Emerging drugs for the treatment of cervical cancer.

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.

Highly pathogenic avian influenza H5N1 virus infections in pinnipeds and seabirds in Uruguay: Implications for bird-mammal transmission in South America.

The highly pathogenic avian influenza viruses of clade 2.3.4.4b have caused unprecedented deaths in South American wild birds, poultry, and marine mammals. In September 2023, pinnipeds and seabirds appeared dead on the Uruguayan Atlantic coast. Sixteen influenza virus strains were characterized by real-time reverse transcription PCR and genome sequencing in samples from sea lions (Otaria flavescens), fur seals (Arctocephalus australis), and terns (Sterna hirundinacea). Phylogenetic and ancestral reconstruction analysis showed that these strains have pinnipeds most likely as the ancestral host, representing a recent introduction of clade 2.3.4.4b in Uruguay. The Uruguayan and closely related strains from Peru (sea lions) and Chile (sea lions and a human case) carry mammalian adaptative residues 591K and 701N in the viral polymerase basic protein 2 (PB2). Our findings suggest that clade 2.3.4.4b strains in South America may have spread from mammals to mammals and seabirds, revealing a new transmission route.

A randomized comparison of cisplatin and oral vinorelbine as radiosensitizers in aged or comorbid locally advanced cervical cancer patients.

OBJECTIVE: Chemoradiation with cisplatin is considered the standard of care for patients with locally advanced cervical cancer; however, cisplatin could be difficult to use in aged patients or patients with comorbidities such as diabetes mellitus and blood hypertension; hence, it is important to investigate nonplatinum drugs for radiosensitization. In addition, oral cytotoxics may overcome the drawbacks of intravenous infusions and could be of easier administration. METHODS: In this small randomized trial, we tested cisplatin against oral vinorelbine as radiosensitizers in these patients. A total of 39 patients 65 years or older or diabetic and hypertensive patients of any age were randomized to cisplatin or oral vinorelbine at 40 mg/m² or 60 mg/m², respectively. Both drugs were administered weekly for 6 courses during pelvic external-beam radiotherapy and brachytherapy radiation. Efficacy and safety were assessed. RESULTS: Nineteen patients received oral vinorelbine, and 20 patients received cisplatin. The median cumulative dose to point A was 80.8 Gy for both groups, and the overall treatment time was 48 (42-54) and 50 (43-55) days for vinorelbine and cisplatin groups, respectively. Patients in both arms received a median of 5 applications of chemotherapy. Treatment was well tolerated in both arms. The most frequent toxicity in both arms was lymphopenia grades 2 and 3. At a median follow-up time of 16 months (4-19), there were no differences in either progression-free survival or overall survival between groups. CONCLUSIONS: Our results suggest that these patient populations can safely be treated with either cisplatin or navelbine as radiosensitizers; however, a larger randomized study is needed to demonstrate the noninferiority of oral vinorelbine as an easier and practical alternative for radiosensitization in cervical cancer.

Emerging drugs for cervical cancer.

INTRODUCTION: There is a shortage of therapeutical agents for invasive cervical cancer in late stages of development; however, a number of promising molecules are currently in early phases of development. AREAS COVERED: This review briefly discusses the current achievements in treating cervical cancer with an emphasis in emerging agents based on a literature search on pubmed and related sites for cervical cancer information. This is not a systematic review. EXPERT OPINION: In advanced disease, modest survival gains have been achieved with cisplatin doublets. Contrariwise, chemoradiation has increased survival rates in locally advanced disease, but there is still room for improvement. Anti-vascular endothelial growth factor and anti-epidermal growth factor receptor monoclonal antibodies are promising molecules that are at present in late-phase development, but a high number of miscellaneous agents are in early development. Strong experimental bases support that the 'Achilles' heel' of cervical cancer are the HPV-E6/E7 oncogenes. Unfortunately, agents aimed at targeting these cervical cancer-driven players are found in very early development; hence, major research efforts must be focused on developing technological strategies for their effective targeting using nucleic acid-based vehicles for safe and effective delivery to cancer cells as well as accelerating the search for small-molecule inhibitors of E6/E7 themselves or their interacting cellular proteins.

Adenocarcinoma metastatic to the uterine cervix: a case series.

AIMS: The objectives of this report are, first, to describe the clinical behavior of cases of carcinoma metastatic to the uterine cervix treated at our institution in order to carry out a systematic review to establish the behavioral patterns of the most frequent metastases to the cervix and, second, to generate guidelines for their diagnosis and treatment. METHODS: At the National Institute of Cancer of Mexico (INCan), we performed a review of the clinical files with a diagnosis of malignant neoplasm metastatic to the uterine cervix between 1990 and 2009. For a systematic review, we conducted a PubMed search between the years 1970 and 2009 of case reports and series of cases of patients with metastatic gastric, breast, ovarian and colorectal cancer. We analyzed each report individually and extracted the patients' clinical data from our cases and reports, including the primary tumor, cervical metastases and survival rates. RESULTS: There were 10 cases of tumors metastatic to the uterine cervix. Metastasis was documented in one-half of the patients during follow up, with two of these cases having the cervix as the only site. We included the following reports in the systematic review: 13 reports of gastric-associated cancer, 30 related to breast cancer, nine with ovarian-associated cancer and 10 related to colorectal cancer. CONCLUSIONS: Metastatic cervical activity is an infrequent event. The prognosis of survival is poor in the presence of gastric or ovarian cancer and cervical metastases.

Gene Promoter-Methylation Signature as Biomarker to Predict Cisplatin-Radiotherapy Sensitivity in Locally Advanced Cervical Cancer.

Despite efforts to promote health policies focused on screening and early detection, cervical cancer continues to be one of the leading causes of mortality in women; in 2020, estimated 30,000 deaths in Latin America were reported for this type of tumor. While the therapies used to treat cervical cancer have excellent results in tumors identified in early stages, those women who are diagnosed in locally advanced and advanced stages show survival rates at 5 years of <50%. Molecular patterns associated with clinical response have been studied in patients who present resistance to treatment; none of them have reached clinical practice. It is therefore necessary to continue analyzing molecular patterns that allow us to identify patients at risk of developing resistance to conventional therapy. In this study, we analyzed the global methylation profile of 22 patients diagnosed with locally advanced cervical cancer and validated the genomic results in an independent cohort of 70 patients. We showed that BRD9 promoter region methylation and CTU1 demethylation were associated with a higher overall survival (p = 0.06) and progression-free survival (p = 0.0001), whereas DOCK8 demethylation was associated with therapy-resistant patients and a lower overall survival and progression-free survival (p = 0.025 and p = 0.0001, respectively). Our results suggest that methylation of promoter regions in specific genes may provide molecular markers associated with response to treatment in cancer; further investigation is needed.

F18-FDG-PET/CT in the evaluation of patients with suspected recurrent or persistent locally advanced cervical carcinoma.

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.

Weekly topotecan as second- or third-line treatment in patients with recurrent or metastatic cervical cancer.

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.

Brachytherapy versus radical hysterectomy after external beam chemoradiation: a non-randomized matched comparison in IB2-IIB cervical cancer patients.

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.

The safety of drug treatments for cervical cancer.

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.

A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer.

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.

Follow-up consultations for cervical cancer patients in a Mexican cancer center. Comparison with NCCN guidelines.

PURPOSE: This study aimed to determine the patterns of follow-up visits for cervix cancer in a national cancer center in Mexico. MATERIALS AND METHODS: The National Cancer Institute of Mexico is cancer center with 119 beds that mostly cares for an underserved and socially disadvantaged population. The medical records of cases of cervical cancer that had at least one year of clinical follow-up after being in complete response at the end of primary treatment were analyzed. We recorded the numbers of total and yearly follow-up visits and these were compared with the number of follow-up visits recommended by the National Comprehensive Cancer Network 2013, version 2 for cervical cancer. RESULTS: Between March and June 2007, the medical records of 96 consecutive patients were reviewed. Twenty (21%) of these met inclusion criteria and were selected. In the first year the median number of visits was 11 (4-20). In the ensuing years, 2nd, 3rd, 4th and 5th, the number of analyzed patients remaining in follow-up decreased to 17, 14, 13 and 9 respectively. There were 462 follow-up visits to primary treating services (Gynecology Oncology, Radiation Oncology and Medical Oncology) as compared to 220 suggested by the NCCN guidelines (X2 test p<0.0001). There were 150 additional visits to other services. CONCLUSIONS: Our results suggest that in our institution there is an overuse of oncological services by cervical cancer patients once treatment is completed.

New pharmacotherapy options for cervical cancer.

INTRODUCTION: Cervical cancer is the fourth leading cause of cancer death in females worldwide. Incorporation of chemotherapy to radiation in locally advanced disease and molecular targeted therapy for advanced disease has increased survival; nevertheless, there is room for further improvement. AREAS COVERED: This review aims to discuss major recent advances in the treatment of invasive cervical cancer from randomized Phase III trials and ongoing late-stage developments. EXPERT OPINION: Combination chemotherapy concurrent with radiation plus adjuvant chemotherapy has demonstrated better survival rates as compared to standard cisplatin chemoradiation and ongoing Phase III trials would eventually confirm these findings. Gemcitabine and paclitaxel are the most evaluated agents added to cisplatin chemoradiation and in the adjuvant setting. Further survival gains combining classical cytotoxics will be limited by toxicity, hence, novel antitumor drugs; in particular angiogenesis inhibitors must be evaluated to increase the efficacy of current chemoradiation regimens. In advanced disease, modest survival gains were recently achieved with cisplatin doublets as compared to single agent cisplatin. Bevacizumab added to standard chemotherapy has for the first time demonstrated that targeted agents are valuable in the treatment of advanced cervical cancer. Ongoing Phase III trials for cervical cancer are limited reflecting the shortage of promising molecules and the need to increase research efforts for this disease.

New molecular targets against cervical cancer.

Cervical cancer is the third most commonly diagnosed cancer worldwide and the fourth leading cause of cancer death in women. Major advances but still insufficient achievements in the treatment of locally advanced and high-risk early stage patients have occurred in the last decade with the incorporation of concurrent cisplatin with radiation and, lately, gemcitabine added to cisplatin chemoradiation. Despite a number of clinical studies incorporating molecular-targeted therapy as radiosensitizers being in progress, so far, only antiangiogenic therapy with bevacizumab added to cisplatin chemoradiation has demonstrated safety and shown encouraging results in a Phase II study. In advanced disease, cisplatin doublets do not have a great impact on the natural history of the disease with median survival rates not exceeding 13 months. The first Phase III study of bevacizumab, added to cisplatin or a non-cisplatin-containing doublet, showed 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. Characterization of the mutational landscape of cervical cancer has already been initiated, indicating that, for now, few of these targetable alterations match with available agents. Progress in both the mutational landscape knowledge and developments of novel targeted therapies may result in more effective and individualized treatments for cervical cancer. The potential efficacy of knocking down the key alterations in cervical cancer - E6 and E7 human papillomavirus oncoproteins - must not be overlooked.

Hydralazine-valproate: a repositioned drug combination for the epigenetic therapy of cancer.

INTRODUCTION: DNA methylation (DNMTi) and histone deacetylase inhibitors (HDACi) are in development for cancer therapy. So far, four epigenetic drugs are approved for myelodysplastic syndrome (MDS) and cutaneous T-cell lymphoma (CTCL). The combination of hydralazine-valproate (TRANSKRIP(™)) is being repositioned as an oral DNMT and HDAC inhibitor. AREAS COVERED: Brief discussion on the current status of epigenetic drugs and studies published on the preclinical and clinical development of the hydralazine-valproate combination. EXPERT OPINION: Drug repositioning is a strategy for prompt and cost-efficient drug discovery. There is evidence that combining DNMTi with HDACi would be more efficacious than administering each agent on its own. Hydralazine-valproate is safe when used alone or in combination with chemotherapy or chemoradiation. The fact that both drugs are orally administered is another advantage over current epigenetic drugs. This combination is promising but larger studies are needed. Among these, the randomized Phase III trials in advanced and in locally advanced cervical cancer combined with chemotherapy and cisplatin-radiation respectively, would eventually confirm its efficacy. Studies on MDS and CTCL would also eventually prove the efficacy of hydralazine valproate so that in the coming years hydralazine-valproate could have a role in cancer epigenetic therapy.

Uterine sarcomas: review of 26 years at The Instituto Nacional de Cancerologia of Mexico.

UNLABELLED: Uterine sarcomas are a group of uncommon tumors that account for approximately 1% of malignant neoplasms of the female genital tract and between 3 and 8.4% of malignant uterine neoplasms. OBJECTIVE: To evaluate the factors associated with the clinical behavior of uterine sarcomas. MATERIALS AND METHODS: In the period from October 1983 to December 2009, clinical files of patients with a confirmed diagnosis of uterine sarcoma at the National Institute of Cancerology of Mexico (INCan) were reviewed and evaluated. RESULTS: We identified 77 cases with complete information; average age at presentation was 51.6 years (range, 14-78 years); most frequent histology was leiomyosarcoma (LMS) in 53/77 (68.8%) cases; most frequent symptom reported at the time of diagnosis was abnormal vaginal bleeding in 36/77 (46.7%) cases, and the most frequent clinical stage was clinical stage (CS) I in 31/77 (40.2%) cases. Initial treatment was total abdominal hysterectomy (TAH) and bilateral salpingo-oophrectomy (BSO) in 53/77 (68.9%) cases. Disease-free period was 27.8 months (range, 0-184 months), with disease recurrence in 33/77 (42.85%) cases, most frequent site as lung in 13/33 (39.39%) cases. Management of recurrences was surgery and chemotherapy (CT) in 5/33 (15.15%) and CT in 10/33 (30.30%) of cases. At present, 40.3% of the patients (31/77) are found to be Disease-free. CONCLUSION: Notwithstanding that uterine sarcomas are aggressive neoplasms, most accepted management to date is TAH + BSO, observing that the fact that this procedure is not performed by oncologists does not affect the DFP nor OS, contrary to what occurs in other gynecological neoplasms.

Pharmacokinetic evaluation of gemcitabine hydrochloride for the treatment of cervical cancer.

INTRODUCTION: Cervical cancer is the third most prevalent cancer in females worldwide. When advanced, the disease requires primary radiation concurrent with chemotherapy. However, chemotherapy alone is the standard treatment for recurrent/persistent/metastatic disease. AREAS COVERED: Areas covered in this review include the treatment of advanced cervical cancer with gemcitabine as radiosensitizer, either alone or in combination with cisplatin. The use of gemcitabine for recurrent/persistent/metastatic cervical cancer is also reviewed. EXPERT OPINION: Statistically significantly better survival rates are achieved with cisplatin doublets against cisplatin alone, in the management of recurrent/persistent/metastatic cervical cancer. The choice of the cisplatin doublet with paclitaxel, vinorelbine, gemcitabine and topotecan arms should be based on physician preference, pre-existing morbidity and patient-related factors. In advanced disease, a recently reported Phase III trial establishes the novel regimen of concurrent gemcitabine plus cisplatin and external radiation, followed by brachytherapy and two adjuvant 21-day cycles of gemcitabine plus cisplatin, as significantly improving survival outcomes when compared with the current standard of care. The increased acute toxicity of this regimen is clear; however, this should not deter its incorporation into clinical practice, in that the toxicity is predictable and manageable; nevertheless, the occurrence of late toxicity and survival at longer follow-up time are reasonable concerns in this regimen.

A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results.

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.

Pharmacotherapy options for locally advanced and advanced cervical cancer.

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.