The utility of strontium-89 (Sr-89) in the treatment of advanced metastatic prostate cancer has been examined in numerous clinical trials. Early phase II efficacy studies demonstrated that the majority of Sr-89-treated patients experienced a decrease in bone pain and analgesia requirements, with overall response rates of 75% to 80%. Toxicity was mainly hematological and clinically insignificant, suggesting that 40 mCi/kg (1.5 MBq/kg) is an optimal palliative Sr-89 dose. A subsequent study verified that the observed clinical response is due to radioactive strontium and is not a chemical effect. Two more recent phase III studies have extended these early results. The TransCanadian study showed that concomitant Sr-89 significantly reduced the appearance of new painful metastases, analgesic requirements, and serum levels of tumor markers compared with radiotherapy alone. Overall, these studies support Sr-89 as an effective systemic radiopharmaceutical for the palliation of bony metastases.

Although many primary malignancies cause metastases, the most important among American males is prostate cancer, with a rate of bone metastasis of at least 50% [1]. The survival time for patients with metastatic disease is approximately 2 years. During this time, patient management must include the treatment of symptoms related to painful bone lesions [2]. Aside from pain, late stage patients are compromised by pathologic fractures, neurologic deficits, decreased mobility, and the associated depression and anxiety that may accompany these physical symptoms. The main goals of treatment are pain palliation and improvement in quality of life. These are also among the major criteria used to evaluate the effectiveness of therapeutic regimens used in stage D prostatic carcinoma.

The management of bone metastases is a difficult problem--therapy is not curative and there is no real consensus among investigators concerning the best therapeutic strategies [2]. Treatment options include conventional analgesics, hormonal manipulation, external-beam radiation, chemotherapy, and radiopharmaceutical therapy [3]. The clinician's challenge in choosing the appropriate therapy for a given patient is to weigh the benefits of a treatment against associated adverse effects.

Since multiple sites of pain are the main therapeutic concern, treatment with narcotic analgesics has traditionally been indicated for bone metastasis [1,3]. However, opiates are less than ideal due to adverse gastrointestinal and sedative effects. Hormonal therapy is another common therapeutic choice for advanced prostate cancer since these tumors are initially androgen dependent. Although an effective first-line management in approximately 70% of prostate cancer patients, androgen deprivation is associated with a high rate of relapse accompanied by disease progression. Second- and third-line hormonal treatment may be appropriate in 30% of these patients, but the benefits are often short-lived. Chemotherapy is considered to provide few benefits at this stage of the disease.

An alternative first-line treatment option is radiotherapy [1]. Although effective for locally confined lesions, local radiation therapy is inadequate for the treatment of multiple metastatic sites [4]. Hemibody irradiation (HBI) is more effective in the latter case, with several studies demonstrating that it provides a palliative response rate of 75% [5]. However, HBI is associated with significant adverse effects such as bone marrow suppression, nausea, vomiting and lung toxicity.

Radiopharmaceutical therapy has recently become a primary treatment for advanced metastatic prostate cancer [6]. The administration of phosphorus-32 (P-32) was first introduced in humans in 1942 for the treatment of metastatic bone cancer [7]. Since that time, attempts to develop this isotope as a radiopharmaceutical have produced efficacy rates of 60% to 90% [6]. However, P-32 is not selectively deposited in bone tissue. Instead, the isotope is taken up by a variety of other tissues and systemic administration results in severe myelosuppression that limits its clinical usefulness.

--The limitations of P-32 created a clinical need for a radiopharmaceutical agent that relieves pain and improves the quality of life for patients with advanced prostate cancer. Systemic delivery of radiation by an isotope selective for bone tissue would maximize efficacy and minimize toxicity. Strontium-89 (Sr-89, Metastron) is such an isotope with several other desirable characteristics that increase its clinical utility.

Chemically, Sr-89 is similar to calcium and is preferentially taken up in osteoblastic tissue while the unabsorbed isotope is excreted in the urine the first 2 to 3 days following injection [1,6]. The tumor-to-marrow absorbed dose ratio for Sr-89 is greater than 10:1, suggesting that patients would experience minimal myelosuppression. This is indeed what is observed clinically. In addition, Sr-89 is a pure beta-emitter with a maximum beta energy of 1.46 MeV and a longer half-life (50.5 days) than P-32 (14.3 days), characteristics that result in minimal irradiation of healthy tissues and a duration of at least 100 days in osteoblastic target sites. These properties provide the rationale for Sr-89 as a therapeutic isotope.


Clinical Trials of Strontium-89 in Patients With Metastatic Bone Disease

The clinical utility of Sr-89 was shown in a series of trials that evaluated its role in the management of patients with advanced prostate cancer. Phase II trials were initiated in both England and the United States with encouraging results reported by both groups. These two early studies, along with later Phase III trials, are summarized in Table 1.

The first of these trials was designed to address the efficacy and safety of Sr-89 treatment [8]. The report summarized data on 202 patients with bone pain from metastatic disease who were treated with Sr-89. The first 20 patients received an intravenous (IV) Sr-89 dose of 30 mCi/kg (1.11 MBq/kg), while the remaining 182 patients received 40 mCi/kg (1.48MBq/kg) as the initial dose. Patients were monitored during the 3-month study by pain and medication diaries, sleep patterns, bone scans, and a Karnofsky Index. The majority of the surviving patients (100) had prostate cancer, while 28 patients had breast cancer and nine patients had other carcinomas.

The results demonstrated that most patients experienced a decrease in bone pain and analgesia with an overall response rate of 80% [8]. The reduced pain level typically occurred 2 to 3 weeks post-injection. Twenty percent of patients had no hematologic toxicity, while the remainder experienced mild hematological depression that consisted of a 15% to 20% decrease in total platelet and white blood cell (WBC) counts.

Kinetic analysis of whole body profiles revealed that 88% of the Sr-89 dose was retained for at least 100 days in one patient with widespread metastases. In addition, Sr-89 retention was observed primarily at metastatic sites, contributing to the beneficial clinical responses.

Based on these clinical findings, Robinson et al recommended Sr-89 therapy for patients with metastatic prostate cancer who fail hormonal treatment. They further concluded that a systemic dose of 40 mCi/kg (1.48 MBq/kg) is safe and effective for the treatment of painful osseous metastases in these patients.

--The clinical experience of Robinson et al was confirmed by the multi-center study of Sr-89 conducted by Laing and colleagues [9]. This study evaluated 83 patients with prostatic carcinoma who failed conventional therapy. Similar to Robinson et al, these investigators found that an Sr-89 dose of 1.5 MBq/kg provided meaningful clinical response to 75% of patients, with 22% becoming pain free. Although the observed mean percentage drop in platelet levels was significantly related (P less than 0.02) to increasing Sr-89 doses (0.7 to 3.0 MBq/kg), the effect was deemed mild and reversible.

It should be noted that, although not included in the efficacy analyses, both studies documented pain relief in some patients who did not survive the three month treatment period [8,9]. Therefore, Sr-89 response rates found in practice may be higher than values reported in these controlled studies. Clearly, the two independent clinical studies reviewed above both demonstrate a therapeutic potential of Sr-89 therapy for the management of metastatic prostate disease.

These early findings were updated by Robinson and colleagues in 1993 [1]. At present, 15 years of accumulated data continues to demonstrate that Sr-89 provides pain relief and improved functional status in 80% of patients with bone metastases with minimal adverse effects.

Chemical vs Radiation Effects of Strontium

--The studies reviewed above provided extremely encouraging results for the palliative effects of Sr-89 in metastatic bone disease. However, they led to the question of whether the observed effects were actually attributable to 

 strontium. To address this, Lewington et al carried out a study to determine the contribution of any chemical effects of strontium in pain palliation of patients with advanced prostate cancer [10].


Clinical response to Sr-89 or elemental strontium (placebo) at 5 weeks post injection in patients with metastatic prostate cancer

Thirty-two patients who failed conventional treatments participated in a randomized, double-blind crossover study comparing Sr-89 with stable strontium as the placebo [10]. Patients received either 50 mg stable Sr chloride (ie, Sr-88) or 150 MBq Sr-89 chloride containing 50 mg stable Sr chloride. Each treatment was spiked with a tracer dose of Sr-85 to insure proper blinding. Patient responses were evaluated by numerical grading of general condition, mobility, analgesics, pain, and overall assessment. Patients were crossed-over to the alternative protocol at 6 weeks post-injection.

The results showed that only those patients receiving Sr-89 reported dramatic improvement, while the majority of patients treated with elemental strontium reported no significant change or deteriorated (P less than 0.01, Figure 1) [10]. In terms of toxicities, differences in platelet counts were documented between the two groups, with Sr-89 treatment resulting in a 25% mean reduction of baseline values that was not clinically significant. Lewington et al concluded that the placebo effect is limited, while there is a clear therapeutic response to Sr-89 with no immediate adverse reactions or significant toxicities.

The previously described studies have provided clinical evidence supporting the effectiveness and safety of Sr-89 as a palliative therapy for patients with metastatic prostate disease. This led to the execution of two major complementary Phase III clinical trials. One consisted of a series of studies in the United Kingdom (UK) (1988-1991) that directly compared Sr-89 with external beam radiotherapy [11]. The second trial, referred to as the TransCanadian study, attempted to determine the potential of Sr-89 as an adjuvant to radiotherapy [12].

--The comparative UK studies involved 305 patients classified by the investigator as eligible for either local radiotherapy (n = 148) or HBI (n = 157) [11]. Patients were randomized to receive either external beam irradiation (20 Gy in five daily fractions or a single fraction of 8 Gy, local radiotherapy; single fractions of 6 Gy for upper or 8 Gy for lower HBI) or Sr-89 (200 MBq [5.4 mCi]). Patients were monitored for original and new sites of pain, analgesic intake, and toxicity and the data was summarized at 3 months post-treatment.

Dramatic pain improvement at the original site was reported by 44.1% of patients after Sr-89 and 36.4% after local radiotherapy (Figure 2) [11]. Importantly, it was further observed that 65% of Sr-89 treated patients were free of new pain sites compared with 46.5% of patients treated with local radiotherapy

(P less than 0.01). This resulted in the added benefit of a significantly lower requirement for additional radiotherapy in the former compared with the latter group (P less than 0.01).

Similar results were found in comparison of Sr-89 and hemibody radiotherapy [11]. At 3 months, pain improvement at the original sites was reported by 66.1% of patients receiving Sr-89 and 63.6% of HBI-treated patients. However, the radio-pharmaceutical resulted in a significantly larger proportion of patients who were free of new pain sites (73.3%) compared with those receiving HBI (54.6%, P less than 0.05).

An important advantage to Sr-89 radiotherapy that was found in this trial was a lower incidence of adverse effects [11]. Gastrointestinal effects were reported by 42.9% of patients after HBI, 27.3% of patients in the local radiotherapy group, and only 10.1% of patients receiving Sr-89. The common adverse events encountered with Sr-89 treatment were hematologic, with a depression of platelet and leukocytes. However, as in earlier trials, this was not considered to be clinically relevant in most cases.

The reduction in the development of new pain sites with Sr-89 is an exciting clinical finding, suggesting disease stabilization. It should be noted that, although there was a trend towards improved patient survival in the Sr-89 group (33 weeks), the result was not significantly different (P = 0.11) from external beam radiotherapy (28 weeks) [11]. However, the data do clearly indicate that Sr-89 offers several advantages over irradiation including an improved quality of life for the patient and less of a drain on hospital resources.

--The TransCanandian study was designed to evaluate the efficacy of Sr-89 adjuvant to local external beam radiation in the management of metastatic prostate cancer [12]. This trial involved 126 patients with hormonal resistant disease and adequate hematologic function. Local field irradiation was typically dosed at 30 Gy (10 fractions over 14 days or 20 Gy in five fractions over 7 days) with the exception of rib lesions that required single fractions of up to 10 Gy. Placebo or IV Sr-89 (10.8 mCi) was administered with 7 days of radiotherapy. Patients were assessed for survival, pain relief and progression, analgesic intake, need for additional radiotherapy, serum tumor markers, quality of life, and toxicities.

The results showed that the rate of complete pain relief ranged from 30% to 60% and was similar in both the placebo and Sr-89 groups [12]. Although adjuvant use of Sr-89 over local field radiation alone demonstrated a consistent trend of improved overall pain relief, this finding was not statistically significant. Important from the patient's point of view, Sr-89 treatment resulted in a significant reduction in the appearance of new painful metastases compared with radiotherapy alone (P less than 0.002, Figure 3). In terms of analgesia requirements, a greater proportion of patients receiving adjuvant Sr-89 reduced their analgesic intake by at least 50% or eliminated analgesic intake entirely (P less than 0.05) compared with the placebo group.

Quality of life is also major concern in the management of this patient population and was evaluated with an extensive questionnaire encompassing nine categories and a supplemental section concerning pain. The Sr-89 group reported a significantly improved overall quality of life (P = 0.006), including particular improvements in physical activity and alleviation of pain (P less than 0.05) compared with those receiving radiotherapy alone (Figure 4).

In addition to improvements in clinical disease parameters, Sr-89 treatment resulted in reductions of tumor markers, suggesting a tumoricidal effect [12]. It was observed that more patients receiving Sr-89 experienced a drop in prostatic acid phosphatase (PAP), prostatic specific antigen (PSA, P less than 0.01) and alkaline phosphatase (P less than 0.01) compared with placebo during the first four study months.

--As more clinicians move towards treating patients with Sr-89, optimization of dosing, amelioration of toxicity, and augmentation of the therapeutic response are areas to be explored. Imminent among these is the question of the usefulness of Sr-89 dose fractionation. RTOG 8821 is a preliminary study designed to address this issue (Porter et al, unpublished). Patients were randomized to receive a 4 mCi Sr-89 with subsequent dose escalation to 6.5, 9 and 11.5 mCi. Hematological toxicities were used as a criteria for evaluating dosing and it was determined that 4-6.5 mCi is efficacious and produces minimal adverse effects (unpublished observations).

While it does appear that a dose response relationship exists between Sr-89 and complete pain relief, the optimal dosage has not yet been definitively established [13]. In addition, the benefits, if any, of Sr-89 dose fractionation need to be determined.

Enhancement of Sr-89 Therapeutic Response

--Enhanced responses to irradiation have been observed with concurrent cisplatin infusion in murine models [14]. This has prompted a phase I/II trial of combination Sr-89/cisplatin therapy in patients with hormone refractory metastatic prostate cancer. Encouraging preliminary data have been reported suggesting good pain relief, reduced analgesic requirements, decreased serum tumor markers, and only mild toxicity. Further evaluation of the effect of Sr-89 sensitization by cisplatin are warranted.

In summary, the clinical data presented in this review clearly advocate a significant role for Sr-89 as a palliative treatment for patients with hormone refractory metastatic prostatic carcinoma. The availability of this agent will allow clinicians further flexibility in the development of novel treatment paradigms in the management of this difficult, progressive neoplasm.

1. Robinson RG, Preston DF, Baxter, KG et al: Clinical experience with Sr-89 in prostatic and breast ca patients. Semin Oncol 20:44-48, 1993.

2. Nielsen OS, Munro AJ, Tannock IF: Bone metastases: Pathophysiology and management policy. J Clin Oncol 9:509-524, 1991.

3. McEwan AJB, Porter AT, Venner PM, et al: An evaluation of the safety and efficacy of treatment with strontium-89 in patients who have previously received wide field radiotherapy. Antibody Immunoconj Radiopharmac 3:91-96, 1990.

4. Porter AT, McEwan AJB: Sr-89 as an adjuvant to external beam radiation improves pain relief and delays disease progression in advanced prostate cancer. Semin Oncol 20:38-43, 1993.

5. Hoskin PJ: Scientific and clinical aspects of radiotherapy in the relief of bone pain. Cancer Surveys 7:69-86, 1988.

6. Robinson RG: Strontium-89 for bone pain due to blastic metastatic disease. Appl Radiol August:44-47, 1993.

7. Friedell HL, Storaasli JP: The use of radioactive phosphorus in the treatment of carcinoma of the breast with widespread metastases to bone. Am J Roentgenol Radium Ther 64:559-75, 1950.

8. Robinson RG, Blake GM, Preston DF, et al: Strontium-89: treatment results and kinetics in patients with painful metastatic prostate and breast cancer in bone. RadioGraphics. 9:271-281, 1989.

9. Laing AH, Ackery DM, Bayly RJ, et al: Sr-89 chloride for pain palliation in prostatic skeletal malignancy. Br J Radiol 64:816-822, 1991.

10. Lewington VJ, McEwan AJ, Ackery DM, et al: A prospective, randomized double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer 27:954-958, 1991.

11. 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. Semin Oncol 20:32-33, 1993.

12. Porter AT, McEwan AJB, Powe JE, et al: Results of a randomized phase-III trial to evaluate the efficacy strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. J Rad Oncol 25;805-813, 1993.

13. Mertens WC, Stitt L, Porter AT: Strontium 89 therapy and relief of pain in patients with prostatic ca metastatic to bone: A dose response relationship? Am J Clin Oncol 16:238-242, 1993.

14. Mertens WC, Porter AT, Reid RH, et al: Strontium-89 and low-dose infusion of cisplatin for patients with hormone refractory prostate carcinoma metastatic to bone: A preliminary report. J Nuclear Med 33:1437-1443, 1992.

Articles

The utility of strontium-89 (Sr-89) in thetreatment of advanced metastatic prostate cancer has been examinedin numerous clinical trials. Early phase II efficacy studies demonstratedthat the majority of Sr-89-treated patients

Use of Strontium-89 in Metastatic Cancer: US and UK Experience

Palliation of bone metastases aims at relief of pain, preservation of function, and maintenance of skeletal integrity. Analgesics relieve pain but do not arrest or reverse the disease process. Chemotherapy is unpredictable and often has significant toxicity. Hormonal therapy for sensitive tumors has a higher response rate and less toxicity than chemotherapy, but resistance eventually occurs. Radiation therapy has been the major treatment modality and frequently can achieve all the stated aims. However, time, dose, and volume parameters are complex, and little consensus exists regarding optimal schedules. This article reviews clinical trials using both local-field and half-body techniques. Endpoints are often vague, and quality-of-life assessments are needed to replace more subjective parameters.

Although death rarely can be prevented, the aims of treatment of metastatic cancer are to relieve pain, preserve mobility and function, maintain skeletal integrity, as well as prolong useful life. Asymptomatic lesions may be treated to prevent predictable future symptoms. Palliative therapy should provide control of the treated lesion for the remainder of a patient's life. Ideally, it should be rapid, convenient, and free of immediate side effects and delayed complications. It should not unduly disturb daily activities, be wasteful of a patient's limited time and money, or consume scarce medical resources better employed for curative treatment.

Pharmacologic treatment has improved in recent years with the more effective use of oral opiate analgesics--both short and long acting--as well as use of transdermal, epidural, and continuous infusions and patient-controlled systems. However, pharmacologic treatment does not arrest or reverse the underlying disease process and does not prevent structural deterioration; there is a threat of pathologic fracture and spinal cord or other neurologic compromise, which usually are irreversible.

Orthopedic intervention is valuable for mechanical stabilization of impending or recent pathologic fractures, and total joint arthroplasties in carefully selected patients may relieve pain dramatically and restore function. In skilled hands, spinal surgery for decompression and stabilization is sometimes worthwhile.

Hormonal therapy--both additive and ablative--and chemotherapy are of major value in patients whose tumors are responsive. However, resistance eventually occurs and with chemotherapy, toxicity is often significant and major responses uncommon.

Various modes of therapy frequently may be used in sequence or in combination. In oncology, decisions involving palliative care are often the most difficult and require considerable experience and expertise as well as various consultations among multiple specialist disciplines to achieve optimum benefit. Although endpoints are often lacking or poorly defined, it is hoped that the trend toward additional quality-of-life assessments will bring more rigorous evaluation of this important and often neglected area.

Radiation therapy remains the major treatment modality of bone metastases, frequently providing major pain relief and often arresting or reversing the destructive disease process. Despite the frequency and magnitude of the problem, there is remarkably little agreement as to the time, volume, and dose schedules for optimal palliation. This may reflect the diversity of the problem, the multitude of confounding variables, and the lack of clearly defined endpoints.

The causes of bone pain are numerous and poorly understood. Why should a small lesion sometimes cause excruciating pain, whereas other times involvement of almost the entire skeleton produces little, if any, pain?

Similarly, the response to treatment can be puzzling. Ablative hormonal therapy by orchiectomy or oophorectomy may result in dramatic pain relief by the time a patient awakens from anesthesia. Hemibody irradiation (HBI) also may produce pain relief within 24 hours. Such responses clearly do not depend on cell death and tumor shrinkage within such a brief period. Chemical mediators of the pain response must be involved, but there is little understanding of their mechanism. Furthermore, pain relief does not correlate well with tumor radiosensitivity. For example, in prostate cancer, which is not highly radiosensitive, pain often responds well to single-dose or fractionated radiation.

Clinical Trials of Radiation Therapy for Bone Metastases

The largest randomized, prospective study of radiation therapy for bone metastases was conducted by the Radiation Therapy Oncology Group (RTOG) in the 7402 study. Of the more than 1,000 patients entered, nearly 750 patients could be evaluated. More patients in the protracted fractionation arms did not complete therapy as assigned, compared with the other arms.

Study entry was determined by the pain and narcotic medication scores. Study requirements included: a pain or narcotic score of at least four, expected survival of at least 3 months, no prior radiation to the study site, and no new chemotherapy within two weeks of study entry. The pain score was the primary response measure, with the narcotic score a secondary response measure (Table 1). The randomization study design used is shown in aFigure 1.

In the analysis of this study by Tong et al, 90% of patients experienced some relief of pain, and 54% eventually obtained complete pain relief [1]. No significant differences were seen among the various treatment arms. Patients with breast and prostate cancer fared better than patients with lung or other cancer, and patients with pain scores under nine also fared better.

Of all patients who eventually experienced minimal pain relief, 96% did so within the first 4 weeks, and almost 50% of those who experienced complete pain relief did so within 4 weeks after the start of treatment. In 70% of patients, pain relief lasted until death. In the group of patients with a solitary metastasis, a dose of 4,050 cGy was associated with a higher incidence of pathologic fracture. In 1985, this study was reanalyzed by Blitzer using different statistical analysis. He concluded that more highly fractionated regimens with higher doses improved the outcome [2] (

A nonrandomized study by Arcangeli et al in 1989 concluded that more complete pain control and less need for retreatment were obtained by fractionated courses of 40 Gy or more [3]. They found no correlation between fraction size and pain relief. In a prospective, randomized study by Price et al, a single 8 Gy fraction was compared with 30 Gy in 10 daily fractions; equally good pain control was demonstrated, with no difference in response rate or speed of onset or duration [4]. In 1989, Cole compared 24 Gy in 6 fractions over 2 or 3 weeks with a single 8 Gy fraction [5]. No differences were seen in pain scores, but 25% of the patients in the 8 Gy group required retreatment.

Although no fractionated scheme of treatment has been shown to be clearly and consistently superior to another, single-dose treatments of 8 Gy may be equally effective, with the advantages of convenience for the patient and reduced work load.

In the 1970s, following the initial report of HBI by Fitzpatrick and Rider from the Ontario Cancer Institute [6], a number of reports on this single-dose, large-field technique appeared [7-10]. The RTOG began the 7810 study of single-dose HBI for the palliation of multiple bone metastases from solid tumors. This was a dose-escalating study (Table 3) that used the same pain and narcotic scores as did the 7402 study. It is important to note that dose corrections were applied for increased lung transmission. Earlier studies showed a significant incidence of fatal radiation pneumonitis before this was appreciated [11-13]. Furthermore, as developed in a Rochester pilot study, adequate hydration, steroids, and antiemetics were utilized [14]. The results showed that 73% of patients achieved pain relief [15]. Approximately 67% of patients experienced better than 50% pain relief, and 20% experienced complete pain relief. A total of 50% of responding patients experienced pain relief within 48 hours, and 80% experienced pain relief within 7 days. Retreatment was required in only 50% of patients for the rest of their lives. The safest and most effective doses were 600 cGy for upper HBI and 800 cGy for lower HBI and mid-body irradiation [15] (Figure 2).

The next study, RTOG 8206, evaluated whether the addition of single-dose HBI to standard fractionated radiation was more effective than local-field irradiation alone [16]. It also explored the possibility that the addition of HBI to local-field irradiation might delay the appearance of new metastases and/or decrease the need for further treatments.

A total of 499 patients entered the study. The time to disease progression was delayed significantly in the local and HBI arm, with only 35% of patients showing disease progression at 1 year compared with nearly 50% of patients showing disease progression in the local only arm of the study (Figure 3). The time to appearance of new metastases was delayed considerably for patients in the local and HBI arms. A total of 50% of patients in the local only arm developed new metastases in 6 months compared with 18 months in patients in the local and HBI arm of the study (Figure 4). The time to new treatment in the targeted HBI was delayed even more significantly (Figure 5). At 12 months, 76% of the patients in the local only group had undergone retreatment compared with 60% of the patients in the local and HBI arms of the study. We concluded that an HBI dose of 8 Gy delays the appearance of new metastases and the progression of existing metastases.

All the outcomes examined showed a significant advantage for HBI. Although survival was not prolonged, no lethal toxicities were noted. As shown in other studies, patients with breast cancer and prostate cancer experienced better survival rates than patients with other malignancies.

This study indicates that HBI might be capable of eradicating micrometastatic disease and eventually could be used as adjuvant therapy in patients at high risk for developing bone metastases. Several nonrandomized reports and studies have provided supporting evidence [17-22].

In an attempt to improve the efficacy of HBI, fractionated, rather than single, doses are being explored [23]. Fractionation may improve the therapeutic ratio over that seen in single-dose treatments. The RTOG recently completed a dose-escalation study (8822) of fractionated HBI in patients with breast and prostate cancer. These particular patients were selected because of their longer survival and improved ability to reach endpoints of significance. Final results are pending analysis.

Studies to date do not show a clear or consistent dose response for fractionated treatment of bone metastases. This applied to both completeness and duration of response. There is evidence that single-dose treatments (of the order of 8 Gy) provide equivalent relief to multidose regimens. This applies to both local and hemibody techniques. Single-dose treatments are obviously advantageous in terms of patient convenience and use of remaining life span. Local-field doses of 8 Gy may be repeated safely if necessary.

The use of sequential hemibody techniques to eliminate micrometastatic disease in an adjuvant setting requires further exploration. To improve the therapeutic ratio of HBI, fractionation studies and the use of biologic response modifiers also are being examined.

1. Tong D, Gillick L, Hendrickson FR: The palliation of symptomatic osseous metastases: Final results of the study by the Radiation Therapy Oncology Group. Cancer 50:893-899, 1982.

2. Blitzer PH: Reanalysis of the RTOG study of the palliation of symptomatic osseous metastasis. Cancer 55:1468-1472, 1985.

3. Arcangeli G, Micheli A, Arcangeli G, et al: The responsiveness of bone metastases to radiotherapy: The effect of site, histology, and radiation dose on pain relief. Radiother Oncol 14:95-101, 1989.

4. Price P, Hoskin PJ, Easton D, et al: Prospective randomized trial of single and multifraction radiotherapy schedules in the treatment of painful bony metastases. Radiother Oncol 6:247-255, 1986.

5. Cole DJ: A randomised trial of a single treatment versus conventional fractionation in the palliative radiotherapy of painful bone metastases. Clin Oncol 1:59-62, 1989.

6. Fitzpatrick PJ, Rider WD: Half body radiotherapy. Int J Radiat Oncol Biol Phys 1:197-207, 1976.

7. Rowland CG: Single fraction half body radiation therapy. Clin Radiol 30:1-3, 1979.

8. Bartelink H, Battermann J, Hart G: Half body irradiation. Int J Radiat Oncol Biol Phys 6:87-90, 1980.

9. Epstein LM, Stewart BH, Antunez AR, et al: Half and total body radiation for carcinoma of the prostate. J Urol 12:330-332, 1979.

10. Rowland CG, Bullimore JA, Smith PJB, et al: Half-body irradiation in the treatment of metastatic prostatic carcinoma. Br J Urol 53:628-629, 1981.

11. Prato F, Kurdyak R, Saibil E, et al: The incidence of radiation pneumonitis as a result of single fraction upper half body irradiation. Cancer 39:71-78, 1976.

12. Fowler J, Travis E: The radiation pneumonitis syndrome in half body radiation therapy. Int J Radiat Oncol Biol Phys 4:1111-1113, 1978.

13. Freyer C, Fitzpatrick P, Rider W, et al: Radiation pneumonitis: Experience following a large single dose of radiation. Int J Radiat Oncol Biol Phys 4:931-936, 1978.

14. Salazar OM, Rubin P, Keller B, et al: Systemic (half-body) radiation therapy: Response and toxicity. Int J Radiat Oncol Biol Phys 4:937-950, 1978.

15. Salazar OM, Rubin P, Hendrickson F, et al: Single dose half-body irradiation for palliation of multiple bone metastases from solid tumors. Cancer 58:29-36, 1986.

16. Poulter CA, Cosmatos D, Rubin P, et al: A report of RTOG 8206: A phase III study of whether the addition of single dose hemibody irradiation to standard fractionated local field irradiation is more effective than local field irradiation alone in the treatment of symptomatic osseous metastases. Int J Radiat Oncol Biol Phys 23:207-214, 1992.

17. Hazra T, Giri S: Prophylactic pelvic girdle irradiation in the treatment of prostatic carcinoma. Int J Radiat Oncol Biol Phys 7:817-819, 1981.

18. Hercbergs A, Werner A, Brenner H: Reduced thoracic vertebrae metastases following postmastectomy parasternal irradiation. Int J Radiat Oncol Biol Phys 11:773-776, 1984.

19. Rees GJC: Influence of parasternal radiotherapy for breast carcinoma on thoracic vertebral metastases. Radiother Oncol 10:183-186, 1987.

20. Kaplan ID, Valdagni R, Cox RS, et al: Reduction of spinal metastases after preemptive irradiation in prostatic cancer. Int J Radiat Oncol Biol Phys 18:1019-1025, 1990.

21. Jacobsson H, Naslund I: Reduced incidence of bone metastases in irradiated areas after external beam radiation therapy of prostatic carcinoma. Int J Radiat Oncol Biol Phys 20:1297-1303, 1991.

22. McLennan MB, Hosni SM, Rubin P: Sequential hemibody radiotherapy in poor prognosis localized adenocarcinoma of the prostate gland: A preliminary study of the RTOG. Int J Radiat Oncol Biol Phys 16:001-004, 1989.

23. Zelefsky MJ, Scher HI, Forman JD, et al: Palliative hemiskeletal irradiation for widespread metastatic prostate cancer: A comparison of single dose and fractionated regimens. Int J Radiat Oncol Biol Phys 17:1281-1285, 1989.

Palliation of bone metastases aims at relief of pain, preservation of function, and maintenance of skeletal integrity. Analgesics relieve pain but do not arrest or reverse the disease process. Chemotherapy is

External Beam Radiotherapy for Metastatic Cancer

The American Cancer Society estimates that 383,000 Americans will be diagnosed with prostatic or breast cancer in 1994.[1] Many of these individuals will develop painful bony metastases. As clinicians, it is imperative that we seek out the most current information on anticancer and palliative breakthroughs for these patients.

Although treatments such as radiotherapy and hormonal therapy have been used for many years, they are constantly being refined in order to optimize both efficacy and safety. Cancer chemotherapy is also continually evolving. Our awareness of developments in these fields is critical to patient care. One of the goals of this supplement is to provide reviews of the current status of these conventional approaches.

With disease progression, the effective management of pain becomes an overriding concern. In fact, it is the physician's obligation and ethical responsibility to alleviate suffering and provide optimal pain relief throughout the course of cancer.[2 ]

Several of the papers included herein focus on strontium-89, the radiopharmaceutical that was approved by the US Food and Drug Administration in the summer of 1993 for the palliation of pain from bony metastases. The drug can make a dramatic impact on the quality of life of many cancer patients only if information concerning its efficacy, safety, and administration, as well as patient selection and follow-up, is properly disseminated. It is our hope that this supplement will help meet this goal.

1. Cancer Facts and Figures-1994, Atlanta, GA. American Cancer Society, pp 1-28, 1994.

2. Clinical Practice Guideline Number 9: Management of Cancer Pain, Rockville, MD. US Department of Health and Human Services, pp 1-257, 1994.

The American Cancer Society estimates that 383,000 The American Cancer Society estimates that 383,000 Americans willbe diagnosed with prostatic or breast cancer in 1994.[1] Manyof these individuals will develop painful bony metastases. Asclinicians, it is imperative that we seek out the most

A Multidisciplinary Approach to the Management of Patients With Metastatic Disease to the Bone

The pharmacoeconomics of patient management is important in the case of the critically ill. Pain palliation and improvements to quality of life are treatment goals for patients with metastatic prostate cancer and can actually lessen healthcare expenses. Radiotherapy and strontium-89 (Sr-89) provide excellent clinical response in these patients. Accumulating data suggest that Sr-89 also significantly slows the appearance of new bone pain sites and reduces analgesic requirements. Analyses of drug costs and hospital services revealed that direct costs of patient management were $28,956 (Can) less and total care was $123,326 less for the Sr-89 group (n = 14) than for the placebo group (n = 15). These group reductions translated into total savings per patient of $7,118 or $209 per week of survival with the addition of Sr-89 to local irradiation protocols. These data provide evidence for the cost-efficacy of Sr-89.

Spiraling health care costs have prompted great interest in evaluating the pharmacoeconomics of all medical treatments [1]. As a result of careful analyses, it has been suggested that the most cost-effective approach to therapy may not necessarily be the least expensive but rather the one that provides the best clinical outcome. Length of hospitalization and incidence of adverse effects or disease complications all exert a major influence on the cost-effectiveness of management strategies. This type of pharmacoeconomic treatment evaluation is particularly important in the case of the critically ill, who typically require longer hospital stays and more intensive treatments than other patients.

Patients with advanced metastatic prostate cancer are certainly included in this population. Their expected survival is approximately 2 years and is substantially less by the time the disease becomes refractory to first-line hormonal therapy [2]. At that point, the treatment of bony metastases, which occur in 85% of these patients, is difficult, and excruciating pain along with a substantially decreased quality of life result [3,4].

The principal goals of therapy are pain palliation and maintenance of daily functioning. Patients with adequately controlled pain not only experience a dramatically improved quality of life, but require fewer medical services and hospitalizations, which can translate into increased cost-effectiveness.

Management options include cytotoxic chemotherapy, opiate analgesia, radiotherapy, and treatment with the systemic radiopharmaceutical, strontium-89 (Sr-89, Metastron). The clinical benefit of chemotherapy is under question, especially in terms of pain palliation [2,3]. Opiates certainly play a role in pain relief, but their use can be complicated by sedation, adverse gastro-intestinal effects, and drug tolerance [4].

It is well established that both local and hemibody irradiation (HBI) represent effective first-line treatments for the pain of advanced prostate cancer [3-6]. Recently, Sr-89 for intravenous injection has been made available as another option for pain palliation. Accumulating efficacy data indicate that external beam radiotherapy and Sr-89 therapy provide similar overall clinical response rates (nearly 80%) and no significant differences in the prolongation of survival have been reported. However, local radiotherapy is not useful in cases of multiple metastases and HBI is associated with significant bone marrow and lung toxicity. In contrast, Sr-89 is associated with minimal adverse effects, and, either as an adjunct to radiotherapy or as monotherapy, provides clinical benefits above and beyond external beam irradiation [5,6].

Comparative data reveal that Sr-89 retards prostate cancer progression (as measured by the appearance of new sites of pain) in a greater proportion of patients than either local irradiation or HBI (P less than 0.05) [6]. This effect translates into substantially lower requirements for additional radiotherapy. When given concomitantly with local field radiotherapy (ie, the TransCanada study), Sr-89 also has been shown to significantly improve quality of life (P = 0.006) and reduce analgesic consumption (Pless than 0.05) compared with irradiation alone [5].

Pharmacoeconomics of Treatment With Sr-89

The direct reduction of drug requirements and medical services combined with the outpatient administration of Sr-89 should have a positive impact on the pharmacoeconomics of prostate cancer patient management [4,5]. This possibility was explored retrospectively using a subset of 29 patients from the Edmonton, Alberta area who participated in the TransCanada study. This phase III trial (the results of which have been published elsewhere) compared the efficacy of local irradiation (20 Gy/5 fractions or 30 Gy/10 fractions) plus placebo (n = 15) or Sr-89 (10.8 mCi) (n = 14).

The aims of the analysis were to define the cost components and calculate direct and indirect patient management costs for these patients with advanced metastatic disease. In addition, the costs of management per week of survival and per patient lifetime were also assessed for each treatment arm of the study.

--A subset of 29 patients from the TransCanada study [5] were included in the study (Table 1). Although the analgesic score was slightly higher and the Karnofsky status slightly lower in the Sr-89 group, the median survival was similar. In contrast, the median length of hospitalization was substantially shorter (21.9 days) for Sr-89-treated patients compared with those receiving radiotherapy alone (37.5 days).

The methods employed in the analysis were chart review, review of TransCanada study data, follow-up corr- espondence to attending physicians, and the collation of management requirements. The costs of selected components of direct and indirect routine management of Canadian patients with prostate cancer that were used in the analysis are presented in Table 2. Other direct costs of care included in the study were radiotherapy and blood transfusions. Data were tabulated and compared for patients receiving placebo/radiotherapy or Sr-89/radiotherapy.

--Although the indirect cost of managing patients throughout the study were similar in both treatment groups, the direct costs associated with care of the Sr-89-treated patient group were substantially less (by nearly $29,000) than those required for the group of patients receiving local irradiation alone ($44,174 vs $73,130, Table 3). Combined with a 38% reduction in the cost of tertiary care, the overall costs of managing the Sr-89 group were 35% less than the placebo group ($231,987 vs $355,313).

Similarly, direct costs per patient and per week of survival were reduced by approximately 35% to 40% with the addition of Sr-89 to radiotherapy. This translated into a per patient treatment savings of over $7,000 (Can) as well as a decrease of $209 (Can) in management costs per week of survival with the addition of Sr-89 to standard local irradiation protocols. The results of this study provide evidence for the overall cost-efficacy of Sr-89 therapy and are in agreement with other published reports of clinical experience with this radiopharmaceutical [4,5].

1. Crane VS: Pharmacoeconomics: Therapeutic and economic considerations in treating the critically ill patient. DICP, Annal Pharmacother 24:S24-27, 1990.

2. Mertens WC, Porter AT, Reid RH, et al: Strontium-89 and low-dose infusion cisplatin for patients with hormone refractory prostate carcinoma metastatic to bone: A preliminary report. J Nucl Med 33:1437-1443, 1992.

3. Robinson RG: Strontium-89 for bone pain due to blastic metastatic disease. Appl Radiol 22:44-47, 1993.

4. Robinson RG, Preston DF, Baxter KG, et al: Clinical experience with strontium-89 in prostatic and breast cancer patients. Semin Oncol 20:44-48, 1993.

5. 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.

6. 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. Semin Oncol 20:32-33, 1993.

The pharmacoeconomics of patient managementis important in the case of the critically ill. Pain palliationand improvements to quality of life are treatment goals for patientswith metastatic prostate cancer and can actually

Metastatic Prostate Cancer: Quality of Life and Cost Considerations

Neuroendocrine differentiation has been found in 50% to 100% of prostate neoplasms of all stages. Furthermore, 10% of prostatic tumors are extensively or fully differentiated. Thus, neuroendocrine-specific growth factors such as bombesin represent novel therapeutic targets and may also be important in the selection of patients for aggressive chemotherapy, which has been rather ineffective in prostate cancer. The use of more reliable prognostic tools or staging systems may overcome this difficulty and a nonhistological prostate cancer staging system has already shown that patients with visceral involvement but minimal bone disease have the highest chance of responding to a combination of doxorubicin, mitomycin-C, and 5-fluorouracil. Favorable response rates have also been demonstrated in trials of ketoconazole/Adriamycin or mitomycin-C combined with vinblastine/estramustine or vinblastine/Adriamycin.

Although hormonal treatment is an important palliative measure in the management of patients with advanced prostate carcinoma, the vast majority of cases end in relapse due to overgrowth of androgen-independent tumor cell populations [1]. Recent studies have focused on neuroendocrine differentiation as a mechanism by which these tumors escape hormonal control [2-4]. This model of disease progression may be an important prognostic tool and have implications for the treatment of patients with stage D malignancy. This review will examine the evidence for the neuroendocrine progression of prostate cancer and the clinical utility of chemothera- peutic agents that are being investigated for the management of late stage disease.

Early data detected neuroendocrine cell types in only about 10% of prostate tumors analyzed [3 ]. However, the proportion of neuroendocrine differentiation was found to be much higher in follow-up studies and it is now thought that 50% to 100% of all prostate neoplasms (including benign prostatic tissue) contain at least some neuroendocrine cells [3,5]. It has been estimated that 10% of these tumors are extensively or fully differentiated. The latter are histologically similar to small cell or carcinoid tumors.

The availability of an anti-androgen receptor (AR) monoclonal antibody has allowed the identification of both AR-positive and AR-negative neuroendocrine subpopulations in both benign and malignant tumors [5]. Combined with observations of neuroendocrine enrichment in cases of poor clinical response to androgen deprivation therapy, these findings support the notion that the clonal expansion of AR-negative neuroendocrine cells may play a critical role in the development of androgen-insensitive metastatic prostate cancer.

The clinical relevance of immunohistological detection of neuroendocrine tissue in prostate cancer patients has been the focus of many investigators.

--Several studies have demonstrated that a large proportion of neuroendocrine differentiated prostatic neoplasms are positive for neuron-specific enolase and chromogranin A [4,6]. Preliminary data suggests that these markers may contribute to prostate cancer progression. Should this be confirmed, this may add to the routine histological grading in patients with progressive prostate cancer [6]. Small-cell carcinomas are stimulated by bombesin/GRP and related peptides and contain receptors for them. Similarly, serum bombesin levels appear to be a useful prognostic tool in cases of neuroendocrine differentiated disease. Data obtained from patients with androgen- independent prostatic carcinoma have revealed that prostate-specific antigen (PSA) correlates with survival in patients with normal bombesin levels. Although indivi- duals with elevated serum bombesin also have elevated PSA, the latter is not a reliable prognostic indicator in these patients (unpublished observations). In addition, recently published case histories involving neuroendocrine differentiated small-cell or carcinoid prostatic tumors have reported normal levels of PSA as well as nearly normal acid phosphatase levels in patients experiencing rapid disease progression [7].

Overall, these data indicate that conventional prostate cancer prognostic tools such as PSA are inadequate to predict behavior of neoplasms as they become androgen-insensitive and neuroendocrine tumor populations expand (Figure 1). In these cases, markers such as neuron-specific enolase, chromogranin A, or bombesin are more suitable predictors of survival than prostatic volume.

--Aside from their use in prognosis, neuroendocrine cells and their growth factors represent good therapeutic targets. It has been observed that neuroendocrine cells secrete peptides such as serotonin, somatostatin, and bombesin, which stimulate tumor proliferation and lead to the biologically aggressive nature of neuroendocrine prostatic carcinoma [2,3]. Small cell carcinomas are also stimulated by bombesin/gastrin-releasing peptide-related peptides and contain receptors for them. Trials of anti-bombesin monoclonal antibodies as a treatment for small-cell lung cancer are already underway [8]. At present, animal data indicate that bombesin/gastrin-releasing peptide inhibition via an antagonist (RC-3095) may have clinical utility for prostate cancer as well [9].

A more complete understanding of the contribution of neuroendocrine elements in malignant prostatic tissue may be important in the development and assessment of aggressive chemotherapeutic regimens. For instance, neuroendocrine markers may be helpful in the identification of those patients who have the best chance of benefiting from early combination chemotherapy that is unnecessary in the majority of prostate cancer patients [6,7].

--There has been growing concern about the variable efficacy of both single and combination chemotherapeutic strategies in patients with hormone refractory prostate cancer [10,11]. It has been suggested that at least part of the difficulty in assessing the effects of these treatments has been the diverse nature of prostate cancer patient populations. The use of more reliable prognostic indices and/or staging systems may overcome this problem and allow a more accurate stratification of drug efficacy by disease severity. In fact, a nonhistological prostate cancer staging system has already been in use for over a decade.

This staging system consists of four clinical categories (Table 1) [11]. An early study classified 62 patients with hormonal refractory disease in this fashion who were treated with a combination of doxorubicin, mitomycin-C, and 5-fluorouracil (DMF). Results indicated that patients with less severe OI disease had a higher response rate (52%) and the VI group had a significantly higher response rate (88%, P less than 0.02) compared with the more serious stage II designations (33% for OII and VII). Responding patients (defined by improvements in bone scans, blastic healing, and lab parameters as well as a more than 50% reduction in the sum of tumor diameters) had a significantly prolonged survival rate compared with nonresponders (47.5 vs 23.8 weeks, P = 0.001).

In addition to predicting survival benefit after chemotherapy, the staging system also predicted response duration [11]. Patients with osseous disease had longer median durations of response (11 and 9.5 months for stages OI and OII, respectively) than those classified as VI (6.5 months) or VII (5 months). These data demonstrate that patients with visceral involvement but minimal bone disease have the highest chance of responding to DMF chemotherapy, while fewer patients with axial and distal skeletal involvement or visceral metastasis outside the lung experienced clinical benefits.

--An in vitro assay for assessing the effect of bone on the progression of androgen-independent prostate tumor growth has recently been developed at the University of Texas. The acellular supernatant derived from patient bone marrow aspirate is added to confluent human prostate cancer cell cultures (LNCaP). In order to evaluate the capacity of bone marrow aspirate to induce in vitro PSA production, serum-free medium from these cultures is analyzed by Northern blot. Since androgens are thought to be the only method of regulating PSA release, it is assumed that induction of PSA by the supernatant should not occur in patients with castrate levels of testosterone. Any in vitro induction would correspond to a bone-specific disease process.

Using this methodology, Logothetis et al found that bone marrow aspirate from patients with localized, androgen-dependent disease, or small-cell carcinoma did not induce LNCaP PSA, presumably because disease progression is not dependent upon bone in these cases (unpublished observation, Figure 2). In contrast, in vitro PSA release occurred most frequently and intensely with bone marrow aspirate obtained from patients with osseous-dependent tumor progression as well as androgen-independent disease. Since it focuses on patients with metastatic lesions, the assay is capable of assessing the antitumor activity of therapies often administered during advanced disease (ie, external beam radiotherapy, strontium-89, aggressive chemotherapy).

--Combination chemotherapeutic regimens are often administered weekly or monthly. Differ- ences in efficacy between mitomycin-C combined with weekly vinblastine/estramustine or monthly vinblastine/Adriamycin (Table 2) may be more depend- ent upon the dosing schedules than inherent differences in drug efficacy. It is possible that increases in clinical benefits derived from weekly schedules are related to effects on the deregulation of programmed tumor cell death (apoptosis) that is known to occur during prostate neoplastic development [12].

--Several groups have evaluated the clinical potential of combination chemotherapy with vinblastine (Velban) and estramustine (Emcyt) (VE), two microtubule inhibitors with independent mechanisms of action that appear to provide additive therapeutic effects [13-15]. Preliminary data obtained from 29 patients with hormone refractory prostate cancer indicated that oral estramustine (140 mg) taken three times daily and weekly intravenous bolus vinblastine (6 mg/m²) provided a clinical response rate of 24% to 50% (as measured by more than 50% reductions in PAP or PSA, respectively) [14]. The overall objective response rate was 30%.

Later studies employing different VE dosing (ie, 4 mg/m² weekly vinblastine, 10 mg/kg or 600 mg/m² estramustine) found 54% to 61% rates of PSA reduction [13,15]. The median duration of response was seven months. In addition, the rates of subjective pain palliation in these studies were 43% to 66%. The estimated overall response rate provided by VE was 58% [15]. Using the same dose and evaluation criteria, estramustine alone produced a clinical response rate of 29% while vinblastine monotherapy resulted in a 21% objective response rate in other studies. These data suggest at least an additive clinical effect of VE treatment. Logothetis et al are involved in ongoing prospective randomized trials to determine the relative contributions of each agent to clinical response during combination therapy.

--Based on their previous clinical experience with VE, Logothetis et al have recently reported that the addition of mitomycin-C to the VE regimen substantially improves efficacy [16]. The rate of PSA reduction among 31 patients with initially elevated PSA was 66% and the duration of response was 2 months. In addition, 7% of 28 patients with osseous disease experienced improved bone scans.

--Suramin (an agent that has been shown to inactivate fibroblast, platelet-derived, and insulin-like growth factors as well as interleukin-2) has also shown clinical potential in patients with hormone-refractory prostatic carcinoma [17]. A recent trial involving 38 patients revealed that suramin treatment resulted in a reduction (by 75% of pretreatment value) or a normalization of pretreatment PSA in a total of 35% of patients with soft tissue disease. This PSA response was more frequent (64%) among patients with metastasis limited to bone. These improvements significantly correlated with increased survival probability among patients with either soft tissue (P = 0.0184) or bone disease (P = 0.016). Pain palliation was also experienced by 71% of patients who were previously receiving opiates and who could reduce or stop analgesia due to suramin.

The number of published clinical trials involving monotherapy or combination treatment with a wide variety of chemotherapeutic agents is too large to be included in this review [12]. As new therapeutically exploitable steps in prostate cancer disease progression become elucidated, novel agents will likely be added to the armamentarium. For now, new methodologies are being developed to more fully characterize androgen independent neoplastic growth, neuroendocrine differentiation and enrichment, and the contribution of host properties to late stage disease progression. Advancements in these areas may allow us to maximize the efficacy of current chemotherapeutic protocols.

1. Denis L: Prostate cancer. Primary hormonal treatment. Cancer 71:1050-1058, 1993.

2. di Sant'Agnese PA, de Mesy Jensen KL: Neuroendocrine differentiation in prostatic carcinoma. Hum Pathol 18:849-856, 1987.

3. di Sant'Agnese PA: Neuroendocrine differentiation and prostatic carcinoma. Arch Pathol Lab Med 112:1097-1099, 1988.

4. Turbat-Herrera EA, Herrera GA, Gore I, et al: Neuroendocrine differentiation in prostatic ca. Arch Pathol Lab Med 112:1100-1105, 1988.

5. Nakada SY, di Sant'Agnese PA, Moynes RA, et al: The androgen receptor status of neuroendocrine cells in human benign and malignant prostatic tissue. Cancer Res 53:1967, 1993.

6. Cohen RJ, Glezerson G, Haffejee Z: Neuro-endocrine cells-a new prognostic parameter in prostate cancer. Br J Urol 68:258-262, 1991.

7. Smith DC, Tucker JA, Trump DL: Hypercalcemia and neuro-endocrine carcinoma of the prostate: A report of three cases and a review of the literature. J Clin Oncol 10:499-505, 1992.

8. Mulshine JL, Avis I, Treston AM, et al. Clinical use of a monoclonal antibody to bombesin-like peptide in patients with lung cancer. Annal NY Acad Sci 360-372, 1988.

9. Pinski J, Halmos G, Schally AV: Somatostatin analog RC-160 and bombesin/gastrin-releasing peptide antagonist RC-3095 inhibit growth of androgen-independent DU-145 human prostate cancer line in nude mice. Cancer Lett 71:189-196, 1993.

10. Petrylak DP, Scher HI, Li A, et al: Prognostic factors for survival of patients with bidimensionally measurable metastatic hormone- refractory prostatic cancer treated with single-agent chemotherapy. Cancer 70:2870-2878, 1992.

11. Logothetis CJ, Samuels ML, von Eschenbach AC, et al: Doxorubicin, mitomycin-C, and 5-fluorouracil (DMF) in the treatment of metastatic hormonal refractory adenocarcinoma of the prostate, with a note on the staging of metastatic prostate cancer. J Clin Oncol 1:368-379, 1983.

12. Yagoda A, Olsson C: Neoplasms of the kidney, bladder, and prostate, in Calabresi P, Schein PS, eds. Medical Oncology, 2nd ed. New York: McGraw-Hill, 1993.

13. Seidman AD, Scher HI, Petrylak D, et al: Estramustine and vinblastine: Use of prostate specific antigen as a clinical trial end point for hormone refractory prostatic cancer. J Urol 147:931-934, 1992.

14. Amato RJ, Logothetis CJ, Dexeus FH, et al: Preliminary results of a phase II trial of estramustine (Emcyt) and vinblastine (VLB) for patients with progressive hormone refractory prostate carcinoma (abstract 1111). Proc Am Assoc Cancer Res 1991;32:186, 1991.

15. Hudes GR, Greenberg R, Krigel RL, et al: Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. J Clin Oncol 10:1754, 1992.

16. Amato R, Logothetis C, Sella A, et al: Preliminary results of a phase II trial of estramustine (Emcyt), vinblastine (VLB) and mitomycin-C (MMC) for patients with progressive androgen independent prostate carcinoma (AIPCa) (abstract 1213). Proc Am Assoc Cancer Res 34:203, 1993.

17. Myers C, Cooper M, Stein C, et al. Suramin: A novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer. J Clin Oncol 10:881-889, 1992.

Neuroendocrine differentiation has been foundin 50% to 100% of prostate neoplasms of all stages. Furthermore,10% of prostatic tumors are extensively or fully differentiated.Thus, neuroendocrine-specific

Chemotherapeutic Approaches in Advanced Prostate Cancer

Following the formal presentations at this conference, the floor was thrown open to questions from the audience. Following are selected questions and answers that were deemed of particular clinical relevance.

· Question: If you plan to give a patient a 4 mCi dose of Sr-89, how do you advise the physicist to prepare the dose?

· Answer: Dr. Porter--Most clinicians use the reference dose and date recorded on the label to determine the dosage at the time of administration. However, the NRC regulations listed in the Federal Register require that any radioisotope dose in excess of 10 mCi must actually be measured. Although this currently applies only to gamma-emitters, the NRC has set forth a proposal that all alpha and beta emitters also require internal measurements, indicating that proper records must be maintained. This is extremely important to those of us involved in Sr-89 therapy.

The current definition of misadministration are: The wrong patient, route, or dose (by greater than 20% of the prescribed dosage).

The problem encountered in Sr-89 calibration is the difficulty measuring the bremsstrahlung (radiation arising from an interaction between beta particles and surrounding atomic nuclei) to the beta radiation, the minor Sr-89 gamma component of 909 KeV (1%), and the variation in the Sr-85 contamination (gamma component, 514 KeV). In addition, the wall thickness and type of container used imposes more variability. For example, with a level of Sr-85 contamination typically between 0.1 and 0.2%, the difference in the calibrated response can be 27%, exemplifying the importance of accurately detailed contamination levels from the manufacturer for each batch of Sr-89.

Therefore, a new radiopharmaceutical rule was proposed by the NRC/NIST in October 1993. It states that all alpha- and beta-emitting radiopharmaceutical dosages must be measured by direct assessment of activity using a combination of measurements and calculations, except for unit dosages obtained from a manufacturer or preparer licensed pursuant to 10 CFR 32.72 or equivalent state requirements. A recognized preparer of pharmaceuticals can be a hospital or licensed regional pharmacy. Clearly, assaying dosages will soon become more complicated.

· Question: What is the durability of strontium for pain relief and how often can you readminister Sr-89 if pain recurs?

· Answer: Dr. Porter--Several studies have indicated that the duration of the pain response is approximately three to 4 months. If hematologic parameters are not significantly altered, the patient can be retreated. In patients who are not hematologically compromised, I often retreat a second time with 3 or 4 mCi doses without notable problems. However, I am more hesitant to administer Sr-89 a third time.

· Question: We have treated ten patients with strontium and one developed signs of extravasation. Have any of you experienced this problem and should there be instructions or cautions regarding possible extravasation for this agent?

· Answer: Dr. Porter--I believe it depends on how the strontium is administered. Did you use a butterfly in the vein? If so, that could be the problem. Butterfly infusion is not recommended.

· Dr. McGowan--I believe that Sr-89 can be safely administered subcutaneously without concern about extravasation. Since physiologically it will be handled as calcium, I would not be concerned about an Adriamycin-like toxicity.

· Comment from an oncologist in the audience--Our staff consists of well- trained chemotherapy nurses who follow the usual precautions. Despite this, one patient who developed edema after treatment with strontium was treated with heat in the emergency room, worsening the condition. After 6 or 7 hours, I saw this patient, applied ice and the edema disappeared in 2 or 3 days. Fortunately, there was no skin desquamation or ulcer formation.

· Dr. Porter--There is probably less of an extravasant reaction with Sr-89 than with infusion of cytotoxic chemotherapeutic agents, due to the dose, the infusion rate, and the fact that the skin has a high tolerance for radiation. For preventive measures, one should not infuse with a butterfly in a vein. It is more desirable to infuse Sr-89 into a running I.V. of saline. This provides a dilutional effect, avoiding the theoretical risk of a cardiac incident, since strontium is very similar to calcium (although, to my knowledge, there have been no cardiac incidents due to Sr-89 therapy). Secondly, this mode of administration insures the patency of the infusion.

· Question: Do you have any recommendations on using centerlines, since strontium is a calcium analog?

· Answer: Dr. Porter--I would be relatively cautious about using an untested centerline.

· Question: Do Board-certified radiation oncologists have reason to be concerned over medicolegal liabilities for administering radioactive agents, as opposed to a Board-certified radiologist?

· Answer: Dr. Porter--I would actually assume the opposite, since our profession is a patient-treating specialty. Strontium-89 is clearly not a diagnostic tool. It is a therapy, which has to be integrated with other available therapies and the extent of disease progression. The training accepted for radiation oncology by the ACGME (Accreditation Committee for Graduate Medical Education) expects us to have an understanding of isotopes. In some ways, this particular point in our training has been abrogated. If radiopharmaceuticals are to become standard in prostate cancer therapy, it behooves us to attain and retain such expertise.

· Question: Who prescribes and administers radioiodine in the United States?

· Answer: Dr. McGowan--In our jurisdiction in Canada, it is almost exclusively administered by the radiation therapist.

· Dr. Stone--At our institution, endocrinologists and nuclear medicine physicians are involved. It is prescribed by the endocrinologists.

· Comment from the audience--In Australia, a radiation oncologist is licensed for external beam radiotherapy, radiopharmaceutical therapy, and the use of seed sources. For a fee, we are licensed to use all three modalities.

· Dr. Poulter--It is variable in our cities. Sometimes it is administered by nuclear medicine physicians and sometimes by radiation oncologists. Proper training is the vital issue with radioiodine handling.

· Dr. Poulter--I would like to make a comment related to this matter. In my experience, nuclear medicine physicians are not sufficiently trained to make therapeutic judgements for metastatic bone disease. They must be made more familiar with alternative therapy options. The administration of the radiopharmaceutical is not the only issue. The appropriateness of Sr-89 treatment must be determined by those with experience in treating metastatic disease.

· Comment from the audience--There are really two factors that must be considered. There is the licensing to prescribe/order the radiopharmaceutical and the licensing by the NRC to administer it. I believe that in the United States, radiation oncologists cannot administer radioactive substances unless they have 30 hours of radioimmunoassay experience and a Board license. Is that correct?

· Dr. Porter--No. Each state actually has different criteria that determine whether a physician is properly credentialed. Some hospitals even have their own criteria and process. The NRC approves the license if you were Board- certified in radiation oncology, nuclear medicine, or radiology before a certain year. In addition, there is no limitation concerning the radiopharmaceuticals you are licensed to administer.

However, the NRC apparently requires dose calibration by the clinician and most dose calibrators do not have Sr-89 settings. The setting must be established with the first Sr-89 shipment, relying on the accuracy of the manufacturers calibration. There is currently no standard or requirements for the physician to take measurements for a pure beta emitter, but they are forthcoming and we must develop this expertise.

· Question: Dr. Poulter, are there significant toxicities associated with hemibody radiotherapy as it is administered today?

Following the formal presentations at this conference, the floorwas thrown open to questions from the audience. Following areselected questions and answers that were deemed of particularclinical relevance.

ONCOLOGY Vol 8 No 11 | Oncology

Use of Strontium-89 in Metastatic Cancer: US and UK Experience

External Beam Radiotherapy for Metastatic Cancer

A Multidisciplinary Approach to the Management of Patients With Metastatic Disease to the Bone

Metastatic Prostate Cancer: Quality of Life and Cost Considerations

Chemotherapeutic Approaches in Advanced Prostate Cancer

Questions and Answers

Case Reports: A Roundtable Discussion

Hormonal Approaches in the Treatment of Bony Metastases