Originally published as JCO Early Release 10.1200/JCO.2008.21.4460 on April 13 2009

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Radiopharmaceutical and Chemotherapy Combinations in Metastatic Castrate-Resistant Prostate Cancer: A New Beginning?

Departments of Medicine and Urology, Tulane Medical School, New Orleans, LA

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 (¹⁵³Sm-EDTMP).^1,2 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^3,4 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.^5,6 One of these agents (⁸⁹Strontium [⁸⁹Sr]), 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 ¹⁵³Sm-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 ⁸⁹Sr translates into less reversible myelosuppression than ¹⁵³Sm-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.⁷ 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. ⁸⁹Sr and ¹⁵³Sm-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,⁸ 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 al⁹ 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 ⁸⁹Sr 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 ⁸⁹Sr 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 (⁸⁹Sr), these results have neither been replicated nor expanded to date. The current reports by Morris et al¹ and Fizazi et al² 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/m² every 3 weeks is the standard of care for patients with bone-metastatic CRPC and attempts to improve on that regimen by adding dose escalated ¹⁵³Sm-EDTMP in a repetitive fashion. Repetitive doses of this short–half-life isotope have previously been demonstrated to be well tolerated,⁷ but studies in combination with docetaxel at this dose and schedule had not previously been reported. Surprisingly, full doses (1 mCi/Kg) of ¹⁵³Sm everyu 6 weeks could be relatively safely administered in combination with 75 mg/M² docetaxel; however, in docetaxel-naïve patients, it is not clear that this dosing combination was optimal. Morris et al¹ hypothesized that patients without prior docetaxel exposure may be better treated with a lower isotopic dosing, thereby maximizing exposure to the known effective chemotherapeutic agent. Dose-limiting toxicity was thrombocytopenia, which was difficult to predict based on clinical or laboratory parameters. In a limited number of patients deemed docetaxel-refractory, combinations of ¹⁵³Sm-EDTMP and docetaxel lead to responses using prostate-specific antigen criteria, suggesting synergy between these two distinct agents.

In the manuscript by Fizazi et al,² four cycles of estramustine plus docetaxel every 3 weeks were planned, and stable/responding bone metastatic CRPC patients were then consolidated with a single dose of ¹⁵³Sm-EDTMP in combination with six weekly docetaxel doses at 20 mg/m². A total of 42 patients were enrolled in the trial, and 41 patients were treated with the consolidation regimen (unlike the Tu et al⁹ trial where nearly one third of patients were not consolidated). The toxicity was quite mild—no febrile neutropenia and only two episodes of grade 3 thrombocytopenias were observed after consolidation. The median overall survival was 29 months, an impressive number for this disease state. Clearly, confirmatory studies will be needed to determine if these results are broadly applicable.

Given these two trials, what is needed next? First, efficacy of combined-modality therapy is difficult to ascertain in the absence of randomized trials. Second, it seems unlikely that a dosing regimen other than 75 mg/m² every 3 weeks of docetaxel monotherapy will be accepted by medical oncologists, thus this docetaxel dosing regimen may be the best point to start the next series of trials. Third, the entry criteria and end points for the next trial must be well defined. Is the focus to be on the chemotherapy-naïve population or the taxane-refractory? Trials in both CRPC populations will be needed to fully understand response and progression-free survival rates. The exact regimen used will be subject to debate.

A new bone-seeking alpha particle-emitting radiopharmaceutical is now under development in bone-metastatic CRPC. Intravenous ²²³radium, as a monotherapy, has demonstrated both a survival advantage and low toxicity in a small randomized European phase II trial.¹⁰ A phase III trial is now underway in a variety of (non-US) countries in bone-metastatic CRPC unsuitable for chemotherapy. Because considerable geographic variation exists in defining chemotherapy usage, applicability from this trial to a US population may become an issue in the future. As of yet, no trials combining ²²³radium and docetaxel have been reported to our knowledge (but such trials have been proposed).

Though the studies of Morris et al¹ and Fizazi et al² have set the stage for additional progress, optimizing therapies for bone-metastatic CRPC disease may very well require multiple agents with distinct mechanisms of action. Combinations of stromal-targeted agents, such as a radiopharmaceutical and an anti-angiogenic agent(s), may be ideal to administer in combination with chemotherapy for this disease.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Oliver Sartor, Cytogen (C), Algeta (C), sanofi-aventis (C) Stock Ownership: None Honoraria: Oliver Sartor, Cytogen Research Funding: None Expert Testimony: None Other Remuneration: None

REFERENCES

1. Morris MJ, Pandit-Taskar N, Carrasquillo J, et al: Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer. J Clin Oncol 27:2436–2442, 2009.[Abstract/Free Full Text]

2. Fizazi K, Beuzeboc P, Lumbroso J, et al: Phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol 27:2429–2435, 2009.[Abstract/Free Full Text]

3. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513–1520, 2004.[Abstract/Free Full Text]

4. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512, 2004.[Abstract/Free Full Text]

5. Porter AT, McEwan AJ, 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.[Medline]

6. Sartor O, Reid RH, Hoskin PJ, et al: Samarium-153-lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology 63:940–945, 2004.[CrossRef][Medline]

7. Berenson A. market forces cited in lymphoma drugs' disuse. New York Times. 2007 7 14. http://www.nytimes.com/2007/07/14/health/14lymphoma.html.

8. Sikes RA, Nicholson BE, Koeneman KS, et al: Cellular interactions in the tropism of prostate cancer to bone. Int J Cancer 110:497–503, 2004.[CrossRef][Medline]

9. Tu SM, Millikan RE, Mengistu B, et al: Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: A randomised phase II trial. Lancet 357:336–341, 2001.[CrossRef][Medline]

10. Nilsson S, Franzén L, Parker C, et al: Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: A randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 8:587–594, 2007.[CrossRef][Medline]

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