Are Aspects of Integrative Concepts Helpful to Improve Pancreatic Cancer Therapy?
Abstract
Simple Summary
Abstract
1. Introduction
2. Standard Oncological Pancreatic Cancer Therapy
3. Targeted Therapy and Selective Precision Medicine
4. Anti-Tumor Mechanisms in PC Treatment
4.1. Anti-Stromal Effects
4.2. Immunomodulation
4.3. Induction of Apoptosis
4.4. Anti-Inflamation
5. Strategies to Overcome the Tumor Barrier
5.1. Nanomedicine
5.2. Hyperthermia
5.3. Electroporation
5.4. Intra-Tumoral Applications
5.5. Vaccines
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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No | Study ID Estimated Completion | Population | Design | Interventions | Outcomes | Locations |
---|---|---|---|---|---|---|
1 | NCT04241276 2024 | 170 PC | Multicentric Phase 2, RCT 2 armed | Oral ATRA in combination with gemcitabine and nab-paclitaxel/only gemcitabine and nab-paclitaxel | PFS; RR; OS; AEs; surgical resection rate; QL | UK |
2a | NCT03541486 2030 | 60 PC neoplasms | Phase 2 2 armed | Vit C infusions in combination with Ctx and Radio standard therapy/only standard therapy | OS; RR; PFS; Tox | USA |
2b | NCT03146962 2023 | 50 PC, colorectal and lung cancer | Multicentric Phase 2 3 armed | (A) High-Dose Vit C IV 2–4 weeks prior surgery; (B) 6 months; (C) 1–2 weeks prior to and following radioembolization of hepatic metastases | RR; Tox; PFS; VitC levels | USA |
2c | NCT03410030 2022 | 36 PC stage IV | Phase 1/2 1 armed | Vit C infusions in combination with Nanoparticles Paclitaxel + Cisplatin + Gemcitabine | Tox; OS; PFS; QL; pain | USA |
2d | NCT01852890 2024 | 16 PC neoplasms | Phase 1 1 armed | Dose-escalation of Vit C infusions in combination with gemcitabine and radiotherapy | AEs during radiation; progression; OS; AEs post-treatment | USA |
2e | NCT02905578 2025 | 65 PC neoplasms | Phase 2, RCT 2 armed | Vit C infusions in combination with gemcitabine and nab-paclitaxel/only Ctx standard therapy | OS; RR; PFS; AEs | USA |
2f | NCT03146962 2023 | 78 PC, colorectal and lung cancer | Phase 2 1 armed | High dose Vit C IV infusions in patients with solid tumor malignancies | Anti-tumor activity; disease control; max tolerated Vit C dose; PFS; AEs | USA |
3a | NCT03520790 2025 | 112 PC stage IV | Phase 1/2 RCT Placebo 2 armed | Paricalcitol (IV or orally) in combination with gemcitabine and Nab-Paclitaxel/Placebo | AEs; OS; RR; PFS | USA |
3b | NCT03331562 2020 | 24 PC | Phase 2, RCT Multicentric Placebo 2 armed | Paricalcitol IV combined with Pembrolizumab/Placebo | Progression; Tox; OS; mutations (sequencing); Vit D receptor binding sites | USA |
3c | NCT02930902 2022 | 24 PC (resectable) | Phase 1 2 armed | Paricalcitol IV and pembro-zumab without and with Ctx | Tox; AEs; resection rate; disease free survival; OS | USA |
3d | NCT03883919 2022 | 20 PC stage IV | Phase 1 Pilot 1 armed | Paricalcitol in combination with liposomal Irinotecan Plus | Tox, RR, PFS; OS; CA19-9 PC-tumormarker; duration of response | USA |
3e | NCT03415854 2023 | 14 PC (untreated) | Phase 2 1 armed | Paricalcitol in combination with cisplatin, paclitaxel, and gemcitabine | RR; CA19-9 PC-tumormarker; biomarker (Paricalcitol, Ctx) | USA |
3f | NCT03138720 2023 | 24 PC (untreated) | Phase 2 1 armed | Paricalcitol in combination with cisplatin, paclitaxel, and gemcitabine | CA19-9 PC-tumormarker; RR; OS | USA |
3g | NCT05365893 2023 | 20 PC (resectable) | Early phase 1 2 armed | Paricalcitol IV + hydroxychloroquine + Losartan in combination with Ctx and surgery/only Ctx and surgery | AEs; feasibility | USA |
3h | NCT04617067 2024 | 43 PC advanced | Phase 2 1 armed | Paricalcitol (orally) in combination with gemcitabine and Nab-Paclitaxel | PFS; OS; TTF; RR; AEs | Ireland |
4a | NCT02948309 2022 | 290 PC inoperable | Phase 3 RCT Placebo 2 armed | Additional sc application of mistletoe-extracts/placebo: sc isotonic saline solution | OS; QL; BMI; corticosteroid consumption; number required visits, AEs; pain | Sweden |
4b | EudraCT2014-002386-30 2020 | 290 locally advanced or metastatic PC | Multicentric RCT 2 armed | Additional sc application of mistletoe-extracts/only standard therapy | OS; fatigue; QL; pain; body weight; AEs | Bulgaria Serbia |
4c | NCT03051477 2022 | 56 advanced solid tumors | Phase 1 1 armed | IV infusions of mistletoe-extracts; dose-escalation | Tox; AEs; maximum tolerated dose; tumor marker kinetics | USA |
5a | NCT01077427 2021 | 336 PC resected | Phase 3 RCT 2 armed | Regional hyperthermia in combination with gem-and capecitabine/only Ctx | PFS; OS; Tox; QL | Germany |
5b | NCT02439593 2021 | 78 PC advanced | Phase 2 RCT 2 armed | Regional hyperthermia in combination with Ctx and radiation/only Ctx and radiation | OS; PFS; Progression; AEs | Switzerland |
5c | NCT03251365 2024 | 42 PC resectable | Phase 2/3 RCT 2 armed | Hyperthermic intra-abdominal and gemcitabine/only gemcitabine | Morbidity; OS | Spain |
5d | NCT02862015 2019 | 100 PC metastatic | Multicentric Phase 2, RCT 2 armed | Whole body hyperthermia combined with Ctx/only Ctx | QL; opioid use; pain; AEs | Korea |
5e | NCT04467593 2022 | 14 PC stage IV | 2 armed | Whole body hyperthermia only/combined with Ctx | AEs; CA19-9 and CEA levels | Belgium |
5f | NCT04858009 2026 | 40 PC (metastatic) | Phase 2 1 armed | Hyperthermic intra-peritonal combined with Ctx | OS; disease control; recurrence; morbidity | USA |
5g | NCT04889742 2028 | 110 recurrent cancer | 1 armed | Local hyperthermia combined with re-irradiation | Tumor recurrence; OS; PFS; OS; QL | Germany |
6a | NCT02343835 2021 | 20 PC (inoperable) | RCT 2 armed | Nanoknife IRE/no treatment | Immune response (intra-tumoral and systemic) | China |
6b | NCT03614910 2022 | 30 PC (advanced, inoperable) | 1 armed | Nanoknife IRE | OS; PFS; RR; complications; CA19-9; Pain | USA |
6c | NCT04310553 2020 | 240 PC (advanced) | Multicentric 1 armed | Nanoknife IRE | OS; time to progress; PFS; RR; disease control rate; QL | China |
6d | NCT02791503 2022 | 74 PC (neoplasm) | RCT 2 armed | Nanoknife IRE in combination with Ctx/Stereotactic Body Radiotherapy in combination with Ctx | OS; PFS; AEs; pain; cost-effectiveness; QL; immune status; CA 19-9 | The Netherlands |
6e | NCT04093141 2024 | 30 PC (inoperable) | 1 armed | IRE after Ctx | 2-year-survival proportion; OS; PFS; progression; complications; QL | Denmark |
6f | NCT02041936 2022 | 12 PC (inoperable) | 1 armed | Nanoknife IRE | AEs; pain; QL | USA |
6g | NCT04276857 2026 | 27 PC (advanced) | 1 armed | Nanoknife IRE after Ctx | PFS; OS; QL; rate of IRE; complications; cost-effectiveness | Canada |
6h | NCT02343835 2021 | 20 PC (advanced) | RCT 2 armed | Nanoknife IRE/no intervention | Immune responses, between non-ablated and ablated PC; OS; PFS | China |
6i | NCT02898649 2019 | 100 PC (advanced) | 1 armed | Nanoknife IRE after standard therapy without response | OS; safety; progression; tumor size; pain; CA19-9 | Korea |
6j | NCT03105921 2021 | 20 PC (untreated) | 1 armed | Nanoknife IRE | R0 resection rate | France |
6k | NCT03257150 2022 | 47 PC (inoperable) | Phase 1/2 1 armed | Nanoknife IRE via laparotomy surgery | AEs; OS; PFS | Canada |
6l | EudraCT2020-004623-17 | 12 PC (metastatic) | Phase 2 1 armed | Nanoknife IRE + Nivolumab | AEs; OS; PFS; tumor response; QL | Denmark |
6m | NCT04612530 2023 | 18 PC | Phase 1 RCT 3 armed | (A) Nivolumab (B) IRE + Nivolumab (C) IRE + Nivolumab + Toll-Like Receptor 9 (intra tumoral) | AEs; OS; PFS; immunomodulation; tumor response; QL | The Netherlands |
6n | NCT03899649 2023 | 532 PC (stage III) | Registry Multicentric 2 armed | Nanoknife IRE/standard therapy | OS | USA |
6o | NCT03899636 2023 | 528 PC (stage III, inoperable) | Phase 3, RCT Multicentric 2 armed | Nanoknife IRE + FOLFIRINOX/only FOLFIRINOX | OS | USA |
6p | NCT05170802 2023 | 30 PC | Registry 1 armed | Nanoknife IRE via laparotomy surgery | AEs; OS; PFS | USA |
7a | NCT03252808 2035 | 36 PC (inoperable) stage III and IV | Multicentric Phase 1, RCT 3 armed | Oncolytic virus (HF10 intra-tumoral) in combination with Gem + Nab-paclitaxel/Tegafur (TS-1) | Tox; AE; RR; PFS | Japan |
7b | NCT02705196 2025 | 55 PC | Phase 1/2 2 armed | Oncolytic virus (LOAd703 intra-tumoral) in combination with Gem + Nab-paclitaxel+/-atezolizumab | Tox; RR; OS | USA |
7c | NCT03225989 2024 | 50 PC, biliary, ovarian, and colorectal cancer | Phase 1/2 1 armed | Oncolytic virus (LOAd703 intra-tumoral) in combination with standard care Ctx | Tox; AEs; tolerability; tumor size; OS; time to progression; PFS; immune activation | Sweden |
7d | NCT03740256 2038 | 39 cancer patients with solid tumors | Phase 1 1 armed | Oncolytic virus (CAdVEC intra-tumoral) in combination with HER2 specific CAR-T cells | Tox; AEs; RR; PFS; OS | USA |
7e | NCT04637698 2022 | 25 PC advanced/metastatic | Phase 1/2 1 armed | Oncolytic virus OH2 intratumoral injection after first-line therapy failed | RR; AEs; disease control; duration of response; PFS; QL | China |
7f | NCT04226066 2022 | 69 PC, stomach or liver cancer (advanced malignant) | Phase 1/2 2 armed | Recombinant oncolytic virus T601 injection after other options failed. dose-escalation/in combination with 5-FC | AEs; RR; disease control; PFS; pharmacokinetics of T601; 5-FC-determination in blood | China |
7g | NCT05361954 2024 | 36 cancer patients with solid tumors | Phase 1 1 armed | Oncolytic virus (STI-1386 intra-tumoral) | AEs; tolerability; disease control; pharmacokinetics; immune activation | USA |
7h | NCT05076760 2025 | 18 cancer patients with solid tumors | Phase 1 1 armed | Oncolytic virus (MEM-288 intra-tumoral) | Tox; AEs; RR; PFS; OS | USA |
Method | Study | Relevant Findings/Clinical Evidence | Reference |
---|---|---|---|
Nanomedicine | 861 advanced PC, RCT; nab-paclitaxel plus gemcitabine versus gemcitabine. | nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate. | [69] |
16 PC patients, Phase 1; dose-escalation with nanoparticle-based curcumin preparations. | Safety and pharmacokinetics analyses revealed higher curcumin plasma levels without increased toxicity. | [70] | |
417 PC patients; RCT Phase 3: irinotecan encapsulated in lipid bilayer liposomes combined with fluorouracil [nal-IRI+5-FU/LV] versus 5-FU/LV. | The survival benefits of nal-IRI+5-FU/LV] versus 5-FU/LV maintained over an extended follow-up, and prognostic markers of survival ≥1 year were identified. | [71,72] NAPOLI | |
Hyperthermia | Systematic review analysis, 1293 articles with a total of 395 PC patients. | Possible benefits of hyperthermia: improved tumor response, reduced adverse effect rate, prolonged overall survival. | [73] |
Observational study on 106 PC patients treated with or without electro-hyperthermia. | Modified electro-hyperthermia may improve tumor response and survival of PC patients. | [74] | |
Irreversible electropolation [IRE] | 200 locally advanced (stage III) PC patients. | The addition of IRE to radiation and chemotherapy appeared to be safe and seemed to prolong overall survival compared with historical controls. | [75,76] |
50 unresectable advanced and recurrent PC patients; multicenter, Phase 2. | IRE revealed an acceptable safety profile and seems to prolong overall survival compared with standard of care. | [77] PANFIRE | |
Intratumoral injection (IT) | Observational study on 123 cancer patients including 59 PC receiving IT of mistletoe preparations. | IT of mistletoe preparations appeared to be safe. | [78,79] |
12 locally advanced PC patients received IT of oncolytic virus HF 10; open-label; Phase 1. | IT of oncolytic virus HF10 in combination with erlotinib and gemcitabine were safe and well tolerated. | [80] | |
11 locally advanced PC patients received IT with a replication-competent adenovirus (Ad5-DS); open-label; Phase 1. | A combination of IT Ad5-DS and gemcitabine is safe and well tolerated. | [81] | |
Vaccines | 29 resp. 9 advanced PC patients, Phase 1/2 dose-escalation study with KIF20A-66 (an epitope peptide of a member of the kinesin super family). | KIF20A-66 peptide vaccination was well tolerated, and overall survival seemed prolonged compared to the historical controls. | [82,83] |
303 metastatic PC, RCT, multicenter, Phase 2 with mesothelin vaccine (CRS-207) + GVAX + cyclophosphamide (Cy). | Cy/GVAX followed by CRS-207 (as third-line therapy for PC) significantly improved overall survival as compared with Cy/GVAX alone. The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. | [84,85] ECLIPSE |
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Oei, S.L.; Schad, F. Are Aspects of Integrative Concepts Helpful to Improve Pancreatic Cancer Therapy? Cancers 2023, 15, 1116. https://doi.org/10.3390/cancers15041116
Oei SL, Schad F. Are Aspects of Integrative Concepts Helpful to Improve Pancreatic Cancer Therapy? Cancers. 2023; 15(4):1116. https://doi.org/10.3390/cancers15041116
Chicago/Turabian StyleOei, Shiao Li, and Friedemann Schad. 2023. "Are Aspects of Integrative Concepts Helpful to Improve Pancreatic Cancer Therapy?" Cancers 15, no. 4: 1116. https://doi.org/10.3390/cancers15041116
APA StyleOei, S. L., & Schad, F. (2023). Are Aspects of Integrative Concepts Helpful to Improve Pancreatic Cancer Therapy? Cancers, 15(4), 1116. https://doi.org/10.3390/cancers15041116