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`Annals of Oncology 3: 331-335. 1992.
`
`Editorial
`
`Hormone refractory metastatic prostate cancer
`
`Prognostic factors
`
`Hormone-refractory prostate cancer is defined as pro-
`gressive disease despite castration serum levels of tes-
`tosterone. No effective systemic treatment has been
`clearly established for this condition. In patients with
`prostate cancer predictive factors such as stage, grade,
`size and extent of the primary rumor, and the presence
`or absence of distant metastases, have been established.
`Factors such as age, degree of pain, performence status,
`associated chronic disease, and a series of biologic
`parameters are less widely accepted [1].
`In this issue of Annals of Oncology, Fossa et al. pre-
`sent a retrospective study of symptomatic patients with
`painful metastases, primarily referred for radiotherapy
`|2|. The authors have created a prognostic model based
`on four independent clinical variables: performance
`status, creatinine, alkaline phosphatase, and duration
`of response to hormone treatment «£1 year. Prostatic
`acid phosphatase was not a significant variable, but the
`value was missing in 17%, and prostate specific antigen
`(PSA) was not analysed. Following androgen depriva-
`tion, the pretreatment serum testosterone level and the
`number of bone metastases on bone scan have been re-
`ported as important variables in other studies |3,4].
`The present study differs from other prospective
`clinical trials of prognostic factors which often select
`good risk patients. The EORTC analyzed 436 pre-
`viously untreated patients, and found performance
`status was the most important prognostic factor fol-
`lowed by acid phosphatase for stage MO patients and
`alkaline phosphatase, T category, and the presence of
`associated chronic disease for Ml patients [1|. A Cana-
`dian study found that only serum testosterone and ex-
`tent of disease on bone scan influenced survival |5|.
`The observation that patients with low pretreatment
`testosterone levels were less responsive to androgen
`deprivation has been made by various investigators [6|.
`Perhaps this condition selects growth of cells which are
`less androgen dependent.
`While changes in PSA are a good indicator of disease
`activity in men with metastatic prostate cancer treated
`with hormonal manipulation, the role in patients treat-
`ed with second line therapy is less clear |7|. A trend
`towards decreased survival has been observed with in-
`creasing values of PSA [5|. However, correlations be-
`tween response in measurable disease and biochemical
`response of serum acid phosphatase and PSA suggest
`that treatment decisions shouldn't be based on these
`parameters alone [8|.
`
`include
`Other new potential prognostic factors
`Ki-67 monoclonal antibody which may provide addi-
`tional information
`to
`traditional histopathological
`grading criteria [9j.
`
`Hormonal therapy
`
`Treatment of advanced prostate cancer centers around
`hormonal manipulation. Monotherapy with orchiec-
`tomy, estrogens, or lutenizing hormone-releasing ago-
`nists produce successful palliation in up to 80% of
`patients. With standard monotherapy 50% will live less
`than 2 years, and 90% will die within 3 years [17].
`The value of total androgen blockade remains con-
`troversial. Different studies have contradictory results.
`It is difficult to appreciate whether this may be due to
`variations in the therapy, different end points or differ-
`ences in patient selection and therefore in prognostic
`factors (11, 12]. Crawford has reported that androgen
`blockade with leuprolide and flutamide results in a
`longer progression-free survival and over-all survival
`than with leuprolide alone, and the subset with minimal
`disease and good performance status appear to benefit
`the most [12]. Similarly a Canadian study demonstrated
`benefit from total androgen blockade [13]. Here, strati-
`fication according to prognostic factors was not done.
`The EORTC evaluated bilateral orchiectomy versus
`zoladex and flutamide. Time to progression was de-
`layed with medical treatment compared with orchiec-
`tomy, but no difference in survival was detected [11|.
`With prostate cancer contrary to breast cancer, the
`development of hormonal resistance is an irreversible
`event which predictably occurs after androgen depriva-
`tion. The median time to progression is from 12-18
`months. Response to second line therapy is rare, and
`does not impact upon survival. The median survival
`after progression is approximately 6 months [14]. Bone
`is the primary and only site of metastases in 65% of
`patients who present with metastatic prostatic cancer.
`Objective measurable or evaluable criteria for response
`evaluation are often lacking. And there is a tendency to
`try to use other criteria for evaluation such as per-
`formance status, acid phosphatase, PSA, analgesic re-
`quirement and prostate size [14]. Subjective criteria
`must also be considered. In many patients bone pain
`and decreased performance status are predominant,
`and relief of these symptoms is as important as prolon-
`gation of survival.
`
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`Second-line hormonal therapy
`
`Management of the hormone-refractory patient is an
`exceedingly difficult problem. In patients whose serum
`testosterone remains at anorchid levels, there is little
`evidence to suggest that changing the form of androgen
`deprivation will achieve disease control. Yet patients
`are not always completely hormone resistant. The
`rationale for secondary hormonal treatment is based
`on the idea that suppression of circulating adrenal
`androgens may cause further tumor regression by
`suppressing any remaining hormone dependent pros-
`tatic cancer cells. Symptom relief often occurs rapidly,
`suggesting a mechanism other than adrenal suppres-
`sion.
`Secondary hormonal therapy, first attempted by
`Huggins in 1945 with bilateral adrenalectomy, may be
`accomplished in a variety of ways (15). Surgical ad-
`renalectomy or pituitary ablation are not used today.
`Drugs which achieve a medical adrenalectomy include
`aminoglutethimide, and ketoconazole. Aminoglutethi-
`mide, a potent inhibitor of adrenal steroidogenesis, in
`association with hydrocortisone may be effective in re-
`ducing serum testosterone and dihydrotestosterone.
`Partial response (PR) is seen in 17%—21% of patients,
`with subjective improvement in up to 60%. Significant-
`ly prolonged survivals, though uncommon, have been
`reported in responders. It is difficult to determine
`whether or not the required cortisone is responsible for
`the beneficiary effects. Erythematous rash and lethargy
`are the most commonly reported side effects |15,16].
`Flutamide may or may not be effective as second-
`line hormonal therapy. Labrie reports a response rate
`of 35%, including stable patients. The median life ex-
`pectancy of responders was 2.5 years; 8 months for
`nonresponders | IV]. Sogani treated 26 patients who
`failed orchiectomy or DES. Response was achieved in
`23%. The duration of response was 3 to 22 months
`|18|. Fossa found subjective response in 5/25 (20%)
`hormone-refractory evaluable patients [19].
`Megace, megesterol acetate, or dexamethasone are
`less expensive secondary hormonal therapies. Objec-
`tive responses are low, however in the order of 10%.
`Usually, the best response is stable disease, with
`median survival of less than 1 year following progres-
`sion [20).
`
`Chemotherapy
`
`Hormone-resistant adenocarcinoma of the prostate is
`refractory for the most part to second-line hormonal
`therapy. It must also be considered a chemotherapeuti-
`cally resistant tumor despite the wide disparity in re-
`ports suggesting efficacy of 40% to 80%. Objective
`tumor regression occurs in less than 10% to 20%. Most
`responses are only partial and have minimal impact on
`survival in randomized phase III trials. Eisenberger re-
`viewed overall objective responses in 3184 patients.
`
`The CR and PR rate was 7% (202 patients), and when
`the category of STAB was added (CR+ PR+ STAB)
`this increased only 15% to 22% (485 patients) [21].
`Some agents may possess marginal to modest antitu-
`mor activity, but the unique proponderance of osseous
`metastases as the major parameter to measure re-
`sponse has hampered clinical trials. The variable natu-
`ral history, the absence of accurate, reliable biochemi-
`cal and biological tumor markers or of bidimension-
`ally measurable lesions have necessitated the use of
`changes in subjective parameters (quality of life scales,
`weight, analgesic use, performance status, sense of
`well-being), as well as changes in serum or prostatic
`acid and alkaline phosphatase, and anemia as response
`criteria. Conclusions of many earlier trials are hin-
`dered by the use of evaluable lesions such as bone
`scans, IVP, digital rectal exams, and peripheral edema.
`If trials are limited to only patients with bidimension-
`ally measurable parameters, no more than 10%-20%
`of patients with advanced prostate cancer are eligible
`[8,14,22].
`A variety of single agents have undergone clinical
`trials. Many oncologists in the United States use weekly
`adriamycin as first-line therapy in hormone-resistant
`cases. At Memorial Sloan-Kettering Cancer Center
`(MSKCC), only 5% of 39 patients (95% confidence
`limits 0-12%) responded. With weekly 20 mg/m2, 12%
`of 32 cases had a PR [23]. The Northern California
`Oncology Group using National Prostate Cancer Pro-
`ject (NPCP) criteria (CR+ PR+ STAB) observed remis-
`sion in 53%. In 25 patients having a median KPS of 70,
`and all having been previously treated with hormones
`and 84% with radiation therapy, 84% had a response
`by NPCP criteria, while 4/12 (33%) with bidimension-
`ally measurable lesions responded [24].
`Other chemotherapeutic agents in the literature
`which have demonstrated some activity include cyclo-
`phosphamide fluorouracil, methotrexate, mitomycin C
`(by the EORTC), vinblastine, and vindesine, studied
`with a wide variety of response criteria [25, 26). Vin-
`blastine was recently re-evaluated using a novel phar-
`macokinetic schedule. The vinca alkaloid given at 1.5
`mg/m2/d for 5 days every 4 weeks, seems more active
`than when given weekly. The response rate was 21 % in
`39 cases. Although the median response duration was
`only 28 weeks, toxicity was notable and the efficacy of
`this schedule requires confirmation [25].
`Other interesting single agents include gallium ni-
`trate which inhibits bone absorption and produces
`hypocalcemia. When administered by continuous infu-
`sion x5 days to 23 patients, remissions were seen in
`10%, but of short duration [27]. Polyamine conversion,
`increased in normal prostate glands and in prostatic
`cancer, can be inhibited by mitoguazone. In a highly
`selected patient population with soft tissue lesions such
`as lung and nodes, 24% of 25 patients had a PR. There
`was no effect on osseous lesions [28]. In another trial
`employing a similar dosage schedule, mitoguazone was
`inactive in 19 patients [29). Trimetrexate, a new antifol.
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`333
`
`was evaluated at MSKCC in 31 men with soft tissue
`lesions. Only 5 (17%) achieved PR. The median dura-
`tion of response was only 3 months [8].
`The FAM combination (5-fluorouracil, adriamycin,
`mitomycin) is best known for its use in gastric and pan-
`creas tumors. Based upon the reported 35% response
`rate at the M.D. Anderson Hospital in prostate cancer,
`a Southwest Oncology Group trial was initiated. The
`overall response rate was 16% in 68 adequately treated
`patients [30].The EORTC obtained a 28% response with
`mitomycin alone. Combining 3 marginally active drugs
`probably doesn't produce better results, particularly
`in this elderly patient population. Another combina-
`tion which needs verification is the report of cisplatin
`and continuous infusion fluorouracil combination.
`Three PR in 7 patients with bidimensionally measur-
`able disease was reported. Eight of 23 had a >50%
`decrease in acid phosphatase, and 12/24 had a >50%
`decrease in PSA [31].
`A randomized trial of combined versus sequential
`chemo-endocrine therapy evaluated the results of
`chemotherapy given earlier in the course of disease.
`Patients were randomized to receive chemotherapy
`(adriamycin and cyclophosphamide) either at the time
`of hormonal therapy or at the time of progression. The
`combination arm had a higher response rate than the
`sequential arm (63% versus 48%), but no significant
`differences in survival [32],
`Androgen priming to increase the sensitivity of pros-
`tate cancer chemotherapy has been attempted. When
`only evaluable patients were considered, the stimula-
`tion arm had a higher response rate (85% versus 72%),
`but more patients were inevaluable (41% versus 16%),
`as a result of the unacceptable toxicity associated with
`androgen stimulation. No significant differences in sur-
`vival have been found [33|.
`Estramustine (estracyt), the combination of norni-
`trogen mustard and estradiol has shown activity in
`experimental systems refractory to estrogen, and been
`extensively studied in clinical trials by the NPCP. Look-
`ing at the various single agent trials or in combination
`with vincristine or cisplatin one can see that the overall
`response rate in the literature has been low, 0-4% in
`the U.S. In a recent multicenter American study using
`different response criteria, activity was nicely demon-
`strated [34]. In Europe response rates have generally been
`higher, in the order of 50% [35]. When estracyt was
`compared to flutamide in a randomized trial, in 220
`hormone refractory patients after orchiectomy, no dif-
`ference was appreciated between the 2 arms. Only 1
`PR occured with flutamide; 31% and 26% respectively
`were stable. Mean survival for both was 48 weeks.
`Nausea, vomiting, and peripheral edema were more
`frequent with estracyt [36].
`The combination of estracyt + vinblastine, two MAP
`(microtubular associated protein) inhibitors has recently
`been studied. The MX). Anderson, using continuous
`infusion vinblastine, has reported a 35%-40% RR and
`other investigators in the U.S. are completing trials and
`
`finding approximately a 30% response. Future random-
`ized studies will compare the combination versus either
`of the single agents.
`
`New agents
`
`Ketoconazole is an oral imidazole derivative with anti-
`fungal properties, that inhibits both adrenal and testi-
`cular androgen synthesis [37]. The testis seems to be
`more sensitive than the adrenals to the steroidogenesis
`blockade of ketoconazole. In unpretreated patients it
`works rapidly to cut off hormone production, with re-
`sponse in approximately 80%. In hormone-refractory
`patients the literature is somewhat confusing, as many
`patients have been simultaneously treated with corti-
`sone [7]. The largest study with 44 patients, reported 1
`complete remission (CR) and 5 PR Stable disease was
`observed in 25 patients. Pain scores decreased on ther-
`apy. The mean benefit was 27 weeks [38]. Trump found
`that 5 of 36 patients had a greater than 50% decrease
`in tumor mass or a regression on bone scan after keto-
`conazole and physiological glucocorticoid therapy [39].
`Other studies have poorer results, with response rates
`<15%. Severe gastric intolerance is the major side ef-
`fect. Ketoconazole is probably active in soft tissue dis-
`ease. A definite action is seen in 2—3 months [38—41].
`Imidazole R75251 is a novel imidazole derivative
`active against the Dunning rat. Denis reported that
`9/17 (53%) of patients wth bidimensionally measur-
`able parameters had a PR. Moreover, R75251 caused a
`>50% decrease in PSA levels in 12/24 (50%), with
`normalization in 2/12 patients. It is well tolerated by the
`stomach, though some had cutaneous symptoms and
`muscle fatigue. In contrast to ketoconazole, circulating
`adrenal androgen levels are not suppressed. Since all
`patients were castrated, and since the substance doesn't
`affect the adrenal androgens, an alternative non-endo-
`crine mechanism of action is proposed [42].
`Another new agent of interest is suramin, a known
`antiparasitic agent, has been found to block a number
`of tumor growth factors. It also inhibits adrenal ster-
`oidogenesis, and was first studied in adrenal cancer at
`the National Cancer Institute (NCI) [43]. The NCI
`enthusiastically reported high response rates in hor-
`mone-resistant prostate cancer, and a flurry of trials
`was instituted in the U.S. and Europe. Responses are
`seen above the 300 microgram/ml dose. There may be
`activity as high as 30%-50% (reduction of PSA) [44].
`Weekly blood levels must be obtained both to monitor
`therapeutic levels of drug and to avoid toxicity. Of
`interest, the combination of suramin plus interferon
`gamma may have additive effects in a hormone unre-
`sponsive prostate cancer cell line |45|.
`
`Radiation therapy
`
`Bone pain is usually associated with metastatic prostate
`cancer and should be approached systematically. Focal
`irradiation to palliate bone pain for solitary painful
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`bone metastases has been supplemented by hemibody
`irradiation for the palliation of widespread metastases.
`After allowing for adequate recovery, the alternate half-
`body may also be irradiated. Side effects include
`nausea, vomiting, diarrhea, hematologic abnormalities
`and pneumonitis. In one study, 82% receiving upper
`hemi-body and 67% receiving lower half-body irradia-
`tion remained pain free until death [46|. Strontium-89
`has recently been reported effective in palliating bone
`pain as well. This bone-seeking radionuclide, has high
`uptake in osteoblastic metastases, and remains in the
`tumor sites up to 100 days, decaying by beta-particle
`emission [47]. Strontium produces significant improve-
`ment in pain control. An 80% response in patients sur-
`viving 3 months after treatment, with 10% completely
`pain free has been observed and confirmed by several
`authors [50|.
`
`Management of end-stage disease
`
`The management of end-stage prostate cancer patients
`often requires a multi-disciplinary approach, involving
`radiation therapists, medical oncologists, nurses and
`social workers in addition to family members. Pain and
`symptom relief such as proper analgesics and antimetics
`in order to palliate end-stage symptoms become crucial
`issues. Innovative treatment strategies are required if
`significant impact on overall survival is to be ac-
`complished in the disease. It will be important in the
`future to identify those patients whose disease is primar-
`ily androgen independent. In these, patients alternative
`treatment might be initiated. If chemotherapy is initiated
`prior to a decrease in performance status, it may be
`better tolerated and produce a better response.
`
`Conclusions
`
`Many new approaches to the treatment of hormone-
`refractory prostate cancer are presently being evalu-
`ated. Estramustine alone or in combination, the imida-
`zole derivatives, and suramin have potential. No pros-
`pective randomized studies have thus far demonstrated
`an advantage for a single or combination regimen. For
`this reason, investigational chemotherapy may be con-
`sidered first-line treatment. Patient selection coupled
`with conscientious management of medical problems
`must be considered when evaluating clinical trials.
`Clinical trials evaluating new treatment modalities
`should stratify patients with regards to the known prog-
`nostic factors in order to identify those most likely to
`benefit. The article by Fossa et al. confirm that routine
`clinical and laboratory data may provide an excellent
`indication of prognosis. Quality of life evaluations must
`be included in all future studies.
`
`Cora N. Stemberg, MD, FACP
`Regina Elena Cancer Institute
`Rome, Italy
`
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