Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone.

PURPOSE: Suramin is a novel agent that has demonstrated preliminary evidence of antitumor activity in hormone-refractory prostate cancer (HRPC). A prospective randomized clinical trial was designed to evaluate pain and opioid analgesic intake as surrogates for antitumor response in HRPC patients with significant, opioid analgesic-dependent pain. PATIENTS AND METHODS: A double-blind, placebo-controlled trial randomized patients to receive a 78-day, outpatient regimen of either suramin plus hydrocortisone (HC, 40 mg/d) or placebo plus HC. Treatment assignment was unblinded when either disease progression or dose-limiting toxicity occurred; placebo patients were allowed to cross-over to open-label suramin plus HC. In addition to pain and opioid analgesic intake, prostate-specific antigen (PSA) response, time to disease progression, quality of life, performance status, and survival were compared. RESULTS: Overall mean reductions in combined pain and opioid analgesic intake were greater for suramin plus HC (rank sum P =.0001). Pain response was achieved in a higher proportion of patients receiving suramin than placebo (43% v 28%; P =.001), and duration of response was longer for suramin responders (median, 240 v 69 days; P =.0027). Time to disease progression was longer (relative risk = 1.5; 95% confidence interval, 1.2 to 1.9) and the proportion of patients with a greater than 50% decline in PSA was higher (33% v 16%; P =.01) in patients who received suramin. Neither quality of life nor performance status was decreased by suramin treatment, and overall survival was similar. Most adverse events were of mild or moderate intensity and were easily managed medically. CONCLUSION: Outpatient treatment with suramin plus HC is well tolerated and provides moderate palliative benefit and delay in disease progression for patients with symptomatic HRPC.

Elevated serum levels of p105(erbB-2) in patients with advanced-stage prostatic adenocarcinoma.

Expression of a truncated or extracellular form (p105erbB-2) of p185erbB-2 has been demonstrated in the sera of breast cancer patients. We examined the levels of p105erbB-2 in the sera of patients with various stages of prostatic adenocarcinoma, in patients with benign prostatic hyperplasia (BPH) and in a series of control male patients hospitalized for illnesses unrelated to the prostate. p105erbB-2 levels did not differ between the controls and BPH patients or between these groups and patients with stage A, B or C adenocarcinomas. In contrast, serum p105erbB-2 levels of patients with stage D adenocarcinomas were significantly elevated when compared with either control or BPH patients. There was no correlation between PSA and p105erbB-2 levels among controls, patients with BPH or patients with prostate cancer. Patients with poorly differentiated tumors (combined Gleason score >7) or moderately differentiated tumors (combined Gleason score 5-7) had higher p105erbB-2 levels as compared to patients with well-differentiated tumors (combined Gleason score <5), though this difference was not statistically significant. There was no correlation between serum p105erbB-2 levels and p185erbB-2 expression in malignant tissue, as determined by immunohistochemistry. However, patients with moderate to strong expression of p185erbB-2 within the adenocarcinomas were approximately 4 times more likely to demonstrate elevated serum p105erbB-2 levels as compared with patients with low expression of p185erbB-2.

Treatment of stage D2 hormone refractory carcinoma of the prostate with 5-fluorouracil and Roferon-A: a Southwest Oncology Group study.

Based upon prior data suggesting that alpha-interferon possesses chemomodulatory activity, the Southwest Oncology Group conducted a study in which patients with hormone refractory, metastatic (stage D2) adenocarcinoma of the prostate were treated with 5-fluorouracil (5-FU) and Roferon-A. All patients had bidimensionally measurable disease. Treatment consisted of 5-FU 750 mg/m2/day by continuous i.v. infusion for 5 days with Roferon-A 9 million units subcutaneously ono days 1, 3 and 5. Roferon-A was continued three times weekly throughout treatment. Following a one week hiatus from 5-FU (week 2), 5-FU was continued at a dose of 750 mg/m2 i.v. bolus weekly. Nineteen patients were evaluable for toxicity. The most common toxicities were gastrointestinal and mucosal, hematologic and a flu-like syndrome. There were no deaths related to treatment. Among the 14 patients evaluable for response, the response rate was 0% (95% confidence interval, 0-18%). Thirteen of the 19 evaluable patients have died with a median survival of 9 months. The combination of 5-FU and Roferon-A does not have sufficient activity against advanced, hormone refractory prostate cancer to warrant further investigation.

Phase II trial of CHIP for the treatment of advanced, hormonally refractory carcinoma of the prostate. A Southwest Oncology Group Study.

CHIP, a second generation analogue of cisplatin, was subjected to a Phase II trial for the treatment of advanced, hormonally refractory carcinoma of the prostate. Forty-six patients were treated with CHIP 300 mg/m2 intravenously every 4 weeks. Evaluations for tumor response were done after three cycles of therapy. Among 40 evaluable patients there were no complete responses, but there were 6 partial responses for an overall response rate of 15% (95% confidence interval of 5.7 to 29.8%). The median time to response was 2.4 months and the median progression-free survival was 4.1 months. Median survival was 8.4 months. The most common toxicities were hematologic and gastrointestinal. While CHIP can be administered on an outpatient basis, its response rate for prostatic carcinoma appears to be similar to that of cisplatin.

Evaluation of low dose alpha-interferon (Roferon-A) in patients with advanced renal cell carcinoma: a Southwest Oncology Group study.

Alpha-interferon (IFN) has been shown to produce antitumor responses among patients with advanced renal cell carcinoma. While responses have been observed over a range of IFN doses and schedules, significant toxicities can be experienced from relatively high doses given three to five times weekly. Based upon the report of a pilot study indicating that low dose daily IFN could produce antitumor responses with minimal toxicity, the Southwest Oncology Group investigated this schema in a phase II trial. Patients with bidimensionally measurable disease were treated with Roferon-A 1 million units subcutaneously daily and tumor assessments were conducted on a monthly basis. There were no dose escalations and no dose reductions for toxicity. The treatment was well tolerated with only two patients withdrawing from treatment because of side effects. Among 56 eligible patients treated, there were five partial responses and one complete response for an overall response rate of 11% (95% confidence interval, 4 - 22%). However, objective antitumor responses could not be determined for 16 of the 56 patients. Among the 40 fully evaluable patients the 6 objective responses yields a response rate of 15% (95% confidence interval, 5.7-30%). It is concluded that this dose and schedule of IFN has activity against advanced renal cell carcinoma. A randomized trial would be required to determine if this low dose regimen is as effective as the higher doses which have been used traditionally.

Rhabdoid tumor of the kidney in an adult: review of the literature and report of a case responding to interleukin-2.

Rhabdoid tumor of the kidney is an uncommon and highly aggressive malignancy usually found in the pediatric age group. This tumor does not respond well to aggressive chemotherapy regimens and survival tends to be short. Only two cases of rhabdoid tumor of the kidney occurring in adults have been described previously. The third case of a rhabdoid tumor of the kidney in an adult is presented here. This clinical case report is unique not only because of the rare occurrence of this tumor in adulthood but because the patient described had an objective antitumor response to outpatient low dose interleukin-2. This single case report may have therapeutic implications for other patients with this tumor.

Phase II trial of amonafide for the treatment of advanced, hormonally refractory carcinoma of the prostate. A Southwest Oncology Group study.

Amonafide (benzisoquinolinedione; NSC 308847) was subjected to a Phase II trial for the treatment of advanced hormone-refractory carcinoma of the prostate. In addition to adequate baseline organ functions, patients were required to have a favorable performance status, bidimensionally measurable disease and no prior chemotherapy. Amonafide was given at a dose of 225 mg/m2 intravenously daily for 5 days. Treatment cycles were repeated every 21 days. Dose escalation and reduction schema were used based upon toxicities from preceding cycles. Of 47 patients enrolled, 43 were evaluable. The most common toxicities were hematologic to include leukopenia (72%), granulocytopenia (32.6%), and thrombocytopenia (44.2%). There were no complete responses and only 5 partial responses for an overall response rate of 12% (95% confidence interval: 4-25%). The results indicate that Amonafide, in the dose and schedule tested, lacks sufficient activity against hormone-refractory prostate cancer to warrant further trials.

Competitive and territorial fighting: two types of offense in the rat.

Two types of fighting (offense) were compared and contrasted in three experiments on the laboratory rat. In Experiment 1, competitive fighting was obtained in pairs of hungry cagemates by placing one food pellet into their food hopper. In Experiment 2, territorial fighting was obtained by introducing an unfamiliar intruder into the home cage of a male and female pair. Both types of fighting had the same motor patterns. Whereas territorial fighting is strongest against intruders of the same sex, competitive fighting is stronger against the smaller opponent (in this case female) regardless of the sex of the test animal. Whereas territorial fighting is stronger in males, competitive fighting is stronger in females. Whereas gonadectomy reduces territorial fighting in males but not females, it reduces competitive fighting in both sexes. In experiment three, it was shown that food deprivation increases competitive fighting, while it reduces territorial fighting. On the basis of these findings a revised model of the organization of the offense motivational system is proposed.

Treatment of advanced colorectal carcinoma with 5-fluorouracil, leucovorin and Roferon-A: a Southwest Oncology Study Group Study.

Based upon prior data suggesting that alpha-interferon possesses chemomodulatory activity, a pilot study was conducted in which patients with advanced colorectal carcinoma were treated with 5-fluorouracil (5-FU), leucovorin (LV) and Roferon-A. Treatment consisted of LV 20 mg/m2 i.v. push followed by 5-FU, 425 mg/m2 i.v. push daily for 5 days every 4 weeks for 2 cycles, then every 5 weeks; Roferon-A 9 million units subcutaneously was given three times weekly every week. Forty-six eligible patients with bidimensionally measurable disease who had received no prior chemotherapy for advanced disease were treated with this regimen. The most frequent toxicity was leukopenia with 80% of patients experiencing some degree of leukopenia and the most severe toxicity was granulocytopenia with 46% of patients experiencing granulocyte counts < 1,000/mm3. Among the 46 eligible patients, the objective response rate was 13% (95% confidence interval, 5-26%). Thirty-five of the 46 patients have died with a median survival of 17 months. This regimen has significant toxicity and insufficient activity against advanced colorectal carcinoma to warrant further trials.

Phase II study of edatrexate in advanced head and neck cancer. A Southwest Oncology Group study.

Fifty-two patients with persistent, recurrent and/or metastatic squamous cell cancer of the head and neck were treated with weekly edatrexate, 80 mg/m2. Nine patients had received previous adjuvant or neoadjuvant chemotherapy. Of the 46 eligible patients, two complete responses and one partial response were observed (6%, 95% confidence interval of 1-18%). The most common toxicities were myelosuppression and mucositis, but dermatologic toxicity was also observed in 25% of patients. Edatrexate appears to have limited activity in advanced head and neck cancer.

Growth-inhibitory effects of coumarin (1,2-benzopyrone) and 7-hydroxycoumarin on human malignant cell lines in vitro.

Coumarin (1,2-benzopyrone) is a natural substance that has shown antitumor activity in vivo. The major human metabolite of coumarin, 7-hydroxycoumarin (7-HC), is the active form of the drug. While the exact mechanism(s) of action of coumarin is unknown, it has been shown previously that this drug possesses immunomodulatory activity in vitro and in vivo. The present investigations examined the direct (non-immunological) antitumor effects of coumarin and 7-HC in vitro. Both coumarin and 7-HC were found to be growth-inhibitory (cytostatic) for the following human malignant cell lines: A549, ACHN, Caki-2, Dakiki, HS-Sultan, H727, HCT-15, HL-60, K562, LNCaP, PC-3, Du 145 COLO-232, MCF-7 and RP-1788. The growth inhibition was dependent on dose and time and was reversible upon removal of cells from medium containing the drug. Coumarin and 7-HC inhibited [3H]thymidine, [3H]uridine and [3H]leucine incorporation. In a similar fashion, coumarin and 7-HC inhibited the intracellular production of prostate-specific antigen by LNCaP cells. Coumarin and 7-HC stimulated apoptosis in HL-60 cells but not in other cell lines tested. It is concluded that coumarin and 7-HC have direct antitumor (cytostatic) activity as well as immunomodulatory activity. Further information is needed in order to determine which activities are responsible for antitumor activity in vivo.

Coumarin (1,2-benzopyrone) for the treatment of prostatic carcinoma.

The unavailability of effective treatment for metastatic hormone-refractory and clinically localized but pathologically unfavorable prostatic carcinoma warrants trial of new and promising treatments. Preliminary studies in patients with metastatic disease have shown (a) subjective but no objective responses to 100 mg coumarin and cimetidine daily; (b) objective responses in 3 of 40 patients treated with 3 g coumarin daily, all of whom had normal performance status and 1 of whom remains with three resolved bone metastases and stable prostate-specific antigen levels after 4 years; (c) toxicity only in bedridden patients. We recently initiated two multi-center trials of 1 g coumarin daily. Metastatic prostatic carcinoma patients of normal performance status were treated in a phase II trial. Patients who had been treated by radical prostatectomy, but had surgical margin, seminal vesicle or lymph node involvement or detectable prostate-specific antigen after radical prostatectomy, were randomized to coumarin or placebo.

An updated review of the clinical development of coumarin (1,2-benzopyrone) and 7-hydroxycoumarin.

Several authors have demonstrated that coumarin (1,2-benzopyrone) in combination with cimetidine can produce objective antitumor responses in some patients with advanced renal cell carcinoma. The purpose of this report is to review the clinical development of coumarin, with or without cimetidine, with special reference to renal cell carcinoma (RCC). Previously unpublished data concerning the survival of a population of patients with RCC, who were treated on a phase I trial of coumarin and cimetidine, are presented. The rationale and study design of an active randomized, double-blinded, placebo-controlled trial of coumarin for RCC are discussed. A progress report is given for an ongoing phase I trial of oral 7-hydroxycoumarin, the major human metabolite of coumarin.

Extended administration of oral etoposide and oral cyclophosphamide for the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study.

PURPOSE: We designed an all-oral regimen of etoposide and cyclophosphamide for use in advanced non-small-cell lung cancer. PATIENTS AND METHODS: Eligible patients were chemotherapy-naive and had histologically confirmed assessable or measurable stage IV non-small-cell lung cancer. Patients received etoposide 50 mg/m2/d orally days 1 through 14 and cyclophosphamide 50 mg/m2/d orally days 1 through 14 every 28 days. Doses on later cycles were adjusted for myelosuppression. RESULTS: Sixty-six patients (64 eligible patients) received 192 cycles of oral extended etoposide/cyclophosphamide therapy (median, two cycles; range, zero to 15). Therapy was well tolerated with the mean dose per cycle being 104% of the originally scheduled dose. Two patients (3%) achieved a complete response and six (9%) achieved a partial response. Leukopenia, anemia, nausea/vomiting, and alopecia were the most common toxicities. Median survival was 6 months, and the 1-year survival rate was 25.6%, comparable to more intensive treatments. CONCLUSION: Oral extended etoposide/cyclophosphamide is a well-tolerated alternative for the treatment of stage IV non-small-cell lung cancer and can be used as a basis for the design of further outpatient regimens.

Phase II trial of echinomycin for the treatment of advanced renal cell carcinoma. A Southwest Oncology Group study.

Forty-nine patients with metastatic or recurrent renal cell carcinoma were treated on a phase II trial of Echinomycin. Treatment consisted of Echinomycin 1.25 mg/m2 intravenously every 28 days. Among the 47 evaluable patients there were no complete responses and only one partial response for an overall response rate of 2% (95% confidence interval, 0-11%). Eighteen patients (38%) experienced toxicity of grade 3 or worse. The most common toxicities were nausea and vomiting. The results of this study indicate that Echinomycin is not sufficiently active to warrant further trials for the treatment of renal cell carcinoma.

Treatment of transitional cell carcinoma of the bladder with intravesical interleukin-2: a pilot study.

Human recombinant interleukin-2 (rIL-2) administered systemically can mediate the regression of solid tumors in some patients. IL-2 has been detected in the bladder effluent from patients treated with intravesical BCG for transitional cell carcinoma of the bladder (TCC), suggesting that IL-2 may be an effector molecule in the mechanism of action of BCG. The purpose of the pilot study was to determine the response rate, duration of response and toxicity of rIL-2 (Cetus) administered intravesically to previously untreated patients and patients who had failed prior intravesical therapy with other agents. Fourteen patients with biopsy proven transitional cell carcinoma (13 Stage TIS/Ta/T1, 1 Stage T2) were treated with 8 weekly instillations of 12 x 10(6) IU of rIL-2. An index lesion was followed with cystoscopy, biopsy and cytology at three months, with identical follow up every three months thereafter if a response was noted in the index lesion at the first evaluation. There were 3 complete responses (duration of response measured from start of treatment to date of progression) of 9+, 3, 9 months; one patient with TIS, and 2 patients with Ta disease. There were 11 non-responders for an overall response rate of 21%. One patient with extensive CIS had a dramatic partial response and was converted to a complete response with a second 8-week course of rIL-2. All of the complete responders had failed prior intravesical therapy with standard agents. Toxicity from rIL-2 given intravesically was minimal. One patient reported malaise for 24 hours after each treatment and two patients developed asymptomatic lower UTIs.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase II evaluation of coumarin (1,2-benzopyrone) in metastatic prostatic carcinoma.

The unavailability of effective treatment of metastatic hormone refractory prostatic carcinoma warrants trials of new and promising treatments. Coumarin is an investigational new drug that has produced objective tumor regression in some patients with metastatic renal cell carcinoma and malignant melanoma. Coumarin has shown activity against prostatic carcinoma in the Dunning R-3327 rat prostatic adenocarcinoma model. Forty-eight patients with metastatic hormone naive (5 stage D1 and 10 stage D2) or hormone refractory (33 stage D3) prostatic carcinoma of average age 67.6 years (range 46-86) and ECOG performance status of 2 or better were given 3 grams coumarin daily by mouth and evaluated monthly for toxicity and response by rigid criteria in a multicenter trial. Toxicity was limited to asymptomatic SGOT elevations in 3 patients and nausea and vomiting in 4 patients that required cessation of therapy in 2. Eligibility and protocol violations removed 6 additional patients from response evaluation. There were no complete responses. Partial responses (3 of 40 patients, 8%) occurred in 2 patients with bidimentionally measurable disease and 1 patient with disease evaluable by bone scan and elevated prostate specific antigen and prostatic acid phosphatase. The remaining patients progressed after 1 to 12 (average 4.4) months. Coumarin is a relatively nontoxic drug that may warrant further trials in a subset of patients with prostatic carcinoma.

Coumarin (1,2-benzopyrone) enhances DR and DQ antigen expressions by peripheral blood mononuclear cells in vitro.

Coumarin (1,2-benzopyrone) is a natural substance that appears to have some clinical activity against renal cell carcinoma and malignant melanoma. Preliminary evidence from in vitro and in vivo studies suggests that coumarin possesses immunomodulatory activity. It was reported previously that coumarin therapy resulted in augmented DR antigen expression by peripheral blood monocytes in cancer patients. The purpose of the present study was to examine the effects of coumarin on DR and DQ antigen expression by normal donor peripheral blood mononuclear cells in vitro. Using monoclonal antibody labeling techniques and FACS analysis, it was shown that both DR and DQ antigen expression by peripheral blood mononuclear cells were enhanced over controls after 48 hours of exposure to coumarin. While monocytes normally express these antigens, enhanced expression is consistent with an activated state. These results support the hypothesis that coumarin acts, at least in part, through immune augmentation.

Phase I evaluation of coumarin (1,2-benzopyrone) and cimetidine in patients with advanced malignancies.

Fifty-four patients with advanced malignancies were treated on this phase I trial of coumarin and cimetidine. The dose of coumarin was escalated, with three patients treated at each dose level, while the cimetidine dose was held constant at 300 mg four times daily. Patients received coumarin alone as a single daily oral dose for 14 days; on day 15, cimetidine was added and both drugs were continued until progression of disease. This trial was initiated with patients receiving coumarin at 400 mg daily and closed at 7 g daily with four of five patients on this dose experiencing nausea and vomiting. Treatment was generally well tolerated over a wide range of coumarin doses. Symptomatic side effects were few, mild, and usually self limited. Side effects included insomnia, nausea, vomiting, diarrhea, and dizziness. Two patients withdrew from therapy because of daily nausea and vomiting. Typically, nausea, vomiting, and dizziness occurred 2.5-3 hours after a dose of coumarin. In most patients, these side effects abated spontaneously with continuation of therapy. There was no significant hematologic or renal toxicity. Hepatotoxicity occurred in only one patient and was manifested by asymptomatic abnormal elevations of serum hepatic transaminases. This toxicity was reversible upon interruption of therapy. Objective tumor regressions were observed in six patients with renal cell carcinoma. Responses occurred at coumarin doses ranging from 600 mg to 5 g daily. Coumarin is a relatively nontoxic, oral, outpatient therapy that warrants further investigations for the treatment of human malignancies. Because of its low toxicity, there is potential for combining coumarin with chemotherapeutic and/or biological agents in an attempt to improve on efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Low incidence of asymptomatic brain metastases in patients with renal cell carcinoma.

Brain metastases from renal cell carcinoma are uncommon. The present study was undertaken to determine the value of routine computerized tomographic (CT) scanning of the brain in patients with renal cell carcinoma. A review of 106 patients with renal cell carcinoma who had undergone CT scan of the brain revealed brain metastases in only 13.2 percent. Brain metastases were accompanied by central nervous system (CNS) symptoms in 78.6 percent of patients, with headaches constituting the most common presenting symptom (64.3%). Brain metastases were detected in only 3.3 percent of patients who had no CNS symptoms at the time of evaluation. It is concluded that CT scanning of the brain should be performed routinely only for those patients who report CNS symptoms at the time of evaluation.