Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102).

BACKGROUND: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival. METHODS: Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1-5, vincristine 0.7 mg m(-2) day 5, mitomycin 7 mg m(-2) day 5, cisplatin 14 mg m(-2) days 1-5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival. RESULTS: A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85). CONCLUSION: Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.

Low response rate of second-line chemotherapy for recurrent or refractory clear cell carcinoma of the ovary: a retrospective Japan Clear Cell Carcinoma Study.

Clear cell carcinoma (CCC) of the ovary has been recognized to show resistance to anticancer agents in the first-line chemotherapy. Our aim was to evaluate the effect of second-line chemotherapy in a retrospective study. A total of 75 patients diagnosed with CCC and treated between 1992 and 2002 in collaborating hospitals were reviewed. Criteria for the patients' enrollment were 1) diagnosis of pure-type CCC at the initial operation, 2) treatment after one systemic postoperative chemotherapy, 3) measurable recurrent or refractory tumor, 4) at least two cycles of second-line chemotherapy and assessable for the response, and 5) adequate clinical information. Regimens of first-line chemotherapy were conventional platinum-based therapy in 33 cases, paclitaxel plus platinum in 24 cases, irinotecan plus platinum in 9 cases, and irinotecan plus mitomycin C in 7 cases. Treatment-free periods were more than 6 months in 24 cases (group A) and less than 6 months in 51 cases (group B). In group A, response was observed in two cases (8%): one with conventional platinum therapy and another with irinotecan plus platinum. In group B, three cases (6%) responded: two with platinum plus etoposide and one case with irinotecan plus platinum. Median overall survival was 16 months in group A and 7 months in group B (P = 0.04). These findings suggest recurrent or resistant CCC is extremely chemoresistant, and there is only small benefit of long treatment-free period in CCC patients. Another strategy including molecular-targeting therapy is warranted for the treatment of recurrent or refractory CCC.

Clear cell carcinoma of the ovary: a retrospective multicentre experience of 254 patients with complete surgical staging.

A retrospective analysis was performed to evaluate the clinical characteristics and prognostic factors in the patients with clear cell carcinoma (CCC) of the ovary. After central pathological review and scanning of the medical records of nine Japanese institutions between 1992 and 2003, a total of 254 patients with CCC of the ovary were enrolled in the present study. Mean age was 52.4 years (range 23-73 years). Tumours were 13% (33/254) stage Ia, 36% (92/254) stage Ic, 13% (33/254) stage II, 30% (80/254) stage III, and 6% (16/254) stage IV. Five-year progression-free survival and overall survival was 84 and 88% in stage I, 57 and 70% in stage II, 25 and 33% in stage III and 0 and 0% in stage IV, respectively. Retroperitoneal lymph node metastasis was observed in 9% in pT1a tumours, 7% in pT1c tumours, 13% in pT2 tumours, and 58% in pT3 tumours, respectively. There was no survival benefit according to chemotherapeutic differences in the patients who received complete surgical staging procedures and conventional chemotherapy. Peritoneal cytological status was an independent prognostic factor in stage Ic patients (P=0.03) and only residual tumour diameter was an independent prognostic factor in stage III, IV patients (P=0.02). Our results suggest that cytoreductive surgery resulting in no residual tumour only could improve the prognosis of advanced CCC patients.

Retroviral vector backbone immunogenicity: identification of cytotoxic T-cell epitopes in retroviral vector-packaging sequences.

Retroviral vectors are the frequently applied gene delivery vehicles for clinical gene therapy, but specificity of the immunogenicity to the protein encoded by the inserted gene of interest is a problem which needs to be overcome. Here, we describe human cytotoxic T-lymphocyte (CTL) clones recognizing epitopes derived from the protein encoded by the retroviral vector backbone, which were established during the course of our attempts to generate CTLs against cytomegalovirus (CMV) or human papilloma virus (HPV) in vitro. In the case of healthy CMV-seronegative donors, CTL lines specific for retrovirally transduced cells were generated in four out of eight donors by stimulating CD8 T cells with CD40-activated B (CD40-B) cells retrovirally transduced with CMV-pp65. Two CTL clones derived from one of the CTL lines were found to recognize epitopes from gag in the context of HLA-B(*)4403 and -B(*)4601, respectively. Similarly, an HLA-B(*)3501-restricted CTL clone from a cervical cancer patient recognized an epitope located in the junctional regions of the gag and pol sequences. These results show that polypeptides encoded by components of the retroviral vector backbone are in fact immunogenic, generating CTLs in vitro in human cells. Thus, potential CTL responses to retroviral products should also be considered in clinical settings.

Associations between tumor diameter and prognostic variables of epithelial ovarian cancer.

PURPOSE: Associations of tumor diameter in epithelial ovarian cancer with clinical and pathological prognostic variables were investigated. METHODS: The clinical and pathological records of 233 patients diagnosed with epithelial ovarian cancer and treated at Aichi Cancer Center were studied. RESULTS: Tumor diameters of 44 patients (18.9%) were < 5 cm, 90 (38.6%) were 5-10 cm, and 99 (42.5%) were > 10 cm. While 90.9% (40/44) of < 5 cm tumors presented with FIGO stage III-IV, 40.4% (40/99) of > 10 cm tumors were advanced. Intra-abdominal disease was also significantly associated with tumor diameter, although differences among lymph-node status were not significant. The incidence of serous and endometrioid adenocarcinoma in < 5 cm tumors were 75.0% (33/44) and 11.4% (5/44), respectively, while those of > 10 cm tumor were 32.3% (32/99) and 17.2% (17/99). Multivariate analysis revealed that tumor diameter was not an independent prognostic variable. CONCLUSION: Tumor diameter of ovarian cancer is associated closely with histological subtypes and stage of disease, especially intra-abdominal disease.

Effects of cobalt-substitution of the active zinc ion in thermolysin on its activity and active-site microenvironment.

Thermolysin is remarkably activated in the presence of high concentrations (1-5 M) of neutral salts [Inouye, K. (1992) J. Biochem. 112, 335-340]. The activity is enhanced 13-15 times with 4 M NaCl at pH 7.0 and 25 degrees C. Substitution of the active site zinc with other transition metals alters the activity of thermolysin [Holmquist, B. and Vallee, B.L. (1974) J. Biol. Chem. 249, 4601-4607]. Cobalt is the most effective among the transition metals and doubles the activity toward N-[3-(2-furyl)acryloyl]-glycyl-L-leucine amide. In this study, the effect of NaCl on the activity of cobalt-substituted thermolysin was examined. Cobalt-substituted thermolysin, with 2.8-fold increased activity compared with the native enzyme, is further activated by the addition of NaCl in an exponential fashion, and the activity is enhanced 13-15 times at 4 M NaCl. The effects of cobalt-substitution and the addition of salt are independent of each other. The activity of cobalt-substituted thermolysin, expressed as k(cat)/K(m), is pH-dependent and controlled by at least two ionizing residues with pK(a) values of 6.0 and 7.8, the acidic pK(a) being slightly higher compared to 5.6 of the native enzyme. These pK(a) values remain constant in the presence of 4 M NaCl, indicating that the electrostatic environment of cobalt-substituted thermolysin is more stable than that of the native enzyme, the acidic pK(a) of which shifts remarkably from 5.6 to 6.7 at 4 M NaCl. Zincov, a competitive inhibitor, binds more tightly to the cobalt-substituted than to native thermolysin at pH 4.9-9.0, probably because of its preference for cobalt in the fivefold coordination. The cobalt substitution has been shown to be a favorable tool with which to explore the active-site microenvironment of thermolysin.

3-hour infusion of single-agent paclitaxel for recurrent ovarian cancer.

BACKGROUND: The clinical response, survival, and toxicity of a 3-h infusion of single-agent paclitaxel (175 mg/m2) for Japanese patients with recurrent ovarian cancer were investigated. We also examined whether or not cancer antigen (CA) 125 would be suitable as an indicator of the effects of the paclitaxel on ovarian cancer. METHODS: Twenty-one patients clinically diagnosed as having recurrent ovarian cancer met the entry criteria, agreed to participate in this study, and received the treatment. RESULTS: One hundred and twenty-six courses were administered to the 21 patients. One patient achieved a complete response, and 5 a partial response; the overall response rate was 35.3%. Using CA125 criteria, 42.1% of patients achieved a response. The median progression-free interval was 4.4 months, and the median overall survival time was 14.5 months. While hematological toxicity was not severe, 3 patients experienced severe peripheral neuropathy, and 2 patients experienced grade 4 myalgia/arthralgia. CONCLUSION: The 3-h infusion of single-agent paclitaxel (175 mg/m2) was an effective treatment for patients with recurrent ovarian cancer. CA125 was a useful indicator of the response to the treatment. While peripheral neuropathy and the myalgia/arthralgia were severe, 3-h infusion of single-agent paclitaxel offers a promising treatment for recurrent ovarian cancer.

A comparison of ovarian metastasis between squamous cell carcinoma and adenocarcinoma of the uterine cervix.

OBJECTIVE: The purpose of our study was to investigate a possible difference in ovarian metastasis between squamous cell carcinoma and adenocarcinoma of the uterine cervix and to confirm clinicopathological variables associated with the metastases. METHODS: Clinical and pathological variables of 1064 patients with invasive squamous cell carcinoma and 240 with adenocarcinoma were studied. RESULTS: Ovarian metastasis was found in 14 patients (1.3%) with squamous cell carcinoma and 15 (6.3%) with adenocarcinoma. The mean age of patients with ovarian metastasis of squamous cell carcinoma was 57.4 years, compared to 50.2 years for adenocarcinoma. Ovarian metastasis of adenocarcinoma was more likely to be visible (40.0%) and present in both ovaries (66.7%), while these two characteristics occurred in only 21.4 and 36.7% of patients with squamous cell carcinoma. A logistic regression analysis with clinical variables indicated that clinical stage beyond IIb was a significant variable of squamous cell carcinoma, and more than 30-mm tumor size was significant in adenocarcinoma. CONCLUSION: The incidence of ovarian metastasis of adenocarcinoma of the uterine cervix was significantly higher than that of squamous cell carcinoma. The incidence of adenocarcinoma was associated more closely with tumor size than clinical stage, whereas it was more associated with clinical stage in squamous cell carcinoma. The results thus suggested that the differences in ovarian metastases were caused by the different characteristics of the two types of carcinoma.

Prognostic factors of stage IV epithelial ovarian cancer: a multicenter retrospective study.

OBJECTIVE: In the present study, we conducted a multicenter retrospective analysis to elucidate the prognostic factors of stage IV epithelial ovarian cancer. METHODS: In November 1999, 24 Japanese institutions received questionnaires regarding stage IV epithelial ovarian cancer patients. Eligibility criteria included all patients with stage IV epithelial ovarian cancer who were surgically confirmed and initially treated in each institution between January 1990 and December 1997. Data were collected regarding age, performance status, tumor histologic subtype, site of metastasis, preoperative CA125, cytoreductive surgery, residual disease after cytoreductive surgery, and response to primary chemotherapy. Survival analysis and comparisons were performed by univariate and multivariate methods. RESULTS: Two hundred twenty-five patients with stage IV ovarian cancer were identified. The median age of the patients was 54 years. The most common site of extraperitoneal disease was malignant pleural effusion (39.6%). Of the 225 patients who underwent an attempt at surgical debulking, 70 (31.1%) were optimally cytoreduced. Most patients received platinum-based combination chemotherapy for primary chemotherapy. In multivariate analysis, performance status, histology, and residual disease after cytoreductive surgery were independent prognostic predictors of outcome. The overall median survival for optimally debulked patients was 32 months compared to 16 months for suboptimally debulked patients (P < 0.0001, hazard ratio: 0.415). CONCLUSION: Optimal surgical debulking, performance status, and histology appear to be important prognostic factors of survival in patients with stage IV epithelial ovarian cancer.

Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: central pathologic review and treatment outcome.

Thirty-nine patients with endometrioid adenocarcinoma (EA) and atypical hyperplasia (AH) of the endometrium who received conservative treatment to preserve fertility were collected from member institutions of the Japan Gynecologic Oncology Study Group. Twenty-nine and ten were originally diagnosed with EA without myometrial invasion and AH, respectively. We performed a central pathological review to make definite diagnoses, and the diagnosis of EA in 29 cases was changed to AH in ten, complex hyperplasia in three and atypical polypoid adenomyoma in three, and AH in ten was changed to EA in one and simple hyperplasia in one. Nine of 12 women (75%) with EA and 15 of 18 women (83%) with AH had an initial response to medroxyprogesterone acetate (MPA) treatment. Two of nine responders with EA later developed relapse, and one of them had metastasis to the left obturator lymph node. Two became pregnant, and one delivered one full-term infant. One of the responders with AH had a relapse in the endometrium. Five became pregnant, and four delivered four normal infants. The young women with endometrial carcinoma localized in the endometrium who wish to preserve fertility may be treated as successfully with MPA as those with AH.

Optimal doses of paclitaxel and carboplatin combination chemotherapy for ovarian cancer: a phase I modified continual reassessment method study.

BACKGROUND: A multicenter, phase I study of combination therapy with paclitaxel and carboplatin for epithelial ovarian cancer was conducted to determine the safety and recommended dosages for Japanese women. METHODS: Paclitaxel was administered intravenously over a 3-h period, followed by carboplatin administered intravenously over a 1.5-h period. A modified continual reassessment method (mCRM) was used in two treatment arms to establish the maximum tolerated dose (MTD) and recommended doses of the combination. In group A, the dose of paclitaxel (175 mg/m2) was constant and the dose of carboplatin was increased from 4 to 7 in terms of the target area under the plasma concentration-versus-time curve (AUC). In group B, the dose of carboplatin was constant (AUC 6) and paclitaxel was administered at two dose levels (160 and 175 mg/m2). In both groups, the carboplatin dose was limited to a maximum of 800 mg/body for each administration. RESULTS: Because the calculated probability of toxicity was greatest at a dose of paclitaxel 175 mg/m2 and carboplatin AUC 7, this dose was designated the MTD in group A. Based on this result, treatment in group B was initiated at doses of paclitaxel of 160 mg/m2 and carboplatin AUC 6. While the dose of paclitaxel was escalated to 175 mg/m2, the safety of the combination was confirmed. The most frequent adverse effect was neutropenia, which resolved promptly with the appropriate use of granulocyte-colony stimulating factor (G-CSF). No other severe hematologic or nonhematologic toxicities were observed. CONCLUSIONS: Our study demonstrated that the recommended dose for this combination regimen should be paclitaxel 175 mg/m2 plus carboplatin AUC 6 (maximum dose, 800 mg/body).

Association between menopausal state and prognosis of endometrial cancer.

The purpose of our study was to examine the menopausal state as an independent prognostic variable of endometrial cancer and determine the conditions under which the menopausal state would be an independent prognostic variable of such cancer. We studied the clinical and pathologic variables of 255 patients with invasive endometrial cancer. In comparisons of the clinicopathologic variables between menopausal states, obesity and deep myometrial invasion were found more frequently in older patients than in younger ones. Multivariate analysis performed on 255 cases with complete pathologic data identified menopausal state, cervical invasion, pelvic lymph node metastasis, and tumor grade as prognostic variables. Univariate analysis revealed that survival of older patients with FIGO pathologic stage Ib disease was significantly poorer than in younger patients, while there was no significant difference in the analyses of stage Ic or advanced disease beyond stage II. We conclude that menopausal state was an independent prognostic variable for patients with early endometrial cancer, but not for patients with advanced disease.

A comparison of prognoses of pathologic stage Ib adenocarcinoma and squamous cell carcinoma of the uterine cervix.

OBJECTIVES: The influence of the histology of adenocarcinoma on recurrence and survival for patients treated with radical hysterectomy and diagnosed as having pathologic stage Ib cervical cancer was investigated. METHODS: Five hundred and nine patients (405 squamous cell carcinomas, 104 adenocarcinomas) with pathologic stage Ib cervical cancer treated initially at the Aichi Cancer Center between 1976 and 1995 were studied. RESULTS: Multivariate analysis identified the prognostic variables as histology of adenocarcinoma, number of lymph nodes involved, and tumor size beyond 4 cm. Five-year overall survival and disease-free survival of patients with adenocarcinoma in the presence of lymph node metastasis were 63.2 and 47.4%, respectively, significantly poorer than for squamous cell carcinoma (83.6 and 80.6%; P < 0.001 and P = 0.002, respectively). These were not different in the absence of lymph node metastasis (adenocarcinoma, 93.9 and 92.7%; squamous cell carcinoma, 97.9% and 96.1%; P = 0.067 and P = 0.250, respectively). CONCLUSIONS: The independent significant risk factors for the recurrence and survival of pathologic stage Ib cervical cancer were the presence of lymph node metastasis, large tumor size beyond 4 cm, and histology of adenocarcinoma. The prognosis of patients with adenocarcinoma was poorer than of patients with squamous cell carcinoma in the presence of lymph node metastasis, while the prognosis of pathologic stage Ib cervical cancer was equivalent when there was no metastasis.

Screening of BRCA1 mutation using immunohistochemical staining with C-terminal and N-terminal antibodies in familial ovarian cancers.

We examined the subcellular localization of BRCA1 proteins using immunohistochemical staining with C-terminal (GLK-2 antibody) and N-terminal (Ab-2 antibody) monoclonal antibodies in 44 familial ovarian cancers. Among these, 24 cases were associated with 13 independent germ-line mutations of BRCA1, and loss of heterozygosity (LOH) at one or more BRCA1 microsatellite markers was found in all 21 informative tumors tested. With GLK-2 antibody, cytoplasmic staining was observed in 15 of 16 tumors (93.8%) with mutation in exon 11, and BRCA1 staining was absent in 8 of 8 tumors (100%) with mutation in exons other than exon 11. When immunohistochemical staining was performed with Ab-2 antibody, both nuclear and cytoplasmic staining were observed in 14 of 16 tumors (87.5%) with mutation in exon 11. Interestingly, nuclear staining was observed in 3 of 3 tumors (100%) with mutation downstream of exon 11, even though no staining was detected in 5 of 5 tumors (100%) with mutation upstream of exon 11. On the other hand, in familial ovarian cancers without BRCA1 mutations, nuclear staining or both nuclear and cytoplasmic staining was observed in 18 of 20 specimens (90%) and 20 of 20 specimens (100%) with GLK-2 antibody and with Ab-2 antibody, respectively. These results suggest that an immunohistochemical assay in combination with employing the C-terminal and the N-terminal antibodies appears to have potential as a reliable and useful technique for the screening of BRCA1 mutations, at least to predict the status of mutation, upstream or downstream of exon 11.

The significance of tumor size in clinical stage IB cervical cancer: Can a cut-off figure be determined?

The purpose of this study was to investigate the influence of tumor size on pathologic variables and the prognosis of patients diagnosed as clinical stage IB cervical cancer. Five hundred sixty six patients with clinical stage IB cervical cancer treated surgically at the Aichi Cancer Center between 1976 and 1995 were studied. The incidence of pathologic variables that increased as tumors enlarged was unchanged beyond 4.0 cm. Although univariate analysis revealed that the prognosis worsened as a tumor enlarged, there was no significant difference in prognoses between 3.1-4.0 cm and 4.1-5.0 cm tumors. While multivariate analysis showed tumor size as an independent prognostic variable, there was no difference between the odd ratios of 3.1-4.0 cm and 4.1-5.0 cm tumors. Tumor size was an independently significant risk factor for the prognosis of clinical stage IB cervical cancer. While the definition of 4.0 cm as a cut-off point was useful as far as determining an association with pathologic variables, it may be an insufficient indicator of poor prognosis. The "bulky" tumors should be defined as clinical lesions greater than 5.0 cm, though few patients would have tumors that meet that criterion.

Molecular diagnostic detection of free cancer cells in the peritoneal cavity of patients with gastrointestinal and gynecologic malignancies.

Free cancer cells exfoliated from cancer-invaded serosa contribute to peritoneal dissemination, the most frequent pattern of recurrence in patients with gastric and ovarian cancers. This study was designed to evaluate the prognostic significance of free cancer cells in peritoneal washes detected using the reverse transcriptase-polymerase chain reaction (RT-PCR) and cytology. RT-PCR analysis with primers specific for the carcinoembryonic antigen (CEA) gene was found to be more sensitive than cytology for detection of free tumor cells in the peritoneal washes, collected at laparotomy from 199 gastric carcinoma patients, with higher detection rates for each of the T-categories in the TNM classification. Six patients with synchronous and 5 with recurrent peritoneal dissemination were found among 25 advanced cancer patients with positive PCR and negative cytology results. Positive PCR results were significantly associated with poor survival of curatively resected advanced gastric carcinoma patients (P < 0.001). A rapid method for detecting CEA mRNA using the LightCycler and the dsDNA binding dye SYBR green I was also developed. The results obtained using this technique were essentially the same as those obtained using the conventional RT-PCR method. Furthermore, RT-PCR analysis with primers specific for MUC1 epithelial mucin were performed on peritoneal washes from patients with ovarian cancer. Peritoneal washes from 21 of 25 ovarian carcinoma patients, including all 17 with positive cytology results, were positive for MUC1 mRNA, again indicating a higher sensitivity using this method than conventional cytology. Highly sensitive and rapid detection of free cancer cells in peritoneal washes, most reliably by RT-PCR, is a powerful technique to predict peritoneal dissemination in patients with gastric and ovarian cancers.

Comparative case-referent study of risk factors among hormone-related female cancers in Japan.

To assess the impact of reproductive and anthropometric factors as a risk indicator for female cancers in hormone-related organs, i.e., the breast, endometrium and ovary, we conducted a comparative case-referent study using data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan. The case group consisted of 1,465, 133 and 99 women who had first been diagnosed as having breast, endometrial and ovarian cancer, respectively. The referents were 25,488 female first-visit outpatients who had not previously been diagnosed with any type of cancer. The odds ratios (ORs) and their 95% confidence intervals (95%CI) were estimated using an unconditional logistic regression model. An inverse association with experience of delivery and a positive association with body mass index (BMI) and with change of BMI after 20 years of age, were observed consistently for all three cancer sites. We observed similar risk and protective factors for breast and endometrial cancer, but the effect of reproduction and overweight condition (BMI> or =25) were more prominent in endometrial cancer. Although the present study failed to find site-specific risk factors for ovarian cancer, the results provided evidence that being overweight and/or weight gain in adult life is a common risk factor for all three cancer sites. The results obtained from this study suggested that avoidance of weight gain may reduce the risk of female hormone-related cancers.

Prognostic factors of adenocarcinoma of the uterine cervix.

OBJECTIVE: The prognostic importance of adenocarcinoma of the uterine cervix was investigated. Methods. One hundred ninety-three patients (144 had stage I disease, 41 stage II, and 8 stage III-IV) with invasive adenocarcinoma of the uterine cervix treated initially at the Aichi Cancer Center between 1964 and 1995 were studied. RESULTS: Of all the invasive cervical cancers, 8.8% were adenocarcinomas that had been increasing during the past decade. The overall 5-year survival for stage I was 88.8%, stage II 44.9%, and stage III-IV 0% In univariate analysis, the clinicopathological factors associated with overall survival and disease-free survival were age of patient, stage of disease, presence of nodal metastasis, number of lymph nodes involved, lymph-vascular space invasion, tumor size, and intraperitoneal metastasis. Multivariate analysis performed in all cases identified the clinical stage of disease, the presence of nodal metastasis, number of lymph nodes involved, lymph-vascular space invasion, and tumor size as the independent risk factors for recurrence and survival. In the analysis of stage I disease, lymph node metastasis and tumor size were the significant prognostic factors, while lymph-vascular space invasion and tumor size were the factors in advanced disease. Tumor grade and histological type were not associated with recurrence and survival. CONCLUSION: These results suggested the association of lymph node metastasis with the prognosis of early stage adenocarcinoma of the uterine cervix and lymph-vascular space invasion with the advanced stage. Tumor size was an independent risk factor throughout all stages.