Clinical trials in gynecological cancer.

The Gynecologic Cancer Intergroup is comprised representatives from international gynecological cancer trials organizations, which collaborate in multicenter studies to answer the clinical challenges in gynecological cancer. This review article highlights the key clinical questions facing clinical trialists over the next decade, the information and infrastructure resources available for trials, and the methods of trial development. We cover human papillomavirus (HPV)-associated neoplasia, including cervical cancer, together with endometrial cancer, ovarian cancer, and vulvar cancer. Infrastructure for clinical trials includes a database for trials, templates for protocol development, patient educational material, and financial support for clinical trials. Other critical issues include support from government and charities and government regulations.

What is the role of conservative primary surgical management of epithelial ovarian cancer: the United States experience and debate.

Certification in Gynecologic Oncology and creation of the Society of Gynecologic Oncologists in the United States have led to the development of a specialty with individuals capable of performing complex abdominal and pelvic operations in the management of epithelial ovarian carcinoma. These operations can be divided into two types. 1) A staging operation to assess the extent of disease through careful palpation, histologic and cytologic assessment of all peritoneal surfaces along with removal of the uterus, ovaries and fallopian tubes, omentum, together with a bilateral pelvic and aortic lymphadenectomy. Such information allows the clinician to determine prognosis and if postoperative adjuvant therapy is indicated. 2) A debulking operation designed to resect or reduce the size of metastatic lesions as well as to remove the primary tumor including a bilateral salpingo-oophorectomy. This operation is designed to improve survival and cure. In spite of this apparently clear paradigm, there has been a steady debate as to the apparent justification of these operations, especially when the former is performed in a women who has not completed her childbearing and especially when the latter requires "ultraradical" procedures. Many feel that the pendulum is now swinging toward fertility-sparing surgery among young women with early invasive cancers and toward either neoadjuvant chemotherapy or less than ultraradical debulking among women with advanced ovarian cancer. The purpose of this study is not to provide an exhaustive review but rather to outline this debate and focus on the American experience with conservative surgery in the management of epithelial ovarian carcinoma.

Chemoradiation: A new approach for the treatment of cervical cancer.

Despite advances in screening, cervical cancer remains a major health problem worldwide. In an effort to improve loco-regional control, both neoadjuvant and chemoradiation have been trialed. Recently, five randomized clinical trials performed by the Gynecologic Oncology Group, the Radiation Therapy Oncology Group and the Southwest Oncology Group have demonstrated a significant advantage both in progression-free and overall survival when cisplatin-based chemotherapy was administered during radiation for advanced stages of cervical cancer. Based on the results of these trials, the US National Cancer Institute released a Clinical Announcement supporting the concurrent use of cisplatin-based chemotherapy with radiation therapy for high-risk early stage and locally advanced stage cervical cancer. Subsequently, an additional prospective randomized trial performed by the National Cancer Institute of Canada was not able to show benefit with the use of chemoradiation compared with radiation alone for patients with locally advanced stage cervical cancer. This article will analyze these six clinical trials in order to determine the role of chemoradiation in the management of patients with cervical cancer. Furthermore, as anemia is one of the most powerful prognostic factors in patients with cervical cancer, we propose to evaluate the relationship between a decreased level of hemoglobin and treatment outcome.

Recent advancements in the treatment of epithelial ovarian cancer.

Important advances in the management of advanced epithelial ovarian cancer have been made in recent years, with much of the knowledge emanating from clinical trials conducted by the Gynecological Oncology Group (GOG). This monograph reviews the trials that have defined current clinical practice and summarizes some innovative techniques and promising new drugs for the future

Bilateral pheochromocytoma in pregnancy heralding multiple endocrine neoplasia syndrome IIA. A case report.

BACKGROUND: Multiple endocrine neoplasia syndrome type IIA (MEN IIA) has rarely been encountered in pregnancy. CASE: A 22-year-old, nulliparous woman developed bilateral pheochromocytomas during pregnancy. This finding aroused suspicion for MEN IIA, and close endocrinologic follow-up was arranged. Four years later, hyperparathyroidism developed, and the diagnosis was established. The patient underwent prophylactic total thyroidectomy with parathyroid exploration. CONCLUSION: This was the first case of MEN IIA in pregnancy in which the diagnosis was established prior to the development of medullary thyroid cancer, thereby allowing prophylactic thyroidectomy. The presence of bilateral neoplastic disease in young patients may be indicative of a hereditary predisposition to malignancy.

Fluorescence detection of cervical intraepithelial neoplasia for photodynamic therapy with the topical agents 5-aminolevulinic acid and benzoporphyrin-derivative monoacid ring.

OBJECTIVE: The aim of this study was to determine whether 2 photosensitizers, benzoporphyrin-derivative monoacid ring and 5-aminolevulinic acid, are selectively absorbed by dysplastic cervical cells after topical administration. STUDY DESIGN: This phase I clinical trial involved 18 women with biopsy-proven cervical intraepithelial neoplasia at the Beckman Laser Institute, Irvine, Calif. Colposcopically directed cervical biopsy specimens obtained after 1.5, 3, or 6 hours of exposure to a randomly assigned photosensitizer were evaluated for selective drug absorption with hematoxylin and eosin staining and fluorescence microscopy. RESULTS: After exposure to 5-aminolevulinic acid, cervical tissue showed maximal fluorescence in dysplastic cells relative to normal cells, with negligible stromal fluorescence. According to our detection methods benzoporphyrin-derivative monoacid ring demonstrated nonselective, diffusion-driven uptake, with fluorescence appearing in the superficial cells, followed by nonselective drug absorption in the remaining cells and stroma of the epithelium. CONCLUSION: Our data demonstrated selective absorption of 5-aminolevulinic acid by dysplastic cervical cells. This agent therefore represents a promising photosensitizing prodrug for the treatment of cervical intraepithelial neoplasia with photodynamic therapy.

Estrogen replacement therapy in endometrial cancer patients: a matched control study.

OBJECTIVE: To determine if estrogen replacement therapy, in women with a history of endometrial cancer, increases the risk of recurrence or death from that disease. METHODS: Two hundred forty-nine women with surgical stage I, II, and III endometrial cancer were treated between 1984 and 1998; 130 received estrogen replacement after their primary cancer treatments and 49% received progesterone in addition to estrogen. Among this cohort, 75 matched treatment-control pairs were identified. The two groups were matched by using decade of age at diagnosis and stage of disease. Both groups were comparable in terms of parity, grade of tumor, depth of invasion, histology, surgical treatment, lymph node status, postoperative radiation, and concurrent diseases. The outcome events included the number of recurrences and deaths from disease. RESULTS: The hormone users were followed for a mean interval of 83 months (95% confidence interval [CI] 71.0, 91.4) and the nonhormone users were followed for a comparable mean interval of 69 months (CI 59.1, 78.7). There were two recurrences (1%) among the 75 estrogen users compared with 11 (14%) recurrences in the 75 nonhormone users. Hormone users had a statistically significant longer disease-free interval than nonestrogen users (P =.006). CONCLUSION: Estrogen replacement therapy with or without progestins does not appear to increase the rate of recurrence and death among endometrial cancer survivors.

Primary invasive carcinoma of the vagina: treatment with interstitial brachytherapy.

BACKGROUND: Because primary carcinoma of the vagina comprises less than 2% of all gynecologic malignancies, the reported experience in the treatment of large numbers of patients is available only from a few major centers and most often encompasses a variety of differences in treatment selection and technique. The objective of this study was to assess the long term results of an interstitial iridium-192 afterloading implant technique using the Syed-Neblett dedicated vaginal plastic template. METHODS: Patients who were treated from 1976 to 1997 were examined retrospectively. RESULTS: Seventy-one patients underwent interstitial implantation with (n = 61 patients) or without external beam radiotherapy. The median age was 59 years (range, 16-86 years). Patients were staged according to the International Federation of Gynecology and Obstetrics system and included Stage I (n = 10 patients), Perez modification Stage IIA (n = 14 patients), Perez modification Stage IIB (n = 25 patients), Stage III (n = 15 patients), and Stage IV (n = 7 patients). Each implant delivered an approximately 20-gray (Gy) minimum tumor dose, with the total tumor dose reaching 80 Gy with integrated external beam radiotherapy. Local control was achieved in 53 patients (75%). The median follow-up was 66 months (range, 15-163 months), and the 2-year, 5-year, and 10-year actuarial disease free survival rates are 73%, 58%, and 58%, respectively. By stage, 5-year disease free survival rates included Stage I, 100% of patients; Stage IIA, 60% of patients; Stage IIB, 61% of patients; Stage III, 30% of patients; and Stage IV, 0% of patients. The factors disease stage and primary lesion size independently influenced the survival rates. Significant complications occurred in 9 patients (13%) and included necrosis (n = 4 patients), fistulae (n = 4 patients), and small bowel obstruction (n = 1 patient). CONCLUSIONS: Interstitial irradiation can effect local control in the majority of patients with primary carcinoma of the vagina with acceptable morbidity. Long term cure is demonstrable in patients with Stage I-III disease.

Bowel resection at the time of primary cytoreduction for epithelial ovarian cancer.

BACKGROUND: The purpose of this study was to determine the morbidity and survival associated with bowel resection at the time of primary cytoreductive surgery for ovarian cancer. STUDY DESIGN: We reviewed all patients undergoing bowel resection by gynecologic oncology faculty at the time of primary cytoreduction for advanced epithelial ovarian cancer diagnosed between 1983 and 1995. RESULTS: There were 105 patients meeting the above criteria. The median age was 65 years (range 34 to 85 years). There were 76 stage III and 25 stage IV cancers. The primary indication for bowel resection was tumor debulking in 92% of the patients. Seventy patients had segmental resection of the colon only, and 22 patients underwent resections that included the large and small bowels. Mean operating time was 260 minutes and mean estimated blood loss was 1,447 mL. Thirty-three (31%) patients were optimally cytoreduced to less than 1 cm residual disease. Ten patients experienced major complications directly related to bowel resection, including bowel fistula (4 patients), early postoperative bowel obstruction (5 patients), and stomal hernia (1 patient). Other morbidity included ileus for more than 10 days (18 patients), cardiac complications (17 patients), pneumonia (8 patients), sepsis (5 patients), and thromboembolism (4 patients). Six patients died and five patients required reexploration within 30 days of operation. Patients with preoperative bowel obstruction and suboptimal residual disease were more likely to have postoperative morbidity. Median survival in the optimally debulked patients was 35 months compared with 18 months in patients suboptimally cytoreduced (p = 0.006). Multivariate analysis demonstrated that optimal debulking (p = 0.009) and platinum chemotherapy (p = 0.00006) were independently associated with improved survival. Age, International Federation of Gynecologia Oncologists stage, American Society of Anesthesiologists class, and paclitaxel chemotherapy did not influence survival. CONCLUSIONS: In patients undergoing bowel resection at the time of primary cytoreduction for ovarian cancer, optimal cytoreduction to less than 1 cm residual disease results in improved survival. Morbidity is common but is comparable to other published series of ovarian cancer patients undergoing primary cytoreductive surgery without bowel resection. Additionally, patients with preoperative bowel obstruction and suboptimal residual disease are more likely to have serious morbidity.

Biomarker conservation in primary and metastatic epithelial ovarian cancer.

PURPOSE: The aim of this study was to compare the overexpression of specific biomarkers in primary advanced and recurrent epithelial ovarian cancers. METHODS: Biomarker expression by epithelial ovarian cancer specimens from primary and metastatic sites was examined by immunohistochemistry and flow cytometry. Biomarker expression by subpopulations of tissues consisting of matched pairs of synchronous and metachronous lesions was also studied. RESULTS: A total of 3173 epithelial ovarian cancer specimens were retrieved from women with FIGO Stage III/IV disease. These included lesions from 1036 primary and 2137 metastatic sites. The percentages of biomarker expression for primary and metastatic lesions, respectively, were MDR1, 12 and 10%; p53, 55 and 60%; HER2, 12 and 11%; EGF-R, 26 and 33%; increased microvessel counts (CD31), 21 and 36%. Approximately 73% of both primary and metastatic specimens were aneuploid, and approximately 57% of both sets had an S-phase fraction >7%. Only EGF-R and CD31 expression were found to be significantly different between the primary and metastatic tumors (P < 0.05). Of the paired synchronous cases (n = 48) evaluated, 88% of aneuploid primary lesions were associated with aneuploid metastases. Similarly, the distributions for MDR1, HER2, and p53 expression did not vary significantly between primary and metastatic sites. Pairings of metachronous cases (n = 66) revealed that nearly 80% of primary aneuploid tumors (n = 39) retained their aneuploid status at the time of relapse. Furthermore, there were no significant changes in MDR1, p53, or HER2 expression at relapse. CONCLUSIONS: With the exception of EGF-R and CD31, clonal divergence of the biomarkers evaluated in this study probably does not play a significant role in imparting clinical heterogeneity during the advanced and recurrent stages of epithelial ovarian cancer. These particular genes likely undergo alterations early in the tumorigenesis process before metastases have become established.

Obstetric emergencies precipitated by malignant brain tumors.

OBJECTIVE: Our goal was to present a case series of pregnancy-associated malignant brain tumors. STUDY DESIGN: A review was conducted from 1978-1998 at 5 hospitals. RESULTS: Ten women were diagnosed with a malignant brain tumor during pregnancy (n = 8) or post partum (n = 2). Patients diagnosed antenatally exhibited severe symptoms, manifest between 27 and 32 weeks' gestation. Six were emergently delivered of their infants because of maternal deterioration, and 2 were delivered electively in the early third trimester after documentation of fetal pulmonary maturity. There were 4 maternal deaths and 1 neonatal death; all of the other infants maintained viability. CONCLUSIONS: Malignant brain tumors rarely occur in pregnancy. In contrast to reports that describe an indolent course, each of the 8 antenatal patients experienced a neurologic crisis. If symptoms are amenable to pharmacologic control, we advocate delivery in the early third trimester after documentation of fetal pulmonary maturity. To minimize temporal lobe or cerebellar herniation in neurologically unstable patients, a consideration should be made for cesarean delivery with the patient under general anesthesia, followed by immediate neurosurgical decompression.

Development and assessment of a general theory of cervical carcinogenesis utilizing a severe combined immunodeficiency murine-human xenograft model.

OBJECTIVE: Currently, we lack a theoretical explanation for why squamous cell cervical cancer develops predominantly in specific sites (i.e., along the squamocolumnar junction). We therefore implanted human cervical tissues containing the transformation zone in severe combined immunodeficiency (SCID) mice and studied morphology, steroid effects, gene expression, and human papillomavirus (HPV) factors. METHODS: Normal and dysplastic human cervical tissues (3 x 2 mm) were placed subcutaneously in SCID-beige mice and later assessed by in situ hybridization for HPV 16/18 DNA and by immunohistochemistry for expression of CD31, keratin, proliferating-cell nuclear antigen, HPV 16 E6, p53, and Notch-1 (a binary cell fate determination protein). Some normal tissues were implanted with either a 90-day release 1.7-mg 17beta-estradiol pellet or a 5-mg tamoxifen pellet; others were infected prior to implantation with human recombinant adenovirus 5 vector containing a human cytomegalovirus promoter-driven beta-galactosidase gene and later assessed by X-gal staining. RESULTS: Murine and human vessels formed anastomoses by 3 weeks. For at least 11 weeks, normal tissue retained the transformation zone and normal cell-type-specific keratin expression and exhibited normal proliferation; Notch-1 was present only in the basal cell layer. Dysplastic tissues exhibited koilocytosis, increased levels of cellular proliferation, and aberrant keratin, p53, and Notch-1 expression; HPV 16/18 DNA and HPV 16 E6 protein were detected for at least 6 weeks. Squamous metaplasia of normal cervical epithelium resulted from estrogen exposure, and a predominant columnar differentiation pattern was associated with tamoxifen administration. Through stable adenovirus infection, beta-galactosidase was expressed for at least 6 weeks. CONCLUSIONS: This small manipulatable xenograft model maintains normal and dysplastic human cervical epithelium through neovascularization. Neoplastic tissue retains HPV 16/18 DNA and a premalignant phenotype, including elevated levels of cellular proliferation and aberrant keratin, p53, and Notch-1 expression. These attributes constitute essential features of a biologic model through which one may study HPV-mediated human disease and may be superior to cell culture and transgenic murine systems. Furthermore, this may serve as a model for gene therapy. Finally, we suggest that the normal cervical epithelium is maintained through putative interactions between the Notch locus and cell cycle growth regulators such as p53 and pRb. Neoplastic cervical epithelium may arise through disruption of this pathway. This theory may be testable in our animal model.

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.

Evaluation of D-methionine as a cytoprotectant in cisplatin treatment of an animal model for ovarian cancer.

BACKGROUND: To evaluate the use of D-methionine(D-met) as a cytoprotectant in the context of clinically relevant doses of cisplatin. MATERIALS AND METHODS: Forty five Fischer rats were injected intraperitoneally with 10(6) NuTu-19 cells and treated as follows: group 1 was the control group and received no treatment, group 2 received cisplatin 4 mg/kg and group 3 received cisplatin 4 mg/kg plus D-met. There were two groups that received high dose cisplatin. Group 4 received cisplatin 8 mg/kg and group 5 received cisplatin 8 mg/kg plus D-met. Treatment was initiated four weeks after injection of the NuTu-19 cells, and consisted of four weekly intraperitoneal injections. Serum BUN and creatinine levels in the high dose groups evaluated nephrotoxicity and clinical outcome was measured by mean survival using Kaplan Meier analysis. RESULTS: There were no significant elevations in serum BUN or creatinine levels in any of the rats treated with high dose cisplatin. In the animals given cisplatin 8 mg/kg plus D-met, death from toxicity was prevented and all animals completed four treatments. In contrast, only two animals in group 4 (cisplatin 8 mg/kg alone) completed 4 treatments. There was a significant improvement in survival for the animals given D-met. (p = .0001) In all treated groups except for group 4, there was an improvement in survival compared to the control group. When comparing groups 2 and 3 (4 mg/kg +/- D-met), there was a subjective decrease in tumor response for group 3 but mean survival was not statistically different. (91 vs. 81 days; p = 0.07) A comparison of groups 2 and 5 revealed no survival benefit using high dose cisplatin with D-met. (91 vs. 79 days; p = 0.10). CONCLUSIONS: Our results indicate that D-methionine provides cytoprotection against cisplatin toxicity without significant compromise of antitumor activity. All though D-methionine allowed for significant dose intensification of cisplatin above standard doses, there was no survival advantage noted in this group of animals. The indications for its use in the treatment of ovarian cancer remain to be determined.

Breast cancer survival and hormone replacement therapy: a cohort analysis.

Controversy exists regarding the safety of hormone replacement therapy (HRT) after a diagnosis of breast cancer. The objective of this study is to perform a matched cohort analysis to evaluate the impact of HRT on mortality in breast cancer survivors. Patients with breast cancer who received HRT after diagnosis of breast cancer were identified. Control subjects were identified from the regional cancer registry. Matching criteria included age at diagnosis, stage of breast cancer, and year of diagnosis. Controls were selected only if they were alive at the time of initiation of HRT of the matched case. Only subjects not included in a previously reported matched analysis were selected. One hundred twenty-five cases were matched with 362 controls. Ninety-eight percent (123/125) of the cases received systemic estrogen; 90/125 (72%) also received a progestational agent. The median interval between diagnosis of breast cancer and initiation of HRT was 46 months (range 0-401 months). The median duration of HRT was 22 months (range 1-357 months). The risk of death was lower among the HRT survivors; odds ratio 0.28 (95% confidence interval 0.11-0.71). This analysis does not suggest that HRT after the treatment of breast cancer is associated with an adverse outcome.

An experience with estrogen replacement therapy in breast cancer survivors.

OBJECTIVE: To evaluate the outcome of breast cancer patients who elected estrogen replacement therapy (ERT). STUDY DESIGN: Breast cancer survivors who elected ERT received the preferred regimen of conjugated estrogen 0.625 mg/day with medroxyprogesterone acetate 2.5 mg/day. RESULTS: 145 patients received ERT for at least 3 months. Thirteen recurrences (9%) were identified; 10 are alive with disease, 3 are dead of disease. The median interval between diagnosis and commencement of ERT was 41 months. Forty-one percent of the study group initiated ERT within 3 years of their breast cancer diagnosis. The median duration of follow-up on ERT was 30 months. CONCLUSION: The concern that ERT might activate growth in occult metastatic sites and promote a rash of recurrences was not confirmed. It is unreasonable to categorically deny all breast cancer survivors ERT.

Interstitial brachytherapy for vaginal recurrences of endometrial carcinoma.

OBJECTIVE: The aim of this study was to evaluate the efficacy of interstitial brachytherapy in the management of vaginal recurrences of endometrial carcinoma. METHODS: Thirty patients received interstitial irradiation, with or without external beam radiotherapy. They were followed for a minimum of 5 years or until death. RESULTS: The median age was 66 years at initial diagnosis of endometrial cancer. FIGO stages included Stage I (n = 18), Stage II (n = 7), and Stage III (n = 5). All patients were treated originally by total abdominal hysterectomy and bilateral salpingo-oophorectomy, with or without lymphadenectomy, and 13 (43%) also received postoperative adjuvant whole pelvis radiotherapy as part of their primary treatment. Vaginal recurrences were diagnosed at a mean interval of 29 months after hysterectomy (range, 3-119 months). No patient had clinical evidence of pelvic sidewall extension or of distant metastatic disease. All patients were treated with interstitial brachytherapy; each implant delivered a mean maximal tumor dose of 25.5 Gy. Eighteen patients (60%) also received external beam radiotherapy (mean dose, 48 Gy) as part of their treatment for vaginal recurrence. Twenty-eight patients (93%) experienced a complete clinical response. Ten patients relapsed in the vagina (n = 5) or at distant sites (n = 5). Eleven patients are dead of disease. From the time of vaginal recurrence, the median overall survival was 60 months and the cause of death adjusted 5-year survival rate was 65%. Major morbidity included radiation proctitis (n = 2), fistula (n = 2), and radiation stricture (n = 1). CONCLUSION: Interstitial irradiation resulted in favorable local control as well as a 5-year survival rate and morbidity comparable to that reported previously for conventional brachytherapy.

Significance of true surgical pathologic staging: a Gynecologic Oncology Group Study.

OBJECTIVE: The object of the study was to determine the true surgical pathologic disease extent in patients with clinical stage II adenocarcinoma of the endometrium. STUDY DESIGN: As part of a Gynecologic Oncology Group surgical pathologic protocol of patients with adenocarcinoma of the endometrium, patients with clinical stage II cancers were evaluated. Among >1000 patients with early stage disease entered into this protocol group study, 148 were in clinical stage II. All patients underwent abdominal hysterectomy, bilateral salpingo-oophorectomy, and selective pelvic and para-aortic lymphadenectomy as the primary therapy. Surgical pathologic material was evaluated to determine true extent of disease. RESULTS: Only 66 of 148 (45%) of patients in clinical stage II had cancer in the cervix. Fifty-seven patients had disease limited to the upper fundus and 25 had disease extending into the lower uterine segment but not into the cervix. Among the 66 patients with disease in the cervix, only 35 had disease limited to the uterus whereas 31 patients had extrauterine disease (lymph nodes, adnexa, etc). Thus among 148 patients with diagnoses of clinical stage II disease only 35 (24%) in fact had true surgical stage II cancer. CONCLUSION: Clinical diagnosis of stage II adenocarcinoma of the uterus is a poor reflection of true surgical stage II cancer. Only when true extent of disease is known can optimally definitive therapy be determined.