Nelson H. Slack

Cancer of the breast: Size of neoplasm and prognosis

In this study we utilized information obtained from more than 2000 operable breast cancer patients who had been entered since 1957 into the National Breast Project by 45 institutions. The purpose was to further evaluate the concept that the size of breast neoplasms influences patient prognosis. Only 5% of patients had tumors smaller than 1.0 cm, 48% were larger than 2.9 cm, and 28% exceeded 4.0 cm. The findings, when compared with those previously reported by others, suggest that little progress has been made since about 1950 relative to the removal of smaller breast tumors. Since these data are probably more nearly representative of the size of breast tumors at surgery in this country during the past decade than most other data that are available, they provide a baseline for the evaluation of the worth of a variety of recently employed and proposed diagnostic procedures. Results obtained categorically agree with current thinking that the larger the tumor the more likely that axillary nodes will be positive, that 4 or more rather than 1‐3 nodes will be involved, and tumor recurrence and mortality rates will be greater. Such an unqualified statement, however, is an oversimplification of the findings, provides no indication of the magnitude of recurrence and mortality differences to be anticipated from tumors of various sizes, and should be accepted only with reservation. It is speculated, as a result of the data presented and certain assumptions, that if all tumors 2.0 cm or larger (70% of the total) had been removed when they were 1.0‐1.9 cm in size, at the end of 5 years the recurrence rate for all patients entered might have only decreased by 10‐18%, and the overall survival might have increased 11‐20%. From certain considerations and the results obtained, it is concluded that size may not necessarily relate to “earliness” or “lateness” of a tumor, nor is it as consequential to the fate of the patient as are other factors relative to the tumor and /or host that may be present from its inception and which determine the development of metastases. Such a conclusion does not deprecate effort toward earlier diagnosis and tumor removal. It does emphasize, however, that the reasons for such an endeavor may be different from those generally considered at present.

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.

Adjuvant progestogen therapy in the primary definitive treatment of endometrial cancer

Abstract On the basis of reported successful hormone therapy for recurrent cancer of the endometrium, a multi-institutional program was established in 1963 and terminated in 1968 to study the adjuvant use of a progestogen in the primary definitive treatment of uterine carcinoma. The research protocol restricted entry to patients with disease limited to the uterine corpus as established by clinical evaluation, surgery, and pathology. Option of surgery alone or surgery plus irradiation was permitted. Depo-Provera and placebo given over 14 wk were randomly assigned in such a way that 285 patients received hormone; 287 served as controls. Survival analysis at 4 yr indicated no significant contribution to results by the adjuvant therapy. Overall excellent survival for treated patients and controls appeared to be the result of the high degree of patient selection incorporated in the protocol design. The influence of patient selection and of variations of disease-related parameters upon the results is discussed especially as it may affect future programs dealing with comparable patient material.

Chemotherapy programs of the National Prostatic Cancer Project (NPCP)

Results of the first nationally randomized trial of the National Prostatic Cancer Project revealed a demonstrable advantage for chemotherapy in the management of advanced disease (Stage D in relapse from endocrine therapy). Both cyclophosphamide and 5‐Fluorouracil showed improved activity over standard therapy. A second trial for patients previously irradiated, with less tolerance to myelosuppressive agents, revealed an advantage for estramustine phosphate and streptozotocin over standard therapy. Subsequently completed trials have revealed activity for prednimustine and imidazole carboxamide (DTIC). Trials currently underway for newly‐diagnosed Stage D and for Stage D disease clinically stable to diethylstilbestrol (DES) show promising activity for DES combined with cyclophosphamide. Current trials with single agents in advanced disease are comparing methyl‐CCNU and hydroxyurea with cyclophosphamide; another is evaluating estramustine phosphate and vincristine alone and in combination. The use of chemotherapy in earlier staged patients as adjuvants to definitive surgery or irradiation is underway in two clinical trials, where the effect of cyclophosphamide and estramustine phosphate as long‐term therapies is compared with no additional 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.

The Heterogeneity of Invasive Bladder Carcinoma and Different Responses to Treatment

AbstractWe studied 475 patients with carcinoma of the bladder to test the effect of adjuvant radiotherapy (4,500R in 28 to 32 days) on the surgical management of patients with histological proof of muscle invasion. The patients were randomized to receive radiotherapy or not and then an appropriate open operation (more than 85 per cent cystectomy). While all patients never completed the protocol of those who did it was almost immediately evident that radiotherapy resulted in apparent destruction of the tumor as determined by pathological examination in a third of the surgical specimens (Po). For several years no advantage to the radiotherapy group was evident but subsequent followup revealed that the Po group was surviving significantly better than the control group. The current analysis, while lacking complete data on all patients, indicates that invasive bladder carcinoma usually is solid and that solid tumors most commonly invade lymphatics and are not radiosensitive. Invasive papillary carcinomas are m...

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.

Serum Prostatic Antigen Measurement in Localized Prostatic Cancer: Correlation with Clinical Course

Serial serum prostatic antigen measurements were performed on patients treated for localized prostatic carcinoma. There was good correlation of mean serum prostatic antigen levels and the surgical stage of the disease. Among patients treated by radical prostatectomy there was good correlation of an elevated serum prostatic antigen and the development of metastatic disease. It appears that serum prostatic antigen is a good indicator and predictor of the development of distant metastasis in this group of patients.

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.

The importance of the stable category for chemotherapy treated patients with advanced and relapsing prostate cancer

Categories of objective response to chemotherapy for 460 advanced relapsing prostate cancer patients evaluated in the initial first four randomized clinical trials of the National Prostatic Cancer Project were compared by survival and other patient and disease characteristics. The response criteria for stable were shown to delineate patients with markedly improved survival and other disease conditions relative to those designated as progression. Survival was similar for stable and partial regression patients despite more frequent reduction of primary tumor and subjective improvement in performance status, pain, and body weight in the partial regression patients. Consequently, we feel that in these studies the stable category is valid and useful for determining efficacy of treatment in patients with advancing prostate cancer.