Case Report
Sinusoidal Obstruction Syndrome after Neoadjuvant FOLFIRINOX for Locally Advanced Pancreatic Cancer
Garrick Trapp1, Michael D. Kluger1, Stephen M. Schreibman2 and Beth A. Schrope1*
1Department of Surgery, Columbia University Medical Center, USA
2Department of Medicine, Columbia University Medical Center, USA
*Corresponding author: Beth A. Schrope, Department of Surgery, Pancreas Center, Columbia University Medical Center, 161 Fort Washington Ave, 8th Floor, New York, NY 10032, USA
Published: 05 Dec, 2016
Cite this article as: Schrope BA. Sinusoidal Obstruction
Syndrome after Neoadjuvant
FOLFIRINOX for Locally Advanced
Pancreatic Cancer. Clin Surg. 2016; 1:
1250.
Abstract
Case Report: A 69-year-old woman diagnosed with locally advanced pancreatic adenocarcinoma due to significant vascular involvement underwent 11 cycles of FOLFIRINOX neoadjuvant chemotherapy. After satisfactory imaging response, the tumor was resected with a pancreaticoduodenectomy procedure with superior mesenteric and portal vein reconstruction. At surgical exploration, the patient’s liver had the appearance of a “blue liver,” consistent with sinusoidal congestion or obstruction, but otherwise the liver was normal size without any metastasis. A day after her surgery, the patient became acidotic, anuric, and pressor dependent, succumbing to multisystem organ failure that evening. FOLFIRINOX contains oxaliplatin, a drug strongly correlated with an increased risk of sinusoidal obstruction syndrome. As neoadjuvent chemotherapy containing oxaliplatin becomes more widely used for locally advanced pancreatic cancer, more research is needed to understand the implications of oxaliplatin toxicity and pancreatic resections to reduce potential perioperative complications with particular attention to patients receiving higher cycle counts of FOLFIRINOX or other oxaliplatin-based treatments.
Introduction
Neoadjuvant chemotherapy is increasingly used for locally advanced pancreatic adenocarcinoma as an effective treatment strategy to qualify patients for potentially curative surgery. Although current neoadjuvant regimens might include traditional gemcitabine-based chemotherapies, newer oxaliplatin combination chemotherapy regimens have been enthusiastically adopted since 2011, following the landmark trial1 that demonstrated the efficacy of FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) for metastatic pancreatic cancer. Here we present a case of a patient who received neoadjuvant FOLFIRINOX for locally advanced pancreatic cancer. After eleven cycles of FOLFIRINOX, she became eligible for a pancreaticoduodenectomy. Unfortunately, the day after her surgery she succumbed to liver failure. In this case study we suggest that her complication was possibly related to her FOLFIRINOX chemotherapy regimen.
Case Presentation
A 68-year-old woman with a history of hypertension and coronary artery disease presented with
decreased appetite, rapid weight loss (13lbs in 4 weeks), increasing fatigue, and upper abdominal
symptoms (burning, nausea, and epigastric pain). CT imaging identified a mass encasing the celiac
axis with significant involvement with the superior mesenteric and portal vein (Figure 1). FNA
confirmed a diagnosis of pancreatic adenocarcinoma in the head of the pancreas that also extended
into the neck region. Initial clinical staging based on imaging was T4NxM0. With this diagnosis,
the patient started neoadjuvant chemotherapy with a plan for evaluation every three months to
assess resectability. In December 2014 she started a first line regimen of gemcitabine and paclitaxel,
completing a total of four cycles. During this first line treatment, in February 2015, she experienced
symptoms of early satiety and intolerance of oral solids in the absence of mechanical obstruction
and was started on parenteral nutrition.
Despite completing a full treatment regimen of gemcitabine and paclitaxel in early April 2015
there was persistent soft tissue around the celiac axis, attenuation of the proximal portal vein, and
increased soft tissue anterior to the inferior vena cava, extending to the right pararenal fascia.
In late April 2015, the patient started a second line of therapy with FOLFIRINOX with a total
of eleven rounds (111 mg/m2 of oxaliplatin, 522 mg/m2 of leucovorin, 235 mg/m2 of irinotecan,
and a total of 3652 mg/m2 of fluorouracil). She tolerated the first nine rounds of FOLFIRONOX
well, but by October 2015, after her ninth round, she developed
thrombocytopenia, requiring suspension of FOLFIRINOX for two
weeks. Once her platelet count rose, she resumed with her tenth
round of FOLFIRINOX followed by another two week break and then
a final eleventh round of FOLFIRINOX. She maintained consistent
body weight throughout the FOLFIRINOX regimen, although she
did have nightly TPN, eating two small meals a day.
After eleven cycles of FOLFIRINOX, the mass had decreased to
2cm (Figure 2)/, and it was determined in December 2015 she was
a candidate for resection: a pancreaticoduodenectomy procedure
with superior mesenteric and portal vein reconstruction. Upon
exploration, her liver had the appearance of a “blue liver,” consistent
with sinusoidal congestion or obstruction but otherwise the liver was
normal size without any metastasis.
During the operation there was minor but persistent bleeding
throughout the case suggestive of mild portal hypertension, but at the
time it was believed the bleeding was related to the superior mesenteric
vein involvement and would be relieved by the reconstruction. The
total clamp time was 83 minutes, but portal flow was maintained
through the inferior mesenteric and splenic veins save for 18 minutes
of total exclusion. Upon completing the pancreaticoduodenectomy
and venous reconstruction with an inner jugular graft, there was no
palpable pressure gradient across the graft. She was transferred to the
surgical intensive care unit, intubated off pressors.
Starting the morning after surgery, she had a rapid rise in her
AST and ALT levels to the 3000s and 2000s respectively. Doppler
ultrasound was performed that showed patent left portal and hepatic
veins but low blood flow to both the hepatic artery and right posterior
portal vein. The patient became acidotic, anuric, and pressor
dependent. She was brought emergently to the operating room for
evaluation. Upon exploration, the vascular anastomosis was soft and
intact, and flow was confirmed by Doppler ultrasound. The hepatic
artery also demonstrated a palpable pulse, which was confirmed
by ultrasound. The liver looked and felt congested. She was made
comfort care by her family and succumbed to multisystem organ
failure that evening.
Figure 1
Figure 1
Pre-FOLIFIRINOX (11-15-2014) CT images showing the narrowing of the portal vein, encasement of the celiac axis and involvement of the SMV.
Literature Review
There are limited chemotherapy options for locally advanced
pancreatic cancer. The oldest regimen to treat pancreatic cancer is
fluorouracil. In1997 gemcitabine was introduced as an alternative to
fluorouracil after a randomized controlled trial with both metastatic
and locally advanced pancreatic cancer patients demonstrated that a
first line therapy with gemcitabine resulted in an improved survival of
1.2 months over fluorouracil [2]. Further advances in chemotherapy
treatment occurred in 2011 when the PRODIGE 4/ACCORD 11
randomized trials demonstrated that the median overall survival for
patients treated with FOLFIRINOX was 4.3 months longer than those
treated with gemcitabine [1]. Since then, FOLFIRINOX has become a
preferred chemotherapy treatment. A recent 2015 patient-level metaanalysis
of 13 FOLFIRINOX studies suggested an even longer median
overall survival of 24.2 months for FOLFIRINOX [3].
Today, FOLFIRINOX is frequently used in the neoadjuvant
setting to downsize borderline resectable patients because it improves
the overall survival rate and slows progression of the cancer [4]. The
standard recommended regimen for FOLFIRINOX includes 85 mg/
m2 of oxaliplatin, 400 mg/m2 of leucovorin, 180 mg/m2 of irinotecan,
and a total of 2800 mg/m2 of fluorouracil, all of which is administered
intravenously once every two weeks. Of course, each patient is
different and can tolerate varying levels of the individual drugs as well
as different number of cycles of the regimen.
The combination of chemotherapy drugs in FOLFIRINOX,
however, is not new to the oncology landscape. The combination is
very similar to colorectal cancer regimens that have been used for
years. Although FOLFIRINOX for pancreatic cancer in the literature
is reported to be “safe” with increased resection rates and better overall
survival [3-6], there is a sizable body of literature since 2004 from
colorectal cancer researchers, documenting the strong correlation
between oxaliplatin and sinusoidal obstruction syndrome [7-11]. In
2004, Rubbia-Brandt et al. [7] found that 78% (34 of 43) of patients
treated with oxaliplatin-based neoadjuvent chemotherapy developed
sinusoidal dilation. Furthermore, oxaliplatin was also associated with
other hepatic injuries including hepatocyte atrophy, perisinusoidal
fibrosis, and nodular regenerative hyperplasia [7]. Subsequent studies
after 2004 found anywhere from 10% to 61% of patients treated
with oxaliplatin also had sinusoidal dilatation [12-14]. Many of
these studies also found that there is some evidence that oxaliplatin
increased morbidity although not mortality [8,14,15]. In two of these
studies liver failure was a complication of surgical patients who
developed sinusoidal obstruction syndrome (SOS) presumably from
the oxaliplatin-based chemotherapy [15-16].
Although the pathogenesis of oxaliplatin related sinusoidal
obstructive syndrome is not fully understood, studies suggest it is
directed against the endothelial cells of the hepatic sinusoids, enlarging
the space of Disse [8,17-19]. It appears that oxaliplatin also affects the
platelets in the liver and that thrombocytopenia occurs at an earlier
stage for patients treated with oxaliplatin [18]. Unfortunately, there is
no clear biomarker for these changes in the hepatocytes, so the gold
standard for diagnosing SOS is still histopathology [19-23].
Additionally, FOLFIRINOX contains irinotecan, which is also
associated with liver toxicity. Several studies correlate irinotecan with
steatohepatitis [24], suggesting that higher dosages of FOLFIRINOX
can increase the risk of hepatic toxicity.
Marsh et al. [25] 2015 review of FOLFIRINOX highlights several
important unanswered questions about the use of FOLFIRINOX
for pancreatic cancer patients including the best management
practices and number of cycles, noting that the “optimal number of
treatment cycles is not well understood.” Marsh is also the first to
remind the pancreatic cancer community that sinusoidal obstruction
syndrome is associated with oxaliplatin. The dangerous unknown
is the appropriate dosing of FOLFIRINOX. A 2016 patient-level
meta-analysis of thirteen FOLFIRINOX studies only had a mean
cycle count of six cycles [3]. This meta-analysis demonstrates many
benefits of FOLFIRINOX, yet the safety of FOLFIRINOX at higher
doses is still unknown. No articles have been published analyzing the
consequences of higher cycle counts of FOLFIRINOX, specifically
patients receiving higher doses of oxaliplatin.
Figure 2
Figure 2
Post-FOLIFIRINOX (11-20-2015) CT images showing (a) a decreased narrowing of the portal vein and (b) a clear fat plane with the tumor regressing from the SMV.
Discussion
This case study highlights a potential caution when planning
complex pancreatic surgery that includes vascular reconstruction in
patients who have received an oxaliplatin-based regimen. Patients
who receive a higher number of cycles of oxaliplatin may be vulnerable
to the development of SOS. It is well recognized in the literature that
liver resection under these circumstances can result in liver injury
or failure because the liver is unable to appropriately regenerate,
or the body is unable to respond to rapid exacerbation in portal
hypertension from loss of parenchyma. Although the liver was not
resected in the current case, the clamp time required to reconstruct
the mesenteric system appears to have overwhelmed this fragile liver.
Resection where the hepatoduodenal ligament is clamped and blood
flow to hepatocytes is reduced in patients with SOS may exacerbate
both ischemic and reperfusion injuries, risking the development of
liver failure.
Although our experience is only a single case, the pancreatic
surgery community must be made aware of this potential issue.
New, similar cases should be reported so that an analysis of both
preoperative (dosing, number of cycles, time between last dose and
surgery) and operative (clamp time) factors can be conducted. This
analysis is requisite to guide decisions about neoadjuvant therapy,
timing of surgery, and resectability.
Conclusion
Oxaliplatin has been correlated with increased risk of sinusoidal obstruction syndrome for colorectal cancer patients. As neoadjuvent chemotherapy becomes the standard for locally advanced pancreatic cancer patients, more research is needed to understand the correlation between oxaliplatin and pancreatic cancer patients to reduce potential perioperative complications with particular attention paid to patients receiving higher cycle counts of FOLFIRINOX or other oxaliplatinbased treatments.
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