Huei-Jean Huang

Randomized trial of surgical staging (extraperitoneal or laparoscopic) versus clinical staging in locally advanced cervical cancer

OBJECTIVE To define the role of pretreatment surgical staging for locally advanced cervical carcinoma. METHODS A two-step randomized trial was conducted to compare clinical staging (arm A) versus surgical staging (arm B) and to compare the laparoscopic (LAP) with the extraperitoneal (EXP) approach in previously untreated locally advanced cervical carcinoma. After the first randomization, those in arm B were randomly allocated to either LAP or EXP. An interim analysis was planned to evaluate the feasibility of LAP versus EXP, which led to the current report. RESULTS A total of 61 patients were eligible (arm A, 29; arm B, 32). The operation time, blood loss, and lymph node yield of LAP and EXP were not significantly different. Serious acute and late toxicity was not different between arm A and arm B, or LAP versus EXP. Para-aortic node metastasis was documented in 25% (95% confidence interval, 10% to 40%) of patients on arm B. An interim analysis was performed in January 2000. Patients on arm B had significantly worse progression-free survival than those on arm A. Hazard ratios of relapse/persistent or death were 3.13 (P = 0.005) and 1.76 (P = 0.150), respectively. Patient accrual was terminated according to the early stopping rules. With further follow-up till December 2001, the difference in progression-free survival remained significant (P = 0.003), and the difference in overall survival became significant (P = 0.024) as the data matured. CONCLUSION The benefit of pretreatment surgical staging for cervical carcinoma remained unproven. The detrimental effects of surgical staging observed in this study must be considered in the design of clinical guidelines or future trials.

Low Value of [18F]-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography in Primary Staging of Early-Stage Cervical Cancer Before Radical Hysterectomy

PURPOSE The role of positron emission tomography (PET) with [18F]-fluoro-2-deoxy-D-glucose (FDG) in early-stage cervical cancer is unclear. We aimed to investigate the clinical benefit of FDG-PET in primary staging before radical hysterectomy and pelvic lymphadenectomy (RH-PLND). PATIENTS AND METHODS Patients with untreated stage IA2 to IIA adenocarcinoma (AD) or adenosquamous carcinoma (ASC) or nonbulky (< or = 4 cm) squamous cell carcinoma cervical cancer with magnetic resonance imaging (MRI) -defined negative nodal metastasis were enrolled onto a prospective study with a two-stage design. All patients had a preoperative dual-phase FDG-PET, technetium-99m-sulfur colloid lymphoscintigraphy, and intraoperative sentinel lymph node (LN) detection at RH-PLND. The gold standard of LN metastasis is histologic. A sample size of 120 patients was calculated to fit study aims (diagnostic efficacy of PET and sentinel LN sampling). An interim analysis was performed when 60 patients were accrued, which led to the current report. RESULTS There were 36 SCCs, 20 ADs, and four ASCs. Of the 60 patients, 10 (16.7%) had pelvic LN metastases, and one (1.7%) had para-aortic LN (PALN) metastasis histologically. FDG-PET detected the single PALN metastasis (one of one patient) but detected only one (10%) of the 10 pelvic LN metastases. The PET false-negative pelvic LN micrometastases measured a median of 4.0 x 3.0 mm (range, 0.5 x 0.5 to 7 x 6 mm). The second stage of this trial will be continued without PET. CONCLUSION This study shows that dual-phase FDG-PET has little value in primary, nonbulky, stage IA2 to IIA and MRI-defined, LN-negative cervical cancer.

Comparison between the Hybrid Capture II Test and an SPF1/GP6+ PCR-Based Assay for Detection of Human Papillomavirus DNA in Cervical Swab Samples

ABSTRACT We compared the efficacy of human papillomavirus (HPV) DNA detection between a PCR-based genechip (Easychip HPV Blot [hereafter referred to as HPV Blot]; King Car, Taiwan) method and Hybrid Capture II (HCII; Digene, Gaithersburg, MD) in women with previous normal (n = 146) or abnormal (≥atypical squamous cells of undetermined significance [ASCUS] [n = 208]) cytology. A total of 354 cervical swab samples were collected for HPV DNA assay by both HCII and SPF1/GP6+ PCR followed by HPV Blot tests. Colposcopy-directed biopsy was performed if clinically indicated. Of the 354 samples, HPV-positive rates by these two methods (HCII and HPV Blot) were 12.6% and 18.2% in 143 normal samples, 36.2% and 45.7% in 105 ASCUS samples, 57.4% and 57.4% in 94 low-grade squamous intraepithelial lesion samples, and 83.3% and 75.0% in 12 high-grade squamous intraepithelial lesion samples, respectively. The concordance of HPV Blot and HCII was 80.8% (286/354), and the agreement between the methods (κ value, 0.68) was substantial. Discrepancies were further investigated by at least one of the following three methods: direct sequencing, type-specific PCR, and HPV Blot genotyping of cervical biopsy tissue. In the 15 HCII-positive samples, HPV Blot detected only non-HCII HPV genotypes; results of further verification methods were consistent with the latter test in the 15 samples. Of the 20 samples with HCII-negative and HPV Blot-positive results, 18 were found to contain the 13 HCII high-risk genotypes by verification methods. In only 16.7% (3/18) of the HCII-positive but HPV Blot-negative samples, further studies detected the 13 HCII genotypes. We conclude that HPV Blot seemed comparable to HCII for detection of HPV DNA in cervical swab samples.

Role of Human Papillomavirus Genotype in Prognosis of Early-Stage Cervical Cancer Undergoing Primary Surgery

PURPOSE Our aim was to evaluate the prognostic significance of human papillomavirus (HPV) genotype in early-stage cervical carcinoma primarily treated with surgery in a large tertiary referral medical center. PATIENTS AND METHODS Consecutive patients who underwent primary surgery for invasive cervical carcinoma of International Federation of Gynecology and Obstetrics (FIGO) stage I to IIA between 1993 and 2000 were retrospectively reviewed. Polymerase chain reaction (PCR) using a general primer set followed by reverse-blot detection of 38 types of HPV DNA in a single reaction was performed for genotyping. E6 type-specific PCR was performed to validate multiple types. RESULTS A total of 1,067 eligible patients were analyzed. HPV DNA sequences were detected in 95.1% of the specimens, among which 9.6% contained multiple types. HPV 16 was detected in 63.8% of the samples, and HPV 18 was detected in 16.5% of the samples. The median follow-up time of surviving patients was 77 months. By multivariate analysis, FIGO stage, lymph node metastasis, depth of cervical stromal invasion, grade of differentiation, and HPV 18 positivity were significantly related to cancer relapse. FIGO stage II, deep stromal invasion, parametrial extension, HPV 18 positivity, and age older than 45 years were significant predictors for death. Using the seven selected variables from either recurrence-free or overall survival analysis, death-predicting (P < .0001) and relapse-predicting (P < .0001) models classifying three risk groups (low, intermediate, and high risk) were constructed and endorsed by internal validation. CONCLUSION The independent prognostic value of HPV genotype is confirmed in this study. The prognostic models could be useful in counseling patients and stratifying patients in future clinical trials.

Tension-free vaginal tape procedure after previous failure in incontinence surgery.

OBJECTIVES To study the efficacy of the tension-free vaginal tape (TVT) procedure for patients with recurrent genuine stress incontinence. METHODS Forty-one women, including 11 with urethral sphincter incompetence (mean age 49.6 years, range 37 to 66), were treated for recurrent genuine stress incontinence with TVT procedure under local or regional anesthesia. Urodynamic studies, a 1-hour pad test, introital ultrasonography on the urethra, a cotton swab test, and subjective symptom analysis were documented before the procedure and at 1 year postoperatively. RESULTS Of the 41 women, 34 (82.9%) were cured, 2 improved, and 5 (12.2%) had treatment failure. Among the women with failure, three had urethral sphincter incompetence with a fixed urethra. No major surgical complications occurred. Four bladder perforations were noted. The 1-hour pad test reduced from a mean of 27.3 to 1.7 g (P <0.001). The operating time was 22 minutes (range 15 to 44), and the postoperative hospital stay was 22.4 hours (range 12 to 72). Spontaneous voiding with adequate postvoid residual urine volume was noted for all patients by the fourth day postoperatively. The preoperative and postoperative cotton swab result was 40.0 degrees (range 10 degrees to 80 degrees ) and 38.7 degrees (range 10 degrees to 76 degrees ), respectively, without statistically significant changes. Of the 36 cured and improved patients, 31 (86.1%) had a cotton swab test result of 30 degrees or more before and after the TVT procedure. Urodynamic parameters related to the voiding dysfunction showed no significant difference before and after the surgery. Urodynamic assessment showed no significant difference in the filling, voiding, and urethral pressure profile (dynamic and static) variables, except for significant increases in the maximal flow rate, bladder volume at the first desire to void, and cystometric capacity, which were measured preoperatively and postoperatively. No de nova detrusor instability or micturition disturbances were found in the cystometric study. CONCLUSIONS The TVT procedure for the treatment of recurrent genuine stress incontinence is a safe, effective, and minimally invasive option requiring only a short hospital stay. However, the immobile urethra seems to be a risk factor for failure. Long-term follow-up is needed to determine whether this surgery achieves long-lasting results.

Human papillomavirus genotype in cervical cancer: A population-based study†

Our aim was to investigate the human papillomavirus (HPV) genotype distribution and correlation between HPV parameters and clinicopathological variables in cervical carcinoma treated in a large tertiary referral medical center in Taiwan. Consecutive patients treated for cervical carcinoma (Stages I–IV according to the International Federation of Gynecology and Obstetrics) between 1993 and 2000 were included. HPV genotyping using SPF1/GP6+ PCR was performed, followed by hybridization with a genechip (Easychip® HPV Blot, King Car, Taiwan). E6 type‐specific PCR was performed to validate multiple‐type. HPV‐negative samples were further verified by type‐specific PCR and a repeat HPV Blot. A total of 2,118 patients were eligible for analysis. HPV DNA sequences were detected in 96.6% (95% CI, 95.8–97.4%) of the specimens, among which 82% harbored single‐type and 18% contained multiple‐type HPV sequences. Thirty‐five types of HPV were identified and the leading 8 were HPV16 (50.0%), HPV18 (17.8%), HPV58 (16.3%), HPV33 (8.7%), HPV52 (6.8%), HPV39 (3.0%), HPV45 (2.5%) and HPV31 (2.3%). HPV58 or 33 or 52 was detected in 30.3% (641/2,118). By multivariate analysis, HPV58‐ or 33‐ or 52‐infection was significantly associated with older age (p < 0.001) and primary radiotherapy or concurrent chemoradiation (RT/CCRT) (p < 0.001). Among HPV‐positive cases, multiple‐type was more frequently seen in those receiving primary RT/CCRT (p < 0.001). The knowledge of HPV genotype distribution will form a basis for guidelines in HPV‐based cervical cancer screening and cost‐effective multivalent HPV vaccine policy in Taiwan and in the world. The association between HPV parameters and clinicopathological variables warrants further investigations.

Recurrent cervical carcinoma after primary radical surgery

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.

18F-fluorodeoxyglucose positron emission tomography in uterine carcinosarcoma

PurposeUterine carcinosarcomas clinically confined to the uterus usually harbor occult metastases. We conducted a pilot study to evaluate the value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in uterine carcinosarcoma.MethodsPatients with histologically confirmed uterine carcinosarcoma were enrolled. Abdominal and pelvic magnetic resonance imaging (MRI)/whole-body computed tomography (CT) scan, and whole-body 18F-FDG PET or PET/CT were undertaken for primary staging, evaluating response, and restaging/post-therapy surveillance. The clinical impact of 18F-FDG PET was determined on a scan basis.ResultsA total of 19 patients were recruited and 31 18F-FDG PET scans (including 8 scans performed on a PET/CT scanner) were performed. Positive impacts of scans were found in 36.8% (7/19) for primary staging, 66.7% (2/3) for monitoring response, and 11.1% (1/9) for restaging/post-therapy surveillance. PET excluded falsely inoperable disease defined by MRI in two patients. Aggressive treatment applying to three patients with PET-defined resectable stage IVB disease seemed futile. Two patients died of disease shortly after salvage therapy restaged by PET. With PET monitoring, one stage IVB patient treated by targeted therapy only was alive with good performance. Using PET did not lead to improvement of overall survival of this series compared with the historical control (n = 35) (P = 0.779).ConclusionsThe preliminary results suggest that 18F-FDG PET is beneficial in excluding falsely inoperable disease for curative therapy and in making a decision on palliation for better quality of life instead of aggressive treatment under the guidance of PET. PET seems to have limited value in post-therapy surveillance or restaging after failure.

Use of intravenous anesthesia for tension-free vaginal tape therapy in elderly women with genuine stress incontinence.

OBJECTIVES To study the efficacy of the tension-free vaginal tape (TVT) procedure for elderly patients. METHODS Forty-five women, 65 years old or older (mean 69.1; range 65 to 85), were treated for genuine stress incontinence with the tension-free vaginal tape procedure under intravenous anesthesia with heavy sedation. Urodynamic studies and 1-hour pad test were performed before the procedure and at 1 year postoperatively. Vigorous manual pressure against the abdominal wall and ensuring no lifting of urethra by intraoperative introital ultrasonography were used to position and adjust the vaginal taping. RESULTS Forty-one (91%) were cured, one improved, and three failed. No major surgical complications occurred. Two bladder perforations were noted. The pad test disclosed a reduction in urine leakage from a mean of 28.9 to 1.6 g/hr (P <0.001). The average blood loss was 72 mL (range 30 to 250), operating time was 21 minutes (range 18 to 35), and postoperative hospital stay was 24.2 hours (range 12 to 72). Spontaneous voiding with an adequate volume of postvoid residual urine was noted for all patients by the fourth day postoperatively. Urodynamic parameters related to the voiding dysfunction showed no significant difference before and after surgery. De novo detrusor instability was observed in 2 patients. CONCLUSIONS With modifications of the technique and the aid of intraoperative ultrasonography, the TVT procedure can be performed under intravenous anesthesia with heavy sedation. The procedure is safe, effective, and minimally invasive for elderly patients. However, long-term follow-up is needed to determine whether this surgery achieves long-lasting results.

Host and viral factors in relation to clearance of human papillomavirus infection: A cohort study in Taiwan

Human papillomavirus (HPV) persistence is essential for cervical cancer development. We accrued nested‐cohort subjects from a population‐based study to investigate the host and viral factors related to outcome of HPV infection. Women (age ≥ 30 years old) with HPV‐positive but normal cytology and negative colposcopy were invited to participate. After signing informed consent, every participant completed a structured questionnaire and had 6‐monthly follow‐ups of Pap smear, HPV testing and colposcopy. Total and type‐specific HPV clearance rates as well as host and viral factors associated with clearance in 3‐year longitudinal follow‐up were analyzed. Adjusted hazard ratios (HRs) of progression to ≥ cervical intraepithelial neoplasia (CIN) 2 according to baseline HPV of the women with normal cytology were calculated from national registry database. Among the 626 eligible women, 526 (median age 47, 29–75) were enrolled and 412 returned for follow‐up at least once. The median follow‐up of enrolled subjects was 23 months (range 6.8–39). The 3‐year cumulative total HPV clearance rate was 49.0% (95% confidence interval [CI]: 43.3–54.7%). The median 3‐year cumulative type‐specific HPV clearance rate was 50.0% (range 0–100.0%) with a median time to clearance of 12.4 months (6.4–24.5). Older age was associated with significantly decreased total HPV clearance and decreased type‐specific clearance in HPV‐18 and ‐53, while high viral load was associated with decreased total and type‐specific clearance. After adjusting confounding variables, the HR of developing ≥CIN2 in baseline HPV‐positive women was 34.0‐fold (95% CI: 15.5–74.7) as compared to HPV‐negative women.