Floor J. Backes

Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations

Although gynecologic cancers account for only 10% of all new cancer cases in women, these cancers account for 20% of all female cancer survivors. Improvements in cancer care have resulted in almost 10 million cancer survivors, and this number is expected to grow. Therefore, determining the most cost-effective clinical surveillance for detection of recurrence is critical. Unfortunately, there has been a paucity of research in what are the most cost-effective strategies for surveillance once patients have achieved a complete response. Currently, most recommendations are based on retrospective studies and expert opinion. Taking a thorough history, performing a thorough examination, and educating cancer survivors about concerning symptoms is the most effective method for the detection of most gynecologic cancer recurrences. There is very little evidence that routine cytologic procedures or imaging improves the ability to detect gynecologic cancer recurrence at a stage that will impact cure or response rates to salvage therapy. This article will review the most recent data on surveillance for gynecologic cancer recurrence in women who have had a complete response to primary cancer therapy.

Combination gemcitabine, platinum, and bevacizumab for the treatment of recurrent ovarian cancer

OBJECTIVE To describe the response rate (RR), progression-free survival (PFS), and toxicity profile of combination gemcitabine, platinum, and bevacizumab (GPB) for the treatment of recurrent epithelial ovarian cancer (EOC). METHODS A chart review of all patients with recurrent EOC who were treated with D1, D15 GPB in a 28-day cycle at a single institution was performed. Standard doses were gemcitabine 1000 mg/m(2), cisplatin 30 mg/m(2) or carboplatin AUC 3, and bevacizumab 10 mg/kg. All patients were analyzed for toxicity. RR and PFS were assessed in all patients who received at least 2 cycles of GPB. RESULTS Thirty-five patients were identified, and 33 received at least 2 cycles of GPB. The majority of patients (80%) were platinum sensitive. Patients received a median of 6 cycles of GPB (range 1-24). Sixteen patients (48%) had a complete response (CR), and 10 patients (30%) had a partial response (PR), for a total RR of 78%. An additional 5 patients (15%) had stable disease, and only 2 (6%) patients had progressive disease. The median overall PFS was 12 months (95% CI 7-15), with a median follow-up time of 10 months (2-22). Two patients (6%) had bowel perforations, and both survived. Hematologic toxicities were most common, with 29% and 14% of patients experiencing grade 3 or 4 neutropenia and thrombocytopenia respectively. CONCLUSIONS The combination of GPB demonstrated excellent efficacy for the treatment of recurrent EOC. However, serious toxicities occurred, and the safety profile of this combination requires further study.

Combined microsatellite instability, MLH1 methylation analysis, and immunohistochemistry for Lynch syndrome screening in endometrial cancers from GOG210: An NRG Oncology and Gynecologic Oncology Group study

Purpose The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. Patients and Methods ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Results Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. Conclusion Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.

Short- and long-term morbidity and outcomes after robotic surgery for comprehensive endometrial cancer staging.

OBJECTIVE Although intra-operative and immediate postoperative complications of robotic surgery are relatively low, little is known about long-term morbidity. We set out to assess both short- and long-term morbidities after robotic surgery for endometrial cancer staging. METHODS All patients who underwent robotic staging for EMCA between 2006 and 2009 from two institutions were identified. Patient charts were retrospectively reviewed for surgical complications and postoperative morbidities. RESULTS Five hundred three patients were identified. No differences in complication rates were found between 2006-2007 and 2008-2009, even though the median BMI increased from 29.9 (range 19-52) to 32 (range 17-70) (p=0.03). 6.4% of cases were converted to laparotomy. Median length of stay was one day (range 1-46). No cystotomies, two enterotomies, one ureteric injury, and five vessel injuries occurred (1.6% intra-operative complications). Thirty-eight (7.6%) patients developed major postoperative complications, 11 (2.2%) had wound infections, and 15 (3%) required a transfusion in the 30-day peri-operative period. The total venous thromboembolism (VTE) rate for robotic cases was 1.7%. Partial cuff dehiscence managed conservatively occurred in 5 (1%) and complete dehiscence requiring closure in 7 (1.4%) patients; Sixty-three (13.4%) patients who had robotic staging developed lymphedema, with 40 (8%) requiring physical therapy. CONCLUSIONS This study provides one of the largest cohorts of patients with robotic-assisted hysterectomy and lymphadenectomy (in 92.6%) with an assessment of morbidity. Our data demonstrates that robotic surgical staging can be safely performed with a low risk of short-term complications and lymphedema is the most frequent long-term morbidity.

Lynch Syndrome Screening Strategies Among Newly Diagnosed Endometrial Cancer Patients

OBJECTIVE: To estimate the cost-effectiveness of screening strategies for Lynch syndrome among newly diagnosed endometrial cancer patients. METHODS: A decision analysis compared four strategies to screen women with newly diagnosed endometrial cancer for Lynch syndrome: 1) Amsterdam criteria strategy, where full gene sequencing was performed for women who meet Amsterdam criteria; 2) Sequence-all strategy, where full gene sequencing was performed for all women with endometrial cancer; 3) Sequence aged younger than 60 years strategy, where full gene sequencing was performed for women aged younger than 60 years with endometrial cancer; and 4) immunohistochemistry/single gene strategy, where immunohistochemistry was performed for the DNA mismatch repair genes for all women after single gene sequencing for specific women lacking protein expression. Prevalence rates, probabilities of immunohistochemistry staining loss, and gene mutation rates were calculated from published data. Costs were estimated from Medicare reimbursement rates. Cost-effectiveness ratios and incremental cost-effectiveness ratios were estimated for each strategy. RESULTS: For the estimated 40,000 women diagnosed annually with endometrial cancer, the sequence-all strategy detects 920 patients with Lynch syndrome at a cost of

Prospective evaluation of DNA mismatch repair protein expression in primary endometrial cancer

105 million. The Amsterdam criteria give the least-expensive strategy (

Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma.

7 million), but detect the fewest patients (n=83) with Lynch syndrome. The immunohistochemistry/single gene sequencing strategy detects 858 patients at a cost of

Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer

17 million; this strategy has an incremental cost-effectiveness ratio of

Endometrial cancer patients and compliance with genetic counseling: Room for improvement

13,812. The sequence aged younger than 60 years strategy was less effective and more costly than other strategies. CONCLUSION: Of the strategies studied, immunohistochemical evaluation of tumor specimens for mismatch repair protein expression after single gene sequencing for patients with endometrial cancer is a cost-effective strategy for detecting Lynch syndrome. LEVEL OF EVIDENCE: III

Robotic Trocar Site Small Bowel Evisceration After Gynecologic Cancer Surgery

OBJECTIVES Immunohistochemical (IHC) stains for mismatch repair (MMR) proteins help screen for Lynch syndrome and identify microsatellite unstable colorectal carcinomas, providing prognostic information. It has been suggested that colorectal and endometrial carcinomas should be screened routinely for a MMR defect, but data are lacking on the practical application of this policy. We report our experience with the prospective evaluation of MMR protein expression in endometrial cancer. METHODS All cases of primary endometrial cancer at a single institution regardless of age, family history or histologic features were prospectively stained for the MMR proteins MLH1, MSH2, MSH6 and PMS2. Clinical and pathologic correlates were collected from the medical record. RESULTS A total of 140 endometrial cancer cases were studied. Over 90% of cases were of endometrioid histology. 119 patients had stage I/II disease, and 21 stage III/IV. Nineteen percent of patients were < age 50. Overall, there was loss of 1 or more MMR proteins in 30 patients (21%), including MLH1 and PMS2 in 24, MSH2 and MSH6 in 4, and MSH6 in 2 patients. None of the patients met clinical criteria for Lynch syndrome. However, using MMR protein expression, age and family history, 11% of patients were referred for genetic counseling. Of these patients, three (20%) scheduled an appointment: one canceled and two tested negative. CONCLUSIONS Prospective staining for MMR proteins is feasible and allows for primary triage for the evaluation of Lynch syndrome in women with endometrial cancer. However, acceptance of genetic consultation and testing is surprisingly low and deserves further investigation.