calcium concentration of 14 mg/dL or more, in a patient with a known malignancy or with a clearly evident malignancy, at time of initial presentation. It portends a poor prognosis. The most common tumors that produce PTHrP are squamous cell carcinomas, most breast cancers, and renal cell carcinoma. In a series of 138 patients with cancer, hypercalcemia and elevated PTHrP levels, solid organ malignancies were seen in 82.6%, hematologic malignancies in 12%, and benign etiologies in 8.7%. The most common solid organ malignancies were squamous cell carcinomas (28.2%) most frequently originating from lung, head and neck, and skin. Adenocarcinomas were almost equally as common (27.5%) with the most common causes adenocarcinoma of unknown primary, breast cancer, renal cell carcinoma, and lung cancer. Other tumors with frequencies above 5% included urothelial and bladder tumors, other non-small cell lung cancers (NSCLC), and non-Hodgkin lymphoma (NHL). In patients with benign disease, 1.4% had community acquired pneumonia and in 7.2% no malignancy was found. Median survival, from the time elevated PTHrP was detected, was 52 days (range 21–132 days). Survival was longer in those with a hematologic etiology, 362 days. In a study at Barnes Jewish Hospital in St. Louis, of patients with a PTHrP level drawn over a 10-year period, evidence of malignancy was found in 242 patients. The most common etiologies were undetermined in 40.5%, HHM in 38%, osteolytic bone lesions in 27.3%, immobilization in 3.3%, and primary hyperparathyroidism in 2.5%.

Patients with adult T-cell leukemia/lymphoma (ATLL) commonly manifest osteolytic bone lesions and hypercalcemia. ATLL results from infection with human T lymphotrophic virus type 1 (HTLV-1). The acute form is resistant to chemotherapy and mean survival is less than a year. In one autopsy series of 18 patients, 72% were hypercalcemic. HTLV-1 infection causes hypercalcemia by several mechanisms. Lymphocytes infected with HTLV-1 produce PTHrP and interleukin (IL)-1. When murine calvaria were exposed to conditioned media from HTLV-1 infected-lymphocytes, increased osteoclast activity was demonstrated that was dependent on receptor activator of nuclear factor kappa-B ligand (RANKL), showing that factors secreted from ATLL cells activate osteoclasts.

Local osteolytic metastases and multiple myeloma

Hypercalcemia from osteolytic metastases occurs in 20% of patients with cancer-related hypercalcemia and was initially assumed to result from direct physical bone destruction by malignant cells. However, subsequent studies showed that the presence of tumor cells in bone was insufficient to cause hypercalcemia and that bone destruction was mediated by osteoclasts. A variety of osteoclastogenic factors are implicated and discussed later.

About one third of patients with multiple myeloma develop hypercalcemia caused by bone destruction. Lesions occur as a result of local osteoclast stimulation by myeloma cells in their microenvironment. Several cytokines are implicated as possible mediators including: IL-6, IL-1β, tumor necrosis factor (TNF-α), macrophage inflammation protein 1-alpha, and lymphotoxin, but their role in inducing osteolytic bone disease in patients with myeloma is not fully defined. In addition, myeloma cells both express on their surface and secrete RANKL. In multiple myeloma, there is a disturbance in the bone microenvironment, with increases in RANKL and a decrease in osteoprotegerin. Osteoprotegerin competes with RANKL for binding to RANK and prevents receptor activation ( Fig. 4.1 ). Depending on the concentration of RANKL, this may induce osteoclast differentiation or prevent apoptosis. Myeloma cells disturb the balance between osteoprotegerin, a decoy receptor for RANKL, and RANK. The balance between the two plays a key role in maintaining the ratio of osteoclast to osteoblast activity and bone remodeling. When RANKL expression increases and osteoprotegerin decreases, bone resorption is favored. Lytic lesions occur when there is increased osteoclast reabsorption without new bone formation.

The receptor activator of nuclear factor kappa-B ligand (RANKL)/RANK/osteoprotegerin (OPG) pathway. A. RANKL is expressed on the surface of osteoblasts. When it binds RANK expressed on the surface of osteoclast precursors it stimulates osteoclast formation, activation, and survival. B. Osteoprotegerin is a decoy receptor for receptor activator of RANKL and prevents its binding to RANK. Osteoprotegerin is secreted by osteoblasts, stromal cells, and B cells. The ratio of RANKL to osteoprotegerin determines the extent of bone resorption.

Adhesion molecules expressed on the myeloma cell surface also interact with the bone marrow microenvironment to stimulate cytokine production and osteoclast formation. In myeloma, osteoblast activity is suppressed. The mechanism is unclear, but several factors were recently implicated including: IL-3, IL-7, blockade of Runx2, and Wnt antagonists. Myeloma cells also induce apoptosis of osteoblasts via the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand.

Osteolytic metastases from solid tumors also produce cytokines that result in bone calcium release. TNF and IL-1 stimulate osteoclast development from precursors and IL-6 stimulates osteoclast production. Breast cancer cells in bone activate osteoclasts and increase bone resorption. Recent studies showed that a MAP kinase isoform, MAPK11 (p38β), is responsible for bone destruction. p38β upregulates monocyte chemotactic protein-1, which stimulates osteoclast differentiation and activity. PTHrP may play a role locally in bone, in breast cancer metastases. Tumor cells produce PTHrP in the bone microenvironment, which is thought to be mediated by transforming growth factor (TGF)-β. A paracrine loop is established, whereby PTHrP stimulates osteoclast activity, with resultant TGF-β release from the reabsorbed bone.

1,25 (OH) ₂ vitamin D ₃ –mediated

Calcitriol is the major humoral mediator of hypercalcemia in patients with Hodgkin and NHL and accounts for less than 1% of cases of hypercalcemia in cancer patients. Incidence of hypercalcemia in Hodgkin and NHL was reported as 5% and 15%, respectively.

In 38 patients with Hodgkin disease, peak total serum calcium levels ranged from 10.9 to 23.1 mg/dL, median level 14.4 mg/dL. The nodular sclerosing subtype was significantly underrepresented. Most patients had infradiaphragmatic disease and only three had lytic bone lesions. Nearly all patients with hypercalcemia, in which calcitriol levels were measured, were elevated.

In NHL, incidence of hypercalcemia varies with histologic grade from 1% to 2% in low grade, to 23% in high-grade subtypes. In 19 cases of NHL, only one had low-grade histology. In 54 patients with NHL and hypercalcemia, 57.4% had diffuse large B-cell lymphoma. Seventeen of these had both a PTHrP and calcitriol level properly collected, seven (41%) had an elevated calcitriol level, suggesting that in the majority, hypercalcemia was mediated by a noncalcitriol, non-PTHrP mechanism. Intermediate to aggressive histologic features were seen in 83%. In six of seven, peak calcium concentration was less than 14.5 mg/dL. Calcitriol elevation correlated with worse progression-free but not overall survival. Of 345 consecutive patients with NHL, 8.1% were hypercalcemic, 55% had elevated calcitriol levels. In an interesting report, a patient with an intermediate grade B-cell lymphoma confined to the spleen, with hypercalcemia mediated by calcitriol, underwent a splenectomy. Immunochemistry showed 1α-hydroxylase expression in CD68-positive macrophages and not bordering lymphoma cells, suggesting that substances produced by malignant cells stimulated macrophages to produce calcitriol.

There are six case reports of hypercalcemia associated with gastrointestinal stromal tumors (GIST). GIST is the most common mesenchymal tumor in the GI tract but is a very rare tumor with an incidence of 11 to 19.6 per million. In four cases where the mechanism of hypercalcemia was examined, three resulted from calcitriol overproduction and one from PTHrP. There is one case report of calcitriol-mediated hypercalcemia with an ovarian dysgerminoma.

Ectopic parathyroid hormone production

Ectopic PTH production is a rare cause of hypercalcemia of malignancy. There are approximately 25 cases reported. In some, the tumor also secreted PTHrP. Tumors reported to secrete PTH include: squamous cell carcinoma of the tonsil, rhabdoid Wilms tumor, small cell lung cancer, pancreatic carcinoma, ovarian carcinoma, endometrial adenosquamous carcinoma, thymoma, papillary and medullary thyroid cancer, primitive neuroectodermal tumor, hepatocellular carcinoma, transitional cell carcinoma of the bladder, ovarian small cell carcinoma, pancreatic neuroendocrine tumors, nasopharyngeal rhabdomyosarcoma, bronchogenic carcinoma, neuroendocrine neck tumor, gastric carcinoma, and squamous cell carcinoma of the penis.

Osteoblastic metastases

Hypocalcemia caused by osteoblastic metastases and increased bone calcium uptake occurs most commonly in patients with prostate followed by breast cancer. It was reported with lung, thyroid, salivary gland, GI, and neuroendocrine tumors. In bone, metastatic prostate cancer cells produce factors that activate osteoblasts including endothelin-1, platelet derived growth factor, and bone matrix proteins. In 143 patients with bone metastases, 16% had hypocalcemia, with prostate cancer as the most frequent etiology. Tucci et al. reported 210 consecutive patients with hormone-refractory prostate cancer. There was a 26.6% incidence of albumin-corrected hypocalcemia. Hypocalcemia did not adversely affect prognosis. Most cases are mild, but there are reports of severe hypocalcemia requiring prolonged calcium supplementation resembling hungry bone syndrome seen after parathyroidectomy. ^, In several reports, hypocalcemia was felt to be exacerbated by bisphosphonate administration. ^, There are two possible explanations for this. The first is that bisphosphonate-induced osteoclast suppression leaves osteoblast activity unopposed or it may increase osteoblast maturation and activity in areas of metastasis.

Tumor lysis syndrome

Tumor lysis syndrome (TLS) results from rapid tumor cell lysis that occurs spontaneously or from treatment, and is the most common oncologic emergency. Although observed most commonly with hematologic malignancies, it is also seen with solid tumors. Phosphorus, potassium, and nucleic acids are released into the ECF. Purines in nucleic acids are metabolized to uric acid ( Fig. 4.2 ). TLS results when rapid entry of these substances into ECF exceeds the ability of homeostatic mechanisms to remove them.

Purine catabolism pathway and mechanism of action of drugs used to treat tumor lysis syndrome. Allopurinol can lead to the accumulation of xanthine, which is poorly soluble in water, and can lead to xanthine nephropathy. Allopurinol can prevent uric acid formation but will not affect uric acid that is already present. Rasburicase (urate oxidase) metabolizes uric acid to the much more soluble allantoin. Urate oxidase is not expressed in humans; as a result uric acid is normally the final endpoint for purine catabolism.

Hypocalcemia is seen in association with hyperphosphatemia, hyperkalemia, and hyperuricemia. Release of phosphorus into ECF results in hypocalcemia from two potential mechanisms. Mathematic models suggest that a rapid phosphate infusion lowers plasma phosphorus concentration via formation of calcium phosphate complexes. There is also evidence that an acute intravenous phosphate load lowers serum calcium concentration because of reduced calcium efflux from bone.

Patients with malignancies that have high turnover rates, large tumor burdens, and are most sensitive to therapy, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and NHL are at highest risk. TLS occurs in as many as 42% with NHL, 17% with AML, and 8.4% with ALL. Patients with solid tumors often have large tumor burdens. TLS was reported in a wide variety of solid tumors, including metastatic prostate cancer and hepatocellular carcinoma.

There are two commonly used systems to define TLS. To diagnose laboratory-based TLS (LTLS), the Cairo-Bishop system requires a change in two or more laboratory values between 3 days before or 7 days after initial treatment. Criteria include serum concentrations of: uric acid 8 mg/dL or more; potassium 6 mEq/L or more; phosphorus 2.1 mmol/L or more; calcium 1.75 mmol/L or less; or a change in any of these parameters by 25% or more from baseline. Clinical TLS (CTLS) is defined as LTLS plus one of the following: arrhythmia; sudden death; seizure; or serum creatinine 1.5 (or more) times the upper limit of normal. CTLS is less common than LTLS. Limitations of this system are that it does not allow for spontaneous TLS in the absence of treatment and patients with chronic kidney disease (CKD) would meet criteria for CTLS.

The Hande-Garrow system requires a 25% or more change in two of the following five laboratory parameters: a 25% or more increase in blood urea nitrogen; uric acid; potassium; or phosphorus concentration; or a 25% or more decrease in serum calcium concentration.

Patients with preexisting kidney disease are at higher risk for AKI. AKI can occur as a result of uric acid nephropathy, tubular calcium phosphate crystallization, or tumor infiltration of the kidneys and portends a poor prognosis. In 772 patients with AML undergoing induction chemotherapy, 17% developed TLS (5% CTLS, 12% LTLS). Kidney dysfunction was strongly predictive for development of CTLS and LTLS with an odds ratio (OR) in multivariable analysis of 2.9 (95% confidence interval [CI], 1.6–6.8) and 10.7 (95% CI, 4.5–25.1), respectively. In patients with CTLS, oliguria occurred in 83%, and hemodialysis was performed in 13%. CTLS was associated with a statistically significant increase in death rate, 79% versus 23%, and renal failure was a major cause of death. In 63 patients with acute hematologic malignancies and TLS, hospital and 6-month mortality were significantly higher in those with AKI (21% vs. 7%). Presence of AKI was associated with higher in-hospital and 6-month mortality, odds ratio of 10.41 (95% CI, 2.01–19.07) and 5.61 (OR, 1.64–54.66), respectively. Finally, a recent retrospective analysis evaluated the impact of acute hemodialysis on a variety of outcomes in TLS. Acute hemodialysis was carried out in 12% of all TLS hospitalizations. Dialysis for AKI in multivariable analysis was associated with an increased mortality (OR, 1.98; 95% CI, 1.60–2.45), and longer length of stay (19 vs. 14.6 days, p <.01). These studies emphasize the importance of risk stratifying patients to identify those at high risk for AKI and to institute prophylactic measures.

Risk stratification systems were developed by several groups. High risk is defined as greater than 5%, intermediate risk 1% to 5%, and low risk less than 1%. For solid tumors and chronic hematologic malignancies, low risk diseases include: most solid tumors except for bulky tumors sensitive to chemotherapy such as small-cell lung cancer, neuroblastomas, and germ-cell tumors; multiple myeloma; chronic myelogenous leukemia (CML) in the chronic phase; and chronic lymphocytic leukemia (CLL) treated with alkylating agents. CLL treated with targeted and/or biologic therapies is intermediate risk. Risk stratification for acute leukemias and lymphomas is more complex and is shown in Tables 4.1 and 4.2 . Other patient-related risk factors include: preexisting kidney disease; volume depletion; age; and preexisting hyperuricemia.

Risk stratification allows one to anticipate and prevent TLS via prophylactic measures. An expert consensus panel in the United States and the British Committee for Standards in Hematology developed recommendations for prophylaxis. ^, For patients at low risk, monitoring, normal hydration, and withholding prophylaxis for hyperuricemia were recommended. There should be a low threshold for adding fluids and allopurinol if needed. With bulky or advanced disease, metabolic abnormalities, or a tumor with a high proliferative rate, allopurinol, an inhibitor of xanthine oxidase, is recommended ( Fig. 4.2 ). Patients with intermediate risk disease should be treated with vigorous hydration (3 L/m ² /day) with nonbicarbonate-containing isotonic fluids and allopurinol (100–300 mg every 8 hours daily) for up to 7 days. Patients at high risk should be hydrated as mentioned earlier, depending on volume status and presence of AKI, and administered rasburicase (recombinant urate oxidase). Dosage in adults is 0.1 to 0.2 mg/kg, or a fixed dose of 3 mg, with repeat dosing as required. If glucose-6-phosphate deficiency is present, allopurinol is substituted for rasburicase.

Other recommendations include: in patients on rasburicase, urate assays should be sent to the laboratory on ice to avoid falsely low values; rasburicase and allopurinol should not be administered simultaneously because allopurinol may reduce the effectiveness of rasburicase; and urinary alkalinization is not recommended. Patients that were originally classified as low or intermediate risk that develop LTLS should receive rasburicase. Asymptomatic hypocalcemia should not be treated. Symptomatic hypocalcemia can be treated with short calcium gluconate infusions with careful monitoring of serum calcium, phosphorus, and creatinine concentrations. Management of other aspects of TLS are covered in the section on hyperphosphatemia.

Drugs

Hypomagnesemia-epidermal growth factor receptor blockers.

A pooled analysis of six randomized controlled trials (RCTs) that recorded hypocalcemic events showed a 16.8% (95% CI, 14.2%–19.7%) incidence of all-grade hypocalcemia with cetuximab versus 9.9% (95% CI, 8.0%–12.2%) in controls. To standardize adverse drug events in cancer treatment, the National Cancer Institute developed a system, the Common Terminology Criteria for Adverse Events (CTCAE), for grading severity of hypercalcemia, hypocalcemia, and hypophosphatemia ( Table 4.3 ). There was a 3.8% incidence of grades 3/4 CTCAE hypocalcemia with cetuximab and panitumumab versus 2% in controls. Of three RCTs reporting grades 3/4 hypocalcemia with cetuximab, relative risk (RR) was 2.12 versus controls (95% CI, 1.30–3.45, p = .003). Although RR was increased (1.14) with panitumumab versus controls, this increase was not statistically significant. The pathogenesis of hypocalcemia with epidermal growth factor (EGF) receptor inhibitors is unclear. It may be related to the well-known association of cetuximab and hypomagnesemia. The EGF receptor is located on the basolateral membrane of the DCT and its activation increases transient receptor potential channel melastatin subtype 6 (TRPM6) activity and surface expression via sarcoma (Src) kinases and Ras-related C3 botulinum toxin substrate (Rac) 1. TRPM6 is a channel located in the DCT apical membrane that mediates magnesium entry and is the rate limiting step for magnesium reabsorption ( Fig. 4.3 ). Hypomagnesemia can result in end-organ resistance to PTH and impair PTH release from parathyroid gland. End-organ resistance occurs at magnesium concentrations of 1 mg/dL or less, whereas a lower concentration, less than 0.5 mg/dL, is required to reduce PTH secretion. Hypocalcemia will not respond to calcium or vitamin D administration until the magnesium deficit is repleted.

Table 4.3

National Cancer Institute Common Criteria for Adverse Events v4.0

Grade	1	2	3	4	5
Hypercalcemia
TC mg/dL TC mmol/L iCa mmol/L	> ULN–11.5 > ULN–2.9 > ULN–1.5	> 11.5–12.5 > 2.9–3.1 > 1.5–1.6 symptoms	> 12.5–13.5 > 3.1–3.4 > 1.6–1.8 Hospitalization indicated	> 13.5 > 3.4 > 1.8 Life threatening	Death
Hypocalcemia
TC mg/dL TC mmol/L iCa mmol/L	< LLN–8.0 < LLN–2.0 < LLN–1.0	7– < 8.0 < 2.0–1.75 < 1.0–0.9 symptoms	6– < 7.0 < 1.75–1.50 < 0.9–0.8 Hospitalization indicated	< 6 < 1.5 < 0.8 Life threatening	Death
Hypophosphatemia
mg/dL mmol/L	< LLN–2.5 < LLN–0.8	2– < 2.5–2.0 < 0.8–0.6 symptoms	1– < 2.0–1.0 < 0.6–0.3 Hospitalization indicated	< 1 < 0.3 Life threatening	Death

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