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Cervical cancer (CC) is one of the most common gynecological tumors and an important health problem, especially in developing countries. The vast majority of patients in early stages are cured of the disease with surgical treatment and with concomitant chemoradiotherapy in locally advanced stages. However, in patients with recurrent, persistent, or metastatic cervical CC, the effectiveness of treatment is limited, except for the combination of chemotherapy based on platinum doublets plus bevacizumab, the treatment that has achieved the best results to date. Programmed cell death-1/PD ligand-1 (PD-1/PD-L1) inhibitors could be a novel and cutting-edge therapeutic option to improve clinical outcomes in this group of patients. Thus far, there are a few Phase I/II clinical trials that have assessed the usefulness of pembrolizumab and nivolumab in this group of patients; these include the KEYNOTE 028, KEYNOTE 158, and CHECKMATE 358 trials, in which clinical benefit has been proven with PD-1/PD-L1 inhibitors in recurrent, persistent, or metastatic CC, as second-line treatment. There are also some ongoing trials that could provide further evidence on the PD-1/PD-L1 pathway as a therapeutic target in CC. In this review, we will focus on the usefulness of these PD-1/PDL1 inhibitors in CC, as well as on trials that are still in the recruitment phase, to confirm their effectiveness in this clinical setting., (Copyright: © 2020 Permanyer.)

Purpose of Review: Recent peer-reviewed publications on the treatment of early, locally advanced and advanced cervical cancer patients are reviewed to gain insight into the main research done in the field., Recent Findings: In early-stage patients where cure is offered to most patients, research focuses on more conservative or less morbid approaches to increase quality of life and reduce the treatment-related sexual dysfunction. No major advances have occurred for treating locally advanced disease since the introduction of concurrent chemoradiation, but efforts are directed to increase efficacy while reducing toxicity with the use of combination chemoradiation and modern radiation technologies. Molecular-targeted therapy and identification of targetable gene alterations as well as immunotherapy are actively pursued in patients with advanced disease., Summary: Although global statistics indicate a trend for decreased age-standardized incidence rates, social and economical factors impede the uptake of therapeutic advances achieved as many patients have no access even to basic resources for treating cancer. The adherence to quality indicators in delivery of optimized standard concurrent chemoradiation and adherence to guidelines in cervical cancer surgery must not be underestimated. Major efforts are needed in both the scientific and social aspects of cervical cancer treatment to reduce mortality.

Introduction: The treatment of some early-stage and most locally advanced disease cervical cancer patients consists of concurrent chemoradiation, while almost all with advanced disease require palliative chemotherapy., Areas Covered: This review is aimed to analyze the safety issues emerging from trials of chemoradiation for early-stage high-risk disease and locally advanced stages, as well as safety issues of trials of palliative chemotherapy for advanced disease. Safety issues on fertility preservation are also discussed., Expert Opinion: Cisplatin chemoradiation produces higher toxicity as compared to radiation alone, yet it is well-tolerated. Further advances would require (i) the development of more effective and tolerated combination chemoradiation regimens, (ii) demonstration of the efficacy and tolerability of adjuvant chemotherapy after cisplatin chemoradiation, and (iii) incorporation of targeted therapies into radiosensitizing regimens. A major problem continues to be the population of patients with advanced disease. The recent incorporation of bevacizumab into chemotherapy regimens represents a step forward; however, toxicity as well as economic issues may impede its wide acceptance worldwide. Preserving fertility in young women with cervical cancer is an issue that must be fully addressed. In this setting, neoadjuvant chemotherapy seems to increase fertlity rate without compromising oncological outcomes.

Introduction: Worldwide, most cervical cancer (CC) patients require the use of drug therapy either adjuvant, concurrent with radiation or palliative., Areas Covered: This review briefly discusses the current achievements in treating CC with an emphasis in emerging agents., Expert Opinion: Concurrent cisplatin with radiation and lately, gemcitabine-cisplatin chemoradiation has resulted in small but significant improvements in the treatment of locally advanced and high-risk early-stage patients. So far, only antiangiogenic therapy with bevacizumab added to cisplatin chemoradiation has demonstrated safety and encouraging results in a Phase II study. In advanced disease, cisplatin doublets yield median survival rates not exceeding 14 months. The first Phase III study of bevacizumab, added to standard chemotherapy cisplatin- or non-cisplatin-containing doublet, has shown significant increase in both overall survival and progression-free survival. Further studies are needed before bevacizumab plus chemotherapy can be considered the standard of care for advanced disease. The characterization of the mutational landscape of CC and developments of novel targeted therapies may result in more effective and individualized treatments for CC. The potential efficacy of knocking down the key alterations in CC, E6 and E7 human papilloma virus oncoproteins must not be overlooked.

Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that has been evaluated in solid tumors as a single agent or in combination with chemotherapy and radiation. Cervical cancer patients who are refractory or progressive to first-line chemotherapy have a dismal prognosis, and no second- or third-line chemotherapy is considered standard. This pilot trial aimed to evaluate the efficacy and safety of nimotuzumab in 17 patients with pre-treated advanced refractory or progressive cervical cancer. Nimotuzumab was administered weekly at 200 mg/m(2) as single agent for 4 weeks (induction phase), then concurrent with 6 21-day cycles of gemcitabine (800 mg/m(2)) or cisplatin (50 mg/m(2)) for 18 weeks (concurrent phase) and then once every 2 weeks (maintenance phase). Nimotuzumab could be continued beyond disease progression. Seventeen patients were accrued and evaluated for safety and efficacy. The median number of nimotuzumab applications was 20 (5-96). The median number of chemotherapy cycles administered was 6 (1-6). No toxicity occurred during induction and maintenance phases (single agent nimotuzumab). In the concurrent phase, grade 3 toxicity events observed were leucopenia, anemia and diarrhea in 11.7%, 5.8% and 11.7% respectively. No complete or partial responses were observed. The stable disease (SD) rate was 35%. The median PFS and OS rates were 163 days (95% CI, 104 to 222), and 299 days (95% IC, 177 to 421) respectively. Nimotuzumab is well tolerated and may have a role in the treatment of advanced cervical cancer.

Purpose: To evaluate the radiosensitizing effects of the DNA methylation inhibitor hydralazine in combination with valproic acid, a histone deacetylase inhibitor in cervical cancer cells., Materials and Methods: Cell viability assays were performed in the SiHa cervical cancer cell line treated with hydralazine and valproic acid for five days with and without cisplatin. Cell irradiation was performed using teletherapy (1.25 MV)., Results: Neither hydralazine, valproic acid or cisplatin as single agents increased the cytotoxicity from radiation, however, the combination of hydralazine with valproic acid at ten microM and one mM, respectively, did induce radiosensitization (p = 0.046). Interestingly, this effect was further increased with the triple combination of hydralazine, valproic acid, and cisplatin (p = 0.041), where cell viability decreased more than 50% as compared to radiation alone., Conclusions: The present results demonstrate that epigenetic drugs increase the efficacy of cisplatin chemoradiation in cervical cancer cells.

Background: The aim of the present study was to demonstrate that radical hysterectomy (RH) leads to improved survival outcomes in FIGO stage IB2-IIB cervical cancer when compared with standard brachytherapy (BCT) after identical external beam chemoradiation (EBRT-CT)., Patients and Methods: EBRT-CT treatment consisted of six courses of cisplatin at 40 mg/m² and gemcitabine at 125 mg/m² per week concurrent with 50.4 Gy of radiation. In the BCT arm, EBRT-CT was followed by BCT to reach a point A dose of 85 Gy, whereas in the experimental arm, a type III RH with bilateral pelvic lymph node dissection and para-aortic lymph node sampling (RH) was carried out within 4-6 weeks after EBRT-CT., Results: Between May 2004 and June 2009, 211 patients were enrolled (BCT, 100 and RH, 111). At a median follow-up time of 36 months (3-80), progression-free survival (PFS) and overall survival (OS) rates were similar in both the arms. PFS rates were 74.8% and 71.7% in the BCT and RH arms [HR 0.6516 (95% confidence interval (CI) 0.3504-1.2116)], P = 0.186. OS rates were 76.3% in the BCT versus 74.5% in the surgical arm [HR 0.6981 (95% CI 0.3106-1.3439)], P = 0.236. No differences were observed in the pattern of local and systemic failures., Conclusions: This study failed to demonstrate that RH after EBRT-CT is superior to standard BCT.

Purpose: To analyze the clinical characteristics and outcome of cervical cancer patients presenting late recurrence., Materials and Methods: The medical records of 16 patients who were treated between 1974 and 1999 at the Institution and whose cancer recurred after a five-year disease-free interval were reviewed., Results: Mean time from initial therapy to recurrence was 162.5 months (60-360 mean). Smear abnormalities, atypical genital bleeding, abdominal and lumbar pain, and respiratory findings were the most common symptoms and signs associated with late recurrence. Fourteen patients were diagnosed by physical examination. Three of the six patients with local recurrence who were re-irradiated developed a vesico-vaginal fistula. At a median follow-up time of 12.5 months (4-38 mean), 12 patients were alive and the median survival time was 30 months., Conclusions: Cervical cancer patients surviving free of disease after the fifth year post-treatment are still at risk for relapse and in most of them, the recurrence is suspected by clinical examination alone.

The reversing of epigenetic aberrations using the inhibitors of DNA methylation and histone deacetylases may have therapeutic value in cervical cancer. This is a randomized phase III, placebo-controlled study of hydralazine and valproate (HV) added to cisplatin topotecan in advanced cervical cancer. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow acetylators, and valproate at 30 mg/kg, beginning a week before chemotherapy and continued until disease progression. Response, toxicity, and PFS were evaluated, and 36 patients (17 CT + HV and 19 CT + PLA) were included. The median number of cycles was 6. There were four PRs to CT + HV and one in CT + PLA. Stable disease in five (29%) and six (32%) patients, respectively, whereas eight (47%) and 12 (63%) showed progression (P = 0.27). At a median follow-up time of 7 months (1-22), the median PFS is 6 months for CT + PLA and 10 months for CT + HV (P = 0.0384, two tailed). Although preliminary, this study represents the first randomized clinical trial to demonstrate a significant advantage in progression-free survival for epigenetic therapy over one of the current standard combination chemotherapy in cervical cancer. Molecular correlates with response and survival from this trial are pending to analyze.

Cervical cancer (CC) is the second most common cancer in Mexican women. Human papillomavirus (HPV) infection is necessary but not sufficient for CC development. Furthermore, genetic factors as polymorphisms could be important susceptibility factors. Controversial results regarding TP53 polymorphisms specifically in codon 72 of CC have been reported. In the present work, the exon 4 sequence of TP53 gene in CC and healthy Mexican-mestizo women were analyzed. A group of 111 women with CC and 126 healthy women (control) were included. Peripheral blood cells for polymorphism analysis and cervical scrape for HPV detection were used. PCR of exon 4 of TP53 were subjected to denaturing high-performance liquid chromatography (DHPLC) analysis and sequencing. HPV detection was subjected to PCR and sequencing. The statistical analysis was carried out using the Arlequin software. Codon 72 Arg/Arg was the most common SNP detected, and Hardy-Weinberg analysis showed equilibrium in control and CC samples (P>0.05). Wild type sequence of TP53 exon 4 was detected in 66 and 57% in control and CC samples, respectively. For codon 72 Arg/Arg, differences between control and CC women were found (P=0.043). An association between HPV 16/18 infection and 72 Arg/Arg in woman with CC was found (P=0.026). Haplotype GC (codon 36 and 72) was statistically significantly associated with CC (P=0.011). HPV 16 was the most common viral type. Codon 72 Arg/Arg is the most common polymorphism in the Mexican population and could be associated to HPV 16 and/or HPV 18 infection in CC.

Background: Cervical cancer (CC) represents the second most common neoplasm and the third cause of death by cancer among women. Recurrent or persistent disease depends on the clinical stage, but can be as high as 70%. Positron emission tomography/computed tomography (PET/CT) is an image study that can detect increased glucose uptake in tumor tissues., Material and Methods: PET/CT was performed in patients with confirmed CC, who had been previously treated, who developed suspected symptoms of recurrence or persistent disease with or without evidence of disease on a CT scan. Sensitivity, specificity, predictive values from PET/CT, and CT scan were evaluated., Results: Sixteen patients with a mean age of 47.2 years were included in the study from April 2007 to June 2008. Thirteen patients (81.2%) were symptomatic. PET/CT was positive in 14/16 (85.7%), of these, 12 True positive (TP) and two, False positive (FP); meanwhile another two cases were True negative (TN) (12.5%). Cervix, retroperitoneal, iliac, obturator, and mediastinal lymph nodes were the most common anatomic sites detected by PET/CT. Mean number of anatomic sites with high Fluoro-deoxy-D-glucose (FDG) uptake was two sites (range 1-7 sites). PET/CT and CT scan had 100 and 91.7% sensitivity, respectively. Specificity for both was 50%. Positive predictive value (PPV) was 85.4 and 84.6%, respectively. Negative predictive value (NPV) was 100 and 66%, respectively, and accuracy was 88 vs. 81%, respectively., Conclusions: PET/CT has the capability for detecting recurrent or persistent cervical cancer; it detects increased metabolic activity mainly in primary site or lymph nodes. Further PET/CT evaluation is required to confirm the real impact of this study on the early detection of CC recurrence.

Purpose: To determine whether addition of gemcitabine to concurrent cisplatin chemoradiotherapy and as adjuvant chemotherapy with cisplatin improves progression-free survival (PFS) at 3 years compared with current standard of care in locally advanced cervical cancer., Patients and Methods: Eligible chemotherapy- and radiotherapy-naive patients with stage IIB to IVA disease and Karnofsky performance score ≥ 70 were randomly assigned to arm A (cisplatin 40 mg/m(2) and gemcitabine 125 mg/m(2) weekly for 6 weeks with concurrent external-beam radiotherapy [XRT] 50.4 Gy in 28 fractions, followed by brachytherapy [BCT] 30 to 35 Gy in 96 hours, and then two adjuvant 21-day cycles of cisplatin, 50 mg/m(2) on day 1, plus gemcitabine, 1,000 mg/m(2) on days 1 and 8) or to arm B (cisplatin and concurrent XRT followed by BCT only; dosing same as for arm A)., Results: Between May 2002 and March 2004, 515 patients were enrolled (arm A, n = 259; arm B, n = 256). PFS at 3 years was significantly improved in arm A versus arm B (74.4% v 65.0%, respectively; P = .029), as were overall PFS (log-rank P = .0227; hazard ratio [HR], 0.68; 95% CI, 0.49 to 0.95), overall survival (log-rank P = .0224; HR, 0.68; 95% CI, 0.49 to 0.95), and time to progressive disease (log-rank P = .0012; HR, 0.54; 95% CI, 0.37 to 0.79). Grade 3 and 4 toxicities were more frequent in arm A than in arm B (86.5% v 46.3%, respectively; P < .001), including two deaths possibly related to treatment toxicity in arm A., Conclusion: Gemcitabine plus cisplatin chemoradiotherapy followed by BCT and adjuvant gemcitabine/cisplatin chemotherapy improved survival outcomes with increased but clinically manageable toxicity when compared with standard treatment.

Cervical cancer continues to be a significant health burden worldwide. Globally, the majority of cancers are locally advanced at diagnosis; hence, radiation remains the most frequently used therapeutic modality. Currently, the value of adding cisplatin or cisplatin-based chemotherapy to radiation for the treatment of locally advanced cervical cancer is strongly supported by randomized studies and meta-analyses. Nevertheless, despite these significant achievements, therapeutic results are far from optimal; thus, novel therapies need to be investigated. A recent, randomized, phase III trial has shown for the first time that combination chemotherapy with cisplatin and gemcitabine concurrently with radiation improves parameters of survival over cisplatin alone and establishes a new standard for the management of locally advanced cervical cancer. On the other hand, advanced disease, presenting either as an International Federation of Gynecology and Obstetrics (FIGO) stage IVB or as persistent or recurrent to primary therapy without local curative options, remains a devastating group of diseases with no options other than palliative chemotherapy. Recent results from the GOG (Gynecologic and Oncologic Group)-204 study demonstrate that cisplatin-doublets with paclitaxel, vinorelbine, gemcitabine or topotecan only produce small improvements in survival, although with different toxicity patterns; hence, patient-related factors are important when choosing any one of these regimens. The role of targeted therapies both in locally advanced and advanced disease is promising, but still at an investigational stage.

Introduction: This trial aimed to evaluate the safety and efficacy of epigenetic therapy associated with cisplatin chemoradiation in FIGO Stage IIIB patients., Methods: Hydralazine containing either 182 mg for rapid-, or 83 mg for slow acetylators and magnesium valproate were administered at 30 mg/kg tid. Both drugs were taken until intracavitary therapy was finished. Pelvic external beam radiation and low-dose rate brachytherapy were administered at a total cumulative dose to point A of at least 85 Gy. Weekly cisplatin at 40 mg/m2 was delivered for six cycles., Results: Twenty-two patients were included and 18 (82%) patients completed treatment. Mean dose to point A was 84.6 + 2.2. Median number of cisplatin cycles was 5.5 (range, 1-6). Brachytherapy was delayed for technical reasons; the mean overall treatment time was 11.8 weeks. Grade 3 anemia, leucopenia, neutropenia, and thrombocytopenia were observed in 9%, 45%, 45%, and 9% of patients, respectively., Conclusions: Hydralazine and valproate are well-tolerated and safe when administered with cisplatin chemoradiation. Unfortunately, the suboptimal administration of brachytherapy for technical reasons in this study, precluded assessing the efficacy of epigenetic therapy. However, the tolerability of this regimen administered concurrent to radiation needs to be further tested.

Imatinib mesylate inhibits platelet-derived growth factor receptor (PDGFR), and there are evidences that the PDGFR participates in development and progression of cervical cancer. This pilot study was set to evaluate the efficacy in response rate and progression-free survival of imatinib. A secondary end point was to evaluate its safety as second-line treatment of recurrent or metastatic cervical cancer expressing PDGFRalpha. Imatinib mesylate was administered in daily dosages of 600 mg. Response was evaluated by positron emission tomography/computed tomography every two 28-day courses, and toxicity was evaluated weekly and thereafter. Twelve patients were included in the study. The median age was 49.8 years; all but 1 tumor were squamous cell carcinomas. First-line palliative chemotherapy with carboplatin-paclitaxel was the most frequently used scheme (75.0%). Ten (83.3%) had pelvic and systemic disease, whereas only 2 had systemic disease alone. All patients expressed the PDGFRalpha in more than 10% of malignant cells, whereas only 4 coexpressed the PDGFRbeta. No patient showed response. A single patient having metastatic disease in the lung showed stabilization for 6 months to then progressing in bone. No severe toxicities were seen except for the patient with worsening of bleeding from proctitis. Grades 1 and 2 gastrointestinal toxicities were common. Despite lack of activity of single-agent imatinib, further studies in cervical cancer are deserved to better define the status of imatinib targets in this tumor and to investigate its activity in combination with cytotoxic drugs.

Background: A current paradigm in the treatment of cervical cancer with radiation therapy is that intracavitary brachytherapy is an essential component of radical treatment. This is a matched retrospective comparison of the results of treatment in patients treated with external beam chemoradiation (EBRT-CT) and radical hysterectomy versus those treated with identical chemoradiation followed by brachytherapy., Methods: In this non-randomized comparison EBRT-CT protocol was the same in both groups of 40 patients. In the standard treated patients, EBRT-CT was followed by one or two intracavitary Cesium (low-dose rate) applications within 2 weeks of finishing external radiation to reach a point A dose of at least 85 Gy. In the surgically treated patients, radical hysterectomy with bilateral pelvic lymph node dissection and para-aortic lymph node sampling were performed within 7 weeks after EBRT-CT. Response, toxicity and survival were evaluated., Results: A total of 80 patients were analyzed. The patients receiving EBRT-CT and surgery were matched with the standard treated cases. There were no differences in the clinicopathological characteristics between groups or in the delivery of EBRT-CT. The pattern of acute and late toxicity differed. Standard treated patients had more chronic proctitis while the surgically treated had acute complications of surgery and hydronephrosis. At a maximum follow-up of 60 months, median follow-up 26 (2-31) and 22 (3-27) months for the surgery and standard therapy respectively, eight patients per group have recurred and died. The progression free and overall survival are the same in both groups., Conclusion: The results of this study suggest that radical hysterectomy can be used after EBRT-CT without compromising survival in FIGO stage IB2-IIB cervical cancer patients in settings were brachytherapy is not available. A randomized study is needed to uncover the value of surgery after EBRT-CT.

Topotecan is active in advanced or metastatic cervical cancer even in patients who have received prior cisplatin-based chemotherapy, although hematologic toxicity has limited its use. Studies in cervical cancer have utilized topotecan administered on days 1-5 of each 21- or 28-day cycle. Alternative schedules, such as weekly schemes, have proven to ameliorate hematological toxicity. The objective of this study was to analyze the results of weekly topotecan as second- or third-line therapy in advanced or metastatic cervical cancer. Eligible patients had histologically confirmed cervical carcinoma, measurable disease, and at least one prior chemotherapy regimen. Topotecan was administered at a dose of 3 mg/m(2) (maximum, 5 mg per dose) diluted in 250 ml of normal saline in a 30-min infusion weekly for every 28 days. We assessed response and toxicity. Twenty-two patients entered this study. Eighteen patients were evaluable for toxicity and response. Patients received a mean 3.5 courses (range, 1-6 courses). No complete or partial responses were observed; five (27.7%) patients exhibited disease stabilization as maximum response (two in irradiated sites, and three in lung/mediastinum). Median progression-free interval was 3.5 months (95% confidence interval [CI]: 3.75-4 months) and median overall survival was 7 months (95% CI: 6-8.7 months). Weekly topotecan administration achieved disease stabilization in 27.7% of heavily pre-treated patients. The achievement could be of worth in this setting in which disease prolongation is desirable.

Cervical cancer is a frequent tumor with established prognostic factors such as FIGO stage and hemoglobin levels among others. Despite the fact that paraneoplastic leukocytosis is relatively common in many solid tumors, only isolated cases of cervical cancer patients presenting this abnormality have been published; hence, the clinical significance of leukocytosis is unknown in this tumor type. Retrospective review on the medical records of 294 consecutive newly diagnosed and untreated locally advanced cervical cancer patients who received radiotherapy and concurrent cisplatin was conducted. Leukocytosis was defined as a persistent white blood cell count exceeding 10,800/microL, determined at least twice before commencing chemoradiation providing that patients were free of any active acute or chronic infection or any other condition known to elevate the leukocyte count. The frequency of leukocytosis and their correlation with clinicopathologic features were investigated, as well as their impact on tumor response and survival. Leukocytosis with a median value of 13,300/microL (11,100-28,800) was observed in 35 (11.9%) patients at diagnosis. Leukocytosis was statistically associated only with advanced stages. Clinical complete response was observed in 57% versus 86% of the patients with and without leukocytosis, respectively. In the univariate analysis, leukocytosis, stage, and hemoglobin levels were significant predictors of survival; however, only leukocytosis and the hemoglobin level remained significant predictors of survival in the multivariate analysis. Leukocytosis is common in cervical cancer patients and has a negative prognostic significance.

Background: The methylation status at the human papilloma virus (HPV) genome found in pre-invasive and invasive cervical lesions suggests that neoplastic transformation can be suppressed by gene hypermethylation, whereas hypomethylation accompanies or causes cancer progression; hence, epigenetic therapy aimed at reactivating cellular suppressor-gene expression has the potential to act as a tumor promoter by enhancing HPV oncoprotein expression in HPV-related malignancies. The objective of this study was to determine the influence of hydralazine and valproate on HPV oncogene expression in cervical cancer cell lines and the primary tumors of patients undergoing treatment with hydralazine and valproate., Results: Overall, hydralazine and valproate either alone or combined exerted a growth inhibitory effect on cervical cancer cell lines. A cell line-specific up-regulating effect was observed on E6/E7 gene expression, which in general correlated with DNA hypomethylation and histone acetylation at the long control region (LCR). Nonetheless, E6/E7 expression was unchanged or decreased in the majority of patients with cervical cancer treated with hydralazine, valproate, or both. In some cervical cancer cell lines, these drugs led to increased transcription of p53, and increased its stabilization due to acetylation at lysines 273 and 282, which allowed a higher bax-protein transactivating effect., Conclusion: The results of this study demonstrate that hydralazine and valproate can be safely administered to HPV-related malignancies such as cervical cancer because they do not increase viral oncoprotein expression. Most importantly, the antitumor effect of hydralazine and valproate in cervical cancer may at least partially depend on an up-regulating effect on p53 gene and on the valproate-induced hyperacetylation of p53 protein, protecting it from degradation by E6.

Objective: Several intratype variants of HPV16 and 18 have been identified. These variants are associated with populations from different geographic regions, and show a differential distribution among the severity of the cervical lesion, most likely due to different pathogenic potential. The objective of this study was to investigate the variant distribution of HPV16 and 18 in a Mexican population and its association with the severity of the cervical lesion and the histological lineage of cervical cancer., Methods: HPV types 16 and 18 detection was performed in 412 samples of preinvasive and invasive specimens from patients attending a Primary Health-Care Center, an Early Cervical Lesion Clinic, or a Cancer Center. Distribution of HPV variants was correlated with the cytological findings and tumor cell types using contingency tables. Statistical difference was tested with the Fisher's Exact Test or its Fisher-Freeman-Halton extension for RXC tables. Alpha value was set at the P < 0.05., Results: Among the 277 women included in this study without cancer, 63.5% (176 cases) had a normal cytology; from the remaining 101 women, 53.5% were LSIL (54 cases), and 46.5% HSIL (47 cases). From a total of 135 invasive carcinomas, 78.5% were squamous (106 cases); 6.6% adenocarcinoma (9 cases); 9.6% adenosquamous (ADSC) (13 cases); and 5.1% were undifferentiated carcinoma (7 cases). HPV16 E and AA-a were evenly distributed among preinvasive and invasive lesions. However, the isolate AA-c was exclusively found in cervical cancer. HPV18 Var-1(E) was almost exclusively found in invasive lesions, while the HPV18 Var-2(Af) predominated in normal or preinvasive lesions. In invasive cancer, this variant was found only in squamous tumors., Conclusions: The differential distribution of HPV16 and 18 variants in cervical lesions we found further supports experimental data on the different pathogenic potential of HPV16 and 18 variants for cervical cancer development.

Cervical cancer remains one of the greatest killers of women worldwide. It is difficult to foresee a dramatic increase in cure rate even with the most optimal combination of cytotoxic drugs, surgery, and radiation; therefore, testing of molecular targeted therapies against this malignancy is highly desirable. A number of epigenetic alterations occur during all stages of cervical carcinogenesis in both human papillomavirus and host cellular genomes, which include global DNA hypomethylation, hypermetylation of key tumor suppressor genes, and histone modifications. The reversible nature of epigenetic changes constitutes a target for transcriptional therapies, namely DNA methylation and histone deacetylase inhibitors. To date, studies in patients with cervical cancer have demonstrated the feasibility of reactivating the expression of hypermethylated and silenced tumor suppressor genes as well as the hyperacetylating and inhibitory effect upon histone deacetylase activity in tumor tissues after treatment with demethylating and histone deacetylase inhibitors. In addition, detection of epigenetic changes in cytological smears, serum DNA, and peripheral blood are of potential interest for development of novel biomolecular markers for early detection, prediction of response, and prognosis.

Persistent infections of the uterine cervix with 'high-risk' human papillomavirus (HPV) are now recognized as necessary for the development of cervical cancer. Among them, HPV types 16 and 18 exhibit numerous variants associated with different risks for cervical cancer development. In this study, the questions of whether different HPV type 18 variants exhibit changes in early gene transcription and the molecular mechanisms underlying these differences were investigated. It was shown that, indeed, type 18 variants exhibited singular differences in E6 transcripts in vivo. Higher levels of the E6*I transcript were detected regularly in clones harbouring the African variant, as opposed to low levels of this transcript detected in clones containing the reference clone (Asian-Amerindian), where significantly higher levels of full-length E6 transcript were usually observed. As a direct consequence, higher levels of p53 protein were found in the presence of African E6, as opposed to the low levels of p53 observed with the Asian-Amerindian E6. These variations in consequence affected the levels of cellular proteins regulated by p53, such as Bax. Similar changes in the relative levels of E6 transcripts were observed when tumours containing type 18 E6 variants were analysed. The different ability of cells containing variant E6 genes to form tumours in nude mice was suggested by the fact that tumour volumes were considerably higher when cells expressed the Asian-Amerindian E6. Mutagenesis analysis of the reference clone showed that a C491A change reverts the phenotype. These results suggest that different splicing patterns of E6 within HPV type 18 variants may possibly have biological implications in viral tumorigenesis.

Background: Radiation therapy with concomitant chemotherapy is the standard treatment for locally advanced cervical cancer. In Mexico, most patients are still treated with radiation therapy alone. The aim of this work was to demonstrate that results obtained with combined treatments in the Mexican population are similar to those reported in the literature., Methods: Survival was analyzed in three sequential phase II studies of combined treatment: neoadjuvant chemotherapy followed by surgery (NEOCT+Sx) -February to July 1999; concomitant chemoradiotherapy (CT/RT) -August to December 1999; and neoadjuvant chemotherapy followed by surgery plus adjuvant chemoradiotherapy (NEOCT+Sx+CT/RT) -December 2000 to June 2001. These results were compared with a historical control group treated with radiation therapy alone between September and December 1998. The Kaplan-Meier product-limit method, log-rank test and Cox proportional hazards model were used for analysis., Results: Results showed that the three combined modalities significantly reduced the risk of death. Treatment with NEOCT+Sx reduced the risk to 0.452 (95% CI 0.246-0.830), p=0.010. The risk reduction with CT/RT was 0.408 (95% CI 0.218-0.762), p=0.005, and for the group of patients receiving NEOCT+Sx+CT/RT risk was reduced to 0.365 (95% CI 0.169-0.787), p=0.010. The corresponding absolute survival benefit was 14% for patients in stages IB2-IIA, 24% for IIB, and 21% for stage IIIB., Conclusions: Within the limitations of a non-randomized study, our results are in agreement with those obtained from published randomized phase III trials which state that radiation therapy alone is a suboptimal treatment for locally advanced cervical cancer; hence, patients should receive cisplatin-based chemoradiotherapy as a standard treatment.

Purpose: To compare gemcitabine and cisplatin (GC) with cisplatin (C) concurrent with radiotherapy in International Federation of Gynecology and Obstetrics Stage IB2, IIA, and IIB cervical carcinoma in a preoperative setting. The main endpoints were the pathologic response rate and toxicity., Methods and Materials: A total of 83 patients were randomized to either C or GC. Treatment consisted of six doses of cisplatin at 40 mg/m(2) every week for Arm 1 (C) and six doses of gemcitabine at 125 mg/m(2) plus cisplatin at 40 mg/m(2) every week for or Arm 2 (GC) Both regimens were administered concurrent with 50 Gy of external beam radiotherapy in 2-Gy fractions for 5 weeks. After chemoradiotherapy, patients underwent radical hysterectomy., Results: All 83 patients were studied for toxicity and 80 for response. The complete pathologic response rate in the C arm and GC arm was 55% (95% confidence interval, 35.5-73%) and 77.5% (95% confidence interval, 57-90%; p = 0.0201). Among those with a partial response, 7 patients each had high and intermediate-high risk factors for recurrence in their surgical specimens in the C arm vs. 2 and 3 patients, respectively, with these characteristics in the CG arm. The number of weekly doses and the dose intensity of GC were lower than for C. The time to complete external beam radiotherapy also favored the C arm. The CG combination produced greater GI and hematologic toxicity., Conclusion: The radiosensitizing combination of GC achieved a greater pathologic response rate than C in the treatment of cervical cancer.

Iron deficiency and tumor bleeding are common causes of anemia in cervical cancer. Anemia has a negative prognostic influence, and its correction is thought to improve prognosis; therefore, most patients are treated with either transfusion and/or erythropoietin. At present little is known about the value of iron stores replenishment to increase hemoglobin levels in this setting. Untreated cervical cancer patients with a hemoglobin <12 g/dL were randomized to intramuscular iron or to transfusion. Iron dose was calculated according to [weight (kg)x(15--actual Hb)x2.4]+500 and administered by injections of 200 mg daily. In both arms, patients who did not achieve at least 10 g/dL hemoglobin before or during chemoradiation were transfused. Patients received standard pelvic radiation plus six weekly doses of cisplatin. Hematic counts were performed before starting chemoradiation and weekly thereafter. Fifteen patients were studied; six were assigned to iron and nine to transfusion. Mean basal hemoglobin levels were 9.9 and 9.5 g/dL respectively. Total iron, saturation index, binding capacity, and ferritin were within normal limits, although there was a high variability among the patients. The mean total dose of iron administered was 1229 mg. Two weeks after randomization, hemoglobin increased to 10.9 and 10.2 g/dL respectively. At wk 1 of treatment and thereafter, levels were higher in the iron arm, in whom the values were close or higher than 12 g/dL (p=0.03). The median number of units transfused were 0 in the iron group and 2 in the transfusion (p=0.02) arm. Parenteral iron seems to be effective to increase hemoglobin in cervical cancer patients.

Ether a go-go (EAG) potassium channels display oncogenic properties. In normal tissues, EAG mRNA is almost exclusively expressed in brain, but it is expressed in several somatic cancer cell lines, including HeLa, from cervix. Antisense experiments against eag reduce cell proliferation in some cancer cell lines, and inhibition of EAG-mediated currents has been suggested to decrease cell proliferation in a melanoma cell line. Because of the potential clinical relevance of EAG, we investigated EAG mRNA expression in the following fresh samples from human uterine cervix: 5 primary cultures obtained from cancerous biopsies, 1 cancerous fresh tissue, and 12 biopsies of control normal tissue. All of the control cervical samples came from patients with negative pap smears. Reverse transcription-PCR and Southern-blot experiments revealed eag expression in 100% of the cancerous samples and in 33% of the normal biopsies. Immunochemistry experiments showed the presence of EAG channel protein in cells from the primary cultures and in cervical cancer biopsies sections from the same patients. In addition, we looked for EAG-mediated currents in the cultures from cervical cancer cells. Here we show for the first time EAG channel activity in human tumors. Patch-clamp recordings showed typical EAG-mediated currents modulated by magnesium and displaying a pronounced Cole-Moore shift. Because EAG expression and channel activity have been suggested to be important in cell proliferation, our findings strongly support the idea of considering EAG as a tumor marker as well as a potential membrane therapeutic target for cervical cancer.

The prognosis of cervical cancer patients with renal failure secondary to obstructive uropathy is poor. Our objective was to analyze our experience in the management with chemoradiation of untreated cervical cancer patients complicated by obstructive nephropathy and kidney dysfunction. Untreated patients with cervical cancer and renal failure as manifested by raised serum creatinine were treated with pelvic radiotherapy concurrently with weekly gemcitabine at 300 mg/m2. Response, toxicity and renal function pre- and post-therapy were evaluated. Eight FIGO stage IIIB and one IVB patients were treated. Pre-treatment serum creatinine ranged from 1.6 to 18.5 mg/100 ml (median 3.3, mean 6.8) and creatinine clearance varied from 4 to 57 mg/ml/min (median 17, mean 22.1). Four patients had a percutaneous nephrostomy placed and four patients had symptoms from kidney failure. All patient completed chemoradiation. Most patients had grade 3 leukopenia and neutropenia. Dermatitis, colitis and proctitis were common. All patients had improvement in creatinine clearance (pre-therapy 22.78, post-therapy 54.3 mg/ml/min) (p=0.0058) and all but one normalized serum creatinine. Eight (89%) of nine patients achieved complete response and one patient had persistence. At a median follow-up of 11 months (range 6-14), all patients are alive, one with pelvic and another with systemic disease. Ureteral obstruction causing any degree of renal insufficiency should not be a contraindication to receive chemoradiation to attempt cure. In this setting where cisplatin-based therapy is contraindicated, the use of gemcitabine may be considered.

It is known that cell-free DNA circulates in plasma/serum of patients with cancer and that part of this DNA circulates as nucleosomes that can be quantified by ELISA. We analyzed the effect of tumor and chemotherapy upon the levels of nucleosomes in vitro, in vivo and in cervical cancer patients. The levels of nucleosomes pre- and post-treatment were correlated with response in 11 patients receiving chemotherapy. Nucleosomes were determined in nude mice treated with or without cisplatin and carrying tumors generated with HeLa cells, and in the cell lysate and supernatant of HeLa cells exposed to cisplatin in culture. In addition, nucleosomes were determined at different time points in patients and in rats receiving chemotherapy. Nucleosomes were higher in patients that controls (1,760 vs. 601, p = 0.0001). After 24 hr of treatment with oxaliplatin and gemcitabine, the levels decreased in 6 patients of whom 5 had response. Nucleosome levels differed between mice xenografted and not xenografted (765 vs. 378, p = 0.001) and between xenografted treated with or without cisplatin (650 vs. 765, p = 0.010), but not in tumor-free animals treated and untreated with cisplatin (378 vs. 379, p = 0.99). In vitro, nucleosomes reached at peak 8 hr in cell lysates to decrease thereafter, whereas in supernatant, levels continued to increase up to 24 hr. Serial determination of nucleosomes in patients showed a rise within 6-12 hr and then a reduction to below the basal at 24 hr. In rats, nucleosomes had no major changes in those receiving oxaliplatin or the triple combination of cisplatin, gemcitabine and paclitaxel as compared to untreated controls. An overdose of this triple combination produced a transient elevation of almost 1,000 AU over the basal. Our results demonstrate that most of circulating nucleosomes originate from the tumor and that chemotherapy produces an early rise most likely due to tumor apoptosis and that nucleosomes are rapidly cleared from circulation. On the contrary, chemotherapy within the therapeutic range of doses has no effect on nucleosome levels in healthy mice and rats. This data suggests that the determination of circulating nucleosomes pre- and post-treatment could be a useful test to predict response to chemotherapy in cancer patients., (Copyright 2003 Wiley-Liss, Inc.)

Induction chemotherapy followed by surgery, particularly with newer agents or combinations, remains to be explored in locally advanced cervical cancer. Gemcitabine cisplatin is a very active combination for this tumor, therefore we explored the activity of gemcitabine in combination with oxaliplatin. Ten untreated patients with histologic diagnosis of cervical carcinoma and staged as IB2 to IIIB were treated with 3 21-day courses of oxaliplatin 130 mg/m day 1 and gemcitabine 1,250 mg/m days 1 and 8 followed by locoregional treatment with either surgery or concomitant chemoradiation. Response and toxicity were evaluated at the end of chemotherapy. All patients were evaluable. The overall clinical response rate was 80%, being complete in 3 patients (30%) and partial in 5 (50%). Seven (70%) patients underwent surgery, and three (30%) had chemoradiation as definitive treatment. Hematologic toxicity was moderate, with leukopenia grades III-IV in 17 and 0%; granulocytopenia grades III-IV in 23 and 3%, respectively. Eight patients had grade I oropharyngeal toxicity. At a median follow-up of 11 months (range: 10-12), all patients are disease free. Gemcitabine oxaliplatin is a very active and well-tolerated combination for locally advanced cervical cancer.

Despite the recent progress in the management of cervical carcinoma, treatment failure is quite common and therefore it is necessary to identify predicting factors for tumor response. It is known that both cell proliferation and apoptosis determine the tumor growth index (TGI) which reflects the overall contribution of gene defects. Here we explored whether the TGI index could be a better predictor of response in comparison to cell proliferation or apoptosis as separate phenomena. Twenty-five patients with cervical carcinoma treated with radiation alone or neoadjuvant chemotherapy plus surgery were analyzed. Cell proliferation and apoptosis determined by PCNA immunohistochemical expression and tumor nucleosomes by ELISA, respectively, were used to calculate the TGI, which was analyzed with regard to early tumor response. Our results show that most patients with a negative TGI had early response suggesting increased tumor sensitivity(p = 0.0186). On the other hand, patients with a positive TGI were more resistant to treatment. TGI was not related to age, clinical stage or tumor size. In conclusion, the results of this study show that the determination of the TGI, but no cell proliferation or apoptosis, as separate events, is able to predict an early treatment response to either radiation or chemotherapy in cervical carcinoma.

Tumor cells exhibit phenotypic and genotypic differences in comparison to normal cells. These differences can be used to identify proteins important for tumor growth and, therefore, potentially used in the diagnosis and follow-up of patients. The objective of this work was to investigate the electrophoretic pattern of cytoplasm membrane proteins from normal and malignant cervix using polyacrylamide-SDS gels. A highly reproducible protein pattern was found in the 29 samples of normal cervix whereas three well-defined patterns of protein bands were observed in the 48 tumor specimens (pattern I: 25%, pattern II: 29.2% and pattern III: 45.8%). A low concentration or absence of high molecular weight proteins was observed (p<0.5) in tumor samples. None of the tumor protein patterns correlated with the clinicopathologic characteristics of patients. Nine out of 11 patients (82%) showing the pattern III had a complete clinical response whereas only 55% (11 out of 20) of those with patterns I and II showed a complete response. However, this difference was non-significant (p=0.1247). In conclusion, we demonstrate that there is a gain and loss of cytoplasmic membrane proteins in tumors, shown as different protein band patterns. These findings could have clinical and biological significance that must be further evaluated.