Pancreatic Adenocarcinoma: Update on Neoadjuvant and Adjuvant Treatment
Adjuvant Therapy
Case Continued
Prior to the planned surgical resection and after undergoing chemoradiation therapy, the patient has an excellent performance status and repeat MRI shows a 1.3 × 1.4 cm head mass with no further vasculature involvement, no evidence of lymphadenopathy, and no distant metastasis. The CA 19-9 level is stable at 18 U/mL. The patient undergoes an uncomplicated partial pancreaticoduodenectomy, and analysis of a surgical pathology specimen reveals T3N0 disease with closest margin of 0.1 cm.
- Would the patient benefit from adjuvant therapy?
Adjuvant chemotherapy for 6 months after pancreatic cancer resection should be offered to all patients based on mature data. Gemcitabine and capecitabine are the current standard of care in adjuvant therapy; alternatively, single-agent gemcitabine can be offered to patients with poor performance status or patients who cannot tolerate the toxicities associated with this combination.28 Adjuvant treatment should be initiated within approximately 8 weeks of surgical resection. The value of radiation therapy remains controversial, but it can be offered within the context of a clinical trial or to patients with positive margins after surgical resection and/or lymph node–positive disease. Based on low-quality supportive evidence, it is strongly recommended that patients who receive neoadjuvant therapy complete a total of 6 months of chemotherapy, factoring in the duration of the preoperative regimen.28 Different adjuvant strategies have been investigated, including chemotherapy alone with a fluoropyrimidine and/or gemcitabine with or without combined chemoradiation therapy.
The European Study Group for Pancreatic Cancer 1 (ESPAC)-1 trial was a randomized clinical trial that evaluated several adjuvant strategies in pancreatic cancer treatment. This trial assigned patients who underwent pancreatic adenocarcinoma resection to adjuvant chemotherapy alone (intravenous fluorouracil 425 mg/m2 and leucovorin 20 mg/m2 daily for 5 days, monthly for 6 months), chemoradiotherapy (20 Gy in 10 daily fractions over 2 weeks with 500 mg/m2 intravenous fluorouracil on days 1–3, repeated after 2 weeks), both chemotherapy and chemoradiation, and observation.44 The results showed no added benefit for adjuvant chemoradiotherapy, with a median OS of 15.5 months in the chemoradiotherapy cohort, as compared to a median OS of 16.1 months in the chemotherapy-alone cohort (hazard ratio [HR] 1.18 [95% CI 0.90 to 1.55], P = 0.24). In addition, there was evidence of a survival benefit for the chemotherapy-alone arm when compared to the combined modality arm, with a median OS of 19.7 versus 14.0 months, respectively (HR 0.66 [95% CI 0.52 to 0.83], P = 0.0005). Although ESPAC-1 has been criticized for being underpowered to perform statistical comparison, it is still considered a landmark trial demonstrating benefit with single-agent chemotherapy alone. A follow-up analysis of ESPAC-1 showed that adjuvant chemotherapy alone conferred a significant 5-year survival benefit while the combined modality had a deleterious effect on survival. 45 Hence, adjuvant chemotherapy alone became the standard of care in the United States following resection.
The results of the multicenter randomized controlled phase 3 CONKO-001 (CharitéOnkologie 001) trial, which were reported in 2007, supported the use of adjuvant gemcitabine for 6 months in patients with resected pancreatic adenocarcinoma. In this study, patients treated with adjuvant gemcitabine (1000 mg/m2 days 1, 8, and 15 every 4 weeks for 6 months) had superior disease-free survival compared with those who received surgery alone.30 A long-term outcome update of this study demonstrated a significant improvement in 5-year OS for patients treated with adjuvant gemcitabine (20.7% [95% CI 14.7% to 26.6%]) compared to those who received surgical resection alone (10.4% [95% CI 5.9% to 15.0%]). This benefit persisted at 10-year follow-up, with an OS of 12.2% (95% CI 7.3% to 17.2%) in the adjuvant gemcitabine group, as compared to 7.7% (95% CI 3.6% to 11.8%) in the resection alone group.31
Fluorouracil and gemcitabine remained equivalent adjuvant treatment options until the results of the ESPAC-3 trial were reported in 2010.32 This large phase 3 trial, conducted mainly in the United Kingdom, compared weekly gemcitabine (1000 mg/m2 weekly for 3 of every 4 weeks) to leucovorin-modulated fluorouracil (Mayo Clinic regimen: leucovorin 20 mg/m2 followed by fluorouracil 425 mg/m2 intravenous bolus days 1 through 5 every 28 days) as adjuvant therapy in resected pancreatic adenocarcinoma. After a median follow-up of 34.2 months, the median OS was similar in the 2 groups (fluorouracil/leucovorin 23.0 months versus gemcitabine 23.6 months; P = 0.39). However, the fluorouracil/leucovorin group experienced more grade 3/4 treatment-related toxicities (mucositis, stomatitis, diarrhea, and hosptializations; 14% versus 7.5%; P < 0.001).46 Following this trial, gemcitabine became the standard of care for adjuvant chemotherapy for resected pancreatic cancer.
The U.S. Radiation Therapy Oncology Group (RTOG) 9704 trial was conducted to investigate the potential benefit of adding radiation therapy to gemcitabine. This trial demonstrated an improved trend among patients with pancreatic head tumors (but not with cancers of the pancreatic body or tail) who received adjuvant gemcitabine followed by chemoradiotherapy (50.4 Gy in 1.8 Gy daily fractions for 5.5 weeks with concurrent infusional fluorouracil 250 mg/m2 daily) and subsequent gemcitabine monotherapy compared to postoperative fluorouracil-based chemoradiotherapy. Results showed a 5-year OS of 22% versus 18%, respectively, although this improvement was not statistically significant (P = 0.08). This trial failed to show a benefit of adding radiotherapy to gemcitabine.47
The ESPAC-4 trial, reported in 2017, evaluated the combination of gemcitabine and capecitabine compared to gemcitabine alone as adjuvant therapy for resected pancreatic adenocarcinoma.48 Patients were randomly assigned after surgical resection, regardless of margin or node status, to 6 months of gemcitabine alone (1000 mg/m2/day on days 1, 8, and 15 of each 28-day cycle) or gemcitabine plus capecitabine (1660 mg/m2/day on days 1 through 21 of each 28-day cycle). Combination therapy had a significant survival benefit compared to single therapy, with median OS durations of 28 months and 25.5 months, respectively (HR for death 0.82 [95% CI 0.68 to 0.98]). The 5-year OS for patients who received combination treatment was 29 months (95% CI 22.9 to 35.2) versus 16 months (95% CI 10.2 to 23.7) for those in the monotherapy group. As expected, grade 3 or 4 treatment-related toxicities (diarrhea, hand-foot syndrome, and neutropenia) were significantly more common with combined therapy, although there were no significant differences in the rates of serious adverse events. The adjuvant combination of gemcitabine and capecitabine became the current and preferred new standard of care following resection of pancreatic ductal adenocarcinoma,28 but single-agent gemcitabine and fluorouracil/leucovorin continue to be viable options,26,28,29 particularly for elderly patients, patients with borderline performance status, or patients with multiple comorbidities.
Evidence showing that a more intensive regimen can improve outcome in the adjuvant setting remains elusive. The phase 3 APACT study (Adjuvant Therapy for Patients with Resected Pancreatic Cancer, NCT01964430) comparing gemcitabine alone to gemcitabine plus nab-paclitaxel in patients with surgically resected pancreatic adenocarcinoma has concluded, with the results projected to be released in 2018. Another phase 3 trial investigating the efficacy of FOLFIRINOX versus gemcitabine alone as adjuvant therapy is underway in France and Canada (PRODIGE24/ACCORD24, NCT01526135). Other strategies with newer targeted therapies and immunotherapy are in the development phase.
