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.

Complete response to topotecan of recurrent fallopian tube carcinoma.

OBJECTIVE: To describe the first complete response of recurrent Fallopian tube carcinoma to topotecan. METHODS: A patient with recurrent Fallopian tube carcinoma previously treated with paclitaxel (Taxol) and carboplatin is described. RESULTS: This patient demonstrated a complete clinical response to topotecan. Radiographic and CA-125 measurements were used to determine response. Response was noted after four cycles and a complete response demonstrated after six treatments. CONCLUSION: Topotecan appears active in recurrent Fallopian tube carcinoma.

Onycholysis associated with weekly administration of paclitaxel.

OBJECTIVE: To report an unusual reaction associated with weekly administration of paclitaxel. CASE SUMMARIES: Onycholysis was seen in four women with recurrent ovarian cancer being treated with low-dose, weekly paclitaxel. Two of the patients had previously received higher doses of paclitaxel on an every-three-week schedule without similar reactions. Onycholysis developed between weeks 10-13 of treatment in three of the patients. In the fourth patient, it developed shortly after initiation of weekly paclitaxel. None of the reactions required dose adjustments or discontinuation of therapy. Direct toxicity to the nail bed or inhibition of angiogenesis are possible mechanisms for this reaction. DISCUSSION: Onycholysis, separation of the nail from the nail bed, is an infrequent adverse effect of drug therapy. Antineoplastic drugs have previously been reported to cause onycholysis, pigmentation, bands, thickening or thinning of the nail bed, and nail shedding. Nail changes with the taxanes, primarily docetaxel, are reported in up to 30-40% of patients. Paclitaxel is not commonly associated with dermatologic reactions, although localized skin reactions and tissue necrosis have been reported. Nail changes, pigmentation or discoloration of the nail bed, occur in 2% of patients receiving paclitaxel. CONCLUSIONS: Onycholysis is an uncommon reaction that may occur in some patients receiving weekly, low-dose paclitaxel therapy. The reaction is not life-threatening and does not warrant discontinuation of therapy. However, clinicians should be aware of the possibility of this effect and be prepared to advise patients who develop signs of nail changes.

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.

Endometrial cancer in polyps associated with tamoxifen use.

We report 5 cases of carcinoma arising within tamoxifen-associated endometrial polyps. In 4 of 5 cases there were no other changes within the endometrium. Given these findings, the sonohysterographic differentiation between a polypoid structure and thickened endometrium does not eliminate the need for histologic sampling of the uterine cavity.

Bipolar electrosurgical loop excision procedure for cervical intraepithelial neoplasia.

OBJECTIVES: We sought to determine the safety and efficacy of a bipolar electrosurgical loop excision instrument in the diagnosis and treatment of cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: Twenty-eight patients underwent treatment for CIN using a 20 x 10-mm bipolar electrosurgical loop device (Valley Forge Scientific, Oaks, PA). A Malis (Valley Forge Scientific) electrosurgical generator unit (60 watts cutting) was used to remove the cervical lesion and transformation zone under colposcopic guidance. Specimens were evaluated for histopathological diagnosis, tissue depth, fragmentation of specimens, mean maximal thermal artifact, and mean maximal endocervical and ectocervical thermal artifact. RESULTS: Final pathology from bipolar electrosurgical loop excision revealed CIN3 (8), CIN2 (4), CIN1 (11), human papillomavirus changes (3), and normal findings (2). Mean operating time was less than 15 minutes, and mean estimated blood loss was less than 10 ml. Average number of tissue pieces was 1.6 (range, 1-4). No complications occurred. Mean maximal thermal artifact was 0.318 mm. Mean endocervical mucosal and ectocervical mucosal thermal artifacts were 0.177 mm and 0.176 mm, respectively. Mean tissue depth of the excised specimen was 0.40 cm. Histopathological diagnosis was possible on all specimens. In five specimens (17.9%), evaluation of the cauterized endocervical margin for CIN was not possible, owing to thermal artifact. No correlation was observed between tissue depth and thermal artifact. CONCLUSION: Bipolar electrosurgical loop excision for the treatment of CIN is a safe and effective alternative to the traditional unipolar electrosurgical loop excision. Thermal artifact did not interfere with histopathological diagnosis, and the presence of artifact at cauterized margins was similar to that reported for historically unipolar specimens. A randomized control trial comparing therapeutic effectiveness of bipolar electrosurgical loop excision and unipolar electrosurgical loop excision is planned.

Clinical significance of histiocytes found on cervical cytology.

OBJECTIVE: Our aim was to determine the incidence of cervical and endometrial pathology associated with the diagnosis of histiocytes on cervical cytology. MATERIALS AND METHODS: A retrospective review was conducted from 1993 to 1995 of cervical cytology reports in which histiocytes were named in the descriptive diagnosis. Charts were reviewed and follow-up was performed on all patients for an additional 2 years. RESULTS: Histiocytes were diagnosed in 226 of 82,018 (0.27%) cytology reports. Histiocytes alone (110), histiocytes and endometrial cells (40), and histiocytes and inflammation (45) were reported in the patients with complete follow-up. Final pathological findings after 2 years of follow-up were normal in 169 cases; other findings included polyps (6), simple hyperplasia (10), complex hyperplasia (1), previously treated cervical cancer (4), and endometrial cancer (5). All patients with endometrial cancer had clinical signs and symptoms of disease. CONCLUSION: The diagnosis of histiocytes on cervical cytology is associated with neoplasia (7.8%) or cancer (2.6%) in some cases. However, significant neoplasia (i.e., carcinoma or atypical hyperplasia) was associated with clinical signs and symptoms. On cytological workup, the finding of histiocytes in the absence of symptoms appears not to be associated with significant pathology.

Dilated fallopian tubes: MR imaging characteristics.

PURPOSE: To determine the magnetic resonance (MR) imaging characteristics of hydrosalpinx and the accuracy of MR imaging for distinguishing hydrosalpinx from other adnexal masses. MATERIALS AND METHODS: Cross-referencing of pathologic records and MR studies from two institutions disclosed 41 study patients with surgically proved dilated fallopian tubes. A set of 38 patients with surgically evaluated adnexal masses, but no hydrosalpinx, were randomly chosen as control subjects. All MR examinations included T1-weighted spin-echo and T2-weighted fast spin-echo imaging in multiple planes with a phased-array multicoil. Two blinded readers scored each adnexa for the presence of a dilated fallopian tube or thickened tubal wall and mucosal folds and the signal intensity of the intratubal fluid. Blinded readings were compared with surgical findings of dilated fallopian tube, endometriosis, and salpingitis. Radiologic-pathologic correlation was performed with adnexal specimens imaged in vitro in three study patients. RESULTS: On a per patient basis, the blinded readers correctly identified dilated fallopian tubes in 31 of 41 study patients and correctly excluded dilated tubes in a mean 34 of 38 control subjects. On T1-weighted images, hyperintense tubal fluid was significantly correlated with the presence of endometriosis in the pelvis at surgery (P < .002, chi 2). CONCLUSION: MR imaging can depict most dilated fallopian tubes and differentiate them from other adnexal masses on the basis of morphologic features. On T1-weighted images, high signal intensity is correlated with the presence of endometriosis affecting the tube.

Secondary response of ovarian tumors to topotecan treatment.

Three patients presented with ovarian cancer that was initially treated with paclitaxel and platinum-based compounds. Although responses to these agents occurred, tumor progression was evident by elevated CA 125 levels after a period of 11 to 35 months. These patients were then treated with topotecan and exhibited a response and stopped therapy. All patients subsequently had progression of disease. The patients were again treated with topotecan and have experienced favorable responses. All three patients are currently receiving treatment with topotecan and have stable disease. The results presented here suggest that re-treatment with anti-tumor agents, such as topotecan, may be able to elicit a response in tumors previously sensitive to these agents.

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.

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)

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.

Neural network-based screening of atypical squamous cells of undetermined significance.

OBJECTIVES: To determine the usefulness of computerized rescreening for detecting high-grade cervical intraepithelial neoplasia (CIN) in patients with cytological evidence of atypical squamous cells of undertermined significance (ASCUS). METHODS: One hundred and eight patients with ASCUS cytology who had undergone colposcopy had their Papanicolaou smears reviewed using PAPNET, a neural network-based instrument. RESULTS: Twenty (18.5%) of the 108 slides were reclassified to a higher-grade lesion. Analysis showed sensitivity (77.8%), specificity (86.9%), and positive (35%) and negative (97.7%) predictive values for detection of high-grade CIN. CONCLUSIONS: PAPNET neural network-based rescreening of ASCUS smears identifies patients with high-grade cancer precursors. It may be a triage test for ASCUS cytology.

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.