A pilot study of whole body hyperthermia and carboplatin in platinum-resistant ovarian cancer.

The aim of this study was to determine whether the addition of whole body hyperthermia (WBH) to carboplatin (CBDCA) can induce responses in patients with platinum-resistant ovarian cancer. 16 pretreated patients with platinum-resistant ovarian cancer were entered on a Systemic Hyperthermia Oncological Working Group (SHOWG) study; (14 patients were eligible with 14 evaluable for toxicity and 12 for response). The patients were treated with WBH (Aquatherm) 41.8 degrees C x 60 min in combination with carboplatin (CBDCA) (area under the curve (AUC) of 8) every 4 weeks. Disease status was evaluated every two cycles. Patients were treated for a maximum of six cycles. One patient had a complete response (CR) and 4 had a partial response (PR). 4 patients had stable disease (SD). 3 patients had progressive disease (PD). 2 patients were unevaluable: 1 had a bowel obstruction shortly after her first treatment; the second patient achieved a CR, but only had one treatment secondary to an idiosyncratic reaction to sedative drugs. 2 patients entered on study were ineligible, as they did not meet criteria for platinum resistance; 1 entered a CR and 1 had SD. Dose-limiting toxicity, which required CBDCA dose reductions, was grade 4 thrombocytopenia. Other toxicities included neutropenia (grade 3/4), and nausea and/or vomiting. Consistent with preclinical modelling, these results suggests that 41.8 degrees C WBH can overcome platinum resistance in ovarian cancer. These observations suggest further investigation of the therapeutic potential of WBH in a group of patients who historically fail to respond to salvage therapies is warranted.

Paclitaxel, carboplatin, and hexamethyl-melamine (taxchex) as first-line therapy for ovarian cancer.

BACKGROUND: The addition of hexamethylmelamine to therapy with cisplatin, cyclophosphamide, and doxorubicin significantly enhanced outcomes of patients with advanced ovarian cancer. Hexamethylmelamine, also known as altretamine, has potent antineoplastic activity when used as a single agent in patients who have failed to respond to both platinum-based and paclitaxel therapy. We have conducted a pilot study to evaluate the efficacy and safety of adding this drug to the popular ovarian cancer regimen of paclitaxel plus carboplatin. METHODS: Patients with advanced ovarian, fallopian tube, or primary peritoneal cancer (International Federation of Gynecology and Obstetrics stages IIA, IIIC, and IV) were prospectively enrolled to receive six cycles, repeated every 4 weeks, of paclitaxel (150 mg/m2 i.v., day 1), carboplatin (AUC 5.0 i.v., day 1), and hexamethylmelamine (150 mg/m2 p.o., days 2-15). Colony stimulating factors were prohibited. Response and toxicity were monitored by use of Eastern Cooperative Oncology Group criteria. RESULTS: Twenty patients were enrolled, 18 with ovarian cancer, one with fallopian tube cancer, and one with peritoneal cancer; 17 of these patients were evaluable for response and toxicity. At a median follow-up of 6.5 months, 13 of the patients had a complete response (76%), and four had progressive disease. Three of those with a complete response had a recurrence within 1 year of completing treatment. Toxicity was acceptable, with myelosuppression the most severe adverse effect; one patient had grade 3 anemia, one patient had grade 4 thrombocytopenia, and 12 patients had grade 4 neutropenia. Quality of life showed improvement over the course of therapy, particularly in the physical well-being subscale. CONCLUSION: The addition of hexamethylmelamine to paclitaxel and carboplatin is a well-tolerated multidrug combination for women with advanced ovarian cancer that deserves further testing in a phase III study.

An experience with estrogen replacement therapy in breast cancer survivors.

OBJECTIVE: To evaluate the outcome of breast cancer patients who elected estrogen replacement therapy (ERT). STUDY DESIGN: Breast cancer survivors who elected ERT received the preferred regimen of conjugated estrogen 0.625 mg/day with medroxyprogesterone acetate 2.5 mg/day. RESULTS: 145 patients received ERT for at least 3 months. Thirteen recurrences (9%) were identified; 10 are alive with disease, 3 are dead of disease. The median interval between diagnosis and commencement of ERT was 41 months. Forty-one percent of the study group initiated ERT within 3 years of their breast cancer diagnosis. The median duration of follow-up on ERT was 30 months. CONCLUSION: The concern that ERT might activate growth in occult metastatic sites and promote a rash of recurrences was not confirmed. It is unreasonable to categorically deny all breast cancer survivors ERT.

Outpatient vaginal cuff brachytherapy for endometrial cancer.

Petereit DG, Tannehill SP, Grosen EA, Hartenbach EM, Schink JC. Outpatient vaginal cuff brachytherapy for endometrial cancer. The objective of this study was to determine the efficacy and complications of postoperative high-dose-rate (HDR) vaginal-cuff brachytherapy (VCB) in patients with endometrial carcinoma. Between August 1989 to September 1997, 191 patients were treated postoperatively after a total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) with outpatient adjuvant HDR VCB for low-risk endometrial cancer (IB-84%, grade 1 or 2-96%). Patients were treated with 2 HDR fractions, delivered one week apart while under conscious sedation (16.2 Gy X 2 to the vaginal surface). All clinical endpoints were calculated using the Kaplan Meier method. The median time in the brachytherapy suite was 60 min in which no acute complications were observed. The 30-day morbidity and mortality rates were both 0%. With a median follow-up of 38 months (12-82 months), the 4-year survival, relapse-free survival, and vaginal-control rates were 95%, 98%, and 100%, respectively. One patient developed a colo-vaginal fistula at 5 years. Adjuvant HDR VCB in 2 outpatient insertions produced 100% vaginal control rates with minimal morbidity. The advantages of high dose-rate compared to low dose-rate vaginal brachytherapy include patient convenience, markedly shorter treatment times (1 h per insertion), and reduction in the cost and potential morbidity of hospitalization. HDR brachytherapy approach is a cost-effective alternative to either low-dose-rate brachytherapy or whole pelvic radiotherapy in carefully selected patients.

Pregnancy-related fibroadenoma of ectopic breast tissue in the vulva.

BACKGROUND: Pregnancy-related vulvar fibroadenoma of ectopic breast tissue is rare. Management involves diagnosing the mass as a fibroadenoma by physical examination and delaying excision until the postpartum period. CASE: A 31-year-old multigravid woman at 29 weeks' gestation had a right labial mass that was increasing in size. Physical examination showed accessory breast tissue in the left axilla and three vulvar masses, the largest vulvar mass measuring 4 × 5 cm. Suspicion of malignancy was low, so the patient was serially examined during the pregnancy and the vulvar masses were excised during the postpartum period. The final diagnosis was fibroadenoma of ectopic breast tissue. CONCLUSION: Fibroadenoma of ectopic breast tissue can occur during pregnancy. Diagnosis and serial physical examinations are the appropriate course of management during pregnancy. A fine-needle aspiration biopsy can be performed during pregnancy to confirm the diagnosis. The tumors seldom regress spontaneously and so should be removed during the postpartum period.

Hormone replacement therapy in breast cancer survivors: a cohort study.

OBJECTIVE: Our purpose was to measure any adverse effect (if one exists) of hormone replacement therapy administered to breast cancer survivors. STUDY DESIGN: Forty-one patients from a group of 77 patients who received hormone replacement therapy after therapy for breast cancer were matched with 82 comparison patients not receiving hormone replacement therapy. Both groups were taken from the same population on the basis of cancer registry of the Cancer Surveillance Program of Orange County and were compared with regard to survival results. RESULTS: An analysis of survival time and disease-free time revealed no statistically significant difference between the two groups. CONCLUSIONS: No obvious adverse effect of hormone replacement therapy could be shown in this pilot study. A case is made for a prospective randomized trial.

Replacement therapy for breast cancer survivors. A pilot study.

BACKGROUND: Traditionally, breast cancer survivors were not considered as candidates for hormone replacement therapy (HRT) because of the possibility that an occult metastatic site of disease might be activated, thus negatively influencing the outcome for the patient. METHODS: A retrospective review of 77 breast cancer survivors who have taken HRT was conducted. RESULTS: Seven recurrences were reported among the 77 patients studied in-depth, with correlations to stage, age, and node and receptor status. There have been no recurrences among the 33 additional patients who were placed on the study after the completion of this analysis. CONCLUSIONS: No significant adverse outcome was detected in this group of breast cancer survivors receiving HRT. Given the established benefits of HRT, a reappraisal of this subject is necessary, and a prospective randomized trial is essential.

Spontaneous release of interleukin-6 by primary cultures of lymphoid and tumor cell populations purified from human ovarian carcinoma.

Interleukin-6 (IL-6) is a cytokine that has been implicated as a growth factor in human ovarian carcinoma, yet the in vivo source of IL-6 in patients remains undefined. We measured IL-6 by ELISA in cell-free ascites (CFA) of 19 patients with ovarian carcinoma. IL-6 was detectable in all samples (mean level 3.3 ng/ml). To identify the cellular source of IL-6, we measured this cytokine by ELISA in 24-48 h supernatants of cultured lymphocyte-, macrophage-, and tumor cell-enriched populations purified from three solid ovarian carcinomas by centrifugal elutriation. All cell populations spontaneously released IL-6; however, tumor cells and tumor-associated macrophage released levels of IL-6 that greatly exceeded those released by tumor-associated lymphocytes. Kinetic studies revealed that IL-6 was detectable at 6 h and that levels increased in all cultures examined over a 48 h time course. These data suggest that both tumor and infiltrating host cells may be the source of the high levels of IL-6 found in carcinomatous ascites. Furthermore, although all three cell types examined may contribute to IL-6 production in patients with ovarian carcinoma, tumor cells are perhaps the most clinically significant source.

Host-tumor interaction in ovarian cancer. Spontaneous release of tumor necrosis factor and interleukin-1 inhibitors by purified cell populations from human ovarian carcinoma in vitro.

The biological activity of tumor necrosis factor (TNF alpha/beta) and interleukin-1 beta (IL-1 beta) can be blocked by soluble, naturally occurring molecules--TNF alpha/beta binding proteins (BP-55 and BP-75), derived from the extracellular portion of the 55- and 75-kDa TNF alpha/beta membrane receptors, and IL-1 receptor antagonist (IL-1ra), respectively. We examined the levels of these cytokines and their inhibitors in cell-free ascites of 18 patients with advanced ovarian carcinoma by ELISA. Levels of both TNF BP and IL-1ra dramatically exceeded those of TNF and IL-1; thus, it is unlikely that these cytokines are active in ascites from patients with this disease. We then elutriated solid tumor samples from three additional patients, yielding pure populations of tumor cells, macrophages, and lymphocytes. Cells were cultured for up to 48 hr and the spontaneous production of TNF, IL-1, and their inhibitors was measured by ELISA. Tumor cells and macrophages both released inhibitors for TNF and IL-1. Tumor cells released IL-1ra and BP-55, while macrophages released IL-1ra and BP-75. Kinetic studies showed that both tumor cells and macrophages produced an initial burst of TNF alpha and IL-1 beta which was overtaken within 48 hr by a sustained production of TNF BP and IL-1ra. Lymphocytes released no TNF alpha or TNF beta, which alone suggests that tumor associated lymphocytes are locally quiescent in vivo. TNF and IL-1 inhibitors originate from tumor cells and tumor associated macrophages and probably block TNF and IL-1 activity locally and regionally in ovarian carcinoma patients. Whether this phenomenon contributes to the pathogenesis of this disease remains to be determined.

A new method of continuous vaginal cuff closure at abdominal hysterectomy.

A new method for vaginal cuff closure at abdominal hysterectomy avoids blood loss and spillage of vaginal contents into the peritoneal cavity. Using two separate running and interlocking absorbable monofilament sutures, the technique keeps the vagina closed at all times and avoids damage to the bladder or ureters. In 77 consecutive patients undergoing abdominal hysterectomy for endometrial cancer, morbidity related to the cuff closure included cuff cellulitis in only 2.6%, granulation tissue in 3.1%, and postoperative bleeding in none of the patients.

Release of soluble TNF/LT receptors from a human ovarian tumor cell line (PA-1) by stimulation with cytokines in vitro.

We have demonstrated the presence of the 55- and 75-kDa receptor for tumor necrosis factor (TNF) and lymphotoxin (LT) (TNF-R) in serum, and ascites from women with ovarian cancer. The present studies were initiated to begin to examine the possible cellular source of these receptors in women with ovarian cancer. Human ovarian tumor cells (PA-1) were cocultured for 24-48 hr with various levels of recombinant human cytokines (IL-1 beta, IL-4, IFN-gamma) and the supernatants were assayed by ELISA for the soluble forms of each receptor. PA-1 cells spontaneously release the 55-kDa TNF-R and low levels of the 75-kDa TNF-R. The release of both 55- and 75-kDa TNF-R was stimulated when PA-1 cells were cultured with IL-1 beta and IFN-gamma but unaffected by IL-4. The level of 55-kDa TNF-R was elevated slightly over spontaneous release but the level of 75-kDa TNF-R increased dramatically. IFN-gamma was the most potent stimulator of receptor release particularly of the 75-kDa TNF-R. IFN-gamma also induced increased expression of cell membrane TNF-R measured by binding of 125I-labeled TNF. Membrane TNF-Rs which were induced by IFN-gamma were the 75-kDa type, because TNF binding was blocked by anti-75-kDa TNF-R antibody. These data suggest that IFN-gamma selectively induced release and expression of 75-kDa TNF-Rs.

Measurement of the soluble membrane receptors for tumor necrosis factor and lymphotoxin in the sera of patients with gynecologic malignancy.

The shed portion of the 55 and 75 kDa membrane receptors for tumor necrosis factor (TNF) and lymphotoxin (LT) have been described in the serum of patients with cancer. This study was designed to determine whether serum levels of the 55 and 75 kDa soluble TNF/LT receptors (sTNFr) had clinical significance in patients with gynecologic malignancies. Serum samples from 79 patients with ovarian, endometrial, or cervical cancer were assayed for CA 125 levels by RIA and the 55 and 75 kDa sTNFr levels by ELISA. Receptor and CA 125 levels were also analyzed with respect to disease status and response to treatment in banked serum samples from 14 patients with epithelial ovarian cancer who had been followed clinically for 1-3 years. Patients resulted were compared to serum samples tested from normal donors. We found that serum levels of both sTNFr's were elevated in the 79 patients with various gynecologic malignancies [55 kDa of 3.07 +/- 3.79 ng/ml (P < 0.02) and 75 kDa of 2.93 +/- 1.27 ng/ml (P < 0.001)] compared to 16 normal controls (55 kDa of 0.65 +/- 0.22 ng/ml and 75 kDa of 1.62 +/- 0.37 ng/ml). Serum levels of 55 and 75 kDa TNF/LT receptors were a more sensitive indicator of active cancer and had greater predictive value for detecting tumor in patients with ovarian cancer than CA 125. The sTNFr's were also more sensitive than CA 125 in detecting persistent or recurrent tumor and measuring response to therapy. These preliminary results suggest that measurement of serum levels of 55 and 75 kDa sTNFr's, even though not tumor specific, may be a uniquely new method for identifying and monitoring patients with gynecologic malignancy.

Blocking factors (soluble membrane receptors) for tumor necrosis factor and lymphotoxin detected in ascites and released in short-term cultures obtained from ascites and solid tumors in women with gynecologic malignancy.

Studies were conducted to identify and establish the cell and tissue source of blocking factors (BF), materials that inhibit the bioactivity of human TNF and LT in vitro. Ascites and samples of solid tumors were collected from women with various gynecologic malignancies. Supernatants were collected from cultures of tumor and ascites cells after 24, 48, and 72 h. Cell-free ascites (CFA) and culture supernatants were tested for their ability to block human recombinant TNF and LT-induced lysis of L929 cells in vitro. Levels of soluble forms of the 55- and 75-kDa TNF/LT receptors were measured by ELISA assay in the same samples. CFA and culture supernatants contained TNF/LT blocking factors and high levels of one or both soluble 55- and 75-kDa TNF/LT membrane receptors. Levels of BF bioactivity and receptors appeared rapidly, peaked at 24 h, and declined thereafter. Soluble TNF/LT receptors may be the active BF in these samples, and tumor tissues and ascitic cells may be a source of these receptors in the ascites fluid of these patients.

Identification of tumor necrosis factor and lymphotoxin blocking factor(s) in the ascites of patients with advanced and recurrent ovarian cancer.

Ascites obtained from human ovarian cancer patients contains material(s) that inhibit the cytolytic activity of tumor necrosis factor (TNF) and lymphotoxin (LT) in vitro. These inhibitor(s) are found in ascites from ovarian cancer patients and are detected in very low amounts in the ascites from patients with nonmalignant hepatic disease. These ascites TNF/LT blocking factors are heat sensitive and heterogeneous with respect to molecular weight. Kinetic studies indicate these factors inhibited cytolysis at the stage of TNF/LT interaction with membrane receptors on L929 cells. Because TNF and LT are key cytokines in host cell-mediated antitumor mechanisms, factor(s) that inhibit these cytokines could have a profound effect on the tumor host interaction and their presence in the ascitic fluid, should be considered before designing clinical trials that employ intraperitoneal administration of TNF or LT for immunotherapy of ovarian cancer.