eUpdate: Cancer of the Pancreas Treatment Recommendations

eUpdate – Cancer of the pancreas treatment recommendations

Published: 15 March 2019Authors: ESMO Guidelines Committee

Note: Other eUpdates may have been published for these guidelines. All currently valid eUpdates can be accessed from the page displaying the full guidelines on this topic

Clinical Practice Guidelines

This update refers to the Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ducreux M, Sa Cuhna A, Caramella C, et al. Ann Oncol 2015; 26(suppl 5): v56-v68.

Section 

Treatment, Adjuvant chemotherapy.

Text update

Postoperative adjuvant chemotherapy has been evaluated in several randomised trials. Two major recent trials evaluating the role of adjuvant chemotherapy (ChT) in pancreatic cancer have been published. They are changing the standard of care of adjuvant treatment of pancreatic cancer.

The first is ESPAC-4, including 732 patients ≥ 18 years of age, who had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas [no tumour cell at the margin (R0) or microscopic tumour at the margin (R1) resection] [1]. Patients were randomised to receive either gemcitabine alone or a combination of gemcitabine and capecitabine for 6 months, starting within 12 weeks of surgery (ESPAC-4 trial) [1]. Median relapse-free survival was 13.1 months (11.6-15.3) in the gemcitabine group and 13.9 months (12.1-16.6) in the gemcitabine/capecitabine group [hazard ratio (HR) 0.86 (95% confidence interval (CI) 0.73-1.02), p=0.082].

The median overall survival (OS) for patients in the gemcitabine/capecitabine group was 28 months (95% CI 23.5-31.5) compared with 25.5 months (22.7-27.9) in the gemcitabine group [HR 0.82 (95% CI 0.68-0.98), p=0.032]. Grade 3-4 adverse events (AEs) were reported more frequently in the combined group but toxicity was considered to be manageable. There was no difference in terms of quality of life between the two groups. There seem to be some differences in efficacy according to prognostic subgroups. R0 patients had a major advantage with the addition of capecitabine: median OS of 39.5 months versus 27.9 months (23.8-34.6); on the contrary, there was no difference for patients with positive margins (R1 resection) with median OS 23.7 (20.7-27.1) in the combined group versus 23.0 months in the monotherapy group.

The second trial (PRODIGE 24/CCTG PA.6 trial) evaluated the role of a modified regimen of 5-fluorouracil (5-FU)/irinotecan/oxaliplatin (mFOLFIRINOX) given after resection of pancreatic cancer compared with gemcitabine alone [2]. At 3-12 weeks after surgery, 493 patients with R0 or R1 resection were included and were randomly assigned to receive mFOLFIRINOX or gemcitabine for 6 months. Median disease-free survival (DFS) was 12.8 months (95% CI 11.7-15.2) in the control group versus 21.6 months (95% CI 17.5-26.7) in the mFOLFIRINOX group, HR 0.59 (95% CI 0.47-0.74). The DFS benefit with mFOLFIRINOX was significant in the majority of subgroups, including R0 and R1 resection. The median OS was 35.0 months (95% CI 28.7-43.9) in the control group versus 54.4 months (95% CI 41.5-not reached), HR 0.66 (95% CI 0.49-0.89). Grade 3-4 toxicity was significantly higher in the mFOLFIRINOX group (grade 3-4 AEs: 75.5% versus 51.1%), with more fatigue, sensory peripheral neuropathy, nausea, vomiting, mucositis and diarrhoea. However, there was no difference in terms of grade 4 AEs between the two groups, or in the risk of febrile neutropaenia, and the only observed death was in a patient treated with gemcitabine.

Considering these results, the standard of care for patients after the resection of their pancreatic tumour should be combined postoperative ChT instead of gemcitabine monotherapy. Although there is no direct comparison between gemcitabine plus capecitabine and mFOLFIRINOX, it seems that the triplet ChT is the best treatment for fit patients.

The arguments in favour of this recommendation are:

  • the best overall OS ever observed with mFOLFIRINOX in these patients;
  • the previous demonstration of a better efficacy of FOLFIRINOX versus gemcitabine in metastatic disease [3];
  • a manageable toxicity of the modified regimen (mFOLFIRINOX), even after pancreatic surgery, when using no bolus of 5-FU and a decreased dose of irinotecan (150 mg/m²).

Recommendations  

  • mFOLFIRINOX should be the first adjuvant therapeutic option after resection of pancreatic cancer in selected and fit patients, in view of survival outcomes and associated toxicity profile [I, A; ESMO-Magnitude of Clinical Benefit Scale (MCBS) v1.1 score: A].
  • In more frail patients (age > 70, Eastern Cooperative Oncology Group performance status 2, or patients who have any contraindication to the drugs used in FOLFIRINOX), gemcitabine/capecitabine could be an option [I, B; ESMO-MCBS v1.1 score A].
  • Gemcitabine alone should be used only in frail patients.

ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) table for new therapies/indications in cancer of the pancreas*

Therapy Disease setting Trial Control Absolute survival gain HR (95% CI) Toxicity/Qol MCBS score**
Nanoliposomal irinotecan and 5-FU/LV  Patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy

Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1) [4]

Phase III

NCT01494506

5-fluorouracil and folinic acid

Median OS:
4.2 months

OS gain:
1.9 months
OS HR:
0.67 (0.49–0.92)
Similar QoL and more frequent grade 3-4 adverse events

2 (Form 2a)

 

Gemcitabine
± capecitabine
Patients with resected pancreatic ductal adenocarcinoma

Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial [1]

Phase III

ISRCTN96397434

Gemcitabine

Median OS: 25.5 months

OS gain: 2.5 months

>10% at 5 years 

OS HR: 0.82 (0.68-0.98)   A (Form 1)
mFOLFIRINOX Patients with resected pancreatic ductal adenocarcinoma

Trial comparing adjuvant chemotherapy with gemcitabine versus mFOLFIRINOX to treat resected pancreatic adenocarcinoma (PRODIGE 24/CCTG PA.6 trial) [2]

Phase III

NCT01526135

Gemcitabine

Median OS: 35.0 months

OS gain: 19.4 months

3-year survival gain: 14.8% 

OS HR:
0.64 (0.48-0.86)
Increased acute toxicity A (Form 1)

*EMA approvals from January 2016.

**ESMO-MCBS version 1.1 [5]. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee.

5-FU, 5-fluorouracil; CI, confidence interval; EMA, European Medicines Agency; HR, hazard ratio; LV, leucovorin; ESMO-MCBS, ESMO-Magnitude of Clinical Benefit Scale; mFOLFIRINOX, modified regimen of 5-FU/irinotecan/oxaliplatin; OS, overall survival; QoL, quality of life.

References

  1. Neoptolemos JP, Palmer DH, Ghaneh P et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 2017; 389: 1011-1024.
  2. Conroy T, Hammel P, Hebbar M et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018; 379: 2395-2406.
  3. Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J Med 2011; 364: 1817-1825.
  4. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 2016; 387: 545-557.
  5. Cherny NI, Dafni U, Bogaerts J et al. ESMO-Magnitude of Clinical Benefit Scale Version 1.1. Ann Oncol 2017; 28: 2340-2366.