Painful Osteoblastic Metastases: The Role of Nuclear Medicine

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(Drug information on 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(Drug information on 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(Drug information on estramustine) (Emcyt), mitoxantrone(Drug information on mitoxantrone) (Novantrone), paclitaxel(Drug information on paclitaxel) (Taxol), carboplatin(Drug information on carboplatin) (Paraplatin), cisplatin(Drug information on cisplatin) (Platinol), and doxorubicin(Drug information on 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(Drug information on 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(Drug information on calcium phosphate) bone salt. There are also data indicating that bisphosphonates inhibit osteoclast activity in resorbing bone. A parenteral bisphosphonate, pamidronate(Drug information on 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.