Recent therapeutic advances have almost doubled the survival of patients with metastatic pancreatic cancer, and the availability of highly active chemotherapy regimens is making personalized medicine a reality.
Wen Wee Ma, MBBS
Associate Professor of Oncology
Roswell Park Cancer Institute
Buffalo, Elm and Carlton Streets
Recent therapeutic advances have almost doubled the survival of patients with metastatic pancreatic cancer, and the availability of highly active chemotherapy regimens is making personalized medicine a reality. The role of chemoradiation following induction chemotherapy in locally advanced, unresectable pancreatic cancer was clarified by the LAP 07 study. A major development has been the identification of the group of patients with resectable disease who have a high risk of margin-positive resection (borderline resectable). The use of neoadjuvant therapy in this group has many potential advantages and is currently under active clinical investigation. Tools available for treating pancreatic cancer have certainly multiplied and improved over last few decades, but the long-term survival rate is still dismal; as such, novel treatments and approaches are still urgently needed, and palliative/supportive care is equally important to improve the lives of patients with pancreatic cancer.
Pancreatic cancer is the fourth leading cause of cancer deaths in the United States.1The survival for metastatic disease has doubled over the last 2 decades, though at the expense of increased adverse events (AEs), and the 2-year survival remains approximately 10%.2The advances over the last few years, albeit small compared with other cancers, have provided several more options for patients with pancreatic cancer.
Many anticancer drugs including molecularly targeted agents have been evaluated in randomized trials since the approval of gemcitabine in advanced pancreatic cancer. A major milestone was reported by Conroy et al in the PRODIGE4/ACCORD11 trial that randomized 342 patients with chemotherapynaïve metastatic pancreatic cancer to FOLFIRINOX or gemcitabine.2The FOLFIRINOX regimen consisted of oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2as a bolus followed by 2400 mg/m2as a 46-hour continuous infusion every 2 weeks. Pertinent eligibility criteria included ECOG performance status (PS) 0 or 1 and bilirubin less than or equal to the upper limit of normal range. Patients aged 76 years or older were excluded. The FOLFIRINOX arm achieved a superior median overall survival (OS) of 11.1 months versus 6.8 months in the gemcitabine arm (HR, 0.57;P<.001). The OS of the FOLFIRINOX group at 6, 12, and 18 months were 75.9%, 48.4%, and 18.6% respectively, compared with 57.6%, 20.6%, and 6.0% respectively in the gemcitabine group. The objective response rates were 31% versus 9.4% in the FOLFIRINOX and gemcitabine arms respectively.
The regimen is now a standard for metastatic disease in the first-line setting, though the higher frequency of toxicities such as neutropenia, febrile neutropenia, fatigue, and diarrhea have required dose modification for better quality of life (QoL). Despite the increased toxicity associated with FOLFIRINOX, a follow-up QoL analysis of the ACCORD11 trial showed that the FOLFIRINOX arm had improvement in global health status (GHS) by the European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire C30 method, and had longer time to definitive deterioration ≥20 points than the gemcitabine arm.3The domains that showed improvement included GHS, functioning (physical, cognitive, and social), fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation. A single-institution retrospective report of real-world experience showed that dose reduction occurred in >80% of patients during the first cycle: irinotecan was reduced/omitted in 80%, oxaliplatin in 28%, bolus fluorouracil in 45%, and infusional fluorouracil in 8%.4The analysis showed that comparable efficacy to the PRODIGE4trial was achieved with the ACCORD11 trial even with dose attenuation. In terms of health economics, an analysis by the Ontario health system in Canada showed that FOLFIRINOX was the most cost-effective option for quality life-year gain compared with gemcitabine/capecitabine, gemcitabine/erlotinib, and gemcitabine in patients with metastatic pancreatic cancer.5As such, this regimen is recommended as a first-line option for younger and fit patients with adequate hepatic and other organ reserves, and modification to the published regimen is generally used and accepted to avoid compromising the expected efficacy.6
Another milestone soon followed, with the positive results from the Metastatic Pancreatic Adenocarcinoma Trial (MPACT), that randomized 861 patients with metastatic pancreatic cancer to receive nabpaclitaxel plus gemcitabine or gemcitabine.7Nabpaclitaxel is an albumin-bound paclitaxel, which is advantageous in lieu of the Cremaphor formulation of paclitaxel and has significantly lower risk for infusion reactions, and neutropenia, while offering more rapid recovery of neuropathy upon halting the therapy.8
In an updated analysis, the median OS for the nabpaclitaxel/gemcitabine arm was 8.7 months versus 6.6 months (HR, 0.72; P <.001).9At 36 months, 4% of patients in the study arm were alive compared with none in the gemcitabine arm. The addition of nab-paclitaxel tripled the response rate, with 23% versus 7% (P <.001) in the study and control arms, respectively. The regimen was well tolerated, and the most common grade 3 and above AEs in the study arm were neutropenia, fatigue, and neuropathy. When compared with FOLFIRINOX, Conroy et al reported that the frequency of neutropenia, febrile neutropenia, diarrhea, and fatigue were lower for nab-paclitaxel/gemcitabine, although the risk for thrombocytopenia and neuropathy were higher for nab-paclitaxel/gemcitabine. The nab-paclitaxelrelated neuropathy improved from grade 3 or higher to grade 1 or lower in a median of 29 days upon discontinuation, which potentially allows re-introduction of nab-paclitaxel in a real-world scenario; whereas, neuropathy related to oxaliplatin may be typically prolonged, and a long recovery interval is needed before reintroduction of the therapy in patients treated with FOLFIRINOX.
The MPACT trial enrolled patients with Karnofsky performance-status score 70 or better which, when compared with the ACCORD11 trial that enrolled ECOG performance status 0 to 1, included patients with better ECOG PS 2. The ACCORD11 trial excluded patients age 76 years or older whereas the MPACT trial included patients up to ages 88 years, though the median age was comparable between both. The MPACT trial excluded patients with bilirubin level above the upper limit of normal (ULN) whereas the ACCORD11 trial included patients with higher bilirubin level (1.5 times ULN). Together with the difference in the toxicity profile between both regimens, these factors can help oncologists to personalize their recommendation for patients in the first-line metastatic pancreatic cancer setting.
The availability of two active regimens now offers meaningful options for patients who progress, or become intolerant to first-line treatment. Prior to the ACCORD11 trial, patients who failed first-line gemcitabinecontaining therapy received fluoropyrimidine-based regimens, typically those containing oxaliplatin.10Several retrospective studies showed that FOLFIRINOX was efficacious in second-line setting after failure of gemcitabine-based therapy, with an acceptable safety profile.11-13Conversely, patients who progressed on FOLFIRINOX in the first-line setting may receive gemcitabine alone or gemcitabinebased combination, provided they have good performance status in the second-line setting. The efficacy of nab-paclitaxel/gemcitabine in the second-line setting and beyond was reported in a single-institution restrospective study.14However, the appropriate sequencing of these regimens in first- and second-line settings to maximize survival has yet to be investigated clinically, and the decisions are currently based on patient’s performance status, organ reserves, and preferences. Several randomized trials specifically for the second-line setting and beyond seemed to be promising, including an on-going trial using ruxolitinib (JAK1/2 inhibitor; [NCT02117479, NCT02119663]) and another using nano-liposal irinotecan (MM398; NAPOLI trial)15that is under regulatory review.
The management of locally advanced unresectable pancreatic cancer has been similar to metastatic disease with certain extrapolations from that of metastatic disease. The main difference has been the use of chemoradiation in the locally advanced setting, which the role was investigated in several recently reported randomized trials. The LAP 07 trial investigated the use of chemoradiation after an initial systemic chemotherapy, and the results was reported at the ASCO Annual Meeting in 2013.16In this international phase III trial, 442 patients with locally advanced pancreatic cancer started treatment by receiving 4 months of systemic chemotherapy (gemcitabine or gemcitabine/erlotinib), and those who did not progress (269 patients) were then randomized to receive chemoradiation with capecitabine or to continue another 2 months of systemic chemotherapy. The planned interim analysis showed that the median OS achieved in the systemic chemotherapy and chemoradiation arms were 16.5 months versus 15.3 months (HR, 1.03; P = .83), concluding that chemoradiation was not superior to continuing systemic chemotherapy in patients who did not progress after an initial 4 months of systemic chemotherapy.
The role of upfront chemoradiation was investigated in two randomized trials. The ECOG 4201 trial randomized 74 patients with locally advanced pancreatic cancer to systemic gemcitabine therapy and chemoradiation with gemcitabine.17The trial was terminated early due to poor accrual though an intention-to-treat analysis showed a trend toward better survival in the chemoradiation arm of 11.1 months versus 9.2 months in the chemotherapy arm (P= .017). The 2000-01 FFCD/SFRO study randomized 119 patients to receive induction chemoradiation using fluorouracil and cisplatin or induction gemcitabine. Both groups then received maintenance gemcitabine until disease progression or toxicity.18The median OS was inferior in the chemoradiation group, with 8.6 months compared with 13 months in the chemotherapy group (P= .03), and patients in the chemoradiation arm experienced more grade 3 to 4 toxicities. As such, evidence so far has shown that upfront chemoradiation does not show a clear survival benefit; and, chemoradiation after induction chemotherapy is not superior to continuing systemic chemotherapy in patients who have disease control following induction chemotherapy. Chemoradiation should be considered in situations where local control is needed, including patients who develop local progression following induction chemotherapy, bleeding, poorly controlled pain, or local obstructive symptoms.19The availability of more active combination chemotherapy such as FOLFIRINOX and gemcitabine/nab-paclitaxel may also impact the effect of chemoradiation.
Surgical resection remains the only curative modality in pancreatic cancer, and postoperative adjuvant therapy had been shown to confer survival benefit.20Currently accepted standards for adjuvant therapy consist of systemic gemcitabine for 6 cycles (CONKO-001) or systemic gemcitabine with chemoradiation (RTOG 97-04).21,22Despite that, the recurrence rate remains unacceptably high, and the 5-year survival rate is ~20% for patients with resected disease.22,23
As such, neoadjuvant, or preoperative, therapy is increasingly used for patients with borderline resectable pancreatic cancer. Borderline resectable disease, in general, refers to localized tumors with high likelihood of margin-positive resection, though the definition varies between various working groups, and readers should refer to the guidelines by the National Comprehensive Cancer Network and Alliance for Clinical Trials in Oncology group for details.24,25
The theoretical advantages of neoadjuvant therapy include: downstaging of disease to improve surgical outcome, selection of patients with aggressive biology who might otherwise not benefit from surgery, and avoidance of therapy initiation delays due to postoperative complications.26The optimal neoadjuvant regimen(s) remains unclear though a number of approaches have been reported and many consist of multimodality approaches incorporating systemic chemotherapy and chemoradiation. The more active combination chemotherapy regimens in metastatic disease (FOLFIRINOX, gemcitabine/nab-paclitaxel) are widely incorporated in an effort to achieve maximal tumor shrinkage prior to surgery.27,28Currently, the choice of chemotherapy regimen and the incorporation of chemoradiation into a neoadjuvant approach is based on institutional preference given the lack of randomized trial data to support one over the other. Importantly, the impact of neoadjuvant therapy on survival compared with upfront pancreatectomy followed by adjuvant therapy remains to be determined.
Randomized trials are under way to investigate the question of whether or not neoadjuvant therapy will confer a survival benefit. The NEOPAC study is a phase III trial that plans to randomize 310 patients with resectable disease to upfront surgery followed by adjuvant gemcitabine for 6 months or neoadjuvant gemcitabine/oxaliplatin followed by surgery and continuation of the same chemotherapy thereafter.29Patients with tumor involvement of portal/superior mesenteric veins (>180°), abutment of major visceral arteries, or distant metastases are excluded. The study has completed enrollment and results have not been reported (NCT01521702). NEPAFOX is an ongoing randomized multicenter phase II/ III study that plans to enroll patients with resectable or borderline resectable pancreatic cancer (NCT02172976).30Eligible patients will be randomized to receive surgery followed by 6 cycles of gemcitabine adjuvant treatment (24 weeks) or 6 cycles of FOLFIRINOX neoadjuvant treatment (12 weeks) and surgery followed by 6 cycles FOLFIRINOX adjuvant treatment (12 weeks). The primary endpoint is OS at 24 months, and secondary endpoints include progression-free survival (PFS), perioperative morbidity and mortality, R0 resection rate, pathological complete remission, and prevalence of iron deficiency anemia.
Patients with pancreatic cancer are afflicted with many debilitating complications unique to this disease, and optimal palliation requires a multidisciplinary approach.24Biliary obstruction is common in pancreatic cancer and can lead to infection and fatigue. Prompt diagnosis, initiation of antibiotics and access to interventional GI endoscopists will help prevent treatment delays and avoid or shorten hospitalization. Cachexia and malnutrition (from the cancer and pancreas insufficiency) are significant in this disease, and pancreas enzyme supplementation and nutrition counseling are often needed. Patients with pancreatic head lesions may also suffer from varying degrees of gastric outlet obstruction and may benefit from promotility agents, and severe cases will require stenting or placement of PEG or feeding tubes. Pain and poor prognosis associated with this disease can often lead to depression and may adversely impact the patient’s functioning and social relationships. Comanagement by dedicated palliative care team and social worker/psychologist will significantly improve the patient’s quality of life.
Though outcomes for patients with pancreatic cancer seems to have improved at a glacial rate, the impact of recent therapeutic advances is significant. Patients with metastatic disease now have access to several active chemotherapy regimens, and their treatment path can be tailored according to the patient’s performance status and preference for efficacy versus impact of the toxicities on quality of life. Several promising therapies are currently undergoing clinical evaluation including an irinotecannano-liposomal formulation that is under regulatory review in the United States.15The role of chemoradiation following induction chemotherapy in locally advanced pancreatic cancer was clarified in the LAP 07 trial. The identification and pre-operative use of highly active chemotherapy regimens with/without chemoradiation in patients with borderline resectable disease has spared patients with micrometastatic or aggressive disease the morbidity of surgery and chemoradiation, though the impact of neoadjuvant therapy on survival is just starting to be evaluated in randomized trials.