The Significance of Para-Aortic Nodal Size and the Role of Adjuvant Systemic Chemotherapy in Cervical Cancer: An Institutional Experience.

OBJECTIVE: Cervical cancer metastatic to the para-aortic lymph nodes (PALNs) carries a poor prognosis. Despite extended-field radiation therapy (EFRT), only 30% to 50% of patients will survive 3 years. We sought to examine the treatment regimens used, associated toxicities, and treatment outcomes in patients with cervical cancer metastatic to PALN. METHODS: A retrospective review was performed of all patients with cervical cancer treated at a single institution between January 1, 2007 and November 1, 2014. Included patients had PALN metastases as the most distant site of disease, and all treatment plans were designated as curative. Excluded patients had other distant disease or treatment plans considered palliative. Standard treatment consisted of EFRT with concurrent platinum-based chemotherapy. RESULTS: Fifty-one of 344 patients (14.8%) fulfilled the inclusion criteria. The median age was 48.4 years. Forty-four patients received standard EFRT; 7 also received adjuvant platinum/taxane chemotherapy. Thirty-nine of 51 (76%) of patients achieved a complete response to primary treatment. Twelve of 51 (24%) had persistent disease or progression at the completion of treatment. Of responders, 15 of 39 (38%) recurred for an overall treatment failure rate of 27 of 51 (53%). Nineteen of 27 (70%) of treatment failures occurred outside the radiated field. Adjuvant chemotherapy following EFRT was not predictive of progression-free survival or overall survival. PALN diameter ≥1 cm was a significant negative prognostic indicator for overall survival. CONCLUSIONS: Over half of patients with cervical cancer metastatic to the PALN failed extended-field chemoradiation. Most failures occurred outside the radiated field suggesting PALN involvement is a surrogate marker of systemic disease. These findings underscore the need for effective systemic therapy, especially in patients with PALN ≥1 cm in size.

Emphasis on Systemic Therapy in Women With Pelvic Bone Metastasis at Time of Diagnosis of Cervical Cancer.

OBJECTIVE: Cervical cancer presenting with metastases to the bony pelvis is rare. No available literature addresses the treatment and prognosis of these patients. Our objective was to review our experience treating women with this rare presentation. METHODS: We performed a review of all patients treated for cervical cancer at a single institution between January 1, 2007 and November 30, 2014. All patients had pretreatment imaging with computed tomography or positron emission tomography/computed tomography. Included patients had evidence of pelvic bone metastases by imaging before initiation of treatment. RESULTS: A total of 349 women were treated for cervical cancer during the study interval. Of these, 13 (3.7%) were identified as having pelvic bone metastases at initial presentation. Four of 13 patients had pelvic-confined disease and were treated with curative-intent radiation. The remainder had disseminated disease and were treated with palliative radiation. Only one complete response was seen. Seven patients received salvage chemotherapy. The median overall survival was 8.5 months. Survival was statistically similar in those who received palliative rather than curative radiotherapy (8.7 vs. 8.1 mo, P=0.76) and in those who received any postradiation chemotherapy (8.9 vs. 6.1 mo, P=0.066). Chemotherapy with bevacizumab resulted in the only 2 long-term survivors (both alive at 32.4 and 37.5 mo). All others have died of disease. CONCLUSIONS: Cervical cancer metastatic to the bony pelvis at initial presentation portends a dismal prognosis. Patients should be informed about this poor prognosis, and allowed to make an informed decision when considering curative-intent versus palliative treatment. Incorporation of bevacizumab appears to improve survival.

Dysregulation of fibulin-5 and matrix metalloproteases in epithelial ovarian cancer.

Fibulin 5 (FBLN5) is an extracellular matrix glycoprotein that suppresses matrix metalloprotease 9 (MMP-9), angiogenesis and epithelial cell motility. Here, we investigated the regulation and function of FBLN5 in epithelial ovarian cancer (EOC). FBLN5 mRNA was down-regulated 5-fold in EOC relative to benign ovary. Not surprisingly, MMP9 mRNA and enzyme activity were increased significantly, and inversely correlated with FBLN5 gene expression. FBLN5 degradation products of 52.8 and 41.3 kDa were increased substantially in EOC. We identified two candidate proteases (serine elastase and MMP-7, but not MMP-9) that cleave FBLN5. MMP-7, but not neutrophil elastase, gene expression was increased dramatically in EOC. Recombinant FBLN5 significantly inhibited adhesion of EOC cells to both laminin and collagen I. Finally, using immunohistochemistry, we found immunoreactive FBLN5 within tumor macrophages throughout human EOC tumors. This work indicates that FBLN5 is degraded in EOC most likely by proteases enriched in macrophages of the tumor microenvironment. Proteolysis of FBLN5 serves as a mechanism to promote cell adhesion and local metastasis of ovarian cancer cells. Promotion of a stable ECM with intact FBLN5 in the tumor matrix may serve as a novel therapeutic adjunct to prevent spread of ovarian cancer.

Third-line Salvage Chemotherapy for Recurrent Carcinoma of the Cervix is Associated With Minimal Response Rate and High Toxicity.

BACKGROUND: Metastatic and recurrent cervical cancer is rarely a curable disease. Systemic chemotherapy is typically recommended for treatment based on clinical trials in the first-line or second-line setting. Rare patients who progress through 2 salvage regimens will have the performance status, medical ability, and desire to continue cytotoxic therapy. For these patients, there are no data to provide effective counseling regarding expected response rates (RRs) and toxicities. We sought to review our experience with this patient population. METHODS: A single institution review was performed of all patients treated for cervical cancer between January 1, 2000 and June 30, 2013. Eligible patients were those who received at least 3 unique salvage chemotherapy regimens following primary surgery or radiation. RRs, survival statistics and toxicities were evaluated. RESULTS: Twenty-three of 710 (3.2%) patients treated for cervical cancer met eligibility criteria. Nineteen received 2 or more cycles of a third-line regimen and were assessed for response and progression-free survival. The remainder were included in analysis of overall survival and toxicity. The RR to third-line chemotherapy was 10% (1 complete, 1 partial). An additional 27% achieved stable disease. In total, 57% suffered a grade 3 or 4 toxicity. The progression-free survival from the beginning of third-line therapy was 3.8 months, and the overall survival was 7.4 months. CONCLUSIONS: Patients eligible to receive third-line chemotherapy for metastatic and recurrent cervical cancer can expect minimal benefit at the cost of significant toxicity. Quality of life considerations should be of paramount importance when counseling regarding the risks and benefits of further cytotoxic therapy.

Hypoalbuminemia is a Predictive Factor for Fistula Formation in Recurrent Cervical Cancer.

OBJECTIVE: Antivascular endothelial growth factor monoclonal antibodies inhibit tumor angiogenesis, consequently impeding the recruitment of new vasculature to existing and new tumor lesions. We sought to evaluate toxicities in women with recurrent cervical cancer after receiving bevacizumab combination chemotherapy. METHODS: A review was conducted of women with recurrent and metastatic cervical cancer who were treated with salvage chemotherapy with or without bevacizumab between 2005 and 2015. Clinicopathologic data and reasons for treatment discontinuation were recorded. Patients that were excluded had other histology than squamous or adenocarcinoma, received 1 cycle of salvage chemotherapy, single agent bevacizumab, currently on treatment, or noncompliant. Statistical analysis was performed using the Fishers Exact Test, logistic regression, and Kaplan-Meier Survival Analysis. RESULTS: A total of 74 patients were included in analysis. Twenty-six patients were treated with bevacizumab (BEV) and chemotherapy and 48 patients with chemotherapy alone (chemotherapy). The progression free survival was significant with median 12 months versus 7 months for the BEV cohort (P<0.01) and the overall survival was a median 74 months versus 23 months for the BEV cohort (P=0.06). Cessation of treatment secondary to severe toxicities was seen in 46% (n=12) of BEV cohort versus 15% (n=7) of chemotherapy cohort (P<0.01). Twenty-seven percent (n=7) of patients in the BEV cohort stopped secondary because of fistula formations. Lower albumin levels and use of bevacizumab were identified as an independent predictor factors for fistula formation (P=0.004 and 0.024, respectively). CONCLUSIONS: Hypoalbuminemia and bevacizumab treatments are significant predictive factors of fistula formation in patients treated for recurrent cervical cancer.

Locally Advanced Cervical Cancer: Outcomes With Variable Adherence to Treatment.

OBJECTIVE: Adherence to treatment regimen and schedule is recommended to improve control of disease and overall survival (OS) in locally advanced cervical cancer. However, treatment-related toxicities and patient and physician factors all impact timely completion of treatment. We sought to correlate adherence to treatment plan with survival and toxicities of patients treated for locally advanced cervical cancer. MATERIALS AND METHODS: A retrospective review of patients treated for advanced cervical cancer at our institution between 2003 and 2011 was performed. Demographics, clinicopathologic variables, treatment, and disease outcomes were collected. Endpoints of disease outcome were disease-free survival and OS. Statistical analyses were performed using the Kaplan-Meier method, log-rank test, and Cox regression analysis. RESULTS: A total of 162 patients met the inclusion criteria and were included in study analysis. A total of 95% of patients were treated with both radiation and concurrent chemotherapy. Mean radiation dose to point A was 72 Gy. In total, 77% had complete response to primary therapy. Severe (grade 3/4) late radiation toxicities were seen in 10.5% of patients. Stage and total radiation dose to point A were significant predictors of survival for the entire cohort. Among patients receiving at least 72 Gy and brachytherapy, duration of treatment was significantly associated with both disease-free survival and OS. CONCLUSIONS: Adherence to both optimal treatment time and radiation dose is significantly associated with improved survival. Total radiation dose is an independent predictor of survival among patients with locally advanced cervical cancer.

Factors associated with clinical trial screening failures in gynecologic oncology.

OBJECTIVE: Low enrollment of adult cancer patients in clinical trials is an ongoing challenge in cancer research. We sought to determine factors associated with clinical trial screening failures in women with gynecologic malignancies at a large urban university health system. METHODS: A retrospective review was conducted of women with gynecologic malignancies who presented to an urban university system between 12/2009 and 12/2012. Data collected included demographic, clinico-pathologic and trial-related factors, as well as reasons for non-participation. RESULTS: Two hundred twenty-one patients were eligible for a clinical trial. Of these, 44% participated while 56% did not. There were more screening failures when trials were offered at the time of primary treatment than at recurrence (62% vs. 38%, p=0.001). There was no significant difference in participation based on age, ethnicity, hospital setting, payor status, family history, comorbidities, prior treatment, substance abuse, recent surgery or trial type. Of the non-participants, 62% declined the study due to perceived harm and 10% due to socio-economic barriers while 20% were excluded due to co-morbidities and 8% due to noncompliance. CONCLUSIONS: Significantly more screening failures for clinical trials occurred when trials were offered at the time of primary treatment. The majority of patients declined based on perceived harm from enrolling in a clinical trial, although 20% of eligible patients were not offered enrollment despite not meeting any exclusion criteria. Our findings underscore the importance of appropriate counseling when offering clinical trials, as well as overcoming physician biases in deciding who is an appropriate candidate.

Primary iliopsoas abscess and pregnancy.

BACKGROUND: Iliopsoas abscesses, a rare complication in pregnancy, typically present as a secondary infection due to direct spread of another nearby infection. CASE: A 30-year-old multigravid patient with a 10-year history of intravenous heroin use and chronic lower-back pain, presented at 23 0/7 weeks of gestation with multiple cutaneous abscesses. As her back pain worsened during antepartum hospitalization, a primary iliopsoas abscess with underlying osteomyelitis was identified requiring percutaneous computed tomography-guided drainage along with extended-course intravenous antibiotics. After treatment and methadone detoxification, her pregnancy resulted in a successful vaginal delivery. CONCLUSION: Primary iliopsoas abscess should be considered in the differential diagnosis of low-back pain among high-risk pregnant women. Clinicians should be vigilant in identifying high-risk factors and aggressive in treating this rare and potentially fatal complication.