Normo- or Hypo-Fractionated Photon or Proton Radiotherapy in the Management of Locally Advanced Unresectable Pancreatic Cancer: A Systematic Review
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Inclusion and Exclusion Criteria
2.3. Data Extraction and Statistical Analysis
2.4. Bias Assessment
3. Results
3.1. Search Results
3.2. Studies and Patient Characteristics
3.3. Radiation Therapy
3.4. Chemotherapy Regimens
3.5. Acute G3/G4 or Higher Toxicity
3.6. Late G3/4 or Higher Toxicity
3.7. Survival Outcomes
3.8. Overall Risk of Bias
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Study | Study Type | N | Dose/Gy | Technique | Chemotherapy | Median OS, Months | 1-Year OS Rate, % | 2-Year OS Rate, % | Local Control | Acute G3/4 Toxicity | Late G3/4 Toxicity |
---|---|---|---|---|---|---|---|---|---|---|---|
Liermann et al., 2022, arm A [17] | (Long-term results of phase II PARC trial) | 35 | 45 Gy/25 fractions with SIB to 54 Gy | IMRT | Concurrent gemcitabine/cetuximab followed by maintenance gemcitabine | 11.9 | 47% | 14.7% | 1-year LC rate approximately 65% (from figure) | G3 nausea: 4% G3/4 leucopenia: 37% G3/4 anemia: 14% | Not observed |
Liermann et al., 2022, arm B [17] | (Long-term results of phase II PARC trial) | 33 | 45 Gy/25 fractions with SIB to 54 Gy | IMRT | Concurrent gemcitabine/cetuximab followed by maintenance gemcitabine/cetuximab | 14.2 | 60.6% | 27% | 1-year LC rate approximately 85% (from figure) | G3 nausea: 9% G3/4 leucopenia: 25% G3/4 anemia: 9% | G3 ileus: 3% G3 GIT Hge: 1% |
Esnaola et al., 2014 [18] | Phase II | 19 | 45.9 Gy/30 fractions with SIB to 54 Gy | IMRT | Induction gemcitabine/oxaliplatin /cetuximab + concurrent capecitabine | 9.3 | NR | NR | 8.3% underwent R0 resection | Combined with BRPC patients | NR |
Hammel et al., 2016, CRT arm [19] | Phase III | 133 | 54 Gy/30 fractions | 3DCRT | Concurrent capecitabine, either induction gemcitabine alone or gemcitabine + erlotinib followed by maintenance therapy | 15.2 | NR | NR | Loco-regional progression rate: 32% | Total hematological toxicity: 3.9% Total non-hematological toxicity: 23.1% | NR |
Ducreux et al., 2014 [20] | Phase II | 51 | Median dose 54 Gy/30 fractions | 3DCRT | Concurrent docetaxel/cisplatin | 9.6 | 41% | NR | CR + PR: 27% SD: 51% PD: 14% (8% not evaluated) | GIT toxicity: 43% hematological toxicity: 8% | NR |
Comb et al., 2013, arm A [21] | Phase II | 57 | A median total dose of 45 Gy/25 fractions with SIB to 54 Gy | IMRT | Concurrent and adjuvant gemcitabine | 11 | 36% | 8% | SD: 88% PD: 5% PR: 7% | Not observed | NR |
Comb et al., 2013, arm B [21] | 198 | Median dose of 52.2 Gy/28 fractions | 3DCRT | Concurrent and adjuvant gemcitabine | 12.3 | NR | NR | SD: 80% PD: 11% PR: 9% | Not observed | NR | |
Youl et al., 2013 [22] | Retrospective | 74 | Median total dose of 52.5 Gy/30 fractions | 3DCRT or IMRT | Induction and concurrent gemcitabine | 12.7 | 53.6% | 14.7% | SD: 60.8% PD: 22.9% | NR | NR |
Mukherjee et al., 2013, capecitabine arm (SCALOP trial) [23] | Phase II | 36 | Median total dose of 50.4 Gy/28 fractions | 3DCRT or IMRT | Induction gemcitabine/capecitabine + concurrent capecitabine | 15.2 | 79.2% | NR | CR: 6% PR: 17% SD: 63% PD: 14% | Both hematological and non-hematological: 12% | NR |
Mukherjee et al., 2013, gemcitabine arm (SCALOP trial) [23] | Phase II | 38 | Median total dose of 50.4 Gy/28 fractions | 3DCRT or IMRT | Induction gemcitabine/capecitabine + concurrent gemcitabine | 13.4 | 64.2% | NR | CR: 0% PR: 19% SD: 67% PD: 14% | Both hematological and non-hematological: 37% | NR |
Hurt et al., 2017 [24] | (Long-term results of SCALOP trial) | Capecitabine arm: 17.6 Gemcitabine arm: 14.6 | |||||||||
Su et al., 2022, GOLF arm [25] | Phase II | 17 | 50.4 Gy/28 fractions | IMRT | Induction GOLF followed by concurrent gemcitabine | 17.9 | 82.1% | 31.8% | PR: 24% SD: 65% PD: 11% | G3/4 leukopenia: 29.4% | NR |
Su et al., 2022, mFOLFIRINOX arm [25] | Phase II | 21 | 50.4 Gy/28 fractions | IMRT | Induction m FOLFIRINOX followed by concurrent 5-FU | 19.6 | 88.9% | 29.6% | PR: 29%, SD: 33% PD: 38% | G3/4 leukopenia: 0% | NR |
Fiore et al., 2017 [26] | Phase II | 27 | 59.4 Gy/33 fractions | 3DCRT | IC gemcitabine/oxaliplatin then concurrent gemcitabine | 14 | Combined with BRPC patients | Combined with BRPC patients | 40.7% became resectable | Combined with BRPC patients | NR |
Kim et al., 2012 [27] | Phase II | 25 | Median total dose of 54 Gy/30 fractions | 3DCRT | Induction gemcitabine/cisplatin—concurrent capecitabine followed by gemcitabine | 16.8 | 69.1% | 16.1% | PD: 14.3% | G3 neutropenia: 4% G3 anemia: 4% G3 nausea/vomiting: 4% G3 diarrhea: 8% | NR |
Sudo et al., 2017 [28] | Phase II | 23 | 50.4 Gy/28 fractions | 3DCRT | Induction gemcitabine/S1 then CRT with S1 followed by maintenance therapy with S1 | 22.9 | 82.6% | 43.5% | Significant reduction in tumor size (median size, from 41 to 32 mm) | G3 neutropenia: 4.3% G3 biliary tract infection: 8.7% | NR |
Ikeda et al., 2013 [29] | Phase II | 53 | 50.4 Gy/28 fractions | 3DCRT | Concurrent S1 followed by maintenance S1 | 16.2 | 72% | 26% | PR: 27%, SD: 67% | G3 leukocytopenia: 10% G3 gastric ulcer: 2% | NR |
Ioka et al., 2021, CRT arm [30] | Phase II | 50 | 50.4 Gy/28 fractions | 3DCRT | Concurrent S1 + maintenance gemcitabine | 19 | 66.7% | 36.9%, | NR | G3 leucopenia: 60% G3 anorexia: 16% G3 biliary infection: 18% | NR |
Ioka et al., 2021, IC-CRT arm [30] | Phase II | 34 | 50.4 Gy/28 fractions | 3DCRT | Induction gemcitabine then CRT + maintenance gemcitabine | 17.2 | 69.3% | 18.9% | NR | G3 leucopenia: 59% G3 anorexia: 4% G3 biliary infection: 27% | NR |
Oh et al., 2018 [31] | Retrospective | 47 | 44 Gy/22 fractions with SIB to 55 Gy | IMRT | Concurrent chemotherapy, with gemcitabine (n = 37) and capecitabine (n = 10) with or without induction chemotherapy | 14.2 | NR | NR | PR: 61.7% SD: 38.3% | G3 hematological toxicity: 12.8% G3 GIT toxicity: 2.1% | G3 anemia: 2.1% |
Study | Study Type | N | Total Dose/Gy | Chemotherapy | Median OS, Months | 1-Year OS Rate, % | 2-Year OS Rate, % | Local Control | Acute G3/4 Toxicity | Late Toxicity |
---|---|---|---|---|---|---|---|---|---|---|
Quan et al., 2018 [32] | Phase II | 16 | 36 Gy/3 fractions | Induction gemcitabine/capecitabine ± adjuvant chemotherapy | 14.3 | 60% | 16% | m LPFS: 28.1 months 1-year LPFS rate: 78% 2-year LPFS rate: 52% | Not observed | NR |
Zhu et al., 2021 [33] | Phase II | 63 | 35–40 Gy/5 fractions | Sequential S1 one month after SBRT | 14.4 | 73% | NR | Local recurrence rate: 15.9% regional recurrences: 30.2% | Total G3 toxicity: 14.3% | Total G3 toxicity: 4.8% |
Moningi et al., 2015 [34] | Retrospective | Unresectable: 74 | 25–33 Gy/5 fractions | Different IC regimens followed by post SBRT chemotherapy | 18.4 | Reported combined with BRPC patients | Reported combined with BRPC patients | 15 patients underwent surgery, LPFS combined with BRPC patients | Reported combined with BRPC patients | reported combined with BRPC patients |
Heerkens et al., 2018 [35] | Phase II | 20 | 24 Gy/3 fractions | ±Post SBRT gemcitabine/nab-paclitaxel or FOLFIRINOX | 8.5 | NR | NR | SD: 39% PD: 61% CR or PR: 0% | Not observed | Not observed |
Comito et al., 2017 [36] | Phase II | 45 | 45 Gy/6 fractions | Pre or post SBRT different chemotherapy regimens | 19 months from diagnosis | 85% from diagnosis | 33% from diagnosis | m FFLP: 26 months | Not observed | Not observed |
Teriaca et al., 2021 [37] | Phase II | 39 | 40 Gy/8 fractions | IC FOLFIRINOX | 18 | 77% | NR | 1-year LC rate: 80%, 3-year LC rate: 53% | Not observed | G3 toxicity or higher: 10% |
Herman et al., 2015 [38] | Phase II | 49 | 33 Gy/5 fractions | Induction and post SBRT Gemcitabine | 13.9 | 59% | 18% | 1-year FFLP rate: 78% | G3 or more gastric ulcer: 2% G3 lymphopenia: 8.2% | G3 or more gastric ulcer: 6.4% |
Chuong et al., 2013 [39] | Retrospective | 16 | 35–50 Gy/5 fractions | Induction gemcitabine followed by SBRT | 15 | 68.1% | NR | Surgical resection: 12.5% (other LC parameters were combined with BRPC) | Not observed | Total G3 toxicity: 5.3% |
Song et al., 2015 [40] | Retrospective | 59 | Median total dose of 45 Gy/5 fractions | 90% of patients received chemotherapy before or after treatment | 12.5 | 53.9% | 35.1% | 1-year FFLP rate was 90.8% | Not observed | G3 GIT reaction: 1 patient |
Lin et al., 2015, SBRT arm [41] | Retrospective | 20 | 35–45 Gy/5 fractions | Different concurrent chemotherapy regimens | 20 | 80% | NR | 1-year LDFS approximately 70% (from the figure) | Not observed | NR |
Study | Study Type | N Patients | Total Dose Gy (RBE) | Technique | Chemotherapy | Median OS, Months | 1-Year OS Rate, % | 2-Year OS Rate, % | Local Control | Acute G3/4 Toxicity | Late G3/4 Toxicity |
---|---|---|---|---|---|---|---|---|---|---|---|
Kim et al., 2020 [42] | Retrospective | 81 | PTV1: 45 or 50 Gy PTV2: 30 Gy/10 fractions | Passive scattered proton beams | Upfront or maintenance chemotherapy or neither ± concurrent fluoropyrimidine chemotherapy | 19.3 | NR | NR | PR: 6.% SD: 80% PD: 14% | Not observed | Not observed |
Terashima et al., 2012 [43] | Phase I/II | 5 | 50 Gy/25 fractions | NR | Concurrent and adjuvant gemcitabine | NR | NR | NR | NR | G3 leukopenia: 20% G3 neutropenia: 20% G3 fatigue: 20% G3 anorexia: 20% | NR |
Terashima et al., 2012 [43] | Phase I/II | 5 | 70.2 Gy/26 fractions | NR | Concurrent and adjuvant gemcitabine | NR | NR | NR | NR | G3 leukopenia: 60% G3 neutropenia: 40% G3 anorexia: 20% | G3 GIT: 20% |
Terashima et al., 2012 [43] | Phase I/II | 40 | 67.5 Gy/25 fractions | NR | Concurrent and adjuvant gemcitabine | NR | 78.8% | NR | 1-year FFLP: 79.9% | G3 hematological toxicity: 66% G4: 7.5%, G3 GIT toxicity: 21% | G3 anorexia: 3%, G3 gastric ulcer: 8% G3 fatigue: 3% G5 gastric ulcer: 3% |
Terashima et al., 2012 [43] | Phase I/II | 50 | 50–70.2 Gy/ 25–26 | NR | Concurrent and adjuvant gemcitabine | 22 (from the curve) | 76.8% | NR | 1-year FFLP: 81.7% | ||
Nichols et al., 2013 [44] | Prospective single institute | Unresectable: 12 | Medan dose 59.4 Gy/33 fractions | NR | Concurrent capecitabine | 8.8 | NR | NR | NR | Not observed | NR |
Sachsman et al., 2014 [45] | Prospective single institute | 11 | 59.4 Gy/33 fractions | Passive scattering proton beams | Concomitant capecitabine | 18.4 | 61% | 31% | 1- and 2-year FFLP: 86% and 6% | Not observed | NR |
Ogura et al., 2022 [46] | Retrospective | 123 | 67.5 Gy/25 fractions | NR | Concurrent and adjuvant gemcitabine | 18.7 | 70.4% | 35.7% | 1-year LPFS: 78.2% 2-year LPFS: 59% | All are hematological: G3: 42% G4: 2% | GIT toxicity: G3: 5% G4: 2% G5: 2% |
Maemura et al., 2017, PT arm [47] | Prospective non-randomized | 10 | 50 Gy or 67.5 Gy/25 fractions | NR | IC followed by concurrent S1 + maintenance S1 | 22.3 | 80% | 45% | PR: 20% SD: 60% PD: 20% | One patient developed G3 ulcer | NR |
Study | Major Domains | Minor Domains | |||||
---|---|---|---|---|---|---|---|
Selection of Participants | Clarification of Intervention | Measurements of Outcomes | Missing Data | Funding | Conflict of Interest | Overall | |
Liermann et al., 2022 [17] | |||||||
Esnaola et al., 2014 [18] | |||||||
Hammel et al., 2016 [19] | |||||||
Ducreux et al., 2014 [20] | |||||||
Comb et al., 2013 [21] | |||||||
Youl et al., 2013 [22] | |||||||
Mukherjee et al., 2013 [23] | |||||||
Hurt et al., 2017 [24] | |||||||
Su et al., 2022 [25] | |||||||
Fiore et al., 2017 [26] | |||||||
Kim et al., 2012 [27] | |||||||
Sudo et al., 2017 [28] | |||||||
Ikeda et al., 2013 [29] | |||||||
Ioka et al., 2021 [30] | |||||||
Oh et al., 2018 [31] |
Study | Major Domains | Minor Domains | |||||
---|---|---|---|---|---|---|---|
Selection of Participants | Clarification of Intervention | Measurements of Outcomes | Missing Data | Funding | Conflict of Interest | Overall | |
Quan et al., 2018 [32] | |||||||
Zhu et al., 2021 [33] | |||||||
Moningi et al., 2015 [34] | |||||||
Heerkens et al., 2018 [35] | |||||||
Comito et al., 2017 [36] | |||||||
Teriaca et al., 2021 [37] | |||||||
Herman et al., 2015 [38] | |||||||
Chuong et al., 2013 [39] | |||||||
Song et al., 2015 [40] | |||||||
Lin et al., 2015 [41] |
Study | Major Domains | Minor Domains | |||||
---|---|---|---|---|---|---|---|
Selection of Participants | Clarification of Intervention | Measurements of Outcomes | Missing Data | Funding | Conflict of Interest | Overall | |
Kim et al., 2020 [42] | |||||||
Terashima et al., 2012 [43] | |||||||
Nicolas et al., 2013 [44] | |||||||
Sachsman et al., 2014 [45] | |||||||
Ogura et al., 2022 [46] | |||||||
Maemura et al., 2017 [47] |
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Elkhamisy, S.A.; Valentini, C.; Lattermann, A.; Radhakrishna, G.; Künzel, L.A.; Löck, S.; Troost, E.G.C. Normo- or Hypo-Fractionated Photon or Proton Radiotherapy in the Management of Locally Advanced Unresectable Pancreatic Cancer: A Systematic Review. Cancers 2023, 15, 3771. https://doi.org/10.3390/cancers15153771
Elkhamisy SA, Valentini C, Lattermann A, Radhakrishna G, Künzel LA, Löck S, Troost EGC. Normo- or Hypo-Fractionated Photon or Proton Radiotherapy in the Management of Locally Advanced Unresectable Pancreatic Cancer: A Systematic Review. Cancers. 2023; 15(15):3771. https://doi.org/10.3390/cancers15153771
Chicago/Turabian StyleElkhamisy, Sally A., Chiara Valentini, Annika Lattermann, Ganesh Radhakrishna, Luise A. Künzel, Steffen Löck, and Esther G. C. Troost. 2023. "Normo- or Hypo-Fractionated Photon or Proton Radiotherapy in the Management of Locally Advanced Unresectable Pancreatic Cancer: A Systematic Review" Cancers 15, no. 15: 3771. https://doi.org/10.3390/cancers15153771