University of Southern California Dissertations and Theses

Cytoreductive radical prostatectomy for prostate cancer patients with oligometastatic disease

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Cytoreductive radical prostatectomy for prostate cancer patients with oligometastatic disease

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Content 1

Cytoreductive Radical Prostatectomy for Prostate
Cancer Patients with Oligometastatic Disease

Masters in Clinical and Biomedical Investigations
University of Southern California

Defended by: Mehrdad Alemozaffar, MD

Degree conferral date: August 2015

Thesis Committee

Dr. Gary Lieskovsky, Chair
Dr. Stanley Azen (Co-Chair)
Dr. David Quinn
Dr. Monish Aron

2

Table of Contents

Section page #

Abbreviations 3
Study Schema 4
Study Summary 5-6
Section 1: Background and Rationale 6-7
Section 2: Study Objectives 7-8
Section 3: Patient Eligibility 8
Section 4: Treatment Plan 8-10
Section 5: Study Procedure 10-11
Section 6: Measurement Effect 12
Section 7: Adverse Events 12-13
Section 8: Drug Information 13
Section 9: Correlative Studies 13-14
Section 10: Statistical Considerations 14
Section 11: Study Mangement 14-20
Section 12: References 20-21
Appendices
- Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 22
- Brief Pain Inventory 23-24
- Expanded Prostate Cancer Inventory Composite for Clinical Practice 25-26

3

ABBREVIATIONS

Health-related quality-of-life: HRQOL

Radical Prostatectomy: RP

Androgen deprivation therapy: ADT

Expanded Prostate Cancer Index: EPIC-CP

Brief Pain Inventory Short-Form: BPI-SH

Short Form Health Survey: SF-12

Statistical Analysis Software: SAS

Severe adverse events: SAE

Common Terminology Criteria for Adverse Events: CTCAE

Progression-Free Survival: PFS

Overall Survival: OS

Data and Safety Monitoring Committee: DSMC

USC Norris Comprehensive Cancer Center: NCCC

Cırculatıng Tumor Cells: CTC

Stereotactic Body Radiotherapy: SBRT

The Numeric Pain Rating Scale: NPRS

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STUDY SCHEMA

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STUDY SUMMARY

Title
Radical Prostatectomy for Local Disease Control in Addition to Best
Systemic Therapy in Patients with Metastatic Prostate Cancer
Short Title Local Disease Control in Metastatic Prostate Cancer
Protocol Number
Phase Pilot study
Methodology Non-randomized, prospective
Study Duration 1 year
Study Center(s) Single-center
Objectives
- Primary Outcomes
a. Technical Feasibility
b. Safety: Complications at 30 and 90 Days

- Secondary Outcomes
Health-related quality-of-life (HRQOL) change scores from baseline to
one year
a. SF-12
b. EPIC-CP
c. BPI
d. NPRS
e. Number of patients requiring procedure for urinary obstruction

- Exploratory Objectives
a. Progression free survival
b. PSA kinetics
Number of Subjects 22 Patients
Diagnosis and Main
Inclusion Criteria
Prostate Cancer, Men with prostate cancer and metastases
Study Product(s), Dose,
Route, Regimen
n/a
Duration of administration n/a
6

Reference therapy Androgen deprivation therapy
Statistical Methodology
This will be a non-randomized, prospective, pilot trial involving patients
with metastatic prostate cancer undergoing RP. The primary objective of
this study is to evaluate safety and feasibility of RP in metastatic prostate
cancer patients. The secondary objective of this study is to asses the
quality of life in these patients post RP.

This study will enroll 22 patients with metastatic prostate cancer who are
suitable candidates for RP (i.e. meet the eligibility criteria). With 22
patients there is a 90% chance (i.e. power) that we will observe a
complication or adverse event which has a true prevalence (i.e. probability
of occurring) in 10% or more of these patients when they undergo RP
(calculation based on exact binomial probabilities).

We anticipate accruring about 1-2 patients a month; therefore it should
take between 18 and 24 months to complete enrollment to this study.

1.0 BACKGROUND AND RATIONALE

1.1 Disease Background
Patients with localized prostate cancer have many treatment options including radiation or radical
prostatectomy (RP). On the other hand, patients with metastatic disease are only offered androgen
deprivation therapy (ADT) to slow the progression of disease as they are considered incurable. There
remain areas of controversy in the treatment of patients with locally advanced disease (spread of
cancer outside the prostate but not to other organs), with lymph node involvement but no distant
metastasis, or minimal metastatic disease (minimal involvement of bony site). Most commonly,
patients with locally advanced, high-risk, or lymph node positive disease are offered multimodal
therapy with a combination of neoadjuvant and adjuvant hormones and radiation instead of surgery.
Traditionally, patients with metastatic disease are only offered hormone therapy with radiation to the
bony metastasis as it is felt there is no reason to expose patients to the side-effects of local control
since there is unlikely to be any survival benefit. However, more recent studies have demonstrated
that there may be a potential benefit in regards to general health-related quality-of-life (HRQOL) and
overall survival (OS) in this population (1). Additionally, with improvements in surgical technique
minimizing side-effects the field is re-evaluating the notion of local control with RP in patients with
metastatic disease. Local control and surgical debulking of tumor has been shown to be result in
improved survival in many cancers including gastrointestinal carcinomatosis, ovarian, brain, liver,
lung, and renal cell cancer. This notion is being has been reviewed for prostate cancer patients with
node positive and metastatic disease and it is suggested that patients will experience improved QOL
and OS with surgical removal of the gland in addition to hormone therapy (3). Further, retrospective
analyses suggests a potential survival advantage to radical prostatectomy (4), however as these tumors
are mostly locally advanced, the surgery may be more challenging and prone to complications.
Therefore a safety and feasibility analysis is necessary prior to larger trials.

1.2 Study Agents Background and Associated Known Toxicities: N/A

1.3 Other Agents: N/A

1.4 Correlative Studies
Studies in prostate cancer patients with lymph node positive disease have demonstrated a 10-year OS
of 65% in patients treated with RP and ADT in comparison to 30% in those treated with ADT
7

alone.(9) Additionally, Widmark et al. looked at patients with locally advanced disease, without
lymph node involvement, treated with radiation and hormone therapy demonstrated a cumulative
cancer specific mortality of 11.9 % at 10 years.(10) These studies suggest an almost 2-fold increase in
disease specific survival at 10 years favoring RP over radiation therapy with hormones in patients
with locally advanced prostate cancer and/or lymph node involvement. One study found that prostate
cancer patients who had previously had a RP and later developed metastatic disease had a statistically
significant decrease in the risk of death (hazard ratio 0.77, 95% confidence interval 0.53 to 0.89)
relative to those who did not undergo earlier prostatectomy.(2) Other reviews have also eluded that
node positive and possibly metastatic prostate cancer patients have the best OS with surgical removal
of the gland in addition to hormone therapy, and have made an argument for studying this in a clinical
trial.(1, 3, 11, 2) This is not an unfamiliar notion as is similar to cytoreductive nephrectomy in renal
cell cancer.(13, 4)

It has been shown that performing RP in patients with high-risk disease or locally advanced disease is
feasible, safe, and provides good cancer control.(15-19) This surgery is similar to what would be
performed in patients with metastatic disease. We recently reviewed our own experience in
performing RP in 316 patients with high-risk disease and showed that there was not any increased rate
of complications, operative time, or estimated blood loss. In addition, 173 patients completed
Expanded Prostate Cancer Index (EPIC) questionnaires postoperatively at a median follow-up of 1
year. 109 (42.7%) reported using 0 pads/day and 34 (13.3%) patients reported using 1 pad/day, with
24 (9.4%) patients reporting having erections firm enough for sexual intercourse.

There are a multitude of factors to consider regarding HRQOL in patients with locally advanced or
metastatic disease being treated with standard therapy with ADT or with RP and ADT. Regarding
urinary function, there is an increased risk of urinary incontinence with RP, however, our techniques
have improved and full urinary continence is achieved in >90% patients. Additionally, prostate cancer
patients can develop urinary obstruction, which requires subsequent procedures as well as suffering
from pain from local disease. Removal of the primary malignant organ has the potential to reduce
urinary obstruction and localized pain by removing the blockage around and pressure on the
surrounding organs and consequently improving HRQOL.(20) Regarding sexual function, it is already
very negatively affected by ADT and many of these patients already have a significant decrease in
libido so the additionally decrease in sexual function that may result from RP would not necessarily
affect these patients.(21) These HRQOL outcomes will be measured by the EPIC-CP. Additionally,
it’s possible that general HRQOL may actually improve with RP as measured by the Medical
Outcomes Study SF-12 and that local control may result in decreased pain as measured by the Brief
Pain Inventory Short-Form (BPI-SF).(22-24)

Stereotactic body radiotherapy(SBRT) is a non-invasive modality for patients considered medically
inoperable for spine metastasis. This can facilitate delivery of an optimal therapeutic dose to a lesion
with a rapid dose fall-off and obtain better local control. Recently Berkovic et al. investigated SBRT
on oligometastatic prostate cancer patients(25). They have demonstrated SBRT as a feasible modality
that defers ADT with a median of 38 months. To evaluate the pain after each SBRT a numerical pain
scale (NRPS) will be utilized at each SBRT treatment and on the follow-up

1.5 Rationale
We hypothesize that RP and potentially SRBT to the metastasis will be: 1) safe and feasible in
prostate cancer patients with metastatic disease (without visceral metastasis), 2) effective and may
delay the initiation of ADT and 3) may achieve improvement in HRQOL and OS.

2.0 STUDY OBJECTIVES

2.1 Primary Outcomes
2.1.2 Technical Feasibility
8

2.1.3 Safety: Complications at 30 and 90 days

2.2 Secondary Outcomes
2.2.3 Health-related quality-of-life (HRQOL) change scores from baseline to one year
a. SF-12
b. EPIC-CP
c. BPI
d. Number of patients requiring procedure for urinary obstruction
e. NPRS

2.3 Exploratory Objectives
. 2.3.1 Progression-free survival (PFS) within the 1
st
year
2.3.2 PSA kinetics.

3.0 PATIENT ELIGIBILITY

3.1 Inclusion Criteria

3.1.1 Men with prostate adenocarcinoma and distant lymph nodes - bony metastasis
3.1.2 Able to have their surgery and follow-up done at USC

3.2 Exclusion Criteria
3.2.1 Evidence of visceral metastasis
3.2.2 Patients over 70 years of age,
3.2.3 PSA > 500 ng/ml
3.2.4 Patients with poor surgical risk
3.2.5 Patients who are not candidates for SBRT or who cannot undergo MRI or CT myelogram.
This includes patients with
a. Spine instability due to a compression fracture
b. > 50% loss of vertebral body height;
c. Frank spinal cord compression or displacement or epidural compression within
3 mm of the spinal cord;
d. Patients with rapid neurologic decline;
e. Bony retropulsion causing neurologic abnormality
f. Prior radiation to the area being treated
g. Patients for whom an MRI of the spine is medically contraindicated
h. Patients allergic to contrast dye used in MRIs or CT scans or who cannot be
premedicated for the use of contrast dye.
i. Patients with pacemakers
3.2.6 Patients with other active cancer diagnoses
3.2.7 Bulky nodal and local disease
3.2.8 Other pathologies such as neuroendocrine , squamous cell etc.

4.0 TREATMENT PLAN

4.1 Overview of study design
We are proposing a non-randomized, pilot, prospective clinical trial to evaluate feasibility and safety
of RP for local theray and SBRT for bony lesions in metastatic prostate cancer. We will enroll 22
patients who undergo RP; all patients will be followed for 1 year post RP.

4.2 Description of treatments
9

Patients electing to undergo RP will undergo surgery with or without robotic assistance will also have
an extended lymph node dissection (up to the level of the ureters crossing the common iliac artery). At
postoperative 6th week SBRT will be used for bone metastasis and any site of lymph node metastasis
which are not resectable.

4.2.1 RP therapy – Robotic or open RP and an extended lymphadenectomy will be performed

4.2.2 SBRT – 6 weeks after the surgery, SBRT will be used for bone and unresectable lymph node
metastasis. SBRT will be performed if the numbers of metastatic sites are <5.
a. Patients will be treated with 16Gy x 1 to each of the metastatic lesions. If organ at risk
(OAR) constraints cannot be met, SBRT will be delivered in 3-5 fractions. Only one lesion
will be treated each day and patients will have 48 hours between treatments.
b. Patients will complete a NRPS at consultation and after each treatment

4.2.3 ADT – LHRH agonists ± antiandrogens. ADT will be given for >2 months and ≤12 months
before RP.

4.2.4 Withdrawl
The subject may withdraw by deciding not to participate in the study prior to surgery by
notifying the Principal Investigator or research staff. A subject may also withdraw after
surgery, and refuse to participate in follow-up. All data that is obtained up to the point of
withdrawal may be used as research data.

4.3 Description of the outcome
4.3.1 Primary Outcome
Technical feasibility and safety assessed by monitoring the 30 day and 90 day complications.

4.3.2 Secondary Outcome
The secondary outcome is the evaluation of HRQOL assessment. SF-12 is a commonly used
standardized instrument in clinical practice and research to measure general HRQOL, as it is a
patient based health care outcome assessment. This outcome instrument assesses eight
dimensions of HRQOL- physical functioning, role physical, bodily pain, general health,
vitality/fatigue, social function, role emotional, and mental health. For our study, our primary
outcomes focus on the physical and mental health components of HRQOL on the SF12 for both
groups. EPIC-CP is a validated domain specific patient reported questionnaire to assess
HRQOL in prostate cancer and retains measure of 5 prostate cancer HRQOL domains, enabling
prostate cancer patient-reported outcomes to be measured in the routine outpatient practice
setting and to become a more standard part of routine clinical PCa care. The BPI was originally
developed to assess pain severity and impact in cancer patients and to evaluate the effect of
analgesic treatment in those patients. BPI-SF will be the tool to assess clinical pain. To evaluate
the pain severity after SBRT, NPRS will be used.

We also have two exploratory objectives. One is PFS the 1
st
year. The second is the assessment
of changes in PSA kinetics as a result of adding RP to standard of care. If a PSA level >0.4 is
detected after the treatment a second PSA evaluation will be done.

4.4 Recruitment, screening and baseline assessment
There are two methods for recruitment. First, we will recruit patients through physicians at the Norris
Comprehensive Cancer Center and Hospital. All patients will be recruited by trained researchers and
Study investigators/PIs. After the subjects are recruited, screening will be performed to determine if
10

the patients fit the inclusion/exclusion criteria for our study. If the patients are deemed to fit the
inclusion criteria, then their physician will administer the NPRS, SF-12, BPI and EPIC-CP survey
before they receive either treatment as baseline assessment.

5.0 STUDY PROCEDURE

5.1 Screening / Baseline Procedure

5.1.1 Medical history - Complete medical and surgical history

5.1.2 Demographics - Age, gender, race, ethnicity

5.1.3 Review subject eligibility criteria

5.1.4 Review previous and concomitant medications

5.1.5 Physical exam including vital signs, height and weight and digital rectal examination

5.1.6 PSA

5.1.7 CTC and CTDNA

5.1.8 Comprehensive Metabolic Panel
Albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes

5.1.9 Complete Blood Count

5.1.10 SF-12 - Assess health-related quality-of-life

5.1.11 BPI-SF - A measurement tool to assess clinical pain

5.1.12 EPIC-CP - To measure to measure Quality of Life issues in patients with prostate cancer

5.1.13 NPRS - To evaluate pain after SBRT treatment

5.1.14 Bone Scan - To assess the number and sites of bone metastases

5.1.15 CT Scan - Abdominopelvic CT scan to determine lymph node and visceral organ status

5.1.16 Multiparametric Prostate MRI - To evaluate the local stage of prostate cancer

5.1.17 Spine MRI - To obtain a more sensitive metastatic evaluation

5.2 Procedures During Treatment
5.2.1 Day 1
Procedure, Comprehensive Metabolic Panel, Complete blood count, Adverse event monitoring

5.2.2 Follow-up Period
The SF-12, EPIC-CP, NPRS and BPI-SF survey will be administered to the patients preop and
at 1,6, and12 months following treatment during a follow-up appointment with their urologist.
We will also keep track of patient deaths, need for subsequent procedures to help with urination,
and other possible adverse events for 1 years following RP.

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5.3 Study Calendar

CLINICAL AND LABORATORY EVALUATIONS AND STUDY CALENDAR
Parameter Baseline Eligibi
lity
Day 1
postop
POD
#1
Disch
arge
1 week
postop
1
month
postop
SBRT 6
weeks
postop
3
month
postop
6
month
postop
1 year
postop
H&P, PE X
Informed
Consent
X
Registratio
n
X
RP X
PSA X X X X X
Gleason
score
Biopsy RP
specim
en

CTC X X X X
CTDNA
Comprehe
nsive
Metabolic
Panel
X X X X X X X X X
Complete
Blood
Count
X X X X X X X X X
SF-12 X X X X
BPI-SF X X X X
EPIC-CP X X X X
NRPS X X X X
Chest-
abdomen-
pelvic CT
X X X X
Bone Scan X X X X
Spine MRI X X X X
Prostate
MRI
X
Adverse
Event
Monitoring
X X X X X X X X
12

6.0 MEASUREMENT EFFECT

6.1 Primary Outcomes

6.1.1 Technical Feasibility assessed at the completion of the RP
For a patient, the procedure will be defined as “technically feasible” if
a. a complete resection of the prostate is achieved
b. adequate lymph node dissection is achieved as defined by removing lymph nodes up to the
level of the ureters crossing the common iliac artery
c. surgical time less than 5 hours
d. blood loss less than 500 cc

6.1.2 Safety will be assessed according to the times listed on the Study Calendar (Section 5.3). At
all times, adverse events will be classified and graded according to the CTCAE v4.3 In
addition the following will be recorded to assess safety

Day of surgery and Day 1 Post-Op – and up to discharge
a. Transfusion requirements (0 vs. 1+)
b. Complications, especially those leading to intervention (e.g. urinary exravasation requiring
drainage, rectal injury, fistula, ureteral damage,….)
c. Admission to the ICU for any reason
d. Delay of discharge of more than 2 days
e. CMP and CBCs Post-Op Period
f. Complications requiring intervention (as above)
g. Re-hospitalization
h. CMP and CBCs

6.2 Secondary Outcomes will involve assessment of HRQOL
6.2.1 SF-12, EPIC-CP, BPI (at baseline, 1, 6, and 12 months)
6.2.2 Procedures required for urinary obstruction

6.3 Exploratory outcomes include
6.3.1 Changes in PSA levels (at baseline, 1,3,6 and 12 months)
6.3.2 PFS within the 1
st
year

7.0 ADVERSE EVENTS

7.1 Experimental Therapy
RP is an established treatment modality in localized or locally advanced prostate cancer. In this study
we will perform RP in metastatic patients. SBRT will be performed if the numbers of metastatic sites
are <5.

7.2 Adverse Event Monitoring
Side effects/Toxicities will be monitored with HRQOL questionairres (SF-12, BPI, EPIC)

7.3 Definitions

7.3.1 Definition of Adverse Event - An adverse event (AE) is any untoward medical occurrence in a
patient receiving study treatment and which does not necessarily have a causal relationship
with this treatment. An AE can therefore be any unfavorable and unintended sign (including
an abnormal laboratory finding), symptom, or disease temporally associated with the use of an
experimental intervention, whether or not related to the intervention.
13

7.3.2 Severity of Adverse Events - Intensity for each adverse event, including any lab abnormality,
will be determined by using the NCI Common Terminology Criteria for Adverse Events
(CTCAE) version 4.0 for toxicity. http://ctep.cancer.gov/reporting/ctc.html. Relationship to
the procedure will be determined for each event (unrelated, possibly, probably or definitely
related). AEs, both serious and non-serious, and deaths that occur during the patient’s study
participation will be recorded in the source documents, including event’s grade and attribution

7.3.3 Serious Adverse Event - A Serious Adverse Event (SAE) will be defined as any adverse event
that:
a. Any death (CTCAE Grade 5 complication) occurring within 1 year of prostatectomy
procedure regardless of the attribution;
b. Is life threatening (i.e., the patient was, in the view of the Investigator, at immediate risk of
death from the reaction as it occurred);
c. Results in persistent or significant disability / incapacity;
d. Prolongs hospitalization over 7 days, requires subsequent hospitalization, or requires a
return to intensive care monitoring
e. Is medically significant, may jeopardize the subject’s prognosis, and may require medical
or surgical intervention to prevent one of the outcomes listed above.

7.4 Reporting Requirements for Adverse Events
All SAEs that occur during the study will be reported to the USC Health Sciences Campus IRB, as
well as to the DSMC at the NCCC as follows: any death shall be reported within 24 hours of the
investigational staff’s knowledge of such event; all other SAEs are to be reported within seven (7)
days of learning of its occurance, even if that event is not felt to be treatment-related. Follow-up
information about a previously reported SAE will also be reported to the IRB and to the DSMC as a
follow up report. All SAEs will be monitored until they are resolved or are clearly determined to be
due to a patient’s stable or chronic condition or intercurrent illness(es).

7.5 Unblinding Procedures For Blinded and Randomized trials- N/A

8.0 DRUG INFORMATION

8.1 LHRH Agonists (Leuprolide asetat, Goserelin )
8.1.1 Other names for the drug(s): LHRH Analogues
8.1.2 Mode of action: Castration by the the down-regulation of LHRH receptor
8.1.3 Preparation: Injectable formula
8.1.4 Route of administration for this study: Subcutaneously
8.1.5 Availability: Commercially available
8.1.6 Side effects: At first week flare syndrome and it’s complications due to testosterone surge will
be prevented by a simultaneously prescribed androgen receptor blocker. Most of the side
effects are related to castration. Fatigue, hot flashes, head ache, impotence, depression are the
most common AEs. Less common but regularly observed side effects of LHRH agonist
therapy can also include sweating, nausea and vomiting, weight gain, and changes in the
texture of the hair and the skin.

9.0 CORRELATIVES/SPECIAL STUDIES

9.1 Circulating Tumor Cells
An additonal blood sample will be obtained for evaluation of circulating tumor cells (CTC’s). We
would draw them before surgery, then at 1 month, 6 months and 12 months. For each patient 3
standard (7.5ml) EDTA tubes will go to the lab. There they will undergo CTC enrichment using
14

several of our platforms (CellSearch, Stem Cell Technologies) followed by pure CTC isolation using
either our Eppendorff motorized micropipette apparatus or the Silicon Systems DepArray. Lysates
from these cells will be used for RNA and DNA preparation for gene expression and genomic
analyses.

10.0 STATISTICAL CONSIDERATIONS

10.1 Study Design/Study Endpoints
We are performing a non-randomized, prospective, pilot trial involving patients with metastatic
prostate cancer undergoing RP and SBRT. The primary objective of this study is to evaluate safety
and feasibility of RP and SBRT in metastatic prostate cancer patients. The secondary objective of
this study to asses the quality of life in these patients post RP.

Our underlying hypothesis is that RP in these patients will be safe and feasible, and that following
RP, these patients will have a QOL that is similar to patients receiving ADT alone. In addition, we
hypothesize that patients with oligometastatic prostate cancer undergoing RP will have superior
PSA kinetics and possibly superior survival as compared to the patients receiving ADT alone. If we
demonstrate, within the context of this small pilot study, that RP in this setting is safe and feasible
without compromising QOL, then a larger comparative study will be considered to evaluate longer
term outcomes in terms of controlling the prostate cancer

10.2 Sample Size and Accrual
This study will enroll 22 patients with oligometastatic prostate cancer who are suitable candidates
for RP (i.e. meet the eligibility criteria). The sample size of 22 was selected for 2 reasons. (a)
With 22 patients there is a 90% chance (i.e. power) that we will observe a complication or adverse
event which has a true prevalence (i.e. probability of occurring) in 10% or more of these patients
when they undergo RP (calculation based on exact binomial probabilities). Therefore, if we do not
see a specific complication, we will conclude that if it can occur in these patients, it will occur in
10% of fewer. Stated differently, this means that we will observe common complications. (b) With
22 patients we will be able to estimate proportion with standard errors that are 0.11 or less. We
anticipate acruring about 1-2 patients a month; therefore it should take between 18 and 24 months
to complete enrollment to this study.

10.3 Data Analyses Plans
10.3.1 All patients who sign an informed consent will be accounted for; all patients who undergo a
RP will be included in all the summaries of feasibility, safety, toxicities, QOL, PSA
kinetics, PFS and OS ( during the 1
st
year). Both PFS and OS will be calculated from the
date of RP.

10.3.2 During the baseline collection, demographic data including age, race, marital status,
presence of heart disease, presence of diabetes, and Gleason scores will also be recorded.

10.3.3 Standard descriptive statistical methods will be used to summarize the safety and feasibility
baseline information and outcome measures and PSA kinetics. Kaplan-Meier plots will be
used to summarize PFS and OS. In addition to plots to display patterns, standard errors and
confidence intervals will be provided in the summary of results.

11.0 STUDY MANAGEMENT

11.1 Conflict of Interest - None

11.2 Data and Monitoring
15

No separate Data Monitoring Committee has been set up for this study. The study will be
monitored by the Cancer Center internal DSMB.

The Data and Safety Monitoring Committee (DSMC) at the USC Norris Comprehensive Cancer
Center (NCCC) is an independent body and is responsible for the safety of study subjects through
the review of all new institutional protocols and those studies deemed by the CIC to require DSMC
oversight to ensure an adequate adverse event reporting plan and through the real-time and periodic
monitoring of severe adverse events (SAEs) or those that require expedited reporting. The DSMC
also performs real-time, quarterly and annual study progress and safety review, as well as
efficacy/futility review as outlined in the NCCC Data and Safety Monitoring Plan (available
through CISO website). After each review, the DSMC reports the results of each review and make
recommendations to the study PI, IRB, and CIC.

11.3 Institutional Review Board (IRB) Approval and Consent Process
11.3.1 It is expected that the IRB will have the proper representation and function in accordance
with federally mandated regulations. The IRB should approve the consent form and
protocol and all study related documents used in the study (e.g. QOL questionnaire, pill
diary, brochure, advertisement etc).

11.3.2 In obtaining and documenting informed consent, the investigator should comply with the
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP)
and to ethical principles that have their origin in the Declaration of Helsinki.

11.3.3 Before recruitment and enrollment onto this study, the patient will be given a full
explanation of the study and will be given the opportunity to review the consent form. Each
consent form must include all the relevant elements currently required by the FDA
Regulations and local or state regulations. Once this essential information has been
provided to the patient and the investigator is assured that the patient understands the
implications of participating in the study, the patient will be asked to give consent to
participate in the study by signing a dated IRBapproved consent form.

11.3.4 Prior to a patient’s participation in the trial, the written informed consent form should be
signed and personally dated by the patient and by the person authorized to obtain the
informed consent

11.4 Required Documentation (for multi-site studies):n/a

11.5 Registration Procedures

10.5.1 Multi-Site Registration: n/a

10.5.2 USC Registration: For patients enrolled at USC, the Research Coordinator must complete
the protocol eligibility form to ensure that the patient is eligible. The PI will review the
patient eligibility (with assistance from the Research Coordinator- who will assemble the
required source documents, and do an initial review) prior to registering the patient on
study.

10.5.3 The Research Coordinator or data manager will then register the patient into the Cancer
Center database, Café, by accessing the Registration forms. Likewise, after the patient has
completed the study, the Off Study forms in cafe will need to be completed, for Off
Treatment and Off Study
16

11.6 Phase I Slot Assignment: n/a

11.7 Records and Data Submission
11.7.1 Confidentiality of Records
The original data collection forms will be kept in secure file cabinets, for USC patients
forms will be kept in the Clinical Investigations Support Office (CISO).

11.7.2 Patient Consent Form
At the time of registration, signed and dated copies of the patient Informed Consent with the
Human Rights and the HIPAA authorization must be given to the patient. Institutional
policy regarding distribution and location of original consent documents should be
followed. When a study is opened at two or more institutions, a copy of the signed consent
and HIPAA should be sent to USC CISO QA team as soon as possible, and not later than
within 5 business days of obtaining consent. For patients consented at USC/LAC,
institutional policy should be followed: a copy of ICF and HIPAA should be uploaded
through True to USC CRO and to CISO QA Team. The original will be kept in the patient
research chart maintained by the study assigned Data Manager.

11.7.3 Registration Eligibility Worksheet
At the time of registration, the completed Eligibility Worksheet will be submitted to the QA
Monitor at CISO for review of eligibility compliance.

11.7.4 Data Collection Forms and Submission Schedule
If a treatment trial, protocol data will be entered into eCRFs in Café.
a. Within two weeks of registration, the data manager will complete the initial set of study
forms and baseline Toxicities
b. Within two weeks of completion of each course of treatment, the data manager must
complete the Course Assessment, Toxicities, and if appropriate Response data.
c. After Off Treatment, within two weeks of each follow up, complete the Follow Up forms.

11.8 Data Management and Monitoring/Auditing
11.8.1 Active Monitoring Program Details
Adherence to Protocol/Per Patient: It is the responsibility of the USC Principal Investigator
(PI) to ensure that patient recruitment and enrollment, treatment, follow-up for toxicities
and response, and documentation and reporting at USC are all performed as specified in the
protocol. When a study is opened at two or more institutions, the PI at each institution will
assume the responsibilities for the day-to-day monitoring of the trial, as described below.

Day-to-Day Monitoring – Eligibility: At USC, the Study Coordinator will assist the
Investigator in reviewing eligibility and will assemble the required source documents, and
do a final review by completing an Eligibility Registration Worksheet. When a study is
opened at two or more institutions, the PI at each institution will review the patient
eligibility in accordance with that institution’s policy.. For all institutions, the Eligibility
Registration Worksheet with a copy of Informed Consent and supporting source documents
will be submitted to CISO QA via email or Fax for verification prior to registering the
patient on study.

Day-to-Day Monitoring – Informed Consent: Prior to registering the patient on study, the
Study Coordinator will review the informed consent, to ensure that the patient has signed
and dated the most current IRB-approved form, and that the form has been signed and dated
by the person obtaining the consent as well as appropriate witnesses. A copy of the ICF will
also be provided to CISO QA for review. CISO SOP 3.3 will be followed.
17

Day-to-Day Monitoring – Treatment: The PI and co-investigators are responsible for
ensuring that treatment is given per protocol. The Study Coordinator will review the
treatment orders with the treating investigator. Regardless of who the treating physician is,
there will be only one responsible Study Coordinator for each study at each of the hospitals
affiliated with the USC Norris Cancer Center. The treating investigator will review the
status of each patient on-study, with the Study Coordinator and treating physicians, on an
on-going basis. When a study is opened at two or more institutions, CISO QA will
periodically audit medical records for the subjects on study at other institutions to ensure
compliance and adherence to the protocol.

Data Management – Patient Charts: When a study is opened at two or more institutions, the
policy in place at each institution will be followed for maintaining medical and research
related records. Such policies will be provided to the CISO QA prior to enrolling 1
st
patient.
At USC, All written source documents not associated with the study research are
maintained in the patient chart, which is stored in the Department of Medical Records at the
appropriate hospital. At the Norris Hospital, the official medical record is the Electronic
Patient File (EPF). Radiographical images are stored in the Department of Radiology and in
an electronic system called Synapse. At Los Angeles County General Hospital the official
medical record is called Affinity. These are the permanent, official documents for each
patient on-study. A copy of the signed informed consent, physician’s notes, orders, test
results and pathology notes are maintained in the patients’ hospital charts. It is the
responsibility of the research staff to ensure that the patient chart contains the required
documents and work closely with treating investigators to ensure all protocol-related
assessments are carefully documented.

Data Management – Research Charts: When a study is opened at two or more institutions,
the policy in place at each institution will be followed for maintaining medical and research
related records. Such policies will be provided to the CISO QA prior to enrolling 1
st
patient.
At USC, to facilitate adherence to the protocol schedule and data management, research
charts are created to collect copies of the relevant notes, orders and results, that are in the
Patient Chart. In Addition, all source documents related to the research, such as original
informed consent forms, HIPAA Forms, AE assessment worksheets, disease response
worksheets and NTFs are maintained in the Research Charts. Protocol calendars,
worksheets, and checklists, are also kept in the research chart. These are maintained in the
Clinical Investigation Support Office until the study is completed and the results are
published and no further need is anticipated. These are then stored off-site. It is the
responsibility of the Data Manager to ensure that the research chart contains all the required
documents.

Data Management – Case Report Forms: It is the responsibility of the Data Manager to
complete the required case report forms. For in-house trials, case report forms are
developed for each trial; these are used to finalize the data entry screens in the Cancer
Center clinical trials database. It is the responsibility of the PI to review the Off-Study
Summary form which summarizes pertinent toxicity, response and adherence information,
once the patient has completed treatment.

18

11.8.2 Quality Assurance Monitoring Committee (QAMC) Oversight
The Quality Assurance and Monitoring Committee (QAMC) of the NCCC has the
responsibility for study auditing and monitoring for protocol compliance, data accuracy,
performance of audits and monitoring of accrual. QAMC procedures are detailed in the
NCCC Data Safety and Monitoring Plan available on CISO Website.

a. QAMC Annual Patient Audits
The QAMC is responsible for conducting audits and providing the initial review of the
audits, for all open institutional (i.e. USC initiated), CCCP-sponsored trials, and any
trials identified by the CIC. These trials are audited by the QAMC once a year. Faculty
and staff at the Cancer Center involved in clinical research – but not directly involved in
the research under evaluation – are asked to serve as auditors. Twenty percent of patients
accrued during the past 12 months – and a minimum of 2 patients – are selected at
random; however, additional patients may be selected for audit if there is some
indication that there might have been a problem or unusual circumstance (possibly
related to compliance, toxicity, response or some indication of an irregularity). The audit
involves a review of the research chart, hospital medical record (i.e., source
documentation) and evaluates the following: documentation of eligibility (including
failure to obtain appropriate informed consent) and baseline status of the patient;
documentation of adherence to protocol-specified treatment and follow-up; evaluation of
toxicity; and evaluation of response or other outcome. In addition, for investigative
agents, a drug audit is also performed for these patients by the Research Pharmacist. In
addition, for Institutional, Investigator Initiated Trials, Data in the CAFÉ database are
compared to the information in the medical record.

b. QAMC Annual Protocol Review
All open trials are reviewed at least once a year by the QAMC (or more often if stipulated
by the CIC). This annual review includes the following: evaluation of the current accrual
relative to the planned total accrual; examination of gender and minority accrual;
examination of all reported violations; review of past audits and correspondence with the
PI; review of results of current audit (by an outside agency or by the NCCC QAMC);
review of previous correspondence between the PI and the QAMC/DSMC. The QAMC
review process is detailed in USC NCCC DSM Plan available on the CISO website.

11.8.3 Data and Safety Monitoring Committee (DSMC) Oversight
The Data and Safety Monitoring Committee (DSMC) is an independent body responsible
for the safety of study subjects through the review of new protocols to ensure an adequate
adverse event assessment/reporting plan, study stopping rules and through the real-time and
periodic monitoring of severe adverse events (SAEs) or those AEs that require expedited
reporting. The DSMC performs quarterly and annual safety reviews as well as interim
efficacy/futility analyses on institutional trials. DSMC procedures are detailed in USC
NCCC DSM Plan available on the CISO website.

11.8.4 Phase I Committee Oversight (for Phase I or I/II IIT only)
The USC Norris Comprehensive Cancer Center Phase I DLT committee reviews all open
institutional phase I studies at regularly scheduled intervals. The committee reviews the
adverse events, serious adverse events, and treatment administration for each patient during
the DLT observation period as specified per protocol. The committee will determine
whether a patient is evaluable for DLT and whether an AE meets the DLT definition or not.
Decisions regarding dose escalation, de-escalation and cohort expansion are made by the
committee in coordination with the PI.

11.9 Adherence to the Protocol

19

Except for an emergency situation in which proper care for the protection, safety, and well-being of
the study patient requires alternative treatment, the study shall be conducted exactly as described in
the approved protocol.

11.9.1 Emergency Modifications
a. Investigators may implement a deviation from, or a change of, the protocol to eliminate
an immediate hazard(s) to trial subjects without prior IRB approval.
b. For any such emergency modification implemented, an IRB modification form must be
completed within five (5) business days of making the change.

11.9.2 Non-Emergency departures from protocol
A protocol deviation is any variance from an IRB approved protocol.
If the deviation meets all of the following criteria, it is considered a minorprotocol deviation
that:
a. Is generally noted or recognized only after it occurs
b. Has no substantive effect on the risks to research participants
c. Has no substantive effect on the scientific integrity of the research plan or the value of the
data collected
d. Did not result from willful or knowing misconduct on the part of the investigator(s).

If the deviation meets any of the following criteria, it is considered a protocol violation:
a. Has harmed or increased the risk of harm to one or more research participants.
b. Has damaged the scientific integrity of the data collected for the study.
c. Results from willful or knowing misconduct on the part of the investigator(s).
d. Demonstrates serious noncompliance with federal regulations, State laws, or University
policies.

Protocol Deviations: personnel will report to any sponsor or data and safety monitoring
committee in accordance with their policies.

Protocol Violations: All protocol violations will be entered in the clinical trial database by
the Research Coordinator. In addition, Research Coordinator and Investigator should report
all protocol violations within one (1) week of the knowledge of the event using iStar.

11.9.3 Amendments to the Protocol
Should amendments to the protocol be required, the amendments will be originated and
documented by the Principal Investigator. It should also be noted that when an amendment
to the protocol substantially alters the study design or the potential risk to the patient, a
revised consent form might be required.

The written amendment, and if required the amended consent form, must be sent to the IRB
as well as to all the sponsoring agencies (FDA, NCI, etc.) for review and for approval prior
to implementation. It is the responsibility of the study PI to ensure that the appropriate
agencies have been informed of the proposed amendments and that these have been
reviewed and approved.

11.10 Record Retention
Study documentation includes all Case Report Forms, data correction forms or queries, source
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient
consent forms).

Source documents include all recordings of observations or notations of clinical activities and all
reports and records necessary for the evaluation and reconstruction of the clinical research study.
20

Government agency regulations and directives require that the study investigator must retain all
study documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug
seeking regulatory approval and marketing, these documents shall be retained for at least two years
after the last approval of marketing application in an International Conference on Harmonization
(ICH) region. In all other cases, study documents should be kept on file until three years after the
completion and final study report of this investigational study.

11.11 Obligations of Investigators
The Principal Investigator is responsible for the conduct of the clinical trial at the site in
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.
The Principal Investigator is responsible for personally overseeing the treatment of all study
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI
regulations and guidelines regarding clinical trials both during and after study completion.

The Principal Investigator at each institution or site will be responsible for assuring that all the
required data will be collected and entered onto the Case Report Forms. Periodically, monitoring
visits will be conducted and the Principal Investigator will provide access to his/her original
records to permit verification of proper entry of data. At the completion of the study, all case report
forms will be reviewed by the Principal Investigator and will require his/her final signature to
verify the accuracy of the data.
Before recruitment and enrollment onto this study, the patient will be given a full explanation of
the study and will be given the opportunity to review the consent form. Each consent form must
include all the relevant elements currently required by the FDA Regulations and local or state
regulations. Once this essential information has been provided to the patient and the investigator is
assured that the patient understands the implications of participating in the study, the patient will
be asked to give consent to participate in the study by signing a dated IRB approved consent form.

Prior to a patient’s participation in the trial, the written informed consent form should be signed
and personally dated by the patient and by the person authorized to obtain the informed consent

12.0 REFERENCES

1. Verhagen PC, Schroder FH, Collette L, Bangma CH. Does local treatment of the prostate in advanced
and/or lymph node metastatic disease improve efficacy of androgen-deprivation therapy? A systematic
review. Eur Urol. 2010;58(2):261-9. Epub 2010/07/16.
2. Thompson IM, Tangen C, Basler J, Crawford ED. Impact of previous local treatment for prostate cancer on
subsequent metastatic disease. J Urol. 2002;168(3):1008-12. Epub 2002/08/21.
3. Swanson G, Thompson I, Basler J, Crawford ED. Metastatic prostate cancer-does treatment of the primary
tumor matter? J Urol. 2006;176(4 Pt 1):1292-8. Epub 2006/09/06.
4. Culp SH, Schellhammer PF, Williams MB Might men diagnosed with metastatic prostate
cancer benefit from definitive treatment of theprimary tumor? A SEER-based study.. Eur Urol. 2014
Jun;65(6):1058-66
5. Engel J, Bastian PJ, Baur H, et al. Survival benefit of RP in lymph node-positive patients with prostate
cancer. Eur Urol. 2010;57(5):754-61. Epub 2010/01/29.
6. Ghavamian R, Bergstralh EJ, Blute ML, Slezak J, Zincke H. Radical retropubic prostatectomy plus
orchiectomy versus orchiectomy alone for pTxN+ prostate cancer: a matched comparison. J Urol.
1999;161(4):1223-7; discussion 7-8. Epub 1999/03/19.
7. Schroder FH, Kurth KH, Fossa SD, et al. Early versus delayed endocrine treatment of T2-T3 pN1-3 M0
prostate cancer without local treatment of the primary tumour: final results of European Organisation for
the Research and Treatment of Cancer protocol 30846 after 13 years of follow-up (a randomised controlled
trial). Eur Urol. 2009;55(1):14-22. Epub 2008/10/01.
21

8. Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation treatment in patients
with node-positive prostate cancer after RP and pelvic lymphadenectomy. Lancet Oncol. 2006;7(6):472-9.
Epub 2006/06/06.
9. Studer UE, Collette L, Sylvester R. Can RP benefit patients despite the presence of regional metastases?
Eur Urol. 2010;57(5):762-3; author reply 3-5. Epub 2010/01/26.
10. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally
advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet.
2009;373(9660):301-8. Epub 2008/12/19.
11. Ischia J, Gleave M. RP in high-risk prostate cancer. Int J Urol. 2013;20(3):290-300. Epub 2013/01/12.
12. Lange PH. Is surgery good for advanced localised prostate cancer? It's time to find out! Eur Urol.
2007;51(4):873-5. Epub 2006/10/31.
13. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared
with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345(23):1655-9. Epub
2002/01/05.
14. Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus interferon-alfa-
based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised
trial. Lancet. 2001;358(9286):966-70. Epub 2001/10/05.
15. Boorjian SA, Karnes RJ, Viterbo R, et al. Long-term survival after RP versus external-beam radiotherapy
for patients with high-risk prostate cancer. Cancer. 2011;117(13):2883-91. Epub 2011/06/22.
16. Karnes RJ, Hatano T, Blute ML, Myers RP. RP for high-risk prostate cancer. Japanese journal of clinical
oncology. 2010;40(1):3-9. Epub 2009/10/21.
17. Gontero P, Marchioro G, Pisani R, et al. Is RP feasible in all cases of locally advanced non-bone metastatic
prostate cancer? Results of a single-institution study. Eur Urol. 2007;51(4):922-9; discussion 9-30. Epub
2006/10/20.
18. Stratton KL, Chang SS. Locally advanced prostate cancer: the role of surgical management. BJU Int.
2009;104(4):449-54. Epub 2009/08/12.
19. Ward JF, Slezak JM, Blute ML, Bergstralh EJ, Zincke H. RP for clinically advanced (cT3) prostate cancer
since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int. 2005;95(6):751-6. Epub
2005/03/30.
20. Friedlander JI, Duty BD, Okeke Z, Smith AD. Obstructive uropathy from locally advanced and metastatic
prostate cancer: an old problem with new therapies. Journal of endourology / Endourological Society.
2012;26(2):102-9. Epub 2011/12/24.
21. Denham JW, Wilcox C, Joseph D, et al. Quality of life in men with locally advanced prostate cancer
treated with leuprorelin and radiotherapy with or without zoledronic acid (TROG 03.04 RADAR):
secondary endpoints from a randomised phase 3 factorial trial. Lancet Oncol. 2012;13(12):1260-70. Epub
2012/11/16.
22. Gater A, Abetz-Webb L, Battersby C, et al. Pain in castration-resistant prostate cancer with bone
metastases: a qualitative study. Health and quality of life outcomes. 2011;9:88. Epub 2011/10/14.
23. Colloca G, Colloca P. Health-related quality of life assessment in prospective trials of systemic cytotoxic
chemotherapy for metastatic castration-resistant prostate cancer: which instrument we need? Medical
oncology. 2011;28(2):519-27. Epub 2010/04/01.
24. Brassell SA, Elsamanoudi SI, Cullen J, Williams ME, McLeod DG. Health-related quality of life for men
with prostate cancer-an evaluation of outcomes 12-24 months after treatment. Urologic oncology. 2012.
Epub 2012/05/23.
25 Berkovic P, De Meerleer G, Delrue L, Lambert B, Fonteyne V, Lumen N, Decaestecker K, Villeirs G,
Vuye P, Ost P.Salvage stereotactic body radiotherapy for patients with limited prostate cancer metastases:
deferring androgen deprivation therapy. Clin Genitourin Cancer. 2013 Mar;11(1):27-32

22

APPENDICES

Common Terminology Criteria for Adverse Events v4.0 (CTCAE)

Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical
descriptions of severity for each AE based on this general guideline:
- Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated.
- Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*.
- Grade 3 Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care
ADL**.
- Grade 4 Life-threatening consequences; urgent intervention indicated.
- Grade 5 Death related to AE.

23

24

http://www.painedu.org/Downloads/NIPC/Brief_Pain_Inventory.pdf

25

26

The SF-12 Short-Form Health Survey
Instructions: This survey asks for your views about your health. This information will help keep track of how you
feel and how well you are able to complete your usual activities.Please mark each response with an X. If you are
unsure about how to answer a question, please give the best answer you can.
1. In general, would you say your health is: Excellent Very Good Good Fair Poor
HSS
- -
2. The following questions are about activities you might do during a typical day. Does your health now limit
you in these activities? If so, how much?
4. During the past 4 weeks, have you had any of the following problems with your work or other regular
daily activities as a result of any emotional problems (such as feeling depressed or anxious)?
5. During the past 4 weeks, how much did pain interfere with your normal work (including both work
outside the home and housework)?
Not at All A little bit Moderately Quite a bit Extremely
a. Have you felt calm and peaceful?
b. Did you have a lot of energy?
c. Have you felt downhearted and blue?
All
of the
time
Most
of the
time
A
good bit
of the
time
Some
of the
time
A
little
of the
time
None
of the
time
6. These questions are about how you feel and how things have been with you during the past 4 weeks.
For each question, please give the one answer that comes closest to the way you have been feeling.
How much of the time during the past 4 weeks?
7. During the past 4 weeks, how much of the time has your physical health or emotional problems
interferred with your social activities (like visiting with friends, relatives, etc)?
a. Accomplished less than you would have liked?
b. Didn't do work or other activities as carefully as usual?
Yes No
a. Accomplished less than you would have liked?
b. Were limited in the kind of work or other activities?
Yes No
Yes,
limited
a lot
Yes,
limited
a little
No, not
limited
at all
a. Moderate activities, such as moving a table,
pushing a vacuum cleaner, bowling, or playing golf.
b. Climbing several flights of stairs.
3. During the past 4 weeks, have you had any of the following problems with your work or other regular daily
activities as a result of your physical health?
Name:
5
All of the time Most of the time Some of the time A little of the time None of the time
3028334496

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Asset Metadata

Creator Alemozaffar, Mehrdad (author)

Core Title Cytoreductive radical prostatectomy for prostate cancer patients with oligometastatic disease

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical and Biomedical Investigations

Publication Date 08/03/2015

Defense Date 05/31/2015

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag cytoreductive,OAI-PMH Harvest,oligometastatic,prostate cancer,radical prostatectomy

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Azen, Stanley P. (committee chair), Lieskovsky, Gary (committee chair), Aron, Monish (committee member), Quinn, David I. (committee member)

Creator Email malemozaffar@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-624494

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Identifier etd-Alemozaffa-3789.pdf (filename),usctheses-c3-624494 (legacy record id)

Legacy Identifier etd-Alemozaffa-3789.pdf

Dmrecord 624494

Document Type Thesis

Format application/pdf (imt)

Rights Alemozaffar, Mehrdad

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Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

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