Patients with pancreatic cancer carry a very poor prognosis. Due to a lack of screening tools and vague presenting symptoms, approximately 40 percent of patients have metastatic disease at the time of diagnosis. Common metastatic sites include the liver, abdominal cavity, and lung. Unfortunately, when metastatic disease is identified, systemic treatment is palliative in nature, so the treatment benefits and side effects associated with therapies need to be clearly explained to patients and their families.
Treatments for metastatic pancreatic cancer have evolved over the last few years. Gemcitabine was approved by the United States Food and Drug Administration for pancreatic cancer in 1996 based on its improvement of quality of life. More than a decade passed before other drugs became available for treatment, including the epidermal growth factor receptor (EGFR) inhibitor erlotinib, aggressive chemotherapy with FOLFIRINOX (5FU, leucovorin, oxaliplatin, irinotecan), and the most recent addition of nab-paclitaxel to the arsenal of treatment options.
While targeted therapy has become mainstream in patients with various hematological and solid malignancies, only erlotinib has yielded modest clinical benefit in patients with pancreatic cancer. Based on a large randomized phase III study, patients with metastatic pancreatic cancer were randomly assigned to receive gemcitabine alone or gemcitabine plus erlotinib. Median overall survival was 6.4 months in the combination arm, compared with 6.0 months in the gemcitabine-alone arm. Erlotinib was approved by the FDA in 2005 to be given in combination with gemcitabine for pancreatic cancer; however, it has not been largely adopted by the oncology community due to its marginal benefit.
To date, there is no conclusive evidence supporting any specific biomarkers that can predict which patient with pancreatic cancer will benefit from EGFR inhibition. Furthermore, despite promising preclinical evaluation in pancreatic tumor animal models, multiple targeted therapies (Hedgehog inhibitor, Notch inhibitor, MEK inhibitors) have failed in the clinical setting and again proven that we underestimate the complexity of this cancer.
Front-Line Therapy FOLFIRINOX
The aggressive chemotherapy regimen of FOLFIRINOX has provided an impressive survival benefit in the front-line setting. A large randomized phase III study has reported a median survival of 11.1 months in patients receiving FOLFIRINOX compared with 6.8 months in patients receiving gemcitabine alone. A higher progression-free survival and response rate were also observed in patients receiving FOLFIRINOX. FOLFIRINOX is associated with moderate toxicities including neutropenia, fatigue, and diarrhea, among others.
In light of the impressive survival benefit but moderate toxicity profile, I carefully select patients with a good performance status (PS) to receive this regimen. Most patients with a PS of 0 or 1 are interested in trying this regimen, so monitoring side effects and maximizing supportive care measures are the key to success for these patients. I commonly don't use FOLFIRINOX at full dose in patients older than 70 years of age. Additionally, I routinely check patients' UGT 1A1 status, and if UGT 1A1 reveals a homogenous 7/7 genotype, one level of dose reduction of irinotecan is my common practice. Most patients on FOLFIRINOX experience a dose reduction and treatment delay at some point during their treatment due to side effects.
For patients who are not candidates for aggressive FOLFIRINOX therapy, a gemcitabine-based regimen is clearly an option. In the past, despite the lack of level 1 evidence for survival benefit, I have used gemcitabine-based doublet chemotherapies such as gemcitabine/oxaliplatin or gemcitabine/cisplatin.
More recently, nab-paclitaxel/gemcitabine has emerged as a viable option for patients with metastatic pancreatic cancer. Dr. Dan Von Hoff has led a phase III multicenter international trial comparing nab-paclitaxel plus gemcitabine with gemcitabine alone as the front-line therapy for patients with metastatic pancreatic cancer. The overall survival was observed to be superior in patients receiving nab-paclitaxel/gemcitabine (8.5 vs. 6.7 months; HR 0.72; p=0.000015). The one-year and two-year survival rates were also better in the combination arm (35% vs. 22%, p=0.0002; 9% vs. 4%, p=0.021). At present, nab-paclitaxel is pending FDA approval for treatment of pancreatic cancer.
Although it is risky to cross-compare survival data between trials, the similar survival reported in the gemcitabine arm in both the FOLFIRINOX and nab-paclitaxel trial encourages me to continue to use FOLFIRINOX as my preferred treatment choice for patients who are candidates for the aggressive regimen.
Nab-paclitaxel plus gemcitabine becomes a viable option in patients with metastatic pancreatic cancer who are not candidates for FOLFIRINOX. Based on an early phase I/II study of nab-paclitaxel/gemcitabine in pancreatic cancer, SPARC levels in tumors have been associated with a favorable clinical outcome toward nab-paclitaxel/gemcitabine, so I am hoping to hear more about molecular correlates such as SPAR levels in the abovementioned phase III study.
For patients who achieve stable disease after six months of systemic therapy, there are two schools of thought for what should happen next. In most studies to date, the treatment course for metastatic pancreatic cancer is about six months, with patients being closely monitored after completing treatment. In clinical practice, though, while some patients are simply monitored without therapy until they develop disease progression, others are offered some type of lighter therapy as maintenance therapy.
In my practice, I commonly offer patients some type of maintenance therapy. For patients who have been on FOLFIRINOX for six months, simply 5FU or FOLFIRI are reasonable options for maintenance therapy. Patients who receive gemcitabine or gemcitabine-based regimens may be able to continue with the same regimen beyond six months.
Despite the aggressive nature of pancreatic cancer, about 40 to 50 percent of patients who progress on front-line regimens are candidates for second-line therapy. Naturally, patients who progressed on FOLFIRINOX can proceed with gemcitabine alone or gemcitabine-based regimens, and alternatively, patients who progressed on gemcitabine-based regimens should receive OFF (5FU and oxaliplatin administered weekly) or 5FU as a single agent.
In my practice, patients are reluctant to engage in weekly visits and therapy so they are treated with FOLFOX (5FU and oxaliplatin administered every two weeks) instead.
Patients who progress on second-line therapies may still be candidates for further treatment. I commonly screen these patients for phase I clinical trials, and although there have been some interesting studies done for refractory patients, no regimen has yet emerged that is beneficial for these patients.
Symptom management is crucial when treating patients with pancreatic cancer. Symptoms common to this patient population include pain control, anorexia, fatigue, and malabsorption. Working with palliative care physicians is particularly helpful in addressing symptoms. Additionally, biliary obstruction or gastric outlet obstruction are common problems, and these can be largely controlled by deployment of a biliary or enteric stent.
In patients with malabsorption symptoms whose most common complaints include frequent, foul-smelling, floating stools, pancreatic enzyme replacements should be considered with each meal and snack. A nutrition consult is extremely helpful for this patient population. I often encourage patients and their families to visit the Pancreatic Cancer Action Network (PANCAN) website for additional information (pancan.org).
Although 90 percent of pancreatic cancer is sporadic, about five to 10 percent of cases are observed in familial clusters. BRCA mutations in pancreatic cancer have gained the national spotlight recently with reports of pancreatic tumors bearing BRCA mutations being sensitive to PARP inhibitors. Although it is still premature to conclude the true benefit of PARP inhibitors in this patient population, I highly recommend that pancreatic cancer patients with BRCA mutations participate in clinical trials studying combination regimens of PARP inhibitors and platinum compounds.
In contrast to the declining death rate of most tumor types in the United States, the death rate of pancreatic cancer is rising. It is predicted that pancreatic cancer will become the second leading cause of cancer-related death in the U.S. by 2020. Although FOLFIRINOX and nab-paclitaxel/gemcitabine have improved overall survival rates compared to gemcitabine alone in the metastatic setting, successful development of novel and effective agents falls far behind what has been accomplished for other tumor types.
The most effective steps we can take as medical oncologists to help improve pancreatic cancer clinical outcomes is to encourage patients with pancreatic cancer to participate in hypothesis-driven clinical trials.
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