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INT. J. IMMUNOTHERAPY XIX(2-4) 41-45 (2003) UKRAIN IN THE TREATMENT OF PROSTATE CANCER PATIENTS Villa Medica Clinic, Edenkoben, Germany.
Summary: Ukrain is a semisynthetic drug with high anticancer activity. A total of 74 patients with different stagesof prostate cancer were treated in our clinic during the period from September 1997 to January 2003. In allpatients, metastases into bones and lymphatic nodes were present. Ukrain dosage was 0.3 mg/kg body weightthree times a week. Regional hyperthermia at 13.56 MHz was delivered to metastatic tumors in bones and lym-phatic nodes, leading to the increase of local temperature to more than 42.5 °C. Analgesics were prescribedaccording to the World Health Organization’s (WHO) Analgesic Ladder. Effectiveness of treatment was estimat-ed according to the standard complex of diagnostic measurements: digital rectal examination, ultrasonography,and prostate-specific antigen (PSA) detection. According to the results of treatment, 54 patients (73%) werecompletely free of cancer. Taking into account the presence of patients with high Gleason scores and the fail-ure of standard treatment, this exceeds the response rate of all existing methods of prostate cancer treatment.
sia, accounting for 29% of such deaths (1, 2). In Ger-many in 2001, 10,483 men died from prostate cancer.
Despite the development of various fresh ap- Carcinoma of the prostate is predominantly a tumor proaches to the treatment of prostate carcinoma, this found in older men, which frequently responds to treat- disease remains one of the major problems in mod- ment even when widespread and may be cured when ern oncology. In the USA in 1999 more than 179,000 localized. The median age of patients at diagnosis is new cases of this disease were recorded, and 37,000 72 years, although the number of patients under 60 patients died from it. In the USA, this malignancy is the most frequent cancer in men, and the second Definitive treatment is usually considered for young- most common cause of male mortality from neopla- er patients without any concomitant illnesses, sinceyounger men are more likely to die of prostate cancer Address for correspondence: B. Aschhoff, Villa Medica than older ones or those with major comorbidity.
Clinic, Klosterstrasse 179, D – 67480 Edenkoben, Germany.
Few prognostic markers are available. Elevations of serum acid phosphatase have been associated in some trials with poor prognosis in both localized and disseminated disease. However, prostate-specific anti- In a large case series of men who underwent the gen (PSA), an organ-specific marker with greater sen- anatomic (nerve-sparing) procedure of radical pro- sitivity and high specificity for prostate tissue, is most statectomy, only about 6% subsequently required the often used both for diagnosis and to monitor response use of pads for urinary incontinence, but an unknown to treatment. After radical prostatectomy, detectable additional proportion had occasional urinary dribbl- PSA levels identify patients at elevated risk of local ing. About 40-65% of men who were sexually potent treatment failure or metastatic disease; however, a before surgery retained potency adequate for vaginal substantial proportion of patients with elevated or ris- penetration and sexual intercourse. Preservation of ing PSA levels after surgery may remain clinically free potency was dependent on tumor stage and patient of symptoms for extended periods of time. age, but the procedure probably induces at least par- After radiation therapy with curative intent, persis- tial deficit in nearly all patients (6).
tently elevated or rising PSA may be a prognostic fac- A cross-sectional survey of prostate cancer pa- tor for clinical disease recurrence. However, reported tients who had been treated in a managed care set- case series have used a variety of definitions of in- ting by radical prostatectomy, radiation or watchful wait- ing, showed substantial sexual and urinary dysfunc- After hormonal therapy, reduction of PSA to unde- tectable levels is associated with a longer duration of Radical prostatectomy may also cause fecal in- progression-free status. However, decreases in PSA of continence, and the incidence may vary with surgical less than 80% may not be very predictive (3). Further- more, since PSA expression is itself under hormonal External beam radiation therapy can result in acute control, androgen-deprivation therapy can decreasethe serum level of PSA, independent of tumor re- cystitis, proctitis and sometimes enteritis (9-11). These sponse. Hence clinicians cannot rely solely on serum conditions are generally reversible but may be chron- PSA levels to monitor patient response to hormone ic, although they rarely require surgical intervention.
therapy, and clinical criteria must also be followed (4).
A cross-sectional survey of prostate cancer patients Nowadays, patient and doctor can choose from who had been treated in a managed care setting by various modes of treatment: surgery (radical prosta- radical prostatectomy, radiation or watchful waiting tectomy), external beam radiation therapy, interstitial showed substantial sexual and urinary dysfunction in brachy therapy, cryosurgery, hormone therapy or com- binations of these. With all of these interventions, var- Radiation therapy can be delivered after extra- peritoneal lymph node dissection without increased Complications of radical prostatectomy can include complications if careful attention is paid to the radia- urinary incontinence, urethral stricture, impotence and tion technique. The treatment field should not include the morbidity associated with general anesthesia and the dissected pelvic nodes. Previous transurethral a major surgical procedure. An analysis of Medicare resection of the prostate (TURP) increases the risk of records of 101,604 radical prostatectomies per- stricture above that seen with radiation alone, but if formed from 1991 to 1994 showed a 30-day opera- radiation is delayed 4 to 6 weeks after TURP then the tive mortality rate of 0.54%, a rehospitalization rate of risk of stricture can be minimized (12). 4.5% and a major complication rate of 28.6%. Over A prospective community-based cohort of men the study period, these rates decreased by 30%, 8% aged 55 to 74 years treated with radical prostatecto- my (n = 1,156) or external beam radiation therapy Ukrain in the treatment of prostate cancer patients (n = 435) sought to compare acute and chronic com- plications of the two treatment strategies after adjust-ing for baseline differences in patient characteristics A total of 74 patients with different stages of pro- and underlying health (13). Regarding acute treat- state cancer were treated in our clinic during the peri- ment-related morbidity, radical prostatectomy was od from September 1997 to January 2003. Charac- associated with higher rates of cardiopulmonary com- teristics of the patients are presented in Tables I and plications (5.5% versus 1.9%), as well as the need for II. In all patients, metastases into bones and lym- treatment for urinary strictures (17.4% versus 7.2%).
Radiation therapy was associated with higher rates of Dosage of Ukrain (Nowicky Pharma, Vienna, Aus- acute proctitis (18.7% versus 1.6%). With regard to tria) was 0.3 mg/kg body weight intravenously three chronic treatment–related morbidity, radical prostate- times a week. Regional hyperthermia, using hyper- ctomy was associated with higher rates of urinary in- thermia device Oncocare (Bruker, Wissenbourg, continence (9.6% versus 3.5%) and impotence (80% France) at 13.56 MHz, was delivered to metastatic versus 62%). Radiation therapy was associated with tumors in bones and lymphatic nodes, leading to the slightly higher rates of deterioration in bowel function. increase of local temperature to more than 42.5 °C.
Several different hormonal approaches can ben- When required, analgesics were prescribed accord- efit men in various stages of prostate cancer. Com- ing to the World Health Organization’s (WHO) plications of approaches such as orchiectomy, estro- gen therapy, luteinizing hormone-releasing hormone Effectiveness of treatment was estimated accord- (LHRH) agonists, antiandrogens, ketoconazole and ing to the traditional complex of diagnostic measure- aminoglutethimide include psychological effects, loss ments: digital rectal examination, ultrasonography of libido, impotence, hot flashes, gynecomastia, pru- (Sinoline SL-200, Siemens, Erlangen, Germany) and ritus, onychodystrophy, osteoporosis and adrenalinsufficiency (14-17). prostate-specific antigen (PSA) detection (Biomeda In summary, standard therapies for prostate can- PSA Detection Kit, Foster City, CA, USA).
cer often lower the health-related quality of life. It is Ukrain was prescribed according to Article 73 of also worth noting that many geriatric patients, in par- the German Medicine Law, and all the patients con- ticular those with localized tumors, may die of other illnesses without ever having suffered significant dis-ability from their cancer (18). These considerations prompted us to seek alter- Table I Duration of diagnosed prostatic cancer in years native methods of treatment for prostate cancer pa- Duration of cancer (years) Number of patients tients. Ukrain, a derivative of alkaloids from greater celandine and thiophosphoric acid and known for its excellent anticancer action, was successfully used in our clinic in the treatment of patients with different stages of cancer of various localizations (19). In the treatment of prostate cancer patients, we combined Table II Grading of patients according to Gleason score exceeds the response rate of all existing methods of The outcomes observed in this study could not have been predicted on the basis of standard anti-cancer therapies. Furthermore, established therapies for prostate cancer are associated with numerousside effects that often worsen patients’ quality of life Ukrain was well tolerated in all cases. Some pa- more severely than the reason for their indication. In tients experienced analgesic effects, and opioid dosage addition, the need to remain in the hospital duringsuch therapy cannot be thought to improve the psy- was reduced or discontinued. Many patients experi- chological status of patients. Both these side effects enced subjective and objective phenomena such as were avoided here. Quality of life improved in all pa- headache, vertigo, thirst, sweating, increased urine tients who received Ukrain, even in those with tumor production, fever, and pain in tumor and metastases recurrence and in those whose tumor did not respond sites. Some patients reported feelings of warmth and to the therapy. In addition, the therapy could be per- heat, especially in the areas of malignancy, with flu- formed on outpatient basis, allowing patients to work like symptoms. Patients’ general condition was ame- liorated in most cases, with normalization of appetite We did not investigate deep mechanisms of pos- and improvement in quality of life. Patients whose sible molecular and cellular action of Ukrain and re- tumors did not respond, or responded only weakly, to gional hyperthermia in our patients. From the results Ukrain therapy had no feeling of warmth, heat or pain observed, we can suppose that at least some of the previously reported properties of the drug were dis- According to the results of treatment (Table III), 54 played: antiangiogenic activity, stimulation of mitotic patients (73%) had complete remission. Taking into block in G2/M phase, inhibition of monomeric tubulin account the presence of patients with high Gleason polymerization, stimulation of the antitumor activity of scores and the failure of standard treatment, this macrophages and improvement in the immune sta-tus of the cancer patient. Table III Results of the treatment of patients with Ukrain and localhyperthermia (1) Cadeddu J.A., Partin A.W., Epstejn J.I., Walsh P.C. Stage D1 (T1-3, N1-3, M0) prostate cancer: A case-controlled comparison of conservative treatment versus radical prostatectomy. Urology, 50(2),251, 1997.
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