Gemzar Delays Recurrence After Successful Pancreatic Cancer Surgery

BERLIN, Germany, Jan. 16 -- After complete resection of pancreatic tumors, Gemzar (gemcitabine), which is FDA-approved for locally advanced or metastatic malignancies, significantly delayed disease recurrence, researchers here reported.

In a multicenter, randomized, controlled phase III trial, the estimated disease-free survival after about four-and-a half years was almost twice as long for the Gemzar-treated patients versus controls not given chemotherapy, with an even greater disparity at five years, according to a report in the Jan. 17 issue of the Journal of the American Medical Association.

Only about 20% of newly diagnosed pancreatic cancer patients are candidates for curative surgery, and only about half of these have successful resections. Nonetheless, the prognosis is often poor even for these patients. So surgery alone is an inadequate approach for long-term disease control in resectable pancreatic cancer, said Helmut Oettle, M.D., Ph.D., of Charit School of Medicine, Campus Virchow-Klinikum here, and colleagues.

The trial, known as CONKO-001 (Charit Onkologie), was conducted from July 1998 to December 2004 in an outpatient setting at 88 academic and community-based oncology centers in Germany and Austria. A total of 368 patients with gross complete (R0 or R1) resection of pancreatic cancer and no prior radiation or chemotherapy were enrolled in two groups. More than 80% of the patients had R0 resection.

Of the patients, 179 received adjuvant chemotherapy with six cycles of Gemzar on days one, eight, and 15 every four weeks, while 175 given observation only served as controls.

The median number of chemotherapy cycles was six (range 0-6). The average weekly dose of Gemzar was 700 mg/m², and the median relative-dose intensity was 86%. Grade 3 or 4 toxicities rarely occurred with no difference in quality of life (by Spitzer index) between the groups, the researchers said.

At a midpoint follow-up of 53 months (4.4 yrs), 133 patients (74%) in the Gemzar group and 161 controls (92%) developed recurrent disease. Median disease-free survival was 13.4 months in the Gemzar group (95% confidence interval, 11.4-15.3) and 6.9 months in the control group (CI, 6.1-7.8; P<.001, log-rank).

The estimated disease-free survival at three and five years was 23.5% and 16.5% in the Gemzar group, and 7.5% and 5.5% in the control group, respectively.

Subgroup analyses showed that the effect of Gemzar on disease-free survival was significant in patients with either R0 or R1 resection.

However, overall survival appeared to be the same in both groups, Dr. Oettle's team said. For the Gemzar group, median survival was 22.1 months (CI, 18.4-25.8). The estimated survival was 34% at three years and 22.5% at five years.

For the controls, median overall survival was 20.2 months (CI, 17-23.4). The estimated survival was 20.5% at three years and 11.5% at five years; P=.06, log-rank).

At the time of analysis, the researchers wrote, there was a nonsignificant trend for improved overall survival in favor of Gemzar in the intent-to-treat population (P= .06 log-rank).

Furthermore, the researchers wrote, at five years, approximately twice as many patients in the Gemzar group compared with the controls were estimated to be alive (22.5% versus 11.5%).

"Therefore," they said, "it seems likely that the difference in overall survival between groups will become statistically significant with a longer follow-up and an increasing proportion of deceased patients."

Discussing the study's limitations the researchers noted that their subgroup analyses by resection, nodal, and T status may be flawed by small patient numbers and that P values were not adjusted for multiple comparisons. Moreover, they said, the classification of the patients was not validated.

Pancreatic resections were done on hospitals of varying sizes and, presumably, surgical expertise. It is also likely that some positive margins were not detected in at least some of the resection specimens classified as R0 in either group.

All this may have affected the reliability of the staging and pathology data. On the other hand, they said, it is reasonable to assume that the study sample was representative of patients seen in routine clinical practice and the quality of patient care may reflect the current standard in Germany.

The question of whether adjuvant treatment of resected pancreatic cancer confers a survival advantage has been the subject of controversy during the last 20 years, the investigators said.

The results of this study should be discussed primarily in the context of the most recent results of two large randomized phase III trials, ESPAC-1 (fluorouracil alone and both chemoradiation and chemotherapy) and especially RTOG 9704 (Gemzar added to 5-FU-based chemoradiotherapy). In that trial, the researchers said, it appeared that the beneficial effect of fluorouracil alone was "small at best."

The results of CONKO-001 indicate that adjuvant treatment with Gemzar in the dose and schedule used has minimal toxicity, does not compromise quality of life, and offers a good, and currently perhaps the best chance for prolonged disease-free survival in this group of patients, the researchers said.

On the basis of these results, Gemzar offers promise to become the new standard treatment in the adjuvant setting, Dr. Oettle and colleagues concluded.

In an editorial with the subtitle "One Small Step Forward," Al B. Benson III, M.D., of Northwestern University in Chicago said that the trial is of considerable importance because of the significant numbers of patients, the appropriateness of the chosen agent, and the validity of the stratification factors. Although the authors clearly described some of the hazards of their subgroup analyses, their multicenter patient population should be viewed as a "real life" population.

The lack of an overall survival advantage was most likely a result of insufficient numbers of patients, Dr. Benson said. However, the observation of survival differences as a trend favoring patients who received Gemzar at years three and five appears important and is most likely related to the chemotherapy effect.

Although it is argued that overall survival should be the optimal endpoint, Dr. Benson said, improved disease-free survival can offer patients with a notoriously lethal disease an opportunity to enjoy longer periods of time relatively free of symptoms. It is also possible, he said, that with additional time, overall survival may become significant.

Addressing the design of future studies for advanced disease and for those with resected tumors, Dr. Benson said that the paucity of biological data to link a tumor's biological profile with intervention efficacy, for example, is a major obstacle.

As new agents emerge, particularly the biologics, integration of research disciplines (molecular biology, experimental imaging, and clinical trials) is imperative.

"Worldwide, there is a need to move away from the question of current chemotherapy agents versus chemoradiation to a research focus based on enhancing understanding of biologic principles." he wrote. "Given the rapid lethality of pancreatic cancer, this is no easy task. Whether it is possible to build on the small steps taken with this study results remains to be seen."

The CONKO-001 trial was supported in part by a grant from Lilly Deutschland, maker of Gemzar. Dr. Oettle reported receiving compensation for clinical lectures from Lilly and Sanofi-Aventis two-and-a half to five years ago. During, the past five years, Dr Oettle received grant support for clinical research projects from the German branches of Amgen, Antisense Therapeutics, Caremark/ Fresenius Kabi GmbH, GlaxoSmithKline, LogoMed, Medac, Merck KG (Darmstadt, Germany), and Novartis.

Co-author Hanno Ries, M.D., Ph.D., has received compensation for clinical lectures and funding by Amgen, AstraZeneca, Bayer, Falk, GlaxoSmithKline, Instrumentation Laboratory, Lilly, Merck KG, Mitsubishi, Pharma, Novartis, Octapharm, Organon, Pfizer, Ribosepharm, Roche, Sanofi-Aventis, Shire, and ZLB Behring.