Treatment of prostate cancer with gonadotropin-releasing hormone agonists.

It is now well established that chronic treatment with GnRH agonists offers an advantageous alternative to orchiectomy and estrogens for the treatment of prostate cancer. Castration levels of androgens can thus be easily achieved without side effects other than those related to castration levels of serum androgens. However, man is unique among species in having a high secretion rate of precursor adrenal steroids which are converted into active androgens in the normal prostate and prostatic cancer. All the enzymes required for the transformation of dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, and androst-5-ene-3 beta, 17 beta-diol are present in prostatic tissue. Moreover, as shown in many systems, castration levels of serum testosterone (T) at 0.2-0.4 ng/ml exert significant androgenic activity in target tissues. In order to inhibit the action of androgens of both testicular and adrenal origin, GnRH agonists have been administered in association with the pure antiandrogen Flutamide in patients having clinical stage D2 (bone metastases) prostate cancer. A positive objective response assessed according to the criteria of the United States National Prostatic Cancer Project (USNPCP) has been observed in 84 of the 88 patients who had received no previous treatment (95.4%). After 2 yr of treatment, the probability of continuing response is 70% compared to 0-10% by previous approaches. In addition, the death rate at 2 yr is at 10.9% as compared to approximately 50% after standard hormonal therapy. When the same treatment was applied to patients who had received previous hormonal therapy (orchiectomy, estrogens or GnRH agonists alone) before showing a relapse, the response rate decreased to 62.9% and the death rate at 2 yr was 52%.(ABSTRACT TRUNCATED AT 250 WORDS)

Daily Objective Physical Activity and Sedentary Time in Adults with COPD Using Spirometry Data from Canadian Measures Health Survey.

Chronic obstructive pulmonary disease (COPD) is expected to be the third leading cause of premature death and disability in Canada and around the world by the year 2020. The study aims to compare objective physical activity (PA) and sedentary time in a population-based sample of adults with chronic obstructive pulmonary disease (COPD) and compare a group, and to investigate whether these behaviors differ according to COPD severity. From the 2007-2013 Canadian Health Measures Survey dataset, accelerometer and prebronchodilator spirometry data were available for 6441 participants, aged 35 to 79. Two weighted analyses of covariance were performed with adjustments for age, sex, body mass index, accelerometer wearing time, season, work, smoking (cotinine), education level, and income. A set of sensitivity analyses were carried out to examine the possible effect of COPD and type of control group. A cross-sectional weighted analysis indicated that 14.6% of study participants had a measured airflow obstruction consistent with COPD. Time in PA (moderate-vigorous and light PA), number of steps, and sedentary duration were not significantly different in participants with COPD, taken together, compared to controls. However, moderate to severe COPD participants (stages ≥2) had a significantly lower daily time spent in PA of moderate and vigorous intensity level compared to controls. Canadian adults with COPD with all disease severity levels combined did not show lower daily duration of light, moderate, and vigorous PA, and number of steps and higher daily sedentary time than those without airflow obstruction. Both groups are extremely sedentary and have low PA duration. Thus, "move more and sit less" public health strategy could equally target adults with or without COPD.

Differences in daily objective physical activity and sedentary time between women with self-reported fibromyalgia and controls: results from the Canadian health measures survey.

Physical activity and sedentary behaviors are important modifiable factors that influence health and quality of life in women with fibromyalgia. The purpose of this study was to compare objectively assessed physical activity and sedentary time in women self-reporting fibromyalgia with a control group. Data were drawn from the Canadian Health Measures Survey cycles 1, 2, and 3 conducted by Statistics Canada. We included women aged 18 to 79 years with complete accelerometer data. We performed one-way analyses of covariance (adjusted-for socio-demographic and health factors) to determine mean differences in physical activity and sedentary variables (minutes per day of moderate and vigorous physical activity, light physical activity, sedentary and daily steps) between women with and without fibromyalgia. In total, 4132 participants were included. A cross-sectional weighted analysis indicated that 3.1% of participants self-reported a diagnosis of fibromyalgia. Participants with fibromyalgia spent less time than controls engaged in moderate and vigorous physical activity (M = 19.2 min/day (SE = 0.7) versus M = 9.1 min/day (SE = 1.2), p = 0.03, η2 = 0.01). No significant differences were found for daily time spent in light physical activity, sedentary activities, and number of steps. Women participants with self-reported fibromyalgia spent significantly less time in moderate and vigorous physical activity than control. Physical activity promotion interventions for women with self-reported fibromyalgia should, as a priority, target physical activities with moderate to vigorous intensity.

Effect of combination endocrine therapy (LHRH agonist and flutamide) on normal prostate and prostatic adenocarcinoma. A histopathologic and immunohistochemical study.

The histopathology of 23 radical prostatectomies from patients with prostatic adenocarcinoma pretreated for 3-6 months with combination therapy including a luteinizing hormone-releasing hormone agonist and the antiandrogen drug flutamide was reviewed and compared with the pretreatment biopsies or transurethral resection material. After combination therapy, benign prostatic glands showed marked atrophy with prominent basal-cell layers, basal-cell hyperplasia, and epithelial-cell vacuolization. Immature squamous-cell metaplasia was present in seven cases. Residual carcinoma, on the other hand, was found in 19 of the 23 cases, and in 8 of these, tumor cells were either vacuolated or had scanty cytoplasm. Residual tumor was present as only one focus in 13 cases, and in 3 of these it was composed of single cells with a "hemangiopericytoma-like" pattern. An immunohistochemical study for prostatic acid phosphatase and prostatic-specific antigen could be carried out on paraffin blocks from 19 biopsies and 18 prostatectomies. After combination therapy, a reduction in staining (intensity and number of positive cells) was observed for the two markers in both normal prostate and carcinoma but with more pronounced effects on the latter. The present data show that temporary combination therapy before radical prostatectomy causes marked and very characteristic changes in normal prostatic tissue as well as in the prostatic tumor. These histologic patterns enter the differential diagnosis of a variety of atrophic, metaplastic, and proliferative lesions of the prostate gland. The pathologist must be aware of these histologic changes when looking at biopsy or resection material of treated patients.

Combination therapy with flutamide and medical (LHRH agonist) or surgical castration in advanced prostate cancer: 7-year clinical experience.

Three hundred and sixty-three patients with clinical stage D2 prostate cancer who had not received previous endocrine therapy or chemotherapy were treated with the combination therapy using the pure antiandrogen Flutamide and the LHRH agonist [D-Trp6,des-Gly-NH2(10)]LHRH ethylamide (or orchiectomy) for an average of 771 days (24-2607 days). Only 31 of the 308 evaluable patients (10.1%) did not show an objective positive response at the start of the combination therapy compared with an average of 18% in five recent studies using monotherapy. The median survival achieved using monotherapy is approximately 24 months while, in the present study, it is increased to 41.2 months, thus giving an additional 17 months of survival with the combination therapy. It should be mentioned that at the time of relapse, combination therapy is continued and, in addition, further blockade of adrenal androgen secretion is achieved with aminoglutethimide and hydrocortisone. While our studies showing the advantages of combination therapy with pure antiandrogen in advanced prostate cancer have been confirmed by independent large-scale randomized studies, our preliminary data clearly suggest the interest of downstaging early stage prostate cancer by temporary combination therapy prior to radical prostatectomy.

Transrectal ultrasound evaluation of local prostate cancer in patients treated with LHRH agonist and in combination with flutamide.

We followed total prostate and prostatic tumor volumes in patients who received combination endocrine therapy with the antiandrogen flutamide and the LHRH agonist [D-Trp6,des-Gly-NH2(10)]LHRH ethylamide. Twenty-three men with proved prostatic adenocarcinoma (Stages B1 to D2) were subjected to a transrectal ultrasound (TRUS) study before and after a three-month period of combination antihormonal therapy. A total prostatic volume reduction ranging from 17 percent to 70 percent (median 47%, p less than 0.0001) was observed. An even greater effect was observed on tumor volume which was reduced by 20 percent to 91 percent (median 81%, p less than 0.01). After treatment, the original suspicious zone became nonvisible in 4 cases. The TRUS measurements were confirmed by direct examination of the radical prostatectomy specimen in 7 cases. TRUS is thus a precise, sensitive, and valid method for evaluating the effect of combined antihormonal therapy on normal and tumoral prostatic tissues. These data indicate that combination therapy induces a rapid and marked reduction in glandular and tumoral prostatic volume which could well improve the success of radical prostatectomy and increase the changes of cure of localized prostatic cancer.

[Combined anti-androgen treatment in adenocarcinoma of the prostate: first use of a new therapeutically efficacious principle in hormone-dependent cancer]. / Traitement anti-androgénique combiné dans l'adénocarcinome de la prostate: première application d'un nouveau principe thérapeutique efficace dans le cancer hormono-dépendant.

Since the first observation reported by Huggins et al. in 1941, hormonal treatment of advanced prostatic cancer has been directed primarily at neutralizing testicular androgens by orchiectomy or estrogen therapy. These two approaches yielded a 60 to 80% positive response rate in the many studies carried out over the last forty years. However, responses were short-lived and the disease recurred rapidly in nearly every case. A possible reason for these limited results may well be related to the fact that a unique characteristic of man as compared to other species is a high level of secretion of adrenal steroids that act as precursors and are converted into androgens within the prostatic tissue itself. Complete neutralization of both testicular and adrenal androgens is therefore mandatory to achieve total suppression of the influence of androgens on the carcinoma. To accomplish this goal, we have used a combination of an LHRH agonist (or orchiectomy) and a pure antiandrogen in fifty-two previously untreated patients with prostatic carcinoma and bone metastases (stage D2). Average duration of treatment was eighteen months (six to thirty-two months). An objective positive response assessed according to the criteria set forward by the National Prostatic Cancer Project (NPCP) was recorded during the first treatment months in every case, a significant improvement over the 60 to 80% positive response rate following previous treatments confined to neutralization of testicular androgens by orchiectomy or estrogens.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of residual C-19 steroids in plasma and prostatic tissue of human, rat and guinea pig after castration: unique importance of extratesticular androgens in men.

The concentrations of dehydroepiandrosterone (DHEA), its sulfate (DHEAS), androstenedione (A-dione), testosterone (T) and dihydrotestosterone (DHT) have been measured before and after castration in men and two animal models, namely the rat and the guinea pig. In adult men, the pre-castration levels of plasma DHEAS and DHEA were measured at 1839 +/- 320 and 2.4 +/- 0.5 ng/ml, respectively, while in both animal models, the concentrations of these two steroids were below 0.3 ng/ml. Orchiectomy in men reduced plasma T and DHT levels from 2.9 +/- 0.1 and 0.60 +/- 0.10 to 0.42 +/- 0.21 and 0.05 +/- 0.01 ng/ml (P less than 0.01), respectively, while there was no significant effect observed on DHEAS, DHEA and A-dione levels. By contrast, castration in the rat reduced the low levels of circulating DHEA and A-dione below the detection of the radioimmunoassay (RIA) used. In castrated guinea pig, a small quantity of plasma A-dione (0.07 +/- 0.02 ng/ml) was measured while DHEA was undetectable. Moreover, in the rat and guinea pig, plasma T and DHT levels became undetectable. Following administration of the antiandrogen Flutamide for two weeks in the castrated rat and guinea pig, prostate weight was not further reduced, thus indicating that there is no significant androgenic activity left following castration of these two species. In fact, castration in the rat and guinea pig caused a decrease in prostatic levels of DHT from 4.24 +/- 0.351 and 9.42 +/- 1.43 ng/g, respectively, to undetectable levels. In men, on the other hand, the prostatic DHT levels were only inhibited from 5.24 +/- 0.59 to 2.70 +/- 1.50 ng/g, respectively. As expected, when Flutamide was administered to the rat and the guinea pig, the levels of prostatic steroids remained undetectable while, in men, the DHT content in the prostate was further reduced to undetectable values. In summary, the plasma levels of DHEAS, DHEA, delta 4-dione are markedly different between men and both animal models used and furthermore, measurements of prostatic levels of androgens suggest that the high plasma levels of these steroids are likely responsible for the presence of important amounts of DHT in human prostate after castration.

Simultaneous administration of pure antiandrogens, a combination necessary for the use of luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer.

Although castration levels of serum androgens are consistently achieved after 2-3 weeks of treatment with luteinizing hormone-releasing hormone (LHRH) agonists, the administration of these peptides alone in adult men is always accompanied by a transient increase in plasma testosterone and dihydrotestosterone levels, which lasts for 5-15 days at the beginning of treatment and is accompanied by disease flare-up in some cases, thus seriously limiting the acceptability of this otherwise efficient and well-tolerated treatment. The present data show that the simultaneous administration of a pure antiandrogen neutralizes the influence of the transient increase in serum androgens on prostate cancer, as indicated by the 60% decrease in serum prostatic acid phosphatase observed within 5 days of combined treatment with an LHRH agonist and a pure antiandrogen. The addition of a pure antiandrogen thus makes fully acceptable the use of LHRH agonists as an advantageous substitute for surgical castration and estrogens in the treatment of prostate cancer.

Benefits of combination therapy with flutamide in patients relapsing after castration.

Two hundred and nine patients with biopsy-proven stage D2 prostatic carcinoma showing disease progression after orchiectomy or treatment with DES (stilboestrol) or an LHRH agonist alone received combination therapy with the pure antiandrogen flutamide. In patients treated with DES, the oestrogen was replaced by the LHRH agonist [D-Trp6]LHRH ethylamide. The objective response to therapy was assessed according to the criteria of the US NPCP. Thirteen patients had a complete response to treatment, while partial and stable responses were achieved in 20 and 39 patients respectively (total objective response rate of 34.5%). The mean duration of response was 24 months. In the non-responders the median survival was 8.1 months with a 17% probability of survival at 2 years; the probabilities of survival at 2 years of the patients who showed partial and stable responses were 87 and 67% respectively. All patients who achieved a complete response are still alive. Combination therapy with Flutamide and castration (surgical or LHRH agonist) appears to be the treatment of choice for prostate cancer patients in relapse after standard endocrine therapy.

Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in advanced prostate cancer: a marked improvement in response and survival.

Eighty-seven previously untreated patients with clinical stage D2 (bone metastases) prostate cancer have received the combination therapy with a pure antiandrogen and an LHRH agonist (or orchiectomy) as first treatment in a multicentre study for up to 34 months (average = 16.2 months). A positive objective response assessed according to the criteria of the US NPCP has been observed in all cases. Pain disappeared in all patients within 1 month and performance become normal in all (including 2 bedridden patients) within 4 months. Progression of the disease after a period of remission has been observed in only 8 patients. Only one patient has died from prostate cancer while 3 have died from other causes. The probability of continuing response and survival at 2 years for the patients who receive the combination treatment (Kaplan-Meier's method) is 81 and 91%, respectively. By contrast, in the randomized group who had orchiectomy alone, 4 of 7 have died from prostate cancer (P less than 0.05 as compared to combination therapy). In addition to a marked improvement in the remission rate and survival, combination therapy maintains a good quality of life, hot flashes and a decrease or loss of libido being the only side-effects.

Advantages of the combination therapy in previously untreated and treated patients with advanced prostate cancer.

In order to achieve a more complete blockade of androgens of both testicular and adrenal origin at the start of treatment, we have administered the pure antiandrogen Flutamide in association with orchiectomy (13 patients) or the LHRH agonist [D-Trp6]LHRH ethylamide (118 patients) to previously untreated patients with clinical stage D2 prostate cancer. The mean duration of treatment was 491 days (102-1208 days). The response was assessed according to the criteria of the U.S. National Prostatic Cancer Project. A complete response has been observed in 30 patients (23%) while partial and stable responses have been achieved in 50 (38%0 and 45 (34%) patients, respectively. A positive objective response has thus been observed in 125 of 131 patients (95%). Serum PAP became normal before 6 months in all except 8 (6.1%) of patients. Quite remarkably, 23 of 48 patients treated for 2 years (47.9%) have achieved a complete response. Of the 20 deaths, 12 (9%) were due to prostate cancer, while 8 (6%) resulted from other causes. The probability of continuing a positive response after 2 years of treatment (according to Kaplan and Meier) is 60% while the probability of survival at the same time interval is 89%. This survival should be compared to values of approx 50% achieved with previous treatments limited to inhibition of testicular androgen secretion or action. The present data demonstrate that the combined blockade of androgens achieved with Flutamide and castration provides an objective response in approx 95% of patients, and markedly prolongs the period of remission while the death rate within the first 2 years is lower than that obtained with previous treatments. The important prolongation of survival is achieved with an excellent quality of life. Two-hundred and three patients have clinical stage D2 prostate cancer previously treated by orchiectomy, estrogens or LHRH agonists alone received, at the time of relapse, the same combination therapy. Patients already castrated received only Flutamide while, for those previously treated with DES, the estrogen was replaced by the LHRH agonist [D-Trp6]LHRH ethylamide in association with Flutamide. Flutamide was given as additional medication to those already receiving an LHRH agonist alone. Complete, partial and stable objective responses assessed according to the criteria of the U.S. National Prostatic Cancer Project were obtained in 11 (5.4%), 17 (8.4%) and 38 (18.7%) patients, respectively, for a total objective response rate of 32.5%. Progression continued in 137 (67.5%) patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in previously untreated patients with clinical stage D2 prostate cancer: today's therapy of choice.

One hundred and ninety-nine patients with clinical stage D2 prostate cancer who had not received previous endocrine therapy or chemotherapy were treated with the combination therapy using the pure antiandrogen Flutamide and the LHRH agonist [D-Trp6]LHRH ethylamide for an average of 26 months (3-59 months). The objective response to the treatment was assessed according to the criteria of the U.S. NPCP. There was a 5.7-fold increase (26.3 vs 4.6%) in the percentage of patients who achieved a complete response compared with the results obtained in five recent studies limited to removal (orchiectomy) or blockade (DES or Leuprolide) of testicular androgens. Only 12 of the 186 evaluable patients (6.5%) did not show an objective positive response at the start of the combination therapy compared with an average of 18% in the same five studies using monotherapy. The duration of response was also significantly improved in the patients who received the combination therapy while the death rate was decreased by approximately two-fold during the first 4 yr of treatment. In fact, while an approximately 50% death rate is observed at 2 yr in all studies using monotherapy, the same 50% death rate is delayed by 2 yr in the present study. It should be mentioned that at the time of relapse under combination therapy, the treatment is continued and, in addition, further blockade of adrenal androgen secretion is achieved with aminoglutethimide. The marked (5.7-fold) improvement in the rate of complete objective responses coupled with the three-fold decrease in the number of non-responders, the increased duration of the positive responses and the two-fold decrease in the death rate during the first 4 yr of treatment are obtained with the combination therapy using Flutamide and castration, thus improving the quality and duration of life with no or minimal side-effects. By blocking the androgen receptors in the prostatic cancer tissue, the antiandrogen decreases the action of the androgens of adrenal origin and thus inhibits the growth of a large number of tumors which, otherwise, would continue to be stimulated by the adrenal androgens left after medical or surgical castration.

Combination therapy with flutamide and castration (orchiectomy or LHRH agonist): the minimal endocrine therapy in both untreated and previously treated patients with advanced prostate cancer.

One hundred fifty-four patients with clinical stage D2 prostate cancer with no previous endocrine therapy or chemotherapy received the combination therapy with the pure antiandrogen Flutamide and the LHRH agonist [D-Trp]LHRH ethylamide for an average of 22 months (3 to 49). The objective response to the treatment was assessed according to the criteria of the US NPCP. There was a 6.3-fold increase (29.2 versus 4.6%) in the percentage of patients who achieved a complete response as compared to the results achieved in 5 recent studies limited to removal (orchiectomy) or blockade (DES or Leuprolide) of testicular androgens. Only 4.5% of patients did not respond to the combination therapy as compared to an average of 18% by standard therapy. The duration of response is also significantly increased in the patients who received the combination therapy while the death rate was decreased by approximately 2-fold between 2 and 3 years of treatment. The marked (6.3-fold) improvement in the rate of complete objective responses coupled with the 4-fold decrease in the number of non responders, the increased duration of the positive responses and the 2-fold decrease in the death rate at 2 to 3 years of treatment are obtained with the combination therapy using Flutamide and castration with no or minimal secondary effects. In addition, two hundred nine patients with biopsy-proven stage D2 prostatic adenocarcinoma showing disease progression after orchiectomy, DES or an LHRH agonist used alone received the combination therapy with the pure antiandrogen Flutamide. In patients treated with DES, the estrogen was replaced by the LHRH agonist [D-Trp6]LHRH ethylamide. Objective response to therapy was also assessed according to the criteria of the US NPCP. Thirteen patients (6.2%) had a complete response to treatment while partial and stable responses were achieved in 20 (9.6%) and 39 (18.7%) patients, respectively, for a total objective response rate of 34.5%. The mean duration of response was 24 months. While, in the non responders, the median survival was 8.13 months with a 17% probability of survival at 2 years, the probability of survival of patients who showed partial and stable responses at 2 years was 87 and 67%, respectively. All patients who achieved a complete response are still alive. Considering the excellent tolerance coupled with an objective response observed in 34.5% of the patients, the combination therapy with Flutamide and castration (surgical or LHRH agonist) appears to be the treatment of choice for prostate cancer patients in relapse after standard endocrine therapy.

Combination therapy with flutamide and castration (orchiectomy or LHRH agonist): the minimal endocrine therapy in both untreated and previously treated patients.

Patients (154) with clinical stage D2 prostate cancer with no previous endocrine therapy or chemotherapy received the combination therapy with the pure antiandrogen Flutamide and the LHRH agonist [D-Trp6]LHRH ethylamide for an average of 22 months (3-49 months). The objective response to the treatment was assessed according to the criteria of the US NPCP. There was a 6.3-fold increase (29.2 vs 4.6%) in the percentage of patients who achieved a complete response as compared to the results achieved in five recent studies limited to removal (orchiectomy) or blockade (DES or Leuprolide) of testicular androgens. Only 4.5% of patients did not respond to the combination therapy as compared to an average of 18% by standard therapy. The duration of response is also significantly increased in the patients who received the combination therapy. The death rate was decreased by approximately 2-fold between 2 and 3 yr of treatment. The marked (6.3-fold) improvement in the rate of complete objective responses coupled with the 4-fold decrease in the number of non-responders, the increased duration of the positive responses and the 2-fold decrease in the death rate at 2-3 yr of treatment are obtained with the combination therapy using Flutamide and castration with no or minimal secondary effects.

Important prognostic value of standardized objective criteria of response in stage D2 prostatic carcinoma.

One hundred and eighty-six previously untreated patients with clinical stage D2 prostate cancer have been followed according to the criteria of objective response of the National Prostatic Cancer Project (NPCP). All patients received combination therapy with the antiandrogen Flutamide and the LHRH agonist (D-Trp6, des-Gly-NH2(10)]LHRH ethylamide (or surgical castration, 10 patients) as first treatment. Forty-nine patients (26.3%) achieved a complete response as best response while 56 (30.1%) and 69 (37.1%) patients had partial and stable responses, respectively, and only 12 patients (6.5%) did not respond to treatment. The median times required to achieve stable, partial and complete responses were 155, 183 and 401 days, respectively. The best response achieved has a major influence on the probability of continuing response and survival. While the 50% probability of continuing response is more than 3 years for the complete responders, it is reduced to 630 and 517 days for partial and stable responders, respectively. While the non-responders have a median life expectancy of 10.0 months, this value is increased to 30.3 and 37.8 months for the stable and partial responders, respectively. The best probability of survival is for the complete responders with a 95.9% probability of survival at 3 years. There is no significant correlation between the time required to achieve a best response (phase 1) and the duration of the response before progression occurs (phase 2) or the time between progression and death (phase 3) for any of the categories of responses. A longer period of time required to achieve a complete response is associated with a longer survival. When analysis is made, in an attempt to predict response, of the baseline characteristics of the patients before treatment, a low number of bone metastases and better performance status are associated with a greater chance of achieving a complete response while partial, stable and progression responses cannot be predicted from the baseline characteristics. The present data show the importance of standardization of the objective criteria of response to treatment in advanced prostate cancer. Thus, the patients who achieve a complete response have a much more favorable prognosis while partial and stable categories of response have a closely similar prognosis which is inferior to the complete responders. Moreover, the present data indicate that the stable category of response has an important prognostic value which is almost superimposable and not statistically different from the partial response in terms of duration of response and survival.(ABSTRACT TRUNCATED AT 400 WORDS)

Combination therapy with castration and flutamide: today's treatment of choice for prostate cancer.

In order to achieve a more complete blockade of androgens of both testicular and adrenal origins, 223 patients with advanced prostate cancer (stage D2 with bone metastases) received the combination therapy with the antiandrogen Flutamide and the LH-RH agonist [D-Trp6,des-Gly-HN10(2)] LH-RH ethylamide as first treatment. As assessed by the objective criteria of the US NPCP, a positive response was obtained in 94% of patients, thus leaving only 6% of patients with no response at the start of treatment while, following standard therapy, 20-40% of patients do not respond to treatment. The duration of response was increased while longer survival (an advantage of approximately 14 months compared to standard therapy, 38.5 vs approximately 24 months) was achieved with no or minimal side effects. Highly positive results were also obtained using the combination therapy in stage C prostate cancer patients while temporary treatment with the combination therapy in stages A and B prostate cancer facilitated radical prostatectomy. The present data supported by the results of independent studies indicate that combination therapy should be the treatment for all patients with advanced disease and possibly also at earlier stages of prostate cancer in combination with surgery.

New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens.

To completely eliminate androgens of both testicular and adrenal origin, 37 previously untreated patients with advanced (stages C or D) prostatic cancer received the combination therapy using an LHRH agonist (HOE-766) and a pure antiandrogen (RU-23908). The response criteria developed by the National Prostatic Cancer Project were used. A positive response (assessed by bone scan and/or serum prostatic acid phosphatase measured by radioimmunoassay was observed in 29 of the 30 cases who could be evaluated by these objective criteria (97%). The objective response was parallel to a rapid and marked improvement of the clinical signs and symptoms related to prostate cancer (prostatism, bone pain, and general well being). In marked contrast, the same combination therapy applied to patients previously treated with high doses of diethylstilbestrol (13 patients) showed a positive objective response in only 55% of cases. In 23 previously castrated patients showing relapse, an objective response was seen in only 25% of cases after neutralization of adrenal androgens by the antiandrogen. Previous treatment with chlorotrianisene (TACE) had no detectable effect on prostatic cancer and patients having previously received such treatment had a rate of positive response similar to previously untreated patients (five of five). In the previously untreated patients receiving the combination therapy, a 60% fall in serum prostatic acid phosphatase was observed as early as five days after starting treatment, at a time when the serum androgen concentration was 100% to 200% above control. Combined treatment with the pure antiandrogen completely prevents flare-up of the disease, a complication previously found in a significant proportion of patients treated with an LHRH agonist alone. The present data show that complete withdrawal of androgens by combined hormonal therapy with the LHRH agonist (or castration) and a pure antiandrogen leads to a positive objective response in more than 95% of cases as opposed to 60%-70% as reported by many groups using the previous partial hormonal therapy (castration or high doses of estrogens). Adrenal androgens are most likely responsible for this difference. The present study also shows that the proportion of androgen-sensitive cells decreases from more than 95% in untreated patients to 25% to 55% after previous partial hormonal therapy. Such data clearly indicate that the previous partial hormonal therapy exclusively aimed at neutralizing testicular androgens left 25% to 55% of cancer cells having a relatively low sensitivity to androgens in a hormonal milieu compatible with their continuous growth. No clinical or biochemical side effect could be detected except those related to reduced serum androgen levels.(ABSTRACT TRUNCATED AT 400 WORDS)

New hormonal therapy in prostatic carcinoma: combined treatment with an LHRH agonist and an antiandrogen.

In order to block the influence of androgens from all sources on the growth of prostatic cancer, we have used a new hormonal therapy based on medical castration achieved with the potent LHRH agonist [D-Ser(TBU)6, des-Gly-NH2(10)]LHRH ethylamide (HOE-766) combined with the administration of a pure antiandrogen that neutralizes the action of adrenal androgens as well as those still secreted in low amounts by the testis during LHRH agonist treatment. This study was performed in ten patients with advanced prostatic carcinoma (9 at stage D2 and one at stage C). Bone pain, prostatism and general well-being were 60 to 90% improved within one month after starting treatment in all patients. After 2 months of treatment, minimal bone pain remained only in one patient who was originally bedridden. Bone scanning showed a 70 to 90% decrease in uptake after 3 to 5 months of treatment in the patients studied. Acid phosphatase levels were 60 to 90% reduced after 2 months of treatment in 3 out of the 4 patients who had elevated levels before therapy. Marked objective and subjective improvement was thus rapidly observed in 9 out of 10 patients treated with the combined therapy, while, in the other patient at stage C, subjective improvement could be documented. Although preliminary, this study indicates that a combined hormonal therapy which neutralizes all androgenic influences on peripheral tissues is of potential benefit in prostatic cancer. Moreover, the ease of application as well as the lack of secondary effects of the present approach should make possible its use early in the disease and should thus minimize the development of metastases and androgen-resistant cell clones. Randomized prospective studies on this potentially beneficial therapy are warranted.