Endometrial carcinoma recurrence according to race and ethnicity: An NRG Oncology/Gynecologic Oncology Group 210 Study.

Non-Hispanic black (NHB) women are more likely to experience an endometrial carcinoma (EC) recurrence compared to non-Hispanic white (NHW) women. The extent to which tumor characteristics, socioeconomic status (SES) and treatment contribute to this observation is not well defined. In the NRG Oncology/Gynecology Oncology Group (GOG) 210 Study we evaluated associations between race/ethnicity and EC recurrence according to tumor characteristics with adjustment for potential confounders. Our analysis included 3,199 NHW, 532 NHB and 232 Hispanic women with EC. Recurrence was documented during follow-up. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between race/ethnicity and EC recurrence in models stratified by histologic subtype (low-grade endometrioid, high-grade endometrioid, serous, mixed cell, carcinosarcoma, clear cell) or stage (I, II, III) and adjusted for age, SES, body mass index, smoking status and treatment. In histologic subtype-stratified models, higher EC recurrence was noted in NHB women with low-grade endometrioid (HR = 1.94, 95% CI = 1.21-3.10) or carcinosarcomas (HR = 1.66, 95% CI = 0.99-2.79) compared to NHWs. In stage-stratified models, higher EC recurrence was noted among NHB women with stage I (HR = 1.48, 95% CI = 1.06-2.05) and Hispanic women with stage III disease (HR = 1.81, 95% CI = 1.11-2.95). Our observations of higher EC recurrence risk among NHB and Hispanic women, as compared to NHW women, were not explained by tumor characteristics, SES, treatment or other confounders. Other factors, such as racial differences in tumor biology or other patient factors, should be explored as contributors to racial disparities in EC recurrence.

Comparison of outcomes in patients treated with multi-agent regiments of cisplatin, adriamycin, and VP-16 versus carboplatin and paclitaxel for advanced and recurrent endometrial cancer.

OBJECTIVE: The objective of this study was to compare the efficacy of two multi-agent chemotherapeutic regiments that were previously used at the Institution for treatment of advanced and recurrent endometrial cancer. METHODS: A retrospective review of patients with Stage III, IV, and recurrent endometrial cancer who received adjuvant chemotherapy at Roswell Park Cancer Institute over a period of 21 years. Two patient groups were defined based on treatment received: cisplatin, adriamycin, and VP-16 with or without megace (PAV-M), or carboplatin and paclitaxel (CT). RESULTS: Forty-two patients with advanced or recurrent endometrial cancer were included in this review based on regimen received. Median duration of follow up was 55 months. Treatment with PAV-M resulted in more dose modifications compared to CT group (42% vs 11%, respectively). There were no significant differences in disease-free survival or overall survival. CONCLUSIONS: PAV/PAV-M is active in patients with advanced or recurrent endometrial cancer. However, toxicity associated with this triplet regimen may limit clinical use.

The impact of aggressive debulking surgery and cisplatin-based chemotherapy on progression-free survival in stage III and IV ovarian carcinoma.

Forty consecutive patients with stage III and IV invasive ovarian carcinoma were treated on a phase II protocol consisting of optimal debulking surgery, induction cisplatin, cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy, 6-month interval laparoscopy, reinduction cisplatin, PAC chemotherapy, and second-look procedure. All 40 patients have either disease progression or have completed the 12-month protocol. Eighty-seven percent of the patients (35) underwent optimal (less than or equal to 2 cm residual) debulking surgery before chemotherapy, in spite of the fact that 50% (20) were referred to Roswell Park Memorial Institute (RPMI) as inoperable after initial surgery elsewhere. There were no postoperative deaths and chemotherapy was started in less than or equal to 14 days in 97% of the patients. Of the 40 patients, 30% (12) achieved a pathologic complete remission (11) or a clinical complete remission (one patient refused second-look surgery). The estimated 3-year survival rate was 62%, but the 3-year progression-free survival rate was only 29%. The median survival time was 48 months. The estimated 3-year progression-free survival rate was 31% for residual disease less than or equal to 2 cm. For the five patients with residual disease greater than 2 cm, four died within 3 years. The median survival time of patients with less than or equal to 2 cm residual disease was 48 months, as compared with 21 months for those with greater than 2 cm residual disease. Although the estimated 3-year survival rate of 62% is noteworthy, the 3-year progression-free survival rate of only 29% is probably indicative that in spite of extensive debulking surgery and cisplatin-based chemotherapy as used in this protocol, the long range proportion of patients "cured" will remain small.

Surgically documented response to intraperitoneal cisplatin, cytarabine, and bleomycin after intravenous cisplatin-based chemotherapy in advanced ovarian adenocarcinoma.

Thirty-one evaluable patients with stages III and IV invasive ovarian adenocarcinoma were treated on a phase II protocol of second-line intraperitoneal cisplatin, cytarabine, and bleomycin. All 31 patients received first-line intravenous (IV) cisplatin-based chemotherapy; the size of the residual cancer was documented surgically before intraperitoneal chemotherapy in all patients. Response to intraperitoneal chemotherapy was documented by a third-look laparotomy in all patients not evidencing progression of disease clinically. There were eight responses (26%): five surgical complete responses and three surgical partial responses. Responders were patients with stage III ovarian cancer, small residual disease of less than or equal to 1 cm (primarily less than or equal to 5 mm), and patients who previously had responded to cisplatin-based IV chemotherapy. Of the 15 patients with stage III ovarian cancer, residual disease less than or equal to 1 cm, and those who had responded to first-line IV cisplatin-based chemotherapy, 53% (eight) responded to second-line intraperitoneal chemotherapy. Intraperitoneal chemotherapy as used in this phase II protocol would appear to be an effective second-line treatment in advanced ovarian cancer in this specific subset of patients.

Interval laparoscopy as predictor of response to chemotherapy in ovarian carcinoma.

Fifty-one patients with FIGO stage III and IV ovarian adenocarcinoma underwent six-month interval laparoscopy for assessment of chemotherapy response. Thirty-nine of these patients were followed by a second-look procedure at 12 months or to disease progression if it occurred earlier. A positive interval laparoscopy was predictive of disease in 91% of patients, whereas a negative interval laparoscopy showed absence of disease at second look in only 70.5% of patients. A positive laparoscopic biopsy at six months showed presence of disease at second look procedure in 100% (11 of 11) of patients. It is concluded that either an intensive initial chemotherapy or change in therapy such as intraperitoneal chemotherapy after positive interval laparoscopy is indicated in future studies.

Pseudomyxoma peritonei: possible prevention of mucinous ascites by peritoneal lavage.

Combined use of intraperitoneal lavage with dextrose 5% and water and an aggressive surgical approach has thus far successfully prevented reaccumulation of pseudomyxoma peritonei originating from bilateral ovarian mucinous cystadenoma associated with multiple peritoneal implants. Three and a half years after treatment the patient remains without clinical or ultrasonographic evidence of recurrence.

Second-look laparoscopy prior to proposed second-look laparotomy.

A prospective study was carried out to evaluate the use of second-look laparoscopy in patients in complete clinical remission after prolonged chemotherapy for advanced ovarian adenocarcinoma. Twenty-two patients with FIGO stages IIB, III, and IV ovarian adenocarcinoma underwent second-look laparoscopy after a median of 23 months of therapy. Eight (36.3%) patients had documented evidence of persistent ovarian cancer and were thus spared second-look laparotomy. Moreover, in 4 patients (18.1%), malignant cells in cytologic washings were the only laparoscopic evidence of persistent ovarian cancer. The absence of visible tumor and malignant cells in cytologic washings allows for the use of second-look laparotomy while the patient is under 1 anesthesia; the presence of tumor or malignant cells in cytologic washings spares the patient second-look laparotomy at that time.

Chemotherapy in ovarian carcinoma recurrent after radiation therapy.

Fifty-seven patients referred to Roswell Park Memorial Institute between 1971-1975 with Stage III or IV epithelial ovarian cancer treated with prior radiation therapy were randomly allocated to treatment with melphalan, 5-fluorouracil (5-Fu) plus melphalan (FUME), actinomycin-D plus 5-fluorouracil plus melphalan (ACFUME), actinomycin-D, or 5-fluorouracil plus cyclophosphamide (ACFUCY). These patients receiving 5-FU plus melphalan had longer median duration of survival with better quality of life. Combination chemotherapeutic agents effected significantly. better responses (P less than 0.05) than single agent chemotherapy. The ACFUME and ACFUCY combinations resulted in higher incidence of severe and life-threatening toxicity. Patients showing complete response had maximum median duration of survival.

Incidence of subclinical metastasis in stage I and II ovarian carcinoma.

The incidence of unsuspected metastasis to the diaphgram, retroperitoneal lymph nodes, and omentum as well as malignant cytologic peritoneal washings in women with presumed localized ovarian cancer is presented. Of the women with presumed Stage I ovarian cancer, from our clinical experience and those reported in the literature, 11.3% were found to have diaphragmatic metastases, 13.3% had aortic lymph node metastases, 8.1% had pelvic lymph node metastases, 3.2% had omental metastases, and 32.9% had malignant peritoneal washings. In Stage II ovarian cancer, 23% were found to have diaphgragmatic metastases, 10.0% had aortic lymph node metastases, 0% had omental metastases, and 12.5% had malignant peritoneal washings.

Paraaortic lymph node evaluation in stage I endometrial carcinoma.

Of 41 women with FIGO stage I endometrial adenocarcinoma who underwent staging paraaortic lymphadenectomy and paraaortic node biopsy, 6 (14.6%) had metastasis to the paraaortic lymph nodes. None of the 11 patients with grade 1 carcinoma had paraaortic node metastasis; 13.6% of grade 2 carcinomas and 37.5% of grade 3 carcinomas were associated with paraaortic node metastasis. None of the 8 patients with tumor limited to the endometrium had paraaortic metastasis, and only 4.5% of the patients with superficial myometrial invasion had metastasis to the paraaortic lymph nodes. However, this increased to 45.5% for tumors deeply invading the myometrium. Of the patients with paraaortic node metastasis, 83.3% had either grade 3 tumors or deep myometrial invasion. Only 1 patient in the study with paraaortic node metastasis did not have either a grade 3 carcinoma or a tumor deeply invading the myometrium. Because of the high incidence of paraaortic node metastasis with grade 3 tumors or deep myometrial invasion, surgical staging by paraaortic lymphadenectomy or lymph node biopsy is recommended at the time of primary surgery for early endometrial adenocarcinoma.

Melphalan, 5-fluorouracil, and medroxyprogesterone acetate in metastatic endometrial carcinoma.

Fifty consecutive patients with recurrent and metastatic endometrial carcinoma were treated with melphalan, 5-fluorouracil, and medroxyprogesterone acetate with or without tamoxifen as first-line chemotherapy. The objective response rate was 48%, with 20% complete responses. The estimated median progression-free survival time was only five months (0.5 to 65 months) with estimated two- and five-year progression-free survival rates of 16 and 13%, respectively. The estimated median progression-free survival time was 24 months for complete responders; the progression-free survival times were significantly longer than the survival times (median = four months) for all other patients (P = .0002). Whether or not the addition of cytotoxic chemotherapy to progesterone hormonal therapy for metastatic endometrial carcinoma lengthens survival time is still open to question.

Prophylactic anticoagulation as a possible cause of inguinal lymphocyst after radical vulvectomy and inguinal lymphadenectomy.

From 1957 to 1982, 115 patients underwent radical vulvectomy and bilateral inguinal lymphadenectomy for invasive squamous carcinoma of the vulva. From 1957 to 1971, 57 patients received perioperative prophylactic sodium warfarin (Coumadin) as prophylaxis against pulmonary embolism. From 1971 to 1976, 27 consecutive patients received dextran-40 as prophylaxis for pulmonary embolism and to improve the microcirculation to the inguinal skin flaps. Because of the report that dextran-40 is a cause of acute renal failure, this study was terminated and the subsequent 19 patients were treated with mini-dose heparin because of the reported benefit as prophylaxis against thromboembolic disease. During the 25-year period, 12 patients received no prophylactic anticoagulants. Mini-dose heparin resulted in a significant morbidity not previously reported in patients undergoing inguinal lymphadenectomy: 43% (8/19) of the mini-dose heparin patients, 7% (2/27) of the dextran-40 patients, 0% (0/57) of the sodium warfarin patients, and none of the 12 patients not receiving perioperative prophylaxis developed inguinal lymphocysts (P less than .001). There was no significant difference in the prevention of pulmonary embolism between the mini-dose heparin (0/19), dextran-40 (0/27), and no treatment groups (0/12) as compared to the 5% (3/57) incidence in the sodium warfarin patients (.10 less than P less than .50). The significant relationship between prophylactic heparin and the subsequent development of inguinal lymphocysts and the need to reassess its role in prevention of pulmonary embolism in patients undergoing lymphadenectomy is discussed.

Evaluation of the nephrotoxicity of iproplatin (CHIP) in comparison to cisplatin by the measurement of urinary enzymes.

Levels of three enzymes, leucine aminopeptidase (LAP), N-acetyl-beta-D-glucosaminidase (NAG), and beta-glucuronidase (BGA) were measured in the urine of patients receiving hematologically toxic doses of iproplatin (a) with or (b) without pretreatment hydration. The maximum post-treatment increases in the levels of each of the enzymes were compared between these two groups of patients. In addition, the maximum increases in urinary enzyme levels in iproplatin-treated patients were compared with those in patients treated with 40 mg/m2 cisplatin, a known nephrotoxic agent. Increases in LAP levels after cisplatin treatment in the periods studied are significantly higher than those after iproplatin treatment (P less than 0.05). No differences were found in the increases in BGA and NAG levels between iproplatin treatment and cisplatin treatment. No differences were found in the increases in levels of any of the enzymes between patients receiving iproplatin with pretreatment hydration and no prior hydration.

Cisplatin plus VP16-213 in refractory ovarian carcinoma.

Twenty-five patients with FIGO stage III and IV ovarian carcinoma were treated with cisplatin plus VP16-213 chemotherapy as the second, third, or fourth line of therapy. There were two (8%) partial responses, 18 with stable disease and five with progression of disease. Neurotoxicity was observed in all patients, with two patients developing severe paresthesias and difficulty in walking.

Five and ten year estimated survival and disease-free rates after intraperitoneal chromic phosphate; stage I ovarian adenocarcinoma.

From 1975 to 1982, 25 evaluable patients with FIGO Stage I ovarian cancer were treated with intraperitoneal chromic phosphate (32P). All patients underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy with (28%) or without (72%) omentectomy, with no other surgical staging procedures prior to referral. Patients were restaged by laparoscopy (inspection of diaphragms, abdomen, and pelvis), biopsy of suspicious lesions, and peritoneal cytologic washings prior to intraperitoneal chromic phosphate therapy. For the 25 patients, the estimated 5- and 10-year recurrence-free rates and the 5- and 10-year survival rates are 84% and 75%, respectively. Excellent 10-year recurrence-free rates were achieved for Stages IA and IC, nonruptured cysts, and Grade I and II tumors. In contrast, very low 10-year survival rates were achieved for patients with Stage IB, ruptured cysts, or Grade III tumors.

Malignant peritoneal cytology in stage I endometrial adenocarcinoma: the effect of progesterone therapy (a preliminary report).

From February 1982-June 1986, 25 consecutive patients with surgical stage I endometrial adenocarcinoma (no evidence of metastasis at surgery or occult cervical or adnexal involvement on histopathologic review) and malignant peritoneal cytologic washings were treated with progesterone therapy. Twenty-two patients have undergone a second look laparoscopy and repeat cytologic washings, one of those also underwent a third look laparoscopy. Two patients refused second look laparoscopy, and in a third patient laparoscopy was medically contraindicated; all three have no evidence of disease (NED) at 15, 46, and 64 months respectively and are off therapy. Of the 22 patients who underwent second look laparoscopy, 21 (95%) had no macroscopic evidence of recurrent endometrial carcinoma and repeat negative peritoneal cytology; 1 patient (5%) had persistent malignant peritoneal cytology but was NED at third look laparoscopy one year later. All 25 patients are off progesterone therapy and remain clinically NED from 12-64 months. Although progesterone therapy for malignant peritoneal cytology resulted in a 100% reversal of malignant peritoneal cytology to normal in the 22 patients who underwent second or third look laparoscopy and all 25 patients remain clinically NED, the true value of progesterone therapy can only be ascertained by a randomized trial of progesterone versus no therapy.

Comparison of CA 125 after three courses of chemotherapy and results of second-look surgery.

OBJECTIVE: To compare CA 125 levels after three courses of cisplatin-based chemotherapy and the results of second-look surgery. METHODS AND MATERIALS: From January 1990 to December 1996, the medical records of 72 patients diagnosed with epithelial ovarian cancer were reviewed. After initial staging surgery, all patients received cisplatin-based chemotherapy. Prior to each course of chemotherapy, patients underwent physical exams and serum CA 125 was obtained. After 6 courses of chemotherapy, if CA 125 levels were normal (< or = 35 IU/ml) and there was no clinical evidence of disease, the patient was offered second-look surgery. The sensitivity, specificity, and negative predicative value of CA 125 levels after 3 courses of chemotherapy and results of second-look surgery were calculated. Survival curves were constructed using Kaplan-Meier actuarial methods. RESULTS: Seventy-two patients were enrolled in the study. After completing 3 courses of chemotherapy, 43 out of 72 patients were reported to have normal CA 125 levels and were offered second-look surgery. Forty-six out of 72 patients underwent second-look surgery, 28 patients (60%) were reported to have positive second-look surgery. Of the patients with normal CA 125 levels after 3 courses of chemotherapy, 23 patients (57.5%) had a positive second-look surgery. The sensitivity and specificity of CA 125 values after 3 courses of chemotherapy were 17.9% and 94.7%, respectively and the negative predicative value was 43.9%. Patients with normal CA 125 values after 3 courses of chemotherapy had a significantly improved survival compared to those who failed to normalized their CA 125 levels after three courses of chemotherapy. CONCLUSION: Normalization of CA 125 after 3 courses of chemotherapy is a poor predicator of findings at second-look surgery.

Prognostic significance of p53, PCNA, and c-erbB-2 in endometrial enocarcinoma.

Previous studies of oncogenes, tumor suppressor genes, and proliferation markers in endometrial adenocarcinoma have obtained conflicting results regarding the usefulness of these markers in predicting prognosis. This study examined p53, PCNA, and c-erbB-2 immunohistochemically to clarify the relationship of these markers to each other and to FIGO stage, myometrial invasion, and survival. We studied 64 cases of endometrial carcinoma, treated between 1988 and 1995, for overexpression of p53, percentage of PCNA expression (PCNA index), and c-erbB-2 cytoplasmic membrane staining. Thirty-two percent of tumors expressed p53, 39% displayed a PCNA index of > = 25%, and 69% expressed c-erbB-2. p53 overexpression was significantly associated with stage (p=0.027), PCNA index > = 25% (p=0.005), c-erbB-2 expression (p=0.018), and vital status (p=0.04). PCNA index > = 25% was associated with stage (p=0.008), myometrial invasion (p=0.008), and c-erbB-2 expression (p=0.05), and weakly associated with vital status (p=0.07). No associations were observed for c-erbB-2 with stage, invasion, or vital status. There was some suggestion of a decreased survival in patients whose tumors overexpressed p53 (Log Rank; p=0.09) or had a PCNA index > = 25% (Log Rank; p=0.13). Additional, larger studies are needed to evaluate the prognostic value of PCNA and p53 expression in endometrial adenocarcinoma.

Weekly cisplatin induction chemotherapy in the treatment of recurrent cervical carcinoma.

Sixty-nine patients with recurrent cervical carcinoma were treated with weekly cisplatin induction chemotherapy. A 27% objective response was obtained in 67 evaluable patients. The highest responses were seen in liver (33%), supraclavicular nodes (40%), and lung (48%), whereas only one out of 24 (4.2%) patients with central recurrence responded. Consolidation therapy with cisplatin combinations administered on a monthly basis did not enhance response to cisplatin. Cisplatin induction therapy was well tolerated with minimal toxicity.

Cisplatin-MECY (methotrexate-leucovorin rescue plus cyclophosphamide) versus cisplatin-CHAD (cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin) as initial chemotherapy in stage III-IV ovarian adenocarcinoma.

Thirty-three patients with advanced-stage ovarian adenocarcinomas, with no prior chemotherapy, were treated with weekly cisplatin (DDP) for four courses followed by five monthly courses of one of two randomly assigned multidrug combinations. These combinations were high-dose methotrexate-leucovorin plus cyclophosphamide (MECY) or cyclophosphamide, hexamethylmelamine, doxorubicin, and DDP (CHAD). Patients with no clinically measurable disease after 6 months of therapy were evaluated by laparoscopy. In the absence of disease progression at the time of the laparoscopy the study design called for a repeat cycle of four weekly DDP courses and another five monthly courses of the assigned multidrug combination. All patients with no evidence of disease after 1 year of treatment had a second-look laparoscopy which, if negative, was followed by a second-look laparotomy. This report includes all of the consecutively entered patients observed for a minimum of 1 year or to death. DDP-MECY and DDP-CHAD were similarly active for overall response rates and complete response rates according to laparoscopic criteria. However, DDP-MECY had a statistically significantly lower relapse rate (P less than 0.02) and a statistically significantly higher negative second-look laparotomy rate than did DDP-CHAD. Using all entered patients, with no exclusions from analysis, eight of 17 patients (47%) treated with DDP-MECY had negative second-looks after 1 year of treatment. This compares with one of 16 (6%) negative second-looks in patients treated with DDP-CHAD (P less than 0.02). The high negative second-look rate with DDP-MECY is exciting. Positive cytologic washings at the 6-month laparoscopic evaluation were highly predictive that residual disease would be found at the 1-year second-look surgery. Only one patient with positive peritoneal cytology after 6 months of treatment was found to have a negative second-look after 1 year of therapy.