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Painful Osteoblastic Metastases: The Role of Nuclear Medicine

Painful Osteoblastic Metastases: The Role of Nuclear Medicine

ABSTRACT: Although bone pain from osteoblastic metastases can be ameliorated 50% to 80% of the time by use of intravenously or orally administered radiopharmaceuticals, we cannot accurately predict who will or will not respond. The radiopharmaceuticals containing phosphorus-32, strontium-89 (Metastron), rhenium-186, samarium-153 lexidronam (Quadramet), and tin-117m are effective, but we do not know which of these is the most efficacious or the safest. Toxicity includes mild-to-moderate pancytopenia and an occasional brief flare of pain, and treatment of patients with disseminated intravascular coagulation must be avoided because it may predispose the patient to severe thrombocytopenia. Treatment may be repeated at approximately 8- to 12-week intervals, depending on the time of return to normal leukocytes and platelet counts. Tumoricidal effects are probably not the sole mechanism of pain relief. [ONCOLOGY 15(2):157-174, 2001]

Introduction

With an incidence of more than
1 million cases per year, approximately one in three US citizens will receive a diagnosis of cancer in his
or her lifetime. Between 125,000 and 150,000 cases of osseous metastases are
detected each year,[1-3] and approximately two-thirds of these require some form
of analgesia. A significant proportion of patients with bone metastases will
have their performance level reduced both by the pain and the side effects of
the analgesics required (especially opiates) to treat the pain. Lethargy and
constipation are particularly troublesome symptoms associated with opiate use.

The overall goal of therapy for patients with bone metastases is
to improve their quality of life, not only by reducing pain but, if possible, by
reducing narcotic use and, in turn, increasing functional status. Ideal pain
therapy would also prevent the development of painful new metastases, reduce
tumor progression, and even prolong patient survival. Data on the
radiopharmaceuticals used to treat the pain of osteoblastic metastases suggest
that all of these goals, except the last, have been realized.

A single focal bone metastasis should be treated with
teletherapy (ie, external-beam radiation therapy),[1] but in this review there
is insufficient space to deal with this approach to pain control. Wide-field
(hemibody) radiation therapy has also been employed for the treatment of
multiple bone metastases, but in the United States today, this modality is
seldom used, despite its unquestionable efficacy.[2] The incidence of adverse
reactions has virtually eliminated wide-field teletherapy.[3]

Radiopharmaceutical
Treatment of Painful
Osteoblastic Metastases

An ideal radiopharmaceutical agent for bone pain would
selectively localize only in a painful osseous site, and the beta or electron
emission would be of sufficient energy, and hence range, to reach all of the
tumor. Ideally, with such selective localization, there would be no adverse
effect on tissues within the bone, particularly bone marrow. The half-life of
any radiopharmaceutical employed should be long enough to allow for cytocidal
doses of radiation to be delivered. The dose or activity of the radiation should
ideally be low enough so as not to require hospitalization under current Nuclear
Regulatory Commission Regulations, since this adds considerably to the cost of
the treatment.

The beta/electron-emitting radiopharmaceuticals that have
demonstrated an effect on painful osteoblastic metastases appear in Table 1. The
emitters in general are found among neutron-rich radionuclides, and therefore,
their production requires a nuclear reactor.

An examination of the physical properties of the
radiopharmaceuticals appearing in Table 1 indicates that, beyond their emission
of a beta particle or electron, they vary in many ways. For example, tin
(Sn)-117m diethylenetriamine-pentaacetic acid (DTPA) has a particle range in
tissue of only 0.2 to 0.3 mm, whereas the mean range of the rhenium (Re)-188
beta particle is 10 times greater—3.1 mm. Similarly, the half-lives of these
agents have a great range, from 0.7 days for Re-188 to 50.5 days for strontium
(Sr)-89 (Metastron). Yet, all of these radiopharmaceuticals are safe and
effective for the treatment of osteoblastic metastases.

Dose-Response Relationships

A dose from a radiopharmaceutical indicates the amount of energy
deposited per gram of tissue, and for electrons and gamma rays this may be
measured in rads or Grays; the dosage is the administered activity (measured in
millicuries or becquerels) actually injected into or ingested by the patient.
Beta emitters give different readings depending on whether a glass vial or
plastic syringe is put in the dose calibrator, and if unrecognized, this can be
a source of significant error in measuring how much activity the patient
receives.

Definitive statements about dose-response relationships in the
use of these radiopharmaceuticals are fraught with difficulties. Calculating the
radiation dose received by metastatic tumor and the osteoblastic bone around it
is a daunting exercise. The distribution of tumor (and marrow) is nonuniform
within the involved bone. Osteoblastic reaction to bone varies from very little
(as in cases with few trabecular spicules to attenuate or intercept emitted beta
particles) to marked (as in prostatic carcinoma, which may involve cortical and
trabecular proliferations that thicken bone and significantly attenuate
emissions).[4]

The metallic chelated radiotracers appearing in Table 1 tend to
chemically absorb to trabecular surface, whereas phosphorus (P)-32 phosphate and
Sr-89 (as the chloride) distribute more widely throughout bone, so that the
sources of radiation within bone differ with the radiopharmaceutical used. Thus,
with such marked heterogeneity of reactive bone radiopharmaceutical uptake,
spicule thickening, and tumor and marrow distribution, patient dosimetry will
vary depending on the assumptions made, although there is usually agreement
within about 50%.[5,6]

Even more difficult, however, is the assessment of response to
the radiopharmaceutical when pain reduction is the end point. Early publications
in this area relied solely on patient reports that the pain had improved. More
recently, changes in mobility and activity levels have been used, assessed by
both the Karnofsky and Eastern Cooperative Oncology Group semiquantitative
scales, which relate to the severity of symptoms, degree of ambulation,
requirement for bed rest, degree of self-administered care, and so forth.[5]
These are reasonably objective and reproducible assessments. However, if a
patient is spending more than 50% of his or her time in bed, this will cause a
difference in activity scores and is difficult to document. Thus,
semiquantitative scales such as activities of daily living, while valuable, have
limitations.

Indicators of the Degree of Pain

The measurement of pain itself is also quite difficult. One of
the better instruments is the visual analog scale, in which a 10-cm line,
preferably vertical, with no numerical values on it, is presented to the
patient. The bottom of the line represents no pain, and the top of the line
represents the worst imaginable pain. The patient is asked to place a pencil
mark on the line corresponding to the degree of perceived pain. This has a
fairly high degree of reproducibility, and changes greater than 20% in the
location of the mark usually have clinical significance.

Diaries noting hours of sleep provide some assistance in
evaluating the degree of pain, but depression and agitation will also alter
sleeping patterns. The Radiation Therapy Oncology Group[1] measures the severity
of the pain by noting the type and frequency of opiate use.

An important technique for integrating both the degree of pain,
medication use, and activities of daily living has come from the University of
Utrecht in the Netherlands which in essence provides a grid allowing for nine
combinations of changes in activities of daily living (ADL) and the medication
dose for achieving a given degree of pain relief (ie, an increase, no change, or
decreased ADL on medication).[7] Thus, if the patient reports a 50% decrease in
pain, but there is any increase in medication use or any decrease in scores from
the scales measuring activities of daily living, this would not indicate a
response to the administered radiopharmaceutical.

Similarly, if a patient has less pain while in bed than when
upright, then bedrest would reduce the pain but
would be reflected by a decrease in activities of daily living, regardless of
the narcotic dose. This would not be considered a pain response to the
radiopharmaceutical.

Radiopharmaceuticals Efficacious in Pain Reduction
for Osteoblastic Metastases

Phosphorus-32

Sodium phosphate as P-32 was one of the first
radiopharmaceuticals used to reduce pain from bone metastases[8] and was the
most widely used radiotracer from the 1940s until the 1980s.[9] Whether injected
or given orally, P-32 sodium phosphate has a physical half-life of 14.3 days
with a mean beta range in soft tissue of 3.0 mm. It has been commercially
available in the United States for many years, providing considerable experience
in pain reduction. Grade 4 leukopenia (leukocyte count < 1.0 ´
109/L)
and thrombocytopenia (platelet count < 25.0 ´ 109/L) are quite rare,
although there is widespread concern in textbooks (but not in the
patient-related peer-reviewed literature) about the use of this
radiopharmaceutical, probably because P-32 has been employed for many years to
treat myeloproliferative disorders.

There is no question that P-32, as sodium phosphate, causes a
significantly greater reduction in colony-forming units in the marrow of mice
who receive it than do other radiotracers, such as Sr-89, which localizes in
bone but not marrow. Phosphorus-32 does appear in a variety of structural
proteins and in all nucleotides, as well as in the widely distributed phosphate
derivatives such as adenosine triphosphate and creatine phosphate to produce
high-energy phosphate bonds. However, the largest proportion of the injected
phosphate becomes incorporated into the hydroxyapatite molecule (ie, the bone
mineral produced in excess in the presence of most osseous metastases).

This radiopharmaceutical is considerably less expensive than the
other available beta/electron emitters discussed in this article and has also
been used orally to achieve pain relief.[9] Oral administration reduces the cost
to an even greater degree, because the material does not have to be supplied in
a sterile or pyrogen-free state.

A misinterpreted abstract from 1950 led to the use of androgens
with P-32 phosphate in prostate and breast carcinomas, and for the next 30
years, this combination was frequently administered, even though exogenous
androgen caused a number of side effects and stimulated prostate cancer to grow
more rapidly.[8] Nevertheless, the reported response rate was about 82%;
parathyroid hormone and/or androgen (or neither) have been employed with P-32
phosphate, with an overall response rate of 75% to 80%. There is no obvious
dose-response relationship when one plots the increasing activity of P-32
against response rates.[9]

Strontium-89

Strontium-89 (prepared as the chloride) is in family II-A of the
periodic table, and is not well distinguished from calcium (also in this family)
by the tissues of the body.[10] Most Sr-89 uptake is in bone, where it appears
to be deposited throughout the osteoblastic tissue.

This material is commercially available, having received US Food
and Drug Administration (FDA) approval several years ago. Numerous studies
employing Sr-89 have been conducted over the past 3 decades, and data have been
acquired for this agent that are as yet unavailable for newer
radiopharmaceuticals, for example, concerning concurrently administered
chemotherapy[11] and efficacy in delaying the onset of new painful
metastases.[12]

About 80% of Sr-89 is excreted through the kidneys and about
20%, through the gastrointestinal system.[10] Its biological half-life is 4 to 5
days. There is evidence of biexponential excretion, such that 20% remains in the
body after 90 days. "Woven" bone around osteoblastic metastases
selectively retains Sr-89 relative to normal osteoblastic tissue.[10]

Strontium-89 therapy data do not indicate an increasing response
rate with increasing dosage, except in one investigation that oddly demonstrated
such a relationship for complete, but not partial, responses. The range of
response to Sr-89 has varied between about 60% and 80%.[6,12-14] Several papers
have compared the response to Sr-89 with that to hemibody radiation or local
teletherapy and have found no significant differences.[14]

In at least two important studies, Sr-89 has been found to
prolong the time to onset of new painful sites of bone metastases.[12,14] As of
this writing, this finding has not been reported for any other
radiopharmaceutical. Only a few controlled studies have evaluated the
beta/electron-emitter radiopharmaceuticals vs a placebo, but several such
studies of Sr-89 have indicated a two to three times greater response to Sr-89
(at a dose of 4 mCi) than to placebo.[15]

Using a 10.8-mCi dose of Sr-89 (which is more than twice the
4-mCi activity administered in the United States), no survival advantage has
been demonstrated for Sr-89. In fact, survival in the group receiving Sr-89 was
slightly less than in the control arm, with a P value of .06.[12] This lack of a
survival advantage has been confirmed.[16]

There are conflicting data as to whether patients with a
Karnofsky performance score greater than 60 achieve a higher response rate with
Sr-89.[16,17] At least one study indicated that this is a predictive factor for
response,[17] although it was not reproduced in another study.[6]

There have been excellent studies of the economic benefits of
Sr-89. For example, use of Sr-89 reduced the lifetime health-care costs by
decreasing both the need for radiotherapy and the need for narcotics and
hospitalization.[18,19] There are also ongoing studies of Sr-89 in combination
with a variety of chemotherapeutic agents, including estramustine (Emcyt),
mitoxantrone (Novantrone), paclitaxel (Taxol), carboplatin (Paraplatin),
cisplatin (Platinol), and doxorubicin (Adriamycin). Only a few of these have
been controlled, however,[11] and the response rates (complete plus partial
response) have ranged from 55% to 80%—a range also seen in multiple
investigations that did not include chemotherapeutic agents.[16]

Strontium-89 vs Phosphorus-32

Although both of these radiotracers have been used for many
years in the treatment of bone pain from osteoblastic metastases, a blinded
comparison of Sr-89 and P-32 was completed only recently.[20] The other variable
in this study was that the P-32 phosphate was given orally rather than
intravenously, because the sponsor, the International Atomic Energy Agency, was
concerned with therapy in developing countries and was interested in finding out
whether the less expensive oral phosphate would approach the efficacy of Sr-89.

The 31 patients studied were comparable in bone scan index
(degree of bone involvement) and in pretherapy mean pain score, although the
patients receiving P-32 were slightly younger. The methods of evaluating
response rate appeared to be reasonably objective. Partial pain relief occurred
in 7 of 15 patients receiving Sr-89 and 7 of 16 receiving P-32, with a complete
response in 7 of 15 in the Sr-89 group and 7 of 16 in the P-32 group, for a
total response rate of over 90% in both groups. There was no significant
difference in the time to onset of response, time to maximum relief, or duration
of response.

As noted previously, hematologic toxicity has been a concern
with the use of P-32, but only mild toxicity was seen in this study: grade 2 for
leukocytes in 2 of 16 P-32 patients (leukocyte count: 2.0-2.9 ´
109/µL), but
no similar toxicity for those receiving Sr-89; and grade 2 for platelets in 6 of
16 P-32 patients (platelet count: 50.0-74.9 ´ 109/µL), but none in those
receiving Sr-89. There were no clinical sequelae. No grade 3/4 toxicity was seen
with either radiotracer.[20]

Samarium-153

Samarium (Sm)-153 lexidronam (Quadramet) was approved by the FDA
in 1997. Samarium-153 is chelated to ethylenediamine tetramethylenephosphonate
(EDTMP). The chelate prevents the formation in vivo of an insoluble samarium
oxide.[21] The phosphonate chelate has a strong affinity for hydroxyapatite,
analogous to the bone scintigraphic agents methylene diphosphonate and
hydroxymethylene diphosphonate. Some of this radiopharmaceutical appears to
chemically absorb to bone, but there is also evidence of transmetallation of
Sm-153 to the surface of hydroxyapatite through a hydrolysis reaction, with the
resultant samarium oxide attached to oxygen atoms on molecules of hydroxyapatite
and water. The physical half-life of Sm-153 is 1.9 days, and the energy of its
beta is less than that of Sr-89, so that the mean range in tissue is 0.6 mm (Table
1
).

There has been more than a decade of experience with this
radiopharmaceutical in pain reduction, and a significant number of publications
show its efficacy.[22-25] There is anecdotal evidence that marrow recovery may
be slightly faster with Sm-153 lexidronam than with Sr-89, but no blinded
comparative study has been performed. No data are yet available demonstrating
that Sm-153 lexidronam delays time to onset of new sites of painful metastases,
but this is under active study.

No statistically significant dose-response relationship has been
found for this agent,[24] although in one study the response to Sm-153, 1
mCi/kg, occurred 1 week earlier than that to 0.5 mCi/kg.[22] Response
duration averages about 6 weeks.[23] Samarium-153 lexidronam therapy may be
repeated multiple times after blood counts return to normal, as can therapy with
Sr-89.

Rhenium-186 Etidronate

Research on Re-186 etidronate, a rhenium chelate, has been
ongoing for two decades.[26] Unlike Sm-153 (chelated by lexidronam), Re-186
reoxidizes (to the perrhenate) relatively easily even when chelated,[27] so that
some Re-186 can be found in the urine for several days after administration. (In
contrast, no Sm-153 lexidronam leaches from bone after 6 hours.[28])

Rhenium-186 etidronate has been approved for the therapy of bone
pain in Europe but not in the United States. The three-dimensional Utrecht pain
response scale was developed employing rhenium-186 etidronate.[7] Response rates
in the range of 55% to 80% have been documented by several investigators,[29,30]
and the mean duration of response is 4 to 6 weeks.[29] Multiple administrations
of Re-186 etidronate have been shown to be efficacious when spaced about 12
weeks apart after blood counts return to normal.[31] The degree of
myelosuppression associated with Re-186 is approximately the same as for the
other radiopharmaceuticals described above.[32,33]

With all of the radiotracers discussed in this article, a
relatively small percentage of patients experience an increase in pain (flare
reaction), usually within 10 days of administration and before a response
begins. With Re-186 etidronate, the prevalence of the flare phenomenon has been
described as ranging from 5% (in our group)[29] to as high as 63%. The
definition of flare, and the techniques employed for measurement of pain,
presumably explain some of this wide variation.

Tin-117m Pentetate

Tin-117m is unique as a radioisotope used to relieve bone pain
because it emits conversion electrons rather than a beta particle. As with the
other radioisotopes discussed, Sn-117m is produced in a nuclear reactor.[34] The
emitted electrons have a very short range in soft tissue (Table 1), and this is
probably the reason that myelosuppression appears to be less severe with Sn-117m
pentetate.[35]

Tin-117m is injected as the pentetate (DTPA) chelate in order to
prevent colloid formation. Pentetate has no affinity for hydroxyapatite,
however. Therefore, the mechanism of localization is believed to be solely the
stannous oxide precipitating on bone surfaces, when the rapidly diffusing
chelate brings that radioisotope from the blood pool compartment close enough to
hydroxyapatite for a hydrolysis reaction to occur.[34,35] The rate of response
(complete plus partial) to Sn-117m is approximately 75%. There is no evidence of
an increasing response with increasing dosage, although with doses in excess of
12 mCi per 70 kg body weight, the time from injection until response shortens on
average from about 2 weeks to less than 1 week.[35]

Bisphosphonates

Phosphonates have been documented to inhibit bone resorption
through chemical absorption to hydroxyapatite, perhaps directly blocking
dissolution of this calcium phosphate bone salt. There are also data indicating
that bisphosphonates inhibit osteoclast activity in resorbing bone. A parenteral
bisphosphonate, pamidronate (Aredia), has been approved by the FDA for treatment
of painful osteolytic bone metastases in breast cancer and multiple myeloma. The
rationale for using oral bisphosphonates in these conditions is less clear-cut
because absorption is quite low, and at least one bisphosphonate has been
associated with a significant number of esophageal adverse reactions.

Pamidronate has been shown in blinded, placebo-controlled trials
to reduce the occurrence of bone pain and pathologic fracture, as well as the
need for radiation therapy or surgery for spinal cord compression in patients
with osteolytic metastases from both breast cancer[36] and myeloma.[37] Survival
was not extended. Pamidronate has not been approved by the FDA for other kinds
of painful osseous metastatic disease, but there are a few published reports
suggesting that it may also be of value in carcinoma of the prostate.

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