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Previous Uterine Cancer Research: 2002-2006   
The Uterine and Cervical Cancer File also contains summaries of past research that has shown promise and may still be standard practice among many physicians. To download earlier research findings on Uterine and Cervical Cancer, click HERE.
 

Latest Research on
Uterine and Cervical Cancer
     
Gynecol Oncol. 2008 Sep;110(3):293-8. Epub 2008 Jul 21.
Utility of pre-operative serum CA-125 in the management of uterine papillary serous carcinoma.
Olawaiye AB, Rauh-Hain JA, Withiam-Leitch M, Rueda B, Goodman A, del Carmen MG.
Department of Obstetrics, Division of Gynecologic Oncology, Harvard Medical School, Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.

OBJECTIVE: To evaluate the usefulness of pre-operative serum CA-125 in the management of women diagnosed with uterine papillary serous carcinoma (UPSC). We hypothesized that elevated pre-operative levels of serum CA-125 correlate with higher disease stage and poorer prognosis. METHODS: Patients diagnosed with UPSC and managed in our institution were identified over a period of 10 years, 1995 to 2005. All required information were extracted from their records. The nonparametric test applied for comparison of data included Kruskal Wallis H-test and Man-Whitney U-test. The chi(2) test and Spearman correlation test were used to examine the association of serum CA-125 with different parameters. Receiver operator characteristic curves (ROC) were used to quantify marker performance. Recurrence and survival were analyzed using Kaplan-Meier method. Multivariate analyses were performed with a Cox proportional regression method. RESULTS: A total of 41 patients met the study criteria. Mean pre-operative serum CA-125 levels were significantly higher in patients with stage IV (1150+/-1297 U/mL), compared with stage III (181+/-232 U/mL; P<0.001), stage II (22+/-9; P<0.001), and stage I (14+/-1; P<0.001). CA-125 correlated strongly with stage (r=0.68, P<0.001). On the ROC, a cut-off of 35 IU/mL provided the best sensitivity and specificity (78% vs. 100% respectively) for extra-uterine disease. Disease free survival (DFS) and overall survival (OS) were longer in patients with CA-125<35 U/mL compared with CA-125>or=35 U/mL [median DFS not reached during study vs. 21.2 months (P=0.009), and median OS not reached during study vs. 25 months, (P=0.0001) respectively]. Multivariate regression model showed CA-125 as the only variable associated with survival (P=0.05). CONCLUSION: Pre-operative serum CA-125 levels correlate with stage of disease in patients with UPSC. This may be important for management planning, prognostication and counseling in these women.

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Gynecol Oncol. 2008 Sep;110(3):308-15. Epub 2008 Jul 7.
Clinical efficacy of modified preoperative neoadjuvant chemotherapy in the treatment of locally advanced (stage IB2 to IIB) cervical cancer: randomized study.
Chen H, Liang C, Zhang L, Huang S, Wu X.
Department of Gynecologic Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China. huijunchen1981@sina.com

OBJECTIVES: The use of preoperative neoadjuvant chemotherapy (NAC) in locally advanced cervical cancer (LACC) was hindered by the disadvantages of a delay of curative treatment for nonresponders and the development of radioresistant cells. However, these disadvantages may be overcome by a 'quick' high-dose scheme administered in a short period before surgery. Our purpose is to assess the efficacy of NAC with short cycle-length, high-dose agents for LACC. METHOD: From 1999 to 2004, 142 of patients with LACC (stage IB2IIB, tumor diameter >or=4 cm) were assigned to randomly receive either NAC followed by surgery or primary surgery directly. A modified NAC scheme with short cycle-length, high-dose agents was used. RESULTS: The overall clinical response rate was 69.4%. The chemotherapeutic response was more favorable in the squamous carcinoma and the tumors smaller than 8 cmP=0.005, P=0.029). Pathologic findings showed that the pelvic metastasis and parametrial infiltration rates were significantly lower in NAC group than in the primary surgery group (P=0.025; P=0.038). Among patients who received NAC, the lymph node metastasis rate was still as high as 45.5% in non-NAC responders, and it decreased to 16.0% in NAC responders (P=0.008). The same thing also occurred with parametrial infiltration: 45.5% in non-NAC responders compared with 16.0% in NAC responders (P=0.008). Survival analysis revealed that although test showed a longer survival in NAC group than in the primary surgery group (P=0.041), Cox hazard analysis did not indicate the therapy modality as a prognostic predictor (P=0.074). However, after further subdivision, we found that NAC responders had longer survival and lower recurrence rate than non-NAC responders (P=0.000; P=0.013). NAC response was also an independent prognostic predictor (P=0.005). CONCLUSION: The modified preoperative NAC is well tolerated and beneficial in reducing tumor size, eliminating pathological risk factors, and improving prognosis for responders. It also avoids the delay of effective treatment for non-NAC responders.

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Gynecol Oncol. 2008 Sep;110(3):304-7. Epub 2008 Jul 2.
MVP expression is related to IGF1-R in cervical carcinoma patients treated by radiochemotherapy.
Lloret M, Lara PC, Bordón E, Rey A, Falcón O, Apolinario RM, Clavo B, Ruiz A.
Radiation Oncology, Dr Negrin University Hospital, Las Palmas de Gran Canaria, Spain. mllosae@hotmail.com

OBJECTIVE: To assess the expression of MVP in cervix carcinoma patients treated by radiochemotherapy, its relation to clinical and pathologic prognostic factors and its role in predicting clinical outcome. In addition the relation to IGF-1R expression in this cohort of patients will be explored. MATERIALS AND METHODS: Sixty consecutive patients suffering from localized cervix carcinoma were prospectively included in this study from July 1999 to December 2003. Follow-up was closed in November 2007. Patients were staged following the TNM classification. All patients received pelvic radiation (45-64.80 Gy in 1.8-2 Gy fractions) followed brachytherapy and concomitant cisplatin at 40 mg/m(2)/week doses. MVP expression was studied by immunohistochemistry in paraffin-embedded tumour tissue. RESULTS: MVP was expressed in 58 patients (96.7%) and no relation was found with clinicopathological variables. High MVP expression was related to high IGF1-R expression (p=0.023). Complete response after treatment was observed in 50 patients (83.3%). Clinical stage of the disease and clinical response to radiochemotherapy were the most important prognostic factors related to survival. High MVP and IGF-1R tumour expression was strongly related to poor local and regional disease-free survival (p=0.006), distant disease-free survival (p=0.050), disease-free survival (p=0.006), and cause-specific survival (p=0.007) in patients achieving a complete response. CONCLUSION: MVP and IGF-1R expression were related in clinical cervical tumours and confer reduced long-term local control in patients who achieved clinical complete response to radiochemotherapy.

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Cancer. 2008 Aug 15;113(4):743-9.
Patterns of care for women with cervical cancer in the United States.
Trimble EL, Harlan LC, Gius D, Stevens J, Schwartz SM.
National Cancer Institute, Surgery Section, Bethesda, Maryland 20892-7436, USA. tt6m@nih.gov

BACKGROUND: Recommendations for pretreatment evaluation and treatment of cervical cancer have significantly evolved over the last decade because of the results of multiple randomized studies comparing the addition of platin-based chemoradiation as well as the widespread dissemination and use of imaging modalities. This analysis was initiated to determine any systemic changes in management of cervical cancers. METHODS: Surveillance, Epidemiology, and End Results program data were used to sample newly diagnosed women in 1997, 2000, and 2001 with cancer of the cervix. A total of 3116 women with no previous diagnosis of cancer were selected. Data were reabstracted, additional information not routinely collected was obtained, therapy was verified with the treating physician, and multiple endpoints were analyzed. RESULTS: A marked rise was observed in the percentage receiving chemotherapy (34% to 85%) as well as concurrent chemoradiation (20% to 72%) from 1997 to 2001. CONCLUSIONS: The significant change in the management and treatment of cervical cancer appears to correspond temporally with the publication of 5 clinical trials, all of which showed a significant improvement in overall survival associated with chemoradiation. This change also corresponded with the NCI Clinical Announcement that was disseminated in 1999 to those oncologists most likely to treat women with cervical cancer. 2008 American Cancer Society

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Am J Obstet Gynecol. 2008 Aug;199(2):191.e1-7; discussion 191.e7. Epub 2008 Jun 13.
The vascular portion of the cardinal ligament: surgical significance during radical hysterectomy for cervical cancer.
Hoffman MS, Williams V, Salihu HM, Gunasekaran S, Sayer RA, Hakam A, Roberts WS.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of South Florida College of Medicine, Tampa, FL, USA. mhoffma1@health.usf.edu

OBJECTIVE: The objective of the study was to analyze the histopathologic content of the vascular portion of the cardinal ligament in patients undergoing radical hysterectomy for cervical cancer. STUDY DESIGN: The vascular portion of the cardinal ligament was completely removed during radical hysterectomy. The maximum cervical diameter and length of the vascular ligament were measured on the fresh specimen. After inking, the pathologist separated and embedded the entire vascular segment from each side. Microscopic examination followed. RESULTS: Eighty-four patients were available for analysis. The mean cervical diameter was 3.9 cm (2-8), whereas the mean vascular segment length on the right and left sides were 4 cm (1-10) and 3.8 cm (1-7), respectively. Mean number of vascular segment lymph nodes were as follows: medial right = 0.7 (0-4), medial left = 0.6 (0-5), lateral right = 0.4 (0-3), and lateral left = 0.6 (0-6). Mean diameter of medial and lateral lymph nodes were 2 mm (0.25-8) and 3.3 mm (0.25-16), respectively. The length of the vascular segment correlated inversely with maximum cervical diameter. Thirty-one percent (26 of 84) had positive pelvic side wall lymph nodes. Fourteen patients had positive vascular segment lymph nodes (1 positive = 7, more than 1 positive = 7). Three of 7 patients had bilateral positive vascular segment lymph nodes; all 7 had microscopic disease in the paravaginal soft tissue, and all 7 had positive pelvic side wall lymph nodes (6 of 7 bilateral). Including the 14 patients, a total of 19 had nodal or nonnodal microscopic disease in the vascular segment. Of these, 7 had disease in the lateral half of the vascular ligament. Histologic sectioning revealed nerve twigs and/or scattered ganglia in the vascular segment but no large nerve trunks. CONCLUSION: Among a population of women with high-risk, early-stage cervical cancer, the lateral vascular segment of the cardinal ligament contained metastatic disease in a substantial number of patients. This segment contains no major nerve trunks. When radical hysterectomy is chosen as primary treatment for such patients, the vascular segment of the cardinal ligament should be completely excised.

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Br J Radiol. 2008 Aug;81(968):659-65.
Factors predicting tumour regression in locally advanced cervical adenocarcinoma treated with balloon-occluded intra-arterial chemotherapy.
Niwa T, Yoshida T, Doiuchi T, Ito K, Nakayama H, Odagiri K, Inoue T.
Department of Radiology, Kanagawa Cancer Centre, 1-1-2 Nakao, Asahi-ku, Yokohama, Japan. tniwa@kcmc.jp

We retrospectively assessed the factors that may impede tumour reduction of locally advanced cervical adenocarcinoma treated with balloon-occluded arterial infusion chemotherapy (BOAI) as initial therapy. We reviewed the medical records and MRI scans of 31 patients (mean age, 54.7 years; age range, 33-78 years). BOAI was performed via uterine arteries in 21 patients, and via the anterior division or main trunk of the internal iliac artery (when the uterine arteries were obscured) in 10 patients. Tumour reduction rate was calculated from the tumour size on MRI before and after BOAI, and patients given chemotherapy were classified as "non-responders" or "responders". Factors including the patient's age, tumour stage (using the International Federation of Gynecology and Obstetrics classification), the artery used for infusion, infused drug, presence of intravenous systemic chemotherapy, initial tumour size, tumour volume and presence of lymph node metastases were assessed for their ability to predict tumour response to BOAI using univariate and multivariate analyses. Patients who underwent chemotherapy included 10 non-responders and 21 responders. The age of non-responders was significantly higher than that of responders (66 years vs 49 years, p<0.001). Internal iliac arterial infusion significantly correlated with "no response" compared with uterine arterial infusion (p<0.001). In multivariate analyses, internal iliac arterial infusion was an independent predictor for BOAI non-responders (odds ratio, 19.6; 95% confidence interval, 1.4-280.6; p = 0.02). These data suggest that uterine arteries being obscured to arterial infusion may be associated with a poor response to BOAI for cervical adenocarcinoma.

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Int J Radiat Oncol Biol Phys. 2008 Aug 1;71(5):1504-10.
Dosimetric comparison of bone marrow-sparing intensity-modulated radiotherapy versus conventional techniques for treatment of cervical cancer.
Mell LK, Tiryaki H, Ahn KH, Mundt AJ, Roeske JC, Aydogan B.
Department of Radiation Oncology, School of Medicine, University of California-San Diego, La Jolla, CA, USA.

PURPOSE: To compare bone marrow-sparing intensity-modulated pelvic radiotherapy (BMS-IMRT) with conventional (four-field box and anteroposterior-posteroanterior [AP-PA]) techniques in the treatment of cervical cancer. METHODS AND MATERIALS: The data from 7 cervical cancer patients treated with concurrent chemotherapy and IMRT without BMS were analyzed and compared with data using four-field box and AP-PA techniques. All plans were normalized to cover the planning target volume with the 99% isodose line. The clinical target volume consisted of the pelvic and presacral lymph nodes, uterus and cervix, upper vagina, and parametrial tissue. Normal tissues included bowel, bladder, and pelvic bone marrow (PBM), which comprised the lumbosacral spine and ilium and the ischium, pubis, and proximal femora (lower pelvis bone marrow). Dose-volume histograms for the planning target volume and normal tissues were compared for BMS-IMRT vs. four-field box and AP-PA plans. RESULTS: BMS-IMRT was superior to the four-field box technique in reducing the dose to the PBM, small bowel, rectum, and bladder. Compared with AP-PA plans, BMS-IMRT reduced the PBM volume receiving a dose >16.4 Gy. BMS-IMRT reduced the volume of ilium, lower pelvis bone marrow, and bowel receiving a dose >27.7, >18.7, and >21.1 Gy, respectively, but increased dose below these thresholds compared with the AP-PA plans. BMS-IMRT reduced the volume of lumbosacral spine bone marrow, rectum, small bowel, and bladder at all dose levels in all 7 patients. CONCLUSION: BMS-IMRT reduced irradiation of PBM compared with the four-field box technique. Compared with the AP-PA technique, BMS-IMRT reduced lumbosacral spine bone marrow irradiation and reduced the volume of PBM irradiated to high doses. Therefore BMS-IMRT might reduce acute hematologic toxicity compared with conventional techniques.

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Cancer Res. 2008 Jul 15;68(14):5699-705.
An in vitro multistep carcinogenesis model for human cervical cancer.
Narisawa-Saito M, Yoshimatsu Y, Ohno S, Yugawa T, Egawa N, Fujita M, Hirohashi S, Kiyono T.
Virology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.

Human papillomaviruses (HPV) are believed to be the primary causal agents for development of cervical cancer, and deregulated expression of two viral oncogenes E6 and E7 in basal cells, mostly by integration, is considered to be a critical event for disease progression. However, lines of evidence suggest that, besides expression of E6 and E7 genes, additional host genetic alterations are required for cancer development. To directly test this hypothesis, we first transduced HPV16 E6 and E7 with or without hTERT into several lines of normal human cervical keratinocytes (HCK) from independent donors and then searched for additional alterations required for carcinogenesis. Oncogenic Hras(G12V) (Hras) provided marked tumor forming ability in nude mice and ErbB2 or c-Myc (Myc) endowed weaker but significant tumor forming ability. Combined transduction of Myc and Hras to HCKs expressing E6 and E7 resulted in the creation of highly potent tumor-initiating cells. These results show that only one or two genetic changes occurring after deregulated expression of high-risk HPV oncogenes might be sufficient for development of cervical cancer.

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Anticancer Res. 2008 Jul-Aug;28(4C):2385-8.
Feasibility study of docetaxel and nedaplatin for recurrent squamous cell carcinoma of the uterine cervix.
Watanabe Y, Nakai H, Etoh T, Kanemura K, Tsuji I, Ishizu A, Hoshiai H.
Department of Obstetrics and Gynecology, Kinki University School of Medicine, 377-2 Ohno-Higashi Osakasayama Osaka 589-8511, Japan. watanabe@med.kindai.ac.jp

BACKGROUND: To determine a new taxane plus platinum treatment regimen for squamous cell carcinoma of the uterine cervix (CSCC), a phase I feasibility study of docetaxel (DTX) plus nedaplatin (CDGP) combination therapy was conducted. PATIENTS AND METHODS: Twenty consecutive patients were enrolled into the study. The starting dose of DTX/CDGP was 60 mg/m2 / 80 mg/m2, every 4 weeks for at least three courses and the dose was escalated to 70 mg/m2 / 100 mg/m2. DTX 60 mg/m2 / CDGP 100 mg/m2 was also evaluated as an extra dose level. RESULTS: Dose-limiting toxicity was granulocytopenia and the maximum tolerated dose was determined as 70 mg/m2 / 100 mg/m2. All 20 patients had measurable disease and a partial response was achieved in 8 (40.0%) patients. CONCLUSION: DTX/CDGP therapy appears to be a tolerable regimen for cervical squamous cell carcinoma, even in patients previously treated by cisplatin concurrent chemoradiotherapy. The recommended doses of DTX and CDGP were determined to be 60 mg/m2 and 100 mg/m2, respectively.

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J Low Genit Tract Dis. 2008 Jul;12(3):181-4.
Human papillomavirus vaccination: the policy debate over the prevention of cervical cancer—a commentary.
Hoops KE, Twiggs LB.
Department of Obstetrics and Gynecology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.

The human papillomavirus (HPV) family causes a variety of benign, premalignant, and malignant lesions in men and women. HPV types 16 and 18 are responsible for causing 70% of all cases of cervical cancer each year. Recently, a vaccine that can prevent cervical cancer by protecting women from infection with the most common types of HPV has been made available. Following Food and Drug Administration approval and endorsement by the Centers for Disease Control and Prevention, it is the right and the duty of the state legislatures to implement vaccination programs. This vaccine, a vaccine for a sexually transmitted disease, has stirred a fierce debate. Religion and sexuality have dominated the discussion, and political calculations are inherent to the process; nonetheless, epidemiological analyses are also essential to the decision to mandate the HPV vaccine. HPV vaccine program implementation processes are at many stages in many states, and programs vary widely. Some provide information to families, whereas others allot a range of funding for voluntary vaccination. Virginia is, thus far, the only state to have enacted a mandate. This article discusses the various programs in place, the proposed legislation, and the debate surrounding the political process.

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Mol Cancer Ther. 2008 Jul;7(7):2090-5.
Cyclooxygenase inhibitors block uterine tumorigenesis in HMGA1a transgenic mice and human xenografts.
Di Cello F, Hillion J, Kowalski J, Ronnett BM, Aderinto A, Huso DL, Resar LM.
Hematology Division, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Uterine cancer is a common cause for cancer death in women and there is no effective therapy for metastatic disease. Thus, research is urgently needed to identify new therapeutic agents. We showed previously that all female HMGA1a transgenic mice develop malignant uterine tumors, indicating that HMGA1a causes uterine cancer in vivo. We also demonstrated that HMGA1a up-regulates cyclooxygenase-2 (COX-2) during tumorigenesis in this model. Similarly, we found that HMGA1a and COX-2 are overexpressed in human leiomyosarcomas, a highly malignant uterine cancer. Although epidemiologic studies indicate that individuals who take COX inhibitors have a lower incidence of some tumors, these inhibitors have not been evaluated in uterine cancer. Here, we show that HMGA1a mice on sulindac (a COX-1/COX-2 inhibitor) have significantly smaller uterine tumors than controls. To determine if COX inhibitors are active in human uterine cancers that overexpress HMGA1a, we treated cultured cells with sulindac sulfide or celecoxib (a specific COX-2 inhibitor). Both drugs block anchorage-independent growth in high-grade human uterine cancer cells that overexpress HMGA1a (MES-SA cells). In contrast, neither inhibitor blocked transformation in cells that do not overexpress HMGA1a. Moreover, xenograft tumors from MES-SA cells were significantly inhibited in mice on sulindac. More strikingly, no tumors formed in mice on celecoxib. These preclinical studies suggest that COX inhibitors could play a role in preventing tumor onset or progression in uterine cancers with dysregulation of the HMGA1a-COX-2 pathway. Importantly, these drugs have lower toxicity than chemotherapeutic agents used to treat advanced-stage uterine cancers.

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Ther Umsch. 2008 Jun;65(6):341-6.
[Follow-up after malignant tumours of the uterus (cancer of the uterine corpus / cervical cancer)]
[Article in German]
Johann S, Mueller MD.
Klinik und Polikliniken für Frauenheilkunde, Inselspital, Universitätskliniken Bern und Universität Bern.

Malignant uterine tumours can affect the corpus or the cervix. The endometrial carcinoma with its different histological subtypes counts for most of the malignomas of the uterine body. But the rare category of uterine sarcomas (carcinosarcomas, leiomyosarcomas as well as endometrial stromal sarcomas) also belongs to this group. Cervical cancer presents an own entitity, regarding both histology and therapeutic options. Endometrial cancer is the most common genital malignoma in Northern Europe and North America. Histologically, the endometrial cancer can be subdivided in two groups: type I is hormonal sensitive and well differentiated, type II represents an undifferenciated aggressive tumour with poor prognosis. In general, the patient is elderly. Due to the main symptom - abnormal vaginal bleeding - endometrial cancer is detected in an early stage in about 75% of all patients. First choice in therapy is stage related surgery. Follow-up schemes have not proved yet to improve survival, therefore clear guidelines are missing. National and international groups recommend regular follow-up visits to detect the early vaginal vault relapse which is curable. Cervical cancer is mainly a squamous cell carcinoma and oncogenic Human Papilloma Virus (HPV) associated. Surgery is only indicated up to stage IIA, advanced stages should be treated by radio-chemotherapy. Several studies have shown that follow-up visits can improve survival rates. Intention is the detection of the curable local relapse.

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Anal Quant Cytol Histol. 2008 Apr;30(2):63-70.
Expression of p53, bcl-2 and Ki-67 in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the uterine cervix.
Looi ML, Dali AZ, Ali SA, Ngah WZ, Yusof YA.
Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.

OBJECTIVE: To assess the expression of p53, bcl-2 and Ki-67 in the progression of cervical neoplasia. STUDY DESIGN: A total of 131 cervical specimens, consisting of normal cervical epithelium (n = 43), cervical intraepithelial neoplasia (CIN) lesions (n =40) and cervical squamous cell carcinomas (SCCs) (n = 48) were examined immunohistochemically in paraffin sections for expression of p53, bcl-2 and Ki-67. RESULTS: Immunoreactivity of p53 was found in 27% of SCC cases, but it had no significant relationship with SCC staging (p = 0.791). Immunoreactivity of bcl-2 was observed in 33% of CIN 3 cases. We found a significant relationship (chi2 test: p = 0.009) between the expression of bcl-2 and CIN grading. Ki-67 index was higher in high grade CIN (HGCIN: CIN 2 and 3) and SCC lesions compared to normal cervices. Ki-67 index showed a correlation with bcl-2 protein expression (p = 0.030), but not with p53 protein expression (p = 0.239). CONCLUSION: HGCIN is an early stage to demonstrate the alteration of bcl-2 and Ki-67 expressions. Progression of neoplasia in the uterine cervix is accompanied by an increase of antiapoptotic protein, bcl-2 as well as cellular proliferation.

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Akush Ginekol (Sofiia). 2007;46(8):31-5.
[Vaccines for precancer and cancer of the uterine cervix. II. Therapeutic HPV vaccines]
[Article in Bulgarian]
Kostova P, Zlatkov V.
Gynecology Clinic, National Hospital of Oncology-Sofia.

Vaccines are one of the most powerful immunomodulators and represent perspective direction in the modern strategy of treatment of cancer. Among the gynecological malignancies cervical cancer is the most perspective localization for the implementation of specific therapeutic vaccine, by reason of clear viral ethiopathogenesis and important medical and social effect of the disease. Nowadays, the therapeutic HPV vaccines under research, for precancer and cancer of uterine cervix aimed to eliminate the persistent viral infection. In the review, the results of several clinical trials concerning the effect of HPV vaccines, created on the basis of viral peptides, viral like particles, DNA and viral vectors have been discussed.

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Gynecol Oncol. 2008 Apr;109(1):86-91. Epub 2008 Feb 14.
Robotic radical hysterectomy: comparison with laparoscopy and laparotomy.
Magrina JF, Kho RM, Weaver AL, Montero RP, Magtibay PM.
Division of Obstetrics and Gynecology, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, Arizona 85054, USA. jmagrina@mayo.edu

OBJECTIVE: Comparison of perioperative results of patients undergoing radical hysterectomy by robotics, laparoscopy, and laparotomy. STUDY DESIGN: Prospective analysis of 27 patients undergoing robotic radical hysterectomy between April 2003 and September 2006. Comparison was made with patients operated by laparoscopy and laparotomy matched by age, BMI, site and type of malignancy, FIGO staging, and type of radical hysterectomy. RESULTS: The mean operating times for patients undergoing robotic, laparoscopy and laparotomy radical hysterectomy were 189.6, 220.4, and 166.8 min, respectively; the mean blood loss was 133.1, 208.4, and 443.6 ml, respectively; the mean rate of blood loss was 0.7, 0.9, and 2.6 ml/min, respectively; the mean number of removed lymph nodes was 25.9, 25.9, and 27.7, respectively; and the mean length of hospital stay was 1.7, 2.4, and 3.6 days, respectively. There were no significant differences in intra- or postoperative complications among the three groups, no fistula formation in any patient and no conversions in the robotic or laparoscopic groups. At a mean follow up of 31.1 months, none of the patients with cervical cancer has experienced recurrence. CONCLUSION: Laparoscopy and robotics are preferable to laparotomy for patients requiring radical hysterectomy. Operating times for robotics and laparotomy were similar, and significantly shorter as compared to laparoscopy. Blood loss, rate of blood loss and length of hospital stay were similar for laparoscopy and robotics and significantly reduced as compared to laparotomy.

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Gynecol Oncol. 2008 Apr;109(1):53-8. Epub 2008 Feb 5.
An evaluation of cervical cancer in women age sixty and over.
Fox KV, Shah CA, Swisher EM, Garcia RL, Mandel LS, Gray HJ, Swensen RE, Goff BA.
Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, Washington 98195, USA. kvfox@u.washington.edu

OBJECTIVE: To assess prior cervical cancer screening, stage at time of diagnosis and outcome in women sixty years of age and over with cervical cancer. METHODS: A retrospective review of cervical cancer patients evaluated at the University of Washington identified a cohort of women age sixty and older with cervical cancer diagnosed between January 1, 1993 and December 31, 2003. Electronic medical records and the University of Washington Tumor Registry were reviewed for age, ethnicity, cervical cancer risk factors, pathology, treatment, and outcome. RESULTS: Six hundred forty-five women with cervical cancer were identified. One hundred (15.5%) women were age 60 or older with a median age of 64 years. At time of diagnosis, 41 were early stage (1A1-1B1) and 59 were advanced stage (1B2-4B). Length of time from last Pap smear significantly correlated with stage. Radical hysterectomy was performed on 29 patients, and 15 received adjuvant treatment. Forty-nine women received primary
chemo-radiation, and 22 were treated with primary radiation. Lymph node metastases were identified in 65% of women with locally advanced cervical cancer. At conclusion of the study period, 80% were alive. Stage and time since last Pap smear correlated with overall outcome. CONCLUSIONS: Women 60 and older make up a significant proportion of cervical cancer patients, often fail to receive screening, present with locally advanced disease, and tolerate standard treatment protocols. Careful consideration of these findings should be made when establishing Pap smear screening guidelines for this population of women.

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Gynecol Oncol. 2008 Apr;109(1):43-8. Epub 2008 Jan 29.
Survival for stage IB cervical cancer with positive lymph node involvement: a comparison of completed vs. abandoned radical hysterectomy.
Richard SD, Krivak TC, Castleberry A, Beriwal S, Kelley JL 3rd, Edwards RP, Sukumvanich P.
Division of Gynecologic Oncology, Magee-Womens Hospital, 300 Halket Street, Pittsburgh, PA 15213, USA.

PURPOSE: Management for stage IB cervical cancer with intraoperative positive pelvic lymph nodes (LNs) is controversial. We compare 5-year survival rates for women with completed vs. abandoned radical hysterectomy (RH) who were treated with postoperative radiation therapy (RT). PATIENTS AND METHODS: We identified all women diagnosed with stage IB cervical carcinoma from the Surveillance, Epidemiology, and End Results database from 1988-1998. Women with positive LN involvement who had undergone a complete pelvic and para-aortic lymphadenectomy were compared for 5-year survival based on whether a RH was completed or abandoned at the time of surgery. All women then received postoperative RT. Survival rates were calculated using the Kaplan-Meier method, and the Chi square test was used for all univariate analysis. RESULTS: From a cohort of 3116 women diagnosed with stage IB cervical cancer, 265 (8.7%) had positive pelvic LNs and a complete pelvic and para-aortic lymphadenectomy. Of these women, 163 had completion of their RH while RH was abandoned in 55. Positive pelvic LNs averaged 2.58+/-2.37 in the completed RH group and 2.42+/-1.63 in the abandoned RH group. Median follow-up was 6.42 years in the completed RH group and 5.75 years in the abandoned RH group. Five-year survival for the completed RH group was 69% compared with 71% in patients with abandoned RH (p=0.46). CONCLUSIONS: Treatment for patients with positive pelvic LNs at the time of RH should be determined by overall morbidity of therapy since equivalent 5-year survival was found between the completed and abandoned RH groups.

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Histopathology. 2008 Feb;52(3):381-6.
Natural history and clearance of HPV after treatment of precancerous cervical lesions.
Aerssens A, Claeys P, Garcia A, Sturtewagen Y, Velasquez R, Vanden Broeck D, Vansteelandt S, Temmerman M, Cuvelier CA.
International Centre for Reproductive Health, Ghent University, Ghent, Belgium.

AIM: To assess the clearance rate of human papillomavirus (HPV) after out-patient treatment of cervical intraepithelial neoplasia (CIN). METHODS AND RESULTS: A total of 122 Nicaraguan women with HPV DNA-positive and histologically confirmed CIN lesions were included in the study. Fifty-five patients with CIN1 and 67 with CIN2-3 were treated by cryotherapy and loop electrosurgical excision procedure (LEEP), respectively. Follow-up visits were scheduled at 6 weeks, 6 months, 1 year and 2 years. Investigations included cytology, HPV DNA testing and colposcopy/biopsy if needed. The clearance rate of HPV was calculated by multivariate logistic regression. Immediately after treatment, a pronounced decrease in presence of HPV was observed in both groups, with a significantly higher clearance in the LEEP group than in the cryotherapy group (P = 0.019). Subsequently, clearance continued over time and was similar between the cryotherapy group and the LEEP group (P = 0.73). Approximately the same detection rates were obtained for persistence of all HPV types and for high-risk types separately: 43.9, 37.6, 29.9 and 17.7% in the cryotherapy group and 24.9, 20.3, 15.3 and 8.4% in the LEEP group at 6 weeks, 6 months, 1 year and 2 years, respectively. CONCLUSIONS: Out-patient treatment of precancerous lesions of the cervix usually results in clearance of HPV. Both LEEP and cryotherapy are highly effective methods of eradicating HPV. HPV DNA testing may have added value in the follow-up of patients.

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Mo Med. 2008 Jan-Feb;105(1):8-11.
HPV vaccine mandates: just say 'no' to the "great big public health experiment".
Onder RF.
Washington University School of Medicine, St. Louis, USA. Bob.Onder@house.mo.gov

While many states are seriously considering requiring vaccination of pre-teen girls as a condition of middle school admission, the case for mandatory human papillomavirus (HPV) vaccine is very weak. Such a requirement lacks the traditional justification for vaccine mandates and therefore represents an unjustified usurpation of parental authority. Moreover, serious questions remain as to whether the vaccine is effective in preventing cervical cancer. The vaccine is the most expensive pediatric vaccine in history. Given the uncertainties surrounding the vaccine, Missouri lawmakers and taxpayers should reject this expensive and intrusive "public health experiment".

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J Natl Compr Canc Netw. 2008 Jan;6(1):101-6.
Conservative management of adolescents with abnormal cytology and histology.
Moscicki AB.
Division of Adolescent Medicine, University of California San Francisco, 3333 California Street, Suite 245, San Francisco, CA 94118, USA. moscickia@peds.ucsf.edu

Adolescents remain vulnerable to human papilloma virus (HPV) infection because of certain physiologic characteristics inherent in this age group and common sexual behaviors, including lack of condom use. The commonness of HPV in this age group also results in frequent abnormal cytology. Fortunately, most of the infections are transient, with frequent clearance of HPV and the lesion. Current strategies for adolescents with abnormal cytology include conservative management, avoiding invasive procedures. For cytologic atypical squamous cells of undetermined significance or squamous intraepithelial lesions (SIL), management can be obtaining cytology only at 1-year intervals for up to 2 years before referral for colposcopy is necessary. For biopsy-proven cervical intraepithelial neoplasia (CIN) I, management is similar with yearly cytology indefinitely or until high-grade-SIL or CIN II/III develops. CIN II in adherent adolescents can be managed with 6-month cytology and colposcopy.

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J Natl Compr Canc Netw. 2008 Jan;6(1):53-7.
Chemotherapy for advanced, recurrent, and metastatic cervical cancer.
Moore DH.
Gynecologic Oncology of Indiana, 5255 East Stop 11 Road, Suite 310, Indianapolis, IN 46237, USA. David.Moore@ssfhs.org

When cervical cancer is beyond curative treatment with surgery or radiation therapy, the prognosis is poor and palliation is the primary objective. Early prospective studies identified cisplatin as an active drug for advanced, metastatic, or recurrent cervical cancer, and results with other platinum analogs seemed inferior to cisplatin. Several phase III trials have established the combination of cisplatin plus paclitaxel as standard therapy for comparison. Using pooled data from 3 Gynecologic Oncology Group (GOG) phase III studies, a predictive model was developed to better identify patients who are unlikely to respond to cisplatin-containing chemotherapy. The GOG is currently developing a phase III trial to investigate the impact of bevacizumab and a regimen containing topotecan instead of cisplatin in combination with paclitaxel chemotherapy and also to externally validate the predictive model. This study has the potential to radically change standard care for cervical cancer chemotherapy. Furthermore, if the predictive model is upheld, then patients with high risk factors for treatment failure may be directed to chemotherapy regimens that do not include cisplatin or to investigational trials.

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J Natl Compr Canc Netw. 2008 Jan;6(1):47-52.
Primary management of early stage cervical cancer (IA1-IB) and appropriate selection of adjuvant therapy.
Gray HJ.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Box 356460, University of Washington School of Medicine, Seattle, WA 98195, USA. hgray@u.washington.edu

Cervical cancer is the third most common gynecologic malignancy in the United States but the leading gynecologic cancer worldwide. Most patients will present with clinical early-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage IA1-IB). These patients are a clinically heterogeneous group, and primary treatment can be either surgery or radiotherapy. Standard surgery is either radical hysterectomy with lymphadenectomy (stage IA2-IB2) or simple hysterectomy for microinvasive disease (stage IA1). Interest has been increasing in using conservative fertility-sparing surgery through radical trachelectomy as an option for select patients with early-stage disease who want future fertility. Primary radiotherapy is delivered as a combination of external-beam teletherapy and brachytherapy. It is given with concurrent cisplatin-based chemotherapy, based on 5 large randomized controlled trials that showed significant improvement in overall survival with the addition of chemotherapy. Using either radical surgery or radiation therapy in stage IB disease yields 5-year survival rates of 87% to 92%. The addition of postoperative adjuvant radiation with concurrent chemotherapy is recommended in patients with high- or intermediate-risk disease after radical hysterectomy to reduce risk for recurrence and improve progression-free survival. In select patients with stage IB2 disease with bulky tumors undergoing primary chemoradiation, adjuvant hysterectomy may provide benefit after treatment.

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Am J Obstet Gynecol. 2007 Dec;197(6):566-71.
Reducing the burden of glandular carcinomas of the uterine cervix.
Herzog TJ, Monk BJ.
Columbia University, Irving Comprehensive Cancer Center, New York Presbyterian Hospital, New York, NY, USA.

Widespread use of the Papanicolaou test for the screening of cervical cancers has lead to a significant decline in overall incidence and mortality rates over the past 3 decades. When different histologic types of cervical cancers are considered and trends are reexamined, it becomes apparent that observed declines are reflective of squamous cell carcinomas predominantly; the rates for adenocarcinomas continue to rise. This rise in incidence may be due to the greater difficulty in screening for glandular precursor lesions that often arise high within the endocervical canal. Reducing the incidence and mortality rates that are associated with adenocarcinomas can be accomplished by using improved screening techniques and large-scale implementation of cervical cancer vaccines that target the predominant oncogenic human papillomavirus types that are associated with adenocarcinoma.

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Obstet Gynecol. 2007 Dec;110(6):1237-43.
Adjuvant radiotherapy in incompletely staged IC and II endometrioid uterine cancer.
Parthasarathy A, Kapp DS, Cheung MK, Shin JY, Osann K, Chan JK.
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California 94143-1702, USA.

OBJECTIVES: To estimate if adjuvant radiotherapy improves the disease-specific survival of patients with clinical stage IC and II endometrioid corpus cancer who did not undergo lymphadenectomy. METHODS: Information was obtained on patients with endometrioid corpus cancer from the National Cancer Institute database between 1988 and 2001. Data were analyzed using Kaplan-Meier and Cox proportional hazards regression methods. RESULTS: A total of 3,664 patients (median age 70 years) with clinical stage IC to II endometrioid carcinoma did not undergo lymphadenectomy, of which 2,170 had stage IC and 1,494 stage II disease. Of these, 1,175 had grade 1, 1,637 had grade 2, 693 had grade 3, and in 159, grade was unknown. The 5-year disease-specific survival rates of clinical stage IC compared with stage II patients were 91.3% and 86.7% (P<.001). Of the 1,964 who received adjuvant radiotherapy, the 5-year disease-specific survival rate was 89.9% compared with 87.8% in those who did not undergo further treatment (P=.04). Adjuvant radiation improved the disease-specific survival rate of those with stage II disease, (86.5% compared with 81.9%; P=.02), but not in those with stage IC disease (91.7% compared with 92.6%; P=.68). The benefit of radiotherapy was significant in patients with grade 3 disease and patients 70 years or older (88.2% compared with 83.3%; P<.001). On multivariable analysis, age, stage, and grade were significant independent prognostic factors for disease-specific survival. CONCLUSION: Adjuvant radiotherapy marginally improved the survival of clinically staged IC-II endometrioid uterine cancer patients without lymphadenectomy. After excluding those without hysterectomy, radiotherapy did not significantly affect disease-specific survival. LEVEL OF EVIDENCE: II.

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J Minim Invasive Gynecol. 2007 Nov-Dec;14(6):698-705.
Robot-assisted laparoscopic myomectomy versus abdominal myomectomy: a comparison of short-term surgical outcomes and immediate costs.
Advincula AP, Xu X, Goudeau S 4th, Ransom SB.
Department of Obstetrics and Gynecology, University of Michigan Medical Center, Women's Hospital, Ann Arbor, MI 48109, USA. aadvincu@umich.edu

STUDY OBJECTIVE: To compare surgical outcomes of myomectomy by robot-assisted laparoscopy with those performed by traditional laparotomy and to analyze the financial impact of these 2 approaches. DESIGN: Retrospective case-matched analysis (Canadian Task Force classification III). SETTING: University teaching hospital. PATIENTS: A total of 58 patients with symptomatic leiomyomata. INTERVENTION: Myomectomy by robot-assisted laparoscopy or traditional laparotomy was administered. MEASUREMENTS AND MAIN RESULTS: An equal number of case-matched patients based on age, body mass index, and myoma weight were analyzed in each group. Among these 3 variables, there were no statistically significant differences between the robotic and laparotomy groups. Mean age was 36.59 +/- 4.93 years (95% CI 34.71-38.46 years) versus 34.86 +/- 4.41 years (95% CI 33.18-36.54 years), mean body mass index was 25.22 +/- 3.85 kg/m(2) (90% central range [CR] 20.30-31.20 kg/m2) versus 28.3 +/- 6.95 kg/m2 (90% CR 21.50-42.80 kg/m2), and mean myoma weight was 227.86 +/- 247.54 g (90% CR 11.60-680.00 g) versus 223.76 +/- 228.28 g (90% CR 11.50-660.00 g), respectively. Patients with robot-assisted laparoscopic myomectomy had decreased estimated blood loss (mean 195.69 +/- 228.55 mL [90% CR 50.00-700.00 mL] vs mean 364.66 +/- 473.28 mL [90% CR 75.00-1550.00 mL]) and length of stay (mean 1.48 +/- 0.95 days [90% CR 1.00-3.00 days] vs mean 3.62 +/- 1.50 days [90% CR 3.00-8.00 days]) when compared with the laparotomy group. Both of these differences were statistically significant at p <.05. Operative times were significantly longer in the robotic group: mean 231.38 +/- 85.10 minutes (95% CI 199.01-263.75 minutes) versus mean 154.41 +/- 43.14 minutes (95% CI 138.00-170.82 minutes, p <.05) in the laparotomy group. Complication rates were higher in the laparotomy group. Professional charges (mean $5946.48 +/- $1447.17 [90% CR $4034.46-$8937.00] vs mean $4664.48 +/- $642.11 [90% CR $3944.36-$6010.90, p <.0002]) and hospital charges (mean $30084.20 +/- $6689.29 [90% CR $22939.81-$45588.22] vs mean $13400.62 +/- $7747.26 [90% CR $8703.20-$26771.22, p <.0001]) were statistically higher for the robotic group. Although professional reimbursement was not significantly different between groups (mean $2263.02 +/- $1354.97 [90% CR $0.00- $4831.08] versus mean $1841.99 +/- $827.51 [90% CR $0.00-$3376.97, p = .2831]), mean hospital reimbursement rates for the robotic group were significantly higher: $13181.39 +/- $10752.00 (90% CR $1081.76-$37396.03) versus $7015.24 +/- $3467.97 (90% CR $2492.48-$10394.83, p = .0372). CONCLUSION: As a new technology, it is not unexpected that a robotic approach to myomectomy costs more than a traditional laparotomy. On the other hand, decreased estimated blood loss, complication rates, and length of stay with the robotic approach in the end may prove to have a significant societal benefit that will outweigh upfront financial impact.

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Gynecol Oncol. 2007 Nov;107(2 Suppl):S27-30.
Long-term efficacy of human papillomavirus vaccination.
Ault KA.
Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Emory University School of Medicine, 69 Jesse Hill Drive, Atlanta, GA 30064, USA. kevin.ault@emory.edu

Achieving long-term protection following vaccination is crucial to ensuring that high levels of immunity are maintained within a population while eliminating the need to introduce booster vaccinations. Based on an analysis of the hepatitis B virus vaccine, several factors have been shown to contribute to long-term protection, namely: specific lymphoproliferation, the in vivo humoral response, and immune memory. To ensure protection against persistent human papillomavirus (HPV) infection and the subsequent development of cervical lesions, an effective HPV vaccine must be able to induce strong humoral immune responses. Mathematical modeling analyses based on a three-dose regimen of HPV type 16 prophylactic vaccine indicated that 99% of 16- to 23-year-old women would have almost life-long detectable anti-HPV-16 levels. Available data on the quadrivalent HPV vaccine demonstrated that long-term immune memory was induced, with anti-HPV geometric mean titers after 5 years remaining at or above those observed with natural infection. Vaccination also resulted in a substantial reduction in the combined incidence of HPV-6/11/16/18 related persistent infection or disease, and there were no cases of precancerous cervical dysplasia compared with six cases in women receiving placebo. Similarly the bivalent HPV vaccine has been shown to induce long-term immunity with >98% seropositivity maintained after 4.5 years of follow-up and geometric mean titres at this time point remaining substantially higher than those noted with naturally acquired infection. Countrywide registration regarding population and health events in a stable population of approximately 25 million makes the Nordic countries an ideal setting for the evaluation of long-term cervical cancer control. Population-based long-term efficacy trials conducted in these countries aim to investigate the long-term efficacy of HPV vaccination with regard to invasive cervical cancer, and the results of these trials are awaited with interest.

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Gynecol Oncol. 2007 Nov;107(2 Suppl):S19-23.
Prevention strategies against the human papillomavirus: the effectiveness of vaccination.
Stanley M.
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK. mas@mole.bio.cam.ac.uk

It has been clearly established that sexually transmitted human papillomavirus (HPV) infections are the major cause of genital warts and cervical cancer and are a contributing factor in the development of other types of anogenital cancers. There is a higher risk of HPV infection with an increasing number of sexual partners. Health education measures aimed at improving the use of condoms, reducing the number of sexual partners and promoting safer sex strategies have been employed with the goal of decreasing the transmission of HPV. Of these intervention strategies, promotion of condom use has been shown to be the most effective. More recently, prophylactic HPV vaccines have been developed with the aim of reducing the burden of HPV-related diseases such as cervical cancer. Two vaccines have been developed: Gardasil, a quadrivalent vaccine targeting HPV-6, -11, -16 and -18) and Cervarix, a bivalent vaccine which targets HPV-16 and -18. HPV-16 and -18 are most commonly associated with cervical cancer. In clinical trials, HPV vaccination has been shown to be safe, immunogenic and highly effective against type-specific HPV infection. Predictive data also indicate that the implementation of HPV vaccination within a national screening program is likely to be cost-effective relative to current clinical practice.

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Am J Obstet Gynecol. 2007 Nov;197(5):503.e1-6. Comment in: Am J Obstet Gynecol. 2007 Nov;197(5):443-4.
Radiation therapy with or without weekly cisplatin for bulky stage 1B cervical carcinoma: follow-up of a Gynecologic Oncology Group trial.
Stehman FB, Ali S, Keys HM, Muderspach LI, Chafe WE, Gallup DG, Walker JL, Gersell D.
Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. fstehman@iupui.edu

OBJECTIVE: The objective of the study was to confirm that concurrent cisplatin (CT) with radiation therapy (RT) is associated with improved long-term progression-free survival (PFS) and overall survival (OS), compared with RT alone in stage IB bulky carcinoma of the cervix, when both groups' therapy is followed by hysterectomy. STUDY DESIGN: Three hundred seventy-four patients entered this trial. There were 369 evaluable patients; 186 were randomly allocated to receive RT alone and 183 to receive CT plus RT. Radiation dosage was 45 Gray (Gy) in 20 fractions followed by low dose-rate intracavitary application(s) of 30 Gy to point A. Chemotherapy consisted of intravenous cisplatin 40 mg/m2 every week for up to 6 weekly cycles. Total extrafascial hysterectomy followed the completion of RT by 6-8 weeks. RESULTS: Preliminary results have been published, at which time there were 292 censored observations, and median duration of follow-up was only 36 months. Patient and tumor characteristics were well balanced between the regimens. The median patient age was 41.5 years; 81% had squamous tumors; 59% were white. Median follow-up is now 101 months. The relative risk for progression was 0.61 favoring CT plus RT (95% confidence interval [CI] 0.43 to 0.85, P < .004). At 72 months, 71% of patients receiving CT plus RT were predicted to be alive and disease free when adjusting for age and tumor size, compared with 60% of those receiving RT alone. The adjusted death hazard ratio was 0.63 (95% CI 0.43 to 0.91, P < .015) favoring CT plus RT. At 72 months, 78% of CT plus RT patients were predicted to be alive, compared with 64% of RT patients. An increased rate of early hematologic and gastrointestinal toxicity was seen with CT plus RT. There was no detectable difference in the frequency of late adverse events. CONCLUSION: Concurrent weekly cisplatin with RT significantly improves long-term PFS and OS when compared with RT alone. Serious late effects were not increased. The inclusion of hysterectomy has been discontinued on the basis of another trial. Pending further trials, weekly cisplatin with radiation is the standard against which other regimens should be compared.

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BMJ. 2007 Nov 24;335(7629):1077. Epub 2007 Oct 24. Comment in: BMJ. 2007 Nov 24;335(7629):1053-4.
Long term risk of invasive cancer after treatment for cervical intraepithelial neoplasia grade 3: population based cohort study.
Strander B, Andersson-Ellström A, Milsom I, Sparén P.
Department of Obstetrics and Gynecology, Sahlgren's Academy, University of Gothenburg, SU/Ostra sjukhuset, SE-416 85, Sweden. bjorn.strander@oc.gu.se

OBJECTIVE: To study the long term risk of invasive cancer of the cervix or vagina after treatment for cervical intraepithelial neoplasia grade 3. DESIGN: Prospective cohort study. SETTING: Swedish cancer registry. PARTICIPANTS: All women in Sweden with severe dysplasia or cervical carcinoma in situ (equivalent to cervical intraepithelial neoplasia grade 3) treated during 1958-2002 (n=132,493) contributing 2,315,724 woman years. MAIN OUTCOME MEASURES: Standardised incidence ratios with risk of cancer in the Swedish general female population as reference, and relative risks in multivariable log-linear regression model, with internal references. RESULTS: Women with previous cervical intraepithelial neoplasia grade 3 had an increased risk of invasive cervical cancer compared with the general female population (standardised incidence ratio 2.34, 95% confidence interval 2.18 to 2.50). The increased risk showed a decreasing trend with time since diagnosis for women treated later than 1970 but the risk was still increased after 25 years. An effect of age was found, with an accentuated increase in risk for women aged more than 50. The excess risk for cervical cancer associated with previous cervical intraepithelial neoplasia grade 3 has steadily increased since 1958. For vaginal cancer the standardised incidence ratio was 6.82 (5.61 to 8.21) but this decreased to 2.65 after 25 years. Adjustments in the multivariable log-linear regression model did not substantially alter these results. CONCLUSIONS: Women previously treated for cervical intraepithelial neoplasia grade 3 are at an increased risk of developing invasive cervical cancer and vaginal cancer. This risk has increased since the 1960s and is accentuated in women aged more than 50. The risk is still increased 25 years after treatment.

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Anticancer Res. 2007 Sep-Oct;27(5B):3525-8.
Bevacizumab therapy in patients with recurrent uterine neoplasms.
Wright JD, Powell MA, Rader JS, Mutch DG, Gibb RK.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. jw2459@columbia.edu

BACKGROUND: Angiogenesis plays an important role in endometrial carcinogenesis. We reviewed our experience with the anti-VEGF monoclonal antibody bevacizumab for the treatment of recurrent uterine neoplasms. PATIENTS AND METHODS: A retrospective analysis of women with recurrent uterine neoplasms treated with bevacizumab was performed. RESULTS: A total of 11 patients were identified, 9 with epithelial endometrial carcinomas and 2 with leiomyosarcomas. All patients had multi-site disease and were heavily pretreated with a median of 3 prior chemotherapy regimens. All received bevacizumab combination therapy which was well-tolerated. Two patients had partial responses, 3 had stable disease, while 5 patients progressed. One subject was not assessable for response. The median progression-free interval was 5.4 months for the entire cohort and 8.7 months for those who achieved clinical benefit (PR or SD). CONCLUSION: Bevacizumab was well-tolerated and displayed promising anti-neoplastic activity in patients with endometrial cancer and uterine leiomyosarcoma.

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Bull World Health Organ. 2007 Sep;85(9):719-26.
Human papillomavirus and HPV vaccines: a review.
Cutts FT, Franceschi S, Goldie S, Castellsague X, de Sanjose S, Garnett G, Edmunds WJ, Claeys P, Goldenthal KL, Harper DM, Markowitz L.
Initiative for Vaccine Research, WHO, Geneva, Switzerland. felicity.cutts@lshtm.ac.uk

Cervical cancer, the most common cancer affecting women in developing countries, is caused by persistent infection with "high-risk" genotypes of human papillomaviruses (HPV). The most common oncogenic HPV genotypes are 16 and 18, causing approximately 70% of all cervical cancers. Types 6 and 11 do not contribute to the incidence of high-grade dysplasias (precancerous lesions) or cervical cancer, but do cause laryngeal papillomas and most genital warts. HPV is highly transmissible, with peak incidence soon after the onset of sexual activity. A quadrivalent (types 6, 11, 16 and 18) HPV vaccine has recently been licensed in several countries following the determination that it has an acceptable benefit/risk profile. In large phase III trials, the vaccine prevented 100% of moderate and severe precancerous cervical lesions associated with types 16 or 18 among women with no previous infection with these types. A bivalent (types 16 and 18) vaccine has also undergone extensive evaluation and been licensed in at least one country. Both vaccines are prepared from non-infectious, DNA-free virus-like particles produced by recombinant technology and combined with an adjuvant. With three doses administered, they induce high levels of serum antibodies in virtually all vaccinated individuals. In women who have no evidence of past or current infection with the HPV genotypes in the vaccine, both vaccines show > 90% protection against persistent HPV infection for up to 5 years after vaccination, which is the longest reported follow-up so far. Vaccinating at an age before females are exposed to HPV would have the greatest impact. Since HPV vaccines do not eliminate the risk of cervical cancer, cervical screening will still be required to minimize cancer incidence. Tiered pricing for HPV vaccines, innovative financing mechanisms and multidisciplinary partnerships will be essential in order for the vaccines to reach populations in greatest need.

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Lancet Oncol. 2007 Sep;8(9):831-41.
Role of complete lymphadenectomy in endometrioid uterine cancer.
Chan JK, Kapp DS.
Division of Gynecologic Oncology, University of California, San Francisco Comprehensive Cancer Center, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine, San Francisco, CA, USA.

Although surgical pathological staging is the standard of care for uterine carcinoma, the benefits of a complete lymphadenectomy remain controversial. Evidence suggests that this procedure provides prognostic information and directs the use of appropriate adjuvant treatment in patients who are node-positive. Furthermore, it eliminates the need for adjuvant treatment in low-risk patients with negative nodes and no extrauterine spread of disease. Although the complications associated with this procedure raise the question as to whether all low-risk patients need a complete lymphadenectomy, the limitations of preoperative and intraoperative pathological analyses mean that lymphadenectomy in low-risk patients might still have merit. Future advances are warranted to enhance preoperative radiological and intraoperative pathological assessment to establish the risk of nodal disease. In this review, we assess the evidence on the prognostic and therapeutic benefits of a complete versus selective lymphadenectomy. Moreover, we discuss the complications associated with lymphadenectomy and identify subsets of low-risk patients who might not need to undergo this procedure.

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Clin Infect Dis. 2007 Sep 1;45(5):609-7. Epub 2007 Jul 25.
Quadrivalent human papillomavirus vaccine.
Barr E, Tamms G.
Merck Research Laboratories, West Point, PA, USA. eliav_barr@merck.com

The lifetime risk of human papillomavirus (HPV) infection exceeds 50%. HPV infection causes >550,000 cases of cervical and anogenital cancer worldwide annually. Infection also causes precancerous lesions and genital warts. HPV types 16 and 18 cause approximately 70% of HPV-related cancers, and HPV types 6 and 11 cause approximately 90% of cases of genital warts. A quadrivalent vaccine for HPV types 6, 11, 16, and 18 (HPV 6/11/16/18) has been developed for prevention of cervical cancer, genital warts, and vulvar and vaginal precancerous lesions. Prophylactic vaccination of young women was 96%-100% effective in preventing HPV 6/11/16/18-related cervical and anogenital precancers and genital warts. Efficacy remained high for at least 5 years following vaccination. Postvaccination anti-HPV levels in adolescents were superior to those observed in women (the population in which efficacy was shown). Vaccination was generally well tolerated. The vaccine is licensed in >80 countries. It has been added to national vaccination programs, including that of the United States. Widespread use of HPV 6/11/16/18 vaccine is expected to greatly reduce the incidence of HPV-related cancers, precancers, and genital warts.

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Am J Obstet Gynecol. 2007 Aug;197(2):205.e1-5; discussion 205.e5-7.
Concurrent carboplatin and paclitaxel with pelvic radiation therapy in the primary treatment of cervical cancer.
Higgins R, Bussey M, Naumann W, Hall J, Tait D, Haake M.
Department of Obstetrics and Gynecology, Carolinas Medical Center, Charlotte, NC, USA.

OBJECTIVE: The objective of the study was to determine the feasibility of weekly carboplatin/paclitaxel with radiation therapy (RT) in the primary treatment of cervical cancer. STUDY DESIGN: Women diagnosed with stage IB-1 to stage IVA untreated primary cervical cancer were eligible. Carboplatin (area under the curve = 2.0) and paclitaxel 40 mg/m2 were administered weekly for 6 weeks with pelvic RT. Brachytherapy was completed after pelvic RT. Acute toxicities and response to treatment were assessed. RESULTS: Twenty-two evaluable patients were enrolled. The median duration of follow-up was 23 months. Carboplatin (mean dose 245 mg) and paclitaxel (mean dose 70 mg) were successfully administered in 97% and 90% of planned treatments, respectively. Median time to complete external radiation therapy was 36.6 days (25-57 days). Grade 3/4 hematologic or gastrointestinal toxicity was unusual. The complete response rate 3 months after completion of therapy was 91%. The estimated 3-yea
r progression-free survival is 70% and overall survival is 65%. CONCLUSION: Weekly carboplatin/paclitaxel and RT is a reasonable treatment regimen for cervical cancer.

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Gynecol Oncol. 2007 Aug;106(2):282-8.
The outcomes of 27,063 women with unstaged endometrioid uterine cancer.
Chan JK, Wu H, Cheung MK, Shin JY, Osann K, Kapp DS.
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco School of Medicine, University of California, San Francisco Comprehensive Cancer Center, San Francisco, CA 94143, USA. chanjohn@obgyn.ucsf.edu

BACKGROUND: Over two-thirds of patients with endometrioid uterine cancer in the Surveillance, Epidemiology and End Results program from 1988 to 2001 did not undergo a lymphadenectomy. These patients were compared to those who had a lymphadenectomy. METHODS: Kaplan-Meier methods and Cox proportional hazards regression analyses were employed. RESULTS: Of 39,396 women (median age: 65 years) with endometrioid uterine cancers, 12,333 (31.3%) underwent surgical staging procedures including lymphadenectomy. The remainder did not receive a lymphadenectomy. The 5-year disease-specific survival (DSS) of stages I-IV women who underwent lymphadenectomy were 95.5%, 90.4%, 73.8%, and 53.3% compared to 96.6%, 82.2%, 63.1%, and 26.9% in those without lymphadenectomy (p>0.05 for stage I; p<0.001 for stages II-IV). In stage I patients, those who did not receive lymphadenectomy had a higher proportion of tumors with grade 1 histology and/or disease limited to the endometrium compared to those who underwent lymphadenectomy (54.8 % vs. 34.7%; p<0.001, grade 1 disease; 26.6% vs. 15.9%; p<0.001, no myometrial invasion). In patients with stage I grade 3 disease, those who underwent lymphadenectomy had a better 5-year DSS than those without lymphadenectomy (90% vs. 85%; p=0.0001); however, no benefit for lymphadenectomy was seen for patients with stage I grade 1 (p=0.26) and grade 2 (p=0.14) disease. On multivariable analysis, younger age, Caucasian race, early-stage disease, low grade histology, and lymphadenectomy were independent prognostic factors for improved disease-specific survival. CONCLUSIONS: Our data suggest that lymphadenectomy is associated with an improved survival in stage I grade 3 and more advanced endometrioid uterine cancers.

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J Minim Invasive Gynecol. 2007 Jul-Aug;14(4):453-62.
Italian multicenter study on complications of laparoscopic myomectomy.
Sizzi O, Rossetti A, Malzoni M, Minelli L, La Grotta F, Soranna L, Panunzi S, Spagnolo R, Imperato F, Landi S, Fiaccamento A, Stola E.
Villa Valeria Hospital, Rome, Italy. ornella.sizzi@alfamedica.it

STUDY OBJECTIVE: To study intraoperative and postoperative complications of laparoscopic myomectomy and patients' characteristics influencing this risk. DESIGN: Prospective study, with a review of the patient records by the first author (Canadian Task Force classification II-2). SETTING: Four Italian referral centers. PATIENTS: The incidence and type of complications occurring in 2050 laparoscopic myomectomies undertaken from January 1998 through December 2004 were recorded. INTERVENTIONS: The surgical technique, as well as the expertise of the operators, was the same for the 4 centers. Injection of vasoconstrictive agents was used in 37%. The serosa was always incised in a vertical fashion; mechanical enucleation of the myoma was completed whenever possible; suture was performed in 1 or 2 layers with deep and large stitches swaged to 1 or 0 polyglactin sutures that were tied intracorporeally or extracorporeally. MEASUREMENTS AND MAIN RESULTS: Single or multiple myomectomies (n = 2050) for symptomatic myomas measuring at least 4 cm in diameter were performed. Most patients (48%) had more than 1 myoma, with a maximum of 15 per patient (myomas removed for patients: 2.26 +/- 1.8, mean +/- SD). Myoma size ranged from 1 to 20 cm (mean 6.40 +/- 2.6 SD). Myomas smaller than 4 cm were removed during myomectomy for larger ones. Total complication rate was 11.1% (225/2050 cases). Minor complications accounted for 9.1% (187/2050 cases) and major complications for 2.02% (38/2050 cases). The most serious events were hemorrhages (14 cases, 0.68%) requiring blood transfusions in 3 cases (0.14%); 10 postoperative hematomas (0.48%, one in the broad ligament and 9 in the myomectomy scar); 1 bowel injury (0.04%); 1 postoperative acute kidney failure (0.04%); and 2 unexpected sarcomas (0.09%). Failure to complete planned surgery occurred in 7 cases (0.34%). Two patients were readmitted for surgery (0.09%): 1 had a laparoscopic hysterectomy because of a severe blood loss, and the other had drainage of a hematoma in the broad ligament. After a follow-up period of 41.70 +/- 23.03 months (mean +/- SD), 386 (22.9%) patients conceived, with a pregnancy rate in patients wishing pregnancy of 69.8%; among them, 1 (0.26%) recorded spontaneous uterine rupture at 33 weeks gestation. Odds ratio computed to estimate the risk of complications in relation to the patient characteristics showed that the probability of complications significantly rises with an increase in the number (more than 3 myomas OR: 4.46, p <.001) and with the intramural (OR: 1.48, p <.05) or the intraligamentous location of myomas (OR: 2.36, p <.01) whereas the myoma size seems to influence particularly the risk of major complications (OR: 6.88, p <.001). CONCLUSIONS: This is one of the largest series reported of laparoscopic myomectomy and the first focused on complications. The complication rate appears to be better than acceptable in comparison with complication rates reported after laparotomic myomectomies. Laparoscopic myomectomy, when performed by an experienced surgeon, can be considered a safe technique with an extremely low failure rate and good results in terms of pregnancy outcome.

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J Minim Invasive Gynecol. 2007 Jul-Aug;14(4):449-52.
Total laparoscopic hysterectomy with and without lymph node dissection for uterine neoplasia.
O'Hanlan KA, Pinto RA, O'Holleran M.
Gynecologic Oncology Associates and Sequoia Hospital, Portola Valley, California 94028, USA. ohanlan@aol.com

STUDY OBJECTIVE: To compare surgical outcomes of patients with uterine neoplasia undergoing total laparoscopic hysterectomy only (TLH) with those having TLH and lymph node dissection (TLHND) from September 5, 1996 through January 13, 2007. DESIGN: Retrospective chart analysis (Canadian Task Force classification II-2). SETTING: Three tertiary surgical centers in California. PATIENTS: 112 patients with uterine neoplasia operated on from 1996 through 2006. INTERVENTIONS: All patients underwent total laparoscopic hysterectomy and bilateral salpingoophorectomy; however, 30 patients with FIGO stage IC or higher, lymph channel involvement, or grade 3 disease also underwent pelvic and aortic node dissection. MEASUREMENTS AND MAIN RESULTS: Of 807 patients having TLH, 112 had a uterine neoplasia: twenty-one hyperplasia, 86 carcinoma, 2 ovarian and endometrial carcinoma, and 3 low-grade endometrial stromal sarcoma; 82 had TLH and adnexectomy; and 30 had TLHND. For both groups, the mean age was 60 (NS), Quatlet index was 31.2 (NS), parity was 1.6 (NS), and the mean blood loss was 148 mL (NS). The node dissection added 56 minutes to TLH (132 vs 188 minutes, p <.001) and yielded a mean of 25 nodes. Patients in both groups spent a median of 1 day in the hospital (NS). There were 7 complications (6.3%) in the series: among the patients in the TLH group, 1 conversion to laparotomy for bleeding from an ovarian artery, 1 vaginal rupture during coitus at 6 weeks, and 1 nonsurgical episode of diverticulitis. There were 4 patients in the TLHLND group with complications: 1 ureteral injury, 1 trocar-site hernia, 1 vaginal laceration, and 1 pelvic abscess. CONCLUSIONS: Node dissection added 56 minutes and entailed no additional blood loss, transfusion, or length of hospital stay, as well as minimal risk of complication. Total laparoscopic hysterectomy with indicated lymph node dissections for endometrial disease is reasonably well tolerated and warrants prospective randomized study to document its role in the therapy of endometrial carcinoma.

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J Clin Oncol. 2007 Jul 10;25(20):2975-82.
Impact of the human papilloma vaccine on cervical cancer.
Chan JK, Berek JS.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford Cancer Center, Stanford, CA 94305, USA.

During the last decade, research progress on cervical cancer has elucidated the role of human papilloma virus (HPV) in the pathogenesis of cervical cancer. Clinical trials on the viral-like particle HPV vaccines have good safety profiles and promising efficacy in preventing genital warts, cervical neoplasia, and cervical cancer. The implementation of the HPV vaccine is a tremendous milestone in our effort toward preventing cervical cancers. However, screening programs will continue to serve as a critical component in prevention due to the limitations of the current vaccines. The greatest impact in cervical cancer incidence worldwide requires improved health care access to underserved areas. Advances are needed to develop single-dose, heat-stable, needle-free, and affordable formulations of the HPV vaccine to overcome the socioeconomic barriers associated with this disease.

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J Clin Oncol. 2007 Jul 10;25(20):2966-74.
Management of metastatic cervical cancer: review of the literature.
Long HJ 3rd.
Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA. long.harry@mayo.edu

This article reviews the English-language literature concerning chemotherapy for advanced, recurrent, or metastatic cervix carcinoma. Specifically, it reviews the available literature for active single agents, doublets, triplets, and multiple drug combination chemotherapy. Until recently, single-agent cisplatin was the drug of choice in metastatic cervix cancer. Various doublets, triplets, and quartlets have been reported to have higher objective response rates than single-agent cisplatin when compared in phase III clinical trials. Some have demonstrated improvements in progression-free survival, but only topotecan plus cisplatin has demonstrated an improvement in overall survival. This benefit is most apparent in patients who have a long disease-free interval from primary therapy and who have not received prior cisplatin as a radiosensitizer.

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J Clin Oncol. 2007 Jul 10;25(20):2952-65.
Multimodality therapy for locally advanced cervical carcinoma: state of the art and future directions.
Monk BJ, Tewari KS, Koh WJ.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chao Family Comprehensive Cancer Center, University of California-Irvine Medical Center, Orange, CA 92868, USA. bjmonk@uci.edu

Globally, cervical cancer is the second most common cause of cancer-related mortality among women causing approximately 234,000 deaths annually among developing countries and killing 40,000 in developed nations. Most of these deaths occur in women with bulky or locally advanced cervical cancer, International Federation of Gynecology and Obstetrics (FIGO) stages IIB through IVA, when lesions are not amenable to high cure rates with surgery or radiation (RT). The standard prescription for RT used to treat locally advanced cervical cancer has been dictated by common practice and patterns of care studies. In contrast, the addition of concomitant chemotherapy to RT has been studied in a number of randomized prospective trials, which are discussed in detail. When added to RT, cisplatin reduces the relative risk of death from cervical carcinoma by approximately 50% by decreasing local/pelvic failure and distant metastases. In 1999, weekly intravenous cisplatin at 40 mg/m2 for 6 week
s in combination with RT was established as a new standard for the treatment of locally advanced cervical carcinoma. More recently, this recommendation has been expanded to include women with FIGO stage IB2 lesions as well as those with bulky stage IIA cancers. This monograph reviews the state of the art in treating locally advanced cervical cancer with combined chemotherapy and RT and discusses clinical and pathologic prognostic factors that impact cure. Quality of life during and after multimodality therapy is considered as well as ongoing clinical trials and future directions.

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Expert Opin Pharmacother. 2007 Apr;8(6):809-16.
Uterine papillary serous carcinoma: a review.
Gehrig PA.
University of North Carolina at Chapel Hill, Department of Obstetrics and Gynecology, CB 7570 MacNider Building, Chapel Hill, NC 27599-7570, USA. pam68@med.unc.edu

The purpose of this article is to review the available literature for uterine papillary serous carcinoma (UPSC). A literature search was conducted to identify publications on UPSC. The literature on UPSC is composed mainly of retrospective, single-institution reports. Despite these limitations, several recommendations can be made. When UPSC is confirmed on preoperative biopsy, complete surgical staging should be performed. Although whole abdominal radiotherapy has a limited role in early-stage UPSC, there may be a role for postoperative chemotherapy in early-stage UPSC. In the setting of optimally debulked advanced-stage disease, a combination of radiation and chemotherapy may be indicated. In the setting of recurrent or suboptimally debulked advanced disease, a platinum-based regimen is recommended. Although comprising a minority of the women with endometrial cancer, women with UPSC do account for a disproportionate percentage of the recurrences. There is a need for clinical trials to determine the optimal therapy for this cohort of patients.

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J Low Genit Tract Dis. 2007 Apr;11(2):90-7.
Outcomes after treatment of cervical intraepithelial neoplasia among women with HIV.
Massad LS, Fazzari MJ, Anastos K, Klein RS, Minkoff H, Jamieson DJ, Duerr A, Celentano D, Gange S, Cu-Uvin S, Young M, Watts DH, Levine AM, Schuman P, Harris TG, Strickler HD.
Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, Springfield, IL 62794-9640, USA. lsmassad@ameritech.net

OBJECTIVE: To describe outcomes after treatment of cervical intraepithelial neoplasia (CIN) in women with HIV. MATERIALS AND METHODS: Women in two prospective cohort studies, the Women's Interagency HIV Study (WIHS) and the HIV Epidemiology Research Study (HERS), were followed every 6 months after treatment of CIN using human papillomavirus (HPV) testing and cytology with colposcopy as indicated. Identification of CIN or a squamous intraepithelial lesion (SIL) within 6 months was defined as treatment failure and later disease as recurrence. RESULTS: Follow-up was available for 170 HIV-seropositive and 15 HIV-seronegative women. Treatment failed in 84 (45%) women (79 HIV seropositive and 5 HIV seronegative). Failure was more likely in women with lower CD4 counts (CD4 < 200 cells/microL: odds ratio [OR] = 2.96; 95% CI = 1.4-6.2) and detectable HPV DNA (OR 8.20; 95% CI = 1.8-37.4; p = .01). After successful treatment, recurrence-free probabilities at 1,2, 3, and 5 years were .79, .64, .49, and .34, respectively. HIV-seronegative women were less likely to recur than HIV-seropositive women (p = .03). In multivariable analysis of HIV-positive women, recurrence was more likely among women treated for CIN 2,3 (hazard ratio [HR] = 2.4; 95% CI = 1.4-4.8), those with CD4 count of less than 200 cells/microL (HR = 2.9; 95% CI = 1.3-6.5) and those with HPV after treatment (HR 2.9; 95% CI = 1.4-6.1); oncogenic HPV was more strongly associated with recurrence than nononcogenic HPV (p(trend) = .009). Most failures and recurrences were low grade, but one adenocarcinoma was diagnosed 4.2 years after therapy for CIN 1. CONCLUSION: Treatment failure and recurrence are common in women with HIV but are usually low grade.

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Nat Clin Pract Oncol. 2007 Apr;4(4):224-35.
Advances in primary and secondary interventions for cervical cancer: human papillomavirus prophylactic vaccines and testing.
Wheeler CM.
Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, House of Prevention Epidemiology, Building 191, 1816 Sigma Chi Road, Albuquerque, NM 87131, USA. cwheeler@salud.unm.edu

Cytologic screening has greatly reduced the incidence of invasive cervical cancer in many industrialized nations. State-of-the-art cervical cancer prevention is costly, however, and includes cytologic screening at repeat intervals, confirmation of abnormalities by colposcopic biopsy, and treatment of precancerous lesions. In resource-limited settings, accessibility to prevention programs for cervical cancer is often poor, or such programs are simply unavailable or inadequately supported. This disease, therefore, remains a leading form of cancer among women living in low-resource regions, and over 250,000 women worldwide die from cervical cancer each year. Persistent cervical infection with one of approximately 15 carcinogenic human papillomavirus (HPV) types causes virtually all invasive cervical cancer and its precursor abnormalities, which can be detected by cytologic screening. Genital HPV infections are primarily transmitted via sexual intercourse. One promising prophylactic HPV vaccine is available and others continue in development as primary cervical cancer prevention strategies in younger women. As secondary interventions, HPV tests are simultaneously evolving for use in cervical cancer screening programs, including routine screening of older women. HPV testing is more sensitive and reproducible than cytology with colposcopy for the detection of cervical precancer and cancer. This article presents current advances and perspectives on HPV vaccines and HPV testing.

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Isr Med Assoc J. 2007 Mar;9(3):156-8.
Human papillomavirus vaccine: the beginning of the end for cervical cancer.
Bornstein J.
Department of Obstetrics and Gynecology, Western Galilee Hospital, Nahariya, Israel mdjacob@gmail.com

The human papillomavirus family of viruses causes a variety of benign, premalignant and malignant lesions in men and women. All cervical cancers are caused by HPV. It is the leading cause of death from cancer in women in developing countries; every year some 493,000 women develop cervical cancer and 230,000 die every year from this disease. The vaccine against HPV includes virus-like particles, composed of the major viral capsid protein of HPV without the carcinogenic genetic core. Large-scale studies have shown that the vaccine is tolerated well, leads to high antibody levels in both men and women, and prevents chronic HPV infection and its associated diseases. To achieve effective coverage the vaccine should be given prior to sexual debut. Introduction of the vaccine into specific countries, particularly Israel, should take into account the local incidence of cervical cancer as well as the increasing incidence of precancerous cervical lesions and genital warts, which reduce quality of life and are associated with considerable costs.

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Int J Gynecol Cancer. 2007 Mar 13; [Epub ahead of print]
Current treatment options in uterine endometrial stromal sarcoma: report of a case and review of the literature.
Ihnen M, Mahner S, Janicke F, Schwarz J.
Klinik und Poliklinik fur Gynakologie, Universitatsklinikums Hamburg-Eppendorf, Hamburg, Germany.

Uterine sarcomas are a rare form of uterine cancer. They occur in women from 40 to 60 years and are generally characterized by poor prognosis, a high rate of local recurrence, and distant metastases. Endometrial stromal sarcoma (ESS) accounts for 0.2% of all gynecological malignancies. Forms of possible treatment include surgery, radiotherapy, chemotherapy, and endocrine treatment. Randomized trials analyzing these treatment options are limited due to the rarity of this disease; therefore, a standard therapy could not be established thus far. To present an overview of the current treatment options of ESS, a search of Medline, Embase, and the Cochrane Library was performed and the results concluded. We report the case of a 32-year-old woman who presented with FIGO stage II ESS. Initial treatment with tamoxifen and local perfusion with cisplatin resulted in disease progression and were discontinued. A novel, therapeutic approach using two cycles of combination chemotherapy with doxorubicin and ifosfamide followed by surgery was applied. Five years after surgery, the patient is still in complete remission. Thus, we conclude that although there is no data from randomized trials available, chemotherapy in advanced or metastatic ESS can provide an opportunity for surgical treatment and can lead to long-term remission.

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Obstet Gynecol. 2007 Mar;109(3):655-62.
Prognostic factors for uterine cancer in reproductive-aged women.
Lee NK, Cheung MK, Shin JY, Husain A, Teng NN, Berek JS, Kapp DS, Osann K, Chan JK.
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California 94143, USA.

OBJECTIVE: To determine the prognostic factors that influence the survival of younger women diagnosed with uterine cancer. METHODS: Demographic and clinico-pathologic data were collected from the National Cancer Institute database between 1988 and 2001. Data were analyzed with Kaplan-Meier methods and Cox proportional hazards regression. RESULTS: Of the 51,471 women diagnosed with uterine cancer in the study period, 2,076 (4.0%) patients were aged 40 years or younger, and 49,395 (96.0%) were older than 40. The mean age in the younger group was 35.6 years, compared with 65.2 years of the older group. The overall distribution by stage was stage I 75.4%, II 8.1%, III 6.7%, and IV 9.8%. Younger patients were more likely to be nonwhite (42.4% versus 18.3%, P<.001) and have stage I disease (79.2% versus 75.3%, P<.001), grade 1 lesions (47.6% versus 35.6%, P<.001), and sarcomas (15.9% versus 8.2%, P<.001) compared with their older counterparts. The overall 5-year disease-specific survival for younger patients was significantly better than that of older women (93.2% versus 86.4%, P<.001). On multivariable analysis, younger age, earlier stage, lower grade, nonblack race, endometrioid histology, and surgical treatment remained as significant independent prognostic factors for improved survival. CONCLUSION: This large population-based study demonstrates that patients 40 years and younger have an overall survival advantage compared with women older than 40 years, independent of other clinico-pathologic prognosticators. LEVEL OF EVIDENCE: III.

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Int J Gynecol Cancer. 2007 Jan-Feb;17(1):215-9.
Early-stage carcinosarcoma of the uterus: the significance of lymph node count.
Temkin SM, Hellmann M, Lee YC, Abulafia O.
Division of Gynecologic Oncology, SUNY, State University of New York-Downstate, 450 Clarkson Avenue, Brooklyn, NY 11203, USA. sarah.temkin@gmail.com

Carcinosarcoma is a rare tumor of the uterus with a poor prognosis, even when identified and treated at an early stage. The purpose of this study was to identify and analyze prognostic pathologic features and treatment outcomes in patient with stages I and II carcinosarcoma of the uterus. Patients with carcinosarcoma of the uterus who received primary surgical treatment between 1984 and 2004 were identified through an institutional tumor registry. Inclusion criteria were clinical stage I/II disease following hysterectomy and selective pelvic and para-aortic lymph node sampling. Regression analysis was used to determine risk factors for recurrence and survival. Disease-free and overall survival were then determined using Kaplan-Meier analysis. Forty-seven patients with stages I and II carcinosarcoma of the uterus were identified. Age, heterologous or homologous histology, and type of adjuvant treatment were not associated with recurrence or survival. Depth of myometrial invasion was found to correlate to disease-free survival but not overall survival. The number of lymph nodes collected correlated to risk of recurrence and survival. Disease-free and overall survival were greater in patients with higher lymph node count. We conclude that the number of lymph nodes collected was the only risk factor that was found to be correlated to recurrence and survival in patients with early-stage carcinosarcoma. These results support mounting evidence that lymphadenectomy is crucial in patients with carcinomas of the uterus in order to discover occult metastatic disease and potentially provide patients with a therapeutic benefit.

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Int J Gynecol Cancer. 2007 Jan-Feb;17(1):137-40.
Resection of recurrent cervical cancer after total pelvic exenteration.
Mourton SM, Sonoda Y, Abu-Rustum NR, Bochner BH, Barakat RR, Chi DS.
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

The objective of this study was to describe the management of patients with recurrent cervical cancer after total pelvic exenteration (TPE). We reviewed the records of patients who underwent TPE for recurrent cervical cancer between June 1992 and December 2003 and subsequently developed recurrent disease. Thirty-seven patients underwent TPE during the study period, and 25 (68%) subsequently developed recurrence proven by radiographic and/or biopsy studies. Recurrence sites included pelvic (12), inguinal (5), retroperitoneal (5), hepatic (4), vulva (2), perineum (1), transposed ovary (1), and lung (1). The median time to recurrence was 7 months (range 2-73 months), with 92% (23/25) occurring within 2 years of TPE. Management of recurrence was known in 21 of 25 patients, which included chemotherapy (10), surgical resection (7), and no further treatment (4). Surgically resected recurrences were isolated to the groin (2), vulva (2), perineum (1), transposed ovary (1), and psoas muscle (1). The four patients who underwent ovarian, perineal, and vulvar resections succumbed to their disease in a median time of 13 months (range 2-21 months). Of the two patients with surgically resected groin recurrences, one is alive with disease 21 months after initial recurrence and the other is alive without evidence of disease 85 months later. One patient had an isolated 4-cm recurrence involving the psoas muscle and the femoral nerve and is without the evidence of disease 9 months later. Resection of isolated recurrences after TPE is a reasonable option in selected patients, particularly in those with solitary inguinal metastases.

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Cancer Res. 2006 Nov 1;66(21):10229-32.
Prospects for cervical cancer prevention by human papillomavirus vaccination.
Schiller JT, Lowy DR.
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. schillej@dc37a.nci.nih.gov

Recent clinical trials in young women have shown that subunit vaccines based on human papillomavirus (HPV) 16 and HPV18 L1 virus-like particles are approximately 100% effective in short-term prevention of persistent cervical infection and of cervical dysplasia by these major oncogenic types. These remarkable efficacy results, together with an excellent safety profile in thousands of vaccinated women, have led to the HPV prophylactic vaccine from one manufacturer having now been licensed for commercial use and the expectation that the vaccine from a second manufacturer will be approved in the near future. These vaccines seem to have great potential for reducing cervical cancer deaths and treatments to remove premalignant cervical lesions. However, before their public health effect can be fully estimated, several issues must be addressed. These include duration of protection, degree of cross-protection against nonvaccine types, efficacy in men, and vaccine availability to economically disadvantaged women.

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Expert Opin Biol Ther. 2006 Nov;6(11):1223-7.
HPV vaccination with Gardasil: a breakthrough in women's health.
Hanna E, Bachmann G.
Women's Health Institute, UMDNJ-Robert Wood Johnson Medical School, 125 Paterson Street, Cab 2104, New Brunswick, New Jersey 08901, USA.

Human papillomavirus (HPV) represents one of the most common sexually transmitted infections. Although infection is often self-limited, a percentage of women with HPV infection will go on to develop cervical precancerous or cancerous lesions. It is estimated that HPV16 is responsible for approximately half of all cervical cancers worldwide. Several studies have tested vaccines directed against specific HPV types, namely types 6, 11, 16 and 18. This paper reviews these studies, particularly focusing on a quadrivalent (type 6, 11, 16 and 18) HPV L1 virus-like particle vaccine under investigation in Phase III trials at present. Data indicate that this vaccine, referred to as Gardasil, can prevent precancerous cervical lesions and early in situ cervical cancers with few adverse effects, and the vaccine has been approved by the FDA for this indication. Another vaccine, HPV16 L1, directed solely against HPV16, has also been demonstrated to be effective (at present, follow-up has been for up to 48 months) in providing protection against persistent infection with this viral strain and preventing HPV16-related cervical intraepithelial neoplasia 2/3, while producing minimal adverse effects in recipients. Given the lack of a pharmacological intervention that can eradicate HPV in infected individuals and the prevalence of cervical cancer secondary to HPV infection across the world, the HPV vaccine represents a significant breakthrough in women's health.

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Oncology (Williston Park). 2006 Oct;20(11):1401-4, 1410; discussion 1410-11, 1415-6.
Topotecan in combination with cisplatin for the treatment of stage IVB, recurrent, or persistent cervical cancer.
Brave M, Dagher R, Farrell A, Abraham S, Ramchandani R, Gobburu J, Booth B, Jiang X, Sridhara R, Justice R, Pazdur R.
Office of Oncology Drug Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993, USA. michael.brave@fda.hhs.gov

PURPOSE: Topotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval. EXPERIMENTAL DESIGN: In a randomized multicenter study enrolling 293 eligible patients, topotecan plus cisplatin (TC) was compared with cisplatin monotherapy. The TC regimen consisted of cisplatin 50 mg/m2 IV over 1 hour on day 1 and topotecan 0.75 mg/m2 IV over 30 minutes on days 1, 2, and 3 every 21 days. RESULTS: There was a clinically relevant and statistically significant improvement in overall survival in the TC treatment arm. Median overall survival was 9.4 months (95% confidence interval [CI]:7.9-11.9) in the TC arm, compared to 6.5 months (95% CI:5.8-8.8) with cisplatin alone. The unadjusted hazard ratio for overall survival between treatment arms was 0.76 (95% CI: 0.59-0.98, P = .033) favoring the combination arm. The most common toxicities with TC included myelosuppression, nausea and vomiting, mucositis, rash, and hepatotoxicity. CONCLUSIONS: This report describes the FDA's review supporting this first approval of a chemotherapeutic drug for advanced cervical cancer based on demonstration of a survival benefit.

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Cleve Clin J Med. 2006 Oct;73(10):929-35.
Using the new HPV vaccines in clinical practice.
Widdice LE, Kahn JA.
Division of Adolescent Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. lea.widdice@cchmc.org

Gardasil, a vaccine against human papillomavirus (HPV), recently became available in the United States for use in girls and women 9 to 26 years of age. A second HPV vaccine, Cervarix, is under development. These vaccines constitute the most significant development in cervical cancer prevention in the last 60 years, having the potential to reduce the incidence of cervical cancer by up to 70%

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Int J Gynecol Cancer. 2006 Sep-Oct;16(5):1927-32.
Laparoscopically assisted radical vaginal hysterectomy (Coelio-Schauta): A comparison with open Wertheim/Meigs hysterectomy.
Sharma R, Bailey J, Anderson R, Murdoch J.
Department of Gynaecology, St. Michaels Hospital, United Bristol Healthcare Trust, Bristol, England.

The objective of this study was to compare the safety, efficacy, and short-term benefits of the Coelio-Schauta procedure with open Wertheim/Meigs radical abdominal hysterectomy. We retrospectively analyzed records of our first 35 consecutive patients undergoing laparoscopically assisted radical vaginal hysterectomy (LARVH) for early cervical cancer and 32 consecutive patients of open radical hysterectomy (ORH) performed between 1999 and 2005 in our institution. We analyzed patient age, bodyweight, previous abdominal surgery, operating time, blood loss, perioperative complications, postoperative bladder dysfunction, other postoperative complications, and histologic type. The FIGO stage, excision margins, node count and node status, follow-up, and recurrence rates were also taken into account. We excluded stage IA and stage II disease patients to reduce the impact of tumor size on the outcome of the surgery. This left 27 patients with stage IIB disease who had LARVH and 28 patients with stage IB disease who had ORH. These patients formed the study group. The cohorts were similar in age, bodyweight, previous abdominal surgery, histologic subtype, FIGO stage, resection margins, node count and node status, length of follow-up, and recurrence. There were statistically significant differences between LARVH and ORH for duration of surgery (mean 160 vs 132 min), intraoperative blood loss (479 vs 715 mL), hospital stay (mean 5 vs 9.3 days), postoperative complications (6 vs 20 patients), and duration of bladder catheterization (mean 4.4 vs 8.8 days). Four LARVH patients and no ORH patients had urinary tract injury that was repaired. None had long-term sequelae. Our data confirm that LARVH is a suitable alternative to ORH hysterectomy for small-volume stage IB1 cervical cancer with similar clinical efficacy and a superior postoperative recovery and postoperative morbidity profile. Urinary tract trauma is a clear risk in the early stages of the learning curve.

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Int J Gynecol Cancer. 2006 Sep-Oct;16(5):1855-61.
Erythropoietin administration during primary treatment for locally advanced cervical carcinoma is associated with poor response to radiation.
Temkin SM, Hellmann M, Serur E, Lee YC, Abulafia O.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, SUNY Downstate Medical Center, Brooklyn, New York 11203, USA. sarah.temkin@gmail.com

The purpose of this study was to determine whether the use of recombinant erythropoietin (r-EPO) during treatment for locally invasive carcinoma of the cervix affects recurrence rates, disease-free survival, and overall survival. Retrospective analysis of outcomes of patients with locally advanced cervical cancer treated with radiation and concurrent chemotherapy between January 1997 and July 2004 was performed. Recurrence rates, disease-free survival, and overall survival were calculated using SPSS statistical software. Throughout P < 0.05 was considered significant. Of 68 patients included in this study, 18 patients received erythropoietin during treatment and 50 did not. Patient age, stage, hemoglobin at presentation, and average weekly hemoglobin (AWH) were similar in both groups of patients. The recurrence rate among patients who received r-EPO was 61% compared with 30% among patients who did not receive r-EPO (P = 0.014). Eight of 18 patients (44%) who received r-EPO were alive at last known follow-up compared to 36 of 50 (72%) who did not receive the medication (P = 0.045). Disease-free survival and overall survival were significantly shorter in patients who received r-EPO during treatment (P = 0.028, 0.032). The administration of r-EPO during primary treatment of patients with locally advanced cervical cancer is associated with increased recurrence rate, increased risk of death due to disease, and decreased disease-free and overall survivals.

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Int J Gynecol Cancer. 2006 Sep-Oct;16(5):1839-45.
Pattern of failure and long-term morbidity in patients undergoing postoperative radiotherapy for cervical cancer.
Jain P, Hunter RD, Livsey JE, Coyle C, Kitchener HC, Swindell R, Davidson SE.
Department of Clinical Oncology, Christie Hospital, Manchester, United Kingdom. pooja.jain@christie-tr.nwest.nhs.uk

The objective of this study was to assess treatment outcomes in a large case series of cervical cancer patients undergoing postoperative radiotherapy in a single center. Case notes of women referred to the Christie Hospital during 1985-1997 for postoperative adjuvant radiotherapy for cervical cancer were reviewed. Of 478 women eligible for analysis, 282 (58.9%) underwent radical hysterectomy and 196 (41.1%) had nonradical hysterectomy. The disease-specific 5-year survival for the study population is 70.1%, with a 5-year risk of developing any recurrence of 30.5% and a 5-year grade 3 morbidity rate of 3.9%. Survival was significantly higher, ie, 80.9% vs 62.7% (P = 0.0001) and recurrence was significantly lower, ie, 18.6% vs 38.8% (P < 0.00005) in the group of women who had adjuvant radiotherapy following a nonradical hysterectomy compared with radical surgery. Thirty percent of women having "radical" surgery had positive resection margins and required postoperative adjuvant pelvic radiotherapy. Women with node-positive disease, who received adjuvant radiotherapy, had a high rate of distant metastases. These women would receive chemoradiotherapy now as primary treatment because of the risk of developing distant metastases. If, despite staging investigations, surgery reveals node-positive disease, then these women should receive adjuvant chemoradiotherapy. Survival was better in women who had nonradical surgery due to smaller volume disease when cancers were unsuspected and hence will have been cured by surgery alone. Multidisciplinary team working, as recommended by national guidelines from 1999, should allow better patient selection for treatment.
  
Previous Uterine Cancer Research: 2002-2006   
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