Clinical Review

Cancer-Related Hypercalcemia
Whitney Goldner, MD

University of Nebraska Medical Center,

Omaha, NE
Abstract
Hypercalcemia has been reported to occur in up to 30% of patients who have a malignancy.
Hypercalcemia is most common in those who have later-stage malignancies and predicts a
poor prognosis for those with it. The most common causes include humoral hypercalcemia
of malignancy mediated by parathyroid hormone–related peptide, osteolytic cytokine
production, and excess 1,25-dihydroxy vitamin D production. However, the etiology is not
always mediated by malignancy. Hypercalcemia can occur in those with malignancy and
an additional etiology for hypercalcemia such as primary hyperparathyroidism or
granulomatous diseases. This paper reviews the cancers associated with hypercalcemia
and their proposed mechanisms, nontumor-mediated hypercalcemia, as well as diagnosis
and treatment strategies for each condition.

INTRODUCTION of the serum calcium. Mild or indolent

ASSOCIATED CONTENT
See accompanying commentaries
on pages 433 and 435
DOI: 10.1200/JOP.2016.011155
Hypercalcemia can occur in up to 30% of
persons with a malignancy.1 In severe cases,
hypercalcemia can be associated with neu-
rocognitive dysfunction as well as volume
depletion and renal insufficiency or failure.
Individual risk of hypercalcemia depends on
the underlying type and stage of malignancy.
The estimated yearly prevalence of hyper-
calcemia for all cancers is 1.46% to 2.74%;
it is four times more common in stage IV
cancer and associated with a poor prog-
nosis. The most common cancers are lung
cancer, multiple myeloma, and renal cell
carcinoma. These are followed by breast and
colorectal cancers, and the lowest rates were
reported in prostate cancer.2 Thirty-day
mortality was previously reported at 50%.3
However, a recent analysis showed a median
length of stay of 4 days, and an in-hospital
mortality rate of 6.8%.4
Hypercalcemia is categorized accord-
ing to the serum total calcium level1: mild
hypercalcemia, 10.5 to 11.9 mg/dL; mod-
erate hypercalcemia, 12 to 13.9 mg/dL;
and severe hypercalcemia, $ 14 mg/dL.
Symptoms are usually dictated by both the
level of serum calcium and the rate of change
hypercalcemia can be asymptomatic, or it
can be associated with mild nonspecific
symptoms such as lethargy and muscu-
loskeletal pain. In contrast, severe, rapidly
progressive hypercalcemia can be asso-
ciated with significant volume depletion and
acute renal insufficiency, as well as dra-
matic neurocognitive symptoms ranging
from altered mental status to coma.
Hypercalcemiaisaresultofabnormalities
in the normal bone formation and deg-
radation cycle. Bone mineralization is a well-
balanced constant cycle of bone formation
stimulated by osteoblasts and bone break-
down (or resorption) stimulated through
osteoclasts. During normal bone turnover,
osteoclast activity is regulated by the binding
of RANK surface receptor on the osteoclast
to the receptor activator RANKL on the
osteoblast. This binding of RANK/RANKL
regulates osteoclastogenesis. Osteoprotegerin
is secreted by osteoblasts and strongly
inhibits bone resorption by binding to
RANKL, thereby blocking the interaction
between RANK/RANKL. If the interaction
between RANK and RANKL is disrupted or
blocked, then the osteoclasts do not mature.

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If there is increased interaction between RANK and RANKL,
then there is more osteoclastic expression and more bone
resorption.5,6
Calcium homeostasis is tightly regulated by many hormones,
including parathyroid hormone (PTH), 1,25-dihydroxy
vitamin D (1,25[OH] 2 D), calcitonin, serum calcium, and
serum phosphorus. 7,8 PTH is produced by the parathyroid
glands. It both increases serum calcium and decreases serum
phosphorus via direct and indirect stimuli of osteoclasts. It
increases renal calcium absorption and decreases renal phos-
phorus absorption. PTH also stimulates the conversion of
25-hydroxy vitamin D (25[OH]D) to 1,25(OH)2D in the kidneys
through 1-a-hydroxylase, which results in increased intestinal
absorption of both calcium and phosphate.7,8
In response to hypercalcemia, calcitonin is secreted by
the parafollicular C cells. Calcitonin lowers serum calcium by
decreasing renal calcium and phosphorus reabsorption and
also by decreasing bone reabsorption.8 Calcitonin is not sig-
nificant in overall calcium homeostasis, but it is an important
therapeutic option. Thus, understanding its mechanism of
action is important.
There have been several proposed mechanisms for
hypercalcemia associated with malignancies, which include:
humoral hypercalcemia of malignancy mediated by increased
parathyroid hormone–related peptide (PTHrP); local oste-
olytic hypercalcemia with secretion of other humoral factors
responsible for hypercalcemia; excess extrarenal activated
vitamin D (1,25[OH]2D); PTH secretion, ectopic or primary;
and multiple concurrent etiologies.
Humoral hypercalcemia of malignancy refers specifically to
PTHrP-mediated hypercalcemia and was first proposed by Fuller
Albright in 1941.9 It is estimated to account for 80% of hyper-
calcemia in cancer patients.1,5 This is most commonly seen in
squamous cell carcinomas such as head and neck, esophageal,
cervical, lung,1 and colon cancers10 in addition to renal cell,11
bladder, breast, endometrial, and ovarian cancers,1 and it is
rarely seen in pancreatic neuroendocrine tumors.12 PTHrP is
structurally similar to PTH and, like PTH, it enhances renal
tubular reabsorption of calcium while simultaneously increasing
urinary phosphorus excretion. The result is both hypercalcemia
and hypophosphatemia.1,5 However, unlike PTH, PTHrP does
not increase 1,25(OH)2D and thus does not increase intestinal
absorption of calcium and phosphorus. PTHrP acts on osteo-
blasts, leading to enhanced synthesis of RANKL.13
Local osteolytic hypercalcemia accounts for 20% of cases1
and is usually associated with extensive bone metastases and
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Hypercalcemia and Malignancy
skeletal tumor burden. It commonly occurs in multiple myeloma
and metastatic breast cancer and less commonly in leukemia
and lymphoma. Previously, the proposed mechanism was direct
destruction of bone by metastases or malignant cells. However, it
is now thought to be because of the release of local cytokines from
the tumor, resulting in excess osteoclast activation and enhanced
bone resorption, often through RANK/RANKL.5
Humoral factors associated with increased remodeling and
resultant hypercalcemia include interleukin 1 (IL-1), IL-3, IL-6,
tumor necrosis factor a, transforming growth factor a and b,
lymphotoxin, and E series prostaglandins.13-15 Macrophage
inflammatory protein 1a has also been reported to play a role in
hypercalcemia associated with multiple myeloma. Macrophage
inflammatory protein 1a was found to be elevated in the bone
marrow of patients with active myeloma, and it is known to
stimulate osteoclastic formation in human bone marrow
cells.5,16 Local cytokines can also be released in the setting of
metastatic breast cancer bone lesions, such as transforming
growth factor b, which stimulate local production of PTHrP.17
Extrarenal production of 1,25(OH)2D by the tumor accounts
for approximately 1% of cases of hypercalcemia in malignancy.1
In normal vitamin D metabolism, stored vitamin D (25[OH]D)
in the liver is converted to 1,25(OH)2D under the influence of
PTH by renal 1-a-hydroxylase in the kidneys. 1,25(OH)2D
causes increased intestinal absorption of calcium and enhances
osteolytic bone resorption, resulting in increased serum
calcium.18 Extrarenal production is most commonly seen with
Hodgkinand non-Hodgkin lymphoma1 and has also been reported
in ovarian dysgerminoma.19 Nonmalignant granulomatous dis-
eases such as sarcoidosis and other inflammatory conditions can
also produce hypercalcemia as a result of extrarenal 1,25(OH)2D
production via autonomous 1-a-hydroxylase activity in tissue
macrophages.20
An additional consideration is vitamin D intoxication. Over-
the-counter vitamin D usage is common, which can result in
excess vitamin D and hypercalcemia.21 A distinguishing feature
of vitamin D intoxication versus extrarenal 1,25(OH)2D pro-
duction is that in vitamin D intoxication, both 25(OH)D and
1,25(OH)2D are elevated with a suppressed PTH. Extrarenal
production of 1,25(OH)2D can be seen with low or normal
25(OH)D in addition to high normal or high 1,25(OH)2D.
PTH-mediated causes of hypercalcemia also need to be
consideredin hypercalcemiaassociated withmalignancy.Ectopic
PTH production by the tumor itself is a rare cause, making up
fewer than 1% of cases.1 However, primary hyperparathyroidism
as a result of parathyroid adenoma(s) or hyperplasia can also
Volume 12 / Issue 5 / May 2016 n jop.ascopubs.org 427
Goldner
occur in patients with malignancy. Overall, primary hyper-
parathyroidism occurs in 1 of 1,000 people; it is three times more
common in women than in men, especially after the age of 45,
with a peak incidence in the seventh decade.22,23 It is also more
common in those with a history of head and neck irradiation24,25
and chronic lithium therapy.26 It is estimated that 5% to 10%
of cases of primary hyperparathyroidism are the result of
hereditary hyperparathyroid syndromes, including multiple
endocrine neoplasia types 1 and 2.27 Parathyroid carcinoma
is a rare cause of primary hyperparathyroidism.28
There have also been many case reports of multiple con-
current etiologies for hypercalcemia in patients with malignancy.
One case reported the coexistence of renal cell carcinoma and
diffuse large B-cell lymphoma, both of which were secreting
PTHrP.29 There are also reports of concurrent primary hyper-
parathyroidism and humoral hypercalcemia of malignancy.30-32
WORK-UP
Obtaining a serum calcium is the first step in the work-up
of suspected hypercalcemia. Total serum calcium, which
measures both bound and unbound calcium, is most com-
monly used. Forty percent of calcium in serum is bound to
albumin, and calcium homeostasis is greatly affected by
albumin concentrations.8 Therefore, a current serum albumin
level is necessary for interpretation of the serum calcium level.
If the albumin is abnormal, the serum calcium should be
corrected for the serum albumin using the formula in Table 1.
If the serum calcium is believed to be inaccurate, then ionized
calcium can be used, but this also has its limitations and can be
inaccurate.
The albumin–calcium system is highly sensitive to pH, and
changes in pH alter the fraction of calcium ions that are bound to
albumin. In respiratory alkalosis caused by hyperventilation, the
ionized calcium decreases acutely, and reductions in pH can
cause the ionized calcium to rise acutely, both resulting in rel-
atively rapid shifts.33 Repeat measurements of calcium should be
done routinely to ensure these are not spurious results.
Serum phosphorus should also be measured because
hypercalcemia can be associated with both hyper- and
hypophosphatemia. Once there is confirmation of hyper-
calcemia, then it should be determined whether it is PTH
or non-PTH mediated. Because the most common cause is
excess PTHrP, this should also be measured routinely. PTH
and PTHrP are similar molecules; therefore, both are not
concurrently elevated unless there are multiple etiologies.
Additional laboratory tests include measurement of 25(OH)D
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Table 1. Laboratory Evaluation of Hypercalcemia
Confirm hypercalcemia:
Serum total calcium (recheck if only one measurement)
Serum corrected calcium equation:
0.8 (4.0 2 serum albumin) 1 serum calcium 5 total estimated
calcium
or
Ionized calcium (if total estimated calcium is believed to be unreliable)
Laboratory evaluations after hypercalcemia is established:
Serum phosphorus
Creatinine with estimated GFR
PTH
PTHrP
25(OH)D
1,25(OH)2D
Additional laboratory evaluations to consider if diagnosis is still uncertain:
SPEP, UPEP serum-free light chains, serum and urine IFE
Skeletal survey
Vitamin A levels
Abbreviations: 1,25(OH)2D, 1,25-dihydroxy vitamin D; 25(OH)D, 25-hydroxy
vitamin D; GFR, glomerular filtration rate; IFE, immunofixation; PTH, para-
thyroid hormone; PTHrP, parathyroid hormone–related peptide, SPEP,
serum protein electrophoresis; UPEP, urine protein electrophoresis.
and 1,25(OH)2D to evaluate for excess vitamin D production
or ingestion. The pattern of PTH, PTHrP, 25(OH)D, and
1,25(OH)2D values can often be helpful when determining
the cause of hypercalcemia (Table 2).
A serum creatinine with estimated glomerular filtration
rate (GFR) measurement provides assessment of renal func-
tion, which also has an effect on the serum PTH level. Renal
insufficiency stimulates PTH production because it inhibits
renal 1-a-hydroxylase. If the etiology is not clear with the
above laboratory tests, and the diagnosis of multiple mye-
loma is in question, then serum and urine protein electro-
phoresis or immunofixation along with a skeletal survey is
indicated. Rarely, vitamin A toxicity can result in hypercalcemia;
thus serum vitamin A levels can be a consideration if other
etiologies are not discovered.
If the etiology is clear based on the above work-up, then I do
not routinely perform a 24-hour urine analysis for calcium and
creatinine. However, if the course has been indolent, there is
a family history of hypercalcemia, and the patient does not
have an active cancer that can account for the hypercalcemia,
then a 24-hour urine calcium clearance to creatinine clearance
ratio can be valuable to differentiate between primary hyper-
parathyroidism and familial hypocalciuric hypercalcemia.34 If
the urine calcium clearance to creatinine clearance ratio is low
Copyright © 2016 by American Society of Clinical Oncology
 Hypercalcemia and Malignancy

Table 2. Laboratory Findings for Specific Etiologies of Hypercalcemia Associated With Malignancy
Etiology PTH PTHrP 1,25(OH)2D 25(OH)D Phosphorus

PTHrP mediated Low High Low or normal Any value Low

1,25(OH)2D mediated Low Low High Low or normal Low

PTH mediated High Low High Low or normal Low

Vitamin D intoxication Low Low High High Normal/high

Abbreviations: 1,25(OH)2D, 1,25-dihydroxy vitamin D; 25(OH)D, 25-hydroxy vitamin D; PTH, parathyroid hormone; PTHrP, parathyroid hormone–related
peptide.

(, 0.01), then familial hypocalciuric hypercalcemia should be
suspected, and definitive evaluation can include testing for
mutations in the CASR, AP2S1, or GNA11 gene.35
TREATMENT
Treatment of the underlying malignancy is always the primary
goal of therapy. However, additional therapies, especially for
moderate to severe hypercalcemia, are essential when simulta-
neously treating the underlying malignancy. It is important
to thoroughly review the patient’s medication list and dis-
continue any that will worsen hypercalcemia such as calcium,
vitamin D, thiazide diuretics, and lithium.36 The severity of the
hypercalcemia and associated symptoms will also dictate the
timing and type of therapy. Mild asymptomatic hypercalcemia
(calcium, 10.5-11.9 mg/dL) may not need to be treated until
after the work-up has been completed and a diagnosis has
been established. However, moderate to severe hypercalcemia
(calcium . 12 mg/dL), especially when associated with severe
renal or neurologic symptoms, requires prompt, often inpatient
management.
Essentially all patients with malignancy-associated hyper-
calcemia have increased osteoclastic bone resorption and
increased renal tubular calcium reabsorption.14 Hence, medical
therapy is aimed at inhibiting bone resorption and promoting
renal calcium excretion. Reducing intestinal calcium reab-
sorption is also important in those with increased extrarenal
intravenous (IV) fluids, specifically isotonic saline, is essential as
initial therapy. Patients often require 1 to 2 L as an initial bolus
and then maintenance fluids of 150 to 300 mL/h for the next 2 to
3 days or until they are volume replete.
One should exercise caution and administer smaller vol-
umes of isotonic saline in patients with congestive heart failure
or anuric renal failure, as they can become volume overloaded.
Fluid replacement, however, is first-line therapy for those with
acute renal insufficiency as a result of volume depletion.
Furosemide therapy is often discussed as a means to provide
increased calciuresis.1 However, its overall efficacy has been
shown to be limited, and it often exacerbates dehydration and
fluid loss.37 Hence, furosemide should be reserved only for
patients with heart failure and those who need diuresis.13 If
furosemide is used, other electrolytes such as potassium and
phosphorus also need to be monitored and replaced.
Hypercalcemia
Treatment mechanisms
based on etiology
Increase calciuresis
Reduce PTH
*IV fluids with isotonic
*Calcitonin
saline

1,25(OH)2D production (Fig 1).

Promoting Renal Calcium Excretion

Patients are generally volume depleted, and many can have Reduce bone
Reduce intestinal resorption
concurrent renal insufficiency as a result. Volume depletion is absorption of calcium *IV bisphosphonates
*Glucocorticoids *SC calcitonin
usually attributed to both decreased oral intake and also a *SC denosumab
component of nephrogenic diabetes insipidus induced by the
hypercalcemia. This causes decreased GFR, renal insufficiency, FIG 1. A treatment approach for hypercalcemia of malignancy. *Treatment
and decreasedurinaryclearanceofcalcium1; thus treatment with mechanism. IV, intravenous; PTH, parathyroid hormone; SC, subcutaneous.

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Goldner
Reducing Bone Resorption
Bisphosphonates are first-line therapy and also the mainstay
for long-term therapy. Through direct mechanisms they induce
osteoclast apoptosis, and through indirect mechanisms acting on
the osteoblasts they can reduce osteoclastic bone resorption.
Bisphosphonates affect proliferation and differentiation of
osteoblasts and prevent their apoptosis, and they can also
neutralize the RANKL-mediated stimulation of osteoclasts.14,38
Bisphosphonates should be given within 48 hours of diag-
nosis, because it takes approximately 2 to 4 days for them to have
effect. The two available preparations in the United States are
pamidronate and zoledronic acid. When compared directly,
zoledronic acid was found to be more potent than pamidronate,
but both are considered acceptable therapies.39 The median
response duration was 32 days with zoledronic acid 4 mg
IV and 18 days with pamidronate 90 mg IV. Pamidronate is
given at 60 to 90 mg IV over 4 to 24 hours. Zoledronic acid is
given at 4 mg IV over 15 to 30 minutes.13
Bisphosphonates, unfortunately, have been associated with
nephrotoxicity. This can create a treatment dilemma because
hypercalcemia is also commonly associated with renal insuf-
ficiency.Treatmentshouldbereservedforpatientsforwhomthe
benefit outweighs the risk, and dose reduction should be used.5
In addition to bisphosphonate therapy, adequate hydration can
enhance renal protection and help preserve renal function when
compared with patients who were dehydrated and received
bisphosphonates for hypercalcemia.40
The zoledronic acid package insert recommends that in
hypercalcemia of malignancy, patients with mild to moderate
renal impairment before initiation of therapy (serum creatinine
, 4.5 mg) do not need dose adjustment. However, it is not
recommended in severe renal impairment (serum creatinine
. 4.5 mg/dL). Patients should be adequately hydrated before
administration of zoledronic acid, and a single dose of 4 mg IV
should be given over no less than 15 minutes. Retreatment with
zoledronic acid 4 mg may be considered for persistent
hypercalcemia, but no sooner than 7 days after the initial
therapy. Renal function must be carefully monitored with
serum creatinine before additional doses of zoledronic acid are
given; if renal function has declined, then redosing may not be
appropriate.
Dosingofzoledronicacidformultiplemyelomaandmetastatic
bone lesions recommends dose reduction according to creatinine
clearance: GFR . 60 mL/min, 4 mg; GFR 50 to 60 mL/min,
3.5 mg; GFR 40 to 49 mL/min, 3.3 mg; and GFR 30 to 39 mL/min,
3.0 mg.41 In rare cases, bisphosphonates have been given to
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persons with renal insufficiency and end-stage renal disease
without significant adverse effects, but not routinely.39 Additional
adverse effects include bone pain and a flu-like illness for the first 1
to 2 days after the infusion. Osteonecrosis of the jaw has also been
associated with IV bisphosphonates and is more common in
those receiving high-dose and prolonged therapy and in those
who have undergone dental procedures while on therapy.42
Calcitonin is also used to acutely lower calcium levels.
When used with bisphosphonates, it can lower calcium more
rapidly than either agent alone. Unfortunately, tachyphylaxis
can occur within 48 hours as a result of downregulation of
the calcitonin receptors. However, glucocorticoids can be used to
enhance the effect of calcitonin by upregulating the cell-surface
calcitonin receptors and creating new ones on the osteoclast.43
Calcitonin is usually dosed at 4 to 8 IU/kg subcutaneously every
6 to 12 hours.14 Interestingly, there is a case report of calcitonin
use for 14 days without evidence of tachyphylaxis in a patient with
bisphosphonate-resistant hypercalcemia of malignancy.44
Glucocorticoids are also given to treat hypercalcemia caused
by excess extrarenal 1,25(OH)2D and multiple myeloma. Ste-
roids inhibit osteoclastic bone resorption by decreasing tumor
production of locally active cytokines, in addition to having
direct tumorolytic effects. Steroids are usually given as hydro-
cortisone 200 to 400 mg/d for 3 to 4 days and then prednisone
10 to 20 mg/day for 7 days,1 or prednisone 40 to 60 mg/d for
10 days.14 If prednisone is not helpful after 10 days, it should be
discontinued.
Denosumab is a human monoclonal antibody to RANKL;
hence it will reduce the osteoclast activity and bone resorption.
Recent studies have shown that denosumab was more efficacious
than zoledronic acid in delaying or preventing hypercalcemia of
malignancy in patients with advanced cancer including breast
cancer, other solid tumors, and multiple myeloma.45 It is also
effective in hypercalcemia refractory to bisphosphonates.46
Denosumab was given to patients with serum calcium
. 12.5 mg/dL and who had received bisphosphonates
for . 7 days and , 30 days before. Denosumab was dosed
as 120 mg subcutaneously on days 1, 8, 15, and 29 and
every 4 weeks thereafter; it lowered serum calcium in 64%
of patients within 10 days.47 Denosumab is not renally cleared,
but the effect may be more pronounced in patients with renal
failure; therefore, dose reduction is recommended to avoid
hypocalcemia.13 Lower-dose, less-frequent administration of
denosumab in patients with hypercalcemia and renal dysfunc-
tion is associated with less hypocalcemia. One recommendation
is for 60 mg subcutaneously once or for a single weight-based
Copyright © 2016 by American Society of Clinical Oncology

dose of 0.3 mg/kg followed by redosing in 1 week if the patient is
persistently hypercalcemic.48
Cinacalcet reduces PTH production and is approved for use
in secondary hyperparathyroidism and refractory parathyroid
carcinoma. It has not been extensively studied in hypercalcemia
ofmalignancy. Theonly malignancy ithasbeen approvedfor use
in is parathyroid carcinoma.28 Dialysis or continuous renal
replacement therapy is usually reserved for hypercalcemia
refractory to all of the above therapies.46,49
Although there are published recommendations for treat-
ment, these algorithms are not always routinely followed. Wright
et al4 found that either pamidronate or zoledronic acid was
administered only to 54.2% of patients with hypercalcemia
of malignancy within 48 hours of diagnosis and to 67.8% of
patients overall. Calcitonin was administered to 27.4% of
patients, and glucocorticoids were given to 26.9% of patients.
Contraindicated medications were continued for 2.8% of
patients, and bisphosphonates were given to 72.2% of those
with acute renal failure. This demonstrates that despite
published recommendations, the care for hypercalcemia is
highly variable and not uniformly evidence based.
CONCLUSION
It is important to understand the pathogenesis, work-up, and
treatment options for hypercalcemia associated with malignancy
so that timely intervention can occur. Therapy focuses on
methods to reduce serum calcium through increased cal-
ciuresis, decreased bone resorption, and reduced intestinal
absorption of calcium. The mainstays of therapy are IV hydra-
tion, bisphosphonates, and calcitonin. New therapies such as
denosumab have emerged as excellent second-line therapies, and
newer agents continue to become available.
Author’s Disclosures of Potential Conflicts of Interest
Disclosures provided by the author are available with this article at
jop.ascopubs.org.
Corresponding author: Whitney Goldner, MD, Division of Diabetes,
Endocrinology, and Metabolism, Department of Internal Medicine,
984120 Nebraska Medical Center, Omaha, NE 68198-4120;
e-mail: wgoldner@unmc.edu.
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 Hypercalcemia and Malignancy

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Cancer-Related Hypercalcemia

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For
more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml.

Whitney Goldner
Leadership: DaVita (I)
Consulting or Advisory Role: Bayer
Research Funding: Eisai, AstraZeneca

Copyright © 2016 by American Society of Clinical Oncology Volume 12 / Issue 5 / May 2016 n jop.ascopubs.org
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.