In this timely article, Dr. Silberstein succinctly and effectively describes the role of several important unsealed radionuclides in the treatment of patients with painful osteoblastic metastases. However, in spite of much current data that describe the use of unsealed sources in the treatment of metastatic disease, there remains much controversy. In general, the notion that unsealed sources belong within the armamentarium of cancer-fighting therapies has not gained the acceptance that we would have expected. Why is this the case?
Growing Literature on Unsealed-Source Therapy
Perhaps some of the reasons underlying this apparent contradiction are suggested in Silberstein’s article, "Painful Osteoblastic Metastases: The Role of Nuclear Medicine." Although nuclear medicine physicians have pioneered many cutting-edge therapies, such as iodine-131 in the treatment of thyroid cancer, the therapeutic aspects of this specialty are generally not as well recognized in mainstream medical and radiation oncology. Thus, much of the literature associated with the treatment of osteoblastic metastases using unsealed-source therapy is not as well known.
However, if we review the literature now available on the use of unsealed-source therapy in the treatment of osteoblastic metastases, beginning with the early work of phosphorus-32 to the more exotic isotopes, such as rhenium-186, samarium-153 lexidronam (Quadramet), strontium (Sr)-89 (Metastron), and tin-117m, several factors are clearly valid.
Current published data on several thousand patients have demonstrated that the use of unsealed sources in the palliative setting can reduce bone pain, with complete and partial response rates between 30% and 90%, and complete response rates between 10% and 30%. From the literature, it does not appear that the palliative responses are associated with any particular isotope. This may, of course, be due to the underlying inhomogeneity of the cases treated in this clinical scenario.
Although much of the older literature did not adequately or objectively measure pain or quality of life, more recent studies have confirmed the validity of earlier results. It is widely accepted that the major side effects associated with all bone-seeking isotopes are hematologic. While it has been suggested that dose dependence is important both in terms of toxicity and efficacy, the wide variability of the studied patient population makes this observation difficult to consistently reproduce.
If unsealed-source therapy is to continue to be important in pain palliation, then the parameters of time to response and duration of response become very important. To be fully accepted and integrated, these new treatments must demonstrate superiority over the best standard analgesic practice. While we have some evidence that this may in fact be the case, there is still much skepticism about whether unsealed-source therapy will offer improved palliation over the best use of analgesia, combined, as necessary, with local-field radiation therapy.
Future Areas of Study
Probably the most exciting area in the evolution of the use of unsealed-source therapy will be in the prepalliative arena. The trans-Canada randomized study demonstrated an adjuvant effect of Sr-89 when applied to local-field radiotherapy. In other words, time to development of painful progression from osteoblastic lesions was significantly prolonged in the group of patients who received Sr-89 in addition to local radiotherapy. These results were replicated in the UK Metastron trial that compared local radiation to Sr-89, as well as Sr-89 to half-body radiation.
These findings may give us clues to a useful therapeutic approach in patients who are currently without other clearly defined treatment optionseg, patients with hormone-refractory metastatic prostate cancer who present with a painful bony lesion that requires local-field radiotherapy. Would the addition of an unsealed radioactive isotope at the completion of therapy provide a longer symptom-free interval in this patient, who would usually progress with other painful sites? It is important that we conduct studies that will evaluate this concept of adjuvant unsealed-source therapy.
A further area that requires study is the augmentation of the effect of unsealed therapy by either sensitization of effect or protection from toxicity. It is well recognized that the main side effects of most unsealed therapies relate to hematologic toxicity, and that many oncologists are concerned with the use of isotopic radiotherapy in terms of its effects on the bone 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 studies using Sr-89 and cisplatin(Drug information on cisplatin) (Platinol) demonstrate that it is possible to augment the effect of the radiopharmaceutical theoretically by reducing the repair of sublethal damage caused by Sr-89, by using cisplatin. In other words, cisplatin reduces the cells’ ability to repair the sublethal damage caused by radiation, thus augmenting and potentiating the effect of strontium. At the same time, it would be possible to exploit the nonadditive toxicities of cisplatin (nephrotoxic) and Sr-89 (hematotoxic).
Multimodality work using isotopes may not only improve the efficacy of isotope therapy, but also push them into mainstream oncology practice. Much exploration still needs to be carried out on the use of isotopes in oncology, and we still need to adequately work out the many variables related to tumor type, dosimetry, and multimodality therapy.
Where exactly within the disease spectrum will isotopes find their ultimate place? This remains uncertain. While isotopes have generally existed within the purview of the specialty of nuclear medicine, to gain full acceptance, their use must gravitate toward the purview of the oncologist, radiation oncologist, and nuclear physician as a team.