Skip to main content

Radiotherapy Considerations and Strategic Approaches in Phase I Trials

  • Chapter
  • First Online:
Phase I Oncology Drug Development


Cellular damage by ionizing radiation relies on time to consider DNA damage, repair, reoxygenation, repopulation and redistribution. This means that both tumor kill and toxicity must be considered differently in phase I trials than those from drugs, and the combination of targeted agents and immunotherapy agents with radiation must also be carefully considered. Additionally, timing and logistics of radiation therapy may cause delays or interruptions in phase I study designs in combination with drugs that must also be carefully considered when designing trials. Dose limiting toxicity trials and maximum tolerated dose trials including RT may require longer follow up to fully evaluate toxicity. Adaptive phase I trial designs that consider longer term toxicity in their study design are advantageous for this purpose.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions


  1. Milas L, Hunter NR, Mason KA, et al. Role of reoxygenation in induction of enhancement of tumor response by paclitaxel. Cancer Res. 1995;55:3564–8.

    CAS  PubMed  Google Scholar 

  2. Shuryak I, Hall EJ, Brenner DJ. Dose dependence of accelerated repopulation in head and neck cancer: supporting evidence and clinical implications. Radiother Oncol. 2018 Apr;127(1):20–26. Epub 2018 Mar 10.

  3. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17(4):425–39.

    Article  CAS  Google Scholar 

  4. Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 2016;18(1):17.

    Article  Google Scholar 

  5. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Ribociclib as first-line therapy for hr-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738–48.

    Article  CAS  Google Scholar 

  6. Marks LB. Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S10–S19.

    Google Scholar 

  7. Steel and Peckham.

  8. Zindler JD, Schiffelers J, Lambin P, Hoffmann AL. Improved effectiveness of stereotactic radiosurgery in large brain metastases by individualized isotoxic dose prescription: an in silico study. Strahlenther Onkol 2018 Jun;194(6):560–569. Epub 2018 Jan 18.

  9. Zindler JD, Thomas CR Jr, Hahn SM, Hoffmann AL, Troost EG, Lambin P. Increasing the therapeutic ratio of stereotactic ablative radiotherapy by individualized isotoxic dose prescription. J Natl Cancer Inst. 2015 Oct 16;108(2). pii: djv305. Print 2016 Feb. Review.

  10. Hartgerink D, van der Heijden B, De Ruysscher D, Postma A, Ackermans L, Hoeben A, Anten M, Lambin P, Terhaag K, Jochems A, Dekker A, Schoenmaekers J, Hendriks L, Zindler J. Stereotactic radiosurgery in the management of patients with brain metastases of non-small cell lung cancer: indications, decision tools and future directions. Front Oncol. 2018 May 9;8:154. eCollection 2018. Review.

  11. Yuan Y, Lee JJ, Hilsenbeck SG. Model-assisted designs for early-phase clinical trials: simplicity meets superiority. JCO Precis Oncol. 2019;

  12. Zhou H, Murray T, Pan H, Yuan Y. Comparative review of toxicity probability interval designs for phase I clinical trials. Stat Med. 2018a;37(14):2208–22.

    Article  Google Scholar 

  13. Zhou H, Yuan Y, Nie L. Accuracy, safety and reliability of novel phase I trial designs. Clin Cancer Res. 2018b;24(18):4357–64.

    Article  Google Scholar 

  14. Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. JNCI J Natl Cancer Inst. 2009;101:708–20.

    Article  Google Scholar 

  15. O’Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for phase I clinical trials in cancer. Biometrics. 1990;46(1):33–48.

    Article  Google Scholar 

  16. Yin G, Yuan Y. Bayesian dose finding in oncology for drug combinations by copula regression. J R Stat Soc Ser C (Appl Stat). 2009a;58(2):211–24.

    Article  Google Scholar 

  17. Yin G, Yuan Y. Bayesian model averaging continual reassessment method in phase I clinical trials. J Am Stat Assoc. 2009b;104(487):954–68.

    Article  CAS  Google Scholar 

  18. Yin G, Yuan Y. A latent contingency table approach to dose finding for combinations of two agents. Biometrics. 2009c;65(3):866–75.

    Article  Google Scholar 

  19. Ji Y, Liu P, Li Y, Nebiyou Bekele B. A modified toxicity probability interval method for dose-finding trials. Clin Trials. 2009;7(6):653–63.

    Google Scholar 

  20. Liu S, Yuan Y. Bayesian optimal interval designs for phase I clinical trials. J R Stat Soc Ser C (Appl Stat). 2015;64(3):507–23.

    Article  Google Scholar 

  21. Yuan Y, Hess K, Hilsenbeck S, Gilbert M. Bayesian optimal interval design: a simple and well-performing design for phase I oncology trials. Clin Cancer Res. 2016a;22:4291–301.

    Article  Google Scholar 

  22. Yuan Y, Nguyen HQ, Thall PF. Bayesian designs for phase I/II clinical trials. Boca Raton, FL: CRC Press; 2016b.

    Google Scholar 

  23. Yan F, Mandrekar SJ, Yuan Y. Keyboard: a novel Bayesian toxicity probability interval design for phase I clinical trials. Clin Cancer Res. 2017;23(15):3994–4003.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cheung YK, Chappell R. Sequential designs for phase I clinical trials with late-onset toxicities. Biometrics. 2000;56(4):1177–82.

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Charles R. Thomas .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Colbert, L.E., Yuan, Y., Zindler, J.D., Fuller, C.D., Thomas, C.R. (2020). Radiotherapy Considerations and Strategic Approaches in Phase I Trials. In: Yap, T.A., Rodon, J., Hong, D.S. (eds) Phase I Oncology Drug Development. Springer, Cham.

Download citation

  • DOI:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-47681-6

  • Online ISBN: 978-3-030-47682-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics