title: Gemcitabine-Based Chemoradiation in the Treatment of Locally Advanced Head and Neck Cancer: Systematic Review of Literature and Meta-Analysis.
abstract: BACKGROUND
  Platinum-based concurrent chemoradiation (CCRT) improves locoregional control and overall survival of locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) when compared to radiotherapy alone, but this approach is hampered by significant toxicity. Therefore, alternative ways to enhance the radiation effects are worth investigating. Gemcitabine (2',2'-difluorodeoxycytidine), in addition to its activity against a variety of solid tumors, including SCCHN, is one of the most potent radiosensitizers, and it has an overall favorable safety profile. In this paper, the clinical experience with gemcitabine-based chemoradiation in the treatment of patients with LA-SCCHN is reviewed.
  
  
  METHODS
  We conducted a review of the literature on the clinical experience with radiotherapy combined with either single-agent gemcitabine or gemcitabine/cisplatin-based polychemotherapy for the treatment of patients with LA-SCCHN. We also searched abstracts in databases of major international oncology meetings from the last 20 years. A meta-analysis was performed to calculate pooled proportions with 95% confidence intervals (CIs) for complete response rate and grade 3-4 acute mucositis rate.
  
  
  RESULTS
  A total of 13 papers were eligible for the literature review. For schedules using a gemcitabine dose intensity (DI) below 50 mg/m(2) per week, the complete response rate was 86% (95% CI, 74%-93%) with grade 3-4 acute mucositis rate of 38% (95% CI, 27%-50%) and acceptable late toxicity. In one of the studies employing such low DIs, survival data were provided showing a 3-year overall survival of 50%. Compared with DI ≥50 mg/m(2) per week, there was no difference in the complete response rate (71%; 95% CI, 55%-83%; p = .087) but a significantly higher (p < .001) grade 3-4 acute mucositis rate of 74% (95% CI, 62%-83%), often leading to treatment interruptions (survival data provided in 8 studies; 3-year overall survival, 27%-63%). Late toxicity comprising mainly dysphagia was generally underreported, whereas information about xerostomia and skin fibrosis was scarce.
  
  
  CONCLUSIONS
  This review highlights the radiosensitizing potential of gemcitabine and suggests that even very low dosages (less than 50 mg/m(2) per week) provide a sufficient therapeutic ratio and therefore should be further investigated. Refinements in radiation schemes, including intensity-modulated radiation therapy, in combination with low-dose gemcitabine and targeted agents, such as cetuximab, are currently being investigated.
  
  
  CONCLUSIONS
  Cisplatin-based concurrent chemoradiation (CCRT) has become the standard treatment of locally advanced head and neck cancer (LAHNC). This approach is hampered by significant toxicity. This paper reviews the studies using gemcitabine as an alternative radio-sensitizer for CCRT in patients with LAHNC. In this capacity, despite its mild intrinsic toxicity, gemcitabine comes with high rates of severe mucositis when used in dosages exceeding 50 mg/m(2) per week. CCRT with low-dose gemcitabine provides a sufficient therapeutic ratio, combining clinical activity, similar to the higher-dose regimens, with lower toxicity. Further investigation is warranted.
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Antwerp University Hospital, Edegem, Antwerp, Belgium Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium olivier.vanderveken@uza.be.
authors.forename: Olivier M
authors.initials: OM
authors.lastname: Vanderveken
authors.affiliation: Department of Medical Oncology, Antwerp University Hospital, Edegem, Antwerp, Belgium Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic School of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Szturz
authors.affiliation: Department of Medical Oncology, Antwerp University Hospital, Edegem, Antwerp, Belgium Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Pol
authors.initials: P
authors.lastname: Specenier
authors.affiliation: Department of Oncology, Santa Croce e Carle General Hospital, Cuneo, Italy.
authors.forename: Marco C
authors.initials: MC
authors.lastname: Merlano
authors.affiliation: Department of Oncology, San Paolo Hospital, Savona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Benasso
authors.affiliation: Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium Department of Radiotherapy, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Van Gestel
authors.affiliation: Scientific Coordination and Biostatistics, Antwerp University Hospital, Edegem, Antwerp, Belgium.
authors.forename: Kristien
authors.initials: K
authors.lastname: Wouters
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Antwerp University Hospital, Edegem, Antwerp, Belgium Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Carl
authors.initials: C
authors.lastname: Van Laer
authors.affiliation: Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium Department of Radiotherapy, Ziekenhuis Netwerk Antwerpen (ZNA), Antwerp, Belgium.
authors.forename: Danielle
authors.initials: D
authors.lastname: Van den Weyngaert
authors.affiliation: Department of Medical Oncology, Antwerp University Hospital, Edegem, Antwerp, Belgium Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Department of Medical Oncology, Antwerp University Hospital, Edegem, Antwerp, Belgium Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Vermorken
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D050397:Radiotherapy, Intensity-Modulated; D000077195:Squamous Cell Carcinoma of Head and Neck; D000093542:Gemcitabine
chemical_list: D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Chemotherapy; Concomitant chemoradiotherapy; Gemcitabine; Head and neck cancer; Neoplasms; Oncology; Radiation; Radiotherapy; Toxicity