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.

Articles

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?

· Answer: Dr. Poulter--In the early days, the major lethal toxicity associated with hemibody radiation was radiation pneumonitis. To the best of my knowledge, correcting for lung transmission and limiting the dose to 700 cGy has eliminated that problem. There were no cases of pneumonitis in the RTOG 8206 study.

In terms of hematologic toxicities, there are decreases in platelets and white blood cell counts, but this reverses spontaneously without treatment. I suspect that this effect could actually be ameliorated by growth factors allowing sequential radiation treatments or higher doses in fractionated therapy. However, with fractionation, organs such as the liver and kidney become dose limiting and shielding must be adopted, making the protocol rather complex.

· Question: How do you treat a patient with a rising PSA after radiotherapy or surgery if they are asymptomatic and the bone scan is negative?

· Answer: Dr. Stone--The question of when to start treatment is an area of much controversy. Recent data demonstrate that hormonal therapy most benefitted patients with minimal disease, typical of those with solid tumors. Early treatment with the best therapy yields the best response. The more difficult case is the patient who relapsed and failed radiation therapy, radical prostatectomy and chemotherapy. The PSA values of these patients often increase slowly and there is no real consensus concerning the best time to start hormonal therapy in these patients.

The Crawford Study consisted of patients with confirmed D1 or D2 disease and significant disease as determined by bone scan or chest x-ray. These patients were not treated due to their rising PSA values, so there is no information on the survival benefit of treating these relapsers with hormonal therapy.

Failing patients are often anxious about the disease progression and want active treatment. If the patient is sexually active, I typically wait until the acid phosphatase level is clearly above normal before starting treatment. If the acid phosphatase is normal, the bone scan is normal and the PSA is slowly increasing, I do not usually recommend therapy. My criteria to initiate hormonal therapy is an acid phosphatase level consistently above normal or a rapidly accelerating PSA (increases of ten or more increments at 3-month evaluation periods).

· Question: Dr. Logothetis, do you include lymph node involvement in the V1-V2 staging system for prostate cancer that you showed? Also, what is the role of the bisphosphonates, APD, etc, in the management of bone metastases?

· Answer: Dr. Logothetis--Since very few patients were referred to us because of nodal metastases, that parameter was not included in the staging system. Subsequently, we have modified the system to include node involvement. Originally, nodal metastases were considered a null variable, since it was assumed all patients had nodal disease prior to bone metastases. In the new modification, there is an N-positive category preceding the 01-02 category and some of these patients are now receiving systemic therapy.

Empirically, the bisphosphonates seem to relieve some symptoms. The results are not dramatic and there is not much organized data that is tumor specific for prostate cancer. Theoretically, the bisphosphonates should work better in lytic disease vs blastic disease.

· Dr. McGowan--Although metastases due to advanced prostatic cancer are often blastic, there is usually accelerated osteolysis, an indication for the use of bisphosphonate treatment. I agree that there is currently limited clinical data evaluating their usefulness for this disease. Two Medical Research Council studies were planned, consisting of patients with and without metastases and addressing the use of bisphosphonate adjuvant treatment.

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.

Questions and Answers

Attendees at this conference, held during the annual meeting of the American Society of Therapeutic Radiology and Oncology, were presented with nine case reports and asked how they would manage each patient. The panel of experts then gave their recommendations for management. Following is a brief description of each patient, the consensus view of the audience, and the discussion by the specialists.

· Dr. Porter: A 61-year-old gentleman is diagnosed with prostate cancer and undergoes a radical prostatectomy and lymph node dissection in 1983. Six years later, he presents with worsening pain in the lumbosacral spine and a PSA of 120. Therapeutic choices include: Hormonal manipulation; hormonal manipulation with radiotherapy to the lumbar cervical spine; isotope therapy; hemibody irradiation; or chemotherapy. How would you manage this patient?

Approximately 25% of our audience here would choose hormonal therapy and 75% would use both hormonal therapy and radiation therapy to the spine. Dr. Stone, what's your opinion?

· Dr. Stone: This patient has an excellent chance of responding completely to hormonal therapy. His presentation implies that he may fit into the category of minimal disease, with metastasis limited to the axial spine. Since these patients respond well to complete hormonal therapy, I would reserve radiation therapy for a relapse after hormonal therapy fails.

· Dr. Poulter: Hormonal therapy would be the obvious choice. The use of radiation therapy would depend on a number of factors, including the severity of pain, the risk of fracture or spinal cord compression, and the rapidity of the response to hormonal manipulation. PSA could be used to assess therapeutic effectiveness. My choice would be to start with one therapy because, when treating pain at a single site with two therapies, you do not know which one is providing the response.

· Dr. Logothetis: I would use hormonal therapy alone.

· Dr. Porter: A patient is referred to you after having received 4 mCi of Sr-89 approximately 5 weeks ago. He now has signs of spinal cord compression at level T10. There are four treatment choices: Local field radiotherapy of 3,000 cGy in 10 fractions; neurosurgery; readminister Sr-89; or chemotherapy. How would you manager this patient?

Responses from our audience indicate that approximately 75% would treat with local field radiation therapy to the area causing the cord compression and 25% would refer the patient to neurosurgery. This case addresses the concern of an additive toxicity from Sr-89 in the spinal cord and external beam radiation . A frequently asked question is--How does one account for the dose of Sr-89 previously administered? Dr. McGowan, what would you recommend in this case?

· Dr. McGowan: I would treat with external beam radiation. I am not concerned about an additive toxicity with Sr-89 in the spinal cord, since the isotope is absorbed mainly in bone, with minimal dosage delivered to the spinal cord. Neurosurgical intervention could also be considered, however, our community of neurosurgeons are very reluctant to operate on a patient with spinal cord compression from prostate cancer.

· Dr. Porter: I agree that there are no additive effects with Sr-89 and external beam radiation, since Sr-89 is a pure beta emitter. In fact, the TransCanadian study reported no increase in additive complications from treating spinal cord compressions with local field radiation followed by Sr-89 treatment.

· Dr. McGowan: I would like to add that I have actually seen several patients develop a spinal cord compression after receiving Sr-89. However, it has usually occurred within a week to 10 days post-treatment, as opposed to the 5-week interval described in this case.

What next for this man who failed leuprolide and flutamide?

· Dr. Porter: A patient with D2 metastatic prostate cancer is treated with total androgen blockade consisting of leuprolide (Lupron) and flutamide (Eulexin). After 2 years on this therapy, he relapses and complains of pain that he describes as "fleeting." His bone scan is positive and his PSA has risen. Treatment choices include: Isotope therapy; hemibody radiotherapy; local field radiotherapy to bone-scan-positive areas; or chemotherapy using estramustine (Emcyt) and VP-16 (etoposide, VePesid).

The majority of attendees in our audience chose isotope therapy.

· Dr. Logothetis: These patients require discussion in choosing the appropriate treatment regimen. If you have an 80-year-old gentleman, there is typically no interest in the inconvenience associated with investigational therapy. Therefore, strontium would be the appropriate choice when pain palliation is the main therapeutic goal. Alternatively, a younger patient or one who would prefer to explore all available options, would be a candidate for investigational therapy. Once these patients understand that these treatment options are unproven, the choices of estramustine, VP-16, or various combinations can be considered. I know of no proven advantages among them at this time.

I have a note on one of the question cards submitted by the attendees inquiring about angiogenesis inhibitors, which we are studying. One such drug, fumagillin, is currently being tested clinically for the treatment of prostatic carcinoma.

· Dr. Porter: An 84-year-old man was treated with 4 mCi of Sr-89 5 months ago. His disease progressed and he died. His family wishes to have him cremated. As the radiation oncologist, should you advise that the body be stored for two half-lives prior to cremation and should you advise the crematory about the Sr-89, or is that not necessary? Is radiation emission from the body not a concern?

There are few rules governing the cremation of a body containing a beta emitting substance. One study, by the International Association of Physicists in Medicine, addressed safety rules concerning Sr-89. This association is not a legal body in the United States. Nonetheless, they recommend that a body could be cremated with a dose of 400 MBq of Sr-89 and buried with a dose of 1000 MBq (divide by 37 to convert MBq to mCi). Since 400 MBq is well above the dosage currently used, a patient could be cremated even if he died the same day the Sr-89 was administered. The cremating facility should, of course, be informed. The Nuclear Regulatory Commission met with us recently and is debating the standards of dose responsibilities for Sr-89.

· Dr. Porter: A patient with well-controlled primary lung cancer requires palliative radiotherapy for a painful metastasis in the lumbar spine. How should this patient be treated in terms of dose fractionation? On the basis of the data that Colin Poulter presented (see page 19), would you use: 800 cGy in a single local field fraction; 2,000 cGy in five fractions; 3,000 cGy in 10 fractions; or 4,000 cGy in 20 fractions.

Responses from our attendees indicate that 3,000 cGy in 10 fractions is considered standard in North America. Colin, what are your thoughts on dose fractionation?

· Dr. Poulter: Our standard treatment dosage is 3,000 cGy in 10 fractions. However, since numerous factors are considered in dose determination, we frequently deviate from the standard protocol. Some patients, for example, would receive a single dose of 800 cGy.

· Dr. McGowan: My standard treatment regimen is 2,000 cGy in 5 fractions or 1,000 cGy in a single fraction. The dose is decreased to 800 cGy in a single fraction for rib metastases. The single treatment patients are often those who must travel long distances. In Canada, some patients have to travel 300 or 400 miles for treatment, prompting most Canadian clinicians to use shorter fractionations for practical reasons.

· Dr. Porter: A 55-year-old lady was diagnosed at age 40 with Stage-2 breast cancer. She was treated by mastectomy and adjuvant CMF chemotherapy. Unfortunately, 3 years ago, at age 52, the disease recurred. Workup revealed a single metastatic lesion in the liver and several lesions in the axial skeleton. She then received six courses of second-line, Adriamycin-based chemotherapy. There was a partial regression of her liver metastasis, but her bone scan worsened. She now presents with pain in her lumbar spine, clavicle, and left hip associated with diffuse metastatic disease on the bone scan. Her hemoglobin is 8.7, white cell count 4.3, and platelet count is 75. Therapeutic choices include: Third-line chemotherapy; sequential hemibody radiation; local field radiotherapy to involved areas; Sr-89 therapy; or opiate analgesia alone.

Most of our audience participants have chosen local field radiation therapy or Sr-89 therapy. This is a patient that a medical oncologist would have been treating. Chris, would you have chosen local field radiotherapy or Sr-89 therapy?

· Dr. Logothetis: My initial concern would be the metastasis to the hip, since it is a primary weight bearing bone. There is such a high rate of fractures with metastatic breast cancer and it is so devastating to the patient that local beam radiation to that site would be indicated immediately. Next, the options of third-line chemotherapy versus strontium would be considered.

· Dr. Poulter: We would prescribe local field radiation for this patient. I would not use hemibody radiation therapy or strontium, given the hematologic parameters presented by this patient.

· Dr. Porter: I agree with Dr. Poulter. Although Sr-89 is indicated for patients with platelet levels as low as 60,000, I am hesitant to treat patients with platelet counts less than 100,000 with Sr-89, especially if they have had prior chemotherapy. Most of these patients have some permanent marrow dysfunction and the administration of Sr-89 could easily result in a Grade III or IV irreversible myelotoxicity. Caution should be exercised with strontium treatment in the presence of previous myelotoxic chemotherapy. Therefore, usually I do not administer Sr-89 to patients with breast cancer and a platelet count less than 100,000.

· Dr. McGowan: Since this patient has breast cancer, I feel that some hormonal therapy is indicated.

A man with metastatic prostate cancer who is in renal failure

· Dr. Porter: A 65-year-old gentleman with prostate cancer metastatic to bone has been treated with total androgen blockade and has failed therapy. He now presents with severe pain that he cannot pinpoint, but describes as "all over." His bone scan confirms multiple metastatic disease. His hemoglobin is 10.6, white cell count is 3.5, platelets 220,000, but his urea and creatinine are raised, indicative of chronic renal failure. Choices of palliative therapy include: Hemibody radiotherapy; isotope radiotherapy; opiate analgesia alone; or cytotoxic chemotherapy.

Approximately 25% of our respondents opted for hemibody radiotherapy and 30% chose isotope radiotherapy. Dr. Stone, if you had a patient with chronic renal failure, how would you proceed?

· Dr. Stone: First, I would verify that the renal failure was not secondary to urethral obstruction, which is so common in these patients and treatable. If nephrotoxic chemotherapy is to be considered, renal function should be optimized first. Since Sr-89 is excreted via the urine, should the dose be moderated in patients with reduced creatinine clearance or does its long half life and bone retention make that unnecessary?

· Dr. Porter: Since 90% of Sr-89 is excreted by the kidneys, how to handle patients with abnormal urea and creatinine is an important issue. Data from the TransCanadian Study demonstrated that patients with borderline increased urea and creatinine did not experience nephritis secondary to Sr-89 treatment. However, since it is a radioactive element that is cleared through the kidneys, I would tend not to treat a patient in renal failure with Sr-89.

· Dr. McGowan: I would not recommend hemibody radiotherapy, but there are two other therapies I would consider. I have administered Sr-89 at a decreased dosage of 3 mCi without any problems. Alternatively, diethylstilbestrol diphosphate is sometimes effective under these circumstances.

· Dr. Porter: You have treated a 73-year-old gentleman with "fleeting" pain and endocrine-refractory, metastatic prostate cancer with 4 mCi Sr-89. Two weeks after therapy, the patient is in excruciating pain that is not localized to any one spot. You decide that this is a pain flare secondary to Sr-89 therapy. Therapeutic options for pain palliation include: Increased analgesia; Decadron (dexamethasone) 2 mg tid, p.o.; inform the patient that the pain duration will be less that 2 weeks and do not treat; re-evaluate for disease progression; or give Megace (megestrol acetate) 40 mg tid.

Responses from our audience indicate that most would increase analgesia, while approximately 30% chose Decadron, and some would suspect disease progression. David, since you have significant experience with this, how would you treat this pain flare?

· Dr. McGowan: The timing of this patient's pain flare is later than what I would expect from strontium administration. Therefore, I would be concerned about the possibility of progressive disease. I would not treat with steroids, but an increase in analgesia is indicated. A pain flare from Sr-89 should diminish in about one week. If the pain persists or worsens, the disease has probably progressed and therapeutic choices must be reconsidered.

· Dr. Porter: I disagree that the timing of this patient's pain flare is not typical. I have observed pain flares after approximately 2 weeks of Sr-89 administration. Decadron 2mg tid will often provide patients with relief. Therefore, I would increase the analgesia and perhaps treat with a steroid to alleviate an edema-mediated problem.

Would Sr-89 be appropriate for this man with pain in the cervical spine?

Eight months ago, a 65-year-old, active man with prostate cancer that is metastatic to bone and is considered refractory to hormonal therapy, developed severe pain in the cervical spine, with disease primarily in C3, C4 and C5. He was treated with radiotherapy and via a single posterior field received 4,000 cGy at 5 cm depth, using Cobalt-60. Treatment was delivered in 200 cGy fractions. The patient did well for 6 months and was relatively pain-free. He now presents with worsening pain, again in the cervical area. A bone scan shows metastatic disease predominantly in C3, C4, and C5 and a new lesion in L2 and in the right femur, which are asymptomatic. An MRI of the spine does not show any cord compression, but does confirm the presence of bone metastases. Therapeutic choices include: Further local radiotherapy to the cervical spine; halo fixation; opiate analgesia; isotope radiotherapy; chemotherapy; or Itrium-90 hypophysectomy, which is in fact what the patient had.

Colin, would you have used Sr-89 in a situation such as this?

· Dr. Poulter: I would not give further local radiotherapy. Sr-89 could be administered, since it will not significantly increase the dose to the spinal cord. Halo fixation, if the cervical spine appears very unstable, may be indicated as a temporary measure. In addition, opium analgesia may be necessary.

Attendees at this conference, held during the annual meetingof the American Society of Therapeutic Radiology and Oncology,were presented with nine case reports and asked how they wouldmanage each patient. The panel

ONCOLOGY Vol 8 No 11 | Oncology

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

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