Phase I and pharmacokinetic trial of intraperitoneal etoposide in combination with the multidrug-resistance-modulating agent dipyridamole.

Dipyridamole synergistically enhances the sensitivity of human ovarian carcinoma cells to etoposide in vitro. We conducted a phase I trial to investigate the feasibility of using dipyridamole to selectively increase the sensitivity to etoposide of tumors confined to the peritoneal cavity. Etoposide and dipyridamole were administered as a continuous 72-hour intraperitoneal infusion to 16 patients. The maximum tolerated dose of etoposide was 175 mg/m2 per day when administered with dipyridamole at a fixed dose of 24 mg/m2 per day. Dose-limiting toxic effects were leukopenia and thrombocytopenia. No other major toxic effects were observed. The free peritoneal etoposide and dipyridamole concentrations varied with the etoposide dose rate, reaching 218.9 and 25.3 microM, respectively, at an etoposide dose rate of 175 mg/m2 per day. The free etoposide and dipyridamole concentrations attained were well within the range needed for synergistic interaction.

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.

Clinical features and treatment outcome of patients with epithelial carcinoma of the ovary metastatic to the central nervous system.

Involvement of the central nervous system with carcinoma of the ovary is being noted with increasing frequency. We report on six patients who presented with central nervous system metastases between 2-61 months after diagnosis. Five patients had elevated serum CA 125 values at the time of diagnosis of central nervous system disease and presenting symptoms, and findings on neurologic examination generally correlated with computed tomography-documented lesions. Eighty-three percent of our patients were symptomatically relieved with a course of 30 Gy given to the whole brain; however, there were no long-term survivors (range 2-24 months). Survival did not appear prolonged in the four patients who received systemic chemotherapy as well as whole-brain irradiation.

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.

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.

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.

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.

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.

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.

Therapeutic and metabolic effects of high (greater than 1 g/m2) systemic cumulative doses of cis-platinum in patients with ovarian carcinoma.

Adverse effects requiring discontinuation of cis-platinum therapy are usually noted after administration of 600 mg/m2 cis-platinum. Metabolic and therapeutic effects of high (greater than 1 g/m2) cumulative lifetime doses of cis-platinum were reviewed for 20 patients treated with multiple courses of chemotherapy for metastatic, recurrent ovarian carcinoma. Median survival in this selected group is 65 months. Common abnormalities included anemia, hypomagnesemia, and elevated renal functions. No patient required cessation of treatment because of metabolic changes and in no case did the abnormality compromise the patient's activities of daily living. We conclude that, in selected patients, repeated treatment, regardless of cumulative dose, with cis-platinum-based chemotherapy can be well tolerated and may be of therapeutic benefit.

A phase II trial of adjuvant cisplatin and doxorubicin in stage I epithelial ovarian cancer.

We have treated 26 patients with Stage I ovarian cancer with platinum-based chemotherapy. Patients received 50 mg/m2 cisplatin and 50 mg/m2 doxorubicin every 21 days for six cycles. Eighteen patients had complete surgical staging defined as total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and aortic node sampling, omentectomy, and cytology. Eight patients had all of the above with the exception of node sampling. The overall median follow-up for the group is 43+ months. Three patients had grade 1 tumors with positive washings or capsule invasion and are disease free with a median follow-up of 53+ months. Of 23 patients with grade 2-3 tumors, 22 are alive and free of disease with a median follow-up of 42+ months. There has been 1 recurrence, at 18 months, in a patient who had complete staging and a grade 2 tumor. The patient recurred with carcinomatosis, documented by laparoscopy. There was no significant hematologic, neurologic, or renal toxicity encountered in any patient. Adjuvant combination chemotherapy is beneficial for selected patients with early-stage ovarian cancer who are at high risk for failure after surgical treatment alone.

Studies in prognostic factors relating to chemotherapy for advanced gastric cancer.

The prognostic value of pretreatment information relating to prior treatment, demography, physical status, symptoms, disease involvement, pathologic, immunologic, and clinical chemistries were analyzed for a series of 322 patients with advanced gastric cancer. All patients received chemotherapy upon entry into Gastrointestinal Tumor Study Group protocols which were active between 1975 and 1978. Multivariate models were used to study relationships between prognostic factors and survival for all patients and objective tumor resonse for a subset of 137 patients with measurable disease. The initial performance status was a leading determinant of survival (P less than 0.0001). In addition, new summary measures relating to blood chemistries (P less than 0.01) and differential counts (P less than 0.001) were shown to influence patient survival. Blood chemistry parameters included SGOT, total serum protein, and total direct bilirubin while differential counts included absolute granulocytes, lymphocytes, and monocytes. Thus, the initial performance status, measurable disease status, blood chemistries, and differential counts are recommended as stratification factors in the design and analysis of trials involving patients with advanced gastric cancer. The initial performance status was examined in relation to other pretreatment data. The performance status at study entry correlated independently with the degree of weight loss (P less than 0.001), blood chemistries (P less than 0.01), differential counts (P less than 0.05), and peritoneal metastases (P less than 0.05). The measurable and nonmeasurable subgroups were compared with respect to baseline characteristics. Patients with measurable disease had more liver metastases (56 versus 35%) and less peritoneal metastases (76 versus 49%) than patients with nonmeasurable disease. Controlling for the imbalance in liver and peritoneal metastases, the presence of measurable disease was less favorable than nonmeasurable disease with respect to survival. Regarding the pathways of disease spread, there was a strong correlation (P less than 0.001) between primary tumor site within the stomach and location of metastases. Diffuse lesions were associated with the lowest frequency (25%) of liver metastases. Diffuse lesions (58%) and tumors of the pyloris (54%) were associated with the highest percentage of peritoneal metastases. Tumors of the cardia or fundus were more likely to metastasize to the liver while diffuse tumors were more likely to spread to the peritoneum. Pretreatment factors under study did not appear to be the dominant factors responsible for prolongation of survival in patients with an objective tumor response. Pretreatment factors predicted a three week advantage; however, a 22 week advantage was observed for responders over nonresponders.

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.

Ovarian intraepithelial neoplasia demonstrated in patients with stage I ovarian carcinoma.

Retrospective review of sections of ovary from 50 patients with stage I, grade 1-3, epithelial ovarian carcinoma was performed to assess presence of cellular and nuclear atypia in noncancerous tissue adjacent to the primary tumor; ovarian tissue from 50 patients undergoing incidental oophorectomy was reviewed as well. Atypia was more common in cancer patients, and finding the combination of nuclear atypia, defined as presence of pleomorphism or irregular chromatin distribution, with cellular atypia, defined as presence of stratification or loss of polarity, allowed separation of cancer and control groups with 98% sensitivity and 100% specificity. Presence of nuclear and cellular atypia was used to define ovarian intraepithelial neoplasia (OIN). If OIN is demonstrated to precede ovarian carcinoma, then it may offer insights into the development of ovarian cancer and may eventually increase the feasibility of screening for this disease.

Induction chemotherapy followed by radical surgery in cervical cancer.

To evaluate the therapeutic potential of cytotoxic therapy in patients with squamous cell carcinoma of the cervix, 28 patients with disease clinically localized to the pelvis were treated with chemotherapy followed by radical pelvic surgery. Treatment consisted of cis-platinum 50 mg/m2, mitomycin C 10 mg/m2, vincristine 1.0 mg/m2, and bleomycin 10 U IM given as a course (over 21 days) of induction chemotherapy followed by radical hysterectomy and pelvic and aortic lymphadenectomy in 26 patients and total pelvic exenteration in 2 patients. The stage distribution of the patients in the study was 4 stage IB, 6 stage IIA, 7 stage IIB, 1 stage IIIA, 11 stage IIIB, and 1 stage IVA. Two patients with stage IIIB cancer were found, at the time of laparotomy, to have carcinomatosis and were excluded from the final evaluation in this study. All patients achieved a clinical and histologic response to chemotherapy. There were 35% complete and 65% partial responses. After chemotherapy, at the time of surgery, 4 patients were found to be histologically free of disease, and the incidence of surgically documented nodal disease after chemotherapy was found to be 32%. There was no significant hematologic or pulmonary toxicity. Induction chemotherapy is well tolerated and may be beneficial in the management of some patients with cervical cancer who are at high risk for failure with conventional treatment.

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.

Clinical features of advanced ovarian mixed mesodermal tumors and treatment with doxorubicin- and cis-platinum-based chemotherapy.

Records of 15 patients with stage III and IV malignant mixed mesodermal tumors of the ovary treated between 1977 and 1988 were reviewed. All patients had primary surgery; 13 were given postoperative chemotherapy including doxorubicin and cis-platinum. Median survival for patients receiving chemotherapy is 16 months; 62% were alive at 12 months and 31% at 24 months. Progression-free responses were seen in 85% of treated patients and 55% of these recurred. All recurrences involved the pelvis and were predominantly mesenchymal. Serum CA-125 values accurately reflected tumor presence in 82% of tested patients. Cytoreductive surgery followed by treatment including doxorubicin- and cis-platinum-based chemotherapy is effective in treatment of disseminated ovarian mixed mesodermal tumors, but additional components must be added to achieve durable responses and consistently prolonged survivals.

Absolute granulocyte, lymphocyte, and moncyte counts. Useful determinants of prognosis for patients with metastatic cancer of the stomach.

Pretreatment absolute granulocyte (less than 6,000/cu mm), lymphocyte (greater than 1,500/cu mm), and monocyte (300 to 900/cu mm) counts are three independent indicators of good prognosis for patients with metastatic gastric cancer. There tests improve the prediction of survival significantly compared with estimates based on ambulatory status alone. If the patient is completely ambulatory, median survival (MS) is 27.6 weeks, and it improves further to 37.6 weeks if results of two hematology tests indicate a good prognosis. If the patient is partially ambulatory, MS is 16.2 weeks; however, if results of two blood tests indicate a good prognosis, MS is 25.7 weeks, and if two tests indicate a poor prognosis, MS is only 11.1 weeks. The model corrected a false assessment of a poor prognosis for 56% of all patients.

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.

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.