TEMOZOLOMIDE AND BEVACIZUMAB THERAPY IN ADVANCED HEMANGIOPERICYTOMA/ SOLITARY FIBROUS TUMOR

Tumors comprising the spectrum of hemangiopericytoma/ malignant solitary fibrous tumor (HPC/SFT) are thought to arise from fibroblasts and represent a small subset of soft tissue sarcomas. Surgery is typically the treatment of choice for localized disease, with reported 10-year overall survival rates of 54-89% after complete surgical resection. However, for the approximately 20% of HPC/SFT patients who eventually develop local recurrences and/or distant metastases, options for effective treatment are limited and are poorly defined. Alternative therapeutic options are therefore needed for improved palliation and disease control. We hypothesize that HPC/SFT are a spectrum of soft tissue tumors with unique clinical, pathological, and molecular makeup and clinical behavior. HPC/SFT respond to unique therapeutic agents that specifically target aberrations specific to these tumors. We retrospectively reviewed the characteristics and the clinical outcomes for all HPC/SFT patients whose tumor specimens have been reviewed at the MD Anderson Cancer Center from January 1993 to June 2007 by a MD Anderson pathologist and were treated at the institution with available electronic medical records. We identified 128 patients, 79 with primary localized disease and 49 with recurrent and/or metastatic disease. For the 23 patients with advanced HPC/SFT who received adriamycin-based, gemcitabine based, or paclitaxel chemotherapy as first- or second-line therapy, the overall RECIST response rate was 0%. Most patients achieved a brief duration of disease stabilization on chemotherapy, with median progression-free survival (PFS) period of 4.6 months. For the 14 patients with advanced HPC/SFT who received temozolomide and bevacizumab systemic therapy, the overall RECIST response rate was 14%, with the overall Choi response rate of 79%. The median PFS for the cohort was 9.7 months with a median 6-month progression free rate of 78.6%. The most frequently observed toxic effect of temzolomide-bevacizumab therapy was myelosuppression. We have designed a phase II study to evaluate the safety and efficacy of temozolomide-bevaciumab in locally advanced, recurrent, and metastatic HPC/SFT in a prospective manner. Combination therapy with temozolomide and bevacizumab may be a potentially clinically beneficial regimen for advanced HPC/SFT patients.

THE ASSOCIATION BETWEEN CANCER-RELATED-FATIGUE, RESPONSE TO FATIGUE TREATMENT, AND CYTOKINES AND THEIR RECEPTORS, IN PATIENTS WITH ADVANCED CANCER

Background: Inflammation is implicated in the development of cancer related fatigue (CRF). However there is limited literature on the mediators of inflammation (namely), cytokines and their receptors, associated with clinically significant fatigue and response to treatment. Methods: We reviewed 37 advanced cancer patients with fatigue (≥4/10), who participated in two Randomized Controlled Trials, of anti-inflammatory agents (Thalidomide and Dexamethasone) for CRF. Responders showed improvement in FACIT-F subscale at the end of study (Day 15). Baseline patient characteristics and symptoms were assessed by FACIT-F, ESAS; serum cytokines [IL-1β and receptor antagonist (IL-1RA), IL-6, IL-6R, TNF-α and sTNF-R1 and R2, IL-8, IL-10, IL-17] levels measured by Luminex. Data were analyzed using principal component analysis (PCA) [reporting cumulative variance (variance) for the first four components] to determine their association with fatigue and response to treatment. Results: Females were 54%. Mean (SD) was as follows for age, 61(14); baseline FACIT (F) scores, 21.4(8.6); ESAS Fatigue item, 6.5(1.9); and FACIT-F change, 6.4(9.7); ESAS (fatigue) change, -2 (2.41). Baseline median in pg/mL for IL-6, TNF-α, IL-1β were 31.9; 18.9; 0.55, respectively. Change in IL-6 negatively correlated with change in FACIT-F scores (p=0.02). Baseline CRF (FACIT-F score) was associated with IL-6, IL-6R and IL-17, Variance = 78% whereas IL-10, IL-1RA, TNF-α and IL-1β were associated with improvement of CRF, Variance=74%. Conversely, IL-6 and IL-8 were associated with no improvement or worsening of CRF, Variance= 93%. Conclusions: Change in IL-6 negatively correlated with change in FACIT-F scores. IL-6, IL-6R and IL-17 are associated with CRF while IL-6 and IL-8 were associated with no improvement of CRF. Further studies are warranted confirm our findings.

THE EFFECTS OF CURCUMIN ON BODY COMPOSITION OF PATIENTS WITH ADVANCED PANCREATIC CANCER

Cachexia is very common among patients with advanced pancreatic cancer and is a marker of poor prognosis. Weight loss in cachexia is due to both adipose and muscle compartments, and sarcopenia (severe muscle depletion) is associated with worse outcomes. Curcumin has shown a myriad of biological effects, including anti-cancer and anti-inflammatory. The ability of curcumin to attenuate cachexia and muscle loss has been tested in animal models, with conflicting results so far. The hypothesis of this study was that patients with advanced pancreatic cancer treated with curcumin for two months have less fat and muscle loss as compared to matched controls not treated with this compound. A matched 1:2 case-control retrospective study was conducted with 22 patients with pancreatic cancer who were treated with curcumin on a previous protocol and 44 untreated controls with the same diagnosis matched by age, gender, time from advanced cancer, body mass index, and number of prior therapies. Data was collected regarding oncologic treatment, medication use, weights, heights, and survival. Body composition was determined by computerized tomography analyses at two timepoints separated by 60±20 days. For treated patients, the first image was at the beginning of treatment and for controls it was determined by the matching time from advanced cancer. The evolution of body composition over time was quantitatively analyzed comparing both groups. All patients lost weight both due to fat and muscle losses, and patients treated with curcumin presented greater losses both in lean adipose body mass. Use of medications, chemotherapy, age, time from advanced cancer, baseline albumin, performance status, and number of prior therapies were not independently correlated with changes in body composition variables. Patients treated with curcumin had borderline shorter survival when compared with untreated patients. Sarcopenic treated patients had significantly shorter survival than non-sarcopenic counterparts, and sarcopenia status was not associated with survival among the controls. Treated patients with shorter survival showed a tendency to lose more lean and especially fat body mass as compared to untreated patients, maybe suggesting an effect of curcumin on shifting weight loss towards the end of life by impacting its mechanisms.

Prognostic significance of xCT polymorphisms and expression in patients with advanced pancreatic cancer treated with chemotherapy

The plasma membrane xc- cystine/glutamate transporter mediates cellular uptake of cystine in exchange for intracellular glutamate and is highly expressed by pancreatic cancer cells. The xCT gene, encoding the cystine-specific xCT protein subunit of xc-, is important in regulating intracellular glutathione (GSH) levels, critical for cancer cell protection against oxidative stress, tumor growth and resistance to chemotherapeutic agents including platinum. We examined 4 single nucleotide polymorphisms (SNPs) of the xCT gene in 269 advanced pancreatic cancer patients who received first line gemcitabine with or without cisplatin or oxaliplatin. Genotyping was performed using Taqman real-time PCR assays. A statistically significant correlation was noted between the 3' untranslated region (UTR) xCT SNP rs7674870 and overall survival (OS): Median survival time (MST) was 10.9 and 13.6 months, respectively, for the TT and TC/CC genotypes (p = 0.027). Stratified analysis showed the genotype effect was significant in patients receiving gemcitabine in combination with platinum therapy (n = 145): MST was 10.5 versus 14.1 months for the TT and TC/CC genotypes, respectively (p = 0.013). The 3' UTR xCT SNP rs7674870 may correlate with OS in pancreatic cancer patients receiving gemcitabine and platinum combination therapy. Paraffin-embedded core and surgical biopsy tumor specimens from 98 patients with metastatic pancreatic adenocarcinoma were analyzed by immunohistochemistry using an xCT specific antibody. xCT protein IHC expression scores were analyzed in relation to overall survival in 86 patients and genotype in 12 patients and no statistically significant association was found between the level of xCT IHC expression score and overall survival (p = 0.514). When xCT expression was analyzed in terms of treatment response, no statistically significant associations could be determined (p = 0.908). These data suggest that polymorphic variants of xCT may have predictive value, and that the xc- transporter may represent an important target for therapy in pancreatic cancer.

Determinants of quality of advanced cancer care in Latin America. A look at five countries: Argentina, Brazil, Cuba, Mexico and Peru

The World Health Organization reports that nearly half a million people died of cancer in Latin America in 2001. As a growing public health problem, cancer is now either the first or second leading cause of death among adults in most Latin American nations. Despite these trends, information on the quality of care people with advanced cancer in Latin America receive has been limited. This study assessed the quality of advanced cancer care in diverse Latin American countries and institutions by surveying cancer care providers from: Argentina; Brazil; Cuba; Mexico; and Peru. This study also identified the most salient factors that influence the quality of this care at the national and institutional levels and compared these factors across countries. This study was based on the secondary analyses of data collected by the University of Texas M. D. Anderson's WHO/PAHO Collaborating Center in Supportive Cancer Care from March 2000 to November 2002. The sample for this survey was a convenience sample of physicians and nurses who treat cancer patients in these regions. Strategies for the dissemination of this survey included: mass mailings; distribution at professional meetings/conferences; collaboration with regional institutions, professional organizations and PAHO; and the posting of online surveys. The strongest predictor of providers' assessments of the quality of advanced cancer care was their ratings of access to care. This major finding reflects a shared equitable notion of quality care among providers from diverse countries and medical institutions that is highly interrelated with providing accessible care to those with advanced cancer. Higher ratings of the affordability of care, an increased reported availability of end-of-life services and opioid analgesics, practicing in either a private hospital or specialized cancer center, and practicing in Cuba were also associated with higher provider ratings of the quality of advanced cancer care. The findings of this study contribute towards the much needed body of knowledge that may guide the formulation of policies and interventions aimed at improving the care for people with advanced cancer in Latin America. ^

Coping with advanced cancer: Caregivers and their patients

Background. Being diagnosed with advanced cancer may be one of the most difficult challenges a person faces. To help deal with advanced cancer, patients and caregivers lean towards the coping skills most familiar to them. Depending on the person, one’s coping may either help or perpetuate the problem. ^ Purpose. To identify predictors of negative coping skills among a group patients and caregivers, and to identify the predictors of prolonged grief among a group of providers, 6-months post loss. ^ Methods. Advanced cancer patients and caregivers were interviewed at the time of their enrollment (baseline) and caregivers were interviewed 6 months after the patient’s death (post-loss). Each participant was administered questionnaires regarding demographics, mental health disorders, mental health service use, coping methods, quality of life, and suicide attempts. Patients were asked about their treatment and diagnosis. Other patient-related information was obtained from medical charts. Moreover, caregivers were given an assessment regarding their alcohol and smoking history. ^ Results. Among White patients, positive coping skills were positively correlated with quality of life and negative coping skills were negatively correlated with quality of life. Gender, psychiatric disorders, suicidality, alcohol and smoking history, and treatment and diagnosis, were significantly related to negative coping skills; however this relationship only held for Hispanic patients. Gender and psychiatric disorders demonstrated predictive value for negative coping skills among all patients. On the other hand, psychiatric disorders, major depression, anxiety disorder, suicidality, and alcohol and smoking history, were not significant predictors of which caregivers experienced prolonged grief. ^ Conclusion. There was a significant relationship between quality of life and positive and negative coping skills of patients and negative coping skills for caregivers. Factors such as gender, psychiatric disorders, suicidality, alcohol and smoking history, and treatment and diagnosis demonstrated predictive value for negative coping skills in patients. ^

Response to chemotherapy, recurrence and survival in advanced-stage ovarian, fallopian tube and primary peritoneal cancer patients with non-Ashkenazi Jewish BRCA mutations, compared to those without

Objectives. Previous studies have shown a survival advantage in ovarian cancer patients with Ashkenazi-Jewish (AJ) BRCA founder mutations, compared to sporadic ovarian cancer patients. The purpose of this study was to determine if this association exists in ovarian cancer patients with non-Ashkenazi Jewish BRCA mutations. In addition, we sought to account for possible "survival bias" by minimizing any lead time that may exist between diagnosis and genetic testing. ^ Methods. Patients with stage III/IV ovarian, fallopian tube, or primary peritoneal cancer and a non-Ashkenazi Jewish BRCA1 or 2 mutation, seen for genetic testing January 1996-July 2007, were identified from genetics and institutional databases. Medical records were reviewed for clinical factors, including response to initial chemotherapy. Patients with sporadic (non-hereditary) ovarian, fallopian tube, or primary peritoneal cancer, without family history of breast or ovarian cancer, were compared to similar cases, matched by age, stage, year of diagnosis, and vital status at time interval to BRCA testing. When possible, 2 sporadic patients were matched to each BRCA patient. An additional group of unmatched, sporadic ovarian, fallopian tube and primary peritoneal cancer patients was included for a separate analysis. Progression-free (PFS) & overall survival (OS) were calculated by the Kaplan-Meier method. Multivariate Cox proportional hazards models were calculated for variables of interest. Matched pairs were treated as clusters. Stratified log rank test was used to calculate survival data for matched pairs using paired event times. Fisher's exact test, chi-square, and univariate logistic regression were also used for analysis. ^ Results. Forty five advanced-stage ovarian, fallopian tube and primary peritoneal cancer patients with non-Ashkenazi Jewish (non-AJ) BRCA mutations, 86 sporadic-matched and 414 sporadic-unmatched patients were analyzed. Compared to the sporadic-matched and sporadic-unmatched ovarian cancer patients, non-AJ BRCA mutation carriers had longer PFS (17.9 & 13.8 mos. vs. 32.0 mos., HR 1.76 [95% CI 1.13–2.75] & 2.61 [95% CI 1.70–4.00]). In relation to the sporadic- unmatched patients, non-AJ BRCA patients had greater odds of complete response to initial chemotherapy (OR 2.25 [95% CI 1.17–5.41]) and improved OS (37.6 mos. vs. 101.4 mos., HR 2.64 [95% CI 1.49–4.67]). ^ Conclusions. This study demonstrates a significant survival advantage in advanced-stage ovarian cancer patients with non-AJ BRCA mutations, confirming the previous studies in the Jewish population. Our efforts to account for "survival bias," by matching, will continue with collaborative studies. ^

A systematic review of personalized therapy in patients with advanced cancer

Background: An increased understanding of the pathogenesis of cancer at the molecular level has led to the development of personalized cancer therapy based on the mutation status of the tumor. Tailoring treatments to genetic signatures has improved treatment outcomes in patients with advanced cancer. We conducted a meta-analysis to provide a quantitative summary of the response to treatment on a phase I clinical trial matched to molecular aberration in patients with advanced solid tumors. ^ Methods: Original studies that reported the results of phase I clinical trials in patients with advanced cancer treated with matched anti-cancer therapies between January 2006 and November 2011 were identified through an extensive search of Medline, Embase, Web of Science and Cochrane Library databases. Odds Ratio (OR) with 95% confidence interval (CI) was estimated for each study to assess the strength of an association between objective response rate (ORR) and mutation status. Random effects model was used to estimate the pooled OR and their 95% CI was derived. Funnel plot was used to assess publication bias. ^ Results: Thirteen studies published between January 2006 and November 2011that reported on responses to matched phase I clinical trials in patients with advanced cancer were included in the meta-analysis. Nine studies reported on the responses seen in 538 of the 835 patients with driver mutations responsive to therapy and seven studies on the responses observed in 234 of the 306 patients with mutation predictive for negative response. Random effects model was used to estimate pooled OR, which was 7.767(95% CI = 4.199 − 14.366; p-value=0.000) in patients with activating mutations that were responsive to therapy and 0.287 (95% CI = 0.119 − 0.694; p-value=0.009) in patients with mutation predictive of negative response. ^ Conclusion: It is evident from the meta-analysis that somatic mutations present in tumor tissue of patients are predictive of responses to therapy in patients with advanced cancer in phase I setting. Plethora of research and growing evidence base indicate that selection of patients based on mutation analysis of the tumor and personalizing therapy is a step forward in the war against cancer.^

Improving Cervical Cancer Nodal Boost Radiation Therapy by Quantifying Uncertainties and Exploring Advanced Radiation Therapy Modalities

Radiation therapy for patients with intact cervical cancer is frequently delivered using primary external beam radiation therapy (EBRT) followed by two fractions of intracavitary brachytherapy (ICBT). Although the tumor is the primary radiation target, controlling microscopic disease in the lymph nodes is just as critical to patient treatment outcome. In patients where gross lymphadenopathy is discovered, an extra EBRT boost course is delivered between the two ICBT fractions. Since the nodal boost is an addendum to primary EBRT and ICBT, the prescription and delivery must be performed considering previously delivered dose. This project aims to address the major issues of this complex process for the purpose of improving treatment accuracy while increasing dose sparing to the surrounding normal tissues. Because external beam boosts to involved lymph nodes are given prior to the completion of ICBT, assumptions must be made about dose to positive lymph nodes from future implants. The first aim of this project was to quantify differences in nodal dose contribution between independent ICBT fractions. We retrospectively evaluated differences in the ICBT dose contribution to positive pelvic nodes for ten patients who had previously received external beam nodal boost. Our results indicate that the mean dose to the pelvic nodes differed by up to 1.9 Gy between independent ICBT fractions. The second aim is to develop and validate a volumetric method for summing dose of the normal tissues during prescription of nodal boost. The traditional method of dose summation uses the maximum point dose from each modality, which often only represents the worst case scenario. However, the worst case is often an exaggeration when highly conformal therapy methods such as intensity modulated radiation therapy (IMRT) are used. We used deformable image registration algorithms to volumetrically sum dose for the bladder and rectum and created a voxel-by-voxel validation method. The mean error in deformable image registration results of all voxels within the bladder and rectum were 5 and 6 mm, respectively. Finally, the third aim explored the potential use of proton therapy to reduce normal tissue dose. A major physical advantage of protons over photons is that protons stop after delivering dose in the tumor. Although theoretically superior to photons, proton beams are more sensitive to uncertainties caused by interfractional anatomical variations, and must be accounted for during treatment planning to ensure complete target coverage. We have demonstrated a systematic approach to determine population-based anatomical margin requirements for proton therapy. The observed optimal treatment angles for common iliac nodes were 90° (left lateral) and 180° (posterior-anterior [PA]) with additional 0.8 cm and 0.9 cm margins, respectively. For external iliac nodes, lateral and PA beams required additional 0.4 cm and 0.9 cm margins, respectively. Through this project, we have provided radiation oncologists with additional information about potential differences in nodal dose between independent ICBT insertions and volumetric total dose distribution in the bladder and rectum. We have also determined the margins needed for safe delivery of proton therapy when delivering nodal boosts to patients with cervical cancer.

Instrumental variable method for the causal relationship between soluble receptor for advanced glycation end-products (sRAGE) and risk of pancreatic cancer

This thesis project is motivated by the potential problem of using observational data to draw inferences about a causal relationship in observational epidemiology research when controlled randomization is not applicable. Instrumental variable (IV) method is one of the statistical tools to overcome this problem. Mendelian randomization study uses genetic variants as IVs in genetic association study. In this thesis, the IV method, as well as standard logistic and linear regression models, is used to investigate the causal association between risk of pancreatic cancer and the circulating levels of soluble receptor for advanced glycation end-products (sRAGE). Higher levels of serum sRAGE were found to be associated with a lower risk of pancreatic cancer in a previous observational study (255 cases and 485 controls). However, such a novel association may be biased by unknown confounding factors. In a case-control study, we aimed to use the IV approach to confirm or refute this observation in a subset of study subjects for whom the genotyping data were available (178 cases and 177 controls). Two-stage IV method using generalized method of moments-structural mean models (GMM-SMM) was conducted and the relative risk (RR) was calculated. In the first stage analysis, we found that the single nucleotide polymorphism (SNP) rs2070600 of the receptor for advanced glycation end-products (AGER) gene meets all three general assumptions for a genetic IV in examining the causal association between sRAGE and risk of pancreatic cancer. The variant allele of SNP rs2070600 of the AGER gene was associated with lower levels of sRAGE, and it was neither associated with risk of pancreatic cancer, nor with the confounding factors. It was a potential strong IV (F statistic = 29.2). However, in the second stage analysis, the GMM-SMM model failed to converge due to non- concaveness probably because of the small sample size. Therefore, the IV analysis could not support the causality of the association between serum sRAGE levels and risk of pancreatic cancer. Nevertheless, these analyses suggest that rs2070600 was a potentially good genetic IV for testing the causality between the risk of pancreatic cancer and sRAGE levels. A larger sample size is required to conduct a credible IV analysis.^

Advanced Protein Modeling Method: Benchmarking and Applications in Computer-Aided Drug Discovery

Development of homology modeling methods will remain an area of active research. These methods aim to develop and model increasingly accurate three-dimensional structures of yet uncrystallized therapeutically relevant proteins e.g. Class A G-Protein Coupled Receptors. Incorporating protein flexibility is one way to achieve this goal. Here, I will discuss the enhancement and validation of the ligand-steered modeling, originally developed by Dr. Claudio Cavasotto, via cross modeling of the newly crystallized GPCR structures. This method uses known ligands and known experimental information to optimize relevant protein binding sites by incorporating protein flexibility. The ligand-steered models were able to model, reasonably reproduce binding sites and the co-crystallized native ligand poses of the β2 adrenergic and Adenosine 2A receptors using a single template structure. They also performed better than the choice of template, and crude models in a small scale high-throughput docking experiments and compound selectivity studies. Next, the application of this method to develop high-quality homology models of Cannabinoid Receptor 2, an emerging non-psychotic pain management target, is discussed. These models were validated by their ability to rationalize structure activity relationship data of two, inverse agonist and agonist, series of compounds. The method was also applied to improve the virtual screening performance of the β2 adrenergic crystal structure by optimizing the binding site using β2 specific compounds. These results show the feasibility of optimizing only the pharmacologically relevant protein binding sites and applicability to structure-based drug design projects.