L. Denis

Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III eortc trial (30853)

Maximal androgen blockade (MAB), the eradication of the effects of adrenal androgens on prostate cancer cells after castration, has been used with differing success in the treatment of prostatic carcinoma. The aim of this randomized phase III study was to compare the efficacy and side effects of bilateral orchiectomy versus a combination of a luteinizing hormone-releasing hormone agonist (LHRH-A) depot formulation, goserelin acetate (3.6 mg s.c. once every four weeks), and flutamide (250 mg three times daily), in patients with metastatic cancer. Treatment usually continued until disease progression (or for a minimum of three months). Efficacy was assessed by response, time to disease progression, and duration of survival. Clinical evaluations, standard laboratory tests, and imaging examinations were carried out regularly. A total of 327 patients were entered in this study. There was a difference in response only for prostatic acid phosphatase (PAP) with a more frequent decrease of the serum values to normal in the serum in patients assigned to MAB treatment. The MAB treatment, however, proved significantly better for time to subjective progression, time to objective progression, time to first (subjective and objective) progression, and duration of survival. The most frequent side effects for both treatments included hot flushes and gynecomastia. In conclusion, significant time to progression and survival benefits are achieved by adding flutamide to an LHRH-A regimen, probably improving the quality of life of patients with metastatic cancer.

Prognostic factors in superficial bladder tumors. A study of the European organization for research on treatment of cancer: Genitourinary tract cancer cooperative group

A randomized clinical trial was performed on 308 patients with stage T1 carcinoma of the bladder to compare the efficacy of transurethral resection alone or followed by bladder instillations of thiotepa or VM-26 (teniposide) for 1 year. With the recurrence rate as the primary end point of interest the data from this trial were used to assess the prognostic importance of the following factors at entry into the study: number of tumors, prior recurrence rate, tumor size, grade, age, treatment group assigned and, finally, the interval between transurethral resection at entry into the study and the start of intravesical treatment. Using multivariate statistical techniques we found that the number of tumors at presentation was the most important prognostic factor followed by, in order of importance, the recurrence rate at entry and the size of the largest tumor. Of particular note was the discovery that patients with less than 1 recurrence per year at entry had a prognosis similar to patients with primary tumors, while those with a higher recurrence rate did uniformly poorly. These results show that patients with stage T1 carcinoma of the bladder form a heterogeneous group and that more aggressive therapy should be considered for patients with a poor prognosis.

Combination Chemotherapy with Cisplatin and Methotrexate in Advanced Transitional Cell Cancer of the Bladder

We studied 53 patients with bidimensionally measurable metastases of transitional cell cancer of the bladder who were treated with a planned regimen of 70 mg. per m. cisplatin intravenously on day 1, and 40 mg. per m. methotrexate intravenously on days 8 and 15 every 3 weeks. The toxicity of this regimen, with agranulocytosis and mucositis as the most important side effects, was so severe that only 17 per cent of the patients actually received the protocol regimen without modification. Six patients were ineligible and 47 were evaluable for toxicity, including 43 who were evaluable for response. The response to treatment was assessed after each second treatment cycle. A complete response was achieved in 10 patients (23 per cent) and a partial response was achieved in 10 (23 per cent). The median duration of response was 64 weeks for patients with a complete response and 23 weeks for those with a partial response, while the median duration of survival was 81 and 37 weeks, respectively. The aforementioned regimen with allowance of routine leucovorin rescue is tested as preoperative chemotherapy in patients with stages T3 to T4 nonmetastatic bladder cancer.

Adjuvant Chemotherapy of Superficial Transitional Cell Bladder Carcinoma:Preliminary Results of a European Organization for Research onTreatment of Cancer Randomized Trial Comparing Doxorubicin Hydrochloride, Ethoglucid and Transurethral Resection Alone

Patients with superficial transitional cell carcinoma of the bladder were entered in a randomized clinical trial to compare the efficacies of transurethral resection alone or followed by bladder instillation of doxorubicin hydrochloride or ethoglucid (Epodyl) for 1 year. Results showed that adjuvant chemotherapy with the selected drugs prolonged the mean interval between recurrences. Mild systemic toxicity and chemical cystitis were observed in 3 and 3 per cent, respectively, of the patients given ethoglucid, and in 5 and 4 per cent, respectively, of those taking doxorubicin.

THE QUALITY OF LIFE OF PATIENTS WITH NEWLY DIAGNOSED M1 PROSTATE CANCER : EXPERIENCE WITH EORTC CLINICAL TRIAL 30853

This study was undertaken to evaluate the quality of life (QoL) of previously untreated patients with M1 prostate cancer before and during androgen-suppressive treatment. Assessment of QoL was included as an optimal component of EORTC protocol 30853, a phase III trial comparing LH-RH (luteinising hormone-releasing hormone) analogue combined with a non-steroidal anti-androgen versus orchiectomy in patients with M1 prostate cancer. At pretreatment and during the follow-up period, patients were asked to complete a questionnaire assessing their physical and psychosocial functioning, and their symptom levels. Physicians rated the patients performance status, pain, urological symptoms and erectile function. Due to its optional nature, only a minority of the patients in the trial were recruited for the QoL investigation. 63 patients completed a pretreatment questionnaire, of whom 49 completed a second questionnaire at least once during the initial 15 month follow-up period. While statistically significant correlations were observed between patients and physicians ratings of physical functioning and pain, these were of only a moderate magnitude (r = 0.43 and 0.30, respectively). No significant association was observed between physicians and patients ratings of micturation problems or of erectile function. Before treatment, fatigue, pain and decreased social role and sexual functioning were the problems most frequently reported by patients. With an average of approximately 1 year follow-up, statistically significant improvements were observed in patients self-reported urological symptoms and metastatic pain. No significant changes were noted for the other QoL domains assessed. The results of this study confirm earlier findings that physicians ratings may not reflect accurately the functional health and symptom experience of their patients. Patient-based QoL questionnaires offer the most direct means of evaluating the subjective morbidity associated with prostate cancer and its treatment. To increase participation and compliance rates in future studies, it is recommended that QoL assessment be made mandatory in those clinical trials in which QoL is considered to be an important study endpoint.

Some limitations of the radioisotope bone scan in patients with metastatic prostatic cancer : a subanalysis of EORTC trial 30853

This article reviews the serial bone scans of 149 of 327 patients entered into a randomized prospective trial comparing orchidectomy versus zoladex and flutamide in patients with metastatic prostatic cancer. Attention is drawn to the difficulty of evaluating the response rate and of the importance of tumor load in determining survival. The use of sequential bone scans once the diagnosis of metastatic disease has been confirmed is of questionable value as the scans are expensive and contribute little to the further management of the patient in the absence of symptoms requiring relief.

Orchiectomy versus goserelin and flutamide in the treatment of newly diagnosed metastatic prostate cancer. Analysis of the criteria of evaluation used in the european organization for research and treatment of cancer–‐genitourinary group study 30853

This European Organization for Research and Treatment of Cancer (EORTC) trial 30853 is the fifth EORTC–‐Genitourinary Group randomized phase III trial of endocrine treatment for patients with newly diagnosed metastatic prostate cancer. Special attention was given to the assessment of response and/or progression. Each of the following factors was assessed separately as nonspecific and subjective criteria of response or progression: performance status, pain, alkaline and acid phosphatase, hemoglobin, urinary symptoms, and prostate‐specific antigen (PSA). Objective progression was based on measurable disease. The observed sequence of progression was: (1) protein‐specific antigen; (2) bone; (3) pain; and (4) performance status. Protein‐specific antigen, an optional parameter, was the first sign of progression in more than 50% of patients whose disease had progressed.

Adjuvant Chemotherapy of Recurrent Superficial Transitional Cell Carcinoma: Results of a European Organization for Research on Treatment of Cancer Randomized Trial Comparing Intravesical Instillation of Thiotepa, Doxorubicin and Cisplatin

A total of 356 patients with recurrent superficial transitional cell carcinoma of the bladder was entered in a randomized clinical trial to compare intravesical thiotepa, doxorubicin and cisplatin with respect to the recurrence rate and disease-free interval. After complete transurethral resection of all visible lesions, the drugs were administered weekly for 4 weeks and monthly for 11 months. The recurrence rates per year were 0.50 for thiotepa, 0.54 for doxorubicin and 0.58 for cisplatin. Of 266 patients (mean followup 41 months) 35 reported an increase in T category and 19 of them had distant metastases. No association between treatment and progression was noted. Thus, there is no difference among treatments with respect to efficacy. However, severe anaphylactic reactions were observed in the cisplatin arm and chemical cystitis was more frequently reported in patients who received doxorubicin.

Chemoresection in Ta-T1 bladder cancer. Members of the EORTC Genito-Urinary Group.

OBJECTIVESnThe authors present the results of two parallel phase II trials, instituted by the EORTC Genito-Urinary Group in 1986, whose aims were to assess the tolerability and ablative capacity of mitomycin C (study 30864) and epirubicin (study 30869) in patients with multiple primary or recurrent Ta-T1 bladder cancer.nnnMETHODSnA well-defined tumour (marker lesion) was left in the bladder after transurethral resection (TUR). All patients received 8 weekly instillations, after which cystoscopy with bladder biopsies +/- TUR was performed. Responses were rated as follows: (1) complete-no visible or microscopic bladder cancer; (2) no change-persistence of the marker lesion; (3) progression-increased marker lesion size, new tumour(s) or presence of muscle-invasive disease at any site.nnnRESULTSnNinety-six evaluable patients were treated with mitomycin and 36 with epirubicin. The overall bladder response in the former group was complete in 50%, no change in 30% and progression in 20% of patients, while the marker lesion response was complete in 57%, no change in 39% and progression in 4%. In the epirubicin group, 56% of the patients achieved a complete overall response, while there was no change in 22% and progression in 22%. The marker lesion response in this group was complete in 67%, no change in 31% and progression in 3%. Only 2 cases of progression were due to the presence of muscle-invasive disease. Both of these were in the mitomycin group; 1 was at the marker lesion site, and 1 was at a remote site.nnnCONCLUSIONSnThe present studies confirm the feasibility and safety of the marker lesion model for the objective evaluation of the antitumoural activity of intravesically administered drugs.

The Importance of Prognostic Factors in the Interpretation of Two EORTC Metastatic Prostate Cancer Trials

Introduction and Objectives: The EORTC conducted two randomized phase III trials of maximal androgen blockade (MAB) in 695 patients with metastatic prostate cancer. Trial 30843 compared orchidectomy or buserelin to buserelin plus cyproterone acetate and showed no significant difference in survival while trial 30853 showed that Zoladex plus flutamide had a significantly longer survival than orchidectomy. Reasons for this discrepancy were sought. Methods: In order to determine whether differences in patient characteristics could explain these possibly contradictory results, a Cox proportional hazards regression model was used to identify prognostic factors for survival in each study. Patients were divided into risk groups (good or poor prognosis with 3.5 and 1.75 years’ median survival, respectively) based on their alkaline phosphatase, hemoglobin, performance status, pain score, T category and G grade at entry on study. Results: The survival advantage of MAB in 30853 was limited to patients with a good prognosis (164/302 (54%) of the patients). In 30843, only 93/337 patients (28%) had a good prognosis so there were insufficient data to draw separate conclusions in these patients. Despite the limitations of subgroup analyses, these results show that patients in 30843 had on the average a worse prognosis than patients in 30853. Hence there were fewer good prognosis patients who could potentially benefit from MAB, thus providing one possible explanation for the overall negative conclusion. Conclusions: These studies once again underline the importance of taking into account patient characteristics when designing and interpreting metastatic prostate cancer trials. They also provide criteria which may be used to define risk groups as part of a protocol’s patient eligibility criteria. In the design of future trials assessing MAB, a sufficient number of good prognosis patients should be entered to reliably assess treatment efficacy in this subgroup.