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Radiation-induced acute toxicities after image-guided intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for patients with spinal metastases (IRON-1 trial)

First results of a randomized controlled trial

Radiogene Akuttoxizität nach bildgeführter intensitätsmodulierter Strahlentherapie versus dreidimensionaler konformaler Strahlentherapie bei Patienten mit Wirbelkörpermetastasen (IRON-1 trial)

Erste Ergebnisse einer randomisierten kontrollierten Studie

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Abstract

Purpose

Radiation therapy (RT) provides an important treatment approach in the palliative care of vertebral metastases, but radiation-induced toxicities in patients with advanced disease and low performance status can have substantial implications for quality of life. Herein, we prospectively compared toxicity profiles of intensity-modulated radiotherapy (IMRT) vs. conventional three-dimensional conformal radiotherapy (3DCRT).

Methods

This was a prospective randomized monocentric explorative pilot trial to compare radiation-induced toxicity between IMRT and 3DCRT for patients with spinal metastases. A total of 60 patients were randomized between November 2016 and May 2017. In both cohorts, RT was delivered in 10 fractions of 3 Gy each. The primary endpoint was radiation-induced toxicity at 3 months.

Results

Median follow-up was 4.3 months. Two patients suffered from grade 3 acute toxicities in the IMRT arm, along with 1 patient in the 3DCRT group. At 12 weeks after treatment (t2), 1 patient reported grade 3 toxicity in the IMRT arm vs. 4 patients in the 3DCRT group. No grade 4 or 5 adverse events occurred in either group. In the IMRT arm, the most common side effects by the end of irradiation (t1) were grade 1–2 xerostomia and nausea in 8 patients each (29.6%), and dyspnea in 7 patients (25.9%). In the 3DCRT group, the most frequent adverse events (t1) were similar: grade 1–2 xerostomia (n = 10, 35.7%), esophagitis (n = 10, 35.8%), nausea (n = 10, 35.8%), and dyspnea (n = 5, 17.9%).

Conclusion

This is the first randomized trial to evaluate radiation-induced toxicities after IMRT versus 3DCRT in patients with vertebral metastases. This trial demonstrated an additional improvement for IMRT in terms of acute side effects, although longer follow-up is required to further ascertain other endpoints.

Zusammenfassung

Zielsetzung

Die Radiotherapie (RT) stellt einen wichtigen Behandlungsansatz in der palliativen Versorgung von Wirbelkörpermetastasen dar. Das Ausmaß der strahleninduzierten Toxizität bei Patienten mit fortgeschrittener Tumorerkrankung und reduziertem Allgemeinzustand hat erhebliche Auswirkungen auf ihre Lebensqualität. Wir haben die Toxizitätsprofile der intensitätsmodulierten Radiotherapie (IMRT) und der konventionellen dreidimensionalen, konformalen Radiotherapie (3DCRT) hinsichtlich normaler Gewebetoxizitäten und klinisch messbarer Nebenwirkungen miteinander verglichen.

Methoden

Es handelte sich um eine prospektive, randomisierte, monozentrische explorative Pilotstudie zur Evaluation der strahleninduzierten Toxizität zwischen IMRT und 3DCRT bei Patienten mit Wirbelkörpermetastasen. Insgesamt wurden vom November 2016 bis Mai 2017 60 Patienten randomisiert. Die RT wurde in 10 Fraktionen von 3 Gy appliziert. Der primäre Endpunkt war die strahleninduzierte Toxizität nach 3 Monaten.

Ergebnisse

Die mediane Nachbeobachtungszeit betrug 4,3 Monate. Im IMRT-Arm litten 2 Patienten an akuter Toxizität Grad 3 und in der 3DCRT-Gruppe 1 Patient. Zwölf Wochen (t2) nach der Behandlung berichtete 1 Patient über eine Grad-3-Toxizität im IMRT-Arm im Vergleich zu 4 Patienten in der 3DCRT-Gruppe. In keiner der beiden Gruppen traten unerwünschte Nebenwirkungen vom Grad 4 oder 5 auf. Im IMRT-Arm waren die häufigsten Nebenwirkungen am Ende der Bestrahlung (t1) Xerostomie Grad 1–2 und Nausea bei jeweils 8 Patienten (29,6%) sowie Dyspnoe bei 7 Patienten (25,9%). In der 3DCRT-Gruppe waren die häufigsten unerwünschten Ereignisse (t1) ähnlich: Xerostomie Grad 1–2 (n = 10; 35,7%), Ösophagitis (n = 10; 35,8%), Nausea (n = 10; 35,8%) und Dyspnoe (n = 5; 17,9%).

Schlussfolgerung

Dies ist die erste randomisierte Studie zur Bewertung strahleninduzierter Toxizität nach IMRT im Vergleich zur 3DCRT bei Patienten mit Wirbelkörpermetastasen. Diese Studie zeigte eine zusätzliche Verbesserung bei Anwendung der IMRT in der Palliativmedizin in Bezug auf reduzierte akute Toxizität, obwohl eine längere Nachbeobachtung erforderlich ist, um weitere Endpunkte zu ermitteln.

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Abbreviations

BS:

Bone survival

CT:

Computed tomography

CTV:

Clinical target volume

3DCRT:

3D conformal radiotherapy

GTV:

Gross tumor volume

IMRT:

Intensity-modulated radiotherapy

KPS:

Karnofsky performance status

OAR:

Organ at risk

OS:

Overall survival

PTV:

Planning target volume

VCF:

Vertebral compression fracture

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Funding

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Authors and Affiliations

  1. Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany

    Tanja Sprave MD, Robert Förster MD, Ingmar Schlampp MD, Tilman Bostel MD, Stefan Ezechiel Welte MD, Eric Tonndorf-Martini, Rami El Shafie MD, Nils Henrik Nicolay MD PhD, Jürgen Debus MD PhD & Harald Rief MD PhD

  2. Department of Radiation Oncology, Allegheny General Hospital, Pittsburgh, PA, USA

    Vivek Verma MD

  3. Heidelberg Institute of Radiation Oncology (HIRO), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Tanja Sprave MD, Robert Förster MD, Ingmar Schlampp MD, Nils Henrik Nicolay MD PhD, Jürgen Debus MD PhD & Harald Rief MD PhD

  4. Department of Radiation Oncology, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland

    Robert Förster MD

  5. Department of Medical Biometry, University Hospital of Heidelberg, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany

    Thomas Bruckner PhD

  6. German Cancer Research Center (DKFZ), Heidelberg Institute of Radiation Oncology (HIRO), 69120, Heidelberg, Germany

    Nils Henrik Nicolay MD PhD

Authors
  1. Tanja Sprave MD
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  2. Vivek Verma MD
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  3. Robert Förster MD
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  4. Ingmar Schlampp MD
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  5. Thomas Bruckner PhD
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  6. Tilman Bostel MD
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  7. Stefan Ezechiel Welte MD
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  8. Eric Tonndorf-Martini
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  9. Rami El Shafie MD
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  10. Nils Henrik Nicolay MD PhD
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  11. Jürgen Debus MD PhD
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  12. Harald Rief MD PhD
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Corresponding author

Correspondence to Harald Rief MD PhD.

Ethics declarations

Conflict of interest

T. Sprave, V. Verma, R. Förster, I. Schlampp, T. Bruckner, T. Bostel, S.E. Welte, E. Tonndorf-Martini, R. El Shafie, N.H. Nicolay, J. Debus and H. Rief declare that they have no competing interests. The sponsors of the study had no role in study design, data analysis, data interpretation, and wording of the report.

Ethical standards

The study was approved by the Heidelberg Independent Ethics Committee (Nr. S‑238/2016).

Additional information

Availability of data and materials

The data used in this analysis are from publications available in the public domain.

Authors’ contributions

HR and JD developed and planned this trial. KH and TB are responsible for statistical considerations/basis of the analysis. TS, VV, HR, TB, NN, SW, RF, RE, and IS performed the examinations and RT supervisions. HR and TS conducted the data collection. ET defined the radiation plans. The corresponding author (HR) had full access to the entire data of the study and had the final responsibility regarding the decision to submit for publication. All authors read and approved the final manuscript.

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Sprave, T., Verma, V., Förster, R. et al. Radiation-induced acute toxicities after image-guided intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for patients with spinal metastases (IRON-1 trial). Strahlenther Onkol 194, 911–920 (2018). https://doi.org/10.1007/s00066-018-1333-z

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