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Strahlentherapie und Onkologie

, Volume 195, Issue 12, pp 1041–1049 | Cite as

Addition of chemotherapy to hyperfractionated radiotherapy in advanced head and neck cancer—a meta-analysis

  • Jan Haussmann
  • Bálint Tamaskovics
  • Edwin BölkeEmail author
  • Freddy-Joel Djiepmo-Njanang
  • Kai Kammers
  • Stefanie Corradini
  • Matthias Hautmann
  • Pirus Ghadjar
  • Kitti Maas
  • Patrick J. Schuler
  • Thomas K. Hoffmann
  • Guido Lammering
  • Wilfried Budach
  • Christiane Matuschek
Original Article

Abstract

Background

Adding concurrent chemotherapy (CTx) to definitive radiation therapy (RT) in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) improves overall survival. A comparable effect has been reported for hyperfractionated radiotherapy (HFX-RT) alone. Adding concurrent CTx to HFX-RT has been investigated in multiple trials, yet an evident effect on oncological outcomes and toxicity profile has not been established to date. Thus, the aim of the current study was to perform a meta-analysis on the clinical outcome and toxicity of the addition of CTx to HFX-RT.

Patients and methods

We performed a literature search for randomized controlled trials comparing HFX-RT alone to HFX-RT + concurrent CTx in patients with LA-HNSCC undergoing definite RT. A meta-analysis was performed using the event rates and effect-sizes for overall survival (OS), progression-free survival (PFS), cancer-specific survival (CSS), distant metastasis-free survival and distant recurrence-free interval (DMFS/DMFI) and locoregional recurrence (LRR) as investigated endpoints. Furthermore, we compared selected acute and late toxicities in the included studies. Statistical analysis was performed using the Microsoft Excel (Microsoft, Redmont, WA, USA) add-in MetaXL 5.3 (EpiGear International, Sunrise Beach, Australia), utilizing the inverse variance heterogeneity model.

Results

We identified six studies (n = 1280 patients) randomizing HFX-RT alone and the concurrent addition of CTx. OS was significantly improved in the HFX-RT + CTx group (HR = 0.77, CI95% = 0.66–0.89; p = <0.001). We found similar results in PFS (HR = 0.74, CI95% = 0.63–0.87; p < 0.001) and CSS (HR = 0.72, CI95% = 0.60–0.88; p = 0.001). In contrast, acute toxicities (≥grade 3 mucositis, ≥grade 3 dysphagia) and late adverse events including ≥grade 3 xerostomia, ≥grade 3 subcutaneous, ≥grade 3 bone, ≥grade 3 skin toxicity, and ≥grade 3 dysphagia did not significantly differ between the two groups.

Conclusion

The addition of CTx to HFX-RT in the definitive treatment of advanced LA-HNSCC improves OS, CSS, PFS, and LRR without a significant increase in high-grade acute and late toxicities.

Keywords

Advanced head and neck cancer Overall survival Progression-free survival Cancer-specific survival Acute and late side effects Squamous cell carcinoma 

Abbreviations

5-FU

5-Fluorouracil

CI

Confidence interval

CRTx

Concurrent chemoradiation

CSS

Cancer-specific survival

CTx

Chemotherapy

d

Day

DFS

Disease free survival

DMFI

Distant recurrence-free interval

DMFS

Distant metastasis-free survival

Gy

Gray

HFX-RT

Hyperfractionated radiotherapy

HNSCC

Head and neck squamous cell carcinoma

HR

Hazard ratio

KI

Konfidenzintervall

LA-HNSCC

Locally advanced squamous cell carcinoma of the head and neck

LRC

Local reginol control

LRFS

Loco-regional progression-free survival

LRR

Locoregional recurrence

MMC

Mitomycin C

OS

Overall survival

PFS

Progression-free survival

q4w

Every 4 weeks

RT

Radiation therapy

SIB

Simultaneous Integrated Boost

UICC

Union International Contre le Cancer

Hinzunahme von Chemotherapie zur hyperfraktionierten Strahlentherapie bei fortgeschrittenen malignen Kopf- und Halstumoren – eine Metaanalyse

Zusammenfassung

Hintergrund

Die simultane Gabe einer Chemotherapie (CTx) zur definitiven Strahlentherapie (RT) führt bei Patienten mit lokal fortgeschrittenen Tumoren der Kopf-Hals-Region (HNSCC) zu einer Verbesserung des Gesamtüberlebens. Ein vergleichbarer Effekt wurde ebenfalls für die hyperfraktionierte Strahlentherapie (HFX + RT) ohne simultane CTx berichtet. Die Zugabe von CTx zu HFX-RT wurde in mehreren Studien untersucht. Bislang wurde kein eindeutiger Effekt hinsichtlich der onkologischen Ergebnisse und des Toxizitätsprofils festgestellt.

Patienten und Methodik

Die Autoren führten eine Literaturrecherche für randomisierte kontrollierte Studien durch, in denen bei Patienten mit lokal fortgeschrittenem Plattenepithelkarzinom der Kopf- und Halsregion (LA-HNSCC) eine HFX-RT allein mit HFX-RT + gleichzeitiger CTx verglichen wurde. Eine Metaanalyse wurde unter Verwendung der Effektgrößen für das Gesamtüberleben (OS), das progressionsfreie Überleben (PFS), das krebsspezifische Überleben (CSS), das kombinierte Fernmetastasen-freie Intervall (DMFI) und -Überleben (DMFS) sowie das lokoregionale Rezidiv (LRR) als untersuchte Endpunkte durchgeführt. Zusätzlich wurden die Früh- und Spättoxizitäten untersucht. Die statistische Analyse wurde mit dem Microsoft-Excel-Add-In (Microsoft, Redmont, WA, USA) MetaXL 5.3 (EpiGear International, Sunrise Beach, Australia) unter Verwendung des inversen Varianz-Heterogenitätsmodells durchgeführt.

Ergebnisse

Es wurden 6 Studien (n = 1280 Patienten) identifiziert, bei denen HFX-RT allein gegen HFT-RT mit simultaner CTx randomisiert wurde. Das OS war in der Gruppe mit HFX-RT + CTx signifikant verbessert (Hazard Ratio, HR = 0,77; 95%-Konfidenzintervall, 95%-KI: 0,66–0,89; p = <0,001). Die Autoren stellten ähnliche Ergebnisse beim PFS (HR = 0,74; 95%-KI: 0,63–0,87; p < 0,001), CSS (HR = 0,72; 95%-KI: 0,60–0,88; p = 0,001) sowie beim LRR fest. Akute Toxizitäten (Mukositis oder Dysphagie, jeweils mindestens dritten Grades) unterschieden sich statistisch nicht zwischen beiden Gruppen. Die Analyse der späten unerwünschten Ereignisse umfasste Xerostomie, subkutane, Knochen‑, Hauttoxizität und Dysphagie, jeweils mindestens dritten Grades, die sich ebenfalls nicht signifikant zwischen den Behandlungsgruppen unterschieden.

Schlussfolgerung

Die simultane Hinzunahme der CTx zur HFX-RT bei der definitiven Behandlung von LA-HNSCC verbesserte alle onkologischen Endpunkte ohne klare Verschlechterung der Raten an schwerwiegenden Nebenwirkungen und sollte eine Therapieoption beim LA-HNSCC darstellen.

Schlüsselwörter

Fortgeschrittene Kopf-Hals-Tumoren Gesamtüberleben Progressionsfreies Überleben Tumorspezifisches Überleben Akut- und Spättoxizität Plattenepithelkarzinom 

Notes

Author Contribution

The authors JH and BT contributed equally to the manuscript. JH and CM had the idea, coordinated the work, and wrote parts of the manuscript. EB did the literature research, prepared the data for analysis, and wrote parts of the manuscript. JH and KK did the statistical analysis. CM, KK, FJDN, SC, MH, PG, KM, and WB wrote parts of the manuscript. JH and BT contributed significantly to the discussion on the interpretation of the results. CM and JH prepared the figures and tables and wrote parts of the manuscript. All authors read and approved the final manuscript. All authors gave consent for the publication.

Compliance with ethical guidelines

Conflict of interest

J. Haussmann, B. Tamaskovics, E. Bölke, F.-J. Djiepmo-Njanang, K. Kammers, S. Corradini, M. Hautmann, P. Ghadjar, K. Maas, P. Schuler, T. Hoffmann, G. Lammering, W. Budach, and C. Matuschek declare that they have no competing interests.

Ethical standards

There was no ethics approval necessary because in this meta-analysis, we pulled numbers from the published manuscripts.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jan Haussmann
    • 1
  • Bálint Tamaskovics
    • 1
  • Edwin Bölke
    • 1
    Email author
  • Freddy-Joel Djiepmo-Njanang
    • 1
  • Kai Kammers
    • 2
  • Stefanie Corradini
    • 3
  • Matthias Hautmann
    • 4
  • Pirus Ghadjar
    • 5
  • Kitti Maas
    • 1
  • Patrick J. Schuler
    • 6
  • Thomas K. Hoffmann
    • 6
  • Guido Lammering
    • 7
  • Wilfried Budach
    • 1
  • Christiane Matuschek
    • 1
  1. 1.Department of Radiation OncologyHeinrich Heine UniversityDusseldorfGermany
  2. 2.Division of Biostatistics and Bioinformatics, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsThe Johns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of Radiation OncologyUniversity Hospital, LMU MunichMunichGermany
  4. 4.Department of Radiation OncologyUniversity of RegensburgRegensburgGermany
  5. 5.Department of Radiation OncologyChariteBerlinGermany
  6. 6.Department of Otorhinolaryngology, Head and Neck SurgeryUniversity of UlmUlmGermany
  7. 7.Radiotherapy Institute Bergisch GladbachBergisch GladbachGermany

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