Clare J. Reade

Risks and benefits of screening asymptomatic women for ovarian cancer: A systematic review and meta-analysis

OBJECTIVE We performed a systematic review and meta-analysis to quantify risks and benefits of screening asymptomatic women for ovarian cancer. METHODS We searched MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL, without language restrictions, from January 1, 1979 to February 5, 2012. Eligible studies randomly assigned asymptomatic women to screening or usual care. Two reviewers independently screened studies for eligibility, extracted data using a standardized, piloted extraction form, and assessed bias and strength of inference for each outcome using the GRADE framework. Chance-corrected agreement was calculated at each step, and disagreements were resolved through consensus. RESULTS Ten randomized trials proved eligible. Screening did not reduce all-cause mortality (relative risk (RR)=1.0, 95% confidence interval (CI) 0.96-1.06), ovarian cancer specific mortality (RR=1.08, 95% CI 0.84-1.38), or risk of diagnosis at an advanced stage (RR of diagnosis at FIGO stages III-IV=0.86, 95% CI 0.68-1.11). Transvaginal ultrasound resulted in a mean of 38 surgeries per ovarian cancer detected (95% CI 15.7-178.1) while screening with CA-125 led to 4 surgeries per ovarian cancer detected (95% CI 2.7-4.5). Surgery was associated with severe complications in 6% of women (95% CI 1%-11%). Quality of life was not affected by screening; however, women with false-positive results had increased cancer-specific distress compared to those with normal results (odds ratio (OR)=2.22, 95% CI 1.23-3.99). CONCLUSIONS Screening asymptomatic women for ovarian cancer does not reduce mortality or diagnosis at an advanced stage and is associated with unnecessary surgery.

Sentinel lymph node biopsy in vulvar cancer: Systematic review, meta-analysis and guideline recommendations.

OBJECTIVES Traditionally, treatment for early stage vulvar cancer has included removal of the primary tumor and inguinofemoral lymph node dissection (IFLD). Sentinel lymph node biopsy (SLNB) has been proposed as an alternative to IFLD for early stage vulvar cancer patients. The aim of this project was to systematically review and assess the potential for harms and benefits with the SLNB procedure in order to make recommendations regarding the adoption of the procedure, selection of patients and appropriate technique and procedures. METHODS A working group with expertise in gynecologic oncology and health research methodology was formed to lead the systematic review and process of guideline development. MEDLINE, Embase and The Cochrane Database of Systematic Reviews were searched for relevant articles published up to September 2014. Outcomes of interest included detection, false negative, complication and recurrence rates and indicators related to pathology. Meta-analyses were conducted where appropriate. RESULTS The evidence-base of a previously published health technology assessment was adopted. An additional search to update the HTAs evidence base located three systematic reviews, and eleven individual studies that met the inclusion criteria. According to a meta-analysis, per groin detection rate for SLNB using radiocolloid tracer and blue dye was 87% [82-92]. The false negative rate with SLNB was 6.4% [4.4-8.8], and the recurrence rates with SLNB and IFLD were 2.8% [1.5-4.4] and 1.4% [0.5-2.6], respectively. An internal and external review process elicited concerns about the necessity of performing this procedure in an appropriate organizational context. CONCLUSION SLNB is recommended for women with unifocal tumors<4 cm and clinically non-suspicious nodes in the groin, provided that specific infrastructure and human resource needs are met. Some recommendations for appropriate techniques and procedures are also provided.

Surgery for early stage cervical cancer: How radical should it be?

OBJECTIVE Less radical or non radical surgery for early-stage cervical cancer has been proposed to reduce morbidity while maintaining oncologic outcomes. Given that a standardized approach to conservative surgery is not yet available, we have summarized the literature on less radical surgery to better inform clinical practice. METHODS MEDLINE R and MEDLINE in-process and non-indexed citations were searched from inception to April 14, 2013 to identify all English-language articles evaluating less-radical or non radical surgery for invasive cervical carcinoma. Articles including patients with squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma were included and a narrative review of the literature is presented. RESULTS Radical surgery is associated with significant adverse effects in terms of urinary function, sexual function, and body image. Radical trachelectomy is an accepted fertility-sparing option, but still leads to morbidity from parametrectomy. The importance of the parametrectomy in patients with small early-stage tumors has been questioned recently, and many studies have found simple hysterectomy and simple trachelectomy can be safe in appropriately selected patients. Cone biopsy may be a fertility-sparing option in those patients with a very low risk of parametrial involvement. Neoadjuvant chemotherapy is also being investigated as a method to reduce the need for radical surgery. Sentinel lymph node biopsy is discussed as a method to reduce the morbidity while increasing the sensitivity of pelvic lymph node assessment in women with early cervical cancers. Finally, the treatment of early adenocarcinoma is addressed. CONCLUSIONS It appears many women with early-stage cervical cancer can be treated less radically than has been done in the past. Large prospective trials are underway to further define candidates for less-radical surgery.

Risk-reducing salpingectomy in Canada: a survey of obstetrician-gynaecologists.

OBJECTIVE Performing risk-reducing salpingectomy (RRS) at the time of hysterectomy or as a method of tubal ligation has been suggested as a way to reduce the incidence of high grade serous carcinoma (HGSC) of the ovary, since this type of cancer is hypothesized to originate in the fallopian tube. We conducted a survey of Canadian obstetrician-gynaecologists to better understand the uptake and knowledge of implementing this procedure, and to identify barriers to doing so. METHODS An anonymous, web-based survey using both quantitative and qualitative methods was sent to obstetrician-gynaecologist members of the Society of Obstetricians and Gynaecologists of Canada and the Society of Gynecologic Oncology of Canada. The survey contained questions about demographics, knowledge and beliefs about RRS, and possible barriers to its implementation in women at average risk for ovarian cancer. RESULTS One hundred ninety-two physicians responded to the survey, a response rate of 25%. Respondents varied in their duration in practice, came from all provinces, and spent a large proportion of their time practising gynaecology. Ninety percent of respondents had heard of RRS; however, 37% were unaware of the evidence supporting the hypothesis that HGSC originates in the fallopian tube, and 38% were unsure whether there would be any population benefit from performing RRS at the time of other gynaecologic surgery. Multiple barriers to implementation were identified. CONCLUSION Most Canadian obstetrician-gynaecologists responding to our survey were aware of RRS as a possible method to prevent ovarian cancer in women at average risk; however, barriers still exist to widespread implementation. Further research is needed to quantify the population benefit of this procedure.

Systemic therapy in squamous cell carcinoma of the vulva: Current status and future directions

OBJECTIVE The advances achieved in the surgical management of vulvar squamous cell carcinoma (SCC) have not been mirrored in systemic therapy options. The objective of this paper is to summarize current evidence regarding systemic therapy in vulvar cancer, review the latest research on the biology of this disease, and identify future strategies to improve patient management. METHODS MEDLINE and EMBASE were searched for all relevant English-language articles from inception to December 10, 2012. Existing evidence regarding systemic therapy in vulvar SCC was synthesized descriptively, with an emphasis on prospective studies when available. Single-patient case-reports were excluded. RESULTS We identified 12 studies of neoadjuvant chemoradiation, 8 studies of neoadjuvant chemotherapy alone, 18 studies of chemoradiation as primary therapy, 4 studies of chemotherapy in the adjuvant setting, and 8 studies of chemotherapy for recurrent or metastatic disease. Review of the biology of vulvar cancer was performed, and promising targets for the future were identified based on the two biologic pathways of disease development. New therapeutic strategies such as immune-therapy and targeted agents hold promise for the future. CONCLUSIONS Advances in systemic therapy for vulvar SCC are urgently needed, especially in the setting of recurrent and metastatic disease. A focus on the investigation of new targeted agents is encouraged and consideration of quality of life and sexual health issues is essential. International cooperation and adaptive trial designs are required to improve outcomes for this group of traditionally under-served women.

Trends in Gynecologic Cancer Care in North America

Overall, there has been tremendous movement over the last decade toward centralization of cancer care into specialized centers. This comes from the recognition that multidisciplinary care, including access to opinions from gynecologic, medical, and radiation oncologists, can improve patient outcomes. In addition to this input, it is important to have access to subspecialty pathology, diagnostic radiology, oncology nursing, and other disciplines as necessary. The population-based literature on quality of care in gynecologic cancers reflects this movement, with many articles evaluating outcomes in terms of structural variables. However, the continued presence of regional and sociodemographic variation in outcomes suggests it is still possible to achieve significant improvements in survival by concentrating efforts to improve the quality of care provided to gynecologic cancer patients. Improved outcomes for patients with ovarian cancer can be achieved by continued centralization of gynecologic cancer care and provision of care by gynecologic oncologists in high-volume centers. Further study is needed to determine if cervical cancer and vulvar cancer outcomes can be improved with centralization. For uterine cancer, at this time there do not appear to be significant improvements in outcomes related to centralization.For all gynecologic cancers, more attention should be paid to the processes of care and their impact on patient outcomes. An appropriate goal for all health care systems is to ensure all women have access to evidence-based care. This is particularly important for high-risk women, older women, and minority women, who suffer a disproportionate amount of the gynecologic cancer–related mortality and often do not receive evidence-based care. Clinical practice guidelines exist to provide guidance to clinicians as to what constitutes evidence-based care and to make recommendations concerning current best practices. Adherence to guidelines can help to reduce variations in care due to sociodemographic factors. As the provision of cancer care becomes more and more centralized, outcomes at the population level will be improved only by focusing on the processes of care. A look at the three North American health care systems shows there are issues with women having access to high-quality, timely care. This fundamental problem must be addressed to systematically improve health at the population level. Governments should strive toward the WHO goal of promoting health development in their populations by reducing inequalities in the access to health care and health promotion activities.

Non-radical surgery for small early-stage cervical cancer. Is it time?

OBJECTIVES Non-radical surgery has been proposed in women with early-stage cervical cancer to reduce morbidity. Our objective was to evaluate the outcomes of women with early-stage cervical cancer treated with non-radical surgery. METHODS Between March 1991 and July 2013, 51 women with early-stage cervical cancer underwent simple hysterectomy or cone biopsy. All patients had assessment of pelvic lymph nodes. Patient demographics, stage, perioperative complications, pathology findings and disease-free interval were collected prospectively. RESULTS Twenty-six women had squamous cell carcinoma (SCC), 22 adenocarcinoma (AC) and 3 adenosquamous (AS) carcinoma. Thirty women were FIGO stage 1A1, 8 women IA2, and 13 women 1B1. Twenty-two (43%) and 29 (57%) women underwent simple hysterectomy and cone biopsy respectively. Median measurable tumor size was 10mm (range 2-11), and median depth of invasion was 2.0mm (range 0.1-12 mm). Lymphovascular space invasion (LVSI) was present in 18 women (35%). Surgical margins were negative in all women. Two women received adjuvant chemoradiation (one had deep stromal invasion with LVSI, and one had two micrometastases to pelvic nodes). Forty-nine women (96%) had their Foley catheter removed on the day of surgery or post-operative day 1. No intraoperative or postoperative complications occurred and the median blood loss was 100ml. Median follow-up was 21 months (range 1-112). None of the 51 women developed a recurrence during follow-up (95% CI: 0-6%). CONCLUSION Non-radical surgery in appropriately selected early-stage cervical cancer patients results in a low complication rate and excellent oncologic outcomes. This approach seems to be a reasonable option in well-selected patients.

Outcomes for patients with the same disease treated inside and outside of randomized trials: a systematic review and meta-analysis

Background: It is unclear whether participation in a randomized controlled trial (RCT), irrespective of assigned treatment, is harmful or beneficial to participants. We compared outcomes for patients with the same diagnoses who did (“insiders”) and did not (“outsiders”) enter RCTs, without regard to the specific therapies received for their respective diagnoses. Methods: By searching the MEDLINE (1966–2010), Embase (1980–2010), CENTRAL (1960–2010) and PsycINFO (1880–2010) databases, we identified 147 studies that reported the health outcomes of “insiders” and a group of parallel or consecutive “outsiders” within the same time period. We prepared a narrative review and, as appropriate, meta-analyses of patients’ outcomes. Results: We found no clinically or statistically significant differences in outcomes between “insiders” and “outsiders” in the 23 studies in which the experimental intervention was ineffective (standard mean difference in continuous outcomes −0.03, 95% confidence interval [CI] −0.1 to 0.04) or in the 7 studies in which the experimental intervention was effective and was received by both “insiders” and “outsiders” (mean difference 0.04, 95% CI −0.04 to 0.13). However, in 9 studies in which an effective intervention was received only by “insiders,” the “outsiders” experienced significantly worse health outcomes (mean difference −0.36, 95% CI −0.61 to −0.12). Interpretation: We found no evidence to support clinically important overall harm or benefit arising from participation in RCTs. This conclusion refutes earlier claims that trial participants are at increased risk of harm.

Sentinel Lymph Node Biopsy in Vulvar Cancer: A Health Technology Assessment for the Canadian Health Care Context

OBJECTIVES Inguinofemoral lymphadenectomy for vulvar cancer is associated with a high incidence of groin wound complications and lymphedema. Sentinel lymph node biopsy (SLNB) is a morbidity-reducing alternative to lymphadenectomy. The objective of this health technology assessment was to determine the clinical effectiveness, cost-effectiveness, and organizational feasibility of SLNB in the Canadian health care system. METHODS A review of the English-language literature published from January 1992 to October 2011 was performed across five databases and six grey-literature sources. Predetermined eligibility criteria were used to select studies, and results in the clinical, economic, and organizational domains were summarized. Included studies were evaluated for methodologic quality using the Newcastle-Ottawa Scale. RESULTS Of 825 reports identified, 88 observational studies met the eligibility criteria. Overall study quality was poor, with a median Newcastle-Ottawa Scale score of 2 out of 9 stars. Across all studies, the detection rate of the sentinel lymph node was 82.2% per groin and the false-negative rate was 6.3%. The groin recurrence rate after negative SLNB was 3.6% compared with 4.3% after negative lymphadenectomy, and complications were reduced after SLNB. No economic evaluations were identified comparing SLNB to lymphadenectomy. Safe implementation of SLNB requires appropriate patient selection, detection technique, and attention to the learning curve. CONCLUSIONS Although study quality is poor, the available data suggest implementation of SLNB may be safe and feasible in Canadian centres with adequate procedural volumes, assuming that implementation includes careful patient selection, careful technique, and ongoing quality assessment. Cost-effectiveness has yet to be determined.

Effectiveness of the risk of malignancy index and the risk of ovarian malignancy algorithm in a cohort of women with ovarian cancer: does histotype and stage matter?

Objective To examine the performance of the Risk of Malignancy Index (RMI) and Risk of Ovarian Malignancy Algorithm (ROMA) by histologic subtype and stage of disease in a cohort of women with ovarian cancer. Methods All patients with confirmed ovarian cancer at the Princess Margaret Hospital between February 2011 and January 2013 were eligible for study inclusion. Preoperative cancer antigen 125, human epididymis protein 4, and ultrasound findings were reviewed, and the sensitivity and false-negative rates of the RMI and ROMA were determined by stage of disease and tumor histology. Results A total of 131 patients with ovarian cancer were identified. High-grade serous (HGS) histology was most frequently associated with stage III/IV disease (n = 46 [72% of stage III/IV]) vs stage I (n = 5 [11% of stage I]; P < 0.0001). Clear cell (CC) and endometrioid (EC) histology presented most commonly with stage I disease (n = 9 [20%] and n = 13 [29% of stage I cases], respectively). Median cancer antigen 125 and human epididymis protein 4 values were significantly higher for HGS than for EC or CC histology. Risk of Malignancy Index II demonstrated the highest sensitivity of the 3 RMI algorithms. All RMIs and ROMA were significantly more sensitive in predicting malignancy in patients with HGS than EC or CC histology. Risk of Malignancy Index II (n = 38) and ROMA (n = 35) exhibited sensitivities of 68% and 54% and false-negative rates of 32% and 46%, respectively, for patients with stage I disease vs sensitivities of 94% and 93% and false-negative rates of 6% and 7% for patients with stage III/IV disease. Conclusion Both RMI and ROMA performed well for the detection of advanced ovarian cancer and HGS histology. These triaging algorithms do not perform well in patients with stage I disease where EC and CC histologies predominate. Clinicians should be cautious using RMI or ROMA scoring tools to triage isolated adnexal masses because many patients with stage I malignancies would be missed.