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In 2012, an estimated 43,920 people will be diagnosed with pancreatic cancer, and approximately 37, 390 people will die of pancreatic cancer in the United States. This disease is the fourth most common cause of cancer-related death among U.S. men (after lung, prostate and colorectal cancer) and women (after lung, breast, and colorectal cancer). Its peak incidence occurs in the seventh and eighth decades of life. Although incidence is roughly equal in both sexes, African Americans seem to have a higher incidence of pancreatic cancer than white Americans. Furthermore, the incidence and mortality rates of pancreatic cancer in the United States have remained approximately the same over the past 40 years.

Treatment for Patients after Curative Surgery (Stage 1)
In the post-operative adjuvant setting, the Gastrointestinal Tumor Study Group reported that patients who receive combined radiation and chemotherapy following curative resection had a median survival rate of 21.0 months compared to a median survival of 10.9 months in the control group who received surgery alone. Accrual to this trial began in 1974. Final results were reported in 1985.

The European Study Group for Pancreatic Cancer evaluated adjuvant therapy patients with resected pancreatic cancer. A total of 289 patients were enrolled over a six year period to receive observation, chemotherapy plus radiation, chemotherapy alone, or concurrent chemo-radiotherapy followed by chemotherapy. The study did demonstrate an improved median survival of 20.1 months favoring the 147 patients who received chemotherapy (with 5-fluorouracil) compared to the 142 patients who did not. The median survival was 15.5 with no chemotherapy. No benefit was seen in patients who received chemo-radiotherapy.

The CONKO-001 trial was a large phase III trial to evaluate the benefits of gemcitabine for patients with resected pancreatic cancer. Three hundred sixty-eight patients were randomly assigned to gemcitabine versus observation. In the final analysis there was no difference in overall survival between the gemcitabine group and the control (observation) group. The overall median survival was 22.1 months and 20.2 months respectively for gemcitabine and observation.

In the United States, the Gastrointestinal Intergroup randomized 538 patients to receive gemcitabine to precede and follow radiation and 5FU versus 5FU alone to precede and follow radiation and 5FU. The addition of gemcitabine provided no overall survival benefit.
The ESPA-3 study was a randomized trial of adjuvant 5FU versus gemcitabine in patients with resected pancreatic cancer. The median survival was 23.0 months for patients treated with 5FU and 23.6 months for patients who received gemcitabine.

Comments on adjuvant therapy by Dr. Isacoff:
Following surgery, both local and systemic relapse rates are high, however local recurrence is a rare cause of death. Most patients die of systemic complications of the disease. If one carefully analyzes all of the published data since 1985 regarding the use of adjuvant treatment in resected patients, it is easy to conclude that there has been no significant advances in overall outcome and survival. Why?
In more than 80% of patients who undergo curative surgery, there is microscopic disease outside the field of surgery or radiation. This significantly impacts survival. Short courses of single agent therapy have thus far proven to be ineffective. Radiation has no chance of treating disseminated disease and is therefore an irrational approach. Radiation in this setting only compromises the ability of patients to tolerate combination chemotherapy; thus far trials for the treatment of patients after curative resection have been poorly designed. For more than 10 years we have debated the use of a chemotherapy only approach but none have been implemented thus far. Single agent chemotherapy has little impact on eradicating systemic micro metastases. Yet combination chemotherapy has not been adequately evaluated because of fears of unacceptable toxicity when utilized with radiation. We need trials of chemotherapy only (no radiation), and that which is employed should have a response rate of greater than 40% when treating advanced metastatic disease.

Treatment for patients with metastatic disease (Stage 4)
Since its approval 13 years ago, gemcitabine has been considered the standard treatment for metastatic disease, based on the improvement in clinical benefit response, when compared to 5FU. In the Burris trial (the pivotal trial upon which the FDA approved gemcitabine) there were no confirmed objective tumor responses with either treatment. The Burris trial has never itself been confirmed and has been criticized because of its flawed design. The number of patients who were randomized and subsequently treated was only 126. Of the 63 patients treated with 5FU, only 28 were eligible to be evaluated for clinical benefit response, the primary end point of the study. In the control arm, the 5FU was administered as a bolus infusion. This has been shown to be a sub-optimal method of administration, and may have not been a valid control against which to evaluate gemcitabine. At the doses of 5FU utilized when given as a 30 minute infusion, it would unlikely achieve therapeutic blood levels. The one-year survival rate for 5FU was unusually low. Other 5FU containing trials have reported survival rates of 6 and 7.6 months. It is possible, that had 5FU been given in a more active form, the comparative benefit attributed to gemcitabine would not have been significant. Stoniolo et al., in an open labeled single-arm design with 2380 patients with locally advanced or metastatic pancreatic cancer treated with gemcitabine, reported a median survival to be only 4.8 months. There is little or no conclusive evidence to show that gemcitabine is superior to 5FU as first line therapy for pancreatic cancer. At this time, no standard single agent can be recommended as first line therapy. Gemcitabine has not improved the median survival, when compared to what preceded it, for patients with stage I, II, III or IV disease. Its continued use prevents the design of more effective trials.

In May 2011, Conroy et al. reported theĀ  results of their randomizedĀ  trial where 342 patients received either FOLFIRINOX every 2 weeks, or gemcitabine weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. The median survival was 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group. At 6 months, 31% of the patients in the FOLFIRINOX group had degradation of their quality of life versus 66% in the gemcitabine group. This is a major step forward for patients with pancreatic cancer and must be considered the new standard of care for both clinical practice and for developmental therapeutics in the area of pancreatic cancer clinical research.

As reported in the December 2011 issue of JCO, Von Hoff et al. combined gemcitabine with nab-paclitaxel as first line therapy for patients with metastatic pancreatic cancer as part of a phase I/II trial. Sixty-seven patients were treated. Eighty-seven percent of all patients were alive for 12 months or more. A phase III trial is ongoing comparing the combination to gemcitabine alone.

Comments on treatment for stage 4 disease by Dr. Isacoff:
Single agent chemotherapy alone is not the answer. Only effective combination chemotherapy will lead to improved survival. However, no combination has thus far been developed with any scientific rationale. FOLFORINOX is the combination of FOLFOX and FOLFIRI. This was first used for the treatment of colon cancer as reported in JCO by Falcone et al. in 2002. The trial utilizing nab-paclitaxel and gemcitabine was initiated and sponsored by a drug company to achieve FDA approval for nab-paclitaxel. The trial design was to achieve FDA approval and not based on a specific scientific rationale. The combination has serious toxicity at the doses utilized in the phase II trial, and will not be a useful platform upon which to test additional drugs. The utility of gemcitabine as a single agent has for years been debated. Adding drugs with marginal activity to gemcitabine has not and will not significantly improve upon that which has been observed over the last decade.
All industry sponsored trials have used gemcitabine in the control arm. Why; not to advance science, but to get drugs approved. Is it at this time even ethical to have single agent gemcitabine as the control for ongoing trials when reliable data has supported the significant superiority of FOLFORINOX compared to gemcitabine with significantly higher survival and response rates?