Phase II trial of carboplatin and infusional cyclosporine with alpha-interferon in recurrent ovarian cancer: a California Cancer Consortium Trial.

The purpose of this study was to estimate the response rate of 26-h continuous infusion cyclosporine A (CSA) combined with carboplatin (CBDCA) and subcutaneous alpha-interferon (IFN), in recurrent ovarian cancer (OC), and to measure their effects on CBDCA pharmacokinetics. OC patients relapsing following platinum-based chemotherapy received CBDCA area under the curve (AUC 3) with CSA and IFN, every 3 weeks. The pharmacokinetics of CSA and CBDCA were determined in a subset of patients. Thirty patients received 84 courses of therapy. Three partial responses were observed. Nine patients were stable for >4 months. Toxicity was similar to that observed in our previously reported phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean end of infusion CSA level (high-performance liquid chromatographic assay [HPLC]) was 1109 +/- 291 microg/mL (mean +/- SD). CBDCA pharmacokinetics revealed a measured AUC of 3.61 versus a targeted AUC of 3, suggesting a possible effect of IFN on CBDCA levels versus errors in the estimation of CBDCA clearance using measured creatinine clearance. Steady-state levels of >1 microg/mL CSA (HPLC assay) are achievable in vivo. Insufficient clinical resistance reversal was observed in this study to warrant further investigation of this combination.

A study of radiotherapy modalities combined with continuous 5-FU infusion for locally advanced gastrointestinal malignancies.

AIM: We describe the feasibility of combining infusional 5-fluorouracil (5-FU) with intraoperative radiation therapy (IORT). METHODS: Patients with surgically resectable locally advanced gastrointestinal cancers were treated concurrently during surgery with IORT and a 72 h infusion of 5-FU. Patients without previous external beam radiation therapy (EBRT) were subsequently treated with EBRT (40-50Gy) concurrent with a 21-day continuous infusion of 5-FU. Pancreatic, gastric, duodenal, ampullary, recurrent colorectal, and recurrent anal cancer were included. RESULTS: During IORT/5-FU, no chemotherapy-related grade III or IV hematologic or gastrointestinal toxicity was noted. Post-surgical recovery or wound healing was not affected. One of nine patients who received post-operative radiation required a treatment break. During follow-up, there were more complications in patients with pelvic tumours, especially those with previous radiation. Nine patients have had local and/or local regional recurrences, two of these in the IORT field. CONCLUSIONS: Treatment with a combination of IORT and 5-FU followed by EBRT and 5-FU is feasible. However, long-term complications may be increased in previously irradiated recurrent pelvic tumours.

Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group.

PURPOSE: To evaluate the antitumor effects and toxicities of whole brain irradiation (WBI) with temozolomide (TMZ) administered by prolonged oral dosing in patients with melanoma metastatic to the brain. BACKGROUND: Patients with melanoma metastatic to the central nervous system (CNS) have an extremely poor prognosis and appear to benefit little from WBI. TMZ is an alkylating agent chemically similar to dacarbazine (DTIC) with good oral bioavailability and CNS penetration. TMZ has broad preclinical antitumor activity which in melanoma is comparable to that of DTIC. The combination of TMZ and WBI may provide enhanced antitumor activity against CNS metastasis from melanoma. PATIENTS AND METHODS: Patients with measurable CNS metastases with or without systemic disease were treated with WBI, 30 Gray over ten fractions (days 1-5 and 8-12). TMZ, 75 mg small middle dotm(2 small middle dot)day, was started on day 1, continued daily for 6 weeks and repeated every 10 weeks. RESULTS: Thirty-one patients were treated. There was one CNS complete response of 4.5 months and two CNS partial responses of 2 months and 7 months duration; the latter patient also had a 4-month complete remission of systemic metastases. Toxicities were limited to a single episode of grade 3 transaminase elevation and two episodes of grade 3 neutropenia, one complicated by fatal sepsis. The median progression-free interval for both CNS and extracranial sites was 2 months (range 1 week-11 months), and median survival 6 months (range 2-12 months). CONCLUSIONS: WBI has lower than expected activity in CNS metastasis of malignant melanoma. Although TMZ can be safely administered with WBI, the combination has limited anti-tumor activity.

Methodologic guidelines for the design of high-dose chemotherapy regimens.

PURPOSE: The objective of this report is to review the research methods that have been used in the design, analysis, and reporting of Phase I dose-escalation studies of high-dose chemotherapy (HDCT) with bone marrow or stem cell support and to propose new guidelines for such studies that incorporate emerging principles of pharmacology, toxicity assessment, statistical design, and long-term follow-up. METHODS: We performed a search of original, English-language, peer-reviewed full-length reports of HDCT (with or without radiotherapy) and unmanipulated hematopoietic precursor support (autologous bone marrow or stem cells or allogeneic bone marrow) in which one or more drug doses were escalated to identify dose-limiting toxicities needed for the design of subsequent Phase II trials. We reviewed the design, execution, analysis, and reporting of these trials to develop a coherent set of guidelines for the initiation of new HDCT regimens. The primary elements included in our analysis were the technique of dose escalation, the choice and application of toxicity grading scale, and the pharmacologic correlates of dose escalation. We also evaluated the methods employed to define dose-limiting toxicities and to select the maximum tolerated dose and the dose recommended for further study. We then examined whether subsequent Phase II trials based on these definitions corroborated the findings from the prior Phase I studies and summarized the findings from pharmacologic analyses that were reported from a subset of these investigations. RESULTS: Thirty-five reports met the criteria for our literature review. Two standard methods of dose escalation (fixed increments or modified Fibonacci increments) were described in detail and were employed in the majority (30/35) of the studies. In 5 studies, the details of dose escalation were either not provided or not adequately referenced. There was marked heterogeneity among toxicity grading methods; scales used included the National Cancer Institute Common Toxicity Criteria (or similar scales such as the United States cooperative group or World Health Organization scales) as well as substantially modified versions of those instruments. Wide variations in the methods used to identify dose-limiting toxicities were observed. Statistical considerations, applied to the identification of the maximum tolerated or Phase II recommended dose, were similarly heterogeneous. Phase II trial designs varied from a simple expansion of the Phase I trial to separate, formally conducted studies. Nine Phase I trials featured pharmacologic analyses, and these ranged from simple pharmacokinetic evaluations to more complex analyses of the relationship between drug dose and the molecular targets of drug action. CONCLUSIONS: Phase I clinical trials in the HDCT setting have been designed, analyzed, and reported using heterogeneous methods that limited their application to Phase II and II investigations. Moreover, correlative pharmacologic analyses have not been routinely undertaken during this critical Phase I stage. We propose guidelines for the design of new Phase I studies of HDCT based on 4 essential elements: (1) rational preclinical and clinical pharmacologic foundation for the regimen and for the agent selected for dose escalation; (2) incorporation of analytical pharmacology in the design and analysis of the regimen under investigation; (3) clear, prospective definitions of the dose- or exposure-limiting toxicities that can be distinguished from modality-dependent toxicities; selection of an appropriate toxicity grading scale, including an assessment of cumulative, delayed, and long-term effects of HDCT, particularly when designing tandem or repetitive cycle regimens; and (4) statistical input into the design, execution, analysis, interpretation, and reporting of these studies.

Dolastatin-10 in metastatic melanoma: a phase II and pharmokinetic trial of the California Cancer Consortium.

Dolastatin-10 is a novel pentapeptide agent originally isolated from the marine mollusk Dolabella auricularia with a mechanism of antitumor activity that involves the inhibition of microtubule assembly. We performed a Phase II trial of Dolastatin-10, 400 microg/m2 in patients with advanced melanoma who had received no prior chemotherapy. Dolastatin-10 pharmokinetics were evaluated in a subset of patients following courses 1 and 2. Twelve patients were treated with a median of 2 cycles of Dolastatin-10, and no patient experienced an objective response. The only grade >2 toxicities were grade 3 neutropenia uncomplicated by infection, occurring in 4 patients following the first treatment cycle. The total systemic clearance and volume of distribution at steady-state were 2.61 +/- 1.9 L/h/m2 and 28.4 +/- 13 L/m2, respectively. Due to prolonged terminal elimination. Dolastatin-10 plasma concentrations of greater than 1 nM were sustained for 24 h in all patients studied. Dolastatin-10 is unlikely to have substantial activity in the treatment of melanoma.

Activity of high-dose toremifene plus cisplatin in platinum-treated non-small-cell lung cancer: a phase II California Cancer Consortium Trial.

PURPOSE: Although cisplatin is an important agent in non-small-cell lung cancer (NSCLC), de novo resistance is common and acquired resistance emerges rapidly during therapy. Proposed mediators of platinum resistance include the protein kinase C (PKC) signal transduction pathway and associated c-FOS overexpression. While estrogen administration has been reported to upregulate PKC and c-FOS expression, the triphenylethylenes tamoxifen and toremifene potentiate platinum cytotoxicity by inhibition of PKC. Downregulation of c-FOS expression has been reported to result from PKC inhibition. In view of these findings, we hypothesized that toremifene would reverse platinum resistance and that this interaction would be influenced by tumor estrogen receptor (ER) status. MATERIALS AND METHODS: A phase II trial of high-dose toremifene (600 mg orally daily on days 1-7) plus cisplatin (50 mg/m2 intravenously on days 4 and 11) every 28 days in NSCLC patients was conducted. A group of 30 patients with metastatic NSCLC who had been previously treated with platinum-based therapy were enrolled. RESULTS: All of the 30 patients were assessable for toxicity and 28 for tumor response. Therapy was well tolerated with minimal hematologic and non-hematologic toxicity. Common toxicity criteria grade 3 hematologic toxicity was seen in only three patients. Five patients achieved a partial response for an overall response rate of 18% (95% CI 6-37). Median overall survival was 8.1 months (95% CI 5.4-17). To assess PKC, ER, and c-Fos expression by immunohistochemistry, 12 informative pretreatment patient tumor specimens were obtained. Four patient tumor specimens were positive for one or both PKC isoforms (alpha and epsilon) while c-Fos was overexpressed in three. None of the responding patient tumors exhibited c-FOS or PKC-epsilon overexpression. ER expression was found to be infrequent (8%), contrasting with previous reports in this tumor type. CONCLUSION: While this phase II study indicates that high-dose toremifene plus cisplatin is feasible, active, and well tolerated in NSCLC patients previously treated with platinum compounds, the mechanism of action remains unclear. Further study of this regimen is warranted.

Human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy maintain activated CD8+ T cell subsets as a strong adaptive immune response to cytomegalovirus.

CD8(+) T lymphocyte function specific for human cytomegalovirus (CMV) was evaluated in 14 patients infected with human immunodeficiency virus (HIV) receiving highly active antiretroviral therapy (HAART) and 26 CMV-seropositive donors without HIV infection. Fifty-seven percent of the HIV-infected group had CMV-specific cytolytic activity in freshly isolated peripheral blood mononuclear cells (PBMC) against targets expressing CMV pp65. Both interferon (IFN)-gamma secretion by CD8(+) T cells and the frequency of human leukocyte antigen (HLA)-tetramer-positive T cells in HLA-A*0201-positive HIV-infected subjects correlated with CMV-specific cytolysis. In contrast, PBMC from healthy CMV-seropositive donors did not have either measurable CMV-specific cytolysis or secretion of IFN-gamma without in vitro stimulation. The T helper response to CMV antigens was vigorous in healthy CMV-seropositive donors but low in the cohort of HIV-infected patients. Potent CD8(+) cytotoxic T lymphocyte responses to CMV in HIV-infected patients receiving HAART is the converse of what is found in healthy CMV-seropositive subjects and may be the predominant adaptive immune response against CMV in HIV-infected patients.

High-dose paclitaxel in combination with doxorubicin, cyclophosphamide and peripheral blood progenitor cell rescue in patients with high-risk primary and responding metastatic breast carcinoma: toxicity profile, relationship to paclitaxel pharmacokinetics and short-term outcome.

We assessed the feasibility and pharmacokinetics of high-dose infusional paclitaxel in combination with doxorubicin, cyclophosphamide, and peripheral blood progenitor cell rescue. Between October 1995 and June 1998, 63 patients with high-risk primary [stage II with >or= 10 axillary nodes involved, stage IIIA or stage IIIB inflammatory carcinoma (n = 53)] or with stage IV responsive breast cancer (n = 10) received paclitaxel 150-775 mg/m(2)infused over 24 hours, doxorubicin 165 mg/m(2)as a continuous infusion over 96 hours, and cyclophosphamide 100 mg kg(-1). There were no treatment-related deaths. Dose-limiting toxicity was reversible, predominantly sensory neuropathy following administration of paclitaxel at the 775 mg/m(2) dose level. Paclitaxel pharmacokinetics were non-linear at higher dose levels; higher paclitaxel dose level, AUC, and peak concentrations were associated with increased incidence of paraesthesias. No correlation between stomatitis, haematopoietic toxicities, and paclitaxel dose or pharmacokinetics was found. Kaplan-Meier estimates of 30-month event-free and overall survival for patients with primary breast carcinoma are 65% (95% CI; 51-83%) and 77% (95% CI; 64-93%). Paclitaxel up to 725 mg/m(2) infused over 24 hours in combination with with doxorubicin 165 mg/m(2) and cyclophosphamide 100 mg kg(-1) is tolerable. A randomized study testing this regimen against high-dose carboplatin, thiotepa and cyclophosphamide (STAMP V) is currently ongoing.

Continuous infusion prochlorperazine: pharmacokinetics, antiemetic efficacy, and feasibility of high-dose therapy.

PURPOSE: The purpose of these sequential phase I studies was to evaluate the antiemetic efficacy and pharmacokinetics of high-dose continuous infusion prochlorperazine. METHODS: A total of 52 patients with advanced cancer were treated in two sequential phase I studies utilizing high-dose prochlorperazine. In study 1, designed to investigate the antiemetic effects of dose-intensive prochlorperazine, various cisplatin-based multiagent chemotherapeutic regimens were administered in combination with escalating doses of prochlorperazine. In study 2, a fixed dose of cisplatin (60 mg/m2) was administered over 24 h as a continuous intravenous infusion in combination with infusional high-dose prochlorperazine. Antiemetic efficacy in the first trial was assessed in terms of the number of episodes of nausea, retching, and/or emesis during the 24 h following cisplatin administration. The pharmacokinetics of high-dose prochlorperazine were evaluated in eight patients treated in study 2 at the two dose levels below those at which dose-limiting toxicity was noted. RESULTS: The maximally tolerated dose of prochlorperazine in combination with cisplatin (60 mg/m2 administered as a continuous infusion over 24 h) was 24 mg/h. The dose-limiting toxicity was grade 4 agitation and confusion noted in one patient treated at 26 mg/h. This patient died 3 days following cessation of chemotherapy due to the toxicity of the regimen in combination with the debilitating pulmonary effects of the disease. The mean end of infusion prochlorperazine level at the 24 mg/h dose level was 1.1 microM, a concentration previously reported to be consistent with the reversal of the multidrug resistance phenotype. Two partial responses were observed in study 2. CONCLUSIONS: We conclude that the antiemetic efficacy of high-dose infusional prochlorperazine does not appear to be improved over more convenient bolus administration. However, prochlorperazine levels consistent with those required in vitro for drug resistance reversal are attainable within the dose range having a tolerable toxicity profile.

Complexity and power in case-control association studies.

A general method is described for estimation of the power and sample size of studies relating a dichotomous phenotype to multiple interacting loci and environmental covariates. Either a simple case-control design or more complex stratified sampling may be used. The method can be used to design individual studies, to evaluate the power of alternative test statistics for complex traits, and to examine general questions of study design through explicit scenarios. The method is used here to study how the power of association tests is affected by problems of allelic heterogeneity and to investigate the potential role for collective testing of sets of related candidate genes in the presence of locus heterogeneity. The results indicate that allele-discovery efforts are crucial and that omnibus tests or collective testing of alleles can be substantially more powerful than separate testing of individual allelic variants. Joint testing of multiple candidate loci can also dramatically improve power, despite model misspecification and inclusion of irrelevant loci, but requires an a priori hypothesis defining the set of loci to investigate.

Variations of dose and electrode spacing for rat breast cancer electrochemical treatment.

Electrochemical treatment (EChT) with direct current delivered through implanted electrodes has been used for local control of solid tumors in humans. This study tested the hypothesis that rat breast cancer responses to EChT are dependent on electrode spacing and dose, and explored suitable parameters for treating breast cancers with EChT. Rat breast cancers were initiated by injecting 1 x 10(6) MTF-7 cells to the right mammary gland fat pad of Fisher 344 female rats. The rats were randomly divided into designated experimental groups when the tumors grew to approximately 2 x 2 x 2 cm. One hundred and thirty rats were used for a survival study and 129 for a pathology study. A 4-channel EChT machine was used to administer coulometric doses. The survival study indicated that local tumor control rate is less than 40% in the 40 coulomb (C) and 60 C groups and more than 70% in the 80 and 100 C groups. Sixty six rats died of primary tumors, including all 10 rats in the control group. Once a rat's primary tumor was controlled, no recurrence was found. The main reason for terminating the primary tumor-free rats (51) was lymph node metastasis. Thirteen tumor-free rats survived for more than 6 months. The pathology study showed a significant dose effect on EChT induced tumor necrosis. At 10, 20, 40, and 80 C, the fraction showing necrosis were 39.7, 52.3, 62, and 77.7%, respectively (P

Gender influences herpes simplex virus type 1 infection in normal and gamma interferon-mutant mice.

Gender influences the incidence and severity of some bacterial and viral infections and autoimmune diseases in animal models and humans. To determine a gender-based difference, comparisons were made between male and female mice inoculated with herpes simplex virus type 1 (HSV-1) by the corneal route. Mortality was higher in the male mice of the three strains tested: 129/Sv//Ev wild type, gamma interferon (IFN-gamma) knockout (GKO), and IFN-gamma receptor knockout (RGKO). Similarly, in vivo HSV-1 reactivation occurred more commonly in male mice, but the male-female difference in reactivation was restricted to the two knockout strains and was not seen in the 129/Sv//Ev control. Comparison among male mice of the three strains showed a higher mortality of the RGKO mice and a higher reactivation rate of the GKO and RGKO mice than of the 129/Sv//Ev males. In contrast, female RGKO and GKO mice did not differ from female 129/Sv//Ev controls in either mortality or reactivation. HSV-1 periocular and eyelid disease was also more severe in male and dihydrotestosterone (DHT)-treated female mice than in control female mice. These results show a consistent gender difference in HSV-1 infection, with a worse outcome in male mice. In addition, the results comparing GKO and RGKO mice to controls show differences only in male mice, suggesting that some effects of IFN-gamma, a key immunoregulatory molecule, are gender specific.

Population coverage by HLA class-I restricted cytotoxic T-lymphocyte epitopes.

Vaccination using cytotoxic T-lymphocyte (CTL) epitopes has become a widely used immunization strategy, especially because their structure makes them an attractive alternative to the delivery of whole proteins as immunogens. Nonetheless, their use is limited, in particular because of their specificity, being recognized only by cognate HLA alleles. The potential for immunizing a substantial portion of an ethnically diverse population using a modest number of peptides has been aided by the identification of HLA supertypes. However, the derivation of epitopes is often guided by methods that do not guarantee cross-reactivity, so we consider the feasibility of providing vaccine coverage to a multi-ethnic population under different assumptions. In particular, two large datasets are used to estimate the number of peptides needed to provide > or =90% group-specific coverage of a multiethnic population, when specificity is assumed to be either to a single serologic or molecular type. These assumptions are evaluated utilizing a clinically important epitope repertoire derived from two human cytomegalovirus proteins, and data on the in vitro memory response elicited by these peptides is presented. In summary, our combined theoretical and empiric studies suggest that 90% coverage of some ethnic groups is attainable with 11 uniquely defined HLA-restricted CTL epitopes. The derivation of four or more additional CTL epitopes is needed to attain 90% coverage of Blacks or Asians, the minimally covered groups. Ninety percent coverage of all major ethnic groups in a multi-ethnic population appears feasible without relying on cross-reactivity, but may require two to three times more CTL epitopes than estimated for serologic data, homogenous populations, or HLA alleles grouped as supertypes.

Phase II trial of high-dose intravenous doxorubicin, etoposide, and cyclophosphamide with autologous stem cell support in patients with residual or responding recurrent ovarian cancer.

This study was performed in order to evaluate the toxicities, progression-free and overall survival of patients with responsive residual or recurrent ovarian cancer treated with high-dose chemotherapy. Twenty-seven patients were treated. Doxorubicin, 165 mg/m(2) over 96 h (days -12 to -8), etoposide 700 mg/m(2) every day x3 (days -6 to -4), and cyclophosphamide 4.2 g/m(2) on d -3 was followed by stem cells and granulocyte colony-stimulating factor. The median days of granulocyte count <500/microl was 14 (range 10-42) and platelets <20,000/microl was 13 (range 2-80). Median numbers of red cell and platelet transfusions were 15 (5-16) and 14 (4-103). Toxicity included mucositis requiring narcotic analgesia in all patients. Asymptomatic decreases in ejection fraction to values <50% were observed in four patients. No clinical congestive heart failure was observed. One death due to sepsis was observed. Median progression-free survival is 7.5 months (1.0-56 months); five patients remain alive, two of whom remain progression-free at 19.5 and 24.5 months post transplant. Median overall survival is 14.0 months (1-68 months). We conclude that high-dose anthracyclines may be safely administered to ovarian cancer patients. The short overall and progression-free survivals observed in our population suggest that this combination is not optimal.

Induction of CTL response by a minimal epitope vaccine in HLA A*0201/DR1 transgenic mice: dependence on HLA class II restricted T(H) response.

CTL play a pivotal role in the immune response during viral infections. In this study, the HLA class II restricted T(H) requirement for optimal in vivo induction of HLA class I restricted CTL responses has been investigated. Towards this goal, transgenic mice expressing both HLA class I (A*0201 or A2.1) and class II (DRB1*0101 or DR1) molecules have been derived. Immunization of these mice with an HLA A*0201-restricted and CMV-specific CTL epitope (pp65(495-503)), and either of three different tetanus toxin-derived MHC class II-binding T(H) epitopes, resulted in a vigorous CTL response. CTL specific for the pp65(495-503) epitope were dramatically enhanced in mice expressing both the HLA-DR1 and HLA-A*0201 transgenes. Notably, preinjection of three TT peptides (TT(639-652), TT(830-843), and TT(947-967)) increased the capability of HLA A*0201/DR1 Tg mice to respond to subsequent immunization with the T(H) + CTL peptide mixture. These results indicate that the use of HLA A*0201/DR1 Tg mice constitute a versatile model system (in lieu of immunizing humans) for the study of both HLA class I and class II restricted T-cell responses. These studies provide a rational model for the design and assessment of new minimal-epitope vaccines based on their in vivo induction of a pathogen-specific CTL response.

Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis.

PURPOSE: To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal carcinomatosis. METHODS: Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma were treated with MTX at loading doses of 200-1500 mg/m2, followed by a 23-h infusion of 800-6000 mg/m2. Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared in patients with and without central nervous system (CNS) disease. RESULTS: Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease, who all had CSF MTX concentrations above the target cytotoxic concentration (1 microM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses. The mean half-life of CSF MTX was 8.7 +/- 3.4 h. The mean plasma clearance of MTX was not significantly different in patients with CNS disease (84 +/- 41 ml/min per m2) versus without CNS disease (59 +/- 38 ml/min per m2). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF. CONCLUSION: This trial demonstrates that potentially cytotoxic CSF MTX concentrations (> 1 microM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m2 and a 23-h infusion of 2800 mg/m2 with leucovorin in less heavily pretreated patients with carcinomatous meningitis.

Phase II trial of combination intraperitoneal cisplatin and 5-fluorouracil in previously treated patients with advanced ovarian cancer: long-term follow-up.

OBJECTIVES: This trial was performed to determine the response rate and progression-free and overall survivals of patients with advanced recurrent ovarian cancer who were treated with intraperitoneal cisplatin and 5-fluorouracil. METHODS: Twenty-four patients with ovarian cancer were entered on this trial and treated with intraperitoneal (ip) cisplatin (DDP) and ip 5-fluorouracil, every 3 weeks for eight cycles. Following iv hydration, the cisplatin and 5-fluorouracil were administered through an ip catheter in 2 liters of 0.9% normal saline with a 4-h dwell. RESULTS: All patients were evaluable for progression-free and overall survival and toxicity analysis, and 22 patients for response. The median age was 59 (range, 35-71); initial disease status included 9 patients with residual disease following chemotherapy prior to entry on this study; 5 patients had progressed, and 10 patients had recurrent disease more than 6 months following initial chemotherapy. Of the 9 patients with residual disease, 1 complete response and 3 partial responses were observed; of 10 patients with recurrent disease, 1 complete and 1 partial response were observed for an overall response rate of 27%. No objective responses were seen in the 7 patients who were platinum-refractory on protocol entry. The median progression-free and overall survivals are 7.0 (range, 0.5-137) and 15.5 (range, 3-147) months, respectively. Toxicity included hypomagnesemia, vomiting, abdominal pain, and mild anemia. Only one patient required a dosage adjustment of cisplatin for a serum creatinine elevation >2.0 mg/dl. CONCLUSIONS: We conclude that the combination of ip cisplatin and 5-FU is an effective regimen for patients with residual or relapsed epithelial ovarian cancer with survival durations, response rates, and toxicity profiles that compare favorably with those of other second-line ovarian cancer regimens. Patients who are primarily platinum-refractory are unlikely to benefit from these agents administered into the peritoneal cavity.

Phase II trial of intraperitoneal cisplatin with intravenous doxorubicin and cyclophosphamide in previously untreated patients with advanced ovarian cancer-long-term follow-up.

Forty-three patients with ovarian cancer were entered on this trial and treated with intravenous (iv) cyclophosphamide (C) and doxorubicin (A), and intraperitoneal (ip) cisplatin (DDP), every 21 days for eight cycles. Following iv hydration, the cisplatin was administered through an intraperitoneal catheter in 2 L of 0.9% normal saline with a 4-h dwell. All patients are evaluable for overall and progression-free survival with a median follow-up of 70 months (range: 3-162 months); 39 patients are evaluable for response. All complete responses were surgically confirmed. The median age was 59 (range 28-82 years); 3 patients were stage IC, 5 were IIC, 14 patients were stage III (optimally debulked), 14 patients were stage III (suboptimally debulked), and 7 patients were stage IV. Two patients had received prior alkylator therapy. Six of 8 patients with Stage IC or II remain without evidence of disease at a mean of 12 years following chemotherapy. Of 14 optimally debulked stage III patients, there were 7 complete responses, 3 partial responses, 1 patient with stable disease, and 3 inevaluable patients. Of 14 suboptimally debulked stage III patients there were 4 complete responses, 4 partial responses, 3 with stable disease, 2 progressions on treatment, and 1 inevaluable patient. Five-year progression-free and overall survivals for stage III optimally debulked patients are 21 and 64%, respectively. At 10 years, progression-free and overall survivals for this group are 21 and 29%, respectively. Toxicity included neutropenia (complicated by sepsis in 2 patients), infrequent thrombocytopenia, and mild anemia. Three patients developed transient serum creatinine elevations >2.0 mg/dl; however, decreased creatinine clearance was noted in 93/258 (36%) of evaluable courses which required a cisplatin dose reduction per protocol. Controllable hypomagnesemia, nausea, and emesis were also observed. We conclude that the combination of iv CA and ip DDP is an effective regimen with long-term progression-free and overall survivals that compare favorably with those of other published studies of intravenous or intraperitoneal chemotherapy. This report is unusual in terms of the prolonged follow-up for all patients enrolled. These long-term results lend further support to recently published trials documenting the efficacy of intraperitoneal chemotherapy for patients with this disease.

Comparison of two doses of intravenous immunoglobulin after allogeneic bone marrow transplants.

Intravenous immunoglobulin has been used after bone marrow transplants to prevent infections and acute graft-versus-host disease. However, the minimum dose required for protection is unknown. This may have significant economic implications. A multicenter randomized clinical trial compared the impact of two intravenous immunoglobulin doses on systemic infections and acute graft-versus-host disease in transplant recipients. Either 250 mg/kg or 500 mg/kg was given weekly from day -8 to day +111. Multivariate analysis was used to assess the effect of dose and other risk factors on event-free survival, systemic infection, and acute graft-versus-host disease. The two-dose cohorts had similar event-free survival and infection frequencies. The higher dose was associated with less acute graft-versus-host disease (P = 0.03).

Recombinant human thrombopoietin in combination with granulocyte colony-stimulating factor enhances mobilization of peripheral blood progenitor cells, increases peripheral blood platelet concentration, and accelerates hematopoietic recovery following high-dose chemotherapy.

Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 micrograms/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 micrograms/kg on days -3, -1, and 1, or 0.6 micrograms/kg on days -1 and 1. G-CSF, 5 micrograms/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34(+) cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 x 10(6)/kg (range, 1.3 to 17.6) versus 0.8 x 10(6)/ kg (range, 0.3 to 4.2), P =.0003. The targeted minimum yield of 3 x 10(6) CD34(+) cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF-mobilized group versus 10% of G-CSF-mobilized patients (P =.001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P =.0001) and platelet recovery (day 9 v 10, P =.07) were accelerated, and fewer erythrocyte (3 v 4, P =.02) and platelet (4 v 5, P =.02) transfusions were needed compared with G-CSF-mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P <.0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 microgram/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF-mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.