J.T. Soper

Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer: I. Correlation of receptor expression with prognostic factors in patients with ovarian cancer*

Previous studies in breast and bladder cancer have suggested that epidermal growth factor receptor is expressed by only a proportion of cancers and is associated with poor clinical outcome. We used a monoclonal antibody specifically reactive with the extracellular domain of the epidermal growth factor receptor to localize this receptor immunohistochemically in frozen sections of normal ovary and epithelial ovarian cancer. Normal ovarian epithelium was found to express epidermal growth factor receptor in all cases. Among 87 ovarian cancers, however, 23% did not express immunohistochemically detectable receptor. Epidermal growth factor receptor expression was not related to histologic grade or stage, but was associated with poor survival (p less than 0.05). The median length of survival of patients with tumors that did not express epidermal growth factor receptor was 40 months compared with 26 months in patients with tumors that did express epidermal growth factor receptor. As in breast and bladder cancer, expression of epidermal growth factor receptor in ovarian cancer appears to be a poor prognostic factor.

Increased serum levels of macrophage colony-stimulating factor in ovarian cancer*

Macrophage colony-stimulating factor is a cytokine that stimulates proliferation and differentiation of phagocytic cells. Macrophage colony-stimulating factor is produced by ovarian epithelial cancer cell lines and might provide a useful serum marker for the disease. Among sera from 69 patients with clinically apparent epithelial ovarian cancer, 47 (68%) had at least 2.5 ng/ml macrophage colony-stimulating factor, whereas only two of 80 apparently healthy donors (2.5%) had a comparable elevation of macrophage colony-stimulating factor. Circulating levels of macrophage colony-stimulating factor did not correlate with serum levels of CA 125. Moreover, 14 of 25 ovarian cancer patients (56%) with clinically evident disease and normal levels of CA 125 (less than 35 U/ml) had elevated levels of macrophage colony-stimulating factor. Among 29 patients with serum CA 125 levels less than 35 U/ml before positive surgical surveillance procedures, 9 (31%) had at least 2.5 ng/ml macrophage colony-stimulating factor. Elevated levels of macrophage colony-stimulating factor were also found in patients with carcinomas from other primary sites and in 31% of 134 patients with benign diseases. If intercurrent benign disease can be taken into account, macrophage colony-stimulating factor deserves further evaluation in combination with CA 125 in monitoring ovarian cancer.

p53 overexpression in advanced-stage endometrial adenocarcinoma

OBJECTIVES Mutation and overexpression of the p53 tumor suppressor gene in endometrial cancers are associated with advanced stage and poor survival. We sought to determine whether p53 overexpression is an independent variable predictive of poor prognosis in advanced endometrial adenocarcinomas. STUDY DESIGN Immunohistochemical evaluation was used to examine p53 expression in paraffin blocks from 179 endometrial adenocarcinomas. RESULTS p53 overexpression was seen in 35% of cancers and was associated with higher stage (p = 0.004), black race (p < 0.001), higher grade (p = 0.02), lack of hormone replacement (p = 0.04), and older age (p = 0.05). In addition to a higher frequency of p53 overexpression (57% vs 26%), black women had a lower survival rate than white women (p = 0.001), but overexpression was associated with poor survival in both races. After we corrected for hormone use, multivariate analysis revealed that older age (p < 0.001), higher stage (p < 0.001), higher grade (p = 0.01), and p53 overexpression (p = 0.04) were predictive of poor survival. CONCLUSIONS Overexpression of p53 in advanced-stage endometrial cancers is an independent variable that is associated with poor survival, occurs more frequently in black women, and may contribute to the racial disparity in survival.

Phase I/II trial of intravenous Doxil® and whole abdomen hyperthermia in patients with refractory ovarian cancer

Objective: A phase I/II study of Doxil® combined with whole abdomen hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase both liposomal delivery and drug extravasation into tumour xenografts resulting in enhanced cytotoxic effects. Patients and methods: Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) Doxil® at a dose of 40 mg m−2 as a 1-h infusion followed by whole abdomen hyperthermia. The phase I portion of the study was performed to determine the maximal tolerated dose (MTD) of hyperthermia. Quality of life (QoL) was performed at baseline, prior to each cycle and every 3 months. Plasma pharmacokinetic studies were performed with the first cycle. Results: Ten patients participated in the phase I portion of the study which demonstrated that the MTD of hyperthermia was 60 min after either average vaginal and rectal temperatures of 40°C had been achieved or after 30 min of power application, whichever was shorter. All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2–8) and six patients had been previously treated with Doxil®. There were three partial responses for a response rate of 10% (95% CI: [2%, 27%]) and eight patients (27%; 95% CI: [12%, 46%]) had disease stabilization. The median time to progression or death was 3.4 months (95% CI: [2.6, 5.2]) and the median survival was 10.8 months (95% CI: [8.8, 17.4]). Twelve patients (40%) experienced palmar-plantar erythrodysesthesia (PPE), but only four (13%) experienced grade 3–4 PPE toxicity. Doxil® systemic exposure was higher in those with grade 3–4 PPE compared to those with no PPE. None of the patients had grade 3–4 thermal toxicity due to hyperthermia. QoL was not decreased in patients responding to therapy. Conclusions: Therapy with intravenous Doxil® and whole abdomen hyperthermia for patients with platinum/paclitaxel resistant ovarian cancer is feasible and does not negatively impact quality of life.

Ploidy analysis of epithelial ovarian cancers using image cytometry

We used a computerized image analysis system to determine the DNA content of 103 epithelial ovarian cancers using touch imprints of frozen tumor samples. Similar to prior studies of ploidy using flow cytometry, we found that most ovarian cancers (78%) were aneuploid while a minority (22%) were diploid. There was no relationship between ploidy and stage, histologic grade, or the ability to perform optimal cytoreductive surgery. Also, like prior studies using flow cytometry, negative second-look laparotomy and survival were somewhat more common in advanced-stage patients with diploid cancers than in those with aneuploid cancers. We conclude that ploidy of ovarian cancers can be determined using a computerized image analysis system to quantitate feulgen staining of cells in touch imprints. Ploidy is unlikely to play a role in treatment planning for patients with advanced-stage disease. Larger studies of patients with early-stage disease are needed, however, to determine whether ploidy is a more accurate means of predicting which patients are most likely to benefit from adjuvant therapy.

CA 125 in peritoneal fluid and serum from patients with benign gynecologic conditions and ovarian cancer

CA 125 was measured in peritoneal fluid from 200 patients with primary ovarian malignancies (35) and benign gynecologic conditions (165). In 86 patients CA 125 was measured both in peritoneal fluid and in serum. Patients with ovarian cancer had markedly greater serum CA 125 levels compared to patients with benign disease. CA 125 levels in peritoneal fluid were usually higher than serum levels. Twenty-six (93%) of 28 patients with ovarian cancer had peritoneal fluid levels which exceeded serum levels in paired samples. peritoneal fluid CA 125 values greater than 200 U/ml identified ovarian cancer patients with 96% sensitivity and 99% specificity. Serum CA 125 values greater than 35 U/ml identified ovarian cancer patients bearing ascites with a sensitivity of 99% and specificity of 94%. Only 2 of 165 patients with benign gynecological conditions had peritoneal fluid values above 200 U/ml. By contrast, only two values below 200 U/ml were found in ascitic fluids from 35 patients with ovarian cancer. CA 125 levels in peritoneal fluid deserve further evaluation for follow-up of patients with ovarian cancer.

Preoperative evaluation of macrophage colony-stimulating factor levels in patients with endometrial cancer

OBJECTIVE Our purpose was to examine the relationship between preoperative serum levels of macrophage colony-stimulating factor, alone and in combination with CA 125, and the presence of prognostic clinicopathologic factors and subclinical metastases in women with endometrial cancer. STUDY DESIGN Ninety-two women who underwent primary exploration for endometrial adenocarcinoma had preoperative serum samples evaluated for macrophage colony-stimulating factor and CA 125 levels. Multivariate analysis was used to determine the associations of surgicopathologic findings with macrophage colony-stimulating factor and CA 125 levels. Logistic regression analysis was used to identify factors associated with the risk of extrauterine disease. The association of macrophage colony-stimulating factor and CA 125 levels with stage, grade, and depth of myometrial invasion and histologic characteristics were analyzed with Fishers two-tailed exact test. RESULTS Elevated levels of macrophage colony-stimulating factor were not associated with depth of myometrial invasion, histologic grade, or histologic cell type; however, advanced stage (p = 0.02) and the presence of lymph node metastases (p = 0.04) were associated with elevated levels. Sensitivity and specificity of macrophage colony-stimulating factor for predicting extrauterine disease were 42% and 89%, respectively. If either an elevated macrophage colony-stimulating factor or an elevated CA 125 level was used to predict extrauterine disease, the sensitivity was increased to 67% but the specificity was decreased to 78%. Macrophage colony-stimulating factor elevations predicted lymph node metastases with a sensitivity of 50% and a specificity of 86%. A multivariate regression model showed CA 125 to be the most significant predictor of extrauterine disease; macrophage colony-stimulating factor also contributed prognostic information (p = 0.02). The sensitivity and specificity of the multivariate model for predicting extrauterine disease were 75% and 73%, respectively. CONCLUSION Macrophage colony-stimulating factor and CA 125 are neither sensitive nor specific enough to be used as predictors of the presence or absence of extrauterine disease in patients with endometrial cancer.

Short gracilis myocutaneous flaps for vulvovaginal reconstruction after radical pelvic surgery

The short gracilis myocutaneous flap derives its blood supply from terminal branches of the obturator artery, and the vascular pedicle derived from the medial femoral circumflex artery is sacrificed. Twenty-one short gracilis myocutaneous flaps were used for vulvovaginal reconstructions in 11 patients undergoing radical pelvic surgery: bilateral flaps in nine patients for neovaginal construction after pelvic exenterations, bilateral flaps in one patient for vulvovaginal reconstruction after radical vulvovaginectomy, and a unilateral flap in one patient for vulvovaginal reconstruction after radical vulvectomy with partial vaginectomy. Major complications consisted of bilateral flap necrosis occurring in one patient who had received preoperative irradiation to the vulva and groin combined with chemotherapy. Minor degrees of necrosis (less than 5%) and/or separation of vaginal suture lines occurred in five patients without marked loss of the flaps. Vaginal caliber and depth are excellent in ten patients (91%) after follow-up of 1-22 months. The short gracilis flap is an excellent alternative to the more bulky gracilis flap, which derives its blood supply from perforating branches of the femoral artery. Based on our experience, the short gracilis flap provides adequately vascularized tissue for vulvovaginal reconstruction in patients after radical pelvic surgery, but should not be used in patients who have received extensive groin irradiation.

Increased serum levels of macrophage colony‐stimulating factor in ovarian cancer

Macrophage colony-stimulating factor is a cytokine that stimulates proliferation and differentiation of phagocytic cells. Macrophage colony-stimulating factor is produced by ovarian epithelial cancer cell lines and might provide a useful serum marker for the disease. Among sera from 69 patients with clinically apparent epithelial ovarian cancer, 47 (68%) had at least 2.5 ng/ ml macrophage colony-stimulating factor, whereas only two of 80 apparently healthy donors (2.5%) had a comparable elevation of macrophage colony-stimulating factor. Circulating levels of macrophage colony-stimulating factor did not correlate with serum levels of CA 125. Moreover, 14 of 25 ovarian cancer patients (56%) with clinically evident disease and normal levels of CA 125 «35 U/ml) had elevated levels of macrophage colony-stimulating factor. Among 29 patients with serum CA 125 levels < 35 U/ml before positive surgical surveillance procedures, 9 (31%) had at least 2.5 ng / ml macrophage colony-stimulating factor. Elevated levels of macrophage colony-stimulating factor were also found in patients with carcinomas from other primary sites and in 31 % of 134 patients with benign diseases. If intercurrent benign disease can be taken into account, macrophage colony-stimulating factor deserves further evaluation in combination with CA 125 in monitoring ovarian cancer. (AM J OBSTET GVNECOL 1991;165:1356-62.)

Phase I/II trial of intravenous liposomal doxorubicin and whole abdomen hyperthermia in patients with refractory ovarian cancer

5089 Background: A phase I/II study of liposomal doxorubicin combined with whole abdominal hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase liposomal extravasation into tumor xenografts resulting in enhanced cytotoxic effects. METHODS Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) liposomal doxorubicin 40 mg/m2 as a 1-hour infusion followed by whole abdominal hyperthermia. Quality of life (QOL) was performed at baseline, prior to each cycle, and every 3 months following treatment. RESULTS All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2-8) and 6 patients had been previously treated with liposomal doxorubicin. There were 3 partial responses for a response rate of 10% and 8 patients (27%) had disease stabilization. The median time to progression was 3.4 months (range, 1.3 to 20.7) and the median survival was 10.8 months (range, 2.7 to 27.2). Twelve patients (40%) experienced palmar-plantar erythrodysesthesia (PPE), but only 4 (13%) experienced grade 3/4 PPE toxicity. None of the patients had grade 3/4 thermal toxicity due to hyperthermia. QOL was stable in patients responding to therapy. CONCLUSIONS Therapy with intravenous doxorubicin and whole abdominal hyperthermia for patients with platinum/paclitaxel resistant ovarian cancer has modest activity and stabilized quality of life. Whole abdomen hyperthermia was well tolerated in this population. Work supported by a grant from the NIH CA42745. [Table: see text].