Michael L. Berman

The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma.

OBJECTIVE The Gynecologic Oncology Group has divided patients with advanced epithelial ovarian cancer into those with optimal residual cancer, in which the maximum diameter of residual is < or = 1 cm, and suboptimal residual cancer, in which the residual disease is > 1 cm. Within the optimal group of patients there is a survival difference between patients with microscopic residual disease and those with any macroscopic disease < or = 1 cm. No analysis of the effect of various residual disease diameters in patients with residual disease > or = 1 cm has been performed. This study evaluates the effect of residual disease diameter in patients with suboptimal disease entered on a randomized trial of intense versus standard chemotherapy. STUDY DESIGN Gynecologic Oncology Group protocol 97 compared cisplatin 50 mg/m2 and cyclophosphamide 500 mg/m2 for eight courses with the same drugs at 100 mg/m2 and 1000 mg/m2 for four courses, respectively. There was no difference in progression-free interval or survival between the two arms. Of the 458 stage III (with residual disease > 1 cm) and stage IV patients entered in this study, 294 stage III patients comprise the current analysis. Surgical reporting forms, operation reports, and pathology reports were reviewed to determine initial greatest tumor diameter and residual tumor diameter. Patients were grouped by residual diameter. Multivariate analysis considered residual diameter of disease, age, histologic characteristics, performance status, and ascites. An adjusted relative hazard of dying of ovarian cancer was calculated for each residual disease group. RESULTS Patients ranged in age from 20 to 80 years, with a median of 60 years. All patients were Gynecologic Oncology Group performance status 0 to 2. Fifty-two percent had grade 3 tumors, and 39% and 9%, respectively, had grade 2 or 1 tumors. All patients had stage III disease. Ninety percent had serous, endometrioid, or mixed epithelial cell type tumors. Multivariate analysis revealed a relative risk of dying as follows: residual disease < 2 cm, relative risk 1.00; 2 to 2.9 cm, relative risk 1.90; 3 to 3.9 cm, relative risk 1.91; 4 to 5.9 cm, relative risk 1.74; 6 to 7.9 cm, relative risk 1.85; 8 to 9.9 cm, relative risk 2.16; > or = 10 cm, relative risk 1.82. The difference in survival between those with < 2 cm residual disease and those with > or = 2 cm residual disease was significant (p < 0.01). There is no significant difference in the risk of dying between groups with residual disease > or = 2 cm. CONCLUSIONS Among patients with suboptimal (> 1 cm residual disease) epithelial ovarian cancer, those who have small diameter residual disease (< 2 cm) tend to survive longer than those who have larger residual disease. Among those with larger residual disease, size does not affect prognosis appreciably.

Reproductive, menstrual, and medical risk factors for endometrial cancer : results from a case-control study

OBJECTIVE Our objective was to evaluate the risk for endometrial cancer in relation to reproductive, menstrual, and medical factors. STUDY DESIGN A case-control study of 405 endometrial cancer cases and 297 population controls in five areas of the United States enabled risk to be evaluated. RESULTS A major risk factor was the absence of a prior pregnancy (relative risk 2.8, 95% confidence interval 1.7 to 4.6). The protective effect of pregnancy appeared to reflect the influence of term births, because spontaneous and induced abortions were unrelated to risk. Among nulliparous women infertility was a significant risk factor, with women having sought medical advice having nearly eight times the risk of those without difficulty conceiving. After adjustment for other reproductive characteristics, age at first birth and duration of breast-feeding were not related to risk. CONCLUSIONS Elevated risks were found for subjects reporting early ages at menarche (relative risk 2.4 for ages < 12 vs > or = 15) and longer days of flow (relative risk 1.9 for > or = 7 vs < 4 days), but there was no relationship with late ages at natural menopause. Height was not associated with risk, but there was a significant relation to weight, with the risk for 200 versus < 125 pounds being 7.2 (95% confidence interval 3.9 to 13.3). After adjustment for weight and other factors, histories of hypertension and gallbladder disease were not significantly related to risk, but an effect of diabetes persisted (relative risk 2.0, 95% confidence interval 1.1 to 3.6). Hirsutism developing at older ages was also significantly related (relative risk 2.0, 95% confidence interval 1.2 to 3.4).

Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: a Gynecologic Oncology Group study.

PURPOSE We report a prospective randomized trial in women with advanced ovarian cancer to evaluate the importance of chemotherapy dose-intensity on survival, progression-free survival (PFS), and response. PATIENTS AND METHODS A total of 485 patients with epithelial ovarian cancer and residual masses more than 1 cm following surgery (stage III presentation) or any stage IV presentation were randomly assigned to receive either standard therapy (cyclophosphamide 500 mg/m2 and cisplatin 50 mg/m2 intravenously every 3 weeks for eight courses) or intense therapy (cyclophosphamide 1,000 mg/m2 and cisplatin 100 mg/m2 intravenously every 3 weeks for four courses). Dose modification was rigidly controlled to maintain intensity. Clinical and pathologic responses were assessed, when appropriate, as well as PFS interval and survival. RESULTS A total of 458 patients met all eligibility criteria and were assessed for survival and PFS. The dose-intensive group received the same total dose of cyclophosphamide and cisplatin, but 1.97 times greater dose-intensity than the standard group. Clinical and pathologic response rates; response duration, and survival were similar in both groups of patients. Hematologic, gastrointestinal, febrile episodes, septic events, and renal toxicities were significantly more common and severe in the dose-intensive group. CONCLUSION A doubling of the dose-intensity in the treatment of bulky ovarian epithelial cancers led to no discernible improvement in patient outcome and was associated with more severe toxicity. This study provides no evidence to support the hypothesis that modest increases in dose-intensity without increasing total dose are associated with significant improvement in overall survival or PFS.

Survival and patterns of recurrence in cervical cancer metastatic to periaortic lymph nodes

Ninety-eight of 621 evaluable patients (16%) with cervical cancer enrolled into Gynecologic Oncology Group protocols were found to have periaortic lymph node metastases at staging laparotomy or at exploration for definitive operative management. As expected there was a progressive increase in the prevalence of periaortic metastases including 5% of 150 patients with Stage IB, 16% of 222 patients with Stage II, and 25% of 135 patients with Stage III. Periaortic lymph node metastases in the absence of pelvic lymph node metastases was an infrequent occurrence in patients so evaluated. The median survival of patients with periaortic metastases was 15.2 months with a survival probability of 25% at 3 years. The median duration of survival following recurrence was only 5 months. Recurrences were divided approximately equally between the pelvis and distant sites.

Malignant germ cell tumors of the ovary

Objective To evaluate the efficacy of adjuvant therapy for ovarian germ cell tumors. Methods We reviewed records of women who had malignant germ cell tumors of the ovary from 1977–1997. Results Seventy-two women had surgical resections of malignant ovarian germ cell tumors and most received adjuvant therapy. Fifty-six women (78%) presented with stage I disease, and 16 (22%) had more advanced disease. Tumor subtypes included dysgerminoma (n = 20), yolk sac tumor (n = 8), immature teratoma (n = 29) and mixed germ cell tumor (n = 15). Surgical management of the 56 with stage I disease consisted of total abdominal hysterectomy, bilateral salpingo-oophorectomy, and extensive surgical staging in ten women, whereas a conservative surgical approach, consisting of unilateral adnexectomy with or without comprehensive surgical staging, was adopted in later years (n = 46). Fifty-six women were treated with postoperative chemotherapy, predominantly platinum-based regimens. The 5-year actuarial survival rate was 93%. None of the 36 women who presented after 1984 have died of disease. Conclusion These data confirmed that platinum-based adjuvant treatments allow most women with ovarian germ cell malignancies to have conservative surgery without compromising survival.

Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium.

OBJECTIVE To evaluate the biological behavior of noninvasive papillary serous carcinoma of the endometrium. METHODS; From 1990 to 2001, all women with noninvasive uterine papillary serous carcinoma (UPSC) at three Southern California hospitals were identified from tumor registry databases. Data for analysis were collected from hospital charts, office records, and tumor registry files. RESULTS Of the 100 patients diagnosed with UPSC, 16 had noninvasive lesions. Twelve underwent a comprehensive surgical staging procedure with omental resection. Six of these 12 women were found to have disease beyond the uterine corpus, including 4 with adnexal involvement, 3 with omental disease, 2 with cervical extension, 1 with pelvic lymph node involvement, and 3 with positive washings. Three women were found to have positive cytology and metastases in more than one location. Of the 12 patients, 1 of the 6 with stage IA disease had distant recurrence and 4 of the 6 with stage II-IV disease recurred. Of the remaining 4 patients who underwent a staging procedure without pathologic omental assessment, 1 was found to have cervical extension. In these 4 women, 1 with stage IA disease recurred. CONCLUSION The typical patterns of spread and prognostic factors for endometrioid carcinoma of the uterus do not apply to UPSC. In our series, omental assessment was necessary to detect the 25% of patients with stage IVB disease due to omental involvement. Thus, women with noninvasive UPSC should undergo a comprehensive staging procedure including omental sampling to determine the extent of disease.

Estrogen replacement in surgical stage I and II endometrial cancer survivors

OBJECTIVE Our purpose was to evaluate our experience with estrogen replacement in women with a history of early-stage endometrial cancer and to determine whether it increased the risk for recurrence or death. STUDY DESIGN A retrospective review was performed of 123 women with surgical stage I and II endometrial adenocarcinoma treated between 1984 and 1994; 62 had received estrogen replacement therapy after cancer therapy. Sixty-one women received no estrogen. Variables analyzed included age parity, surgical stage, grade, depth of myometrial invasion, presence of intercurrent illnesses, duration of follow-up, and duration of estrogen replacement, if applicable. Outcome variables assessed included recurrence rate, time to recurrence, and disease-free interval. RESULTS The estrogen replacement therapy group had earlier stage disease (p = 0.04) and less severe depth of invasion (p = 0.003); however, the total number of deaths in each group was not significantly different. The disease-free survival in the estrogen replacement therapy group did not differ significantly compared with those not receiving estrogen replacement therapy. The data are suggestive of improved disease-free survival in the estrogen replacement therapy group, which may be related to differences in age, stage, grade, and depth of invasion. The overall recurrence rate was 6.5%, with an overall death rate of 1.6%. CONCLUSIONS There is no evidence to suggest that estrogen decreased the disease-free interval or increased the risk for recurrence in early-stage disease.

Value of preoperative CA 125 level in the management of uterine cancer and prediction of clinical outcome.

Objective To enhance cost-effective management of uterine cancer by predicting the likelihood of extrauterine disease and survival on the basis of preoperative parameters. Methods A retrospective review of preoperative CA 125 levels from 210 women with endometrial carcinoma was performed. The relationship of preoperative CA 125 levels to various preoperative and postoperative histopathologic factors was investigated. Methods Elevated CA 125 (greater than 35 U/mL) correlated (P < .05) with higher stage, higher grade, increased depth of myometrial invasion, positive cytology, pelvic or para-aortic lymph node metastases, and reduced actuarial survival (P < .001). Multivariate analysis of preoperative factors showed that an elevated CA 125 level was the most important predictor for poor survival (P < .001). Moreover, a preoperative CA 125 level greater than 65 U/mL was the most significant predictor of extrauterine disease and carried a 6.5-fold higher risk (95% confidence interval 2.5, 17.1). A logistic model to predict extrauterine disease was developed. The model has a sensitivity of 62%, specificity of 91%, positive predictive value of 69%, and negative predictive value of 88%. Conclusion A CA 125 level should be included as part of the preoperative workup for all patients with uterine cancer. Patients with a preoperative CA 125 level less than or equal to 20 U/mL should be considered as candidates for vaginal hysterectomy unless unfavorable histology or a high-grade (grade II or III) tumor is present. In our series, this approach would have eliminated 24% of the abdominal staging procedures, with a risk of less than 3% for extrauterine disease, while lowering treatment-related morbidity and cutting costs in the treatment of this common female cancer.

Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: a Gynecologic Oncology Group Study.

Ifosfamide (isophosphamide) and mesna (2-mercaptoethane sodium sulfonate) were administered intravenously at monthly intervals to 46 patients with advanced epithelial ovarian carcinoma refractory to or recurrent after cisplatin-containing combination chemotherapy. Initially, ifosfamide was given as 1.5 g/m2/d x 5 days and mesna as 300 mg/m2 every 4 hours for three doses following ifosfamide, but the initial dose of ifosfamide was reduced to 1.2 g/m2 because of toxicity. Four of the patients initially entered were found to be ineligible: two who had had more than one prior chemotherapy regimen and two who did not have ovarian primaries. One patient received an inadequate trial and four patients had discontinuation of therapy because of toxicity, leaving 41 evaluable for response. Three patients (7.0%) had complete responses and five (13.0%) had partial responses for an overall response rate of 20.0%. Response duration ranged from 2.1 to 20.3 + months with a median of 6.9 + months. Two patients died of renal failure, one of whom had no known renal disease and received 1.5 g/m2/d x 5 days ifosfamide. The second patient received the 1.2 g/m2 dose and was found to have chronic pyelonephritis and pyonephrosis at autopsy. Gynecologic Oncology Group (GOG) grade 3 or 4 granulocytopenia was seen in eight (19.5%), grade 3 or 4 thrombocytopenia in four (9.8%), and grade 3 or 4 neurotoxicity in six (14.6%) of the 41 patients evaluable for toxicity. Ifosfamide/mesna is active in epithelial ovarian cancer. GOG trials in untreated patients are being initiated and toxicity is being evaluated.

Clinical and histologic features of vulvar carcinomas analyzed for human papillomavirus status: Evidence that squamous cell carcinoma of the vulva has more than one etiology

The association between the human papillomavirus (HPV) and malignant neoplasms of the uterine cervix is well established; however, its role in the pathogenesis of vulvar cancer has not been well defined. This study correlates the clinical and histopathologic features of 21 invasive carcinomas of the vulva with the presence of HPV DNA as detected by Southern blot and polymerase chain reaction (PCR) analysis. By one or both techniques, HPV DNA was detected in 10 of the 21 tumors analyzed; all HPVs containing tumors hybridized with HPV-16 probes, although PCR also detected HPV-6 in two of the HPV-16-containing tumors. No HPV-18 DNA was detected in any tumor by PCR or Southern blot hybridization. Both the invasive cancer and the surrounding intraepithelial disease tended to display histopathologic features that usually could distinguish HPV-associated cancers from those without HPV DNA. The intraepithelial lesions associated with HPV-containing tumors were of the bowenoid type with koilocytosis, while tumors lacking HPV generally demonstrated a simplex type of intraepithelial lesion. Invasive tumors with no viral DNA were more frequently keratinizing than the HPV-containing cancers. Race, parity, hormonal therapy, and alcohol use did not affect the HPV status; however, HPV DNA was more prevalent in the tumors of younger women and in those with a history of tobacco use. Human papillomavirus status had no impact on the stage of disease or its prognosis. These findings identify two subsets of vulvar carcinoma cases based on HPV hybridization data and the histopathologic characteristics of the tumor.