Impact of postoperative intensity-modulated radiation therapy (IMRT) on the rate of bowel obstruction in gynecologic malignancy.

OBJECTIVE: The purpose was to determine the potential impact of IMRT on the rate of bowel obstruction (BO), in patients with gynecologic malignancies undergoing postoperative pelvic RT. METHODS: We performed a retrospective review of all patients with endometrial or cervical cancer who received postoperative pelvic RT at our institution from 2000 to 2012. Patients who received definitive or palliative RT, or those with BO due to disease progression, were excluded. Standard two-sided statistical tests were used to evaluate for associated risk factors. Kaplan-Meier, Log rank and Cox proportional hazards regression analysis tests were performed for actuarial analysis. RESULTS: A total of 224 patients were identified, 120 (54%) received postoperative pelvic IMRT and 104 (46%) 3-dimentional (3-D) RT. Median follow-up time was 67months. BO was grade 1 (asymptomatic) in 2/228 (0.9%), grade 2 (conservative management) in 4 (1.8%), and grade 3≥ in 4 (1.8%). Overall, the 5-year actuarial rate of BO was 4.8%. The 5-year rate of BO in the IMRT group was 0.9% compared to 9.3% for 3-D RT (p=0.006). Patients with BMI≥30kg/m(2) were less likely to develop BO (2.6% vs. 8.3; p=0.03). On multivariate analysis, only IMRT retained its significance as an independent predictor of less BO (p=0.022). CONCLUSIONS: The use of postoperative IMRT for cervical and endometrial cancer was associated with significant reduction in the rate of bowel obstruction. This difference maintained its statistical significance on multivariate analysis. Such finding if confirmed by others will help further solidify the benefit of IMRT in gynecologic cancers.

Pelvic insufficiency fractures in patients with cervical and endometrial cancer treated with postoperative pelvic radiation.

OBJECTIVE: There is an increased awareness of pelvic insufficiency fractures (PIF) as a potential morbidity of pelvic radiotherapy (RT). The purpose of this study was to determine the incidence of PIF and assess prognostic factors, including intensity-modulated RT (IMRT), in gynecologic oncology patients treated with postoperative pelvic RT. METHODS: We performed a retrospective review of all patients with endometrial or cervical carcinoma who received postoperative pelvic RT at our institution during 2000-2008. Patients who received definitive or palliative RT were excluded. RESULTS: A total of 222 patients were identified, of whom 11 (5%) developed PIF at a median time of 11.5months (range, 5.5-87.3months) from RT completion. The 5-year actuarial rate was 5.1% (95% CI 3.3-6.9). In patients with osteoporosis, the 5-year rate was 15.6% compared with 2.9% for those without (P=0.01). Similarly, patients who were on prior hormone-replacement therapy (HRT) had a higher rate (14.8% vs 4.1%, P=0.009). The median body-mass index (BMI) for patients who developed PIF was significantly lower than those who didn't (25.9 vs 27.2, P=0.016). The rate of PIF was 4.9% whether patients received IMRT or conventional RT. CONCLUSIONS: The 5-year risk of PIF for postoperative pelvic RT in cervical and endometrial cancer is 5.1%. Women with history of osteoporosis, prior HRT, or low BMI need to be counseled about the risk of PIF. The use of IMRT did not decrease PIF, but further studies are needed to determine if a dose/volume relationship exists between RT and PIF.

Postoperative pelvic intensity-modulated radiotherapy and concurrent chemotherapy in intermediate- and high-risk cervical cancer.

OBJECTIVE: According to national surveys, the use of intensity-modulated radiation therapy (IMRT) in gynecologic cancers is on the rise, yet there is still some reluctance to adopt adjuvant IMRT as standard practice. The purpose of this study is to report a single-institution experience using postoperative pelvic IMRT with concurrent chemotherapy in intermediate- and high-risk early stage cervical cancer. METHODS: From 1/2004 to 12/2009, 34 patients underwent radical hysterectomy and pelvic lymph node dissection (28 median nodes were removed) for early stage cervical cancer. Median dose of postoperative pelvic IMRT was 50.4 Gy (range, 45-50.4). All patients received concurrent cisplatin. RESULTS: With a median follow-up of 44 months, 3 patients have recurred; 1 vaginal recurrence, 1 regional and distant, and 1 distant. The 3- and 5-year disease-free survival (DFS) was 91.2% (95% CI, 81.4-100%) and overall survival (OS) was 91.1% (95% CI, 81.3-100%). All failures and all deaths were in the high-risk group (n=3/26). There was 32.3% G3-4 hematologic toxicity, 2.9% acute G3 gastrointestinal toxicity, and no acute G3 or higher genitourinary toxicity. There were no chronic G3 or higher toxicities. CONCLUSIONS: Oncologic outcomes with postoperative IMRT were very good, with DFS and OS rates of >90% at median follow-up of 44 months, despite a preponderance (76.5%) of high-risk features. Toxicity was minimal even in the setting of an aggressive trimodality approach. Data from this study and emerging data from the Phase II RTOG study (0418) demonstrate the advantages of postoperative IMRT in early stage cervical cancer.

Postoperative pelvic intensity-modulated radiotherapy in high risk endometrial cancer.

OBJECTIVE: According to national surveys, the use of intensity-modulated radiation therapy (IMRT) in gynecologic cancers is on the rise, yet there is still some reluctance to adopt adjuvant IMRT as standard practice. The purpose of this study is to report a single-institution experience using postoperative pelvic IMRT with or without chemotherapy in high-risk endometrial cancer. METHODS: From 11/2004 to 12/2009, 46 patients underwent hysterectomy/bilateral salpingo-oophorectomy for stage I-III (22% stage I/II and 78% stage III) endometrial cancer. Median IMRT dose was 50.4Gy. Adjuvant chemotherapy was given to 30 (65%) patients. RESULTS: With a median follow-up of 52months, 4 patients recurred: 1 vaginal plus lung metastasis, 2 isolated para-aortic recurrences, and 1 lungs and liver metastasis. Five-year relapse rate was 9% (95% CI, 0-13.6%). Five-year disease-free survival (DFS) was 88% (95% CI, 77-98%) and overall survival (OS) was 97% (95% CI, 90-100%). There were 2 patients with non-hematological grade 3 toxicity: 1 (2%) acute and 1 (2%) chronic gastrointestinal toxicity. In patients treated with IMRT and chemotherapy (n=30), 5 had grade 3 leukopenia, 8 grade 2 anemia, and 2 grade 2 thrombocytopenia. CONCLUSIONS: Oncologic outcomes with postoperative IMRT were very good, with DFS and OS rates of >88% at median follow-up of 52months, despite a preponderance (78%) of stage III disease. Toxicity was minimal even in the setting of an aggressive trimodality (65% of patients) approach. Data from this study and emerging data from RTOG trial 0418 demonstrate the advantages of IMRT in high-risk endometrial cancer.

Is minimally invasive surgery for clinical stage I uterine carcinosarcoma safe?

Minimally invasive surgery (MIS) has been a mainstay of the surgical management of uterine cancer since the mid-2000s. We aim to determine the role and safety of MIS in women with uterine carcinosarcoma (UCS). An Institutional Review Board-approved study identified all patients with UCS between January 2011 and December 2017 at our institution. Demographic and outcome measures were abstracted from the medical records and tumor registry. Cox proportional hazard models, log rank tests, and comparisons of means were used to calculate significance (p < 0.05). 129 women with UCS were identified during the study period. 62 cases (48%) were open procedures and 67 cases (52%) were MIS with the majority of the MIS group having robotic surgery. 55% of the patients had pathological stage 1 disease. Thirty-eight percent of UCS tumors were heterologous. 93% of patients received adjuvant therapy in the form of chemotherapy and/or radiation therapy. There was no difference in the recurrence-free survival (RFS) or overall survival (OS) between the open surgery and the MIS groups as well as between the heterologous and homologous UCS groups (p > 0.05). UCS represents a rare and aggressive subtype of endometrial cancer. Our data suggest that MIS is a safe surgical approach for staging in women with UCS.

A microRNA survival signature (MiSS) for advanced ovarian cancer.

OBJECTIVES: MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression primarily through post-transcriptional modification. We tested the hypothesis that miRNA expression is associated with overall survival in advanced ovarian cancer. METHODS: Cases included newly diagnosed patients with stage III or IV serous ovarian cancer. RNA from a training set of 62 cases was hybridized to an miRNA microarray containing 470 mature human transcripts. Cox Regression was performed to identify miRNAs associated with overall survival. External validation was performed using quantitative RT-PCR miRNA assays in an independent test set of 123 samples. MiRNA targets and associated biologic pathways were predicted in silico. RESULTS: Of all patients, 80% had high-grade, stage IIIC tumors and 64% underwent optimal cytoreduction. The median survival for the entire cohort was 49±4 months. The training set identified 3 miRNAs associated with survival--miR-337, miR-410, and miR-645. An miRNA signature containing miR-410 and miR-645 was most strongly associated with overall survival in the training set (HR=2.96, 95% CI: 1.51-5.78). This miRNA survival signature (MiSS) was validated in the test set (HR=1.71, 95% CI: 1.05-2.78). The MiSS was independent of FIGO stage and surgical debulking. CONCLUSIONS: The data suggest that an MiSS that contains miR-410 and miR-645 is negatively associated with overall survival in advanced serous ovarian cancer. This signature, when further validated, may be useful in individualizing care for the ovarian cancer patient. Pathway analyses identify biologically plausible mechanisms.

Yolk sac tumor of the endometrium in a post-menopausal woman: Case report and review of the literature.

•Seven of eighteen postmenopausal female endometrial YST cases were pure YST.•IHC supports somatic tumor cell retro-differentiation yielding extra-gonadal YST.•Studying genetic alterations in endometrial YST may elucidate its histiogenesis.

Patterns of recurrence and role of adjuvant chemotherapy in stage II-IV serous ovarian borderline tumors.

OBJECTIVE: The objective of this study was to evaluate patterns of recurrence and prognostic factors as well as the role of adjuvant chemotherapy in stage II-IV ovarian SBT. METHODS: We performed a retrospective review of all patients with advanced-stage SBT treated at our institution from 1979 to 2008. Advanced stage was defined as FIGO stage II-IV. Progression-free survival (PFS) was defined as the time of diagnosis to time of recurrence/death or last follow-up. Kaplan-Meier method was used to report the PFS rate. RESULTS: A total of 80 stage II-IV patients were identified, of which 15 (19%) were stage II, 63 (79%) were stage III, and 2 (2.5%) were stage IV. The site of metastasis was pelvis in 15 patients (19%), omentum in 29 patients (36%), isolated lymph nodes in 2 patients (2.5%), lung in 1 patient (1%), axilla in 1 patient (1%), and multiple sites in 32 patients (40%). With a median follow-up of 4.8 years, 17 patients (21%) developed recurrent disease. Only patients with metastasis to the omentum or multiple sites developed recurrent disease. Of the 65 stage III/IV patients, 17 patients (26%) received adjuvant chemotherapy following diagnosis. The 3-year progression-free survival (PFS) was 89.9% (95% CI, 77.3-95.7) for patients who did not receive adjuvant chemotherapy compared with 70.6% (95% CI, 43.1-86.6) for patients who received adjuvant chemotherapy. CONCLUSIONS: While advanced-stage ovarian SBT generally has a good prognosis, nearly 21% of patients develop recurrent disease with intermediate follow-up. It is unclear from these data if adjuvant chemotherapy influenced PFS.

Overall Survival and Adjuvant Therapy in Women with Ovarian Carcinosarcoma: A Single-Institution Experience.

BACKGROUND: Carcinosarcoma of the ovary (CSO) is a rare and aggressive variant of ovarian cancer. Due to the rare nature of the disease there is insufficient evidence to make recommendations regarding standard management and overall prognosis. METHODS: An Institutional Review Board-approved study identified all our patients with CSO between January 2011 and May 2018. Demographic and outcome measures were abstracted from the medical records and tumor board files. Cox proportional hazard models, log rank tests, and comparisons of means were used to calculate significance (p < 0.05). RESULTS: 27 women with CSO were identified. The median age at diagnosis was 65 years (range 48-91). Five women (18%) presented with early stage disease (Stage I or II) and 22 patients (82%) presented with late stage III or IV disease. Twenty patients (74%) received intravenous platinum-based combination chemotherapy. Seven patients did not receive chemotherapy during their treatment course. The median overall survival was 23 months (range 2-68 months). Overall survival was not significantly worsened by the stage of disease at diagnosis. There was no difference in survival based on the age at diagnosis, tobacco status or ethnicity (p > 0.05). CONCLUSION: This is one of the largest single institution experiences with CSO. The majority of our patients presented with advanced stage disease and received adjuvant platinum-based chemotherapy after cytoreductive surgery. The median overall survival of 23 months was not affected by the stage of the disease. The optimal management of this rare disease needs further study with collaborative, prospective multi-institutional trials.

Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer.

High-grade serous ovarian carcinomas (HGSOCs) with BRCA1/2 mutations exhibit improved outcome and sensitivity to double-strand DNA break (DSB)-inducing agents (i.e., platinum and poly(ADP-ribose) polymerase inhibitors [PARPis]) due to an underlying defect in homologous recombination (HR). However, resistance to platinum and PARPis represents a significant barrier to the long-term survival of these patients. Although BRCA1/2-reversion mutations are a clinically validated resistance mechanism, they account for less than half of platinum-resistant BRCA1/2-mutated HGSOCs. We uncover a resistance mechanism by which a microRNA, miR-622, induces resistance to PARPis and platinum in BRCA1 mutant HGSOCs by targeting the Ku complex and restoring HR-mediated DSB repair. Physiologically, miR-622 inversely correlates with Ku expression during the cell cycle, suppressing non-homologous end-joining and facilitating HR-mediated DSB repair in S phase. Importantly, high expression of miR-622 in BRCA1-deficient HGSOCs is associated with worse outcome after platinum chemotherapy, indicating microRNA-mediated resistance through HR rescue.

Molecular subtypes of uterine leiomyosarcoma and correlation with clinical outcome.

The molecular etiology of uterine leiomyosarcoma (ULMS) is poorly understood, which accounts for the wide disparity in outcomes among women with this disease. We examined and compared the molecular profiles of ULMS and normal myometrium (NL) to identify clinically relevant molecular subtypes. Discovery cases included 29 NL and 23 ULMS specimens. RNA was hybridized to Affymetrix U133A 2.0 transcription microarrays. Differentially expressed genes and pathways were identified using standard methods. Fourteen NL and 44 ULMS independent archival samples were used for external validation. Molecular subgroups were correlated with clinical outcome. Pathway analyses of differentially expressed genes between ULMS and NL samples identified overrepresentation of cell cycle regulation, DNA repair, and genomic integrity. External validation confirmed differential expression in 31 genes (P < 4.4 × 10(-4), Bonferroni corrected), with 84% of the overexpressed genes, including CDC7, CDC20, GTSE1, CCNA2, CCNB1, and CCNB2, participating in cell cycle regulation. Unsupervised clustering of ULMS identified two clades that were reproducibly associated with progression-free (median, 4.0 vs 26.0 months; P = .02; HR, 0.33) and overall (median, 18.2 vs 77.2 months; P = .04; HR, 0.33) survival. Cell cycle genes play a key role in ULMS sarcomagenesis, providing opportunities for therapeutic targeting. Reproducible molecular subtypes associated with clinical outcome may permit individualized adjuvant treatment after clinical trial validation.

Maximal cytoreductive effort in epithelial ovarian cancer surgery.

The surgical management of advanced epithelial ovarian cancer involves cytoreduction, or removal of grossly-evident tumor. Residual disease after surgical cytoreduction of ovarian cancer has been shown to be strongly associated with survival. The goal of surgery is "optimal" surgical cytoreduction, which is generally defined as residual disease of 1 cm or less. However, the designation of "optimal" surgical cytoreduction has evolved to include maximal surgical effort and no gross residual disease. In order to achieve this, more aggressive surgical procedures such as rectosigmoidectomy, diaphragm peritonectomy, partial liver resection, and video-assisted thoracic surgery are reported and increasingly utilized in the surgical management of advanced ovarian cancer. The role of maximal surgical effort also extends to the recurrent setting where the goal of surgery should be complete cytoreduction. Patient selection is important in identifying appropriate candidates for surgical cytoreduction in the recurrent setting. The purpose of this article is to review the role of maximum surgical effort in primary and recurrent ovarian cancer.