NATURAL HISTORY AND PATTERNS OF TREATMENT FAILURE

Rational anticancer therapy for solid malignancies is based on an accurate knowledge of the natural history and patterns of treatment failure for each tumor type. Pancreatic cancer spreads early to regional lymph nodes, and subclinical liver metastases are present in the majority of patients at the time of diagnosis, even when findings from imaging studies are normal. Patient survival depends on the extent of disease and performance status at diagnosis. Extent of disease is best categorized as resectable, locally advanced, or metastatic. Patients who undergo surgical resection for localized nonmetastatic adenocarcinoma of the pancreatic head have a long-term survival rate of approximately 20% and a median survival of 15 to 19 months (Table 32.4-2) (Table Not Available) . As will be discussed, survival is clearly maximized by combining surgery with either preoperative or postoperative 5-fluorouracil (5-FU)-based chemotherapy and radiation therapy (chemoradiation). However, disease recurrence following a potentially curative pancreaticoduodenectomy remains common. Local recurrence occurs in up to 85% of patients who undergo surgery alone; local-regional tumor control is maximized with combined-modality therapy in the form of chemoradiation and surgery. With improved local-regional disease control, liver metastases become the dominant form of tumor recurrence and occur in 50% to 70% of patients following potentially curative combined-modality treatment.
Patients with locally advanced, nonmetastatic disease have a median survival of 6 to 10 months. A survival advantage has been demonstrated for patients with locally advanced disease treated with 5-FU-based chemoradiation compared with no treatment or radiation therapy alone. Patients with metastatic disease have a short survival (3 to 6 months), the length of which depends on the extent of disease and performance status.

Knowledge of the prognosis and patterns of treatment failure associated with adenocarcinoma of the pancreas leads to the following basic treatment principles:

The treatment must not be worse than the disease. The low cure rate and modest median survival following pancreatectomy mandate that treatment-related morbidity be low and treatment-related death be rare.

2.Improvements in patient survival and quality of life will result from the development of innovative treatment strategies directed at the known sites of tumor recurrence. Data to date have clearly demonstrated that as local-regional treatment becomes more effective, the dominant site of failure has shifted to hepatic metastases.

Therefore, future improvements in survival duration will result either from effective systemic or regional therapy directed at subclinical liver metastases or from strategies for screening and early diagnosis directed at increasing the number of patients eligible for potentially curative surgery. Future improvements in the quality of patient survival will result from the application of innovative multimodality therapy to carefully selected (staged) patients and the avoidance of unnecessary patient morbidity due to the inappropriate use of surgery, radiation, or chemotherapy or any combination thereof in poorly selected (advanced disease) patients.