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The effects of metformin on ovarian cancer: a systematic review

Dilokthornsakul P, Chaiyakunapruk N, Termrungruanglert W, Pratoomsoot C, Saokaew S, Sruamsiri R

Int. J. Gynecol. Cancer, 2013 Nov;23(9):1544-51.
PMID: 24172091 DOI: 10.1097/IGC.0b013e3182a80a21

OBJECTIVE: The potential therapeutic effects of metformin on several cancers were reported. However, the evidence of the effects of metformin on ovarian cancer is still limited and inconclusive. This systematic review and meta-analysis study aim to summarize the existing evidence of the therapeutic effects of metformin on ovarian cancer.
METHODS: We performed systematic searches using electronic databases including PubMed and EMBASE until December 2012. Key words included "metformin" AND ("ovarian cancer" OR "ovary tumor"). All human studies assessing the effects of metformin on ovarian cancer were eligible for inclusion. All articles were reviewed independently by 2 authors with a standardized approach for the purpose of study, study design, patient characteristics, exposure, and outcomes. The data were pooled using a random-effects model.
RESULTS: Of 190 studies retrieved, only 3 observational studies and 1 report of 2 randomized controlled trials were included. Among those studies, 2 reported the effects of metformin on survival outcomes of ovarian cancer, whereas the other 2 reported the effects of metformin on ovarian cancer prevention. The findings of studies reporting the effects on survival outcomes indicated that metformin may prolong overall, disease-specific, and progression-free survival in ovarian cancer patients. The results of studies reporting the effects of metformin on ovarian cancer prevention were meta-analyzed. It indicated that metformin tended to decrease occurrence of ovarian cancer among diabetic patients with the pooled odds ratio of 0.57 (95% confidence interval, 0.16-1.99).
CONCLUSIONS: Our findings showed the potential therapeutic effects of metformin on survival outcomes of ovarian cancer and ovarian cancer prevention. However, most of the evidence was observational studies. There is a call for further well-conducted controlled clinical trials to confirm the effects of metformin on ovarian cancer survival and ovarian cancer prevention.
Gestational trophoblastic neoplasia and human immunodeficiency virus infection: a 10-year review

Tayib S, van Wijk L, Denny L

Int. J. Gynecol. Cancer, 2011 Dec;21(9):1684-91.
PMID: 21997172 DOI: 10.1097/IGC.0b013e31822d8ffd

OBJECTIVES: The objective of the study was to describe the management of gestational trophoblastic neoplasia (GTN), with particular reference to concurrent human immunodeficiency virus (HIV) infection.
METHODS: This retrospective descriptive study comprised all cases of GTN managed at Groote Schuur Hospital over a 10-year period (1999-2008).
RESULTS: Seventy-six patients, with a median age of 30 years at presentation, were included in the study. Only 36 patients (47.4%) had known HIV status. Fourteen (18.4%) were HIV positive, and of these, 4 (28.6%) were on antiretroviral treatment (ARV). The mean CD4 count was 142 cells/μL for those on ARV and 543 cells/μL for those not on ARV (P = 0.001). Histologically, 44 patients (58%) had hydatidiform mole, and 21 (28%) had choriocarcinoma. In the remaining 10 cases, a clinical diagnosis was made. Based on the revised International Federation of Gynecology and Obstetrics (FIGO)/modified World Health Organization scoring, 43 patients (56.6%) were low risk, and 33 (43.4%) were high risk. Thirty-eight patients (50%) were staged as FIGO stage I. Of 73 patients who received chemotherapy, 56 (76.7%) achieved complete remission, 9 (12.3%) did not achieve any remission, 7 (9.6%) had a relapse, and 1 (1.4%) was lost to follow-up. Patients who never went into remission had frequent treatment delays due to poor compliance or inadequate blood counts. The overall survival at 60 months was 81.9%. Of the 13 patients (17.1%) who have died, 5 (38.5%) were HIV positive. The overall 5-year survival rates for FIGO stages I, II, III, and IV were 97.4%, 66.7%, 77.8%, and 46.2%, respectively. The overall 5-year survival for HIV-positive patients was 64.3% versus more than 85% for both the HIV-negative and HIV-unknown groups.
CONCLUSIONS: Apart from more advanced stage, HIV seropositivity and poor compliance with treatment also portend poorer outcome in GTN patients. In HIV-positive patients with poor CD4, little clarity is available whether ARV should be commenced speedily, and the administration of chemotherapy delayed until immune reconstitution occurs.
Gene expression profiling and cancer-related pathways in type I endometrial carcinoma

Saghir FS, Rose IM, Dali AZ, Shamsuddin Z, Jamal AR, Mokhtar NM

Int. J. Gynecol. Cancer, 2010 Jul;20(5):724-31.
PMID: 20973258

INTRODUCTION: Malignant transformation of type I endometrium involves alteration in gene expression with subsequent uncontrolled proliferation of altered cells.
OBJECTIVE: The main objective of the present study was to identify the cancer-related genes and gene pathways in the endometrium of healthy and cancer patients.
MATERIALS AND METHODS: Thirty endometrial tissues from healthy and type I EC patients were subjected to total RNA isolation. The RNA samples with good integrity number were hybridized to a new version of Affymetrix Human Genome GeneChip 1.0 ST array. We analyzed the results using the GeneSpring 9.0 GX and the Pathway Studio 6.1 software. For validation assay, quantitative real-time polymerase chain reaction was used to analyze 4 selected genes in normal and EC tissue.
RESULTS: Of the 28,869 genes profiled, we identified 621 differentially expressed genes (2-fold) in the normal tissue and the tumor. Among these genes, 146 were up-regulated and 476 were down-regulated in the tumor as compared with the normal tissue (P < 0.001). Up-regulated genes included the v-erb-a erythroblastic leukemia viral oncogene homolog 3 (ErbB3), ErbB4, E74-like factor 3 (ELF3), and chemokine ligand 17 (CXCL17). The down-regulated genes included signal transducer and activator transcription 5B (STAT5b), transforming growth factor A receptor III (TGFA3), caveolin 1 (CAV1), and protein kinase C alpha (PKCA). The gene set enrichment analysis showed 10 significant gene sets with related genes (P < 0.05). The quantitative polymerase chain reaction of 4 selected genes using similar RNA confirmed the microarray results (P < 0.05).
CONCLUSIONS: Identification of molecular pathways with their genes related to type I EC contribute to the understanding of pathophysiology of this cancer, probably leading to identifying potential biomarkers of the cancer.
Combination of zerumbone and cisplatin to treat cervical intraepithelial neoplasia in female BALB/c mice

Abdul AB, Abdelwahab SI, Bin Jalinas J, Al-Zubairi AS, Taha MM

Int. J. Gynecol. Cancer, 2009 Aug;19(6):1004-10.
PMID: 19820360 DOI: 10.1111/IGC.0b013e3181a83b51

Recent in vitro and in vivo studies have demonstrated that zerumbone (ZER) possesses anticancer properties. The main objective of this study was to examine the effectiveness of the combination of ZER and cisplatin (CIS) to treat cervical intraepithelial neoplasia (CIN) in vivo. Microculture tetrazolium assay and immunohistochemistry of proliferating cellular nuclear antigen were used to study the antitumor effect of ZER. Prenatally exposed female BALB/c mice were used as a model. The progenies with CIN were injected peritoneally with isotonic sodium chloride solution (positive control), CIS, ZER, and a combination of both compounds. All treated and untreated mice were humanely killed, and serum and cervix were obtained for interleukin 6 analysis and histopathologic studies using hematoxylin and eosin staining, respectively. Zerumbone has revealed an antitumor effect on human cervical cancer cells and downregulates immunoexpression of proliferating cellular nuclear antigen (P < 0.05). In vivo study indicates that ZER at 16 mg/kg and CIS at 10 mg/kg have a regressing effect on CIN. The combination of ZER and CIS also showed similar effectiveness in regressing CIN. Our results indicate that the combination of ZER and CIS has modulated the serum level of interleukin 6 when compared with that in mice treated with isotonic sodium chloride solution (P < 0.05). The effectiveness of combining ZER and CIS could be further explored as a new therapeutic intervention of early precancerous stages of carcinogenesis before the invasive stage begins.
Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical intraepithelial neoplasia across 5 countries in Asia

Quek SC, Lim BK, Domingo E, Soon R, Park JS, Vu TN, et al.

Int. J. Gynecol. Cancer, 2013 Jan;23(1):148-56.
PMID: 23221730 DOI: 10.1097/IGC.0b013e31827670fd

OBJECTIVE: Independent, prospective, multicenter, hospital-based cross-sectional studies were conducted across 5 countries in Asia, namely, Malaysia, Vietnam, Singapore, South Korea, and the Philippines. The objectives of these studies were to evaluate the prevalence of human papillomavirus (HPV) types (high risk and others including coinfections) in women with invasive cervical cancer (ICC) and high-grade precancerous lesions.
METHODS: Women older than 21 years with a histologic diagnosis of ICC and cervical intraepithelial neoplasia [CIN 2 or 3 and adenocarcinoma in situ (AIS)] were enrolled. Cervical specimens were reviewed by histopathologists to confirm the presence of ICC or CIN 2/3/AIS lesion and tested with short PCR fragment 10-DNA enzyme immunoassay-line probe assay for 14 oncogenic HPV types and 11 non-oncogenic HPV types. The prevalence of HPV 16, HPV 18, and other high-risk HPV types in ICC [including squamous cell carcinoma (SCC) and adenocarcinoma/adenosquamous carcinoma (ADC/ASC)] and CIN 2/3/AIS was estimated.
RESULTS: In the 5 Asian countries, diagnosis of ICC was confirmed in 500 women [SCC (n = 392) and ADC/ASC (n = 108)], and CIN 2/3/AIS, in 411 women. Human papillomavirus DNA was detected in 93.8% to 97.0% (84.5% for the Philippines) of confirmed ICC cases [94.0%-98.7% of SCC; 87.0%-94.3% (50.0% for the Philippines) of ADC/ASC] and in 93.7% to 100.0% of CIN 2/3/AIS. The most common types observed among ICC cases were HPV 16 (36.8%-61.3%), HPV 18 (12.9%-35.4%), HPV 52 (5.4%-10.3%), and HPV 45 (1.5%-17.2%), whereas among CIN 2/3/AIS cases, HPV 16 (29.7%-46.6%) was the most commonly observed type followed by HPV 52 (17.0%-66.7%) and HPV 58 (8.6%-16.0%).
CONCLUSIONS: This article presents the data on the HPV prevalence, HPV type distribution, and their role in cervical carcinogenesis in 5 Asian countries. These data are of relevance to public health authorities for evaluating the existing and future cervical cancer prevention strategies including HPV-DNA testing-based screening and HPV vaccination in these Asian populations.
Radical hysterectomy and pelvic lymphadenectomy for early invasive cancer of the cervix - 14-year experience

Sivanesaratnam V, Sen DK, Jayalakshmi P, Ong G

Int. J. Gynecol. Cancer, 1993 Jul;3(4):231-238.
PMID: 11578351

During a 14-year period, 397 radical hysterectomies and pelvic lymphadenectomies were performed for early invasive carcinoma of the cervix. Twenty-one patients were in stage IA2 with lymphatic/vascular channel permeation (5.2%), 340 in stage IB (85.6%) and 34 in early stage 2A disease (8.5%). Eighteen patients (4.5%) were pregnant. Adenocarcinoma comprised 26.9% of cases. The mean operative time was 4.14 h; the intraoperative blood loss was less than 1.51 in 77.3% patients. There was no operative mortality; one patient died 3 weeks after surgery from clostridium difficile enterocilitis. Eleven patients (2.7%) developed venous thrombosis; severe lymphedema occurred in four (1%). The incidence of uretero-vaginal fistula was 0.2% and that of vesico-vaginal fistula 0.5%. Ovarian metastases were noted in 4.3% of cases with adenocarcinoma. Sixty-six patients had positive nodes (16.6%). Five-year survival in patients with more than 2 positive nodes was 68%. The use of adjuvant chemotherapy in patients with 'high risk' factors resulted in survival rates approaching those without risk factors. Neo-adjuvant chemotherapy was used in 10 patients with large bulky tumors; the results were favorable. Recurrences occurred in 47 patients (11.8%); 36 patients have died (9.1%). Age did not appear to influence survival. The overall 5-year survival was 92.2%.
Cervix Cancer Research Network (CCRN): Improving Access to Cervix Cancer Trials on a Global Scale

Gaffney D, Small B, Kitchener H, Young Ryu S, Viswanathan A, Trimble T, et al.

Int. J. Gynecol. Cancer, 2016 Nov;26(9):1690-1693.
PMID: 30814204 DOI: 10.1097/IGC.0000000000000823

Eighty-seven percent of cervix cancer occurs in less-developed regions of the world, and there is up to an 18-fold difference in mortality rate for cervix cancer depending on the region of the world. The Cervix Cancer Research Network (CCRN) was founded through the Gynecologic Cancer InterGroup with the aim of improving access to clinical trials in cervix cancer worldwide, and in so doing improving standards of care. The CCRN recently held its first international educational symposium in Bangkok. Sixty-two participants attended from 16 different countries including Pakistan, India, Bangladesh, Thailand, Malaysia, Singapore, Philippines, Taiwan, China, Vietnam, Korea, Japan, Columbia, Brazil, Canada, and the United States. The focus of this symposium was to evaluate progress, to promote new clinical trials for the CCRN, and to provide education regarding the role of brachytherapy in the treatment of cervical cancer.
Cervix Cancer Research Network (CCRN): Improving Access to Cervix Cancer Trials on a Global Scale

Gaffney D, Small B, Kitchener H, Young Ryu S, Viswanathan A, Trimble T, et al.

Int. J. Gynecol. Cancer, 2016 11;26(9):1690-1693.
PMID: 27779548

Eighty-seven percent of cervix cancer occurs in less-developed regions of the world, and there is up to an 18-fold difference in mortality rate for cervix cancer depending on the region of the world. The Cervix Cancer Research Network (CCRN) was founded through the Gynecologic Cancer InterGroup with the aim of improving access to clinical trials in cervix cancer worldwide, and in so doing improving standards of care. The CCRN recently held its first international educational symposium in Bangkok. Sixty-two participants attended from 16 different countries including Pakistan, India, Bangladesh, Thailand, Malaysia, Singapore, Philippines, Taiwan, China, Vietnam, Korea, Japan, Columbia, Brazil, Canada, and the United States. The focus of this symposium was to evaluate progress, to promote new clinical trials for the CCRN, and to provide education regarding the role of brachytherapy in the treatment of cervical cancer.
Persuasive messaging for human papillomavirus vaccination by adolescent providers in a five-country multi-site study

Rwamwejo J, Ramos S, Morgan K, Richter K, Kim CJ, Peris M, et al.

Int. J. Gynecol. Cancer, 2019 02;29(2):250-256.
PMID: 30718309 DOI: 10.1136/ijgc-2018-000004

OBJECTIVE: Strong persuasive messaging by providers is a key predictor for patient acceptance of prophylactic human papillomavirus vaccination. We aimed to determine optimal messaging to promote human papillomavirus adolescent vaccination across different geographical sites.
METHODS: Adolescent providers (n = 151) from Argentina, Malaysia, South Africa, South Korea, and Spain were surveyed on messages, family decision makers, and sources of communication to best motivate parents to vaccinate their adolescent daughters overall, and against human papillomavirus. Multivariate logistic regression assessed the likelihood of recommending messages specifically targeted at cervical cancer with providers' characteristics: gender, medical specialization, and previous administration of human papillomavirus vaccination.
RESULTS: Mothers were considered the most important human papillomavirus vaccination decision makers for their daughters (range 93%-100%). Television was cited as the best source of information on human papillomavirus vaccination in surveyed countries (range 56.5%-87.1%), except Spain where one-on-one discussions were most common (73.3%). Prevention messages were considered the most likely to motivate parents to vaccinate their daughters overall, and against human papillomavirus, in all five countries (range 30.8%-55.9%). Optimal messages emphasized cervical cancer prevention, and included strong provider recommendation to vaccinate, vaccine safety and efficacy, timely vaccination, and national policy for human papillomavirus vaccination. Pediatricians and obstetricians/gynecologists were more likely to cite that the best prevention messages should focus on cervical cancer (OR: 4.2, 95% CI: 1.17 to 15.02 vs other medical specialists).
CONCLUSIONS: Provider communication messages that would motivate parents to vaccinate against human papillomavirus were based on strong recommendation emphasizing prevention of cervical cancer. To frame convincing messages to increase vaccination uptake, adolescent providers should receive updated training on human papillomavirus and associated cancers, while clearly addressing human papillomavirus vaccination safety and efficacy.