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Purpose of Investigation: Peritoneal metastasis presenting at initial diagnosis of squamous carcinoma of the uterine cervix is extremely rare. However, one such case was treated successfully with curative treatment., Case: A 43-year-old woman presented with FIGO Stage IVA cervical carcinoma and underwent concurrent chemoradiation (CCRT) with weekly cisplatin. During CCRT, she suffered from acute lower abdominal pain, high fever, and leukocytosis. Computed tomography (CT) favored a tubo-ovarian abscess, while [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) showed a lesion midway between the umbilicus and symphysis pubis. An exploration by laparoscopy, an omental metastasis adhering to the bladder dome was excised. This patient finished CCRT encompassing the disease extent including the trochar sites and no evidence of disease was noted 50 months after initial diagnosis., Conclusion: Though peritoneal metastasis above the pelvis seems ominous, curative treatment may still be viable in selected patients, even in surgical Stage IVB.

Purpose of Investigation: To evaluate the outcome and prognostic factors of patients with supraclavicular lymph node (SCLN) involvement at primary diagnosis., Methods: We reviewed the medical records of cervical cancer patients primarily treated at Chang Gung Memorial Hospital between 1987 and 2005. Thirty-three patients with histologically confirmed SCLN metastasis at primary diagnosis were eligible for analysis. Clinical and pathological features were analyzed for association with outcome., Results: The 3- and 5-year survival rates of patients with SCLN metastasis were 16.5% and 16.5%, respectively. Multivariate analysis showed the serum level of squamous cell carcinoma antigen (SCC-Ag) < 15 ng/ml at initial diagnosis (p = 0.021) and staging/restaging including [18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) (p = 0.006) to be associated with a better prognosis., Conclusion: Primary SCLN metastasis in cervical cancer is not incurable. The benefit from PET findings might help in selecting appropriate patients for curative primary and/or salvage treatment.

Cervical cancer patients with histologically documented re-recurrence after curative salvage therapy or unexplained tumor marker elevation (negative computed tomography and/or magnetic resonance imaging [CT-MRI]) proven to be a re-recurrence when a further attempt for cure (or control of cancer) appeared feasible were enrolled. Lesion status was determined from pathology or clinical follow-up for at least 12 months. Management decisions were recorded with CT-MRI alone and incorporating [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), respectively. The benefits calculated were based on clinical impact because of the FDG-PET findings. Cox proportional hazards model was used to select independent prognostic covariates. Of the 26 patients who were eligible for analysis, 12 (46.2%) patients had positive impacts due to PET. Squamous cell carcinoma (SCC, P = 0.029), re-recurrence at distant metastasis only (P = 0.012), and level of SCC antigen < or = 4 ng/mL (P = 0.005) were significantly associated with better survival. A scoring system using these covariates defined three distinct prognostic groups (P = 0.0001). Patients with score 0 had a 36-month cumulative survival rate of 80%. Using this prognostic scoring system, FDG-PET may facilitate selecting appropriate management for the individual patient with re-recurrent cervical cancer.

The aim of this study was to evaluate the accuracy of human papillomavirus (HPV) genotyping by a polymerase chain reaction (PCR)-based genechip method and to determine the prognostic value of HPV genotype in bulky stage IB or IIA cervical carcinoma treated with neoadjuvant chemotherapy (NAC) and radical surgery. A total of 149 patients had adequate tissue for the study. The SPF1/GP6+ primers were used to amplify a 184 bp fragment. The amplimers were submitted for direct sequencing and hybridization with a genechip using revert-blot detection of 39 types of HPV DNA in a single reaction. Two runs of PCR with respective hybridization were performed for each tumor. The complete concordance of HPV genotyping was 80.5% (120/149) of the paired genechip results. The kappa coefficient was 0.634 (P < 0.0001). HPV DNA sequences were detected in 100% of the specimens, among which 67.8% harbored single type and 32.2% contained multiple types. HPV-16 was detected in 98.7%, HPV-18 in 22.8%, HPV-31 in 0.7%, HPV-45 in 1.3%, HPV-52 in 2.0%, HPV-58 in 6.7%, HPV-59 in 4.7%, and HPV-67 in 0.7%. In multivariate analyses, the HPV genotype [HPV-18 or HPV-16 and HPV-18 only versus all others: relative risk (RR), 2.33; 95% CI, 1.17-4.64; P = 0.016] and pre-NAC tumor size (>5 versus

The purpose of this study was to investigate pretreatment variables related to prognosis and to evaluate long-term outcome in patients with bulky early-stage cervical carcinoma who were enrolled into a protocol treatment of neoadjuvant chemotherapy (NAC) followed by radical surgery. Between 1988 and 1999, 162 women with previously untreated bulky (>/=4 cm) stage IB or IIA carcinoma of the uterine cervix registered to receive cisplatin, vincristine, and bleomycin for three cycles followed by radical hysterectomy and pelvic lymphadenectomy, were enrolled into this study. The 5-year relapse-free (RFS) and overall survival (OS) rates of the whole series were 65% and 69%, respectively. In multivariate analyses, age (< 35 vs. >/= 35-year-old: relative risk [RR], 2.06; 95% confidence interval [CI], 1.02-4.14; P = 0.043) and histologic type (adeno-adenosquamous vs. squamous carcinoma: RR, 2.60; 95% CI, 1.26-5.39; P = 0.010) were independent variables associated with RFS, and age (< 35 vs. >/= 35-year-old: RR, 2.53; 95% CI, 1.24-5.14; P = 0.010) and pre-NAC tumor size (> 5 vs. = 5 cm: RR, 2.06; 95% CI, 1.09-3.90; P = 0.027) were significantly related to OS. Narrowing down patient selection to squamous carcinoma and age older than 35 years with stratification of tumor size (break point of 5 cm) is recommended in future trials involving cisplatin-based NAC plus radical surgery.

Background: The treatment of isolated hepatic metastasis from carcinoma of the uterine cervix has yet to be established. We tested the efficacy of percutaneous injection of ethanol and acetic acid as a curative-intent treatment modality for this rare event., Cases: Under real-time sonographic guidance, two patients with a solitary hepatic metastasis from carcinoma of the cervix were treated with 99.5% percutaneous ethanol injection (one patient) and 50% percutaneous acetic acid injection (the other patient). The treatment was repeated weekly if laboratory data permitted and aspiration cytology interpreted on site showed tumor cells. Cytology after complete treatment showed no residual tumor cells in either case. Both patients had no evidence of disease during follow-up for 12 and 24 months, respectively., Conclusion: Treatment was successful in two patients with isolated hepatic metastatic lesions from carcinoma of the cervix who received percutaneous injection of 99.5% ethanol or 50% acetic acid.

Purpose: To evaluate the clinical features of isolated paraaortic lymph node (PALN) recurrence after definitive radiotherapy, and analyze the prognostic factors and effect of salvage treatment., Methods and Materials: Of a total 876 patients who received pelvic radiotherapy after the diagnosis of primary cervical carcinoma, 26 were found to have isolated PALN recurrence as the first recurrent site, and these patients enrolled in this study. Only those with primary-site carcinoma controlled and who were free of other distant metastases were eligible. Nineteen of the 26 patients accepted salvage therapy. Fourteen patients accepted concurrent chemoradiation (CCRT), 1 accepted radiation to the paraaortic region, and 4 accepted chemotherapy alone. Clinical parameters evaluated included tumor markers (SCC and CEA) and image studies., Results: Seven of the 26 patients were alive and disease-free. All 7 survivors had salvage treatment with radiation to the paraaortic region and concurrent cisplatin-based chemotherapy. None of the patients receiving chemotherapy or radiation alone enjoyed long-term, disease-free survival. The 5-year survival rate for isolated PALN recurrence of the 14 patients who accepted salvage concurrent chemoradiation (CCRT) was 51.2%. The presence of a clinical symptom at the time of PALN recurrence was analyzed. Seven of the 12 asymptomatic patients and none of the 14 symptomatic patients survived without disease after salvage treatment. The SCC levels at recurrence showed a statistically significant relationship to disease-free survival., Conclusions: An SCC level of < or = 4 ng/ml and a lack of symptoms at the time of recurrence were good prognostic factors in isolated PALN recurrence after primary radiation therapy. In addition to concurrent CCRT, periodical surveillance with tumor markers and imaging studies allowed early detection and salvage of those patients.

Objective: Our aim was to evaluate human papillomavirus deoxyribonucleic acid testing after conization in predicting residual disease in the subsequent hysterectomy specimen., Study Design: A prospective study was conducted on 75 patients with grade 3 cervical intraepithelial neoplasia who had cone margins or endocervical curettage specimens showing disease and who elected to undergo hysterectomy after conization. All patients underwent high-risk human papillomavirus deoxyribonucleic acid testing by the Hybrid Capture II (Digene Corporation, Gaithersburg, MD) system before conization and at the time of hysterectomy (within 2-7 weeks after conization). The presence of human papillomavirus deoxyribonucleic acid in cells obtained by endocervical brush before hysterectomy was correlated with residual disease in the hysterectomy specimens., Results: Of the 92 patients enrolled, 75 were eligible. Of these 75 patients, 52 (69.3%) had persistent human papillomavirus deoxyribonucleic acid after conization, and 27 (36.0%) of the 75 patients had residual cervical neoplasia in the hysterectomy specimens. Those with negative results for human papillomavirus deoxyribonucleic acid after conization were all (23/23) without residual disease in the uterus (100% negative predictive value). All those who had residual disease (27/27) had positive results for human papillomavirus deoxyribonucleic acid at the time of hysterectomy (100% sensitivity). Postconization human papillomavirus deoxyribonucleic acid status (odds ratio, 4.000; 95% confidence interval, 1.531-10.449; P =.005) and grade of dysplasia after endocervical curettage (classified as grade 2 cervical intraepithelial neoplasia or less severe disease vs grade 3 cervical intraepithelial neoplasia: odds ratio, 6.612; 95% confidence interval, 2.837-15.409; P =.0002) were significantly associated with residual tumor in the uterus., Conclusions: This prospective study confirms an excellent sensitivity and negative predictive value of human papillomavirus deoxyribonucleic acid testing after conization in predicting residual cervical neoplasia. A strategy of managing patients with grade 3 cervical intraepithelial neoplasia, based on postconization human papillomavirus deoxyribonucleic acid findings and endocervical curettage results, is proposed.

Objective: To evaluate the histologic nature of low grade intraepithelial lesion (LSIL) in a region with a high prevalence of invasive cervical carcinoma and to propose a management protocol., Study Design: Comparing the follow-up of 877 women with LSIL during a 43-month period, taking into consideration the histologic nature determined by colposcopic biopsy, endocervical curettage, conization or hysterectomy as the final pathologic diagnosis., Results: During the study period, from July 1994 to February 1998, a total of 128,925 Pap smears were performed at our institute, with 877 (0.68%) diagnosed as LSIL. Among these, 722 women with CIN1-SIL and 32 with human papillomavirus-related changes (HPV-SIL) were enrolled in the study. Of the 543 women with CIN 1/squamous intraepithelial lesion, 145 (27%) cases of high grade squamous intraepithelial lesion were disclosed histologically, as were 16 (3%) cases of microinvasion. Among those followed at an interval of three months with a Pap smear alone, the persistence rate was 46.8%, while the regression rate was 40%. Thirty-two women with HPV/SIL underwent histologic evaluation, revealing 18% CIN 2/3 with no microinvasion., Conclusion: A high percentage of CIN 2/3 as well as microinvasive lesions will go unnoticed in the absence of colposcopic evaluation.

Background: Adenocarcinomas/adenosquamous carcinomas (AC/ASC) are relatively uncommon histological subtypes in cervical cancer. In this study, we retrospectively compared the clinical behaviors and responses to radiation of squamous cell carcinomas (SCC) and AC/ASC in patients with stage I-IVA cervical cancer primarily treated by radiotherapy (RT)., Methods: Nine hundred twenty-eight patients with cervical cancer primarily treated with RT were included in this study. Ninety-four percent of the patients had SCC and 6% had AC/ASC. The association of histological subtype to various clinical parameters was assessed. Tumor response and failure patterns were analyzed, and the prognostic significance of histological subtype and other clinical parameters were evaluated by univariate and multivariate analyses., Results: (1) Patients with AC/ASC had a significantly higher percentage of bulky I-IIA disease, a younger age (< 45 years), and an elevated carcinoembryonic antigen (CEA) level, but a lower percentage of elevated squamous cell carcinoma antigen (SCC-Ag) level, than patients with SCC. Hemoglobin (Hb) levels and lymph node status were not significantly different between SCC and AC/ASC patients. (2) A higher percentage of AS/ASC patients had residual induration 2 to 3 months after RT than those with SCC (40% vs. 21.6%, p = 0.008). Higher local failure rates were found for AC/ASC patients compared to SCC patients (38% vs. 15%, p = 0.001). (3) The 5-year disease-specific survival rate was 66% and 50% for SCC and AC/ASC patients, respectively (p = 0.016). Advanced stages, Hb levels lower than 10 g/dl, positive lymph nodes, AC/ASC histological subtype, and SCC-Ag levels higher than 10 ng/ml were independent prognostic factors for worse survival for all patients. For patients with AC/ASC in particular, only stage and positive lymph nodes were significant prognostic factors., Conclusion: Cervical cancer patients with AC/ASC are relatively younger and have a higher incidence of elevated CEA and a lower incidence of elevated SCC-Ag levels than those with SCC. For AC/ASC patients, the tumor responses to RT were relatively slow and poor. This group of patients had a worse survival rate than patients with SCC, mainly because of the higher incidence of uncontrolled local disease for AC/ASC patients.

Purpose: To compare the efficacy of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy with that of radiotherapy (R/T) for bulky early-stage cervical cancer., Patients and Methods: Women with previously untreated bulky (primary tumor >/= 4 cm) stage IB or IIA non-small-cell carcinoma of the uterine cervix were randomly assigned to receive either cisplatin 50 mg/m(2) and vincristine 1 mg/m(2) for 1 day and bleomycin 25 mg/m(2) for 3 days for three cycles followed by radical hysterectomy (NAC arm) or receive primary pelvic radiotherapy only (R/T arm). The ratio of patient allocation was 6:4 for the NAC and R/T arms. Women with enlarged para-aortic lymph nodes on image study were ineligible unless results of cytologic or histologic studies were negative., Results: Of the 124 eligible patients, 68 in the NAC arm and 52 in the R/T arm could be evaluated. The median duration of follow-up was 39 months. Thirty-one percent of patients in the NAC arm and 27% in the R/T arm had relapse or persistent diseases after treatment, and 21% in each group died of disease. Estimated cumulative survival rates at 2 years were 81% for the NAC arm and 84% for the R/T arm; the 5-year rates were 70% and 61%, respectively. There were no significant differences in disease-free survival and overall survival., Conclusion: NAC followed by radical hysterectomy and primary R/T showed similar efficacy for bulky stage IB or IIA cervical cancer. Further study to identify patient subgroups better suited for either treatment modality and to evaluate the concurrent use of cisplatin and radiation without routine hysterectomy is necessary.

Objective: To determine whether high-risk human papillomavirus (HPV) DNA testing could improve the detection of cervical intraepithelial neoplasia (CIN) and cancer in older women (> or = 50 years old) with mildly abnormal results on conventional cytology., Study Design: The study was based on 119 patients aged over 50 (median, 62; range, 50-78) referred for colposcopy with Pap smears reported as atypical squamous cells of undetermined significance (ASCUS) or low grade squamous intraepithelial lesion (LSIL) from February 1997 to September 1998. The presence of high-risk HPV DNA (including HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) was determined with the Hybrid Capture II (Digene, Inc., Silver Spring, Maryland) microplate method. Cytologic examination by Pap smear was based on the Bethesda System and, cervical biopsy was done via colposcopy., Results: High-risk HPV DNA was demonstrated in 75.6% (34/45) of patients with LSIL and 52.7% (39/74) with ASCUS. Those who were HPV positive were significantly more likely to have CIN or cancer (odds ratio, 33.40; 95% confidence interval, 11.89-93.97; P < .0001). The sensitivity of HPV assay for detection of lesions more severe than CIN 2 was 100%, specificity 64.8%, positive predictive value 66.7% and negative predictive value 100%., Conclusion: The addition of a high-risk HPV DNA assay to cytologic examination appears to provide excellent sensitivity and negative predictive value for early detection of high grade CIN or cancer in older women with minimally abnormal Pap smears.

Purpose: This study was undertaken to evaluate the efficacy of postoperative radiotherapy (post-OP RT) and to investigate the prognostic factors for early-stage cervical cancer patients who were treated by radical surgery, and the pathological findings suggested a relatively high risk of relapse with surgery alone., Materials and Methods: From January 1990 to December 1995, 222 patients with stage IB-IIA cervical cancer, treated by radical surgery and a full course of post-OP RT, were included in this study. The indications for post-OP RT were based on pathological findings, including lymph node metastasis, positive surgical margins, parametrial extension, lymphovascular permeation, and invasion of more than two-thirds of the cervical wall thickness. The radiation dose of external beam was 44-45 Gy to the whole pelvis and 50-54 Gy to the true pelvis. One hundred seventy-two patients also received intravaginal brachytherapy as a local boost. The minimal follow-up period was 2 years., Results: The actuarial 5-year overall and disease-specific survival rates for all patients were 76 and 82%, respectively. The tumor control rate within the pelvis reached 94%, and distant metastasis was the major cause of treatment failure. Univariate analysis of clinical and pathological parameters revealed that clinical stage, bulky tumor size, positive lymph nodes, parametrial extension, and histologic type were significant prognostic factors. After multivariate analysis, only positive lymph nodes (P = 0.01), bulky tumor size (P = 0.02), and parametrial extension (P = 0.05) independently influenced the disease-specific survival (DSS). For patients with lymph node metastasis, the number and location of the nodal involvement significantly affected the prognosis. The 5-year DSS for patients with no, one, and more than one lymph node metastasis were 87, 84, and 61% (P = 0.0001), respectively. Patients with upper pelvic lymph node metastasis had a higher incidence of distant metastasis (50% vs 16% in lower pelvic node group, P = 0.03). In the subgroup of single lower pelvic nodal metastasis, the prognosis was similar to that of patients without lymph node involvement (5-year DSS 85% vs 87%, P = 0.71)., Conclusion: Our results indicate that post-OP RT can achieve very good local control in stage IB-IIA cervical cancer patients whose pathological findings show risk features for relapse after radical surgery. The prognostic factors for treatment failure identified in this study can be used as selection criteria for clinical trials to test the effects of other adjuvant treatments, such as chemotherapy. Patients with a single lower pelvic lymph node metastasis have a relatively good prognosis and may not need adjuvant treatment beyond radiation therapy., (Copyright 1999 Academic Press.)

Objective: This study was undertaken to investigate prognostic factors in patients with recurrent cervical carcinoma who had undergone a primary radical hysterectomy and pelvic lymphadenectomy., Study Design: A retrospective analysis of 177 patients with recurrent cervical carcinoma after radical hysterectomy and pelvic lymphadenectomy for stage IB to II disease at a single institution was performed to evaluate clinicopathologic parameters, time to recurrence, pattern of failure, use of salvage therapy, and survival after recurrence., Results: The 5-year survival rate from diagnosis of recurrence in this series was 10.1%. Survival after recurrence was significantly decreased in patients with pelvic lymph node metastasis at primary surgery and adenocarcinoma-adenosquamous carcinoma histologic type. Patients with extravaginal recurrences receiving chemoradiation for recurrent cervical carcinoma had significantly better outcomes than those receiving radiation alone. Six patients who had a distant relapse at a sole site had prolonged survival after salvage therapy, which was accomplished by chemoradiation, surgery plus radiotherapy, or surgery alone., Conclusions: Our results demonstrate the benefit of adding chemotherapy to radiotherapy in the treatment of recurrent cervical carcinoma. Salvage multimodality treatment should be offered to selected patients who have isolated relapse at a single distant site.

Clinical complete response (CR) to chemotherapy is not uncommon in small cell carcinoma. To understand its pathologic response, we conducted a phase II trial with neoadjuvant chemotherapy followed by hysterectomy in patients with small cell cervical cancer and reviewed all reported cases receiving neoadjuvant chemotherapy followed by hysterectomy through a MEDLINE search. From December 1993 to December 1997, the enrolled patients were treated with two to three courses of vincristine, adriamycin and cyclophosphamide alternating with cisplatin and etoposide (VAC/PE) before hysterectomy. Another three courses of chemotherapy were added after surgery. A total of seven patients was enrolled. Clinical CR was observed in six patients, but microscopic residual tumor was present in all. Lymphatic permeation, scattered residual tumor clusters and residual superficial invasive adenocarcinoma over the cervix presented in five cases, and another had a metastatic pelvic node with no residual cervical tumor. Three of these seven patients have been alive with no evidence of disease for 16.2, 45.2 and 56.6 months, respectively. The other four died from disease 10.3-23.6 months after diagnosis. These findings indicate the discrepancy between clinical and pathologic responses in small cell cervical cancer after chemotherapy and emphasize the necessity of local treatment.

Objective: The aim of this study was to evaluate the specimen adequacy and the histological interpretation of loop conization for microinvasive cervical carcinoma., Methods: We retrospectively reviewed the histopathological findings of the original cone specimens together with the final hysterectomy specimens in patients with microinvasive carcinoma of the cervix. From 1990 to 1995, 63 consecutive patients with microinvasive carcinoma of the cervix were included in the study, of which 35 patients underwent loop conization and 28 underwent cold-knife conization. All patients had a hysterectomy., Results: The mean width, depth, and cone volume of the conization specimens were 2.44 cm, 2.15 cm, and 3.96 cm3, respectively, in the loop group versus 2.3 cm, 2.35 cm, and 4.38 cm3 in the cold-knife group. No significant differences were seen between the two groups. The application of loop conization was completed in a single slice in 27 patients (77.1%) and multiple slices by the loop in 8 (22.9%), in spite of the attempt to perform conization in a one-pass application when possible. In assessing these cone specimens microscopically, the rate of transection of tissue was significantly higher in the loop cone than in the cold-knife cone (17.1% versus 0%, P = 0.02). Because of transection of tissue and misorientation, pathologic determination of the depth and width of stromal invasion was undetermined in two loop cone specimens compared with none in the cold-knife cones., Conclusion: Our study suggests that cold-knife conization is a preferred method in assessing microinvasive carcinoma of the cervix if multiple applications of loop conization are inevitable., (Copyright 1999 Academic Press.)

Background: The purpose of this study was to investigate pretreatment variables that could predict prognosis and to evaluate the impact of postoperative adjuvant therapy on the outcomes of patients with Stage IB or II cervical carcinoma with or without pelvic lymph node metastases., Methods: Eight hundred ninety-one patients with Stage IB or II cervical carcinoma who underwent radical hysterectomy and bilateral pelvic lymphadenectomy as primary treatment at a single institution were analyzed. Potential prognostic variables were studied., Results: Among the variables that could be assessed before treatment, depth of cervical stromal invasion (determined by magnetic resonance imaging), clinical stage, tumor size, grade of differentiation, and DNA index (determined by flow cytometry) were independent predictors of outcome in multivariate analysis using a Cox regression model. Three distinct prognostic groups (low, intermediate, and high risk) were defined using these variables. Five-year recurrence free survival (RFS) rates for the low, intermediate, and high risk groups were 94.6%, 82.7%, and 62.3%, respectively (P = 0.0001), and overall survival (OS) rates were 98.4%, 84.5%, and 68.7%, respectively (P = 0.0001). Among patients with pelvic lymph node metastases who were free of parametrial extension, those who received postoperative chemotherapy or chemoradiotherapy had significantly better RFS (P = 0.017) and OS (P = 0.043) than those who received no adjuvant therapy. Among patients without pelvic lymph node metastases but at high risk of recurrence, those who received adjuvant radiotherapy had significantly better RFS (P = 0.015) and marginally improved OS (P = 0.087) compared with those who received no adjuvant therapy., Conclusions: A model containing assessable pretreatment variables for predicting the prognoses of patients with early stage cervical carcinoma was formulated. Subsets of patients for whom postoperative chemotherapy or radiotherapy might be beneficial were identified. The data from this retrospective review may be useful when future prospective trials of the treatment of early stage cervical carcinoma are designed.

Background: Lymph node metastasis is established as a poor prognostic factor in cervical carcinoma patients undergoing primary surgery. However the optimal postoperative therapy for node-positive patients remains to be defined., Materials and Methods: To determine the role of adjuvant therapy in stage Ib-IIa cervical carcinoma patients who had pelvic node metastases after radical hysterectomy, a single institutional randomized controlled trial with factorial design, comparing concurrent chemo-radiotherapy (CT + RT) versus chemotherapy (CT) or radiotherapy (RT) alone was conducted. Study endpoints included site of recurrence, time to recurrence, relapse-free and overall survivals, and toxicity of treatment., Results: At a median follow-up of 61 months, the 6-year relapse-free and overall survival rates of the 39 patients entered into this trial were 78.2% and 85.2%, respectively. This trial was prematurely closed due to suboptimal accrual and protocol violation. It is inconclusive regarding the efficacy of CT because of the limitation of the sample size and the imbalance of prognostic features by actual treatment. A model for risk group classification of patients with stage Ib-II cervical carcinoma with pelvic node metastases from a retrospective analysis was validated by this prospective cohort. The results of this failed trial suggest that adjuvant CT alone seemed comparable to RT alone or CT + RT in survival but was associated with significantly less morbidity., Conclusion: It is warranted to consider a CT alone arm in comparison with either observation or CT + RT according to risk of recurrence in future prospective trials. However, this important issue can only be addressed by a large multicenter trial.

Background: Small cell carcinoma of the uterine cervix is an uncommon tumor associated with high mortality even among patients with early stage disease. The role of adjuvant chemotherapy after surgery has been suggested by regimens used for small cell lung carcinoma. During the years 1980-1997, 19 cases in which various adjuvant chemotherapies were given after hysterectomy were reported in the literature published in English., Methods: Adjuvant chemotherapy was administered consecutively to 23 patients with Stage Ib-II small cell cervical carcinoma who had been primarily treated with radical hysterectomy and had adequate bone marrow, renal, and hepatic functions. A combination of vincristine, doxorubicin, and cyclophosphamide alternating with cisplatin and etoposide (VAC/PE) was administered to 14 patients during the years 1988-1996 according to a prospective study protocol. A combination of cisplatin, vinblastine, and bleomycin (PVB) was administered to 8 patients, and another regimen was administered to 1 patient during the years 1984-1988. Prognostic factors were evaluated by analyzing both the data on these 23 patients and the pooled data on the cases retrieved from the literature and our own files., Results: Ten of the 14 patients who received VAC/PE had no evidence of disease during a median follow-up of 41 months, whereas 3 of the 9 who received PVB or another regimen survived. Of the 10 patients who died of their disease, all died of distant metastasis within 10 months after recurrence. Meta-analysis of the pooled data showed that 68% of patients who received regimens containing VAC or PE survived, whereas 33% of patients who received regimens not containing VAC/PE survived (P = 0.0078, log rank test). Seventy percent of patients with no lymph node metastasis at hysterectomy and 35% with lymph node metastasis survived (P = 0.05). All patients who died of disease had extrapelvic metastasis., Conclusions: Chemotherapies containing VAC or PE are favorable regimens for patients with early stage small cell cervical carcinoma after radical hysterectomy.

Purpose: To investigate the prognostic significance of the pre- and posttreatment serum squamous cell carcinoma antigen (SCC) levels in patients with Stage I-IVA squamous cell carcinoma of the cervix primarily treated by radiotherapy., Materials and Methods: 401 patients with squamous cell carcinoma of cervix primarily treated with radiotherapy (RT) were included in this study. All had preRT, and 249 patients had postRT serum SCC values. The association of pretreatment SCC level with the clinical parameters, including stage, hemoglobin (Hb) level, age, cell differentiation, and lymph node status, was assessed by univariate and multivariate analysis. The prognostic significance of pretreatment SCC level and these clinical parameters were evaluated. The impact of postRT residual induration and SCC levels on survival was analyzed., Results: 1. PreRT SCC level strongly correlated with stage. After controlling for stage, only SCC levels higher than 10 ng/ml were associated with enlarged lymph nodes shown in CT scan. No association of preRT SCC level with other clinical parameters was found. 2. SCC level higher than 10 ng/ml, but not between 2-10 ng/ml, had significant impact on survival in a multivariate analysis. Stage, Hb levels (<10 g/dl) and positive lymph node shown by CT scan were also independent prognostic factors for survival. No significant difference in failure pattern in terms of local and/or distant sites was found in patients with different SCC levels. 3. Patients with residual induration and/or persistently elevated SCC level at 2-3 months after RT had a significantly higher incidence of treatment failure. Persistently elevated SCC level is a stronger predictor for treatment failure than residual induration by pelvic examination, and is associated with a higher incidence of distant metastasis. One third of patients with initial SCC level higher than 10 ng/ml had persistently elevated SCC., Conclusion: Pretreatment SCC levels higher than 10 ng/ml are an independent predictor for poor prognosis in patients included in this study, and can be used as one of the prognostic factors for selection of patients for intensive treatment. Persistently elevated SCC levels after RT is a strong predictor for treatment failure. A combination of clinical pelvic examination and SCC levels provides useful information for the need of further work-up and management.

Cervical carcinoma IA1 is defined as invasive cervical cancer with measured invasion of the stroma no greater than 3 mm in depth and no wider than 7 mm in diameter. It has been managed by extrafascial or modified radical hysterectomy. For young female patients who want to preserve future fertility, conservative treatment using therapeutic conization should be considered. In Taiwan, there has been little information about conservative treatment for cervical carcinoma IA1. We present 4 cases of young women with cervical carcinoma IA1 treated by conization alone. Pathological reports of all specimens demonstrated squamous cell carcinoma with free margins, stroma invasion less than 3 mm and no evidence of lymphovascular space invasion (LVSI). After 5-year follow-up with pelvic examination, pap smear, and colposcopy, there was no evidence of disease recurrence. We believe that conservative treatment for cervical carcinoma IA1 without LVSI is appropriate for selected patients to preserve future fertility.

We report on a 52-year-old female patient with a bulky, recurrent cervical carcinoma involving the vagina and bladder, who developed entero-recto-vesicovaginal fistulas and sepsis with pelvic cellulitis after external radiation of 40 Gy and 2 courses of concurrent chemotherapy. Chemoradiation was interrupted and an ileostomy was performed. After recovery, no residual tumor was detectable. Thirteen months after ceasation of chemoradiation, repair of vesicovaginal and rectovaginal fistulas via posterior sagittal approach was performed. Revision of double bowel ileostomy and ileo-T-colostomy was performed 17 months later. The patient enjoyed the restoration of enteral and urinary function only temporarily. She developed rectovesical fistula and underwent an ileostomy again 6 months later. She had another episode of peritonitis and upper gastrointestinal bleeding and expired at 4 years from initiation of salvage therapy. She had no evidence of cancer recurrence during a series of laparotomies and biopsies. The dramatic regression of the tumor may be attributed to its extraordinary radiosensitivity or chemosensitivity. The acute pelvic inflammatory complications may also contribute to the tumor cell killing. The prognosis of recurrent cervical carcinoma is invariably poor except in small tumors confined to vagina. This case gives support to the efficacy of chemoradiation and the potential role of biologic therapy in treatment of this dismal disease.

The purpose of our study was to determine whether the chemoradiation is better than radiotherapy alone with respect to survival and treatment toxicity in patients with advanced carcinoma of the cervix. From October 1990 to April 1995, a total of 122 patients with advanced cervical carcinoma were included in this study and randomly assigned to either radiotherapy or concurrent chemotherapy and radiotherapy. The patients in the concurrent group received cisplatin, vincristine, and bleomycin every 3 weeks for a total of four courses, in combination with radiotherapy concurrently. Sixty patients were randomized to the concurrent chemoradiotherapy, and 62 were randomized to the radiotherapy alone. A tumor response was observed in 88.3% of the patients in concurrent group and in 74.2% of the patients in radiotherapy group (P = 0.04). After a median follow-up of 46.8 months, the overall disease-free survival and actuarial survival rate at 3 years were 51.7 and 61.7% in the concurrent group, and 53.2 and 64.5% in the radiotherapy group, respectively. Treatment-related toxicity appears to be higher with the combination of radiotherapy and chemotherapy compared with radiotherapy alone (36.7% versus 17.7%, P = 0.02). However, analysis by Kaplan-Meier method showed that the actuarial survival was not statistically different between the chemoradiotherapy and radiotherapy groups (mean survival time: 38.1 months versus 41.5 months, P = 0.27). In conclusion, this study showed that concurrent multiagent chemoradiotherapy did not prove to be a superior definitive therapy over radiotherapy alone for patients with advanced cervical carcinoma.

Objective: The objectives of this study were to evaluate the effect of chemotherapy on the continual presence of human papillomavirus deoxyribonucleic acid sequences in bulky cervical cancer tissues and the relationship between the presence of human papillomavirus and the response of these patients to chemotherapy., Study Design: Multiple tissue sections obtained from 33 patients with bulky cervical cancer both before and after chemotherapy were analyzed for the presence of human papillomavirus types 16 and 18 by deoxyribonucleic acid amplification., Results: The cytotoxic effects of chemotherapy did not significantly alter the continual presence of human papillomavirus deoxyribonucleic acid sequences in these tissues (p = 0.8048). The presence of human papillomavirus type 16 deoxyribonucleic acid in tumors treated with neoadjuvant chemotherapy was significantly associated with favorable tumor response compared with type 18-positive patients and type 16/18-negative patients (94.7% vs 42.9%, p = 0.0059 and 94.7% vs 44.4%, p = 0.0004, respectively). Additionally, patients with type 18 deoxyribonucleic acid had a significantly higher risk of recurrence than did type 16-positive patients (p = 0.0123)., Conclusions: These results seem to suggest that the presence of human papillomavirus deoxyribonucleic acid sequences may serve as a marker to predict the response of bulky cervical cancer to chemotherapy and may be useful in reassessing neoadjuvant treatment for those patients who are free of human papillomavirus or those with type 18 deoxyribonucleic acid.

All patients with bulky (> or =4 cm) Stage Ib or IIa cervical carcinoma treated at Chang Gung Memorial Hospital between August 1988 and December 1991 using a strategy of neoadjuvant chemotherapy with cisplatin, vincristine, and bleomycin and radical hysterectomy were reviewed. Fifty-nine evaluable patients received 1 to 3 courses of chemotherapy, and 51 underwent subsequent hysterectomy. The remaining 8 patients, not completing planned surgery, were treated with definitive radiotherapy. The overall clinical response rate was 81.4% (48/59) with 18.6% complete response. Clinical response to chemotherapy was not different by stage, histologic type, tumor size, level of squamous cell carcinoma antigen, or DNA ploidy. However, tumors with DNA indices (DI) greater than 1.3 were associated with higher clinical response rates than tumors with DI < or = 1.3 (P = 0.043). Histologically proven pelvic node metastases was noted in 18.5% (10/54) who had laparotomy. Concomitant pregnancy and more than one node metastases had significant adverse influence on recurrence and death. The 5-year survival rate of those patients who received hysterectomy was 80.3%, while only 1 of the 8 patients without hysterectomy survived. Of the 7 patients received hysterectomy despite clinical poor response, only 2 had node metastases and 3 died, whereas all the 4 patients deterred hysterectomy for poor response died. This study demonstrates the value of DNA flow cytometry in predicting chemosensitivity. However, with a DI cutoff at 1.3, only 29.2% patients could be selected. Further studies are necessary to find additional indicators that predict histological response to select better candidates for this approach and to determine optimal adjunctive treatment in case that poor prognostic features are found.

We report on a case of ureteral injury during laparoscopically radical hysterectomy to treat a patient with a stage IA2 carcinoma of the uterine cervix. The advantage of laparoscopically radical hysterectomy is the prevention of the identification and dissecting of the ureter from a vaginal approach, the main problem in the Schauta technique. However, ureteral injury may still occur while resecting the cardinal ligament without good visualization of the ureter during a vaginal procedure. Because the ureter was well identified and freed laparoscopically, a vaginal approach after uterine removal may be an option for treatment. Moreover, using the ureteral stent as a marker during a modified Schauta technique is helpful in the prevention of ureteral injury during laparoscopically assisted radical vaginal hysterectomy.

Background: The role of flow cytometry in predicting prognosis for cervical carcinoma remains unclear., Methods: Flow cytometric analysis was performed on tissues, fixed in formaldehyde solution and embedded in paraffin, from 411 patients with Stage IB or II cervical carcinoma who had been treated with radical abdominal hysterectomy and bilateral pelvic lymphadenectomy., Results: DNA aneuploid-multiploid tumors were found in 37.5%, tetraploid in 4.6%, and diploid-peridiploid in 57.9%. Five-year recurrence-free survival rates of the three groups were 74.3%, 77.8%, and 76.4%, respectively (P > 0.05). DNA aneuploidy and DNA index (DI) of greater than 1.3 were highly correlated to parametria extension. In univariate analysis, pelvic lymph node metastases, stage, parametrial extension, depth of cervical stromal invasion, tumor size, and DI (1.3, 1.4, 1.5 as breakpoint) were significant prognostic factors. DNA ploidy, S-phase fraction, and S-G2M fraction were not significant. In multivariate analysis, DI of greater than 1.3, pelvic node metastases, clinical Stage II, and depth of stromal invasion greater than two-thirds of full cervical thickness were independent and significant variables. The prognostic index (PI), defined by the model, was able to categorize the patients into three distinct risk groups. The 5-year recurrence free survival rates of the low-, intermediate-, and high-risk groups were 89.5%, 73.0%, and 58.9%, respectively (P < 0.0001)., Conclusions: The prognostic value of the DI as a single variable is promising and warrants additional investigation to establish its appropriate use.

Three hundred seventy cases of clinical stage Ib-II cervical carcinoma treated with radical abdominal hysterectomy and bilateral pelvic lymphadenectomy at Chang Gung Memorial Hospital between 1981-1986 were reviewed retrospectively. Of these, 105 patients had pelvic lymph node metastases. Clinicopathological variables including flow cytometric DNA analysis and the use of adjuvant therapy were studied. Recurrence-free survival was significantly worse among patients with positive pelvic nodes by parametrial extension, increasing number of positive nodes, and DNA index greater than 1.3. In patients with positive nodes and negative parametria, the number of positive nodes remained a significant predictor of survival. Utilizing these significant variables, we identified three distinct risk groups. Those patients who had negative parametria, only one positive node, and a DNA index not greater than 1.3 were categorized as the low-risk group. Those who had either positive parametria or more than three positive nodes were categorized as the high-risk group. All the others fell into the intermediate-risk group. Five-year recurrence-free survival rates were 84.6, 71.6, and 42.1%, respectively (P = 0.0006). Applying this risk group classification and the significant risk factors, we may select more appropriate subsets of patients and good stratification for future prospective trials in surgically treated early-stage cervical carcinoma patients with pelvic node metastases.

Twenty-four patients with bulky (greater than 4 cm), advanced (stages IIB-IVA) carcinoma of the uterine cervix were prospectively treated with a concurrent combination of radiotherapy (RT) and chemotherapy (CT). RT consisted of 4400 cGy (22 fractions) to the whole pelvis and a 1400-cGy boost to the parametrium. This was followed by two to three intracavitary brachytherapy courses. CT consisted of one to four course (median, three) of cisplatin (50 mg/m2) on Day 1, vincristine (1 mg/m2) on Day 2, and bleomycin (25 mg/m2) on Days 2-4. CT was started on the first day of external radiation and the scheduled course interval was 21 days. Among the 20 evaluable patients who completed at least one course of chemotherapy and a full course of radiation, 13 (65%) achieved complete response and 5 (25%) had partial response. Fatal complication occurred in 1 patient with stationary disease who died of septic shock due to ruptured pyometra. The other patient with primary stage IVA disease had progressive disease with ascites appearance after two courses of CT and later expired. Transient drug fever occurred in 19 (40.4%) of the 47 bleomycin-containing CT cycles. Grade 2 or 3 hematological toxicities occurred in 16 (30.2%) of a total of 53 CT cycles. Treatment delays of 1 to 7 days occurred in 15 (28.3%) CT cycles. Except for the case of septic shock, all of the other toxicities were generally tolerable and reversible. From this preliminary result we concluded that this particular combination of RT and CT in bulky, advanced cervical carcinoma is effective in enhancing local pelvic tumor control and well tolerated if strict selection of accrued patients is applied. Further investigation to assess its impact on long-term survival is in progress.

Neoadjuvant chemotherapy consisting of 2-3 courses of cisplatin, vincristine, and bleomycin was used in the primary treatment of 36 consecutive patients with locally advanced early-stage cervical carcinoma [International Federation of Gynecology and Obstetrics (FIGO) stages Ib or IIa; tumor size, greater than or equal to 4 cm]. The effectiveness of the preoperative chemotherapy was evaluated in the surgical specimens. Among the 33 evaluable patients, the overall clinical response rate was 84.8%, which included a complete response in 8 patients (24.2%) and a partial response in 20 subjects (60.6%). No residual tumor was found in the surgical specimens obtained from 2 complete responders. This therapy induced varying degrees of tumor shrinkage and rendered radical surgery feasible in all evaluable cases despite the initial bulky size of the lesions. No significant difference was observed in the response rate according to age and disease stage. Lymph-node metastases were found after chemotherapy in 18.2% (6/33) of the patients. Grade II and III hematological toxicities occurred in 23.3% of the 90 chemotherapy cycles completed. Nausea and vomiting occurred to a mild to moderate degree in 75 (83.3%) cycles. These preliminary results suggest that the administration of induction chemotherapy involving two to three courses of cisplatin, vincristine, and bleomycin prior to surgery is effective in reducing the tumor volume and in providing better circumstances for surgical removal of the early yet bulky cervical tumors and results in tolerable toxicity. This protocol is now undergoing prospective randomized trials to test its impact on long-term survival.

The polymerase chain reaction (PCR) was used to identify human papillomavirus (HPV) in cervicovaginal cells in normal individuals and in patients with cervical intraepithelial neoplasia (CIN). By use of a set of primers encoding the E6 region of the HPV genome, the presence of HPV DNA was demonstrated in the cervicovaginal cells of 43 (42.2%) of 102 normal individuals and in all 12 CIN patients. High sensitivity of the PCR method produced an additional 9 positive results on second sampling from 48 individuals who were initially HPV-negative. On the other hand, 26 (24.3%) of 107 HPV-positive individuals were HPV-negative when sampled a second time 5-7 days later. The data suggested that retest probably should be considered for patients clinically suspected of having HPV infection whose initial test results are negative for HPV DNA. Also, single HPV DNA-positive results should be accepted with caution.

Three hundred and sixty-eight cases of invasive cervical cancer (stage IB through early stage IIB) were treated with radical abdominal hysterectomy and bilateral pelvic lymphadenectomy at Chang Gung Memorial Hospital. Of these patients, 172 were classified postoperatively as a high-risk group after surgical-pathological assessment of tumor extent. Among these high-risk patients, 40 received adjuvant chemotherapy with cisplatin, vinblastine, and bleomycin (PVB), 38 received adjuvant radiotherapy, and 79 refused adjuvant treatment. The 3-year cumulative disease-free survival rate was 91.6% for the low-risk group and 59.7% for those at high risk. Among patients in the high-risk group, the 3-year survival rate was 75.0% for patients treated with adjuvant chemotherapy and 46.8% for those not treated with adjuvant therapy (P less than 0.05). The preliminary results of this pilot study showed a significant activity of adjuvant chemotherapy, which warrants further investigation of its role in the treatment of cervical cancer.