Long-Term Outcomes of Cervical Cancer Patients Treated With Definitive Chemoradiation Following a Complete Metabolic Response.

AIMS: A complete metabolic response (CMR) on early post-treatment 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a positive prognostic factor for cervical cancer patients treated with definitive chemoradiation, but long-term outcomes of this group of patients are unknown. Patterns of failure and risk subgroups are identified. MATERIALS AND METHODS: Patients who received curative-intent chemoradiation from 1998 to 2018 for International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IVA cervical cancer and had a CMR on post-treatment FDG-PET within 5 months of treatment completion were included. Cox proportional hazards models determined factors associated with locoregional and distant failure. Kaplan-Meier estimates of freedom from any recurrence (FFR) of patient subgroups were compared with Log-rank tests. RESULTS: There were 402 patients with a CMR after chemoradiation on FDG-PET. Initial T stage was T1 (38%)/T2 (40%)/T3 (20%)/T4 (2%); initial FDG-avid nodal status was no nodes (50%)/pelvic lymph nodes (40%)/pelvic and para-aortic lymph nodes (10%). After a median follow-up of 6 years, 109 (27%) recurred. The pattern of recurrence was locoregional (27%), distant (61%) or both (12%). No factors were associated with locoregional failure. Distant recurrence was more likely in patients with T3-4 lesions (hazard ratio = 2.4, 95% confidence interval 1.5-3.8) and involvement of pelvic (hazard ratio = 1.6, 95% confidence interval 1.0-2.7) or para-aortic lymph nodes (hazard ratio = 2.7, 95% confidence interval 1.4-5.0) at diagnosis. The 5-year FFR rates for T1-2 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 85, 76 and 62%, respectively (P = 0.04, none versus para-aortic nodes). The 5-year FFR for T3-4 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 68, 56 and 25%, respectively (P = 0.09, none versus para-aortic nodes). CONCLUSIONS: T3-4 tumours and para-aortic nodal involvement at diagnosis are poor prognostic factors, even after a CMR following chemoradiation.

Concomitant chemotherapy and radiation for the treatment of advanced-stage endometrial cancer.

INTRODUCTION: Ccombination chemotherapy and radiation therapy is used for adjuvant treatment of stage III-IV endometrial cancer. The goal of this study was to review the treatment duration, toxicity, and survival for patients treated with concomitant chemotherapy and radiation. METHODS: Women with stage III-IV endometrial cancer treated with concurrent chemotherapy and radiation between 2006 and 2013 were included. Toxicities were classified per CTCAE v3.0 and RTOG/EORTC late radiation morbidity scoring. Descriptive statistics were used to quantify treatment and toxicities. Kaplan-Meier method was used to estimate survival. RESULTS: Fifty-one patients met our inclusion criteria. Median age was 60 (range 33-85). Thirty-six patients (70.6%) had endometrioid histology, 13 patients (25.5%) had serous, clear cell, or mixed histology, and 2 women (3.9%) had carcinosarcoma. Forty-eight patients had stage III disease and three patients were stage IVB. Mean treatment duration was 107 ± 19 days. Forty-two patients received all planned chemotherapy, and 16 patients required a dose reduction. Thirty-four patients (66.7%) experienced grade 3-4 toxicities, the majority of which were hematologic. There were no deaths related to therapy. Eighty-six percent of patients received leukocyte growth factors, and 25% of patients received a blood transfusion. Seven late grade 3-4 complications occurred: four gastrointestinal and two genitourinary, and one patient had ongoing neuropathy. Median progression-free survival was 42.8 months (range 4.4-81.5 months) and median overall survival was 44.9 months (range 5.1-82.6 months). Three-year overall survival was 80%. CONCLUSION: Concomitant chemotherapy and radiation is an adequately tolerated treatment modality that allows for shorter treatment duration.

Restriction of placental vasculature in a non-human primate: a unique model to study placental plasticity.

The limits of placental plasticity, i.e., the ability of the placenta to adapt and alter its growth trajectory in response to altered fetal requirements, are not known. We report fetal and placental hemodynamic adaptations in a novel non-human primate model in which the fetal inter-placental bridging vessels were surgically ligated. Doppler ultrasound studies showed that the rhesus placenta compensates for an approximate 40% reduction in functional capacity by increased growth and maintenance of umbilical volume blood flow. This unique experimental animal model has applications for mechanistic studies of placental plasticity and the impact on fetal development.

SU-E-T-305: Limitations of Using DICOM Data for BrachyVision Treatment Plan Evaluation.

PURPOSE: To evaluate the accuracy of a real-time automated method of performing dosimetric quality assurance using Eclipse DICOM files for patients receiving HDR-brachytherapy and IMRT. METHODS: GYN patients are treated with concurrent high-dose rate brachtherapy and IMRT. The dosimetric parameters were obtained through an in-house QA program developed using Matlab. The DICOM files containing DVH data for organsat-risk (OAR) were analyzed Dosimetric data for 7 patients (total 42 fractions) were collected for bladder, rectum and sigmoid. The accuracy of the dosimetric parameters was estimated by comparing the parameters obtained from the DICOM based QA program and those in BrachyVision. RESULTS: The maximal dose values (Dmax) for the OARs obtained using the DICOM-based program are significantly smaller than those valued reported in BrachyVision by 36.2%-48.3%. The mean dose has a deviation from 1% - 2.4%. The dose for the volume of 2cc (D2cc) has a difference up to 7.6% for structures with the volume larger than 200 cc. The average difference of D2cc is 0.5% for structures less than 200 cc. We found that Eclipse BrachyVision only exports DVH data down to a volume equivalent to 1% of the maximum volume for a given structure. Therefore, the reported maximal dose values obtained from DICOM RT dose file do not accurately reflect the maximum dose in a treatment plan. This will also slightly affect the mean dose calculation and D2cc when the structure volume is larger than 200cc. CONCLUSIONS: The automatic QA tool based on DICOM files provides a quick retrieval of dose to organs-at-risk and coverage of targets. However, maximal dose to structures is not accurate due to the truncationof the DVH information contained in DICOM files.

FDG-PET/CT: new horizons in anal cancer.

Anal cancer is an uncommon tumor with an incidence of about one case per 100,000 in most countries. Its incidence seems to be increasing because of exposure to human immunodeficiency virus (HIV) and human papillomavirus (HPV). Traditional pretreatment evaluations include physical examination and CT imaging of the pelvis. Current treatment guidelines include fluorodeoxyglucose positron emission tomography integrated with computed tomography (FDG-PET/CT) as part of the standard pretreatment workup of patients diagnosed with anal cancer. At diagnosis, FDG-PET/CT is used to evaluate primary tumor size, lymph node status and to evaluate for distant metastases. FDG-PET/CT can also be used for radiation therapy treatment planning by clearly defining sites of metabolically active tumor. Posttherapy FDG-PET/CT to determine response to therapy is highly predictive of long-term clinical outcomes. This imaging modality can also be used to evaluate sites of recurrent disease. FDG-PET/CT is an imaging modality which greatly affects the management of patients with anal cancer.

Nuclear imaging and cervical cancer.

The staging of patients with cervical cancer is in accordance with the International Federation of Gynecology and Obstetrics (FIGO) clinical staging system. The traditional and current radiographic imaging studies allowed by FIGO to influence the clinical stage of the disease are the chest X-ray, the intravenous urogram and plain X-rays of the skeleton. The development and use of complimentary imaging studies may guide and direct therapy, but it does not change the clinical stage of the disease. Other X-ray studies that have been used are the barium enema and the lymphangiogram. Both computerized tomography (CT) and magnetic resonance imaging (MRI) have become commonplace in the evaluation of these patients. Most recently, position emission tomography (PET) with CT (PET/CT) is the preferred whole-body imaging study for patients with invasive cervical cancer. Single photon emission computed tomography (SPECT) combined with CT, the SPECT/CT, is also now being utilized in patients with cervical cancer. These new imaging modalities permit increased accuracy in the diagnosis and staging of cervical cancer, improve the selection and guidance of therapy, reduce uncertainties in the monitoring of response to therapy, and provide a means for objective long-term surveillance.

Exploring feature-based approaches in PET images for predicting cancer treatment outcomes.

Accumulating evidence suggests that characteristics of pre-treatment FDG-PET could be used as prognostic factors to predict outcomes in different cancer sites. Current risk analyses are limited to visual assessment or direct uptake value measurements. We are investigating intensity-volume histogram metrics and shape and texture features extracted from PET images to predict patient's response to treatment. These approaches were demonstrated using datasets from cervix and head and neck cancers, where AUC of 0.76 and 1.0 were achieved, respectively. The preliminary results suggest that the proposed approaches could potentially provide better tools and discriminant power for utilizing functional imaging in clinical prognosis.

MicroRT-small animal conformal irradiator.

A novel small animal conformal radiation therapy system has been designed and prototyped: MicroRT. The microRT system integrates multimodality imaging, radiation treatment planning, and conformal radiation therapy that utilizes a clinical 192Ir isotope high dose rate source as the radiation source (teletherapy). A multiparameter dose calculation algorithm based on Monte Carlo dose distribution simulations is used to efficiently and accurately calculate doses for treatment planning purposes. A series of precisely machined tungsten collimators mounted onto a cylindrical collimator assembly is used to provide the radiation beam portals. The current design allows a source-to-target distance range of 1-8 cm at four beam angles: 0 degrees (beam oriented down), 90 degrees, 180 degrees, and 270 degrees. The animal is anesthetized and placed in an immobilization device with built-in fiducial markers and scanned using a computed tomography, magnetic resonance, or positron emission tomography scanner prior to irradiation. Treatment plans using up to four beam orientations are created utilizing a custom treatment planning system-microRTP. A three-axis computer-controlled stage that supports and accurately positions the animals is programmed to place the animal relative to the radiation beams according to the microRTP plan. The microRT system positioning accuracy was found to be submillimeter. The radiation source is guided through one of four catheter channels and placed in line with the tungsten collimators to deliver the conformal radiation treatment. The microRT hardware specifications, the accuracy of the treatment planning and positioning systems, and some typical procedures for radiobiological experiments that can be performed with the microRT device are presented.

Myometrial prostaglandin E2 synthetic enzyme mRNA expression: spatial and temporal variations with pregnancy and labour.

We have investigated the hypothesis that the expression of the enzymes involved in PGE(2) synthesis in the human uterus is co-ordinated. We have studied (i) the mRNA expression of the enzymes involved in PGE(2) synthesis [phospholipases (cPLA(2) and sPLA(2)), prostaglandin H synthase (PGHS)-2 and PG E synthases (PGES-1 and -2)] and their relationship to the expression of inflammatory cytokines in samples of myometrium obtained from pregnant women undergoing caesarean section (LSCS) either before or after the onset of labour at or before term; and (ii) the effect of IL-1beta, IL-6, TNF-alpha, PGE(2) and stretch on PGE(2) enzyme mRNA expression. We found that cPLA(2), sPLA(2) and PGHS-2 mRNA expression were greater in labour samples; cPLA(2), sPLA(2), PGHS-2, PGES-1 and -2 mRNA expression were greater in lower- than upper-segment samples; and there was no effect of gestational age. PGHS-2 mRNA levels correlated with those of PGES-1, cPLA(2), IL-1beta and IL-8; PGES-1 mRNA levels correlated with those of IL-1beta, IL-8 and cPLA(2). In primary cultures of uterine myocytes, cPLA(2) mRNA expression was increased by IL-1beta and IL-6; PGHS-2 mRNA expression was increased by IL-1beta, PGE(2) and stretch; and PGES-1 mRNA expression was increased by IL-1beta only. These data show that labour is associated with increased expression of the enzymes involved in PGE(2) synthesis and their expression is greater in the lower uterine segment. The presence of associations between the levels of PGE(2) enzyme mRNA expression and the effects of IL-1beta suggest that their expression is co-ordinated and that IL-1beta is the responsible factor.

Gene expression patterns in advanced human cervical cancer.

The purpose of this study was to evaluate gene expression patterns in human cervical tumors by extent of lymph node metastases at diagnosis. Pretreatment whole-body fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging was performed in eight patients with invasive squamous cell carcinoma of the cervix to evaluate the extent of lymph nodes metastases. Pretreatment tumor tissue samples were subjected to laser-capture microdissection, and isolated RNA was linearly amplified and hybridized to Affymetrix Human U95A GeneChip microarrays. Molecular FDG-PET imaging revealed that three patients had lymph node involvement in the supraclavicular region and five patients did not. Microarray data were segregated into two groups based on the extent of regional lymph node involvement. Supervised clustering analysis identified 75 of about 12,000 gene transcripts represented on the array whose average expression was at least threefold different. We identified 12 of the 75 transcripts that demonstrated a statistically significant difference in expression between the two patient groups (P < 0.05). Five transcripts were upregulated and seven downregulated. Both overall and cause-specific survivals were different between these two patient groups (P= 0.006). This limited data set identified candidate biomarkers of extent of lymph node metastases that correlated with poor survival outcome.

Postoperative vaginal brachytherapy alone is the treatment of choice for grade 1-2, stage IC endometrial cancer.

The aim was to determine outcome and toxicity in grade 1-2, FIGO stage IC endometrial cancer patients treated with external beam radiotherapy plus vaginal cuff brachytherapy or vaginal cuff brachytherapy alone. Between 1986 and 1999, a total of 132 patients were diagnosed with FIGO stage IC endometrial carcinoma. The median age was 67.5 years (range, 36-88). Median follow-up was 54 months (range, 6-157). Grade 1 disease was present in 64 patients, grade 2 in 45 patients, and grade 3 in 23 patients. Patients with grade 3 disease usually received external radiotherapy and were excluded from this analysis. Of the patients with grade 1-2 disease, 31 received brachytherapy alone and 78 received both external radiotherapy and brachytherapy. Ten (8%) patients experienced failure. Isolated pelvic relapse occurred in five patients. Three patients experienced both distant and local relapse. Two patients had isolated distant relapse. Nine failures occurred in patients treated with both external radiotherapy and brachytherapy. Only one failure occurred in those treated with brachytherapy alone. Overall survival and disease-free survival at 5 years were 85% and 92%, respectively. For those treated with both external radiotherapy and brachytherapy, 5-year locoregional control was 95%. For those treated with brachytherapy alone, 5-year locoregional control was 96.4%. There was no significant survival or local control difference between the two groups. Nine patients (9%) treated with both external radiotherapy and brachytherapy developed Radiation Therapy Oncology Group grade 3-4 toxicity. No patient treated with vaginal cuff brachytherapy alone developed grade 3-4 toxicity (P < 0.001). In patients with well-differentiated (grade 1-2) stage IC endometrial cancer, external beam radiotherapy plus brachytherapy versus vaginal cuff brachytherapy alone achieved equivalent local control and survival. However, vaginal cuff brachytherapy alone produced significantly less toxicity.

Prostanoid receptors in human uterine myocytes: the effect of reproductive state and stretch.

In the human, prostanoids are known to be important mediators of uterine relaxation and contraction during pregnancy and parturition. We have previously shown that stretch of uterine smooth muscle cells increased prostaglandin H synthase 2 (PGHS-2) mRNA expression, PGHS-2 peptide synthesis and activity, however, the net effect on uterine contractility of this increase in prostaglandin synthesis would be determined by the expression of the different prostanoid receptors. Therefore, the aims of this study were to establish the expression of prostanoid receptor mRNA in uterine myocytes obtained from women in different reproductive states and to test the hypothesis that stretch of uterine myocytes alters prostanoid receptor mRNA expression to promote uterine contractility. Myocytes were isolated from women undergoing hysterectomy (NP) and pregnant women undergoing LSCS either before (NL) or after the onset of labour (L) and were subjected to 11% stretch for 1 h (n = 6 in all cases). Copy numbers of the individual receptors varied widely with reproductive state but followed the pattern: FP > IP = DP = EP-4 > TP = EP-3 = EP-2 > EP-1. FP mRNA expression was significantly lower in the NL group compared to the NP group and EP-3, EP-4 and TP mRNA expression was significantly lower in both NL and L groups compared to NP group levels. The level of mRNA expression of EP-1, EP-2, DP and IP did not differ between NP, NL and L groups. Stretch of cells derived from the NP group resulted in a significant decrease in EP-4 mRNA expression alone and of the NL group a significant decrease in EP-2 mRNA expression alone. Stretch had no effect on cells derived from the L group. These data show that pregnancy is associated with a significant reduction in 3 of 4 pro-contraction associated prostanoid receptor mRNA expression and 1 of 4 pro-relaxant. Stretch elicited no consistent change in prostanoid receptor mRNA expression.

Prospective phase I/II study of irradiation and concurrent chemotherapy for recurrent cervical cancer after radical hysterectomy.

The purpose of the present study was to evaluate the long-term toxicity and efficacy of irradiation and concurrent chemotherapy for patients with a pelvic recurrence of cervical cancer after a hysterectomy. This prospective phase I / II study was designed to administer irradiation and three cycles of concurrent chemotherapy with cisplatin and 5-FU to patients with recurrent cervical cancer confined to the pelvis. Initial therapy was a hysterectomy and none received prior pelvic irradiation. A total of 22 patients were entered into the study. Patients received irradiation and three cycles of concurrent cisplatin and 5-FU. The acute toxicity from chemotherapy and irradiation was grade 3 in 18% and grade 4 in 9%. No patient died from a treatment-related complication. Follow-up times ranged from 7.2 to 17.6 years. At last follow-up, 14 patients died of metastatic cervical cancer and eight were alive. The 10- and 15-year overall survivals were 35%. Long-term complications included leg edema, vesico-vaginal, and recto-vaginal fistulae. Pelvic abscesses developed in three of the four patients with a fistula. By logistic regression, the only significant factor for survival was total irradiation dose (P = 0.04). In conclusion, long-term survival with this treatment regimen is possible but is accompanied by significant late toxicity.

Myometrial activation and preterm labour: evidence supporting a role for the prostaglandin F receptor--a review.

An increase in the myometrial expression of the prostaglandin (PG) receptors, and especially the PGF(2alpha) receptor (FP), may be an important component of the process initiating preterm labour. In this review of the literature and presentation of new possibilities, evidence will be discussed that demonstrates an increase in mouse uterine FP mRNA occurs at preterm birth whereas uterine PGF(2alpha) concentrations do not increase, suggesting elevated uterine receptor expression and sensitivity is a mechanism for preterm labour initiation. The first examination of the complete human myometrial FP promoter will be described and evidence presented that demonstrates the pro-inflammatory cytokine, interleukin-1beta, stimulates FP mRNA expression. Finally new data showing that administration of a specific FP antagonist delays preterm birth in sheep will be presented.

Long-term follow-up of RTOG 92-10: cervical cancer with positive para-aortic lymph nodes.

PURPOSE: The purpose of this study was to evaluate the late toxicity and efficacy of twice-daily external irradiation to the pelvis and lumbar para-aortic region with brachytherapy and concurrent chemotherapy for carcinoma of the cervix with positive para-aortic lymph nodes. PATIENTS AND METHODS: This study was designed to administer twice-daily radiation doses of 1.2 Gy to the pelvis and lumbar para-aortic lymph nodes (simultaneously) at 4-6-h intervals, 5 days per week. The total external radiation doses were 24-48 Gy to the whole pelvis, 12-36 Gy parametrial boost, and 48 Gy to the lumbar para-aortic region with an additional boost to a total dose 54-58 Gy to the positive para-aortic lymph node(s). One or two intracavitary implants were performed to deliver a minimum total dose of 85 Gy to point A. Cisplatin (75 mg/m(2); Days 1, 22, and 43) and 5-fluorouracil (1,000 mg/m(2)/24 h x 4 consecutive days, beginning on Days 1, 22, and 43) were given for two or three cycles. RESULTS: Thirty patients with clinical Stages I-IV carcinoma of the cervix with biopsy-proven para-aortic lymph node metastases were enrolled in this study. Hyperfractionated external irradiation was completed in 87% (26 of 30). Brachytherapy was given in two implants to 47% (14 of 30) and in one implant to 33% (10 of 30); 13% (4 of 30) did not receive brachytherapy, 1 patient had three implants, and 1 had five high-dose-rate implants. Radiotherapy was completed per protocol in 70%. Three cycles of chemotherapy were given to 23% (7 of 30); 73% (22 of 30) received two cycles, and 1 patient did not receive chemotherapy. The acute toxicity from chemotherapy was Grade 1 in 3%, Grade 2 in 17%, Grade 3 in 48%, and Grade 4 in 28%. Acute toxicity from radiotherapy was Grade 1 in 7%, Grade 2 in 34%, Grade 3 in 21%, and Grade 4 in 28%. Late toxicity was Grade 1 in 10%, Grade 2 in 17%, Grade 3 in 7%, and Grade 4 in 17%. Grade 5 toxicity occurred in 1 patient during the course of therapy, but none had a late Grade 5 toxicity. The median follow-up time for the 7 patients alive at the time of last follow-up was 57 months. The overall survival estimates were 46% at 2 years and 29% at 4 years. The probability of local-regional failure was 40% at 1 year and 50% at 2 and 3 years. The probability of disease failure at any site was 46% at 1 year, 60% at 2 years, and 63% at 3 years. CONCLUSION: The results suggest that twice-daily external irradiation to the pelvis and lumbar para-aortic region with brachytherapy and concurrent chemotherapy resulted in an unacceptably high rate (17%, 5 of 29) of Grade 4 late toxicity. One patient died of acute complications of therapy. The survival estimates seem no better than standard fractionation irradiation without chemotherapy.

Current management of patients with invasive cervical carcinoma.

After the logic of evidence-based medicine, there are several conclusions to be reached from these recent prospective, randomized phase III clinical trials. Patients with stages IB2 and IIA cervical carcinoma, although technically manageable, should be treated with external pelvic irradiation and brachytherapy and weekly (cisplatin 40 mg/m2 x 6 wk), if it is suspected that the likelihood of positive lymph nodes or margins requiring adjuvant treatment after radical surgery would be significant. In those patients in whom the risks of either positive margins or lymph nodes are low, either radical surgery or radiation are equally efficacious options. A recent report that surveyed the Surveillance, Epidemiology, and End Results program database suggested that there may be a survival advantage for surgical intent-to-treat patients compared with the radiation intent-to-treat patients for tumors 4 cm or smaller in patients with stage IB and IIA cervical cancers. Certainly, toxicity criteria for these patients in terms of long-term problems need to be further examined. For those patients who undergo a radical hysterectomy and lymph node dissection, postoperative irradiation is indicated if high-risk factors such as large tumor size, lymph vascular space invasion, and deep stromal invasion are identified. Patients who are found to have positive lymph nodes, positive parametrial invasion, or positive margins at the time of hysterectomy should receive postoperative irradiation with chemotherapy. All other patients with more advanced clinical stages of cervical carcinoma should be treated with external pelvic irradiation, brachytherapy, and concurrent chemotherapy. Based on the results of the randomized studies, there appears to be no role for either hydroxyurea or fluorouracil. The chemotherapy agent of choice, at present, is cisplatin administered concurrently with irradiation at a dose of 40 mg/m2 weekly for 6 weeks. Concurrent chemotherapy should be avoided in patients with a poor performance status and other severe comorbidities, and these patients should be treated with irradiation alone. Further refinement of treatment for those patients who require combined chemo/radiation versus those with comorbidities such that combination chemotherapy is actually too toxic must be defined.

Inhibition of prostaglandin synthesis and its effect on uterine activity during established premature labor in sheep.

OBJECTIVE: Continuous infusion of the selective prostaglandin synthase type-2 inhibitor nimesulide, together with the oxytocin receptor antagonist atosiban, inhibits glucocorticoid induction of labor in sheep. We evaluated the effectiveness of this treatment commencing after the onset of premature labor when prostaglandin concentrations are already significantly elevated. METHODS: Premature labor was induced in chronically cannulated fetuses by constant fetal dexamethasone infusion. After the onset of active labor in each ewe, defined as uterine electromyographic (EMG) activity twice basal levels, ewes received combined nimesulide and atosiban (20.0 and 4.12 mg/kg per day, respectively; n = 6) or vehicle (n-methyl-2-pyrrolidone and saline each 1 mL/hour; n = 4) infusions for 48 hours. Maternal and fetal plasma PGFM (13,14-dihydro-15-keto PGF2alpha, the stable metabolite of prostaglandin (PG) F2alpha) and PGE2 concentrations were measured before, during, and after infusions. RESULTS: Four nimesulide- and atosiban-treated ewes successfully completed the 48-hour infusion period with no deliveries occurring during inhibitor treatment, or up to 6 hours after inhibitor treatment. Delivery was delayed in two other ewes, compared with control animals. Uterine EMG activity in nimesulide- and atosiban-treated ewes (n = 4) was significantly reduced during the 48-hour inhibitor treatment period. Maternal and fetal prostaglandin concentrations were significantly decreased in inhibitor-treated ewes during and after the infusions. CONCLUSIONS: The combination of nimesulide and atosiban treatment for 48 hours successfully inhibited the progression of active premature labor to delivery. This study further supports the potential value of this treatment regime for the inhibition of premature labor.

Lymph node staging by positron emission tomography in patients with carcinoma of the cervix.

PURPOSE: The aim of this study was to compare the results of computed tomography (CT) and positron emission tomography (PET) with [18F]-fluoro-2-deoxy-D-glucose (FDG) for lymph node staging in patients with carcinoma of the cervix and to evaluate the relationship of the imaging findings to prognosis. PATIENTS AND METHODS: We retrospectively compared the results of CT lymph node staging and whole-body FDG-PET in 101 consecutive patients with carcinoma of the cervix. Patients were treated with standard irradiation and chemotherapy (as clinically indicated) and observed at 3-month intervals for a median of 15.4 months (range, 2.5 to 30 months). Progression-free survival was evaluated by the Kaplan-Meier method. RESULTS: CT demonstrated abnormally enlarged pelvic lymph nodes in 20 (20%) and para-aortic lymph nodes in seven (7%) of the 101 patients. PET demonstrated abnormal FDG uptake in pelvic lymph nodes in 67 (67%), in para-aortic lymph nodes in 21 (21%), and in supraclavicular lymph node in eight (8%). The 2-year progression-free survival, based solely on para-aortic lymph node status, was 64% in CT-negative and PET-negative patients, 18% in CT-negative and PET-positive patients, and 14% in CT-positive and PET-positive patients (P <.0001). A multivariate analysis demonstrated that the most significant prognostic factor for progression-free survival was the presence of positive para-aortic lymph nodes as detected by PET imaging (P =.025). CONCLUSION: This study demonstrates that FDG-PET detects abnormal lymph node regions more often than does CT and that the findings on PET are a better predictor of survival than those of CT in patients with carcinoma of the cervix.

Cervical cancer: combined modality therapy.

Prospective, randomized studies conducted over the past 10 years have changed the management of patients with advanced cervical cancer. The reviewed studies evaluated the use of surgery, irradiation, and chemotherapy in patients with various stages of cervical carcinoma in the absence and presence of high-risk factors for recurrence. A study by the Radiation Therapy Oncology Group (RTOG) compared pelvic with pelvic plus prophylactic para-aortic irradiation in patients with stages IB (> 4 cm), IIA, and IIB cervical cancer. The 10-year survival advantage was 11% for patients treated with prophylactic para-aortic irradiation. A follow-up study compared pelvic plus prophylactic para-aortic irradiation and brachytherapy with pelvic irradiation, brachytherapy, and chemotherapy with cisplatin and 5-FU in patients with IB-to IVA-stage cervical cancer. Overall and disease-free survivals were significantly improved in patients receiving chemotherapy. In patients with a prevalence of stage IIB and III, the Gynecologic Oncology Group (GOG) demonstrated that treatment with hydroxyurea alone was inferior to cisplatin or cisplatin, 5-FU, and hydroxy-urea in patients treated concurrently with pelvic irradiation and brachytherapy, and the GOG adopted irradiation and weekly cisplatin as standard therapy. Further GOG studies suggest that irradiation and weekly cisplatin chemotherapy without hysterectomy is the optimal treatment for patients with stage IB cervical cancer. High-risk factors for recurrence include tumor size, depth of tumor invasion, lymphovascular space involvement, and lymph node involvement. Prospective, randomized studies conducted by the GOG evaluated the effectiveness of various treatments in patients with high-risk factors. In one study that did not use chemotherapy, the recurrence-free interval was about 10% better for stage IB patients receiving postoperative irradiation after radical hysterectomy and pelvic lymphadenectomy compared with those who received no further therapy. Patients with Stages IB and IIA disease who, following radical hysterectomy and lymph node dissection, are identified as having positive pelvic lymph nodes and positive parametrial involvement, are at higher risk for recurrence and death than the high-risk group described above. An intergroup study conducted by the GOG, RTOG, and Southwest Oncology Group compared postoperative pelvic irradiation alone with postoperative pelvic irradiation plus concurrent chemotherapy in this group of patients. Overall and progression-free survivals were superior for patients receiving chemotherapy, and their greatest survival occurred in patients who received 3 or 4 chemotherapy cycles compared with 1 or 2 cycles or no chemotherapy. These findings are summarized with respect to their implications fortreatment of patients with advanced cervical cancer.