Phase I/II study of sagopilone (ZK-EPO) plus carboplatin in women with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: Sagopilone is the first fully synthetic epothilone in clinical development and has demonstrated promising preclinical activity. This phase I/II, prospective, open-label trial investigated the efficacy and safety of sagopilone plus carboplatin in patients with recurrent platinum-sensitive ovarian cancer (OC). METHODS: In phase I (dose-escalation stage), patients with OC recurring at least 6 months after platinum-containing chemotherapy received 3-h infusions of sagopilone (initial dose of 12 mg m(-2)) followed by carboplatin every 3 weeks, for 2-6 treatment courses. Patients enrolled in phase II received 3-h infusions of 16 mg m(-2) sagopilone. Efficacy was assessed using modified Response Evaluation Criteria in Solid Tumors (modRECIST) and Gynecologic Cancer InterGroup CA125 criteria. The safety and tolerability of sagopilone were also evaluated. RESULTS: In all, 45 patients received sagopilone at 12 mg m(-2) or 16 mg m(-2). There were 29 confirmed tumour responses (21 modRECIST and 8 CA125) across both treatment groups, indicating that the primary objective of the study was reached. The main adverse events (AEs) reported were peripheral neuropathy (75.6%), fatigue (71.1%) and nausea (64.4%). Grade ≥3 AEs occurred in 35 patients (77.8%). No deaths related to the study drug were reported. CONCLUSION: Sagopilone in combination with carboplatin was effective and toxicities were manageable in patients with recurrent platinum-sensitive OC.

A phase II trial of pyrazoloacridine (PZA) in squamous carcinoma of the cervix--a Gynecologic Oncology Group Study.

PURPOSE: The Gynecologic Oncology Group performed a Phase II study to determine the response rate of Pyrazoloacridine (PZA) in patients with advanced, persistent or recurrent squamous carcinoma of the cervix. METHODS: PZA was administered at a dose of 750 mg/m2 intravenously over three hours every three weeks. RESULTS: Among 21 evaluable patients, there were no complete and one (4.2%) partial response. The major toxicities were hematologic. CONCLUSION: PZA at the dose and schedule employed has insignificant activity in this population.

Increase in tumor GADD153 mRNA level following treatment correlates with response to paclitaxel.

PURPOSE: We investigated the relationship between the basal and treatment-induced change in the tumor expression of the drug resistance gene MDR1 and the cellular injury response gene GADD153, and clinical response to paclitaxel treatment. METHODS: MDR1 and GADD153 mRNA levels were measured by reverse transcriptase polymerase chain reaction (RT-PCR) in tumor samples obtained by fine needle aspiration biopsy from 14 patients before and 24 h after paclitaxel infusion. RESULTS: There was no difference between responders and non-responders with respect to either the basal MDR1 mRNA level or the change in MDR1 mRNA level at 24 h after treatment (P = 0.464). Likewise, there was no difference in basal GADD153 mRNA level between responders and non-responders. However, there was a significantly greater increase in GADD153 mRNA at 24 h in responders compared with non-responders (P = 0.005). An increase in GADD153 mRNA level of 1.5-fold or higher predicted response with a sensitivity of 86% and a specificity of 100%. CONCLUSIONS: An increase in GADD153 mRNA level reflects chemotherapy-induced damage sufficient to be manifest as a clinically detectable reduction in tumor volume. Measurement of the change in GADD153 mRNA level successfully identified patients destined to respond as early as 24 h post-treatment.

Estimation of the duration of the preclinical phase of cervical adenocarcinoma suggests that there is ample opportunity for screening.

OBJECTIVE: The purpose of this study was to determine the mean time for progression from cervical adenocarcinoma in situ (ACIS) to invasive cervical adenocarcinoma in order to assess the feasibility of screening and secondary prevention. METHODS: To approximate time to progression from in situ to invasive lesions, we calculated and compared mean ages at diagnosis of ACIS and invasive adenocarcinoma from patients registered in the SEER (NCI's Surveillance, Epidemiology, and End Results) public-use database from 1973 to 1995 [1]. Findings are contrasted with means calculated from patients with squamous lesions registered during the same period. Statistical significance was tested with the t test for independent samples. RESULTS: The database includes 5845 patients with glandular lesions; 1476 (25%) have ACIS and 4369 (75%) have invasive adenocarcinoma. There are 143,333 women with squamous lesions; 120,317 (84%) have squamous CIS and 23,016 (16%) have invasive squamous cancers. Mean age (std error) at diagnosis is 38.8 (0.3) years for ACIS and 51.7 (0.3) years for invasive adenocarcinoma; the mean difference is 13.0 (0.5) years. Mean age (std error) for squamous CIS is 33.6 (0.0) and for invasive squamous cancer is 51.4 (0.1); mean difference is 17.9 (0.1). CONCLUSIONS: While not quite as long as for squamous lesions, the average of 13 years that elapses during progression from cervical ACIS to invasive adenocarcinoma allows ample time for screening for the preinvasive lesion and for secondary prevention of invasive cervical adenocarcinoma. The similar mean ages at diagnosis suggest that women who will develop cervical adenocarcinoma should be as amenable and accessible to screening programs as are those with squamous lesions.

A phase II/pharmacokinetic trial of high-dose progesterone in combination with paclitaxel.

PURPOSE: The purpose of this study was to investigate the effect of high-dose progesterone, an inhibitor of P glycoprotein, on the pharmacokinetics and toxicity of paclitaxel. PATIENTS AND METHODS: A total of 29 patients with various tumors were treated with single-agent paclitaxel (125 mg/m2 administered over 3 h once every 3 weeks) until progression of disease, at which point high-dose progesterone (3 g administered i.v. over 24 h) was added to the paclitaxel treatment program in 20 patients (13 women, 7 men). Pharmacokinetic studies of paclitaxel administered alone and with progesterone were performed in eight patients. RESULTS: The pharmacokinetic parameters of paclitaxel were highly variable. High-dose progesterone increased the peak plasma levels (3.00 +/- 0.94 vs. 4.15 +/- 1.63 microM; P = 0.029; mean +/- SD) and the area under the curve (AUC; 14.3 +/- 4.75 vs. 17.3 +/- 5.59 microM x h; P = 0.006) of paclitaxel. The absolute neutrophil and platelet nadir counts did not differ significantly between the paclitaxel and the combined treatment cycles. Three of the 20 patients documented to have progressive disease on paclitaxel alone had partial responses when high-dose progesterone was added to the paclitaxel regimen. CONCLUSION: Progesterone had a statistically significant impact on the pharmacokinetics of paclitaxel. The addition of high-dose progesterone to paclitaxel is feasible, but the small number of patients prevents conclusions being drawn about the clinical efficacy of combined progesterone and paclitaxel.

Phase I and pharmacokinetic study of intraperitoneal topotecan.

OBJECTIVE: To determine the maximum tolerated dose and pharmacokinetics of topotecan when administered by the intraperitoneal route. METHODS: A dose-escalating Phase I trial was conducted in which fifteen % of the total dose was given as an intraperitoneal bolus in two litres of D5W and the remainder was given as a continuous intraperitoneal infusion over 24 hours. Treatments were given every 21 days. Pharmacokinetic analyses were performed at the recommended phase II dose. RESULTS: Seventeen patients received a total of 43 cycles at 21-day intervals. The maximum tolerated dose was 4 mg/m2 and acute dose-limiting toxicity was neutropenia. Other toxicities included leukopenia, anemia, emesis, fever, and abdominal pain. Although no objective responses were achieved, five of ten patients with ascites had a decrease in fluid accumulation with administration of intraperitoneal topotecan. The recommended phase II dose is 3 mg/m2. Pharmacokinetic analysis performed at a dose of 3 mg/m2 demonstrated that elimination from the peritoneal cavity followed second-order kinetics with k1 = 1.6 hr(-1), k2 = 0.3 hr(-1) and first and second-phase half-lives of 0.49 and 2.7 hours, respectively. Plasma pharmacokinetic behavior was best described by first-order kinetics with k = 0.5 hr(-1) and a half-life of 3.9 hours. The pharmacologic advantage, expressed as the peritoneal to plasma AUC ratio was 31.2. CONCLUSIONS: Intraperitoneal administration of topotecan at 3 mg/m2 results in a substantial increase in drug exposure for the peritoneal cavity without compromising systemic exposure; this may be beneficial for the treatment of patients with ovarian cancer or intraperitoneal carcinomatosis.

Field cancerization: why late "recurrent" ovarian cancer is not recurrent.

OBJECTIVE: Late "recurrence" of ovarian cancer may result from either regrowth of dormant tumor cells or from development of a new cancer caused by the phenomenon of field cancerization. Clinically, some recurrent ovarian cancers show the same therapeutic sensitivities to chemotherapy and surgery as did the primary disease, whereas others are refractory to all therapy. We hypothesize that recurrent ovarian cancers are distinguishable on the basis of a molecular genetic fingerprint and that some are actually new primary cancers of the peritoneum rather than recurrent ovarian cancer. STUDY DESIGN: We constructed molecular genetic fingerprints of 13 paired primary and late recurrent ovarian cancers to study their clonal relationships. The tumor pairs were analyzed for p53 mutations and allelotypes, patterns of X-chromosome inactivation, loss of heterozygosity, and microsatellite instability at 12 different loci on 6 different chromosomes. Techniques used included single-strand conformational polymorphism mutation screening and polymerase chain reaction-based sequence analysis of the p53 locus, restriction digestion of the androgen receptor locus to determine X-chromosome inactivation, and polyacrylamide gel electrophoresis of highly polymorphic dinucleotide, trinucleotide, and tetranucleotide repeats. RESULTS: The average age at initial diagnosis for this cohort was 54.7 years (range 45.3 to 65.5). Mean interval to recurrence was 42.7 months (range 28 to 62). Molecular fingerprints were characterized for 4 to 8 informative loci per tumor pair. The fingerprints of 10 (77%) differed significantly, strongly suggesting that a second primary cancer had developed. The remaining 3 tumor pairs demonstrated identical allelotypes consistent with regrowth of dormant tumor cells. CONCLUSION: Our results are consistent with the "field cancerization" hypothesis of ovarian carcinogenesis but could also be explained by a polyclonal tumor origin, which contrasts with the currently accepted monoclonal theory of ovarian carcinogenesis. Late development of a new primary cancer may herald the proband as a member of a familial cancer phenotype. These studies provide a molecular genetic rationale that both explains and prognosticates the clinical course of recurrent ovarian cancer.

Endometrioid ovarian carcinoma in a premenarchal girl: report of a case.

In children and adolescents, ovarian neoplasms are predominantly germ cell and sex cord stromal tumors. Carcinomas are quite rare, and, in particular, endometrioid adenocarcinomas are extremely rare in this age group. We report the case of a 13-year-old girl with FIGO stage I, grade I endometrioid adenocarcinoma of the ovary. To our knowledge this is the first report of an endometrioid carcinoma of the ovary occuring in the premenarchal age group and only the second case reported before age 15. Our patient has been treated by conservative surgery without postoperative chemotherapy. Menarche occured 3 months after surgery. Twelve months after surgery she is free of disease.

Impact of ethnicity on the incidence of high-risk endometrial carcinoma.

OBJECTIVE: To evaluate the impact of race/ethnicity on histology in endometrial cancer. METHODS: California Cancer Registry data on 11,674 white and 423 black women with endometrial cancer registered from 1988 to 1992 were used to compare the average annual age-adjusted incidence rate/100,000 women of low-risk (grades 1 and 2 endometrioid adenocarcinoma) and high-risk (grade >2 endometrioid carcinomas, papillary serous, clear cell, and adenosquamous histologies) lesions in black and white women. RESULTS: Of the white patients, 9059 (78%) had low-risk and 2615 (22%) had high-risk lesions. Of the black patients, 236 (56%) had low-risk and 187 (44%) had high-risk lesions. The overall average annual age-adjusted incidence of endometrial cancer in white women is 20.1/100,000 and for black women is 9.4/100,000; however, the incidence of low-risk tumors is 15.9/100,000 in white women and only 5.3/100,000 in black women. The incidence of high-risk disease is identical in black and white women (4.2/100,000). CONCLUSIONS: Black women in the general population have the same likelihood as white women of developing high-risk endometrial cancer. Black women have a significantly lower incidence of low-risk tumors compared to white women. The increased incidence of low-grade lesions in white women may be due to differences in socioeconomic factors or other factors yet to be identified.

A phase II trial of intraperitoneal high-dose carboplatin and etoposide with granulocyte macrophage-colony stimulating factor support in patients with ovarian carcinoma.

Based upon results obtained in a Phase I study, we conducted a Phase II trial of high-dose CBDCA and etoposide administered via the intraperitoneal (IP) route in patients with ovarian cancer. CBDCA at a dose of 600 mg/m2 and etoposide at a dose of 400 mg/m2 were administered rapidly into the peritoneal cavity. The total dose of each agent was calculated and given daily over 3 days in amounts equal to one-third of the total dose. On day 1 of therapy, one-third of the dose was mixed in 2 liters of D5W and administered intraperitoneally as rapidly as possible. On days 2 and 3, one-third of the dose was mixed in 1 liter of D5W and administered similarly. GM-CSF was begun on day 4 as a subcutaneous injection at a dose of 500 micrograms/m2/day. A total 53 courses of treatment was administered to 18 patients; 9 of 13 patients (69%) with evaluable disease demonstrated evidence consistent with a partial response; however, the majority were response determined by a decrease in tumor marker (CA-125). One patient who had pathologic evidence of disease at second look laparotomy, but no measurable disease, was treated and shown at subsequent reexploration to have no further evidence of disease. This patient remains free of disease at 17+ months. The toxicity encountered in this trial was formidable, resulting in the removal of 78% of the patients from the study prior to completing 6 cycles of therapy.

Phase I trial of cisplatin in combination with glutathione.

We treated 16 patients in a phase I trial of escalating doses of intravenous cisplatin in combination with the chemoprotectant glutathione given every 21 days. Forty-three of 44 cycles (98%) were evaluable, 85% of cycles were given on time, and the median number of cycles per patient was 2. Dose-limiting nephrotoxicity was reached at a dose of 175 mg/M2 of cisplatin. Other toxicities included ototoxicity in 7 patients (44%) and grade 3 to 4 nausea and vomiting in 15 evaluable cycles (34.9%). Myelosuppression was infrequent. An increase to 175% of standard cisplatin dose intensity is attainable with the administration of glutathione; however, toxicity is substantial and the number of tolerated cycles is limited. Alternatives to the single bolus dose schedule studied in the present trial should be explored in order to better define the clinical utility of glutathione in combination with high-dose cisplatin.

A comparison of intravenous versus intraperitoneal chemotherapy for the initial treatment of ovarian cancer.

A phase III study was conducted comparing intraperitoneal (ip) versus intravenous (iv) cisplatin-based therapy for patients with newly diagnosed ovarian cancer to determine if the pharmacologic advantage of ip delivery could be translated into an improved response and survival rate. Twenty-nine patients were randomized to receive six cycles of ip cisplatin 200 mg/m2 plus ip etoposide 350 mg/m2 with iv thiosulfate protection given every 4 weeks; thirty-three patients were randomized to receive six cycles of iv cisplatin 100 mg/m2 plus iv cyclophosphamide 600 mg/m2 administered every 3 weeks. Patients were stratified by stage (IIC-IV) and size of residual disease (> or < or = 1 cm). The study was conducted in a community-wide setting. The complete response in evaluable patients was 48% in the ip group and 52% in the iv group. The surgical complete response rate for all patients on study, underestimated because not all patients in complete clinical remission had a second-look laparotomy, was 31% in the ip group and 33% in the iv group. There was no difference in the response rates between the treatment arms as a function of residual disease < or = or > 1 cm. With a median follow-up of 46 months (range 21-70 months) there is no difference in response duration or survival. Both regimens were well tolerated with comparable hematologic and nonhematologic toxicity.

A phase I trial of intraperitoneal carboplatin and etoposide with granulocyte macrophage colony stimulating factor support in patients with intraabdominal malignancies.

BACKGROUND: Although somewhat controversial, there are data to suggest that patients with ovarian cancer may experience a survival advantage if the dose intensity of platinum-containing regimens can be maximized. Administration of chemotherapeutic agents via the intraperitoneal route offers the opportunity to increase dose intensity of several chemotherapeutic agents. METHODS: The authors conducted a Phase I trial of intraperitoneal carboplatin and etoposide in combination with granulocyte macrophage colony stimulating factor (GM-CSF) in an attempt to determine the maximum tolerated dose of carboplatin. The starting dose for carboplatin was 300 mg/m2 and for etoposide 400 mg/m2. The dose of carboplatin was escalated while the etoposide was maintained at the initial dose. The total dose of each agent was calculated and given daily over 3 days in amounts equal to one-third of the total dose. On day 1 of therapy, one-third of the dose was mixed in 2 liters of dextrose (D5W) and administered intraperitoneally (IP) as rapidly as possible. On Days 2 and 3, one-third of the dose was mixed in 1 liter of D5W and administered similarly. GM-CSF was begun on Day 4 as a subcutaneous injection at a dose of 500 micrograms/m2/d. RESULTS: Unacceptable hematologic toxicity was encountered at a carboplatin dose of 800 mg/m2; therefore, a carboplatin dose of 600 mg/m2 is recommended for Phase II studies. An overall response rate of 54% with a complete response rate of 17% was observed in patients with ovarian cancer. The overall response rate for all patients was 45%. CONCLUSION: Because of the significant toxicity encountered in this study, it is recommended that this regimen be used only in the context of a clinical study. The recommended Phase II study dose for this combination is carboplatin 600 mg/M2 and a total dose of etoposide 400 mg/M2 total dose given as three equal parts IP over 3 days. GM-CSF should begin on Day 4 at a dose of 500 micrograms/m2/day subcutaneously and should continue until the absolute neutrophil count is greater than 1000 granulocytes on 3 successive days.

Phase I/pharmacokinetic study of high-dose progesterone and doxorubicin.

PURPOSE: We developed a new formulation of progesterone that permits administration of up to 10 g of progesterone as a continuous intravenous infusion over 24 hours and conducted a phase I clinical trial to determine whether progesterone could modulate the in vivo cytotoxicity of the P-glycoprotein substrate doxorubicin. PATIENTS AND METHODS: Thirty-four patients with advanced malignancies were treated with increasing doses of progesterone and a fixed dose of 60 mg/m2 of doxorubicin given as an intravenous bolus 2 hours after starting a 24-hour intravenous infusion of progesterone. RESULTS: Progesterone enhanced doxorubicin-induced myelotoxicity in a dose-dependent fashion without altering the pharmacokinetics of doxorubicin. The steady-state plasma concentration of progesterone at a dose level of 4 g was 4.1 +/- 0.9 mumol/L, which was higher than the minimal concentration required to reverse multidrug resistance (MDR) in vitro. CONCLUSION: Progesterone enhanced the hematologic toxicity of doxorubicin without altering its pharmacokinetics, suggesting that progesterone could modulate P-glycoprotein at the level of pluripotent hematopoietic stem cells. Adequate tissue concentrations of progesterone could be achieved in vivo to modulate doxorubicin toxicity in the bone marrow and thus potentially in tumor tissue as well. Selectivity may potentially be gained by using hematopoietic growth factors to offset the enhanced hematologic toxicity of doxorubicin while leaving the enhancement of toxicity to tumor cells unchanged.

A phase I and pharmacokinetic study of intraperitoneal carboplatin and etoposide.

BACKGROUND: We attempted to determine the maximum tolerated dose and toxicity of etoposide (VP-16) when administered in combination with carboplatin (CBDCA) (300 mg m-2) and administered via the intraperitoneal (IP) route. METHODS AND MATERIALS: A total of 26 patients were treated on this trial. CBDCA was administered at a fixed dose of 300 mg m-2) while VP-16 was started at a dose of 200 mg m-2 and escalated at 50 mg m-2 increments. Both agents were mixed together in 2 litres of 5% Dextrose and administered as quickly as possible into the peritoneal cavity. Pharmacokinetic studies were performed at the maximum tolerated dose (MTD). RESULTS: The MTD for this regimen was CBDCA 300 mg m-2 and VP-16 350 mg m-2. Patients > or = 70 years of age or who had received more than six cycles of previous chemotherapy, tolerated this regimen poorly. The MTD for this group of patients was CBDCA 200 mg m-2 and VP-16 50 mg m-2. Neutropenia was the dose limiting toxicity for both groups. The mean peritoneal/plasma peak ratio was 18.3 for CBDCA and 12.7 for VP-16. The pharmacologic advantage (peritoneal/plasma AUC ratio) was 14.9 for CBDCA and 8.8 for VP-16. Although measurable disease was not a requirement for entrance into this study a response rate of 27% was noted in 15 patients with evaluable disease who had ovarian cancer. CONCLUSIONS: A pharmacologic advantage exists for both CBDCA and VP-16 when administered together via the IP route.

Phase I and pharmacokinetic study of intraperitoneal ormaplatin.

Ormaplatin is a cisplatin analog which has demonstrated activity against cisplatin-resistant tumors in preclinical studies. We delivered 28 cycles to 14 patients in a phase I trial of intraperitoneal ormaplatin given every 28 days. The maximum tolerated dose was 88.4 mg/m2 and acute dose-limiting toxicity was abdominal pain. Other toxicities include nausea, emisis, fever, and severe neuropathy seen in 1 patient at a cumulative dose of 399 mg/m2. No objective responses were observed. Hematologic toxicity was mild. The dose recommended for future trials of intraperitoneal ormaplatin is 66.5 mg/m2. Pharmacokinetic analysis performed at a dose of 66.5 mg/m2 demonstrated that the initial phase of elimination from the peritoneal cavity follows first-order kinetics with k = 0.69 hr-1 and half-life of 1.4 hr. Plasma pharmacokinetic behavior is best described by biexponential model with k1 = 0.369 hr-1, k2 = 0.107 hr-1, and first half-life of 2.9 hr and second half-life of 8.4 hr. Pharmacologic advantage, calculated by ratio of peritoneal to plasma AUC, is 17.1. If site-specific activity is demonstrated, then the intraperitoneal route of administration of ormaplatin at 66.5 mg/m2 may be beneficial.

High-dose biweekly intraperitoneal cisplatin: an effective way to increase cisplatin dose intensity.

The amount of cisplatin (DDP) delivered per unit time (dose intensity, expressed in mg/m2/week) may be an important factor in determining the clinical outcome in tumors such as ovarian carcinoma. In this neoplasm, intraperitoneal chemotherapy is an effective form of treatment. In this trial we have explored the tactic of shortening the cycle interval as a way to increase the dose intensity of ip DDP. Sixteen patients with a variety of solid tumors received a total of 77 cycles of DDP 180 mg/m2 instilled ip concurrent with i.v. sodium thiosulfate at the dose of 4 g/m2 as loading dose, followed by 12 g/m2 over 6 hr. Each cycle was repeated every 2 weeks. The number of cycles delayed for 3 or more days was 28 (36%). The mean DDP dose intensity received by these patients was 77% of the planned dose or 69 mg/m2/week (confidence interval 95%, 60.5-77.5). The treatment was generally well tolerated: myelotoxicity was mild, only 1 patient had an increase in serum creatinine to > 2 mg/dl. Five patients (31%) developed symptoms of peripheral neuropathy. All patients were evaluable for response. The overall response rate (complete plus partial) in these heavily pretreated patients was 19%. When DDP is given in high doses by the ip route concurrently with systemic sodium thiosulfate, the dosing interval can be reduced to every 2 weeks permitting a marked increase in DDP dose intensity.

Profiles of women age 30-39 and age less than 30 with epithelial ovarian cancer.

OBJECTIVE: To study a group of women diagnosed with epithelial ovarian cancer at a young age (less than 40). METHODS: Tumor registry data were analyzed with respect to age at diagnosis, stage, grade, frequency of nulligravidity, and family history of breast or ovarian cancer. Frequencies were analyzed using contingency tables, and survival distributions were analyzed according to the method of Kaplan and Meier. Multivariate survival analysis was performed with the Cox method. RESULTS: We found significantly higher frequencies of low-grade tumors (90 versus 37%; P = .0003, chi 2 test) and early-stage tumors (45 versus 17%; P = .03, Fisher exact test) in women less than 30 at the time of diagnosis (very young patients) than in those between 30-39. We also found a significant (P = .017, Breslow statistic) survival advantage for the very young women. Multivariate analysis demonstrated tumor grade as the independent variable for survival. CONCLUSION: These findings support the concept of a preclinical phase of epithelial carcinoma and show that young women may derive substantial benefit from ovarian cancer screening programs.