Stephen C. Rubin

Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1.

BACKGROUND We tested the hypothesis that ovarian cancers associated with germ-line mutations of BRCA1 have distinct clinical and pathological features as compared with sporadic ovarian cancers. METHODS We reviewed clinical and pathological data on patients with primary epithelial ovarian cancer found to have germ-line mutations of BRCA1. Survival among patients with advanced-stage cancer and such mutations was compared with that in control patients matched stage, grade, and histologic subtype of the tumors. A combination of single-strand conformation and sequencing analyses was used to examine the 22 coding exons and intronic splice-donor and splice-acceptor regions of BRCA1 for mutations in pathological specimens. Alternatively, some patients were known to be obligate carriers of the mutant BRCA1 gene because of their parental relationships with documented mutant-gene carriers. RESULTS We identified 53 patients with germ-line mutations of BRCA1. The average age at diagnosis was 48 years (range, 28 to 78). Histologic examination in 43 of the 53 patients showed serous adenocarcinoma. Thirty-seven tumors were of grade 3, 11 were of grade 2, 2 were of grade 1, and 3 were of low malignant potential. In 38 patients, the tumors were of stage III; 9 patients (including those with tumors of low malignant potential) had stage I disease, 5 had stage IV, and 1 had stage II. As of June 1996, with a median follow-up among survivors of 71 months from diagnosis, 20 patients had died of ovarian cancer, 27 had no evidence of the disease, 4 were alive with the disease, and 2 had died of other diseases. Actuarial median survival for the 43 patients with and advanced-stage disease was 77 months, as compared with 29 months for the matched controls (P<0.001). CONCLUSIONS As compared with sporadic ovarian cancers, cancers associated with BRCA1 mutation appear to have a significantly more favorable clinical course.

Ten-year follow-up of ovarian cancer patients after second-look laparotomy with negative findings

OBJECTIVE To determine long-term survival and predictors of recurrence in patients with platinum-treated ovarian cancer who were followed for 10 years after second-look laparotomy with negative findings. METHODS Records were reviewed of 91 consecutive patients with negative findings on second-look laparotomy after platinum-based chemotherapy between January 1978 and January 1987. Statistical analysis used Kaplan-Meier survival curves, Cox proportional hazards, and multiple logistic regression. RESULTS Mean age of patients was 57 (range 30-79) years. Distribution by stage and grade was as follows: stage I, ten; II, 18; III, 57; IV, six; grade 1, 18; 2, 28; 3, 45. Forty-seven of 91 women had optimal initial cytoreduction. Recurrence-free survival rates for all subjects were 75% at 2 years, 55% at 5 years, and 52% at 10 years. For women with stage I disease, the recurrence-free survival rate was 90% at 2, 5, and 10 years. For women with stage II disease, recurrence-free survival rates were 78, 72, and 66% at 2, 5, and 10 years, respectively. Patients with stage III or IV disease had recurrence-free survival rates of 72, 44, and 40% at 2, 5, and 10 years, respectively. Risk of recurrent disease was related to tumor stage (relative risk [RR] 2.02; 95% confidence interval [CI] 1.2, 3.3; P = .005), grade (RR 2.00; 95% CI 1.3, 3.2; P = .004), and presence of a residual tumor of more than 2 cm at the end of initial surgery (RR 3.19; 95% CI 1.2, 8.5; P = .02). CONCLUSION Ovarian cancer patients face an appreciable risk of recurrence in the first 5 years after second-look laparotomy with negative findings after platinum-based chemotherapy, but those who remain disease free at 5 years have excellent long-term survival rates. Tumor stage, grade, and presence of a residual tumor of more than 2 cm after initial surgery are significant predictors of recurrence.

Treatment of endometrial stromal tumors

We reviewed 31 cases of endometrial stromal tumors treated on the Gynecology Service at Memorial Sloan-Kettering Cancer Center from 1970 to 1984. Twenty-two patients had endolymphatic stromal myosis and 9 patients had endometrial stromal sarcoma. Twenty-six patients initially had disease confined to the uterus. Following hysterectomy, 7 patients received various adjuvant therapies, but no active adjuvant regimen was identified. All 3 patients who presented with advanced endometrial stromal sarcoma died of rapidly progressive disease; only 2 of 6 patients with stage I endometrial stromal sarcoma developed recurrence. Among patients with endolymphatic stromal myosis, a higher recurrence rate was noted in patients with residual ovarian tissue (100%) than in those without residual ovarian tissue (43%). Fifteen patients were treated for recurrent disease (13 with endolymphatic stromal myosis, 2 with endometrial stromal sarcoma). Following attempts to resect disease surgically, objective responses were attained with both chemotherapy (57%) and radiation (40%). The median survival following treatment of recurrent disease was 46 months. Actuarial survival for all patients in this study was 76% at 5 years and 69% at 10 years.

Randomized Prospective Trial of 5 versus 10 Cycles of Cyclophosphamide, Doxorubicin, and Cisplatin in Advanced Ovarian Carcinoma'

Five versus ten cycles of cyclophosphamide, doxorubicin, and cisplatin (CAP) were compared in advanced ovarian carcinoma by a prospective randomized study of 78 patients, 41 receiving 5 cycles (CAP5) and 37 receiving 10 cycles (CAP10) of chemotherapy. Patients were stratified by histologic grade and size of residual disease. Cyclophosphamide, 600 mg/m2, doxorubicin, 40 mg/m2, and cisplatin, 100 mg/m2, were administered every 4 weeks for 5 or 10 cycles. Second-look laparotomy was performed to evaluate response and plan further therapy. CAP5 patients found a second-look laparotomy to have partially responded to chemotherapy were treated with 5 additional cycles of CAP. CAP10 was more toxic than CAP5 with respect to myelosuppression, hospital admissions for nadir fever, median elevation of creatinine, and degree of peripheral neuropathy. Median follow-up is 64 months. CAP5 and CAP10 were equivalent in surgically documented complete responses (34 versus 35%) and survival (P = 0.41). Twelve partial responders to CAP5 received additional CAP chemotherapy; one complete response resulted. We conclude that CAP5 is preferable to CAP10 in treatment of advanced ovarian cancer as it is equally effective and less toxic.

Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: A Gynecologic Oncology Group study

OBJECTIVE Patients with persistent/recurrent epithelial ovarian cancer/primary peritoneal cancer (EOC/PPC) have limited treatment options. AKT and PI3K pathway activation is common in EOC/PPC, resulting in constitutive activation of downstream mTOR. The GOG conducted a phase II evaluation of efficacy and safety for the mTOR inhibitor, temsirolimus in EOC/PPC and explored circulating tumor cells (CTC) and AKT/mTOR/downstream tumor markers. METHODS Eligible women with measurable, persistent/recurrent EOC/PPC who had received 1-3 prior regimens were treated with 25mg weekly IV temsirolimus until progression or intolerable toxicity. Primary endpoints were progression-free survival (PFS) ≥6-months, tumor response, and toxicity. CellSearch® system was used to examine CTC, and AKT/mTOR/downstream markers were evaluated by archival tumor immunohistochemistry. Kendalls tau-b correlation coefficient (r) and Cox regression modeling were used to explore marker associations with baseline characteristics and outcome. RESULTS Sixty patients were enrolled in a two-stage sequential design. Of 54 eligible and evaluable patients, 24.1% (90% CI 14.9%-38.6%) had PFS ≥6 months (median 3.1 months), 9.3% (90% CI 3.7%-23.4%) experienced a partial response. Grade 3/4 adverse events included metabolic (8), gastrointestinal (8), pain (6), constitutional (5) and pulmonary (4). Suggested associations were between cyclin D1 and PFS ≥6 months, PFS or survival; positive CTC pre-treatment and lack of response; and high CTC expression of M30 and PFS ≥6 months/longer PFS. CONCLUSIONS Temsirolimus appears to have modest activity in persistent/recurrent EOC/PPC; however, PFS is just below that required to warrant inclusion in phase III studies in unselected patients. Cyclin D1 as a selection marker and CTC measures merit further study.

Generation of a Syngeneic Mouse Model to Study the Effects of Vascular Endothelial Growth Factor in Ovarian Carcinoma

Vascular endothelial growth factor (VEGF) performs multifaceted functions in the tumor microenvironment promoting angiogenesis, suppressing anti-tumor immune response, and possibly exerting autocrine functions on tumor cells. However, appropriate syngeneic animal models for in vivo studies are lacking. Using retroviral transfection and fluorescence-activated cell sorting, we generated a C57BL6 murine ovarian carcinoma cell line that stably overexpresses the murine VEGF164 isoform and the enhanced green fluorescent protein. VEGF164 overexpression dramatically accelerated tumor growth and ascites formation, significantly enhanced tumor angiogenesis, and substantially promoted the survival of tumor cells in vivo. In vitro, VEGF164 overexpression significantly enhanced cell survival after growth factor withdrawal and conferred resistance to apoptosis induced by cis-platin through an autocrine mechanism. VEGF/green fluorescent protein-expressing tumors were not recognized by the adaptive immune system. After vaccination, a specific anti-tumor T-cell response was detected, but tumor growth was not inhibited. This engineered murine carcinoma model should prove useful in the investigation of the role of VEGF in modulating the tumor microenvironment and affecting the complex interactions among angiogenesis mechanisms, anti-tumor immune mechanisms, and tumor cell behavior at the natural state or during therapy in ovarian carcinoma.

Influence of secondary cytoreduction at the time of second-look laparotomy on the survival of patients with epithelial ovarian carcinoma

The value of secondary cytoreductive surgery at the time of second-look laparotomy in patients with epithelial ovarian carcinoma is not established. Sixty-seven patients with residual carcinoma found at the time of second-look laparotomy performed at Memorial Sloan-Kettering Cancer Center between December 1, 1978, and May 30, 1986, were evaluated for survival relative to the success of secondary cytoreductive surgery. At second-look laparotomy, 17 patients had microscopic disease, 28 patients had disease less than 2 cm and 22 patients had disease greater than 2 cm. After secondary cytoreductive surgery 33 patients had microscopic disease, 26 patients had disease less than 2 cm, and 7 patients had disease greater than 2 cm (1 unknown). Five-year survival by Kaplan-Meier calculation was 62% for patients found to have microscopic disease at second-look laparotomy and 51% for patients whose disease was rendered microscopic by secondary cytoreductive surgery (P = 0.55). Patients left with gross disease (either less than or greater than 2 cm) had 5-year survivals of less than 10% (P = 0.013 compared with microscopic residual). Secondary cytoreductive surgery at the time of second-look laparotomy in patients with epithelial ovarian carcinoma may result in improved survival of patients who are reduced to microscopic residual disease.

Palliative surgery for intestinal obstruction in advanced ovarian cancer

Abstract Intestinal obstruction in ovarian cancer patients is a major complication which frequently affects survival and quality of life. After a reasonable trial of conservative management fails, surgery is the only hope for relief of obstruction. In an effort to evaluate the success of such surgery we have reviewed the outcome of 54 operations (52 patients) for relief of intestinal obstruction performed over the 3-year period 1983–1985. Possible predictive factors for success and survival following surgery were analyzed. The sites of intestinal obstruction in the 54 procedures were as follows: small intestine 24 (44%); large intestine 18 (33%); combined small and large intestine 12 (22%). In 11 operations no surgical correction of the obstruction was possible. In 43, major intestinal procedures were performed, including 14 bypasses, 13 resections, and 20 colostomies. Of the 43 instances in which intestinal procedures were performed, 4 patients expired without leaving the hospital. At the time of discharge from the hospital the remaining 34 of these 43 patients were eating a regular or low-residue diet. Successful palliation of intestinal obstruction was thus achieved in 79% of the 43 instances in which a definitive procedure could be performed, and in 63% of the total of 54 operations. Mean survival following surgery was 6.8 months for the group undergoing a definitive procedure, and 1.8 months for the group undergoing exploration only. There was no significant difference between the two groups with regard to age, time from diagnosis, prior radiotherapy, number of prior laparotomies, site of obstruction, or use of total parenteral nutrition. None of the multiple clinical variables analyzed correlated with survival following definitive surgery. Most patients explored for intestinal obstruction due to advanced ovarian cancer can have their obstruction relieved and be discharged from the hospital. We were not able to define criteria that would allow selection of patients unlikely to benefit from Surgery.

Paget's disease of the vulva

Abstract Thirty-six patients with Pagets disease of the vulva were reviewed. Median age of the patients at diagnosis was 64 years (range 41–84 years). Five patients (14%) had an associated invasive adenocarcinoma of the vulva at the time of diagnosis. Of 31 patients with superficial noninvasive Pagets disease, 28 were available for follow-up. Treatment of patients with superficial Pagets disease was surgical and based on the extent of disease. Procedures performed included total vulvectomy (25), wide local excision (4), and skinning vulvectomy with skin graft (1). The median follow-up was 108 months (range 6–266 months). Twenty-two of twenty-eight patients remained free of disease. Six patients have required multiple procedures for recurrent superficial Pagets disease. Treatment of Pagets disease of the vulva is surgical. Radical surgery is the preferred treatment of patients with an associated invasive adenocarcinoma; three of five patients with an invasive adenocarcinoma were long-term survivors. Patients with superficial Pagets disease of the vulva should be treated by local excision utilizing frozen-section margin evaluation as a guide to extent of excision. Only one patient with an initial diagnosis of superficial Pagets disease of the vulva developed invasive adenocarcinoma.

Prognostic factors for recurrence following negative second-look laparotomy in ovarian cancer patients treated with platinum-based chemotherapy

Prior studies of the risk of recurrence following negative second-look laparotomy have included patients treated with a variety of chemotherapeutic regimens, including nonplatinum regimens. We have examined the long-term outcome and risk factors for recurrence among a homogeneous group of platinum-treated patients. During the years 1978-1987, 91 patients at Memorial Sloan-Kettering Cancer Center had a negative second-look laparotomy following platinum-based chemotherapy for epithelial ovarian cancer. The mean age at diagnosis was 57 years, with a range of 30 to 79. Distribution by stage was as follows: I, 10; II, 18; III, 57; IV, 6. The mean number of cycles of platinum prior to second-look surgery was 6.3. The mean number of biopsies taken at negative second-look laparotomy was 12. Lymph node biopsies were done in 47/91 (52%) of patients. Median follow-up from the date of second-look laparotomy was 54.6 months among survivors. Forty of ninety-one patients (44%) have had recurrence, almost 40% of which were outside the peritoneal cavity. The mean interval from negative second-look laparotomy to recurrence was 24 months (range, 2-70 months). By multivariate analysis the risk of recurrence was significantly related to stage (P = 0.017), histologic grade (P = 0.041), and the amount of tumor remaining after the first operation for ovarian cancer (P = 0.015). Recurrence by stage was as follows: stage I, 1/10 (10%); stage II, 5/18 (28%); stage III, 31/57 (54%); stage IV, 3/6 (50%). Recurrence by grade was as follows: grade 1, 4/18 (22%); grade 2, 11/28 (39%); grade 3, 25/45 (56%). There was no relationship between the risk of recurrence and the number of cycles of platinum, the number of biopsies performed at second-look, or the number of months from primary surgery to second-look. Patients having negative second-look laparotomy following platinum-based chemotherapy for advanced epithelial ovarian cancer have a substantial risk of recurrence, particularly within the first 3 years. Such patients should be offered participation in clinical trials of consolidation therapy directed against both intraperitoneal and extraperitoneal disease.