Prostate Cancer in the Late 1990s: Hormone Refractory Disease Options.
This educational activity is designed for nurses and other health care professionals who care for and educate patients regarding prostate cancer. The multiple choice examination that follows is designed to test your achievement of the following educational objectives. After studying this offering, you will be able to:
1. Explain the progression of prostate cancer to the hormone-refractory prostate cancer (HRPC) phase.
2. Explore pain management strategies for prostate cancer.
3. Discuss current pharmacologic management of HRPC.
Prostate cancer is the most common tumor and second most common cause of cancer deaths in men in the United States, with an estimated 179,000 new cases expected in 1999 (Landis, Murray, Bolden, & Wingo, 1999). Because of the impact of public awareness and screening with the prostate specific antigen (PSA) blood test, the incidence peaked at 317,000 cases in 1996 and then declined to more steady state levels. Prostatic tumors spread to the regional pelvic lymph nodes and via the bloodstream to the bones, where they classically cause osteoblastic metastases in the axillary skeleton; however, screening has led to fewer cases of metastatic disease in the late 1990s. Specifically, the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute (NCI) found that the population-adjusted rate of advanced prostate cancer has declined in the last 5 years (Stephenson, 1998). Patients may either present initially with bony metastases, called stage D2 or M1 disease, or they can progress to this stage after unsuccessful treatment of earlier stage disease.
Metastatic Disease (M1)
Metastatic prostate cancer is diagnosed by radionuclide bone scans, computed tomographic (CT) scans, magnetic resonance imaging (MRI) scans, and most recently the ProstaScint[R] radionucleide scan which is an immunoconjugate containing a monoclonal antibody directed toward prostate-specific membrane antigen (PSMA) (Kahn et al., 1994). Radioactive indium-111 labeling enables ProstaScint (an imaging agent) detection by gamma camera imaging after it has localized to sites of prostate cancer expressing PSMA. An elevated prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and/or alkaline phosphatase blood test value may also suggest bony metastatic disease. An index of suspicion based on the blood test(s) would lead a clinician to order a bone scan. Only in equivocal cases would the other radiographic tests such as MRI, CT, or ProstaScint be indicated.
Hormonal therapy, which is treatment based on lowering the body's male sex hormone testosterone and its derivatives, is the primary treatment for patients with metastatic prostatic carcinoma (Crawford, 1994; Moul, 1998). Eighty-five percent of patients will have a response to hormonal treatment. Previously, there was a debate as to whether hormone therapy should be administered at the time of diagnosis of metastatic disease or withheld until the patient becomes symptomatic. There is now evidence suggesting that early hormone therapy prolongs survival and decreases cancer-related morbidity including spinal cord compression and bladder outlet obstruction (The Medical Research Council Prostate Cancer Working Party Investigators Group, 1997). Although most androgens come from the testes, a small but significant amount is derived from the adrenal secretion of androstenedione and peripheral conversion to testosterone. Standard hormonal therapy has been targeted at eliminating testicular androgens by orchiectomy or LH-RH injections. Several studies have suggested that combined androgen blockage directed at both testicular and adrenal sources of androgens results in a modest prolongation of survival (Caubet et al., 1997; Prostate Cancer Trialists' Collaborative Group, 1995). Limited data suggest that patients with low-volume metastatic disease may derive the most benefit from combination therapy (Caubet et al., 1997). Nevertheless, the use of combined androgen blockage remains controversial, especially in men who choose orchiectomy rather than LH-RH injections. In particular, a recent intergroup study showed that the addition of the anti-androgen flutamide was not beneficial in prolonging survival in stage D2 prostate cancer patients treated with orchiectomy (Eisenberger et al., 1998). Conversely, the antiandrogen Nilandron[R] has consistently shown a survival benefit in orchiectomy patients (Bertagna et al., 1994).
Testicular androgens can be eliminated by surgical castration called an orchiectomy (an outpatient procedure) or medical castration with estrogens or luteinizing hormone-releasing hormone (LHRH) agonist injections. There is little benefit to combining surgical castration with estrogens or LHRH agonist. Diethylstilbestrol (DES) was previously a commonly used estrogen but had cardiovascular side effects and caused gynecomastia and is no longer commonly used in the United States. LHRH agonists initially result in an increase in testosterone production followed by a decrease to castrate levels. An anti-androgen should be administered with LHRH agonist when initiating androgen ablation to prevent a "flare" of the prostate tumor associated with the initial stimulation of androgen production.
In a patient with symptomatic metastatic prostate cancer, such as bony metastases with bone pain, this flare, if not prevented with an anti-androgen, will increase bone pain. There are three FDA-approved anti-androgen medications: flutamide (Eulexin[R]) 250 mg 3 times daily; bicalutamide (Casodex[R]) 50 mg once daily; and nilutamide (Nilandron[R]) 300 mg once daily for the first month, then 150 mg once daily thereafter. Most clinicians will continue the anti-androgen medications as combination hormonal therapy (CHT; however, some only continue the antiandrogen for several weeks or months for the "flare." LHRH agonist can be administered as depot injections (leuprolide [Lupron[R]] or goserelin [Zoladex[R]]). These depot injections are available as 1, 3, and 4-month formulations. Side effects include hot flushes (which can be treated with megestrol acetate [Megace[R]] at 20 mg twice daily) and diminished muscle mass, libido, and sexual potency. The median survival of patients with metastatic prostate cancer tre ated with androgen ablation is approximately 3 years, although there is wide variation depending on the severity of metastatic disease. Furthermore, in the late 1990s many more patients have very early metastatic disease with fewer metastases and survival of 5 to 15 years is common.
A decline in the PSA level indicates a response to hormonal therapy. In patients who had bone pain at the start of hormonal therapy, the vast majority will have dramatic, rapid, complete relief of this pain. Patients who do not respond to initial hormonal therapy should have the level of serum testosterone measured to ensure that it is indeed at the castration level. A subsequent increase in the PSA level and/or return of symptoms, including bone pain, is an indicator of tumor progression. At this point, the patient has what is called hormone-refractory prostate cancer (HRPC) or what some clinicians also call stage D3 disease (Vogelzang, Crawford, & Zeitman, 1998). This is the stage of prostate cancer that is most commonly associated with painful bone metastases and other symptoms.
Prostate Cancer and Pain Control
Over the past several years it has been very encouraging to see patient awareness and support groups for men with prostate cancer -- such as Us Too and Man-to-Man -- springing up throughout the United States. Members are committed and highly informed individuals eager to be on the cutting edge of the most up-to-date information about prostate cancer. Like members of support groups for other types of cancer, these articulate men have challenged the medical community to examine the importance of pain management. Many patients with metastatic cancer have made it clear that pain -- not death -- is their worst apprehension about their illness. With prostate cancer, which may metastasize to the bones and cause enormous pain, this fear is not unfounded.
Yet until recently, the focus among health care providers has always been on eradicating the disease, and not on controlling its painful symptoms. Up until recently, this oversight has been reflected in medical school textbooks and classrooms, as well as in professional papers on cancer, which have not given a great deal of attention to the need for pain control (Bernabei et al., 1998; Cleeland, 1998).
In fact, many physicians are still reluctant to prescribe adequate pain medicine for cancer patients. Chief among their reasons are:
* Fear that a patient will become addicted to the drugs. In fact, this almost never happens with cancer patients.
* Side effects of the narcotic drugs, such as vomiting, constipation, and drowsiness.
* Concern about possible legal surveillance if they frequently write prescriptions for narcotics.
* Risk of robbery if it becomes known that narcotics are kept in the office.
* Fear that narcotics may cause cardiac arrest, respiratory problems, or drug overdoses.
* The existence of inappropriate dosing guidelines for cancer pain.
As a result of these concerns, health professionals have tended to err on the side of caution, and the result has been an under-treatment of cancer pain. This fact was documented in a 1991 study of 1,777 physicians belonging to the Eastern Cooperative Oncology Group (ECOG), 85% of whom said that they believed most cancer patients in the United States were under-medicated for pain (Dawson, 1997).
Physicians' concerns aside, one might ask why patients are themselves hesitant to ask for medication to relieve their pain. Perhaps the most obvious reason is that they, like their physicians, have the unfounded fear that they might get "hooked" on narcotics. Many patients also are uncomfortable with the possibility of clouding their mental abilities, a frequent side effect of these drugs. And finally, they are probably aware of their physicians' reluctance to prescribe pain medication, and therefore are simply afraid to ask. However, there is new hope on a number of fronts for cancer patients.
New Federal Guidelines
First of all, physicians and consumers have finally been provided with guidelines developed by the Agency for Health Care Policy and Research (a part of the U.S. Department of Health and Human Services). The guidelines help health care professionals assess a cancer patient's level of pain and suggest methods for relieving it. Literature has been developed that underscores the shared responsibilities of the patient, his family, and the health care team in learning about cancer pain and pain management options. There are several pain assessment tools -- from detailed questions to rating scales -- to enable all parties to evaluate a patient's pain and to help document the efficacy of pain relief after starting or changing treatment.
Treatment Options for Bone Pain
Treatment options for bone pain associated with hormone-refractory metastatic prostate cancer include oral non-narcotic and narcotic pain medication, parenteral pain medication, chemotherapy, external beam radiotherapy, and radioactive pharmaceuticals.
The analgesic requirement is considered before a specific medication or route of administration is selected. Route and desired dosing interval are dictated by the patient's needs. While morphine is most commonly used for cancer pain, and is considered the standard for comparison, no one medication is best for all patients. The duration of analgesia depends on a variety of factors including the route of administration and distribution characteristics of the drug. Drug selection generally follows the guidelines established by the World Health Organization (WHO) and American Pain Society.
In 1986, the WHO published guidelines (also referred to as the Analgesic ladder) for the use of analgesic drugs for cancer patients. These guidelines, based on a three-step approach, help provide a logical approach to management and when applied should reduce the incidence of under-treatment.
Step I. Patients with mild pain should be treated first with a nonopioid drug (aspirin, acetaminophen, or a nonsteroidal anti-inflammatory drug [NSAID]), if these are not contraindicated due to gastropathy, bleeding tendencies, renal dysfunctions, neutropenia, or sensitivity.
Treatment may be supplemented with an adjuvant (co-analgesic) drug, if specifically indicated. This usually refers to the use of an antidepressant or anticonvulsant for neuropathic pain.
Step II. For persistent or increasing (moderate) pain, treatment should progress to the administration of a weak opioid (codeine, oxycodone, hydrocodone, or dihydrocodeine). If indicated, treatment may be supplemented with a Step I nonopioid drug and/or adjuvant drug. The opioid component of the regimen should be administered around the clock (rather than by symptom), with caution to avoid acetaminophen or aspirin toxicity.
Step III. For persistent or increasing (severe) pain, treatment should progress to the administration of a potent opioid (for example, morphine, hydro-morphine, fentanyl). If indicated, treatment should be supplemented with a Step I nonopioid drug and or adjuvant drug. The potent opioid should be administered around the clock (rather than by symptom) to control basal pain and supplemented with a short-acting Step II or Step III opioid, as needed for breakthrough pain. Alternate routes of administration should be considered if the oral route proves ineffective or cannot be used.
Patients may access the ladder at any tier if the pain is severe on initial presentation, a potent opioid may be needed from the start. Also, progression through the ladder often needs to progress rapidly, so that patients do not experience prolonged periods of uncontrolled pain.
Routes of administration. When feasible, oral administration of analgesics is the preferred route of administration. Dosage forms include tablets, capsules, elixirs, and controlled-release tablets and capsules. Whenever possible, other routes of administration seen in home care include intraspinal, intraventricular, intrapleural, topical, transdermal, and rectal administration.
Adenocarcinoma of the prostate has been considered resistant to most chemotherapeutic regimens, but trials of single and multiple-agent chemotherapy for hormone-refractory prostate cancer are ongoing (Vogelzang et al., 1998; Waselenko & Dawson, 1997). The evaluation of chemotherapy treatment response in HRPC has been a major problem for both investigators and clinicians. The majority of patients have disease confined to bone, a site not readily amenable to objective response assessment. Bone scan response assessment is complicated by the slow improvements in true responders and the difficulty in distinguishing improvement from progression, both of which may appear as an increase in signal intensity. Similarly, evaluation of soft-tissue disease, which may involve only a minority of patients, is also difficult. Biochemical responses may be inferred from declines in PSA; however, it is difficult to know whether a PSA response reflects true reduction in tumor bulk or some direct effect of the treatment on the pr oduction of this serum marker. In addition, there have been attempts to quantify disease-related symptomatology using symptom score tools and quality-of-life (QOL) scales although these instruments are still being validated.
Survival and progression-free survival remain important endpoints in the setting of randomized, controlled studies. However, there is no accepted standard therapy for HRPC and no drug to date has demonstrated a survival advantage over other acceptable therapies (Vogelzang et al., 1998).
Objective responses occur infrequently and are difficult to define given the heterogeneity of tissues involved by the disease. For these reasons, disease palliation and pain control are now accepted endpoints and are recognized by the Food and Drug Administration (FDA) with regard to prostate cancer treatments. With this in mind, mitoxantrone (Novantrone[R]), a chemotherapeutic agent similar to adriamycin, was recently FDA approved for hormone refractory prostate cancer in combination with prednisone or hydrocortisone and is effective in palliation of bone pain, although a survival benefit has not been demonstrated (Kantoff et al., 1996; Tannock et al., 1996).
Two recent clinical trials employed quality-of-life and pain-scale measures to assess mitoxantrone efficacy in HRPC. One, by Tannock et al. (1996), reported that the combination of mitoxantrone plus prednisone was superior to prednisone alone in producing durable palliative responses. This Canadian trial comprised 161 HRPC patients with ECOG performance status of 0 to 3 and who had received no prior chemotherapy, glucocorticoids, or recent radiation or radiochemical therapy. Patients were randomized to either mitoxantrone at 12 mg/m2 by IV bolus every 3 weeks along with prednisone 5 mg twice daily, or prednisone alone. Patients failing prednisone were permitted to cross-over to the combination therapy arm. The primary efficacy endpoint was a two-point decrease in pain based on a sixpoint assessment scale (McGill-Melzack Pain Questionnaire) completed by patients without an increase in analgesic use and maintained for at least 3 weeks. Patients were evaluated for duration of palliative response and overall sur vival. In addition, three quality-of-life scales were employed to assess treatment responses. The sample size was chosen to detect a two-fold difference in the frequency of palliative response between the two arms.
At study entry, the patients' median age was 67 to 69 years, 95% to 98% had bone metastases, and a median PSA of 158 to 209 ng/dl. There was a median of 2.9 to 3.0 years from diagnosis to study entry. A median of six cycles of chemotherapy were administered. There were 2.4 fold more patients who received mitoxantrone and prednisone who achieved a palliative benefit than for patients receiving prednisone alone (29% vs. 12% respectively, p=0.01). In addition, the duration of palliative benefit was 2.3 fold longer for patients treated with the combination than for prednisone alone (11 vs. 4.5 months, p[less than]0.0001). Patients receiving mitoxantrone were also more likely to decrease their use of narcotics. However, the median overall survival was not significantly prolonged by this therapy (12 vs. 11 months, combination vs. prednisone respectively, p=0.27). There was a slight trend in favor of mitoxantrone to produce PSA responses. Lastly, mitoxantrone was well tolerated with only 7% of patients experiencing febrile neutropenia and 5% with congestive heart failure of any severity.
The results of a second study by the Cancer and Leukemia Group B support those of the Canadian study (Kantoff et al., 1996). In this trial, 242 men with HRPC were randomized to hydrocortisone 40mg daily with or without mitoxantrone, 14 mg/m2 every 3 weeks. A greater than 50% decline in PSA was seen in 33% of men on the combined therapy arm compared to 18% on hydrocortisone alone (p=0.035). In addition, a longer time-to-disease progression was seen on the combined therapy arm (7.3 vs. 4.1 months, p=0.065) and more patients receiving mitoxantrone with hydrocortisone achieved symptom palliation than for hydrocortisone alone.
Aside from mitoxantrone and glucocorticoids, current trials are focusing on ketoconazole, estramustine phosphate, vinblastine, and suramin (Vogelzang et al., 1998; Waselenko & Dawson, 1997). The most widely studied combination in the last 5 years has been estramustine phosphate and vinblastine (Vogelzang et al., 1998). Although a number of phase II trials showed an approximate 40% response defined as a PSA decline [greater than]50% (Vogelzang et al., 1998), a recently reported phase III trial of estramustine and yinblastine vs. vinblastine alone did not show any difference in median survival time (Hudes et al., 1997). The combination arm, however, was superior in terms of progression-free survival and Vogelzang and colleagues (1998) feel that estramustine phosphate plus vinblastine combination chemotherapy is a worthy choice for off-protocol use in HRPC.
A variant combination is estramustine phosphate plus etoposide, both oral agents. Initial experience by Pienta et al. (1994) found this combination to be active but toxic in patients with HRPC; however, a more recent report described a less toxic dosing regimen that is also active (Pienta et al., 1997).
Most recently, estramustine is being combined with other plant alkaloid family chemotherapy agents including vincristine, vinorelbine, paclitaxel, and docetaxel (Vogelzang et al., 1998; Waselenko & Dawson; 1997), although there are no phase III trials of those new combinations.
Suramin is a polysulfonated naphthylurea which bas cell growth suppressing effects seen on prostate cancer in vitro and in vivo (Vogelzang et al., 1998; Waselenko & Dawson, 1997). Most recently, a phase III trial of suramin plus hydrocortisone vs. hydrocortisone alone showed a significantly better palliative response for the suramin-treated men (Small et al., 1998). Despite this response, the FDA did not approve suramin when it came to a review panel late in 1998. Future trials will likely compare suramin to mitoxantrone and combine suramin and/or mitoxantrone with plant alkaloids and other chemotherapy agents such as estramustine (Vogelzang et al., 1998).
One of the more important breakthroughs for cancer patients is the availability of new, non-narcotic drugs to treat painful bone metastase. There are now two FDA-approved radioactive pharmaceuticals called strontium-89 (Metastron[R]) and samarium 153-lexidronam (Quadramet[R]).
Strontium-89 was first used in 1941 at the University of California at Berkeley in a prostate cancer patient suffering from bone pain (Crawford et al., 1994). The beta-radiation emitting medication is injected intravenously and follows the same biologic pathway as the mineral calcium which is critical to growth and development, particularly of the bones. It is taken up by the body's skeletal system, to a greater degree by the cancerous areas in the bone than by normal areas. This absorption of the radioactive agent may kill some cancerous cells, but it specifically works to reduce bone pain.
Patients usually begin to notice a reduction in pain between 10 and 20 days after the injection. Pain reduction lasts from 4 to 15 months, but on average about 6 months. If the pain returns, the patient can get another injection as often as every 3 months, with no limit on the total number of injections he can receive.
From 1976 to 1993, six clinical trials involving 550 patients evaluated the safety and effectiveness of strontium-89 (Crawford et al., 1994). Of these individuals, about 10% to 50% had complete or dramatic response, with bone pain completely or virtually eliminated. A partial or complete response was reported by 20% to 97% of patients in the different studies. On average, 80% of the men reported a partial or complete response rate. In other words, most of the men got some relief.
One of the studies also showed that strontium-89 decreased the number of new sites of bone metastasis (Porter et al., 1993). This study was a randomized trial in which some patients were given a placebo and others received strontium. Patients given the drug had significantly fewer new, painful bone lesions than those receiving placebo. Furthermore, one of the clinical trials also showed that patients receiving strontium had a considerably lessened need for extemal beam radiation.
Samarium 153-lexidronam has also undergone large-scale controlled testing in the United States and Europe (Collins et al., 1993). like strontium-89, there was improvement of pain in the majority of patients and relatively rapid onset of action, specifically within 1 week in many patients. The duration of pain control is variable but a single samarium 153-lexidronam injection typically was effective for 3 to 4 months. Both strontium-89 and samarium 153 may affect bone marrow function principally in the form of decreased platelet counts, but this side effect is relatively mild and reversible. Investigators are now conducting phase II trials combining radiopharmaceuticals with chemotherapy. Combinations being evaluated include strontium plus estramustine and vinblastine, strontium plus doxorubicin, and strontium plus mitoxantrone and hydrocortisone (Vogelzang et al., 1998).
Prostate cancer is a very common disease of older American men. As our population ages and remains healthy longer, prostate cancer will grow in importance. Unfortunately, despite improved public awareness and screening, some men still develop metastatic prostate cancer which is commonly associated with painful skeletal sites of spread. Hormonal therapy to lower male androgenic hormone levels is very effective initially, but many men will eventually develop hormone-refractory prostate cancer (HRPC). At the HRPC stage, bone pain from metastases is treated with oral and/or parenteral non-narcotic and narcotic medications according to the WHO guidelines. In addition, over the last few years, the FDA has recognized pain palliation as a critical endpoint to approve new treatments for HRPC. Mitoxantrone with glucocorticoids is a recently approved chemotherapy for HRPC and is effective for pain palliation. Radioisotopes are also effective for pain palliation and two agents, strontium-89 and samarium-153-lexidronam, are currently available. Studies of many other combinations of chemotherapies, chemotherapies plus radiopharmaceuticals, and these agents combined with biologicals, such as suramin, are underway.
Judd W. Moul, MD, FACS, is an Associate Professor of Surgery, Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD; and a member of the Urology Service, Walter Reed Army Medical Center in Washington, DC.
David R. Lipo, RPh, is Medical Director, Option Care Home IV and Nutrition Service, Dunmore, PA
Note: The opinions and assertions contained herein are the private views of the authors and are not to be construed as reflecting the views of the US Army or the Department of Defense, or Option Care, Inc.
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|Author:||Moul, Judd W.; Lipo, David R.|
|Date:||Jun 1, 1999|
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