Impact of Splenectomy on Thrombocytopenia,
Chemotherapy, and Survival in Patients
with Unresectable Pancreatic Cancer
Timothy R. Donahue & Kevork K. Kazanjian &
William H. Isacoff & Howard A. Reber & O. Joe Hines
Received: 28 December 2009 /Accepted: 23 February 2010 /Published online: 23 March 2010
# 2010 The Author(s). This article is published with open access at Springerlink.com
Background Patients with unresectable pancreatic cancer (PDAC) or endocrine tumors (PET) often develop splenic vein
thrombosis, hypersplenism, and thrombocytopenia which limits the administration of chemotherapy.
Methods From 2001 to 2009, 15 patients with recurrent or unresectable PDAC or PET underwent splenectomy for
hypersplenism and thrombocytopenia. The clinical variables of this group of patients were analyzed. The overall survival of
patients with PDAC was compared to historical controls.
Results Of the 15 total patients, 13 (87%) had PDAC and 2 (13%) had PET. All tumors were either locally advanced (n=6,
40%) or metastatic (n=9, 60%). The platelet counts significantly increased after splenectomy (p<0.01). All patients were
able to resume chemotherapy within a median of 11.5 days (range 6–27). The patients with PDAC had a median survival of
20 months (range 4–67) from the time of diagnosis and 10.6 months (range 0.6–39.8) from the time of splenectomy.
Conclusions Splenectomy for patients with unresectable PDAC or PET who developed hypersplenism and thrombocyto-
penia that limited the administration of chemotherapy, significantly increased platelet counts, and led to resumption of
treatment in all patients. Patients with PDAC had better disease-specific survival as compared to historical controls.
Keywords Pancreatic cancer.Palliative splenectomy.
Pancreatic endocrine tumors
The pancreas has a diverse cellular heterogeneity and
function, and can give rise to a number of histologically
distinct malignancies. Most malignant cancers originate
from the ductal epithelium or endocrine cells and include
pancreatic ductal adenocarcinomas (PDAC) and malignant
endocrine tumors (PETs). Each histologic type has a
different molecular signature and clinical course; PDACs
are associated with the worst prognosis, and PETs are
usually less aggressive.1,2Most patients with PDAC (85%)
present with locally advanced or metastatic tumors that are
unresectable. Treatment with gemcitabine-based chemo-
therapy has been shown to significantly improve survival,
albeit to only a small degree.3In contrast, PETs usually
present at an earlier stage. Chemotherapy is determined by
the grade of the tumor, with high-grade tumors more likely
to respond.4–6Thus, the goal of treatment for unresectable
PDAC or PET is treatment with chemotherapy.
By virtue of the anatomic location of the pancreas,
locally advanced PDAC or PETs can lead to thrombosis or
Presented at the Western Surgical Association Annual Meeting on
November 11th, 2009 in San Antonio, TX.
T. R. Donahue (*):K. K. Kazanjian:H. A. Reber:O. J. Hines
Department of Surgery, Division of General Surgery,
David Geffen School of Medicine at University
of California Los Angeles (UCLA),
10833 Le Conte Avenue, CHS, Room 72-215,
Los Angeles, CA 90095-6904, USA
W. H. Isacoff
Department of Medicine, Division of Hematology Oncology,
David Geffen School of Medicine at University
of California Los Angeles (UCLA),
Los Angeles, CA, USA
J Gastrointest Surg (2010) 14:1012–1018
occlusion of the splenic, superior mesenteric (SMV), and/or
portal (PV) vein(s) with resultant hypersplenism. As in
patients with cirrhosis and portal hypertension, the en-
hanced splenic function often produces thrombocytopenia.
In addition, cytotoxic chemotherapeutic regimens, especial-
ly gemcitabine, often induce bone marrow suppression,
which results in thrombocytopenia. When this occurs, many
patients must stop their treatment, since serious and
potentially lethal side effects could develop.
We hypothesized that a palliative splenectomy for
patients with locally advanced unresectable PDAC or PETs
who developed hypersplenism and thrombocytopenia that
limited the administration of chemotherapy, would extend
the duration of treatment and improve disease-specific
survival (DSS). To investigate our hypothesis, we analyzed
our experience with 15 patients who were managed with
this novel treatment strategy and compared the survival of
the PDAC subgroup of patients with stage-matched
Material and Methods
Approval from the University of California, Los Angeles
Office for the Protection of Research Subjects Institutional
Review Board was obtained prior to initiating this study.
Using a prospectively collected pancreatic cancer database,
we performed a review of all patients from 2001 to 2009
with locally advanced or metastatic fine needle aspirate or
biopsy (core needle, incisional, or excisional) confirmed
PDAC or PET who were unresectable and underwent a
splenectomy for severe thrombocytopenia that developed
during administration of chemotherapy. The pathology
reports were generated by one of four gastrointestinal
pathologists on faculty at UCLA. The clinical, radiograph-
ic, and histopathologic findings; treatment and perioper-
ative variables; and DSS of these patients were examined.
Clinical variables analyzed included gender, age, and
stage at the time of diagnosis, and tumor histology (PDAC
and PET). Radiographic variables analyzed included
location of the tumor and PV/SMV/splenic vein status
(patent vs. nonpatent) on high resolution computed tomog-
raphy (CT) or magnetic resonance imaging (MRI) scans.
Treatment variables analyzed included the pre- and post-
splenectomy chemotherapeutic regimen administered and
tumor response. Variables directly related to splenectomy
that were examined included length of hospital stay, need
for conversion to an open operation, white blood cell
count and hemoglobin immediately after surgery (postop-
erative day 1), and pre- and postoperative platelet counts.
Preoperative platelet counts were recorded at the last clinic
visit prior to surgery. Postoperative platelet counts were
recorded on the day of hospital discharge. The time to
resumption of chemotherapy after splenectomy was also
For survival analysis, the DSS of all patients with PDAC
from the time of diagnosis or splenectomy was examined.
For those patients who died, the date of death was
determined from the clinic charts when available, or
alternatively, the social security death index (http://ssdi.
rootsweb.ancestry.com/cgi-bin/ssdi.cgi) by an exact match
between the patient's name and birth date. If alive, the date
of last follow-up was taken as the last time the patient was
seen in clinic. The two patients with PET were not included
in the survival analysis, as PET are less clinically
aggressive than PDAC.
For significance analysis, X2and Fisher's exact test were
used as appropriate. DSS was estimated using the Kaplan–
Meier method. All statistical analyses were performed using
JMP statistical software (SAS Corporation, Cary, NC).
Significance was assigned at the 0.05 level.
Clinical, Radiographic, and Histopathologic Findings
From 2001 to 2009, 15 patients with unresectable pancre-
atic cancer who developed hypersplenism and thrombocy-
topenia, which limited the administration of their
chemotherapy, underwent a splenectomy at UCLA Medical
Center. The distribution of the clinical, radiographic, and
histopathologic findings for these patients is listed in
composite in Table 1 and individually in Table 2. Thirteen
patients (87%) had primary disease; two patients (13%)
recurred after a Whipple operation. The median age of
patients was 56 years (range 25 to 62 years). Nine patients
were male (60%) and 6 (40%) were female. Most patients
had PDAC (n=13, 87%), while only two patients had PET
(13%). All patients had locally advanced, stage 3 (n=6,
40%) or metastatic, stage 4 (n=9, 60%) disease. Nine
tumors (60%) were located in the head/uncinate process
and 6 (40%) were located in the body/tail. On high-
resolution CT/MRI, the portal or splenic veins were
thrombosed in 12 (80%) patients (Fig. 1); the three other
patients had documented splenomegaly on CT/MRI. In fact,
splenomegaly was not routinely reported in the radiology
report per the usual practice of the UCLA gastrointestinal
J Gastrointest Surg (2010) 14:1012–10181013
radiologists for pancreas-protocol CT scans or MRIs. The
median spleen weight was 348 g (range 164–525) but may
be an underestimate of the actual spleen size due to
morcellation prior to extraction. The spleen volumes are
likewise not reported for similar reasons.
Treatment and Procedure Variables
The median time from the initial diagnosis of cancer to
splenectomy was 9.8 months (0.3–58) during which all
patients were administered chemotherapy. Chemotherapy
was stopped due to thrombocytopenia within 2 weeks of
surgery for all patients. Most patients with PDAC were
administered a gemcitabine-based combination therapy
(n=9, 69%) both before and after splenectomy; a 5-
fluorouracil (5-FU)-based combination regimen was used
less frequently (n=4, 31%). All patients had at least a
partial tumor response to both drug treatments; there were
no complete responses.
There was minimal morbidity associated with the
splenectomy. A laparoscopic splenectomy was successfully
performed for 11 (73%) patients, while the procedure was
converted to an open operation for 4 (27%) patients. Excess
blood loss was the primary reason for conversion. The
median hospital stay was 3 days (range 2–6) and did not
differ between the laparoscopic and open groups (p>0.05).
Recorded immediately after surgery, the white blood cell
count (median 11.05×103/µL, range 4.26×103–21×103)
and hemoglobin (median 11.75 g/dL, range 9.2–13.3) did
not reveal evidence of bone marrow suppression due to
preoperative chemotherapy. At the time of splenectomy, 12
patients had National Cancer Institute (NCI)/Eastern Coop-
erative Oncology Group (ECOG) Grade 1 thrombocytope-
nia (defined by 75×103–150×103), two patients had NCI/
ECOG Grade 2 (defined by 50×103–74×103), and one
patient had impending NCI/ECOG-defined thrombocytope-
nia. The platelet counts significantly responded to splenec-
tomy in all patients, preoperative (median 87×103/µL,
range 66×103–160×103) vs. postoperative taken immedi-
ately prior to discharge (median 425×103/µL, range 229×
103–994×103), (p<0.01). All patients were able to resume
full dose of the same chemotherapy regimen after splenec-
tomy within a median of 11.5 days (range 6–27).
The median follow-up for all survivors was 35 months
(range 13–63) from the time of diagnosis and 25 months
(range 0.6–51) from the time of splenectomy. The 13
patients with PDAC had a median survival of 20 months
(range 4–67) with a 5-year DSS of 25% from the time of
diagnosis, and a median DSS of 10.6 months (range 0.6–
39.8) from the time of splenectomy (Fig. 2). Both patients
with PET had well-differentiated tumors. One patient died
of disease after 107 months, and the other is still alive with
disease after 60 months.
PDAC is the fourth leading cause of cancer-related deaths
in the United States, with an overall 5-year survival of 4%.
In 2009, 42,770 patients in the USA were diagnosed with
PDAC and 35,240 died from their disease.7The poor
outcome of patients with PDAC has been attributed to the
advanced stage of disease at diagnosis, the poor response to
current systemic and local therapies, and the aggressive
biologic nature of the disease. Resection for PDAC
provides the only chance for cure, but only about 15% of
patients are eligible for surgery.8Even those patients who
undergo a “curative resection” have a 5-year survival rate
of 35% in the best series.9Most patients (85%) present with
locally advanced or metastatic tumors, and they have a
median survival of less than 12 or 5 months, respectively.7
Chemotherapy can significantly extend DSS and decrease
PETs have been studied much less frequently than
PDAC primarily due to their low prevalence; only about
2,500 new PETs are diagnosed annually in the United
States.10–12PETs are categorized as functional or nonfunc-
tional depending on whether the secreted peptide is
biologically active and produces a clinical syndrome; about
50% of nonfunctional PETs secrete peptides that are
Table 1 Composite Patients' Clinical, Radiographic, Treatment, and
Age (median years)
Splenectomy (procedure type)
Laparoscopic converted to open
Hospital stay (median days)
1014 J Gastrointest Surg (2010) 14:1012–1018
clinically silent.13Insulinomas are the most common type
of PET, and a majority are benign.14In contrast, approx-
imately 60% of non-insulin-secreting PETs are malig-
nant.11,15Due to their less aggressive clinical behavior
than PDAC and resistance to most current chemotherapeu-
tic agents, PETs are treated aggressively with resectional
therapy. However, cytotoxic chemotherapy is given to
patients with unresectable PETs. Therapy is determined by
the grade of the tumor.4–6Thus, chemotherapy is the
primary goal of treatment for unresectable PET or PDAC
for as long as the patient can tolerate it.
Locally advanced or recurrent pancreatic tumors of
either histologic type in the head of the gland can involve
the splenic vein, SMV, or PV. Tumors in the body or tail
can involve the splenic vein. Either can cause venous
0 1020 3040 5060 70
Months (from time of diagnosis)
Figure 2 Disease-specific survival of 13 patients with PDAC.
Median survival was 20 months (range 4–67 months).
Figure 1 Representative pancreas-protocol CT scan from a patient
with a PDAC located in the body/tail who has complete occlusion of
the splenic vein and an enlarged spleen.
Table 2 Individual Patient's Clinical, Radiographic, Treatment, Histopathologic, and Survival Characteristics
8 B/T PDAC3 91361 20 DOD9.311.2 1.9
4 66864 10AWD 9.660.3 50.7
H/U head or uncinate tumor, B/T body or tail, DOD died of disease, AWD alive with disease, CiFU continous infusion 5FU, LV leukovorin, MitoC
mitomycin C, Gemzar gemcitabine, GFLIP gemcitabine+5FU+leukovorin+irinotecan+persantine, Temodar temozolomide, GTX gemcitobine+taxotere
J Gastrointest Surg (2010) 14:1012–10181015
occlusion from compression by the tumor mass or
thrombosis of the vessel.16Left-sided portal hypertension,
hypersplenism, and thrombocytopenia may result, which
limits the patients' ability to tolerate aggressive chemother-
apy. In this study, we examined the perioperative morbidity
and effectiveness of splenectomy on restoring platelet
counts to normal, administration of chemotherapy, and
survival in our small series of 15 patients. A similar
analysis was performed on 11 patients with hepatitis C,
cirrhosis, and portal hypertension.17In this series, splenec-
tomy reversed the hypersplenism-induced thrombocytope-
nia, and patients could resume pegylated interferon therapy.
A recent meta-analysis3of 50 trials (7,043 participants)
on the effectiveness of 5-FU- or gemcitabine-based che-
motherapy and radiotherapy for inoperable pancreatic
cancer found that chemotherapy can significantly improve
1-year mortality (p<0.00001) in patients with locally
advanced or metastatic PDAC and can also significantly
decrease morbidity. Gemcitabine–platinum combinations
significantly reduced 6-month mortality on subgroup
analysis (p<0.001) and currently are the standard of care
for the disease. Unfortunately, a number of factors often
limit administration of chemotherapy to patients with
pancreatic cancers. These include a poor functional or
nutritional status; an unresponsive tumor and thus no
clinical benefit to giving the drugs; bone marrow suppres-
sion that can result in severe anemia, leucopenia, and
thrombocytopenia,18or isolated thrombocytopenia. The
potential causes of isolated thrombocytopenia include
hypersplenism, bone marrow suppression with preferential
inhibition of platelet production, or other very rare causes
such as gemcitabine-associated thrombotic microangiop-
athy,19or capecitabine (Xeloda)-induced idiopathic throm-
bocytopenic purpura. In fact, a major side-effect profile
listed on the gemcitabine package insert includes thrombo-
cytopenia. Thus, patients who are receiving chemotherapy,
particularly gemcitabine-based regimens, are at risk of
developing thrombocytopenia. With concurrent hypersplen-
ism, the risk is even higher, as bone marrow production of
platelets is usually be suppressed. Hypersplenism may
unmask subclinical thrombocytopenia.
A recent study to develop a prognostic score that would
predict survival after resection for PETs, using 3,851
patients from the National Cancer Data Base (1985–
2004), found that age, grade, and distant metastases were
the most significant predictors.20Administration of adju-
vant chemotherapy was not associated with increased
survival. Nevertheless, cisplatin and etoposide combination
therapy is effective in treating patients with poorly
differentiated PETs, while streptozocin, doxorubicin, and
5-fluorouracil is the standard cytotoxic regimen for func-
tional PETs.21In fact, several studies suggest that PETs are
more responsive to chemotherapy than endocrine tumors in
other parts of the gastrointestinal tract, most notably
carcinoid tumors. Our two patients with PETs who
underwent splenectomy and aggressive chemotherapy
have had excellent survival outcomes. As listed in
Table 2, one patient is still alive with disease after
60 months and recently underwent an extensive resection
of the primary tumor and multiple liver metastases. The
other patient eventually died of disease after a rather long
Patients, with either PDAC or PET, who are offered
splenectomy must demonstrate a good functional status,
preferably with thrombocytopenia as the only factor limiting
treatment. A complete blood cell count should be obtained
preoperatively to exclude cytotoxic chemotherapy-induced
bone marrow suppression as the primary cause of thrombo-
cytopenia. If other blood elements are also low, particularly
the absolute neutrophil count, then the chemotherapy should
be considered as the primary cause of thrombocytopenia and
splenectomy deferred. In this case, the dose of chemotherapy
should be lowered or combination changed; alternatively, one
might elect to give drugs that stimulate bone marrow
production, such as granulocyte colony-stimulating factor or
erythropoietin. If isolated thrombocytopenia is present, with
the other elements normal, and there is evidence of hyper-
splenism on high-resolution imaging (e.g., portal vein
thrombosis or an enlarged spleen), then splenectomy should
be pursued. Ideally, we prefer that patients have a good
size or extent of disease on imaging and tumor markers;
although,thiswasnot the caseinthe present series,aspatients
underwent splenectomy over a wide time range from the time
of diagnosis. CA19-9 is the best serum marker of response for
PDAC;22chromogranin, synaptophysin, pancreatic polypep-
tide, or gastrin can be used for PET.23Patients must not have
end-stage disease and severe malnutrition. We require that
patients have a preoperative abdominal CT or MRI scan,
which are usually being done for disease surveillance during
treatment. The primary tumor is evaluated to ensure that it is
not growing into the splenic hilum or to note additional
features (varices, etc.) that will help in planning the
procedure. In addition, the abdomen is evaluated for any
signs of carcinomatosis and/or ascites. By using these
stringent preoperative criteria prior to splenectomy, perioper-
ative morbidity and mortality can be minimized, and platelet
counts are likely to respond.
Patients who are not operative candidates can alterna-
tively undergo splenic artery embolization or external beam
splenic irradiation, as these two treatments can also
potentially reverse hypersplenism-induced thrombocytope-
nia.24Embolization should be considered as second-line
treatment after splenectomy because it can be associated
with significant postoperative pain and splenic abscesses.25
Furthermore, splenic irradiation is rarely performed for
1016J Gastrointest Surg (2010) 14:1012–1018
hypersplenism but can be effective for relief of pain
associated with splenomegaly in patients with hematologic
disorders.26In our experience, as discussed previously,
splenectomy is safe and can be performed with minimal
morbidity and a short hospital stay.
There were no deaths in our series; hospital stay was
short (median 3 days), and patients' platelet counts
responded rapidly with quick resumption of chemotherapy
(median 11.5 days). The median follow-up for all survivors
was 35 months (range 13–63) from the time of diagnosis.
The 13 patients with PDAC had a median survival of
20 months (range 4–67) with a 5-year DSS of 25% from the
time of diagnosis, and a median survival of 10.6 months
(range 0.6–39.8) from the time of splenectomy.
In conclusion, while the optimal treatments for patients
with locally advanced or metastatic PDAC or PET are in
evolution, we found that our novel strategy of splenectomy
for the development of hypersplenism-induced thrombocy-
topenia that limited chemotherapy treatment was effective.
Splenectomy was performed with minimal morbidity, and
was associated with a rapid increase in platelet counts and a
short time before resuming chemotherapy. In addition,
patients with PDAC who underwent this novel treatment
strategy had significantly improved DSS as compared to
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