Topotecan has substantial antitumor activity as first-line salvage therapy in platinum-sensitive epithelial ovarian carcinoma: A Gynecologic Oncology Group Study.

PURPOSE: Topotecan is known to be active in recurrent ovarian cancer, but most prior studies have focused on platinum-resistant or refractory populations. This study was undertaken to define the response rate and progression-free interval in platinum-sensitive patients. PATIENTS AND METHODS: Patients with recurrent ovarian cancer after one or two prior chemotherapy regimens and in whom the interval between prior platinum therapy and the initiation of protocol therapy was greater than 6 months were treated with topotecan 1.5 mg/m(2) intravenously over 30 minutes daily for 5 days, with this cycle repeated every 21 days. RESULTS: Forty-eight patients were entered onto the study; 47 were assessable for toxicity and 46 for response. The response rate was 33% (two complete responses and 13 partial responses), with a median response duration of 11.2 months. Hematologic toxicity predominated but was manageable in most patients with frequent incorporation of cytokines and RBC and platelet transfusions. Fatigue was reported in 15 patients and resulted in the discontinuation of therapy in five responding patients. CONCLUSION: Topotecan is an active drug in platinum-sensitive ovarian cancer, with significant but manageable hematologic toxicity. Fatigue is also a common problem that may be dose-limiting in some patients.

New options for the treatment of advanced ovarian cancer.

Over the last decade, platinum-based combination chemotherapy regimens have led to higher response rates and longer survival for advanced ovarian cancer patients than previous regimens based on alkylating agents. The advent of paclitaxel for salvage therapy and, more recently, as a component of first-line treatment in advanced disease has further improved response rates and prolonged survival. Nonetheless, even with current treatments, relapse rates remain high and most women with advanced ovarian cancer ultimately will die of their disease. For this reason, the development of new, effective second-line treatments, as well as better first-line agents, for advanced disease remains a high priority. To maximize the efficacy of second- or third-line drugs, new agents should be non-cross-resistant with platinum or paclitaxel. Chemotherapy drugs for advanced ovarian cancer with novel mechanisms of action include topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA), a topoisomerase I inhibitor. Topotecan was recently shown to be effective in platinum-refractory or -resistant patients, with response rates ranging from 14% to 23%. Results from a phase III clinical study indicate that topotecan compares favorably with paclitaxel as a second-line treatment for stage III and IV patients who have failed platinum-based regimens. Moreover, a phase II study demonstrated clinical responses with topotecan in patients who had failed both paclitaxel- and platinum-based therapies. Other agents for advanced ovarian cancer are also under investigation, including docetaxel, oral etoposide, liposome encapsulated doxorubicin, gemcitabine, ifosfamide, and hexymethylmelamine.

Autologous, hapten-modified vaccine as a treatment for human cancers.

We have devised a novel approach to active immunotherapy based on modification of autologous cancer cells with the hapten, dinitrophenyl (DNP). The treatment program consists of multiple intradermal injections of DNP-modified autologous tumor cells mixed with BCG. Administration of DNP-vaccine to patients with metastatic melanoma induces a unique reaction- the development of inflammation in metastatic masses. Histologically, this consists of infiltration of T lymphocytes, most of which are CD8+. These T cells usually produce interferon-gamma in situ. Moreover, they represent expansion of T-cell clones with novel T-cell receptor (TCR) structures. Occasionally, administration of DNP-vaccine results in regression of measurable metastases. The most common site of regression has been small lung metastases. Administration of DNP-vaccine to patients in the postsurgical adjuvant setting produces a more striking clinical effect. Of 62 patients with clinically evident stage III melanoma who had undergone lymphadenectomy, the 5-year relapse-free survival rate was 45% and the overall survival rate was 58%. These results appear to be better than those obtained with high-dose interferon, although a randomized phase III trial is required to prove that point. A recent phase I study suggests that this therapeutic approach is also applicable to stage III ovarian cancer. There appear to be no insurmountable impediments to applying this approach to much larger numbers of patients or to developing it as a standard cancer treatment.

Overexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline ovarian tumors.

Ovarian epithelial tumors are classically divided into benign, malignant, and borderline or of low malignant potential. It is controversial whether this last group of tumors should be considered benign or malignant. Expression of cell cycle markers has recently been linked to tumor behavior and response to treatment. It has been shown that one of the pathways through which the p53 gene controls the cell cycle is by transactivating p21WAF1/CIP1, a cyclin-dependent kinase (cdk) inhibitor. By inhibiting cdks, p21WAF1/CIP1 blocks the G-1 to S-phase transition in the cell cycle. p53 can be regulated by MDM2 (murine double minute-2) through direct inactivation or promotion of its cytoplasmic degradation. In an attempt to investigate the cell cycle checkpoint mechanisms of these tumors, we studied the expression of p53, Ki-67, MDM2, and p21WAF1/CIP1 by immunohistochemistry. We analyzed the expression of these proteins in 19 cystadenomas (8 serous and 11 mucinous), 40 borderline tumors (31 serous and 9 mucinous), and 18 serous carcinomas of the ovary. p21WAF1/CIP1 was expressed in 7 of 19 (37%) benign cystadenomas, 32 of 40 (80%) borderline tumors (93.5% of serous and 33% of mucinous), and in 9 of 18 (50%) serous carcinomas. Ki-67 was only weakly expressed in 8 of 19 (42%) benign cystadenomas, all borderline tumors showed Ki-67 staining in less than 50% of the cells, and 55% of serous carcinomas stained in more than 50% of tumor cells. p53 was absent in all but 1 of the cystadenomas, was expressed in 9 of 40 (22.5%) borderline tumors (25.8% of serous and 11% of mucinous), and in 10 of 18 (55%) carcinomas. All 11 implants of serous borderline tumors expressed p21WAF1/CIP1. Most serous borderline tumors expressed higher levels of MDM2 compared with the benign cystadenomas and carcinomas. Four of the serous borderline implants (40%) expressed MDM2. Coexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline tumors of the ovary and their implants, which suggests that these cell cycle control proteins are important in these tumors and may be related to tumor progression. Low expression of p53 protein in serous borderline tumors might be in part mediated by MDM2. This suggests that the p53 pathway is intact in most of these tumors, in contrast with carcinomas, in which high expression of p53 has been related to mutations of this gene.

Epiurethral suprapubic vaginal suspension: a report on 52 cases.

Fifty-two epiurethral suprapubic vaginal suspension procedures for the treatment of stress urinary incontinence were reviewed. The long-term results (80.5% success rate) were comparable to those of other urethropexy procedures. Complications included deep vein thrombophlebitis (3.8%), excessive bleeding (5.8%), prolonged (more than seven days) postoperative catheterization (32.7%), or tape rejection (3.8%). The performance of a simultaneous or previous hysterectomy had no effect on the outcome of the procedure (P greater than .10). These results differ from those in the other published report on this procedure.

National trends in the surgical staging of corpus cancer: a pattern-of-practice survey.

OBJECTIVE: To survey general gynecologists regarding the nature of surgical staging of corpus cancer as practiced in the United States. METHODS: A survey tool was designed to ascertain issues related to surgical staging of corpus cancer among gynecologists in the United States. The survey elicited data pertaining to the demographics and practice characteristics of the respondents. The questionnaire was sent to 700 practicing gynecologists selected randomly from the ACOG membership list. RESULTS: Responses were obtained from 227 physicians; however, only 193 could be analyzed. Most of the respondents classified themselves as general gynecologists (93%) and nonacademicians (90%). In a typical year, 60% evaluated fewer than five patients with corpus cancer. A minority of respondents carry out surgical staging of their patients, which includes total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO), removal of pelvic and para-aortic lymph nodes, and cytologic evaluation of peritoneal fluid. No uniformity was observed regarding the numeric definition of an appropriate "sampling" (median 5, range 1-25) or "dissection" (median 10, range 1-40) of lymph nodes. Most respondents would not return a corpus cancer patient to the operating room to carry out lymph node dissection if a referring colleague had performed TAHBSO but had not removed the nodes. In such a scenario, private practitioners were approximately three times less likely to reoperate on lymph nodes than academic physicians. CONCLUSION: Complete surgical staging is not performed by most physicians caring for women with corpus cancer. The relatively high proportion of nonresponders and nonevaluable responses suggests that these results should be corroborated by other investigators.

A comparative analysis of Ki-67, p53, and p21WAF1CIP1 expression in tamoxifen associated endometrial carcinomas.

OBJECTIVE: To determine clinicopathologic parameters, expression of proliferation markers, and immunohistochemical oncogene expression in endometrial cancers in patients with a history of breast cancer with and without tamoxifen use. METHODS: Thirty endometrial carcinoma specimens were examined from patients with a previous history of breast cancer. Patients who had taken tamoxifen (15) were compared to non-users (15). Immunohistochemical staining was performed for p53, Ki-67, and p21WAF1/CIP1, overexpression was defined as greater than 10% positivity. RESULTS: Patient populations were statistically similar. P53 was overexpressed in 73% of tamoxifen users compared to 53% of non-users. Ki-67 was overexpressed in over 90% of user and non-user specimens. p21WAF1/CIP1 was overexpressed in 33% of users and 47% of non-users. Tamoxifen users had shorter time to diagnosis of endometrial cancer than non-users. CONCLUSIONS: In this small study, tamoxifen associated tumors expressed p53 more frequently than non-users, while the opposite was observed with p21WAF1/CIP1. This suggests that p53 mutations might play a role in development of tamoxifen associated tumors.

Malignant melanoma of the vulva: a review.

Vulvar melanoma is an unusual tumor with a poor prognosis. Most surgeons have abandoned radical vulvectomy as the treatment of choice. The role of elective node dissection is controversial. Currently effective adjuvant therapy is lacking. In this paper 51 sources concerning melanoma and/or melanoma of the vulva were reviewed, 43 of these sources were considered to be pertinent and current enough to include in this review. The objective was to describe current knowledge about the natural history, staging, pathology, and treatment of melanoma of the vulva. It has been found that melanoma continues to be difficult to treat when in advanced stages. Microstaging systems offer clinicians the best prognostic information. In many patients, less radical surgical treatment offers equal cure rates with decreased morbidity.

Margin status and excision of cervical intraepithelial neoplasia: a review.

UNLABELLED: Excisional biopsy of the cervix for diagnosis and treatment of cervical neoplasia is common. Management of patients with involved margins of resection is unresolved. Data concerning use of thermal techniques show that this technique yields equivalent results in most cases. Important exceptions are microinvasive squamous disease and adenocarcinoma. Conservative management of involved squamous margins is possible. Techniques for follow-up include cytology, colposcopy, and endocervical curettage. Adenocarcinoma in situ (AIS) should be treated with cold-knife conization. The standard of care for AIS is hysterectomy except in certain specific indications. Data concerning technique, follow-up, use of endocervical curettage, and the need for reexcision will be presented. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader will be able to compare the efficacy of the various excisional procedures in the treatment of cervical dysplasia, list the indications for additional surgery after positive margins on cervical excisions, and describe the proper management of a patient with adenocarcinoma in situ.

Uterine papillary serous carcinoma: a review.

Uterine papillary serous carcinoma, a histologic subtype of endometrial cancer, is characterized by a propensity for deep myometrial invasion, upper abdominal spread, and poor prognosis. We reviewed its histologic and clinical characteristics and compared them to those of endometrial adenocarcinoma with papillary features.

Endometrial hyperplasia and the risk of carcinoma.

Recent reports suggest that atypical endometrial hyperplasia diagnosed by biopsy or curettage is accompanied by a higher than expected risk of coexistent invasive cancer. In order to test this hypothesis we reviewed the pathology and clinical history of all patients at our institution who underwent hysterectomy for endometrial hyperplasia with or without cytologic atypia. We found 24 patients of 45 with a preoperative diagnosis of hyperplasia with cytologic atypia, and 21 with simple or complex hyperplasia without atypia. No cancers were found at surgery in the latter group nor were any significant historical differences found between the two groups. Of the patients with atypia, 12/24 (50%) had an endometrial carcinoma and nine patients (37.5%) were stage IB or greater. This is a significantly greater risk than previously reported in the literature. Endometrial hyperplasia with cytologic atypia may carry a higher risk of coexistent invasive endometrial carcinoma than previously believed. Methods to identify those patients at highest risk should be determined.

Phase I/II study of concomitant irradiation and carboplatin for locally advanced carcinoma of the uterine cervix: an interim report.

The outcome of women treated with either definitive irradiation alone or in combination with cisplatin-based chemotherapy for locally advanced (>IIb) squamous cell carcinoma of the cervix has been disappointing. To improve upon our reported results with irradiation alone, a trial using irradiation plus carboplatin chemotherapy was designed for these patients. Twenty-seven women with unresectable squamous cell carcinoma of the uterine cervix were referred to our institution between July 1991 and September 1994. Seven of these patients were enrolled in a phase I/II protocol combining concurrent irradiation and carboplatin chemotherapy. Megavoltage irradiation was used to deliver 45-50.4 Gy to the pelvis (and paraaortic chain when nodes were involved) through a multiple-field technique followed by the application of Fletcher-Suit-Delclos tandem and ovoids to boost the point A dose to 85 Gy. Chemotherapy consisted of intravenous carboplatin (60 mg/m2) administered in conjunction with irradiation to a total dose of 300 mg/m2. The enrolled patients consisted of six women with stage IIIb disease and one with stage IIa with concomitant paraaortic adenopathy. All seven patients enrolled in the study completed the planned course of treatment and tolerated the treatment without severe acute morbidities. No dose modifications were required for the radiation therapy regimen. For one patient, a dose of carboplatin was withheld to allow recovery from thrombocytopenia. The overall response rate was 100% (four complete response, three partial response). The combination of concurrent irradiation (pelvic or pelvic + paraaortic fields) and carboplatin chemotherapy can be safely administered to patients with locally advanced squamous cell carcinoma of the cervix. The treatment is well tolerated and is associated with a high rate of response. Longer follow-up will be necessary to assess the durability of response. In the meantime, we have elected to escalate the dose of carboplatin (90 mg/m2) in the hope of increasing the rate of complete response without incurring unacceptable toxicity.

Concomitant irradiation and dose-escalating carboplatin for locally advanced carcinoma of the uterine cervix: an updated report.

The combination of radiotherapy and carboplatin is associated with high response rates among women who have cervical cancer. To improve control rates for patients who have locally advanced carcinoma of the uterine cervix, oncologists have explored combinations of radiotherapy and chemotherapy. Carboplatin is an analogue of cisplatin, with similar efficacy against cervix cancer and a toxicity profile that is theoretically appealing for this group of patients because it is not nephrotoxic. Fifteen women with International Federation of Gynecology and Obstetrics (FIGO) stages IB2 through IIIB or recurrent carcinoma of the cervix were treated with megavoltage irradiation and weekly intravenous carboplatin (7 women, 60 mg/m2; 8 women, 90 mg/m2). Response was documented among all patients treated at 60 mg/m2 (three complete responses, four partial responses) and in 6 women treated with 90 mg/m2 (four complete responses, two partial responses). The two nonresponders in the series presented with recurrent glassy cell carcinoma of the cervix. All patients completed the planned course of therapy without the need for treatment interruption. At 60 mg/m2, one dose of carboplatin was withheld because of grade 2 thrombocytopenia. At 90 mg/m2, one case of grade 2 leukopenia was documented. The leukocyte counts remained within normal limits for all 3 patients who were irradiated through extended portals that encompassed the paraaortic nodes (2 women, 60 mg/m2; 1 woman, 90 mg/m2). To date, 2 of 7 patients treated at the lower dose level have died of disease (one local progression and distant failure at 11 months, one distant failure alone at 6 months). The remaining patients treated at 60 mg/m2 are alive at a median of 24 months (range, 21-37 months). Among those treated at the higher dose level, 1 patient is alive with local and distant failure at 14 months, and 1 woman succumbed to local and distant disease at 4 months. The remainder are alive at a median follow-up of 6 months (range, 2-10 months). The regimen was unsuccessful in salvaging women with recurrent glassy cell carcinoma. We conclude that the combination of radiotherapy and carboplatin can be safely delivered at both of the chemotherapy schedules studied. The regimen should not be offered to women who have recurrent glassy cell tumors. To prove the efficacy of this approach, phase III testing should be considered that compares the combination of agents to irradiation alone.

Stereotactic Irradiation: potential new treatment method for brain metastases resulting from ovarian cancer.

Stereotactic irradiation (radiosurgery) is a method of precisely focusing well-defined beams of radiation at small intracranial targets. The technique has been applied to the treatment of brain lesions that are benign (e.g., arteriovenous malformations, meningiomas, pituitary adenomas) and malignant (e.g., gliomas, metastases). This paper introduces preliminary data suggesting the possible value of radiosurgery in the management of ovarian cancer metastatic to the brain. Among 32 women with ovarian cancer metastatic to the brain treated with whole brain irradiation, nine (29%) experienced a complete radiographic response, compared with two of the five patients (40%) treated with radiosurgery. The 2-year survival rate was 60% among those treated with radiosurgery and 15% among those who received whole brain irradiation without radiosurgical boost. Stereotactic irradiation may be of clinical benefit to select patients with brain metastases resulting from ovarian cancer. A prospective randomized trial has been implemented by the Radiation Therapy Oncology Group (RTOG 95-08) to determine whether such observations are reproducible on a national scale.

Endocervical brush versus cotton swab for obtaining cervical smears at a clinic. A cost comparison.

Use of the nylon endocervical brush has been shown to increase the proportion of Papanicolaou smears with endocervical cells in a variety of populations. Each endocervical brush is approximately 100 times more expensive than the cotton swab that has been used routinely for cervical cytology collection. We sought to determine prospectively whether the endocervical brush would be cost effective by reducing the need for repeat sampling due to Papanicolaou smears' lacking endocervical cells. Cervical cytology specimens showed no endocervical cells in 114 (20%) of 561 women sampled with a cotton swab and Ayre spatula. In contrast, 37 (7%) of 511 women sampled with the endocervical brush and Ayre spatula had no endocervical cells in their specimens. A cost analysis showed that at our clinic, where approximately 3,300 Papanicolaou smears are performed annually, annual savings of > $22,000 would be realized by use of endocervical brushes.

Repair of vaginal vault prolapse with abdominal sacropexy.

Ten women were treated for complete eversion of the vaginal vault with an abdominal sacropexy technique utilizing rectus fascia as graft material. The vault was suspended from the anterior sacral ligament by a strip of rectus fascia. Nine of ten patients had complete cure of the prolapse. All patients who remained sexually active have reported normal coital function. Abdominal sacropexy using rectus fascia is a safe, effective method for the long-term cure of vaginal vault prolapse.

Treatment of cervical carcinoma with ionizing irradiation using moving fields.

This study was designed to assess the effectiveness and risk of complications from radiotherapy delivered by the moving field technique as opposed to the more commonly used fixed field technique. Between 1975 and 1985, 131 patients were treated for cervical cancer with a combination of teletherapy and brachytherapy. For teletherapy, 4-MeV photons were used and delivered by moving field technique (120 degrees to 160 degrees arcs, or a 360 degrees rotation). Most patients received one intracavitary radium implant using Fletcher-Suit applicators and the Manchester technique. Twenty-two percent of the patients had stage I disease, 37% stage II, 25% stage III, 13% stage IV, and 2% were unstaged. The cumulative 5-year survival for all patients was 57%. The survival by stage was: stage I, 82%, stage II, 62%, stage III, 53%, and stage IV, 6%. Chronic complications developed in 10 (7.6%) patients. The survival and complication rate of patients treated for cervical cancer with radiation using moving fields compares favorably with that of patients treated with the conventional parallel opposed (AP-PA) fields or the four-field box technique. Further studies are necessary to definitively determine if the moving field technique offers advantages over other techniques.

Evaluation of the atypical cytologic smear. Validity of the 1991 Bethesda System.

The 1991 Bethesda System states that atypical squamous or glandular cells of undetermined significance should be further classified as reactive or premalignant/malignant. The validity of this qualification for identification of patients with cervical intraepithelial neoplasia (CIN) was tested. One hundred twenty-four cytologic smears with squamous atypia were reviewed retrospectively by two cytopathologists blind to the colposcopy results. The smears were classified as favoring either reactive or premalignant/malignant processes. Subjective criteria used in the classification were based on the pathologists' experience. All patients underwent colposcopy and selected biopsy under the direction of a gynecologic oncologist. Of the 124 atypical smears, 69 were classified as favoring reactive processes and 55 as favoring premalignant/malignant processes by cytopathologist 1. Cytopathologist 2 classified 68 as reactive and 56 as premalignant/malignant. Colposcopy and selected biopsy revealed the following lesions: 34 cases of human papillomavirus (27.4%), 17 of CIN 1 (13.7%), 4 of CIN 2 (3.2%), 2 of CIN 3 (1.6%) and 67 without pathology (54.0%). All six patients with squamous atypia and underlying CIN 2 and 3 lesions had their cytology classified as premalignant/malignant by the cytopathologists. In these patients this qualification had high sensitivity (100%) and negative predictive value (100%). The 1991 Bethesda System classification above, when applied to patients with squamous atypia, was effective in identifying patients with serious pathologic cervical lesions. If used as a triage method, colposcopy should be reserved for atypical lesions classified as premalignant/malignant, potentially decreasing the cost of health care without decreasing the quality of that care.

Colposcopy, cervicography, speculoscopy and endoscopy. International Academy of Cytology Task Force summary. Diagnostic Cytology Towards the 21st Century: An International Expert Conference and Tutorial.

ISSUES: The colposcope was developed in 1925 and is well established in clinical gynecologic practice for defining and delineating cytologically detected lesions mainly of the cervix but also the vagina and vulva. Additionally, various endoscopic procedures in gastroenterology, pulmonary and urologic lesions enhance the cytologic detection and histologic verification of precancerous and cancerous lesions. The cost-effectiveness of all these devices and their applicability, particularly in countries with a limited health budget, is a major issue. This task force considered aspects of the present state of the art and the challenges in the 21st century. CONSENSUS POSITION: Automated cytology can interface with colposcopic examination in a number of significant ways. Automated cytologic analysis of conventional cervical smears can potentially direct colposcopic examination by predicting the nature of a lesion, assist in determining which patients should receive colposcopy and, in some settings, thereby reduce the number of colposcopies. Potentially, various combinations of automated cytology and colposcopy may be used to generate screening protocols that might result in more effective and inexpensive screening. The role of cervicography, or high-resolution cervical photography, as a screening device remains to be defined. Sensitivity for high grade lesions is generally no greater than that in cytology, and specificity appears lower. The interpretation of cervical photographs in triage of mildly abnormal cytology may prove to be useful in countries with established cytology programs. In areas of the world where cytology screening programs are not in place, the interpretation of cervical photographs may have its most dramatic effect. Cost-effectiveness analyses are needed. There are, at present, insufficient data for the evaluation of speculoscopy, a procedure using chemiluminescent illumination of the cervix for visualization of acetowhite areas. Basic training in colposcopy should be integrated into the residency programs of obstetrics and gynecology. Criteria for the adequate training of colposcopists should be developed. Continuing education programs in colposcopy should be developed when they are not already in existence. The cost-effectiveness of integrating colposcopy as a primary screening technique should be evaluated. Following a high-grade squamous intraepithelial lesion (HSIL) cytology result, colposcopically directed punch biopsy should be taken with or without endocervical curettage. This generally should precede the loop electrosurgical excision procedure (LEEP); however, in certain circumstances direct LEEP may be indicated. LEEP under colposcopic vision is an efficient way to treat an HSIL lesion of the cervix because the histologic extent and margins can be determined, unlike with laser surgery or cryosurgery. It is also more cost-effective than cold knife conization because general anesthesia and an operating room are unnecessary. Following LEEP, the endocervical canal should be examined colposcopically for any evidence of involvement. Lesions in the endocervix can then be removed with a different-shaped loop. Further research into Raman spectroscopy as a diagnostic aid in cervical pathology is needed, as is the use of micrococolpohysteroscopy for in vivo cytologic analyses, especially of the endocervical canal and transformation zone. Hysteroscopy is the most direct method for the diagnosis and treatment of intrauterine diseases. Hysteroscopic endometrial biopsy is more accurate than conventional biopsy methods. Cervical invasion of endometrial cancer can be detected by hysteroscopy. The depth of invasion, however, is more accurately determined by magnetic resonance imaging or computed tomography. ONGOING ISSUES: Many topics for ongoing research and/or implementation are mentioned under "Consensus Position," above. (ABSTRACT TRUNCATED)