Daniel D. Von Hoff, MD
The results are from the phase III Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), which found that nab-paclitaxel added to gemcitabine significantly improved overall survival (OS), the primary efficacy endpoint, as well as the secondary endpoints of progression-free survival (PFS) and response rate.
“This large, randomized, international phase III study showed that nab-paclitaxel plus gemcitabine led to a significant improvement in survival at all time points,” Daniel D. Von Hoff, MD, distinguished professor and physician-in-chief at the Virginia G. Piper Cancer Center at Scottsdale Healthcare/Translational Genomics Research Institute, and colleagues write.
The team randomized 861 patients to receive nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 days 1, 8, and 15 every 4 weeks or gemcitabine alone 1000 mg/m2 weekly for 7 weeks, and afterwards on days 1, 8, and 15 every 4 weeks in the first-line setting. Study participants had a Karnofsky performance-status score ≥70 and had not previously received chemotherapy for metastatic disease.
On the basis of the trial’s results, the FDA recently approved the nab-paclitaxel/gemcitabine combination for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas. Pancreatic cancer is the fourth leading cause of cancer-related mortality in Europe and the United States, the authors pointed out. Gemcitabine has long been the standard first-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer. The 5-year survival rate in patients with metastatic disease is 2%. Patients receiving gemcitabine have been found to have 1-year survival rates of 17% to 23%. The present study was prompted by findings from a phase I-II trial of nab-paclitaxel combined with gemcitabine that demonstrated promising efficacy and a manageable safety profile in previously untreated patients with metastatic pancreatic adenocarcinoma.
In the present study, the median OS was 8.5 months for the nab-paclitaxel-gemcitabine group and 6.7 months for the gemcitabine monotherapy. The 1-year survival rates were 35% and 22% in the two groups, respectively, whereas the 2-year survival rates were 9% and 4%.
The nab-paclitaxel-gemcitabine cohort had a median PFS of 5.5 months versus 3.7 months for the gemcitabine monotherapy cohort. The response rate determined by independent review was significantly higher with nab-paclitaxel plus gemcitabine than with solo gemcitabine. Combination therapy was superior for most prespecified subgroups.
The median duration of treatment was 3.9 months for combination therapy and 2.8 months for treatment with gemcitabine alone.
The overall safety profile for the two treatment regimens was in line with that cited in earlier reports. The rate of serious life-threatening events was similar with the two regimens, and adverse events were usually grade 3 or lower and resolved without specific treatment.
Peripheral neuropathy, however, occurred more often in patients who received combination therapy but generally rapidly resolved when nab-paclitaxel was withdrawn temporarily after which the dosage was decreased and treatment resumed.
The investigators point out that the study was conducted at academic and community centers in North America, Europe, and Australia. Additional strengths included the use of randomization and the large sample, which produced similar treatment groups.
They added that a shortcoming of their study was that they did not measure quality of life.
Nurse Perspective on MPACT Study
John Theurer Cancer Center
The results of the MPACT study are very exciting to any oncology nurse. Those of us of a certain age remember when essentially all we had to offer was fluorouracil (5FU) or palliative care.
Gemcitabine was approved in 1996 as first-line treatment for patients with locally advanced or metastatic adenocarcinoma of the pancreas for patients previously treated with 5FU. Gemcitabine not only increased overall survival (OS) but improved quality of life, and became the gold standard for treating adenocarcinoma of the pancreas. Over the years it was used in various combinations, ie, GTX (gemcitabine/docetaxel/ capecitabine).
In 2004, a retrospective study looked at GTX and determined it demonstrated excellent response rates and superior survival; however, no phase III studies were done comparing it with gemcitabine alone. Gemcitabine was also used in combination with oxaliplatin (gem/ox); however, this never became a standard of care.
In 2010 the PRODIGE 4/ACCORD 11 trial found the FOLFIRINOX (fluorouracil/leucovorin/irinotecan/ oxaliplatin) regimen doubled median progression-free survival and improved median overall survival from 6.8 months to 11.1 months when compared to gemcitabine in patients with metastatic adenocarcinoma of the pancreas. This essentially revolutionized the treatment of metastatic pancreatic cancer. The downside is that this is a very difficult regimen for patients to tolerate. It requires growth factor support, aggressive antiemetics, and, frequently, visits to our center for intravenous fluids due to dehydration either from inadequate intake or diarrhea. In addition, those patients who are elderly and/or with many comorbidities might not be good candidates for such an aggressive therapy.
Now in 2013 comes MPACT which showed that the addition of nab-paclitaxel to gemcitabine significantly improved OS, as well as progression-free survival (PFS) and response rate compared with gemcitabine alone. This led to its approval for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas. Unbelievably, we now have another weapon in our arsenal. This regimen would certainly be appropriate for many of the patients who either are not be able to tolerate FOLFIRINOX, or even for those patients who progress on FOLFIRINOX, and would certainly offer a better outcome than gemcitabine alone. While outcomes are still not what we would like to see, we certainly are able to offer patients better outcomes than we could even 5 years ago. Hopefully, this trend will continue.