Primary cervical cancer screening with HPV testing compared with liquid-based cytology: results of round 1 of a randomised controlled trial -- the HPV FOCAL Study.

BACKGROUND: Round 1 data of human papillomavirus (HPV) FOCAL, a three-arm, randomised trial, which aims to establish the efficacy of HPV DNA testing as a primary screen for cervical cancer, are presented. METHODS: The three arms are: Control arm - liquid based cytology with atypical squamous cells of unknown significance (ASC-US) triage with hrHPV testing; Intervention Arm - hrHPV at entry with liquid-based cytology (LBC) triage of hrHPV positives, with exit screen at 4 years; Safety check arm - hrHPV at entry with LBC triage of hrHPV positives with exit screen at 2 years. RESULTS: A total of 6154 women were randomised to the control arm and 12 494 to the HPV arms (intervention and safety check). In the HPV arm, the baseline cervical intraepithelial neoplasia (CIN)2+ and CIN3+ rate was 9.2/1000 (95%CI; 7.4, 10.9) and 4.8/1000 (95%CI; 3.6, 6.1), which increased to 16.1/1000 (95%CI 13.2, 18.9) for CIN2+ and to 8.0/1000 (95%CI; 5.9, 10.0) for CIN3+ after subsequent screening of HPV-DNA-positive/cytology-negative women. Detection rate in the control arm remained unchanged after subsequent screening of ASC-US-positive/hrHPV DNA-negative women at 11.0/1000 for CIN2+ and 5.0/1000 for CIN3+. CONCLUSION: After subsequent screening of women who were either hrHPV positive/cytology negative or ASC-US positive/HPV negative, women randomised to the HPV arms had increased CIN2+ detection compared with women randomised to the cytology arm.

The prognostic effects of performance status and quality of life scores on progression-free survival and overall survival in advanced ovarian cancer.

OBJECTIVE: Performance status (PS) is an important prognostic factor in advanced ovarian cancer. The purpose of this study was to evaluate the prognostic significance of PS and quality of life (QoL) assessment on progression-free survival (PFS) and overall survival (OS) in patients with advanced ovarian cancer. METHODS: We studied Canadian patients participating in an intergroup study in ovarian cancer (NCIC-OV10), which randomized patients to receive either standard chemotherapy using cisplatin/cyclophosphamide or cisplatin/paclitaxel chemotherapy. QoL was assessed using the EORTC quality of life questionnaire (QLQ-C30+3). The effects of multiple variables including the relevant clinical variables, PS and QoL scores were analyzed by Cox stepwise regression at baseline and again 3 months after completion of chemotherapy. RESULTS: At baseline and at 3 months after chemotherapy, there were 151 and 93 patients respectively who completed the QLQ-C30+3 questionnaires. Baseline PS, global QoL score and treatment were independent predictors for both PFS and OS. Baseline cognitive functioning score was also an additional independent predictor for OS. At 3 months after completion of chemotherapy global QoL score, PS and grade were significant independent predictors of OS; however, only physical functioning score, emotional functioning score and tumor grade predicted for PFS. CONCLUSIONS: Performance status and global quality of life scores at baseline are prognostic factors in advanced ovarian cancer for both PFS and OS. Higher baseline cognitive functioning scores were also associated with improved survival. Global QoL scores at 3 following completion of chemotherapy proved to be of prognostic significance for OS but not PFS.

Future opportunities of the Gynecological Cancer Intergroup.

The Gynecologic Cancer Intergroup (GCIG) is an international collaboration of cooperative clinical trials groups who conduct randomized phase III clinical trials in the population of women affected by gynecologic cancer. This collaboration amongst 18 member groups allows for rapid accrual of women to such trials with outcomes that are rapidly generated and readily generalizable to a broad population. Future considerations should include studies in prevention and translational research through improved processes and new global partnerships.

The human papillomavirus status of 114 endocervical adenocarcinoma cases by dot blot hybridization.

The reported rate of human papillomavirus (HPV) positivity in cases of endocervical adenocarcinoma averages 38% (range, 0% to 100%) and, in contrast to cervical squamous cell carcinoma, HPV type 18 rather than type 16 is the predominant type. The HPV positivity rate and distribution of types (status) in 114 endocervical adenocarcinoma cases (37 in situ and 77 invasive) were determined by dot blot hybridization using biotinylated probes to HPV types 6, 11, 16, 18, 31, 33, and 35. Human papillomavirus DNA was present in 27% of in situ and in 44% of invasive adenocarcinomas, and in nearly all histologic subtypes of invasive adenocarcinoma. Human papillomavirus status was not predictive of tumor grade, volume, depth of invasion, lymph-vascular space involvement, age at presentation, or year of diagnosis. Type of HPV might influence the histologic subtype of invasive adenocarcinoma, as HPV type 16 predominated in the adenosquamous carcinomas while HPV type 18 was more frequently found in all other subtypes. Since only types 16, 18, and 33 were identified, an oncogenic role for HPV in endocervical carcinogenesis was supported.

The human papillomavirus status of invasive cervical adenocarcinoma: a clinicopathological and outcome analysis.

Accumulating evidence highlights the human papillomavirus (HPV) as a risk factor for cervical adenocarcinoma. However, the part played by the HPV in predicting tumor outcome or the increasing frequency of cervical adenocarcinoma is incompletely studied. In a retrospective study the association between HPV status and the clinicopathological characteristics of 77 cases of cervical adenocarcinoma was investigated. The data were then analyzed for temporal differences in HPV status and to identify outcome predictors. Human papillomavirus status was determined by dot blot hybridization using probes for HPV 6, 11, 16, 18, 31, 33, and 35, followed by polymerase chain reaction amplification of the dot blot negative cases. Seven type-specific and consensus HPV primers were used. Human papillomavirus type 16, 18, or 33 was present in 53 (70%) cases. Human papillomavirus status did not correlate with disease outcome or any clinicopathological variable, except that tumors presenting in and after 1981 were more frequently HPV positive than those presenting before 1981 (P = .014). In a multivariate analysis only clinical stage at presentation was predictive of disease outcome. Because temporal differences in clinicopathological characteristics were not identified, the increasing frequency of cervical adenocarcinoma may relate to a more important oncogenic role for the HPV in tumors presenting after 1980.

Estrogen and progesterone receptor, human papillomavirus, and DNA ploidy analysis in invasive carcinoma of the cervix in pregnancy.

From 1980 to 1991, 13 patients had pregnancy-associated invasive carcinoma of the cervix: four carcinomas were stage IA; eight were stage IB; and one was stage IVB. Gestational ages range from 8 weeks to 3 months postpartum. Two patients are dead of disease and a third is alive with metastases. Results of immunoenzyme studies for estrogen receptors (ER) were variably positive in all except one tumor, whereas results of studies for progesterone receptors (PR) were uniformly negative. Thus, these hormone receptor studies are unlikely to be of prognostic significance. Six tumors contained human papillomavirus (HPV) DNA by in situ or dot blot hybridization (three, HPV 16; two, HPV 18; one, HPV 31/33/35). Thus, neither ER nor PR expression appears to be related to the infecting HPV type. Using flow cytometry, three tumors were determined to be aneuploid and a fourth, tetraploid. To correlate HPV or DNA flow cytometry data with prognosis will require study of larger numbers of patients from multiple centres.

Carbon dioxide laser surgery.

Lower genital tract intraepithelial neoplasia was the predominant indication for CO2 laser surgery in 203 patients treated at Wayne State University. One hundred nineteen patients had cervical intraepithelial neoplasia (CIN) III and, in the 99 patients who were adequately followed, the failure rate following the first treatment was 9%. Secondary treatment with laser surgery, cryosurgery or, in one instance, hysterectomy, was effective in treating all persistent CIN. Success in treating vaginal intraepithelial neoplasia with laser surgery was most favorable in patients who had not had prior pelvic irradiation. Small (less than 1.5 cm) vulvar intraepithelial neoplasia III was successfully treated in seven patients. Recalcitrant condyloma acuminata responded well to laser surgery in 31 patients.

Development of ovarian carcinoma in a cyclosporin A immunosuppressed patient.

This is the first report of an ovarian carcinoma developing in a patient immunosuppressed by Cyclosporin A. Thirteen months before the diagnosis of malignancy, the patient received a living related donor kidney transplant whose rejection was controlled by Cyclosporin A and prednisone. The tumor was rapidly fatal five weeks from diagnosis. The literature on malignant transformation in the immunosuppressed patient is reviewed with emphasis on a gynecologic perspective.

Cervico-vaginal screening in an STD clinic.

From May 1986 to March 1988, there were 3,622 "new" female clients at the Calgary Sexually Transmitted Disease (STD) Clinic of whom 2,278 registered for the first time. A cervico-vaginal (Pap) smear was obtained from those who had not had one in the previous 6 to 12 months and any history of venereal warts (VW) was recorded. 621 smears were accessed of which 611 were suitable for inclusion in this study. 65 (10.6%) smears revealed human papillomavirus (HPV) and/or cervical intraepithelial neoplasia (CIN). Any history of VW increased the likelihood of an abnormal smear by 5.3 times. Those with currently visible VW were more likely (8.8 times) to have an abnormal smear than those with a past history (3.5 times). These data re-affirm the recommendation of the first "Walton Report" that Pap smears should be obtained in STD Clinics.

Age is prognostic variable in cervical squamous cell carcinoma.

A clinico-pathologic review was performed on all younger (under 35 years) and older (55 years or over) women with a diagnosis of cervical squamous cell carcinoma assessed at the Tom Baker Cancer Centre from 1980 to 1985 to determine the effect of age at diagnosis on survival. 45 younger women were identified: 32 were Stage IB; 10, Stage II; and 3, Stage III. 64 older women were identified: 16 were Stage IB; 30, Stage II; 14, Stage III; and 4, Stage IV. For Stage IB women, 40.6% of younger patients developed persistent or recurrent disease and all except one are dead; only one (6.2%) older woman's tumour recurred and she is alive with disease. Younger women had a poorer disease-free survival not only for Stage IB disease (p = 0.014) but also in Stages II and III (p = 0.020). In this study age at diagnosis was an independent prognostic variable with younger women having a poorer disease-free and overall survival.

A paired comparison of dot blot hybridization and PCR amplification for HPV testing of cervical scrapes interpreted as CIN 1.

The rate of Human Papillomavirus (HPV) detection in CIN 1 lesions is quite variable for several reasons. Amongst these, the sensitivity level of the HPV detection system probably ranks supreme. The prevalence of HPV DNA in cervical scrape samples from 234 patients referred for colposcopic investigation of a CIN 1 lesion was compared using dot blot hybridization (DBH) and polymerase chain reaction (PCR) amplification. Both methods were performed on the same patient sample so that determinants of HPV positivity other than the detection system could be controlled. Probes and primers to HPV 6, 11, 16, 18, 31, 33, and 35, and consensus HPV primers were used. The overall HPV positivity rate was 24% using DBH and 70% using PCR. Identified types by DBH and PCR respectively were; HPV 6/11: 1% and 2%, HPV 16/18: 16% and 41%, and HPV 31/33/35: 7% and 14%. PCR detected unidentified types in 13%. Since PCR resulted in a 2.9 times higher HPV DNA detection rate, the choice of detection system has a major impact on the HPV status of cervical smears interpreted as CIN 1.

The HPV determinants of CIN I.

Correlates of HPV amongst a cohort of women with a CIN I detected by a screening Pap test were investigated. Co-incident CIN II/III lesions were identified and their influence on the HPV status and HPV determinants of screening detected CIN I was assessed. Based on both the colposcopic impression and repeat Pap test, 537 women referred for examination of a Pap test classified as CIN I were triaged into two groups. Group A lesions were assessed as /= CIN II; n = 195 (36.3%). Clinical, demographic, reproductive, and risk factor for cervical cancer correlates were collected. HPV typing of cervical scrapes collected at the colposcopic examination was done by PCR amplification using seven sets of type specific and one set of consensus primers. HPV positivity was identified in 47% of all scrapes; types 16/18 (28%), 31/33/35 (10%), 6/11 (2%), and unknown (7%). The HPV status of the cohort and group A were very similar. Group B had a slightly higher rate of HPV positivity (52%) due to an increase in types 16/18. Statistically significant correlates of HPV prevalence or type were not identified either for the entire group or both triage groups, however in each group, HPV positive women tended to be younger and to have more sexual partners. Co-incident CIN II/III spuriously increased the HPV prevalence rate of CIN I detected by a screening Pap test. The HPV appears to be sexually transmitted both in low and high grade lesions and explains why the HPV determinants of the entire cohort were unaffected by the co-incident CIN II/III.

Predictors of co-incidental CIN II/III amongst a cohort of women with CIN I detected by a screening Pap test.

Approximately 20-40% of lesions interpreted by a screening Pap test as CIN I and subsequently examined by colposcopy include a co-incidental CIN II/III. Since the HPV profiles of CIN I and CIN II/III differ, HPV typing may predict these co-incidental higher grade lesions. Based on both the colposcopic impression and repeat Pap test, 537 women referred for examination of CIN I as classified by a screening Pap test were triaged into group A (/= CIN II). Clinical, demographic, reproductive, and risk factor data was collected by questionnaire and HPV typing of cervical scrapes was done by PCR. Group A included 342 (63.7%) women and group B 195 (36.3%). Group B women more frequently were current cigarette smokers (p<0.001) and had a high school or lesser level of education (p=0.04). HPV positivity amongst younger group B women (

The natural history of CIN I lesions.

The published literature indicates 11% of CIN I lesions on average progress to a higher grade dysplasia and the remainder either regress or persist. Reliable markers of disease outcome are yet to be identified. A longitudinal study of 342 women referred for colposcopic examination of a CIN I detected by a screening Pap test, and classified by the colposcopic impression and Pap test at that exam as

Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective.

Ovarian cancer is leading cause of gynecologic cancer mortality in Canada. To date, overall survival (os) has been the most-used endpoint in oncology trials because of its relevance and objectivity. However, as a result of various factors, including the pattern of sequential salvage therapies, measurement of os and collection of os data are becoming particularly challenging. Phase ii and iii trials have therefore adopted progression-free survival (pfs) as a more convenient surrogate endpoint; however, the clinical significance of pfs remains unclear. This position paper presents discussion topics and findings from a pan-Canadian meeting of experts that set out to evaluate the relevance of pfs as a valid endpoint in ovarian cancer;reach a Canadian consensus on the relevance of pfs in ovarian cancer; andtry to address how pfs translates into clinical benefit in ovarian cancer.Overall, the findings and the group consensus posit that future studies should ensure that trials are designed to evaluate pfs, os, and other clinically relevant endpoints such as disease-related symptoms or quality of life;incorporate interim futility analyses intended to stop accrual early when the experimental regimen is not active;stop trials early to declare superiority only when compelling evidence suggests that a new treatment provides benefit for a pre-specified, clinically relevant endpoint such as os or symptom relief; anddiscourage early release of secondary endpoint results when such a release might increase the frequency of crossover to the experimental intervention.

Phase II multicenter open-label study of carboplatin and pegylated liposomal doxorubicin in uterine and cervical malignancies.

The results of a multicenter phase II study investigating carboplatin and pegylated liposomal doxorubicin (PLD) in patients with recurrent/metastatic uterine and cervical malignancies (UCM) are presented here. Fifty-three subjects with measurable, untreated, advanced UCM were enrolled. Fifty-one were evaluable for response. Prior combined-modality treatment was permitted if a component of primary therapy. Patients received carboplatin AUC = 5 with PLD 35 mg/m(2) intravenously once every 4 weeks. Overall response rate was 33% (35% stable disease). Overall survival (OS) at six months was 86% (95% CI 76%-96%). Six-month progression-free survival (PFS) was 43% (95% CI 30%-57%). Median PFS was 22.9 weeks (range 16.0-35.3) and median OS was 49.1 weeks (range 41.4-75.1). The most frequent grade 3-4 nonhematological adverse events were: abdominal pain (n = 7), fatigue (4), vomiting (4), nausea (3), and shortness of breath (3). There was 1 report of grade 3 hand-foot syndrome and none of grade 4. Twelve patients had first infusion reactions with only 1 discontinuing treatment. Grade 3-4 neutropenia occurred in 26/230 cycles (11.3%). There were no treatment-related deaths. The combination of carboplatin and PLD is well tolerated with sufficient activity to justify additional evaluation in clinical trials and might be suited to the addition of a taxane.

Ruptured benign cystic teratomas mimicking gynecologic malignancy.

Ruptured benign cystic teratomas of the ovary mimicking gynecologic malignancy are uncommon, but frequently misdiagnosed. Two cases are reported that, preoperatively, were believed to represent ovarian carcinoma, but were found to have diffuse granulomatous peritonitis, secondary to perforation of the teratomas. Intra-abdominal adhesions and/or masses are frequent sequelae. A diagnosis of malignancy must be confirmed prior to performing radical surgery. A review of the literature is presented.

Outpatient laser cone biopsy under local anesthesia.

The authors report on 60 patients who had abnormal findings on cervical cytologic examination, necessitating conization of the cervix. The procedure was done in an ambulatory setting, with a carbon-dioxide laser unit and local anesthesia. The average operative time was 16.9 minutes. Fifty-one (85%) patients experienced no complications, and there were no cases of excessive bleeding. In all patients, the specimen was satisfactory for histologic review. Only 5% (three) of patients would have preferred to have the procedure performed under general anesthesia. Laser cone biopsy of the cervix can be performed in an outpatient setting, with local anesthesia. Morbidity is minimal and there is potential for economic saving when compared with conventional methods for biopsy of the cervix.

Carcinoma of the cervix following conservative management of cervical intraepithelial neoplasia.

The purpose of this study was to identify the reasons for treatment failures in patients managed with cervical intraepithelial neoplasia who subsequently developed invasive carcinoma of the cervix. Of 672 patients seen with cervical carcinoma from 1980 to 1990 inclusive, at the Tom Baker Cancer Centre, 24 (3.6%) had previously undergone conservative treatment for CIN and represent the current study population. The initial colposcopic-guided biopsy showed metaplasia (2), CIN 2 (5), and CIN 3 (17). The conservative treatment methods included observation (5), electrocautery (1), laser ablation (3), surgical cone (5), and cryotherapy (10). The mean time interval in months from conservative treatment of CIN to diagnosis of cervical cancer was 21.8 with cryotherapy and 26.7 with laser ablation. The FIGO stage of invasive cervical cancer was Stage 1A (7), Stage 1B (15), Stage 2A (1), and Stage 3 (1). The single death was a patient aged 30 with metastatic small cell cervical carcinoma arising within 4 years of cryotherapy for CIN 3. Of the 24 patients, 13 were managed appropriately yet developed carcinoma, 3 deviated from an accepted standard colposcopy protocol, 5 had inadequate follow-up, 2 refused treatment, and 1 developed de novo disease. The principle reason for treatment failure according to the literature is blatant deviation from protocol. This study, however, suggests that established invasive disease may have gone undetected prior to an ablative therapy. Difficulties related to diagnosis are discussed. The importance of peer reviews becomes evident if practices are to be evaluated and changes to protocols are to be implemented.