Radiopharmaceutical and chemotherapy combinations in metastatic castrate-resistant prostate cancer: a new beginning?

Two manuscripts in this issue of Journal of Clinical Oncology are focused on patients with bone-metastatic castrate-resistant prostate cancer (CRPC) treated with a combination of docetaxel and samarium-ethylenediaminetetramethylenephosphonic acid (Sm-EDTMP). These data are significant from a variety of perspectives, not only because they involve novel combinations of therapy, but also because they potentially lay a foundation for new approaches to treat this common and too often fatal disease. The propensity for prostate cancer to metastasize to bone is well delineated, though debate continues on why this is so. Two recent trials indicate that 84% to 92% of patients with metastatic CRPC have radiographic evidence of bone metastases. By contrast, measureable soft tissue disease (mostly nodal) was present in 39% to 44% of patients. Given the bone-tropic nature of prostate cancer metastases, and the number of men affected by this disease each year, a variety of bone-targeted agents are currently under development. The first bone-targeted agents to gain US Food and Drug Administration approval in the United States for treatment of prostate cancer were two bone-seeking beta particle-emitting radiopharmaceuticals. One of these agents (Strontium [Sr]), is a calcium homolog with a long half-life (50.5 days) and relatively high-energy average beta emission (0.58 MeV). The other is Sm-EDTMP, which binds to the hydroxyapetite crystals in blastic bone lesions and emits a low-energy beta (0.22 MeV) with a relatively short half-life (46 hours). The physical half-life of the isotopes in part determines their toxicity profile. The longer half-life of Sr translates into less reversible myelosuppression than Sm-EDTMP (which is the only notable toxicity encountered with these agents). These agents are approved for the palliative treatment of advanced prostate cancer but have had a relatively limited use. The reasons for limited use are multifactorial. Palliative agents (other than analgesics) have had relatively limited acceptance in the broad oncologic community. Systemic radiopharmaceuticals, even those quite effective in controlling cancer progression, have not been widely adopted by oncologists because of a variety of market forces. Additionally, despite some evidence to the contrary, concerns that systemic radio-isotopes may interfere with subsequent chemotherapy dosing has potentially limited use of these agents. The mechanism of action whereby bone-seeking radiopharmaceuticals exert favorable effects is currently debated. Sr and Sm-EDTMP both target the bone stroma and, as such, may be viewed as part of a new class of oncotherapies termed stromal-targeted therapies. Of note, antiangiogenic agents such as bevacizumab and thalidomide also target stromal rather than cancerous elements. Stromal-targeted agents have the advantage of targeting a relatively homogeneous stroma as compared with genetically heterogeneous cancer cells. Though direct tumoricidal effects are clearly plausible for the bone-targeted radiopharmaceuticals, effects on tumor stromal cells may be equally important. Given the vicious cycle that is hypothesized to occur between epithelial tumors and bone stroma, any effect on one cellular compartment may reverberate in another. For bone-metastatic CRPC, combinations of bone-seeking radiopharmaceuticals and chemotherapy have engendered considerable prior interest. Synergy between these two classes of agents was initially suggested in a small randomized phase II trial published by Tu et al in 2001. This trial used an innovative design in which all patients with bone-predominant metastatic disease were treated with a multi-agent chemotherapy before random assignment between Sr and doxorubicin or doxorubicin alone. Patients intolerant of, or having progression after, two to three cycles of the initial chemotherapy were randomly assigned. This design had the benefit of excluding patients with a poor prognosis, thereby enriching the randomly assigned population in patients more likely to benefit from therapy. The results were impressive in patients treated with combined-modality therapy. Overall survival was nearly 11 months longer (27.7 months) in the Sr plus doxorubicin arm as compared with the doxorubicin-alone arm (16.8 months). By comparison, the enrolled but non–randomly assigned patients (nearly one third of patients in this trial) had an 11.1 month survival, suggesting that rapid progression or intolerance of the multi-agent chemotherapy was a poor prognostic marker. Despite the initial promise of the combining a relatively noneffective chemotherapy (doxorubicin) with an US Food and Drug Administration–approved bone-seeking isotope (Sr), these results have neither been replicated nor expanded to date. The current reports by Morris et al and Fizazi et al provide another attempt to move these concepts forward. The designs of these studies are distinct. The Morris et al study makes the assumption that the docetaxel at 75 mg/m every 3 weeks is the standard of care for patients with bonemetastatic CRPC and attempts to improve on that regimen by adding dose escalated Sm-EDTMP in a repetitive fashion. Repetitive doses of this short–half-life isotope have previously been demonstrated to be well tolerated, but studies in combination with docetaxel at this JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 15 MAY 2