Treatment Of Advanced Cervical Cancer Research Articles

Weekly Cisplatin and Volumetric-Modulated Arc Therapy With Simultaneous Integrated Boost for Radical Treatment of Advanced Cervical Cancer in Elderly Patients: Feasibility and Clinical Preliminary Results.

To evaluate the feasibility and clinical preliminary results of weekly cisplatin and volumetric-modulated arc therapy to the pelvis with simultaneous integrated boost to macroscopic disease in a cohort of elderly patients. Inclusion criteria of this prospective study were age ≥70 years, Karnofsky performance status 70 to 100, locally advanced histologically proven squamous cervical carcinoma, and patients unable to undergo brachytherapy. Radiation doses prescribed were 66 Gy to the macroscopic disease and 54 Gy to the pelvic nodes in 30 fractions. Weekly cisplatin dose was 40 mg/mq. A total of 30 patients were recruited. Median follow-up was 32 months (range: 8-48 months). Median age was 72 years (range: 70-84 years). The 3-year overall survival and local control were 93% and 80%, respectively. The median time to progression was 24 months (range: 6-30 months). Analyzing clinical outcome grouping based on the stage of disease, II versus III, the 3-year overall survival was 100% and 85%, respectively. The 3-year local control was 91% for stage II and 67% for stage III. Acute and late toxicities were acceptable without severe events. Weekly cisplatin and volumetric-modulated arc therapy-simultaneous integrated boost for radical treatment of advanced cervical cancer in the current cohort of elderly patients were feasible. Long-term results and prospective randomized trials are advocated.

Enhanced efficacy against cervical carcinomas through polymeric micelles physically incorporating the proteasome inhibitor MG132.

Treatment of recurrent or advanced cervical cancer is still limited, and new therapeutic choices are needed for improving prognosis and quality of life of patients. Because human papilloma virus (HPV) infection is critical in cervical carcinogenesis, with the E6 and E7 oncogenes of HPV degrading tumor suppressor proteins through the ubiquitin proteasome system, the inhibition of the ubiquitin proteasome system appears to be an ideal target to suppress the growth of cervical tumors. Herein, we focused on the ubiquitin proteasome inhibitor MG132 (carbobenzoxy‐Leu‐Leu‐leucinal) as an anticancer agent against cervical cancer cells, and physically incorporated it into micellar nanomedicines for achieving selective delivery to solid tumors and improving its in vivo efficacy. These MG132‐loaded polymeric micelles (MG132/m) showed strong tumor inhibitory in vivo effect against HPV‐positive tumors from HeLa and CaSki cells, and even in HPV‐negative tumors from C33A cells. Repeated injection of MG132/m showed no significant toxicity to mice under analysis by weight change or histopathology. Moreover, the tumors treated with MG132/m showed higher levels of tumor suppressing proteins, hScrib and p53, as well as apoptotic degree, than tumors treated with free MG132. This enhanced efficacy of MG132/m was attributed to their prolonged circulation in the bloodstream, which allowed their gradual extravasation and penetration within the tumor tissue, as determined by intravital microscopy. These results support the use of MG132 incorporated into polymeric micelles as a safe and effective therapeutic strategy against cervical tumors.

Survival Outcomes of Advanced and Recurrent Cervical Cancer Patients Treated with Chemotherapy: Experience of Northern Tertiary Care Hospital in Thailand.

Chemotherapy is the primary treatment for advanced and recurrent cervical cancer. To evaluate the survival outcomes of chemotherapy and the prognostic factors in this setting, we conducted a retrospective study by reviewing the medical records of advanced and recurrent cervical cancer patients treated with systemic chemotherapy at our institute between January, 2008 and December, 2014. One hundred and seventy-three patients met the criteria with a mean age of 50.9 years. 4.1% of them were HIV positive. The most common initial stage was stage IVB (30.1%) and the most common histology was squamous cell carcinoma (68.6%). Ninety-two (53.2%) patients were previously treated with concurrent chemoradiation with 53% developing combined sites of recurrence. The median recurrence free interval was 16.7 months. Cisplatin + 5 fluorouracil (5FU) (53.2%) was the most frequent first line chemotherapy followed by carboplatin + paclitaxel (20.2%) with an objective response of 39.3%. Seventy-two patients received subsequent chemotherapy. The median overall survival of all studied patients was 13.2 months. Only a recurrence free interval of less than 12 months was an independent prognostic factor for survival outcome. In conclusion, chemotherapy treatment for advanced and recurrent cervical cancer patients showed modest efficacy with a shorter recurrence free survival less than 12 months as a significant poor prognosis factor.

Global strategies for the treatment of early-stage and advanced cervical cancer.

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. 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. 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.

β-Catenin Expression Negatively Correlates with WIF1 and Predicts Poor Clinical Outcomes in Patients with Cervical Cancer.

Aberrant activation of the canonical Wnt pathway plays a significant role in cervical cancer (CC). However, limited data show the correlation between the cancer clinicopathological characteristics and the key molecules such as β-catenin and Wnt inhibitory factor 1 (WIF1). In this study, β-catenin and WIF1 expression were analyzed by immunohistochemistry for 196 patients with CC, 39 with cervical intraepithelial neoplasia (CIN), and 41 with normal cervical epithelium (NCE). Significant overexpression of β-catenin was detected in CC (67.9%) when compared to CIN (43.6%) or NCE (34.1%), p < 0.01, while low WIF1 expression was detected in CC (24.0%) when compared to CIN (59.0%) or NCE (58.5%), p < 0.001. Negative correlation was shown between β-catenin and WIF1 expression (r = −0.637, p < 0.001). In addition, multivariate analysis revealed that both lymph node metastasis and β-catenin expression were the independent prognostic factors not only for disease-free survival (HR = 5.029, p < 0.001; HR = 2.588, p = 0.035, resp.), but also for overall survival (HR = 5.058, p < 0.001; HR = 2.873, p = 0.031, resp.). Our findings indicate that, besides lymph node metastasis, β-catenin expression may also be a poor prognostic factor for CC while WIF1 could be a potential drug target for treatment of advanced CC.

Model assessment of individual tumor control rate and adverse effects in comparing locally advanced cervical cancer treatment using intracavitary with and without interstitial brachytherapy.

PurposeThis study assessed the modeled probability of tumor control and organ at risk toxicities in locally advanced cervical cancer in patients treated by external beam radiation plus brachytherapy using intracavitary combined with interstitial brachytherapy (IC/IS) vs. intracavitary brachytherapy (IC) alone.Material and methodsTwenty cervical cancer patients with a mean HR-CTV volume of 47.4 cm3 and a mean width of 54 mm were planned with both IC/IS and IC brachytherapy alone. A probit model was utilized to model 3-year (3-yr) local control rate (LC), 3-yr cancer specific survival rate (CSS), and the adverse effect (AE) of the organ at risk by using a modeled data set from multiple institutions. Modeling results were used to estimate the LC, CSS, and AE of the treatments in this study.ResultsUsing the IC/IS technique, an EQD2 increase of 12.3 Gy to D90 (from 76.1 Gy to 88.3 Gy) of HR-CTV is expected to increase 3-yr LC and 3-yr CSS by 12.5%, and 11.0%, respectively. Comparing IC/IS to IC alone, the expected G2+ AE were 7.7% vs. 7.9% for the bladder, and 5.9% vs. 6.8% for the rectum.ConclusionsThe IC/IS technique improved dose coverage to the HR-CTV without significantly increasing dose to 2 cm3 of the organ at risk (OAR) surrounding it. With different regimens of EBRT combined with BT, IC/IS can be used to increase the probability of LC and CSS, or decrease the risk of AE.

D01* - MITO (Multicentre Italian Trials in Ovarian cancer) - CERV 2 trial: a randomized phase II study of carboplatin and paclitaxel +/- cetuximab, in advanced and/or recurrent cervical cancer

Background: Carboplatin (C) plus paclitaxel (P) is among standard options for treatment of advanced or recurrent cervical cancer (ARCC) patients (pts). Cervical cancer cells often express Epidermal Growth Factor receptor (EGFR). Cetuximab (CET), an anti-EGFR monoclonal antibody, can be safely combined with CP. MITO-CERV 2 is a comparative randomized phase 2 study, testing the addition of CET to CP. Methods: ARCC pts, <2 previous chemotherapy, ECOG PS = 1, were randomized to CP (C AUC5 + P 175 mg/m2, d1q21) for 6 cycles +/- CET (400 mg/m2 one week before starting CP, then 250 mg/m2 weekly) until disease progression or unacceptable toxicity. Primary endpoint was event-free survival (EFS), i.e. time from randomization to progression, death, definitive discontinuation of the whole treatment or loss to follow-up, whichever occurred first. With a 4.5 mos expected median EFS and a 6.4 mos auspicated EFS (HR 0.70), 0.20 one-tailed a and 80% power, 89 events were required for the final intent-to-treat analysis. Results: 108 pts were randomly assigned to CP (n = 53) or to CP-CET (n = 55). Median age was 50, 69% were PS0, 76% had recurrent disease, 91% had distant metastasis and 57% had received previous chemotherapy. A median number of 6 CP cycles was given in both arms. After a median follow-up of 23 mos (95% CI:20-26), 102 pts had an event, 97 progressed and 61 died. Median EFS was 4.7 and 6.0 mos (one-tail p = 0.43), median PFS was 5.2 and 7.6 mos (one-tail p = 0.20) and median OS was 17.7 and 17 mos (one-tail p = 0.27), with CP and CP-CET, respectively. One patient died for a stroke during standard treatment. There was no difference in the occurrence of severe side-effects, except grade 3-4 skin toxicity reported only with CP-CET (8 cases, 6 with acneiform rash, p = 0.004). Out of 86 patients eligible for RECIST, objective response rate was 43% and 38% with CP and CP-CET respectively (p = 0.63). Conclusion: The addition of CET to CP is not worthy of further investigation in unselected ARCC pts. Efforts are ongoing to retrospectively collect tumor samples for an exploratory biomarker analysis. ClinicalTrials.gov NCT00997009. Partially supported by Merck Serono.

MITO (Multicentre Italian Trials in Ovarian cancer): CERV 2 trial—A randomized phase II study of carboplatin and paclitaxel +/- cetuximab, in advanced and/or recurrent cervical cancer.

5520 Background: Carboplatin (C) plus paclitaxel (P) is among standard options for treatment of advanced or recurrent cervical cancer (ARCC) patients (pts). Cervical cancer cells often express Epidermal Growth Factor receptor (EGFR). Cetuximab (CET), an anti-EGFR monoclonal antibody, can be safely combined with CP. MITO-CERV 2 is a comparative randomized phase 2 study, testing the addition of CET to CP. Methods: ARCC pts, < 2 previous chemotherapy, ECOG PS≤1, were randomized to CP (C AUC5 + P 175 mg/m², d1q21) for 6 cycles +/- CET (400 mg/m² one week before starting CP, then 250 mg/m² weekly) until disease progression or unacceptable toxicity. Primary endpoint was event-free survival (EFS), i.e. time from randomization to progression, death, definitive discontinuation of the whole treatment or loss to follow-up, whichever occurred first. With a 4.5 mos expected median EFS and a 6.4 mos auspicated EFS (HR 0.70), 0.20 one-tailed α and 80% power, 89 events were required for the final intent-to-treat analysis...

A limited access phase I trial of paclitaxel, cisplatin and ABT-888 in the treatment of advanced, persistent, or recurrent carcinoma of the cervix: An NRG/GOG study.

5600 Background: The poly (ADP-ribose) polymerase (PARP) family of proteins is a family of nuclear enzymes required for the repair of single-stranded DNA damage. Preclinical studies demonstrate that PARP inhibition (PARPi) not only augments the apoptotic response in cervical cancer cell lines, but also sensitizes cells to the effects of alkylating agents like cisplatin. Given the use of cisplatin and paclitaxel as primary treatment for advanced, recurrent or metastatic cervical cancer before the findings of the benefit of adding bevacizumab in GOG 240, we aimed to evaluate whether PARPi can enhance the chemotherapy effectiveness in the treatment of cervical cancer. Methods: Patient eligibility criteria: Females age ≥ 18 years with persistent or recurrent squamous or adenocarcinoma of the cervix with documented disease progression (disease not amenable to curative therapy). Patients were not required to have measurable disease; have had concurrent chemotherapy and radiation for management of their disease;...

Impact of older age on chemotherapy toxicity and quality of life in women with advanced or recurrent cervical cancer: A NRG Oncology-GOG Ancillary Study.

5604 Background: To evaluate chemotoxicity and quality of life (QOL) in older women undergoing treatment for recurrent and advanced cervical cancer within Gynecologic Oncology Group (GOG) phase III...

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/m2 as single agent for 4 weeks (induction phase), then concurrent with 6 21-day cycles of gemcitabine (800 mg/m2) or cisplatin (50 mg/m2) 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 were163 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.

Bevacizumab for advanced cervical cancer: patient-reported outcomes of a randomised, phase 3 trial (NRG Oncology–Gynecologic Oncology Group protocol 240)

GOG 240 was a practice-changing randomised phase 3 trial that concluded that chemotherapy plus bevacizumab for advanced cervical cancer significantly improves overall and progression-free survival, and the proportion of patients achieving an overall objective response, compared with chemotherapy alone. In this study, we aimed to analyse patient-reported outcomes in GOG 240. Eligible adult participants (aged ≥18 years) had primary stage IVB or recurrent or persistent carcinoma of the cervix with measurable disease and GOG performance status of 0-1. Participants were randomly assigned by web-based permuted block randomisation (block size 4) in a 1:1:1:1 ratio to the four treatment groups: cisplatin (50 mg/m(2) intravenously on day 1 or 2 of the treatment cycle) and paclitaxel (135 mg/m(2) intravenously over 24 h or 175 mg/m(2) intravenously over 3 h on day 1), with or without bevacizumab (15 mg/kg intravenously on day 1 or 2), or paclitaxel (175 mg/m(2) over 3 h on day 1) and topotecan (0·75 mg/m(2) for 30 min on days 1-3) with or without bevacizumab (15 mg/kg intravenously on day 1). Treatment assignment was concealed at randomisation (everyone was masked to treatment assignment, achieved by the use of a computer encrypted numbering system at the National Cancer Institute) and became open-label when each patient was registered to the trial. Treatment cycles were repeated every 21 days until disease progression or unacceptable toxicity, whichever occurred first. The coprimary endpoints of the trial were overall survival and safety; the primary quality-of-life endpoint was the score on the Functional Assessment of Cancer Therapy-Cervix Trial Outcome Index (FACT-Cx TOI). For our analysis of patient-reported outcomes, participants were assessed before treatment cycles 1, 2, and 5, and at 6 and 9 months after the start of cycle 1, with the FACT-Cx TOI, items from the FACT-GOG-Neurotoxicity subscale, and a worst pain item from the Brief Pain Inventory. All patients who completed baseline quality-of-life assessments and at least one further follow-up assessment were evaluable for quality-of-life outcomes. This study is registered with ClinicalTrials.gov, number NCT00803062. Between April 6, 2009, and Jan 3, 2012, a total of 452 patients were enrolled in the trial, of whom 390 completed baseline quality-of-life assessment and at least one further assessment and were therefore evaluable for quality-of-life outcomes. In these patients, patient-reported outcome completion declined from 426 (94%) of 452 (at baseline) to 193 (63%) of 307 (9 months post-cycle 1), but completion rates did not differ significantly between treatment regimens (p=0·78). The baseline FACT-Cx TOI scores did not differ significantly between patients who received bevacizumab versus those who did not (p=0·27). Compared with patients who received chemotherapy alone, patients who received chemotherapy plus bevacizumab reported FACT-Cx TOI scores that were an average of 1·2 points lower (98·75% CI -4·1 to 1·7; p=0·30). Improvements in overall survival and progression-free survival attributed to the incorporation of bevacizumab into the treatment of advanced cervical cancer were not accompanied by any significant deterioration in health-related quality of life. Patients responding to anti-angiogenesis therapy who maintain an acceptable quality of life could be suitable at progression for treatment with other novel therapies that might confer additional benefit. National Institutes of Health.

Laparoscopic Anterior Exenteration With Intracorporeal Uretero-Sigmoidostomy

To demonstrate the feasibility of laparoscopic anterior exenteration with intracorporeal ureterosigmoidostomy. After Institutional Review Board approval was obtained, patients who had undergone laparoscopic anterior exenteration with intracorporeal ureterosigmoidostomy were analyzed. Fifty-seven patients with advanced cervical carcinoma, stage IV A, since 2005 were analyzed retrospectively. The preoperative workup was done with contrast-enhanced computed tomography abdomen-pelvis and positron emission tomography (PET) scans. Patients were analyzed for operative time, blood loss, and complications. Patient follow-up was done monthly for the first 3 months, every 3 months for 1 year, and then every 6 months for 3 years. Postoperative follow-up was done with PET scans. Galaxy Care Laparoscopic Institute, Pune, India. Operative steps were as follows: The mean operative time was 180 minutes (range, 140-240 minutes), and mean blood loss was 100 mL (range, 50-200 mL), as measured by the amount of blood in the suction machine. The median duration of hospital stay was 4 days (range, 3-7 days). The mean number of lymph nodes retrieved was 12 (range, 9-21). Surgical margins were negative in all patients with a lateral margin >2 cm. Twenty-eight patients had positive lymph nodes. Chemoradiotherapy was given to the patients with positive lymph nodes. Minor leak was present in 11 patients in the immediate postoperative period, for which no active intervention was required. Hyperchloremic metabolic acidosis which was seen on biochemical parameter but clinically patient have no manifestation and was treated with sodium bicarbonate. A postoperative PET scan was done at 6 months after the completion of adjuvant therapy in lymph node-positive patients and 6 months after surgery in node-negative patients. Exenteration has a definitive role in the treatment of advanced cervical cancer. Results have demonstrated the feasibility of this procedure [1-4].

The effect of carbogen breathing and nicotinamide added to standard (chemo)radiation treatment of advanced cervical cancer in Indonesia.

Chemoradiation is the standard therapy for advanced stages of cervical cancer. In developing countries, where 80% of cervical cancers occur, this is not always available. Carbogen breathing and oral nicotinamide (CON) therapy, aimed at overcoming tumor hypoxia, has shown to improve treatment efficacy in some epithelial tumors. This study investigates the effect of CON during (chemo)radiation of advanced stages of cervical cancer on overall survival, local and regional control, and toxicity. From December 2006 to February 2010, 139 patients with stage IB2 to IVA cervical cancer were nonrandomly assigned to receive radiotherapy (RT) or chemoradiation (CRT) with or without CON. Differences in overall survival, local and regional control after 1 year, and toxicity were assessed in 113 evaluable patients. Thirty-two patients received RT, 16 received CRT, 45 received CON-RT, and 20 received CON-CRT. The CON-RT and RT groups contained significantly more patients with a poor performance status and IIIB and IVA tumors. Despite these differences in baseline characteristics, overall survival and local and regional control at 1 year were not significantly different (P = 0.10 and P = 0.19, respectively). Toxicity scores also did not differ (P = 0.60 and P = 0.73 for acute and late toxicity). Addition of CON to standard (chemo)radiation gives comparable survival and control rates. The effect of CON might be underestimated due to differences in baseline characteristics. Because chemotherapy cannot always be (completely) administered in low-resource settings, CON could be a worthy substitute. The CON treatment is feasible and safe.

Observation of the effect of neoadjuvant chemotherapy for patients with advanced cervical cancer

Objective To observe the effect of neoadjuvant chemotherapy for patients with advanced cervical cancer.Methods According to the digital table ,106 patients with advanced cervical cancer were randomly divided into the two groups ,53 cases in each group .The observation group was given TP Scheme neoadjuvant chemotherapy before surgery ,the control group underwent surgery directly .The total effective rate of chemotherapy and the changes of diameter of tumor before and after chemotherapy were observed .The serum levels of vascular endothelial growth fac-tor（VEGF） and matrix metalloproteinase-9（MMP-9） of the observation group were detected ,and the operation condi-tions were compared between the two groups .Results After chemotherapy ,the total effective rate of the observation group was 60.4%.Before and after chemotherapy ,the average tumor diameter of the observation group was （5.24 ± 1.35）cm,（2.64 ±0.67）cm,respectively,the difference was significant （t=3.947,P〈0.05）.The operative time, blood loss and lymph node metastasis in the observation group were significantly less than those in the control group （t=3.725,5.392,χ2 =4.28,P〈0.05 or P〈0.01）.After chemotherapy,the serum levels of VEGF and MMP-9 were significantly lower than that before chemotherapy （t=3.130,4.724,all P〈0.05）.Conclusion Neoadjuvant chemotherapy in the treatment of advanced cervical cancer can significantly reduce serum VEGF and MMP-9 expression. Key words: Uterine cervical neoplasms; Antineoplastic combined chemotherapy protocols; Vascular endothe-lial growth factors; Matrix metalloproteinase 9

Abstract 5411: Curcumin nanoformulation: A new therapeutic approach for cervical cancer treatment

Abstract Background: Cervical cancer is one of the most common and deadly cancers among women worldwide and is associated with persistent Human Papillomavirus (HPV) infection. Currently, Cisplatin based chemo and radio therapy is the best standard treatment for cervical cancer. While screening for cervical cancer can reduce the incidence and mortality, treatment of advanced stage cervical cancer is difficult and often unsuccessful. Resistance to chemo-radio therapy with prolonged treatment, resulting in an invasive form of cancer, requires the development of novel therapeutic modalities to conquer chemo resistance and improve overall life expectancy of patients. Nanotechnology provides targeted delivery of anti-cancer drugs and indicates a new approach for cancer diagnosis and treatment. Our lab has developed PLGA (poly [lactic-co-glycolic acid]), an FDA approved polymer coated nanoparticle(s) using a well-known anti-cancer drug Curcumin (CUR) for the enhanced bioavailability and improved therapeutic efficacy of CUR. Therefore, “we hypothesized that having targeted drug delivery, curcumin nanoparticles (NC) will show improved anti-cancerous effects on cervical cancer cells and will also overcome drug (Cisplatin) resistance when compared with free curcumin.” Methods: The effect of NC on the proliferation of Caski cervical cancer cells was determined by MTS and colony formation assay. Annexin V/7AAD and propidium iodide (PI) staining was analyzed by flow cytometry to determine NC's effect on apoptosis and cell cycle inhibition, respectively. The expression of apoptotic markers such as poly (ADP-ribose) polymerase (PARP), Caspase 3 and Caspase 9 was determined by immunoblotting. The potential of NC to modulate the expression of miRNAs associated with drug resistance was determined by quantitative RT-PCR. In order to assess efficacy of NC to reduce tumor growth, an orthotopic mouse model was generated using Caski cells stably transfected with fluorescent gene td tomato. Results: NC effectively inhibited Caski cell growth and also induced apoptosis as determined by staining for Annexin V/7AAD and immunoblotting for cleaved PARP, Caspase 3, and Caspase 9. PI staining clearly revealed that NC treatment arrests growth cycle of Caski cells in the G1- S phase. Additionally, NC treatment caused a marked decrease in the levels of miRNA 21, an oncomiRNA associated with chemoresistance, and enhanced miRNA 214, a tumor suppressor, when compared to free Curcumin. Moreover, NC formulation effectively reduces the tumor burden in athymic nude mice. Conclusion: Our findings show that PLGA based NC significantly inhibits Caski cervical cancer cell growth and regulates the expression of miRNAs, associated with cervical cancer. In vivo experiments show that NC is efficacious in reducing the tumor burden. Therefore, NC may be a novel chemo-preventive and therapeutic modality for the overall management of cervical cancer. Citation Format: Mohd Saif Zaman, Neeraj Chauhan, Diane M. Maher, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan. Curcumin nanoformulation: A new therapeutic approach for cervical cancer treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5411. doi:10.1158/1538-7445.AM2014-5411

Multimodal treatment of patients with advanced cervical cancer

Local progressive tumor growth involving the urinary tract with no distant metastases is known to be one of the features of cervical cancer in the advanced stages. Approximately 68 % of patients in stage T3-T4 have various uroevolution disorders. The severity of their condition often is caused by an increasing renal failure or a fever, those are associated with obstructive pyelonephritis and often are interpreted as the carcinogenic intoxication. Therefore, any special antineoplastic therapy methods are considered as unpromising even for patients without concomitant diseases. The authors conducted a retrospective analysis of 11 patients with the treatment of advanced non-metastatic cervical cancer, which included both surgery and neoadjuvant polychemotherapy (PCT). Our results demonstrate the advisability of multimodal phasing treatment of those patients, compared with palliative radiotherapy and symptomatic treatment.

Cost-Effectiveness Analysis of 3D Image-Guided Brachytherapy Compared to 2D Brachytherapy in the Treatment of Locally Advanced Cervical Cancer

3D Image-guided brachytherapy (IGBT) is a significant advancement in locally advanced cervical cancer treatment. Prospective and retrospective data have shown improved local control and decreased morbidity with this technique. However, the cost-effectiveness of this approach, which requires additional resources including repetitive cross-sectional imaging, is not known. We performed a cost-effectiveness (C/E) analysis of IGBT compared to conventional (2D) brachytherapy in the treatment of locally-advanced cervical cancer. A Markov model using a 1-month cycle with a 3-year follow-up period after completion of treatment was constructed to model locally advanced cervical cancer treated with five fractions of high-dose rate brachytherapy. The model captured clinical parameters (including improvement in survival, local control and RTOG late Grade 3 and above complication rates), quality of life utility, and cost associated with IGBT and 2D brachytherapy. Model assumptions regarding clinical outcomes and quality of life utility were obtained through a comprehensive literature review. Cost was based on Medicare reimbursement in 2013. Strategies were compared using the incremental cost effectiveness ratio (ICER), and effectiveness was measured in quality-adjusted life years (QALYs). To account for uncertainty, one-way and Monte Carlo probabilistic sensitivity analyses were performed. Strategies were evaluated from the health care system perspective with a willingness-to-pay threshold of $50,000/QALY gained. The base cost of treatment for five fractions of IGBT and 2D brachytherapy was $21000 and $17000, respectively. In the base case analysis, the IGBT strategy cost $3555 more than 2D while gaining 0.16 QALYs, resulting in an ICER of $22,453 per QALY gained. In one-way sensitivity analyses, which varied all parameters individually, results were most sensitive to variation of treatment costs (range: ICER of -$4000 to $49000/QALY gained), but the ICER remained <$50,000/QALY gained if IGBT costs were <$25,400 (baseline $21,000). Variation of survival, local control, and complication rates were less influential. A Monte Carlo probabilistic sensitivity analysis, which varied all model parameters simultaneously 5000 times, demonstrated that IGBT was favored in 63% of model iterations at a $50,000/QALY gained threshold. IGBT for locally-advanced cervical cancer is a cost effective option compared to 2D brachytherapy based upon the ICER analysis. These findings were robust to variation of parameter values, both individually and collectively, supporting the routine use of IGBT in locally-advanced cervical cancer.

Chemotherapy in the treatment of metastatic, persistent, and recurrent cervical cancer.

Patients with cervical cancer represent a vulnerable population with limited chemotherapeutic options. This year, two large trials focusing on detection/screening and treatment of advanced stage cervical cancer were featured in the opening plenary session of the American Society of Clinical Oncology Annual Meeting. As such, a review of the evolution of chemotherapy in the treatment of this disease is warranted. Following the establishment of cisplatin as an effective single-agent regimen in patients with advanced stage, recurrent, or persistent cervical cancer, several platinum-containing combinations were studied. Ultimately, the adoption of cisplatin chemosensitizing radiation resulted in relative 'cisplatin resistance' and the concept of nonplatinum doublets emerged as an active area of investigation. In an era of biologics, combined therapy with cytotoxic drugs and molecular targeted agents, as well as the use of nonplatinum doublets, represent an exciting area yet to be fully explored.

Phase II trial of paclitaxel, 13-cis retinoic acid, and interferon-alfa-2b in the treatment of advanced stage or recurrent cervical cancer

Phase II trial of paclitaxel, 13-cis retinoic acid, and interferon-alfa-2b in the treatment of advanced stage or recurrent cervical cancer