CLINICAL OUTCOME OF ADVANCED RENAL CELL CARCINOMA IN TAIWAN, A RETROSPECTIVE NHIA DATABASE ANALYSIS
Conditions: Renal Cell Carcinoma
Sponsor: Pfizer

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Study information 
Title 
Clinical Outcome Of Advanced Renal Cell 
Carcinoma In Taiwan, A Retrospective NHIA 
Database Analysis 
Protocol number 
A6181222 
Protocol version identifier 
Ver. 1 
Date of last version of protocol 
31, August, 2016 
Active substance 
Sunitinib (ATC code: L01XE04) 
Pazopanib (ATC code: L01XE11) 
Medicinal product 
Sutent® capsules 12.5mg 
Votrient® tablets 200mg 
Research question and objectives 
1. 
Utilization of sunitinib and pazopanib in 
Taiwanese patients with advanced renal cell 
carcinoma 
2. 
RCC related costs of sunitinib and pazopanib in 
Taiwanese patients with advanced renal cell 
carcinoma 
3. 
Overall survival and occurrence of hypertension 
of Sunitinib and Pazopanib in Taiwanese RCC 
Patients 
Author 
, Professor and 
 
School of Pharmacy 
Institute of Clinical Pharmacy and Pharmaceutical 
Sciences 
Health Outcome Research Center 
National Cheng Kung University, Tainan, Taiwan 
PPD
PPD

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Email: 
 
Tel: 
 
Fax: 
 
 
, Post-doctoral Fellow 
Institute of Clinical Pharmacy and Pharmaceutical 
Sciences 
Health Outcome Research Center  
National Cheng Kung University, Tainan, Taiwan 
Email: 
 
Tel: 
 
Fax: 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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TABLE OF CONTENTS 
1. LIST OF ABBREVIATIONS ................................................................................................5 
2. RESPONSIBLE PARTIES ....................................................................................................6 
3. ABSTRACT ...........................................................................................................................7 
4. AMENDMENTS AND UPDATES .......................................................................................8 
5. MILESTONES .......................................................................................................................9 
6. RATIONALE AND BACKGROUND ..................................................................................9 
7. RESEARCH QUESTION AND OBJECTIVES .................................................................10 
8. RESEARCH METHODS ....................................................................................................10 
8.1. Study design ............................................................................................................10 
8.2. Setting ......................................................................................................................10 
8.3. Variables ..................................................................................................................12 
8.4. Data sources ............................................................................................................14 
8.5. Study size ................................................................................................................15 
8.6. Data management ....................................................................................................15 
8.7. Data analysis ...........................................................................................................15 
8.8. Quality control .........................................................................................................17 
8.9. Limitations of the research methods .......................................................................17 
8.10. Other aspects .........................................................................................................17 
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................18 
9.1. Patient Information and Consent .............................................................................18 
9.2. Patient withdrawal ...................................................................................................18 
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............18 
9.4. Ethical Conduct of the Study ..................................................................................18 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................19 
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........19 
12. REFERENCES ..................................................................................................................19 
13. LIST OF TABLES .............................................................................................................20 
14. LIST OF FIGURES ...........................................................................................................20 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................20 

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ANNEX 2. ADDITIONAL INFORMATION .........................................................................20 
 

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1. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
RCC 
Renal cell carcinoma 
ATC 
Anatomical therapeutic chemical 
CIPD 
Catastrophic illness patient database 
ED 
Emergency Department 
ICD9 
Classifications of Diseases-9 codes 
mRCC 
Metastatic renal cell carcinoma 
mTOR 
Mammalian target of rapamycin 
NCCN 
National Comprehensive Cancer Network 
NCI index 
National Cancer Institute index 
NHI 
National health insurance 
SEER 
The Surveillance, Epidemiology, and End Results 
Program 
TKI(s) 
Tyrosine kinase inhibitor(s) 
 

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2. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol 
 
Name, degree(s)
Title
Affiliation
Address 
 
Professor and 
 
School of Pharmacy, 
National Cheng Kung 
University, Tainan, 
Taiwan 
No 1, University 
Road, Tainan, 
Taiwan 
, MD 
NIS Lead 
Pfizer Taiwan Ltd 
177 Chung Cheng 
East Road, Sec 2, 
Tamsui Dist. New 
Taipei City, Taiwan
PPD
PPD
PPD

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3. ABSTRACT 
z 
Title: Clinical Outcome Of Advanced Renal Cell Carcinoma In Taiwan, A 
Retrospective NHIA Database Analysis 
 Main author: 
, Professor and 
. School of Pharmacy, 
Institute of Clinical Pharmacy and Pharmaceutical Sciences and Health Outcome 
Research Center, National Cheng Kung University, Tainan, Taiwan 
z 
Rational and Background: Sunitinib and pazopanib have been used to treat Taiwanese 
patients with mRCC for more than 5 years while the prescribing patterns, RCC-related 
medical costs and their effectiveness and safety profiles were not yet explored. 
z 
Question and objectives: The objectives are: 
1. To identify the incidence and the prevalence of mRCC in Taiwanese population 
2. To describe the prescribing pattern of sunitinib and pazopanib in Taiwanese mRCC 
patients 
3. To calculate RCC-related cost in sunitinib and pazopanib users 
4. To estimate the overall survival in sunitinib and pazopanib users 
5. To evaluate the incidence of sunitinib- and pazopanib-related hypertension 
z 
Study design: retrospective cohort study 
z 
Population: incident Taiwanese mRCC patients during 2010 to 2014 
z 
Data source: Taiwan HNI datasets and CIPD 
z 
Data size: Not applicable for this study 
z 
Data analysis: descriptive statistics for prescribing patterns, medical costs, overall 
survival and time to hypertension. 
z 
Milestones: Interim report (sunitinib data only) before 30, October, 2016 and Final 
study report before 30, September, 2017 
PPD
PPD

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4. AMENDMENTS AND UPDATES 
  
Amendment 
number 
Date 
Substantial or 
administrative 
amendment 
Protocol 
section(s) 
changed  
Summary of amendment(s)
Reason 
NONE 
 
 
 
 
 
 
 
 
 
 
 
 

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5. MILESTONES 
 
6. RATIONALE AND BACKGROUND 
Renal cell carcinoma comprises approximately 3.8% of all new cancers, with a median 
age at diagnosis of 64 years. Approximately 90% of renal tumors are RCC, and 
approximately 80% of these are clear cell tumors1,2. Analysis of the SEER database indicates 
that the 5-year survival rate for kidney cancer has increased over time for localized disease 
(from 88.4% during 1992–1995 to 91.8% during 2004–2010) and for advanced disease (from 
7.3% during 1992–1995 to 12.3% during 2004–2010)3. 
Cytoreductive nephrectomy before systemic therapy is generally recommended in 
patients with a potentially surgically resectable primary tumor mass. According to NCCN 
guideline, systemic treatment is suggested for patients with metastatic disease. Interferon-
alpha, interleukin, TKIs (sunitinib and pazopanib) and mTOR inhibitors (everolimus and 
temsirolimus) are treatments that widely used in RCC patients with metastatic disease4. 
Sunitinib and pazopanib are 2 TKIs approved to treat patients with metastatic RCC in 
Taiwan currently. Sunitinib was reimbursed by NHI in January, 2010 and pazopanib was 
reimbursed by NHI in August, 2012. In a phase 3 trial, sunitinib demonstrates longer overall 
survival compared with interferon-alpha plus improvement in response and progression-free 
survival in the first-line treatment of patients with metastatic RCC5. Pazopanib is a newer 
generation of TKI to treat RCC. Compared with sunitinib, pazopanib showed similar efficacy, 
but favorable safety and quality-of-life profile6. 
Although being used to treat RCC patients with metastatic disease for more than 5 years, 
the prescribing pattern, the RCC-related medical cost, as well as effectiveness and the safety 
of sunitinib and pazopanib utilization among Taiwanese population is not yet well 
understood. In this study, we will describe the prescribing pattern of sunitinib and pazopanib 
Milestone 
Planned date 
Interim report (sunitinib data only) 
30, October, 2016 
Final study report 
30, September, 2017 

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and estimate the medical costs among users. We also aim to evaluate the survival benefits 
and safety of sunitinib and pazopanib in Taiwanese population. 
 
7. RESEARCH QUESTION AND OBJECTIVES 
The objectives are: 
1. To identify the incidence and the prevalence of mRCC in Taiwanese population 
2. To describe the prescribing pattern of sunitinib and pazopanib in Taiwanese mRCC 
patients 
3. To calculate RCC-related cost in sunitinib and pazopanib users 
4. To estimate the overall survival in sunitinib and pazopanib users 
5. To evaluate the incidence of sunitinib- and pazopanib-related hypertension 
 
8. RESEARCH METHODS  
8.1. Study design  
This is a retrospective cohort study using NHI datasets from January, 2004 to December, 
2014. We define patients that were diagnosed with RCC with both records in CIPD and NHI. 
We will then identify RCC patients that were treated with TKIs (sunitinib and pazopanib) 
and describe the prescribing pattern, including time from the initial diagnosis to first TKI 
prescription, systemic treatment prior and after TKI(s), treatment duration and cumulative 
doses per every 3 months during treatment. 
We will estimate RCC-related medical cost between sunitinib and pazopanib users based 
on the expenditure of claims. We will also evaluate the overall survival and the occurrence of 
hypertension among sunitinib and pazopanib users. 
 
8.2. Setting 
Objective 1: mRCC incidence and prevalence 
We will identify patients who were newly diagnosed as RCC with NHI claims and 
records in CIPD. Patients who had at least one outpatient visit or admission and ED records 
with a primary and/or secondary diagnosis of RCC (ICD9 codes: 189, 1890 and 1899) will be 

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included. The RCC diagnosis will be reconfirmed by records in CIPD. The RCC diagnosis 
date is defined as the first RCC diagnosis record identified in the database. 
We will report RCC incidence and prevalence based on the year of the diagnosis date. 
 
Objective 2: prescribing pattern of sunitinib and pazopanib 
We will describe how sunitinib and pazopanib were prescribed in Taiwanese mRCC 
patients with claims in NHI datasets since January 2010 to December 2014. 
TKI users would be followed since the first TKI prescription to the end of the study 
period. We estimate the time from diagnosis date to first TKI prescription, RCC treatment 
prior and after TKI(s), treatment duration of TKI, average daily doses and cumulative doses 
per every 3 months during treatment. 
 
Objective 3: RCC-related medical costs of sunitinib and pazopanib 
We estimate direct costs that related to RCC treatments in sunitinib users and pazopanib 
users respectively. We will calculate RCC-related medical costs from the diagnosis date to 
the first dose of TKI and the cost from the first dose of TKI to the end of observation periods. 
All TKI users will be grouped by the initial TKI that they were prescribed.  
 
Objective 4: the overall survival in sunitinib and pazopanib users 
We will estimate the overall survival in sunitinib users and pazopanib users. The survival 
benefits will be described descriptively. Patients will receive follow-up from the date of the 
first TKI prescription to the end of study period or death. Death is defined by the record on 
CIPD. 
Objective 5: the incidence of sunitinib- and pazopanib-related hypertension 
For the risk assessment of TKI-related hypertension, we will include hypertension-free 
incident mRCC patients that received sunitinib or pazopanib. TKI users will receive follow-
up from the date of the first prescription to the end of study period, occurrence of 
hypertension or death.  

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We will also report the changes in prescribing patterns of antihypertensive agents before 
and after TKI initiation among TKI users with hypertension. As blood pressure increment has 
been reported after 4 weeks and 10 weeks of treatments7, we will compare the changes in 
prescribing pattern at 1 month, 3 months, 6 months and 1 year after TKI initiation. 
 
8.3. Variables 
Objective 1 & 2: mRCC incidence and prescribing pattern of sunitinib and pazopanib 
The variables include patient baseline characteristics (age, sex, income levels, co-morbid 
conditions and co-medications), health resource utilization (hospital level and geography 
location), sunitinib and pazopanib exposures, treatment duration, persistence and cumulative 
doses. 
Co-morbid conditions include hypertension (ICD-9 codes: 401-409, excluded 402.11, 
402.91), coronary arterial diseases (ICD-9 codes: 410-414, excluded 414.1, 36.0, 36.1), 
diabetes mellitus (ICD-9 code: 250), dyslipidemia (ICD-9: 272) and chronic kidney disease 
(ICD-9: 585, 586).  
We also define information about medication to treat these comorbidities. Patients will 
be considered as taking these medications if there were at least 2 prescriptions a year prior 
sunitinib/ pazopanib initiation. The medications included: beta blockers (ATC: C07), 
dihydropyridine calcium channel blockers (ATC: C08C, C08E, C08G, C09BB, C09Db, 
C09XA53 and C09XA54), non-dihydropyridine calcium channel blockers (ATC: C08D), 
diuretics (in all kinds of administration routes; ATC: C02L, C03, C07B, C07C, C07D, C08G, 
C09BA, C09DA, C09XA52 and C09XA54), angiotension converting enzyme inhibitors 
(ATC: C09A, C09B), angiotension receptor blockers (ATC: C09C, C09D), insulins (ATC: 
A10A), biguanides (ATC: A10BA, A10BD01, A10BD02, A10BD03, A10BD05, A10BD07, 
A10BD08, A10BD10, A10BD11, A10BD13, A10BD14, A10BD15), alpha-glucosidase 
inhibitors (ATC: A10BF), sulfonylureas (ATC: A10BB, A10BC, A10BD01, A10BD02, 
A10BD04, A10BD06, A10BD14), dipeptidyl peptidase 4 inhibitors (ATC: A10BH, 
A10BD07, A10BD08, A10BD09, A10BD10, A10BD11, A10BD12, A10BD13, A10BD18), 
thiazolidinediones (ATC: A10BG, A10BD03, A10BD04, A10BD05, A10BD06, A10BD09, 

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A10BD12 ), antiplatelets (ATC: B01AC, C10BX01, C10BX02, C10BX04, C10BX05, 
C10BX06, C10BX08), anticoagulants (ATC: B01AA), statins (ATC: C10AA, C10BA, 
C10BX), fibrates (ATC: C10AB, C10BA03, C10BA04), bile acid sequestrants (ATC: 
C10AC), nicotinic acids (C10AD, C10BA01) and ezetimibe (C10AX09, C10BA02, 
C10BA05, C10BA06). 
We will also record RCC treatments other than TKIs. These treatments/procedures are 
surgery (partial nephrectomy and radical nephrectomy, defined by procedure codes in NHI 
datasets) and systemic treatment, including interferon- 2a (ATC code: L03AB04), 
interleukin-2 (ATC code: L03AC) and mTOR inhibitors (everolimus and temsirolimus, ATC 
code: L01XE10/L04AA18 and L01XE09, respectively). 
Treatment durations of TKIs will be calculated from the date of the first TKI prescription 
to the last dose of the last prescription. We will compute the cumulative doses per every 3 
months during the first year after TKI initiation.  
All information was retrieved from the inpatient and outpatient claims from the NHI 
datasets. 
 
Objective 3: RCC-related medical costs of sunitinib and pazopanib 
We will calculate the direct medical costs that relate to RCC with NHI datasets. 
Outpatient visits and admission of the following settings will be considered to be RCC-
related: 
1. 
Claims with a diagnosis code (either primary or secondary) that indicated RCC (cost 1) 
2. 
 Urologist or oncologist outpatient visits and admissions to urology or oncology wards, 
regardless of the diagnosis of the claims (cost 2) 
We assess the overall RCC-related medical costs by summing up cost 1 and cost 2. 
 
Objective 4: the overall survival in sunitinib and pazopanib users  

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The variables include patient baseline characteristics (age, sex, income levels, co-
morbid conditions and co-medications) and health resource utilization (hospital level and 
geography location). 
The definitions of comorbidities and co-medications have been described previously of 
this section (in the statements of the objective 1 & 2). 
We will define the date of death using records from CIPD.  
 
Objective 5: the incidence of sunitinib- and pazopanib-related hypertension 
Patients are considered to be newly diagnosed as hypertension after TKI(s) if there are at 
least 2 claims or prescriptions of antihypertensive agents that are at least 30 days apart during 
the follow-up period. 
For hypertensive patients, we will report the antihypertensive agents that had been 
applied before and 1, 3, 6 months and 1 year after TKI initiation. We will also compare 
antihypertensive prescriptions at the different time points (before and after TKIs) for each 
TKI users and classify the patterns of changes into unchanged, switched, increased and 
decreased. Shifting to other class(es) of antihypertensive agents without changes in counts of 
antihypertensive medication is defined as being switched. Dosage titration and/or addition in 
types of antihypertensive agents received are defined as increment.  Dosage tapering and/or 
reductions in types of antihypertensive agents received are defined as decrement.  
 
8.4. Data sources  
We will apply information from NHI datasets and CIPD to determine exposures, 
outcomes and all other variables relevant to the study objectives, such as potential 
confounding variables. 
 

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8.5. Study size 
This is a descriptive study and we do not know the expected number of patients eligible 
for the study. 
 
8.6. Data management 
We will analyze and report the results based on data availability. The results in Study 
Progress Report 1 and Interim Report are based on the datasets from 2004 to 2013. Because 
pazopanib is available since August, 2012, we acknowledge that the prescriptions of 
pazopanib might be limited. When NHI datasets of 2014 becomes available, supposedly at 
the end of 2016, we will have more information about pazopanib prescribing and a longer the 
follow-up period for overall survival and hypertension after TKI(s). 
We will present Final Report base on the NHI datasets from 2004 to 2014. 
 
8.7. Data analysis  
Objective 1: mRCC incidence and prevalence 
We will estimate the annual crude rate of mRCC incidence and prevalence from 2010 to 
2014. The crude mRCC incidence/prevalence is calculated by dividing the 
incident/prevalence mRCC case numbers during a particular year (for example, year 2010) 
with the total population number at the end of that year. 
We will report sex-specific and overall mRCC crude incidence/prevalence and age-
adjusted mRCC incidence/prevalence. 
 
Objective 2: prescribing pattern of sunitinib and pazopanib 
We will present patient characteristics and prescribing patterns with descriptive 
statistics. For continuous variable, mean (SD) and median (min-max) will be both present. 
Proportion (%) will be present for all categorical variables. 

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We will also apply the Cochran-Armitage trend test to estimate the trends of sunitinib 
and pazopanib prescribing pattern over the observation periods. 
 
Objective 3: RCC-related medical costs of sunitinib and pazopanib 
We will assess the overall RCC-related medical cost (from the RCC diagnosis date to 
the first TKI prescription and TKI initiation to the end of follow-up period) and the cost 
during TKI treatment (from the initial TKI dose to the day that the last dose of TKI was 
given). We will also report the RCC-related medical cost of sunitinib users and pazopanib 
users during the first year of treatment separately. 
We will present the mean (SD) and the median (min-max) of the medical cost. 
 
Objective 4: the overall survival in sunitinib and pazopanib users  
We will calculate the survival time from the date of the first TKI prescription to the 
date of death. Survival time will be presented with descriptive statistics (mean, median, 
minimum and maximum of survival time). We will plot the survival curves for sunitinib 
users and pazopanib users using Kaplan-Meier method. We will report the 1-, 2-, 3- and 4-
year overall survival among sunitinib users. 1- and 2-year overall survival of pazopanib users 
will be reported. 
 
Objective 5: the incidence of sunitinib- and pazopanib-related hypertension 
A sub-cohort of incident mRCC cohort that included TKI users without a previous 
history of hypertension will be used to estimate the risk of hypertension. Time to 
hypertension will be presented with descriptive statistics. We will plot the cumulative 
incidence curves for sunitinib users and pazopanib users. We will report the 1-, 3-, 6-months 
and 1-year cumulative incidence for hypertension among sunitinib and pazopanib users. 
For hypertensive patients, we will report changes in the antihypertensive agent 
prescribing patterns before and 1, 3, 6 months and 1 year after TKI initiation.  

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8.8. Quality control 
Annual incident RCC patient counts in Taiwan Cancer Registry will be the external 
referent for the estimates with our protocol. 
 
8.9. Limitations of the research methods 
We believe that the records regarding RCC diagnosis in CIPD to be valid because a 
diagnosis of RCC in NHI datasets needs a histologic or image confirmation to be reported in 
the Registry for Catastrophic Illness Patient Database. However, we cannot exclude the 
possible misclassification for non RCC patients as RCC patients, as vice versa, because the 
information regarding the validity of the diagnosis codes that will be used to identify patients 
with RCC is not available. 
Under the infrastructure of NHI criteria, sunitinib and pazopanib are indicated for mRCC 
patients and patients could only using reimbursed-sunitinib or pazopanib after approvals. 
Sunitinib and pazopanib users are mRCC patients for sure but for patients without any 
systemic treatment, we cannot identify the metastatic disease status. We thus cannot have an 
estimation on percentage of TKI users among mRCC population. 
It is unknown whether non-users had chosen to pay out of pocket for sunitinib and/or 
pazopanib in NHI datasets. The percentage of TKI users will thus be underestimated. For a 
patient who received 50mg sunitinib once daily for on a schedule of 4 weeks on treatment 
followed by 2 weeks off (Schedule 4/2), the cost per every 3 months would be more than 
290,000 NTD. For a pazopanib user who received an 800 mg daily dosage, the cost would be 
more that 220,000 NTD per every 3 months. Since sunitinib and pazopanib are very 
expensive, the number of patients who would have been able to afford sunitinib and 
pazopanib are deemed very limited.  
 
8.10. Other aspects 
Not applicable 
 

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9. PROTECTION OF HUMAN SUBJECTS 
9.1. Patient Information and Consent 
All parties will ensure protection of patient personal data and will not include patient 
names on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.  In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of patient personal data. 
Informed consent is not required for this study as it is a secondary data collection study  
without identified subjects data.  
 
9.2. Patient withdrawal 
Not applicable 
 
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study 
protocol, protocol amendments, and informed consent forms, and other relevant documents, 
(e.g., recruitment advertisements), if applicable, from the IRB/IEC.  All correspondence with 
the IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should 
be forwarded to Pfizer. 
 
9.4. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as 
well as with scientific purpose, value and rigor and follow generally accepted research 
practices described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by 
the International Society for Pharmacoepidemiology (ISPE), Good Epidemiological Practice 
(GEP) guidelines issued by the International Epidemiological Association (IEA), Good 
Practices for Outcomes Research issued by the International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR) and Pharmacovigilance (ENCePP) Guide on 
Methodological Standards in Pharmacoepidemiology, and FDA Guidance for Industry: Good 
Pharmacovigilance and Pharmacoepidemiologic Assessment, FDA Guidance for Industry 

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and FDA Staff: Best Practices for Conducting and Reporting of Pharmacoepidemiologic 
Safety Studies Using Electronic Healthcare Data Sets. 
 
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
This study includes unstructured data (e.g., narrative fields in the database) that will be 
converted to structured (i.e., coded) data solely by a computer using automated/algorithmic 
methods and/or data that already exist as structured data in an electronic database.  In these 
data sources, it is not possible to link (i.e. identify a potential association between) a 
particular product and medical event for any individual. Thus, the minimum criteria for 
reporting an adverse event (i.e., identifiable patient, identifiable reporter, a suspect 
product, and event) are not available and adverse events are not reportable as individual 
AE reports. 
  
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
Final study report and/or manuscript will be developed for this study.   
COMMUNICATION OF ISSUES 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer product, 
Pfizer should be informed immediately.   
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this NI study protocol that the investigator becomes aware of. 
 
 
12. REFERENCES 
1. 
Moch H, Gasser T, Amin MB, Torhorst J, Sauter G, Mihatsch MJ. Prognostic utility 
of the recently recommended histologic classification and revised TNM staging 
system of renal cell carcinoma: a Swiss experience with 588 tumors. Cancer. 
2000;89(3):604-614. 

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2. 
Leibovich BC, Lohse CM, Crispen PL, et al. Histological subtype is an independent 
predictor of outcome for patients with renal cell carcinoma. The Journal of urology. 
2010;183(4):1309-1315. 
3. 
SEER. Stat Fact Sheets: Kidney and Renal Pelvis Cancer. 2016; 
http://seer.cancer.gov/statfacts/html/kidrp.html. Accessed 27, April, 2016. 
4. 
NCCN. NCCN Clinical Practice Guideline in Oncology: Kidney Cancer 2016; 
https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed 27, 
April, 2016. 
5. 
Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for 
sunitinib compared with interferon alfa in patients with metastatic renal cell 
carcinoma. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2009;27(22):3584-3590. 
6. 
Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-
cell carcinoma. The New England journal of medicine. 2013;369(8):722-731. 
7. 
Kappers MH, van Esch JH, Sluiter W, Sleijfer S, Danser AH, van den Meiracker AH. 
Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with 
increased circulating endothelin-1 levels. Hypertension (Dallas, Tex. : 1979). 
2010;56(4):675-681. 
 
13. LIST OF TABLES  
None 
14. LIST OF FIGURES 
None 
ANNEX 1. LIST OF STAND ALONE DOCUMENTS 
None 
ANNEX 2. ADDITIONAL INFORMATION 
Not applicable