From randomized trial to practice: single institution experience using the GOG 172 i.p. chemotherapy regimen for ovarian cancer.

BACKGROUND: The objective of the study was to evaluate completion rates and toxic effects of an i.p. chemotherapy regimen in a cross-section of nonselected patients with ovarian cancer (OC). PATIENTS AND METHODS: All patients with stage IIIC OC consecutively operated at our institution from January 2006 to December 2007 were prospectively collected and analyzed. RESULTS: Eighty-nine patients with stage IIIC OC optimally debulked were evaluated for this study. An i.p. port was primarily placed in 53 of 89 (60%), and i.p. chemotherapy was recommended in 55 patients. Reasons for not recommending i.p. chemotherapy in patients optimally debulked included postoperative complications (n = 7: 8%), poor nutritional/functional status (n = 5: 6%), and extensive surgery including bowel resection (n = 9: 10%). Thirty-three patients (33/55: 60%) recommended to receive i.p. chemotherapy-initiated i.p. treatment. Fifty-two percent of those beginning i.p. therapy (17/33) received three or more cycles with 36% (12/33) successfully completing six cycles. Reasons for discontinuation included grade 3-4 nephrotoxicity in 3 of 21 (14%), febrile neutropenia/sepsis in 3 of 21 (14%), port infection or malfunction in 8 of 21 (38%). CONCLUSIONS: The i.p. chemotherapy regimen used in a consecutive cohort of patients carries could be completed in only a small percentage of patients. Less toxic regimens with higher acceptability should be considered.

Phase II study of ifosfamide-etoposide-mesna in adults with advanced nonosseous sarcomas.

Between April 1987 and July 1988, 44 adults with histologically proven, objectively assessable advanced nonosseous sarcomas were treated with 2.5 g of ifosfamide/m2, 100 mg of etoposide/m2, and 2.5 g of mesna/m2 (500 mg/m2 X 5) daily for 3 consecutive days every 4 weeks. This regimen was generally well tolerated as outpatient treatment. Because of the potential CNS effects of ifosfamide, we recommended that elderly patients, persons receiving high doses of opiates, and patients susceptible to the syndrome of vertigo, perspiration, and hypotension (without tachycardia) be hospitalized for treatment. At initial treatment, leukocyte count nadirs were less than 1,000/microL and platelet count nadirs were less than 100,000/microL in 38% and 15%, respectively, of the 39 patients for whom such data were available. Objective tumor regression occurred in approximately 16% (95% confidence interval, 7%-30%) of the 44 patients (six, partial responses; one, complete response). For the 44 patients, median time to disease progression was 2.3 months; median time to death was 9.4 months. While this regimen was effective in three of 20 patients who had been previously treated with a doxorubicin-based regimen, only one of the 12 patients whose tumors had been primarily refractory to the doxorubicin-based regimen experienced objective tumor regression on our ifosfamide-based regimen.

Phase II evaluation of carboplatin in advanced endometrial carcinoma.

Carboplatin was administered by iv bolus every 28 days to 26 patients who had extensive metastatic or recurrent endometrial adenocarcinoma and no prior chemotherapy exposure. The dose level was 400 mg/m2 in 5 patients with and 4 patients without prior irradiation and 300 mg/m2 in 16 patients with prior pelvic irradiation. Partial disease regressions were seen in 28% of patients (95% confidence interval, 12%-50%), with a median response duration of 129 days. Median survival of all patients was 215 days; median time to disease progression for all patients was 117 days. We conclude that carboplatin is an active agent in advanced endometrial carcinoma and is worthy of further investigation in single-agent and combination chemotherapy.

Phase I study of recombinant leukocyte A human interferon combined with BCNU in selected patients with advanced cancer.

Interferons manifest diverse immunomodulatory and antiproliferative characteristics. Since their spectrum of toxicities includes primarily fatigue and anorexia rather than the myelosuppression concomitant with cytotoxic therapies, it is conceptually appealing to combine both modalities. We conducted a phase I trial among 18 patients using the combination of leukocyte A recombinant interferon (IFN-rA) and BCNU. The intramuscular (IM) IFN-rA dose for the initial 12 patients was 12 X 10(6) U/m2 three times a week for an anticipated duration of 12 weeks. Among these patients, we escalated the monthly intravenous (IV) BCNU dose from 50 mg/m2 to 150 mg/m2. Six subsequent patients received IFN-rA 12 X 10(6) U/m2, days 1 to 3, and BCNU 150 mg IV on day 3 of each monthly cycle. Dose-limiting toxicities from both regimens were fatigue and myelosuppression. We recognize the limitation of small sample sizes. Nevertheless, in the absence of a significant number of life-threatening toxicities, it appears that near maximal doses of BCNU and concomitant IFN-rA can be administered with safety in an outpatient setting.

Phase II study of recombinant leukocyte A interferon (IFN-rA) plus cimetidine in disseminated malignant melanoma.

Thirty-five eligible patients with disseminated malignant melanoma received intramuscular recombinant leukocyte interferon (IFN-rA), 50 X 10(6) U/m2 three times weekly (TIW) for an intended duration of 12 weeks concomitant with daily oral cimetidine, 1,200 mg/d in four divided doses. For all study participants, the median survival time was six months. Among 21 "good risk" patients (performance score [PS] 0, 1 and no prior chemotherapy), we observed seven partial regressions (33%). Six patients had stability of disease (29%), seven had immediate disease progression, and one discontinued treatment after two doses without tumor evaluation due to side effects. Times to disease progression of five patients with regressions of soft-tissue disease were 2.1, 3.3, 3.5, 3.7, and 4.3 months. Two patients had partial regressions of lung nodules for 2.0 and 3.8 months. We observed one regression among 14 "poor risk" patients (PS 2, 3, or prior chemotherapy). A 46-year-old woman with prior treatment had a partial regression of soft-tissue disease for 4.1 months. Four "poor risk" patients achieved disease stability, and nine progressed immediately. Leukopenia (WBC count less than 4,100/microL) affected 21 (66%) of 32 patients with WBC count data. The median count was 3,100/microL; range, 1,300 to 8,400/microL. We detected two cases of mild thrombocytopenia (100,000 and 120,000/microL). Other noteworthy toxicities included moderate-to-severe nausea (34%), anorexia (63%), and fatigue (80%). All patients experienced myalgias. Twenty patients had dosage decreases during the first cycle, and 14 of the 16 patients remaining on study after the first cycle required dosage reductions. The overall response rate is similar to our prior studies with IFN-rA as a single agent using TIW doses of 50 X 10(6) U/m2 and 12 X 10(6) U/m2 among 31 and 30 patients, respectively.

Randomized trial of tamoxifen alone or combined with aminoglutethimide and hydrocortisone in women with metastatic breast cancer.

A randomized clinical trial was performed to compare the efficacy of tamoxifen (TAM) alone with that of TAM plus aminoglutethimide (AG) and hydrocortisone (HC). Patients failing TAM could receive AG and HC. Objective responses to therapy were seen in 21 of 49 TAM patients (43%) and 25 of 51 TAM, AG and HC patients (49%). Time to disease progression and survival distributions were not significantly different between the treatment arms. Toxicity was greater for patients treated with TAM, AG, and HC and the trial was discontinued early for this reason. Twenty-four patients received AG and HC after TAM therapy and three (12%) achieved a response. We conclude that the combination of TAM, AG, and HC is not recommended over TAM alone because toxicity appears to outweigh any potential therapeutic advantage.

Phase II study of low-dose recombinant leukocyte A interferon in disseminated malignant melanoma.

Thirty patients with disseminated malignant melanoma received intramuscular recombinant leukocyte A interferon (rIFN-alpha A), 12 X 10(6) U/m2, three times weekly for a planned treatment duration of three months. This dose was selected in view of our prior phase II data indicating that 50 X 10(6) U/m2 three times weekly produced excessive toxicity. In this current trial we observed three objective partial regressions (20%) among the 15 better-risk patients (performance score 0, 1, and no prior chemotherapy) with times to disease progression of 1.9, 9.6, and 12.9+ months. There were also three regressions (one complete and two partial) among the 15 poor-risk patients (performance score 2, 3, or prior chemotherapy) with progression times of 3, 3.2, and 9.6+ months. For all patients, the median survival time was 4.2 months. One half of the patients were observed to have progressive disease within one month of commencing treatment. Responding metastatic lesions were limited to soft tissue, although one patient also had a partial response of a lung nodule. The most substantial toxicities were moderate-to-severe myalgias (27%), nausea (33%), anorexia (47%), and fatigue (50%). Among the 22 patients with weight loss, the median was 2.3 kg (range, 0.6 to 8.4 kg). Hematologic and hepatic toxicity was transient and of little clinical significance. Our study indicates that rIFN-alpha A in the dose and schedule that we used is clinically tolerable and has antitumor activity in malignant melanoma. The response rate was similar to results observed in our previous study of a higher dose regimen.

Randomized clinical trial of tamoxifen alone or combined with fluoxymesterone in postmenopausal women with metastatic breast cancer.

A randomized clinical trial was performed to determine if combination hormonal therapy with tamoxifen (TAM) and fluoxymesterone (FLU) was more efficacious than TAM alone for the treatment of postmenopausal women with metastatic breast cancer. Patients failing TAM could subsequently receive FLU. The dose of both drugs was 10 mg orally twice daily. Objective responses were seen in 50 of 119 TAM patients (42%) and 63 of 119 TAM plus FLU patients (53%) (one-sided P = .05). Time to disease progression distributions were better for TAM plus FLU (median, 350 days v 199 days), but the log rank test only approached statistical significance (one-sided P = .07). Duration of response and survival distributions were similar between the two treatment arms. Toxicities, in terms of androgenic side effects, were greater on the TAM plus FLU regimen. Fifty-two patients are evaluable for response with FLU following TAM and 21 (40%) have achieved a response. We conclude that the advantages in terms of response rate and time to progression observed with TAM plus FLU probably represent a biological effect, but are not of sufficient magnitude to justify the routine clinical use of this combination given the lack of survival advantage and side effects encountered.

Phase III clinical trial of the combination of cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant melanoma.

PURPOSE: A prospective randomized phase III clinical trial was conducted to assess whether the addition of tamoxifen (TAM) to the three-agent regimen of cisplatin (CDDP), dacarbazine (DTIC), and carmustine (BCNU) significantly increased the progression-free survival and overall survival of patients with advanced malignant melanoma. PATIENTS AND METHODS: Patients with advanced malignant melanoma were treated with CDDP + DTIC + BCNU (CDB) with or without TAM. The dose schedule was CDDP 25 mg/m(2) given intravenously (IV) for 30 to 45 minutes in 500 mL of dextrose and (1/2) normal saline (NS) on days 1 to 3 of a 3-week cycle; DTIC 220 mg/m(2) IV for 1 hour in 500 mL of dextrose and (1/2) NaCl on days 1 to 3 of a 3-week cycle; BCNU 150 mg/m(2) IV for 2 to 3 hours in 750 to 1,000 mL of dextrose and 5% water on day 1 of every odd 3-week cycle; and TAM 20 mg taken orally every morning. RESULTS: There were 184 eligible patients enrolled. These patients were observed until death or for a minimum of 1.3 years. At last contact, 12 were still alive. The median time to progression was 3.4 months on the CDB arm and 3.1 months on the CDB + TAM arm. The median survival time was 6.8 months with CDB and 6.9 months with CDB + TAM. Progression-free survival (P =.429) and overall survival (P =.545) were not found to differ by treatment. CONCLUSION: The addition of TAM to this three-agent regimen of CDB was not found to provide a meaningful clinical advantage in the treatment of patients with advanced malignant melanoma.

Moderate and advanced Alzheimer's patients exhibit platelet activation differences.

We previously reported that platelets from advanced sporadic Alzheimer's disease (AD) patients exhibit two defects: first, an aberrant signal transduction presenting as a thrombin-induced hyperacidification, which is more severe for donors with the apolipoprotein E4 allele (apoE4), and second, an AD-specific Amyloid Precursor Protein (APP) processing defect that presents as retention of APP on the activated platelets' surface and in independent of the apo E allele. This retention of membrane APP correlates with decreased release of soluble APP. To determine at what stage in the disease progression these defects appear, we performed signal transduction and secretion studies on moderate AD patients. Thrombin-activated platelets from these patients do not exhibit either hyperacidification or APP retention; their APP processing and secretion are normal by Western blotting, suggesting that the two platelet defects appear in the advanced stages of AD.

Activated Alzheimer disease platelets retain more beta amyloid precursor protein.

Upon activation, platelet alpha-granules' soluble contents are secreted and membrane-bound contents are translocated to the plasma membrane. Membrane-bound proteins include the beta-amyloid precursor protein (APP) from which the beta-amyloid (A beta) deposits found surrounding the cerebrovasculature of patients with Alzheimer's Disease (AD) may originate. We show here that activated platelets from AD patients exhibit less APP processing, retain more of the protein on their surface, and secrete less as soluble fragments than do controls. Surface labeling demonstrated that there is little APP or CD62 on the surface of resting platelets. Upon activation, control platelets exhibited more of both proteins on their surface, while advanced AD patients exhibited similar amounts of CD62 as controls, but retained significantly more surface APP. AD platelets secreted similar amounts of most soluble alpha-granule contents as controls, but less APP fragments. Together these results suggest a processing defect that may account for greater deposition of A beta-containing products in the vasculature to which activated platelets adhere.

Paclitaxel (Taxol): a novel anticancer chemotherapeutic drug.

OBJECTIVE: To review the literature on the clinical activity and toxic effects of paclitaxel (Taxol). DESIGN: Results of phase I and II trials of Taxol in patients with various types of tumors are provided. MATERIAL AND METHODS: Taxol is the first drug in a new class of antineoplastic agents known as the taxanes. These drugs demonstrate a novel mechanism of action characterized by promotion of the assembly of microtubules and stabilization of the tubules against depolymerization, resulting in mitotic arrest. RESULTS: Numerous phase I and phase II trials have demonstrated the efficacy of Taxol in refractory ovarian carcinoma, breast carcinoma, lung cancer, head and neck cancer, and lymphoma. Various durations of infusions of Taxol have been used in several studies. In the treatment of most patients with ovarian cancer, Taxol can probably be administered by either short infusion or 24-hour infusion with no compromise in antitumor effect. Neutropenia seems to be less common when 3-hour infusions are used. Additional phase II trials are currently in progress, as are combination chemotherapy trials. CONCLUSION: Taxol has definite antitumor activity in advanced ovarian and breast cancers and seems to have activity in lung cancer. Further clinical trials will determine the spectrum of activity of Taxol in other malignant tumors and define its role in combination chemotherapy for sensitive tumor types.

Severe exfoliative dermatitis associated with hand ischemia during cisplatin therapy.

BACKGROUND: Platinum is one of the most widely used agents in clinical oncology today. Serious toxic effects are well recognized. FINDINGS: To our knowledge, the current report describes the first case of severe allergic exfoliative dermatitis associated with ischemia and necrosis of the hands in a patient who had received multiple doses of this agent. We postulate that the tissue damage was caused by vasospasm of small vessels from the initial injury triggered by platinum or its associated immune complexes. CONCLUSION: Platinum has become an integral part of combination chemotherapy for various solid tumors. Clinicians must recognize its toxic side effects and control them within tolerable limits.

Beta amyloid fragments derived from activated platelets deposit in cerebrovascular endothelium: usage of a novel blood brain barrier endothelial cell model system.

Amyloid precursor protein (A betaPP) processing results in generation of amyloid beta peptide (A beta) which deposits in the brain parenchyma and cerebrovasculature of patients with Alzheimer's disease (AD). Evidence that the vascular deposits derive in part from A betaPP fragments originating from activated platelets includes findings that individuals who have had multiple small strokes have a higher prevalence of AD compared to individuals who have taken anti-platelet drugs. Thus, determination of whether platelet A betaPP fragments are capable of traversing the blood-brain barrier (BBB) is critical. We have established that activated platelets from patients with AD retain more surface transmembrane-bound A betaPP (mA betaPP) than control platelets. We report here that this mA betaPP can be cleaved to A beta-containing fragments which pass through a novel BBB model system. This model utilizes human BBB endothelial cells (BEC) isolated from brains of patients with AD. These BEC, after exposure to activated platelets which have been surface-labeled with fluorescein and express surface-retained mA betaPP, cleave fluorescein-tagged surface proteins, including mA betaPP, resulting in passage to the BEC layer The data confirm that BEC contribute to processing of platelet-derived mA betaPP and show that the processing yields A beta containing fragments which could potentially contribute to cerebrovascular A beta deposition.

Blood brain barrier endothelial cells express candidate amyloid precursor protein-cleaving secretases.

Proteolytic cleavage of the amyloid precursor protein (A beta PP) results in the generation of the amyloidogenic fragment known as amyloid beta peptide (A beta). Deposition of A beta in the brain parenchyma and cerebrovasculature is a feature of Alzheimer's disease (AD). To date, the process whereby A beta is generated and deposited remains unclear. We have previously established that activated platelets from AD patients retain more A beta PP on their surface than control platelets. We report here that an endothelial cell-derived enzyme can cleave this surface platelet A beta PP. Human blood brain barrier endothelial cells from brains of AD patients were assayed for potential A beta PP-cleaving enzymes using synthetic peptide substrates encompassing the A beta N-terminus cleavage site. A protease activity capable of cleaving A beta PP on the surface of AD platelets was noted. The A beta PP cleavage is partially inhibited by EDTA, by ZincOV, as well as by a specific inhibitor of the Zn metalloprotease E.C.3.4.24.15. Furthermore, the protease is recognized by an antibody directed against it, using immunohistochemistry, Western blot analysis and flow cytometry. The protease is not secreted, but rather resides intracellularly as well as on the surface of the endothelial cells. The data suggest that E.C.3.4.24.15 synthesized by brain endothelial cells may process the platelet-derived A beta PP, yielding fragments which could contribute to cerebrovascular A beta deposits.

Phase II study of a combination of mitomycin, doxorubicin and cisplatin in advanced sarcomas.

In all 63 patients were treated monthly with a combination of mitomycin, doxorubicin, and cisplatin, and 27 (43%) experienced objective regression of their advanced sarcomas during a 3-month trial. The observed regression rate is numerically higher than any previously observed at our institution.

A phase II clinical trial of the combination mitomycin C, adriamycin, and cis-diamminedichloroplatinum in patients with advanced upper aerodigestive cancer.

Twenty-seven patients with assessable, regionally advanced, or metastatic upper aerodigestive cancer of diverse histology received a combination of mitomycin C, adriamycin, and cis-diamminedichloroplatinum. All patients had previously received extensive surgery and/or radiation therapy. We observed an overall 46% partial response rate (12/26). This included seven of 15 (47%) responders with squamous cell carcinoma. Six of those seven patients responded within the initial month of treatment. For all study participants, the median time to progression and survival was 3.8 months and 7.3 months, respectively. Moderate-to-severe nausea, vomiting, anorexia, and alopecia were the most common toxicities. Myelosuppression (WBC less than 4,100 cells/mm3) and thrombocytopenia (PLTS less than 130,000 cells/mm3) occurred in 100% and 71% of the 21 patients with nadir data recorded, respectively. There were no episodes of sepsis nor did we detect any meaningful impairment in renal function. This regimen is active in the previously treated head and neck cancer patient and can be conveniently administered on an outpatient basis with acceptable and manageable side effects.

Phase II clinical trial of the combination VP-16, bleomycin, and cis-diamminedichloroplatinum in patients with advanced upper aerodigestive squamous cell carcinoma.

Fifteen patients with advanced upper aerodigestive carcinomas of squamous cell histology received the three-agent cytotoxic regimen of VP-16, bleomycin, and cis-diamminedichloroplatinum (CDDP) administered as a continuous 120-h infusion. The objective response rate was 40%. Median times to progression and survival were 3.2 months and 4.3 months, respectively. Hematologic and gastrointestinal toxicities were relatively transient and manageable. Our experience indicates that this three-drug program does not offer a substantial therapeutic advantage compared with more conventional single agent cytotoxic approaches for advanced head and neck cancer.

Lack of value for cisplatin added to mitomycin-doxorubicin combination chemotherapy for carcinoma of unknown primary site. A randomized trial.

Fifty-five patients with metastatic carcinomas of unknown primary site (50 adenocarcinomas) were randomized, after stratification, to treatment with either mitomycin and doxorubicin (MA) or mitomycin, doxorubicin, and cisplatin (MAP). There was a moderate but nonsignificant improvement in regression frequency (14 vs. 27%) and a slight but also nonsignificant worsening of survival (median 5.5 months vs. median 4.6 months) by the addition of cisplatin at 60 mg/m2 to the MA regimen.

Evaluation of bisantrene administered by 72-hour infusion in women with metastatic breast cancer.

Bisantrene was administered by 72-h continuous infusion at a dosage level of 240 mg/m2 to 17 patients with metastatic breast cancer who had received only one prior chemotherapy regimen and no prior doxorubicin. Three patients (18%) achieved partial regressions lasting 51, 106, and 213 days. For all patients, the median time to disease progression was 83 days and median survival was 280 days. Eleven patients received doxorubicin after removal from protocol and were evaluable for response, and four (36%) achieved a partial regression. We conclude that bisantrene administered by the method we employed is not associated with substantial clinical benefit in this population of patients.