Investigational New Drugs

, Volume 36, Issue 4, pp 667–673 | Cite as

A phase I/II trial of pemetrexed plus radiotherapy in elderly patients with locally advanced non-small cell lung cancer

  • Akihiro Tamiya
  • Masahiro Morimoto
  • Shoichi Fukuda
  • Yoko Naoki
  • Tatsuya Ibe
  • Kyoichi Okishio
  • Hideto Goto
  • Akihiro Yoshii
  • Toshiyuki Kita
  • Naoyuki Nogami
  • Yuka Fujita
  • Shinji Atagi


Background Radiotherapy (RT) is an effective treatment for elderly patients with locally advanced non-small-cell lung cancer (NSCLC); however, no clinical trials have investigated combination RT with pemetrexed (PEM) in chemotherapy-naive patients ≥71 years old. We conducted a phase I/II study to evaluate the appropriate PEM dose, efficacy, and safety of PEM plus RT in elderly patients. Methods Patients ≥71 years with performance status (PS) scores of 0–2 who had pathologically confirmed stage IIIA/IIIB NSCLC received PEM (500 mg/m2 on day 1 of a 28-day cycle, 4 courses) and RT (a single 2 Gy daily fraction on 5 consecutive days weekly from day 1; 60 Gy total). The primary endpoint was the objective response rate (ORR); the secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results Forty-one patients with a median age of 79 years were enrolled; 31 were men. Eighteen patients had squamous cell carcinoma, 27 had stage IIIA disease, and 38 had PS scores 0–1. The ORR was 80.5%, while the median OS and PFS rates were 24.9 and 6.9 months, respectively. Two treatment-related deaths occurred owing to RT-related pneumonitis and severe infection, respectively. Common hematological AEs were leucopenia and neutropenia; common non-hematological AEs were anorexia and constipation. Three patients developed PEM-induced interstitial lung disease; however, most AEs were RT-related. Conclusions Combination PEM and RT shows promising efficacy but relatively severe RT-related toxicities. Therefore, this treatment should be prescribed to elderly patients with caution. Trial registration UMIN 000005036.


Pemetrexed Radiotherapy Geriatric patients Pneumonitis 



adverse events


alanine transaminase


aspartate aminotransferase








computed tomography


dose limiting toxicity


epidermal growth factor receptor






maximum tolerated dose


non-small cell lung cancer


objective response rate


overall survival


progression disease




progression-free survival


performance status


recommended dose


Response Evaluation Criteria in Solid Tumors





We wish to thank all the participants (patients, patients’ family and caregivers) of this study.


This research was supported by research funding from the national hospital organization network program.

Compliance with ethical standards

Conflict of interest

About this study, all authors received the grant from national cancer hospital organization as a research fee (the national hospital organization network program). And all authors report no conflicts of interest in this work.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The institutional research committee is Clinical trial review board of Kinki-chuo Chest Medical Center, and the approved number is 305.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Gridelli C, Langer C, Maione P, Rossi A, Schild SE (2007) Lung cancer in the elderly. J Clin Oncol 25:1898–1907CrossRefPubMedGoogle Scholar
  2. 2.
    Non-small Cell Lung Cancer Collaborative Group (1995) Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small cell lung Cancer collaborative group. BMJ 311:899–909CrossRefGoogle Scholar
  3. 3.
    Segawa Y, Kiura K, Takigawa N, Kamei H, Harita S, Hiraki S, Watanabe Y, Sugimoto K, Shibayama T, Yonei T, Ueoka H, Takemoto M, Kanazawa S, Takata I, Nogami N, Hotta K, Hiraki A, Tabata M, Matsuo K, Tanimoto M (2010) Phase III trial comparing docetaxel and cisplatin combination chemotherapy with mitomycin, vindesine, and cisplatin combination chemotherapy with concurrent thoracic radiotherapy in locally advanced non-small-cell lung cancer: OLCSG 0007. J Clin Oncol 28:3299–3306CrossRefPubMedGoogle Scholar
  4. 4.
    Yamamoto N, Nakagawa K, Nishimura Y, Tsujino K, Satouchi M, Kudo S, Hida T, Kawahara M, Takeda K, Katakami N, Sawa T, Yokota S, Seto T, Imamura F, Saka H, Iwamoto Y, Semba H, Chiba Y, Uejima H, Fukuoka M (2010) Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer: West Japan thoracic oncology group WJTOG0105. J Clin Oncol 28:3739–3745CrossRefPubMedGoogle Scholar
  5. 5.
    Atagi S, Kawahara M, Yokoyama A, Okamoto H, Yamamoto N, Ohe Y, Sawa T, Ishikura S, Shibata T, Fukuda H, Saijo N, Tamura T, Japan Clinical Oncology Group Lung Cancer Study Group (2012) Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan clinical oncology group (JCOG0301). Lancet Oncol 13:671–678CrossRefPubMedGoogle Scholar
  6. 6.
    Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543–3551CrossRefPubMedGoogle Scholar
  7. 7.
    Bischof M, Weber KJ, Blatter J, Wannenmacher M, Latz D (2002) Interaction of pemetrexed disodium (ALIMTA, multitargeted antifolate) and irradiation in vitro. Int J Radiat Oncol Biol Phys 52:1381–1388CrossRefPubMedGoogle Scholar
  8. 8.
    Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E (2016) PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 34:953–962CrossRefPubMedGoogle Scholar
  9. 9.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefPubMedGoogle Scholar
  10. 10.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41CrossRefPubMedGoogle Scholar
  11. 11.
    Shirasaka T, Nakano K, Takechi T, Satake H, Uchida J, Fujioka A, Saito H, Okabe H, Oyama K, Takeda S, Unemi N, Fukushima M (1996) Antitumor activity of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res 56:2602–2606PubMedGoogle Scholar
  12. 12.
    Aoe K, Takigawa N, Hotta K, Maeda T, Kishino D, Nogami N, Tabata M, Harita S, Okada T, Kubo T, Hosokawa S, Fujiwara K, Gemba K, Yasugi M, Kozuki T, Kato Y, Katsui K, Kanazawa S, Ueoka H, Tanimoto M, Kiura K (2014) A phase II study of S-1 chemotherapy with concurrent thoracic radiotherapy in elderly patients with locally advanced non-small-cell lung cancer: the Okayama lung Cancer study group trial 0801. Eur J Cancer 50:2783–2790CrossRefPubMedGoogle Scholar
  13. 13.
    Locher C, Pournel N, Le Caer H (2013) Phase II study of concurrent chemo-radiotherapy (CRT) with weekly cisplatinum plus oral vinorelbine in fit elderly patients with nonresectable locally advanced non-small-cell lung cancer (NSCLC) assessed by standardized geriatric assessment (RACCOSA, GFPC 08-06 study): interim analysis. J Thorac Oncol 8:S848Google Scholar
  14. 14.
    Niho S, Kubota K, Nihei K, Sekine I, Sumi M, Sekiguchi R, Funai J, Enatsu S, Ohe Y, Tamura T (2013) Dose-escalation study of thoracic radiotherapy in combination with pemetrexed plus cisplatin followed by pemetrexed consolidation therapy in Japanese patients with locally advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer 14:62–69CrossRefPubMedGoogle Scholar
  15. 15.
    Ohe Y, Ichinose Y, Nakagawa K, Tamura T, Kubota K, Yamamoto N, Adachi S, Nambu Y, Fujimoto T, Nishiwaki Y, Saijo N, Fukuoka M (2008) Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. Clin Cancer Res 14:4206–4212CrossRefPubMedGoogle Scholar
  16. 16.
    Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar MC, Paul S, Paoletti P, Einhorn L, Bunn PA Jr (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589–1597CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Akihiro Tamiya
    • 1
  • Masahiro Morimoto
    • 2
  • Shoichi Fukuda
    • 1
  • Yoko Naoki
    • 1
  • Tatsuya Ibe
    • 3
  • Kyoichi Okishio
    • 1
  • Hideto Goto
    • 4
  • Akihiro Yoshii
    • 5
  • Toshiyuki Kita
    • 6
  • Naoyuki Nogami
    • 7
  • Yuka Fujita
    • 8
  • Shinji Atagi
    • 1
  1. 1.Department of Internal MedicineNational Hospital Organization Kinki-chuo Chest Medical CenterSakai-cityJapan
  2. 2.Osaka International Cancer InstituteOsaka-cityJapan
  3. 3.National Hospital Organization Nishisaitama-chuo National HospitalTokorozawa-cityJapan
  4. 4.National Hospital Organization Yokohama Medical CenterYokohama-cityJapan
  5. 5.National Hospital Organization Shibukawa Medical CenterShibukawa-cityJapan
  6. 6.National Hospital Organization Kanazawa Medical CenterKanazawa-cityJapan
  7. 7.National Hospital Organization Shikoku Cancer CenterMatsuyama-cityJapan
  8. 8.National Hospital Organization Asahikawa Medical CenterAsahikawa-cityJapan

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