Hypercalcemia Associated with Cancer

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Hypercalcemia Associated with Cancer

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• ???????????
• Andrew F. Stewart, M.D.
• N Engl J Med 2005 Volume 352373-379 January 27,
  2005 Number 4

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Outline

• Case report
• The Clinical Problem
• Strategies and Evidence
• Dx
• Therapeutic Considerations
• General Supportive Measures
• Saline Hydration and Calciuresis
• Medications
• Other Pharmacologic Agents
• Dialysis
• Areas of Uncertainty
• Guidelines
• Recommendations

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Case report

• A 47-year-old woman with a history of breast
  cancer presents with confusion and dehydration.
• The serum Ca is 18.0 mg /dl (4.5 mmol /l). She
  has postural hypotension and low central venous
  pressure on examination of the jugular veins.
• The serum phosphorus is 5.0 mg /dl (1.6 mmol
  /l), the BUN is 80.0 mg /dl (28.6 mmol /l), the
  serum Cr is 2.0 mg /dl (177 µmol /l), and the
  Alb is 3.3 g /dl.
• A bone scintigraphic scan reveals no evidence of
  skeletal involvement by the tumor.
• How should she be treated?

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The Clinical Problem (1)

• Hypercalcemia has been reported to occur in up to
  20 to 30 of p'ts with cancer at some time
  during the course of their disease.
• This incidence may be falling owing to the wide
  use of bisphosphonates in p'ts with either
  multiple myeloma or breast cancer, although data
  are lacking.
• Hypercalcemia leads to progressive mental
  impairment, including coma, as well as renal
  failure. These complications are particularly
  common terminal events among p'ts with cancer.
• The detection of hypercalcemia in a p't with
  cancer signifies a very poor prognosis 50 of
  such p'ts die within 30 days.

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Cancer-associated hypercalcemia morbidity and
mortality. Clinical experience in 126 treated
p'ts.

• STUDY OBJECTIVE To review the effects of
  antihypercalcemic Tx on morbidity and mortality
  in cancer-associated hypercalcemia.
• DESIGN Retrospective study of 126 consecutive
  p'ts with cancer-associated hypercalcemia.
• SETTING Inp't referrals from a teaching hospital
  in the United Kingdom.
• INTERVENTION Medical antihypercalcemic therapy
  supplemented by specific anticancer therapy where
  possible.

Ann Intern Med 1990112499-504
6

• MEASUREMENTS AND MAIN RESULTS Median survival
  was 30 days. Survival did not differ in p'ts
  treated with different antihypercalcemic regimens
  but was longer (median, 135 days P less than
  0.001) in a subgroup of 26 p'ts for whom specific
  anticancer therapy was available. Polyuria and
  polydipsia improved after therapy in 83 of
  cases, central nervous system symptoms in 71,
  constipation in 70 , nausea and vomiting in 56,
  anorexia in 50, and malaise and fatigue in 47
  (all significant, P less than 0.001, pre-Tx
  compared with post-Tx). Pain control improved in
  only 23 of cases (not significant). Only 7 of
  p'ts with post-Tx serum Ca values above 3.50
  mmol/L improved clinically compared with 80
  whose Ca values fell below 2.80 mmol/L (P less
  than 0.001). Corresponding figures for the
  proportion of p'ts discharged from the hospital
  were 0 and 68 (P less than 0.001).
• CONCLUSIONS Life expectancy is poor in
  cancer-associated hypercalcemia even in p'ts who
  are actively treated. Antihypercalcemic therapy
  has an important palliative role, however,
  because symptoms are usually improved and, in
  many cases, p'ts may be made well enough to be
  discharged from the hospital during the terminal
  stages of their illness.

Ann Intern Med 1990112499-504
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The Clinical Problem (2)

• Hypercalcemia with cancer can be classified into
  four types (Table 1).
• In p'ts with local osteolytic hypercalcemia, the
  hypercalcemia results from the marked increase in
  osteoclastic bone resorption in areas surrounding
  the malignant cells within the marrow space.
• The condition known as humoral hypercalcemia of
  malignancy (HHM) is caused by systemic secretion
  of PTHrP by malignant tumors.
• PTHrP causes increased bone resorption and
  enhances renal retention of Ca. The tumors that
  most commonly cause HHM are listed in Table 1,
  but essentially any tumor may cause this
  syndrome.
• Some lymphomas secrete the active form of vitamin
  D, 1,25(OH)2D, causing hypercalcemia as a result
  of the combination of enhanced osteoclastic bone
  resorption and enhanced intestinal absorption of
  Ca.
• Finally, ectopic secretion of authentic PTH is a
  rare cause of hypercalcemia, having been well
  documented in only eight p'ts to date.

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Figure 2. Regulation of Bone Resorption (Panel A)
and Bone Formation (Panel B).

• Both systemic factors and locally acting factors
  induce the formation and activity of osteoclasts
  (Panel A). Systemic hormones such as PTH,
  1,25(OH)2D, and thyroxine (T4) stimulate the
  formation of osteoclasts by inducing the
  expression of receptor activator of nuclear
  factor-?B ligand (RANKL) on marrow stromal cells
  and osteoblasts.
• In addition, osteoblasts produce IL-6, IL-1,
  prostaglandins, and colony-stimulating factors
  (CSFs), which induce the formation of
  osteoclasts. Accessory cells such as T cells can
  produce cytokines that can inhibit the formation
  of osteoclasts, such as IL-4, IL-18, and
  interferon-?. TGF-ßdenotes transforming growth
  factorß . Plus signs indicate stimulation, and
  minus signs inhibition.

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• Both systemic factors and locally acting factors
  can enhance the proliferation and differentiation
  of osteoblasts (Panel B). These include PTH,
  prostaglandins, and cytokines as well as growth
  factors such as platelet-derived growth factor
  (PDGF) produced by lymphocytes.
• In addition, bone matrix is a major source of
  growth factors, which can enhance the
  proliferation and differentiation of osteoblasts.
  These include the bone morphogenetic proteins
  (BMPs), TGF-ß, insulin-like growth factors
  (IGFs), and fibroblast growth factors (FGFs).
  Corticosteroids can induce apoptosis of
  osteoblasts and block bone formation.

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Strategies and Evidence ---Dx (1)

• Although clinical laboratories generally measure
  the total serum Ca , it is occasionally valuable
  to measure the serum ionized Ca, because
  increases or decreases in the Alb may cause
  misleading increases or decreases, respectively,
  in the total serum Ca .
• In addition, in rare p'ts with myeloma in whom
  Ca-binding immunoglobulins are produced,
  measurement of total serum Ca may substantially
  overestimate the serum ionized Ca .
• There are formulas with which to calculate the
  serum ionized Ca or to "correct" the total Ca
  (e.g., add 0.8 mg /dl to the total Ca for every
  1.0 g /dl of serum Alb below the of 3.5 g /dl),
  but they are not precise or always reliable.
• Thus, measurement of serum ionized Ca should be
  considered whenever there is doubt about the
  validity of the measurement of total Ca. The test
  can be performed rapidly in most hospital
  laboratories or neonatal ICUs.

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Strategies and Evidence ---Dx (2)

• If the Ca is elevated, a further evaluation
  should consider not only the mechanisms that are
  potentially related to the cancer but also causes
  of the elevation of the Ca that are unrelated to
  the cancer (e.g., primary hyperparathyroidism,
  the use of thiazide diuretics, and granulomatous
  disease, among other causes).
• The tumors present in hypercalcemia associated
  with malignant disease are generally large and
  readily apparent notable exceptions are small
  neuroendocrine tumors (such as islet tumors and
  pheochromocytomas).
• Intact PTH should be measured routinely. Although
  ectopic hyperparathyroidism is extremely rare in
  hypercalcemia associated with cancer, concomitant
  primary hyperparathyroidism is not (we found that
  in 8 of 133 p'ts with cancer and hypercalcemia,
  primary hyperparathyroidism was the cause).

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Strategies and Evidence ---Dx (3)

• Although most p'ts with typical HHM (Table 1)
  have increased circulating PTHrP, the Dx is
  usually obvious on clinical grounds PTHrP should
  therefore be measured in the occasional cases in
  which the Dx of HHM cannot be made on clinical
  grounds or when the cause of hypercalcemia is
  obscure.
• Plasma 1,25(OH)2D should be measured when
  sarcoidosis, other granulomatous disorders, or
  the 1,25(OH)2D lymphoma syndrome is considered in
  the differential Dx.
• A bone scan (or a skeletal survey, in the case of
  myeloma) is useful to assess the skeletal tumor
  burden in p'ts with cancer and hypercalcemia, if
  the test was not previously performed for tumor
  staging.

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Therapeutic Considerations (1)

• In planning therapy for p'ts with hypercalcemia
  associated with malignant disease,
  antihypercalcemic therapy should be considered an
  interim measure, one with no ultimate effect on
  survival.
• Thus, it is imperative that antitumor therapy be
  implemented promptly control of the serum Ca
  merely buys time in which such therapy can work.
• Another critical point is that when all the
  available therapies have failed, withholding
  antihypercalcemic therapy (which will eventually
  result in coma and death) may be an appropriate
  and humane approach.
• In cases in which Tx is considered appropriate,
  an assessment of the severity of the
  hypercalcemia is needed to guide therapy.

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Therapeutic Considerations (2)

• Although there are no formal guidelines, I
  consider mild hypercalcemia to be a serum Ca of
  10.5 to 11.9 mg /dl (2.6 to 2.9 mmol /l),
  moderate hypercalcemia 12.0 to 13.9 mg /dl (3.0
  to 3.4 mmol /l), and severe hypercalcemia 14.0
  mg /dl (3.5 mmol /l) or greater.
• In general, the neurologic and renal
  complications of hypercalcemia worsen with
  increasing severity of hypercalcemia, but other
  factors also influence the response to
  hypercalcemia. For example, the rate of the
  ascent of the serum Ca is important a rapid
  increase to moderate hypercalcemia frequently
  results in marked neurologic dysfunction, whereas
  chronic severe hypercalcemia may cause only
  minimal neurologic symptoms.
• Similarly, older p'ts with preexisting neurologic
  or cognitive dysfunction may become severely
  obtunded in the presence of mild hypercalcemia,
  whereas younger p'ts with moderate-to-severe
  hypercalcemia may remain alert.
• Finally, the concomitant administration of
  sedatives or narcotics may worsen the neurologic
  response to hypercalcemia.

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Therapeutic Considerations (3)

• The optimal therapy for hypercalcemia associated
  with cancer is one that is tailored both to the
  degree of hypercalcemia and to its underlying
  cause.
• True hypercalcemia (i.e., an elevated serum
  ionized Ca) occurs through three basic
  mechanisms enhanced osteoclastic bone resorption
  (in local osteolytic hypercalcemia, HHM,
  1,25(OH)2D-secreting lymphomas, and the rare case
  of ectopic hyperparathyroidism) enhanced renal
  tubular reabsorption of Ca (in HHM and ectopic
  hyperparathyroidism) and enhanced intestinal
  absorption of Ca (in 1,25(OH)2D-secreting
  lymphomas and possibly ectopic hyperparathyroidism
  ).
• Therapy should be targeted accordingly.

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General Supportive Measures (1)

• The important general supportive measures include
  the removal of Ca from parenteral feeding
  solutions (a measure often overlooked)
  discontinuation of the use of oral Ca supplements
  in enteral feeding solutions or as Ca tablets
  discontinuation of medications that may
  independently lead to hypercalcemia (e.g.,
  lithium, calcitriol, vitamin D, and thiazides)
  an increase in the weight-bearing mobility of the
  p't, if possible and discontinuation of the use
  of sedative drugs, including analgesic drugs, if
  possible, to enhance the p't's mental clarity and
  promote weight-bearing ambulation.

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General Supportive Measures (2)

• Hypophosphatemia develops in most p'ts with
  hypercalcemia associated with cancer at some
  point during the course of the disease,
  regardless of the underlying cause, because of
  decreased food intake, saline diuresis, the use
  of loop diuretics, the phosphaturic effects of
  PTHrP, the hypercalcemia itself, and Tx with
  calcitonin or antacids.
• In general, the presence of hypophosphatemia
  increases the difficulty of treating the
  hypercalcemia, and in animal models
  hypophosphatemia has been shown to cause
  hypercalcemia.
• Phosphorus should be replaced orally or
  administered through a nasogastric tube as
  neutral phosphate.

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General Supportive Measures (3)

• The serum phosphorus and Cr should be followed
  closely, in an effort to keep the phosphorus in
  the range of 2.5 to 3.0 mg /dl (0.98 to 1.0 mmol
  /l), the serum Cr in the normal range, and the
  Caphosphorus product below 40, ideally in the
  range of 30 (when both are expressed in mg/dl).
• IV phosphorus replacement should not be given
  except in dire circumstances, when oral or NG
  administration is impossible, because its use can
  result in severe hypocalcemia, seizures, and
  acute renal failure.
• These general support measures alone may be
  sufficient to treat p'ts with mild hypercalcemia.
  

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Saline Hydration and Calciuresis (1)

• P'ts with hypercalcemia associated with cancer
  are substantially dehydrated as a result of a
  renal water-concentrating defect (nephrogenic DI)
  induced by hypercalcemia and by decreased oral
  hydration resulting from anorexia and nausea,
  vomiting, or both.
• The dehydration leads to a reduction in the GFR
  that further reduces the ability of the kidney to
  excrete the excess serum Ca.
• First, therefore, parenteral volume expansion
  should be initiated, with the administration of
  NS. Although there are no randomized clinical
  trials to guide this therapy, in general practice
  NS is administered at a rate of 200 to 500 ml
  /hr, depending on the baseline of dehydration
  and renal function, the p't's CV status, the
  degree of mental impairment, and the severity of
  the hypercalcemia.
• These factors must be assessed with the use of
  careful clinical monitoring for physical findings
  that are consistent with fluid overload.

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Saline Hydration and Calciuresis (2)

• The goals of Tx are to increase the GFR, thus
  increasing the filtered load of Ca that passes
  through the glomerulus into the tubular lumen,
  and to inhibit Ca reabsorption in the proximal
  nephron (because saline itself is calciuretic).
• Increasing the GFR to or above the normal range
  (within safe limits) also permits the use of loop
  diuretics (Table 2) to increase the renal
  excretion of Ca (loop diuretics block Ca
  reabsorption in the loop of Henle and make
  possible increased administration of saline,
  which induces further Ca excretion).
• Loop diuretics should not be administered until
  after full hydration has been achieved, because
  these agents can cause or worsen dehydration,
  leading to a decline in the GFR and the filtered
  load of Ca.
• In contrast to loop diuretics, thiazide diuretics
  should not be administered, since they stimulate,
  rather than inhibit, renal Ca reabsorption.

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Medications (1)

• IV bisphosphonates are by far the best studied,
  safest, and most effective agents for use in p'ts
  with hypercalcemia associated with cancer. These
  drugs work by blocking osteoclastic bone
  resorption.
• Because they are poorly absorbed when given
  orally ( 1 to 2 of an oral dose is absorbed),
  only IV bisphosphonates are used for this
  indication. In the USA, the two drugs approved by
  FDA and are currently considered the agents of
  choice in the Tx of mild-to-severe hypercalcemia
  associated with cancer are pamidronate and
  zoledronate.
• In continental Europe, the United Kingdom, and
  other countries, ibandronate and clodronate are
  also widely used. Etidronate, which was the first
  to be used for this indication, has been replaced
  by these more potent bisphosphonates.
• A number of randomized clinical trials comparing
  bisphosphonates to saline and diuretics alone, to
  other bisphosphonates, and to other
  antiresorptive agents such as calcitonin have
  confirmed the superiority of bisphosphonates.

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Medications (2)

• Bisphosphonate therapy should be initiated as
  soon as hypercalcemia is discovered, because a
  response requires two to four days, and the nadir
  in serum Ca generally occurs within four to seven
  days after therapy is initiated.
• 60 to 90 of p'ts have normal serum Ca within
  four to seven days, and responses last for one to
  three weeks.
• As compared with pamidronate, zoledronate has the
  advantage of rapid and simpler administration (15
  minutes vs. 2 hours for infusion), whereas
  pamidronate is less expensive. Although a direct
  comparison of the two drugs in a randomized
  clinical trial showed a statistically significant
  increase in the efficacy of zoledronate, the
  difference in control of calcemia was small (mean
  nadir serum Ca , 9.8 mg /dl 2.4 mmol /l with
  zoledronate and 10.5 mg /dl 2.6 mmol /l with
  pamidronate the proportion of p'ts in whom a
  corrected serum Ca of 10.8 mg /dl 2.7 mmol /l
  was achieved by day 10 was 88 and 70 ,
  respectively).
• Thus, the differences are of arguable clinical
  importance, and the choice is largely one between
  convenience and cost. Either pamidronate or
  zoledronate is acceptable therapy.

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Single-dose IV therapy with pamidronate for the
Tx of hypercalcemia of malignancy comparison of
30-, 60-, and 90-mg dosages

• PURPOSE To determine the efficacy, dose-response
  relationship, and safety of 30, 60, and 90 mg of
  a single IV dose of an aminobisphosphonate,
  pamidronate (APD), for the Tx of moderate to
  severe hypercalcemia of malignancy.
• P'ts AND METHODS P'ts with histologically proven
  cancer and a corrected serum Ca of at least 12.0
  mg/dL after 48 hours of NS hydration were
  enrolled in a double-blind, multicenter,
  randomized clinical trial. Pamidronate in 30-,
  60-, or 90-mg doses was administered as a single
  24-hour infusion. Serum Ca corrected for Alb,
  urine hydroxyproline, and Ca excretion, and serum
  PTH (1-84) were determined before and after
  pamidronate therapy.

Am J Med 199395297-304
27

• RESULTS Thirty-two men and 18 women entered the
  study. A dose-response relationship for
  normalization of corrected serum Ca was seen
  after pamidronate administration. Corrected serum
  Ca normalized in 40 of p'ts who received 30 mg,
  in 61 of p'ts who received 60 mg, and in 100 of
  p'ts who received 90 mg of pamidronate. The
  decline in the serum Ca was associated with
  decreased osteoclastic skeletal resorption
  evidenced by a decrease in urine Ca and
  hydroxyproline excretion. Among those with a
  normalized corrected serum Ca , the mean (median)
  duration of normalization of the corrected serum
  Ca value was 9.2 (4), 13.3 (5), and 10.8 (6) days
  in the 30-, 60-, and 90-mg Tx groups,
  respectively. The response of hypercalcemia to
  pamidronate was not significantly influenced by
  the presence of skeletal metastases. PTH 1-84,
  suppressed in p'ts on entry into this study,
  increased to a greater extent in those p'ts with
  osteolytic skeletal metastases compared with
  those with humoral hypercalcemia of malignancy.
  Clinical improvement, including improved mental
  status and decreased anorexia, accompanied the
  decline in the corrected serum Ca in all three
  Tx groups. Side effects included low-grade fever,
  asymptomatic hypocalcemia, hypomagnesemia, and
  hypophosphatemia.
• CONCLUSIONS A single-dose infusion of 60 to 90
  mg of pamidronate was highly effective and well
  tolerated and normalized corrected serum Ca in
  nearly all p'ts (61 to 100) with hypercalcemia
  of malignancy.

Am J Med 199395297-304
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Zoledronic Acid Is Superior to Pamidronate in the
Tx of Hypercalcemia of Malignancy A Pooled
Analysis of Two Randomized, Controlled Clinical
Trials

• PURPOSE Two identical, concurrent, parallel,
  multicenter, randomized, double-blind,
  double-dummy trials were conducted to compare the
  efficacy and safety of zoledronic acid and
  pamidronate for treating hypercalcemia of
  malignancy (HCM).
• P'ts AND METHODS P'ts with moderate to severe
  HCM (corrected serum Ca CSC 3.00 mmol/L 12.0
  mg/dL) were treated with a single dose of
  zoledronic acid (4 or 8 mg) via 5-minute infusion
  or pamidronate (90 mg) via 2-hour infusion. A
  protocol-specified pooled analysis of the two
  parallel trials was performed. Clinical end
  points included rate of complete response by day
  10, response duration, and time to relapse.

J Clin Oncol 200119558-567.
29

• RESULTS Two hundred eighty-seven p'ts were
  randomized and evaluated for safety 275 were
  evaluated for efficacy. Both doses of zoledronic
  acid were superior to pamidronate in the Tx of
  HCM. The complete response rates by day 10 were
  88.4 (P .002), 86.7 (P .015), and 69.7 for
  zoledronic acid 4 mg and 8 mg and pamidronate 90
  mg, respectively. Normalization of CSC occurred
  by day 4 in 50 of p'ts treated with zoledronic
  acid and in only 33.3 of the pamidronate-treated
  p'ts. The median duration of complete response
  favored zoledronic acid 4 and 8 mg over
  pamidronate 90 mg with response durations of 32,
  43, and 18 days, respectively.
• CONCLUSION Zoledronic acid is superior to
  pamidronate 4 mg is the dose recommended for
  initial Tx of HCM and 8 mg for relapsed or
  refractory hypercalcemia.

J Clin Oncol 200119558-567.
30
Medications (3)

• In animal models, bisphosphonates have been
  associated with azotemia and thus, their use in
  p'ts with renal failure is a potential concern.
  However, because hypercalcemia is a frequent
  cause of renal dysfunction in p'ts with
  hypercalcemia associated with cancer, effective
  Tx of the hypercalcemia associated with cancer
  often improves renal function.
• The manufacturer and the American Society of
  Clinical Oncology do not recommend the use of a
  reduced dose of pamidronate or zoledronate for
  p'ts with serum Cr values of less than 3.0 mg /dl
  (265.2 µmol /l), but they do advise that the
  recommended duration of the infusion not be
  shortened.
• Pamidronate and zoledronate have been reported to
  cause or exacerbate renal failure, but this
  effect has generally occurred in p'ts receiving
  multiple doses.
• In p'ts whose condition fails to respond to a low
  initial dose of bisphosphonates, the use of a
  second, larger dose (an approach that has not
  been approved by the FDA) or a second-line agent
  may be considered.

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Zoledronic acid

• Zoledronic acid (zoledronate) is a new generation
  bisphosphonate that inhibits osteoclast bone
  resorption.
• It was much more potent than other
  bisphosphonates at inhibiting 1,25(OH)2D-induced
  hypercalcaemia in a rat model and Ca release in
  vitro. A single 5-minute IV infusion of
  zoledronic acid (4 or 8 mg) was significantly
  more effective than a 2-hour infusion of
  pamidronic acid (pamidronic acid disodium,
  pamidronate disodium) 90 mg in normalising
  serum Ca in p'ts with hypercalcaemia of
  malignancy and resulted in a significantly longer
  median time to relapse (pooled analysis from 2
  randomised, double-blind, parallel-group trials).
  
• There were no differences in tolerability between
  zoledronic acid and pamidronic acid in
  comparative trials the most common events in
  pivotal trials were fever, anaemia, nausea,
  constipation and dyspnoea.
• Fever, hypophosphataemia and hypocalcaemia were
  the most common events in a small phase I trial.

Drugs 200161799-805
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Toxic acute tubular necrosis following Tx with
zoledronate (Zometa)

• BACKGROUND Renal failure and toxic acute tubular
  necrosis (ATN) may be seen following exposure to
  a variety of therapeutic agents. Zoledronate
  (Zometa) is a new, highly potent bisphosphonate
  used in the Tx of hypercalcemia of malignancy. We
  report the first clinical-pathologic study of
  nephrotoxicity associated with this agent.
• METHODS A cohort of six p'ts (four males and two
  females) with a mean age of 69.2 years received
  bisphosphonate therapy for multiple myeloma (five
  p'ts) or Paget's disease (one p't). In all p'ts,
  zoledronate was administered at a dose of 4 mg IV
  monthly, infused over at least 15 minutes, and
  the duration of therapy was mean 4.7 months
  (range, 3 to 9 months).

Kidney Int 200364281-289
33

• RESULTS All p'ts developed renal failure with a
  rise in serum Cr from a mean baseline of 1.4
  mg/dL to 3.4 mg/dL. Renal biopsy revealed toxic
  ATN, characterized by tubular cell degeneration,
  loss of brush border, and apoptosis.
  Immunohistochemical staining revealed a marked
  increase in cell cycle-engaged cells (Ki-67
  positive) and derangement in tubular
  Na,K-ATPase expression. Importantly, although
  all p'ts had been treated with pamidronate prior
  to zoledronate, no biopsy exhibited the
  characteristic pattern of collapsing focal
  segmental glomerulosclerosis observed in
  pamidronate nephrotoxicity. Following renal
  biopsy, Tx with zoledronate was discontinued and
  all six p'ts had a subsequent improvement in
  renal function (mean final serum Cr, 2.3 mg/dL at
  1 to 4 months of follow-up).
• CONCLUSION The close temporal relationship
  between zoledronate administration and the onset
  of renal failure and the partial recovery of
  renal function following drug withdrawal strongly
  implicate this important and widely used agent in
  the development of toxic ATN.

Kidney Int 200364281-289
34
Other Pharmacologic Agents

• Several agents commonly used before the advent of
  bisphosphonates are now used infrequently,
  usually when bisphosphonates are ineffective or
  contraindicated (Table 2).
• Glucocorticoids may still have a role in the Tx
  of some p'ts, such as those with lymphomas
  resulting in elevated s of 1,25(OH)2 vitamin D.
  Calcitonin may result in a more rapid reduction
  in serum Ca than do other agents (the maximal
  response occurs within 12 to 24 hours), but its
  value is questionable because the reductions are
  small ( 1.0 mg /dl 0.25 mmol /l) and transient.
  
• Mithramycin, which was the mainstay of therapy
  for hypercalcemia associated with cancer before
  the bisphosphonates became available, remains
  effective, but its use is limited by potential
  adverse effects (Table 2).
• Gallium nitrate is also approved for Tx, but the
  need for continuous IV administration over a
  period of five days limits its use.

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Effect of calcitonin and glucocorticoids in
combination on the hypercalcemia of malignancy.

• The effects of the combination of glucocorticoids
  and calcitonin on serum Ca were compared with the
  responses to calcitonin alone in 14 p'ts with
  malignant disease and hypercalcemia.
• The serum Ca of those p'ts treated with
  calcitonin alone returned to preTx levels within
  48 hours, whereas those treated with the
  combination of calcitonin and glucocorticoids
  maintained the lower serum Ca for more than 4
  days.
• These results suggest that the combination of
  calcitonin and glucocorticoids is a rapidly
  effective form of medical Tx for hypercalcemia
  and that glucocorticoids help to maintain the
  acute response to calcitonin in p'ts with
  hypercalcemia.

Ann Intern Med 198093269-272
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Dialysis

• In p'ts who have cancers that are likely to
  respond to therapy but in whom acute or chronic
  renal failure is present, aggressive saline
  infusion is not possible, and other therapies
  such as bisphosphonates should be used with
  caution, if at all.
• In these circumstances, dialysis against a
  dialysate containing little or no Ca is a
  reasonable and highly effective option for
  selected p'ts.
• There are no specific guidelines with regard to
  how low the GFR must be for dialysis to be a
  rational choice in treating hypercalcemia, but in
  general, when the rate falls below 10 to 20 ml
  /min, or when the presence of CHF contraindicates
  an adequate administration of saline, or both,
  dialysis should be considered.

37
Ca-free HD for the management of hypercalcemia

• The drug therapies for hypercalcemia of
  malignancy have been known to be associated with
  either limited efficacy or cumulative toxicity in
  p'ts with advanced renal failure.
• To establish the guidelines for the use of
  dialysis and to determine its optimal
  prescription for hypercalcemia, Ca-free HD was
  performed in 6 hypercalcemic p'ts with renal
  failure not responding enough to forced saline
  diuresis.
• Ca-free dialysate contained Na 135, K 2.5, Cl
  108, Mg 0.75, bicarbonate 30 mmol/l. Mean HD time
  was 160 /- 27 min and mean Kt/V urea was 0.75
  /- 0.2. Plasma Ca fell from a mean value of
  2.92 /- 0.21 mmol/l (range 2.55-3.25) to 2.58
  /- 0.16 mmol/l at 1 h of HD and to 2.16 /- 0.33
  mmol/l (range 1.63-2.53) following 2-3 h of HD.
  The ionized Ca (n 4) decreased from 1.44 /-
  0.14 mmol/l to 0.99 /- 0.2 mmol/l. No p't showed
  any hypocalcemic symptoms and signs during HD.
  The rate of decrease in plasma Ca did not appear
  to produce adverse effects in any of the p'ts.
  There was a significant positive correlation
  between the decrease in plasma Ca and the Kt/V
  urea (y 1.4x - 0.29, r 0.92, p lt 0.01).
• We conclude that Ca-free HD is indicated when the
  presence of severe renal failure prevents the
  administration of large volumes of IV fluids to
  hypercalcemic p'ts. The amount of dialysis (Kt/V
  urea) can be used to predict the decrease in
  plasma Ca during Ca-free HD.

Nephron 199672424-428
38
Areas of Uncertainty (1)

• The receptor activator of nuclear factor-?B
  ligand (RANKL) system is the molecular pathway
  that leads to osteoclast recruitment and
  differentiation and bone resorption in
  hypercalcemia associated with cancer.
• Agents that interfere with the system, such as
  recombinant osteoprotegerin (a decoy receptor for
  RANKL) or monoclonal antibodies directed against
  RANKL, have been proposed as novel Txs for
  hypercalcemia associated with malignant disease,
  as have monoclonal antibodies, which neutralize
  PTHrP.

39
The Inhibition of RANKL Causes Greater
Suppression of Bone Resorption and Hypercalcemia
Compared with Bisphosphonates in Two Models of
HHM

• HHM is mediated primarily by skeletal and renal
  responses to tumor-derived PTHrP. PTHrP mobilizes
  Ca from bone by inducing the expression of
  receptor activator for nuclear factor- ?B ligand
  (RANKL), a protein that is essential for
  osteoclast formation, activation, and survival.
• RANKL does not influence renal Ca reabsorption,
  so RANKL inhibition is a rational approach to
  selectively block, and thereby reveal, the
  relative contribution of bone Ca to HHM.

Endocrinology, August 1, 2005 146(8) 3235 -
3243.
40

• We used the RANKL inhibitor osteoprotegerin (OPG)
  to evaluate the role of osteoclast-mediated
  hypercalcemia in two murine models of HHM.
  Hypercalcemia was induced either by sc
  inoculation of syngeneic colon (C-26)
  adenocarcinoma cells or by sc injection of
  high-dose recombinant PTHrP (0.5 mg/kg, sc, twice
  per day). In both models, OPG (0.25 mg/kg)
  caused rapid reversal of established
  hypercalcemia, and the speed and duration of
  hypercalcemia suppression were significantly
  greater with OPG (5 mg/kg) than with high-dose
  bisphosphonates (pamidronate or zoledronic acid,
  5 mg/kg).
• OPG also caused greater reductions in osteoclast
  surface and biochemical markers of bone
  resorption compared with either bisphosphonate.
  In both models, hypercalcemia gradually returned
  despite clear evidence of ongoing suppression of
  bone resorption by OPG.
• These data demonstrate that osteoclasts and RANKL
  are important mediators of HHM, particularly in
  the early stages of the condition.
• Aggressive antiresorptive therapy with a RANKL
  inhibitor therefore might be a rational approach
  to controlling HHM.

41
Areas of Uncertainty (2)

• Preliminary data from studies in animals or small
  studies involving women with osteoporosis
  indicate reductions in bone resorption with these
  approaches.
• Whether these agents will prove to be safe and
  effective in humans with hypercalcemia associated
  with cancer, whether they can be produced
  commercially at a cost competitive with that of
  bisphosphonates, and whether they can reverse
  hypercalcemia more effectively than the potent
  bisphosphonates remain unknown.

42
The effect of a single dose of osteoprotegerin in
postmenopausal women

• Osteoprotegerin (OPG), a TNF receptor family
  member, is a critical regulator of bone
  resorption. It is an important inhibitor of the
  terminal differentiation and activation of
  osteoclasts.
• This randomized, double-blind, placebo-controlled,
  sequential dose escalation study was conducted
  in postmenopausal women to determine the effect
  of a single S.C. dose of OPG on bone resorption
  as indicated by the biochemical markers, urinary
  N-telopeptide (NTX) and deoxypyridinoline (DPD),
  which are stable collagen degradation products.
  NTX decreased within 12 h after OPG
  administration.
• At the highest dose administered (3.0 mg/kg), a
  mean percent decrease in NTX of 80 was observed
  4 days after dosing. Six weeks after dosing a
  mean decrease of 14 in NTX was observed.

J Bone Miner Res 200116348-360
43

• The bone-specific alkaline phosphatase (BSAP), a
  marker of bone formation, did not change for 3
  weeks after dosing. Thereafter, a modest
  decrease, reaching 30 at 6 weeks, was observed
  in the 3.0-mg/kg dose group.
• The rapid decrease from baseline in NTX and
  delayed decrease in BSAP indicated that OPG acted
  primarily on osteoclasts to decrease bone
  resorption. OPG injections are well tolerated.
• This study, for the first time, indicates that a
  single s.c. injection of OPG is effective in
  rapidly and profoundly reducing bone turnover for
  a sustained period and that OPG therefore may be
  effective in Tx of bone diseases characterized by
  increased bone resorption such as osteoporosis

44
A single-dose placebo-controlled study of AMG
162, a fully human monoclonal Ab to RANKL, in
postmenopausal women

• The safety and bone antiresorptive effect of a
  single S.C. dose of AMG 162, a human monoclonal
  Ab to RANKL, was investigated in 49
  postmenopausal women. AMG 162 is a potent
  antiresorptive agent for diseases such as
  osteoporosis.
• INTRODUCTION RANKL is an essential osteoclastic
  differentiation and activation factor.
• MATERIALS AND METHODS The bone antiresorptive
  activity and safety of AMG 162, a fully human
  monoclonal Ab to RANKL, were evaluated in
  postmenopausal women in this randomized,
  double-blind, placebo-controlled, single-dose,
  dose escalation study. Six cohorts of eight to
  nine women were randomly assigned to receive a
  single S.C. injection of either AMG 162 or
  placebo (31 ratio). AMG 162 doses were 0.01,
  0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg.Subjects were
  followed up to 6 months in all cohorts and 9
  months in the three highest dose cohorts. Second
  morning void urinary N-telopeptide/Cr (NTX
  Osteomark), serum NTX, and serum bone-specific
  alkaline phosphatase (BALP, Ostase) were assessed
  as bone turnover markers.

J Bone Miner Res 2004191059-1066
45

• RESULTS AND CONCLUSIONS Forty-nine women were
  enrolled. A single SC dose of AMG 162 resulted in
  a dose-dependent, rapid (within 12 h), profound
  (up to 84), and sustained (up to 6 months)
  decrease in urinary NTX. At 6 months, there was a
  mean change from baseline of -81 in the 3.0
  mg/kg AMG 162 group compared with -10 in the
  placebo group serum NTX changes were -56 and
  2, respectively. BALP did not decrease
  remarkably until after 1 month, indicating that
  the effect of AMG 162 is primarily
  antiresorptive. Intact PTH increased up to
  3-fold after 4 days in the 3.0 mg/kg dose group,
  but returned toward baseline with follow-up.
  Alb-adjusted serum Ca did not decrease gt10 on
  average in any group, and no subject had values
  below 2 mmol/liter. AMG 162 was well tolerated.
  No related serious adverse events occurred. No
  clinically meaningful laboratory changes, other
  than those described above, were observed.
• In summary, a single SC dose of AMG 162 resulted
  in a dose-dependent rapid and sustained decrease
  from baseline in bone turnover and could be an
  effective and convenient Tx for osteoporosis.

J Bone Miner Res 2004191059-1066
46
Tx of malignancy-associated hypercalcemia and
cachexia with humanized anti-PTH-related protein
Ab

• PTHrP plays a central role in HHM, which is one
  of the most frequent paraneoplastic syndromes.
  PTHrP produced by the tumor acts through a common
  PTH/PTHrP receptor to promote bone resorption,
  inhibit Ca excretion from the kidney, and induce
  hypercalcemia. P'ts with HHM often develop
  cachexia associated with typical symptoms such as
  anorexia, malaise, nausea, constipation,
  polyuria, polydipsia, and confusion. The etiology
  of the cachexia is not fully understood but is
  thought to be caused by hypercalcemia and various
  cytokines such as IL-6, TNF-alpha, leukemia
  inhibitory factor, and others. In this study, we
  investigated the role of PTHrP in hypercalcemia
  and cachexia in HHM by using humanized anti-PTHrP
  Ab.
• A mouse monoclonal Ab that binds to PTHrP amino
  acid sequence 1-34 and inhibits PTHrP function
  has been humanized to create a specific and
  potent agent for the Tx of p'ts with HHM. The
  mouse monoclonal Ab has been shown to have
  antihypercalcemic activity against nude mice
  bearing human tumors.

Semin Oncol 200330Suppl 16167-173
47

• Because a mouse Ab is highly immunogenic in human
  p'ts, the complementarity-determining regions
  from the mouse Ab were grafted into a human Ab.
  The resulting humanized Ab specifically
  recognizes PTHrP(1-34) and neutralizes PTHrP
  functions in vitro and in vivo. The humanized
  anti-PTHrP Ab was administered IV to HHM model
  animals bearing tumors such as LC-6 human lung
  carcinoma. These animals showed symptoms similar
  to those of p'ts with HHM (eg, hypercalcemia and
  cachexia). The humanized anti-PTHrP Ab-treated
  animals responded with normalization of blood
  ionized Ca through an improvement of bone
  metabolism and Ca excretion. Moreover, the
  treated animals also showed an improvement in BW,
  ultromotivity, metabolic alkalosis, food
  consumption, water intake, serum phosphorus, and
  renal function. Consequently, the humanized
  Ab-treated animals experienced complete
  resolution of hypercalcemia and cachexia.
• These results suggest that the humanized Ab would
  be an effective and beneficial agent for p'ts
  with HHM, and that PTHrP is a major pathogenetic
  factor of hypercalcemia and cachexia in p'ts with
  HHM.

Semin Oncol 200330Suppl 16167-173
48
Guidelines

• No guidelines are available from the major
  professional societies for the Tx of
  hypercalcemia associated with cancer.

49
Recommendations (1)

• The p't described in the vignette, who has breast
  cancer and a large, obvious tumor burden, is
  typical of p'ts with hypercalcemia associated
  with cancer in general and with HHM in
  particular.
• As in all cases of hypercalcemia in p'ts with
  cancer, other causes of the hypercalcemia need to
  be carefully considered.
• Coexisting primary hyperparathyroidism should
  routinely be ruled out by measurement of
  immunoreactive PTH.
• In the p't described, HHM is the most likely
  cause of the hypercalcemia thus, immunoreactive
  PTH would be suppressed and circulating PTHrP
  would be elevated (however, I do not routinely
  measure PTHrP unless the Dx is uncertain).

50
Recommendations (2)

• When a p't presents with hypercalcemia associated
  with cancer, the physician should first consider
  whether Tx is appropriate according to an
  assessment of the overall prognosis.
• The cornerstones of successful antihypercalcemic
  therapy are vigorous rehydration (with the use of
  NS at 200 to 500 ml /hr, depending on the p't's
  CV status and renal function) aggressive
  calciuresis with the use of loop diuretics, after
  normovolemia has been restored and inhibition of
  bone resorption with the use of IV
  bisphosphonates (in the USA, the administration
  of either pamidronate an infusion of 60 to 90 mg
  over a 2-hour period or zoledronate 4 mg over a
  15-minute period).

51
Recommendations (3)

• Pamidronate is at present less expensive, whereas
  zoledronate is more convenient to use and results
  in slightly greater mean reductions in the serum
  Ca , although the differences are small.
• The expectation with the use of either regimen is
  that the serum Ca will begin to fall within 12
  hours after the therapy is initiated and will
  reach the nadir within four to seven days.
• The serum Ca generally will remain in the normal
  or near-normal range for one to three weeks,
  allowing time to institute other Txs for the
  malignant disease responsible for the
  hypercalcemia.

52
Thank you for your attention !
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