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Hyperfractionated accelerated radiation therapy plus cetuximab plus cisplatin chemotherapy in locally advanced inoperable squamous cell carcinoma of the head and neck

Final 5‑year results of a phase II study

Hyperfraktionierte akzelerierte Bestrahlung plus Cetuximab plus Cisplatin-Chemotherapie beim lokal fortgeschrittenen, inoperablen Plattenepithelkarzinom im Kopf-Hals-Bereich

5-Jahres-Ergebnisse einer Phase-II-Studie

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Abstract

Background

Cetuximab (CET) is a potent inhibitor of the epidermal growth factor receptor and has been shown to have activity in squamous cell carcinoma of the head and neck (SCCHN). We conducted a single-arm phase II trial of a combination therapy comprising cisplatin (CIS), CET and hyperfractionated accelerated radiotherapy (HART).

Patients and methods

Patients with UICC stage III or IVA/B, M0 SCCHN were enrolled and treated with an initial dose of CET (400 mg/m2) and then with a weekly dosage of 250 mg/m2 during HART. HART was started with a prescribed dosage of 2.0 Gy per day for 3 weeks, followed by 1.4 Gy twice daily to a total dose of 70.6 Gy to the gross tumour volume. CIS (40 mg/m2) was administered weekly (days 1, 8, 15, 22, 29 and 36). The primary objective of the phase II study was to determine the 2‑year progression-free survival (PFS).

Results

Between November 2007 and November 2010, a total of 74 patients were enrolled in the study, of whom 65 were evaluable (83% were men). Median age was 56 years (range 37–69 years). An Oropharyngeal primary tumour was diagnosed in 49%, T4a,b in 65% and N2/3 in 96% of the patients. Of these patients, 85% were smokers or ex-smokers. Complete remission (CR) was observed in 23 patients (35%). The most common toxicity grade was ≥3, including mucositis (58%) and dysphagia (52%). The 2‑ and 5‑year overall survival rates were 64 and 41%, the 2‑ and 5‑year PFS rates were 45 and 32%, and the 2‑ and 5‑year locoregional control rates were 47 and 33%, respectively.

Conclusion

The combination of weekly CIS with HART plus CET is a feasible regimen for these unfavourable smoking-induced cancers. However, the parallel US study (RTOG 0522) showed no advantage of the enhanced triple therapy compared to chemoradiotherapy alone.

Zusammenfassung

Hintergrund

Cetuximab (CET) ist ein potenter Inhibitor des epidermalen Wachstumsfaktor-Rezeptors, der schon bei Plattenepithelkarzinomen des Kopf-Hals-Bereichs (SCCHN) Wirkung gezeigt hat. Wir führten eine prospektive, einarmige Phase-II-Studie einer Kombinationstherapie mit Cisplatin (CIS), CET und hyperfraktionierter akzelerierter Strahlentherapie (HART) durch.

Patienten und Methoden

Patienten mit einem M0-SCCHN im UICC-Stadium III oder IVA/B wurden eingeschlossen und mit einer CET-Anfangsdosis von 400 mg/m2 und dann einer wöchentlichen Dosis von 250 mg/m2 während HART behandelt. HART wurde mit 2,0 Gy pro Tag für 3 Wochen begonnen und danach mit 2‑mal täglich 1,4 Gy bis zu einer Gesamtdosis von 70,6 Gy auf das Gesamttumorvolumen fortgesetzt. CIS (40 mg/m2) wurde wöchentlich (Tag 1, 8, 15, 22, 29 und 36) verabreicht. Primäres Ziel der Phase-II-Studie war das progressionsfreie 2‑Jahres-Überleben (PFS).

Ergebnisse

Von den zwischen November 2007 und November 2010 74 in die Studie eingeschlossen Patienten waren 65 auswertbar (83 % Männer). Das Durchschnittsalter betrug 56 Jahre (Spanne 37–69 Jahre). Oropharynxkarzinome wurden bei 49 % diagnostiziert, T4a,b bei 65 % und N2/3 bei 96%. Von diesen Patienten waren 85 % Raucher oder Exraucher. Eine komplette Remission erreichten 23 Patienten (35 %). Die häufigsten Toxizitäten ≥ Grad 3 waren die Mukositis (58 %) und Dysphagie (52 %). Die 2‑ und 5‑Jahres-Überlebensraten lagen bei 64 % und 41 %, die 2‑ und 5‑Jahres-PFS-Raten bei 45 % und 32 % und die lokoregionale Kontrolle nach 2 und 5 Jahren bei 47 % und 33 %.

Schlussfolgerung

Die Kombination von wöchentlichem CIS mit HART plus CET ist eine durchführbare Therapie für diese ungünstigen durch das Rauchen verursachten Karzinome. Die parallel durchgeführte US-Studie (RTOG 0522) ergab aber keinen Vorteil der erweiterten Tripeltherapie im Vergleich zur alleinigen Radiochemotherapie.

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Acknowledgements

We thank the patients and their families and the medical staff at the various centres who contributed to the patients’ care. We also thank the coordinating centre of the clinical studies at the Martin Luther University Halle-Wittenberg for data monitoring and the Merck KGaA (Darmstadt, Germany) for providing the study medication.

Author information

Authors and Affiliations

  1. Department of Imaging and Radiation Medicine, Clinic of Radiooncology, University of Leipzig, Stephanstr. 9a, 04103, Leipzig, Germany

    Thomas Kuhnt

  2. Private Praxis for Radio Oncology Dresden, Dresden, Germany

    Andreas Schreiber

  3. Department of Radiation Oncology, University of Rostock, Rostock, Germany

    Anett Pirnasch

  4. Department of Radiotherapy, University of Regensburg, Regensburg, Germany

    Matthias G. Hautmann

  5. Department of Radiotherapy, Otto von Guericke University of Magdeburg, Magdeburg, Germany

    Peter Hass

  6. Department of Radiotherapy, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany

    Frank P. Sieker

  7. Department of Radiotherapy, Philipps University Marburg, Marburg, Germany

    Rita Engenhart-Cabillic

  8. Coordination Centre for Clinical Trials Halle, Halle (Saale), Germany

    Michael Richter

  9. Department of Radiation Oncology, University of Kiel, Kiel, Germany

    Kathrin Dellas & Jürgen Dunst

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  1. Thomas Kuhnt
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  2. Andreas Schreiber
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  10. Jürgen Dunst
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Corresponding author

Correspondence to Thomas Kuhnt.

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Conflict of interest

T. Kuhnt, A. Schreiber, A. Pirnasch, M.G. Hautmann, P. Hass, F.P. Sieker, R. Engenhart-Cabillic, M. Richter, K. Dellas and J. Dunst 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.

Additional information

Clinical trial number: ISRCTN47339346

Caption Electronic Supplementary Material

66_2017_1145_MOESM1_ESM.docx

Fig. 2 CONSORT flow chart showing phase I and II. Fig. 3 Median locoregional progression-free survival (LPFS) in months with 95% confidence interval (CI) 18.0 [10.8, 42.1], censored n = 25, intention to treat (ITT) n = 65. Fig. 4 Median overall survival (OS) in months with 95% confidence interval (CI) 40.1 [24.8,not reached]; censored n = 30; intention to treat (ITT) n = 65

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Kuhnt, T., Schreiber, A., Pirnasch, A. et al. Hyperfractionated accelerated radiation therapy plus cetuximab plus cisplatin chemotherapy in locally advanced inoperable squamous cell carcinoma of the head and neck. Strahlenther Onkol 193, 733–741 (2017). https://doi.org/10.1007/s00066-017-1145-6

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  • DOI: https://doi.org/10.1007/s00066-017-1145-6

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