Skip to main content

Advertisement

SpringerLink
Log in

Incidence of and risk factors for non-hematologic toxicity with combined radiotherapy and CDK4/6 inhibitors in metastatic breast cancer using dose-volume parameters analysis: a multicenter cohort study

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

There is a lack of data on combined radiotherapy (RT) and cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) risk factors and toxicity. This study aimed to assess the incidence of and risk factors for non-hematologic toxicities in patients treated with combined RT and CDK4/6i using dose-volume parameter analysis.

Methods

We conducted a retrospective multicenter cohort study of patients with metastatic breast cancer receiving RT within 14 days of CDK4/6i use. The endpoint was non-hematologic toxicities. Patient characteristics and RT treatment planning data were compared between the moderate or higher toxicities (≥ grade 2) group and the non-moderate toxicities group.

Results

Sixty patients were included in the study. CDK4/6i was provided at a median daily dose of 125 mg and 200 mg for palbociclib and abemaciclib, respectively. In patients who received concurrent RT and CDK4/6i (N = 29), the median concurrent prescribed duration of CDK4/6i was 14 days. The median delivered RT dose was 30 Gy and 10 fractions. The rate of grade 2 and 3 non-hematologic toxicities was 30% and 2%, respectively. There was no difference in toxicity between concurrent and sequential use of CDK4/6i. The moderate pneumonitis group had a larger lung V20 equivalent dose of 2 Gy per fraction and planning target volume than the non-moderate pneumonitis group.

Conclusions

Moderate toxicities are frequent with combined RT and CDK4/6i. Caution is necessary concerning the combined RT and CDK4/6i. Particularly, reducing the dose to normal organs is necessary for combined RT and CDK4/6i.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Raw data of this analysis is available from the corresponding author upon request.

Abbreviations

AI:

Aromatase inhibitor

BED:

Biologically effective dose

CDK4/6i:

Cyclin-dependent kinase 4 and 6 inhibitors

Dmax:

Maximum dose

DVH:

Dose-volume histogram

ECOG PS:

Eastern Cooperative Oncology Group performance status

EQD2:

Equivalent dose of 2 Gy per fraction

HER2− :

Human epidermal growth factor receptor 2 negative

HR + :

Hormone receptor positive

MLD:

Mean lung dose

PTV:

Planning target volume

RT:

Radiotherapy

References

  1. Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373:209–19.

    Article  CAS  PubMed  Google Scholar 

  2. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29:1541–7.

    Article  CAS  PubMed  Google Scholar 

  3. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial. JAMA Oncol. 2020;6:116–24.

    Article  PubMed  Google Scholar 

  4. Fleming GF, Pagani O, Regan MM, Walley BA, Francis PA. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2022;33:658.

    Article  CAS  PubMed  Google Scholar 

  5. Chowdhary M, Sen N, Chowdhary A, Usha L, Cobleigh MA, Wang D, et al. Safety and efficacy of palbociclib and radiation therapy in patients with metastatic breast cancer: initial results of a novel combination. Adv Radiat Oncol. 2019;4:453–7.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ippolito E, Greco C, Silipigni S, Dell’Aquila E, Petrianni GM, Tonini G, et al. Concurrent radiotherapy with palbociclib or ribociclib for metastatic breast cancer patients: preliminary assessment of toxicity. Breast. 2019;46:70–4.

    Article  PubMed  Google Scholar 

  7. Beddok A, Xu HP, Henry AA, Porte B, Fourquet A, Cottu P, et al. Concurrent use of palbociclib and radiation therapy: single-centre experience and review of the literature. Br J Cancer. 2020;123:905–8.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Guerini AE, Pedretti S, Salah E, Simoncini EL, Maddalo M, Pegurri L, et al. A single-center retrospective safety analysis of cyclin-dependent kinase 4/6 inhibitors concurrent with radiation therapy in metastatic breast cancer patients. Sci Rep. 2020;10:13589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kawamoto T, Shikama N, Sasai K. Severe acute radiation-induced enterocolitis after combined palbociclib and palliative radiotherapy treatment. Radiother Oncol. 2019;131:240–1.

    Article  PubMed  Google Scholar 

  10. Messer JA, Ekinci E, Patel TA, Teh BS. Enhanced dermatologic toxicity following concurrent treatment with palbociclib and radiation therapy: a case report. Rep Pract Oncol Radiother. 2019;24:276–80.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Nasir UM, Mozeika AM, Sayan M, Jan I, Kowal N, Haffty B, et al. Severe gastrointestinal mucositis following concurrent palbociclib and palliative radiation therapy. Anticancer Res. 2020;40:5291–4.

    Article  PubMed  Google Scholar 

  12. David S, Ho G, Day D, Harris M, Tan J, Goel S, et al. Enhanced toxicity with CDK 4/6 inhibitors and palliative radiotherapy: non-consecutive case series and review of the literature. Transl Oncol. 2021;14: 100939.

    Article  CAS  PubMed  Google Scholar 

  13. Lee CL, Oh P, Xu ES, Ma Y, Kim Y, Daniel AR, et al. Blocking cyclin-dependent kinase 4/6 during single dose versus fractionated radiation therapy leads to opposite effects on acute gastrointestinal toxicity in mice. Int J Radiat Oncol Biol Phys. 2018;102:1569–76.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Borst GR, Ishikawa M, Nijkamp J, Hauptmann M, Shirato H, Bengua G, et al. Radiation pneumonitis after hypofractionated radiotherapy: evaluation of the LQ(L) model and different dose parameters. Int J Radiat Oncol Biol Phys. 2010;77:1596–603.

    Article  PubMed  Google Scholar 

  15. Newcomb CH, Van Dyk J, Hill RP. Evaluation of isoeffect formulae for predicting radiation-induced lung damage. Radiother Oncol. 1993;26:51–63.

    Article  CAS  PubMed  Google Scholar 

  16. Barendsen GW. Dose fractionation, dose rate and iso-effect relationships for normal tissue responses. Int J Radiat Oncol Biol Phys. 1982;8:1981–97.

    Article  CAS  PubMed  Google Scholar 

  17. Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transpl. 2013;48:452–8.

    Article  CAS  Google Scholar 

  18. Ratosa I, Orazem M, Scoccimarro E, Steinacher M, Dominici L, Aquilano M, et al. Cyclin-dependent kinase 4/6 inhibitors combined with radiotherapy for patients with metastatic breast cancer. Clin Breast Cancer. 2020;20:495–502.

    Article  CAS  PubMed  Google Scholar 

  19. Kim KN, Shah P, Clark A, Freedman GM, Dastgheyb S, Barsky AR, et al. Safety of cyclin-dependent kinase4/6 inhibitor combined with palliative radiotherapy in patients with metastatic breast cancer. Breast. 2021;60:163–7.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Al-Rashdan A, Quirk S, Roumeliotis M, Abedin T, Amaro CP, Barbera L, et al. Radiation therapy with cyclin-dependent kinase 4/6 inhibitors: a multi-institutional safety and toxicity study. Int J Radiat Oncol Biol Phys. 2022. https://doi.org/10.1016/j.ijrobp.2022.07.005.

    Article  PubMed  Google Scholar 

  21. Yap YS, Kim SB, Chiu JWY, Lim E, Broom R, Liu Z, et al. 48P Abemaciclib combined with adjuvant endocrine therapy in patients from Asia with high risk early breast cancer: monarchE. Ann Oncol. 2021;32:S41–2.

    Article  Google Scholar 

  22. Bosacki C, Bouleftour W, Sotton S, Vallard A, Daguenet E, Ouaz H, et al. CDK 4/6 inhibitors combined with radiotherapy: a review of literature. Clin Transl Radiat Oncol. 2021;26:79–85.

    Article  CAS  PubMed  Google Scholar 

  23. Fairchild A, Harris K, Barnes E, Wong R, Lutz S, Bezjak A, et al. Palliative thoracic radiotherapy for lung cancer: a systematic review. J Clin Oncol. 2008;26:4001–11.

    Article  PubMed  Google Scholar 

  24. Sprave T, Verma V, Förster R, Schlampp I, Hees K, Bruckner T, et al. Quality of life and radiation-induced late toxicity following intensity-modulated versus three-dimensional conformal radiotherapy for patients with spinal bone metastases: results of a randomized trial. Anticancer Res. 2018;38:4953–60.

    Article  PubMed  Google Scholar 

  25. Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35:3638–46.

    Article  CAS  PubMed  Google Scholar 

  26. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875–84.

    Article  CAS  PubMed  Google Scholar 

  27. Rugo HS, Diéras V, Gelmon KA, Finn RS, Slamon DJ, Martin M, et al. Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial. Ann Oncol. 2018;29:888–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kalash R, Iarrobino NA, Beriwal S, Sun M, Glaser SM, Champ CE. Palbociclib enhances pulmonary fibrosis in patients undergoing thoracic radiation therapy: a case series and review of the literature. Int J Radiat Oncol Biol Phys. 2018;102: e610.

    Article  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan

    Terufumi Kawamoto & Naoto Shikama

  2. Department of Radiation Oncology, Graduate School of Biomedical Health Sciences, Hiroshima University, Hiroshima, Japan

    Nobuki Imano

  3. Department of Radiation Oncology, Kobe University Hospital, Kobe, Japan

    Hikaru Kubota

  4. Department of Radiation Oncology, Fujieda Municipal General Hospital, Fujieda, Japan

    Takashi Kosugi

  5. Department of Radiation Oncology, Kita-Harima Medical Center, Ono, Japan

    Shuhei Sekii

  6. Division of Radiation Therapy, Radiation and Proton Therapy Center, Shizuoka Cancer Center Hospital, Shizuoka, Japan

    Hideyuki Harada

  7. Department of Radiation Oncology, Seirei Mikatahara General Hospital, Shizuoka, Japan

    Kazunari Yamada

  8. Department of Radiation Oncology, Juntendo Nerima Hospital, Tokyo, Japan

    Yutaka Naoi

  9. Department of Radiology, Showa General Hospital, Kodaira, Japan

    Kazunari Miyazawa

  10. Department of Radiation Oncology, Dokkyo Medical University Saitama Medical Center, Saitama, Japan

    Yasuhiro Hirano

  11. Department of Radiology, Akita University Graduate School of Medicine, Akita, Japan

    Yuki Wada

  12. Department of Radiation Oncology, Kyorin University Hospital, Mitaka, Japan

    Ayako Tonari

  13. Department of Radiation Oncology, Arao Municipal Hospital, Kumamoto, Japan

    Tetsuo Saito

  14. Department of Radiation Oncology, Tokyo Saiseikai Central Hospital, Tokyo, Japan

    Nobue Uchida

  15. Department of Radiation Oncology, Kyoto Medical Center, Kyoto, Japan

    Norio Araki

  16. Department of Radiation Oncology, St. Marianna University School of Medicine Hospital, Kawasaki, Japan

    Naoki Nakamura

Authors
  1. Terufumi Kawamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naoto Shikama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nobuki Imano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hikaru Kubota
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takashi Kosugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuhei Sekii
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hideyuki Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazunari Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yutaka Naoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kazunari Miyazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yasuhiro Hirano
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yuki Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ayako Tonari
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Tetsuo Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Nobue Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Norio Araki
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Naoki Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TK prepared the manuscript and conducted the literature search; TK reviewed and edited the manuscript; and TK, NS, NI, HK, TK, SS, HH, KY, YN, KM, YH, YW, AT, TS, NU, NA, and NN reviewed the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Terufumi Kawamoto.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent to be included in the study was obtained from all patients. The study protocol was approved by the participating centers’ institutional review boards.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kawamoto, T., Shikama, N., Imano, N. et al. Incidence of and risk factors for non-hematologic toxicity with combined radiotherapy and CDK4/6 inhibitors in metastatic breast cancer using dose-volume parameters analysis: a multicenter cohort study. Breast Cancer 30, 282–292 (2023). https://doi.org/10.1007/s12282-022-01422-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-022-01422-5

Keywords

Search

Navigation