Pain Management in Patients With Advanced Prostate Cancer

The article by Olson and Pienta is a thorough review of the important issues facing men with metastatic prostate cancer and their caregivers. Many recent reports have documented physicians’ lack of awareness about cancer pain, which underscores the significance of proper evaluation and management. As the authors note, any evaluation of current and future therapies must focus not only on the efficacy of pain control but also on how a particular treatment affects a patient’s overall quality of life.

In this review, the authors first outline an appropriate patient evaluation in terms of pain syndromes, pain assessment, and diagnostic imaging. As they report, radionuclide scintigraphy is a highly sensitive (approximately 80%) but nonspecific tool in the evaluation of osseous disease, often requiring correlation with plain films to evaluate positive findings. However, magnetic resonance imaging (MRI) can directly image the fatty and cellular tissue elements and, contrary to the authors’ contention, is preferable to computed tomography (CT) for clarifying an equivocal bone scan.[1-3]

The rest of the article focuses on the various currently available local and systemic therapies for managing pain in patients with advanced prostate cancer, including analgesics, external-beam radiation therapy, radionuclide therapy, and newer systemic agents, such as the bisphosphonates and certain chemotherapeutic agents. Although not explicitly stated in the review, androgen deprivation is an effective first-line modality in advanced prostate cancer and should be considered in nearly all patients.

The analgesic ladder of the World Health Organization (WHO) is well described in the article, and Olsen and Pienta expertly detail the salient points of its application. From my perspective as a radiation oncologist, the efficacy of external-beam radiation therapy and radionuclide therapy in relieving pain is well established. Current investigations of radiotherapeutic approaches for the management of the bone metastasis warrant further comment.

Local Radiation Therapy

Osseous metastasis is a major cause of cancer-related pain. The goal of palliative care is not only to provide durable pain control but also to preserve mobility and maintain skeletal integrity—benefits that are not afforded by analgesics. For this reason, external-beam radiation remains a mainstay in the management of limited metastatic sites. Offering effective pain relief in 70% to 80% of patients, external radiation completely relieves symptoms in 30% to 50% of treated men.[4-7]

Optimal Dose and Fractionation—The optimal dose and fractionation schedule remain controversial, however. Shorter treatment courses reduce patient inconvenience and are less costly but may be associated with a less durable response and higher toxicity. Standard palliative regimens have used 30 to 40 Gy in 10 to 20 fractions, as compared with a more hypofractionated schedule of 4 to 20 Gy delivered in 1 to 5 fractions.

Several randomized trials have addressed this issue; these are summarized in Table 1. In the United States, the Radiation Therapy Oncology Group (RTOG) randomized patients with a solitary bone metastasis to receive either 40.5 Gy in 15 fractions or 20 Gy in 5 fractions, while patients with multiple sites of pain received 30 Gy in 10 fractions, 15 Gy in 5 fractions, 20 Gy in 5 fractions, or 25 Gy in 5 fractions. The primary end point of this trial was improvement in pain scores, as assessed by the treating physician. When the groups were analyzed separately, no statistically significant differences were noted with regard to overall or complete pain relief, duration of response, or retreatment rates.

In a reanalysis of the data, Blitzer combined the groups and expanded the end points to include improvement in narcotic scores and incidence of retreatment to the same site. He concluded that prolonged courses of treatment were significantly associated with improved outcomes.[8]

At the British Royal Marsden Hospital, Price et al compared a single fraction of 8 Gy to with 30 Gy in 10 fractions. Response at 4 weeks, as assessed by patients, revealed similar overall response rates with a single dose as with the more protracted course (67% vs 75%); complete response rates were also similar (27% vs 27%).[5]

A subsequent trial at the same institution, reported by Hoskin et al, suggested that 4 Gy in one fraction was inferior to 8 Gy in one fraction in terms of response (69% vs 44%). Retreatment was also more common in the low-dose group.[6]

According to Olsen and Pienta, an advantage of regimens using a single fraction is that retreatment is possible if pain returns. This suggests that retreatment is impossible following multifraction therapy, which is incorrect in a majority of situations. In addition, the need for more frequent retreatment should be viewed as a drawback of single-fraction therapy, as it suggests the ineffectiveness of initial therapy.

Shortcomings of many of the trials described above include a lack of statistical power, no standard assessment of response, and the absence of validated quality-of-life measures. Obtaining this type of data should greatly enhance our ability to assess the effectiveness of palliative therapy.

In Denmark, Nielsen et al recently reported the results of a multicenter trial that compared 8 Gy in one fraction to 20 Gy in four fractions using sophisticated assessment tools. Although both of these schedules would be considered short by US standards, it is encouraging that the trial found no differences between the two with respect to toxicity or quality-of-life measurements.[7]

In an effort to determine whether the largely European/Canadian approach of single-fraction therapy is effective and tolerable, the RTOG is currently randomizing patients to either 8 Gy in 1 fraction or 30 Gy in 10 fractions (RTOG 97-14). Importantly, the objectives of the study include a detailed investigation of quality of life, pain assessment, and economic impact.

Prescribing Patterns of Radiation Oncologists—Despite the results of these aforementioned randomized trials, there appears to be little change in the prescribing habits of radiation oncologists, at least in the United States. In a 1985 survey of 268 radiation oncologists, Coia et al found that most respondents used 30 Gy in 10 fractions.[9]

A more recent survey, reported in 1998, showed that 90% of radiation oncologists continue to use longer fractionation schemes, defined as at least 10 treatments. In comparison, 20 Gy in 5 fractions and single-fraction therapy were used sparingly, by 6% and 1%, respectively. The tendency to use longer fractionation schemes was most pronounced among private practitioners and those who began practicing before 1982.[10]

Systemic Radiation Therapy

Wide-field (hemibody) radiation therapy may be appropriate for patients with multiple sites of pain. With a response rate of approximately 70%, this therapy can be delivered either as a single dose or in a fractionated course. Used as a single modality or in combination with local field radiation, hemibody radiation therapy is limited by potential acute and subacute toxicity (eg, nausea and vomiting, diarrhea, pneumonitis, hypotension, and hematologic effects).

Strontium-89 (Metastron) is a pure beta-emitting radioisotope. It is preferentially incorporated in diseased bone and delivers dose over a very short range, largely sparing normal surrounding bone marrow. Despite these favorable properties and a response rate of nearly 80%, use of strontium-89 is limited by thrombocytopenia and leukopenia, particularly in men with significant bone marrow involvement.

A promising approach is to combine local external-beam radiation therapy with radionuclide therapy. The rationale for this approach stems from the knowledge that many patients who initially present with only one or two sites of pain develop multiple sites within a short time period. Instead of treating these areas with a “postage stamp” approach, patients may receive local therapy to the initial site(s) followed by “prophylactic” strontium-89 administration.

As Olsen and Pienta report, this approach was tested in a large Canadian randomized trial.[11] Patients with multiple sites of pain and adequate hematologic function received local exter-

nal-beam radiation therapy, followed by either placebo or a single injection of strontium-89 (10.8 mCi). The strontium-89 group demonstrated a superior response, as indicated by a significant reduction in the development of new sites of pain and a longer interval to further palliative radiation (51 vs 23 weeks). As expected, the primary toxicity of the combination therapy was hematologic (23% incidence of grade 3/4 thrombocytopenia). A subsequent cost analysis demonstrated a benefit of strontium-89, deriving from a reduction in the requirement for additional external-beam therapy.[12]

A follow-up study surveyed US physicians, asking them to choose treatment approaches to hypothetical scenarios. Results of this survey suggested that 40% of physicians would supplement local-field radiation with strontium, indicating an emergence of this approach.[10] In my experience, strontium use in the United States is more restricted, however. It is also noteworthy that the standard lower adjuvant dose (4 mCi) was more commonly recommended by survey respondents. This finding underscores the lack of consensus on the most appropriate use of strontium.

Bisphosphonates and New Chemotherapeutic Agents

The bisphosphonates and newer chemotherapeutic agents also offer great promise in slowing the progression of metastatic disease. Although the bisphosphonates are generally well tolerated and randomized data support their use in osseous metastasis from breast cancer (as noted by the authors), their role in the management of prostate cancer pain remains largely unproven.[13]

Similarly, newer chemotherapeutic regimens have demonstrated some efficacy in controlling pain and producing a prostate-specific antigen (PSA) response but, at present, are not considered part of standard management. Finally, despite the therapeutic challenge posed by an increase in bone marrow toxicity, limited experiences have demonstrated that the combination of chemotherapy and radionuclides is feasible and produces responses in some patients with advanced prostate cancer.

Summary

This report by Olson and Pienta is a valuable resource for individuals involved in caring for patients with prostate cancer. As the authors point out, determining the most appropriate therapy requires careful evaluation and individualization. Hormones and analgesics are effective first-line agents. The WHO analgesic ladder guidelines serve as a useful reference.

From the radiation oncology perspective, external-beam therapy remains an important component of the management of limited, painful osseous prostate metastasis. Until the results of RTOG 97-14 become available, treatment schedules of 20 Gy in 5 fractions or 30 Gy in 10 fractions should be considered the current standards for local presentations. An acceptable alternative in patients with a poor performance status or short life expectancy may be 8 Gy in one fraction.

The combination of strontium-89 and external-beam therapy appears to be an emerging new approach, while the bisphosphonates and newer chemotherapeutic agents also hold great promise in the management of patients with multiple sites of painful disease. Determination of the optimal dose and schedule of strontium delivery and its use in conjunction with external-beam radiation therapy and the other systemic agents will require further evaluation.

References:

1. Freedman G, Negendank W, Hudes G, et al: Preliminary results of a bone marrow magnetic resonance imaging protocol for patients with high-risk prostate cancer. Urology 54:118-123, 1999.

2. Turner J, Hawes D, Williams R: Magnetic resonance imaging for detection of prostate cancer metastatic to bone. J Urol 149:1482-1484, 1993.

3. Fujii Y, Higashi Y, Owada F: Magnetic resonance imaging for the diagnosis of prostate cancer metastatic to bone. Br J Urol 75:54-58, 1995.

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

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

6. Hoskin P, Price P, Easton D, et al: A prospective randomized trial of 4 Gy or 8 Gy single doses in the treatment for metastatic bone pain. Radiother Oncol 23:74-78, 1992.

7. Nielson O, Bentzen S, Sandberg E, et al: Randomized trial of single dose vs fractionated palliative radiotherapy of bone metastasis. Radiother Oncol 47:233-240, 1998.

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

9. Coia L, Hanks G, Martz K, et al: Practice patterns of palliative care for the United States 1984-1985. Int J Radiat Oncol Biol Phys 14:1261-1269, 1988.

10. Ben-Josef E, Shamsa F, Williams A, et al: Radiotherapeutic management of osseous metastases: A survey of current patterns of care. Int J Radiat Oncol Biol Phys 40:915-921, 1998.

11. Porter A, McEwan A, Powe J, 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.

12. Malmberg I, Persson U, Ask A, et al: Painful bone metastases in hormone-refractory prostate cancer: Economic costs of strontium-89 and/or external beam radiotherapy. Urology 50:747-753, 1997.

13. Bloomfield D: Should bisphosphonates be part of the standard therapy of patients with multiple myeloma or bone metastases from other cancers? An evidence-based review. J Clin Oncol 16:1218-1225, 1998.