A phase II evaluation of mitolactol in patients with advanced squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study.

Sixty patients with advanced squamous cell carcinoma of the cervix (SCC) who had received no prior chemotherapy were entered onto a study of mitolactol (dibromodulcitol [DBD]). The drug was administered orally at an initial dose of 180 mg/m2 per day for 10 days and repeated every 4 weeks. There were 55 evaluable patients, of whom one (2%) had a complete response (CR), and 15 (27%) had a partial response (PR), (CR plus PR, 29%). A 95% confidence interval for the true response rate is 18.8% to 42.1%. Myelosuppression was appreciable at this dose and schedule, with 13 patients experiencing life-threatening thrombocytopenia and two drug-related deaths. The level of activity in this disease encourages us to determine a tolerable dose of this drug in combination with cisplatin for further study.

Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study.

The Gynecologic Oncology Group has conducted a randomized prospective trial comparing cisplatin 50 mg/m2 every 21 days (regimen 1), 100 mg/m2 every 21 days (regimen 2), and cisplatin 20 mg/m2 for five consecutive days repeated every 21 days (regimen 3). Four hundred ninety-seven evaluable patients have been accrued on this study. The response rates were 20.7%, 31.4%, and 25.0%, for regimens 1, 2, and 3, respectively; the complete remission rates were 10.0%, 12.7%, and 8.6% for regimens 1, 2, and 3, respectively. The median duration of response ranged from 3.9 to 4.8 months, the median progression-free interval from 3.7 to 4.6 months, and the median survival time from 6.1 to 7.1 months. The difference in response rates for regimens 1 and 2 is statistically significant (P = .015) but less than the magnitude originally considered clinically significant. The differences in complete remission rates, response duration, progression-free interval, and survival times are not statistically significant. The following types of toxicity were observed: serum creatinine level greater than 2 mg/dL and/or BUN level greater than 40 mg/dL was 7%, 14%, and 17% on regimens 1, 2, and 3, respectively; leukocyte count less than 4,000/microL was 27%, 44%, and 41% on regimens 1, 2, and 3, respectively. Nausea and vomiting occurred in 74 patients (83%). The regimen consisting of a 100-mg/m2 single dose has produced a statistically significant higher response rate than the 50 mg/m2 regimen while producing no appreciable differences in complete remission rate, response duration, progression-free interval, or survival. In addition, the higher dose regimen was associated with greater myelosuppression and nephrotoxicity.

Hydroxyurea versus misonidazole with radiation in cervical carcinoma: long-term follow-up of a Gynecologic Oncology Group trial.

PURPOSE: Long-term follow-up data of a randomized trial that compared hydroxyurea and the hypoxic-cell radiosensitizer to misonidazole as adjuncts to standard radiation therapy in locally advanced carcinoma of the cervix are reported. PATIENTS AND METHODS: Three hundred eight women were entered, and all 294 eligible patients are assessable as randomized. Eighty-one percent of patients have been monitored for 5 years or to death. RESULTS: There was an advantage for hydroxyurea in progression-free interval and survival (P = .05 and P = .066, respectively). There was no significant difference in the distribution of sites of failure between the regimens. For the 39% of patients with stages III to IVA disease, the advantage in progression-free interval for hydroxyurea was significant (47.8% v 33.6%). More leukopenia occurred on the hydroxyurea regimen than on the misonidazole regimen. CONCLUSION: In summary, these data provide stronger evidence than our previous analysis that hydroxyurea is superior to misonidazole as an adjunct to radiation therapy. For patients with locally advanced carcinoma of the cervix, hydroxyurea continues to be the adjunct of choice with radiation.

Ten-year follow-up of patients receiving cisplatin, doxorubicin, and cyclophosphamide chemotherapy for advanced epithelial ovarian carcinoma.

Fifty-six patients were randomly assigned to receive either one-day cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy (PAC-I) or five-day PAC (PAC-V) for advanced epithelial ovarian carcinoma. Follow-up has been 120+ months or to death. Ninety-one percent had either suboptimal stage III or stage IV disease and 55% had grade 2 or 3 lesions. Two patients died of toxicity and were free of disease at autopsy. A third patient died of congestive heart failure with no disease at 103 months. Additionally, eight patients had a negative second-look laparotomy, and three (37.5%) are alive with no evidence of disease (NED) 133 to 144 months after diagnosis. Five patients (62.5%) died of disease 2 to 123 months after negative second-look. Patients with optimal stage III disease had a longer median progression-free interval (PFI) and survival (33.3 and 44.5 months, respectively) than those with suboptimal or stage IV disease (16.4 and 22.5 months, respectively), and the difference in median PFI is significant (P less than .02). Patients with ascites at diagnosis had a shorter median PFI and survival (14.7 and 18 months) than those without ascites (30.0 and 33.0 months). Both differences were significant (PFI, P less than .04; survival, P = .005). PAC produces response rates that are superior to those obtained historically with single-agent alkylating therapy. Late recurrences after negative second-look laparotomy suggest that 5-year survival data may be inadequate in ovarian carcinoma.

What is the appropriate management of early stage cervical cancer (International Federation of Gynecology and Obstetrics stages I and IIA), surgical assessment of lymph nodes, and role of therapeutic resection of lymph nodes involved with cancer?

It is well recognized that lesion size, tumor volume, depth of stromal invasion, and lymphatic space permeation are all important predictors of lymph node involvement in early stage cervical cancer. Pelvic lymph node involvement is the most important (negative) predictor of survival for these patients with early stage cervical cancer. The number of involved nodes and the size of involved and unresected nodes may also be prognostically significant. It is uncertain whether lesion size, tumor volume, depth of stromal invasion, or lymphatic space permeation are independent negative predictors of survival when correcting for lymph node positivity. Lymphadenectomy has traditionally been considered a diagnostic procedure. There is accumulating evidence to suggest that lymphadenectomy may have therapeutic benefit for patients with cervical cancer metastatic to lymph nodes. This hypothesis awaits further evidence.

Concurrent chemoradiation in carcinoma of the uterine cervix.

Carcinoma of the cervix is most commonly treated with radiotherapy when the disease is locally advanced. Tumor bulk often limits the efficacy of this therapy, as does the tolerance of adjacent healthy tissue. Cytotoxic chemotherapeutic agents have been used with concomitant radiotherapy. Extensive data are available on dose and schedule tolerance for cisplatin, 5-fluorouracil, and a number of combination regimens. Phase III data that confirm any advantage in terms of local control, disease-free survival, or overall survival have been published only for hydroxyurea. Hydroxyurea, an S-phase-specific inhibitor of ribonucleotide reductase, lacks single-agent activity against metastatic, squamous cell cervical cancer. Further studies are required before agents other than hydroxyurea can be considered standard therapy with concomitant radiotherapy for locally advanced carcinoma of the cervix.

Experience with hydroxyurea as a radiosensitizer in carcinoma of the cervix.

Since 1968, hydroxyurea has been used as a radiosensitizer in combination modality treatments for carcinoma of the cervix. The drug has shown an advantage over placebo in several randomized trials. Although hydroxyurea is given orally on an outpatient basis, it has not gained widespread acceptance. Previous reports are reviewed and possible future uses are discussed.

Adenocarcinoma corpus et colli: analysis of diagnostic variables.

Between January 1973 and December 1983, 469 patients with carcinoma of the endometrium were seen at this institution. Eighty-one patients were identified with adenocarcinoma involving both the uterine body and the cervix. Patients were divided into three groups for evaluation. Group A (n = 58) had a positive cervical biopsy or endocervical curettage, but a normal-appearing cervix at clinical examination. Group B (n = 18) had gross tumor involving the cervix which was confirmed by biopsy. Group C (n = 5) had unsuspected cervical involvement revealed at hysterectomy. Fourteen Group A patients received preoperative radiation therapy. Thirty of the 44 Group A patients (68.2%) who did not receive preoperative radiation, had no involvement of the cervix by tumor in the hysterectomy specimen. Seventy-six patients were eligible for follow-up of at least 18 months. There were 24 recurrences among these 76 patients. Recurrence was more common with advancing grade and with increasing myometrial invasion. Pelvic failures occurred with comparable frequency in both Groups A and B. Only 4 of 11 patients who were found to have extrauterine disease at surgery are still alive. In this study, we found that endocervical curettage has a significant false-positive rate, both histologic grade and volume of cervical involvement should be considered in treatment planning, primary operation should be considered in the management of selected patients with Stage II endometrial carcinoma, and extrauterine disease is a grave prognostic factor.

Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study.

PURPOSE: The objective of this study was to determine if groin radiation was superior to and less morbid than groin dissection. METHODS AND MATERIALS: Members of the Gynecologic Oncology Group randomized 58 patients with squamous carcinoma of the vulva and nonsuspicious (N0-1) inguinal nodes to receive either groin dissection or groin radiation, each in conjunction with radical vulvectomy. Radiation therapy consisted of a dose of 50 Gray given in daily 200 centiGray fractions to a depth of 3 cm below the anterior skin surface. RESULTS: The study was closed prematurely when interim monitoring revealed an excessive number of groin relapses on the groin radiation regimen. Metastatic involvement of the groin nodes was projected to occur in 24% of patients based on this Group's previous experience. On the groin dissection regimen, there were 5/25 (20.0%) patients with positive groin nodes. These patients received post-operative radiation. There were five groin relapses among the 27 (18.5%) patients on the groin radiation regimen and none on the groin dissection regimen. The groin dissection regimen had significantly better progression-free interval (p = 0.03) and survival (p = 0.04). CONCLUSION: Radiation of the intact groins as given in this study is significantly inferior to groin dissection in patients with squamous carcinoma of the vulva and N0-1 nodes.

Poorly differentiated (small cell) carcinoma of the ovary in young women: evidence supporting a germ cell origin.

The clinical and pathologic features, including immunohistochemistry and electron microscopy, of six cases of poorly differentiated carcinoma of the ovary (small cell carcinoma) are presented. These tumors occurred in six young patients ranging in age from 10 to 24 years. Two patients had hypercalcemia. All tumors were unilateral, and four patients had advanced stage disease at presentation. Histologic features included sheets, nests, and cords of cells in a fibrous stroma, focal microcysts, and a dimorphic population of small and large cells. Eosinophilic, hyaline globules occurred in five cases, intercellular basement membrane-like substance in two cases, and glycogen in all cases. Five of six cases stained strongly for cytokeratin and vimentin; intracytoplasmic laminin was identified in three cases; and three cases were believed to show faint positivity for alpha-1-antitrypsin. Stains for alpha-fetoprotein were negative. Ultrastructural examination of two cases showed granular material in dilated rough endoplasmic reticulum, intermediate filaments, intracytoplasmic dense globules, maculae adherens, and extracellular basement membrane-like material. All of the cases proved rapidly fatal despite various therapies, as did a histologically similar testicular tumor that was admixed with seminoma and teratoma. We interpret these findings to indicate that this ovarian cancer is most likely of germ cell origin, and it may be related to yolk sac tumor, although it is clearly distinct from the classical yolk sac tumor.

Eaton-Lambert syndrome as a harbinger of recurrent small-cell carcinoma of the cervix with improvement after combination chemotherapy.

Eaton-Lambert or myasthenic syndrome was diagnosed in a young woman with recurrent small-cell carcinoma of the cervix. Therapy with vincristine, doxorubicin, and cyclophosphamide resulted in a partial response of the tumor and marked improvement in neurologic symptoms. Diagnosis and treatment of this paraneoplastic syndrome are discussed.

Human papillomavirus deoxyribonucleic acid in lesions of the female genital tract: evidence for type 6/11 in squamous carcinoma of the vulva.

Tissue specimens from 51 patients with genital condyloma acuminata or invasive cervical or vulvar carcinomas were analyzed for the presence of human papillomavirus deoxyribonucleic acid (DNA) using the dot blot technique. Of ten condylomas, 80% contained DNA related to human papillomavirus 6 or 11. Sixty percent had evidence of DNA related to human papillomavirus 16, and 30% contained DNA related to human papillomavirus 18. Of 24 squamous cervical carcinomas, 58% had human papillomavirus type 16-related DNA, 33% had type 6- or 11-related DNA, and 4% had type 18-related DNA. Nine primary or recurrent vulvar carcinomas were analyzed. Seventy-eight percent contained human papillomavirus type 6- or 11-related DNA, 33% type 16-related DNA, and 22% type 18-related DNA. Whereas invasive cervical carcinomas predominantly contained DNA related to human papillomavirus 16 or 18, invasive vulvar carcinomas predominantly contained DNA related to types 6 or 11. Thus, human papillomavirus type alone cannot distinguish benign from malignant epithelial disease in the female genital tract.

Quality assessment and assurance programs in the Gynecologic Oncology Group.

The Gynecologic Oncology Group (GOG), a program of ACOG, is one of 12 cooperative groups conducting clinical trials supported by the National Cancer Institute. Recently, an occurrence of research fraud was found in one of the other cooperative groups. The GOG maintains a quality assessment and assurance program that includes three primary functions: Original source documentation is examined to verify accuracy of treatment modalities, all protocols are regularly scrutinized for consistency and validity, and regular on-site audits are conducted at all institutions. The group endeavors to reassure physicians and their patients that research fraud is not rampant in the cooperative group system and that data published by the cooperative groups are reliable.

Estrogen and progesterone receptors in uterine sarcomas.

Estrogen and progesterone receptors were measured in tissues from 43 patients with various uterine sarcomas using the dextran-coated charcoal assay. Estrogen receptor was present in 55.5% and progesterone receptor in 55.8% of samples, at median estrogen and progesterone receptor concentrations of 10.7 and 15.8 fmol/mg cytosol protein, respectively. These median values are much lower than those in 30 consecutive endometrial adenocarcinomas and 50 breast carcinomas assayed in our laboratory. Progesterone receptor status correlated strongly with estrogen receptor status in uterine sarcomas (P = .001). Estrogen and progesterone receptor levels were not influenced by stage, grade, or mitotic count. Patients 50 years of age or less had significantly higher progesterone receptor than those over 50. No such age effect was seen for estrogen receptor. Endometrial stromal sarcoma had higher estrogen and progesterone receptor levels than other histologic types. Low-grade endometrial stromal sarcomas had higher median estrogen receptors (238.9 fmol/mg) and better survival (all patients alive at 6-12 months) than did high grade (N = 7) endometrial stromal sarcomas (median ER = 6.6 fmol/mg, all dead of disease at 8-27 months). For all histologic types, evaluable patients with stage I or II disease (N = 16) were more likely to survive longer than one year than those with stage III or IV disease (N = 13, P = .003). Evaluable patients with estrogen receptor-positive sarcomas were more likely to survive longer than one year than those with estrogen receptor-negative tumors (P = .006). With one exception, an endometrial stromal sarcoma, hormonal therapy exerted no beneficial effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group.

Although cure rates are high, the morbidity of radical operation for carcinoma of the vulva is substantial. Between 1983-1989, member institutions of the Gynecologic Oncology Group entered 155 patients in a prospective evaluation of modified radical hemivulvectomy and ipsilateral inguinal lymphadenecctomy for clinical stage I vulvar cancer. Only patients with neoplastic thickness of 5 mm or less, without vascular space invasion, and negative inguinal lymph nodes were eligible for this study. There have been 19 recurrences and seven deaths from disease among the 121 eligible and evaluable patients. Patients whose disease recurred on the vulva were frequently (eight of ten patients) salvaged by further operation. Five of the seven deaths due to cancer occurred among patients whose first recurrence was in the groin. Acute and long-term morbidity as well as hospital stay were each less than in the Group's previous experience in a comparable patient population treated with radical vulvectomy and bilateral inguinal-femoral lymphadenectomy. There was a significantly increased risk of recurrence but not death when compared with these same historic controls. Modified radical hemivulvectomy and ipsilateral inguinal lymphadenectomy is an alternative to traditional radical operation for these selected patients with stage I carcinoma of the vulva. The number of patients who experienced recurrence in the operated groin is of concern and may be attributable to the decision to leave the femoral nodes intact.

The importance of peritoneal cytology in endometrial carcinoma.

From 1971-1986, peritoneal washings were obtained for cytologic examination at the time of primary exploratory laparotomy in 340 patients with endometrial adenocarcinoma. Seventy-two samples (21.2%) contained malignant cells. The finding of malignant cytology increased with stage of disease: stage I, 17%; stage II, 19.5%; stage III, 68.7%; and stage IV, 85.7% (P less than .001). In 248 patients with clinical stage I disease for whom uterine evaluation was complete, there was an increasing incidence of malignant cytology with increasing grade (P = .002), depth of myometrial invasion (P = .003), and adnexal spread (P less than .001). Twelve of 41 patients (29.3%) with clinical stage I and positive cytology developed recurrent disease, compared with six of 207 (2.9%) with negative cytology (P less than .001). Survival for all stages together was poorer in patients with positive washings than in those with negative washings (P less than .001). This difference in survival was also observed in patients with clinical stage I disease (P less than .001). Among patients with surgical stage I disease, disease-free survival was also superior in the group with negative cytology. In both clinical and surgical stage I, intra-abdominal recurrences were more common among patients with malignant peritoneal cytology.

Immunohistochemical study of HER-2/neu, epidermal growth factor receptor, and steroid receptor expression in normal and malignant endometrium.

HER-2/neu oncogene protein, epidermal growth factor receptor, progesterone receptor, and estrogen receptor were examined immunohistochemically in specimens of normal and neoplastic endometrium. Tissues obtained at the time of hysterectomy were snap-frozen at liquid nitrogen temperature and serially sectioned at 4 microns. Normal endometrial epithelial cells stained with anti-epidermal growth factor receptor and anti-HER-2/neu with intensities graded from 0 to 3+. Of the 49 endometrial malignancies studied, seven (14%) contained tissue exhibiting HER-2/neu staining in excess (4+) of any of the normal tissues or the other 42 cancer specimens. Expression of both HER-2/neu and steroid receptors was heterogeneous within these seven tumors. To examine this heterogeneity more closely, sections of these and other tumors were double-stained for HER-2/neu and progesterone receptor. It was found that the cells exhibiting 4+ HER-2/neu staining were progesterone receptor-negative. Conversely, cells that were progesterone receptor-positive within the same specimen exhibited HER-2/neu immunostaining equal to or less than 3+. All specimens containing 4+ HER-2/neu tissue were graded 1 or 2 adenocarcinomas, stage I. Thus, there is an inverse relationship between overexpression of HER-2/neu and progesterone receptor in endometrial cancer. On the other hand, overexpression of HER-2/neu in endometrial cancer does not seem to be related to loss of other differentiated characteristics. The prognostic value of these observations awaits continued study.

Gynecologic cancers metastatic to the breast.

BACKGROUND: We report a series of gynecologic cancers metastatic to the breast, illustrating the diagnostic and prognostic implications of this rare event. STUDY DESIGN: By reviewing the gynecologic oncology data base, we identified 10 women with gynecologic cancer metastatic to the breast who were treated at Indiana University School of Medicine between August 1978 and February 1995. Medical records were reviewed for pertinent data concerning the presentation, evaluation, and treatment of the primary gynecologic malignancy and the metastatic breast tumor. RESULTS: The mean patient age was 56.8 years (range, 30-80 years). The most common gynecologic malignancy was ovarian cancer (five patients), followed by cervical cancer (two patients) and cancers of the vagina, endometrium, or peritoneum (one patient each). A palpable solitary breast mass was found in 8 of 10 patients (80%), and the upper outer quadrant of the breast was the most common site of tumor involvement. One woman presented with examination findings resembling inflammatory breast cancer, and one patient presented with multiple firm subcutaneous nodules. Despite further treatment, which in all cases consisted of systemic chemotherapy, 83% of the patients died with a breast metastasis within 1 year of presentation. CONCLUSIONS: Secondary breast malignancy should be suspected in any patient with a breast tumor and a known history of gynecologic cancer. A breast metastasis implies widespread tumor dissemination and a poor prognosis. Radical breast surgery should be avoided.

Intraperitoneal 5-fluorouracil for pseudomyxoma peritoneii.

Pseudomyxoma peritoneii has an indolent course but a 5-year survival rate of 40-45%. The role for postoperative intraperitoneal chemotherapy is unclear. Nine patients with pseudomyxoma arising from mucinous neoplasms of the ovary and intestinal tract received a total of 89 courses of intraperitoneal 5-fluorouracil (IP5FU). Each course consisted of eight 4-h exchanges of 1 g of 5FU in 2 l of 1.5% Inpersol(R). Median follow-up after diagnosis was 30 months (range 6-74). All patients were evaluable for toxicity and response. There was one treatment-related death due to renal failure and sepsis. Three patients developed disease progression prior to scheduled second-look laparotomy. At second-look laparotomy two patients demonstrated pathologic complete responses, one had stable disease and one had progression of disease. One patient remained clinically free of progression after refusing second-look laparotomy. The projected 5-year survival by Kaplan-Meier estimate was 87% for patients treated with IP5FU compared to a 52% 5-year survival seen in a series of 11 patients treated prior to the use of IP5FU (P = 0.12). This preliminary analysis suggests that IPFU in the described schedule fails to improve survival statistically compared to previously used regimens for patients with pseudomyxoma peritoneii.

A phase II study of PALA (NSC 224131) in patients with advanced ovarian carcinoma. A Gynecologic Oncology Group study.

Pala, 5G /M2 i.v. every 3 weeks was given to 32 evaluable patients with ovarian carcinoma (31 previously treated). No complete or partial responses were noted. Ten patients had stable disease for a median progression-free interval of 4.7+ months, while the remainder had progression of disease from the start of therapy. The major toxicity was dermatologic, and five patients had severe skin rash with desquamation or ulceration. There was no substantial hematologic or gastrointestinal toxicity. PALA displays no useful activity in previously-treated patients with ovarian cancer.