John F. Gaeta

Treatment of newly diagnosed metastatic prostate cancer patients with chemotherapy agents in combination with hormones versus hormones alone

A prospective trial from July 1976 to September 1980 by the National Prostatic Cancer Project randomized newly diagnosed metastatic prostate cancer patients to DES 1 mg orally three times daily or orchiectomy; or DES, 1 mg, three times daily, plus cyclophosphamide at 1 mg/m2 iv every three weeks, or cyclophosphamide 1 g/m2 iv every three weeks plus estramustine phosphate (Estracyt) at 600 mg/m2 orally daily in three divided doses. There were 246 patients evaluated for response of 301 entered. These consisted of 83 on the DES/orchiectomy arm, 77 on DES plus cyclophosphamide, and 86 on Estracyt plus cyclophosphamide. Objective response rates, initially evaluated at 12 weeks, were similar among the treatments. However, chemotherapy as used in this study early in the diagnosis of metastatic disease appears to exhibit an improved effect on overall survival compared to hormone therapy alone. Analysis within groups having pain versus no pain at entry revealed a marked advantage after 80 weeks for chemotherapy when pain was initially present and a slight advantage during treatment (throughout follow‐up) when the pain was absent. Median survival times were 92, 91, and 94 weeks, respectively, for the three treatments. The progression‐free interval for responders showed no difference between initial treatments, although nearly one half of the patients are still in remission; hence, further follow‐up will be essential. Side effects were not excessive for the chemotherapy treatment arms and patient compliance was good. This national multicenter trial provides the basis for further testing of chemotherapy agents at an earlier phase for patients with newly diagnosed metastatic prostate cancer.

Histologic Grading of Primary Prostatic Cancer: A New Approach to an Old Problem

A simple and objective system for grading prostatic carcinoma was evaluated in a retrospective analysis of 169 cases followed during a 16-year period. The system identified and separated 4 grades of increasing malignancy based on the combined evaluation of gland differentiation and nuclear anaplasia as separate but complementary factors. The system demonstrates significant correlation with mortality rates for each grade group. Retrospective evaluation of the extent of the disease at the time of initial diagnosis also indicates correlation between prostatic grades and clinical stages.

Superficial bladder tumor: Aspects of clinical progression☆

Abstract The clinicopathologic staging of bladder cancer is the main prognostic aid in superficial tumor since it has close relation to the degree of differentiation of the tumor and the observed degree of its progression in the 238 cases of this series. The survival rate of the patients was related to the depth of penetration and degree of histologic differentiation of the tumor. Thus both the stage and the grade of the tumor together had prognostic value. Primary clinical staging correlated well with the size of the initial lesion, but not with the location, number of primary lesions or subsequent recurrences, or time of the appearance of progression of the primary lesion. Almost one third of the patients with superficial bladder cancer died from bladder cancer. Two thirds of the cases with known pathologic stage at autopsy showed extravesical extension of the lesion. Prior external radiation to the superficial tumors apparently did not affect progression of the primary lesion.

Lung metastases in prostatic carcinoma: Clinical significance*

Abstract Lung metastases is a frequent postmortem finding in prostatic carcinoma. The clinical diagnosis of pulmonary involvement appears more frequently than anticipated. Survival rate of patients with lung metastases is dependent to some degree on the clinical stage of the primary prostatic carcinoma. Bone metastases are seen in almost every patient with lung metastases. Bone rather than lung metastases were first diagnosed in the course of the disease. Evidence that further dissemination of the tumor to peripheral sites, such as endocrine organs, is influenced by the presence of the tumor first in the bones and lungs, is presented. However, the course of lung metastases in prostatic carcinoma does not appear to be dependent on the clinical staging of the primary prostatic lesions or in the interval between the first diagnosis of the disease and its detection, or on the chemical enzymatic activity of acid and alkaline phosphatases. Further, no change, or decrease in some of the pulmonary lesions, was not found to be of prognostic value. On the other hand, progression of these lesions was associated with the short survival rate in these patients. Adrenalectomy or hypophysectomy performed as secondary treatment at the time of relapse with associated lung metastases was found more frequently to improve the appearance of the lung metastatic lesions than other forms of treatment.

Comparison of Estramustine Phosphate, Methotrexate and cis-Platinum: in Patients with Advanced1 Hormone Refractory Prostate Cancer

In this clinical trial of men with advanced prostatic cancer no longer responsive to hormone therapy 189 were randomized to receive estramustine phosphate, methotrexate or cis-platinum. Response evaluations were done in 158 cases. Objective response rates (complete, partial or stabilization of disease) were 34 per cent for estramustine phosphate, 36 per cent for cis-platinum and 41 per cent for methotrexate. Subjective parameters indicated a substantial advantage for pain improvement with methotrexate or cis-platinum over estramustine phosphate. Probabilities of continued response indicated some advantage for methotrexate and median response durations at this time were twice as long for methotrexate (32 weeks) as for cis-platinum (16 weeks), with estramustine phosphate intermediate (23 weeks). Survival rates for the original treatment randomization groups were not different at this time. Side effects of estramustine phosphate consisted primarily of nausea and vomiting and/or anorexia but to a lesser extent than with cis-platinum. These effects were somewhat less for methotrexate, for which the major side effects were stomatitis and leukopenia, as well as hepatic toxicity reflected by elevated serum glutamic oxaloacetic transaminase levels. Other side effects of cis-platinum were less than for methotrexate (no stomatitis), except for signs of renal toxicity (elevations in blood urea nitrogen and serum creatinine), which were greater. Methotrexate had a relatively high level of activity against metastatic, progressive, hormone nonresponsive prostatic cancer, with side effects that were substantial but manageable.

A comparison of estramustine phosphate and streptozotocin in patients with advanced prostatic carcinoma who have had extensive irradiation.

AbstractIn this second nationally randomized cooperative chemotherapy trial of the National Prostatic Cancer Project 125 patients with histologically confirmed progressing advanced carcinoma of the prostate (clinical stage D) who had had prior pelvic irradiation of at least 2,000R received as initial therapy 1 of 2 non-myelosuppressive agents—estramustine phosphate or streptozotocin—for comparison with patients randomized to receive standard treatment. Patients whose disease was progressive after 12 weeks on chemotherapy were crossed over to receive the alternate therapeutic agent. Response to treatment was evaluated in 105 patients on the basis of previously established and defined criteria.All known prognostic factors were comparable among the 3 treatment arms. The objective response rates to therapy were 19 per cent in the standard arm (stable only), 30 per cent in the estramustine phosphate arm (stable and partial regression) and 32 per cent in the streptozotocin arm (stable arm). Thus far, 4 patients...

Comparison of Estramustine Phosphate and Vincristine Alone or in Combination for Patients with Advanced, Hormone Refractory, Previously Irradiated Carcinoma of the Prostate

There were 121 men with hormonally refractory metastatic cancer of the prostate who were randomized to receive estramustine phosphate or vincristine, or the combination of these 2 agents. All patients had received prior radiation therapy (greater than 2,000 rad). There were 90 patients who could be compared for response. The objective response rates (partial regression or stabilization of disease) for the 3 treatment groups were 26 per cent for estramustine phosphate, 24 per cent for estramustine phosphate plus vincristine and 15 per cent for vincristine. Subjective parameters varied little among the 3 regimens. The median duration of response for those responding to estramustine phosphate was similar (20 weeks) to that for vincristine (22 weeks) and greater than that for the combination (13 weeks). The probability of survival did not differ significantly for patients randomized to each of the 3 regimens. The addition of vincristine to estramustine phosphate did not enhance the response rate achieved by estramustine phosphate alone and vincristine alone produced the lowest response rate. Estramustine phosphate continues to be the most active agent in previously irradiated patients with hormonally refractory metastatic cancer of the prostate.

Comparison of Procarbazine, Imidazole-Carboxamide and Cyclophosphamide in Relapsing Patients with Advanced Carcinoma of the Prostate

In this third cooperative chemotherapy trial of the National Prostatic Cancer Project 165 patients with histologically confirmed, relapsing clinical stage D prostatic cancer were randomized to receive either imidazole-carboxamide, procarbazine or cyclophosphamide. All patients had received and failed previous hormonal therapy. Patients whose disease progressed after 12 weeks on initial therapy were crossed over or randomized to receive an alternate drug. There were 129 patients available for comparison of treatments. The objective response rates (partial regression plus stable disease) were 26% for cyclophosphamide, 27% for imidazole-carboxamide and 14% for procarbazine. Subjective responses were noted in pain relief, improvement in performance status and weight gain. Procarbazine was associated with excessive toxicity, resulting in many patients (28%) discontinuing therapy within the first 3 weeks and closure of this particular arm of the study. The regimen of initial imidazole-carboxamide therapy with a later cross-over to cyclophosphamide when the disease continues to progress is associated with the longest increase in survival. Imidazole-carboxamide and cyclophosphamide appear to be active agents in advanced prostatic cancer and are worthy of continued use in this disease.

A Comparison of Estramustine Phosphate Versus Cis-platinum Alone Versus Estramustine Phosphate Plus Cis-platinum in Patients with Advanced Hormone Refractory Prostate Cancer Who Had Had Extensive Irradiation to the Pelvis or Lumbosacral Area

Single and combination chemotherapy was compared in a clinical trial for men with advanced, metastatic prostate cancer who had received prior pelvic irradiation and had had progression of disease despite hormonal therapy. The 149 patients were randomized to receive estramustine phosphate or cis-platinum alone or in combination. Of the 149 patients 25 (17 per cent) were excluded from the study but 124 were evaluated for response and survival. Entry variables were distributed similarly among patients in each treatment arm. There were no complete or partial responders but there were nearly twice as many patients whose disease was stabilized (33 per cent) on the combination regimen compared to estramustine phosphate (18 per cent) and about a third more than for cis-platinum (21 per cent). Analysis of survival revealed some advantage for patients on combination therapy. Major toxicities for all treatments were nausea and vomiting (62 to 88 per cent) and accompanying anorexia (72 to 95 per cent). Azotemia developed in 45 per cent of the patients receiving combination therapy. In addition an elevation in serum creatinine occurred in 22 per cent of the patients receiving combination therapy and in 17 per cent of those receiving cis-platinum alone. Myelosuppression occurred infrequently.

Inhibition of Implantation of Murine Bladder Tumor by Thiotepa in Cauterized Bladder

This study was designed to determine the role of immediate intravesical instillation of single dose thiotepa post transurethral resection of bladder tumor in the prevention of recurrence by tumor implantation, using murine bladder tumor line 2 and 201 C3H/He mice. Previous studies have suggested implantation may take place as early as the first hour and reach its maximum in 24 hours after resection of bladder tumor. An in vitro dose response curve of MBT2 to thiotepa was established by treatment with various concentrations of thiotepa of 0.00, 0.01, 0.21, 0.44, and 1.91 mg./ml. In a group of 201 mice, the bladder was catheterized with a 24G angiocatheter, and a fine copper wire was inserted through the lumen. The bladder was cauterized by touching the wire with a Bovie coagulator for four seconds at the lowest setting. All bladders were instilled with 1 x 10(6) cells of murine bladder tumor line 2, followed by instillation of 1.91 mg./ml. of thiotepa with various time delays per treatment group. The bladder implantation rates were 30.4% (17/56), 3.4% (2/59), 6.5% (2/31) and 26.9% (7/26) in the control, immediate, one-hour delay and 24-hour delay groups, respectively. The urethral implantation rates were 21.4% (12/56), 0% (0/59), 6.5% (2/31) and 0% (2/26), respectively. The overall implantation rates (bladder, urethra, or both) were 42.9% (24/56), 3.4% (2/59), 6.5% (2/31) and 25.9% (7/27), respectively. Implantation rates were significantly higher in the control and 24-hour delay groups than in the immediate and one-hour instillation groups (p less than 0.05, Fisher Exact Test). We conclude from this animal model that intravesical instillation of single dose thiotepa, to be effective, should be initiated within the first hour after tumor resection, since it dramatically decreased the incidence of bladder and urethral implantation.