Elizabeth K. Senekjian

Adaptive control of etoposide administration: Impact of interpatient pharmacodynamic variability

We sought to use a previously derived pharmacodynamic model for 72‐hour etoposide infusions to adaptively control administration of this agent and to demonstrate that more predictable toxicity could be obtained with this dosing scheme. A randomized crossover study design was used to compare “standard” dosing (125 mg/m2/day) to adaptive control, with dose adjustment at 28 hours based on the 24‐hour plasma level. A total of 31 patients received 86 cycles of chemotherapy, 36 by standard dosing and 50 by adaptive control. However, there was no demonstrable advantage to the adaptive control scheme, because of apparent bias of the previous model. A new model was proposed that also included serum albumin, performance status, and prior RBC transfusions as measures of interpatient pharmacodynamic variability. We conclude that adaptive control dosing of etoposide is feasible but that the therapy must be individualized for both pharmacokinetic and pharmacodynamic variability.

Poorly differentiated (small cell) carcinoma of the ovary in young women:: Evidence supporting a germ cell origin

The clinical and pathologic features, including immunohistochemistry and electron microscopy, of six cases of poorly differentiated carcinoma of the ovary (small cell carcinoma) are presented. These tumors occurred in six young patients ranging in age from 10 to 24 years. Two patients had hypercalcemia. All tumors were unilateral, and four patients had advanced stage disease at presentation. Histologic features included sheets, nests, and cords of cells in a fibrous stroma, focal microcysts, and a dimorphic population of small and large cells. Eosinophilic, hyaline globules occurred in five cases, intercellular basement membrane-like substance in two cases, and glycogen in all cases. Five of six cases stained strongly for cytokeratin and vimentin; intracytoplasmic laminin was identified in three cases; and three cases were believed to show faint positivity for alpha-1-antitrypsin. Stains for alpha-fetoprotein were negative. Ultrastructural examination of two cases showed granular material in dilated rough endoplasmic reticulum, intermediate filaments, intracytoplasmic dense globules, maculae adherens, and extracellular basement membrane-like material. All of the cases proved rapidly fatal despite various therapies, as did a histologically similar testicular tumor that was admixed with seminoma and teratoma. We interpret these findings to indicate that this ovarian cancer is most likely of germ cell origin, and it may be related to yolk sac tumor, although it is clearly distinct from the classical yolk sac tumor.

An evaluation of squamous cell carcinoma antigen in patients with cervical squamous cell carcinoma

In a prospective study, serum concentrations of squamous cell carcinoma antigen, a subfraction of tumor antigen (TA-4), were determined by radioimmunoassay from healthy donors, pregnant women, and subjects with various benign and malignant gynecologic diseases. Ninety-six percent of 99 healthy persons including all 52 female controls, the 15 pregnant patients, and all 23 subjects with benign gynecologic tumors, had squamous cell carcinoma antigen levels less than 2.0 ng/ml. Seven of 51 (14%) patients with cervical intraepithelial neoplasia and 16 of 24 (67%) patients with cervical squamous cell carcinoma had squamous cell carcinoma antigen levels greater than 2.0 ng/ml. Declining and rising levels of squamous cell carcinoma antigen, which were determined sequentially in nine cases of cervical carcinoma that were associated with elevated pretreatment levels of squamous cell carcinoma antigen, correlated with regression and progression of the disease. Serial serum levels of squamous cell carcinoma antigen provide a noninvasive means of monitoring the effects of individual therapy in patients with cervical squamous cell carcinoma.

Infertility among daughters either exposed or not exposed to diethylstilbestrol

Infertility was examined among 343 diethylstilbestrol-exposed and 303 unexposed daughters whose mothers participated in an evaluation of diethylstilbestrol use during pregnancy 35 years ago. Of the married individuals who were not using contraception and who were actively trying to conceive, a greater proportion of diethylstilbestrol-exposed women than unexposed subjects experienced primary infertility (33% versus 14%, p less than 0.001). Among those with primary infertility, abnormal hysterosalpingograms were observed in 46% of the diethylstilbestrol-exposed group and in none of the unexposed group (p less than 0.02), while tubal abnormalities were found in 42% of the exposed and in none of the unexposed (p = 0.02). First pregnancies were achieved by 40 (58%) women exposed to diethylstilbestrol and 18 (64%) unexposed subjects. Twenty-four (60%) of the exposed women and 15 (83%) of the unexposed individuals who conceived had a live-born infant who survived. The estimated cumulative rate of first pregnancy was 16% for the exposed group and 36% for the unexposed group at 12 months after the diagnosis of primary infertility (p less than 0.05).

Vinblastine, cisplatin, cyclophosphamide, bleomycin, doxorubicin, and etoposide in the treatment of small cell carcinoma of the ovary

This report presents five adolescent girls and adult women with small cell carcinoma of the ovary (SCCO) who were treated with a polychemotherapy regimen consisting of vinblastine, cisplatin, cyclophosphamide, bleomycin, Adriamycin (doxorubicin), and etoposide (VPCBAE). Two patients had Stage IA, one Stage IIC, and two Stage IIIA disease. Initial therapy consisted of unilateral salpingo‐oophorectomy in two cases and total abdominal hysterectomy and bilateral salpingo‐oophorectomy in three cases. Three patients remained clinically free of disease after six courses of VPCBAE and the two patients who had measurable pelvic disease before the administration of chemotherapy had objective responses. Four patients died of disease from 11 to 18 months after initial laparotomy. One patient is alive and disease‐free at 29 months. The VPCBAE combination appears to be effective in select cases of SCCO. A study of the efficacy of VPCBAE in a larger group of patients with SCCO seems to be indicated.

Local therapy in stage I clear cell adenocarcinoma of the vagina

Of the 219 cases of Stage I vaginal clear cell adenocarcinoma reviewed, 176 had conventional therapy and 43 underwent local therapy. The two groups appear to be similar with respect to symptoms, stage, location of the lesion in the vagina, greatest tumor diameter, surface area, depth of invasion, predominant histologic pattern, grade, and number of mitoses; nonetheless, firm conclusions cannot be drawn because of missing data. Actuarial survival rates at 5 and 10 years for the local therapy group (92% and 88%, respectively) were essentially equivalent to those for the conventional therapy group (92% and 90%, respectively), however, the recurrence experience after local therapy was less favorable. Local therapy consisted of vaginectomy in nine cases, local excision alone in 17 cases, and local irradiation (with or without local excision) in 17 cases. The subgroup of patients receiving local irradiation had a recurrence experience as favorable as that of the conventional therapy group and more favorable than that of either the subgroup treated with vaginectomy or local excision alone. The data suggest that when employed, local therapy should include local irradiation.

Evaluation of bolus cis-platinum and continuous 5-fluorouracil infusion for metastatic and recurrent squamous cell carcinoma of the cervix

The combination of cis-platinum and 5-fluorouracil has been reported to act synergistically with improved response rates in squamous cell carcinomas of the head and neck. The activity of bolus cis-platinum and continuous infusion of 5-fluorouracil in 24 patients with recurrent and metastatic squamous cell carcinoma of the cervix was evaluated. Twelve patients were stage I, 3 were stage II, 5 were stage III, and 4 were stage IV cervical carcinomas. Among the 24 patients, there were 4 complete and 8 partial responses (50%). The overall median response was 24 weeks. The overall cumulative survival was 55% at 40 weeks and 40% at 1 year after beginning this regimen. Complications included 4 patients who developed leukopenia, 3 thrombocytopenia, 11 stomatitis, 14 nephrotoxicity, 4 peripheral neuropathy, and 6 ototoxicity. The combination of cis-platinum and continuous infusion of 5-fluorouracil appears to have useful activity in patients with recurrent or metastatic squamous cell carcinoma of the cervix.

Conservative management of primary cervical lymphoma using combination chemotherapy: A case report

A 22-year-old nulligravida presented with a stage IE/IIIB primary malignant lymphoma of the cervix which measured 8 cm in diameter. In order to preserve reproductive potential, a 12-week course of methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin was administered. One month later a 4-cm-diameter left parametrial mass was excised at laparotomy; no tumor was detected in the specimens obtained. Menses resumed after an additional 6 months. The patient was clinically disease-free at the 33-month follow-up.

Clear cell adenocarcinoma (CCA) of the vagina and cervix in association with pregnancy

The effect of pregnancy on patients with CCA of the vagina and cervix was evaluated based upon a review of 503 cases. Eighty-five had been pregnant (24 at diagnosis), 408 had never been pregnant, and the pregnancy history was unavailable in 10 cases. All of the 24 patients pregnant at diagnosis were over 16 years of age; 14 were in the first trimester, 6 in the second, and 4 in the third trimester. By FIGO criteria, 15 were stage I, 7 stage II, and 2 were stage III. The 24 pregnant and 408 never pregnant (age corrected) cases were compared with regard to maternal hormone history, symptoms, stage, location, predominant histologic or cell type, greatest tumor diameter, surface area, depth of invasion, grade, and number of mitoses. No significant differences were detected. Twelve of the 24 pregnant patients had radical hysterectomy with or without irradiation (9 stage I, 3 stage II); of the 7 treated by local therapy (5 stage I, 2 stage II), 3 required additional therapy due to persistent disease; 4 had radiotherapy alone (1 stage I, 2 stage II, and 1 stage III); one had teletherapy followed by exenteration (stage III). Six of the 24 died 2 to 12 years after diagnosis (1 stage I, 3 stage II, 2 stage III). Eighteen are alive at 1 to 17 years. The overall 5 and 10 year actuarial survival rates (age adjusted) for the group pregnant at diagnosis (86 and 68%) do not differ significantly from the never pregnant group. Pregnancy does not seem to adversely affect the outcome of CCA. Guidelines are presented to treat pregnant patients with CCA.

An evaluation of stage II vaginal clear cell adenocarcinoma according to substages

Of the 76 cases of stage II vaginal clear cell adenocarcinoma reviewed, the lesion involved the vesicovaginal and/or rectovaginal septa (IIc) in 19, the paravaginal/parametrial tissues without extension onto the pelvic sidewall (IIb) in 8, and the subvaginal tissue without paravaginal/parametrial or septal infiltration (IIa) in 36; the substage could not be determined in 13 cases. The three substage groups were similar with regard to maternal hormone history, greatest tumor diameter, depth of invasion, cross-sectional tumor area, location of the lesion in the vagina, predominant histologic pattern and cell type, mitoses, grade, lymph node status, and treatment modality. Actuarial survival rates at 5 and 10 years for all patients with stage II vaginal clear cell adenocarcinoma were 83 and 62%, respectively. The recurrence and survival experiences for the three substage groups were similar. The data available do not suggest any clinical benefit to categorizing cases of stage II vaginal clear cell adenocarcinoma into substages.