The effect of residual mass size on response to chemotherapy after surgical cytoreduction for advanced ovarian cancer: long-term results.

We report an observational study of chemotherapeutic regression of ovarian tumor implants according to decrements in residual mass size after surgical cytoreduction. Cytoreductive operations were attempted on 74 consecutive patients with stages IIIB-IV disease referred for this purpose. Thirty-two patients had received one to four courses of preoperative chemotherapy (22 responses, no progressions). Postoperative chemotherapy followed current protocols at Dana Farber Cancer Institute (n=61) or referring institutions (n=13); 57 regimens contained cisplatin. Postchemotherapy response was assessed clinically or by second-look procedures. Negative findings were considered a complete remission. Masses > 1 cm were excised from 62 patients. Twelve patients were inoperable. Twenty-eight patients had complete remissions and the correlation between these and decrements in residual mass size was highly significant (P < 0.0001). Complete remissions had a uniform effect and were the only outcome predictive of survival. Preoperative treatment greatly facilitated cytoreduction but only masses 0-0.2 cm were sensitive to postoperative chemotherapy. Masses 0.5 cm or less were optimal. They made up 77% of operable patients and supplied 25 (89%) of the complete remissions. Cytoreduction is not always required but even large-volume disease in the upper abdomen can be safely excised. The concept that masses larger than 10 cm indicate general chemoresistance has not been sustained.

Mucinous adenocarcinomas of the vulva.

An 80-year-old nullipara had a 2.0-cm cystic tumor of the right labium majus. Histologic diagnosis was mucinous eccrine carcinoma. Seventy-five percent of these rare skin adnexal tumors arise on the face, eyelid, or scalp; but none has been reported on the vulva. Indolent localized growth is usual with regional nodal spread in 11% and distant metastases in 3%. A 67-year-old multipara had a 1.2-cm polypoidal nodule of the posterior fourchette. Histologically, a colonic type mucinous carcinoma was arising within a villous adenoma. Mucicarmine and CEA stains were positive. Extensive workup failed to reveal other primary cancers in either patient. Both patients are well 19 and 17 months after radical vulvectomies and node-negative groin dissections. These cases illustrate further the diversity in cell type and biologic behavior of vulvar adenocarcinomas.

Occult pleural involvement in stage III ovarian carcinoma: role of diaphragm resection.

In a 2-year period 12 diaphragmatic resections were performed on 11 patients with invasive metastases from ovarian carcinoma without significant complications, via transabdominal approach in 10 instances and thoracoabdominal incision in 1. Full-thickness penetration of the diaphragm by tumor occurred in all instances without prior evidence of pleural involvement (occult Stage IV). Six patients had primary disease (Group A) and 5 had recurrent disease (Group B). Ten patients who underwent excision of nonpenetrating diaphragmatic metastases were analyzed for comparison (Group C). Mean diameters of the metastases were as follows: Group A, 7.84 +/- 1.60 cm; Group B, 7.00 +/- 2.24 cm; Group C, 2.51 +/- 1.08 cm. The difference in mean diameter between the penetrating (Groups A and B) and nonpenetrating (Group C) tumors was highly significant (P less than 0.01). Penetrating tumors were 5.0 cm or greater; nonpenetrating tumors were 4.0 cm or less. Invasiveness of diaphragmatic metastases was inversely related to survival in patients with primary but not recurrent disease. Group A patients had a marked survival disadvantage (median survival time of 8 months; range 7-25 months) compared to Group C (median survival time of 26 months; range 13-96+ months; P less than .05). In contrast, Group B patients appeared to gain salutory palliation despite large diaphragmatic masses involving the pleural surface (4/5 alive at 16(+)-33+ months following surgery). Previous reports of response and survival in patients with Stage III Ovarian cancer may have included patients with "occult Stage IV" disease.

Predictive factors for long-term survival in patients with advanced ovarian cancer.

A total of 107 patients with carcinoma of the ovary were entered in a study combining extensive primary surgery and intensive chemotherapy. Because of evidence supporting the effectiveness of both single agent platinum (P) and the combination of cyclophosphamide and doxorubicin (CA), patients were treated with alternating cycles of CA and CP. Primary surgery to remove the bulk of tumor to less than 2 cm was possible in 45% of the 85 eligible patients, and an additional 17% had similar surgery after two to four cycles of chemotherapy. Fifteen percent of patients progressed on chemotherapy. Of the 68 who were clinically and radiologically without disease at the completion of chemotherapy, 91% had second-look surgery. Forty-eight percent of these women had residual disease. All patients but one are at risk for greater than 60 months, with a median follow-up of 86 months. Overall 5-year survival is 26%, with a median survival of 33 months. Twenty patients survived over 5 years with 11 continuing to be free of disease (13% of all eligible patients). Patients with modified Broder's grade I,II tumors have not yet reached a median survival. Grade, stage, and primary mass size were the only variables with independent prognostic value in a Cox multivariate analysis.

Ovarian clear cell carcinoma. A clinicopathologic analysis of 44 cases.

The clinical aspects and pathologic findings in 44 cases of pure clear cell carcinoma of the ovary are presented. The patients ranged in age from 28 to 78 years (mean, 50.6 years); 54% were nulliparous. Thirty-three percent of the patients had endometriosis in the involved ovary, and an additional 25% had endometriosis only in sites distant from the tumor. Microscopically, three architectural patterns (papillary, tubulocystic, and solid) and four cell types (clear, hobnail, eosinophilic, and flattened) were seen. A predominant tubulocystic architectural pattern was a good prognostic factor (p less than 0.01); however, no significant difference in survival by cell type was found. Grading of the tumors by conventional architectural and cytologic criteria had no predictive value for survival. Stage at presentation was the most important prognostic factor (p less than 0.001), with a 5-year overall survival of 34% and stage I survival of 55%. The poor stage I survival reflects the 15 patients (34%) in the study with stage Iaii lesions. In the 25 patients who developed recurrence, both distant organ involvement (40%) and lymph node involvement (40%) were frequent. Ovarian clear cell carcinoma has unusual pathologic and clinical features, and it represents a distinct histologic type of ovarian carcinoma.

Clear cell adenocarcinoma of the ovary: a clinical analysis and comparison with serous carcinoma.

Forty-four patients with clear cell adenocarcinoma of the ovary diagnosed between 1944 and 1981 were compared with a matched cohort of 55 patients with the most common epithelial malignant lesion, serous adenocarcinoma, in terms of their presentation and clinical course. None were lost to follow-up. Median follow-up was 9 years. Fifty percent of clear cell patients presented in Stage I versus 31% of serous patients. Patients with clear cell carcinoma presented more often with pelvic masses (84% vs 65%) and had larger (diameter greater than 10 cm) primary tumors (73% vs 29%). Forty-nine percent of clear cell patients were nulligravid compared with 24% of serous patients and endometriosis was strikingly more common in clear cell patients (58% vs 12%). When compared stage for stage, clear cell tumors were uniformly associated with poorer 5-year survival rates with an overall rate of 34%. In patients with recurrent disease, lymph node involvement was much more common in patients with clear cell carcinoma (40% vs 7%). Parenchymal organ involvement was also more common in the clear cell group (40% vs 13%). Ovarian clear cell adenocarcinoma has distinctly different clinical behavior compared to serous carcinoma and should be regarded as an aggressive epithelial histologic type.

Elevated CA 125 serum levels and epithelial ovarian cancer metastatic to retroperitoneal lymph nodes.

Elevations in CA 125 levels have been reported in approximately 80% of patients with epithelial ovarian cancer. Studies demonstrate that elevations of CA 125 at the time of second-look procedures correlate with the presence of tumor in 100% of cases. Two cases are reported with elevated CA 125 in which clinical examination and noninvasive studies with CAT scans failed to demonstrate tumor. In both cases laparotomy was performed because of the elevation of CA 125. Although intraabdominal exploration did not reveal the source of the CA 125 elevation, extensive retroperitoneal dissection demonstrated microscopic tumor in retrocaval lymph nodes in both cases. The ability to monitor patients with CA 125 is demonstrated and the importance of elevated antigen levels emphasized. Benign conditions associated with falsely positive CA 125 are discussed.

Trends in drug orientations and behavior: changes in a rural community, 1975-1982.

This paper examines trends in rural American rates of marijuana use and drug-related orientations over an 8-year period. The younger rural youths (13-year-olds) in our three surveys (1975, 1979, and 1982) reported significant declines in rates of use and expressed a general trend toward conservatism. The attitudes and orientations of older youths (16-year-olds) changed also, and in the same directions, but those changes were not statistically significant. Use rates for 16-year-olds, on the other hand, increased, but again the changes were not statistically significant. In at least one cohort we studied, attitudes changed prior to shifts in behavior. We also observed that the predictive ability of the selected attitudes and orientations increased considerably from 1975 to 1982. In the midst of a movement toward conservatism on drug issues, liberalness was even more closely linked to marijuana use than in the previous decade. Lastly, we evaluate the implications of these findings for drug prevention policy and future research.

Intraperitoneal immunotherapy of epithelial ovarian carcinoma with Corynebacterium parvum.

Corynebacterium parvum was administered intraperitoneally to 21 patients with epithelial ovarian cancer. Nineteen patients had surgically measurable disease and two received adjuvant therapy. Surgically confirmed responses were documented in six of 19 patients (31.6%), with two complete responses (10.5%) and four partial responses (21.1%). Three patients (15.8%) had stable disease, and 10 patients (52.6%) had disease progression. The mean survival of the patients who had a complete response was 35.5 months; the four patients who had a partial response the mean survival was 26.6 months, and of the nonresponders the mean survival was 12.6 months (p less than 0.02). The mean survival of the entire group was 18.2 months. Initial response and patient survival correlated with the amount of disease pretreatment. Thus six responding patients had less than or equal to 5 mm maximum diameter tumors, that is, minimal residual disease. Toxicity in the 86 courses of therapy included abdominal pain in 78% of cases, fever in 56%, nausea in 40%, and vomiting in 22%. Stimulation of cytotoxic lymphocytes resulted from the administration of C. parvum, which induced a significant increase of both intraperitoneal natural killer lymphocyte cytotoxicity and antibody-dependent cell-mediated cytotoxicity in six of nine patients tested; these two types of cytotoxicity correlated with response to therapy and may be partially responsible for the surgically documented tumor regression. While the clinical usefulness of intraperitoneal C. parvum is limited because of its toxicity, intraperitoneal immunotherapy may prove useful in patients with minimal residual ovarian cancer when more refined agents become available.

A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer.

The murine monoclonal antibody OC 125 reacts with an antigen (CA 125) common to most nonmucinous epithelial ovarian carcinomas. An assay has been developed to detect CA 125 in serum. By this assay, only 1 per cent of 888 apparently healthy persons and 6 per cent of 143 patients with nonmalignant disease had serum CA 125 levels above 35 U per milliliter. In contrast, 83 of 101 patients (82 per cent) with surgically demonstrated ovarian carcinoma had elevated levels of antigen. In 38 patients with epithelial ovarian carcinoma monitored on 2 to 18 occasions during 2 to 60 months, antigen levels ranged from less than 1 to more than 8000 U per milliliter. Rising or falling levels of CA 125 correlated with progression or regression of disease in 42 of 45 instances (93 per cent). Determination of CA 125 levels may aid in monitoring the response to treatment in patients with epithelial ovarian cancer.

Intraperitoneal immunotherapy of human ovarian carcinoma with Corynebacterium parvum.

Corynebacterium parvum has been administered i.p. to 14 patients with advanced ovarian cancer. Two patients had responded completely to cytoreductive surgery and combination chemotherapy prior to immunotherapy, and one patient with residual disease had received only a single course of C. parvum due to i.p. catheter malfunction. Among the 11 patients with residual disease evaluable for response, from three to eight i.p. treatments with C. parvum produced surgically confirmed tumor regression in five patients (45%) with three partial responses and two complete responses of 5 and 12 months duration. All responders had (a) multiple tumor nodules less than 0.5 cm at the initiation of immunotherapy, and (b) severe abdominal pain and fever after C. parvum injection. Overall, 58 courses of immunotherapy were associated with abdominal pain (91%), fever (67%), nausea (52%), vomiting (31%), and hypotension that responded promptly to i.v. infusion of fluids (10%). Use of i.p. cathethers was associated with two episodes each of infection and intraabdominal bleeding. Administration of C. parvum i.p. has augmented the ability of human peritoneal cells to lyse human ovarian carcinoma cell lines in the presence of specific rabbit heteroantiserum. C. parvum administered i.p. has inhibited the growth of human ovarian carcinoma and may prove useful for modulating the activity of human effectors for antibody-dependent cell-mediated cytotoxicity.

Youth at risk: marijuana use among Native American and Caucasian youths.

An exploration is undertaken of the relationships between legal control, peer and parental influences, and perceptions of marijuana smoking as risk-taking behavior; and of the use of marijuana in a rural school district that serves a culturally diverse community. Specifically, data were obtained from the school district by means of an anonymous, self-administered questionnaire. A total of 605 questionnaires were obtained from the district, including 104 completed by Native American youth. The linkages between the social control variables, personal biographical data, risk assignments, and self-reported marijuana smoking were significantly different for each of the groups studied. In fact, the variables that revealed the most about Caucasian marijuana smoking revealed the least about this activity among the Native Americans, and vice versa. These findings and their implications are explored.

The mesothelial keratins: a new family of cytoskeletal proteins identified in cultured mesothelial cells and nonkeratinizing epithelia.

The cytoskeletal proteins of cultured normal human mesothelial cells were found to consist of six major components, including actin, vimentin, the 40 kd keratin and the 44, 52 and 55 kd proteins, plus a minor 46 kd protein. Two-dimensional gel electrophoresis, peptide mapping and immunoprecipitation tests showed that the 40-55 kd mesothelial proteins are a family of keratins distinct in size, charge or peptide map from the "epidermal keratins" synthesized by cultured keratinocytes. Unique combinations of keratins from the epidermal and mesothelial keratin families were found to be synthesized by cultured bladder, esophageal, conjunctival, mammary, exocervical and ovarian surface epithelial cells. Mesothelial cells were the only epithelial cell type that synthesized vimentin at more than trace levels. We have also found that many carcinoma cell lines express keratins different from those of their cell type of origin.

Laparoscopy for second-look evaluation in ovarian cancer.

Although second-look laparotomy to ascertain primary therapeutic effect on ovarian cancer has been generally accepted, laparoscopy for this purpose has been controversial. Between 1974 and 1978, 119 consecutive laparoscopic examinations were performed on 57 patients with ovarian cancer to monitor the effect of chemotherapy or to determine disease status. Most procedures included intraperitoneal biopsy and cytologic evaluation of peritoneal washings. Seventy-three percent of the procedures were successful. Fourteen percent of the patients had major complications requiring laparotomy, most of which involved bowel perforation. Complications were significantly reduced when routine laparoscopy was preceded by needle laparoscopy. A negative laparoscopy including biopsy and cytologic evaluation was associated with a significant increase in survival when compared with the entire patient group. Repetitive laparoscopy permitted early detection of recurrence and identified patients whose risk of recurrence after 24 months was low. With each successive negative laparoscopy, the mean duration of remission was longer and the probability of recurrence lower.

cis-Diamminedichloroplatinum(II) therapy for advanced ovarian cancer.

Eleven of 32 patients (34%) with advanced ovarian cancer previously treated with conventional therapies had partial or complete responses to 5-day courses of cis-diamminedichloroplatinum(II) (CDDP) (20 mg/m2/day) with nine showing objective response prior to initiation of the second course. Median duration of response was 6 months (range, 2-18 +). Response to CDDP was not correlated with age, pathologic subtype, tumor grade, or bulk disease but was correlated with response to prior treatment. Eight of 15 patients previously responsive to either single alkylating agents or cyclophosphamide plus doxorubicin (Adriamycin) responded to CDDP. In contrast, response to CDDP was observed in only three of 17 patients showing no response to this prior chemotherapy. The highest response rate to CDDP was seen in that subset of patients sensitive to cyclophosphamide and doxorubicin (seven of ten patients).

Combination chemotherapy with adriamycin-cyclophosphamide for advanced ovarian carcinoma.

Combination chemotherapy with Adriamycin-cyclophosphamide was employed after surgical treatment in 60 women with Stage III-IV ovarian adenocarcinoma. Of 53 evaluable patients, objective response was noted in 34 of 41 (83%) without prior cytotoxic therapy but in only two of 12 (17%) who had failed a single alkylating agent or radiotherapy (P < .005). Complete response was confirmed by a negative biopsy at the site(s) of prior disease in 12 patients. Eleven of the 12 biopsy-confirmed complete responses were achieved in patients without pretreatment palpable tumor. Twenty-four out of 41 patients with palpable masses responded but only one was confirmed as complete. Confirmed complete responses had a median duration of 24 months, whereas the median duration of all other responses was only seven months. The median survival for patients in whom Adriamycin-cyclophosphamide was the initial chemotherapy was 24 months. The median survival in patients with palpable tumor exceeds that of historical controls matched for age, tumor cell type, and grade (P = .05); the median survival for the confirmed complete responders has not been reached. The toxicity of this regimen was acceptable at doses of Adriamycin and cyclophosphamide of 45 mg and 500 mg/M2 body surface area, respectively. Extensive excision of tumor followed by effective combination chemotherapy offers the best current approach toward improved patient survival in advanced ovarian cancer.

Radiation therapy in stage II ovarian carcinoma: the influence of histologic grade.

Between September 1968, and December 1975, 40 patients with Stage II epithelial tumors of the ovary were treated at the Joint Center for Radiation Therapy. Thirty-six patients had undergone a total abdominal hysterectomy and bilateral salpingo-oophorectomy (BSOH) with attempted total removal of disease, and all patients received postoperative pelvic irradiation. The five-year actuarial relapse-free survival rate is 66% and the overall survival rate 70% for the entire group of patients. The histology was reviewed in all cases and graded for the percentage of solid vs. papillary or glandular in the specimen. Of the 36 patients treated with a BSOH, 18 had well-differentiated tumors defined as containing less than a 10% solid architectural pattern. There have been no relapses in this group of patients. In contrast, 9 of 18 patients with moderately or poorly differentiated tumors containing a 10% or more solid pattern have relapsed; five diffusely in the abdomen, two in the pelvis, and two in the lungs or pleura. It appears that a BSOH followed by pelvic irradiation is sufficient treatment for Stage II patients with well-differentiated tumors showing less than a 10% solid pattern. In contrast, patients with less well-differentiated tumors have a high risk of relapse outside of the pelvis and need additional treatment. Alternative treatment options are discussed.

High-dose methotrexate with leucovorin rescue in ovarian cancer: a phase II study.

Methotrexate (MTX) (1--7.6 g/m2) with leucovorin rescue was given to 19 women with stage III-IV ovarian carcinoma after induction of remission with surgical treatment and chemotherapy or after relapse. Adequate hydration with alkalinization prevented nephrotoxicity and no cumulative myelosuppression was observed. Serum MTX levels in nontoxic patients averaged 1 X 10(-6) M 24 hours following a 30-minute iv infusion of MTX at 3 g/m2. Among nontoxic women there was a 50-fold difference in the MTX level which correlated with the mean serum creatinine level. Response was assessed after 6--12 weeks of treatment by laparoscopy in patients with nonpalpable intra-abdominal tumor implants or by physical examination in patients with palpable masses. Despite the high levels of MTX achieved with the weekly schedule, only one partial response occurred among eight patients with visible or palpable metastatic lesions. Progressive disease was observed after 6--12 weeks of treatment in four of eleven women who began to receive MTX without evidence of disease or with lesions of less than 1.5 cm in diameter. MTX at the dose and schedule used in the present study appears to be of no benefit in the treatment of advanced ovarian cancer.