Platinum resistance in gynecologic malignancies: Response, disease free and overall survival are predicted by biochemical signature: A metabolomic analysis.

OBJECTIVE: Platinum resistance, defined as the lack of response or relapse within six months of platinum-based chemotherapy, is an important determinant of survival in gynecologic cancer. We used quantitative Mass Spectrometry to identify metabolic signatures that predict platinum resistance in patients receiving chemotherapy for gynecologic cancers. METHODS: In this study 47 patients with adenocarcinoma of the ovary or uterus who were candidates for carboplatin plus paclitaxel submitted blood for quantitation of metabolites and surgical specimens for the isolation 3-dimensional organoids used to measure individual patient platinum resistance, ex vivo. Results were correlated with response, time to progression and survival. RESULTS: Of 47 patients, 27 (64.3%) achieved complete remission with a mean time to progression of 1.9 years (± 1.5), disease-free survival of 1.7 years (± 1.4) and overall survival of 2.6 years (± 1.6) and a mean cisplatin lethal concentration 50% (LC50) = 1.15 µg/ml (range 0.4-3.1). Cisplatin LC50's correlated with a non-significant decrease in complete remission (RR [95% CI] =0.76 [0.46-1.27]), diminished disease-free survival (median: 1.15 vs. 2.99 years, p = 0.038) and with biochemical signatures of 186 metabolites. Receiver operating curves (ROC) of lipid ratios, branched chain amino acids and the tryptophan to kynurenine ratio identified patients at the highest risk of relapse and death (AUC = 0.933) with a sensitivity of 92.0% and specificity of 86.0% (p < 0.001). CONCLUSIONS: Metabolic signatures in gynecologic cancer identify patients at the highest risk of relapse and death offering new diagnostic and prognostic tools for management of the advanced gynecologic tumors.

Clinical outcomes in ovarian cancer patients receiving three versus more cycles of chemotherapy after neoadjuvant treatment and interval cytoreductive surgery.

OBJECTIVES: To compare clinical outcomes for stage IIIC and IV ovarian cancer patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery followed by up to three versus more cycles of post-operative chemotherapy. METHODS: We conducted a multi-institution retrospective cohort study of patients treated from January 2005 to February 2016 with neoadjuvant platinum-based therapy followed by interval surgery and post-operative chemotherapy. The following were exclusion criteria: more than four cycles of neoadjuvant chemotherapy, bevacizumab with neoadjuvant chemotherapy, non-platinum therapy, prior chemotherapy, and elevated CA125 values after three post-operative chemotherapy cycles. Progression-free and overall survival and toxicity profiles were compared between groups receiving up to three cycles versus more that three cycles post-operatively. RESULTS: A total of 100 patients met inclusion criteria: 41 received up to three cycles and 59 received more than three cycles. The groups were similar in terms of age, body mass index, performance status, tumor histology, optimal cytoreduction rates, and median number of neoadjuvant chemotherapy cycles. Median progression-free survival was 14 vs 16.6 months in those receiving up to three cycles versus more than three cycles, respectively (HR 0.99, 95% CI 0.58 to 1.68, p=0.97). Similarly, median overall survival was not different at 47.1 vs 69.4 months, respectively (HR 1.96, 95% CI 0.87 to 4.42, p=0.10). There were no differences in grade 2 or higher chemotherapy-related toxicities. CONCLUSIONS: Extending post-operative chemotherapy beyond three cycles in patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery with normalization of CA125 levels was not associated with improved survival or greater toxicity. Future study in a larger cohort is warranted to define optimal length of cytotoxic treatment.

Same-day discharge is feasible and safe in patients undergoing minimally invasive staging for gynecologic malignancies.

OBJECTIVE: The objective of the study was to evaluate the feasibility and safety of same-day discharge of patients undergoing minimally invasive comprehensive surgical staging for endometrial and cervical cancer. STUDY DESIGN: We performed a retrospective review of consecutive patients from January 2008 to December 2011 undergoing comprehensive staging for endometrial or cervical cancer by traditional laparoscopy or robotic-assisted laparoscopy and intended for same-day discharge. Patients accomplishing same-day discharge were compared with those who required admission. Clinical and demographic data, perioperative outcomes, and postoperative patient contacts within 6 weeks were collected. Multivariate logistic regression modeling was used to determine factors associated with admission and unscheduled patient contacts within 2 weeks of surgery. RESULTS: A total of 141 patients were identified. One hundred eighteen patients (83.7%) underwent same-day discharge and 23 (16.3%) required overnight admission. The variables that significantly predicted overnight admission were severe pain in the postanesthesia care unit (odds ratio [OR], 6.81; 95% confidence interval [CI], 1.74-26.6; P = .006), delayed ability to tolerate oral intake (OR, 9.3; 95% CI, 2.25-38.6, P = .002), traditional laparoscopic vs robotic-assisted surgical approach (OR, 9.05; 95% CI, 2.34-35.1; P = .001), and surgery start time at 2:00 pm or later (OR, 36.8; 95% CI, 6.19-219.3; P < .0001). There was no difference in the readmission rate between patients undergoing same-day discharge compared with overnight admission (11% vs 17%, P = .48). No variables significantly predicted unscheduled patient contact within 2 weeks of surgery at P < .01. CONCLUSION: Same-day discharge for patients undergoing laparoscopic or robotic-assisted laparoscopic staging for endometrial or cervical cancer is feasible and safe. There are low complication rates and few readmissions or unscheduled patient contacts within 2 weeks of surgery.

Current aims and challenges associated with cervical cancer prevention.

This chapter will review the current modalities available to the clinician to screen for premalignant and malignant cervical lesions, which cast a broad net. The majority who test positive are not destined to suffer from or die from cervical cancer. Many who undergo screening and are triaged are young and subsequently face a number of aggressive and destructive therapies. This calls into question whether higher-risk patients should be managed more aggressively than an average-risk patient represented in the study population used to craft the guidelines.

Predictors of resolution of complex atypical hyperplasia or grade 1 endometrial adenocarcinoma in premenopausal women treated with progestin therapy.

OBJECTIVE: To identify clinical and pathologic predictors of response to progestin treatment in premenopausal women with complex atypical hyperplasia (CAH) and Grade 1 endometrial adenocarcinoma (Grade 1 EA). METHODS: Forty premenopausal patients with Grade 1 EA or CAH who underwent progestin therapy for a minimum of 8 weeks were retrospectively identified. Patient characteristics and histopathologic features of pretreatment and first follow-up endometrial specimens were evaluated as predictors of resolution, defined as absence of hyperplasia or carcinoma. RESULTS: Kaplan-Meier analysis indicated 63% resolution at 18 months of follow-up. Multivariate classification analysis showed that resolution rates were higher in individuals with a low pre-treatment qualitative abnormal architecture score and a BMI <35 (Standardized Resolution Ratio (SRR)=1.48, p=0.03). The diagnosis of benign endometrium or simple hyperplasia on the first follow-up specimen was highly predictive of resolution (SRR=2.25, p=0.002). Resolution rates were lower among subjects with a high pre-treatment qualitative abnormal architecture score (SRR=0.37, p<0.03) and lowest in subjects whose first follow-up specimen showed persistent complexity, atypia, or carcinoma with adjacent stromal decidualization (SRR=0.24, p=0.002). CONCLUSIONS: Clinical and pathologic parameters can predict response to progestin therapy in premenopausal women with CAH and Grade 1 EA. A low likelihood of resolution is predicted by an unfavorable pre-treatment architectural score and lack of pathological response in the first specimen, despite adjacent stromal decidualization.

Disparities in Adherence to National Comprehensive Cancer Network Treatment Guidelines and Survival for Stage IB-IIA Cervical Cancer in California.

OBJECTIVE: To evaluate the association of sociodemographic and hospital characteristics with adherence to National Comprehensive Cancer Network treatment guidelines for stage IB-IIA cervical cancer and to analyze the relationship between adherent care and survival. METHODS: This is a retrospective population-based cohort study of patients with stage IB-IIA invasive cervical cancer reported to the California Cancer Registry from January 1, 1995, through December 31, 2009. Adherence to National Comprehensive Cancer Network guideline care was defined by year- and stage-appropriate surgical procedures, radiation, and chemotherapy. Multivariate logistic regression, Kaplan-Meier estimate, and Cox proportional hazard models were used to examine associations between patient, tumor, and treatment characteristics and National Comprehensive Cancer Network guideline adherence and cervical cancer-specific 5-year survival. RESULTS: A total of 6,063 patients were identified. Forty-seven percent received National Comprehensive Cancer Network guideline-adherent care, and 18.8% were treated in high-volume centers (20 or more patients/year). On multivariate analysis, lowest socioeconomic status (adjusted odds ratio [OR] 0.69, 95% CI 0.57-0.84), low-middle socioeconomic status (adjusted OR 0.76, 95% CI 0.64-0.92), and Charlson-Deyo comorbidity score 1 or higher (adjusted OR 0.78, 95% CI 0.69-0.89) were patient characteristics associated with receipt of nonguideline care. Receiving adherent care was less common in low-volume centers (45.9%) than in high-volume centers (50.9%) (effect size 0.90, 95% CI 0.84-0.96). Death from cervical cancer was more common in the nonadherent group (13.3%) than in the adherent group (8.6%) (effect size 1.55, 95% CI 1.34-1.80). Black race (adjusted hazard ratio 1.56, 95% CI 1.08-2.27), Medicaid payer status (adjusted hazard ratio 1.47, 95% CI 1.15-1.87), and Charlson-Deyo comorbidity score 1 or higher (adjusted hazard ratio 2.07, 95% CI 1.68-2.56) were all associated with increased risk of dying from cervical cancer. CONCLUSION: Among patients with early-stage cervical cancer, National Comprehensive Cancer Network guideline-nonadherent care was independently associated with increased cervical cancer-specific mortality along with black race and Medicaid payer status. Nonadherence was more prevalent in patients with older age, lower socioeconomic status, and receipt of care in low-volume centers. Attention should be paid to increase guideline adherence.

Cervical cancer survivorship: long-term quality of life and social support.

PURPOSE: Surgery, radiotherapy, and chemotherapy are the mainstays of cervical cancer treatment. Many patients receive multiple treatment modalities, each with its own long-term effects. Given the high 5-year survival rate for cervical cancer patients, evaluation and improvement of long-term quality of life are essential. METHODS: Pertinent articles were identified through searches of PubMed for literature published from 1993 to 2014. We summarize quality of life data from long-term follow-up studies of cervical cancer patients. We additionally summarize small group interviews of Hispanic and non-Hispanic cervical cancer survivors regarding social support and coping. FINDINGS: Data are varied in terms of the long-term impact of treatment on quality of life, but consistent in suggesting that patients who receive radiotherapy as part of their treatment have the highest risk of increased long-term dysfunction of bladder and bowel, as well as sexual dysfunction and psychosocial consequences. Rigorous investigations regarding long-term consequences of treatment modalities are lacking. IMPLICATIONS: Continued work to improve treatment outcomes and survival should also include a focus on reducing adverse long-term side effects. Providing supportive care during treatment and evaluating the effects of supportive care can reduce the prevalence and magnitude of long-term sequelae of cervical cancer, which will in turn improve quality of life and quality of care.