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.

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.

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.

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.

Postoperative chemotherapy in advanced ovarian granulosa cell tumors.

The objective of this research is to assess the use of first-line postoperative chemotherapy in patients with advanced ovarian granulosa cell tumor (GCT). A retrospective population-based case series identified 60 women with stage IC or greater ovarian GCT over a 25-year period. Five patients were excluded because of incomplete information. None of the patients had received chemotherapy or radiotherapy prior to the diagnosis of advanced GCT. All patients had, at a minimum, a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pathology was centrally reviewed and the diagnosis confirmed. Of the 55 eligible patients, the 21 women with stage III and IV disease were the main focus of the study. Clinical outcomes and survival were compared between 13 women who received combination chemotherapy and eight who did not. Univariate analysis was conducted to assess the impact of age at diagnosis, size of residual disease, and adjuvant use of radiation therapy on prognosis. For the 55 patients, median age at diagnosis was 54 years (range 22-79). Median length of follow-up was 4.4 years (range 0.3-23.3). Median time to progression was 2.3 years (range 0.3-5.3). Sixty percent of those with no macroscopic disease after primary surgery recurred within 4.5 years of diagnosis. All patients with gross residual disease (>2 cm) were dead within 4 years of diagnosis. Overall 5 years survival rate was 61.6% (95% CI (49.3-76.9)). Among stage III and IV patients, there were no differences with respect to age at diagnosis and use of radiation therapy between those who did and did not receive chemotherapy. The only statistically significant difference was the presence of macroscopic residual disease (82% vs. 22%). Although there was no statistical significant difference in overall survival, there was a trend toward a poorer outcome in the group that received chemotherapy. Survival of patients with macroscopic residual disease was not influenced by use of chemotherapy (P = 0.976). We conclude that the presence of macroscopic residual disease after primary surgery was the most important prognostic factor. Although these patients were more likely to receive postoperative chemotherapy, there was no evidence to document a beneficial effect of systemic therapy in this group of women.