A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients.

OBJECTIVE: Topotecan is an established topoisomerase I inhibitor for the treatment of relapsed ovarian cancer. Myelotoxicity and suboptimal patient convenience associated with daily topotecan, however, have prompted investigators to explore alternate regimens, including a weekly regimen of topotecan. The objective of this study was to determine the maximum tolerated dose (MTD) of topotecan given as a weekly bolus in previously treated ovarian cancer patients. METHODS: Second- and third-line ovarian cancer patients with measurable disease or elevated cancer antigen 125 received weekly bolus topotecan intravenously starting at 1.5 mg/m(2). Topotecan was escalated in dose increments of 0.5 mg/m(2) every 21 days as tolerability allowed. Dose-limiting toxicity was defined as grade 3/4 neutropenia or thrombocytopenia. RESULTS: Thirty-two of 35 patients were evaluable for safety and tolerability. No notable toxicity was observed with weekly topotecan doses < 4 mg/m(2). Additionally, there was an absence of dose-limiting myelotoxicity and thrombocytopenia with weekly topotecan. The MTD of weekly topotecan without the use of granulocyte colony-stimulating factor support was 4 mg/m(2), with grade 2 anemia, chronic fatigue, and grade 2 gastrointestinal toxicity limiting further dose escalation. Weekly topotecan also demonstrated antitumor activity at doses >2 mg/m(2). CONCLUSIONS: The establishment of a well-tolerated, weekly regimen of topotecan (4 mg/m(2), with a maximum recommended dose of 6 mg/m(2)) provides the basis for further investigation in phase II studies of single-agent and combination regimens in previously treated ovarian cancer patients.

Ovarian cancer. Current outlook on this deadly disease.

The lifetime risk of ovarian cancer in the US population is about 1.4%. The risk is increased in women who have a strong family history of the disease. Unfortunately, no accurate screening tests are available. Transvaginal sonography and CA-125 determinations can be valuable in selected patients. Attempts at prevention with oral contraceptive use and indicated or prophylactic oophorectomy should be seriously considered. Conservative treatment is appropriate in selected patients with early-stage ovarian cancer. However, because the majority of patients present with advanced disease, maximum cytoreductive surgery followed by chemotherapy is usually required. Such an approach results in a high incidence of initial clinical remission and can prolong survival to 2 or 3 years. Eventually, however, relapse and death often occur in spite of additional therapy. Another operation may be needed for secondary cytoreduction or palliation. Bowel obstruction, recurrent ascites, and pleural effusion are often terminal events.

Extraovarian stage IV peritoneal serous papillary carcinoma presenting as an asymptomatic skin lesion--a case report and literature review.

An 81-year-old G2 P2 white female in good health with the exception of well-controlled hypertension presented to her family physician with a newly discovered lesion in the skin of the abdominal left lower quadrant. Initially, this nodule was viewed as innocuous and was followed with the expectation that it would soon resolve. Three months later, the lesion was biopsied, revealing a pattern consistent with papillary serous carcinoma from a presumed ovarian primary. CT scan revealed a pelvic mass. Subsequent laparotomy revealed a benign tubal cystadenofibroma, but otherwise normal pelvic viscera. Additional findings, however, included multiple small parietal peritoneal nodules histopathologically diagnosed as extraovarian peritoneal serous papillary carcinoma similar to the skin lesion. All gross disease was extirpated. The patient received chemotherapy as for advanced ovarian cancer.

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.

Hysteroscopy may transport malignant cells into the peritoneal cavity. Case report.

The purpose of this report is to caution against the use of hysteroscopy at the time of uterine curettage performed in women with postmenopausal bleeding suspected of having endometrial carcinoma. A 63 year old postmenopausal woman had endometrial carcinoma diagnosed by hysteroscopically guided curettage. At the time of hysterectomy three weeks later, malignant cells were found in pelvic washings. Although a causal relationship between hysteroscopy and malignant peritoneal cytology cannot be postulated, we believe that hysterescopy should be used with caution in the work up of postmenopausal bleeding.

Stage IB carcinoma of the cervix: are all staging tests and procedures necessary?

The prognostic value and cost effectiveness of generally recommended ancillary tests and staging procedures in 115 patients with clinical Stage IB carcinoma of the cervix were retrospectively reviewed. All 112 intravenous pyelograms, 108 barium enemas, 102 cystoscopies and 98 sigmoidoscopies were normal. No malignant cells were found in pelvic washings. Of 111 patients who had paraaortic lymph node biopsies, only one had a positive node. This node was grossly enlarged and clinically suspicious. Paraaortic lymph node status was not influenced by tumor grade, prior conization, lymphovascular space involvement, depth of stromal invasion, positive pelvic lymph nodes or number of paraaortic nodes biopsied. The tests evaluated in this study are unnecessary and should no longer be performed in patients with clinical Stage IB carcinoma of the cervix. In addition, paraaortic lymph node biopsies in the absence of clinically suspicious nodes are not warranted. Eliminating these tests and procedures would result in substantial savings in health care cost.

'Abnormal' Papanicolaou smears and colposcopy in pregnancy: ante- and post-partum findings.

Abnormal Papanicolaou smears and colposcopic findings suggesting human Papilloma virus (HPV) infection and cervical intraepithelial neoplasia (CIN) may occur during pregnancy. Condylomata acuminata often grow rapidly during pregnancy and may regress spontaneously following delivery. However, the post-partum outcome of the untreated ante-partum abnormal cytologic smear and colposcopy has not been defined clearly. Seventy-three pregnant patients were examined by colposcopy because of genital warts and/or abnormal Papanicolaou smears. Cytologic, colposcopic and histologic re-evaluation was conducted after delivery. Only one of the patients had a normal ante-partum colposcopic examination. This number increased to 15 after delivery. Forty-one patients had normal post-partum cytologic smears, but only 13 had normal histology. Abnormal post-partum cytology was highly predictive of abnormal colposcopy and histology. In contrast, normal post-partum cytology was not very accurate in predicting normal colposcopy and histology. It is concluded that a few pregnant patients may have partial regression of clinical HPV infection and abnormal cytology and colposcopy after delivery. However, the majority will continue to have abnormal findings 4 months following delivery in spite of normal post-partum cytology and even colposcopy.

The prognostic implications of low serum CA 125 levels prior to the second-look operation for stage III and IV epithelial ovarian cancer.

Second-look laparotomy is performed to evaluate response to chemotherapy and to determine the need for additional treatment. The relationship between absolute levels of serum CA 125 less than 35 u/ml and disease status at second-look operation was evaluated in 95 patients with advanced-stage epithelial ovarian cancer. Eighty-six patients had Stage III disease and nine patients had Stage IV cancer. Residual tumor was documented at second-look laparotomy in 52 (55%) of the patients studied. Forty-nine percent of the 82 patients with serum CA 125 values less than 20 u/ml had residual disease. In contrast, 12 of 13 (92%) patients with serum CA 125 values of 20-35 u/ml had residual tumor at second-look laparotomy. All patients with serous cystadenocarcinomas and serum CA 125 values of 20-35 u/ml had residual tumor, and two-thirds of these cases had grossly visible disease. The positive predictive value of a serum CA 125 level of 20-35 u/ml was 0.92. These data suggest that second-look laparotomy should be deferred in patients with advanced-stage ovarian cancer until serum CA 125 values are less than 20 u/ml.

Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer.

PURPOSE: To compare cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide as primary chemotherapy for stage III (suboptimal) and stage IV ovarian cancer. PATIENTS AND METHODS: Three hundred forty-two patients were randomly assigned to treatment with six courses of intravenous (i.v.) cisplatin 100 mg/m2 plus i.v. cyclophosphamide 600 mg/m2, or i.v. carboplatin 300 mg/m2 plus i.v. cyclophosphamide 600 mg/m2. RESULTS: The estimated median survivals were 17.4 and 20.0 months for the cisplatin and carboplatin study arms, respectively. The null hypothesis of a 30% survival superiority with the cisplatin arm was rejected at the P = .02 level. Clinical response rates were 52% for the cisplatin arm and 61% for the carboplatin arm. Pathologic complete response rates were similar for both study arms. There was less thrombocytopenia on the cisplatin arm (P less than .001); however, there was less nausea and emesis (P less than or equal to .001 for courses 1 to 5), renal toxicity (P less than .001), anemia (P = .01), hearing loss (P less than .001), tinnitus (P = .01), neuromuscular toxicities (P = .001), and alopecia (P less than .001) on the carboplatin arm. CONCLUSION: Carboplatin-cyclophosphamide proved to have a significantly better therapeutic index than cisplatin-cyclophosphamide in patients with stage III (suboptimal) and stage IV ovarian cancer.

Randomized comparison of cisplatin plus epirubicin or doxorubicin for advanced epithelial ovarian carcinoma. A multicenter trial.

Stage III and IV epithelial ovarian cancer patients were prospectively randomized to receive eight courses of 60 mg/m2 of cisplatin plus either 75 mg/m2 of epirubicin (62 patients) or 60 mg/m2 of doxorubicin (54 patients). Clinical response rates for cisplatin/epirubicin of 42% [15% complete response (CR) and 27% partial response (PR)] and for cisplatin/doxorubicin of 55% (24% CR and 31% PR) were not statistically different (p = 0.14). The negative second look rate was 35% (10/29) for cisplatin/doxorubicin and 17% (5/30) for cisplatin/epirubicin (p = 0.12). The progression-free interval for cisplatin/epirubicin (13 months) was not statistically different (p = 0.09) from that for cisplatin/doxorubicin (19 months). The median survivals for cisplatin/epirubicin (756 days) and cisplatin/doxorubicin (739 days) were similar (p = 0.70). Cardiotoxicity was greater for the cisplatin/doxorubicin group (p = 0.0003). With similar survival and less cardiotoxicity, the cisplatin/epirubicin regimen had the more favorable therapeutic index.

Endosalpingiosis as a source of psammoma bodies in a Papanicolaou smear. A case report.

Psammoma bodies are concentric, laminated structures produced by cross-sectioning the tips of calcified papillary formations and are usually associated with papillary carcinoma of the thyroid gland, meningiomas and serous papillary tumors of the ovary. These structures have occasionally been seen in cytologic smears obtained from women with endometrial or ovarian carcinoma. A woman had Papanicolaou smears that continued to show psammoma bodies for over two years, eventually leading to a hysterectomy. Even though the presence of psammoma bodies on a Papanicolaou smear should always alert the physician to the possibility of ovarian carcinoma, leading to a thorough search for this malignancy, a variety of benign conditions, such as endosalpingiosis, may also be associated with this finding.

Esorubicin in advanced endometrial cancer: an ineffective and potentially toxic therapy. A Southwest Oncology Group study.

The Southwest Oncology Group conducted a phase II study of esorubicin treatment in patients with advanced endometrial cancer who had received no prior chemotherapy. Twenty of 31 patients were fully evaluable for response and toxicity. There were no clinical responses to treatment and 60% (12/20) of the patients developed severe or life threatening leukopenia on therapy. One evaluable patient was removed from study after a cumulative dose of 150 mg/M2 due to a reduction in left ventricular ejection fraction on MUGA scan and another developed congestive heart failure several months after discontinuation of treatment. Esorubicin has significant toxicity and limited clinical activity in patients with advanced endometrial cancer.

A potential hazard of the use of the surgical ultrasonic aspirator in tumor reductive surgery.

The surgical ultrasonic aspirator (USA) is a recently developed surgical instrument being used for an increasingly wide range of surgical procedures including tumor reductive surgery in patients with advanced ovarian carcinoma. This paper introduces a potential hazard of the use of this instrument. It was determined that the mist produced by the ultrasonic aspirator during tumor reductive surgery contains intact and possibly viable cancer cells.

Debridement of vaginal radiation ulcers using the surgical Ultrasonic Aspirator.

The surgical Ultrasonic Aspirator (USA) is a fairly new surgical instrument used for an increasingly wide range of procedures. This paper introduces a new application: debridement of vulvovaginal necrotic ulcers resulting from intracavitary radiation therapy. The ultrasonic aspirator allowed removal of the soft, necrotic tissue while preserving underlying healthy, firm tissue and blood vessels.

Gynecologic surgery in the aged.

Aged women, those over 75 years, experience a high incidence of nearly all gynecologic neoplasms as well as associated chronic medical illnesses. In this study, 773 women underwent major surgery, while 711 underwent minor procedures. Fifty-two patients (3.5%) were 75 years of age or older. Forty-three of the 52 (83%) had a total of 119 associated medical complications. Eighty-nine surgical procedures were performed. A total of 17 postoperative complications occurred in 15 patients. Thirty-eight patients (73%) had no postoperative complications. One patient died because of infarction of the bowel diagnosed within 30 days of her primary surgical procedure. The aged patients in this study did well postoperatively with routine preoperative medical evaluation and postoperative care. Same-day admission and surgery did not increase morbidity. Aged patients can safely undergo major pelvic and abdominal surgery at a community medical center if one manages their associated medical conditions in a routine manner similar to that utilized in younger patients with similar problems. The associated medical complications and not age per se should be the deciding factor.

Prognostic factors and the significance of cytologic grading in invasive squamous cell carcinoma of the vulva: a clinicopathologic study.

Clinical staging, tumor size, histologic differentiation, cytologic grading, depth of stromal invasion, and vascular channel involvement by tumor cells were studied in 42 patients with invasive squamous cell carcinoma of the vulva who were treated with radical vulvectomy and inguinal-femoral lymphadenectomy. All parameters were found to correlate well in predicting groin node metastasis. Cytological grading was found to be more significant compared to histologic grading in regard to nodal metastasis (P less than 0.02). No patient with cytologic or histologic grade 1 tumor and less than 5 mm stromal invasion was found to have nodal metastasis.

"Nongynecologic" surgical procedures performed on a gynecologic oncology service.

One thousand fifty-eight patients had major surgery in a community-based, university-affiliated gynecologic oncology service. Of these, 233 underwent a total of 275 "nongynecologic" surgical procedures. Two hundred twenty patients suffered from gynecologic malignancies, whereas 13 had surgery for benign disorders. Eighty-two procedures were performed on the gastrointestinal tract, 44 on the urinary tract, and 149 on extrapelvic lymph nodes. Except for ovarian carcinoma and benign conditions the majority of gastrointestinal or urinary tract operations were preceded by radiation therapy. When the nongynecologic operation was necessitated at a time subsequent to initial therapy of the malignancy, a high incidence of recurrent disease was discovered. Of the 275 procedures, reoperation because of early or late complications was necessary in only 8 instances. Only one postoperative death was caused by complications of surgery. Other mild postoperative complications were transient and responded to routine noninvasive care. The complication rate and morbidity of nongynecologic surgical procedures performed on a gynecologic oncology service are low and should encourage gynecologic oncologists to continue their present comprehensive approach to patient care.

Significance of lymphoplasmocytic infiltration around tumor cell in the prediction of regional lymph node metastases in patients with invasive squamous cell carcinoma of the vulva: a clinicopathologic study.

Histologic material from 42 patients treated for invasive squamous cell carcinoma of the vulva was studied to determine the prognostic significance of lymphoplasmocytic infiltration around tumor cells in the prediction of regional lymph node metastases. No correlation was found between lymphoplasmocytic infiltration and nodal metastasis with respect to degree of tumor differentiation, stage of disease, and vascular channel involvement. The presence or absence of lymphoplasmocytic infiltration around tumor cells appears to have no prognostic value in predicting nodal metastases.

Endometrial adenocarcinoma: therapeutic impact of preoperative histopathologic examination of endometrial tissue.

Adenocarcinoma of the endometrium is diagnosed by the histologic evaluation of endometrial tissue. In stage I disease, five-year survival depends upon a number of prognostic factors. Histologic grade and type of carcinoma are most important. The need for pelvic and para-aortic lymphadenectomy is often based on the preoperative histologic grade and type of tumor. The purpose of this study was: 1) to compare preoperative histology of endometrial carcinoma to that found at hysterectomy, 2) to determine if preoperative histology can accurately predict depth of myometrial invasion or extra-uterine spread, 3) to determine whether para-aortic lymphadenectomy could be deleted based only on the preoperative finding of well differentiated carcinoma. In 19 (28%) of the 68 patients studied, the histologic grade or pattern at hysterectomy was different from that found preoperatively. In seven (13%) of the 52 "good prognosis" patients with grades 1 and 2 preoperative histology, hysterectomy revealed a more serious histologic type. Three of the seven (43%) had extrauterine spread. In the 16 "poor prognosis" patients with preoperative grade 3 or papillary serous/clear cell carcinoma, 14 (88%) had a similar histologic pattern at hysterectomy. Three of these patients had metastatic disease. Depth of myometrial invasion could not be predicted by preoperative histology even though the data suggested that extrauterine spread could. Clinical stage I endometrial carcinoma, grade 1 or 2, should not be treated without para-aortic nodal sampling based only on a supposedly favorable preoperative histologic pattern. Confirmed para-aortic nodal disease will alter the fields of post-operative radiation therapy should that become necessary. In these patients, however, pelvic lymphadenectomy is not justified.2 +

A phase II trial of vinblastine in patients with advanced or recurrent endometrial carcinoma. A Southwest Oncology Group Study.

Forty-one patients with advanced or recurrent endometrial carcinoma no longer amenable to control with surgery and/or radiotherapy were entered into study. Five of these were ineligible for study. One eligible patient never received any treatment, another had no baseline information recorded; these were thus inevaluable. The remaining 34 patients received continuous infusion vinblastine (1.5 mg/m2) as a 24-h infusion daily for 5 days every 3 weeks. One complete and 3 partial responses were observed among these 34 patients, for an overall objective response rate of 12%. Two of these 4 responders are deceased, and 2 remain alive with disease at 18 and 22 months, respectively. The most common toxicity noted was leukopenia in 22 patients (65%); 12 (35%) of these had severe or life-threatening leukopenia (less than 2,000 WBC/microliter). Fourteen of the 34 (41%) experienced nausea and vomiting. Other adverse effects were less common. Overall, 15 of the 34 patients (44%) experienced severe or life-threatening toxicity. In this trial, continuous infusion vinblastine was toxic and had minimal to moderate efficacy at best. These facts suggest that the drug at the dose and schedule tested has no role in the management of advanced or recurrent endometrial carcinoma.