Advertisement

Incidence of second primary cancers after radiotherapy combined with platinum and/or cetuximab in head and neck cancer patients

  • Olgun ElicinEmail author
  • Burim Sermaxhaj
  • Beat Bojaxhiu
  • Mohamed Shelan
  • Roland Giger
  • Daniel Rauch
  • Daniel M. Aebersold
Original Article
  • 77 Downloads

Abstract

Purpose

The second primary cancer (SPC) incidence after treatment with platinum-based chemotherapy and cetuximab in combination with radiotherapy has not been previously reported. Our aim was to compare SPC risk following radiotherapy in combination with these agents for the treatment of head and neck squamous cell carcinoma (HNSCC).

Methods

The charts of 296 cases treated for loco-regionally advanced HNSCC between 2009 and 2015 were retrospectively reviewed for patient, tumor, and procedural characteristics. All patients were planned to undergo radiotherapy either with platinum compounds (group: Platinum) or monoclonal antibody cetuximab (group: Cetuximab). A third group of patients switched from platinum compounds to cetuximab due to toxicity (group: Switch). Treatment groups were evaluated for the incidence of SPC with log-rank test. Possible confounders were investigated with multivariate Cox’s proportional hazards model. All tests were two-sided, and a p < 0.05 was set to indicate statistical significance.

Results

Median follow-up was 36 months. Platinum, Cetuximab, and Switch groups consisted of 158, 101, and 37 patients, respectively. Three-year overall survival in the whole cohort was 70%. The rate of SPC was comparable between Platinum (9.2%) and Cetuximab (11.5%) groups (p = 0.98), whereas the patients in the Switch group were exposed to a significantly higher incidence of SPC (23.3%) in 3 years (p = 0.01). The multivariate model indicated Switch to be the only variable correlating with an increased risk for SPC.

Conclusions

The Switch strategy may expose the patients to an increased risk of developing SPC. The use of switch should be advocated with caution until robust pre-clinical and clinical data are available.

Keywords

Squamous cell carcinoma Radiation Anti-epidermal growth factor receptor Cisplatin Carboplatin Secondary malignancies 

Abbreviations

EGFR

Epidermal growth factor receptor

HNSCC

Head and neck squamous cell carcinoma

HPV

Human papillomavirus

OS

Overall survival

SPC

Second primary cancer

UICC

Union for International Cancer Control

Inzidenz von metachronen Zweitkarzinomen nach Strahlentherapie in Kombination mit Platin und/oder Cetuximab bei Patienten mit Kopf-Hals-Tumoren

Zusammenfassung

Zielsetzung

Über die Inzidenz von metachronen Zweitkarzinomen („second primary cancer“, SPC) nach platinbasierter Chemotherapie und Cetuximab in Kombination mit einer Radiotherapie ist bisher nichts bekannt. Ziel war es, das SPC-Risiko bei Patienten mit Plattenepithelkarzinomen des Kopf-Hals-Bereichs (HNSCC) nach durchgeführter kombinierter Radiotherapie mit den genannten Substanzen zu evaluieren.

Methoden

Zwischen 2009 und 2015 wurden 296 Patienten aufgrund eines lokoregionär fortgeschrittenen HNSCC behandelt und bezüglich patienten-, tumor- und therapieassoziierten Charakteristika retrospektiv analysiert. Alle Patienten wurden entweder für eine Radiotherapie mit platinbasierter Chemotherapie (Platin-Gruppe) oder Antikörpertherapie mit Cetuximab (Cetuximab-Gruppe) eingeplant. Die dritte Gruppe bestand aus Patienten, die aufgrund einer Platinunverträglichkeit einen Substanzwechsel auf Cetuximab vollzogen (Switch-Gruppe). Die Inzidenz des SPC wurde mit dem Log-rank-Test errechnet. Mögliche Confounder wurden durch das multivariate Cox-Regressionsmodell (Cox’s proportional hazards model) detektiert. Alle Tests erfolgten zweiseitig; ein p-Wert <0,05 galt als statistisch signifikant.

Ergebnisse

Die mediane Nachbeobachtungszeit betrug 36 Monate. In der Platin-Gruppe waren 158, in der Cetuximab-Gruppe 101 und in der Switch-Gruppe 37 Patienten. Die 3‑Jahres-Gesamtüberlebensrate der gesamten Kohorte war 70%. Die SPC-Raten waren zwischen der Platin- (9,2 %) und Cetuximab-Gruppe (11,5 %) vergleichbar (p = 0,98). In der Switch-Gruppe ließ sich hingegen nach 3 Jahren eine signifikant höhere Inzidenz (p = 0,01) von SPC (23,3 %) nachweisen. Im multivariaten Modell korrelierte ein Substanzwechsel als einzige Variable mit einem erhöhten SPC-Risiko.

Schlussfolgerung

Der Substanzwechsel von einer platinbasierten Substanz auf Cetuximab könnte für Patienten ein erhöhtes Risiko für eine SPC-Entwicklung darstellen. Ein Substanzwechsel sollte aufgrund fehlender, robuster präklinischer und klinischer Daten vorsichtig ausgeübt werden.

Schlüsselwörter

Plattenepithelkarzinom Radiotherapie Anti-epidermal growth factor receptor Cisplatin Carboplatin Systemische Therapie 

Notes

Acknowledgements

We thank Dr. Emanuel Stutz for his valuable input to the manuscript.

Authors’ contributions

Conception and design of the study: OE; data acquisition and quality control of data: BS, BB, MS, OE; statistical analysis: OE; manuscript preparation, editing, review and approval: all co-authors.

Compliance with ethical guidelines

Conflict of interest

O. Elicin received honoraria for his consulting role in the advisory boards of AstraZeneca, Merck, and Merck Serono. B. Sermaxhaj, B. Bojaxhiu, M. Shelan, R. Giger, D. Rauch, and D.M. Aebersold declare that they have no competing interests.

Ethical standards

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

References

  1. 1.
    Pignon J‑P, le Maître A, Maillard E, Bourhis J (2009) Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92:4–14.  https://doi.org/10.1016/j.radonc.2009.04.014 CrossRefPubMedGoogle Scholar
  2. 2.
    National Comprehensive Cancer Network (2018) National Comprehensive Cancer Network guidelines for head and neck cancers (version 1.2018). http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed 28 Feb 2018Google Scholar
  3. 3.
    Grégoire V, Lefebvre J‑L, Licitra L, Felip E, EHNS-ESMO-ESTRO Guidelines Working Group (2010) Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(Suppl 5):v184–v186.  https://doi.org/10.1093/annonc/mdq185 CrossRefPubMedGoogle Scholar
  4. 4.
    Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK et al (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5‑year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11:21–28.  https://doi.org/10.1016/S1470-2045(09)70311-0 CrossRefPubMedGoogle Scholar
  5. 5.
    Bourhis J, Sun xu S, Sire C, Tao Y, Martin L, Khoury C et al (2016) Cetuximab-radiotherapy versus cetuximab-radiotherapy plus concurrent chemotherapy in patients with N0-N2a squamous cell carcinoma of the head and neck (SCCHN): results of the GORTEC 2007-01 phase III randomized trial. J Clin Oncol 34(15 suppl):6003CrossRefGoogle Scholar
  6. 6.
    Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS et al (2014) Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 32:2940–2950.  https://doi.org/10.1200/JCO.2013.53.5633 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Peddi P, Shi R, Nair B, Ampil F, Mills GM, Jafri SH (2015) Cisplatin, cetuximab, and radiation in locally advanced head and neck squamous cell cancer: a retrospective review. Clin Med Insights Oncol 9:1–7.  https://doi.org/10.4137/CMO.S18682 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Koutcher L, Sherman E, Fury M, Wolden S, Zhang Z, Mo Q et al (2011) Concurrent cisplatin and radiation versus cetuximab and radiation for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 81:915–922.  https://doi.org/10.1016/j.ijrobp.2010.07.008 CrossRefPubMedGoogle Scholar
  9. 9.
    Magrini SM, Buglione M, Corvò R, Pirtoli L, Paiar F, Ponticelli P et al (2016) Cetuximab and radiotherapy versus Cisplatin and radiotherapy for locally advanced head and neck cancer: a randomized phase II trial. J Clin Oncol 34:427–435.  https://doi.org/10.1200/JCO.2015.63.1671 CrossRefPubMedGoogle Scholar
  10. 10.
    Chera BS, Amdur RJ (2018) Current status and future directions of treatment deintensification in human papilloma virus-associated oropharyngeal squamous cell carcinoma. Semin Radiat Oncol 28:27–34.  https://doi.org/10.1016/j.semradonc.2017.08.001 CrossRefPubMedGoogle Scholar
  11. 11.
    Elicin O, Albrecht T, Haynes AG, Bojaxhiu B, Nisa L, Caversaccio M et al (2016) Outcomes in advanced head and neck cancer treated with up-front neck dissection prior to (chemo)radiotherapy. Otolaryngol Head Neck Surg 154:300–308.  https://doi.org/10.1177/0194599815608370 CrossRefPubMedGoogle Scholar
  12. 12.
    Shelan M, Anschuetz L, Schubert AD, Bojaxhiu B, Dal Pra A, Behrensmeier F et al (2017) T1-2 glottic cancer treated with radiotherapy and/or surgery. Strahlenther Onkol 193:995–1004.  https://doi.org/10.1007/s00066-017-1139-4 CrossRefPubMedGoogle Scholar
  13. 13.
    Cooper JS, Pajak TF, Rubin P, Tupchong L, Brady LW, Leibel SA et al (1989) Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implications based on the RTOG experience. Int J Radiat Oncol Biol Phys 17:449–456CrossRefGoogle Scholar
  14. 14.
    Yamamoto E, Shibuya H, Yoshimura R, Miura M (2002) Site specific dependency of second primary cancer in early stage head and neck squamous cell carcinoma. Cancer 94:2007–2014.  https://doi.org/10.1002/cncr.10444 CrossRefPubMedGoogle Scholar
  15. 15.
    Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB et al (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578.  https://doi.org/10.1056/NEJMoa053422 CrossRefPubMedGoogle Scholar
  16. 16.
    Wolff HA, Wolff CRM, Hess CF, Jung K, Sennhenn-Kirchner S, Hinterthaner M et al (2013) Second primary malignancies in head and neck cancer patients: high prevalence of curable-stage disease. Strahlenther Onkol 189:874–880.  https://doi.org/10.1007/s00066-013-0404-4 CrossRefPubMedGoogle Scholar
  17. 17.
    Ermiş E, Teo M, Dyker KE, Fosker C, Sen M, Prestwich RJ (2015) Definitive hypofractionated radiotherapy for early glottic carcinoma: experience of 55 Gy in 20 fractions. Radiat Oncol 10:203.  https://doi.org/10.1186/s13014-015-0505-6 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Rusthoven K, Chen C, Raben D, Kavanagh B (2008) Use of external beam radiotherapy is associated with reduced incidence of second primary head and neck cancer: a SEER database analysis. Int J Radiat Oncol Biol Phys 71:192–198.  https://doi.org/10.1016/j.ijrobp.2007.09.045 CrossRefPubMedGoogle Scholar
  19. 19.
    Martel M, Alemany L, Taberna M, Mena M, Tous S, Bagué S et al (2017) The role of HPV on the risk of second primary neoplasia in patients with oropharyngeal carcinoma. Oral Oncol 64:37–43.  https://doi.org/10.1016/j.oraloncology.2016.11.011 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Radiation Oncology, Inselspital, Bern University HospitalUniversity of BernBernSwitzerland
  2. 2.Department of Otorhinolaryngology, Head and Neck Surgery, InselspitalBern University HospitalBernSwitzerland
  3. 3.Department of Medical Oncology, Inselspital, Bern University HospitalUniversity of BernBernSwitzerland

Personalised recommendations