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