By Gary R. Shapiro, MD
Medical Director, Cancer Center of Western Wisconsin, New Richmond, Wisconsin
Dr. Shapiro reports no financial relationships relevant to this field of study.
It is indeed ironic that 16 years after the landmark Burris study, innovations in pancreatic cancer treatment still lack essential quality-of-life data.
Synopsis: The combination of nab-paclitaxel and gemcitabine is more effective than gemcitabine alone in treating patients with metastatic adenocarcinoma of the pancreas. Median overall survival was 8.5 months in the combination group, compared to 6.7 months in the gemcitabine group, with 35% and 22% 1-year survival rates, respectively. Response rates were also higher with the combination, 23% vs 7%.
Source: Von Hoff DD, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-1703.
This Phase 3, multi-institutional study randomly assigned 861 metastatic pancreatic adenocarcinoma patients, who had a good performance status (Karnofsky score ≥ 70), to receive nab-paclitaxel (125 mg/m2) followed by gemcitabine (1000 mg/m2 on days 1, 8, and 15 every 4 weeks) or gemcitabine monotherapy (1000 mg/m2 weekly for 7 of the first 8 weeks, and then days 1, 8, and 15 every 4 weeks for the subsequent cycles). The patients were treated until their disease progressed or they had unacceptable toxicity.
The median overall survival of patients in the nab-paclitaxel group was 8.5 months compared to 6.7 months in the gemcitabine monotherapy group (hazard ratio [HR] = 0.72, P < 0.001). The median progression-free survival was 5.5 months with nab-paclitaxel compared to 3.7 months for those receiving only gemcitabine (HR = 0.69, P < 0.001). The combination also demonstrated a superior overall response rate of 23% compared to 7% for gemcitabine alone (P < 0.001). Additionally, the survival rate was 35% in the combination group vs 22% in the gemcitabine group at 1 year, and 9% vs 4% at 2 years, respectively.
This favorable treatment effect was consistent across all subgroups in Von Hoff's analysis. In general, the greatest reduction in the risk of death was seen in patients with more advanced disease: poorer performance status, liver metastasis, more than three sites of metastatic disease, metastatic disease at presentation, or a very high CA 19-9 (≥ 9 × ULN). A similar trend was observed for progression-free survival.
Approximately 40% of patients in both groups went on to receive second-line anticancer therapy. Those initially randomized to the nab-paclitaxel plus gemcitabine arm had a significantly longer survival (9.4 months) than those initially treated with gemcitabine alone (6.8 months; HR, 0.68; P < 0.001).
Serious (grade 3 and 4) adverse events were more common in the nab-paclitaxel group, and included neutropenia (38% vs 27%), fatigue (17% vs 7%), and neuropathy (17% vs 1%). Febrile neutropenia was uncommon in both groups (3% vs 1%).
COMMENTARY
Burris's 1997 groundbreaking study1 established gemcitabine as the standard first-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer, as much for how it improved quality of life (24% of patients) as its modest effect on longevity (median overall survival 5.65 months, 1-year survival 18%). Recently, FOLFIRINOX has emerged as an alternative to gemcitabine. Although this regimen has a superior survival outcome (median overall survival 11.1 vs 6.8 months; HR, 0.57; P < 0.001),2 it is not appropriate for frail patients for whom gemcitabine, with its relatively low toxicity, remains the first-line treatment of choice. Now, in this well-designed, randomized, phase 3 international study, Von Hoff and his colleagues provide a third alternative for oncologists to consider for patients seeking palliative chemotherapy for their advanced pancreatic cancer.
Both the nab-paclitaxel–gemcitabine and FOLFIRINOX trials excluded those with a poor performance status, but the nab-paclitaxel study cutoff was higher. Indeed 8% of its subjects had a performance status corresponding to 2 on the ECOG scale, a group that was excluded from the FOLFIRINOX study. It is also noteworthy that where the FOLFIRINOX study excluded patients older than 75, 10% of patients in the nab-paclitaxel study were 75 years of age or older.
Although the gemcitabine control arm in both the nab-paclitaxel–gemcitabine and the FOLFIRINOX trials showed remarkably similar median overall survival (6.7 vs 6.8 months, respectively), it is important not to assume that it necessarily follows that the FOLFIRINOX regimen (OS 11.1 months) is superior to the nab-paclitaxel–gemcitabine combination (8.5 months). Only a head-to-head, randomized trial of FOLFIRINOX vs nab-paclitaxel–gemcitabine will provide these data.
It is unfortunate that Von Hoff chose not to include a tool to measure the quality of life of those patients participating in his study. Indeed, it was with the original Burris pancreatic cancer study1 that the oncology community first began to appreciate the importance of adding quality of life to the traditional list of outcome measurements used in cancer clinical trials. Quality-of-life measures were included in the FOLFIRINOX-gemcitabine study, and at 6 months, 31% of the patients in the FOLFIRINOX group had a "definitive degradation" of quality of life vs 66% in the gemcitabine group (HR, 0.47; P < 0.001).2
That the nab-paclitaxel–gemcitabine combination and gemcitabine monotherapy had reasonably comparable rates of serious life-threatening adverse events is reassuring, but, as tempting as it may be to draw a favorable analogy between the two regimens, toxicity outcomes are not always good surrogates for quality-of-life outcomes. For example, one wonders if those among the majority of patients with persistent nab-paclitaxel peripheral neuropathy were as pleased as the investigators that "44% resumed treatment at a reduced dose of nab-paclitaxel within a median of 23 days." Peripheral neuropathy is a worrisome complication in older individuals who are subject to falls and may have preexisting neuropathic symptoms.
It is indeed ironic that 16 years after the landmark Burris study, innovations in pancreatic cancer treatment still lack essential quality-of-life data. Is treatment worth it? Rebecca Miksad eloquently addressed both the quality-of-life and economic aspects of this question in her 2007 letter to the editor of the Journal of Clinical Oncology.3 She was responding to a recently published study4 that was the first randomized, Phase 3 clinical trial to "demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine." With a design similar to that used by Von Hoff (including the absence of quality-of-life measures), Moore randomized 569 advanced pancreatic cancer patients to either erlotinib and gemcitabine or gemcitabine. Though objective response rates were not significantly different between the groups, overall survival was significantly prolonged on the erlotinib-gemcitabine arm (6.24 vs 5.91 months; HR, 0.82; P = 0.038) and 1-year survival was also greater with erlotinib (23% vs 17%, P = 0.023).
Miksad concluded that the overall survival benefit of 0.33 months, though statistically significant, was so small that it did not justify the increased risk of toxicity (diarrhea, interstitial lung disease, and treatment-related death) or the high financial cost of adding erlotinib to gemcitabine. In contrast, the FOLFIRINOX study had a higher overall survival benefit (4.3 months), and, despite its higher incidence of adverse events, demonstrated that the quality of life of patients receiving FOLFIRINOX deteriorated slower than those treated with gemcitabine.
The overall survival benefit (1.8 months) of the relatively less toxic nab-paclitaxel–gemcitabine regimen was also greater than that seen in the erlotinib study, but these statistics fail to provide the important quality-of-life information that is essential to answering the question, "Is it worth it?"
In the absence of clear data regarding the quality of life of those treated with nab-paclitaxel–gemcitabine and a direct comparison of this combination to FOLFIRINOX, the nab-paclitaxel–gemcitabine regimen seems applicable to a broader patient population, especially those who are older and less robust. It is noteworthy that the Von Hoff study did include older patients, but, like the underrepresentation of those with a poor performance status, the number of patients in this study who were older than 75 limits our ability to generalize their findings to the majority of patients with advanced pancreatic cancer: the elderly and the frail. For this group, the balance of burdens and benefits may still favor single agent gemcitabine in those who wish palliative chemotherapy.
References
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Burris HA III, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997;15:2403-2413.
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Conroy T, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-1825.
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Miksad RA, et al. Does a statistically significant survival benefit of erlotinib plus gemcitabine for advanced pancreatic cancer translate into clinical significance and value? Letter to the Editor. J Clin Oncol 2007;25:4506-4507.
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Moore MJ, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960-1966.
