The prognosis of the large majority cancer types has gradually improved over the past
decades. Pancreatic cancer (PC) is one of the few exceptions where the 5-year survival
still lies under the 10% threshold. Surgery is the only treatment modality that can
contribute to long-term survival. However, only about 20% of the patients qualify for
surgery since PC often presents as spread disease at the time of diagnosis. Even after
curatively intended surgery the prognosis is still dismal, with a 5-year survival of
about 20%. Chemotherapy can reduce the risk for recurrence after surgery.
A factor that complicates surgery is the anatomical location of the pancreas. It overlies
the large abdominal vessels, which provide blood supply to the liver and the small bowel.
Approximately 25% of the patients present at diagnosis with what is labeled as borderline
(BR) or locally advanced pancreatic cancer (LAPC). BR and LAPC refer to different degree
of tumoral involvement of the large abdominal vessels. Previously, resection of tumors
with this type of vascular involvement has not been a treatment alternative, since the
postoperative complication rate has been unacceptably high and there has not been a
potent oncologic treatment to address potential micrometastatic spread. Therefore, the
survival of patients with BR/LAPC has for long been almost as short as the survival of
patients with spread PC.
The introduction of the potent combination chemotherapy FOLFIRINOX significantly improved
the survival of patients with BR/LAPC and metastatic PC compared to the previous standard
gemcitabine. Patients with BR/LAPC who could be resected after induction chemotherapy
with FOLFIRINOX had furthermore chance for long-term term survival compared to unresected
patients. Even other types of combination therapy, such as gemcitabine-nab-paclitaxel,
have shown to lead to long-tern survival of patients with BR/LAPC who could be resected
after initial chemotherapy.
Generally, the larger the tumor size the higher the risk for vascular invasion, lymph
node metastases and elevated CA19-9, all associated with worse prognosis. Neoadjuvant
chemotherapy contributes to decreased tumor size, lower probably for lymph node
metastases and lower CA19-9. In this way the risk for recurrence decreases while the
potential benefit of surgery increases. Theoretically, repeated cycles of chemotherapy
under longer period would have the possibility to destroy more cancer cells. In studies
it has been shown that the duration of chemotherapy is correlated with better histologic
tumor regression and chance for negative lymph nodes. On the contrary, it could also be
that longer treatment periods induce resistant cell clones which can reverse the previous
beneficial treatment effects and decondition the patients. Often there is a limit to what
the patient can tolerate in terms of side effects and general condition.
Since the outcome of technically advanced pancreatic surgery has been shown to correlate
with volume, a national level structure has been implemented in Sweden, limiting the
surgical treatment of BR/LAPC to two national centers with the intention to increase
patient safely and improve postoperative outcome. Regarding the length of preoperative
chemotherapy, two alternative regimens have been used by the two centers - either six
cycles of modified FOLFIRINOX or four cycles of gemcitabine-nab-paclitaxel. Previously
published data confirmed that long-term survival can be achieved by these treatment
setups. However, internationally it is more common to apply eight or more cycles of
FOLFIRINOX for BR/LAPC. In larger international multicenter studies, showing the efficacy
of FOLFIRINOX when used with palliative intent or as adjuvant treatment, the aimed number
of treatment cycles has been set to twelve. When gemcitabine-nab-paclitaxel has been
intended for the treatment of LAPC, six cycles have been administered.
Both FOLFIRINOX and gemcitabine-nab-paclitaxel are well established treatment
alternatives in the neoadjuvant setting for BR/LAPC, however, the most optimal treatment
duration is unknown. The purpose of this study is to determine the optimal duration of
neoadjuvant treatment for BR/LAPC, in an attempt to increase the number of patients who
can be resected, and increase the survival of the resected ones and the whole group of
patients with BR/LAPC.
The goal of this multicenter randomized controlled phase III trial is to compare two
durations of neoadjuvant chemotherapy (NAT) with mFOLFIRINOX or
gemcitabine-nab-paclitaxel (GnP) before attempt for surgical resection in patients with
borderline (BR) and locally advanced pancreatic cancer (LAPC). Patients with
histologically confirmed non-metastatic BR/LAPC evaluated to potentially tolerate any of
the treatment regimens and pancreatic surgery will be randomized to receive either
standard duration NAT with 6 cycles mFOLFIRINOX or 4 cycles GnP or prolonged duration NAT
with either 12 cycles mFOLFIRINOX or 6 cycles GnP before attempt for surgical resection,
provided there is no evidence of disease progression. The primary objective is to compare
the overall survival at 24 months after randomization of all treated patients and among
the resected patients with BR/LAPC. Furthermore, overall and progression-free survival in
the who group and among the resected patients will be compared after 60 months in
intention-to-treat and in the per protocol treated cohorts. Furthermore, survival will be
compared among patients with BR or LAPC separately and between the groups of BR and LAPC.