Adjuvant Pancreatic Cancer Management: Towards New Perspectives in 2021
Abstract
:Simple Summary
Abstract
1. Introduction
2. Summary of Past Experience in Adjuvant Treatment of Operated PDAC
2.1. Chemotherapy
2.2. Radiation Therapy
3. The Current Limitations of Available Therapeutic Options
3.1. GemCap: Methodological Limitations
3.2. FOLFIRINOX: Not for Everyone
3.3. APACT Study: Main Objective with GemNab Combination (DFS) Was not Achieved Despite OS Was Improved
3.4. Particularity of S1 Regimen
4. New Issues
4.1. Induction Strategy
4.2. Which Adjuvant Treatment in Operated Patients Who Receive Neoadjuvant or Induction Strategy?
4.2.1. Adjuvant Treatment according to Response to Induction Treatment
Lymph Node Ratio
R0 Resection Rate
Tumor Regression Score
4.2.2. Adjuvant Treatment According to Induction Chemotherapy Regimen?
Gemcitabine
GemNab
FOLFIRINOX
S1
4.3. What Is the Optimal Delay to Start Adjuvant Treatment?
4.4. In Which Patients?
5. Paradigm Shift, Looking for Biomarkers of Adjuvant Chemotherapy Efficacy
5.1. Biological Markers
5.1.1. Circulating Tumor DNA
5.1.2. CA19-9 Oncomarker
5.1.3. Immune Inflammatory Markers
5.2. Predictive Pathological Biomarkers
5.3. Molecular Markers (see Table 4)
5.3.1. Chemotherapy Signatures Using Organoids
5.3.2. Molecular Classifications
5.3.3. Patients with Germinal or Somatic BRCA Mutation
5.3.4. Patients with a High Microsatellite Instability/Mismatch Repair-Deficient Cancer
6. Better Management of Adjuvant Setting with Supportive Care
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Type of Chemotherapy | Design of the Study | DFS Results | OS Results | Reference |
---|---|---|---|---|
5FU | Phase 3, international, multicentric (N = 541). -CRT (20 Gy in 10 fractions/2 weeks with 500 mg/m2 5FU IV on days 1–3, repeated after 2 weeks) -CT (IV 5FU 425 mg/m2 and folinic acid 20 mg/m2 daily for 5 days, monthly for 6 months). | CRT: -Median DFS: NA CT: -Median DFS: NA | CRT -Median OS: 15.5 months with CRT vs. 16.1 months without; HR: 1.18 (95% CI 0.90–1.55), p = 0.24 CT -Median OS: 19.7 months with CT vs. 14.0 months without; HR 0.66 (0.52–0.83), p = 0.0005. | ESPAC-1 [13] |
Gemcitabine | Phase 3, international, multicentric (N = 368). -gemcitabine 1000 mg/m2 IV once a week for 3 of every 4 weeks for 6 months -or observation | Gemcitabine -Median DFS: 13.4 months (95% CI, 11.4–15.3) Observation -Median DFS 6.9 months (95% CI, 6.1–7.8); p < 0.001. | Gemcitabine -Median OS: 22.1 months (95% CI, 18.4–25.8) Observation -Median OS: 20.2 months (95% CI, 17–23.4) | ISRCTN34802808 [14] |
Gemcitabine vs. 5FU | Phase 3, international, multicentric (N = 287) Chemotherapy -5FU IV 425 mg/m2 administered 1 to 5 days every 28 days or gemcitabine 1000 mg/m2 IV once a week for 3 of every 4 weeks for 6 months. -or observation | -Two chemotherapy groups Median DFS: 5FU: 23.0 months (95% CI, 17.0–51.9 months) Gemcitabine: 29.1 months (95% CI, 19.5–45.4 months) -Observation: 19.5 months (95% CI, 14.2–30.3 months) | -Two chemotherapy groups Median OS: 43.1 (95%, CI, 34.0–56.0); HR: 0.86 (95% CI, 0.66–1.1), p = 0.25. Observation: Median OS: 35.2 months (95% CI, 27.2–43.0) | ESPAC-3 [15] |
GemCaP | Phase 3, open-label, international multicentric (N = 732) Randomisation 1:1 Six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine (=GemCap group) administered for 21 days followed by 7 day’ rest (one cycle). | GemCap: -Median DFS 13.9 months (12.1–16.6) Gemcitabine -Median DFS 13.1 months (11.6–15.3); HR 0.86, 95% CI 0.73–1.02, p = 0.082. | GemCap Median OS: 28.0 months (95% CI 23.5–31.5) Gemcitabine Median OS: 25.5 months (22.7–27.9) HR: 0.82 (95% CI 0.68–0.98), p = 0.032. | ESPAC-4 [11] |
GemNab | Phase 3, international, multicentric (N = 866) Randomisation 1:1 Nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 (GemNab group) or gemcitabine 1000 mg/m2 (Gem group) for 3 of every 4 weeks for 6 months. | GemNab: -Median independent reviewer-assessed DFS: 19.4 months Gemcitabine Median independent reviewer-assessed DFS: 18.8 months HR: 0.88 (95% CI, 0.729–1.063); p = 0.1824. | GemNab: -Interim OS: 40.5 months Gemcitabine: -Interim OS: 36.2 months HR, 0.82; 95% CI, 0.680–0.996; nominal p = 0.045). | APACT [10] |
mFOLFIRINOX | Phase 3, international, multicentric (N = 493) mFOLFIRINOX regimen (combining 5FU 2400 mg/m2, irinotecan 150 mg/m2 and oxaliplatin 85 mg/m2 every 14 days for 12 cycles) versus gemcitabine 1000 mg/m2 during 6 months. | mFOLFIRINOX: -Median DFS: 21.6 months Gemcitabine: Median DFS: 12.8 months; stratified HR for cancer-related event, second cancer, or death: 0.58 (95% CI, 0.46–0.73); p < 0.001. | mFOLFIRINOX: -Median OS: 54.4 months (95% CI, 41.8 to not reached) Gemcitabine: -Median OS: 35.0 months (95% CI, 28.7 to 43.9) (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; p = 0.003) | PRODIGE 24 [9] |
S1 | Phase 3, multicentric, in Japan (N = 385) Randomised 1:1 gemcitabine 1000 mg/m2 IV once a week for 3 of every 4 weeks for 6 months or S-1 40 mg, 50 mg, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14 days rest, every 6 weeks (one cycle), for up to 4 cycles. | S1: Median DFS 22.9 months (17.4–30.6) Gemcitabine: Median DFS: 11.3 months (95% CI 9.7–13.6) -HR for relapse 0.60 (95% CI 0.47–0.76, p < 0·0001). | S1: Median OS: 46.5 months (37.8–63.7) Gemcitabine: Median OS: 25.5 months (95% CI 22.5–29.6) -HR of mortality: 0.57 (95% CI 0.44–0.72), p non-inferiority < 0.0001, p < 0.0001 for superiority | JASPAC-01 [12] |
CAP Score Index | Description |
---|---|
0 | No viable cancer cells (complete response) |
1 | Single cells or rare small groups of cancer cells (near complete response) |
2 | Residual cancer with evident tumor regression, |
3 | Extensive residual cancer with no evident tumor regression (poor or no response) |
Type of Chemotherapy | Design of the Study | DFS Results | OS Results | Reference |
---|---|---|---|---|
Gemcitabine | Randomized phase III multicentric (N = 248) Patients with (borderline) resectable pancreatic cancer Arm A: immediate surgery Arm B: preoperative CRT Both followed by adjuvant gemcitabine. The preoperative CRT consisted of 15 times of 2.4 Gy combined with gemcitabine 1000 mg/m2 on days 1, 8 and 15, preceded and followed by a cycle of gemcitabine. | Median DFS Arm A: 7.7 months Arm B: 8.1 months; HR 0.73; p = 0.032. | Median OS Arm A: 13.5 months Arm B: 17.1 months; HR 0.71; p = 0.047. | PREOPANC-1 [34,38] |
Gemcitabine vs. mFOLFIRINOX | Randomized phase II multicentric trial (N = 102) Patients with resectable pancreatic cancer. Peri-op CT (12 weeks pre-, 12 weeks post-op) with either mFOLFIRINOX (Arm 1) or Gem/nab (Arm 2). | Median DFS: Arm 1: 10.9 months Arm 2: 14.2 months p = 0.87 | Median OS: Arm 1: 22.4 months Arm 2: 23.6 months | SWOG S1505 [49] |
S1 | Randomized phase II/III multicentric trial (N = 364) Resectable PDAC Neoadjuvant chemotherapy with gemcitabine + S1 or upfront surgery. Adjuvant S-1 was administered for 6 months to patients with curative resection. | Median DFS: not yet communicated | Median OS Neoadjuvant Gemcitabine + S1: 36.7 month Upfront surgery+adjuvant S1: 26.6 months; HR 0.72 (95% CI 0.55–0.94); p = 0.015. | JSAP-05 [50,51] |
Prognostic Factor | Design, Type of Study | N | Multivariate Analysis | Reference | ||
---|---|---|---|---|---|---|
HR (95% CI) | Outcome | p-Value | ||||
Biological markers | ||||||
Pre-operative ctDNA | Pre- and post-operative samples for ctDNA analysis collected. PCR-based-SafeSeqS assays used to identify mutations of KRAS in the primary tumor and to detect ctDNA | 112 patients in the study In 42 plasma available samples, KRAS mutated ctDNA detected in 62% (23/37) pre-operative and 37% (13/35) post-operative | HR 4.1 | RFS | p = 0.002 | [62] |
HR: 4.1 | OS | p = 0.015 | ||||
Post-operative ctDNA | HR: 5.4 | RFS | p < 0.0001 | |||
HR: 4.0 | OS | p = 0.003 | ||||
CA 19-9 | Prospective analysis of CA 19-9 levels in patients treated with adjuvant CRT in RTOG 9704 phase III trial | 385 patients with assessable CA 19-9 | HR: 3.53 | Cutoff 180 significant survival difference favoring patients with CA 19-9 < 180 | p < 0.0001 | [65] |
HR: 3.4 | Cutoff 90 significant survival difference in patients with CA 19-9 < or = 90 (HR, 3.4; p < 0.0001) | p < 0.0001 | ||||
Neutrophil to lymphocyte ratio | Meta-analysis retrospective studies | 1519 patients (8 studies) | Pooled HR: 1.77 | Association between a “high” pre-operative NLR and OS. | p < 0.01 | [71] |
Pathological markers | ||||||
hENT1 | Ancillary study of ESPAC3 Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody | 380 patients (87.6%) and 1808 cores were suitable and included in the final analysis. | HR: 9.87 | “Low” hENT1 expression: Median survival with gemcitabine 17.1 (95% CI = 14.3 to 23.8) months | p = 0.002 | [73] |
“high” hENT1 expression: Median survival: 26.2 (95% CI = 21.2 to 31.4) months | ||||||
Molecular markers | ||||||
BRCA | Prospective studies are warranted in adjuvant setting | [80] | ||||
MSI-H | Prospective studies are warranted in adjuvant setting | [84] | ||||
Organoids | Prospective studies are warranted in adjuvant setting | [77] | ||||
Molecular classifications | Prospective studies are warranted in adjuvant setting | [78] |
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Turpin, A.; el Amrani, M.; Bachet, J.-B.; Pietrasz, D.; Schwarz, L.; Hammel, P. Adjuvant Pancreatic Cancer Management: Towards New Perspectives in 2021. Cancers 2020, 12, 3866. https://doi.org/10.3390/cancers12123866
Turpin A, el Amrani M, Bachet J-B, Pietrasz D, Schwarz L, Hammel P. Adjuvant Pancreatic Cancer Management: Towards New Perspectives in 2021. Cancers. 2020; 12(12):3866. https://doi.org/10.3390/cancers12123866
Chicago/Turabian StyleTurpin, Anthony, Mehdi el Amrani, Jean-Baptiste Bachet, Daniel Pietrasz, Lilian Schwarz, and Pascal Hammel. 2020. "Adjuvant Pancreatic Cancer Management: Towards New Perspectives in 2021" Cancers 12, no. 12: 3866. https://doi.org/10.3390/cancers12123866