Heterogeneity of stage IIIA endometrial carcinomas: implications for adjuvant therapy.

The purpose of this study was to evaluate overall survival (OS) and determine prognostic subclassifications for stage IIIA endometrial cancer. Stage IIIA endometrial cancer patients treated at M.D. Anderson Cancer Center from 1989 to 2002 were reviewed. Clinical information was obtained from the medical record. Cox regression analyses were performed to evaluate the association of pathologic criteria and OS. Patients were divided into four groups based on this analysis: E1, endometrioid/pelvic cytology only; E2, endometrioid/adnexa +/- serosal spread; NE1, nonendometrioid/pelvic cytology only; and NE2, nonendometrioid/adenexa +/- serosal spread. Forty-nine patients were identified. By multivariate analysis, histology and extent of disease were the only factors associated with OS. Five-year OS in the four subgroups based on histology and extent of disease were: E1, 79%, E2, 65%, NE1, 64%, and NE2, 13%. Histologic subtype and extent of pelvic disease are the only prognostic factors associated with OS. Patients with endometrioid tumors and extent of pelvic disease limited to positive cytology had a favorable outcome, with or without adjuvant therapy. Future prospective clinical trials should consider subclassifying patients with stage IIIA disease to better evaluate the role of adjuvant therapy.

Retrospective review: re-treatment of patients with ovarian cancer with carboplatin after platinum resistance.

The objective of the analysis was to determine the effectiveness of re-treating patients with ovarian cancer, primary peritoneal cancer, and fallopian tube cancer with carboplatin after being deemed platinum resistant. From a database period January 1, 1996, to December 12, 2002, 34 patients were identified who received nonplatinum agents before resuming treatment with carboplatin. The median age was 65 years, and a median of two nonplatinum chemotherapy (range 1-5) prior to re-treatment with carboplatin was received. The median platinum-free interval from the time platinum was last received to re-treatment with carboplatin was 15.2 months (95% confidence interval [CI] 12.6-17.9; range 6.2-47.0). A median number of four cycles of carboplatin (range 1-11) was received. Two patients (5.9%) achieved partial response, while 21 patients (61.7%) achieved stable disease. The median time to progression for these 23 patients after re-treatment with carboplatin was 5.7 months (95% CI 5.2-6.3; range 1.8-15.3). Twenty-seven patients have died, and all patients have progressed. Seven patients are still receiving salvage therapy. The median overall survival from the time deemed to be platinum resistant is 23.2 months (95% CI 20.1-26.4). Patients who have been deemed platinum resistant may still benefit from platinum re-treatment after an interval of treatment with nonplatinum agents.

Analysis of 96 patients with advanced ovarian carcinoma treated with high-dose chemotherapy and autologous stem cell transplantation.

The purpose of this study was to identify characteristics significant to survival and progression-free survival in patients with advanced ovarian cancer receiving high-dose chemotherapy. In all, 96 patients received autologous stem cell transplantation. Regimens included paclitaxel with carboplatin (PC), topotecan, melphalan, cyclophosphamide (TMC) and cyclophosphamide, BCNU, thiotepa (CBT). At the time of transplantation, 43% of patients were in clinical CR, 34% were in clinical PR, 18% had progressive disease and 5% had stable disease. There were no treatment-related deaths. The 6-year survival by Kaplan-Meier was 38%. For patients who received transplantation for remission consolidation, the 6-year survival was 53% with a PFS of 29%. On univariate analysis, the CBT regimen, clear cell histology and disease status other than CR prior to treatment were statistically significant adverse prognostic factors. This analysis has demonstrated that patients in clinical remission are most likely to benefit from autologous transplantation, with the exception of patients with clear cell histology. The TMC combination appeared to be superior to the PC and CBT combinations. Comparative studies of different consolidation approaches will be necessary to determine if autologous transplantation is the preferred treatment for this patient population.

Utility of lymphangiography in the prediction of lymph node metastases in patients with cervical cancer.

Our objective was to assess the value of lymphangiography in selecting patients for surgical staging of locally advanced cervical cancer. We reviewed our computerized database to identify patients with cervical cancer who had abnormal findings on lymphangiography and underwent retroperitoneal lymph node dissection between September 1991 and January 1996. The records of these patients were retrospectively reviewed, and the following data were retrieved: clinical tumor stage and findings on lymphangiography at surgery, and on pathologic examination of resected lymph nodes. The lymphangiograms were reviewed and reinterpreted in blinded fashion by two of the authors. The positive and negative predictive values of lymphangiography for the presence of lymph node metastases were calculated, with findings on pathologic examination of lymph nodes used as the gold standard. The positive and negative predictive values of surgeons' clinical assessments at surgery were also calculated. Fifty patients met the selection criteria and constituted the study population. Fourteen patients (28%) had histologically negative nodes, and 36 patients (72%) had lymph node metastases. Thirty-three patients had metastases to pelvic nodes, 1515 patients had metastases to common iliac nodes, and 1616 patients had metastases to para-aortic nodes. The positive predictive value of lymphangiography for lymph node metastases was 74% for pelvic nodes, 73% for common iliac nodes, and 88% for para-aortic nodes. The negative predictive value of lymphangiography for lymph node metastasis was 76% for common iliac nodes and 77% for para-aortic nodes. Overall, 46% of the patients selected for surgical exploration had histologic findings of either common iliac or para-aortic lymph node metastases; these findings led clinicians to extend radiation fields to cover the para-aortic lymph nodes. Lymphangiography is helpful in selecting patients with cervical cancer who have a high risk of common iliac or para-aortic lymph node metastasis. However, more accurate and more readily available noninvasive methods of evaluating cervical patients for the presence of regional disease continue to be needed.

Mixed choriocarcinoma in a postmenopausal patient.

Gestational trophoblastic disease rarely presents in patients beyond the reproductive years. To our knowledge, this is the first case of mixed trophoblastic disease in a postmenopausal woman. We present here a case of a 60-year-old woman with evidence of a pelvic mass and pulmonary metastasis. Surgery revealed an 8 x 6 x 6 cm multinodular uterine tumor involving the right adnexa. Histologic review was consistent with choriocarcinoma with intermediate trophoblastic features. Postoperative beta-hCG was 381 561 mIU/ml. We conclude that maintaining a high index of suspicion facilitates the identification of postmenopausal patients with metastatic gestational trophoblastic disease. This case reconfirms the deceptive presentation of the "great masquerader".

Metastatic uterine papillary serous carcinoma to the pericardium.

BACKGROUND: Uterine papillary serous carcinoma is an aggressive tumor with a high propensity for distant spread. Metastases to the heart or pericardium are rare in gynecologic malignancies and usually fatal. CASE: A 64-year-old African American woman was diagnosed with recurrent uterine papillary serous carcinoma metastatic to the pericardium. Her case at presentation was significant for an elevated serum CA-125, evidence of metastatic disease to the liver, and massive cardiomegaly. Cytologic analysis of fluid obtained by pericardiocentesis confirmed recurrence. Despite treatment with paclitaxel and a pleuropericardial window, the patient succumbed to her disease. CONCLUSION: The prognosis for patients whose recurrent uterine papillary serous carcinoma has metastasized to the heart or pericardium is extremely poor. Effective adjuvant and salvage therapies are essential.

Intraoperative lymphatic mapping and sentinel node identification with blue dye in patients with vulvar cancer.

OBJECTIVE: To determine the effectiveness of intraoperative lymphatic with blue dye alone as a means of localizing sentinel nodes in patients with vulvar cancer. METHODS: All patients undergoing primary surgical treatment for vulvar cancer were eligible for this prospective study. Isosulfan blue dye was injected intradermally at the edge of the primary tumor closest to the adjacent groin. Bilateral dye injections and groin dissections were performed if the tumor was within 2 cm of the midline. RESULTS: Fifty-two patients were enrolled in the study between 1993 and 1999. The median age was 58 years. Eighty-seven percent of the patients had T1 or T2 lesions, and 92% had nonsuspicious lymph nodes on palpation. Sixty-seven percent of the patients had squamous cell carcinoma; the remaining patients had melanoma or adenocarcinoma. The sentinel node was identified in 46 of the 52 patients (88%), comprising 22 of the 25 patients with lateral tumors and 24 of the 27 patients with midline lesions. The sentinel node was successfully identified in 57 of the 76 (75%) dissected groins. Sentinel node identification in the groin was hampered by the effects of prior excisional biopsy vs punch biopsy (11 of 25 vs 8 of 51, P = 0.007) and by the lateral vs midline location of the tumor (22 of 25 groins vs 35 of 51 groins, P = 0.067). During the first 2 years (1993-1994), a sentinel node could not be identified in 4 of the 25 (16%) patients and 13 of the 36 (36%) groins dissected, compared with 2 of the 27 (7%) of patients treated and 6 of the 40 (15%) groins dissected from 1995 through 1999 (P = 0.034). A total of 556 nodes were removed (median, 7 per groin), of which 83 (median, 1 per groin) were sentinel. The sentinel node was not identified in 2 of the 12 groins that proved to have metastatic disease. Both events occurred in the first 2 years of the study. There were no false-negative sentinel nodes. Since 1995, we have successfully identified the sentinel node in 16 of the 16 patients (25 of 25 groins) with T1 or T2 primary lesions, squamous histology, and nonsuspicious groin nodes on physical examination. CONCLUSIONS: Experience and careful patient selection can permit sentinel node identification with blue dye injection alone in more than 95% of patients with vulvar cancer.

High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of advanced ovarian cancer.

OBJECTIVE: The goal of this study was to determine the optimal dose of topotecan when used in combination with high-dose melphalan and cyclophosphamide (TMC), and to assess the toxicity and efficacy of the regimen in patients with advanced ovarian cancer. METHODS: Fifty-three patients with persistent or recurrent ovarian cancer were treated. Disease status at study entry included: platinum-sensitive recurrent disease (15 patients), platinum-resistant or refractory recurrent disease (15 patients), positive second-look surgery (16 patients), failure to achieve a primary clinical complete response (CR) (7 patients). Following stem cell mobilization and collection, patients were given cyclophosphamide 1 g/m(2)/day on Days -6, -5, -4; melphalan 70 mg/m(2)/day on Days -3, -2; and topotecan at escalating doses from 1.25 to 4.0 mg/m(2)/day on Days -6 to -2. Peripheral blood stem cells were infused on Day 0. RESULTS: The optimal topotecan dose selected for future trials was 4.0 mg/m(2)/day x 5 days. The regimen had acceptable toxicity with no regimen-related death. Toxicity (Bearman toxicity criteria) was limited mostly to grade 1-2 mucositis and diarrhea. The overall response rate of patients with measurable or evaluable disease was 93%. Median survival has not yet been reached, but with a median follow up of 18 months (range: 11-37) 77% of patients are alive. CONCLUSION: With a topotecan dose of 4.0 mg/m(2)/day x 5 days, the TMC regimen has acceptable toxicity and produces high response rates. In the setting of ovarian cancer, high-dose chemotherapy should be administered only as part of well-designed clinical trials. TMC should be considered a potential regimen for future randomized trials in patients with advanced ovarian cancer.

Sigmoid perforation following radiation therapy in patients with cervical cancer.

OBJECTIVE: We describe the clinical presentation, evaluation, management, and outcome of patients experiencing sigmoid perforation following radiation therapy for cervical cancer. METHODS: A database consisting of over 5000 patients with stage IB-IIIB cervix cancer treated between 1963 and 1992 revealed 35 patients with sigmoid perforation. Twenty-seven were diagnosed and managed at one institution, and they form the study group. RESULTS: The median age at the time of perforation was 50 years, and the median follow-up care was 78 months (range 6-396). The median time from completion of radiotherapy to perforation was 13 months (range 3-98). The mean interval from the first documented complaint to the index admission was 90 days. Nine (33%) of 27 patients were treated with high-dose radiation therapy. The most common complaint was abdominal pain in 25 (93%) patients, nausea occurred in 12 (44%) patients, weight loss in 12 (44%) patients, and vomiting in 10 (37%) patients. The pain was described as mild in 16 (73%) of 22 patients. Only 5 (18.5%) of 27 patients had physical signs of acute peritonitis, 8 (30%) of 27 patients had some form of tenderness, and 11 (41%) of 27 had a benign exam. A total of 20 (74%) patients had an abdominal radiograph, and 12 (44%) patients had a contrast enema for evaluation. Evidence of perforation was present in 5 (25%) of 20 plain abdominal radiographs and 1 (8%) of 12 contrast enemas. Following admission, 17 (63%) patients were observed initially with subsequent surgery after symptoms either failed to resolve or worsened. The median duration under observation was 4 days (range 1-23). Surgery was performed immediately in 8 patients (30%), and 2 (7%) were observed without operation. In these 2 patients, perforation was diagnosed postmortem. Seventeen (68%) of 25 patients had a localized abscess. Three of the patients who underwent immediate exploration and 7 who had surgery after a period of observation died postoperatively (10/25, 40%). Five (55%) of 9 patients in the group who received high-dose radiation therapy died because of sigmoid perforation. When the time frame of presentation was evaluated, we noted that 10 (50%) of 20 patients died between 1960 and 1979 and 1 (14%) of 7 died between 1980 and 1992. CONCLUSIONS: Sigmoid perforation following pelvic radiation for cervical cancer does not usually present with the typical signs of a ruptured viscus. A high degree of suspicion remains a priority in the care of radiated patients who present with abdominal pain given the atypical presentation of perforation in this group.

Treatment of uterine papillary serous carcinoma with paclitaxel.

OBJECTIVE: The aim of this study was to determine the effectiveness and toxicity of monthly treatment with intravenous paclitaxel for women with advanced or recurrent uterine papillary serous carcinoma (UPSC). METHODS: Consenting women with histologically confirmed advanced (FIGO stage III or IV) or recurrent UPSC were treated on an Institutional Review Board approved protocol of a 24-h intravenous infusion of 200 mg/m(2) of paclitaxel every 3 weeks. Both measurable and nonmeasurable disease cases were enrolled. Treatment was continued until disease progression, patient intolerance, or (in women with nonmeasurable disease) completion of six courses. RESULTS: Twenty patients received from 1 to 11 cycles of therapy. Two women died of disease after 1 cycle of therapy and were not evaluable for response. Among 13 women with measurable tumor receiving 2 or more cycles of therapy, 4 had a complete clinical response and 6 had a partial response (objective response rate, 77%). The median time to progression was 7.3 months (range, 2-21 months). All 3 remaining patients with measurable disease had stable disease for a median of 6 months. The 5 patients without evaluable disease received 5 to 6 cycles of adjuvant paclitaxel. Three developed recurrence (range, 4-10 months; median, 7.2 months). Neutropenia was the major toxicity. Eleven of the 20 patients required G-CSF support, and 9 were hospitalized for neutropenic fever. One woman had reversible cardiac symptoms, which might have been related to paclitaxel treatment. At the time of analysis (mean follow-up, 23 months; range, 4.3-59.9 months), 13 women had died of disease, 4 were alive with disease, and 2 were disease free. All 3 disease-free patients had been treated for nonmeasurable advanced stage disease. CONCLUSION: Paclitaxel appears to have excellent activity in the treatment of advanced or recurrent UPSC, an uncommon but aggressive malignancy. Longer survival appears to be more common among women with small-volume disease.

Replication factors MCM2 and ORC1 interact with the histone acetyltransferase HBO1.

The minichromosome maintenance (MCM) proteins, together with the origin recognition complex (ORC) proteins and Cdc6, play an essential role in eukaryotic DNA replication through the formation of a pre-replication complex at origins of replication. We used a yeast two-hybrid screen to identify MCM2-interacting proteins. One of the proteins we identified is identical to the ORC1-interacting protein termed HBO1. HBO1 belongs to the MYST family, characterized by a highly conserved C2HC zinc finger and a putative histone acetyltransferase domain. Biochemical studies confirmed the interaction between MCM2 and HBO1 in vitro and in vivo. An N-terminal domain of MCM2 is necessary for binding to HBO1, and a C2HC zinc finger of HBO1 is essential for binding to MCM2. A reverse yeast two-hybrid selection was performed to isolate an allele of MCM2 that is defective for interaction with HBO1; this allele was then used to isolate a suppressor mutant of HBO1 that restores the interaction with the mutant MCM2. This suppressor mutation was located in the HBO1 zinc finger. Taken together, these findings strongly suggest that the interaction between MCM2 and HBO1 is direct and mediated by the C2HC zinc finger of HBO1. The biochemical and genetic interactions of MYST family protein HBO1 with two components of the replication apparatus, MCM2 and ORC1, suggest that HBO1-associated HAT activity may play a direct role in the process of DNA replication.

Adjuvant chemotherapy for high-risk endometrial cancer.

Identification of histopathologic factors that predict the risk of tumor recurrence allows for selection of women with endometrial cancer who might benefit from adjuvant therapy. Most studies of adjuvant treatment have focused on external-beam irradiation or oral progestational agents and have failed to document a survival advantage for treated patients. Although recurrent or metastatic endometrial tumors often respond to salvage treatment with cytotoxic agents, there is relatively little experience with postoperative systemic chemotherapy used in an adjuvant setting. A few nonrandomized trials-using doxorubicin/platinum-based regimens-have suggested that adjuvant chemotherapy may be beneficial in some patient subsets. Data from larger-scale, randomized trials do not exist. Additional clinical experience is needed before a definite role for adjuvant chemotherapy can be established.

Adenovirus-mediated expression of p53 or p21 in a papillary serous endometrial carcinoma cell line (SPEC-2) results in both growth inhibition and apoptotic cell death: potential application of gene therapy to endometrial cancer.

Papillary serous endometrial carcinoma is an aggressive tumor characterized by late-stage presentation, i.p. spread, and poor prognosis. It is histologically similar to serous papillary carcinoma of the ovary. Preclinical studies have shown that adenovirus-mediated expression of p53 in ovarian cancer cell lines causes growth inhibition and apoptosis in vitro and in vivo. Such studies provide the rationale for Phase I Adp53 gene therapy clinical trials in ovarian cancer. In the present study, we compared the efficacy of adenoviral vectors containing p53 (Adp53) or p21 (Adp21) in a papillary serous endometrial tumor cell line (SPEC-2) that contains mutated p53. Growth assays revealed that both Adp53 and Adp21 were efficacious in decreasing cell proliferation as assessed by anchorage-dependent and anchorage-independent growth assays. However, as compared with Adp53, the effects of Adp21 tended to be more transient and less marked. Strikingly, Adp21, but not Adp53, induced a G1 arrest in SPEC-2 endometrial adenocarcinoma cells. In contrast, as assessed by induction of hypodiploid peaks, free DNA ends detected by a terminal deoxynucleotidyl transferase-based assay, and annexin V positivity, p53 was more effective than p21 in inducing cell death by apoptosis. Compatible with the more efficient induction of apoptosis, Adp53, but not Adp21, induced a marked increase in expression of the preapoptotic molecule BAX without a concomitant change in expression of the antiapoptotic mediator Bcl-2. The differential effects of Adp53 and Adp21 on cell cycle progression and apoptosis may be related to the reversibility of p21-induced cell cycle arrest and the irreversibility of p53-induced apoptosis. Thus, at least in the papillary serous endometrial carcinoma cell line SPEC-2, Adp53 may be more effective than Adp21 as a gene therapeutic. Nevertheless, these preclinical studies suggest that papillary serous endometrial carcinoma is a potential target for p53- or p21-mediated gene therapy.

Early cervical cancer.

Early cervical cancer includes a broad range of disease, from clinically undetectable microinvasive cancer to large, bulky tumors that replace the entire cervix. Further subgrouping of this category is therefore necessary to define the optimal treatment approach for individual cases. The International Federation of Gynecology and Obstetrics (FIGO) staging system stratifies stage I tumors into two broad categories, stage IA (microinvasive) and stage IB (gross tumor). Management of women with stage IA disease is controversial. In the United States, patients with stromal invasion of less than 3 mm and no lymphvascular involvement are usually treated conservatively with simple hysterectomy. In selected patients who desire fertility, cone biopsy with negative surgical margins is also considered. Patients with invasion of more than 3 mm or lymphvascular space involvement are at risk for pelvic lymph node metastasis and are most often treated with radical hysterectomy and pelvic lymphadenectomy. Stage IB1 cervical cancer is managed by either radical surgery or radiotherapy with equivalent recurrence and survival rates. In patients with tumors less than 4 cm in diameter, the decision between radical surgery and radiotherapy is guided by patients' overall health and treatment preferences. For younger women, radical surgery is preferred because ovarian function can be preserved and vaginal stenosis secondary to radiation can be avoided. Radiation therapy is preferred for women who may not tolerate radical surgery. We always prefer primary radiation therapy for patients with tumors larger than 4 cm in diameter. Recent data convincingly demonstrate that the addition of cisplatin-based chemotherapy significantly improves overall survival rates in cervical cancer patients who undergo radiation therapy.

A phase I trial of intravenous melphalan, paclitaxel, and cisplatin plus granulocyte-colony stimulating factor in patients with suboptimal advanced epithelial ovarian carcinoma or peritoneal carcinoma.

BACKGROUND: The primary purpose of this study was to establish the maximum tolerated dose (MTD) of intravenous melphalan in combination with paclitaxel and cisplatin plus granulocyte-colony stimulating factor (G-CSF) in patients with suboptimal advanced epithelial ovarian carcinoma or primary peritoneal carcinoma. METHODS: Patients with suboptimal (>2 cm residual tumor) Stage III or Stage IV epithelial ovarian carcinoma or peritoneal carcinoma were eligible for this Phase I study. In the first stage of the study, the doses of paclitaxel and cisplatin were fixed at 135 mg/m(2) and 75 mg/ m(2), respectively, and the dose of intravenous melphalan was escalated in consecutive cohorts of 3-6 patients depending on toxicity. The planned dose escalation levels of melphalan were 6 mg/m(2), 10 mg/m(2), and 14 mg/m(2). In the second stage of the study, the doses of cisplatin and melphalan were fixed at 75 mg/m(2) and the MTD level, respectively, and the dose of paclitaxel was escalated. The planned dose escalation levels of paclitaxel were 150 mg/m(2), 175 mg/m(2), 200 mg/m(2), 225 mg/m(2), and 250 mg/m(2). G-CSF was administered for 12-19 days with each cycle, and cycles were repeated every 4 weeks for a total of 6 cycles. Other end points included clinical or surgical response, progression free survival, and survival. RESULTS: Between January 1993 and May 1996, 34 women with untreated advanced stage epithelial ovarian carcinoma or primary peritoneal carcinoma were treated with 192 cycles of therapy. The MTD of melphalan was 10 mg/m(2), with the dose-limiting toxicity being thrombocytopenia. Paclitaxel was escalated to a dose level of 200 mg/m(2) with a toxicity rate of < 33%. The clinical response rate was 80% in 29 patients with measurable disease. Of 11 patients who underwent second-look surgery, 5 (45%) had a surgical pathologic complete response. The median progression free survival was 16.8 months and the median survival was 32.8 months. CONCLUSIONS: The combination of intravenous melphalan, paclitaxel, and cisplatin was found to have acceptable toxicity and good activity. A Phase II study of this combination appears to be warranted.

The current status of surgical staging of ovarian serous borderline tumors.

BACKGROUND: The purpose of the current study was to evaluate the current practice of surgical staging of ovarian serous borderline tumors. METHODS: Women with a diagnosis of ovarian serous borderline tumors whose pathology slides were sent to the M. D. Anderson Cancer Center for second-opinion diagnostic consultation between 1990-1996 were identified. The original pathology reports and M. D. Anderson Cancer Center consultation reports of 255 cases were reviewed for the frequencies of frozen-section analyses and staging biopsies, biopsy results, the specialty of the surgeon, and hospital type. RESULTS: The majority (78%) of ovarian borderline tumors primarily were encountered and staged by general obstetrician-gynecologists. Overall, 66% of patients had at least 1 staging biopsy performed. Approximately 12% of subjects underwent complete surgical staging, defined as having biopsy samples taken from pelvic and abdominal peritoneum, omentum, and retroperitoneal lymph nodes. Gynecologic oncologists performed complete staging in 50% of cases, obstetrician-gynecologists performed complete staging in 9% of cases, and general surgeons performed complete staging in 0% cases. The overall frequency of a positive staging biopsy was 37%. Approximately 47% (80 of 169) of patients who underwent biopsies were upstaged as a result of positive biopsies, - with 41% (70 of 169) having extrapelvic spread. CONCLUSIONS: Currently, surgical staging for women with ovarian serous borderline tumors remains inadequate, although a significant proportion of patients who undergo staging are noted to have extrapelvic spread.

Radiation treatment of advanced or recurrent granulosa cell tumor of the ovary.

BACKGROUND: Because granulosa cell tumors of the ovary are rare, the optimal treatment for women with gross residual disease after primary surgery or recurrence is not known. Our objective was to review the results of radiotherapy for advanced or recurrent granulosa cell tumor of the ovary. METHODS: This retrospective review identified 34 patients with ovarian granulosa cell tumors treated with radiation at the University of Texas M. D. Anderson Cancer Center between 1949 and 1988. Fourteen received treatment for clinically measurable disease; 20 received adjuvant radiotherapy after surgery for minimal residual (<1 cm) or microscopic residual disease. The 14 patients with measurable disease formed the basis for this review. RESULTS: Ten of 14 patients were treated with moving-strip whole-abdomen radiation (27-28 Gy), 9 with 60Co, and 1 with 6-MeV photons and a pelvic boost of 28 Gy with 22-25 MeV photons. The other 4 patients were treated with pelvic radiotherapy (45-61 Gy) with 22-25 MeV photons. Six of 14 patients (43%) had a clinical complete response to radiotherapy, with a median follow-up of 13 years (range, 5-21 years). Three of 6 who responded to radiation had relapse 4-5 years later; 2 of these 3 died of disease and 1 was alive with disease at last follow-up. Three responders remain alive without evidence of disease 10-21 years after treatment. The 8 nonresponders had a median survival of 12.3 months (range, 1-60 months). CONCLUSIONS: Radiotherapy can induce a clinical response with occasional long-term remission in patients with persistent or recurrent granulosa cell tumor of the ovary.

A phase I study of a daily x3 schedule of intravenous vinorelbine for refractory epithelial ovarian cancer.

PURPOSE: To determine the toxicity and activity of intravenous vinorelbine given daily for 3 consecutive days every 3 weeks in patients with platinum-resistant epithelial ovarian cancer. PATIENTS AND METHODS: Between September 1994 and October 1995, 23 women with refractory epithelial ovarian cancer were entered onto this phase I study. All patients had measurable disease and platinum-resistant tumor, and prior therapy was limited to a maximum of two prior regimens. Nineteen (83%) were assessable for toxicity and 20 (87%) were assessable for response. Vinorelbine was administered intravenously daily for 3 consecutive days; this was repeated every 21 days. The starting dose was 20 mg/m2 daily x3, with dose escalation by 5 mg/m2 daily x3. Dose-limiting toxicity (DLT) was defined as grade 4 granulocytopenia for >3 days, grade 4 thrombocytopenia, neutropenic fever, or grade 3 or greater nonhematologic toxicity. The maximal tolerated dose (MTD) was defined as the highest dose level at which <50% of patients developed a DLT. Once the MTD of vinorelbine without granulocyte colony-stimulating factor (filgrastim) support was defined, dosing was begun at the MTD level and administration of 5 microg/kg filgrastim was initiated on day 4 and continued until WBC counts reached >10,000/microL. Clinical response, progression-free survival, and survival were also determined. RESULTS: Nineteen patients evaluable for toxicity received a total of 135 cycles of vinorelbine. The major DLT was neutropenia. The MTD of vinorelbine without filgrastim support was established as 20 mg/m2 daily x3. The MTD of vinorelbine with filgrastim support was established as 25 mg/m2 daily x3. Of 20 patients evaluable for response, 2 patients (10%) had a complete response and 4 (20%) had a partial response, for an overall response rate of 30%. CONCLUSION: These results warrant further study of vinorelbine in patients with platinum-resistant epithelial ovarian cancer. However, further study of the daily x3 schedule may not be warranted because of failure to achieve higher weekly dose intensity and because of nonhematologic toxicity in the form of intense bone pain.

A phase II study of prolonged oral etoposide in advanced or recurrent carcinoma of the cervix.

OBJECTIVE: To evaluate the efficacy and toxicity of prolonged oral etoposide as single agent chemotherapy in patients with advanced or recurrent carcinoma of the cervix. METHODS: Between May 1991 and February 1993, 44 patients with advanced or recurrent carcinoma of the cervix were entered onto this study. Patients were eligible if they had received no more than two prior cytotoxic regimens. The initial dose of etoposide was 37.5 mg/m2 administered orally on a daily basis on days 1-21 of a 28-day cycle. Subsequent doses were unchanged, reduced, escalated, or omitted according to toxicity. Patients were evaluated for response and toxicity using standard Gynecologic Oncology Group criteria. RESULTS: Forty-four patients were evaluable for response and toxicity. The overall response rate was 9.1% (2 CR, 2 PR). In patients with no prior chemotherapy the response rate was 4/25 compared to 0/19 for those who had prior therapy. The mean response duration was 2.7 months and the median survival from treatment for all patients was 7.7 months. The major toxicity was granulocytopenia, with 11% of patients having grade 3 or 4 toxicity. Gastrointestinal toxicity of some degree occurred in 11% of patients, and alopecia was universal. CONCLUSION: Prolonged oral etoposide has limited activity in advanced or recurrent carcinoma of the cervix. Its use as palliative therapy for this disease is not indicated.

Phase II study of vinorelbine in advanced and recurrent squamous cell carcinoma of the cervix.

PURPOSE: To evaluate the efficacy and toxicity of intravenous vinorelbine as single-agent chemotherapy in patients with advanced or recurrent squamous cell carcinoma of the cervix. PATIENTS AND METHODS: Between August 1993 and July 1995, 35 patients with advanced or recurrent squamous cell carcinoma of the cervix were entered onto this study. Patients had received no prior therapeutic chemotherapy. The initial dose of vinorelbine 30 mg/m2 was administered as a weekly intravenous infusion. Subsequent doses were unchanged, reduced, escalated, or omitted according to observed toxicity. Patients were evaluated for response and toxicity using standard Gynecologic Oncology Group (GOG) and World Health Organization criteria, respectively. RESULTS: Thirty-three of 35 patients were assessable for response and 35 of 35 for toxicity. The overall response rate was 18% (one complete response [CR], five partial responses [PR]). The mean response duration was 5.2 months and the median survival from treatment for all patients was 11.0 months. The major toxicity was leukopenia, with 61% of patients who had grade 3 or 4. Gastrointestinal and neurotoxicity were infrequent and mild. CONCLUSION: Vinorelbine has moderate activity in advanced or recurrent squamous cell carcinoma of the cervix. Further studies of combination regimens with this agent are justified in this patient population.