Incidence of skin toxicity in squamous cell carcinoma of the head and neck treated with radiotherapy and cetuximab: A systematic review

doi:10.1016/j.critrevonc.2017.10.011

Critical Reviews in Oncology/Hematology

Volume 120, December 2017, Pages 98-110

https://doi.org/10.1016/j.critrevonc.2017.10.011 Get rights and content

Highlights

•
The rate of skin toxicity due to concomitant use of cetuximab and RT is unknown.
•
A systematic review was performed to define its incidence in head and neck cancer.
•
Out of 2152 patients, the mean rate of severe radiation dermatitis was 32.5%.
•
Contributing factors to its development and limitations of our study were analyzed.

Abstract

Purpose

Radiotherapy plus cetuximab is an effective combination therapy for locally advanced head and neck squamous cell carcinoma. The aim of our study was to determine the frequency of skin toxicity in patients receiving the combined treatment.

Results

Forty-eight studies were included in our analysis, for a total of 2152 patients. The mean rates of G3/G4 radiation dermatitis and acneiform rash were 32.5% (SD: 20.4; 95% CI: 28.5–36.5) and 13.4% (SD: 11.5; 95% CI: 11.2–15.6), respectively. The majority of studies referred to CTCAE scales for reporting both side effects (85.7% and 92.1%, respectively). Data on the management of skin toxicity were available in only 35.4% of the reviewed literature.

Conclusions

severe radiation dermatitis is a frequent side effect induced by the combination of radiotherapy and cetuximab in head and neck cancer. The lack of predictive biomarkers of toxicity hampers the possibilty to design preventive measures on a personalized basis.

Introduction

The incidence of head and neck cancer is increasing: overall, it represents the sixth most common neoplasm (Kamangar et al., 2006), with over 600.000 new cases diagnosed annually worldwide. In over 60% of patients, the disease is discovered at a loco-regionally advanced stage that requires a combined multimodal strategy if a curative intent is pursued. Currently, cisplatin-based concomitant chemo-radiation is the standard non-surgical approach in locally advanced squamous cell carcinoma of the head and neck (SCCHN) (Pignon et al., 2009), although hampered by the occurence of severe side effects and poor compliance. Given the observation that more than 90% of SCCHN overexpress the Epidermal Growth Factor Receptor (EGFR) and that EGFR-mediated pathways play a crucial role in SCCHN proliferation, an alternative strategy to the cisplatin-based regimen was recognized in the inhibition of EGFR signaling. In 2006, Bonner and colleagues published the results of the IMCL 9815 trial (Bonner et al., 2006), showing that the addition to radiation (RT) of Cetuximab (CTX), a chimeric mouse IgG1 monoclonal anti-EGFR antibody, led to better median loco-regional control and overall survival (OS) compared with RT alone without an increased rate of > G3 acute toxicity or a detrimental effect on quality of life (Curran et al., 2007). In light of the evidence provided by this randomized study, the concomitant regimen received FDA approval for the treatment of locally advanced SCCHN. However, the issue of tolerability to the concurrent treatment was raised by case reports, cooperative (Giro et al., 2009) and early institutional (Pryor et al., 2009) experiences reporting a high rate of severe skin side effects. In particular, several authors described the occurrence of an enhanced, rapidly developing dermatitis with distinct clinical features partly different from what usually observed with RT alone, namely due to the presence of worsened xerosis, a generally more intense inflammatory response in the affected tissue, coexistence of desquamation and papulo-pustular (“acneiform”) rash and finally a peculiar, painful and sometimes hemorrhagic crusty exudate with potential septic complications. The frequency of this overlapping “in-field” toxicity induced by the combination of RT and CTX has yet to be clearly determined. Overall, the correct recognition, grading and therapeutic management of the ad-hoc defined “bio-radiation” dermatitis (BRD) (Bernier et al., 2011) represent still today potential limitations (Langendijk and Oosting, 2011) towards the use of CTX in locally advanced SCCHN, since in this regard the indications from the literature are heterogeneous and lack prospective validation in controlled clinical trials. Moreover, at present no specific patient, disease and treatment related-features allow to predict the onset or the degree of severity of BRD throughout a standard 7-week course of radiation. In order to assess the cumulative incidence of acute skin toxicity in SCCHN patients treated with CTX and RT, we performed a systematic review of the literature focusing on studies published after the IMCL 9815 trial. We also aimed to analyze what grading scales were used to report on treatment side effects and to check whether specific supportive care interventions were adopted, if any.

Section snippets

Materials and methods

Following the methodology of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (Liberati et al., 2009), a systematic review of the literature was conducted, focusing on the development of skin toxicity due to the concomitant use of CTX and RT in locally advanced SCCHN. Relevant articles were identified searching Medline (through PubMed) by use of the appropriate MeSH terms for the following search items: bio-radiation dermatitis, radiation dermatitis,

Studies characteristics

Out of 547 references identified by using our predefined search criteria, 253 papers were screened through abstracts assessment (Fig. 1). Overall, 107 articles were evaluated for eligilibity: 48 of them (Giro et al., 2009, Pryor et al., 2009, Pfister et al., 2006, Teoh et al., 2008, Lord et al., 2008, Fountzilas et al., 2009, Chan et al., 2009, Koutcher et al., 2009, Tomková et al., 2010, Buiret et al., 2010, Koukourakis et al., 2010, Kuhnt et al., 2010, Walsh et al., 2011, Kao et al., 2011,

Discussion

The exceptional feature of the IMCL 9815 trial was that the addition of CTX to RT led to an absolute improvement of about 9% in 5-year OS compared with RT alone (45.6% vs 36.4%; hazard ratio for death with combined treatment, 0.73; 95% CI: 0.56–0.95, p = 0.018) without increasing the frequency of adverse events commonly induced by radiation (Bonner et al., 2006, Bonner et al., 2010). In particular, except for the incidence of acneiform rash (G3-G5: 17% vs 1%; p < 0.001) and infusion reactions

Conclusions

The toxicity profile of a RT − CTX concurrent regimen was confirmed to be relevant from our systematic review due to a non-negligible rate of severe dermatitis. Translational research should be aimed at understanding the individual predisposition to severe skin reactions induced by the addition of CTX to RT, beside looking for potential efficacy biomarkers. The unpredictability of skin toxicity development and the large heterogeneity in its frequency, reporting and management may have

Conflict of interest statement

None.

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ReviewIncidence of skin toxicity in squamous cell carcinoma of the head and neck treated with radiotherapy and cetuximab: A systematic review

Highlights

Abstract

Purpose

Results

Conclusions

Introduction

Section snippets

Materials and methods

Studies characteristics

Discussion

Conclusions

Conflict of interest statement

Cancer/Radiotherapie

Ann. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Ann. Oncol.

Ann. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Cancer Radiother.

Lancet Oncol.

Radiother. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Clin. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Radiother. Oncol.

Ann. Oncol.

Radiother. Oncol.

Lancet Oncol.

Eur. J. Cancer

Am. J. Otolaryngol.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Ann. Oncol.

Ann. Oncol.

Radiother. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Clin. Oncol.

Ann. Oncol.

Ann. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Radiother. Oncol.

Radiother. Oncol.

Oral Oncol.

Radiother. Oncol.

Oral Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Ann. Oncol.

Crit. Rev. Oncol. Hematol.

Int. J. Radiat. Oncol. Biol. Phys.

A phase 2 trial of induction nab-paclitaxel and cetuximab given with cisplatin and 5-fluorouracil followed by concurrent cisplatin and radiation for locally advanced squamous cell carcinoma of the head and neck

Cancer

Cetuximab with radiotherapy in patients with loco-regionally advanced squamous cell carcinoma of head and neck unsuitable or ineligible for concurrent platinum-based chemo-radiotherapy: ready for routine clinical practice?

Indian J. Cancer

Prospective phase II trial of cetuximab plus VMAT-SIB in locally advanced head and neck squamous cell carcinoma: feasibility and tolerability in elderly and chemotherapy-ineligible patients

Strahlentherapie Und Onkol

Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522

J. Clin. Oncol.

Induction docetaxel, cisplatin, and cetuximab followed by concurrent radiotherapy, cisplatin, and cetuximab and maintenance cetuximab in patients with locally advanced head and neck cancer

J. Clin. Oncol.

Using the skindex-16 and common terminology criteria for adverse events to assess rash symptoms: results of a pooled-analysis (N0993)

Support. Care Cancer

Combined cetuximab and reirradiation for locoregional recurrent and inoperable squamous cell carcinoma of the head and neck

Strahlentherapie Und Onkol

Reirradiation with cetuximab in locoregional recurrent and inoperable squamous cell carcinoma of the head and neck: feasibility and first efficacy results

Int. J. Radiat. Oncol. Biol. Phys.

Phase I trial of cetuximab, intensity modulated radiotherapy (IMRT), and ipilimumab in previously untreated, locally advanced head and neck squamous cell carcinoma

Ann. Oncol.

Outcome and toxicity of radiotherapy combined with chemotherapy or cetuximab for head and neck cancer: our experience in one hundred and twenty-five patients

Clin. Otolaryngol.

Cetuximab, paclitaxel, carboplatin, and radiation for head and neck cancer: a toxicity analysis

Am. J. Clin. Oncol.

Cetuximab, paclitaxel, carboplatin, and radiatio for head and neck cancer: a survival analysis of a brown university oncology group phase II study

Am. J. Clin. Oncol.

Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck

NEJM

Review
Incidence of skin toxicity in squamous cell carcinoma of the head and neck treated with radiotherapy and cetuximab: A systematic review