Treatment-Related Radiation Toxicity Among Cervical Cancer Patients.

OBJECTIVE: The purpose of this study is to identify incidence of and factors associated with severe late toxicity in women treated with radiation for cervical cancer. MATERIALS AND METHODS: All patients with cervical cancer treated with radiation as primary or adjuvant therapy from 2005 to 2017 in a single academic institution were included. Records were reviewed for demographic information, Charlson Comorbidity Index, treatment details, toxicities, and outcomes. Patients with and those without severe late gastrointestinal toxicity (SLGIT), severe late genitourinary toxicity (SLGUT), or any SLGIT or SLGUT, defined as any toxicity (AT), were compared. Overall survival and progression-free survival were also compared. RESULTS: Of 179 patients identified, 21.2% had AT, 17.3% had SLGIT, and 10% had SLGUT. Estimated AT rate at 3 years was 24.2%. The mean duration of follow-up was 37 months (range, 3-146 months). Most patients (84.1%) received 3-dimensional conformal therapy, and 15.9% received intensity-modulated radiation therapy. Factors associated with AT were lower body mass index (24.9 vs 28.3, P = 0.043), white race (63.2% vs 44%, P = 0.035), and active tobacco smoking during treatment (59.5% vs 40.2%, P = 0.036). Any toxicity was not associated with 3-dimensional versus intensity-modulated radiation therapy planning, low-dose versus high-dose-rate brachytherapy or time to complete radiation treatment. Higher total cumulative radiation dose to clinical target volume was associated with SLGIT. Progression-free survival and overall survival were similar among patients with AT compared to those without toxicity. CONCLUSIONS: In patients with cervical cancer, radiation toxicity is correlated with lower body mass index, white race, and smoking. Despite technologic advances in radiotherapy planning and delivery, toxicity remains high and interventions to reduce the burden of treatment are needed.

OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies.

We examined the interaction between OSU-03012 (also called AR-12) with phosphodiesterase 5 (PDE5) inhibitors to determine the role of the chaperone glucose-regulated protein (GRP78)/BiP/HSPA5 in the cellular response. Sildenafil (Viagra) interacted in a greater than additive fashion with OSU-03012 to kill stem-like GBM cells. Treatment of cells with OSU-03012/sildenafil: abolished the expression of multiple oncogenic growth factor receptors and plasma membrane drug efflux pumps and caused a rapid degradation of GRP78 and other HSP70 and HSP90 family chaperone proteins. Decreased expression of plasma membrane receptors and drug efflux pumps was dependent upon enhanced PERK-eIF2α-ATF4-CHOP signaling and was blocked by GRP78 over-expression. In vivo OSU-03012/sildenafil was more efficacious than treatment with celecoxib and sildenafil at killing tumor cells without damaging normal tissues and in parallel reduced expression of ABCB1 and ABCG2 in the normal brain. The combination of OSU-03012/sildenafil synergized with low concentrations of sorafenib to kill tumor cells, and with lapatinib to kill ERBB1 over-expressing tumor cells. In multiplex assays on plasma and human tumor tissue from an OSU-03012/sildenafil treated mouse, we noted a profound reduction in uPA signaling and identified FGF and JAK1/2 as response biomarkers for potentially suppressing the killing response. Inhibition of FGFR signaling and to a lesser extent JAK1/2 signaling profoundly enhanced OSU-03012/sildenafil lethality.

A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix: an NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: The aim of this study was to evaluate the tolerability and efficacy of poly(ADP-ribose) polymerase (PARP) inhibition by veliparib during cytotoxic topotecan administration with filgrastim or pegfilgrastim neutrophil support in women with persistent or recurrent uterine cervix cancer. EXPERIMENTAL DESIGN: This phase I-II trial examined twice-daily oral veliparib (10 mg) given during once-daily intravenous topotecan (0.6 mg/m²) on days 1 to 5 of each treatment cycle. Cycles were repeated every 21 days until disease progression or until toxicity prohibited further therapy. Toxicity and objective response rate were primary endpoints. RESULTS: Twenty-seven women were enrolled. Frequently reported grade 3 or higher treatment-related toxicities were anemia (59%), thrombocytopenia (44%), leukopenia (22%), and neutropenia (19%). There were 2 partial responses (7% [90% confidence interval, 1%-22%]). Four patients had a disease progression date more than 6 months after the start of veliparib-topotecan therapy. Patients with low immunohistochemical expression (0-1+) of PARP-1 in their primary uterine cervix cancer were more likely to have a longer progression-free interval (hazard ratio, 0.25; P = 0.02) and survival (hazard ratio, 0.12; P = 0.005) after veliparib-topotecan therapy. CONCLUSIONS: Clinical activity of a veliparib-topotecan combination was minimal in women with persistent or recurrent uterine cervix cancer. Women whose uterine cervix cancers express PARP-1 at low levels may benefit preferentially from PARP inhibitors combined with cytotoxic therapies, suggesting further study of PARP expression as an integral triage biomarker.

Low-grade Endometrial Stromal Sarcoma Primarily Arising in the Vagina: A Case Report.

BACKGROUND: Endometrial stromal sarcoma (ESS) is a rareform of endometrial cancer, comprising < 0.2% of all uterine malignancies and 10% of all uterine sarcomas. To date, the English-language literature contains 6 reports of extrauterine ESS arising primarily in the vagina. We describe the seventh such case, and the first case in which the origin is at the introitus of the vagina. CASE: A 43-year-old, nulligravid, Caucasian woman presented for an annual gynecologic examination and was found to have an asymptomatic 5 x 5-mm, rubbery, soft tissue mass at the 5 o'clock position of the vaginal introitus. As has been reported in several cases of low-grade ESS, this case originated at a site of endometriosis. CONCLUSION: Based on our experience as well as a thorough review of the literature, it appears that early stage low-grade ESS arising in the vagina can be treated effectively with surgical resection followed by close observation for recurrence.

Quantitative multiparametric MRI of ovarian cancer.

PURPOSE: To identify parameters associated with ovarian malignancy using multiparametric quantitative magnetic resonance imaging (MRI). MATERIALS AND METHODS: After Institutional Review Board (IRB) approval, women with ovarian masses underwent preoperative imaging with 3 T MRI. Dynamic contrast-enhanced (DCE)-MRI with pharmacokinetic modeling, quantitative T2 mapping, and diffusion-weighted imaging with quantitative mapping of the water diffusion parameters were performed. Ovarian masses had one or more discreet regions of interest, categorized as cystic or solid, and histologically diagnosed as benign or malignant. Mean region of interest (ROI) values were compared between benign and malignant masses using generalized estimating equations. In addition, we compared classification accuracy for the mean ROI value to a combination of histogram characteristics (standard deviation, skewness, and kurtosis) from T2 map ROIs using logistic regression and ROC curve. The significance level was P = 0.05. RESULTS: Several DCE-MRI parameters differentiated solid benign from malignant masses. Toft's rate constant (kep ) was significantly higher in malignant masses (P < 0.001), as well as quantitative T2 values (P = 0.003), and signal intensity on T2 weighted imaging (P = 0.008). A linear combination of the mean, standard deviation, skewness, and kurtosis of T2 within solid regions (area under the curve [AUC] 0.90) provided better classification accuracy than the mean of T2 alone (AUC 0.81). CONCLUSION: Quantitative parameters from DCE-MRI and T2 mapping can differentiate benign from malignant ovarian masses.

Water-fat MRI for assessing changes in bone marrow composition due to radiation and chemotherapy in gynecologic cancer patients.

PURPOSE: To assess the feasibility of using fat-fraction imaging for measuring marrow composition changes over large regions in patients undergoing cancer therapy. MATERIALS AND METHODS: Thirteen women with gynecologic malignancies who were to receive radiation and/or chemotherapy were recruited for this study. Subjects were imaged on a 3T magnetic resonance (MR) scanner at baseline (after surgery but before radiation or chemotherapy), 6 months, and 12 months after treatment. Water-fat imaging was used to generate high-resolution, 3D signal fat fraction (sFF) maps extending from mid-femur to L3. Treatment changes were assessed by measuring marrow sFF in the L4 vertebra, femoral necks, and control tissues. RESULTS: Pretreatment and 6-month scans were compared in nine women. sFF increased significantly in both the L4 vertebral marrow (P = 0.04) and the femoral necks (P = 0.03), while no significant change was observed in control regions. Qualitatively, chemotherapy changes were more uniform in space, whereas the radiation-induced changes were largest in marrow regions inside and close to the target radiation field. CONCLUSION: Water-fat MRI is sensitive to changes in red/yellow marrow composition, and can be used for quantitative and qualitative assessment of treatment-induced marrow damage.

Change in vaginal length and sexual function in women who undergo surgery ± radiation therapy for endometrial cancer.

PURPOSE: Endometrial Cancer (EC) is the most common gynecologic malignancy in the United States. Standard treatment is TAH/BSO with radiation therapy (RT) and chemotherapy given based on risk. Treatment can cause significant vaginal changes, including shortening, narrowing, loss of elasticity, atrophy, and dryness. These are not life threatening, but affect a woman's physical, psychological, and social functioning. Adjuvant vaginal dilator use is often advised, but there are inconsistent recommendations on use. This prospective study compared vaginal length changes and sexual function in women compliant with dilation versus not after surgery and RT. METHODS AND MATERIALS: Enrolled patients underwent surgery for Stage I-IIIC EC ±RT. Vaginal dilator use was recommended for women receiving RT (external beam or brachytherapy). Vaginal length was measured with a vaginal sound and the Female Sexual Function Index (FSFI) was used to assess sexual function. RESULTS: Forty-one enrolled patients had sufficient data for analysis. Dilation significantly increased FSFI scores (p = 0.02) while RT without dilation showed a significant decrease (p = 0.04). Dilation helped maintain vaginal length for all patients (0 cm vs. 1.8 cm loss (p = 0.03)). Individual arms did not show statistically significant changes in length with dilation, though the trend showed RT without dilation had an average loss of 2.3 cm as compared to only 0.2 cm for regular dilation. Notably, there was no difference in length change with dilation for surgery alone versus surgery and RT (p = 0.14). CONCLUSION: This data provides novel, prospective evidence of the benefit of vaginal dilation for maintaining vaginal length and improving sexual health after any pelvic treatment for EC. This evidence also supports that the addition of RT after surgery does not appear to significantly worsen vaginal shortening. This study has important implications for providing a strong foundation for future studies and helping to establish solid clinical management criteria for the prevention of vaginal stenosis and promotion of female sexual health.

A prospective clinical trial of lenalidomide with topotecan in women with advanced epithelial ovarian carcinoma.

BACKGROUND: Lenalidomide is an anti-angiogenic IMiD(®) immunomodulatory drug. The objective of this study was to determine the maximum tolerated dose (MTD), overall safety profile, and activity of oral lenalidomide in combination with topotecan in women with advanced epithelial ovarian or primary peritoneal carcinoma. METHODS: In this Phase I/II open-label, dose-escalation study, patients with histologically or cytologically confirmed advanced ovarian or primary peritoneal carcinoma with disease progression or recurrence following first-line therapy with a platinum agent and paclitaxel were eligible. The Phase I trial utilized a standard dose-escalation design to define the MTD and evaluate the safety profile of lenalidomide and topotecan. The starting doses were lenalidomide 5 mg, days 1-14, and intravenous topotecan 1.25 mg/m(2), days 1-5 of a 21-day cycle. Only the lenalidomide dose was escalated, in 5-mg increments up to 25 mg. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The Phase II portion was designed to evaluate the antitumor activity based on objective response rate of lenalidomide and topotecan. RESULTS: Five women with advanced epithelial ovarian carcinoma were enrolled, each receiving 5 mg oral lenalidomide and 1.25 mg/m(2) topotecan. Four patients discontinued because of dose-limiting toxicity, most commonly grade 4 neutropenia (n = 3). One patient discontinued because of lack of therapeutic effect. The study was terminated early for reasons of toxicity. CONCLUSION: The addition of lenalidomide to topotecan is not a feasible drug combination in women with advanced epithelial ovarian carcinoma because of dose-limiting toxicity.

Idiopathic Adrenal Hemorrhage in a Patient with Gestational Trophoblastic Neoplasia.

BACKGROUND: Idiopathic unilateral adrenal hemorrhage is rare. Described is the first case reported in the setting of nonmetastatic gestational trophoblastic neoplasia. CASE: A primigravida presented with abdominal pain, fever, and a right upper quadrant mass during the workup for gestational trophoblastic neoplasia. She was diagnosed with idiopathic unilateral adrenal hemorrhage. She was treated with surgical resection and single-agent chemotherapy and had complete remission. CONCLUSIONS: Idiopathic unilateral adrenal hemorrhage is a rare condition and must be considered in the presentation of abdominal pain, fever, and an abdominal mass.

Effect of patient age on outcomes and compliance in women with minimally abnormal pap tests.

OBJECTIVE: To assess follow-up and histologic outcomes by age for an indigent urban cohort of women with minimally abnormal cytology. STUDY DESIGN: Retrospective analysis of Pap tests was performed (January 2, 2002, to June 30, 2005). Adolescents (age < 21) and women with atypical squamous cells of undetermined significance (ASCUS)/high-risk human papillomavirus (HPV) and low-grade squamous intraepithelial lesions (LSIL) Pap results were studied and followed for outcomes at 2 years. The chi2 test was performed to evaluate differences among groups; statistical significance was established as p < or = 0.05. RESULTS: A total of 2,266 women were studied--676 adolescents, 1,063 women aged 21-30 years, and 527 women > 30 years of age. Results included 619 ASCUS/ high-risk HPV and 1,647 LSIL results. Compliance was similar across age-groups; 31% never returned for follow-up. CIN2 was detected in 18.8% of adolescents, 21.6% of women aged 21-30, and 15.7% of women > 30 years (p = 0.53). CIN3 was detected in 8.5% of adolescents, 8.1% of women aged 21-30, and 7.7% of women > 30 years (p = 0.55). CONCLUSION: Adolescents and women had similar rates of loss to follow-up after having a minimally abnormal Pap test. The likelihood of detecting CIN2-3 was similar regardless of age.

Increasing age predicts poor cervical cancer prognosis with subsequent effect on treatment and overall survival.

PURPOSE: Stage and histology are well-established prognostic factors for cervical cancer, but the importance of age has been controversial and a clear role for this factor has not yet been defined. Thus, we aim with this study to evaluate the significance of age as an independent prognostic factor in women with cervical cancer and evaluate the therapeutic consequences and survival outcomes as they relate to this factor. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results (SEER) database was used to retrospectively analyze patients diagnosed with cervical cancer from 1973 to 2013 in the United States. Data collected included demographics, tumor histology and stage, treatment details, and survival outcomes. Age was grouped into 20-49, 50-69, ≥70 years. Stage was localized (FIGO IA-IB1), regional (IB2-IVA), and distant (IVB). Treatments were classified as "aggressive" (surgery, external beam radiation therapy [XRT] + brachytherapy [BT], surgery + BT, surgery + XRT, or surgery + XRT + BT) or "nonaggressive" (XRT alone, BT alone, or no treatment). Statistical analysis performed on these data included the use of the Log-Rank test, χ2 analysis, and the Cox proportional hazards model. RESULTS: Forty-six thousand three hundred fifty women with cervical cancer were identified using the SEER database. 54% were aged <50 years, 33% 50-69 years, and 13% ≥70 years. Older women, particular those over age 70 years, show significantly decreased survival trends when stratified by stage and histology (p < 0.0001). Furthermore, taking stage, histology, race, and treatment into account, increasing age demonstrates negative prognostic significance with a hazard ratio of 2.87 for women over age 70 years and 1.46 for women aged 50-69 years. In addition, women over 70 years, regardless of stage, are significantly more likely to receive nonaggressive treatment regimens (<0.0001), or no treatment at all (p < 0.0001). Finally, older women gain a significant survival advantage from treatment, even with less-aggressive regimens, as compared with no treatment at all (p < 0.0001), with BT alone showing the greatest survival benefit (p < 0.0001 vs no treatment; p < 0.0087 vs XRT) among less-aggressive therapies. When evaluated by stage, BT continues to hold a significant survival advantage for localized, regional, and distant disease in individuals over age 70 years (localized: p = 0.0009 vs no treatment; regional and distant: p < 0.0001 vs no treatment), with both an overall survival and disease-specific survival benefit over XRT seen as well for women with distant disease (p < 0.0001). CONCLUSIONS: Older women with cervical cancer show a poor overall survival trend that remains consistent among various stages and histologic subtypes. Risk analysis of this study population supports that age is an independent negative prognostic factor, even when accounting for stage, histology, and race. Furthermore, older women receive less-aggressive treatment as compared with their younger counterparts, with a significant number receiving no treatment at all. Despite this, older women still obtain a significant survival benefit with less-aggressive therapies, particularly with BT alone. Most interesting is that BT shows a survival benefit for older women among all cervical cancer stages, supporting the immense potential clinical benefit. In fact, women over 70 years with more advanced stage disease showed a significant survival benefit, both overall survival and disease-specific survival, with BT over external beam radiotherapy as well. Previous studies have created a foundation of literature, which shows that inclusion of BT in treatment regimens among all age groups improves survival and that older women in general are less likely to be adequately treated for cervical cancer. The novelty of this study lies in the fact that it demonstrates that older women, who we show are at risk for a poorer overall prognosis because of their age, are not only receiving appropriate treatment less often, they are also dying more frequently because of it. Our data support that older women are a high-risk group of patients who would benefit significantly from treatment, even if that treatment is BT alone. BT for cervical cancer is a tolerable procedure, even for most elderly women, and should, therefore, remain a standard clinical option for this population, regardless of their stage or histology at diagnosis.

A case of bowel perforation after neoadjuvant chemotherapy for advanced epithelial ovarian cancer.

BACKGROUND: Bowel perforation is a rare complication of chemotherapeutic treatment of cancer, and may result from tumor necrosis within involved bowel or as a function of the mechanism of the chemotherapeutic agent itself. CASE: We present a case of a 71-year-old woman who experienced a spontaneous bowel perforation after a single cycle of carboplatin and paclitaxel during neoadjuvant treatment of advanced epithelial ovarian cancer. This is, to our knowledge, the first reported case of a gastrointestinal perforation with neoadjuvant chemotherapy for ovarian cancer. The clinical circumstances were highly suggestive of a tumor lysis mechanism for the perforation. CONCLUSION: Bowel perforation can occur as a direct consequence of cytotoxic neoadjuvant chemotherapy for advanced ovarian cancer. This potential serious complication may be worthy of consideration when deciding between neoadjuvant chemotherapy and primary surgical management.

Celecoxib enhances [sorafenib + sildenafil] lethality in cancer cells and reverts platinum chemotherapy resistance.

The present studies sought to determine whether the lethality of the drug combination [sorafenib + sildenafil] could be enhanced by the anti-inflammatory agent celecoxib, using ovarian cancer and other tumor cell lines as models. Also, in a dose dependent fashion celecoxib enhanced [sorafenib + sildenafil] lethality in multiple ovarian cancer cell lines. In a dose dependent fashion celecoxib enhanced the ability of [sorafenib + sildenafil] to reduce expression of multiple chaperone proteins in parallel with lower levels of the drug efflux pumps ABCB1 and ABCG2. Over-expression of GRP78 and HSP27 maintained pump expression in the presence of drugs. Cell killing by the 3 drug combination was mediated by mitochondrial / caspase 9 -dependent apoptotic signaling and by RIP-1 / caspases 2 and 4 / AIF -dependent necroptotic signaling. Pre-treatment of intrinsically resistant primary ovarian cancer cells with [celecoxib + sorafenib + sildenafil] significantly enhanced tumor cell killing by a subsequent cisplatin exposure. Similar data were obtained in some cancer cell lines, but not all, using the related platinum containing drugs, oxaliplatin and carboplatin. As our prior publications have also validated in vivo the combinations of [celecoxib + sildenafil] and [sorafenib + sildenafil] as cytotoxic to multiple tumor cell types, combined with the present findings, we would argue that the combination of celecoxib/sorafenib/sildenafil should be explored in a new phase I trial in ovarian cancer.

Necrotizing fasciitis after placement of intraperitoneal catheter.

•Necrotizing fasciitis has not previously been reported in association with placement of intraperitoneal port at time of cytoreductive surgery.•Consensus is lacking regarding the placement of intraperitoneal ports at the time of bowel surgery.•Delayed placement of intraperitoneal ports may be considered in patients undergoing bowel resection.

Vulvar and vaginal cancer.

Vulvar cancer is becoming more common as the population ages and is primarily a disease of the elderly. Most vulvar cancers are diagnosed at a localized stage and can be cured with surgery and adjuvant radiotherapy. More conservative therapy has been the mainstay in vulvar cancer treatment, which has lessened short-term and long-term morbidity without sacrificing efficacy. Recent national and international studies continue to prove the value of sentinel lymph node technology, which is moving toward a new standard of care for women with early stage vulvar cancer. Vaginal cancer is a rare cancer that also affects elderly women. Prognosis is poor; however, adequate treatment can be delivered with a combination of external beam radiotherapy and brachytherapy, and with surgical resection for a select group of patients.

Ovarian Cancer Tests and Treatment.

Lack of symptoms in early-stageovarian cancer leads to a high mortality rate overall. Tests and therapy are discussed here, along with the symptom index.

Cervical Cancer Tests and Treatment.

Advances in screening and treatment of cervical cancer have been made in recent years. Here we discuss tests, stages of disease, and strategies for treatment.

Antiestrogen therapy in recurrent ovarian cancer resulting in 28 months of stable disease: a case report and review of the literature.

Hormonal therapy for adjuvant treatment of ovarian cancer may provide a low toxicity option in some patients with refractory disease. A 53 year-old patient with stage IIIC papillary serous ovarian cancer previously treated with multiple chemotherapy regimens with platinum-resistant disease was treated with antiestrogen therapy for 28 months before requiring reinstitution of cytotoxic chemotherapy. Hormonal therapy may be effective in a subset of epithelial ovarian cancer patients with endocrine sensitivity and should be considered in the treatment of platinum-resistant patients.