Nodal metastasis in endometrial cancer.

PURPOSE: Besides hysterectomy and bilateral salpingo-oophorectomy, the goal of surgery in early endometrial cancer is to identify extrauterine disease. The purpose of this study was to evaluate disease characteristics and survival of patients found to have nodal metastasis at staging for endometrial cancer. METHODS: All patients presenting to our practice from January 1993 to July 2009 with a new diagnosis of early endometrial cancer underwent pelvic and paraaortic lymph node sampling at the time of surgery as permitted by the body mass index. Patient and disease characteristics of patients with nodal metastasis were abstracted by retrospective chart review. Factors contributing to disease-free and overall corrected survival were evaluated. RESULTS: Forty-three patients with an early endometrial cancer were found to have pelvic and/or paraaortic nodal metastasis. Thirty-three percent of patients with nodal metastasis had papillary serous or clear cell cancers. Such tumors were often superficially invasive, yet were more likely to demonstrate lymphovascular space involvement as compared to endometrioid cancers. Furthermore, in a global model of disease-free and overall corrected survival, only tumor histology (endometrioid vs non-endometrioid) was a significant prognostic factor. Excluding clear cell and papillary serous tumors, only tumor grade was a significant prognostic factor in disease-free survival and overall corrected survival in patients with endometrioid adenocarcinomas and nodal involvement. Following adjuvant treatment after surgery, the recurrences were nearly evenly divided between pelvic, paraaortic nodal and distant sites. Only four of 33 (12%) patients treated with adjuvant pelvic radiation experienced a failure in the irradiated field. Furthermore, none of the patients experiencing a paraaortic nodal recurrence received adjuvant radiation to this site. CONCLUSIONS: The data suggest a benefit to the use of adjuvant radiation for local control of disease. Furthermore, the use of paclitaxel and carboplatinum chemotherapy also appears a promising adjunct in patients with endometrioid histologies and nodal spread. Papillary serous and clear cell cancers contributed disproportionately to the incidence of nodal metastasis and an adverse prognosis following further adjuvant therapy of patients with nodal disease. Despite taxol/carboplatinum chemotherapy, over half of the patients with non-endometrioid cancers recurred, as opposed to one of 19 endometrioid cancers so treated. The ideal form of adjuvant treatment for such patients remains problematic.

Hormonal treatment of endometrial cancer: past, present and future.

The concept that hormonal therapy may be useful in the treatment of endometrial cancer antedated the pharmaceutical availability of progestational compounds. By 1959, initial studies demonstrated the ability of progestins to reverse endometrial hyperplasias. Thereafter, progestins and other hormonal agents have been used in various roles as treatment for endometrial cancers. This chapter reviews the use of hormonal agents for the treatment of primary and metastatic/recurrent endometrial cancer, as well as such treatment in an adjuvant setting. Major problems in enhancing the efficacy of endocrine therapy of cancers arising from hormonally responsive tissues are also considered. The regulations of steroid-hormone receptor expression in endometrial and breast cancers continues to be an active area of research interest.

Hyperfractionated radiation therapy plus chemotherapy in locally advanced cervical cancer: results of two phase I dose-escalation Gynecologic Oncology Group trials.

OBJECTIVE: The aims of this study were to assess the early and late toxicities of multiple-daily-fraction whole pelvic radiation plus concurrent chemotherapy with either hydroxyurea or 5-fluorouracil (5-FU)/cisplatin and to determine the maximum tolerated external radiation dose in conjunction with brachytherapy, when given with either of these drug regimens, as treatment for locally advanced carcinoma of the cervix. METHODS: The first study (GOG 8801) of 38 patients utilized hydroxyurea as a single oral dose of 80 mg/kg to a maximum of 6 g at least 2 h prior to a radiation treatment twice every week. In the second study (GOG 8901) of 30 patients, cisplatin and 5-FU were used concomitantly with radiotherapy. Fifty milligrams per square meter of cisplatin was administered on days 1 and 17 of external radiation. 5-FU was given by continuous intravenous infusion at a dose of 1000 mg/m(2)/day for 4 consecutive days on days 2, 3, 4, 5, and 18, 19, 20, and 21 of external radiation therapy. Both studies utilized external radiation given by an accelerated hyperfractionated regimen of 1.2 Gy per fraction, two fractions per day. All patients were treated 5 days per week with a minimum of 4 h between fractions. RESULTS: Acute toxicity was manageable on both protocols but nausea, vomiting, and myelosuppression were more severe with hydroxyurea. Chronic toxicity was primarily enteric and appeared to be dose-related. There was no obvious correlation seen between pelvic failure rates and the radiation dose or between the chemotherapy regimens used. CONCLUSIONS: The defined maximal tolerated dose of whole pelvic radiation was 57.6 Gy in 48 fractions which could be delivered in a hyperfractionated setting with concomitant chemotherapy, followed by brachytherapy. Follow-up is now sufficient that further adverse events should be rare.

Risk of venous access device wound complications in patients undergoing paclitaxel chemotherapy for gynecologic malignancies.

OBJECTIVE: To determine if wound complications after placement of a central venous catheter access device are related to the type of postsurgical cytotoxic chemotherapy administered. METHODS: All patients in a 10-year period undergoing placement of central venous access device followed by postsurgical chemotherapy for gynecologic malignancies were included in this retrospective case-control study. RESULTS: Sixty-eight patients underwent 78 placement procedures followed by chemotherapy. Six catheters (7.7%) in five patients developed wound complications. Variables evaluated included the type of gynecologic malignancy, previous use of chemotherapy, patient age and weight, preoperative white blood cell count, type of access device and insertion site, use of prophylactic antibiotics, type of chemotherapy and interval to administration, development of wound complication, and catheter removal. Univariate analysis shows an association between subsequent catheter site wound complication and paclitaxel use (P = 0.02) as well as wound complication and combined paclitaxel and cisplatin use (P = 0.005). Multivariate analysis with stepwise linear regression confirms that a paclitaxel containing regimen is associated with an increase in wound breakdown (P = 0.04). CONCLUSION: The use of a paclitaxel containing chemotherapeutic regimen administered after placement of an indwelling central venous access device in gynecologic oncology patients is associated with wound complications of the catheter site.

Ovarian cancer complicating pregnancy.

Ovarian cancer is the second most frequent gynecologic cancer complicating pregnancy. Although uncommon, this is a topic that encompasses multiple aspects of obstetrics and gynecology. The management of the adxenal mass in pregnancy, surgery for ovarian cancer, chemotherapy during gestation, and the use of tumor markers during pregnancy are discussed.

A phase II trial of amonafide in patients with mixed mesodermal tumors of the uterus: a Gynecologic Oncology Group study.

Amonafide demonstrated a poor response rate and substantial toxicity in patients who had measurable, advanced mixed mesodermal tumors of the uterus. Amonafide-a drug that acts through intercalation of tumor DNA-was used to treat 16 patients who had measurable, advanced mixed mesodermal tumors of the uterus as part of a Gynecologic Oncology Group (GOG) Phase II study. The starting dose was 300 mg/m2 intravenously over 1 hour for 5 consecutive days every 3 weeks. Severe or life-threatening hematologic toxicity occurred in 50% of the patients. Two patients experienced vomiting requiring hospitalization. Other toxicities were not severe. One patient had a partial response and one had stable disease, each lasting 4 months. This dose schedule was associated with poor response rate and substantial toxicity.

Hexamethylmelamine as a single second-line agent in ovarian cancer: follow-up report and review of the literature.

From December 1982 to December 1986, 52 patients with recurrent ovarian cancer were treated with single-agent HMM. Chemotherapy was given for a period of 1 year unless progression of disease or toxicity was noted. Survival was determined from the time of diagnosis to the date of death or September 30, 1992. The regimen was well tolerated with only one case of severe gastrointestinal toxicity. Nine patients were found to be clinically free of disease following completion of HMM treatment; they had initially responded to cisplatin-based therapy (i.e., potentially cisplatin-sensitive) and subsequently recurred. Four were found to have gross disease at the time of reassessment laparotomy. Three of these 9 patients are alive 81-92 months since diagnosis, having maintained disease-free intervals of up to 6 years. The median survival for the 9 patients without evidence of disease at the end of therapy was 75 months versus 9 months for the nonresponders. No patient who had progressive disease on first-line cisplatin-based combination chemotherapy (i.e., primary cisplatin-resistant) responded to second-line single-agent oral hexamethylmelamine. With a follow-up close to 10 years, our data show that hexamethylmelamine, with reasonable toxicity, can provide an extended, disease-free interval to a selected group of patients.

The prognostic value of HER-2/neu oncogene in cervical cancer.

BACKGROUND: Expression of the HER-2/neu oncogene has been suggested to confer added virulence or aggressive behavior in gynecologic malignancies. The aim of this study is to determine the frequency of HER-2/neu expression in invasive cervical cancer and its impact on survival in women with cervical cancer. DESIGN: Archival tissue from 150 patients with cervical carcinoma was evaluated immunohistochemically for HER-2/neu oncoprotein expression. Survival information was retrieved retrospectively from patients' medical records. RESULTS: The HER-2/neu expression was observed in 34 out of 150 tumors (22%). The HER-2/neu positive tumors exhibited considerable heterogeneity in the distribution of immunoreactive tumor cells. Tumor grade and histology did not influence the pattern or intensity of HER-2/neu expression. There was no statistically significant difference in survival of patients with HER-2/neu positive and those with HER-2/neu negative tumors (P = 0.50). Tumor stage at diagnosis was the only covariate with prognostic significance in patient survival (P < 0.001). CONCLUSION: Expression of HER-2/neu oncogene is a rare event in cervical cancer. Immunohistochemical detection of HER-2/neu expression is neither a predictor of survival of patients with cervical cancer nor does it identify subgroups of patients at higher risk for recurrence of disease.

Gestational trophoblastic disease presenting as a large metastasis to the finger.

Cutaneous metastases of gestational trophoblastic disease are extremely uncommon. A patient with metastatic, poor prognosis disease and a large metastatic lesion on her left fifth digit is presented. The clinical course and complete response to EMACO chemotherapy are outlined. The presence of metastatic disease in a reproductive-age woman requires consideration of gestational trophoblastic disease in the differential diagnosis.

Stage I squamous cell cervical carcinoma in pregnancy: planned delay in therapy awaiting fetal maturity.

PURPOSE: It is not known whether intentional delay to allow fetal maturity in patients with Stage I cervical carcinoma diagnosed during pregnancy will affect the survival of these patients. The purpose of this study is to report our experience with invasive squamous cervical carcinoma after planned delay in therapy for fetal indications, to assess maternal morbidity due to treatment delay, and to report maternal and fetal survival. METHODS: Between 1989 and 1994, eight pregnant women with Stage I squamous cervical carcinoma, who declined immediate therapy in order to improve fetal outcome, were prospectively followed until the late third trimester. Serial MRIs were used to follow the lesion in two patients. RESULTS: Stage IB cervical cancer was diagnosed in seven pregnant women. All lesions were less than 2.5 cm. The mean diagnosis-to-treatment interval was 109 days (range, 21-201; median, 112). One woman conceived in the cycle after diagnosis and had a diagnosis-to-treatment interval of 282 days. All were delivered by cesarean section-radical hysterectomy late in the third trimester. There was no clinical progression of disease detected during any of the pregnancies. Serial MRI examination confirmed stable disease in one patient and suggested an increase in tumor volume in one patient that was not pathologically confirmed. All are alive and disease free after a mean follow-up of 37 months (range, 13-68; median, 33). Neonatal morbidity was encountered in one infant (spontaneous pneumothorax). CONCLUSIONS: With a median follow-up of 33 months, patient-requested delays in therapy between 3 and 40 weeks (mean, 19) did not affect progression.

Surgical predictors of para-aortic metastases in early-stage cervical carcinoma.

Radical pelvic surgery for cervical carcinoma is contraindicated in the presence of para-aortic node metastases. However, the incidence of para-aortic nodal involvement is very low in early-stage disease. Therefore, it may not be necessary to subject all patients to para-aortic lymphadenectomy prior to radical hysterectomy. Medical records for 408 patients with early-stage cervical carcinoma treated at the Pennsylvania State University-M.S. Hershey Medical Center were reviewed to ascertain if clinical factors can be utilized intraoperatively to accurately predict those patients at minimal risk for para-aortic lymph node metastases. The presence of clinically suspicious (abnormally enlarged or firm) pelvic or para-aortic lymph nodes or extracervical spread of tumor at the time of exploration were significant predictors of para-aortic metastases (P < 0.001). The majority of patients (85%) had none of these risk factors, and no patient had para-aortic metastases in the absence of these predictors. Suspicious pelvic or para-aortic lymph nodes were present in the minority of patients (15%) and identified all patients with para-aortic metastases. Therefore, para-aortic lymphadenectomy may be safely omitted at the time of exploration for radical hysterectomy in the absence of enlarged or abnormally firm pelvic or para-aortic lymph nodes. In the presence of either of these factors or extracervical spread of disease a para-aortic lymphadenectomy is necessary to rule out metastases.

Staging and recurrence of disease in squamous cell carcinoma of the vulva.

In order to determine the prognostic significance of applying the revised FIGO staging system and identify factors contributing to survival after documentation of recurrent disease, a retrospective chart review of our vulvar cancer population was performed. Over a 17-year interval 135 patients were uniformly treated with primary surgical treatment consisting of radical vulvectomy and bilateral groin dissection. Factors contributing to disease-free survival were analyzed using a Cox proportional hazards model. Covariates of survival after recurrence of disease were analyzed using the log-rank method. Neither the clinical assessment of the groin nodes, nor the presence or absence of perineal involvement were related to outcome. Only lesion size and surgical status of the inguinal nodes were significant predictors of disease-free survival (P = 0.02 and P = 0.03, respectively). In addition, there was a statistically significant relationship between the extent of groin involvement (negative, unilateral positive, and bilateral positive nodes) and associated decrement in disease-free survival (P = 0.01). Thirty patients developed recurrence of disease from 2.0 to 47.3 months following surgery. The location of the recurrence, interval from primary therapy to recurrence, and status of the groin nodes at initial surgery were significant prognostic factors in subsequent survival. The revised staging system demonstrated an improvement in patient stratification compared to the criteria of the prior classification. The data are also consistent with the distinction made between Stage III and IV disease in the new classification. The status of the groin nodes at original surgery remained an important prognostic factor even in those patients who later demonstrated recurrence of disease.

Endometrial squamous cell carcinoma following whole pelvic radiation therapy: response to carboplatin.

A case of Stage IV endometrial squamous cell carcinoma occurring 8 years after a low anterior resection and whole pelvic radiation therapy for a Dukes D colon carcinoma is presented. Koilocytosis was present in the tumor. There was no evidence of human papillomavirus antigen or DNA in the tumor. The patient was treated with surgery followed by six cycles of carboplatin chemotherapy. At the completion of chemotherapy there was no clinical or radiological evidence of disease. The tumor recurred 9 months postchemotherapy and the patient died of disease 17 months postdiagnosis.

Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities.

PURPOSE: Diethyldithiocarbamate (DDTC) blocks cisplatin-induced toxicities in animal models without inhibiting antitumor effects. DDTC chemoprotection was tested in a randomized, multicenter, double-blind comparison versus placebo (PB) in patients with lung or ovarian cancer. Primary end points were nephrotoxicity, ototoxicity, neuropathy, and completion of therapy. PATIENTS AND METHODS: Between April 1990 and February 1992, 221 patients were registered with small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), or ovarian cancer. Cisplatin (100 mg/m2) and cyclophosphamide (in ovarian cancer) or etoposide (in lung cancer) were administered with either DDTC (1.6 g/m2 over 4 hours) or PB intravenously, every 4 weeks for a planned six cycles. RESULTS: At an interim safety analysis, data were available for 195 patients from the combined lung and ovarian cancer populations (PB, 99 patients; DDTC, 96 patients). Withdrawal for chemotherapy-induced toxicities occurred in 9% of PB-treated patients and 23% of DDTC-treated patients (P = .008). The mean cisplatin delivered dose-intensity (DDI) was 23 mg/m2/wk on both arms. However, the mean cisplatin cumulative dose delivered (CDD) was 379 mg/m2 on the PB arm, compared with 247 mg/m2 on the DDTC arm (P = .0001). At the time of interim analysis, 28% of PB-treated patients had completed all six cycles of therapy, compared with only 6% of DDTC-treated patients (P < .001). Although, clinical hearing loss, neuropathy, emesis, and myelosuppression were equivalent in the two treatment arms, DDTC-treated patients had more nephrotoxicity as determined by changes in serum creatinine concentration. Toxicities related to DDTC infusion included transient hypertension, flushing, and hyperglycemia. DDTC did not compromise response rates in either tumor type. CONCLUSION: This study did not demonstrate a significant chemoprotective effect against cisplatin-induced toxicities with the DDTC dose schedule tested. Patients who received DDTC received lower cumulative doses of cisplatin, but were more likely to be withdrawn from treatment early due to chemotherapy-related toxicities.

Tissue distribution of TAG-72 in malignant mixed müllerian tumors of the uterus.

Malignant mixed müllerian tumors are the most frequent sarcomas arising from the uterus. Since these tumors are traditionally associated with a poor prognosis, tumor-associated antigens may be useful in the evaluation and follow-up of affected patients. The purpose of this study was to determine the frequency and tissue distribution of TAG-72, an antigen frequently expressed in endometrial carcinomas, and to compare it to CA 125 and CA 19-9 expression in malignant mixed müllerian tumors of the uterus. Consecutive, paraffin-embedded sections from 35 tumors were immunohistochemically evaluated using primary antibodies directed against the tumor-associated antigens. These antigens were demonstrated in the neoplastic glandular epithelium and not in the sarcomatous portion of the tumor. The degree of antigen expression was unrelated to the nature of the sarcomatous element present (homologous vs heterologous). Positive staining (> or = 5% of the glandular epithelium) for TAG-72 was present in 66% of the tumors; another 6% of the tumors contained focal staining (< 5% of the glandular epithelium) for TAG-72. Although cytoplasmic and intraluminal staining were present, cell surface staining was the most prominent feature of TAG-72 expression. Tumors were more likely to be positive for TAG-72 than either CA 125 (P = 0.046) or CA 19.9 (P = 0.004). The extent of TAG-72 expression was unrelated to the extent of disease (intrauterine vs extrauterine) and overall patient survival. However, antigen expression was correlated with the differentiation of the glandular component present.(ABSTRACT TRUNCATED AT 250 WORDS)

CA 125 and CA 19-9 immunolocalization in normal, hyperplastic, and carcinomatous endometrium.

BACKGROUND: Elevated levels of tumor-associated antigens, such as CA 125, have been reported in patients with endometrial carcinomas. This study was done to evaluate the frequency and tissue distribution of CA 125 and CA 19-9 in normal and neoplastic endometrium. METHODS: Consecutive tissue sections were immunohistochemically evaluated using primary antibodies directed against CA 125 and CA 19-9. Antibody-antigen binding was demonstrated using the avidin-biotin technique. RESULTS: CA 125 expression was related to the phase of the menstrual cycle and was most prominent during secretory phase. Positive staining (5% or more of the glandular epithelium) for CA 19-9 was noted in only 4 of 20 patients with normal endometrium. Positive staining for CA 125 (5% or more of the epithelium) was present in 68% of the carcinomas; another 8% of the tumors contained focal staining for CA 125. Positive staining for CA 19-9 was demonstrated in 60% of tumors; another 8% of the tumors showed focal staining for CA 19-9. The markers were concordant in 76% of the tumors evaluated. CONCLUSIONS: Although CA 125 was uniformly expressed by the glandular cells in normal endometrium, CA 19-9 expression appeared to be related to the prevalence of the Lewis A phenotype. Endometrial carcinomas also frequently express these antigens, and the degree of expression was related to the grade and cell type of the tumor.

Tissue CA 125 and CA 19-9 in malignant, mixed mesodermal tumors of the uterus.

Mixed mesodermal tumors of the uterus are biphasic neoplasms composed of both a malignant epithelium and a sarcomatous stromal component. Elevated levels of tumor-associated antigens, such as CA 125, have been reported in some patients with these tumors. The purpose of this study was to determine the frequency and tissue distribution of CA 125 and CA 19-9 in malignant mixed mesodermal tumors of the uterus treated with primary surgery. Consecutive, paraffin-embedded sections from 35 tumors were immunohistochemically evaluated using primary antibodies directed against CA 125 and CA 19-9. CA 125 and CA 19-9 were demonstrated in the neoplastic glandular epithelium and not in the sarcomatous portion of the tumor. The localization of CA 125 and CA 19-9 suggested that both antigens were epithelial secretory products. Positive staining (> or = 5% of the glandular epithelium) for CA 125 was present in 46% of the tumors; another 14% of the tumors contained focal staining (< 5% of the glandular epithelium) for CA 125. Positive staining for CA 19-9 was demonstrated in 34% of tumors; another 17% contained focal staining for CA 19-9. The markers were concordant in 77% of the tumors examined. Antigen expression was unrelated to the nature of the sarcomatous element (homologous vs heterologous), the extent of disease, and patient survival. However, the epithelial component of these sarcomas frequently expressed these antigens and the degree of expression was related to the cell type and the histologic grade of the glandular element.

Correction of massive vaginal prolapse in an older population: a four-year experience at a rural tertiary care center.

OBJECTIVE: To ascertain the success of complex reconstructive vaginal surgery in older women. DESIGN: Retrospective review of hospital and outpatient records. SETTING: Rural tertiary care referral center, Pennsylvania State University Hospital, Hershey, Pennsylvania. PATIENTS: Twenty-four patients referred for massive erosion of the vagina and/or complete procidentia. MEASUREMENTS: Symptoms and anatomic correction of patients' complaints. RESULTS: After surgery, 83 percent were asymptomatic without pelvic relaxation, 4 percent were asymptomatic with pelvic relaxation, 4 percent were symptomatic without pelvic relaxation, and 9 percent were symptomatic with relaxation. CONCLUSIONS: Older women can undergo major vaginal reconstructive surgery with relief of symptoms and restoration of vaginal depth and axis.

Detection and patterns of treatment failure in 300 consecutive cases of "early" endometrial cancer after primary surgery.

From November 1977 to July 1987, 300 consecutive patients with endometrial carcinoma clinically confined to the uterine corpus underwent primary surgery consisting of at least abdominal hysterectomy and adnexectomy. Patients with aggressive disease characteristics received postoperative radiotherapy. Forty-seven patients (16%) demonstrated recurrent disease from 2 to 125 (median of 12.8) months after surgery. Forty-seven percent of the recurrences were detected within the first year following surgery and 70% by 2 years after hysterectomy. Of the 47 recurrences, 29 were at distant sites, 16 were within the pelvis, and 2 consisted of both local and distant recurrences. Patients treated with pelvic radiotherapy after hysterectomy were more likely to experience distant, rather than local recurrences. Only 7 of the 148 patients (5%) treated with postoperative radiotherapy recurred in the pelvis. Approximately half of the recurrences were detected in asymptomatic individuals; physical examination and chest X-ray were the most useful means to detect disease in patients without symptoms. The combination of history, physical examination, pap smear, and chest X ray detected all of the recurrences. Actuarial survivals at 12, 24, and 36 months after recurrence were 42, 24, and 17%, respectively. The site of recurrence, time interval of surgery to recurrence, and use of postoperative pelvic radiotherapy were statistically related to patient prognosis. The identification of patients at risk of recurrence and more effective adjuvant therapy need to be developed in order to decrease the frequency of recurrence. In order to substantially improve the survival of patients with recurrent disease, more sensitive methods of detection, as well as more effective salvage therapy, will be required.