Painful Osteoblastic Metastases: The Role of Nuclear Medicine

In this timely article, Dr. Silbersteinsuccinctly and effectively describesthe role of several important unsealed radionuclides in the treatment ofpatients with painful osteoblastic metastases. However, in spite of much currentdata that describe the use of unsealed sources in the treatment of metastaticdisease, there remains much controversy. In general, the notion that unsealedsources belong within the armamentarium of cancer-fighting therapies has notgained the acceptance that we would have expected. Why is this the case?

Growing Literature onUnsealed-Source Therapy

Perhaps some of the reasons underlying this apparentcontradiction are suggested in Silberstein’s article, "PainfulOsteoblastic Metastases: The Role of Nuclear Medicine." Although nuclearmedicine physicians have pioneered many cutting-edge therapies, such asiodine-131 in the treatment of thyroid cancer, the therapeutic aspects of thisspecialty are generally not as well recognized in mainstream medical andradiation oncology. Thus, much of the literature associated with the treatmentof osteoblastic metastases using unsealed-source therapy is not as well known.

However, if we review the literature now available on the use ofunsealed-source therapy in the treatment of osteoblastic metastases, beginningwith the early work of phosphorus-32 to the more exotic isotopes, such asrhenium-186, samarium-153 lexidronam (Quadramet), strontium (Sr)-89 (Metastron),and tin-117m, several factors are clearly valid.

Current published data on several thousand patients havedemonstrated that the use of unsealed sources in the palliative setting canreduce bone pain, with complete and partial response rates between 30% and 90%,and complete response rates between 10% and 30%.[1] From the literature, it doesnot appear that the palliative responses are associated with any particularisotope. This may, of course, be due to the underlying inhomogeneity of thecases treated in this clinical scenario.

Although much of the older literature did not adequately orobjectively measure pain or quality of life, more recent studies have confirmedthe validity of earlier results. It is widely accepted that the major sideeffects associated with all bone-seeking isotopes are hematologic. While it hasbeen suggested that dose dependence is important both in terms of toxicity andefficacy, the wide variability of the studied patient population makes thisobservation difficult to consistently reproduce.

If unsealed-source therapy is to continue to be important inpain palliation, then the parameters of time to response and duration ofresponse become very important. To be fully accepted and integrated, these newtreatments must demonstrate superiority over the best standard analgesicpractice. While we have some evidence that this may in fact be the case, thereis still much skepticism about whether unsealed-source therapy will offerimproved palliation over the best use of analgesia, combined, as necessary, withlocal-field radiation therapy.

Future Areas of Study

Probably the most exciting area in the evolution of the use ofunsealed-source therapy will be in the prepalliative arena. The trans-Canadarandomized study demonstrated an adjuvant effect of Sr-89 when applied tolocal-field radiotherapy.[2] In other words, time to development of painfulprogression from osteoblastic lesions was significantly prolonged in the groupof patients who received Sr-89 in addition to local radiotherapy. These resultswere replicated in the UK Metastron trial that compared local radiation toSr-89, as well as Sr-89 to half-body radiation.[3]

These findings may give us clues to a useful therapeuticapproach in patients who are currently without other clearly defined treatmentoptions—eg, patients with hormone-refractory metastatic prostate cancer whopresent with a painful bony lesion that requires local-field radiotherapy. Wouldthe addition of an unsealed radioactive isotope at the completion of therapyprovide a longer symptom-free interval in this patient, who would usuallyprogress with other painful sites? It is important that we conduct studies thatwill evaluate this concept of adjuvant unsealed-source therapy.

A further area that requires study is the augmentation of theeffect of unsealed therapy by either sensitization of effect or protection fromtoxicity. It is well recognized that the main side effects of most unsealedtherapies relate to hematologic toxicity, and that many oncologists areconcerned with the use of isotopic radiotherapy in terms of its effects on thebone marrow, and thus its potential for compromising delivery of further therapy(usually chemotherapy).

However, by combining isotopes with certain chemotherapy agents,it may be possible to improve the therapeutic ratio. For example, early studiesusing Sr-89 and cisplatin (Platinol) demonstrate that it is possible to augmentthe effect of the radiopharmaceutical theoretically by reducing the repair ofsublethal damage caused by Sr-89, by using cisplatin. In other words, cisplatinreduces the cells’ ability to repair the sublethal damage caused by radiation,thus augmenting and potentiating the effect of strontium. At the same time, itwould be possible to exploit the nonadditive toxicities of cisplatin(nephrotoxic) and Sr-89 (hematotoxic).

Conclusions

Multimodality work using isotopes may not only improve theefficacy of isotope therapy, but also push them into mainstream oncologypractice. Much exploration still needs to be carried out on the use of isotopesin oncology, and we still need to adequately work out the many variables relatedto tumor type, dosimetry, and multimodality therapy.

Where exactly within the disease spectrum will isotopes findtheir ultimate place? This remains uncertain. While isotopes have generallyexisted within the purview of the specialty of nuclear medicine, to gain fullacceptance, their use must gravitate toward the purview of the oncologist,radiation oncologist, and nuclear physician as a team.

References:

1. Mertens WC, Filipczak LA, Ben-Josef E, et al: Systemicbone-seeking radionuclides for palliation of painful osseous metastases: Currentconcepts. CA Cancer J Clin 48(6):361-374, 1998.

2. Porter AT, McEwan AJB, Powe JE, et al: Results of arandomized phase III trial to evaluate the efficacy of strontium-89 adjuvant tolocal field external beam irradiation in the management of endocrine resistantmetastatic prostate cancer. Int J Radiat Oncol Biol Phys 25:805-813, 1993.

3. Bolger JJ, Dearnaley DP, Kirk D, et al: Strontium-89(Metastron) versus external beam radiotherapy in patients with painful bonemetastases secondary to prostatic cancer: Preliminary report of a multicentertrial. UK Metastron Investigators Group. Semin Oncol 20(suppl 2)32-33, 1993.