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Peer-reviewedCC BY 4.0Cancers

PemToxTrial: An Observational Study of PEMetrexed-Associated Severe HematoTOXicity in Lung Adenocarcinoma with Bone Metastases

  • Christian Riedel1
  • Christian Neumann2,3
  • Raban Heller4
  • Arthur Bauer2,3
  • Patrick Büchele3,5
  • Konrad Steinestel3,6
  • Michael Grunert3,7,8
  • Jan Sölter3,9
  • Niklas Gebauer10
  • Annette Arndt6
  • Matthias Müller2,3
  • Armin Riecke2,3
1 more authors
  • Hanno Witte2,11
11 affiliations
  1. 1Department of Gastroenterology, Bundeswehrkrankenhaus Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany
  2. 2Department of Hematology and Oncology, Bundeswehrkrankenhaus Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany
  3. 3Lung Cancer Center Ulm, Bundeswehrkrankenhaus Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany
  4. 4Department for Trauma Surgery and Orthopaedics, Reconstructive and Septic Surgery, Sportstraumatology, Bundeswehrkrankenhaus Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany
  5. 5Department of Pneumology, Bundeswehrkrankenhaus Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany
  6. 6Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany
  7. 7Department of Nuclear Medicine, Bundeswehrkrankenhaus Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany
  8. 8Department of Nuclear Medicine, University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany
  9. 9Department of Thoracic Surgery Bundeswehrkrankenhaus Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany
  10. 10Department of Hematology and Oncology, University Hospital Schleswig-Holstein (UKSH) Campus Lübeck, Ratzeburger Allee 160, 23566 Lübeck, Germany
  11. 11Department of Hematology and Oncology, University Ulm, Albert Einstein Allee 23, 89081 Ulm, Germany
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Abstract

Introduction: Pemetrexed, an antifolate, is a standard therapy for lung adenocarcinoma (LUAD). Since folic acid is vital for nucleic acid metabolism, disrupting its pathway affects both tumor cells and regenerating healthy cells. The PemToxTrial examined the impact of pemetrexed on severe hematotoxicity and mortality. Methods: This retrospective analysis included 136 LUAD patients (UICC8 stage IVA/B) receiving palliative treatment. Ninety-two patients received pemetrexed-based therapy, while 44 received pemetrexed-free treatment (68 and 38 with immune-checkpoint inhibitors). Bone metastasis (BM) was present in 47 patients in the pemetrexed group and 22 in the comparison group. The primary endpoint was grade III–V hematotoxicity; secondary endpoints included mortality, progression-free survival (PFS), and overall survival (OS). Hematologic outcomes following a subsequent change in clinical practice were prospectively assessed in a post-implementation cohort of 15 patients with bone-metastatic LUAD receiving pemetrexed-free regimens. Results: Median age was 66 years, 59.6% were male and median follow-up was 13.5 months. Grade III-V hematotoxicity was most frequent (81%) in patients with BM receiving pemetrexed (n = 47), significantly higher than in other subgroups (p < 0.0001). Mortality was also increased in this group (66% vs. 29%, p < 0.0001), with hematotoxicity directly contributing to death in 42% versus 11.5% of cases. PFS was significantly inferior (5.2 vs. 8.6 months). Multivariable analysis identified BM as the only independent predictor of severe hematotoxicity and mortality. Only a mutational burden of ≥4 potential driver alterations was associated with inferior PFS. Bone-derived total lesion glycolysis (TLG) on PET-CT strongly correlated with high-grade hematotoxicity (p < 0.0001). Conclusions: The PemToxTrial identified a strong association between pemetrexed exposure, bone metastases, and severe hematotoxicity, supporting further prospective evaluation of bone metastasis status as a potential clinical risk factor for treatment-associated hematotoxicity.

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Cite

BibTeXRIS
BibTeX
@article{riedel2026pemtoxtrial,
  title = {{PemToxTrial: An Observational Study of PEMetrexed-Associated Severe HematoTOXicity in Lung Adenocarcinoma with Bone Metastases}},
  author = {Christian Riedel and Christian Neumann and Raban Heller and Arthur Bauer and Patrick Büchele and Konrad Steinestel and Michael Grunert and Jan Sölter and Niklas Gebauer and Annette Arndt and Matthias Müller and Armin Riecke and Hanno Witte},
  journal = {Cancers},
  year = {2026},
  month = oct,
  doi = {10.3390/cancers18203281},
  url = {https://www.mdpi.com/2072-6694/18/20/3281},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - PemToxTrial: An Observational Study of PEMetrexed-Associated Severe HematoTOXicity in Lung Adenocarcinoma with Bone Metastases
AU  - Christian Riedel
AU  - Christian Neumann
AU  - Raban Heller
AU  - Arthur Bauer
AU  - Patrick Büchele
AU  - Konrad Steinestel
AU  - Michael Grunert
AU  - Jan Sölter
AU  - Niklas Gebauer
AU  - Annette Arndt
AU  - Matthias Müller
AU  - Armin Riecke
AU  - Hanno Witte
PY  - 2026
DA  - 2026/10/01
JO  - Cancers
DO  - 10.3390/cancers18203281
UR  - https://www.mdpi.com/2072-6694/18/20/3281
AB  - Introduction: Pemetrexed, an antifolate, is a standard therapy for lung adenocarcinoma (LUAD). Since folic acid is vital for nucleic acid metabolism, disrupting its pathway affects both tumor cells and regenerating healthy cells. The PemToxTrial examined the impact of pemetrexed on severe hematotoxicity and mortality. Methods: This retrospective analysis included 136 LUAD patients (UICC8 stage IVA/B) receiving palliative treatment. Ninety-two patients received pemetrexed-based therapy, while 44 received pemetrexed-free treatment (68 and 38 with immune-checkpoint inhibitors). Bone metastasis (BM) was present in 47 patients in the pemetrexed group and 22 in the comparison group. The primary endpoint was grade III–V hematotoxicity; secondary endpoints included mortality, progression-free survival (PFS), and overall survival (OS). Hematologic outcomes following a subsequent change in clinical practice were prospectively assessed in a post-implementation cohort of 15 patients with bone-metastatic LUAD receiving pemetrexed-free regimens. Results: Median age was 66 years, 59.6% were male and median follow-up was 13.5 months. Grade III-V hematotoxicity was most frequent (81%) in patients with BM receiving pemetrexed (n = 47), significantly higher than in other subgroups (p < 0.0001). Mortality was also increased in this group (66% vs. 29%, p < 0.0001), with hematotoxicity directly contributing to death in 42% versus 11.5% of cases. PFS was significantly inferior (5.2 vs. 8.6 months). Multivariable analysis identified BM as the only independent predictor of severe hematotoxicity and mortality. Only a mutational burden of ≥4 potential driver alterations was associated with inferior PFS. Bone-derived total lesion glycolysis (TLG) on PET-CT strongly correlated with high-grade hematotoxicity (p < 0.0001). Conclusions: The PemToxTrial identified a strong association between pemetrexed exposure, bone metastases, and severe hematotoxicity, supporting further prospective evaluation of bone metastasis status as a potential clinical risk factor for treatment-associated hematotoxicity.
SN  - 2072-6694
ER  -