T.M. Chu

Carcinoembryonic antigen in patients with tumors of the urogenital tract

Carcinoembryonic antigen (CEA) was elevated in 35 (30%) of 116 patients with cancer of the urogenital tract and in only one of 17 patients with benign urologic disease. No positive results were seen in any of 17 patients with well‐controlled prostatic carcinoma, whereas 7 of 11 patients with active disease had positive results. In carcinoma of the bladder, 2 of 24 patients with inactive disease and 10 of 20 with active disease had positive results. The test seems to be useful in the follow‐up of cancer patients and in evaluating the results of therapy, but the use of the CEA assay as a diagnostic procedure must await the characterization of more specific antigens obtained from urologic tissues.

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.

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.

A comparison of hydroxyurea, methyl-chloroethyl-cyclohexy-nitrosourea and cyclophosphamide in patients with advanced carcinoma of the prostate

This is the fifth completed randomized clinical trial of the National Prostatic Cancer Project. There were 125 patients with histologically confirmed relapsing clinical stage D prostatic cancer randomized to receive hydroxyurea, methyl-chloroethyl-cyclohexy-nitrosourea or cyclophosphamide. All patients had received and failed previous hormonal therapy. Patients whose disease progressed after 12 weeks on the initial therapy were crossed over or randomized to receive an alternate drug. There were 98 patients available for comparison of treatments. Objective responses included patients with complete or partial regression as well as stable disease. The response rates were 35 per cent for cyclophosphamide, 30 per cent for methyl-chloroethyl-cyclohexy-nitrosourea and 15 per cent for hydroxyurea. Subjective response parameters included improvement in performance status and relief of pain. Pain was improved in a fifth of the patients on each treatment area. Methyl-chloroethyl-cyclohexy-nitrosourea and hydroxyurea showed activity in advanced prostatic cancer patients but at the expense of excessive toxicity. Cyclophosphamide continues to be the most active single agent in this type of patient, particularly with regard to duration of response and survival. There was a statistically demonstrable advantage for cyclophosphamide over hydroxyurea and a marginal advantage over methyl-chloroethyl-cyclohexy-nitrosourea in survival experience.

The use of estramustine and prednimustine versus prednimustine alone in advanced metastatic prostatic cancer patients who have received prior irradiation.

Estramustine has been shown previously to be an effective drug in the treatment of metastatic prostatic cancer, demonstrating significant objective and subjective responses in long-term non-randomized trials and in other randomized trials. In this study prednimustine alone has shown a minimal over-all objective response rate of 12.9% of the cases, although with marked subjective improvement of pain relief and patient performance status. The combination of prednimustine with estramustine did not result in improvement of objective or subjective response parameters. The effects in terms of responses or in terms of toxicity for either agent were not additive when they were given in combination. Cross-over for those patients whose disease progressed on prednimustine therapy to estramustine had some benefit in over-all survival. Prednimustine alone or in combination with estramustine may be used safely and could improve markedly the quality of life for irradiated patients with advanced prostatic cancer who failed on hormonal treatment and have too poor a bone marrow reserve to be treated by other currently available myelosuppressive agents.

Clinical Significance of Serum Alkaline Phosphatase Isoenzyme Levels in Advanced Prostatic Carcinoma

The alkaline phosphatase isoenzymes in 105 patients with stage D carcinoma of the prostate who entered the National Prostatic Cancer Study were analyzed and these values were correlated to clinical response. Only patients with at least 3 measurements of alkaline phosphatase were evaluated. In 91% of patients with metastatic bone disease, bone alkaline phosphatase was elevated. Those patients with higher pre-treatment levels of alkaline phosphatase generally showed a poorer response to therapy. The results of alkaline phosphatase isoenzyme estimation indicate that these biological markers may be used in the evaluation of patients with metastatic prostatic cancer to predict and monitor their response to chemotherapy. The evaluation of bone and liver alkaline phosphatase isoenzymes in earlier stages also may be valuable.

Biologic markers in cancer diagnosis and treatment.

We have reviewed several tumor markers that our advocates feel are now clinically useful, involve current assay technology, and are based on already available information. These include, in selected instances, estrogen receptors for breast cancer, thyrocalcitonin for medullary cancer of the thyroid, prostatic acid phosphatase for cancer of the prostate, alpha-fetoprotein for hepatocellular cancer, and carcinoembryonic antigen for monitoring colon cancer. We have considered the potential use of measurement of serum proteases and protein degradation products due to their activity as possible future areas of development, and we have explored measurement of tissue aryl hydrocarbon hydroxylase to identify populations at risk of cancer resulting from chemical carcinogenesis. It is clear that the study of tumor markers is already improving patient care in some specific areas and offers exciting potential for the future.