Medical Student Research Fellowship for Summer 2012
Primary Mentor: D. Nathan Kim, M.D., Ph.D.,
Secondary Mentor: Debabrata Saha, Ph.D.
Collaborators: Debabrata Saha, Ph.D., Chul Ahn, Ph.D. (Biostatistics), Lotan Yair, M.D. (Urology), Claus Roehrborn, M.D. (Urology)
Department: Radiation Oncology
Room number: NF3.302A
Mail Code: 9183
Phone number: 214-645-8525
Analysis of long term outcome data on patients treated with salvage radiation therapy after failing primary surgical therapy for prostate cancer.
Human subjects IRB approved project number (where applicable):
STU- 032011-206: Registry for Determining Clinical Outcomes in Patients with Prostate Cancer
STU 072010-098: Tissue Procurement and Outcome Collection for Radiotherapy Treated Patients
Animal subjects IRB approved project number (where applicable): N/A
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) – Patient based research
Brief Description of Project:
Identification of clinical/pathological characteristics, and radiation therapy technique characteristics, that affect therapy outcome in cohort of prostate cancer patients treated with salvage radiation therapy after failing primary surgical therapy.
Local PSA recurrence after radical prostatectomy can occur in 15-25% of patients following surgery (termed biochemical recurrence), and in patients with high risk factors (positive margin, pT3 disease), biochemical recurrence rate has been shown to be significantly higher. UT Southwestern has a large number of patients treated with surgical therapy for prostate cancer, and is a tertiary referral center for such procedures. At UT Southwestern and many other institutions the current post operative approach calls for close surveillance of patients (both with and without high risk factors) with intent to treat with salvage radiation therapy when PSA recurrence (biochemical failure) occurs. Stan Liauw et al. (former UTSW medical student) created a database of salvage radiation therapy patients about a decade ago and published the initial findings of the UT Southwestern salvage radiation therapy experience in 2003 (Urology, 2003 Jun; 61(6): 1204-10). This data was also incorporated into a consortium experience of 5 academic centers published by Stephenson et. Al. in 2004 (Stephenson, A.J., et al. JAMA 2004 Mar 17; 291(11): 1325-32). Since 2003, this experience at UTSW has not been updated. We have a unique opportunity therefore to follow up on the experience of these patients and to determine their long term outcomes at this point. Furthermore, we have the opportunity at this time to update this database with the patients that have been treated since 2003 (2003-2011). Since 2003, there have also been significant improvements in both surgical and radiation therapy techniques ( e.g. robot assisted laparoscopic prostatectomy – surgery, and intensity modulated radiation therapy – radiation), and therefore, analysis of patient outcomes with the use of more modern treatment approaches can be evaluated and retrospectively compared to the historical approaches.
From this updated database, we will perform statistical analysis to determine clinical/pathologic characteristics and radiation therapy techniques that may influence patient outcomes for patients treated with radiation therapy.
Interestingly, a number of studies have identified anticoagulant and aspirin use as being correlated with patient outcome in prostate cancer patients. Furthermore, a number of studies have also suggested that radiation therapy dose escalation permitted by improvement in radiation therapy delivery techniques (from 2D, to 3D to IMRT based therapy), have improved patient outcome for prostate cancer patients. We will plan to perform correlative analysis of such factors in our database to see if this observation holds true in the cohort of prostate cancer patients treated with salvage intent for surgical failure.
Analysis of patients for this study will be permitted by IRB protocol STU- 032011-206: Registry for Determining Clinical Outcomes in Patients with Prostate Cancer. Medical student Chris Straka has already been added into this IRB protocol. We will plan to determine outcome results including PSA free survival, metastases free survival, progression free survival, and toxicity profile (long term, and short term) on patients treated at UTSW for biochemically recurrent prostate cancer with salvage intent. Database of 51 patients initially analyzed by 2003 will be updated for long term outcome data (survival, progression free survival, psa free survival, metastases free survival). Furthermore, patients treated with radiation therapy for salvage intent after biochemical failure following surgery from year 2003 onwards will be identified from our radiation therapy database (MOSAIQ system), de-identified and coded. Pertinent information to be coded will include patient identifiers (will be de-identified and coded), date of diagnosis, date of surgery, date of initiation of salvage radiation therapy, PSA data prior to and after salvage radiation therapy, Stage, Pathology (Gleason score, % core biopsy positivity, % gland occupied by cancer, seminal vesicle involvement, lymph node involvement, extracapsular extension, perineural invasion, apex involvement, margin positivity – location and length, lymphovascular invasion), imaging data before and after radiation therapy, co-morbid conditions at time of therapy, medication use during radiation therapy, radiation therapy dose, radiation therapy technique (2D vs 3D vs IMRT), Toxicity (GI, GU, skin, sexual – erectile dysfunction), use, duration, and timing of hormone therapy, last date known alive, date of treatment failure (local vs. metastatic). Treatment-related toxicities will be scored using the RTOG criteria. Radiation related toxicities will be divided into acute and late effects. Toxicities occurring within 90 days from the start of RT will be considered acute. Any toxicities continuing or newly reported after 90 days will be considered late. Any late gastrointestinal toxicity (eg, proctitis, bowel obstruction, bleeding) that required surgery, laser treatment, cauterization, or transfusion will be scored as grade 3 to 4.
Biostatistical analysis will be performed by Dr. Chul Ahn’s biostatistics group with the Simmons Comprehensive Cancer Center. All time-related end points will be estimated by the Kaplan-Meier method, with the log-rank statistic used to test for differences. Univariate and multivariate analysis will be performed using Cox logistics methods. Additional analysis if needed will be performed per discussion with Dr. Ahn’s group.
Project #2. Development of pilot study of DAB2IP as a marker of radiation response and progression free survival in prostate cancer patients treated with radiation therapy for salvage intent after failing primary surgical therapy.
Decreased expression of DAB2IP correlates with patient outcome in patients with prostate cancer treated with salvage radiation therapy for surgical failure.
A. DAB2IP and human malignancies
DAB2IP gene has been linked with the risk of aggressive prostate cancer. The results of this study were combined with data from the publicly available CGEMS (Cancer Genetic Markers of Susceptibility) study and after SNP analysis (approximately 60000) the SNP rs1571801 located in DAB2IP gene was shown to be correlated with aggressive PCa. This gene was originally cloned and characterized by Dr. JT Hsieh’s group at UT Southwestern. Although complete deletion of DAB2IP is rare in human tumors, decreased expression of DAB2IP is often detected in PCa cells and this loss of DAB2IP is primarily due to altered epigenetic regulation (i.e., DNA methylation and histone modification) of its promoter region. IHC analysis of more than 200 PCa patients by Min et al. (70% were DAB2IP negative, ~10% were weak and ~18% were moderate in Gleason G5) clearly demonstrated the causal role of DAB2IP loss in PCa progression. Preliminary results by Saha et al. demonstrate a striking correlation between DABP2IP levels and radiation response in locally advanced prostate cancer patients. Unlike de-novo treated low risk prostate cancer patients with intact prostate, either with radiation or surgical therapy, who have 90% biochemical recurrence free survival at 5 years, the local control outcome in patients treated with salvage radiation therapy with recurrence following surgery is much less favorable (in the order of 50% PSA control rate). This suggests that these patients represent a higher risk cohort of patients than the average patient that has been treated with definitive intent with intact prostates. Therefore, the goal of this project is to perform a pilot study to determine whether DAB2IP may prove to be a useful marker for treatment failure in patients treated with salvage radiation therapy following surgical failures.
An existing IRB approved study, STU 072010-098 entitled “Tissue Procurement and Outcome Collection for Radiotherapy Treated Patients”, provides a mechanism to collect tissue samples needed for this study. We will identify patients diagnosed with prostate cancer between 2003-2011 from all the clinical facilities associated with the UT Southwestern Medical Center that have been treated with salvage radiation therapy following surgical failure. The research study coordinator (in the Radiation Oncology Department) contacts these eligible patients by phone or during clinical visits and informed consent forms are obtained prior to acquiring tissue samples. We will expand our patient cohort, and follow PSA trends over time to improve our data set. Furthermore, clinical data on these patients will be collected and coded in to the salvage prostate cancer patient database being established in project #1. Pertinent information to be coded will include but not be limited to patient identifiers (will be de-identified and coded), date of diagnosis, medications, comorbid conditions, date of surgery, date of initiation of radiation therapy, PSA data prior to and after radiation therapy, stage, pathology (Gleason score, % core biopsy positivity, % gland occupied by cancer, seminal vesicle involvement, lymph node involvement, extracapsular extension, perineural invasion, apex involvement, margin positivity – location and length, lymphovascular invasion), imaging data before and after radiation therapy, radiation therapy dose, radiation therapy technique (2D vs 3D vs IMRT), acute and delayed toxicity (GI, GU, skin, sexual – erectile dysfunction), use, duration, and timing of hormone therapy, last date known alive, date of treatment failure (local vs. metastatic), and sites of metastatic disease. This will be a collaborative study with the University Hospital system (Urology, Pathology, Radiation oncology and Neuropathology core) for the tissue collection and staining of DAB2IP. Radiation oncology Clinical Research Manager, Jean Wu, will supervise patient consent and tissue collection. We will plan to collaborate with Dr. Saha’s laboratory, who has active collaborations with board certified pathologist, Dr. Payal Kapur who has expertise in examining the status of DAB2IP in these samples and statistician Dr. Daniel Zhao will analyze with biochemical (PSA) recurrence free survival of these patients after radiation treatment. Dr. Zhao will also correlate DAB2IP status with other clinical outcomes such as local failure, distant failure and survival. Dr. Saha also has active collaboration with Dr. J.T. Hsieh’s group for all DAB2IP related projects.
The proportions of patients with biochemical failures will be compared between patients without or with DAB2IP using the Fisher’s exact test. Power analysis will be performed to determine the total number of patients with or without DAB2IP needed achieve 80% power for detecting a difference of 37.5% in proportion of biochemical failure using a Fisher’s exact test and a 2-sided .05 alpha level.
Medical student trainee Chris Straka’s specific tasks for the projects:
Previous Research Activities or Publications with Medical Students/Technicians/pre-med students:
Dong Wook Nathan Kim M.D., Ph.D.- I am a new faculty member at UT Southwestern Radiation Oncology Department. I have had experience directly mentoring a summer medical student, and technicians (two of them were in transition between college and medical school) at Vanderbilt University Medical Center and Boston University Medical Center. At Vanderbilt University, I mentored them initially at the level of a Holman Pathway resident/postdoctoral fellow in Dr. Hallahan’s laboratory, and transitioned to be a research faculty member, at an instructor level prior to completing my residency. At Boston University, I was a Ph.D. student of Dr. Sonenshein, where I directly supervised and mentored Lee Gazourian. They are as follows:
1. Lauren Leavitt – entered medical school program at Texas Tech after finishing in my laboratory.
2. Shiv Tumkur – summer research visiting medical student in Dr. Hallahan’s laboratory, who worked directly with me on several projects.
3. Jessica Huamani – technician. She decided not to pursue medical school, and currently works as clinical research staff at Emory.
4. Lee Gazourian – entered Boston University Medical School as a medical student after completing his technician year with me in Dr. Sonenshein’s laboratory.
Publications with above individuals:
Debabrata Saha, Ph.D