Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup.

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

Disease detection at the 48-month exit round of the HPV FOCAL cervical cancer screening trial in women per-protocol eligible for routine screening.

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high-risk human papillomavirus (HPV) and the control arm received liquid-based cytology (LBC) at baseline and 24 months. Both arms received 48-month exit HPV and LBC cotesting. Exit results are presented for per-protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow-up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25-65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56-1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43-1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14-65) and intervention 43 (95% CI: 25-73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1-0.7). This per-protocol analysis found that screening with HPV using a 4-year interval is as safe as LBC with a 2-year screening interval. LBC screening in HPV negative women at exit identified few additional lesions.

Effect of Screening With Primary Cervical HPV Testing vs Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 Months: The HPV FOCAL Randomized Clinical Trial.

Importance: There is limited information about the relative effectiveness of cervical cancer screening with primary human papillomavirus (HPV) testing alone compared with cytology in North American populations. Objective: To evaluate histologically confirmed cumulative incident cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) detected up to and including 48 months by primary HPV testing alone (intervention) or liquid-based cytology (control). Design, Setting, and Participants: Randomized clinical trial conducted in an organized Cervical Cancer Screening Program in Canada. Participants were recruited through 224 collaborating clinicians from January 2008 to May 2012, with follow-up through December 2016. Women aged 25 to 65 years with no history of CIN2+ in the past 5 years, no history of invasive cervical cancer, or no history of hysterectomy; who have not received a Papanicolaou test within the past 12 months; and who were not receiving immunosuppressive therapy were eligible. Interventions: A total of 19 009 women were randomized to the intervention (n = 9552) and control (n = 9457) groups. Women in the intervention group received HPV testing; those whose results were negative returned at 48 months. Women in the control group received liquid-based cytology (LBC) testing; those whose results were negative returned at 24 months for LBC. Women in the control group who were negative at 24 months returned at 48 months. At 48-month exit, both groups received HPV and LBC co-testing. Main Outcomes and Measures: The primary outcome was the cumulative incidence of CIN3+ 48 months following randomization. The cumulative incidence of CIN2+ was a secondary outcome. Results: Among 19 009 women who were randomized (mean age, 45 years [10th-90th percentile, 30-59]), 16 374 (8296 [86.9%] in the intervention group and 8078 [85.4%] in the control group) completed the study. At 48 months, significantly fewer CIN3+ and CIN2+ were detected in the intervention vs control group. The CIN3+ incidence rate was 2.3/1000 (95% CI, 1.5-3.5) in the intervention group and 5.5/1000 (95% CI, 4.2-7.2) in the control group. The CIN3+ risk ratio was 0.42 (95% CI, 0.25-0.69). The CIN2+ incidence rate at 48 months was 5.0/1000 (95% CI, 3.8-6.7) in the intervention group and 10.6/1000 (95% CI, 8.7-12.9) in the control group. The CIN2+ risk ratio was 0.47 (95% CI, 0.34-0.67). Baseline HPV-negative women had a significantly lower cumulative incidence of CIN3+ at 48 months than cytology-negative women (CIN3+ incidence rate, 1.4/1000 [95% CI, 0.8-2.4]; CIN3+ risk ratio, 0.25 [95% CI, 0.13-0.48]). Conclusions and Relevance: Among women undergoing cervical cancer screening, the use of primary HPV testing compared with cytology testing resulted in a significantly lower likelihood of CIN3+ at 48 months. Further research is needed to understand long-term clinical outcomes as well as cost-effectiveness. Trial Registration: isrctn.org Identifier: ISRCTN79347302.

The Impact of an International Network (Gynecologic Cancer InterGroup) for Clinical Research on Global Capacity for Gynecologic Cancer Clinical Trials.

OBJECTIVE: The objective of this study was to demonstrate that the construction of the Gynecologic Cancer InterGroup (GCIG) has increased collaboration and accrual to high-quality phase 3 trials at a global level. MATERIALS AND METHODS: The GCIG is a collaboration of 29 international cooperative clinical trial groups committed to conduct of high-quality phase 3 trials among women with gynecologic cancer. A complete bibliography of the reported phase 3 trials has been developed and is available on the GCIG Web site http://www.gciggroup.com. A "GCIG trial" is a trial in which any 2 or more GCIG member groups are formally involved. We reviewed the output of the GCIG from 1997 to 2015 with respect to member participation and quality of publication (impact factor and citation index). The publications are considered in 3 cohorts, 1997 to 2002, 2003 to 2008, and 2009 to 2014, for the purposes of comparison and progress. A social network map has been developed for these publications to identify how the GCIG has increased capacity for clinical trials globally. RESULTS: Using a global map, the number of member groups in the GCIG has increased in each of the 3 periods. The total annual number of publications and citations within the 1997 to 2015 period has increased significantly. The average number of citations per publication is demonstrated in each of the 3 periods. The steady increase in the number of citations is used as a proxy for the impact of the publications. The impact factor of the journal and the number of citations are reported for the 10 most highly cited publications. Finally, using a social networking methodology, networking has visibly and numerically increased in each of the 3 periods. CONCLUSIONS: Evidence supports that the construction of the GCIG has increased collaboration and accrual to high-quality phase 3 trials at a global level among women with gynecologic cancer.

Projected Impact of HPV and LBC Primary Testing on Rates of Referral for Colposcopy in a Canadian Cervical Cancer Screening Program.

OBJECTIVE: To estimate the impact of implementing primary human papilloma virus liquid-based cytology (LBC) screening on four-year rates of referral for colposcopy in the British Columbia screening program. METHODS: We used data on referral for colposcopy from an RCT (HPV FOCAL) comparing HPV testing every four years with LBC testing every two years. We also used data from population screening with conventional cytology among women aged 25 to 69. The predicted effect of adoption of either trial protocol on rates of referral for colposcopy was estimated using trial age-specific result and screening result-specific rates weighted by their screening program distribution. The cumulative age-specific rates of referral for colposcopy over four years were calculated. RESULTS: Use of HPV testing initially increased rates of referral for colposcopy in the trial, but over four years the cumulative rates of referral were similar to those for LBC except in women aged 25 to 29, in whom a substantial excess persisted. Four-year rates of referral for colposcopy declined with age in women screened with HPV testing, LBC, and conventional cytology. Extrapolating the trial results to the distribution in the provincial screening program, implementation of either HPV or LBC throughout the provincial population would approximately double the current rates of referral for colposcopy. CONCLUSION: Compared with LBC screening, primary screening for HPV increased rates of referral for colposcopy only among women aged 25 to 29. In contrast to current practice, referral for colposcopy was largely driven by the trial protocol recommendations for the management of abnormal results and not by which screening test was used.

Objectif : Estimer les effets de la mise en œuvre d'un dépistage primaire du virus du papillome humain par cytologie en milieu liquide (CML) sur les taux d'orientation en colposcopie sur quatre ans, dans le cadre du programme de dépistage de la Colombie-Britannique. Méthodes : Nous avons utilisé les données sur l'orientation en colposcopie issues d'un ECR (HPV FOCAL) comparant le dépistage du VPH tous les quatre ans au dépistage par CML tous les deux ans. Nous avons également utilisé des données issues du dépistage populationnel par cytologie conventionnelle mené auprès des femmes de 25 à 69 ans. Le taux d'orientation en colposcopie en fonction de l'âge et le taux d'orientation en colposcopie en fonction des résultats de dépistage ont été pondérés en fonction de la distribution de leurs programmes de dépistage respectifs, ce qui a permis d'estimer l'effet populationnel prévu de l'adoption de l'un ou l'autre des protocoles d'essai en question sur les taux d'orientation en colposcopie. Les taux cumulatifs (en fonction de l'âge) de l'orientation en colposcopie sur quatre ans ont été calculés. Résultats : Le recours au dépistage du VPH a initialement mené à la hausse des taux d'orientation en colposcopie dans le cadre de l'essai; toutefois, sur quatre ans, les taux cumulatifs d'orientation ont été semblables à ceux de la CML, sauf chez les femmes de 25 à 29 ans (chez lesquelles un excès substantiel a persisté). Les taux d'orientation en colposcopie sur quatre ans ont connu une baisse en fonction de l'âge chez les femmes ayant fait l'objet d'un dépistage du VPH, d'une CML et d'une cytologie conventionnelle. En extrapolant les résultats de l'essai à la distribution qui existe au sein du programme provincial de dépistage, nous avons constaté que la mise en œuvre du dépistage du VPH ou de la CML au sein de la population provinciale mènerait au doublement approximatif des taux actuels d'orientation en colposcopie. Conclusion : Par comparaison avec le dépistage par CML, le dépistage primaire du VPH n'a entraîné la hausse des taux d'orientation en colposcopie que chez les femmes de 25 à 29 ans. Contrairement à la pratique actuelle, l'orientation en colposcopie était largement motivée par les recommandations du protocole d'essai en ce qui concerne la prise en charge des résultats anormaux, et non par le test de dépistage utilisé.

Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer.

BACKGROUND: Primary debulking surgery before initiation of chemotherapy has been the standard of care for patients with advanced ovarian cancer. METHODS: We randomly assigned patients with stage IIIC or IV epithelial ovarian carcinoma, fallopian-tube carcinoma, or primary peritoneal carcinoma to primary debulking surgery followed by platinum-based chemotherapy or to neoadjuvant platinum-based chemotherapy followed by debulking surgery (so-called interval debulking surgery). RESULTS: Of the 670 patients randomly assigned to a study treatment, 632 (94.3%) were eligible and started the treatment. The majority of these patients had extensive stage IIIC or IV disease at primary debulking surgery (metastatic lesions that were larger than 5 cm in diameter in 74.5% of patients and larger than 10 cm in 61.6%). The largest residual tumor was 1 cm or less in diameter in 41.6% of patients after primary debulking and in 80.6% of patients after interval debulking. Postoperative rates of adverse effects and mortality tended to be higher after primary debulking than after interval debulking. The hazard ratio for death (intention-to-treat analysis) in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% confidence interval [CI], 0.84 to 1.13; P=0.01 for noninferiority), and the hazard ratio for progressive disease was 1.01 (90% CI, 0.89 to 1.15). Complete resection of all macroscopic disease (at primary or interval surgery) was the strongest independent variable in predicting overall survival. CONCLUSIONS: Neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary debulking surgery followed by chemotherapy as a treatment option for patients with bulky stage IIIC or IV ovarian carcinoma in this study. Complete resection of all macroscopic disease, whether performed as primary treatment or after neoadjuvant chemotherapy, remains the objective whenever cytoreductive surgery is performed. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003636.)

Multisite gynecologic endometrioid adenocarcinomas: Can mutation profiling be used to distinguish synchronous primary cancers from metastases?

It is well recognized that some patients with endometrioid gynecological cancers have tumors arising in multiple sites (ovary, endometrium, and endometriosis) at the time of diagnosis. Molecular analysis has helped discern whether these multisite cancers represent synchronous primary tumors or alternatively metastatic disease. We present a complex case of a patient with endometrioid carcinomas arising in multiple sites. We discuss the use of mutation profiling to discern clonality and highlight how this information may inform the clinical management of such cases.

The significance of surgical staging in intermediate-risk endometrial cancer.

OBJECTIVE: The objective was to evaluate rates of nodal disease in endometrial cancer within risk groups based on uterine factors, and to estimate the rate of potential undertreatment and impact on survival if nodal status was unknown. METHODS: This was a population-based retrospective cohort study of endometrioid-type endometrial cancer in British Columbia from 2005 to 2009. All women with a preoperative grade 2/3 cancer underwent hysterectomy, bilateral salpingo-oophorectomy (HBSO) and lymphadenectomy, and those with intermediate- or high-risk disease based on uterine factors after HBSO alone underwent secondary lymphadenectomy. We compared rates of node-positivity and potential undertreatment in each group if nodal status had been unknown (chi-square test), and estimated the survival benefit from lymphadenectomy. RESULTS: There were 222 women who underwent primary or secondary lymphadenectomy. Median age was 65 (range 38-86) and median number of lymph nodes was 10 (range 2-39). Of the 66 women with intermediate-risk disease (grade 1 or 2 tumor, deep myometrial invasion), 6 had nodal disease (9.1%) and received adjuvant chemotherapy. They remain disease-free after 24 months (range 8-55). They would not have qualified for chemotherapy based on uterine factors alone, and would have been undertreated compared to other risk groups (chi-square p=0.071). A 1% survival benefit was estimated from lymphadenectomy. CONCLUSION: Women with a grade 1 or 2 tumor and deep myometrial invasion have a 9% risk of nodal disease. Lymphadenectomy is significant for this subgroup as they would have been undertreated based on uterine risk factors alone, although the survival benefit is limited.

The global impact of the Gynecologic Cancer InterGroup in enhancing clinical trials in ovarian cancer.

The Gynecologic Cancer InterGroup (GCIG) has developed from a small network of ovarian cancer researchers to a large international forum addressing multiple issues related to research in gynecologic cancers. Member groups of the GCIG have collaboratively conducted pivotal clinical trials in cancers of the ovary, endometrium, and cervix. The participation of operational and statistical personnel from the GCIG member groups has facilitated a collegial approach to international differences and restrictions.One of the powerful initiatives of the GCIG is the facilitation of the Ovarian Cancer Consensus Conference every few years. The 4th Ovarian Cancer Consensus Conference was held in Vancouver, Canada, in June 2010, and the resulting publications (herein) provide an invaluable resource to researchers in the field of gynecologic oncology.

2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference.

2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer. This report provides the outcomes from the Fourth Ovarian Cancer Consensus Conference.

First-line therapy in ovarian cancer trials.

At the 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG) held in Vancouver, Canada, in June 2010, representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. The process focused on 13 predetermined questions. Group A, 1 of the 3 discussion groups, addressed the first 5 questions, examining first-line therapies in newly diagnosed ovarian cancer patients. A1: What are the appropriate end points for different trials (maintenance, upfront chemotherapy trials including molecular drugs)? A2: Are there any subgroups defined by tumor biology who need specific treatment options/trials? A3: Is the 2004 GCIG-recommended standard comparator arm still valid? A4: What is the role of modifying dose, schedule, and delivery of chemotherapy? A5: What role does surgery play today?

Clinical trials in recurrent ovarian cancer.

The 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup was held in Vancouver, Canada, in June 2010. Representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. Group C, 1 of the 3 discussion groups, examined recurrent ovarian cancer, and we report the consensus reached regarding 4 questions. These included the following: (1) What is the role of cytoreductive surgery for recurrent ovarian cancer? (2) How do we define distinct patient populations in need of specific therapeutic approaches? (3) Should end points for trials with recurrent disease vary from those of first-line trials? (4) Is CA-125 progression alone sufficient for entry/eligibility into clinical trials?

Role of molecular agents and targeted therapy in clinical trials for women with ovarian cancer.

There is now a greater understanding of the molecular pathways in ovarian cancer, and using this knowledge, a large number of new therapeutic agents can be tested. The success of these drugs will depend on selecting drugs that target known key dysfunctional molecular pathways. To make best use of these compounds, prognostic and predictive biomarkers need to be identified. Novel methods of assessment such as functional imaging need to be developed as additional biological end points to evaluate these therapies. Promising antitumor activity has been observed with some drugs, and careful consideration is needed to determine in what circumstances new agents, such as antiangiogenic compounds, could be considered as a standard therapy. These areas were discussed at the 4th Ovarian Cancer Consensus Conference.

A randomized controlled trial of Human Papillomavirus (HPV) testing for cervical cancer screening: trial design and preliminary results (HPV FOCAL Trial).

BACKGROUND: In the HPV FOCAL trial, we will establish the efficacy of hr-HPV DNA testing as a stand-alone screening test followed by liquid based cytology (LBC) triage of hr-HPV-positive women compared to LBC followed by hr-HPV triage with > or = CIN3 as the outcome. METHODS/DESIGN: HPV-FOCAL is a randomized, controlled, three-armed study over a four year period conducted in British Columbia. It will recruit 33,000 women aged 25-65 through the province's population based cervical cancer screening program. Control arm: LBC at entry and two years, and combined LBC and hr-HPV at four years among those with initial negative results and hr-HPV triage of ASCUS cases; Two Year Safety Check arm: hr-HPV at entry and LBC at two years in those with initial negative results with LBC triage of hr-HPV positives; Four Year Intervention Arm: hr-HPV at entry and combined hr-HPV and LBC at four years among those with initial negative results with LBC triage of hr-HPV positive cases DISCUSSION: To date, 6150 participants have a completed sample and epidemiologic questionnaire. Of the 2019 women enrolled in the control arm, 1908 (94.5%) were cytology negative. Women aged 25-29 had the highest rates of HSIL (1.4%). In the safety arm 92.2% of women were hr-HPV negative, with the highest rate of hr-HPV positivity found in 25-29 year old women (23.5%). Similar results were obtained in the intervention arm HPV FOCAL is the first randomized trial in North America to examine hr-HPV testing as the primary screen for cervical cancer within a population-based cervical cancer screening program. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register, ISRCTN79347302.

The reliability of telephone interviews compared with in-person interviews using memory aids.

PURPOSE: Information obtained by telephone interviews and in-person interviews is generally considered comparable, but it is unclear if extensive memory aids can be used effectively with telephone interviews. We compared a telephone interview to an in-person interview using the same questionnaire and memory aids in both. METHODS: A convenience sample of 103 women, aged 25 to 69 years, completed a telephone interview and at least four weeks later, completed an in-person interview. Memory aids included a life events calendar, cue lists, and worksheets. RESULTS: Agreement values, measured by kappa/weighted kappa, were as follows: parity (1.00), age at menarche (0.76), menopausal status (0.95), a history of reproductive organ surgery (0.98) or tubal ligation (0.91), self-reported infertility (0.76), and a first degree family history of breast/ovarian cancer (0.90). Agreement values for duration variables, measured by the intraclass correlation, were as follows: lactation (0.96), oral contraceptive use (0.98), any hormone replacement therapy (0.98), exclusive estrogen and progesterone therapy (0.83), and exclusive estrogen therapy (0.99). CONCLUSIONS: The good to excellent level of agreement found in this study indicates that telephone administration of our questionnaire with extensive memory aids is a reliable method of obtaining detailed exposure information relative to in-person interviews.

First-line treatment regimens and the role of consolidation therapy in advanced ovarian cancer.

Current first-line management for advanced ovarian cancer consists of cytoreductive surgery followed by chemotherapy, usually with a platinum/taxane combination. Although this approach has been shown to achieve overall response rates of 70-80% in clinical trials, the majority of patients relapse. A number of different approaches have been investigated to improve the efficacy of therapy, including the introduction of newer agents, such as topotecan, into chemotherapy regimens and the use of consolidation therapy. Encouraging results have been obtained in clinical trials of topotecan administered using a variety of different approaches, including replacement regimens, triplet regimens, and sequential doublet regimens. Other treatment modalities have included the use of drug resistance modifiers and intraperitoneal delivery of treatment. A variety of approaches to consolidation therapy have also been investigated, including radiotherapy, cytotoxic therapy, and intraperitoneal therapy. The use of topotecan has also shown promise in this setting, although further data from large, controlled trials are required. In summary, while good response rates are obtained using current first-line treatments, the high relapse rate indicates the need to develop more effective and durable treatment regimens including new agents with, perhaps, an increased emphasis on maintaining remission through the use of consolidation therapy.

Update on granulosa cell tumours of the ovary.

PURPOSE OF REVIEW: Granulosa cell tumours of the ovary are an uncommon ovarian sex-cord stromal tumour. These neoplasms provide a spectrum of clinical presentations that span from the first to the tenth decade. Surgery represents the primary therapy for early stage disease; however, management of women with advanced disease is less clear. Because of their relative rarity, evidence to support decision-making in the management of granulosa cell tumours is limited. The purpose of this review is to provide the clinician with an updated knowledge of the clinical and molecular aspects of granulosa cell tumours in order to guide therapy. RECENT FINDINGS: The clinical stage, mitotic index and cellular atypia correlate most strongly with prognosis. However, these tumours may demonstrate heterogeneous genetic aberrations that can predict behaviour and response to therapy. Case series and reports suggest that postoperative combination chemotherapy is of most benefit in advanced disease. Serial measurements of serum inhibin may be helpful in the follow-up of these women, particularly in the post-menopausal group. SUMMARY: The pathology and treatment of women with granulosa cell tumours of the ovary is complex. Such women should be managed in a multidisciplinary gynaecological oncology unit. A better understanding of the molecular pathology may assist treatment.

The computer synoptic operative report--a leap forward in the science of surgery.

BACKGROUND: Quality of surgery is a proven prognostic factor in many tumors. It is critical to ensure that an effective method is in place to evaluate surgery accurately. MATERIAL AND METHODS: A provincial Cancer Surgery Working Group designed and piloted a computerized synoptic operative report template (WebSMR) in rectal cancer surgery, to replace the standard narrative operative record (NR). This included a precise description of the procedure, data on demographics, diagnostic evaluation, staging, and functional measures. A total of 70 items for anterior resection (AR) and 63 items for abdominoperinal excision (APR) were included. The WebSMR was assessed for comparison with 40 NR randomly selected from seven hospitals in Southern Alberta from 2001 to 2003. RESULTS: The NR contained 45.9% of the specified data elements and the WebSMR captured 99%. The most complete NR data (68.8% to 97%) concerned hospital and patient data, anesthetist and surgeon information, approach, and closure details. The important details of laparotomy and tumor resection were the next most complete data (33.5% to 47.5%) and the least complete (0 to 25%) concerned preoperative treatment, comorbidity, and metastatic and local assessment. All differences among these groups were statistically different (P < .001). No statistically significant differences were seen in the completeness of the NR according to the type of surgery (AR vs. APR; P = .1) or the dictating surgeon (colorectal vs. general vs. resident; P = .175). The time needed to complete the WebSMR test was only 6 minutes. CONCLUSION: The science of surgical technique can be better measured by this unique instrument and will create accountability in surgery.

Workshop: options for therapy in ovarian cancer.

Current and future options for sequential therapy for first and subsequent relapses in ovarian cancer were discussed in three workshops centered around a number of case studies. The participants included investigator oncologists from the USA, Europe, and Asia. For a platinum-resistant patient, topotecan or pegylated liposomal doxorubicin was considered the treatment of choice at first relapse. Since optimal tolerability with topotecan is achieved in less heavily pretreated patients, it may be best to use it earlier rather than later in the treatment schedule. For subsequent relapse within 6 months, most clinicians would use liposomal-encapsulated doxorubicin if the prior treatment had been topotecan and vice versa. Alternative agents may be considered with the aim of achieving symptom palliation rather than prolongation of survival. For late relapse after optimal debulking and treatment with carboplatin/paclitaxel, retreatment with carboplatin/paclitaxel (possibly after further surgery) was considered the best approach in platinum-sensitive patients. For first relapse after 10 months in a suboptimally debulked patient, retreatment with carboplatin/paclitaxel was also considered a viable option. Alternatively, single-agent therapy with paclitaxel, pegylated liposomal doxorubicin, or topotecan may be appropriate to prolong the platinum-free interval. For second relapse, oral etoposide was felt to be useful. Treatment for subsequent relapses included gemcitabine, docetaxel, and agents above not previously utilized. Topotecan tolerability and convenience may be improved by employing a lower dose, shorter schedule, 21-day continuous infusion or weekly dosing in relapsed/refractory disease. The progression-free interval may be extended by continuing topotecan until disease progression in patients with stable disease or by topotecan consolidation therapy in treatment responders.

Evidence of a role for the INK4 family of cyclin-dependent kinase inhibitors in ovarian granulosa cell tumors.

Granulosa cell tumors (GCTs) of the ovary are relatively rare and account for <5% of all ovarian cancers. The molecular pathogenesis of these tumors is not well understood. We tested the hypothesis that cyclin-dependent kinase inhibitors, specifically the inhibitors of the cyclin-dependent kinase 4 (INK4) family, are targets for altered gene expression in GCTs. The status of RB1, INK4A, INK4B, INK4C, INK4D, and ARF in 13 adult and 2 juvenile ovarian GCTs was determined by reverse transcription-polymerase chain reaction of total RNA and exon-specific sequencing of genomic DNA. Tumors showing loss of INK4A expression were assayed further by exon-deletion analysis and methylation-specific PCR. None of the juvenile tumors demonstrated altered expression, but 7/12 (58%) adult GCTs lacked expression of INK4A, INK4B, or both. In one of these cases, we noted a homozygous deletion of the INK4A locus, and in the remaining tumors we found hypermethylation of the promoter region, a mechanism that can lead to gene inactivation. These data support a role for the INK4 family of CDK inhibitors in the biology of GCTs.