A Phase II Study of Intra-arterial Chemotherapy With Cisplatin and Mitomycin-C
Phase: PHASE2
Conditions: Hepatocellular Carcinoma, Liver Cancer
Sponsor: University of Southern California

 
 
Local Protocol #: 3L-03-1 
Protocol Title: A Phase II Study of Intra-Arterial Chemotherapy 
with Cisplatin and Mitomycin-C in Patients with Hepatocellular 
Carcinoma 
Protocol version date: 10/01/2010 
 
ClinicalTrialsgov #: NCT00183885 
 
 

10/1/2010 
 
1
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR. 
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
CLINICAL INVESTIGATIONS SUPPORT OFFICE 
1441 Eastlake Avenue, Room 7408 MS-74 
Los Angeles, California 90089-9177 
Telephone (323) 865-0450 
 
PROTOCOL NUMBER: 
3L-03-1 
 
TITLE: 
A Phase II study of intra-arterial 
chemotherapy with cisplatin and mitomycin-
C in patients with Hepatocellular Carcinoma 
 
SITE:  
Liver 
 
HISTOLOGY: 
Hepatocellular 
 
STAGE: 
Unresectable but confined to the liver 
 
MODALITY: 
Chemotherapy  
 
TYPE:  
Phase II 
 
ARMS:  
Single 
 
PRINCIPAL INVESTIGATORS: 
Syma Iqbal, MD 
 
CO-INVESTIGATORS: 
John Daniels, MD 
 
Anthony El-Khoueiry, M.D. 
 
 
Heinz-Josef Lenz, MD 
 
IRB ANNIVERSARY DATE: 
 
 
IRB FINAL APPROVAL DATE: 
 
 
IRB NUMBER: 
 
 
 
 
PARTICIPANTS: 
LAC+USC Medical Center 
 
 
USC/Norris Comprehensive Cancer Center 
& Hospital 
 
AMENDMENTS/REVISIONS: 
9/14/2005, 10/09/07, 1/14/08, 03/18/08, 
3/19/2009, 8/7/2009, 10/1/2010 
 
**************************************************************************************************** 
THE UNIVERSITY OF SOUTHERN CALIFORNIA ASSUMES NO 
RESPONSIBILITY FOR THE USE OF THIS EXPERIMENTAL PROTOCOL 
OUTSIDE THE PARTICIPATING INSTITUTIONS  
 

10/1/2010 
 
2
TABLE OF CONTENTS 
1.0 
Objectives 
1.1 
Primary Objectives 
1.2 
Secondary Objectives 
2.0 
Background and Hypotheses 
2.1 
Incidence of Hepatocellular Carcinoma 
2.2 
Current Strategies for Treatment of Hepatocellular Carcinoma 
2.3 
Current proposed therapy 
2.4 
Prognostic Index 
2.5 
Molecular Correlates 
3.0 
Drug Information 
3.1 
Cisplatin 
3.2 
Mitomycin-C 
4.0 
Staging 
5.0 
Eiligibility Criteria 
6.0 
Stratification/Descriptive Factors 
6.1 
Two descriptive factors will be used in this analysis 
7.0 
Outline of Study Treatment 
7.1 
Treatment Plan 
7.2 
Radiofrequency ablation (RFA)  
7.3 
Criteria for Removal from Treatment 
7.4 
Follow-up 
8.0 
Toxicities To Be Monitored and Dosage Modifications 
8.2 
Dose modification steps for mitomycin-C/cisplatin 
8.3 
Toxicity Grade and Dose Modification 
8.4 
Procedure related untoward outcomes 
8.5 
Adverse Events (AE)  
9.0 
Study Calendar 
10.0 
Criteria for Evaluation and Endpoint Definitions 
10.1 
Measurability of tumor lesions at baseline 
10.2 
Specifications by methods of measurements 
10.3 
Response Criteria 
10.4 
Endpoint Definitions 
11.0 
Special Instructions 
11.1 
Experimental Methods and Procedures 
11.2 
Handling of blood samples for Pharmacogenetics 
11.3 Handling of tumor tissues 
12.0 
Statistical Considerations 
12.1 
Study Design 
12.2 
Analysis of Results 
12.3 
Monitoring for Excessive Unacceptable Toxicity 
13.0 
Registration Guidelines 
14.0 
Minorities and Women Statement 
15.0 
Ethical and Regulatory Considerations 
16.0 
References 
 

10/1/2010 
 
3
1.0 
Objectives 
1.1 
Primary Objectives 
1.1.1 
To assess response rate in patients with unresectable HCC receiving 
intra-arterial chemotherapy with cisplatin and mitomycin-C. 
 
1.2 
Secondary Objectives 
1.2.1 
To assess toxicity for intra-arterial chemotherapy with cisplatin and 
mitomycin-C in patients with unresectable HCC. 
1.2.2 
To document the definitive therapy used following induction IA treatment  
with cisplatin and mitomycin-C and assess time to progression and 
overall survival in these patients according to type of post induction 
treatment received. 
1.2.3 
To evaluate the validity of a internally developed prognostic index, which 
was developed previously, in the context of chemoembolization 
1.3  
Exploratory Objectives 
1.3.1 
To examine associations of molecular markers that may predict response, 
survival and toxicity in patients with HCC receiving intra-arterial 
chemotherapy with cisplatin and mitomycin-C. 
 
 
2.0 
Background and Hypotheses 
2.1 
Incidence of Hepatocellular Carcinoma 
Hepatocellular carcinoma causes about 1 million deaths annually, with 
most of these deaths occurring in the Far East and in sub-Saharan Africa. 
Accordingly, the disease is uncommon in the United States and Western 
Europe with an annual incidence of about 3 cases /100,000 population. 
The disease is predominantly found in males. There is evidence that 
Hepatitis B infection alone or in combination with other factors leads to 
most cases worldwide. Hepatitis C infection is also strongly associated with 
HCC. Additionally, about 80% of patients with HCC have cirrhosis. Other 
potential etologies that have been implicated in this disease include: 
aflatoxins produced by Aspergillus flavus and related fungi, long-term use 
of oral contraceptives and alcohol abuse, which is modestly associated 
with HCC but markedly increases the risk in patients with Hepatitis C 
infection. 
2.2 
Current Strategies for Treatment of Hepatocellular Carcinoma 
Definitive treatment of hepatoma generally involves resection, local 
ablation or transplantation. Advanced stage or hepatic cirrhosis limit 
resection options, and donor liver supply restricts the transplantation 
option. Regional arterial therapy may offer palliation and life extension and 
also may be used in individual cases during the wait for a donor liver. 

10/1/2010 
 
4
Intravenous chemotherapy usually results in low objective response rates, 
a median survival of 3 to 6 months, and a 2 year survival of 5% and has not 
shown a survival benefit over palliative care.[1] [2] [3] [4] [5] Older 
published intra-arterial chemotherapy experience tends to be similar to 
intravenous chemotherapy, with median survival time of 6 months, 
although longer survival times have been reported.[6] [7] [8] [9]  Recently a 
study was done in patients done in patients with advanced hepatocellular 
carcinoma (patients in which surgery or locoregional treatments are not 
indicated as disease is not confined to the liver).  Patients with Child-Pugh 
status A were randomized to receive sorafenib 400 mg bid or placebo. This 
trial was stopped at the interim analysis, as based on 321 deaths 
(sorafenib n=143, placebo n=178), the hazard ratio for overall survival 
(sorafenib vs. placebo) was 0.69 (95% CI: 0.55, 0.87; p=0.0006), 
representing a 44% improvement in overall survival.  Median overall 
survival was 10.7 for sorafenib versus 7.9 months for placebo. Sorafenib is 
the first agent to demonstrate a statistically significant improvement in 
overall survival for patients with advanced hepatocellular carcinoma. This 
effect is clinically meaningful and establishes sorafenib as first-line 
treatment for these patients.[10] 
Chemoembolization is the concurrent administration of drug and particle to 
increase drug dwell time within the target. Chemoembolization experiences 
have been reported using a variety of agents and catheter techniques. We 
have submitted a Phase II chemoebolization study in 85 hepatocellular 
carcinoma patients who were not considered to be operative 
candidates.[11] In this study the median survival time was 12.7 months.   
The current treatment standard at USC is intra-arterial drug administration. 
Intra-arterial drug administration became more refined with the introduction 
of steerable micro-catheters that facilitate selective access through the 
femoral artery.[12] Placement of the catheter tip within selected intra-
hepatic branches reduces the risk of non-target perfusion or embolization 
and enhances drug delivery to the target. Our current non-protocol 
experience suggests that we can expect response rates in the range of 
50% and that toxicity requiring hospitalization is rare. 
Intra-arterial chemotherapy is currently the standard of care in patients with 
unresectable hepatocellular carcinoma and disease confined to the liver.  
This is mainly due to the results of two studies in this patient population.  In 
one study 80 patients were randomized to receive a) chemoembolization 
with an emulsion of cisplatin in lipiodol and gelatin-sponge particles through 
the hepatic artery or b) symptomatic treatment.  The results showed a 
survival advantage for the chemoembolization group (1 year, 57%; 2 years, 
31%; 3 years, 26%) over the symptomatic treatment group (1 year, 32%; 2 
years, 11%; 3 years, 3%; P =.002). When adjustments for baseline 
variables that were prognostic on univariate analysis were made with a 
multivariate Cox model, the survival benefit of chemoembolization 
remained significant (relative risk of death, 0.49; 95% CI, 0.29-0.81; P 
=.006).[13] A study by Llovet et. al randomized patients to receive a) 
arterial embolization with gelatin sponge b) chemoembolization with gelatin 
sponge plus doxirubicin or c) conservative treatment (palliative care).  This 
study was stopped when an interim analysis showed chemoembolization 

10/1/2010 
 
5
had survival benefits compared with conservative treatment (hazard ratio of 
death 0.47 [95% CI 0.25-0.91], p=0.025). Survival probabilities at 1 year 
and 2 years were 75% and 50% for embolization; 82% and 63% for 
chemoembolization, and 63% and 27% for control (chemoembolization vs 
control p=0.009). Chemoembolization induced objective responses 
sustained for at least 6 months in 35% (14)of cases, and was associated 
with a significantly lower rate of portal-vein invasion than conservative 
treatment. Treatment allocation was the only variable independently related 
to survival (odds ratio 0.45 [95% CI 0.25-0.81], p=0.02).[14] 
Although intra-arterial chemotherapy is standard of care in this patient 
population, no evidence indicating the best chemotherapy agents to use, 
thus regimens based on doxorubicin, mitomycin and cisplatin are 
commonly used as they have shown benefit. [13] [14] [15] The goal of this 
therapy is to shrink tumors enough that they may benefit from 
radiofrequency ablation or cryotherapy. 
Percutaneous image-guided radiofrequency ablation (RFA) uses thermal 
energy for the local treatment of solid malignancies. It has been shown to 
be safe and effective for the treatment of hepatocellular carcinomas, 
particularly those less than 5 cm. It has been shown to be more effective 
than percutaneous alcohol injection for the treatment of small 
hepatocellular carcinomas < 3cm.  
Percutaneous RFA is typically performed under conscious sedation. With 
direct image guidance by ultrasound or CT, a 12-14g multi-tine needle is 
introduced to the target tumor within the liver. The tines are deployed and 
their position ascertained with imaging. Radio-frequency energy is then 
applied according to a standard escalating protocol to produce an 
appropriate area of tissue necrosis. At the conclusion of the ablation 
program the needle tract is treated as well, if possible, to preclude tumor 
seeding. 
A limitation of RFA treatment is the inability to reliably create a large 
enough area of complete thermal tumor destruction and to unequivocally 
include the actual tumor margins that may be inaccurately inferred from 
imaging. Tumor foci may survive RFA because of biophysical limitations 
such as perfusion-mediated tissue cooling which occurs near large vessels 
or because foci of tumor exist beyond the margin of burn. Additionally, RFA 
may fail due to multi-focal disease. 
2.3 
Current proposed therapy 
In the current study intra-arterial chemotherapy will be administered twice 
at an 8 week interval (up to 4 times at physician discretion). Response to 
the initial chemotherapy will result in reduced volume, better-delineated 
margins and treatment of satellite foci.  
2.4 
Prognostic Index 
A Prognostic Index (PI) for patients with hepatoma was developed from the 
USC chemoembolization study.[11] The Prognostic Index effectively 
identifies patient groups most likely to benefit from chemoembolization. 
Patients in the more favorable prognostic groups had higher objective 

10/1/2010 
 
6
response rates, and responders appeared to live longer than non-
responders. 
The PI described is calculated by adding two points for elevated LDH and 1 
point each for abnormal ALP (>200 u/L), abnormal AST (>100 u/L), and 
presence of ascites on baseline imaging. LDH, the dominant component of 
this index, is often cited as a prognostic indicator for outcome in malignant 
disease.[16] [17] [18] In hepatoma, one would expect increases in LDH both 
from the tumor and as a function of liver injury. When established 
prognostic systems were compared as predictors for this patient 
population, only the Okuda stage was significantly associated with survival. 
The superiority of the PI developed during this analysis is shown in Table 1 
below. Both a lower p-value and a higher correlation coefficient are 
associated with the PI, demonstrating its superiority as a prognostic 
indicator for survival. 
Responses were usually obtained for patients with PI scores between 0 
and 2 and response in these groups was associated with meaningful 
extension of survival. Confirmation of the usefulness of the PI as a tool for 
prognostic evaluation of individual cases needs to be done with further 
studies of additional patients with hepatoma. 

10/1/2010 
 
7
Table 1 
 
Group 
N 
# 
Deaths 
MST 
(mo.)
Estimated Survival (%) 
p-value 
RR 
 
 
 
 
1-yr
2-yr
3-yr 4-yr 5-yr 
 
 
All Patients 
85 
73 
12.7 
52 
26 
16 
11 
8 
 
 
PI – 0 
24 
19 
25.9 
85 
58 
39 
24 
14 
<0.0001 
1 
PI - 1 
20 
17 
13.2 
56 
13 
11 
11 
11 
 
1.8 
PI - 2 
10 
10 
15.3 
55 
25 
5 
0 
0 
 
1.3 
PI - 3 
10 
9 
5.4 
15 
- 
- 
- 
- 
 
4.3 
PI – 4 
11 
11 
2.9 
0 
0 
0 
0 
0 
 
10 
PI - 5 
6 
6 
2.3 
0 
0 
0 
0 
0 
  
9.5 
 
2.5 
Molecular Correlates 
2.5.1 
Apoptosis 
By understanding the role that some major regulators of apoptosis play 
either at the commitment or execution phases of cell death in 
hepatocellular carcinoma tissue, we will be in a better position to design 
and explore new therapeutic modalities. The bcl-2 and ICE gene family 
products are intrinsic proteins regulating the decision of a cell to survive or 
die and executing part of the cell death process. Among the various bcl-like 
proteins, the effects and functions of the bcl-x and bax proteins in 
controlling apoptosis induced by cancer chemotherapy have been recently 
studied. In human cancer variant cell lines show differential expression of 
the bcl-xL protein. A preventive effect of bcl-xL on cell death induced by 
various cytotoxic drugs has been observed, with greater effects in cells 
containing the highest level of bcl-xL expression. Similarly, overexpression 
of bax in cancer cell lines sensitizes these cells to some cancer 
chemotherapy compounds. Modulation of apoptosis either negatively by 
bcl-xL or positively by bax resides downstream of the primary mechanism 
of action of anticancer drugs, suggesting that they act primarily as intrinsic 
control points following cytotoxic drug injuries.[19-21] We will test the 
hypothesis that gene expression levels of bcl-2, bcl-xL, bcl-xS and bax will 
predict response and survival in patients with hepatocellular carcinoma 
treated with intra-arterial mitomycin-C and cisplatin. 
2.5.2 
DNA repair 
The presence of intact DNA repair is an important prognostic indicator for 
colorectal cancer. In studies of colorectal cancer cell lines containing DNA 
mismatch repair gene mutations (MMR), lack of response to 
chemotherapeutic agents in vitro is found in cell lines with microsatellite 
instability (MIN) which is the landmark for DNA mismatch repair gene 
defects, where tumors without MIN remain sensitive. For example, HCT 
116 cells lack hMLH1 function, and are insensitive to 5-FU in vitro. When 

10/1/2010 
 
8
chromosome 3, which contains hMLH1, is transferred to HCT116 cells, 
mismatch repair function is restored, and cells are inhibited by culture in 5-
FU.[22] Colorectal cancer cell lines with MMR defects are resistant to 
methylating agents.[22] Lothe et al demonstrated, using PCR-based 
analysis of 7 microsatellite loci, that 17% of patients without and 31% of 
patients with a strong family history of cancer exhibited changes at one or 
more loci.[23] Patients with tumors expressing MIN exhibited increased 
survival when compared to patients with tumors lacking MIN. Recently, 
Garioboldi et al reported that human colon cancer cell line HCT116, which 
is defective in mismatch repair, is hypersensitive to mitomycin-c.[24] 
HCT116 cells that had undergone transfer with human chromosome 2 or 3 
to correct the mismatch repair deficiency were 3- to 4-fold resistant to CPT-
11. These results suggest that DNA mismatch repair is involved in 
processing CPT-induced DNA damage, and that mitomycin-c and its 
derivatives may be selective for tumors with mismatch repair deficiency. 
We will test the hypothesis that the DNA mismatch repair status will be a 
predictor of response and survival in patients with hepatocellular carcinoma 
treated with intra-arterial mitomycin-c and cisplatin.  
Moreover, analysis of the 7 human colon carcinoma cell lines of the NCI 
Anticancer Drug Screen showed that defects in replicon elongation and G2 
breakthrough capability correlate with sensitivity to mitomycin-c, suggesting 
that misrepair of damaged replicons and/or alterations in DNA damage 
checkpoints is critical to defining chemosensitivity to CPT-induced DNA 
damage.[25] Analysis of expression of different genes potentially involved 
in DNA repair and in cell responses to chemotherapy showed a significant 
correlation between topoisomerase I and ERCC1 expression indicating 
some regulatory relationship between these two genes.[26] ERCC1 is an 
essential enzyme for nucleotide excision repair. Recently, our group 
demonstrated that ERCC1 is a significant predictor of response to cisplatin 
in patients with gastric cancer.[27] DNA repair enzymes such as ERCC1 
may play some role in repairing DNA damage induced by mitomycin-C and 
therefore may be a predictor of therapy efficacy.[28] We will test the 
hypothesis that ERCC1 gene expression will predict response and survival 
in patients with hepatocellular carcinoma treated with intra-arterial cisplatin 
and mitomycin-C. 
2.5.3 
p53 and p21 
Clinically relevant exposures to platinum compounds will lead to a tumor 
injury response (TIR) that shares characteristics with the response 
produced by many other injurious agents. Although very little is known 
about the specifics of the signal transduction pathway activated by platinum 
injury, it is possible to identify the general nature of this response. It is 
thought that the capacity to induce growth arrest in response to injurious 
conditions arose from the advantages of delaying replication of defective 
DNA templates until damage has been repaired (G1/S arrest) and delaying 
the segregation of sister chromatids until DNA breaks have been corrected 
(G2/M). The function of p53 is to send cells with damaged DNA either into 
G1 arrest for repair or into programmed cell death through apoptosis.[29, 30] 
Neither G1 arrest nor the apoptotic program is initiated by drug treatment in 
cells with mutated p53 genes, suggesting that tumors with mutant p53 

10/1/2010 
 
9
might be resistant to DNA damaging agents. In vitro studies confirmed that 
p53 is a major modulator of sensitivity to drugs such as 5-FU, etoposide, 
adriamycin and cisplatin.[31, 32] Tumors in mice expressing wt p53 contained 
a high proportion of apoptotic cells and regressed after radiation or 
adriamycin, whereas tumors expressing mutated p53 did not respond to 
treatment indicating the relevance of p53 as a predictor of response to 
chemotherapy.[33] p53 is not only an important predictive marker but also 
a possible therapeutic agent. In fact, Fujiwara and colleagues were able to 
increase the cellular sensitivity to cisplatin by transfection of wt p53 into 
tumor spheroids of human non-small cell lung cancer cells.[34] All these 
results have strengthened the image of p53 as a predictor of 
chemosensitivity and have obvious clinical relevance for GI cancer, which 
has up to 70% p53 mutations. Many of the effects of p53 such as G1 cell 
cycle arrest and apoptosis in most cases can be attributed to biological 
functions of downstream p53-regulated genes, such as WAF1/CIP1.[35] 
WAF1/CIP1 plays an important role in the p53 induced G1 arrest by 
coordinately inhibiting the functions of both CDKs and PCNA which arrest 
DNA replication while permitting active DNA repair.[29, 36] WAF1/CIP1 has 
been shown to be directly induced by wt p53 in vitro but its expression is 
lost when active p53 is absent.[37]  While the presence of p53 mutations 
can be easily established, to date no easily measurable biochemical 
parameter has been identified that would be indicative of p53 function. 
WAF1/CIP1 is thought to be a direct mediator of p53 cell-cycle regulation 
activity and p53-mediated apoptosis.[36, 38] These findings suggest that 
WAF1/CIP1 expression levels can be used as a direct indicator of p53 
functionality in cells. That is, low or absent expression of WAF1/CIP1 
should indicate a lack of p53 function while partial expression of 
WAF1/CIP1 should indicate some retention of p53 activity.  
These findings suggest that p21 level may be useful as an indicator of p53 
function in cells and may be a link between p53 status and TS expression. 
If p21 expression is a reflection of the p53 function, low or absent 
expression of p21 may indicate a lack of p53 transcriptional activity, while 
partial expression of p2l should indicate some retention of p53 activity. p21 
expression may not only help to identify p53 mutations which may have 
partial wild-type activity but may also help to identify tumors with false 
negative p53 staining due to deletion, non-sense and misplaced mutations. 
However, p21 may be regulated in a p53-independent manner through 
activation of the type II TGFβ receptor.[35] Therefore, p21 expression may 
occur in the face of mutant p53 through this p53-independent pathway. We 
will test the hypothesis that p53 status and p21 expression levels are 
predictors of response, tumor recurrence and survival in patients with 
hepatocellular carcinoma treated with intra-arterial cisplatin and mitomycin-
C. 
Cancer cells may also exhibit imbalance of cell cycle regulation and fail to 
arrest in G1 or G2 to prevent further lesions and/or to repair existing DNA 
damage. p53 and p21 play an important part in DNA damage checkpoint, 
cell cycle arrest and initiation of apoptosis. The relationship between 
chemosensitivity and p53 is currently considered from two mutually 
exclusive points of view: (1) wt p53 increases chemosensitivity due to 
apoptosis and (2) wt p53 decreases chemosensitivity due to growth arrest 

10/1/2010 
 
10
and DNA repair. A p53-expressing adenovirus (Ad-p53) was used to 
directly evaluate effect of p53 on sensitivity to anticancer drugs. When p53 
was expressed at sublethal levels, it sensitized cells to the DNA-damaging 
drugs such as adriamycin, cisplatin and mitomycin-C. This sensitization 
was observed in cancer cell lines regardless of endogenous p53 status. 
The degree of sensitization appeared to be greater in cancer cells with 
mutant p53, indicating that p53 may play an important role in 
chemoresistance.[39] 
2.5.4 
Ribonucleotide Reductase 
Recent evidence suggests that in addition to its essential role in DNA 
synthesis, Ribonucleotide reductase (RR) plays a critical role in DNA repair 
and is induced by DNA damaging drugs.[40] Furthermore, Fan et al have 
demonstrated that overexpression of the M2 subunit plays an important 
role with ras in malignant progression.[41] M2 overexpression, as expected, 
produces resistance to hydroxyurea. Our own data suggest that M2 mRNA 
expression, measured by RT-PCR in tumors, is 10-20 fold higher than 
expression in adjacent normal tissue, indicating that RR may play a role in 
chemoresistance to DNA damaging drugs (unpublished data). In this study 
we will test whether the expression levels of RR will predict to resistance to 
intra-arterial cisplatin and mitomycin-C in for patients with hepatocellular 
carcinoma.  
2.5.5 
Metallothioneins 
Elevation of glutathione (GSH) is widely observed in cellular resistance to 
platinum agents.[42] Previous studies have shown that sublines of human 
ovarian carcinoma cell line A2780, which exhibited low levels of resistance 
to oxaliplatin, showed elevated steady state levels of mRNA and activity of 
gamma-glutamyl transpeptidase (gamma-GT, EC 2.3.2.2), but not of 
gamma-glutamylcysteine synthetase (gamma-GCS, EC 6.3.2.2).[43, 44] 
Single exposures of cells to oxaliplatin induced a time- and concentration-
dependent increase in the mRNA of gamma-GT, but not of gamma-GCS. 
Cisplatin also induced an elevation in gamma-GT mRNA, but to a lower 
degree. The gamma-GT enzyme activity increased corresponding to the 
elevation in mRNA expression. The gamma-GT-induced cells showed an 
increase in cellular GSH when incubated in medium containing GSH. The 
data suggest that a) single, brief exposures to pharmacologically relevant 
concentrations of platinum complexes induce elevation in mRNA of 
gamma-GT, b) elevation in gamma-GT mRNA translates into elevated 
gamma-GT activity and increase in GSH salvage, and c) the degree of 
induction of gamma-GT mRNA differs between platinum complexes. 
Elevation of glutathione (GSH) is commonly observed in cellular resistance 
to a number of anticancer agents. The most frequently reported changes in 
GSH metabolism that are associated with the elevated GSH levels are 
increased mRNA expression and activity of gamma-glutamyl cysteine 
synthetase (gamma GCS), the first enzyme of the GSH biosynthetic 
pathway. Sublines of the A2780 ovarian carcinoma cell line (C10 and C25) 
have been shown to be 8- and 12-fold resistant to oxaliplatin by repeatedly 
exposing the cells to increasing concentrations of the platinum agent. The 
GSH levels in C10 and C25 cell sublines are 3.1-and 3.8-fold higher than 
the parent A2780 cell line. The increase in GSH in C10 and C25 was 

10/1/2010 
 
11
associated with an elevation in gamma GT mRNA (2.5- and 8-fold) and 
gamma GT activity (2.7- and 2.8-fold). No changes were observed in 
gamma GCS mRNA levels or activity. The data indicate that alterations in 
GSH metabolism leading to elevations in cellular GSH in A2780 ovarian 
carcinoma cells selected for low levels of resistance to oxaliplatin are 
mediated by gamma GT, the “salvage’ pathway, rather than an increase in 
GSH biosynthesis.[42, 44] In this study we will test whether mRNA levels of 
gamma glutamyl transpeptidase are predictive of response to intra-arterial 
cisplatin and mitomycin-C for patients with hepatocellular carcinoma.  
2.5.6 
GST-P1 
Glutathione transferases consist of a super-family of phase II metabolic 
enzymes that catalyze the conjugation of reduced glutathione. The 
detoxifying character of these reactions is responsible for the protection of 
cellular macromolecules from damage caused by carcinogenic and 
cytotoxic agents.[45, 46] GSTP1-1 has been shown to be widely expressed 
in human epithelial tissues and to be over-expressed in several tumors 
including colon tumors.[47, 48] [49, 50] Increased levels in tumors may be in 
part responsible for the observed resistance to chemotherapy as it has 
been found in several tumors, but the mechanism still remains 
unknown.[51] Factors that influence the expression level of GSTP1 may 
become important tools to predict therapy response and survival of patients 
treated with certain drugs or drug combinations. 
A G→A transition in exon 5 at nucleotide 313 leads to an amino acid 
exchange in the protein from isoleucin to valine, as previously reported by 
Board and colleagues.[52] In-vitro cDNA expression studies revealed an 
association between this amino acid change and a reduced activity level of 
the GSTP1 enzyme.[53]  Recently it has been found that the 105Val allele 
variant of the GSTP1 gene at exon 5 is associated with a low GST enzyme 
activity in normal lung tissue and esophageal Barrett’s epithelium.[54, 55] 
Additionally, it has been shown that the 105Val allele is associated with 
increased risk for testicular, bladder cancer and esophageal carcinoma, but 
not for colon or breast cancer.[56] This Ile105Val substitution has been 
shown to be associated with better survival in women with breast cancer 
who received chemotherapy (cyclophosphamide, 5-FU, adriamycin).[57] 
Nishimura and collegues showed that the response rate of patients with 
head and neck cancer receiving platinum-based chemotherapy was 
significantly higher for patients with low GST protein expression.[58] Based 
on these encouraging data we genotyped 81 patients with advanced 
colorectal tumors that received combination chemotherapy of 5-
FU/oxaliplatin. We found a significant association between survival and the 
Ile105Val polymorphism at exon 5 of the GSTP1 gene. Patients 
homozygous for the amino acid substitution had a significant survival 
benefit. According to previous in-vitro reports and studies in different 
human tissues the Val/Val genotype is associated with a lower GST 
enzyme activity compared to the heterozygous and the ILE/ILE 
genotype.[54, 57] Considering these results, patients with the VAL/VAL 
genotype and respectively a lower GST enzyme activity benefit from 
treatment with 5-FU/oxaliplatin compared to heterozygotes and the ILE/ILE 
genotype group. A lower GST enzyme activity is thought to be less efficient 

10/1/2010 
 
12
in glutathione conjugation of drug intermediates, which leads to a longer 
and most likely more efficient exposure of the active drug to the tumor cell. 
This might explain the survival benefit for patients with two or at least one 
VAL allele compared to the ILE/ILE genotype. In this study we will test 
whether mRNa levels of GST-P1 and the 105Val allele variant of the 
GSTP1 gene at exon 5 are predictive of response to and survival after 
intra-arterial cisplatin and mitomycin-C for patients with hepatocellular 
carcinoma. 
2.5.7 ERCC1 and XRCC1 polymorphisms determine cisplatin resistance 
Surveillance and repair of DNA damage are essential for maintaining the 
integrity of the genetic information that is needed for normal development. 
Several multienzyme pathways, including the excision repair of damaged 
or missing bases, carry out DNA repair in mammals, including excision 
repair of cisplatin-induced damaged. Accumulating evidence suggests that 
increased repair of cisplatin-induced DNA damage by either increased 
levels of repair enzymes or polymorphic variants is associated with 
cisplatin resistance.  
ERCC1 (excision repair cross complementation group 1) is an essential 
and highly conserved enzyme specific to the nucleotide excision repair 
(NER) pathway.[59] Defects in ERCC1 seem to be associated with the 
most severe DNA repair deficiency.[60] Studies have shown that increased 
ERCC1 mRNA levels are directly related to clinical resistance to cisplatin in 
both human ovarian and cervical cancer.[28, 61] Lenz and colleagues have 
shown that ERCC1 mRNA levels are also directly correlated to clinical 
resistance to combination 5-FU/cisplatin in gastric cancer patients and with 
response and survival in patients with metastatic colorectal cancer treated 
with combination 5FU/oxaliplatin.[27, 62]  More recently, Lenz and 
colleagues have shown that a very common polymorphism at codon 118 
(exon 4) in the ERCC1 gene, resulting in a single nucleotide CÆT change, 
correlates with significantly different intratumoral levels of mRNA, response 
to 5FU/oxaliplatin and survival in patients with colorectal cancer 
(unpublished data). Patients with the T/T or C/T genotype were significantly 
more likely to have elevated ERCC1 mRNA levels than patients with the 
C/C genotype (p = 0.049). The median survival of patients with at least one 
copy of the T allele was 256 days compared to 531 days without (p = 
0.056) (unpublished data).  
XRCC1 is a DNA repair gene with a central role in single strand break 
repair, base excision repair and optimal activity of DNA ligase III. It has 
been shown to be essential for mammalian (murine) survival and cells 
lacking XRCC1 are extremely sensitive to ionizing radiation and alkylating 
agents and exhibit elevated spontaneous frequencies of chromosome 
aberrations.[63] Transfection of functional murine XRCC1 into EM9 cells 
efficiently corrected (94-100%) the high sister-chromatid-exchange 
defect.[64] 
XRCC1 polymorphisms have been associated with different susceptibilities 
to DNA damaging agents and to the development of certain malignancies. 
Cigarette smokers with the polymorphic XRCC1 399Gln allele have been 
shown to have significantly more DNA adducts and sister chromatid 

10/1/2010 
 
13
exchange (SCE) frequencies than smokers with the 399Arg/Arg 
genotype.[65] Polymorphisms in codon 399 have been associated with 
higher AFB1-adducts and GPA somatic mutations as well as with lung 
cancer risk, colon cancer risk in Egyptians, and prostate cancer risk. A 
polymorphism in exon 6 has been shown to have a protective effect against 
bladder cancer development.[66-68] 
Based on these data, Lenz and colleagues investigated whether the 
XRCC1 allele 399 polymorphism correlated with response in 45 patients 
with colorectal cancer treated with a new platinum agent, oxaliplatin, 
combined with 5FU. The XRCC1 399 Arg/Arg. Arg/Gln and Gln/Gln 
polymorphisms were found in 18, 22 and 5 patients, respectively. The 
Arg/Arg polymorphism was strongly associated with chemotherapy 
response (observed in 5 of 6 responding patients); the Gln/Gln 
polymorphism was strongly associated with chemotherapy resistance (4 of 
5 patients with the Gln/Gln genotype had disease progression) (p = 0.0063, 
99% CI = 0.0043 – 0.0083, two-sided testing) (unpublished data). In this 
study we will test whether ERCC1 and XRCC1 polymorphisms are 
predictive of response to and survival after intra-arterial cisplatin and 
mitomycin-C for patients with hepatocellular carcinoma.  
2.5.8 
XPD 
The XPD protein is thought to participate in transcription and nucleotide 
excision repair. Several polymorphisms in the XPD gene have been 
identified, though their functional status is still uncertain. Recently, a 
polymorphism in codon 751 of the XPD gene was shown to be associated 
with differential DNA repair proficiency.[69] This single nucleotide 
polymorphism (CÆA) causes an amino acid change LysÆGln at codon 
751. Lymphocytes from individuals with the Lys/Lys genotype were shown 
to have higher number of chromatid aberrations after exposure to X-rays 
compared to those with the Gln allele, thus suggests a decreased ability for 
DNA repair. Increased DNA repair is a well-established mechanism for 
chemoresistance, especially platinum based compounds. Our hypothesis is 
that patients with the Lys allele will respond at a higher rate to platinum 
compounds compared to those without the Lys allele.[65, 69] We assessed 
the XPD codon 751 polymorphic status of 62 patients with metastatic 
colorectal cancer and determined their response to 5-FU/oxaliplatin 
treatment. The overall response rate was 16% (10/62). We found that 25% 
(5/20) of patients with the Lys/Lys genotype responded, compared to 13% 
(4/32) and 10% (1/10) of those with the Lys/Gln and Gln/Gln genotypes 
respectively (p= 0.017 Fisher’s exact test). More significantly, of those with 
the Gln/Gln genotype, 50% (5/10) had progressive disease compared to 
10% (2/20) and 6% (2/32) of patients with the Lys/Lys and Lys/Gln 
genotypes respectively. To our knowledge this was the first study that 
shows an association between the XPD polymorphism at codon 751 and 
clinical response to chemotherapy. It is our conclusion that genotyping 
patients for the XPD codon 751 polymorphism may be useful in predicting 
clinical response to platinum based chemotherapy. This may in turn aid in 
the selection of patients who will most likely benefit from the treatment, as 
well as avoiding the risk for toxic side effects for patients who are not likely 
to respond to the agent. In this study we will test whether XPD 

10/1/2010 
 
14
polymorphisms are predictive of response to and survival after intra-arterial 
cisplatin and mitomycin-C for patients with hepatocellular carcinoma. 
3.0 
Drug Information 
3.1 
Cisplatin 
3.1.1 
Description 
Cisplatin is a heavy metal complex containing an atom of platinum 
surrounded by two chloride molecules and two ammonia molecules in the 
cis configuration. It is soluble in water or saline. 
3.1.2 
Drug Administration 
Patients will receive intravenous hydration pre and post the administration 
of cisplatin, consisting of at least one liter of NS 150 cc/hr. Prior to the 
cisplatin administration enough hydration should be given to establish a 
urine output of at least 75 cc/hr. Cisplatin will be administered as a 5 to 10 
minute intra-arterial infusion diluted in 0.9% Sodium Chloride to a 
concentration of 1 mg/mL. Needles or intravenous sets containing 
aluminum parts that may come in contact with cisplatin should not be used 
for preparation or administration. Aluminum reacts with cisplatin, causing 
precipitate formation and a loss of potency. 
3.1.3 
Storage and Stability 
Cisplatin is supplied as Platinol-AQ in 10 mg and 50 mg vials. It is stored at 
room temperature. Each vial is labeled with an expiration date. 
3.1.4 
Toxicity 
Dose related and cumulative renal toxicity of cisplatin, but it may be 
ameliorated by vigorous hydration. Ototoxicity may occur and is manifested 
by tinnitus and/or hearing loss in the high frequency range. Nausea and 
vomiting are also frequently seen. Less frequent toxicities include 
hyperuricemia, hypomagnesemia, peripheral neuropathy, 
myelosuppression and anaphylactoid reactions. 
3.1.5 
Source of drug 
This drug is commercially available. 
3.2 
Mitomycin-C 
3.2.1 
Description 
Mitomycin-C exerts its cytotoxic activity by a mechanism similar to 
that of the alkylating agents. The drug is converted to an active 
compound that forms cross-links between strands of DNA, inhibiting 
DNA synthesis. Mitomycin also inhibits RNA and protein synthesis 
to a lesser extent. 
3.2.2 
Drug Administration 
Mitomycin-C will be administered as a 5 to 10 minute intra-arterial 
infusion diluted in 0.9% Sodium Chloride to a concentration of .5 
mg/mL. 
3.2.3 
Storage and Stability 

10/1/2010 
 
15
Mitomycin-C is supplied in 5 mg, 20 mg and 40 mg vials. It is stored 
at room temperature. Each vial is labeled with an expiration date. 
3.2.4 
Toxicity 
Thrombocytopenia and leukopenia may be delayed up to eight 
weeks and may be cumulative with succesive doses. Frequent side 
effects include nausea, vomiting, anorexia, diarrhea, reversible 
alopecia, and fever. Less frequent, but serious side effects include 
interstitial pneumonitis, septicemia and microangiopathic hemolytic 
anemia (characterized by thrombocytopenia, renal failure and 
hypertension). 
3.2.5 
Source of drug 
This drug is commercially available. 
4.0 
Staging 
This is a phase II study open for patients with hepatocellular carcinoma, 
with evident disease limited to the liver. Patients should be staged for their 
disease by the appropriate, TNM staging system (sixth edition), of the 
American Joint Committee on Cancer. 
5.0 
Eiligibility Criteria 
5.1. 
Inclusion Criteria 
5.1.1. Unresectable hepatocellular carcinoma (HCC), with evident disease 
limited to liver.  
The diagnosis of hepatocellular carcinoma should be based on at least 
one of the following (a-c): 
a. The presence of one or more liver lesions, measuring ≥ 2 cm, with 
characteristic arterial enhancement and venous washout in the setting 
of liver cirrhosis and/or hepatitis B or C infection 
b. The presence of liver lesion(s) with AFP ≥ 400 
c. Tissue confirmation in the absence of a and/or b 
 
Tissue availability is desired and will be sought, but tissue availability 
is not mandated for accrual to the study 
5.1.2. Patients must agree to have a 20 cc blood sample drawn in addition to 
routine labs at baseline. 
5.1.3. Patients must have measurable disease. If prior radiation therapy was 
administered, measurable disease must be outside the radiation field. 
5.1.4. Patients must be ≥18 years of age. 
5.1.5. Patients must have a Zubrod performance status of 0-2. 
5.1.6. Patients must have a predicted life expectancy of at least 12 weeks. 

10/1/2010 
 
16
5.1.7. Patients must have a pre-treatment granulocyte count (i.e., segmented 
neutrophils + bands) of > 1,500/mm3, a hemoglobin level of ≥ 9 gm/dl, 
and platelet count ≥ 50,000/mm3.  The granulocyte requirement may be 
waived if in the investigator’s opinion the lower count reflects 
hypersplenism with adequate bone marrow reserves.  
5.1.8. Patients must have adequate renal function as documented by a 
calculated creatinine clearance > 50. 
5.1.9. Patients must have adequate hepatic function as documented by a serum 
bilirubin ≤ 2x the institutional upper limit of normal, regardless of whether 
patients have liver involvement secondary to tumor. Patients may not 
have ascites or the ascites must be responsive to diuretics. 
5.1.10. Patients must have signed the informed consent. 
5.2 Exclusion Criteria 
5.2.1 Patients who have received prior chemotherapy for unresectable disease 
5.2.2 Patients with any active or uncontrolled infection, including known HIV 
infection. (Patients with active hepatitis B will be placed on lamivudine. 
Patients with active hepatitis C will be eligible if liver tests qualify (5.1.9) 
5.2.3 Patients with psychiatric disorders that would interfere with consent or 
follow-up.  
5.2.4 Patients with a history of prior malignancy, except for adequately treated 
basal cell or squamous cell skin cancer, in-situ cervical cancer, or other 
cancer for which the patient has been disease-free for at least five years. 
5.2.5 Pregnant or lactating women. Men and women of reproductive potential 
may not participate unless they have agreed to use an effective 
contraceptive method. 
5.2.6 Patients with any other severe concurrent disease, which in the judgment 
of the investigator, would make the patient inappropriate for entry into this 
study. 
6.0 
Stratification/Descriptive Factors 
6.1 
Two descriptive factors will be used in this analysis: 
Institution: LAC/USC vs. Norris or University Hospital 
 
Prognostic Index: The potential score ranges from 0 (most  
favorable) to 5 (least favorable). 
 
Prognostic Index 
Parameter 
Range 
    Points 
LDH 
>normal 
      2 
ALP 
> 200 u/L 
      1 
AST 
> 100 
      1 
Ascites 
present 
      1 
 

10/1/2010 
 
17
The institutional stratification anticipates potential outcome impacts that 
may result from either institutional or socio-economic differences with 
respect to compliance and details of supportive care. 
7.0 
Outline of Study Treatment 
7.1 
Treatment Plan 
All patients will receive at least two cycles of chemotherapy, and at most four 
cycles of IA chemotherapy at 8 week intervals.  Patients will be evaluated for 
eligibility for other treatment options after 2, 3 and 4 cycles of chemotherapy.   As 
soon as it is determined that it is in the patient’s best interest to terminate IA 
chemo treatment and proceed with no further treatment or a different treatment, 
they will go off study.   
7.1.1 
IA treatment 
Intra-arterial cisplatin 60 mg/m2 and mitomycin-C 12 mg/m2 every 8 weeks 
(+/- 2 weeks) with evaluation of response at week seven of each treatment 
cycle. Treatment beyond 2 cycles will be continued at the discretion of the 
physician with the option of lengthening treatment intervals. 
Drug administration will be based on actual calculated body surface area. 
All patients will be pre-medicated with Decadron and Kytril or Anzemet and 
Kytril or Anzemet will be repeated the next day. 
 
Cisplatin and mitomycin will be infused intra-arterially over 30-90 minutes, 
either separately or mixed. Intravenous fluids will consist of 300 mL 3% 
NaCl initiated at the start of angiography followed by NS at 100 mL/hr. A 
minimum of 1 L NS will be administered. Subsequent hydration is at the 
discretion of the investigator. 
7.1.2 
Drug Doses, Schedule of Agents, Number of Courses 
The length of the treatment cycle is 8 weeks, +/- 2 weeks. The doses of the 
drugs utilized, the schedule of the agent, and the number of courses, are 
outlined in Table 2 below.  
Table 2 
 
AGENT 
DOSE 
ROUTE 
DAYS 
COURSES 
Cisplatin 
60 mg/m2 
IA 
1 
2-4 
Mitomycin-C 
12 mg/m2 
IA 
1 
2-4 
 
On each day of treatment patients will undergo an angiogram. A catheter 
will then be threaded into the appropriate vessel(s) and the cisplatin and 
mitomycin-C will be infused  sequentially or together over 30-90 minutes. 
7.2 
Criteria for Removal from Treatment 
7.2.1 
Patients will be removed from protocol after disease progression.  
7.2.2 
Treatment will be discontinued if a patient continues to experience 
toxicities to the point that they go more than 12 weeks with no treatment. 

10/1/2010 
 
18
7.2.3 
A patient may always be removed from treatment whenever he or she 
wishes. 
7.2.4 
Patients will be removed from the protocol once it is determined that 
another therapy would be more beneficial to them (such as, but not 
limited to transplant, local regional therapy (such as RFA and cryo) or no 
further treatment),  
7.3 
Follow-up 
All patients who go off study will be followed up for death and disease 
recurrence via telephone calls or review of medical records. This will be 
done every four months for two years, or more frequently at the 
investigator’s discretion. 
8.0 
Toxicities To Be Monitored and Dosage Modifications 
8.1 
General Approach to Patient Experiencing Toxicity 
All toxicities will be graded according to the NCI Common Toxicity Criteria 
(Version 3.0). A full list of toxicities can be found on http://ctep.info.nih.gov. 
If multiple toxicities are seen, the dose administered should be based on 
the most severe toxicity experienced. 
8.2 
Dose modification steps for mitomycin-C/cisplatin. 
Dose Modification Steps 
Drug 
Starting 
Dose 0 
Dose Level 
–1 
Dose Level 
–2 
Dose Level –3 
Mitomycin-C 
12 mg/m2 
 8 mg/m2 
 5 mg/m2 
Off Study 
Cisplatin 
60 mg/m2 
40 mg/m2 
30 mg/m2 
Off Study 
 
8.3 
Toxicity Grade and Dose Modification 
Prior to retreatment patients must recover granulocytes, platelet count, bilirubin 
and ascites status to eligibility level measured within one week of retreatement.  
The following table describes the recommended dose modifications. Non-
hematologic  dose modifications should be based on the worst preceding 
toxicity. If either the cisplatin or the mitomycin-C is delayed, the other drug 
should be delayed as well, until toxicities have resolved and patients can 
start a new course of therapy. 

10/1/2010 
 
19
Mitomycin-C and Cisplatin dose modifications 
Toxicity  
NCI Grade* (Value) 
Mitomycin-C  
Cisplatin  
Neutropenic fever 
(Grade 4 neutropenia & 
≥ Grade 2 fever) 
↓ 1 dose levels of mitomycin-C 
when resolved 
↓ 1 dose level when resolved 
Stomatitis / Mucositis 
1 painless ulcers, mild 
sores 
2 painful but can eat 
3 painful, requiring IV 
hydration 
 
4 severe ulceration, 
requiring TPN, 
intubation 
 
-Maintain dose level 
 
-↓ 1 dose level  
-Delay dose, then ↓ 1 dose level, 
when resolved to ≤ Grade 2 
 
-Delay dose, then ↓ 1 dose levels 
when resolved to ≤ Grade 2  
 
 
-Maintain dose level 
 
-Maintain dose level 
- Delay dose, then ↓ 1 dose 
level, when resolved to ≤ 
Grade 2  
-Delay dose, then ↓ 1 dose 
level when resolved to ≤ 
Grade 2  
Renal Toxicity 
1. 0-25% decrease of 
creatinine clearance 
2. 26-50% decrease in 
creatinine clearance 
3. 51% or more decrease 
in creatinine clearance  
 
4. Creatinine clearance < 
50 
 
 
-Maintain dose level 
 
-Maintain dose level  
 
-Maintain dose level  
 
 
-Off Study 
 
-Maintain dose level  
 
-↓ 1 dose level  
 
-Decrease -2 dose level 
 
 
-Off Study  
Duodenal ulceration, 
gastric ulceration, 
gastritis, 
gastrointestinal 
bleeding (should be 
documented 
endoscopically) 
1. grade 1 or 2 
2. grade 3 or 4 
 
 
 
Institute anti-ulcer therapy** 
 
 
 
 
Institute anti-ulcer therapy** 
 
Hepatic Toxicity 
AST, ALT and/or 
alkaline phosphatase*** 
 
1. Grade 1 
 
2. Grade 2 
 
3. Grade 3 or more 
 
 
 
 
-Maintain dose level 
 
-↓ 1 dose level  
 
-Delay dose, then ↓ 1 dose level, 
when resolved to ≤ Grade 2 
  
 
 
 
 
-Maintain dose level  
 
-↓ 1 dose level  
 
-Delay dose, then ↓ 1 dose 
level, when resolved to ≤ 
Grade 2 
  

10/1/2010 
 
20
Mitomycin-C and Cisplatin dose modifications 
Toxicity  
NCI Grade* (Value) 
Mitomycin-C  
Cisplatin  
* National Cancer Institute Common Toxicity Criteria version 3.0 
** Anti-ulcer therapy should consist of proton pump inhibitors or h2 blockers  
*** When a patient is experiencing toxicity in more than on of these lab values, treatment should 
be based on the highest grade toxicity.  
 
If a patient experiences unacceptable toxicities requiring a dose reduction 
at the start of a course and that course is completed with no further 
toxicities greater than grade 2, then the dose may be increased, at the 
investigator’s discretion, one level at a time during an entire course, in the 
following courses. 
 
For toxicities which are considered by the Investigator unlikely to develop into 
serious or life–threatening events (e.g. alopecia, altered taste etc.), treatment will 
be continued at the same dose without reduction or interruption.  
 
For any event Grade 1-3 event which is apparent at baseline, the dose 
modifications will apply according to the corresponding shift in toxicity grade, if 
the investigator feels it is appropriate.  (e.g. if a patient has grade 1 asthenia at 
baseline which increases to grade 2 during treatment, this will be considered as a 
shift of 1 grade and treated as a grade 1 toxicity for dose modification purposes). 
 
A new course of treatment may begin when the granulocyte count is 
≥1500/mm3 or baseline and the platelet count is ≥ 50,000/mm3, AST, ALT 
and alkaline phosphatase are resolved to Grade 2 or less and any other 
treatment-related toxicities are ≤ Grade 1. If after a one-week delay, all 
toxicities are ≤ Grade 1, then proceed with treatment at the dose level 
based on the preceding table. If toxicities are not resolved to ≤ Grade 1 
after a one-week delay, then treatment will be held again, and the patient 
will be evaluated weekly. Treatment may continue, if clinically appropriate, 
once toxicity has resolved, but with a dose modification. If a patient 
continues to experience toxicities so that they go more than 12 weeks with 
no treatment, they will be taken off study. 
8.4 
Procedure related untoward outcomes. 
Potential catheter related untoward events include hematoma at the arterial 
puncture sites, pseudoaneurysm formation, and embolic events. RFA 
untoward events include subcapsular hemorrhage, bileoma formation, and 
biliary duct stricture. 
8.5 
Adverse Events (AE) 
Any untoward medical occurrence in a patient or clinical investigational 
subject administered a pharmaceutical product, which does not necessarily 
have to have a causal relationship with this treatment. 

10/1/2010 
 
21
The Investigator is required to provide appropriate information concerning 
any findings that suggest significant hazards, contraindications, side 
effects, or precautions pertinent to the safety of the drug under 
investigation. 
8.5.1  
Types of Adverse Events 
The term “adverse event” could include any of the following events, 
which develop or increase in severity during the course of the study: 
(a) 
any signs or symptoms whether thought to be related or 
unrelated to the condition under study 
(b) 
any clinically significant laboratory abnormality 
(c) 
any abnormality detected during physical examination 
Sign or Symptoms will be graded by the Investigator according to 
the NCI Common Toxicity Criteria, version 3.0. 
8.5.2 
Serious Adverse Events (SAE) 
Any untoward medical occurrence that at any dose: 
(a) results in death 
(b) is life threatening (NOTE: The term “life threatening” in the 
definition of “serious” refers to an event in which the patient 
was at risk of death at the time of the event, it does not refer to 
an event which hypothetically might have caused death if it 
were more severe.) 
(c) requires inpatient hospitalization or prolongation of existing 
hospitalization  
(d) results in persistent or significant disability/incapacity 
(e) is a congenital anomaly/birth defect 
(f) is an important medical event, based upon appropriate medical 
judgment, that may jeopardize the patient or subject or may 
require medical or surgical intervention to prevent one of the 
other outcomes defining serious. 
8.5.3 
Adverse Event Reporting Obligations 
Serious events, whether or not unexpected or considered to be 
associated with the use of the study drug, must be communicated, 
by telephone (323-865-0451), to USC immediately (within 24 hours) 
upon awareness of the event. The call then must be followed-up 
with a completed Serious Adverse Event Report and faxed within 
48 hours of telephone contact, to USC (323-865-0089). The report 
must include, at least: 
(a) 
site identifiers  
(b) 
the patient identifiers 
(c) 
description of the event  

10/1/2010 
 
22
(d) 
the investigator’s opinion of its causality/relationship to study 
drug 
(e) 
onset date of adverse event 
(f) 
date event became serious 
(g) 
institutional PI’s assessment of patient’s recovery. 
8.5.4 
Follow-up of Adverse Events 
All “serious” adverse events must be followed with appropriate 
medical management until resolved or stabilized for 30 days. 
 
Phase II Reporting Guidelines 
 
Unexpected Reaction 
 
Expected Reaction 
 
Grades 1-3 
 
Grades 4 and 5 
 
Grades 1-3 
 
Grades 4 and 5 
 
Written report 
within 10 working 
days. 
 
Report by phone to 
IDB within 24 hours. 
Written report to 
follow within 10 
working days. 
 
ADE reporting 
NOT required. 
 
Written report within 10 
working days. 
 
Grade 4 myelosuppression 
does not have to be reported 
as an ADE, but should be 
submitted as part of study 
results. 
 
 
Reporting requirements and timing of reporting are dependent on the grade, 
attribution and prior experience [expected (known) or unexpected (unknown). 
Attribution - Report only if the ADE has an attribution of possible, probable 
or definite relation to the investigational agent. An ADE is NOT required for 
adverse events with an attribution of unrelated or unlikely. 
A list of expected adverse events can be found in Section 3.0. 

10/1/2010 
 
23
9.0 
Study Calendar 
One cycle will consist of eight weeks (+/- 2 weeks). Patients will receive intra-arterial 
cisplatin and mitomycin-C on day one of each cycle. Patients will receive 2-4 cycles of IA 
chemotherapy.  Patients will be evaluated for eligibility for other treatments after 2, 3 and 
4 cycles of chemotherapy.  As soon as it is determined that another therapy would be 
more beneficial to them (such as, but not limited to transplant and local regional therapy) 
they will go off study.  All patients will be evaluated every two weeks, more frequently at 
the physician’s discretion. 
 
Parameter 
Pre-Rx4
Day 1 
of 
Each 
Cycle  
Days 
14 and 
28 
of Each 
Cycle  
Week
7 of  
Each 
Cycle 
RFA9
Off  
study 
History & Physical Exam 
X 
X10
 
 
 
 
Weight, Performance Status 
X 
 
 
  X 
 
X 
WBC (differential), Hgb, Platelets
X 
X 
X 
X 
 
 
Toxicity assessment 
X 
X 
X 
X 
 
 
Electrolytes, BUN, Cr 
X 
X 
 
X 
 
 
Calculated creatinine clearance5 
X 
 
 
 X5 
 
 
LFT (Alk Phos, ALT, AST, LDH, 
 Total Bili) 
X 
X 
 
 
 
 
Hepatitis panel 
X6 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
AFP 
X 
 
 
X 
 
 
EKG 
X 
X
2 
 
 
 
 
CXR (or chest CT) 
X 
 
 
 
 
 
Pregnancy Test 
X
8 
 
 
 
 
 
Tumor Biopsy 
X
3 
 
 
 
 
 
Liver image (CT, MR or US) for  
tumor dimensions 
X1 
 
 
X 
 
 
Blood for  
Pharmacogenetics7 
X 
 
 
 
 
 
Calculate Prognostic Index 
X 
 
 
 
 
 
 
1Record tumor dimensions 
2As clinically indicated. 
3If paraffin embedded tissue section is not available and tissue is needed for diagnosis of disease 
4, All tests must be done within 30 days of the start of study treatment, with the exception of radiologic studies. Radiologic 
studies must be completed within 28 days before the start of therapy. 
5Calculated Creatinine clearance, calculated with Cockcroft-Gault equation  
  Men=((140-age) x weight in kg) / (72 x serum creatinine) 
  Women=.85 x ((140-age) x weight in kg) / (72 x serum creatinine)  
6 Hepatitis panel will include HBsAb, HbsAg, HCAb, HB DNA by PCR, HC RNA by PCR (quantitative). Repeat RNA/DNA 
for elevations of AST/ALT. The panel will be obtained within 4 months of the study entry. HB DNA will be obtained 
only for HB+ patients, HC RNA for HC+ patients 
7 One purple top and one red top tube 
8 For women of child bearing potential  
9Patients will be evaluated for eligibility for other treatments after 2, 3 and 4 cycles of chemotherapy.   As soon as it is 
determined that another therapy would be more beneficial to them (such as, but not limited to transplant and  local 
regional therapy) they will go off study. - 
10Within 10 days of treatment cycle 

10/1/2010 
 
24
10.0 
Criteria for Evaluation and Endpoint Definitions 
All patients who are registered will be accounted for in the report of the 
results. Patients who complete 1 cycle of chemotherapy and who are 
followed a minimum of 3 weeks after completion of the first cycle of 
chemotherapy or who experience dose limiting toxicity, will be evaluable for 
toxicity. 
The outcome status (in terms of toxicity, response, reason off study, 
progression, and survival) of all eligible patients will be reported. Patients 
with measurable tumor who complete one cycle, or who terminate 
treatment for reasons of toxicity, or who progress prior to completion of one 
cycle, will be included in analysis of tumor response and time to 
progression, and in any decision to terminate the study early. All eligible 
patients who begin treatment will be included in the analysis of survival and 
time-to-failure. A modified Response Evaluation Criteria In Solid Tumors 
(RECIST) and the CTCAE version 3.0 toxicity criteria will be used. The 
modification to RECIST is that although all lesions will be followed, only the 
treated lesions will be included in the assessment of response. Additionally, 
all lesions will be evaluated according to the following criteria: Presence of 
arterial enhancement: Yes or No. 
10.1 
Measurability of tumor lesions at baseline. 
At baseline, tumor lesions will be categorized as: 
 
measurable:  
Treated lesions that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as 
≥ 20 mm with conventional techniques or as ≥ 10 mm 
with spiral CT scan  
 
OR 
 
 
non-measurable:  
all other treated lesions, including small lesions (longest 
diameter < 20 mm with conventional techniques or < 10 
mm with spiral CT scan) and truly non-measurable 
lesions. 
All measurements should be recorded in metric notation, using a 
ruler or calipers. All baseline evaluations should be performed as 
close as possible to the treatment start and never more than 4 
weeks before the beginning of the treatment. 
Lesions that are considered as truly non-measurable include the 
following: bone lesions; leptomeningeal disease; ascites; pleural / 
pericardial effusion; inflammatory breast disease; lymphangitis cutis 
/ pulmonis; abdominal masses that are not confirmed and followed 
by imaging techniques; cystic lesions. 
10.2 
Specifications by methods of measurements 
10.2.1 
The same method of assessment and the same technique should be 
used to characterize each identified and reported treated lesion at 
baseline and during follow-up. Imaging based evaluation is preferred to 

10/1/2010 
 
25
evaluation by clinical examination when both methods have been used to 
assess the anti-tumor effect of a treatment. 
10.2.2 
Study patients will have disease limited to liver. Serial measurements will 
be obtained from abdominal CT scans. MRI or ultrasound may be 
substituted for CT scan under special circumstances but whatever 
modality is used for baseline measurements should be consistently used 
in follow-up evaluations. Conventional CT and MRI should be performed 
with cuts of 10 mm or less in slice thickness contiguously. Spiral CT 
should be performed using a 4 mm contiguous reconstruction algorithm. 
As equipment becomes available volume estimates from 3 dimension 
reconstructions will be used. 
10.2.3 
Screening for the appearance of metastatic disease will be by abdominal 
CT and chest X-ray.  
10.2.4 
Unexplained elevations of serial AFP will trigger a more extensive search 
for metastatic disease. 
10.2.5 
AFP Tumor marker  
Tumor markers alone cannot be used to assess response. If 
markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical 
response except when corroborative transaminase and viral levels 
convincingly demonstrate that the elevation is secondary to a 
hepatitis flare. 
10.2.6 
Assessment of overall tumor burden and measurable disease 
To assess objective response, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for 
subsequent measurements. Only patients with measurable disease 
at baseline should be included in protocols where objective tumor 
response is the primary endpoint. Measurable disease is defined by 
the presence of at least one measurable lesion (as defined in 
section 10.1). If the measurable disease is restricted to a solitary 
lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
10.2.7 
Baseline documentation of “Target” and “Non-Target” lesions 
All treated measurable lesions up to a maximum of 10 lesions 
representative of all involved organs should be identified as target 
lesions and will be recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repetitive 
measurements (either by imaging techniques or clinically). A sum of 
the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD. The baseline sum LD will be used 
as reference to further characterize the objective tumor response of 
the measurable dimension of the disease. 
All other treated lesions should be identified as non-target lesions 
and should also be recorded at baseline. Measurements are not 

10/1/2010 
 
26
required and these lesions should be followed as “present” or 
“absent”. 
Additionally, all lesions will be evaluated according to the following 
criteria: Presence of arterial enhancement: Yes or No. 
 
10.3 
Response Criteria 
At each evaluation (see Study Calendar in Section 9.0), all lesions will be 
evaluated according to the following criteria: Presence of arterial 
enhancement: Yes or No and response will be classified as : 
10.3.1 
Evaluation of target lesions 
 
Complete Response (CR) 
Absence of enhancing tumor areas, reflecting 
complete tissue necrosis. 
Partial Response (PR) 
A decrease > 50% of enhanced areas, reflecting 
partial tissue necrosis. 
Progression (PD) 
An increase > 25% in the size of > 1 measurable 
lesion(s) or the appearance of new lesions in the 
treated area (ie, specific segment or lobe of liver 
targeted by the intra-arterial infusion)  
Stable Disease (SD) 
A tumor response between PR and PD. 
 
10.3.2 
Evaluation of non target lesions 
 
Complete Response (CR) 
Absence of enhancing tumor areas, 
reflecting complete tissue necrosis 
 
Non-Complete Response (non-CR) /  
Non–Progression (non-PD) 
persistence of one or more non-target 
lesion or/and maintenance of tumor 
marker level above the normal limits. 
Progression (PD) 
appearance of one or more new lesions 
in the treated area. Unequivocal 
progression of existing non-target 
lesions in the treated area.  
 
10.3.3 
Evaluation of best overall response 
The best overall response is the best response recorded from the 
start of the treatment until disease progression/recurrence (taking 
as reference for progressive disease the smallest measurements 
recorded since the treatment started). In general the patient's best 
response assignment will depend on the achievement of both 
measurement and confirmation criteria (see section 10.3.4 below). 
 

10/1/2010 
 
27
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Note: 
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration”. Every effort should be made to document the 
objective progression even after discontinuation of treatment.  
In some circumstances it may be difficult to distinguish residual 
disease from normal tissue. When the evaluation of complete 
response depends upon this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) 
before confirming the complete response status. 
 
In the case of SD, follow-up measurements must have met the SD criteria 
at least once after the start of treatment at a minimum interval of 28 days 
after start of treatment.   
 
10.3.4 
Confirmatory measurement 
To be assigned a status of PR or CR, changes in tumor 
measurements must be confirmed by repeat studies. The protocol 
specified interval is 7 weeks. 
Note: Repeat studies to confirm changes in tumor size may not 
always be feasible or may not be part of the standard practice in 
protocols. In such cases, patients will not have “confirmed 
response” and this will be made clear when reporting the outcome 
of such studies. 
10.3.5 
Biopsy determination of response 
At the time of RFA a biopsy will be obtained. Histologic 
demonstration of ≤ 10% of tumor in an adequate specimen will be 
considered a response even if dimension criteria are not met. This 
is viewed as appropriate because after IA therapy there is 
frequently a residual non-viable mass. 
10.3.6 
Duration of overall response 
The duration of overall response is measured from the time 
measurement criteria are met for CR/PR (whichever is first 
recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive 

10/1/2010 
 
28
disease the smallest measurements recorded since the treatment 
started). 
The duration of overall complete response is measured from the 
time measurement criteria are first met for CR until the first date 
that recurrent disease is objectively documented. 
10.3.7 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started. 
10.4 
Endpoint Definitions 
10.4.1 
Overall Survival. Defined as the time from first day of treatment to time of 
death due to any cause. If a patient is still alive, survival time is censored 
at the time of last follow-up. 
10.4.2 
Progression-free survival. Defined as the time from first day of treatment 
to the first observation of disease progression or death due to any cause. 
If a patient has not progressed or died, progression-free survival is 
censored at the time of last follow-up. 
10.4.3 
Time to progression. Defined as the time from first day of treatment to the 
first observation of disease progression or death due to disease. If failure 
has not occurred, failure time is censored at the time of last follow-up. 
11.0 
Special Instructions 
11.1 
Experimental Methods and Procedures 
11.1.1 Polymorphism: We will isolate genomic DNA from whole blood samples. An 
approximate 230bp region of the TS gene containing the polymorphic site will be 
PCR amplified using a P-33 end-labeled forward primer and an unlabeled 
reverse primer. PCR products will be separated on sequencing gels and 
autoradiographed, and products will be sized by comparison to known 
genotypes. 
11.1.2 Quantitation of mRNA levels: The cDNA library created from each tumor as 
part of this technology (RT-PCR) contains a quantitative and qualitative record of 
all of the tumor's expressed genes, and mRNA quantitation as well as mutations 
screening of 30-40 expressed genes is possible with material obtained from an 
average tumor biopsy. We have successfully quantitated gene expression in 
specimens of less than 1 mg and fine needle biopsies only by changing the PCR 
conditions. Quantitative RT-PCR is carried out essentially as previously 
described in with some modifications (31-37). The choice of the internal standard 
is critical for obtaining meaningful results with PCR quantitation. This gene 
should be one that is expressed constitutively with a level of per cell expression 
that is constant among different tissues or at least in similar tissues from different 
individuals. 
11.2 
Handling of blood samples for Pharmacogenetics 
Purple top and red top blood samples should be sent within 2 hours to Dr. 
Lenz Laboratory at room temperature: Questions should be referred to 
Dana Agafitei or Dr. Zhang. 

10/1/2010 
 
29
Dr. Wu Zhang Norris 5th Floor: 5410, Tel 323 865 0572.  
11.3 Handling of tumor tissues 
Tumor samples should be submitted when available, which have been 
collected at the time of diagnosis or prior to entry into this protocol. 
Unstained Paraffin embedded tumor section 10x 10um thick containing 
tumor and normal tissue should be send by room temperature to Dana 
Agafitei. A tumor block (paraffin embedded tumor tissues) can be used 
instead of sending the unstained slides. Questions should be referred to 
Dana Agafitei.  
 
Dana Agafitei 
 
USC/Norris Comprehensive Cancer Center 
 
CISO office 7th floor 
 
1441 Eastlake Ave 
 
Los Angeles, CA 90033 
 
Tel: 323 865 0467 
12.0 
Statistical Considerations 
This is a one-stage Phase II study conducted at USC to evaluate intra-
arterial chemotherapy with cisplatin and mitomycin-C as a 1st line 
chemotherapy for patients who are diagnosed with unresectable 
hepatocellular carcinoma with evident disease limited to liver and have 
never received prior treatment for advanced disease.  
12.1 
Study Design 
 
This study was originally a two stage study of IA chemotherapy with cisplatin and 
mitomycin-C, followed by radio-frequency ablation (RFA).  At the interim analysis, 
it was found that although the response rate was promising, patients were not 
going on to receive RFA after IA chemotherapy.  The trial, thus has been 
amended, and the primary objective changed to response rate to IA 
chemotherapy with cisplatin and mitomycin-C.  Prior to the amendment 29 
patients were accrued, these patients will be included in the analysis of the 
primary endpoint. 
  
The primary endpoint in this study will be response rate. If at least 15 objective 
responses are observed in 60 evaluable patients, this regimen would be 
considered worthy of further testing in this disease.  This design yields at least 
96% power to detect a true objective response rate of 35%.  It yields at least .97 
probability of a negative result if the true objective response rate is no more than 
15%.  
 
12.2 
Analysis of Results 
12.2.1 
Analysis of Clinical Endpoints 
The outcome status (in terms of response rate (the primary 
endpoint), toxicity, time to progression, reason off study, and 
survival) of all eligible patients who are registered, will be reported. 
Patients who complete at least 1 cycle of chemotherapy and are 
followed at least 3 weeks after completion of the first cycle, or who 

10/1/2010 
 
30
experience any unacceptable toxicity will be included in the analysis 
of toxicity. Patients with measurable tumor who complete at least 
one cycle of chemotherapy, or who terminate treatment for reasons 
of toxicity, or who progress prior to completion of one cycle of 
chemotherapy, will be included in analysis of tumor response and 
time to progression. All eligible patients who begin treatment will be 
included in the analysis of overall survival. 
Toxicities observed will be summarized in terms of type (organ 
affected, laboratory determination), severity (by NCI Common 
Toxicity Criteria and nadir or maximum values for the laboratory 
measures), time of onset (i.e. course number), duration, and 
reversibility or outcome. Tables will be created to summarize these 
toxicities and side effects by course. Demographic and baseline 
clinical information (i.e., performance status or prognostic index) will 
be presented to describe the patients treated in this study. 
Tumor response will be assessed using the RECIST criteria at 
week 7 of each treatment cycle (lasting 8 weeks) of the IA regimen 
of cisplatin and mitomycin-C followed by RFA. Patients who receive 
less than one full course due to unacceptable toxicity or progressive 
disease will still be evaluable for response. All responses will be 
reported. Response rates will be calculated as the percent of 
evaluable patients whose best response is a CR or PR, and exact 
binomial 95% confidence intervals will be calculated for this 
estimate. Contingency tables will be constructed to summarize the 
associations between the categorical factors (i.e., genomic 
polymorphisms) and tumor response. Fishers’ exact tests will be 
used to formally test for associations. 
Time to progression, progression-free survival, and overall 
survival will be summarized with Kaplan-Meier plots to describe the 
outcome of patients treated on this protocol. The median time and 
95% confidence intervals (CIs) of median time to progression and 
survival will be calculated. In addition the probability of progression 
at 3, 6, 9 months and survival at 6, 12, 18 months and Greenwood’s 
standard errors will be summarized. The log-rank test will be used 
to examine whether prognostic factors are associated with time to 
progression, progression-free survival, or overall survival. The 
relative risk and corresponding 95% CIs will be used to summarize 
the differences in time to event of interest by prognostic factors. 
       
12.2.2 
Description of definitive therapy 
Patients will be categorized according to the post-induction therapy they 
receive following completion of this study. Patients are expected to go 
one to receive on of the following: 
1) Transplant 
2) Local regional therapy 
a) RFA 

10/1/2010 
 
31
b) Cryo 
                        3) More IA chemo off trial 
 
 
4) No further treatment  
a) Due to Progressive Disease 
 
 
            b) Due to Stable Disease 
 
 
 
 
 
The proportion of patients going on to each of these treatments will be  
computed and time to progression, progression free survival and overall 
survival will be summarized for each group separately.     
 
12.2.3 
Analysis of the prognostic index (PI) 
The PI is defined as a sum of 2 points for elevated LDH and 1 point 
each for abnormal ALP (>200 u/L), abnormal AST (>100 u/L), and 
presence of ascites on baseline imaging. The PI will be ranged from 
0 to 5. Categorization will be considered if a small number of 
patients are in a subgroup of the PI. A contingency table and 
percentages will be constructed to summarize the association 
between the PI and tumor response. Fishers’ exact test will be used 
to formally examine the association. Kaplan-Meier plots will be 
constructed to describe time to progression, progression-free 
survival, and overall survival across the categories of the PI. The 
log-rank test will be performed to test the association between the 
PI and time to progression, progression-free survival, and overall 
survival. The analysis of the PI in association with clinical outcome 
will examine whether the PI developed in patients receiving 
chemoemolization is applicable to unresectable HCC patients. 
12.2.4 
Analysis of molecular biomarkers 
Gene expression levels of (1) genes associated with induction of 
apoptosis or cell cycle regulation (bcl-2, bcl-xL, bcl-xS, bax, and 
p21), (2) DNA repair (ERCC1, RR, gamma-GT) will be summarized 
overall and according to tumor response, using medians, quartiles 
and ranges – or if a transformation is found to render the data 
compatible with the normal assumptions, with means, standard 
deviations, and 95% confidence intervals. The association with 
progression-free survival or overall survival will be assessed by 
categorizing the measures of gene expression at median (or by 
previously established cut-points) and constructing Kaplan-Meier 
plots. The log-rank test will be used to examine whether gene 
expressions are associated with time to progression, progression-
free survival, or overall survival. 
Association of types of polymorphisms for genes involved in the 
DNA repair (p53, ERCC1, XRCC1, and XPD) will be summarized 
overall and by response, using contingency tables and 
percentages. The association with progression-free survival or 
overall survival will be assessed by constructing the Kaplan-Meier 

10/1/2010 
 
32
curves according to the polymorphisms observed. The log-rank test 
will be used to examine whether genomic polymorphisms are 
associated with time to progression, progression-free survival, or 
overall survival. 
The analyses of associations between the molecular biomarkers 
and clinical outcome will be conducted in the end of this study. 
These analyses of the molecular biomarkers will be descriptive and 
exploratory, in order to identify questions and patterns for future 
study; the numbers of patients expected (nearly 100% for the 
specimens obtained at baseline) will not permit formal comparisons 
of patients according to response, but will allow us to estimate the 
patient-to-patient variability in this well-defined group of patients. 
These analyses will be descriptive in nature. 
Justification of Study Design 
There is sparse information on the association between molecular 
biomarkers and tumor response, time to progression, or survival 
among this group of patients. With 60 patients, we will have at least 
90% power to detect the difference of 1.0 standard deviation in 
gene expressions between responders and non-responders (we 
expect that there will be at least 15 responders if this regimen is 
promising). 
With 60 patients, we will have 84% power to identify the differences 
(at least 30%, equivalent to a hazard ratio of 2.4) in proportions 
without progression at 8 months when the prevalence of a predictor 
with favorable outcome varies from 33% to 67% (Table 2). There is 
a power of at least 78% that we will observe the difference in 
proportions of survival at 15 months (Table 2).  
Table 2. Power to Test Differences in Clinical Outcome (Time to 
Event of Interest) by Prevalence of Prognostic Index, Genomic 
Polymorphisms, or Genetic Profile with Poorer Outcome  
% of Patients in 
the poorer 
prognosis group 
Power to Detect a Difference of 0.30 
Proportion without Progression at 8 
months: 0.35 vs. 0.65* 
Power to Detect a Difference of 
0.30 Proportion Surviving at 15 
months: 0.35 vs. 0.65* 
75% 
78% 
70% 
67% 
84% 
78% 
50% 
90% 
85% 
33% 
87% 
83% 
25% 
82% 
77% 
 
Notes: Power calculations using methods in Rubinstein, Gail, and Santner, 
as programmed by Buckley, are based on a two-sided .05-level logrank 
test with annual accrual rate of 30 patients per year, 18 months of 
additional follow-up for time without progression and 2 years of additional 
follow-up for survival, and at most 2% of patients lost to follow-up annually. 
* If the time to progression follows the exponential distribution (at least 
approximately), the proportion of 35% and 65% without progression at 8 
months is equivalent to about 5.3 and 12.9 months of median progression, 

10/1/2010 
 
33
respectively. Similarly, the proportion of surviving of 35% and 65% at 15 
months is equivalent to about 9.9 and 24.1 months of median survival, 
respectively. 
12.3 
Monitoring for Excessive Unacceptable Toxicity 
Although we expect that this regimen to be well tolerated, the guidelines 
listed below will be used to raise a flag if the number of patients who 
experience unacceptable toxicity is large enough to strongly suggest that 
the true probability of unacceptable toxicity is > 20%. Unacceptable toxicity 
will be defined as  
any Grade 3 non-hematologic toxicity not reversible to Grade 1 or 
less within 96 hours or 
any Grade 4 non-hematologic toxicity or  
any Grade 4 hematologic toxicity not resolving to Grade 1 or less 
within 5 days, despite supportive care or  
Grade 4 neutropenia associated with fever or  
Grade 4 thrombocytopenia 
An unacceptable toxicity, regardless of attribution, observed during any 
course, will be used in the decision to suspend accrual. 
To be evaluable for unacceptable toxicity a patient must complete 1 course 
of treatment or have experienced unacceptable toxicity. Patients who do 
not complete 1 course and who do not experience any unacceptable 
toxicity will not be used in the decision to continue or suspend accrual to 
the trials, for reasons for excessive unacceptable toxicity. Every time 
unacceptable toxicity is observed, the number of patients (X) who have 
experienced unacceptable toxicity will be compared to the number of 
patients (N) who are evaluable for unacceptable toxicity. If the number of 
patients, N, is greater than NX, the number given in column 2 of the Table 
3, below, then accrual will not be suspended. If N is less than or equal to 
NX, then accrual will be suspended for review of the data. 
Table 3: Criteria for Continuing Accrual 
 
X = Total Number of Patients with 
Unacceptable Toxicity 
NX: Suspend the Trial if Number of Evaluable Patients 
Is Less Than or Equal to: 
4 
≤ 6 
5 
≤ 10 
6 
≤ 14 
7 
≤ 18 
8 
≤ 22 
9 
≤ 27 
10 
≤ 31 
11 
≤ 35 
12 
≤ 39 
13 
≤ 43 
14 
≤ 47 
15 
≤ 52 

10/1/2010 
 
34
16 
≤ 56 
≥17 
Suspend 
 
Using this rule with 60 patients, the probability of correctly suspending this 
regimen for review toxicities is 0.93 if the true chance of unacceptable 
toxicity is 35% or greater. The probability of falsely suspending this 
regimen for review toxicities is 0.04, if the true chance of unacceptable 
toxicity is ≤ 15%. Estimation of the probabilities of suspending this regimen 
is based on 10,000 simulations 
 
13.0 
Registration Guidelines 
All patients will have signed an informed consent for participation in research 
activities in accord with all institutional, NCI and Federal regulations, and will 
have been given a copy of the Experimental Subject's Bill of Rights. 
Note: At the time of registration, two copies of a signed and dated patient 
Informed Consent form with Bill of Rights must be available (an original for 
patient’s medical chart; one copy for the patient; and the other for the CISO 
office). 
14.0 
Minorities and Women Statement 
This study will be open to patients undergoing treatment at USC/Norris Cancer 
Center, USC University Hospital and LAC+USC Medical Center. 

10/1/2010 
 
35
 
ETHNIC AND GENDER DISTRIBUTION OF NEWLY DIAGNOSED CANCER 
PATIENTS(1) 
IN LOS ANGELES COUNTY IN 1999(2) 
 
Primary Site of Tumor 
Total # of 
Patients 
Males
% 
Females 
% 
White
% 
Black 
% 
Hispanic
% 
Asian/Other
% 
ALL INVASIVE TUMORS 
33,194 
49 
51 
61 
12 
18 
10 
ORAL CAVITY/PHARYNX 
749 
66 
34 
64 
13 
12 
11 
DIGESTIVE SYSTEM 
6,727 
52 
48 
56 
12 
18 
13 
 Esophagus 
294 
72 
28 
61 
13 
17 
10 
 Stomach 
823 
60 
40 
41 
12 
27 
21 
 Colon 
2,677 
49 
51 
62 
14 
14 
11 
 Rectum/Anus 
547 
49 
51 
63 
10 
17 
10 
 Liver 
479 
66 
34 
34 
10 
29 
27 
 Pancreas 
718 
50 
50 
63 
11 
18 
9 
RESPIRATORY SYSTEM 
4,341 
56 
44 
64 
15 
11 
10 
 Lung and Bronchus 
3,949 
54 
46 
65 
15 
11 
10 
BONES AND JOINTS 
72 
58 
42 
43 
11 
33 
13 
SOFT TISSUE INCL. HEART 
223 
54 
46 
49 
14 
27 
9 
MELANOMAS OF THE SKIN 
1,101 
56 
44 
91 
1 
7 
1 
BREAST 
5,489 
1 
99 
63 
11 
16 
11 
FEMALE GENITAL SYSTEM 
2,334 
0 
100 
54 
9 
26 
11 
 Cervix Uteri 
573 
0 
100 
35 
10 
45 
10 
 Corpus Uteri 
954 
0 
100 
63 
10 
18 
9 
 Ovary 
684 
0 
100 
56 
8 
23 
13 
MALE GENITAL SYSTEM 
5,404 
100 
0 
59 
16 
18 
7 
Testis 
195 
100 
0 
54 
2 
41 
4 
 Prostate 
5,176 
100 
0 
59 
17 
17 
7 
URINARY SYSTEM 
1,549 
65 
35 
65 
11 
18 
7 
 Invasive Bladder 
656 
73 
27 
73 
8 
12 
8 
 Renal 
830 
59 
41 
58 
13 
23 
7 
EYE AND ORBIT 
59 
63 
37 
66 
7 
24 
3 
BRAIN /NERVOUS SYSTEM 
481 
55 
45 
61 
8 
24 
6 
ENDOCRINE/THYROID 
656 
26 
74 
53 
6 
26 
15 
HODGKIN'S DISEASE 
245 
49 
51 
53 
10 
33 
4 
NON-HODGKIN'S LYMPHOMA 1,430 
55 
45 
62 
8 
20 
10 
MULTIPLE MYELOMA 
408 
57 
43 
49 
23 
20 
8 
LEUKEMIA 
841 
61 
39 
56 
8 
26 
9 
 Lymphocytic Leukemia 
330 
60 
40 
55 
10 
31 
5 
 Non-Lymphocytic Leukemia 
511 
61 
39 
57 
8 
23 
12 
IN SITU DISEASE 
 
 
 
 
 
 
 
in situ Breast 
1,063 
1 
99 
67 
10 
12 
11 
in situ Bladder 
648 
77 
23 
78 
6 
8 
8 
in situ Melanoma 
658 
54 
46 
92 
1 
6 
1 
(1) Invasive cancer with the inclusion of specified in situ breast, melanoma and bladder cancer cases. 
Data provided by Los Angeles County Cancer Surveillance Program; Department of Preventive Medicine; 
University of Southern California; 1540 Alcazar St.; LA CA 90033. 
 

10/1/2010 
 
36
The numbers above reflect the ethnic and gender distribution of cancer patients 
in the County of Los Angeles. Although distributions may vary by disease type, 
our recruitment procedures have been developed to enroll patients who are 
representative of the target population. 
15.0 
Ethical and Regulatory Considerations 
All institutional, NCI, and Federal regulations concerning the Informed Consent 
form will be fulfilled. 

10/1/2010 
 
37
16.0 
References 
 
1. 
Ihde, D.C., et al., Prognostic Factors In Patients With Hepatocellular Carcinoma 
Receiving Systemic Chemotherapy. Identification Of Two Groups Of Patients 
With Prospects For Prolonged Survival. American Journal Of Medicine, 1985. 
78(3): p. 399-406. 
2. 
Bezwoda, W.R., et al., Combination Chemotherapy Of Hepatocellular Cancer. 
Comparison Of Adriamycin + Vm 26 + 5-Fluorouracil With Mamsa + Vm 26 + 5-
Fluorouracil. Oncology, 1987. 44(4): p. 207-9. 
3. 
Okada, S., et al., Prognostic Factors In Patients With Hepatocellular Carcinoma 
Receiving Systemic Chemotherapy. Hepatology, 1992. 16(1): p. 112-7. 
4. 
Sciarrino, E., et al., Adriamycin Treatment For Hepatocellular Carcinoma. 
Experience With 109 Patients. Cancer, 1985. 56(12): p. 2751-5. 
5. 
Patt, Y.Z., et al., Hepatocellular Carcinoma. a Retrospective Analysis Of 
Treatments to Manage Disease Confined to the Liver. Cancer, 1988. 61(9): p. 
1884-8. 
6. 
Oconnell, M.J., et al., Chemotherapy Of Malignant Hepatomas With Sequential 
Intraarterial Doxorubicin and Systemic 5-Fluorouracil and Semustine. Cancer, 
1988. 62(6): p. 1041-3. 
7. 
Anonymous, Intra-Arterial Administration Of Epirubicin In the Treatment Of 
Nonresectable Hepatocellular Carcinoma. Epirubicin Study Group For 
Hepatocellular Carcinoma. Cancer Chemotherapy and Pharmacology, 1987. 
19(3): p. 183-9. 
8. 
Patt, Y.Z., et al., Hepatic arterial infusion of floxuridine, leucovorin, doxorubicin, 
and cisplatin for hepatocellular carcinoma: effects of hepatitis B and C viral 
infection on drug toxicity and patient survival. Journal Of Clinical Oncology, 1994. 
12(6): p. 1204-11. 
9. 
Kajanti, M., et al., Regional Intra-Arterial Infusion Of Cisplatin In Primary 
Hepatocellular Carcinoma. a Phase Ii Study. Cancer, 1986. 58(11): p. 2386-8. 
10. 
Llovet, J., et al., Sorafenib improves survival in advanced Hepatocellular 
Carcinoma (HCC): Results of a Phase III randomized placebo-controlled trial 
(SHARP trial). Journal of Clinical Oncology , ASCO Annual Meeting Proceedings 
Part I. Vol 25, No. 18S (June 20 Supplement), Abstract LBA1, 2007. 
11. 
Daniels, J.R., et al., Chemoembolization of hepatocellular carcinoma. Experience 
with 85 patients and the development of a prognostic index. J Clin Oncol, 
Submitted. 
12. 
Daniels, J.R., E.T. Engelson, and G.B. Vegh, Catheter device. 1987: United 
States. 
13. 
Lo, C.M., et al., Randomized controlled trial of transarterial lipiodol 
chemoembolization for unresectable hepatocellular carcinoma. Hepatology, 
2002. 35(5): p. 1164-71. 
14. 
Llovet, J.M., et al., Arterial embolisation or chemoembolisation versus 
symptomatic treatment in patients with unresectable hepatocellular carcinoma: a 
randomised controlled trial. Lancet, 2002. 359(9319): p. 1734-9. 
15. 
Herber, S., et al., [TACE: therapy of the HCC before liver transplantation--
experiences]. Rofo, 2005. 177(5): p. 681-90. 
16. 
Finck, S.J., A.E. Giuliano, and D.L. Morton, LDH and melanoma. Cancer, 1983. 
51(5): p. 840-3. 
17. 
Bosl, G.J., Prognostic factors for metastatic testicular germ cell tumours: the 
Memorial Sloan-Kettering cancer model. Eur Urol, 1993. 23(1): p. 182-7. 

10/1/2010 
 
38
18. 
Yamamoto, N., et al., Construction and validation of a practical prognostic index 
for patients with metastatic breast cancer. J Clin Oncol, 1998. 16(7): p. 2401-8. 
19. 
Cao, X.X., et al., Histone deacetylase inhibitor downregulation of bcl-xl gene 
expression leads to apoptotic cell death in mesothelioma. Am J Respir Cell Mol 
Biol, 2001. 25(5): p. 562-8. 
20. 
Leech, S.H., et al., Induction of apoptosis in lung-cancer cells following bcl-xL 
anti-sense treatment. Int J Cancer, 2000. 86(4): p. 570-6. 
21. 
Strobel, T., et al., BAX enhances paclitaxel-induced apoptosis through a p53-
independent pathway. Proc Natl Acad Sci U S A, 1996. 93(24): p. 14094-9. 
22. 
Liu, L., S. Markowitz, and S.L. Gerson, Mismatch repair mutations override 
alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis(2-
chloroethyl)nitrosourea. Cancer Res, 1996. 56(23): p. 5375-9. 
23. 
Lothe, R.A., et al., Genomic instability in colorectal cancer: relationship to 
clinicopathological variables and family history. Cancer Res, 1993. 53(24): p. 
5849-52. 
24. 
Gariboldi, M., et al. Increased sensitivity to camphothecin in human colon 
carcinoma cell lines with mismatch repair deficiency. in Proceedings of The 
American  Association of Cancer Research. 1996. 
25. 
Goldwasser, F., et al., Correlations between S and G2 arrest and the cytotoxicity 
of camptothecin in human colon carcinoma cells. Cancer Res, 1996. 56(19): p. 
4430-7. 
26. 
Codegoni, A.M., et al., Expression of genes of potential importance in the 
response to chemotherapy and DNA repair in patients with ovarian cancer. 
Gynecol Oncol, 1997. 65(1): p. 130-7. 
27. 
Metzger, R., et al., ERCC1 mRNA levels complement thymidylate synthase 
mRNA levels in predicting response and survival for gastric cancer patients 
receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol, 
1998. 16(1): p. 309-16. 
28. 
Dabholkar, M., et al., Messenger RNA levels of XPAC and ERCC1 in ovarian 
cancer tissue correlate with response to platinum-based chemotherapy. J Clin 
Invest, 1994. 94(2): p. 703-8. 
29. 
Akiyama, T., et al., G1 phase accumulation induced by UCN-01 is associated 
with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK 
inhibitor p21/Cip1/WAF1/Sdi1 in p53-mutated human epidermoid carcinoma 
A431 cells. Cancer Res, 1997. 57(8): p. 1495-501. 
30. 
Lowe, S.W., et al., p53 status and the efficacy of cancer therapy in vivo. Science, 
1994. 266(5186): p. 807-10. 
31. 
Allegra, C.J., et al., Investigation of the prognostic and predictive value of 
thymidylate synthase, p53, and Ki-67 in patients with locally advanced colon 
cancer. J Clin Oncol, 2002. 20(7): p. 1735-43. 
32. 
Elsaleh, H., et al., P53 alteration and microsatellite instability have predictive 
value for survival benefit from chemotherapy in stage III colorectal carcinoma. 
Clin Cancer Res, 2001. 7(5): p. 1343-9. 
33. 
He, A.W. and J.G. Cory, Effect of doxorubicin on wild-type and deoxyadenosine-
resistant mouse leukemia L1210 cells. Int J Oncol, 1999. 14(5): p. 891-5. 
34. 
Fujiwara, T., et al., Induction of chemosensitivity in human lung cancer cells in 
vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res, 
1994. 54(9): p. 2287-91. 
35. 
Li, C.Y., L. Suardet, and J.B. Little, Potential role of WAF1/Cip1/p21 as a 
mediator of TGF-beta cytoinhibitory effect. J Biol Chem, 1995. 270(10): p. 4971-
4. 

10/1/2010 
 
39
36. 
Li, R., et al., Differential effects by the p21 CDK inhibitor on PCNA-dependent 
DNA replication and repair. Nature, 1994. 371(6497): p. 534-7. 
37. 
Waga, S., et al., The p21 inhibitor of cyclin-dependent kinases controls DNA 
replication by interaction with PCNA. Nature, 1994. 369(6481): p. 574-8. 
38. 
Khanna, K.K. and S.P. Jackson, DNA double-strand breaks: signaling, repair and 
the cancer connection. Nat Genet, 2001. 27(3): p. 247-54. 
39. 
Blagosklonny, M.V. and W.S. El-Deiry, Acute overexpression of wt p53 facilitates 
anticancer drug-induced death of cancer and normal cells. Int J Cancer, 1998. 
75(6): p. 933-40. 
40. 
Filatov, D., et al., Induction of the mouse ribonucleotide reductase R1 and R2 
genes in response to DNA damage by UV light. J Biol Chem, 1996. 271(39): p. 
23698-704. 
41. 
Fan, H., C. Villegas, and J.A. Wright, Ribonucleotide reductase R2 component is 
a novel malignancy determinant that cooperates with activated oncogenes to 
determine transformation and malignant potential. Proc Natl Acad Sci U S A, 
1996. 93(24): p. 14036-40. 
42. 
el-akawi, Z., et al., Induction of gamma-glutamyl transpeptidase mRNA by 
platinum complexes in a human ovarian carcinoma cell line. Oncol Res, 1996. 
8(10-11): p. 415-23. 
43. 
el-akawi, Z., et al., Altered glutathione metabolism in oxaliplatin resistant ovarian 
carcinoma cells. Cancer Lett, 1996. 105(1): p. 5-14. 
44. 
Pendyala, L., et al., Intracellular glutathione and cytotoxicity of platinum 
complexes. Cancer Chemother Pharmacol, 1995. 36(4): p. 271-8. 
45. 
Tsuchida, S. and K. Sato, Glutathione transferases and cancer. Crit Rev 
Biochem Mol Biol, 1992. 27(4-5): p. 337-84. 
46. 
Zimniak, P., et al., Naturally occurring human glutathione S-transferase GSTP1-1 
isoforms with isoleucine and valine in position 104 differ in enzymic properties. 
Eur J Biochem, 1994. 224(3): p. 893-9. 
47. 
Bellincampi, L., et al., Glutathione transferase P1 polymorphism in 
neuroblastoma studied by endonuclease restriction mapping. Clin Chem Lab 
Med, 2001. 39(9): p. 830-5. 
48. 
Kelders, W.P., et al., The association between glutathione S-transferase P1 
genotype and plasma level in head and neck cancer. Laryngoscope, 2002. 
112(3): p. 462-6. 
49. 
Miyanishi, K., et al., Glutathione S-transferase-pi overexpression is closely 
associated with K-ras mutation during human colon carcinogenesis. 
Gastroenterology, 2001. 121(4): p. 865-74. 
50. 
Singletary, K. and C. MacDonald, Inhibition of benzo[a]pyrene- and 1,6-
dinitropyrene-DNA adduct formation in human mammary epithelial cells 
bydibenzoylmethane and sulforaphane. Cancer Lett, 2000. 155(1): p. 47-54. 
51. 
Nakajima, T., et al., Reversal of multiple drug resistance in cholangiocarcinoma 
by the glutathione S-transferase-pi-specific inhibitor O1-hexadecyl-gamma-
glutamyl-S-benzylcysteinyl-D-phenylglycine ethylester. J Pharmacol Exp Ther, 
2003. 306(3): p. 861-9. 
52. 
Board, P.G., G.C. Webb, and M. Coggan, Isolation of a cDNA clone and 
localization of the human glutathione S-transferase 3 genes to chromosome 
bands 11q13 and 12q13-14. Ann Hum Genet, 1989. 53 ( Pt 3): p. 205-13. 
53. 
Fryer, A.A., et al., Use of site-directed mutagenesis of allele-specific PCR 
primers to identify the GSTM1 A, GSTM1 B, GSTM1 A,B and GSTM1 null 
polymorphisms at the glutathione S-transferase, GSTM1 locus. Biochem J, 1993. 
295 ( Pt 1): p. 313-5. 

10/1/2010 
 
40
54. 
Watson, M.A., et al., Human glutathione S-transferase P1 polymorphisms: 
relationship to lung tissue enzyme activity and population frequency distribution. 
Carcinogenesis, 1998. 19(2): p. 275-80. 
55. 
van Lieshout, E.M., et al., Polymorphic expression of the glutathione S-
transferase P1 gene and its susceptibility to Barrett's esophagus and esophageal 
carcinoma. Cancer Res, 1999. 59(3): p. 586-9. 
56. 
Hamajima, N., T. Takezaki, and K. Tajima, Allele Frequencies of 25 
Polymorphisms Pertaining to Cancer Risk for Japanese, Koreans and Chinese. 
Asian Pac J Cancer Prev, 2002. 3(3): p. 197-206. 
57. 
Sweeney, C., et al., Association between survival after treatment for breast 
cancer and glutathione S-transferase P1 Ile105Val polymorphism. Cancer Res, 
2000. 60(20): p. 5621-4. 
58. 
Nishimura, T., et al., Association between expression of glutathione-associated 
enzymes and response to platinum-based chemotherapy in head and neck 
cancer. Chem Biol Interact, 1998. 111-112: p. 187-98. 
59. 
Saijo, M., et al., Sequential binding of DNA repair proteins RPA and ERCC1 to 
XPA in vitro. Nucleic Acids Res, 1996. 24(23): p. 4719-24. 
60. 
Yu, J.J., et al., Comparison of two human ovarian carcinoma cell lines 
(A2780/CP70 and MCAS) that are equally resistant to platinum, but differ at 
codon 118 of the ERCC1 gene. Int J Oncol, 2000. 16(3): p. 555-60. 
61. 
Britten, R.A., et al., ERCC1 expression as a molecular marker of cisplatin 
resistance in human cervical tumor cells. Int J Cancer, 2000. 89(5): p. 453-7. 
62. 
Shirota, Y., et al., ERCC1 and thymidylate synthase mRNA levels predict survival 
for colorectal cancer patients receiving combination oxaliplatin and fluorouracil 
chemotherapy. J Clin Oncol, 2001. 19(23): p. 4298-304. 
63. 
Tebbs, R.S., et al., Requirement for the Xrcc1 DNA base excision repair gene 
during early mouse development. Dev Biol, 1999. 208(2): p. 513-29. 
64. 
Brookman, K.W., et al., Isolation and characterization of mouse Xrcc-1, a DNA 
repair gene affecting ligation. Genomics, 1994. 22(1): p. 180-8. 
65. 
Duell, E.J., et al., Polymorphisms in the DNA repair genes XRCC1 and ERCC2 
and biomarkers of DNA damage in human blood mononuclear cells. 
Carcinogenesis, 2000. 21(5): p. 965-71. 
66. 
Goode, E.L., C.M. Ulrich, and J.D. Potter, Polymorphisms in DNA repair genes 
and associations with cancer risk. Cancer Epidemiol Biomarkers Prev, 2002. 
11(12): p. 1513-30. 
67. 
Divine, K.K., et al., The XRCC1 399 glutamine allele is a risk factor for 
adenocarcinoma of the lung. Mutat Res, 2001. 461(4): p. 273-8. 
68. 
Abdel-Rahman, S.Z., et al., Inheritance of the 194Trp and the 399Gln variant 
alleles of the DNA repair gene XRCC1 are associated with increased risk of 
early-onset colorectal carcinoma in Egypt. Cancer Lett, 2000. 159(1): p. 79-86. 
69. 
Lunn, R.M., et al., XPD polymorphisms: effects on DNA repair proficiency. 
Carcinogenesis, 2000. 21(4): p. 551-5.