The American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging of pancreatic cancer takes into account the location and size of the tumor, the involvement of lymph nodes, and distant metastasis. This information is then combined to assign a stage (Fig. 93-3). From a practical standpoint, patients are grouped according to whether the cancer is resectable, locally advanced (unresectable, but without distant spread), or metastatic.
Treatment: Pancreatic Cancer
Approximately 10% of patients present with localized nonmetastatic disease that is potentially suitable for surgical resection. Approximately 30% of patients have R1 resection (microscopic residual disease) following surgery. Those who undergo R0 resection (no microscopic or macroscopic residual tumor), and who receive adjuvant treatment have the best chance of cure, with an estimated median survival of 20–23 months and a 5-year survival of approximately 20%. Outcomes are more favorable in patients with small (< 3 cm), well-differentiated tumors, and lymph node-negative disease.
Patients should have surgery in dedicated pancreatic centers that have lower postoperative morbidity and mortality rates. The standard surgical procedure for patients with tumors of the pancreatic head or uncinate process is a pylorus-preserving pancreaticoduodenectomy (modified Whipple's procedure). The procedure of choice for tumors of the pancreatic body and tail is a distal pancreatectomy, which routinely includes splenectomy.
Postoperative treatment, either chemotherapy or CRT, improves long-term outcomes in this group of patients. Adjuvant chemotherapy, comprising six cycles of fluorouracil (5FU) and folinic acid (FA) or gemcitabine, is common practice in Europe based on data from three randomized controlled trials (Table 93–1): Results from the European Study Group for Pancreatic Cancer 1 trial (ESPAC-1) revealed a median survival improvement from 14.7 months with surgery alone to 20.1 months with surgery plus adjuvant 5FU/FA, and patients did not benefit from CRT in this study. The Charité Onkologie trial (CONKO 001) found that the use of gemcitabine after complete resection significantly delayed the development of recurrent disease compared with surgery alone. The ESPAC-3 trial, which investigated the benefit of adjuvant 5FU/FA versus gemcitabine, revealed no survival difference between the two drugs. However, the safety profile of adjuvant gemcitabine, with respect to the incidence of stomatitis and diarrhea, was superior to 5FU/FA.
Table 93–1 Phase III Studies of Adjuvant Chemotherapy in Resected Pancreatic Cancer |Favorite Table|Download (.pdf)
Table 93–1 Phase III Studies of Adjuvant Chemotherapy in Resected Pancreatic Cancer
|Study||Comparator Arm||Patient Number||PFS/DFS (months)||Median survival (months)|
|ESPAC 1 Neoptolemos et al. (2004)||Chemotherapy (Folinic acid + bolus 5FU) vs No chemotherapy||550||PFS 15.3 vs 9.4. (p = 0.02)||20.1 vs 14.7 (HR 0.71, 95% CI 0.55 to 0.92, p = 0.009)|
|CONKO 001 Oettle et al. (2007)||Gemcitabine vs Observation||368||Median DFS 13.4 vs 6.9 (p < 0.001)||22.1 vs 20.2 (p = 0.06)|
|ESPAC 3 Neoptolemos et al. (2010)||5FU/LV vs Gemcitabine||1088||23 vs 23.6 (HR 0.94, 95% CI 0.81 to 1.08, p = 0.39)|
A different treatment strategy using adjuvant 5FU based CRT following gemcitabine as advocated by the Radiation Therapy Oncology Group (RTOG) 97-04 trial is preferred in the United States. This approach may be most beneficial in patients with bulky tumors involving the pancreatic head, and in patients with R1 resection.
Inoperable Locally Advanced Disease
Approximately 30% of patients present with locally advanced unresectable but nonmetastatic pancreatic carcinoma. The median survival with gemcitabine is 9 months, and patients who respond to or achieve stable disease after 3–6 months of gemcitabine may derive benefit from consolidation radiotherapy.
Approximately 60% of patients with pancreatic cancer present with metastatic disease. Patients with poor performance status do not benefit from chemotherapy. Gemcitabine is the standard treatment with a median survival of 6 months and a 1-year survival rate of only 20%. The toxicities associated with gemcitabine need to be weighed against the potential benefits of treatment.
Adding other drugs to gemcitabine to improve outcome has been generally unsuccessful with the exception of erlotinib, an oral HER1/EGFR tyrosine kinase inhibitor. The combination of erlotinib with gemcitabine resulted in an improved 1-year survival compared with gemcitabine alone (23% versus 17%,p = 0.023) (Table 93–2). Capecitabine, an oral fluoropyrimidine, has been combined with gemcitabine (GEM-CAP) in a phase III trial that showed an improvement in response rate and progression-free survival over single-agent gemcitabine, but no survival benefit. However, pooling of two other randomized controlled trials with this trial in a meta-analysis resulted in a survival advantage with GEM-CAP.
Table 93–2 Selected Phase III Studies Evaluating Chemotherapy Treatment in Advanced Pancreatic Cancer |Favorite Table|Download (.pdf)
Table 93–2 Selected Phase III Studies Evaluating Chemotherapy Treatment in Advanced Pancreatic Cancer
|Study||Comparator Arm||Patient Number||PFS (months)||Median survival (months)|
|Moore M et al. (2007)||Gemcitabine vs Gemcitabine + erlotinib||569||3.55 vs 3.75 (HR 0.77, 95% CI 0.64 to 0.92, p = 0.004)||5.91 vs 6.24 (HR 0.82, 95% CI 0.69 to 0.99, p = 0.038)|
|GEM-CAP Cunningham et al. (2009)||Gemcitabine vs Gemcitabine + capecitabine (GEM-CAP)||533||3.8 vs 5.3 (HR 0.78, 95% CI 0.66 to 0.93, p = 0.004)||6.2 vs 7.1 (HR 0.86, 95% CI 0.72 to 1.02, p = 0.08)|
|GEM-CAP meta-analysis Cunningham et al. (2009)||Gemcitabine vs GEM-CAP||935||Overall survival in favor of GEM-CAP (HR 0.86, 95% CI 0.75 to 0.98, p = 0.02)|
A trial in good performance status patients with metastatic pancreatic cancer showed improved survival with the combination of 5FU/FA, irinotecan and oxaliplatin (FOLFIRINOX) compared with gemcitabine, but with increased toxicity. Nab-paclitaxel (Abraxane), an albumin bound nano-particle formulation of paclitaxel, given with gemcitabine also shows promising activity.