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

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

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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.

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.

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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

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Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Edwin Bölke.

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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.

Additional information

The data were presented at the Annual ESTRO meeting in Milano 2019.

Raw data are available in the published trials and given figures.

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Haussmann, J., Tamaskovics, B., Bölke, E. et al. Addition of chemotherapy to hyperfractionated radiotherapy in advanced head and neck cancer—a meta-analysis. Strahlenther Onkol 195, 1041–1049 (2019). https://doi.org/10.1007/s00066-019-01511-z

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