in vivo 19: 787-792 (2005) Administration of Estramustine in Response to Changes in the Prostate-specific Antigen and Karnofsky Index in the Treatment of Prostate Cancer OLIVÉR PINTÉR1, JOSEPH MOLNÁR2, CSABA TÓTH3, ZOLTÁN SZABÓ4, JOSEPH LIPTÁK5, PÁL FÉL6, GYÖRGY PAPP7, ENDRE HOLLMAN8, LAJOS HAZAY9, BÉLA STREIT10, LÁSZLÓ KISBENEDEK11, MIKLÓS FEHÉR12, ISTVÁN KOCSIS13 and LÁSZLÓ PAJOR1 1Department of Urology and 2Department of Microbiology, Medical Faculty, University of Szeged; 3Department of Urology, Medical Faculty, University of Debrecen; Departments of Urology 4Kecskemét, 5Nagykanizsa, 6Dombóvár, 7Budapest, 8Kiskunhalas, 9Dunaújváros, 10Szekszárd, 11Budapest, 12Miskolc and 13Eger, Hungary Abstract. Androgen ablation is palliative and does not cure cancer was formerly diagnosed at around the age of 70. advanced prostate cancer. The hormone-sensitive cells die and However, following the introduction of the early diagnostic the hormone-resistant cells overgrow, resulting in disease protocol based on prostate-specific antigen (PSA), the progression. The drug of choice for secondary treatment is average age at the time of diagnosis has decreased to estramustine (Estracyt). The success of the therapy is followed around 60 years. The time that elapses prior to recognition by changes of the prostate-specific antigen level and Karnofsky is influenced by a number of factors, such as the sensitivity scale. In the present study, the results of estramustine treatment of the screening test, the rate of development of the tumour of 79 patients with advanced prostate cancer in 12 hospitals and the age of the patient. were evaluated. The mean prostate-specific antigen level It has been known since the 1940s that a proportion of improved for 6 months, but rose from the ninth month on. The prostate cancer tumour cells are sensitive to androgen improvement in the subjective condition of the patients withdrawal (3), which is the basis of the therapy. Some 60 paralleled the change in the prostate-specific antigen level. The years later, this procedure remains palliative: hormone- short time of improvement was a consequence of the very high resistant cells can be detected even at the beginning of prostate-specific antigen level and the poor general condition. treatment and, independently of androgen withdrawal, these Estramustine administration is recommended when the persist or even multiply. In consequence, they may come prostate-specific antigen level becomes more than doubled into a relative excess after the primary treatment of total following primary treatment. At a starting prostate-specific androgen blockade (TAB). The literature data indicate that antigen level of >100 ng/ml, the treatment leads to total previously androgen-sensitive cells adapt to androgen androgen blockade. If the prostate-specific antigen level has ablation treatment (4-6). Accordingly, hormone-refractory not decreased after treatment for 3 months, the secondary prostate carcinoma develops, the process displaying the strategy is to apply chemotherapy. signs of progression despite the primary and secondary hormone treatment. The disease is incurable and, although Prostate cancer is one of the most frequent diseases of considerable progress has been made in diagnosis and males over the age of 50. In Hungary, it is in the third place treatment, the local process and/or metastases during of cancer mortality (1), while in the western world it is progression usually lead to the death of the patient. It falls currently the second leading cause of death (2). Prostate to the urologist to seek possibilities for the treatment of the resulting complications (7). It is not clearly understood why the lymph node metastases totally regress in response to treatment (or recur Correspondence to: Dr Olivér Pintér, Department of Urology, Medical only rarely), whereas the bone metastases generally only Faculty, University of Szeged, Szeged Kálvária sgt. 57. H-6722 partially disappear and the tumour cells may reappear at the Hungary. Tel: (+) 36-62-490-590, e-mail: [email protected] same site (8). This indicates that cells at different szeged.hu localizations react to chemotherapy in different ways. This Key Words: Advanced prostate cancer, Estracyt/estramustine, may be explained by the fact that a two-directional paracine prostate-specific antigen. indicating system operates between the epithelial cells and 0258-851X/2005 $2.00+.40 787 in vivo 19: 787-792 (2005) the stroma cells of the bone. In the course of invasion of the etc.), how (i.v. or orally) and at what dose (the prescribed tumour, the transition between the local and metastatic dose is 4-6 capsules daily, though a higher dose than this states means a change in the stromal microenvironment for was applied in many published studies) the patient receives the tumour cells and, thus, the paracrine hormonal the drug. ii). It is important whether the estramustine is environment may be an important determinant of the initially given in monotherapy, or in combination with other development of the tumour (9). cytostatics. The chemotherapy of prostate cancer has lagged far Accordingly, we studied the following features: i). The behind (by close to 20 years) the similar treatment of other effectiveness of treatment as concerns the changes in the solid tumours. The publications that appeared in the 1980s PSA level and the Karnofsky index. ii). The side-effects of clearly stated that chemotherapy is not effective for the the treatment and the need for pain-killers. iii). Is treatment of prostate cancer, although they were published estramustine of value in the primary treatment? prior to the development of PSA examinations. In the majority of studies, individual drugs were investigated and Materials and Methods the results were evaluated on the basis of the changes measured in the tumour. Such changes could be observed in A total of 79 patients with advanced, hormone-refractory, only 10-30% of the patients; hence, the disappointing metastatic prostate cancer were enrolled in the study from 12 findings probably related only to a subgroup with a poor Hungarian urological centres in 2000 and 2001. Their average age prognosis rather than to a lack of effectiveness of the was 72 years (range: 61-79 years). treatment (10). The introduction of PSA examinations Inclusion criteria. The inclusion criteria were: a deterioration in the facilitated the early recognition of these tumours and their condition of a patient with histologically confirmed prostate cancer curative treatment. Following definitive treatment, tumour who had earlier been treated hormonally or castrated surgically, or recurrence is seen in one-third of the cases. Unfortunately, who had participated in radiotherapy; a PSA level >5 ng/ml; even today, around 70% of the cases of prostate tumours in normal or only mildly elevated liver function data; a cardially Hungary are in an advanced stage when they are compensated condition; no known gastrointestinal disease; no recognized. Curative treatment is hopeless. The accepted hypersensitivity to the medication; no other confirmed primary modes of treatment lead to temporary success in 80% of the tumour; no previous chemotherapy. cases; then, after the development of a hormone-resistant state, attention must be turned to a new mode of treatment, Exclusion criteria. The exclusion criteria were: a simultaneous different tumour; failure of the patient to agree to participate; a chemotherapy. The 14th International Congress on Anti- severe accompanying disease; hypersensitivity to the medication; Cancer Treatment, held in Paris on 1-4 February, 2003, anaemia, unless it could be controlled; progression; the occurrence declared that the treatment of prostate cancer is not of side-effects; failure of the patient to collaborate. hopeless. The results reveal that a therapeutic effect can be The condition was assessed via a detailed anamnesis, physical discerned if the data on a sufficiently large group of patients examination, a chest X-ray, abdominal and small pelvic CT, are evaluated (10). McLaren et al. (11) found that only the ultrasound examination, bone isotope examination, a full blood PSA level and the time required for this to double picture, PSA level determination and, in some cases, free PSA determination. The laboratory examinations were carried out by (determined during the follow-up) correlated significantly different methods in the various centres; accordingly, to facilitate a with the clinical progression and other end-points. A uniform evaluation of the laboratory results, each centre also number of publications have reported that the PSA level reported their normal ranges. The patients were asked to attend indicates the progression and the outcome after the control examinations at 3-month intervals. They received medical potentially curative treatment of prostate cancer (12, 13). care if any intermediate event occurred. As for the collection of However, attention should also be paid to the finding, by scientific data, the study was performed with the approval of the Stephenson et al. (14), that the clinical condition may ethical committee at each of the centres. The medication applied was Estracyt injection (300 mg) and Estracyt capsules (140 mg), deteriorate even without a PSA level increase. both supplied by Pharmacia Upjohn AB, Stockholm, Sweden. The The choice of 12 centres was made in the hope that drug is currently marketed by Pfizer. The injection was retrospective studies could be performed on a considerable administered