Lymphovascular space invasion in uterine corpus cancer: What is its prognostic significance in the absence of lymph node metastases?

OBJECTIVE: Lymphovascular space invasion (LVSI) is a poor prognostic indicator in uterine cancer, primarily due to its association with lymph node metastases. We sought to determine if LVSI provides any prognostic information for uterine cancer subjects in the absence of nodal disease. METHODS: A retrospective review was performed using a database of women treated for uterine cancer at MUSC from 2005 to 2012. Subjects with negative nodes after complete staging were identified. Multiple regression modeling was used to adjust for demographic and histopathologic covariates. The C-index was calculated for models of survival that included LVSI and those that did not. Competing risks analysis was conducted to examine factors associated with time to recurrence. RESULTS: Two hundred and five subjects were completely staged and had negative nodes, 24 with LVSI and 181 without. Factors significantly associated with survival included age, race, stage, grade, histology, and LVSI. Regression models for recurrence-free survival (RFS) and overall survival (OS) had similar C-indices regardless of whether LVSI was included. Competing risks analysis confirmed no significant difference in time to recurrence for subjects with LVSI compared to those without, after adjusting for other prognostic factors (P=0.53). CONCLUSIONS: LVSI is associated with shorter recurrence-free and overall survival in uterine cancer subjects with negative lymph nodes. However, after adjusting for other prognostic factors, LVSI status does not provide additional prognostic information. This finding suggests that recurrence-free and overall survival for uterine cancer patients with negative lymph nodes can be estimated without factoring in LVSI.

A case of parametrial lymph node involvement in stage IA2 squamous cell carcinoma of the cervix treated with radical hysterectomy and a review of the literature: a case report.

Cervical cancer classified as stage IA2 and IB1 according to the International Federation of Gynecology and Obstetrics has historically been treated with radical hysterectomy and bilateral lymph node dissection, but recent recommendations suggest more conservative treatment modalities. We report a woman with stage IA2 cervical cancer at low risk for parametrial spread including no lymphovascular space invasion, clear conization margins, and tumor size less than 2 cm, who underwent radical hysterectomy and was found to have a single positive metastatic parametrial lymph node. This case report is an important reminder that parametrial involvement occurs in low-risk early-stage cervical cancers.

Cost-effectiveness of combination versus sequential docetaxel and carboplatin for the treatment of platinum-sensitive, recurrent ovarian cancer.

BACKGROUND: In a randomized controlled trial (RCT) of patients with recurrent, platinum-sensitive ovarian cancer, the combination weekly docetaxel and carboplatin was associated a with progression-free survival (PFS) of 13.7 months compared with 8.4 months for sequential, single-agent docetaxel followed by carboplatin. The objective of the current study was to construct a cost-utility model to compare these 2 regimens with the incorporation of prospectively collected quality-of-life (QoL) data. METHODS: An RCT of concurrent docetaxel and carboplatin (cDC) versus docetaxel followed by carboplatin (sequential docetaxel and carboplatin [sDC]) was the basis for a Markov decision model, and the primary effectiveness outcome was PFS. Costs were estimated using US dollars based on Medicare reimbursements for chemotherapy regimens, bone marrow support, and management of adverse events. QoL data obtained using the Functional Assessment of Cancer Therapy-General questionnaire were converted to utilities. Costs and incremental cost-effectiveness ratios (ICERs) were reported in US dollars per quality-adjusted life year (QALY). Extensive 1-way sensitivity analyses and a Monte Carlo probabilistic sensitivity analysis were performed. RESULTS: The least expensive strategy was sDC, which cost an average of $20,381, compared with cDC, which cost an average of $25,122. cDC had an ICER of $25,239 per QALY compared with sDC. cDC remained cost-effective, with an ICER <$50,000 per QALY, over a range of costs and estimates. In Monte Carlo sensitivity analysis using a $50,000 per QALY willingness-to-pay threshold, cDC was either dominant or cost-effective with an ICER <$50,000 per QALY in 83% of simulations. CONCLUSIONS: Combined weekly cDC appeared to be cost-effective compared with sDC as treatment strategy for patients with platinum-sensitive ovarian cancer, even when accounting for slightly lower QoL during treatment.

A multicenter, randomized, phase 2 clinical trial to evaluate the efficacy and safety of combination docetaxel and carboplatin and sequential therapy with docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: The aim of this randomized clinical trial was to evaluate the efficacy and safety of combination (cDC) and sequential (sDC) weekly docetaxel and carboplatin in women with recurrent platinum-sensitive epithelial ovarian cancer (EOC). METHODS: Participants were randomized to either weekly docetaxel 30 mg/m(2) on days 1 and 8 and carboplatin area under the curve (AUC) = 6 on day 1, every 3 weeks or docetaxel 30 mg/m(2) on days 1 and 8, every 3 weeks for 6 cycles followed by carboplatin AUC = 6 on day 1, every 3 weeks for 6 cycles or until disease progression. The primary endpoint was measurable progression-free survival (PFS). RESULTS: Between January 2004 and March 2007, 150 participants were enrolled. The response rate was 55.4% and 43.2% for those treated with cDC and sDC, respectively. The median PFS was 13.7 months (95% confidence interval [CI], 9.9-16.8) for cDC and 8.4 months (95% CI, 7.1-11.0) for sDC. On the basis of an exploratory analysis, patients treated with sDC were at a 62% increased risk of disease progression compared to those treated with cDC (hazard ratio = 1.62; 95% CI, 1.08-2.45; P = .02). The median overall survival time was similar in both groups (33.2 and 30.1 months, P = .2). The incidence of grade 2 or 3 neurotoxicity and grade 3 or 4 neutropenia was higher with cDC than with sDC (11.7% vs 8.5%; 36.8% vs 11.3%). The sDC group demonstrated significant improvements in the Functional Assessment for Cancer Therapy-Ovarian, Quality of Life Trial Outcome Index scores compared with the combination cohort (P = .013). CONCLUSIONS: Both cDC and sDC regimens have activity in recurrent platinum-sensitive EOC with acceptable toxicity profiles. The cDC regimen may provide a PFS advantage over sDC.

Health-related quality of life outcomes of docetaxel/carboplatin combination therapy vs. sequential therapy with docetaxel then carboplatin in patients with relapsed, platinum-sensitive ovarian cancer: results from a randomized clinical trial.

OBJECTIVES: A phase II clinical trial compared docetaxel in combination with carboplatin to sequential single agent docetaxel followed by carboplatin for treatment of recurrent platinum-sensitive ovarian, peritoneal, or tubal cancer. This manuscript reports prospectively collected health-related quality of life (HRQL). METHODS: Participants were randomized to either weekly docetaxel 30 mg/m(2)/days 1 and 8 and carboplatin AUC 6/day 1 every 3 weeks (cDC) or docetaxel 30 mg/m(2)/days 1 and 8, repeated every 3 weeks for 6 cycles followed by carboplatin AUC 6/day 1 every 3 weeks for 6 cycles or until disease progression (sDC). The primary HRQL endpoint was the trial outcome index (TOI) score of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) instrument, and was assessed as an intent-to-treat analysis. The secondary HRQL endpoints included the FACT-O total score, the FACT-General, and several domain scores of the FACT-O instrument (physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and the ovarian cancer specific (OCS) module). The FACT-O was administered at randomization, prior to each of 6 cycles of treatment, and at study endpoint. RESULTS: One hundred forty-eight participants were randomized to each group. Sequential docetaxel followed by carboplatin (sDC) was associated with significant improvements in the FACT-O TOI (p=0.013), FACT-O total score (p=0.033), and OCS (p=0.029) compared to the combination docetaxel and carboplatin group (cDC). CONCLUSIONS: Sequential single agent docetaxel followed by carboplatin is associated with improved HRQL when compared to cDC. The improved progression-free survival observed with cDC should be weighed against lower quality of life during treatment.

The role of radiotherapy in the management of resected uterine papillary serous and clear cell carcinoma.

OBJECTIVE: Primary uterine papillary serous (PS) and clear cell (CC) carcinoma are aggressive histologies characterized by elevated risk of loco-regional recurrence and disease-specific mortality following hysterectomy. The impact of adjuvant radiotherapy remains to be elucidated. The present study is a single institution, retrospective cohort comparison to determine whether post-hysterectomy radiotherapy improves loco-regional control and/or disease-specific survival outcomes in a population of women with PS and/or CC. STUDY DESIGN: Between June 1992 and November 2006, 50 women underwent hysterectomy alone (H) or hysterectomy with adjuvant radiotherapy (H+RT) for primary uterine PS and/or CC. RT involved either high dose-rate (HDR) brachytherapy, external beam RT, or both. RESULTS: At a median survivor follow-up of 27 months (range 2.7-137.3) for the H+RT group and 61 months (range 11.9-114.6) for the H group (range 3-137), patients in the H+RT group demonstrated a trend toward superior disease-free survival (not yet attained at 26 months versus 25 months; p=0.0625). For patients with > or =24 months of follow-up, disease recurrence was significantly higher in H patients over H+RT patients (45% versus 12.5%; p<0.05). Additionally, the H+RT group demonstrated significant improvement in loco-regional control (0% versus 37.5%; p<0.001), most pronounced within FIGO stages I-II H+RT patients (0% versus 70%; p<0.001). Overall survival was not significantly different between the two cohorts (H=32 months, H+RT=not yet attained at 26 months; p=non-significant). CONCLUSIONS: Hysterectomy with adjuvant radiotherapy significantly improves disease-free survival within 2 years post-hysterectomy and significantly reduces loco-regional failures over hysterectomy alone.

Controversies surrounding lymphadenectomy and postoperative radiotherapy in the treatment of carcinoma of the endometrium.

Hysterectomy and bilateral salpingo-oophorectomy have long been acknowledged to be the centerpiece of therapy for carcinoma of the endometrium. However, 30 years ago, realization of the metastatic potential of this disease, particularly to regional lymph nodes, led many clinicians to include lymphadenectomy in the surgical management of uterine cancer. Retrospective studies have since demonstrated that lymphadenectomy is associated with an acceptably low level of surgical morbidity. The incorporation of lymphadenectomy into the surgical management of uterine cancer has accompanied a dramatic reduction in the use of peri-operative radiotherapy. Though not confirmed by prospective data, retrospective series have associated complete lymphadenectomy with an improvement in survival, even in node-negative patients. Contributing to a reduction in the use of postoperative radiation in endometrial cancer have been several randomized trials demonstrating a reduction in locoregional recurrence, but at the cost of significant radiation-induced toxicity and no improvement in overall survival.

Prognosis of papillary serous, clear cell, and grade 3 stage I carcinoma of the endometrium.

OBJECTIVE: The purpose of this study was to evaluate patients with uterine papillary serous carcinoma (UPSC), clear cell (CC), and grade 3 endometrioid (G3) surgically stage I endometrial cancer. METHODS: The 25th Annual Report (AR) of FIGO was used to identify patients with endometrial cancers who were surgically staged. For comparison, all cancers reported were evaluated with particular interest in patients with stage I UPSC, CC, and G3. Incidence, substage, post-surgical treatment, and survival were identified. RESULTS: Of 5694 endometrial cancer patients reported to the AR, 3996 (70%) were surgically stage I. There were 148 UPSC, 59 CC, and 325 with G3 lesions. UPSC and CC represent 5.2% of all stage I cancers while 8.1% are G3. Although there were greater number of UPSC, CC, and G3 with extrauterine disease, about 50% of UPSC and CC were stage I. This compares to 81% for G1, 68% for G2, and only 42% for G3. There were more IA cancers with UPSC and CC than G3 (22%, 33%, and 17%, respectively). Survival (5 years) for UPSC and CC was 72% and 81%, respectively, compared to 76% for G3 lesions. Postoperative radiation improved survival somewhat (6-8%) but the difference was not significant. CONCLUSION: UPSC and CC histotypes when diagnosed as stage I have a better survival than commonly perceived and equal to G3 endometrioid cancers. Postoperative radiation improves survival but not significantly so. The role of chemotherapy has not been defined.

Is lymph vascular space involvement an independent prognostic factor in early cervical cancer?

OBJECTIVE: To determine whether lymph vascular space involvement (LVSI) in women with early cervical carcinoma is an independent prognostic factor. METHODS: The literature was reviewed using Medline and known literature to determine if LVSI is an independent risk factor as determined by multivariant analysis with survival being the end point in patients undergoing radical hysterectomy and pelvic lymphadenopathy. RESULTS: A total of 25 articles were identified that satisfied the evaluation criteria. Only three (12%) identified LVSI as an independent risk factor while 88% and 61% of those evaluated, noted lymph node metastasis and tumor size/depth of invasion to be significant risk factors for survival. CONCLUSIONS: Using LVSI as the sole determining factor for consideration of post radical hysterectomy radiotherapy appears questionable.

Circulating levels of insulin-like growth factor-II and IGF-binding protein 3 in cervical cancer.

OBJECTIVE: We aimed to further document that elevated levels of circulating insulin-like growth factor II (IGF-II) are associated with cervical cancer and to test the hypothesis that there may be an inverse association between IGF-II and IGF-binding protein 3 (IGF-BP3). METHODS: Serum IGF-II and IGF-BP3 levels were measured, using ELISA kits (Diagnostic Systems Laboratories), in 23 controls; 16 ASC-US with normal biopsies; 14 ASC-US with advanced CIN; 2 pretherapy CIN-I; 8 successfully treated CIN-I; 24 persistent CIN I; 14 pretherapy CIN II/III; 10 posttherapy CIN II/III with normal biopsies; 18 persistent CIN-II/III; 7 with pretherapy cervical cancer; 19 with posttherapy cervical cancer under remission; 15 with posttherapy persistent/recurrent cervical cancer; 10 with persistent ovarian or endometrial cancer; and 3 with endometrial or vulvar with cervical cancer. Student's t test and linear regression analysis were used. RESULTS: Compared to controls (493 +/- 90 ng/ml) and women with other gynecological cancers, serum IGF-II levels were significantly increased in women with ASC-US, with advanced CIN on biopsy (P < 0.0001), persistent CIN-I (993 +/- 262 ng/ml; P < 0.0001), pretherapy advanced CIN (1086 +/- 240; P < 0.0001), pretherapy cervical cancer patients (1746 +/- 318 ng/ml; P < 0.0001) and posttherapy persistent/recurrent CIN (1094 +/- 300; P < 0.0001); and cervical cancer (1395 +/- 189; P < 0.0001). After therapy, the IGF-II levels returned to normal in both CIN and cervical cancer patients under remission. Elevated serum IGF-II levels had 100% sensitivity and 87% specificity for cervical cancer and 81% sensitivity and 82% specificity for CIN. The levels of IGF-BP3 were significantly reduced in women with CIN before and after therapy (P < 0.0001) and in cervical cancer patients before and after therapy (P < 0.001). There was an inverse relationship between serum IGF-II and BP-3 levels (P < 0.01). Decreased serum IGF-BP3 levels had a sensitivity of 72% and specificity of 75% for cervical cancer and 81% sensitivity and 83% specificity for CIN. When both markers were considered together the sensitivity was 72% and specificity 84% for cervical cancer, while for CIN, the sensitivity was 57% and specificity 81%. CONCLUSION: Serum IGF-II may be a reliable marker for early diagnosis and monitoring therapy efficacy (sensitivity and specificity of 100% versus normal controls), while IGF-BP3 levels can be reliably used to predict prognosis.