Abeloff: Clinical Oncology, 2nd ed., 2000.

TREATMENT OF TUMOR INDUCED HYPERCALCEMIA

The serum calcium concentration can be lowered in almost all patients with
tumor-induced hypercalcemia. A wide variety of antihypercalcemic regimens
remains in common use, although the wide therapeutic index and high success
rates of the newer bisphosphonates has resulted in their use as first-line
management in the majority of cases. Although it has been possible to target
osteoclast-mediated bone resorption in a fairly specific way, the same
cannot be said for enhanced renal tubular calcium reabsorption or
gastrointestinal calcium absorption.
Selection of therapy should be geared to a knowledge of the individual tumor
type (and hence the likely mechanism underlying the hypercalcemia), and to
the state of the patient's renal function and bone marrow reserve. Any
specific antineoplastic therapy that can be used, be it surgical,
radiotherapeutic, or chemotherapeutic, will be a powerful adjuvant to
antihypercalcemia therapy.

Ethical Considerations

The first decision is whether or not to treat this complication. Unless
specific antitumor therapy is available, the majority of patients who
develop hypercalcemia of malignancy are in the last few weeks of their lives
(Fig. 31 - 5)
<http://home.mdconsult.com/das/book/body/52259202/897/#F031005>  . Thus, it
can be argued that treatment is not indicated for all cases of hypercalcemia
associated with malignancy. For some, however, the use of an effective, safe
treatment to ameliorate the substantial morbidity of hypercalcemia and to
allow patients to return home, is clearly warranted.

General Considerations

The best treatment is one directed specifically and effectively at the
underlying malignant disease. Early mobilization is a laudable but often
unachievable goal in patients with advanced malignant disease. Thiazide
diuretics should be avoided, since they promote renal tubular calcium
reabsorption.
While dietary restriction of calcium seems intuitively appropriate,
gastrointestinal calcium absorption is low in most cases of hypercalcemia
associated with malignant disease. A notable exception is in patients whose
tumors are equipped with a substrate-dependent 1alpha-hydroxylase which
allows continued production of

<http://home.mdconsult.com/das/book/body/52259202/897/I167.fig#top>
<http://home.mdconsult.com/das/book/body/52259202/897/I167.fig#top> Figure
31-5 Survival curves for cancer patients with hypercalcemia. Solid circles,
specific anticancer therapy; open circle, no anticancer therapy. (Modified
from Ralston SH, Gallacher SJ, Patel U, et al: Cancer-associated
hypercalcemia: morbidity and mortality. Ann Intern Med 112:499, 1990, with
permission.)

calcitriol. Patients taking supplemental vitamin D and vitamin A
(beta-carotene) should be advised of the hypercalcemic effects of these
agents.

Extracellular Fluid Volume Expansion

Most patients with hypercalcemia of malignancy are significantly volume
depleted (on the order of 5 to 10 L), due to the combined effects of
anorexia, vomiting, and nephrogenic diabetes insipidus. In this state, the
glomerular filtration rate is reduced and the proximal convoluted tubular
response is to increase sodium retention. Concomitantly, proximal tubular
resorption of calcium is also increased. The aim of fluid replacement in
these circumstances should be to induce a state of mild fluid overload.
Restoration of a normal circulating blood volume will restore the glomerular
filtration rate and increase the fractional excretion of calcium. Further
salt loading will induce a natriuresis and a concomitant calciuresis. Care
must be taken to avoid severe congestive cardiac failure in elderly patients
or patients with poor cardiac reserve. Because of the hypoalbuminemia that
frequently accompanies advanced malignant disease, dependent edema is to be
expected during volume expansion. Care must also be taken to ensure an
adequate intake of free water. In the presence of severe hypercalcemia, a
resistance to the distal tubular actions of antidiuretic hormone may
predispose obtunded patients to significant hypernatremia. After restoration
of euvolemia, a maintenance infusion of 3 L/d of 0.9 percent saline solution
will induce a continued natriuresis. Patients should be encouraged to drink
freely. During such aggressive fluid management, other electrolyte
abnormalities are likely to be uncovered or precipitated. Despite impaired
renal function, both hypokalemia and hypomagnesemia are frequent findings,
and appropriate supplementation may be required.
While the serum calcium can be expected to fall on this regimen, restoration
of normocalcemia is unlikely



(Fig. 31 - 6)
<http://home.mdconsult.com/das/book/body/52259202/897/#F031006>  . A failure
to restore normal fluid balance, however, will greatly detract from the
success of subsequent therapeutic measures.

Calciuretic Therapy

Aside from the calciuretic effects of saline overload, two other agents are
commonly employed to induce renal calcium wasting.

Furosemide

Furosemide is a diuretic agent whose main site of action is in the thick
ascending limb of the loop of Henle ( loop diuretic), where it completely
and reversibly inhibits the Na+ /K+ /2Cl- co-transporter. In the euvolemic
and volume-expanded state, the fractional excretion of calcium can be
increased by up to 30 percent by loop diuretics. However, if the patient is
volume depleted, enhanced proximal tubular sodium and calcium resorption can
obviate this response. Thus the potential exists for loop diuretics to
aggravate hypercalcemia if adequate attention is not paid to volume status.
In the initial report of the effectiveness of this treatment the regimen
involved the administration of doses of furosemide in the region of 100 mg
every 2 hours. [ 53
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010053> ]
This aggressive therapy would require the facilities of an intensive care
unit to ensure adequate fluid monitoring. While substantial falls in the
serum calcium can be achieved, a rationale for the use of this treatment for
other than very acute situations is lacking, in that the primary cause of
the hypercalcemia -- increased bone resorption -- is not affected. Given the
risks of severe electrolyte disturbances and the availability of potent
antiresorptive medication, the use of loop diuretics should be primarily
reserved for situations of fluid overload, rather than used as
antihypercalcemic agents.

Calcitonin

The renal actions of calcitonin are complex. The calciuretic effect appears
to be due to inhibition of calcium reabsorption in the distal tubules. This,
in turn, is dependent on an adequate delivery of calcium to the distal
nephron, a situation that is compromised by the extracellular fluid volume
depletion in hypercalcemia. However, this renal tubular effect is rapid, and
in a study by Hosking and Gilson [ 54
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010054> ]
accounted for a mean fall of 0.35 ± 0.057 mmol/L in 11 patients who
responded well (Fig. 31 - 7)
<http://home.mdconsult.com/das/book/body/52259202/897/#F031007>  . This can
be of great value as an adjunct to more potent antiresorptive therapies.

Antiresorptive Therapy

Given that bone resorption is increased in the majority of cases of
hypercalcemia of malignancy, the best treatment after that designed to
combat the tumor itself is one directed at bone resorption. The osteoclasts
represent the final common pathway for bone resorption in both humoral and
local osteolytic hypercalcemia. The following agents, which inhibit
osteoclast function, not surprisingly are highly effective antihypercalcemia
treatment.

<http://home.mdconsult.com/das/book/body/52259202/897/I168.fig#top>
<http://home.mdconsult.com/das/book/body/52259202/897/I168.fig#top> Figure
31-6 Effect of rehydration on 16 hypercalcemic patients. (Data from Hosking
DJ, Cowley A, Bucknall A: Rehydration in the treatment of severe
hypercalcemia. Q J Med 200:473, 1981.)


Bisphosphonates

The bisphosphonates are a class of compounds, structural analogues to
pyrophosphate (PPi ), in which the P-O-P bond is replaced by a P-C-P bond
stable to enzymatic cleavage. Figure 31 - 8
<http://home.mdconsult.com/das/book/body/52259202/897/#F031008>  shows the
structure of some of the available bisphosphonates as compared with that of
PPi .
Pharmacokinetic and pharmacodynamic studies of bisphosphonates indicate that
these compounds are absorbed poorly from the gastrointestinal tract after
oral administration. Studies in healthy adult male volunteers [ 55
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010055> ]
[ 56
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010056> ]
have shown that gastrointestinal absorption is on the order of 1 to 3
percent, but varies between individuals. Diet has a profound effect on
gastrointestinal absorption, reducing the effective availability of the drug
to zero if it is taken with food. [ 57
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010057> ]
Once absorbed, it appears that approximately 50 percent of the compound is
excreted unchanged in the urine, the rest being sequestered in bone and soft
tissue, [ 58
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010058> ]
where its

<http://home.mdconsult.com/das/book/body/52259202/897/I169.fig#top>
<http://home.mdconsult.com/das/book/body/52259202/897/I169.fig#top> Figure
31-7 Effect of calcitonin (100 U/d) in 21 hypercalcemic patients. (Data from
Hosking DJ, Gilson D: Comparison of the renal and skeletal actions of
calcitonin in the treatment of severe hypercalcemia of malignancy. Q J Med
211:359, 1984.)





<http://home.mdconsult.com/das/book/body/52259202/897/I170.fig#top>
<http://home.mdconsult.com/das/book/body/52259202/897/I170.fig#top> Figure
31-8 Structural formulae of commonly studied bisphosphonates in relation to
the generic biphosphonate and to pyrophosphate.

half-life (in rats) is 4 months. [ 59
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010059> ]
From the experiments of Jung and colleagues, [ 60
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010060> ]
it appears that bone mineral has a very high affinity for bisphosphonates.
Although the bulk of any absorbed bisphosphonate is rapidly relocated to
bone, this is nonhomogeneous, and varies with the state of bone activity.
Indeed, this principle is made use of for isotope bone scanning using 99m
Tc-labeled bisphosphonates. Furthermore, it is likely that the release of
bisphosphonate will be enhanced in areas of rapid bone turnover, leading to
an unpredictable recirculation of the drug. [ 61
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010061> ]
The precise mechanism of action of these compounds is unclear. Evidence for
a marked physicochemical effect of bisphosphonates came from work by
Robertson and colleagues, [ 62
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010062> ]
who demonstrated that compounds such as PPi and bisphosphonates had major
effects on the ionic makeup of the hydration layer usually surrounding
hydroxyapatite crystals in suspension. This interaction alters the calcium
phosphate product both at the surface of the crystal and in the immediate
vicinity, and so inhibiting further crystal development and dissolution. An
effort has been made to relate physicochemical effects to the structure of a
great many bisphosphonates, but it became rapidly clear that the
physicochemical interactions between bisphosphonates and bone mineral
represented only a small part of the spectrum of activities of these agents,
and no correlation between structure and activity could be demonstrated.
 63
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010063> ]
Lysosomal enzyme systems in osteoclasts have been implicated in the process
of bone resorption, [ 64
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010064> ]
and it is possible that inhibition of these enzymes, notably the acid
hydrolases but also the enzymes responsible for energy production and
protein synthesis by bisphosphonates, could account in some way for their
effects. [ 65
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010065> ]
[ 66
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010066> ]
In an extensive coverage of the cellular morphologic changes induced by
bisphosphonates, Plasmans and colleagues [ 67
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010067> ]
investigated changes in osteocyte, osteoblast, and osteoclast morphology
induced by etidronate in a model of heterotopic bone formation. They
discovered that the normal ruffled border of the osteoclasts appeared to
shrink, and coined the term frustrated osteoclasts. Furthermore, transient
abnormal calcium storage in the mitochondria of osteoblasts was noted, and
the osteocytes appeared to be stimulated into greater activity, with
enhancement of subcellular organelles. Although in many in vivo studies, no
evidence for a failure in the development of osteoclasts had been shown, in
vitro work by Boonekamp and colleagues [ 68
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010068> ]
has suggested that pamidronate, but not etidronate or clodronate, was able
to inhibit the accession of mononuclear osteoclast precursors into a
previously osteoclast-free system.

Etidronate.

Etidronate (1-hydroxy-ethylidene-1,1-bisphosphonate) was the first
bisphosphonate licensed for use in the management of metabolic bone disease.
Oral administration of this agent became well established in the treatment
of Paget's disease of bone, and clinical trials have shown it may be of use
in the management of osteoporosis. [ 69
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010069> ]
[ 70
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010070> ]
Like all currently available bisphosphonates, etidronate suffers from poor
and unpredictable oral bioavailability. The hypocalcemic response to
intravenous etidronate is not as marked as with newer bisphosphonates (Fig.
31 - 9) <http://home.mdconsult.com/das/book/body/52259202/897/#F031009>  . A
conservative estimate suggests that normocalcemia can be restored in
approximately 40 percent of patients. Evidence for a sequential beneficial
effect of oral etidronate following normalization of serum calcium exists,
but is poor (see "Long-Term Treatment," below). Etidronate differs from
other bisphosphonates studied in that its use is frequently associated with
hyperphosphatemia.

Clodronate.

The use of intravenous clodronate (dichloromethylene bisphosphonate) for the
control of the hypercalcemia of malignancy was investigated by several
groups in the United States and Europe in the early 1980s. The appearance of
three cases of acute leukemia in 664 patients led to the temporary
withdrawal from use of this agent pending analysis of the likelihood of
leukemia being a true side effect. [ 72
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010072> ]
Thereafter, much of the investigation of this agent has been limited to
groups in Europe and, more recently, Canada,




<http://home.mdconsult.com/das/book/body/52259202/897/I171.fig#top>
<http://home.mdconsult.com/das/book/body/52259202/897/I171.fig#top> Figure
31-9 Effect of etidronate (50 to 1,000 mg/d) in 13 hypercalcemic patients.
(Data from Jung A: Comparison of two parenteral diphosphonates in
hypercalcemia of malignancy. Am J Med 72:221, 1982.)

where clodronate has approval for use as an antihypercalcemic agent.
Clodronate is a very effective agent in restoring normocalcemia. Oral
clodronate also appears able to induce a normocalcemic response, [ 73
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010073> ]
but in the clinical situation of the acute management of hypercalcemia, the
intravenous route is preferred.
Impairment of renal function has been reported in patients receiving rapid
infusions of intravenous clodronate in the setting of multiple myeloma. [ 74
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010074> ]
It is unclear if a direct cause-and-effect relationship holds, given the
underlying renal complications in patients with multiple myeloma.

Pamidronate.

Pamidronate disodium was the first of the aminobisphosphonates licensed for
clinical use. Like clodronate, pamidronate is a very effective agent at
restoring normocalcemia. [ 75
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010075> ]
An early dose-response study from Europe carried out by Body and colleagues
in 1987 [ 76
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010076> ]
showed little advantage to increasing the dose beyond 0.25 mg/kg. More
recently, however, Thiebaud and colleagues [ 77
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010077> ]
showed a more impressive dose-response effect using single intravenous
infusions of pamidronate (from 30 to 90 mg) in terms of both restoration of
normocalcemia and duration of the normocalcemic response. This finding has
been confirmed in a large multicenter trial in the United States. [ 6
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010006> ]
In the early studies, pamidronate was given in divided doses over a period
of several days. It is possible, however, to achieve the same effect with
single-dose therapy. [ 78
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010078> ]
Dodwell and colleagues have studied more rapid infusion rates [ 79
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010079> ]
and have shown that the drug can be given safely and efficaciously over a
2-hour period.

Comparative studies involving bisphosphonates.

An early study involving 30 patients with hypercalcemia and malignant
disease showed that, while volume repletion had only minor beneficial
effects in terms of lowering the serum calcium level (3.15 ± 0.12 to 3.0 ±
0.11 mmol/L), pamidronate disodium in doses ranging from 15.75 to 300 mg
(over 3 to 10 days) lowered the serum calcium on average from 3.0 ± 0.11 to
2.19 ± 0.07. [ 80
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010080> ]
Ralston and colleagues [ 81
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010081> ]
compared the hypocalcemic effect of pamidronate disodium with that of
mithramycin and a combination of corticosteroids and calcitonin. They
demonstrated that pamidronate induced a more effective fall in serum calcium
than either mithramycin or the combination of corticosteroids and
calcitonin, although the time to the onset of the effect was longer.
Thurlimann and colleagues [ 82
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010082> ]
performed a comparative, randomized, crossover study to compare the
hypocalcemic effects of a single intravenous dose of 60 mg pamidronate with
20 mug/kg mithramycin. There were no primary failures in the
pamidronate-treated group (11 of 11), but 6 of 14 patients in the
mithramycin-treated group failed to achieve normocalcemia. When those
patients, along with two others from this group who had become hypercalcemic
again, were treated with pamidronate, all eight became normocalcemic.
A comparative study involving the three commonly available bisphosphonates
in Europe demonstrated that a single intravenous infusion of 30 mg
pamidronate induced a more rapid and more pronounced fall in serum calcium
than 600 mg of clodronate as a single intravenous dose or 7.5 mg/kg
etidronate intravenously for 3 days. [ 83
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010083> ]
A multicenter U.S. study comparing the hypocalcemic effects of etidronate
and pamidronate confirmed the superiority of the latter bisphosphonate. [ 84
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010084> ]

Effect of tumor type on response to bisphosphonates.

Although the primary mechanism in the generation and maintenance of
hypercalcemia in malignant disease is enhanced bone resorption, tumor types
differ significantly in the way they bring this about. Morton and colleagues
[ 75
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010075> ]
could detect no statistically significant difference between hypercalcemic
patients with squamous carcinoma of the bronchus ( n = 12), carcinoma of the
breast ( n = 6), or multiple myeloma ( n = 5) in their response to 60 mg
pamidronate. More recently, it has been suggested that a low renal phosphate
threshold (indicative of the effects of PTHrP) may be used to indicate the
likelihood of a poor response to treatment, [ 85
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010085> ]
and Dodwell and colleagues [ 86
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010086> ]
have demonstrated a statistically significant relationship between the
circulating PTHrP concentration and the time to normalization of
hypercalcemia.

Duration of response to bisphosphonate therapy.

The duration of response to bisphosphonates is difficult to determine and
varies considerably between individuals. Elucidation of the duration of
response is also compounded by the high mortality in this group of patients
due to their tumor, and by the introduction of specific and effective
antineoplastic therapy for patients with cancer of the breast and multiple
myeloma. In the patients treated by Morton and colleagues, [ 75
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010075> ]
only 11 of 30 patients (37 percent) survived longer than 1 month following
the onset of their hypercalcemia. In this study, the median time to
recurrence of hypercalcemia was approximately 3 weeks. The same median
duration of normocalcemia was also found by Harinck and



Bijvoet [ 87
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010087> ]
; however, a longer one of 35 days was reported by Thiebaud and colleagues.
[ 77
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010077> ]
Unfortunately, it is not possible to predict the length of time that any
specific patient will remain normocalcemic.

Side effects of bisphosphonates.

In general, bisphosphonate therapy is well tolerated. Low-grade pyrexia is
noted in 10 to 15 percent of patients. The use of rapid intravenous
infusions of clodronate and etidronate has been associated with
deterioration in renal function in patients with previously diminished renal
reserve. Hyperphosphatemia is noted with etidronate therapy, but
hypophosphatemia is seen with clodronate and pamidronate treatment. The
mechanisms of phosphate imbalance are unclear, although etidronate appears
to have a specific effect on renal phosphate handling. [ 88
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010088> ]
Prolonged use of etidronate has been associated with a fracturing
osteomalacia in patients with Paget's disease of bone, but this is of little
relevance in hypercalcemic individuals. Oral bisphosphonates are associated
with gastrointestinal intolerance, and are probably best avoided in the
acute situation.

New bisphosphonates.

Alendronate disodium is a potent aminobisphosphonate that is being used in
an oral form in the management of osteoporosis. A dose-response study
demonstrated that alendronate 10 mg intravenously over 2 hours restored
normal calcium levels in 90 percent of patients. [ 89
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010089> ]
No long-term studies with oral alendronate in hypercalcemic patients are
available.
Ibandronate is a bisphosphonate that is approximately 50 times more potent
than pamidronate in animal models of bone resorption. A dose-response study
of this agent showed that an intravenous dose of 6 mg was highly effective
at restoring normal calcium levels. [ 90
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010090> ]
The highly potent cyclic imidazole bisphosphonate zoledronate is also highly
effective at restoring normocalcemia at doses of 0.02 to 0.04 mg/kg.
Despite increases in relative potency, it is unlikely that the newer
bisphosphonates will achieve better response rates than pamidronate.
Advantages of newer agents may include more rapid infusion times and
alternate routes of drug delivery.

Plicamycin (Mithramycin)

This bacteriostatic antibiotic agent was used in the late 1960s for the
treatment of germ cell tumors. [ 91
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010091> ]
A side effect of this agent in normocalcemic individuals was hypocalcemia.
The mechanism of the hypocalcemia is unclear, although in vitro studies
suggest that a direct toxic effect on osteoclasts is responsible. [ 92
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010092> ]
Despite a long list of side effects, including marrow, hepatic, and renal
toxicity, plicamycin remains a widely used agent for the management of
hypercalcemia. Plicamycin is effective at restoring normocalcemia in
approximately 80 percent of patients, and many consider the toxic effects to
be overstated, since the antihypercalcemic effect is seen at doses 10 times
lower than those used in the original antineoplastic regimens. A standard
infusion of 25 mug/kg over 4 to 6 hours is most often used. Longer durations
of infusion may reduce the nausea caused by this agent, but will add to the
risk of extravasation and local irritation. The hypocalcemic effect is seen
within the first 24 hours, but the duration of response is unpredictable.
One serious reported drawback with plicamycin is the development of severe,
rapid, rebound hypercalcemia that occurs in an unpredictable fashion. [ 93
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010093> ]
Furthermore, most of the toxic effects of plicamycin are cumulative. Thus,
its use in the long-term management of hypercalcemia is limited.
While the safer (and more effective) aminobisphosphonates have replaced
plicamycin as first-line antiresorptive therapy, this agent may be of use in
the infrequent individual whose hypercalcemia proves resistant.

Calcitonin

Since calcitonin has both calciuretic and antiresorptive actions, it would
appear that this would be the ideal antihypercalcemic agent. The
antiresorptive effects of calcitonin are related to a direct osteoclast
toxicity, and, possibly to inhibition of new osteoclast recruitment. When
used as a single agent, the hypocalcemic effect of calcitonin is modest at
best, and resistance to the effects of calcitonin develops rapidly.
Nonetheless, a major role for calcitonin in combination with powerful
antiresorptive agents is emerging. Fatemi and colleagues [ 94
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010094> ]
reported an enhanced and more rapid hypocalcemic effect with the combination
of etidronate and calcitonin, as had Ralston and colleagues [ 91
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010091> ]
with pamidronate and calcitonin.
While originally recommended for subcutaneous use, newer routes of delivery,
including suppositories and nasal sprays, have been developed with varying
levels of efficacy.
In cases of life-threatening hypercalcemia, or where neurologic symptoms are
a major feature, we recommend the use of 8 MRC (Medical Research Council)
units/kg given intramuscularly every 6 hours for 1 or 2 days in association
with an intravenous bisphosphonate. This regimen has the advantage of
combining the rapid calciuretic effect of calcitonin with the powerful and
prolonged antiresorptive effect of the bisphosphonate. [ 95
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010095> ]

Gallium Nitrate

Hypocalcemia was noted as a side effect of therapy in patients receiving
gallium nitrate for the management of lymphoma. [ 96
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010096> ]
Thereafter, its effectiveness was confirmed by Warrell and colleagues [ 97
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010097> ]
in open-labeled studies and in a randomized, double-blind comparative study
with calcitonin. [ 98
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010098> ]
The mechanism of action of gallium is unknown, although it is clear that
urinary calcium excretion is reduced. By implication, bone resorption is
reduced, although no histologic changes were noted in explants of fetal long
bones exposed to this agent.
Gallium nitrate requires intravenous administration. The best investigated
regimens involve sequential 5-day




MANAGEMENT OF HYPERCALCEMIA OF MALIGNANCY
The most effective way to control the hypercalcemia of malignant disease is
by therapy aimed at eradicating or reducing the tumor burden. Chemotherapy,
radiation therapy, and surgical therapy all have a role to play. In the
absence of effective antitumor therapy, the patient's general condition and
immediate prognosis should be used to guide the decision to embark on
aggressive antihypercalcemic therapy or active palliation, or both. The
introduction of agents with high efficacy and few side effects has broadened
the oncologist's options.
Our practice is to discuss treatment options with the patients and their
families, emphasizing that the drugs used to control the hypercalcemia will
not influence the progression of the underlying cancer, but will help the
symptoms of the hypercalcemia. Volume expansion with 0.9 percent saline is
begun immediately. The rate is determined by the state of hydration of the
individual patient as assessed by the clinician. An infusion of intravenous
pamidronate is begun at the same time as saline volume expansion. The dose
of pamidronate chosen depends on the corrected serum calcium level. For a
calcium concentration of 3.0 mmol/L or greater, a dose of 90 mg pamidronate
over 24 hours is used. For a calcium concentration less than 3.0 mmol/L, a
dose of 60 mg pamidronate infused over 8 hours is used. In the presence of
severe hypercalcemia and neurologic symptomatology, calcitonin 8 MRC
units/kg intramuscularly every 6 hours is used in conjunction with the
pamidronate.
Biochemical response is rapid. The serum calcium can be expected to fall
after 24 hours. Most patients reach a nadir calcium value in 5 to 7 days. We
maintain a natriuresis by continuing the saline infusion until normocalcemia
is reached. Volume overload, as evidenced by an elevation of the jugular
venous pressure, the development of a fourth heart sound, pulmonary
congestion, or peripheral edema, is treated using furosemide, which has the
added benefit of inducing a calciuresis. Care is taken to avoid volume
depletion when using the diuretic. Close attention is paid to renal function
and electrolyte balance, since hypokalemia, hypomagnesemia, and
hypophosphatemia are common sequelae of this treatment approach. In cases
resistant to the initial dose of pamidronate, re-treatment can be given at a
dose 30 mg higher than the previously attempted dose to a maximum of 180 mg
over 24 hours. Failure to respond to bisphophonate is a poor prognostic
feature, but alternative antiresorptive therapy can be attempted (gallium
nitrate, plicamycin).
In the absence of effective antitumor therapy, the hypercalcemia will almost
certainly recur if the patient survives long enough. The duration of
normocalcemia is variable, and further antihypercalcemic therapy must be
individualized. Patients are advised to maintain a high fluid intake (3
L/d). Corrected calcium concentration is determined weekly. We re-treat
patients when the corrected serum calcium exceeds 2.7 mmol/L, and at regular
intervals thereafter. Re-treatment is done on an outpatient basis when
possible. The dose of pamidronate is based on the last dose that reversed
the hypercalcemia.
Often the malignant process is at such an advanced stage that death occurs
within a few weeks of the development of hypercalcemia. Because of this we
involve palliative care early in the management of hypercalcemic patients.


infusions of 200 mg/m2 /d. At this dose, the drug is relatively free of side
effects, although caution is required if other nephrotoxic agents (e.g.,
aminoglycosides) are being used.

Prostaglandin Synthesis Inhibitors

As discussed above, prostaglandins (notably prostaglandin E2 ) have potent
bone resorbing effects in relationship to certain tumor types. Thus it was
hoped that a significant subset of patients might be found who would respond
to prostaglandin synthesis inhibitors such as indomethacin. Although
well-characterized case reports have shown a good response to these agents,
in general they are ineffective for the treatment of tumor-induced
hypercalcemia. [ 99
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010099> ]
Seyberth and colleagues [ 100
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010100> ]
attempted to characterize those patients who might be responsive in terms of
their biochemical parameters. As one would intuitively expect, those
patients with a high urinary excretion of prostaglandin E2 metabolites
showed the best response. In general, however, no reliance can be placed on
prostaglandin synthesis inhibitors in this clinical setting.

Other Therapies


Corticosteroids

Glucocorticoids are commonly employed in the management of tumor-induced
hypercalcemia despite significant evidence that their usefulness is limited.
The mechanism of any hypocalcemic effect produced by these agents is
unclear. In patients with multiple myeloma and lymphoid malignancies,
glucocorticosteroids form part of the antineoplastic regimen (e.g.,
melphalan and prednisone, VAD, vincristine, doxorubicin, and dexamethasone;
MOPP, mechlorethamine, vincristine, procarbazine, and prednisone; CHOP,
cyclophosphamide, doxorubicin, vincristine, and prednisone,)  because of
their known cytotoxic effect on lymphoid tissue. Furthermore,
glucocorticosteroids block the absorption of calcium from the gut, thus they
could be expected to be useful in patients with vitamin D - mediated
hypercalcemia where gastrointestinal absorption of calcium is enhanced.
In patients with solid tumors, corticosteroids are not usually effective and
have no role in the management of hypercalcemia. [ 101
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010101> ]

Phosphate

The use of intravenous phosphate to complex calcium and induce precipitation
in the extracellular fluid and soft tissue can no longer the supported.
 102
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010102> ]
Oral phosphate, however, is less toxic, and may be tried for the long-term
management of hypercalcemia. The dose-limiting side effect of the oral agent
is diarrhea. Oral phosphate, while acting primarily as a gastrointestinal
calcium chelator, may also have some inhibitory effects on osteoclast
function.

Dialysis

Hemodialysis using a dialysate bath free of calcium can be used in the
emergency treatment of hypercalcemia. However, the authors (a nephrologist
and an oncologist) have never been called upon to use this therapy in over
10 years of clinical practice.

Experimental Agents


WR-2721

The radioprotectant organic thiophosphate S-2-(3-aminopropylaminoethyl)
phosphorothioic acid, also known as WR-2721, is an agent with unique effects
on calcium metabolism. This agent inhibits parathyroid hormone secretion by
an unknown mechanism [ 103
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010103> ]
but, more importantly from the point of view of the management of the
hypercalcemia of malignancy, it also appears to inhibit PTH-independent
calcium reabsorption. [ 104
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010104> ]
Although this agent is relatively nontoxic, it is not widely available for
the management of hypercalcemia.

Cis-platinum

A clinical study by Lad and colleagues [ 105
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010105> ]
involving 23 episodes of hypercalcemia in 13 patients showed a complete
response rate of 69 percent. Patients were selected for whom it was
considered unlikely that the cis-platinum would have a specific antitumor
effect. The duration of the hypocalcemic effect was on the order of 1 month.
The authors comment that at the given dose (100 mg/m2 ), this therapy was
nontoxic.

Carbonic Anhydrase Inhibitors

The generation of an acid environment for the activation of acid hydrolases
is crucial to osteoclastic function. Protons for transport into the
extracellular lysosome at the site of bone resorption are produced by the
enzyme carbonic anhydrase II, [ 106
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010106> ]
which catalyzes the hydration of carbon dioxide to carbonic acid.
Acetazolamide is a carbonic anhydrase inhibitor that has been widely used
for the treatment of glaucoma, and as a diuretic agent. Brown and colleagues
[ 107
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010107> ]
demonstrated that acetazolamide caused a significant fall in calcium level
in hypercalcemic rats bearing an H500 Leydig's cell tumor. Carbonic
anhydrase inhibitors also produce a metabolic acidosis (because of renal
bicarbonate wasting), and the investigators note that this acidosis must be
prevented to allow the hypocalcemic effect.
No study of the efficacy of carbonic anhydrase inhibitors in human
hypercalcemia has been published to date.

Long-Term Treatment

In patients for whom no antitumor therapy is available, long-term survival
is unusual. By implication, there are few good long-term studies on the
management of hypercalcemia, and most results are anecdotal.
Individualization of therapy is the rule. Patients should be advised to
drink an adequate volume of fluid (2 to 3 L/
TABLE 31-5 -- OPTIONS FOR LONG-TERM MANAGEMENT OF HYPERCALCEMIA OF
MALIGNANCY
AGENT
DOSE
FREQUENCY *
<http://home.mdconsult.com/das/book/body/52259202/897/#T031005.01>
Intravenous pamidronate
<http://home.mdconsult.com/das/book/body/52259202/897/#T031005.02>
60-90 mg over 2-4 h
Every 2-3 weeks
Oral pamidronate
<http://home.mdconsult.com/das/book/body/52259202/897/#T031005.03>
200-1,200 mg
Daily
Oral clodronate §
<http://home.mdconsult.com/das/book/body/52259202/897/#T031005.04>
3,200 mg
Daily
Oral etidronate
<http://home.mdconsult.com/das/book/body/52259202/897/#T031005.05>
20 mg/kg
Daily
Oral phosphate
2-3 g
Daily
Corticosteroids
Variable
Daily
  Multiple myeloma


  Carcinoma of the breast


NSAIDs
Variable
Daily
Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs.
*Suggested frequencies and doses may be altered to suit individual patients.
Data from Dodwell et al. [ 79
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010079> ]
Data from Thiebaud et al. [ 109
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010109> ]
§ Data from chapuy et al. [ 73
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010073> ]
Data from Ringenberg and Ritch [ 110
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010110> ]
and Hasling et al. [ 111
<http://home.mdconsult.com/das/book/body/52259202/897/258.html#R031010111> ]
  _____







d) and to maintain their mobility for as long as possible. They should be
reminded of the symptoms of hypercalcemia and urged to present early should
those symptoms arise. Table 31 - 5
<http://home.mdconsult.com/das/book/body/52259202/897/#T031005>  shows
suggested maintenance treatments for the hypercalcemia of malignancy.
The importance of palliative care cannot be overemphasized in the management
of these unfortunate individuals.
A logical therapeutic regimen for the acute management of tumor-induced
hypercalcemia is shown in the preferred treatment box. This regimen
represents one approach to this problem. Other equally valid regimens are
possible, and individualization of regimens is mandatory for long-term
therapy.
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.