Lua R. Eiriksson

Performance characteristics of screening strategies for Lynch syndrome in unselected women with newly diagnosed endometrial cancer who have undergone universal germline mutation testing

Immunohistochemistry (IHC) for mismatch repair protein expression, microsatellite instability (MSI) testing, tumor morphology, and family history were compared to determine which screening strategy is superior in identifying Lynch syndrome (LS) in unselected women with newly diagnosed endometrial cancer (EC) who have undergone universal germline mutation testing.

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.

Sentinel lymph node mapping in cervical cancer: the future?

Please cite this paper as: Eiriksson L, Covens A. Sentinel lymph node mapping in cervical cancer: the future? BJOG 2012;119:129–133.

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.

Combined methotrexate–dactinomycin: An effective therapy for low-risk gestational trophoblastic neoplasia

OBJECTIVE The objective of this study is to examine the outcomes of combined chemotherapy using methotrexate and dactinomycin in the management of women with low-risk gestational trophoblastic neoplasia (GTN). The primary outcome is the total number of cycles of chemotherapy required to achieve a normal level of human chorionic gonadotropin (hCG). The secondary outcome is treatment-related toxicity. METHODS A retrospective chart review of all patients with GTN treated between 1996-2007 and 1991-2007 was performed at the Alberta Cross Cancer Institute and the British Columbia Cancer Agency, respectively. Patients with low-risk GTN, treated with 0.6 mg/m(2) dactinomycin (days 1 and 2) and methotrexate 100mg/m(2) were included. Toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events. The number of cycles to achieve normalization of hCG was determined, and multivariate analyses were performed to identify factors associated with treatment duration. RESULTS One hundred women were eligible. The average age was 29 years (range 15-46). The median number of cycles to achieve a normal hCG was 3 (range 1-11). Two patients required second-line treatment and one patient chose to proceed with hysterectomy. Ninety-eight percent of patients were primarily cured with this regimen, and 2 were cured with second line treatment. Grade 3 and 4 hematologic toxicities were experienced by 12% and 8% of patients, respectively. Grade 2 and 3 stomatitis or mucositis were noted in 44% and 3% of patients, respectively. CONCLUSIONS Low-risk GTN is reliably and rapidly cured with combined methotrexate-dactinomycin. Toxicity is modest.

Assessment of outcomes in surgically staged I/II endometrial adenocarcinoma patients treated with postoperative vaginal vault radiotherapy only.

Objective: To examine the efficacy of vaginal vault radiotherapy as adjuvant treatment for patients with high-grade, stage I/II endometrial adenocarcinoma who have been surgically staged. Methods: A retrospective chart review of 77 women between 1995 and 2006 with high-grade surgically staged I and II endometrial adenocarcinoma, who were treated with postoperative vaginal vault radiotherapy alone, was performed. The primary study end points were recurrence risk and sites of recurrence. The secondary end points were disease-free and overall survival. Kaplan-Meier estimates were calculated for overall and disease-free survival. Results: Seventy-seven women were identified and met inclusion criteria. Sixty-seven (87%) had grade 3 histologic features on final pathologic report. Forty-two patients (55%) were classified as stage IB, having superficial myometrial invasion; 21 (27%) were stage IC, with deep invasion; and 6 (8%) were stage II, involving the cervix. The median follow-up was 80 months (6.6 years). There were 10 recurrences (13.0%), of which 3 were local: 1 involving the vaginal apex; 1, the lower vagina and pelvic sidewall; and 1, the lower vagina. The 5-year recurrence risk was 11.2% and the 5-year survival probability 88.9%. Conclusions: It seems that for this cohort of 77 patients with surgically staged I and II grade 3 endometrial adenocarcinoma, adjuvant vaginal vault radiotherapy alone leads to acceptable recurrence rates and survival while minimizing morbidity.

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.

Advancing fertility-sparing treatments in cervical cancer: Where is the limit?

One of the certainties in medicine is that indications and contraindicationswill continually be challenged.Whatwas previously thought impossible or irrational may become possible and rational. What was previously unthinkable may become standard of care. Technologies will continue to be advanced such that treatment associated morbidities will diminish while success and cure rates will climb. In the treatment of cancer, the issue of concern for most patients is whether their diseasewill be cured.Many arewilling to undergo highly morbid procedures in order to achieve this end. However, if equivalent oncologic outcomes can be achieved with more conservative treatments, this is indisputably preferred. The optimal balance is difficult to define. When disparate oncologic outcomes are expected, the choice between treatment options is tempered by patient priorities and desires as well as the clinicians duty to inform and avoid harm. While an increased risk of recurrence may seem acceptable to a patient in order to preserve fertility, few clinicians would comfortably offer a less effective treatment when cure with an alternative regimen is vastly more likely. In the treatment of early stage breast cancer, lumpectomy with sentinel lymph node sampling has developed as the standard of care over earlier standards consisting of mastectomy with axillary lymph node dissection. Form and function are preserved through the introduction of multi-modal treatments, including surgery, radiation and chemotherapy, while maintaining established survival rates. Women with cervical cancer may also wish for preservation of function, particularly as it pertains to fertility. The option to pursue childbearing has significant emotional and psychosocial implications. Cancer-related infertility has been associatedwith increasing rates of depression, stress and sexual dysfunction [1].WhenDargent first described radical trachelectomy, preservation of fertility became possible for a select subset of patients with stage IB1 cervical cancer [2]. However, for themost part, this procedure is restricted towomenwith cervical tumors ≤2 cm. Women with larger cervical lesions are commonly excluded from this procedure due to the increased risks of nodal metastases and recurrence. For the latter group of patients, fertility-sparing surgery has been restricted to ovarian transposition or oocyte/ovarian harvesting, both of which ultimately require a surrogate gestational carrier. Neoadjuvant chemotherapy in cervical cancer has been studied for decades [3,4]. While its value over traditional surgery or chemo-radiotherapy has not been proven, its use prior to fertility-sparing surgery holds promise. Reports of optimal responses to chemotherapy allowing for conservative surgery and successful obstetrical outcomes are accumulating [5–8]. In this issue of Gynecologic Oncology, Vercellino et al. speak to this issue, reporting outcomes for women with large cervical lesions (FIGO IB1>2 cm and IB2) for whom neoadjuvant chemotherapy and fertility-sparing surgery are considered. Eighteen patients are

Performance characteristics of a brief Family History Questionnaire to screen for Lynch syndrome in women with newly diagnosed endometrial cancer.

OBJECTIVE The brief Family History Questionnaire (bFHQ) was developed to identify endometrial cancer patients whose family histories suggest Lynch syndrome (LS). We compared the bFHQ, extended Family History Questionnaire (eFHQ) and dictated medical records (DMRs) to determine which family history screening strategy is superior in identifying LS in unselected women with newly diagnosed endometrial cancer that have undergone universal germline testing. METHODS Prospective cohort study recruited women with newly diagnosed endometrial cancer to evaluate screening strategies to identify LS. Participants completed bFHQ and eFHQ, had tumor assessed with immunohistochemistry (IHC) for mismatch repair proteins (MMR) and micro-satellite instability testing and underwent universal germline testing for LS. The sensitivity, specificity, positive and negative predictive values (PPV, NPV) were compared between the family history screening strategies as well as IHC. RESULTS 118 of 182 eligible patients (65%) consented; 87 patients (74%) were evaluable with both family history and germline mutation status. Median age was 61years (range 26-91). All 7 patients with confirmed LS were correctly identified by bFHQ, compared to 5 and 4 by eFHQ and DMR, respectively. The sensitivity, specificity, PPV and NPV values of bFHQ were 100%, 76.5%, 25.9% and 100%, respectively, performing similar to IHC testing. While eFHQ was more specific than bFHQ (86.7% vs. 76.5%, P=0.007), 2 cases of LS were missed. CONCLUSIONS The patient-administered bFHQ effectively identified women with confirmed LS and is a good screening tool to triage women with endometrial cancer for further genetic assessment.

Outcomes of Adjuvant Therapy for Stage IA Serous Endometrial Cancer

Purpose: Serous adenocarcinoma is a rare, aggressive histologic subtype of endometrial cancer with a high rate of recurrence and a poor prognosis. The optimal adjuvant treatment for early-stage patients is unclear. Our objective was to evaluate the outcomes of stage IA serous endometrial cancers only treated at a single institution and determine whether our current approach of chemotherapy plus vaginal brachytherapy (VBT) is sufficient. Methods: A retrospective chart review of our institutions pathology database, including all cases of stage IA serous endometrial carcinoma from 2000-2014 was completed. Kaplan-Meier estimates were calculated for Overall and Recurrence-Free Survival (OS and RFS); hazard ratios were calculated using Cox proportional hazards modeling for independent prognostic factors. Results: There were 63 patients with stage IA serous endometrial cancer of whom 79.4% were surgically staged. Percent RFS was 76.5% at five years while OS was 84.7% for the whole cohort. One of the 23 patients receiving VBT and chemotherapy recurred at the vagina versus four of 32 patients who were observed. Two patients in the observation group recurred in the pelvis while there were no first pelvic recurrences in the VBT and chemotherapy group (non- significant). Overall survival was 95% in the brachytherapy and chemotherapy group versus 79.6% in the observation group (non-significant). Post-operative management included observation (n=33), combination VBT and chemotherapy (n=21), or chemotherapy with or without external beam radiation therapy (EBRT) (n=9). Discussion: We report one of the largest cohorts of serous endometrial cancer stage IA patients. Our results emphasize the inferior RFS and OS of stage IA serous versus endometrioid endometrial cancer patients. While some centers continue to use EBRT for these patients, our results demonstrate low pelvic recurrence rates with radiotherapy limited to VBT, as well as the high systemic risk regardless of treatment. We advocate for combination chemotherapy and brachytherapy given the poor outcomes in these patients.