Frederick B. Stehman

Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma

BACKGROUND Bulky stage IB cervical cancers have a poorer prognosis than smaller stage I cervical cancers. For the Gynecologic Oncology Group, we conducted a trial to determine whether weekly infusions of cisplatin during radiotherapy improve progression-free and overall survival among patients with bulky stage IB cervical cancer. METHODS Women with bulky stage IB cervical cancers (tumor, > or =4 cm in diameter) were randomly assigned to receive radiotherapy alone or in combination with cisplatin (40 mg per square meter of body-surface area once a week for up to six doses; maximal weekly dose, 70 mg), followed in all patients by adjuvant hysterectomy. Women with evidence of lymphadenopathy on computed tomographic scanning or lymphangiography were ineligible unless histologic analysis showed that there was no lymph-node involvement. The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A (cervical parametrium) and 55 Gy to point B (pelvic wall). Cisplatin was given during external radiotherapy, and adjuvant hysterectomy was performed three to six weeks later. RESULTS The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95 percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively. The rates of both progression-free survival (P<0.001) and overall survival (P=0.008) were significantly higher in the combined-therapy group at four years. In the combined-therapy group there were higher frequencies of transient grade 3 (moderate) and grade 4 (severe) adverse hematologic effects (21 percent, vs. 2 percent in the radiotherapy group) and adverse gastrointestinal effects (14 percent vs. 5 percent). CONCLUSIONS Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers.

Carcinoma of the cervix treated with radiation therapy I. A multi‐variate analysis of prognostic variables in the gynecologic oncology group

Between 1977 and 1985, the Gynecologic Oncology Group (GOG) conducted three clinical trials in locally advanced carcinoma of the cervix, clinical Stages I to IVA as classified by the International Federation of Gynecology and Obstetrics (FIGO). All 626 patients had primary carcinoma of the cervix and underwent operative assessment of the para‐aortic (PA) lymph nodes. Patients received standardized external radiation therapy to the pelvis or to the pelvis and PA lymph nodes followed by one or two brachytherapy applications. To date, no statistically significant differences in progression‐free interval (PFI) or survival time have been identified between the randomization treatment arms on any of these studies. Basic similarities among these studies led us to pool these data to identify patient characterisitcs and tumor characteristics associated with an increased risk of treatment failure. Multi‐variate analysis showed patient age, performance status (PS), PA lymph node status, tumor size, and pelvic node status to be significantly associated with PFI. When modeling for survival, all these factors and clinical stage and bilateral extension were significant.

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.

A prospective surgical pathological study of stage I squamous carcinoma of the cervix: A Gynecologic Oncology Group study

Thirty-three institutions collaborating in the Gynecologic Oncology Group gathered surgical and pathological data on 1125 patients with primary, previously untreated, histologically confirmed stage I cervical carcinoma with more than 3 mm of invasion who were selected to undergo radical hysterectomy and paraaortic and pelvic lymphadenectomy. Of the 940 eligible, evaluable patients, 732 had squamous carcinoma. Of the study group, 87 (12%) did not undergo radical hysterectomy because of gross disease beyond the uterus or microscopic aortic node involvement documented at exploratory laparotomy. Among the 645 patients undergoing pelvic and paraaortic lymphadenectomy and radical hysterectomy, five risk factors were significantly associated with microscopic pelvic lymph node metastasis: depth of invasion (P = 0.0001), parametrial involvement (P = 0.0001), capillary-lymphatic space invasion (P = 0.0001), tumor grade (P = 0.01), and gross versus occult primary tumor (P = 0.009). The factors identified as independent risk factors for pelvic lymph node metastasis by multivariate analysis were capillary-lymphatic space involvement (P less than 0.0001), depth of invasion (P less than 0.0001), parametrial involvement (P = 0.0005), and age (P = 0.02). The model was used to predict the chance of a patient having nodal metastasis for any combination of risk factors.

Steroid receptors and clinical outcome in patients with adenocarcinoma of the endometrium

Progesterone receptor content was measured in tissue samples from 175 patients with endometrial adenocarcinoma by use of the dextran-charcoal method. The estradiol receptor content was determined in 138 of these samples. Ninety-two tumors (52.6%) tested positive for progesterone receptors (greater than 50 fmol/mg cytosol protein) and 111 (80.4%) tested positive for estradiol receptors (greater than 6 fmol/mg). Median follow-up was 27.3 months (range 1 to 152 months). Progesterone receptor status correlated significantly with grade, histology, adnexal spread, age, and recurrence rate in stage I cancer. There was no correlation between progesterone receptor status and clinical stage, myometrial invasion, peritoneal cytology, retroperitoneal lymph node involvement, or spread to the cervix. Estradiol receptor status correlated with adnexal spread and recurrence rate. Recurrence in patients with stage I disease was significantly more common if tumors were negative for progesterone receptor (16 of 43, 37.2%) than if they were positive (four of 57, 7%; p less than 0.001). Recurrence was also more common if tumors were negative for estradiol receptor (seven of 17, 41.2%) than if they were positive (eight of 63, 12.7%; p = 0.02). In recurrent or advanced disease, response to progestin was independent of estradiol receptor content, but tumors positive for progesterone receptors responded significantly more often than those lacking progesterone receptors. Overall survival was superior for patients with progesterone receptor-positive tumors (p = 0.001). Although survival in clinical stages I and II was also superior in patients with lesions positive for progesterone receptors (p = 0.13), there was no statistical difference in survival between patients with progesterone receptor-positive or -negative cancers and surgical stages I and II disease (p = 0.12). Estradiol receptor status had no apparent correlation with survival.

Secondary ovarian neoplasia. A clinicopathologic study of 35 cases

The authors reviewed the clinical and pathologic features of 35 cases of secondary ovarian neoplasms in which the clinical presentation was that of a primary ovarian tumor. The most common secondary neoplasms to mimic an ovarian tumor were colonic adenocarcinoma, breast carcinoma, lymphoma, carcinoid, and gastric adenocarcinoma. It was found that a classification based on gross appearance was useful in evaluating these neoplasms. Solid neoplasms with either a diffuse or nodular gross appearance had distinct histologies so that accurate diagnosis was possible. Cystic neoplasms, especially colon adenocarcinomas, were deceptive and frequently misclassified as primary ovarian adenocarcinoma. Since all of the metastatic colonic carcinomas had mucus‐containing cells, the main differential diagnosis was between metastatic colonic carcinoma and primary mucinous carcinoma of the ovary. The absence of a mucus‐cell predominant pattern and the lack of transition from benign‐appearing epithelium to malignant epithelium are two useful criteria in making this important distinction. Other features may also prove helpful. Cancer 53:1164‐1174, 1984.

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.

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.

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.

Malignant papillary lesions of the endometrium

In a review of 440 patients treated for endometrial adenocarcinoma at this center since 1974, 21 patients with tumors of papillary histology were identified. Eleven (2.5%) lesions contained histologic changes characteristic of uterine papillary serous carcinoma: complex papillary architecture, high nuclear/cytoplasmic ratio, and irregular epithelial tufting. Ten lesions (2.3%) containing areas of papillary morphology but lacking the criteria for the diagnosis of papillary serous tumors were termed papillary endometrioid adenocarcinoma. Patient age, stage, and the presence of obesity, hypertension, and diabetes were similar in both groups and reflected those characteristics well established for endometrial adenocarcinoma in general. Fewer papillary serous tumors (16.7%) and papillary endometrioid tumors (33.3%) contained progesterone receptors than did other adenocarcinomas (52.3%). In clinical stage I, surgical findings indicating a more advanced stage were present in 40% of patients with papillary serous tumors compared to 10% in papillary endometrioid tumors and 12.5% in nonpapillary adenocarcinomas (P = 0.03, Fishers exact test). Recurrences were observed in 50% of patients with papillary serous lesions compared to 42.9% in papillary endometrioid lesions and 24.3% in other adenocarcinomas. Survival for clinical stage I papillary serous tumors was worse than that for nonpapillary grade 3 controls (P = 0.042) and survival for papillary endometrioid lesions was not different from that of the same controls. These findings support those of J. L. Chen, D. C. Trost, and E. J. Wilkinson (Int. J. Gynecol. Pathol. 4, 279-288 (1985)) that papillary serous and papillary endometrioid adenocarcinomas represent two distinct subtypes of papillary endometrial neoplasia.