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Grading system and management guidelines for dermatitis induced by head and neck radiotherapy plus cetuximab: clinical validation required

2011; Elsevier BV; Volume: 22; Issue: 10 Linguagem: Inglês

10.1093/annonc/mdr410

1569-8041

Johannes A. Langendijk, Sjoukje F. Oosting,

Head and Neck Surgical Oncology

Head and neck squamous cell carcinoma (HNSCC) represents a rather heterogeneous group of neoplasms originating from the oral cavity, oropharynx, hypopharynx and larynx. In the last decades, prognosis significantly increased as a result of the introduction of new treatment strategies, such as the addition of concomitant chemotherapy to radiation [1.Pignon J.P. le Maitre A. Maillard E. Bourhis J. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients.Radiother Oncol. 2009; 92: 4-14Abstract Full Text Full Text PDF PubMed Scopus (2214) Google Scholar], the use of altered fractionation schedules [2.Bourhis J. Overgaard J. Audry H. et al.Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis.Lancet. 2006; 368: 843-854Abstract Full Text Full Text PDF PubMed Scopus (853) Google Scholar] and, more recently, the use of taxane-based induction chemotherapy [3.Vermorken J.B. Remenar E. van Herpen C. et al.Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer.N Engl J Med. 2007; 357: 1695-1704Crossref PubMed Scopus (1360) Google Scholar, 4.Posner M.R. Hershock D.M. Blajman C.R. et al.Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer.N Engl J Med. 2007; 357: 1705-1715Crossref PubMed Scopus (1362) Google Scholar]. Although outcome in terms of locoregional control and overall survival (OS) are improved, most of these regimens have come to the expense of severe acute and late radiation-induced side-effects, such as mucositis and subsequent swallowing dysfunction. Despite the fact that there is still ample room for improvement, further intensification of concurrent chemoradiation regimens is expected to result in unacceptable acute toxicity rates. In this regard, there has been and will be a growing need for new combined modality strategies that improve treatment efficacy without enhancing radiation-induced side-effects. In 2006, Bonner et al. reported on the results of a prospective study in which patients with locally advanced (stage III and IV) HNSCC originating from the oropharynx, hypopharynx and larynx were randomly assigned to receive radiotherapy alone or radiotherapy plus cetuximab, a monoclonal antibody against the extracellular domain of the epidermal growth factor receptor [5.Bonner J.A. Harari P.M. Giralt J. et al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N Engl J Med. 2006; 354: 567-578Crossref PubMed Scopus (4220) Google Scholar]. The addition of cetuximab to radiotherapy significantly improved time to locoregional progression and OS [5.Bonner J.A. Harari P.M. Giralt J. et al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N Engl J Med. 2006; 354: 567-578Crossref PubMed Scopus (4220) Google Scholar]. The 5-year OS rate for radiotherapy alone was 36.4% compared with 45.6% for radiotherapy plus cetuximab (hazard ratio = 0.49, 0.35–0.72; P = 0.002) [6.Bonner J.A. Harari P.M. Giralt J. et al.Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.Lancet Oncol. 2010; 11: 21-28Abstract Full Text Full Text PDF PubMed Scopus (1588) Google Scholar]. Of interest is that the addition of cetuximab to radiotherapy did not result in a significant increase in radiation-induced side-effects, such as mucositis, xerostomia and dysphagia. Moreover, although the addition of cetuximab to radiation resulted in a marked and significant increase in acneiform rash and infusion reactions, the percentage of patients that developed grade III to IV radiation dermatitis was comparable between the two arms, i.e. 18% for patients treated with radiotherapy alone versus 23% for those treated with radiotherapy plus cetuximab (not significant). Concurrent chemoradiation is considered the standard in locally advanced HNSCC but has not been compared directly to radiotherapy with cetuximab. The latter regimen is increasingly used but mainly for patients with locally advanced HNSCC who are considered ineligible for chemoradiation. Since the introduction of concurrent radiotherapy and cetuximab in routine clinical practice, several authors published the results of their first experiences and reported much higher incidences of severe radiation dermatitis than were observed in the Bonner trial [5.Bonner J.A. Harari P.M. Giralt J. et al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N Engl J Med. 2006; 354: 567-578Crossref PubMed Scopus (4220) Google Scholar]. Giro et al. [7.Giro C. Berger B. Bolke E. et al.High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: results of a survey in EORTC institutes.Radiother Oncol. 2009; 90: 166-171Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar] described the results of a retrospective study, including 71 assessable patients from 28 European Organisation for Research and Treatment of Cancer (EORTC) institutions in 11 countries. They found 21% grade III and 28% grade IV radiation dermatitis, respectively, which is twofold higher than in the Bonner trial. In addition, Pryor et al. [8.Pryor D.I. Porceddu S.V. Burmeister B.H. et al.Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer.Radiother Oncol. 2009; 90: 172-176Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar] reported a 77% incidence of grade III to IV radiation dermatitis among the first 13 consecutive patients with locally advanced mainly oropharyngeal and hypopharyngeal cancers treated with the same regimen, of whom 46% required hospital admission and 31% treatment breaks. In reply to this paper, Chan et al. [9.Chan A. Teoh D. Sanghera P. Hartley A. Radiotherapy compliance is maintained with hypofractionation and concurrent cetuximab in locally advanced head and neck cancer.Radiother Oncol. 2009; 93: 654Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar] reported that they observed a 61% rate of grade III to IV radiation dermatitis among HNSCC patients treated with concurrent hypofractionated radiotherapy and cetuximab. In a prospective non-randomised comparative clinical study, concurrent cetuximab and radiotherapy resulted in a 31% increase in the rate of grade III to IV radiation dermatitis compared with patients treated in the same time period with concurrent chemoradiation [10.Studer G. Brown M. Salgueiro E.B. et al.Grade 3/4 dermatitis in head and neck cancer patients treated with concurrent cetuximab and IMRT.Int J Radiat Oncol Biol Phys. 2010; 81: 110-117Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. These reports demonstrate that severe radiation-induced skin toxicity is an important and clinically relevant problem in HNSCC patients treated with radiotherapy and cetuximab outside the setting of a clinical trial. Dermatitis is not only burdensome to patients; it sometimes necessitates interruption of radiation treatment, which has a significant adverse impact on locoregional tumour control. In a phase II study combining chemoradiotherapy with cetuximab, 18 out of 20 patients (90%) developed grade III to IV radiation dermatitis, suggesting that chemotherapy further aggravates radiation-induced skin toxicity when combined with radiotherapy and chemotherapy [11.Suntharalingam M. Kwok Y. Goloubeva O. et al.Phase II study evaluating the addition of cetuximab to the concurrent delivery of weekly carboplatin, paclitaxel, and daily radiotherapy for patients with locally advanced squamous cell carcinomas of the head and neck.Int J Radiat Oncol Biol Phys. 2011; (May 19. [Epub ahead of print])Google Scholar]. These findings launched further investigations on the pathogenesis, risk factors, grading and management of radiation dermatitis. It is clear that, with regard to the incidence and severity of radiation dermatitis during concurrent radiotherapy with cetuximab, there is a striking difference between the results observed in the Bonner trial and the reports on the first experience in routine clinical practice. A possible explanation for these differences is the use of different toxicity grading systems. In the Bonner trial, acute radiation toxicity was determined using the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria [5.Bonner J.A. Harari P.M. Giralt J. et al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N Engl J Med. 2006; 354: 567-578Crossref PubMed Scopus (4220) Google Scholar], while others used different versions of the National Cancer Institute—Common Toxicity Criteria and Adverse Events (NCI–CTCAE) grading system [7.Giro C. Berger B. Bolke E. et al.High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: results of a survey in EORTC institutes.Radiother Oncol. 2009; 90: 166-171Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar]. In some reports, it even remained unclear which toxicity scoring system was used. However, as the definitions of grade II, III and IV only slightly differ between these scoring systems, it is unlikely that the use of different scoring systems is sufficient to explain the discrepancies in the incidences reported. Another explanation may be publication bias. Out of the 111 EORTC institutions asked to participate in the retrospective study by Giro et al. [7.Giro C. Berger B. Bolke E. et al.High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: results of a survey in EORTC institutes.Radiother Oncol. 2009; 90: 166-171Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar], only 28 institutions responded. It is not unlikely that those institutions that experienced high rates of acute skin reactions were more inclined to respond than others. This may have biased the results and may have lead to an overestimation of the incidence of grade III and IV radiation dermatitis in that study. On the other hand, as acute toxicity was not scored prospectively, the results could have been biased in the opposite direction as well. Finally, radiation dose and technique may influence the incidence and severity of dermatitis. Giro et al. [7.Giro C. Berger B. Bolke E. et al.High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: results of a survey in EORTC institutes.Radiother Oncol. 2009; 90: 166-171Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar] found a gradual increase in the rate of grade III to IV radiation dermatitis during the radiation course. This observation suggests a dose–response relationship for either radiotherapy or cetuximab or both. However, Studer et al. [10.Studer G. Brown M. Salgueiro E.B. et al.Grade 3/4 dermatitis in head and neck cancer patients treated with concurrent cetuximab and IMRT.Int J Radiat Oncol Biol Phys. 2010; 81: 110-117Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar] did not find an obvious correlation between the number of cetuximab cycles and the incidence of grade III to IV radiation dermatitis. In that study, a significant association was found between the dose to the skin and grade III to IV radiation dermatitis. Although not specified in the initial paper of the Bonner trial, given the time period in which patients were included, they were most likely treated with three-dimensional conformal radiotherapy and not with intensity-modulated radiotherapy (IMRT). On the contrary, most patients included in the studies that reported higher rates of radiation dermatitis were treated with IMRT. In some studies, IMRT with frequent use of bolus [build-up material on the skin to ascertain adequate radiation dose to the superficial planning target volume (PTV) in case of PTV’s extending to just under the skin] was given [10.Studer G. Brown M. Salgueiro E.B. et al.Grade 3/4 dermatitis in head and neck cancer patients treated with concurrent cetuximab and IMRT.Int J Radiat Oncol Biol Phys. 2010; 81: 110-117Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar], which increases the dose to the skin considerably. Dosimetric studies using IMRT in the head and neck region showed that the skin dose may vary widely depending on the margins taken for PTV shrinkage related to the clinical target volume in the proximity of the skin [12.Shiau A.C. Lai P.L. Liang J.A. et al.Dosimetric verification of surface and superficial doses for head and neck IMRT with different PTV shrinkage margins.Med Phys. 2011; 38: 1435-1443Crossref PubMed Scopus (14) Google Scholar]. As the policies in radiation departments may differ with regard to the radiotherapy treatment planning objectives, the definition of the PTV immediately under the skin surface, and the use of bolus or not, may all interfere with the actual skin dose delivered during radiation and thus with the probability on severe skin reactions. Although the landmark study [5.Bonner J.A. Harari P.M. Giralt J. et al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N Engl J Med. 2006; 354: 567-578Crossref PubMed Scopus (4220) Google Scholar] did not show an increased incidence of grade III to IV radiation dermatitis, there are abundant data that indicate that patients who are currently selected for concurrent cetuximab with IMRT-based radiation have a high risk on severe acute skin reactions during the course of treatment. Therefore, there is a need for well-defined and concise management guidelines. In the current issue of Annals of Oncology, Bernier et al. [13.Bernier J. Russi E.G. Homey B. et al.Management of radiation dermatitis in patients receiving cetuximab and radiotherapy for locally advanced squamous cell carcinoma of the head and neck: proposals for a revised grading system and consensus management guidelines.Ann Oncol. 2011; 22: 2191-2200Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar] present consensus guidelines for the management of grade III to IV radiation dermatitis in patients receiving concurrent radiotherapy and cetuximab. They also propose a modification of the NCI–CTCAE grading system of radiation dermatitis as they felt that the current system was not adequately designed for this specific type of radiation dermatitis and thus may lead to misclassification and subsequent inappropriate management [13.Bernier J. Russi E.G. Homey B. et al.Management of radiation dermatitis in patients receiving cetuximab and radiotherapy for locally advanced squamous cell carcinoma of the head and neck: proposals for a revised grading system and consensus management guidelines.Ann Oncol. 2011; 22: 2191-2200Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. Without any doubt, physicians perform not so very well in scoring radiation-induced toxicity when treating patients in clinical trials and in routine clinical practice. A number of studies have shown that physicians tend to underestimate the incidence and severity of treatment-related toxicity [14.Davidson S.E. Trotti A. Ataman O.U. et al.Improving the capture of adverse event data in clinical trials: the role of the International Atomic Energy Agency.Int J Radiat Oncol Biol Phys. 2007; 69: 1218-1221Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. Moreover, interobserver agreement in scoring skin reactions ranges from 65% to 97% depending on the toxicity item [15.Berthelet E. Truong P.T. Musso K. et al.Preliminary reliability and validity testing of a new Skin Toxicity Assessment Tool (STAT) in breast cancer patients undergoing radiotherapy.Am J Clin Oncol. 2004; 27: 626-631Crossref PubMed Scopus (52) Google Scholar]. A prerequisite for proper and unambiguous scoring of toxicity with high interobserver agreement is a scoring system that is easy to perform and interpret in a busy clinical environment. The NCI–CTCAE toxicity scoring system has been widely adopted by the oncology community and is used nowadays in most clinical trials. This has resulted in more homogeneous scoring and reporting of treatment-related side-effects. The NCI–CTCAE scoring system has been updated and modified several times based on advancing clinical experience and knowledge of the pathophysiology of side-effects. Bernier et al. identified some shortcomings in the latest version of the NCI–CTCAE scoring system for radiation dermatitis, for which they propose modifications. For example, as radiation dermatitis resulting from the concurrent use of radiotherapy and cetuximab is clinically characterised by the presence of crusts, it is generally impossible to determine the presence of skin necrosis or ulceration of the full thickness of the dermis, as defined in the CTCAE v4.03 (classified under Injury, Poisoning and Procedural Complications). In this regard, it is important to mention that in the retrospective multicenter study on radiation dermatitis during radiotherapy and cetuximab [7.Giro C. Berger B. Bolke E. et al.High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: results of a survey in EORTC institutes.Radiother Oncol. 2009; 90: 166-171Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar], major differences were noted in the reported incidences of grade IV radiation dermatitis between different institutions. Indeed, this may reflect the difficulty in the distinction between grade III and IV as defined by the CTCAE. Although the modifications proposed appear sound, the question arises whether these modifications will really result in more appropriate and accurate scoring and eventually in improved interobserver agreement. One of the shortcomings of toxicity scoring systems is that they are mainly based on common sense and general consensus but lack clinical validation. This is surprising, especially when considering the extensive validation procedures that are required for quality of life questionnaires before introduction into clinical trials (http://groups.eortc.be/qol/documentation_manuals.htm). Validation is of major importance not only for enabling inter-institutional and inter-trial comparisons but also to ensure a safe translation of the proposed management guidelines into routine clinical practice. Shifting the paradigm from expert-based to evidence-based scoring of major toxicity should be the scope of future research, focussing on feasibility, interobserver variability and comparison with the golden standard, being the latest version of the CTCAE. These types of studies could run in parallel with intervention trials as secondary end points.