ADJUVANT GEMCITABINE IN PANCREATIC CANCER

Gemcitabine (Gemzar) is the standard chemotherapy for advanced pancreatic cancer. It has also become the mainstay of adjuvant therapy in pancreatic cancer, even though its effect on survival after surgery has been unclear. Now, findings from an extended follow-up in patients who underwent surgery lend support to its use in the adjuvant setting.

In patients who had undergone complete, curative-intent resection of pancreatic cancer, gemcitabine for 6 months increased both overall and disease-free survival, German researchers found.

Results from the extended follow-up of the Charité Onkologie CONKO-001 trial were published in the October 9 issue ofJAMA.

Median overall survival was significantly better in patients treated with gemcitabine than in those treated with observation (22.8 vs 20.2 months; P = .01).

Previous results from the CONKO-001 trial were published in JAMA (2007;297:267-277), and were presented at the 2008 annual meeting of the American Society of Clinical Oncology, as reported at that time by Medscape Medical News.

"The main result of this trial is that treatment with adjuvant gemcitabine for 6 months leads to a 24% improvement in overall survival, with a statistically significant absolute 10.3% improvement in the 5-year overall survival rate (20.7% vs 10.4%) and a 4.5% improvement in the 10-year survival rate (12.2% vs 7.7%), compared with observation alone," write the authors, led by Helmut Oettle, MD, PhD, from the Charité-Universitätsmedizin Berlin, Germany.

Results Lend Support

Despite the lack of a clear consensus, "gemcitabine has been the mainstay of the adjuvant treatment. The significant improvement in overall survival after long-term follow-up provides further support for its use," said Vaibhav Sahai, MBBS, MS, assistant professor of medicine at the University of Michigan in Ann Arbor, who was approached for independent comment.

However, "the role of chemoradiation is less clear, especially after the recent LAP 07 trial results, which showed no benefit of chemoradiation over chemotherapy alone in patients with locally advanced pancreatic adenocarcinoma," he told Medscape Medical News.

Final results from the phase 3 international LAP 07 study, presented at the 2013 annual meeting of the American Society of Clinical Oncology, showed that neither radiation nor the targeted therapy erlotinib (Tarceva, Astellas Pharma) improved survival.

Adjuvant chemotherapy with gemcitabine for 6 months, as was used in the CONKO-001 trial, is the current standard, explained Dr. Sahai. However, chemoradiation is still being used, both on and off clinical trials. This use is driven by the oncologist and/or institution, he explained.

"The controversy lies in the role of chemoradiation in addition to adjuvant chemotherapy after R0 or R1 resection of pancreatic adenocarcinoma," he continued. "The ongoing RTOG 0848 phase 3 clinical trial was designed to finally address the addition of 5-FU- or capecitabine-based radiation in the treatment of adjuvant pancreatic adenocarcinoma."

But accrual to this trial has been slow, with only a third of the projected participants enrolled. "In the absence of randomized data, some medical oncologists continue to discuss and offer adjuvant chemoradiation to patients," Dr. Sahai said.

No other drugs or regimens are really being used in this patient population. "Currently, there is no role for erlotinib, FOLFIRINOX, or nab-paclitaxel in the adjuvant setting," Dr. Sahai pointed out. "We are eagerly looking forward to the initiation of the randomized trial comparing gemcitabine plus nab-paclitaxel and gemcitabine alone in the adjuvant treatment of pancreatic adenocarcinoma."

Superior Disease-Free Survival

The CONKO-001 trial was designed to compare gemcitabine with observation alone in the adjuvant setting in patients who had undergone complete resection with curative intent.

Dr. Oettle and colleagues randomized the 354 eligible patients to either adjuvant gemcitabine (1 g/m² on days 1, 8, and 15, every 4 weeks for 6 months) or observation alone. The enrollment period ran from July 1998 to December 2004, and the follow-up period ended in September 2012.

The median duration of follow-up was 136 months.

Of the 308 patients (87%) who relapsed, 145 were in the gemcitabine group and 163 were in the observation group.

Median disease-free survival better with gemcitabine than with observation (13.4 vs 6.7 months; hazard ratio, 0.55; P < .001).

In addition, 5-year disease-free survival was better with gemcitabine than with observation (16.6% vs 7.0%), as was 10-year disease-free survival (14.3% vs 5.8%). The treatment effect was consistent across all subgroups, the authors report.

As noted above, the differences in overall and disease-free survival between the 2 groups were statistically significant.

By the cutoff date, 316 of the 354 patients (89.3%) had died. Of the 38 patients who remained alive, 23 were in the gemcitabine group and 15 were in the observation group.

On multivariable analysis, T and N stage remained the dominant prognostic factors for survival, aside from treatment with gemcitabine, the authors note.

The trial was supported in part by a grant from Lilly Germany, the manufacturer of gemcitabine, and support from the German Cancer Society and a research grant from the Charité-Universitätsmedizin Berlin. Dr. Oettle reports receiving honoraria from Roche Pharma, Cellgene, and Fresenius. Coauthor Hanno Riess, MD, PhD, reports receiving honoraria from Bayer Vital, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche Pharma, and sanofi-aventis. Coauthor Michael B. Arning, MD, PhD, reports being a former employee of Eli Lilly & Co and owning Lilly stock.

JAMA. 2013;310:1473-1481. Abstract