Adjuvant Therapy for Resected Pancreatic Adenocarcinoma

Rationale for Adjuvant Chemotherapy after Resection of PDAC

Gemcitabine or 5-fluorouracil (FU)

Even when R0 resection is achieved in pancreatic adenocarcinoma, relapse rates are still high. Only about 15% to 20% of PDACs are cured by resection alone. Several trials have examined the role of adjuvant chemotherapy given after resection in PDAC. The European ESPAC-1 trial was a large study examining adjuvant chemotherapy alone and chemoradiotherapy in resected PDAC.1In this 2x2 factorial design trial, adjuvant chemotherapy conferred better survival benefit compared to no chemotherapy (20.1 months vs 15.5 months, P = 0.009). Adjuvant chemoradiotherapy did not improve survival compared to those who did not receive this. The subsequent CONKO-001 trial compared no adjuvant therapy to adjuvant gemcitabine after PDAC resection and showed improved 5-year overall survival (OS) of 11% (21% vs 10%) with addition of 6 months of adjuvant gemcitabine.2Similarly, a smaller Japanese trial also showed disease-free survival (DFS) benefit with adjuvant gemcitabine over observation.3

ESPAC 3 trial compared adjuvant gemcitabine with adjuvant bolus leucovorin-modulated 5-FU in resected PDAC and found no differences in survival outcomes between both arms.4However, patients who received fluoropyrimidines had more grade III and IV toxicities like stomatitis and diarrhea. Similarly, in the RTOG 9704 trial, there were no survival differences between patients who received gemcitabine versus those who received fluoropyrimidines.5

The NCCN, ESMO and Canadian guidelines all recommend gemcitabine or 5-FU as adjuvant chemotherapy for resected PDAC.

TS-1

More recently, JASPAC-01 trial showed that adjuvant oral TS-1 alone was not inferior to adjuvant gemcitabine in resected PDAC.6Two-year survival with TS-1 was 70% and 53% with gemcitabine (HR = 0.54, P <0.001). TS-1 was also better tolerated than gemcitabine though the former had more incidences of stomatitis and diarrhea. The NCCN, ESMO and Canadian guidelines do not recommend TS-1 as adjuvant therapy as this drug is not available in some of these countries and TS-1 data in their PDAC populations is lacking.

All patients with resected PDAC should be considered for adjuvant therapy.

Role of Radiation Therapy as Part of Adjuvant Therapy

In the 1980s, the GITSG trial that was conducted in the USA showed that adjuvant bolus 5-FU with radiation therapy (40 Gy) followed by adjuvant 5-FU for 2 years after PDAC resection doubled survival rates over observation alone (2-year OS, 20% vs 10%).7This trial was stopped early due to poor recruitment. The Europeans tried to reproduce these results in the EORTC trial done in the late 1990s, comparing continuous infusion 5-FU concurrent with split course radiation (40 Gy) therapy as adjuvant therapy with observation alone in resected PDACs.8This trial only showed a trend towards improved survival with chemoradiation and no differences in local recurrence.

The ESPAC-1 trial, which tried to compare adjuvant chemotherapy, adjuvant chemoradiation and observation found that patients who received adjuvant chemoradiation did worse than patients in the other groups.1Thus, based on EORTC and ESPAC-1, ESMO guidelines do not recommend adjuvant chemoradiation after PDAC resection. On the other hand, the American guidelines still recommend adjuvant chemoradiation based on the positive results of the GITSG trial and other uncontrolled series and the opinion that the flaws in the European trials preclude any firm conclusions.

Rationale for Postsurgery Imaging

Pancreatic cancer has an extremely high rate of systemic recurrence (>80%) and a very high rate of local recurrence (>20%). Some patients develop recurrence within 8 weeks of surgery, thus it is recommended that imaging scans are performed prior to initiation of adjuvant therapy. For patients for whom adjuvant chemoradiation is planned after adjuvant chemotherapy is started, an imaging scan is recommended prior to start of chemoradiation phase.

Recommendations Regarding Adjuvant Therapy for Resected Pancreatic Adenocarcinoma

1. Adjuvant gemcitabine or adjuvant TS-1 are both reasonable options postsurgical resection for PDAC.

2. Adjuvant radiation therapy concurrent with fluoropyrimidine is not recommended routinely for these patients unless resection margin is positive.

3. A full restaging scan should be performed prior to start of adjuvant chemotherapy to rule out any metastases.