Metastatic Pancreatic Adenocarcinoma

Anubha Bharthuar
1
, Lori Pearce
1
, Alan Litwin
2
, Charles LeVea
3
,
Boris Kuvshinoff
4
, Renuka Iyer
1
Departments of Medicine
1
, Radiology
2
, Pathology
3
and Surgery
4
, Roswell Park Cancer Institute.
Buffalo, NY, USA
ABSTRACT
Context Pancreatic adenocarcinoma and renal cell carcinoma are relatively frequent cancers that have been rarely reported as
synchronous primary malignancies. When present simultaneously, they pose a therapeutic challenge given the many available
targeted agents with reported efficacy in renal cell cancer and limited options for metastatic pancreatic cancer. Case report We
report the case of a 43-year-old Caucasian gentleman diagnosed simultaneously with metastatic pancreatic adenocarcinoma and
localized renal cell carcinoma treated with combination chemotherapy, consisting of gemcitabine and sunitinib. Patient had a
radiographic response and prolonged progression free survival of twenty six weeks; side effects were manageable and included grade
3 neutropenia and grade 2 hypertension. Conclusion This encouraging response, safety profile and progression free survival
response suggest that we should further examine this and other such regimens to improve clinical outcomes for maximum efficacy
with minimal side-effects.
INTRODUCTION
Synchronous primary malignancies at presentation are
a recognized yet unusual phenomenon. It is more
frequently seen in individuals with hereditary or
familial cancer syndromes, such as those associated
with colon, breast and ovarian cancers. Von Hippel-
Lindau disease [1] and Birt-Hogg-Dube syndrome [2]
are autosomal dominant disorders where individuals
have a genetic predisposition for renal cell carcinoma.
Patients with Von Hippel-Lindau disease may manifest
with pancreatic abnormalities such as cysts, serous
cystadenomas, and neuroendocrine tumors however
they do not have an increased risk of pancreatic
adenocarcinoma [3].
Renal cell carcinoma has nonetheless been shown to be
associated with a higher risk of a second primary
malignancy, which can be antecedent, synchronous or
subsequent [4, 5]. The cancers that are most commonly
associated with this tumor include cancers of the
prostate, bladder, lung, breast, colon and rectal cancer,
malignant melanomas and non-Hodgkin’s lymphomas
[4, 6]. Renal cell carcinoma is the ninth most frequent
cancer in the United States with a 2008 projected
incidence of 54,390 and mortality of 13,010.
Pancreatic cancer carries a more dismal prognosis as
the estimated new cases and deaths from pancreatic
cancer for 2008 is 37,680 and 34,290 respectively [7].
While both cancers are common entities in their own
right, it is unusual for renal cell carcinoma and
pancreatic adenocarcinoma to be present
simultaneously. There are only a handful of case
reports of patients with synchronous renal cell
carcinoma and pancreatic ductal adenocarcinoma, and
as they were not metastatic on diagnosis were able to
undergo surgical resection [8, 9].
Alexakis et al. described two patients with renal cell
carcinoma of which one had a synchronous and two
had metachronous pancreatic cancer. The patient was a
67-year-old man who presented with obstructive
jaundice and CT scan revealed a mass in the head of
the pancreas as well as a 6.5 cm left renal mass. He
underwent left nephrectomy for a stage 1 clear cell
carcinoma and 6 weeks later underwent Whipple
pancreaticoduodenectomy (R1 resection) for the
pT3N1b pancreatic adenocarcinoma. He expired fifteen
months later due to pancreatic cancer recurrence [8].
Olgyai et al. presented a case report of a 72-year-old
woman who was diagnosed with synchronous renal cell
carcinoma and pancreatic adenocarcinoma who
successfully underwent distal pancreatectomy,
Received April 9th, 2009 - Accepted June 10th, 2009
Key words gemcitabine; Kidney Neoplasms; Pancreatic
Neoplasms; sunitinib
Correspondence Anubha Bharthuar
Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo,
NY 14263, USA
Phone: +1-716.845.8547; Fax: +1-716.845.8008
E-mail: anubha.bharthuar@roswellpark.org
Document URL http://www.joplink.net/prev/200909/02.html

Page 2
JOP. J Pancreas (Online) 2009 Sep 4; 10(5):523-527.
JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 10, No. 5 - September 2009. [ISSN 1590-8577]
524
splenectomy and nephrectomy followed by
chemotherapy and was well at 6 months’ follow-up [9].
We report the first case of a patient with concurrent
metastatic pancreatic adenocarcinoma and localized
renal cell carcinoma treated with standard
chemotherapy along with a novel agent.
CASE REPORT
A 43-year-old Caucasian gentleman presented to a local
emergency room in April, 2006 with sudden onset right
upper quadrant abdominal pain and jaundice. CT scan of
the abdomen revealed a 2.2 cm mass in the head of the
pancreas and a 3.2x2.7 cm necrotic right renal mass,
suspicious for carcinoma. Total bilirubin was elevated at
8.4 mg/dL (reference range: 0.2-1.3 mg/dL) and CA 19-9
was 310 U/mL (reference range: 0-35 U/mL). An
endoscopic retrograde cholangiopancreatogram (ERCP)
was performed with placement of a temporary biliary
stent for decompression. Bile duct brushings at the time
of ERCP demonstrated marked atypical cells. This was
followed by a magnetic resonance cholangiopancreato-
graphy (MRCP) that revealed biliary ectasia and a 2 cm
common bile duct obstruction, with a mass at the head of
the pancreas. There was evidence of intra and extra-
hepatic biliary ductal dilatation terminating at the 2 cm
pancreatic head mass. The MRI also noted the right renal
mass. Ultrasound guided needle biopsy of the renal mass
was performed and pathology was consistent with
Fuhrman’s grade 2, clear cell type renal cell carcinoma
(Figure 1). Subsequent restaging CT scans of the chest,
abdomen, and pelvis also identified a small 5 mm lesion
in the liver and increase in size of the pancreatic mass to
4x3 cm, with stable right kidney hypervascular mass.
Due to the extracapsular extension of the pancreatic mass
and the hypodense liver lesion the patient underwent a
diagnostic laparoscopy in May 2006. Intra-operative
biopsy of the pancreatic head mass and liver lesion was
performed; the pathology from both was consistent with
invasive moderately to poorly differentiated
adenocarcinoma (Figures 2 and 3). This confirmed the
diagnosis of metastatic pancreatic cancer with a
concurrent second primary of renal cell carcinoma,
thereby excluding surgical resection as a therapeutic
option.
The patient then started treatment with systemic
chemotherapy consisting of gemcitabine and sunitinib, as
it was felt that this would regimen would simultaneously
control both the malignancies. The dose of gemcitabine
planned was 750 mg/mintravenously days one, eight
and fifteen repeated on a twenty-eight-day cycle; and the
dose of sunitinib was 37.5 mg orally four weeks on
followed by two weeks off. These doses were based on
selected planned phase I studies of this combination.
Dose intensity was maintained for the first two cycles,
and restaging CT scan after two cycles showed an almost
complete resolution of the liver lesion, with no change in
the size of the pancreatic mass, consistent with stable
disease and decrease in the size of the renal cell
carcinoma, consistent with partial response per Response
Evaluation Criteria In Solid Tumors (RECIST) criteria
(Figure 4) [10].
Figure 1. Kidney needle core biopsy: This photomicrograph shows a
renal cell carcinoma. (Magnification 200x).
Figure 2. Pancreas needle core biopsy: This photomicrograph shows
a ductal carcinoma within dense fibrous stroma. (Magnification
200x).
Figure 3. Liver needle core biopsy. Metastatic pancreatic ductal
carcinoma (middle to upper right) to the liver (lower left).
(Magnification 200x).

Page 3
JOP. J Pancreas (Online) 2009 Sep 4; 10(5):523-527.
JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 10, No. 5 - September 2009. [ISSN 1590-8577]
525
Subsequently however patient had three interruptions
secondary to grade 3 neutropenia, and four delays due to
patient preference. Growth factors were not used in
keeping with the American Society of Clinical Oncology
(ASCO) guidelines [11]. Dose intensity could not be
maintained despite dose reduction of gemcitabine to 700
mg/m2, and in total patient received fourteen doses of
gemcitabine over twenty-five weeks. He also had an
episode of hyperbilirubinemia and migration of biliary
stent, requiring a repeat ERCP. He tolerated the sunitinib
fairly well, but did develop grade 2 hypertension, and
restaging CT scan after three cycles of this regimen
continued to show stable disease.
Unfortunately repeat CT of the chest, abdomen, and
pelvis in November 2006 revealed multiple new liver
metastases. The CA 19-9, which had decreased initially
with chemotherapy from 764 U/mL to 479 U/mL, started
to trend upwards and at this time was 12,219 U/mL. He
thereafter developed small bowel obstruction due to
invasion of the duodenum by the pancreatic mass and had
a rapid decline in his performance status, and received no
further chemotherapy and quickly succumbed to his
disease in December 2006.
DISCUSSION
Gemcitabine is standard of care first line therapy for
patients with metastatic pancreatic adenocarcinoma
with a median overall survival of 5.65 months,
progression free survival of 9 weeks and a clinical
benefit response of 23.8% [12]. Our patient had
prolonged progression free survival of 26 weeks that
may be attributable to the addition of sunitinib. Overall
survival was as expected for patients receiving single
agent gemcitabine and was similar to that reported
from other clinical trials of combination therapy with a
targeted molecular agent in addition to traditional
chemotherapy in pancreatic malignancy [13, 14].
Erlotinib is the only oral epidermal growth factor
tyrosine kinase inhibitor that has been shown to
prolong overall survival in patients with advanced
pancreatic cancer, although the benefit appears to be
modest. It was approved by the Food and Drug
Administration (FDA) in 2005, in combination with
gemcitabine for treatment of patients with locally
advanced, unresectable or metastatic pancreatic
carcinoma [15].
Sunitinib malate is an oral multi-kinase inhibitor
targeting several receptor tyrosine kinases
(PDGFRalpha and PDGFRbeta; VEGFR1, VEGFR2
and VEGFR3; KIT, FLT3, CSF-1R and RET) that was
approved by the FDA in 2006 for treatment of
metastatic renal cell carcinoma. In a randomized phase
III trial, sunitinib prolonged median progression-free
survival (11 months) in comparison to interferon-alpha
(5 months); corresponding to a hazard ratio of 0.42
(95% confidence interval: 0.32 to 0.54; P<0.001) for
patients with advanced renal cell cancer. Sunitinib was
also associated with a higher objective response rate
than interferon-alpha (31% vs. 6%; P<0.001) [16].
However, the majority of patients (48%) had stable
diseases and it also was not shown to improve overall
survival. Our patient too, had disease stabilization of
his renal cell carcinoma.
Clinical trials involving other tyrosine kinase inhibitors
and anti-angiogenic agents in pancreatic cancer are
currently ongoing. Results of the Cancer and Leukemia
Group B (CALGB) 80603 phase II clinical trial of
sunitinib in patients with previously-treated pancreatic
adenocarcinoma, which was recently presented at the
ASCO 2008 annual meeting, showed that sunitinib has
definite value in pancreatic carcinoma; with a response
rate of 21% (1% complete response and 20% stable
disease) [17].
The rationale for combining gemcitabine with sunitinib
in our patient was to exploit the anti-angiogenic and
anti-proliferative effect of sunitinib to control both the
renal cell carcinoma and pancreatic carcinoma.
Gemcitabine was used in addition as it is the accepted
standard of care for pancreatic cancers and has also
been shown to have increased anti-tumor activity when
incorporated with a targeted molecular therapy [15].
The potential efficacy and safety of combination
chemotherapy with sunitinib in addition to gemcitabine
is currently being tested in a number of phase I and II
clinical trials, but at the time that our patient was
treated with gemcitabine and sunitinib these trials were
unavailable as they had not been initiated. The
preliminary results of phase I study of sunitinib malate
Figure 4. CT scan showing kidney mass at diagnosis (a.) and after 2
months of therapy (b.).

Page 4
JOP. J Pancreas (Online) 2009 Sep 4; 10(5):523-527.
JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 10, No. 5 - September 2009. [ISSN 1590-8577]
526
continuously dosed and standard-infusion gemcitabine
in solid tumors (NCT00462553) also presented at the
ASCO 2008 annual meeting indicate that this
combination has significant promise for the treatment
of pancreatic cancer, as at the dose level 1
(gemcitabine 800 mg/m2
intravenously weekly x3
every 28 days and sunitinib 25 mg orally daily) two of
the four patients with advanced pancreatic cancer had
confirmed partial response, and the treatment was
fairly well tolerated [18]. Our patient’s response to this
regimen is certainly in accordance with this study,
although the doses that he received were different.
The combination of gemcitabine and sunitinib has also
shown efficacy in a number of clinical trials for renal
cell carcinoma. A phase I study of sunitinib and
gemcitabine in advanced renal cell carcinoma and other
solid tumors explored two different dosing schedules:
1) sunitinib given 4 weeks on, followed by 2 weeks off
(4/2); and 2) two weeks on, followed by 1 week off
(2/1) with gemcitabine administered i.v. over 30 min
on days 1, 8, 22, and 29 on schedule 4/2 and days 1 and
8 on schedule 2/1. Nineteen patients from the total of
34 had renal cell carcinoma and had significant
response to this therapy especially those with poor-risk
or high-grade renal cell carcinoma (doses: sunitinib
37.5 mg plus gemcitabine 750 mg/m2; sunitinib 37.5
mg plus gemcitabine 850 mg/m2; sunitinib 37.5 mg
plus gemcitabine 1,000 mg/m2) [19]. Gemcitabine was
also shown to delay disease progression in some
patients with renal cell carcinoma who developed
resistance to sunitinib alone. Gemcitabine was
administered 750 mg/mi.v. on days 1 and 8 and
sunitinib was given at a dose of 37.5 mg/day on days 2-
15 over a 21 day cycle. Of the nine patients treated
with this regimen one patient had a partial response,
four patients had stable disease and four patients had
progressive disease documented per RECIST criteria
[20].
The results of these and other ongoing clinical trials
will help us to refine this regimen and determine the
optimum doses and cycle length, for the most favorable
results with minimum toxicities.
CONCLUSION
Gemcitabine and sunitinib combination chemotherapy
led to a radiographic response and produced a
prolonged progression free survival in this patient with
metastatic pancreatic cancer and primary renal cell
cancer, which is unusual for metastatic pancreatic
carcinoma. The toxicities were as expected and
manageable, although optimal dosing to maintain dose
intensity needs to be determined. Gemcitabine and
erlotinib is now an FDA approved regimen for patients
with metastatic pancreatic cancer and the success of
this combination merits exploration of other targeted
therapies such as sunitinib, sorafenib and mTOR
inhibitor such as temsirolimus which have established
efficacy in renal cell carcinoma in combination with
chemotherapy for patients with pancreatic and renal
cell cancer. While the search for the best gemcitabine
based backbone for advanced pancreatic cancer
continues, studies of anti-angiogenic agents alone or in
combination with traditional chemotherapy should be
undertaken as they may improve overall survival in this
group of poor prognosis patients.
Conflict of interest The authors have no potential
conflicts of interest
References
1. Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore
AT, et al. Clinical features and natural history of von Hippel-Lindau
disease. Q J Med 1990;77:1151-63.
2. Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B,
Linehan WM, et al. Renal tumors in the Birt-Hogg-Dube syndrome.
Am J Surg Pathol 2002;26:1542-52.
3. Hammel PR, Vilgrain V, Terris B, Penfornis A, Sauvanet A,
Correas JM, et al. Pancreatic involvement in von Hippel-Lindau
disease. The Groupe Francophone d'Etude de la Maladie de von
Hippel-Lindau. Gastroenterology 2000;119:1087-95.
4. Beisland C, Talleraas O, Bakke A, Norstein J. Multiple primary
malignancies in patients with renal cell carcinoma: a national
population-based cohort study. BJU Int 2006;97:698-702.
5. Sato S, Shinohara N, Suzuki S, Harabayashi T, Koyanagi T.
Multiple primary malignancies in Japanese patients with renal cell
carcinoma. Int J Urol 2004;11:269-75.
6. Rabbani F, Grimaldi G, Russo P. Multiple primary malignancies
in renal cell carcinoma. J Urol 1998;160:1255-9.
7. Society AC. Cancer Facts and Figures Atlanta, Ga. American
Cancer Society 2008.
8. Alexakis N, Bosonnet L, Connor S, Ellis I, Sutton R, Campbell
F, et al. Double resection for patients with pancreatic cancer and a
second primary renal cell cancer. Dig Surg 2003;20:428-32.
9. Olgyai G, Haulik L, Olah A. [Double resection for synchronous
pancreatic and renal cell cancer--case report]. Magy Seb
2004;57:287-9.
10. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS,
Rubinstein L, et al. New guidelines to evaluate the response to
treatment in solid tumors. European Organization for Research and
Treatment of Cancer, National Cancer Institute of the United States,
National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-
16.
11. Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO,
Balducci L, et al. 2006 update of recommendations for the use of
white blood cell growth factors: an evidence-based clinical practice
guideline. J Clin Oncol 2006;24:3187-205.
12. Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff
M, et al. Phase II trial of bevacizumab plus gemcitabine in patients
with advanced pancreatic cancer. J Clin Oncol 2005;23:8033-40.
13. Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne
WL, Szawlowski A, et al. Phase III trial of gemcitabine plus
tipifarnib compared with gemcitabine plus placebo in advanced
pancreatic cancer. J Clin Oncol 2004;22:1430-8.
14. Philip PA, Benedetti J, Fenoglio-Preiser C, Zalupski M, Lenz H,
O'Reilly E, et al. Phase III study of gemcitabine [G] plus cetuximab
[C] versus gemcitabine in patients [pts] with locally advanced or
metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study. J
Clin Oncol (Meeting Abstracts) 2007;25:LBA4509-.
15. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger
S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone
in patients with advanced pancreatic cancer: a phase III trial of the
National Cancer Institute of Canada Clinical Trials Group. J Clin
Oncol 2007;25:1960-6.

Page 5
JOP. J Pancreas (Online) 2009 Sep 4; 10(5):523-527.
JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 10, No. 5 - September 2009. [ISSN 1590-8577]
527
16. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski
RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic
renal-cell carcinoma. N Engl J Med 2007;356:115-24.
17. O'Reilly EM, Niedzwiecki, D. D., R. Hollis, T. S. Bekaii-Saab,
T. Pluard, A. Duffy, F. Overcash, S. P. Ivy, R. M. Goldberg. A phase
II trial of sunitinib (S) in previously-treated pancreas
adenocarcinoma (PAC), CALGB 80603. J Clin Oncol 2008;26.
18. Brell JM, Bokar J. A. ,Cooney M. M. , S. S. Krishnamurthi, J.
Gibbons, C. J. Nock, P. Savvides, E. Batts, S. P. Ivy, A. Dowlati.
Phase I study of sunitinib malate continuously dosed and standard-
infusion gemcitabine in solid tumors. J Clin Oncol 2008;26.
19. Michaelson M, Schwarzberg A, Ryan D, McDermott D, Shapiro
G, Tye L, et al. A phase I study of sunitinib in combination with
gemcitabine in advanced renal cell carcinoma and other solid tumors.
ASCO Genitourinary Cancers Symposium 2008;Abstract No 362.
20. Pandya S, Mier J, Cho D, McDermott D. The role of adding
gemcitabine at time of sunitinib resistance in patients with metastatic
renal cell cancer. ASCO Genitourinary Cancers Symposium 200

There are no products listed under this category.