A Pilot Study of Pre- and Post-surgery Chemotherapy With mFOLFIRINOX in Localized, Resectable Pancreatic Adenocarcinoma
A Pilot Study of Pre- and Post-surgery Chemotherapy With mFOLFIRINOX in Localized, Resectable Pancreatic Adenocarcinoma
The purpose of the study is to demonstrate that it is possible to administer chemotherapy
 prior to and following surgery for pancreatic cancer which is considered operable. The
 chemotherapy chosen is that which has been shown to be the most effective in treating
 metastatic disease, and the goal is both to investigate whether this is tolerable and also to
 investigate the efficacy of this approach in terms of disease response and survival.
Pancreatic ductal adenocarcinoma is a highly lethal disease. It is estimated that in 2010
 there were approximately 43,140 new cases in the United States and 36,800 deaths which ranks
 fourth among cancer related deaths . At diagnosis, roughly 17,000 of the initial 43,000
 patients have disease which appears to be localized to the pancreatic bed, but unfortunately,
 only a minority of these patients (15-20%) are immediately operable (on imaging studies their
 disease appears to be both localized to the pancreas and technically resectable with clear
 margins, and at surgery no unexpected findings preclude an R0 resection ). It should be noted
 that of those patients deemed immediately operable on clinical grounds, between 20 and 57%
 are found to have inoperable disease on exploration depending on the series and on the extent
 and nature of preoperative staging. The majority of patients have locally advanced,
 borderline resectable or unresectable disease owing to involvement of critical structures,
 most particularly sentinel blood vessels such as the SMA, celiac axis, hepatic artery, SMV,
 or portal vein. Furthermore, despite recent advances in systemic therapy, even those
 fortunate few able to undergo immediate surgery remain largely incurable, with a five year
 survival of slightly less than 20%.

 The current standard of care for adjuvant therapy in resectable pancreatic cancer is based on
 the CONKO-001 study which randomized patients to 6 cycles of postoperative adjuvant therapy
 with gemcitabine versus observation alone. Results favored adjuvant gemcitabine in both
 disease free survival (13.4 vs 6.9 months, p<0.001) and overall survival (24.2 months vs 20.5
 months p=0.02) strongly supporting the use of adjuvant gemcitabine in the setting of both R0
 and R1 resections. An RTOG study - 97-04 - concluded that gemcitabine was probably superior
 to 5FU when used pre and postoperatively in combination with 5FU/RT, with a HR of 0.82. The
 role of radiation therapy in this setting remains controversial, with studies such as the
 GITSG trial (pro) and ESPAC 1 (con) criticized either for questionable design, outdated
 chemotherapy or unconventional radiation therapy. Current studies in progress examining
 postoperative therapy include RTOG 0848 (phase III looking at adjuvant gemcitabine versus
 gemcitabine plus erlotinib plus/minus chemo/RT using fluorouracil), ACOSOG Z5041 evaluating
 gemcitabine plus erlotinib in the pre and postoperative setting and ESPAC 4 evaluating
 gemcitabine versus gemcitabine plus capecitabine.

 Many studies have explored the use of neoadjuvant therapy in initially resectable, borderline
 resectable and unresectable disease. The majority of these have been single arm, single
 institution phase I/II studies, and results have been mixed. Potential benefits of a
 neoadjuvant approach include: downstaging of disease with an increased percentage of margin
 negative and lymph node negative resections; no delay in systemic therapy aimed at
 eradicating micrometastatic disease; the detection of biologically aggressive tumors, as
 evidenced by early progression/metastases during this phase of therapy, thereby avoiding
 inappropriate surgery; and the greater likelihood of completing all intended therapy as
 opposed to postoperative treatment, where fully 22 - 35% of patients do not complete their
 intended program.

 A comprehensive meta-analysis and systematic review of neoadjuvant therapy in both resectable
 and unresectable pancreatic cancer has recently been published. The conclusion reached in
 resectable patients was that resection frequency and survival following neoadjuvant therapy
 was similar to that in patients undergoing primary resection followed by adjuvant therapy. In
 patients with initially unresectable disease, fully one third had resectable tumors following
 neoadjuvant therapy with survival comparable to initially resectable patients. In aggregate,
 these observations indicate that a neoadjuvant approach is feasible and effective, and that
 this sequence does not compromise resectability or survival, even in those patients with the
 best prognosis.

 With respect to specific studies in resectable disease, investigators at MD Anderson Cancer
 Center have published their most recent results. In their first study, 86 patients with
 resectable disease in the head of the pancreas received radiation therapy (30 Gy in 10
 fractions over 2 weeks) plus 7 weekly infusions of gemcitabine at 400 mg/m2/week. 85% of
 these patients were taken to surgery and 74% were able to undergo the intended
 pancreaticoduodenectomy. Median survival for patients whose disease was resected was 34
 months, but it was only 7 months for those whose disease could not be resected. In a second
 study of patients with resectable adenocarcinoma of the pancreatic head, 90 patients were
 enrolled with the goal of administering chemotherapy alone for eight weeks, using gemcitabine
 and cisplatin, followed by combined low dose gemcitabine and radiation therapy (30 Gy in 10
 fractions). Ultimately, 79 (88%) patients completed the full course of preoperative therapy
 and 62 of these (78%) patients were taken to surgery. 52 (66%) had their disease resected
 with a median survival of 31 months for those who had surgery, versus 10.5 months for those
 who did not. They concluded that initial combination chemotherapy with gemcitabine and
 cisplatin followed by chemotherapy/RT did not improve on the results achieved with
 chemotherapy/RT alone. This result is perhaps not surprising as gemcitabine, both alone and
 in doublet combinations, has simply not been active enough to materially impact on the
 outcome of this disease. Interestingly, the longer preoperative interval did not result in
 local tumor progression.

 These findings are similar to those of other major centers reporting studies of neoadjuvant
 gemcitabine based chemoradiation for potentially resectable disease, and suggest that this is
 a valid strategy for further study in this setting.

 Recently, investigators in Europe reported their results with a novel combination of
 docetaxel 30 mg/m2 weekly and RT of 45 Gy in 34 patients with resectable disease. 32% had
 progression, 59% stable disease and 9% partial remission. 50% of the original cohort had
 pancreaticoduodenectomy with 100% R0 resection and a median survival of 32 months. The
 numbers are small and the overall resection rate disappointingly low, but the R0 resection
 rate and median survival for those resected is equivalent to patients receiving gemcitabine
 based regimens.

 In locally advanced, unresectable disease, results have recently been reported from Austria
 with neoadjuvant gemcitabine/oxaliplatin without RT (39% of patients undergoing resection of
 disease with 69% R0 and 22 months median survival), Italy with neoadjuvant PEFG/PEXG
 (cisplatin, epirubicin, 5-fluorouracil (F)/capecitabine (X), gemcitabine) or PDXG (docetaxel
 substituting for epirubicin) followed by RT plus X, F or G (14% resected with median survival
 16.2 months)and Japan with neoadjuvant gemcitabine 1000 mg/m2/wk and RT 50 Gy in T3 disease
 followed by postoperative 5FU liver perfusion (82% of patients with disease resected, 43% 5
 year survival). In each of these studies, there is a mixture of borderline resectable and
 unresectable disease with the result that the interpretation of outcomes is problematic.
 However, it is clear that a neoadjuvant approach is feasible and active.

 It is clear from an examination of the NCI CTEP database that the neoadjuvant approach has
 been widely embraced for future study. More than 40 active protocols are listed, including
 the following select few: a UVA study of hypofractionated RT plus chronomodulated
 capecitabine in resectable and borderline resectable disease; a UT Southwestern phase I study
 of SBRT or SBRT plus gemcitabine; an Emory phase I study of FOLFIRINOX and SBRT; a Fred
 Hutchinson study of GTX and oxaliplatin with IMRT and adjuvant gemcitabine; a UF phase II
 study of risk adapted gemcitabine plus abraxane; a European randomized phase II study of
 gemcitabine plus oxaliplatin pre and gemcitabine postoperatively versus gemcitabine
 postoperatively only; a Memorial Sloan Kettering phase II study of gemcitabine plus
 oxaliplatin preoperatively plus gemcitabine postoperatively; and an ACOSOG study of
 gemcitabine plus erlotinib pre and postoperatively.

 Looking to the future there have been a number of recent innovations in chemotherapy. In an
 ongoing effort to discover non-gemcitabine based chemotherapy for those who have progressed
 on gemcitabine, and also a new regimen with more efficacy than those currently used in
 patients with pancreatic cancer, the combination of 5FU, leucovorin, oxaliplatin and
 irinotecan has been tested. This combination was initially studied in colorectal cancer, in a
 regimen known as FOLFOXIRI. It was established that this combination was both tolerable and
 effective in this setting. Subsequently, the regimen was modified slightly to the current
 FOLFIRINOX format (oxaliplatin 85mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 , 5FU 400
 mg/m2 on day 1, then 5FU 2400 mg/m2 as a 46 hour continuous infusion) and tested in a phase
 II study in pancreatic cancer. 47 chemotherapy-naïve patients with metastatic disease were
 enrolled and 46 were treated. Confirmed response rate was 26% with 4% complete responses.
 Median time to progression was 8.2 months and median overall survival was 10.2 months. Grade
 3/4 toxicities included neutropenia (52%), nausea (20%), vomiting (17%), diarrhea (15%), and
 neuropathy (15%). No toxic death occurred. FOLFIRINOX was then tested after failure of
 previous gemcitabine therapy in metastatic disease and was deemed to be promising. 13
 patients were treated, with 9 evaluable for response - 6 had stable disease with a mean time
 to progression of 6.6 months, and 3 progressed.

 As a consequence of the previously mentioned phase II study in chemo-naïve patients, a
 randomized phase II/phase III study comparing gemcitabine (G) to FOLFIRINOX (F) as first line
 treatment of metastatic pancreatic cancer was conducted. This study was terminated
 prematurely by the study IDMC as it was determined that additional patient accrual would not
 add to the statistical power of the study. 342 patients were accrued with roughly one third
 of the primary disease involving the head of the pancreas. Overall objective response rate
 was 32% for F versus 9.4% for G. PFS was 6.4 months versus 3.4 months and overall survival
 11.1 months versus 6.8 months, all in favor of F.

 The overall survival rate of 11.1 months is the best result achieved thus far in a randomized
 phase III study of chemotherapy in metastatic pancreatic cancer. Notable toxicities of at
 least grade III/IV, which were all worse with F, were neutropenia (45.7 vs 18.7%), febrile
 neutropenia (5.4 vs 0.6%), fatigue (23.7 vs 14.2%), vomiting (14.5 vs 4.7%) and diarrhea
 (12.7 vs 1.2%). These results indicate that this is a notably active regimen with an
 encouraging response rate. However, the potential toxicities are significant, and it is a
 regimen that should be offered only to patients with ECOG 0-1 performance status and
 excellent supportive care. In this regard, in an attempt to ameliorate these toxicities,
 modifications to the published regimen have already been proposed by the French group and
 others. In their forthcoming study of FOLFIRINOX in the adjuvant setting, the French will
 omit the bolus of 5FU which contributes significantly to the myelosuppression but which is
 thought to have minimal impact on the therapeutic efficacy. In addition, most physicians now
 incorporate the routine use of neulasta with each treatment cycle. This study will similarly
 incorporate these modifications and the regimen will be named mFOLFIRINOX.

 Thus, in the context of perioperative therapy, we have identified a regimen - FOLFIRINOX -
 with the best results to date in the treatment of metastatic disease and by inference,
 promise of improved outcome in those patients with resectable disease. If successful, this
 has the potential to improve DFS and overall survival (until now no better than 15-20% at 5
 years) in these patients, and may establish a new paradigm for future studies.
Inclusion Criteria:

 -  Histologic or cytologic diagnosis of adenocarcinoma of the pancreas.

 -  Resectable primary tumor of the head, body or tail of the pancreas defined as a
 visible mass in the pancreas and:

 -  No extrapancreatic disease

 -  A patent superior mesenteric (SMV)- portal vein (PV) confluence (assuming the
 technical ability to resect and reconstruct this venous confluence if needed)

 -  A definable tissue plane between the tumor and regional arterial structures including
 the celiac axis, common hepatic artery, and SMA.

 -  Confirmation of resectability by surgical oncology consultation.

 -  Presentation at a multidisciplinary conference at either University of Chicago or
 NorthShore University

 -  No previous therapy for pancreatic cancer

 -  Short removable metal stents rather than plastic stents are preferred but not required
 for palliation of initial obstructive jaundice

 -  Karnofsky performance status 80 or better

 -  Age > 21 years

 -  No currently active second malignancy

 -  No CVA within 6 months, no MI within 6 months

 -  The effects of mFOLFIRINOX on the developing human fetus are unknown. For this reason
 and because chemotherapy agents as well as other therapeutic agents used in this trial
 are known to be teratogenic, women of child-bearing potential and men must agree to
 use adequate contraception (hormonal or barrier method of birth control; abstinence)
 prior to study entry and for the duration of study participation. Should a woman
 become pregnant or suspect she is pregnant while she or her partner is participating
 in this study, she should inform her treating physician immediately.

 -  Negative pregnancy test in females of reproductive age

 -  Life expectancy of greater than 3 months.

 -  Anticoagulation is permitted but patients may only be on lovenox for this purpose.

 -  Patients must have normal organ and marrow function as defined below:

 -  absolute neutrophil count >1,500/mcL

 -  platelets >100,000/mcL

 -  total bilirubin <1.5X upper limits of normal

 -  AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal

 -  creatinine within normal institutional limits OR

 -  creatinine clearance >60 mL/min/ per Cockcroft-Gault equation for patients with
 creatinine levels above institutional normal.

 -  Ability to understand and the willingness to sign a written informed consent document.

 Exclusion Criteria:

 -  Patients who have had previous chemotherapy or radiotherapy for pancreatic
 adenocarcinoma prior to entering the study.

 -  Pathologic subtypes other than pure adenocarcinoma; acinar cell carcinoma, squamous
 cell carcinoma, spindle cell carcinoma, neuroendocrine cancer, and mixed types are not
 eligible.

 -  Patients who are receiving any investigational agents.

 -  Patients with borderline resectable, locally advanced or metastatic disease.

 -  History of allergic reactions attributed to 5FU, leucovorin, irinotecan or oxaliplatin
 or to compounds of similar chemical or biologic composition.

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, active liver disease including viral or non-viral hepatitis and cirrhosis,
 chronic diarrhea or inflammatory disease of the colon or rectum, or psychiatric
 illness/social situations that would limit compliance with study requirements.

 -  Pregnant women are excluded from this study. mFOLFIRINOX is a regimen containing more
 than one chemotherapy agent with the potential for teratogenic or abortifacient
 effects. Because there is an unknown but potential risk for adverse events in nursing
 infants secondary to treatment of the mother with FOLFIRINOX, breastfeeding should be
 discontinued if the mother is treated with these agents. These potential risks may
 also apply to other agents used in this study.

 -  HIV-positive patients on combination antiretroviral therapy are ineligible because of
 the potential for pharmacokinetic interactions with mFOLFIRINOX. In addition, these
 patients are at increased risk of lethal infections when treated with
 marrow-suppressive therapy. Appropriate studies will be undertaken in patients
 receiving combination antiretroviral therapy when indicated.

 -  Currently active second malignancy other than non-melanoma skin cancer or carcinoma
 in-situ of the cervix. Patients are not considered to have a "currently active"
 malignancy if they have completed therapy and have no evidence of recurrence for at
 least 5 years.

 -  Pre-existing neuropathy greater than grade 1.

 -  Anticoagulants other than low molecular weight heparin.