Minimally invasive trans-sulcal parafascicular surgical resection of cerebral tumors: translating anatomy to early clinical experience.

The minimally invasive port-based trans-sulcal parafascicular surgical corridor (TPSC) has incrementally evolved to provide a safe, feasible, and effective alternative to access subcortical and intraventricular pathologies. A detailed anatomical foundation is important in mitigating cortical and white matter tract injury with this corridor. Thus, the aims of this study are (1) to provide a detailed anatomical construct and overview of TPSCs and (2) to translate an anatomical framework to early clinical experience. Based on regional anatomical constraints, suitable parafascicular entry points were identified and described. Fiber tracts at both minimal and increased risks for each corridor were analyzed. TPSC-managed cases for metastatic or primary brain tumors were retrospectively reviewed. Adult patients 18 years or older with Karnofsky Performance Status (KPS) ≥ 70 were included. Subcortical brain metastases between 2 and 6 cm or primary brain tumors between 2 and 5 cm were included. Patient-specific corridors and trajectories were determined using MRI-tractography. Anatomy: The following TPSCs were described and translated to clinical practice: superior frontal, inferior frontal, inferior temporal, intraparietal, and postcentral sulci. Clinical: Eleven patients (5 males, 6 females) were included (mean age = 52 years). Seven tumors were metastatic, and 4 were primary. Gross total, near total, and subtotal resection was achieved in 7, 3, and 1 patient(s), respectively. Three patients developed intraoperative complications; all recovered from their intraoperative deficits and returned to baseline in 30 days. A detailed TPSC anatomical framework is critical in conducting safe and effective port-based surgical access. This review may represent one of the few early translational TPSC studies bridging anatomical data to clinical subcortical and intraventricular surgical practice.

Cost-effectiveness analysis of first and second-generation EGFR tyrosine kinase inhibitors as first line of treatment for patients with NSCLC harboring EGFR mutations.

BACKGROUND: Tyrosine-kinase inhibitors (TKIs) have become the cornerstone treatment of patients with non-small cell lung cancer that harbor oncogenic EGFR mutations. The counterpart of these drugs is the financial burden that they impose, which often creates a barrier for accessing treatment in developing countries. The aim if the present study was to compare the cost-effectiveness of three different first and second generation TKIs. METHODS: We designed a retrospective cost-effectiveness analysis of three different TKIs (afatinib, erlotinib, and gefitinib) administered as first-line therapy for patients with NSCLC that harbor EGFR mutations. RESULTS: We included 99 patients with the following TKI treatment; 40 treated with afatinib, 33 with gefitinib, and 26 with erlotinib. Median PFS was not significantly different between treatment groups; 15.4 months (95% CI 9.3-19.5) for afatinib; 9.0 months (95% CI 6.3- NA) for erlotinib; and 10.0 months (95% CI 7.46-14.6) for gefitinib. Overall survival was also similar between groups: 29.1 months (95% CI 25.4-NA) for afatinib; 27.1 months (95% CI 17.1- NA) for erlotinib; and 23.7 months (95% CI 18.6-NA) for gefitinib. There was a statistically significant difference between the mean TKIs costs; being afatinib the most expensive treatment. This difference was observed in the daily cost of treatment (p < 0.01), as well as the total cost of treatment (p = 0.00095). Cost-effectiveness analysis determined that afatinib was a better cost-effective option when compared with first-generation TKIs (erlotinib and gefitinib). CONCLUSION: In our population, erlotinib, afatinib, and gefitinib were statistically equally effective in terms of OS and PFS for the treatment of patients with advanced EGFR-mutated NSCLC population. Owing to its marginally increased PFS and OS, the cost-effectiveness analysis determined that afatinib was a slightly better cost-effective option when compared with first-generation TKIs (erlotinib and gefitinib).

Survival of Patients with Advanced Non-Small Cell Lung Cancer Enrolled in Clinical Trials.

BACKGROUND: Up-to-date oncological therapy has been accomplished through the results of clinical trials (CTs). We analyzed the overall survival (OS) of patients with non-small cell lung cancer (NSCLC) and its relation to CT enrollment. METHODS: The study included 1,042 patients with advanced NSCLC treated at the Instituto Nacional de Cancerología. All patients received treatment according to the national and international guidelines. Data were collected from medical records. Patients were subgrouped on the basis of their CT enrollment as follows: participants in any CT (ACT), exclusively intervention CTs (ICT) or exclusively pharmaceutical-sponsored CTs (PCT). RESULTS: The CT enrollment effect was assessed through a multivariate Cox proportional hazards model. Thirty percent of the patients were in ACT, 28.3% in ICT and 13.7% in PCT. Female gender (p = 0.001), adenocarcinoma histology (p = 0.018), positive EGFR mutation (p = 0.006), and better ECOG performance status (<2) (p ≤ 0.0001) were more frequent in patients enrolled in CT; further, tobacco smoking (p ≤ 0.0001) and KRAS mutation (p = 0.001) were more frequent in patients who were not enrolled in a CT. CONCLUSION: Enrollment in ACT was associated with a better OS (hazard ratio: 0.47-0.74). NSCLC patients enrolled in a CT have an improved survival in an independent manner to other prognostic factors.

Ion Channels and Personalized Medicine in Gynecological Cancers.

Targeted therapy against cancer plays a key role in delivering safer and more efficient treatments. In the last decades, ion channels have been studied for their participation in oncogenic processes because their aberrant expression and/or function have been associated with different types of malignancies, including ovarian, cervical, and endometrial cancer. The altered expression or function of several ion channels have been associated with tumor aggressiveness, increased proliferation, migration, invasion, and metastasis of cancer cells and with poor prognosis in gynecological cancer patients. Most ion channels are integral membrane proteins easily accessible by drugs. Interestingly, a plethora of ion channel blockers have demonstrated anticancer activity. Consequently, some ion channels have been proposed as oncogenes, cancer, and prognostic biomarkers, as well as therapeutic targets in gynecological cancers. Here, we review the association of ion channels with the properties of cancer cells in these tumors, which makes them very promising candidates to be exploited in personalized medicine. The detailed analysis of the expression pattern and function of ion channels could help to improve the clinical outcomes in gynecological cancer patients.

Ion Channels as Potential Tools for the Diagnosis, Prognosis, and Treatment of HPV-Associated Cancers.

The human papilloma virus (HPV) group comprises approximately 200 genetic types that have a special affinity for epithelial tissues and can vary from producing benign symptoms to developing into complicated pathologies, such as cancer. The HPV replicative cycle affects various cellular and molecular processes, including DNA insertions and methylation and relevant pathways related to pRb and p53, as well as ion channel expression or function. Ion channels are responsible for the flow of ions across cell membranes and play very important roles in human physiology, including the regulation of ion homeostasis, electrical excitability, and cell signaling. However, when ion channel function or expression is altered, the channels can trigger a wide range of channelopathies, including cancer. In consequence, the up- or down-regulation of ion channels in cancer makes them attractive molecular markers for the diagnosis, prognosis, and treatment of the disease. Interestingly, the activity or expression of several ion channels is dysregulated in HPV-associated cancers. Here, we review the status of ion channels and their regulation in HPV-associated cancers and discuss the potential molecular mechanisms involved. Understanding the dynamics of ion channels in these cancers should help to improve early diagnosis, prognosis, and treatment in the benefit of HPV-associated cancer patients.

Prophylactic Cranial Irradiation Reduces Brain Metastases and Improves Overall Survival in High-Risk Metastatic Non-Small Cell Lung Cancer Patients: A Randomized phase 2 Study (PRoT-BM trial).

PURPOSE: To date, studies regarding the use of prophylactic cranial irradiation (PCI) versus standard of care (SoC) for patients with non-small cell lung cancer (NSCLC) have not shown a significant effect in terms of overall survival (OS). Additionally, the effect of PCI among high-risk patients has been scarcely studied. The objective of this randomized phase 2 study was to evaluate the role of PCI in a population of patients at high risk for development of brain metastases (BM). METHODS AND MATERIALS: Eligible patients had histologically confirmed NSCLC without baseline BM, harboring epidermal growth factor receptor mutations, anaplastic lymphoma kinase rearrangements, or elevated carcinoembryonic antigen levels at the time of diagnosis. Participants received systemic therapy according to molecular status, those without progressive disease were then assigned to receive SoC or SoC + PCI (25 Gy in 10 fractions). The primary outcome was cumulative incidence of brain metastases (CBM). The secondary endpoints included progression-free survival and OS. Quality of life and neurocognitive function are discussed in a separate article (Clinicaltrials.gov: NCT01603849). RESULTS: From May 2012 to December 2017, 84 patients were enrolled in the study, with 41 patients allocated to receive PCI and 43 received SoC. Patients allocated to receive PCI had a CBM at 24 months of 7% versus 38% in those allocated to the SoC arm. PCI was associated with a hazard ratio of 0.12 (95% confidence interval, 0.035-0.42) for developing BM. A benefit in OS was also observed (64.5 vs 19.8 months; hazard ratio: 0.41 (95% confidence interval, 0.22-0.78; P =∙007). CONCLUSIONS: Among a selected population at high risk for developing BM, PCI significantly decreased CBM in addition to increasing progression-free survival and OS. To our knowledge, this is the first study to evaluate PCI in epidermal growth factor receptor mutations, anaplastic lymphoma kinase rearrangements, or elevated carcinoembryonic antigen levels in patients with NSCLC, showing a significant improvement in CBM. This relevant information should be of particular importance in the context of patients without access to third-generation targeted agents. Further studies are warranted to ascertain this effect.

Brain metastasis development and poor survival associated with carcinoembryonic antigen (CEA) level in advanced non-small cell lung cancer: a prospective analysis.

BACKGROUND: Central nervous system is a common site of metastasis in NSCLC and confers worse prognosis and quality of life. The aim of this prospective study was to evaluate the prognostic significance of clinical-pathological factors (CPF), serum CEA levels, and EGFR and HER2 tissue-expression in brain metastasis (BM) and overall survival (OS) in patients with advanced NSCLC. METHODS: In a prospective manner, we studied 293 patients with NSCLC in IIIB-IV clinical stage. They received standard chemotherapy. CEA was measured prior to treatment; EGFR and HER2 were evaluated by immunohistochemistry. BM development was confirmed by MRI in symptomatic patients. RESULTS: BM developed in 27, and 32% of patients at 1 and 2 years of diagnosis with adenocarcinoma (RR 5.2; 95% CI, 1.002-29; p = 0.05) and CEA > or = 40 ng/mL (RR 11.4; 95% CI, 1.7-74; p < 0.01) as independent associated factors. EGFR and HER2 were not statistically significant. Masculine gender (RR 1.4; 95% CI, 1.002-1.9; p = 0.048), poor performance status (RR 1.8; 95% CI, 1.5-2.3; p = 0.002), advanced clinical stage (RR 1.44; 95% CI, 1.02-2; p = 0.04), CEA > or = 40 ng/mL (RR 1.5; 95% CI, 1.09-2.2; p = 0.014) and EGFR expression (RR 1.6; 95% CI, 1.4-1.9; p = 0.012) were independent associated factors to worse OS. CONCLUSION: High CEA serum level is a risk factor for BM development and is associated with poor prognosis in patients with advanced NSCLC. Surface expression of CEA in tumor cells could be the physiopathological mechanism for invasion to CNS.

Radical consolidative treatment provides a clinical benefit and long-term survival in patients with synchronous oligometastatic non-small cell lung cancer: A phase II study.

OBJECTIVES: Evidence is rapidly accumulating for the use of radical consolidative treatment (RCT) for patients with oligometastatic non-small cell lung cancer (NSCLC). Nonetheless, published studies have several limitations, including a selection of patients whose favorable characteristics might dictate therapeutic success, as well as scarce prospective data regarding overall survival (OS). The objective of this study was to determine whether RCT increases OS in patients with oligometastatic NSCLC. MATERIALS AND METHODS: In this prospective, single-arm phase II study, we sought to evaluate the efficacy of RCT in patients with oligometastatic NSCLC in terms of OS. Patients with pathologically confirmed stage IV NSCLC who presented ≤5 synchronous, any-site metastases (including central nervous system [CNS] metastases), as assessed by PET-CT, were included. All patients received four initial cycles of systemic treatment. Following, those with stable disease/partial response received RCT to the primary site and metastases. The response to RCT was evaluated with PET-CT. The primary end-point was OS. Secondary end-points included progression-free survival (PFS) and best response by PET-CT. The study is registered in clinicaltrials.gov (NCT02805530). RESULTS: Thirty-seven patients were included in the analysis. The mean age was 55.8 years (range: 33-75 years). At diagnosis, 43.2% of patients presented with CNS metastases. Following RCT, 19 (51.4%) patients achieved a complete-response (CR) by PET-CT, while 18 (48.6%) had a non-complete response (NON-CR). The median OS was nonreached (NR) and was positively affected by CR on PET-CT (NR vs. 27.4 [95% CI: 16.4-38.3]; p = 0.011). The median PFS was 23.5 months (95% CI: 13.6-33.3) and was positively affected by CR on PET-CT (NR vs. 14.3 [95% CI: 11.7-16.9]; p < 0.001; HR: 0.19 [0.07-0.52]; p=0.001). CONCLUSION: Patients with oligometastatic NSCLC who undergo RCT have a high response rate and favorable OS. Patients with a CR by PET-CT have significantly longer OS, rendering this an important potential prognostic marker.

Breast cancer in Latin America: results of the Latin American and Caribbean Society of Medical Oncology/Breast Cancer Research Foundation expert survey.

The incidence of breast cancer in Latin American countries is lower than that in more developed countries, whereas the mortality rate is higher. These differences probably are related to differences in screening strategies and access to treatment. Population-based data are needed to make informed decisions. A 65-question telephone survey that included 100 breast cancer experts from 12 Latin American countries was conducted in 2006 as an exploratory analysis of the current state of breast cancer treatment in these regions at both at the country level and at the center level. Greater than 90% of countries had no national law or guideline for mammography screening. The access rate to mammography was 66.3% at the country level and 47% at the center level. Variation in care based on level (country vs center) was indicated for the timing of treatment after diagnosis, timing from initial diagnosis to treatment, and the time from surgery to initial chemotherapy. However, the more sophisticated diagnostic testing for hormone receptors and biomarkers were available at most centers (>80%), and, overall, nearly 80% of patients started treatment within 3 months of diagnosis. Variation in care between breast cancer care at the center level versus the country level indicated a need for national cancer care programs. Alternative data collection strategies for understanding the state of breast cancer control programs in developing countries can help identify areas of improvement.

High Smac/DIABLO expression is associated with early local recurrence of cervical cancer.

BACKGROUND: In a recent pilot report, we showed that Smac/DIABLO mRNA is expressed de novo in a subset of cervical cancer patients. We have now expanded this study and analyzed Smac/DIABLO expression in the primary lesions in 109 cervical cancer patients. METHODS: We used immunohistochemistry of formalin-fixed, paraffin-embedded tissue sections to analyze Smac/DIABLO expression in the 109 primary lesions. Seventy-eight samples corresponded to epidermoid cervical cancer and 31 to cervical adenocarcinoma. The median follow up was 46.86 months (range 10-186). RESULTS: Smac/DIABLO was expressed in more adenocarcinoma samples than squamous tumours (71% vs 50%; p = 0.037). Among the pathological variables, a positive correlation was found between Smac/DIABLO immunoreactivity and microvascular density, a marker for angiogenesis (p = 0.04). Most importantly, Smac/DIABLO immunoreactivity was associated with a higher rate of local recurrence in squamous cell carcinoma (p = 0.002, log rank test). No association was found between Smac/DIABLO and survival rates. CONCLUSION: Smac/DIABLO expression is a potential marker for local recurrence in cervical squamous cell carcinoma patients.

Inhibitors of apoptosis proteins in human cervical cancer.

BACKGROUND: It has been shown that IAPs, in particular XIAP, survivin and c-IAP1, are overexpressed in several malignancies. In the present study we investigate the expression of c-IAP1, c-IAP2, XIAP and survivin and its isoforms in cervical cancer. METHODS: We used semiquantitative RT-PCR assays to analyze 41 cancer and 6 normal tissues. The study included 8 stage I cases; 16 stage II; 17 stageIII; and a control group of 6 samples of normal cervical squamous epithelial tissue. RESULTS: c-IAP2 and XIAP mRNA levels were similar among the samples, cervical tumors had lower c-IAP1 mRNA levels. Unexpectedly, a clear positive association was found between low levels of XIAP and disease relapse. A log-rank test showed a significant inverse association (p = 0.02) between XIAP expression and tumor aggressiveness, as indicated by disease relapse rates. There were no statistically significant differences in the presence or expression levels of c-IAP1 and c-IAP2 among any of the clinical variables studied. Survivin and its isoforms were undetectable in normal cervical tissues, in contrast with the clear upregulation observed in cancer samples. We found no association between survivin expression and age, clinical stage, histology or menopausal state. Nevertheless, we found that adenocarcinoma tumors expressed higher levels of survivin 2B and DeltaEx3 (p = 0.001 and p = 0.04 respectively, by Kruskal-Wallis). A multivariate Cox's partial likelihood-based analysis showed that only FIGO stage was an independent predictor of outcome. CONCLUSION: There are no differences in the expression of c-IAP2 and XIAP between normal vs. cancer samples, but XIAP expression correlate in cervical cancer with relapse of this disease in the patients. Otherwise, c-IAP1 was downregulated in the cervical cancer samples. The expression of survivin was upregulated in the patients with cervical cancer. We have found that adenocarcinoma presented higher levels of survivin isoforms 2B and DeltaEx3.

A phase II study of gemcitabine plus cisplatin in previously untreated advanced ovarian cancer.

BACKGROUND: The primary objective was the evaluation of the effects of gemcitabine plus cisplatin on the overall response rate (ORR) of patients with advanced ovarian cancer; the secondary assessments included toxicity, time to progressive disease (TtPD) and the duration of response. MATERIALS AND METHODS: Chemonaive patients with stage III/IV ovarian cancer received gemcitabine 1250 mg/m2 (d 1,8) and cisplatin 75 mg/m2 (d 1), every 21 days for a maximum of six cycles. RESULTS: Between March 1999 and June 2003, 28 patients (median age 52 years, range 23-72) had received chemotherapy. Of 26 assessable patients, the ORR was 57.7% (95% CI, 42.7%-83.6%) based on four complete responses and eleven partial responses, six patients experienced stable disease, while five had progressive disease. The median survival was 28.1 months (95% CI, 11.4-33.4 months), the median TtPD was 10.5 months (95% CI, 1.4-44.2 months) and the median duration of response was 24.3 months (95% CI, 12.3-33.4 months). The most common grade 3/4 toxicities were nausea/vomiting (15.2%) and neutropenia (10.7%). There was no grade 3 or 4 thrombocytopenia. CONCLUSION: Gemcitabine plus cisplatin exhibited activity in advanced ovarian cancer with an acceptable toxicity profile.

Routine management of locally advanced cervical cancer with concurrent radiation and cisplatin. Five-year results.

BACKGROUND: Globally, cervical cancer primarily affects socially disadvantaged women. Five randomized trials were the foundation for adopting cisplatin-based chemotherapy during radiation as the standard of care for high-risk patients after primary radical hysterectomy who require adjuvant radiation and for locally advanced patients treated with definitive radiation. These results were obtained in clinical trials performed in carefully prepared academic centers; hence, we sought to determine whether these results could be reproduced when patients were treated on an out-of-protocol basis. METHODS: We reviewed the files of 294 patients with locally advanced cervical cancer who received radiation plus weekly cisplatin as routine management between 1999 to 2003, and analyzed treatment compliance, response rate, toxicity, and survival. RESULTS: A total of 294 patients who received radiation and cisplatin were analyzed. Mean age was 43.8 years (range, 26-68 years). The majority of cases were squamous cell carcinoma (87.8%), and distribution according to International Federation of Gynecology and Obstetrics (FIGO) stage was as follows: IB2-IIA, 23%; IIB, 53.3%, and IIIB, 23%; there were only two IVA cases. Overall, 96% of patients completed external beam, and intracavitary therapy. The majority of patients (67%) received the planned six courses of weekly cisplatin. Complete responses were achieved in 243 (83%) patients, whereas 51 (17%) had either persistent (32 patients, 10.8%) or progressive (19 patients, 6.4%) disease. At median follow-up (28 months; range, 2-68 months), 36 patients (12.2%) have relapsed (locally 30.5, and systemically, 69.5%). The most common toxicities were hematologic and gastrointestinal, in the majority of cases considered mild-moderate. At median follow-up (28 months; range, 2-68 months), overall and progression-free survival are 76.5 and 67%, respectively. CONCLUSION: Our results support use of chemoradiation with six weekly applications of cisplatin at 40 mg/m2 during external radiation for routine management of locally advanced cervical cancer.

Radiation-sparing managements for cervical cancer: a developing countries perspective.

Cervical cancer is the seventh most frequent cancer worldwide but more than 80% of cases occur in developing countries. Till date, radiation therapy with external beam and brachytherapy remains as the core treatment for most stages of cervical cancer. However, radiation treatment protocols and equipment modelled on the best developed countries can be seldom applied directly to developing countries owing to financial constraints and lack of qualified personnel, thus, a substantial proportion of patients do not have access to even palliative radiation therapy. Treatment options when the standard therapy is either not available or difficult to reproduce in particular settings is highly desirable with the potential to save lives that otherwise could be lost by the lack of adequate treatment. These options of treatment ideally had to have show, 1) that these are not inferior to the "standard" in terms of either survival or quality of life; 2) that these can be delivered in settings were the "standard" is not available or if available its quality is poor; and 3) that the treatment option be accepted by the population to be treated. Based on these considerations, it is obvious that cervical cancer patients, particularly those who live in countries with limited resources and therefore may not have sufficient radiation therapy resources are in need of newer therapeutical options. There is now a considerable amount of information emanating from clinical studies where surgery has a major role in treating this disease. These forms of "radiation-sparing" treatments include total mesometrial resection that could make unnecessary the use of adjuvant radiation; neoadjuvant chemotherapy that could avoid the use of adjuvant radiation in around 85% of patients and preoperative chemoradiation that could make brachytherapy dispensable. The feasibility and therapeutical value of these potential forms of management need to be prospectively evaluated.

Prognostic significance of pathological response after neoadjuvant chemotherapy or chemoradiation for locally advanced cervical carcinoma.

BACKGROUND: Cisplatin-based chemoradiation is the standard of care for locally advanced cervical cancer patients; however, neoadjuvant modalities are currently being tested. Neoadjuvant studies in several tumor types have underscored the prognostic significance of pathological response for survival; however there is a paucity of studies in cervical cancer investigating this issue. METHODS: Four cohorts of patients with locally advanced cervical carcinoma (stages IB2-IIIB); included prospectively in phase II protocols of either neoadjuvant chemotherapy with 1) cisplatin-gemcitabine, 2) oxaliplatin-gemcitabine, 3) carboplatin-paclitaxel or 4) chemoradiation with cisplatin or cisplatin-gemcitabine followed by radical hysterectomy were analyzed for pathological response and survival. RESULTS: One-hundred and fifty three (86%) of the 178 patients treated within these trials, underwent radical hysterectomy and were analyzed. Overall, the mean age was 44.7 and almost two-thirds were FIGO stage IIB. Pathological response rates were as follows: Complete (pCR) in 60 cases (39.2%), Near-complete (p-Near-CR) in 24 (15.6 %) and partial (pPR) in 69 cases (45.1%). A higher proportion rate of pCR was observed in patients treated with chemoradiotherapy (with cisplatin [19/40, 47.5%]; or with cisplatin-gemcitabine [24/41, 58.5%] compared with patients receiving only chemotherapy, 6/23 (26%), 3/8 (37.5%) and 8/41 (19.5%) for cisplatin-gemcitabine, oxaliplatin-gemcitabine and carboplatin-paclitaxel respectively [p = 0.0001]). A total of 29 relapses (18.9%) were documented. The pathological response was the only factor influencing on relapse, since only 4/60 (6.6%) patients with pCR relapsed, compared with 25/93 (26.8%) patients with viable tumor, either pNear-CR or pPR (p = 0.001). Overall survival was 98.3% in patients with pCR versus 83% for patients with either pNear-CR or pPR (p = 0.009). CONCLUSION: Complete pathological response but no Near-complete and partial responses is associated with longer survival in cervical cancer patients treated with neoadjuvant chemotherapy or chemoradiotherapy.

Pathologic response and toxicity assessment of chemoradiotherapy with cisplatin versus cisplatin plus gemcitabine in cervical cancer: a randomized Phase II study.

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.

Pre-exenterative chemotherapy, a novel therapeutic approach for patients with persistent or recurrent cervical cancer.

BACKGROUND: Most cervical cancer patients with pelvic recurrent or persistent disease are not candidates for exenteration, therefore, they only receive palliative chemotherapy. Here we report the results of a novel treatment modality for these patients pre-exenterative chemotherapy- under the rational that the shrinking of the pelvic tumor would allow its resection. METHODS: Patients with recurrent or persistent disease and no evidence of systemic disease, considered not be candidates for pelvic exenteration because of the extent of pelvic tumor, received 3-courses of platinum-based chemotherapy. Response was evaluated by CT scan and bimanual pelvic examination; however the decision to perform exenteration relied on the physical findings. Toxicity to chemotherapy was evaluated with standard criteria. Survival was analyzed with the Kaplan-Meier method. RESULTS: Seventeen patients were studied. The median number of chemotherapy courses was 4. There were 9 patients who responded to chemotherapy, evaluated by bimanual examination and underwent pelvic exenteration. Four of them had pathological complete response. Eight patients did not respond and were not subjected to surgery. One patient died due to exenteration complications. At a median follow-up of 11 months, the median survival for the whole group was 11 months, 3 months in the non-operated and 32 months in those subjected to exenteration. CONCLUSION: Pre-exenterative chemotherapy is an alternative for cervical cancer patients that are no candidates for exenteration because of the extent of the pelvic disease. Its place in the management of recurrent disease needs to be investigated in randomized studies, however, its value for offering long-term survival in some of these patients with no other option than palliative care must be stressed.

Oxaliplatin activity in head and neck cancer cell lines.

Oxaliplatin (cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)-O,O'] platinum; Eloxatin) is a third-generation platinum compound with a 1,2-diaminocyclohexane (DACH) carrier ligand, which has a wide spectrum of anticancer activity in vitro systems and has displayed preclinical and clinical activity in a wide variety of tumors. To investigate its in vitro activity against head and neck cancer, we exposed two head and neck cancer cell lines to the compound, created a variant resistant to cisplatin to study cross-resistance to the compound and analyzed the potential radiosensitizing effect of the drug. We report here that oxaliplatin was cytotoxic at similar doses to cisplatin in these cells. There was no cross-resistance to cisplatin, as demonstrated by different IC50 values in these cell lines and the sensitivity to oxaliplatin of the cisplatin-resistant cell line. There was an effective radiosensitizer effect of the compound in either cell line. Additional in vitro and in vivo experimentation is warranted in order to support the use of oxaliplatin as a radiosensitizer in head and neck cancer patients.

A clinical and biological overview of gastrointestinal stromal tumors.

In the last few years a body of knowledge has been generated on the molecular basis of gastrointestinal stromal tumors (GIST). These mesenchymal tumors are characterized by the expression of KIT protein and because they have an activating mutation in a class III receptor tyrosine kinase gene (KIT or PDGFRA). Several KIT-activating mutations, which are largely responsible for the development of this tumor, promote cell survival, proliferation, and migration through different pathways such as MAPK p42/44, AKT, S6K, STAT1, and STAT3. Likewise, gene-activating mutations in the gene PDGFRalpha which codes for the receptor tyrosine kinase, Platelet-derived growth factor receptor alpha have been identified in GIST lacking KIT mutations. This means that KIT and PDGFRalpha mutations appear to be alternative and mutually exclusive oncogenic pathways for GIST development. These tumors may occur anywhere along the gastrointestinal tract (GI). The most frequently involved sites are stomach and small intestine. They are typically chemo- and radioresistant. The discovery of a specific inhibitor of this tyrosine kinase, imatinib mesylate, has radically changed the prognosis of patients with unresectable disease. Only 4 yr after the first patient was successfully treated with imatinib, multiple phase II and III trials have been published and, currently, imatinib mesylate is the only effective systemic treatment available of these tumors. Response rates are approximately 70-90% with acceptable toxicity. GIST are the first model of a solid tumor efficiently treated with a molecular-targeted agent. This review summarizes the clinical and biological aspects of this unique neoplasm.

Modern management of locally advanced cervical carcinoma.

Radiation was until recently the key and only modality for the routine treatment of locally advanced cervical carcinoma. However after years of studying multi-modality treatments as an alternative to radiation alone in randomized phase III trials, the standard treatment has changed to chemo-radiation based on cisplatin. Three recent meta-analyses have confirmed that cisplatin-based chemo-radiation adds an absolute 12% benefit in five-year survival over radiation therapy alone. Neoadjuvant chemotherapy followed by radiation has not been of proven benefit, but when neoadjuvant chemotherapy is followed by surgery, an absolute increase of 15% in five-year survival over radiation alone is seen. This benefit in survival is comparable to that obtained with the current chemo-radiation schedules based on cisplatin. Despite these encouraging results there remains room for improvement as the five-year survival of patients treated with chemo-radiation ranges from nearly 80% in bulky IB tumours to only 25% in stage IVA disease. Other therapeutic approaches need to be fully evaluated including the use of chemo-radiation after neoadjuvant chemotherapy; the use of new drug combinations and the multi-modality combination of neoadjuvant chemotherapy followed by radical surgery plus adjuvant chemo-radiation. Likewise, the addition of radiosensitizers to cisplatin, preoperative chemo-radiation and/or adjuvant chemotherapy may eventually improve the currents results of cisplatin-based chemo-radiation. Nevertheless, it is hard to foresee a dramatic increase in cure rate, even with the most optimal combination of cytotoxic drugs, surgery and radiation, and thus the testing of molecular targeted therapies against cervical cancer is a logical step to follow.