Newer Concepts in the Treatment of Hormone-Refractory Prostate Cancer with Bone Metastases: Combinations of Bone-Seeking Radiopharmaceuticals and Chemotherapy
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PCRI Insights May 2005 vol. 8, no. 2
By Oliver Sartor, MD Chief, Hematology-Oncology Section; Director, Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA

PAIN FROM BONE METASTASIS IS ONE OF THE MOST DIFFICULT CLINICAL PROBLEMS IN PATIENTS WITH HORMONE-REFRACTORY PROSTATE CANCER (HRPC). Radiographic evidence of distant metastatic spread to bone occurs in the vast majority of cases of late stage disease, and in most patients these lesions are osteoblastic (bone-forming) in nature.

The most reliable method of detecting bone metastases in a prostate cancer patient is a conventional bone scan. However, even in a patient with prostate cancer, not all areas of enhanced uptake on bone scan are associated with metastatic disease, particularly in the case of solitary lesions or uptake in joints. Confirmation of metastases by additional imaging modalities such as plain radiographs or MRI scans may be needed prior to making a clear diagnosis. Bone metastases may or may not be associated with painful symptoms when initially detected.1

Conventional bone scan (99mTc-MDP) versus 153Sm-EDTMP
Conventional bone scan (99mTc-MDP) versus 153Sm-EDTMP demonstrating identical uptake. 153Sm-EDTMP emits an imageable 103 keV gamma photon that can be viewed up to 3-5 days after the initial injection by either planar or single photon emission computed tomography (SPECT). Uptake and distribution of 153Sm-EDTMP are similar to those of 99mTc-MDP used in bone scans. Comparison of the two images produced by gamma radiation emitted by gamma radiation emitted from 153Sm-EDTMP and 99mTc-MDP in the same patient illustrates how similar the radiographs produced by 153Sm-EDTMP are. Thus, 153Sm-EDTMP may also be used for diagnostic imaging.   Images courtesy of Todd Hoover.

In patients initially diagnosed with bone metastases and then subsequently treated with hormonal therapy, Newling and colleagues have determined that increases in serum PSA occur approximately six months prior to changes in bone scan which in turn occur approximately four months prior to patient reports of pain.2 The timing of this sequence of events in patients treated with hormonal therapy before the onset of bone metastases (most patients today) has not been well studied, but the interval between PSA rise and the onset of a positive bone scan is suspected to be much longer (more than two years on average).

Even in patients with a positive bone scan who report painful symptoms, a comprehensive examination may be needed to establish the cause of the pain and evaluate any possible complicating factors such as spinal cord compression, neuropathic conditions, and pathologic fractures. Patients with bone metastases may also have non-malignant sources of bone pain, and the causes of such pain need to be evaluated on a case by case basis. It is not uncommon for arthritis or other benign problems to cause pain in a patient with cancer.

Therapies for Hormone Refractory Prostate CancerA number of therapies for advanced prostate cancer are available, including secondary hormonal manipulations, external beam radiation, bone-seeking radiopharmaceuticals, and systemic chemotherapy (see Table 1). External beam radiation provides excellent palliation for focal painful lesions, but in patients with systemic disease, repeated courses are typically required for effective treatment.

The approach to decreasing the intensity of pain from bone metastases varies depending on a number of factors including degree of symptoms, extent of disease and prior treatments. Analgesics, anti-tumor agents, hormones, chemotherapy, steroids, local surgery, bisphosphonates, anesthesia, and radiation therapy (local and systemic) are all appropriate treatments under selected circumstances. In general, a combination of systemic and local modalities is required, and no single treatment regimen is effective for an extended period of time. Of the many options available for HRPC, one treatment option that I will focus upon in this brief discussion involves the newer concept of combining intravenous radiopharmaceuticals with chemotherapy for possible synergy.

Three radionuclides are currently approved for the treatment of metastatic bone pain: phosphorous-32 (32P), strontium-89 (89Sr) or Metastron®), and samarium-153 (153Sm-EDTMP or Quadamet®). These radionuclides all localize to regions of enhanced bone turnover and deliver high local doses of radiation through the emission of beta particles. The mechanism of bone targeting varies for each of them. Phosphorous-32 is targeted to bone through inorganic phosphate pathways while strontium-89 is taken up as a calcium analog. Samarium-153 is targeted to bone via its chemical conjugation to EDTMP (ethylenedi-aminetetramethylenephosphonic acid). The relevant nuclear decay properties of these radionuclides are shown in Table 2.

Nuclear Decay Properties and Bone Penetration Depth of Radionuclides

Decay properties such as half-life and particle energy play significant roles in such important clinical characteristics of these agents as onset and duration of palliative effects and degree of and time to recovery from bone marrow suppression. The particle emission energies of 32P and 89Sr and the corresponding ranges in bone and soft tissue are much greater than those of 153Sm. Higher energy particles are associated with greater marrow toxicity as the result of the larger volumes of marrow exposed to radiation. The shorter physical half-life of 153Sm (1.9 days) results in a more rapid delivery of radiation than either 32P (14.3 days) or 89Sr (50.5 days). For example, delivery of 90% of the total dose of radiation requires approximately 3.5 half-lives of decay, a time interval of approximately one week for 153Sm, seven weeks for 32P, and 25 weeks for 89Sr.

Indications and Contraindications to the use of Bone Targeted RadiophamaceuticalsThe current relative indications and contraindications for the use of bone-targeted radiopharmaceuticals are presented in Table 3. Baseline complete blood counts are necessary to establish adequate retreatment levels of platelets and white blood cells since all of these agents result in some suppression of bone marrow function. Severe renal dysfunction is a contraindication to the use of bone targeted radionuclides because currently available agents are predominantly excreted by the kidney.

Several prospective randomized controlled studies3,4 have been performed to evaluate the effectiveness of using bone-seeking radiopharmaceuticals to relieve the pain of bone metastases in HRPC patients. One of the largest of these trials was published by Sartor and colleagues4 in 2004 evaluating 153Sm-EDTMP. In this prospective, multi-center, randomized, double-blind, placebo-controlled study in patients with bone metastases from hormone-refractory prostate cancer, 152 patients were randomized in a 1:2 ratio to placebo (n=51) or a 1.0 mCi/kg dose of the active drug (n=101) and were followed for up to 16 weeks. Pain intensity was measured twice daily (by patients) using validated linear and non-linear scales. Daily opioid analgesic use was also recorded. Patients who received the active drug exhibited significant improvements (as compared to the placebo group) in pain scores at each of the first four weeks following administration. This decrease in pain occurred while pain medications were decreased.These data clearly demonstrate that 153Sm-EDTMP can reduce pain from bone metastases in patients with HRPC. Toxicity was mild and was limited to transient decreases in white cells and platelets.

Recently, considerable interest has emerged in the use of skeletal targeted radionuclides in combination with chemotherapeutics. The first of these trials was published by Tu and colleagues5,who used a combination of 89Sr and doxorubicin. Patients were randomized to receive either doxorubicin alone or in combination therapy after first being treated with a combination therapy of ketoconazole, doxorubicin, estramustine, and vinblastine. Of note, this combination of agents is no longer used. Only patients with stable disease or responding disease after the preliminary therapy were eligible for the randomization. Patients randomized to the combination of 89Sr and doxorubicin had a longer survival compared to those patients who were treated with doxorubicin alone.This trial supports the concept that targeting bone and using a radiosensitizing chemotherapy (in combination) might be an effective therapeutic approach.

Preliminary data is available regarding the combination of 153Sm-EDTMP and docetaxel in patients with hormone refractory prostate cancer. In a phase I study conducted in Sweden by Widmark and colleagues6 that examined preliminary efficacy, six patients were treated with weekly docetaxel at a dose of 30 mg/m2, in combination with a dose of 1.0 mCi/kg given in week four, 24 hours prior to treatment with docetaxel. Optimal uptake by tumor sites was seen 8-24 hours after injection. Five of the six patients had a decrease in PSA of >50% and four of the six had a decrease in PSA of >80% which persisted for more than six months. Toxicity was not dose limiting; only one episode of neutropenic fever was reported.This study clearly deserves additional follow up and expanded patient numbers.

In another preliminary study (by Arnsmeier and colleagues)7, six patients with metastatic prostate cancer were treated with paclitaxel 200 mg/m2 q for three weeks with estramustine and of 153Sm-EDTMP. Subsequent groups of six patients were each treated with paclitaxel 90 mg/m2 q for three weeks. 153Sm-EDTMP was administered with chemotherapy, starting with a dose of 1 mCi/kg and escalating in 0.5 mCi/kg dose increments. Moderate decreases in white cells were seen in one of the six patients at the 1.5 mCi/kg dose level, but no significant toxicity had been reached at the time of the report.

Chemotherapy, particularly with non-bone marrow suppressing agents such as weekly taxanes, 5-FU infusion, or capecitabine, clearly has the potential to augment activity of bone-seeking radiopharmaceuticals and additional studies are warranted to determine best dosing, best agents, and optimal timing of such therapies.

Summary and Conclusion
Bone metastases with pain represent a common and significant problem for patients with advanced prostate cancer. Data from prospective randomized clinical trails now support the use of 153Sm-EDTMP in patients with HRPC and painful bone metastases. Pain relief and decreases in analgesic consumption can be expected in the majority of patients treated. Side effects are limited to transient and relatively mild platelet and white blood cell suppression. Combination therapies that incorporate cytotoxic agents in combination with 89Sr or 153Sm-EDTMP regimens are now being actively explored in clinical trials. This approach has the potential of promoting synergy between active agents. Preliminary data suggest that this might be of considerable interest, although additional trials are needed to optimize this approach.

References

1.Gandhok N and Sartor O.Bone-targeted therapy for prostate cancer. In: Klein EA, ed. Current clinical urology: Management of prostate cancer, second edition. Totowa: Humana Press, 2004:589-606.

2. Newling DW,Denis L,Vermeylen K.Orchiectomy versus goserelin and flutamide in the treatment of newly diagnosed metastatic prostate cancer. Analysis of the criteria of evaluation used in the European Organization for Research and Treatment of Cancer- Genitourinary Group Study 30853. Cancer 1993;72(12 suppl): 3793-3798.

3. Serafini AN, Houston SJ, Resche I, et al, Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: A double-blind placebo-controlled study. J Clin Oncol 1998;16:1574-1581.

4. Sartor O, Reid RH, Hoskin PJ, et al, Samarium-153-lexidronam complex for the treatment of painful bone metastases in hormone refractory prostate cancer.Urology 2004;63:940-945.

5. 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. 2001; 357(9253):336-41.

6. Widmark A, Linne T, Modig H, Johansson L. Optimizing the time of co-administration of docetaxel and samarium-153 for advanced androgen independent carcinoma of the prostate [abstract]. Proc Am Soc Clin Oncol 2003;22:433.

7. Arnsmeier SL, Spies S, Shervin D, et al. Phase I/II study of taxane and estramustine with samarium in patients with hormone refractory prostate cancer [abstract]. Proc Am Soc Clin Oncol 2004;23:438.

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