What is the role of chemotherapy in the treatment of pancreatic cancer?

Updated: Mar 07, 2019
  • Author: Tomislav Dragovich, MD, PhD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Answer

In patients with metastatic disease, the combination of gemcitabine and erlotinib has led to a significantly higher median survival and 1-year survival than has the use of gemcitabine alone. [65] This has led to US Food and Drug Administration (FDA) approval of erlotinib for use in combination with gemcitabine in advanced, unresectable pancreatic cancer. The recommendation that this combination should now constitute standard therapy for metastatic or unresectable local disease is premature and problematic. The improvements in response rates seen, although significant, were not great and were obtained with no small amount of patient toxicity.

The combination should be used with considerable care, and the use of gemcitabine alone should still be considered as appropriate therapy for patients with metastatic disease. Gemcitabine alone should also be considered as appropriate therapy for patients with unresectable disease; there is no meaningful significant benefit obtained to adding radiotherapy in this situation. Such an addition simply increases toxicity. [66]

The combination of gemcitabine and capecitabine in advanced pancreatic cancer has been investigated by several groups. A randomized, multicenter, phase III clinical trial in 319 patients by the Central European Cooperative Oncology Group found that clinical response or quality of life was no better with the combination than with gemcitabine alone. [67]

This finding contrasts with the results of the phase III United Kingdom National Cancer Research Institute GEMCAP trial, an open-label, randomized study of gemcitabine alone versus gemcitabine combined with capecitabine in 533 patients. Compared with gemcitabine alone, treatment with the gemcitabine-capecitabine combination produced a significantly higher objective response rate (12.4% vs 19.1%, respectively) and progression-free survival and was associated with a trend toward improved overall survival.

In addition, a meta-analysis of two additional studies involving 935 patients showed a significant survival benefit in favor of the gemcitabine-capecitabine combination. Accordingly, these researchers recommended considering gemcitabine-capecitabine as one of the standard first-line options in locally advanced and metastatic pancreatic cancer. [68]

Results of the phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) show that the addition of nanoparticle albumin-bound (nab)-paclitaxel to gemcitabine significantly improves overall survival in treatment-naive patients with metastatic pancreatic cancer compared with gemcitabine alone. [4] Overall survival was approximately 2 months longer in patients treated with combination therapy (8.5 vs 6.7 months). One-year and 2-year survival rates were also higher in the combination therapy group (35% vs 22% and 9% vs 4%, respectively).

The results of a European phase III trial (ACCORD/PRODIGE) that compared the nongemcitabine regimen FOLFIRINOX (leucovorin plus 5-fluorouracil [LV5-FU] plus oxaliplatin plus irinotecan) to gemcitabine in patients with metastatic pancreatic cancer were reported in May 2011. [3] The median survival on the FOLFIRINOX arm was 11.1 months, versus 6.8 months on the gemcitabine arm. Of note, the incidence of adverse events and febrile neutropenia was significantly higher on the FOLFIRINOX arm, despite the fact that only patients with ECOG performance status of 0-1 were included in this trial.

It remains to be seen how well this regimen will be integrated into the care of patients with pancreatic cancer and good performance status worldwide. The NCCN recommends FOLFIRINOX as a preferred first-line treatment for patients with metastatic or locally advanced unresectable disease with good performance status. [2]

The phase III PRODIGE 24/CCTG PA.6 trial demonstrated that modified FOLFIRINOX (mFOLFIRINOX) also provides significantly longer survival than gemcitabine in patients with pancreatic ductal adenocarcinomas who have undergone R0 or R1 resection. [8]  This study is potentially practice changing. [9]

At a median follow-up of 33.6 months, the median disease-free survival in PRODIGE 24/CCTG PA.6 was 21.6 months in the mFOLFIRINOX group versus 12.8 months in the gemcitabine group; median overall survival was 54.4 vs 35.0 months, respectively. Time until the appearance of metastases was a median of 30.4 months with mFOLFIRINOX versus 17.0 months with gemcitabine). Overall, more patients experienced severe side effects (mainly hematologic) in the mFOLFIRINOX group than in the gemcitabine group (76% vs 53%), but the side effects were manageable. [8]

Paclitaxel protein bound was approved by the FDA in September 2013 for metastatic pancreatic cancer. [5] The treatment regimen includes paclitaxel protein bound 125 mg/m2 plus gemcitabine 1000 mg/m2 IV over 30-40 min on days 1, 8, and 15 of each 28-day cycle. The NCCN also recommends the combination as a preferred first-line treatment for patients with metastatic or locally advanced unresectable disease with good performance status. [2] This regimen may be considered instead of FOLFIRINOX in patients unlikely to tolerate toxicities associated with FOLIRINOX. [4]

For patients with metastatic or locally advanced unresectable disease who have poor performance status, the NCCN recommends gemcitabine monotherapy. [2]

Capecitabine alone or capecitabine plus erlotinib may provide second-line therapy benefit in patient's refractory to gemcitabine. [6] There is no advantage to giving gemcitabine in any dose or time of infusion other than 1000 mg/m² over 30 minutes intravenously.

Combinations of gemcitabine with cisplatin, oxaliplatin, irinotecan, or docetaxel have in phase III trials not shown superior benefit over gemcitabine alone.

A new encapsulated form of irinotecan in a long-circulating nanoliposome (Onivyde) was approved by the FDA in October 2015 for patients with advanced pancreatic cancer who have been previously treatment with gemcitabine-based chemotherapy. Irinotecan liposomal is indicated for use in combination with fluorouracil and leucovorin.

Approval of irinotecan liposomal was based on a 3-arm, randomized, open-label study (NAPOLI-1 trial), which was conducted in 417 patients with metastatic pancreatic adenocarcinoma whose cancer had progressed after treatment with gemcitabine alone or in combination with other agents. The regimen used in the trial was a combination of liposomal irinotecan (70 mg/m² IV infused over 90 min [dosage for free-base irinotecan]) administered prior to fluorouracil (2400 mg/m² infused over 46 h) and racemic leucovorin (400 mg/m² infused over 30 min) every 2 weeks.

Patients treated with this combination of liposomal irinotecan plus fluorouracil/leucovorin lived for an average of 6.1 months, compared with 4.2 months for those treated with only fluorouracil/leucovorin or 4.2 months for patients treated with irinotecan liposomal alone. Improvement in progression-free survival was also observed, to a median of 3.1 months with irinotecan liposomal plus fluorouracil/leucovorin compared with 1.5 months for fluorouracil/leucovorin alone. [69]


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