//Weekly epidoxorubicin therapy in hormone-refractory metastatic prostate cancer
Weekly epidoxorubicin therapy in hormone-refractory metastatic prostate cancer2017-04-05T18:51:34+00:00

Weekly epidoxorubicin therapy in hormone-refractory metastatic prostate cancer

Stenosi uretrale, uretra

pdf chirurgia uretrale

Enzo Palminteri et Al.



Center for Urethral and Genitalia Reconstructive Surgery, Arezzo, Italy



In a pilot trial, we treated thirty-three hormone resistant metastatic prostate cancer patients with a combination of androgen blockade plus weekly cytotoxic therapy and determined both response and toxicity in 32 of them. Their median Karnofsky performance status at the time of entry was 65. We administered Epidoxorubicin (EpiDx) intravenously, at a dose of 35 mg/m2, every week for 4 months. Initially, all patients had only hormonal therapy and chemotherapy was added once they progressed. In terms of W.H.O. criteria, 9 patients (28%) had a partial response, the disease was stable in 14 (44%), and progressive in 9 (28%); even in this last group, 6 patients with bone metastases experienced lasting relief from pain. No patients had to interrupt treatment due to leukopenia or cardiotoxicity. Other toxicities, including nausea and vomiting, mucositis and alopecia, were mild. Pretreatment prostate-specific antigen (PSA) levels decreased significantly (p < 0.05) in 26 patients (81%) after treatment. In our view, weekly EpiDx administration serves as an active regimen in hormone-refractory prostate cancer.

In many countries of the worid (1), among them the 15 member states of the European Community, prostate cancer is the second most common form of cancer in men (2). Moreover, the incidence of prostate canee l’ is on the rise in several geographic areas, with the largest increments – around 25-30 per cent every five years – occurring in North America and southern Europe (3). We have known since 1941 that blocking hormonal production in advanced prostate canee l’ can reduce tumor growth. Consequently the effective withdrawal of androgen produced in the testes through surgical or medicai castration via LH-RH analog administration has become the standard first-line palliative treatment for this disease (4). Hormonal therapies, however, serve only to reduce tumor progression, so that, as predicted by Isaacs and Coffey’s (5) model of clonai selection, progressive disease ultimately develops in hormonally refractory pro state cancer cells (6). The evolution of androgen-independent prostate cancer has been associated with the upregulation of blc-2 oncogene expression (78) that protects cells from apoptosis induced by a variety of chemotherapeutic agents (9-10). Chemotherapy so far has mainly been used as a second-line treatment, since the results of many studies with various chemotherapeutic compounds have proved disappointing. Among single agents, anthracycline derivatives are capable of inducing apoptosis in bcl-2 expressing prostate carcinoma cells, circumventing the protective action of bcl-2 and obtaining effective celi death (11) with high response rate (12). Even though chemotherapy in metastatic prostatic carcinoma has up to now been regarded as a palliative treatment, we undertook this study to assess the impact of weekly administrations of Epidoxorubicin (EpiDx) on response rate, response duration, generai toxicity, pain relief and quality of life in hormonerefractory prostate cancer patients.


Patients and Methods

Belween Mareh 1993 and Aprii 1996, 33 patients with metastatic prostate carcinoma who had prpgressed during hormonal therapy entered the stlldy and were treated with intravenolls chemotherapy. Ali patients were aware of the investigational nature of the treatment a nel had given informed consent, in line with institlltional reglil ations. Patients were eligible il’ they had histologically confirm ed adenocarcinoma of the prostate refraetOly to androgen deprivation, as shown by new metastatie localiza tions or by three consecutive increases in prostate-specific antigen (PSA) of more than 50% above the baseline, measured by the Hybriteeh method (13). Other criteria included: no eontempormy radiotherapy, age < 75, a seore > 40 on the Karnofsky performace status scale (14) and life expectancy of more than 6 months. The minimun haematological requireme nts were white blood celi count > 3,500frtl , platelet cOtlnt > 100,000frtl, serum creatinine < 1.4 mg!dl, bilirubin < 1.5 rng!dl, anel hepatic transaminase not exceeding normal va ltles by more than 50%. A history of myocareli al infarction, heart failure, angina, arrhythmias or severe hypertension served to excl tlele patients from the sttlely. Pretreatment evalu ation included medicai history, physical examination with measurement 01′ so ft tissue elisease as applicable, chest X-ray, computed tomographic scan of the abelomen and pelvis, and bone sca no Clinical characteristics of the patients anel the sites 01′ metastatic locali zations are reporteel in Table I.
Treatment was provieleel on an outpatient bas is and continueel l’or 4 months on a scheel ule that enableelus to aelminister a cumulative elose 01′ EpiOx which, while effective, would not trigger careliotoxic symptoms. Hormonal treatment consisteel of a.subcutaneous injection of LH-RH agonist every 4 weeks. At the same time EpiOx was given intravenously every week at a elose of 35 mg!m2. Oisease response was evaluated al’ter each t\Vo months 01′ therapy, and toxicity anel PSA were measured monthly. A complete response (CR) reqtlireel the resolution 01′ lesions. A partial response (PR) requireel that the sum of the product 01′ the two la rgest perpenelicular eliameters elecrease by > 50% for at least two assessments. Patie nts with measurable elisease \Vere consielereel to have stable elisease (SO) if the product of the two largest perpenelicular diameters elecreaseel < 50%. For patients with bo ne me tastases, a PR was recordeel for those whose bone scans showed l’ewer les ions after treatment or who reporteel complete relief l’rom bone pain il’ present. Osseous disease patients were considereel to have SO if their bone scans revealed no new lesions. Treatment toxicities are reporteel in terms of W.H.O’s common toxicity criteria (15). Slalislica! alla!ysis. Since PSA dosages were eletermineel before a nel t\Vo months after EPIOX treatme nt, so that each va lue effectively serveel as its o\Vn control, \Ve useel the paireel t – test to test the hypothesis that the treatment proeluces a change. P values < 0.05 were conside reel statisti cally significant.



The study extended from March 1993 to Aprii 1996. Thirtytwo of the 33 patients who entered the trial could be assessed for response, time to progression and toxicity. One paiient refused to continue therapy after 3 cycJes. Ali patients showed objective evidence of progression at the start of the study and presented pathologic serum PSA levels. In responsive patients, responses became apparent after six weeks of therapy (range: three to eight) and are summarized in Table II. Nine patients (28%) achieved a partial response (PR), stable disease (SD) was observed in fourteen (44%), whereas the remaining nine patients (28%) had progressive disease (PD). Table III lists response rates by dominant disease site. We found no evidence for any prefe rential si te for response. CR occurred in two patients with Iymph no de metastases, in one with liver localization and in one patient with bone disease. The median ‘ response duration in responding patients was 41 weeks (range 28 63). Serum PSA was measured at the onset of the study and monthly during treatment in 32 patients. Figure 1 shows PSA serum levels before and after two months of treatment. The PSA decline was > 75% in 11 patients (34%), > 50% in lO patients (31 %) and > 25% in 5 patients (16%). Although there was a strong association between objective response and PSA reduction, not ali patients with PSA reduction achieved an objective response. There was a significant difference (p < 0.05) in PSA values before and after therapy. Seventeen of 32 evaluable patients (53%) showed an improvement of 20% or more in Karnofsky peliormance status and 6 of 21 with bone metastases (29%) experienced marked reduction in pain.
AlI 32 patients were evaluable for toxicity. Haematological and non-haematological si de effects reported during treatment are shown in Table IV. Myelosuppression tended to be cumulative after two months of therapy, although it did not reach severe degrees (W.H.O. toxicity grade > 3) in any of the patients. Moreover, none required hospitalization for infections, ali of which were manageable on an outpatient basis. Gastrointestinal toxicity was mild and neither vomiting nor mucositis were major problems. Alopecia was not frequent and was reversible in ali patients. The maximal dose of EPIDX administered was 600 mg/m2 and no evidence of cardiac toxicity was recorded.



Since 1940, prostate cancers have been known to retain androgen sensitivity and neady ali patients with metastatic prostate cancer treated with surgically or chemically induced castration show an initial, often dramatic, beneficiaI response to such androgen withdrawal (16). The major cause of relapse following androgen ablation is the heterogeneity of the prostate cancer celi population whose various c1ones, through a number of different mechanisms, select over time a subpopulation of androgen – independent celi (17). Thus to be effective, therapy must be targeted against these androgen refractory cancer cells (18). Many standard chemothera;Jeutic agents partially active in prostate cancer are un?~rgoing. a reevaluation in the PSA era; among these doxorublcm and ItS derivative, epidoxorubicin, have displayed promisinging results (19,20).
Our trial yielded an overall response rate of 28% (PR) wlth a median survival time of lO months in responding patients. Four CRs for single metastatic localizations were obtained – two in Iymph nodes, one in liver and one in bone. Response was associated with symptom control, marked improvement in performance status and in most cases with a significant decrease in PSA circulating levels. The weekly EpiDx regimen was well tolerated; myelosuppression was not a problem and no patients experienced weight loss or appetite reduction ascribable to the chemotherapeutic regimen employed.
Given that the median survival for patients with hormonally resistant disease is only six months (21), any treatment of such patients has to have symptom relief and improvement in overall quality of Iife as its primmy goals. The results of this phase II trial suggest that a weekly EpiDx schedule is an active chemotherapeutic regimen in the treatment of hormone-refractOlY prostate cancer. Acknowledgements We wish to acknowledge the assistanee ol’ Dr Eda Be rger 01 the revision ol’ this manuscript. This work \Vas partially supported by the “Associazione Toscana Cure e Ricerche Oneologiche”.

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