Prostatic Disorders
`
`Edited and with Contributions by
`
`DAVID F. PAULSON, M.D .
`Professor and Chief
`Division of Urology
`Department of Surgery
`Duke University Medical Center
`Durham, North Carolina
`
`30 Contributors
`
`Lea & Fe big er
`
`Philadelphia
`London
`
`1989
`
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`22
`Management of Metastatic Carcinoma of the
`Prostate-Treatment Options and Controversies
`
`Marc B. Garnick
`
`INCID ENCE
`
`Prostate cancer is the second most common carcinoma in males in the United
`States and the third leading cause of male death from neoplasia. 1 In the United
`States in 1987, 83,000 cases were diagnosed in whites (44.7 per 100,000 pop(cid:173)
`ulation) and 13,000 (79 per 100,000) in blacks. More than 26 ,000 men died of
`prostate carcinoma in the United States in 1987. The cause of the disease is
`unknown. Moreover, this disease occurs more frequently in first-generation
`Japanese in this country than in native Japanese.
`American blacks have the highest prostate cancer rate in the world. Although
`no explanations for such racial differences are universally accepted, recent data
`suggest that college-aged black males have a 15% higher testosterone level and
`a 13% higher dihydrotestosterone level than white college students. 2 These
`higher levels have been postulated as a possible explanation for this increased
`rate of cancer.
`
`PATHOLOGIC FEATURES AND STAGING
`
`Prostatic neoplasms are nearly always adenocarcinomas. The prognosis can
`be correlated with grade of the cancer. Using the system devised by Gleason
`(Fig. 22-1) , in which five separate histologic patterns are identified, one may
`correlate the incidence of metastases, bone pain, hydronephrosis , elevation of
`acid phosphatase levels, and ultimately, cancer deaths both with histologic
`features and with differentiation (Fig. 22-2). Although no universal grading
`schema exists, clinical pathologic correlations of the primary lesion are usua lly
`based on three grades of adenocarcinoma: well-differentiated (Gleason patterns
`1 and 2); moderately differentiated (Gleason pattern 3); and poorly differenti(cid:173)
`ated (Gleason patterns 4 and 5). Based on more than 3000 cases from the
`Veterans Administration studies, patients with well-differentiated tumors had
`a good prognosis , whereas those with poorly differentiated tumors had more
`advanced disease and neoplasms that were more biologica ll y virulent than
`either well or moderately differentiated tumors. 3
`Stage Dl indicates metastases to the pelvic lymph nodes below the aortic
`
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`METASTATIC CARCINOMA OF THE PROSTATE- TREATMENT OPTIONS AND CONTROVERSIES 357
`
`plus DES (5 mg daily). The hypothesis under investigation was whether the
`combination of orchiectomy and DES was superior to either treatment alone.
`Because patients in the placebo group received hormonal therapy at the time
`of symptomatic progression, the term "delayed hormonal therapy" was more
`applicable than " placebo." In this study, 992 stage C patients were randomized.
`The lowest survival rate occurred in the group who had undergone orchiectomy
`plus DES. In the 772 stage D patients, survival rates were lower in the placebo(cid:173)
`treated group. The stage D patients who underwent endocrine treatment had
`a lower cancer mortality rate, whereas cardiovascular complications and death
`rates were higher in the DES-treated group.
`The second VACURG study randomized stage C and stage D patients to 1 of
`4 treatments: placebo; DES (0 .2 mg daily) ; DES (1 mg daily); or DES (5 mg
`daily). In 294 stage C patients, survival rates were much higher in the placebo
`group than in the 5-mg DES group . In these stage C patients, no statistical
`difference in survival rate was seen among the placebo, 0.2-mg DES, and 1.0-
`mg DES groups. The 1-mg DES dosage was associated with fewer cardiovascular
`deaths than the 5-mg dosage. In stage D patients, the 1-mg DES regimen was
`believed to be superior because the cardiovascular death rate was minimal and
`control of prostate cancer was as effective as with the 5-mg dosage. Survival
`rates were better in the 1-mg DES group than in placebo-treated patients, the
`group with the lowest survival rate.
`The overall VACURG conclusions indicated that the optimal use of DES is
`in stage D patients, at a dose of 1 mg/day. In clinical practice today, a daily
`DES dose of 3 mg is commonly prescribed because it decreases and maintains
`plasma testosterone levels as well as a 5-mg dose. In contrast, although many
`patients treated with a 1-mg DES dose have short-term suppression of plasma
`testosterone levels, these values are not at castrate levels 6 to 12 months later.
`Based on the VACURG studies, in terms of subjective response and tumor
`regression, no evidence suggests that orchiectomy is superior to DES treatment,
`nor are the two in combination superior to either alone.
`The use of hormonal therapy results in " objective responses " of tumor re(cid:173)
`gression in approximately 40 to 50% of patients, and an additional 30% note
`an improvement in subjective complaints. The magnitude of such responses
`depends on the specific response criteria. The duration of hormonal respon(cid:173)
`siveness is approximately 18 to 24 months, depending upon the clinical sit(cid:173)
`uation at the time treatment is initiated. Some patients who become refractory
`to hormonal therapy in the presence of castrate level of testosterone note a
`subjective improvement with second-line therapies , although objective re(cid:173)
`sponses are rare.
`
`Hormonal Therapy
`
`Over the past decade, a variety of new hormonal therapies have been intro(cid:173)
`duced , to attempt to improve the overall duration and quality of survival (Fig.
`22- 3). Despite decades of study of various hormonal therapies and novel hor(cid:173)
`monal compounds, however, the following questions remain: (1) What is the
`optimal time for initiating hormonal therapy in patients with metastatic dis(cid:173)
`ease? (2) Does the actual type of hormonal therapy influence the ultimate
`outcome of the disease? (3) Does any role exist for combined hormonal ther-
`
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`METASTATIC CARCINOMA OF THE PROSTATE- TREATMENT OPTIONS AND CONTROVERSIES 359
`
`in the United States for oral palliation of metastatic or progressive cancer of
`the prostate, has been available in Europe since 1975. Estramustine is a com(cid:173)
`bination of the estrogen estradiol and a nitrogen mustard, but the extent to
`which each of these substances contributes to the agent's antitumor activity is
`not clear. Two studies noted that about 20% of patients with advanced prostate
`cancer refractory to estrogens responded subjectively to treatment with estra(cid:173)
`mustine. 9 ·10 In a double-blind prospective trial comparing estramustine with
`DES in 153 patients not previously treated with hormones , the 2 drugs were
`comparable in effectiveness; after 6 months, 76% of patients taking estramustine
`and 67% of those taking DES showed no progression of disease. 11 Although
`estramustine phosphate is probably no more effective than DES for the initial
`treatment of advanced prostatic cancer, it may help to control subjective symp(cid:173)
`toms in patients with hormonally refractory disease.
`Aminoglutethimide. This derivative of glutethimide affects the blockage of
`several cytochrome P-450 hydroxylation-dependent steps in the conversion of
`cholesterol to pregnenolone, as well as in the aromatization of androgens to
`estrogens, and thus inhibits adrenal steroidogenesis and estrogens.12 Amino(cid:173)
`glutethimide is usually given in combination with hydrocortisone to prevent
`reflex rises in adrenocorticotropic hormone (ACTH) that would override its
`metabolic-inhibitory capabilities. The inhibition of adrenal androgen produc(cid:173)
`tion has become popular in the management of patients with prostate cancer,
`many of whom have undergone bilateral orchiectomy. Reports suggest that
`approximately 20 to 25% of hormonally refractory patients note some subjective
`improvement with aminoglutethimide. Appropriate evaluation of such re(cid:173)
`sponses is difficult, however, given the independent palliative effect of hydro(cid:173)
`cortisone its elf .1 3
`Progestational Agents. Megestrol acetate and cyproterone acetate, with or
`without estrogen, may induce subjective or objective responses in patients with
`prostate cancer. Megestrol and other progestational agents, which decrease lu(cid:173)
`teinizing hormone (LH) release and exhibit antiandrogen actions by competing
`with dihydrotestosterone (DHT) receptors, may also compete with testosterone
`for 5-alpha-reductase. 14·1s
`Antiandrogens. Prostate cancer cells are under the trophic influence of male
`hormones. When testosterone is converted to dihydrotestosterone by a 5-alpha(cid:173)
`reductase, it binds to a cytoplasmic receptor, which in turn is transported to
`a nuclear receptor that influences transcription and translation.16 The antian(cid:173)
`drogens, of which flutamide and cyproterone are prototypic drugs,17 •18 interfere
`with cytoplasmic receptor binding and nuclear translocation. Although drugs
`such as flutamide are active in the peripheral handling of androgens at the
`level of prostate cancer cells, they have minimal central activity in the control
`of LH and follicle-stimulating hormone (FSH) release. Side effects of flutamide
`include diarrhea, flushing, and gynecomastia. The advantage of such com(cid:173)
`pounds is that they do not interfere with potency, mainly because serum tes(cid:173)
`tosterone levels do not decrease and may actually increase.
`Other antiandrogens include cyproterone and medroxyprogesterone. 1 5 These
`compounds inhibit gonadotropins released from the anterior pituitary and thus
`decrease the production of testosterone by the primary gonad. Moreover, these
`compounds may actually inhibit 5-alpha-reductase enzymes necessary for the
`conversion of testosterone to dihydrotestosterone.
`
`MYLAN PHARMS. INC. EXHIBIT 1105 PAGE 8
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`360
`
`PROSTATIC ADENOCARCINOMA
`
`Ketaconazole. This antifungal agent inhibits a variety of cytochrome P-45 0-
`dependent enzymes and rapidly decreases circulating levels of testosterone
`when administered in high doses. Trachtenberg reported that testosterone val(cid:173)
`ues may fall to castrate levels 4 to 8 hours after an initial 400-mg dose. 19
`Ketaconazole has not yet undergone large-scale clinical trials to compare it
`with other, more standard forms of hormonal therapy. Side effects of ketacon(cid:173)
`azole include rare episodes of hepatotoxicity, nausea and vomiting, anaphy(cid:173)
`laxis, xerostomia, and potential adrenal insufficiency.20
`LHRH Analogues. The use of luteinizing-hormone-releasing hormone
`(LHRH) analogues has had a major impact on the overall management of patients
`with metastatic prostate cancer. Physiologically, these analogues act as both
`agonists and antagonists in controlling the release of native LHRH. 21 Under
`normal circumstances, LHRH or gonadotropin-releasing hormone (GNRH) is
`secreted in a pulsatile fashion by the hypothalamus. LHRH occupies receptors
`at the level of the anterior pituitary gonadotrope. In turn, the redistribution of
`the calcium-binding protein calmodulin allows "prepackaged" amounts of both
`FSH and LH to be released. The testis responds to the surge of gondadotropins
`by the production of androgen-binding proteins (from Sertoli's cell) involved
`in spermatogenesis and testosterone (from Leydig's cell). The negative feedbac k
`of hypothalamic pituitary gonadal control is accomplished by circulating levels
`of inhibiting androgens at the level of the hypothalamus and pituitary. Addi(cid:173)
`tionally, elaboration of Sertoli's cell peptide hormone, known as inhibin, in(cid:173)
`hibits gonadotropin release.
`Many agonistic-antagonistic analogues of LHRH have substitutions of o(cid:173)
`amino acids at the sixth position, as well as additional substitutions or mod(cid:173)
`ifications on the ninth and tenth amino acid. Because these substitutions pro(cid:173)
`long biologic half-life, these analogues have a half-life measured in hours ,
`unlike native material, whose half-life is several minutes. Long-term admin(cid:173)
`istration of these analogues causes complete receptor downregulation and cas(cid:173)
`trate levels of testosterone and dihydrotestosterone.
`The prototype analogue, leuprolide, has been subjected to several clinical
`trials, including a prospective, randomized, multicenter trial, comparing this
`agent to DES. 22 In essence, this trial of 200 patients showed that leuprolide
`was as effective as a 3-mg dose of DES, but with more tolerable side effects
`than DES. Objective response rates, time to treatment failure, and survival rates
`were similar in both the leuprolide and DES groups. Hot flashes were more
`common in the leuprolide than in the DES group, whereas gynecomastia (breast
`tenderness), nausea and vomiting, and peripheral edema were substantially
`much more frequent in the DES than the leuprolide group . Moreover, patients
`taking DES had more vascular complications, including phlebitis, pulmonary
`embolism, and congestive heart failure, than those taking leuprolide. Additional
`randomized, prospective studies have compared the effectiveness of other an(cid:173)
`alogues, such as ICI 118630, to that of bilateral orchiectomy. 23 The therapeutic
`efficacy of these analogues is similar to that of conventional therapy, including
`bilateral orchiectomy or DES administration.
`
`Chemotherapy
`Chemotherapy has not been used extensively in the management of patients
`with prostate cancer. 24 Table 22-1 shows a compendium of studies in which
`
`MYLAN PHARMS. INC. EXHIBIT 1105 PAGE 9
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`

`

`Treatment B
`5FU + Cyclophosphamide
`Cyclophosphamide + 5FU +
`doxorubicin
`Cyclophosphamide + 5FU +
`doxorubicin
`Cyclophosphamide + 5FU +
`methotrexate
`Prednimustine +
`estramustine
`Cyclosphophamide + 5FU +
`methotrexate
`Vincristine
`
`Cyclophosphamide
`
`Cyclophosphamide
`
`Prednimustine
`
`Lomustine
`
`Estramustine
`
`Estramustine
`
`Cisplatin
`
`Table 22-1. Randomized Trials of Single Agents versus Combination Chemotherapy in Hormone Refractory Metastatic
`Prostatic Carcinoma*
`Treatment A
`Doxorubicin
`5-Fluorouracil (5FU)
`
`Treatment C
`
`Group
`
`Mayo
`Southeastern Oncology
`Group
`Western Group
`
`Conclusions
`No difference
`No difference
`
`No difference
`
`Bowman Gray
`
`No difference
`
`National Prostate
`Cancer Project
`Memorial Sloan-Kettering No survival difference
`
`No difference
`
`NPCP
`
`NPCP
`
`No difference
`
`Estramustine +
`vincristine
`Estramustine +
`Ongoing study, no sta(cid:173)
`tistical difference
`cisplatin
`* Adapted from Torti, F.M., and Lum, B.L.: Chemotherapy in prostate cancer. In Contemporary Issues in Clinical Oncology. Vol.
`5. Edited by M.B. Garnick. New York, Churchill Livingstone, 1985.
`
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`MYLAN PHARMS. INC. EXHIBIT 1105 PAGE 10
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`

`362
`
`PROSTATIC ADENOCARCINOMA
`
`chemotherapy was evaluated, predominantly in hormonally refractory patients.
`Although results of such trials indicate no improvement in survival rates , some
`patients note a subjective improvement in bone pain. It is often difficult to
`administer full doses of systemic chemotherapy to patients with metastatic
`prostate cancer, mainly because of extensive prior radiotherapy for the initial
`disease or as palliation in multiple bone areas. Nonetheless, the possibility of
`new agents and the combination of hormonal and chemotherapy in early treat(cid:173)
`ment of this disease are under study.
`
`Chemotherapy Followed by Hormonal Therapy
`
`Investigators at the National Cancer Institute have used intensive chemo(cid:173)
`therapy as the first-line treatment in patients with metastatic prostate cancer.
`Because cytotoxic chemotherapy has traditionally been administered in later
`stages of disease, when patients are not optimal candidates, the true effective(cid:173)
`ness of such a regimen is difficult to ascertain. Thus, this investigation has
`addressed the following issues: (1) whether patients can tolerate intensive
`chemotherapy with cyclophosphamide, doxorubicin, or cisplatin; (2) whether
`such therapy improves response rates; and (3) whether response to subsequent
`hormonal therapy is altered by the administration of initial chemotherapy.
`Although the rate of response to initial chemotherapy was low (approximately
`30%), the patients tolerated it reasonably well. Most important was that patients
`who had subsequent hormonal therapy, whether bilateral orchiectomy or DES
`administration, had response rates similar to those in patients who had not
`received chemotherapy. Additional studies, including our own at the Dana(cid:173)
`Farber Cancer Institute, are currently underway.
`
`MAJOR CONTROVERSIES
`
`Timing of Hormonal Therapy Initiation
`
`Although this topic has been addressed in many studies, no consensus exists
`on the optimal timing for initiation of treatment. Animal studies provided
`support for early initiation of hormonal therapy, whereas in the VACURG stud(cid:173)
`ies, the early institution of hormonal therapy seemed not to prolong overall
`survival. Indeed, the palliative potential of endocrine therapy was reduced if
`it was used early in asymptomatic patients. The VACURG studies concluded
`that patients with metastatic prostate cancer should receive hormonal therapy
`if and when symptoms develop, especially sexually active patients. Although
`therapy does not make the asymptomatic patient feel better, it is likely to cause
`impotence.
`The definition of "asymptomatic" in patients with prostate cancer is im(cid:173)
`portant. A patient with no urinary obstructive symptoms or other problems
`relating to the prostate itself, with one or two isolated, painless rib lesions, is
`"asymptomatic;" however, a patient who has no symptoms yet has bilateral
`hydronephrosis secondary to para-aortic lymphadenopathy or extensive ver(cid:173)
`tebral disease with epidural extension is not "asymptomatic," even though he
`does not have any "symptoms." In patients with metastatic disease, hormonal
`therapy should be instituted early, rather than late, to try to prevent the com-
`
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`METASTATIC CARCINOMA OF THE PROSTATE-TREATMENT OPTIONS AND CONTROVERSIES 363
`
`plications of bilateral hydronephrosis and urinary tract obstruction or im(cid:173)
`pending spinal cord compression.
`It is difficult for the physician to face a patient with asymptomatic metastatic
`prostate cancer and to state that "no therapy" and expectant observation are
`potential options. The pros and cons of waiting for symptoms to develop must
`be clearly understood by the patient before such a regimen is accepted.
`More difficult yet is the optimal timing of hormonal therapy in patients who
`have stage Dl disease (positive lymph nodes below the aortic bifurcation). In
`this population, expectant observation has been the routine treatment, in the
`absence of localized obstructive symptoms. Nonprospective, nonrandomized
`data from the Mayo Clinic suggest, however, that patients who have positive
`lymph nodes may benefit by bilateral pelvic lymph node dissection, radical
`prostatectomy, and the institution of early hormonal therapy in the form of
`orchiectomy. 25 Although these data have been widely publicized, a critical
`analysis of the information suggests that the overall survival benefit seems to
`be related not to a decrement in prostate cancer deaths, but rather, to an in(cid:173)
`creased number of deaths unrelated to prostate cancer in the nonhormonally
`treated population; 26 nonetheless, the possibility of early hormonal therapy has
`been raised again and remains controversial.
`Day-to-day practice suggests that in patients without impending spinal cord
`compression or obstructive urinary symptoms, the delay of hormonal therapy
`until the time of symptomatic metastatic progression is probably best; however,
`this point is controversial, as previously discussed. Several investigators have
`even suggested "intermittent" hormonal therapy in which patients with symp(cid:173)
`tomatic disease are treated until symptoms abate; therapy is then stopped and
`is reinstituted when symptoms develop. This approach theoretically prevents
`or delays the development of hormone-resistant cancer cells and enhances the
`growth of hormone-sensitive cells. 27
`
`Differences Among Hormonal Therapies
`
`The efficacy of various hormonal therapies seems to be equal. The selection
`of one agent over another generally depends on side effects. Studies comparing
`DES to bilateral orchiectomy or LHRH analogues to orchiectomy or estrogen
`have confirmed that these methods of treatment are similar in efficacy, but
`their side effects differ. Thus, the decision to use initial hormonal therapy is
`based on the wishes of the patient and on the potential side effects. Clearly,
`bilateral orchiectomy is the most cost-effective way of treating metastatic car(cid:173)
`cinoma of the prostate, and the medical complications are few. As many as
`50% of patients undergoing bilateral orchiectomy experience hot flashes similar
`in magnitude to those caused by LHRH, however. 23 Psychologically, many
`patients want to avoid a "surgical castration" and would rather be treated
`medically. In the compliant patient, medicinal alternatives are as effective as
`surgical treatment, whereas in the noncompliant patient, bilateral orchiectomy
`ensures castrate levels of testosterone, and the physician has to worry less
`about whether the patient takes prescribed tablets or injections. Whether some
`of the newer agents, such as the antiandrogens, will be as effective in first-line
`therapy as DES, bilateral orchiectomy, or LHRH analogue administration is the
`subject of many current investigations.
`
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`364
`
`PROSTATIC ADENOCARCIN OMA
`
`These major controversies complicate hormonal therapy for patients with
`prostate cancer. Early investigations suggested that the combination of bilateral
`orchietomy or an LHRH analogue with an antiandrogen could provide " com(cid:173)
`plete" or "total" androgen blockade. In essence, testicular steroidogenesis
`would be inhibited by surgical removal of the steroid-producing organ or by
`the inhibition of steroid production by LHRH analogues . The addition of an
`antiandrogen would abrogate the effects of adrenal androgens, which account
`for approximately 5% of the circulating levels of male hormone. In some pre(cid:173)
`liminary and uncontrolled data, the death rate and rate of disease progression
`were lower in patients treated with combined androgen blockade than in those
`treated with single-agent hormonal therapy. 28
`At present, several large, randomized trials are assessing the efficacy of com(cid:173)
`bined hormonal therapy and are comparing an LHRH analogue with the com(cid:173)
`bination of LHRH and an antiandrogen ,29 whereas other studies are evaluating
`orchiectomy plus placebo, as opposed to orchiectomy plus antiandrogen.30
`Several smaller studies have failed to show a benefit from combined hormonal
`therapy.31 ·32 A large , prospectively randomized trial comparing leuprolide plus
`placebo to leuprolide plus flutamide has shown a delay to progressive disease
`for approximately 1.7 months in patients in the antiandrogen group.29
`In a smaller, independent Canadian study, patients were randomized to re(cid:173)
`ceive orchiectomy plus placebo or orchiectomy plus an antiandrogen. At the
`time of disease progression, patients who were treated with orchiectomy alone
`were offered the antiandrogen. In essence, this study, although preliminary,
`has shown a statistically significant survival advantage in patients treated with
`antiandrogen. The median duration of survival in the antiandrogen group was
`6 months longer (median duration of survival: 26 months) than in patients
`treated with orchiectomy alone (median duration of survival: 20 months) . In
`addition , the best overall objective response , using the National Prostate Cancer
`Project (NPCP) criteria, was superior in the antiandrogen group (84% , as com(cid:173)
`pared to 61 %). 30 Even these preliminary data suggest some potential improve(cid:173)
`ment in survival rates with combined hormonal therapy, although a longer
`followup and larger studies are needed.
`
`Second-line Hormonal Therapy
`
`This subject is encountered daily in both oncology and urology. Overall, the
`use of second- or third-line hormonal therapies in patients with prostate cancer
`yields subjective response rates of 20 to 22% . Again, the objectification of
`response is difficult, especially in patients with only osseous disease. In pre(cid:173)
`viously heavily irradiated patients who have responded to one type of hormonal
`therapy, one may consider second- and possibly third-line hormonal treatment.
`Estramustine is indicated for palliation in patients refractory to first-line hor(cid:173)
`monal therapy. Most series report subjective response rates of 20 to 25% . The
`usefulness of this agent is controversial, however. Other anecdotal reports ad(cid:173)
`vocate the use of progestational agents , antiandrogens , aminoglutethimide , and
`the LHRH analogue leuprolide. Although the quantification of response to
`second-line therapies is difficult, it has become routine. A more appropriate
`determination of efficacy should be available if subsequent investigations pro(cid:173)
`duce more quantitative ways of measuring response rates in bone. In general
`
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`METASTATIC CARCINOMA OF THE PROSTATE-TREATMENT OPTIONS AND CONTROVERSIES 365
`
`practice, the use of second- and third-line hormonal treatments is common,
`although expectations must be conservative.
`
`PALLIATIVE THERAPY
`
`A compassionate physician who is familiar with all treatment methods is
`essential for the management of patients with terminal prostate carcinoma.
`Palliative spot-radiation therapy should be used for individual bone lesions
`that are painful. The judicious use of narcotic analgesics is an important adjunct
`to treatment when the disease becomes refractory to systemic therapies . On
`occasion, patients with back pain from vertebral metastases benefit by the use
`of a transepidermal nerve stimulator (TENS) applicator. Most important, the
`physician must be responsive to the patient's needs in the terminal stage of
`this disease, once systemic therapy has lost is effectiveness.
`
`FUTURE CONSIDERATIONS
`
`Clearly, many challenges face the physician who treats the patient with
`metastatic prostate cancer. A variety of current investigations are evaluating
`the use of combined hormonal therapy, with or without chemotherapy, as well
`as the administration of chemotherapy followed by hormonal therapy. Addi(cid:173)
`tionally, the stimulation of prostate cancer with an androgenic compound in
`combination with cell-cycle-specific chemotherapy after maximum stimula(cid:173)
`tion, as well as hormonal therapy, has been investigated by several groups ,
`with guarded results. 32
`Perhaps the major obstacle to a true understanding of the biologic effects of
`a therapeutic intervention is our inability to measure bone metastases quan(cid:173)
`titatively. In the patient with exclusively osseous metastases , the objectification
`of response is difficult. Quantification of radionuclide injections of bone scan
`has had promising early results. 34 In addition, the future and more routine use
`of prostatic ultrasonography, 35 magnetic-resonance imaging,36 abdominal pel(cid:173)
`vic computed-tomographic scanning, and biochemical markers, such as pros(cid:173)
`tatic-specific antigen, 37 may enable investigators to identify actual tumor bur(cid:173)
`den precisely in patients with both osseous and soft tissue metastatic disease .
`Clearly, this obstacle must be overcome before a rational investigative approach
`can be designed.
`
`REFERENCES
`1. Silverberg, E., and Lubera, J.: Cancer statistics: 198 7. CA, 37:2. 1987 .
`2. Ross, R .. et al. : Serum testosterone levels in healthy yo ung black and white men. )NCI , 76:45,
`1986.
`3. Gleaso n, D.F .. and the Veterans Ad ministration Cooperati ve Urol ogica l Research Gro up: His(cid:173)
`tologic grading and cl in ical staging of prostatic carci noma. In Uro logic Pathology: The Prostate.
`Edited by M. Tannenbaum . Philadelphia , Lea & Febiger, 1977 .
`4. Huggins, C. and Hodges , C. V.: Studi es on prostate ca ncer. I. The effect of castratio n, of estrogen
`and of and roge n injection on serum phos phatases in metas tatic carcinoma of the prostate.
`Cancer Res .. 1: 293 , 194 1 .
`5. Huggins , C., Stevens. R.E .. Jr., and Hodges, C.V. : Stu dies on pros tatic cancer. II. The effects of
`castration on ad va nced carcinoma of the prostate gland. Arch. Surg .. 43:20 9, 1941 .
`
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`366
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`PROST A TIC ADENOCARCINOMA
`
`6.
`
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