Adjuvant therapy for pancreatic cancer: A time that has not yet come

Pancreatic cancer has a dismal prognosis with almost all patients diagnosed with this disease succumbing to it; the vast majority of pancreatic cancers are not detected until metastasis has occurred or there is locally advanced disease. Survival is short with the median survival being only a few months. Even when diagnosed at an early stage, the survival after resection is poor. Thus, although surgery will result in long-term survival for some patients, effective additional (adjuvant or neo-adjuvant) treatment would be necessary to increase the survival of these patients as discussed by Dr. Kennedy and Dr. Yeo in their review of the subject. However, just because something can be done does not mean it should be done. During the past 30 years, adjuvant therapy has been shown to improve the disease-free and overall survival rates of many pediatric cancers and, to a lesser extent, of some adult cancers including breast cancer and colorectal cancer. Lessons learned from the evaluation of these therapies have resulted in the establishment of several principles for adjuvant therapy to be beneficial. First, drugs used in the adjuvant setting must be effective when administered to patients with metastatic disease. Second, when combinations of drugs are used, the different agents must have different mechanisms of actions. Third, the drugs should have non-overlapping toxicities. Finally, randomized, prospective trials comparing similar groups of patients (stratified prospectively according to stage and other established prognostic variables) are required to demonstrate the value of adjuvant treatment when compared to a concomitantly diagnosed, evaluated, and surgically treated control group. If we first look at management of advanced pancreatic cancer, few drugs have demonstrated a benefit. For many years 5-fluorouracil (5-FU) was the only effective agent, but the response rate was low and survival benefit modest, at best. More recently gemcitabine has been added to the therapeutic armamentarium but, again, despite some objective responses, there has only been a modest improvement in survival. Other drugs have not demonstrated a benefit in the metastatic setting and, therefore, would not be expected to be of value in the adjuvant management of patients with pancreatic cancer. Radiotherapy has been used alone and in combination with chemotherapy for the management of pancreatic cancer. It is effective in controlling pain or bleeding, but appears to result in few objective responses alone or in combination when used in patients with advanced cancer. Although the group from M.D. Anderson has reported that neo-adjuvant chemo-radiation allows a substantial percentage of locally advanced pancreatic cancers to become resectable, others have not been able to replicate this experience. Using a similar regimen of radiation and chemotherapy, we have treated over 50 patients with locally advanced pancreatic cancer but have not converted any to resectable; many of these patients were explored both before and after neo-adjuvant therapy (unpublished data). Other series also show that few, if any, patients become resectable after planned preoperative chemoradiotherapy. Therefore, I believe that neo-adjuvant therapy cannot be considered to be standard treatment in 2006. What about post-operative treatment? Many nonrandomized studies have been reported utilizing chemotherapy with or without radiation therapy administered after pancreatic resection. Survival has then been compared to historical ‘‘controls’’ or patients treated during similar time frames who did not receive adjuvant treatment. Many of these reports have purportedly demonstrated a benefit of adjuvant treatment, but even