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
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
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 (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.
1. Mertens WC, Filipczak LA, Ben-Josef E, et al: Systemic
bone-seeking radionuclides for palliation of painful osseous metastases: Current
concepts. CA Cancer J Clin 48(6):361-374, 1998.
2. Porter AT, McEwan AJB, Powe JE, et al: Results of a
randomized phase III trial to evaluate the efficacy of strontium-89 adjuvant to
local field external beam irradiation in the management of endocrine resistant
metastatic 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 bone
metastases secondary to prostatic cancer: Preliminary report of a multicenter
trial. UK Metastron Investigators Group. Semin Oncol 20(suppl 2)32-33, 1993.