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Skin Cancer - Original Paper

Free Access

Efficacy and Tolerance of Cetuximab Alone or Combined with Chemotherapy in Locally Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: An Open Study of 14 Patients

Dereure O.a · Missan H.a · Girard C.a · Costes V.b · Guillot B.a

Author affiliations

aDepartment of Dermatology, INSERM U1058, and bLaboratory of Pathology, University of Montpellier, Montpellier, France

Corresponding Author

Olivier Dereure

Department of Dermatology, University of Montpellier

Hôpital Saint-Eloi, 80 Avenue Augustin Fliche

FR-34295 Montpellier Cedex 5 (France)

E-Mail o-dereure@chu-montpellier.fr

Related Articles for ""

Dermatology 2016;232:721-730

Abstract

Background/Aims: Previous reports highlighted the potential interest of cetuximab alone or in combination with chemotherapy in locally advanced or metastatic cutaneous squamous cell carcinomas (cSCC) care. Material and Methods: To further evaluate the efficiency and safety of cetuximab in advanced cSCC, a single-center retrospective study including all patients treated with cetuximab alone or combined with carboplatin for locally advanced or metastatic cSCC was conducted in a tertiary referral center. The primary end point was the overall response rate (ORR) after 2 cycles of treatment. Secondary end points were best overall disease control rate (DCR), overall survival (OS), best response duration, progression-free survival (PFS), and toxicity profile. Results: Of the 14 enrolled patients, no complete response was obtained after 2 cycles of treatment, but 3 partial responses and 6 stable diseases were observed. ORR and DCR were 21.4 and 64.3%, respectively. Median OS and PFS were 9.25 and 2.65 months, respectively. Median PFS was longer with combined treatment compared with cetuximab monotherapy (9.03 vs. 3.55 months). The safety profile was acceptable with a trend toward a relationship between acne-like rash and longer response (median PFS 5.2 vs. 2.2 months). Discussion/Conclusion: In all series including ours, disease control is usually rapidly obtained with cetuximab alone or combined with conventional chemotherapy, although with a minority of partial responses and no complete response. However, this control is of short duration in most cases. The safety profile is acceptable. A randomized phase III trial is warranted to better assess the benefit/risk ratio.

© 2017 S. Karger AG, Basel


Introduction

Cutaneous squamous cell carcinoma (cSCC) represents about 20% of nonmelanoma skin cancers in western countries [1] with a rapidly increasing incidence [2]. In France, its incidence is estimated to be at least 30 per 100,000 persons per year, and the mean age at diagnosis is 74.4 years in males and 77 years in females. Although easily treated by surgical excision with an excellent overall prognosis in most patients, some cSCC can progress to more advanced stages, either locally or with distant extension, that are impossible to treat by surgical excision alone and for which therapeutic options are limited. Cytotoxic chemotherapies mainly using platinum salts or 5-fluorouracil and radiotherapy are commonly used in this setting, alone or in combination, but the general condition of these patients, who are often elderly and affected with numerous significant comorbidities, usually precludes the implementation of any aggressive chemotherapy [2]. The epidermal growth factor receptor (EGFR) represents a promising alternative therapeutic target since it is often overexpressed and/or abnormally activated in several epithelial malignancies including cSCC [3]. In this setting, cetuximab, a chimeric human monoclonal antibody binding competitively and with high affinity to the EGFR, prevents receptor stimulation by endogenous ligands and inhibits proliferation, enhances apoptosis, and reduces angiogenesis, invasiveness, and metastatic spreading in target tissues. By analogy with advanced head and neck SCC where it proved efficient alone or associated with radiotherapy and/or chemotherapy [4,5,6,7], a number of case reports, small series reports [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26], and scarce clinical trials or larger series [27,28,29] recently suggested that cetuximab may help control metastatic or locally advanced, unresectable cSCC, either alone or in combination with other therapies including systemic chemotherapy and/or radiotherapy. In order to add further information regarding its interest in advanced cSCC, the efficacy and safety of cetuximab alone or combined with chemotherapy in patients with locally advanced and metastatic cSCC treated at our institution were retrospectively analyzed.

Patients and Methods

For further details, see the supplementary materials (for all online suppl. material, see www.karger.com/doi/10.1159/000461578) (Fig. 1).

Fig. 1

Flowchart of Patients and Methods.

/WebMaterial/ShowPic/836276

Results

Patients' Baseline Characteristics and Treatments

A total of 14 patients were enrolled in this study. The median age of the population under scope at treatment implementation was 72.5 years (range: 18-92) with 93% males. Of these, 7 patients had an unresectable locally advanced disease, 3 had regional lymph node involvement, and 4 had distant metastases; 10/14 and 4/14 patients received cetuximab in monotherapy (CM) or in combination with carboplatin (CC), respectively. The median and the mean number of cetuximab infusions administered during the study were 9.5 and 12.25, respectively (range: 1-40 infusions). Analgesic radiotherapy was used during the last infusions in 2/10 patients receiving cetuximab alone and was also performed in some patients after relapse or primary failure. All corresponding data are summarized in Tables 1 and 2.

Table 1

Patients' characteristics

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Table 2

Clinical response and outcome

/WebMaterial/ShowPic/836279

Initial Response, Overall Response Rate, Disease Control Rate, and Duration of Response

Patients' data regarding response to treatment were submitted to intention-to-treat analysis. With respect to the primary end point, no complete response (CR) was obtained after 2 cycles of treatment, while 3 partial responses (PR; Fig. 2a, b, 3a, b) were observed for an overall response rate (ORR) of 21.4% (20 and 25% for CM and CC patients, respectively); 6 stable diseases (SD) and 1 PR were also identified with a best overall disease control rate (DCR) of 63.4 % (70 and 50% for CM and CC patients, respectively). Interestingly, both best overall DCR and best ORR obtained throughout the whole follow-up were similar to the DCR and ORR at week 8 (after the first 2 cycles of treatment) in all evaluable patients, meaning that best response was clearly obtained after 2 months of treatment with no further improvement upon treatment continuation.

Fig. 2

Patient 4: partial response of regional lymph node metastasis of cutaneous SCC according to CT scan at baseline (a) and after 2 cycles of treatment with cetuximab alone (b).

/WebMaterial/ShowPic/836275

Fig. 3

Patient 14: locally advanced, multicentric cSCC of the trunk at baseline (a) and partial clinical regression after 6 cycles of combined treatment with cetuximab and carboplatin (b).

/WebMaterial/ShowPic/836274

A total of 4/14 patients (2 CM and 2 CC) could not be properly assessed for tumor response after the first 2 cycles of treatment as initially planned and were considered as early failure: rapid tumor progression-related death (1 patient) or early treatment interruptions during the first (2 patients) or second (1 patient) cycle due to the occurrence of serious adverse events (AEs): grade 3 infusion-related general reaction during the first cetuximab infusion precluding further administration, general status alteration with grade 3 asthenia, and nephrotic syndrome, respectively). Altogether, including the patient with progressive disease (PD) at first evaluation, 5/14 patients therefore failed to respond to treatment according to intention-to-treat analysis. Response data are summarized in Table 2.

All responding patients but one relapsed during follow-up. A 76-year-old female with stage II widespread cSCC of the trunk experienced PR after 2 cycles of cetuximab + carboplatin, a result maintained by 4 further cycles of the combined regimen followed by cetuximab alone, with an ongoing control of the disease at the last report after 8.5 months of overall follow-up. Median progression-free survival (PFS) and overall survival (OS) were 2.65 months (2.65 vs. 4.87 months for CM and CC patients) and 9.25 months (10.35 vs. 7 months for CM and CC patients).

The treatment provided long-term disease control in 4 patients: 3/3 partial responders with a median duration of response of 8.5 months (2 CM patients with stage IV disease: 7.2 and 18 months; 1 CC patient with stage II disease: 8.5 months), and 1/6 patients with SD (CC patient with stage IV disease: 9.06 months).

Regarding a possibly differential efficiency based on clinical stage, ORR and best overall DRC were 28.5% and 57%, respectively, in locally advanced diseases compared with 14.3% and 71.5% in patients with metastatic disease (regional nodal metastases and/or distant metastases) with a trend for a more prolonged median PFS in this latter subset compared with patients with locally advanced cSCC (7.7 vs. 4.1 months, respectively). Conversely, the ORR/DCR ratio was slightly higher in locally advanced patients (50% of 4 controlled patients) than in patients with metastatic disease (20% of 5 controlled patients). A PFS actuarial curve of patients with locally advanced or metastatic disease and experiencing initial disease control is provided in Figure 4.

Fig. 4

Actuarial curve of progression-free survival in patients with locally advanced (blue) or metastatic disease (red) and displaying initial disease control.

/WebMaterial/ShowPic/836273

AEs and Safety

AEs were reported in all patients including grade 3 AEs in 43%; however, no grade 4 AE or AE-related death was observed. The large majority of AEs were consistent with those previously reported in clinical trials using cetuximab. Interestingly, the patient with Hallopeau-Siemens recessive dystrophic epidermolysis bullosa experienced no particularly conspicuous AE and more specifically no worsening of his genetic disease. The frequency and description of AEs are listed in Table 3.

Table 3

Frequency and distribution of adverse events

/WebMaterial/ShowPic/836278

The most frequent AE was as expected a follicular inflammatory, acne-like rash occurring in 57% of the patients (1 grade 1, 6 grade 2, 1 grade 3) after a median time of 12 days following cetuximab initiation (range: 3-48 days). Cutaneous lesions mostly resolved after transient treatment interruption or with oral tetracyclines and topical steroids. Psychiatric disorders of all types (“split personality,” confusion, anxiety, depression, and hallucinations) were observed in 28.5% of patients, rated grade 1, 2, and 3 in 1, 2, and 1 patients, respectively. However, these latter AEs have not been previously recorded with cetuximab or platinum salts, and their direct relationship with treatment therefore remains doubtful. Finally, a higher than expected incidence of anemia and asthenia was reported, but this might be more a consequence of general status alteration, age, advanced cSCC, and comorbidities than related to the treatment itself.

A total of 3/14 patients permanently discontinued cetuximab because of early AE occurrence either during the first cycle of treatment (2 patients: grade 3 cetuximab-related hypersensitivity reaction during the first infusion, and grade 3 cetuximab-related asthenia along with impaired general condition) or during the second cycle (1 patient: progressively worsening nephrotic syndrome). Two further patients definitively interrupted the treatment after the second cycle of treatment owing to severe AE occurrence (1 grade 3 secondary infection of the primary lesions and 1 grade 3 severe psychiatric symptomatology with a feeling of “split personality”) but could be assessed for clinical response owing to the completion of the first 2 cycles, allowing primary end point evaluation. Other patients with grade 3 AEs were symptomatically managed and could pursue the treatment.

Association of Treatment-Induced Acne-Like Rash and Disease Control

Among the 8/10 assessable patients after the first 2 cycles who experienced acne-like rash, 2 PR and 6 SD were obtained, whereas 1 PR and 1 PD were observed in the 2 patients who remained free of this AE. PFS was quite similar in both subsets (5.2 vs. 5.15 months).

Discussion

This single-center retrospective study was mostly designed to assess the efficacy and safety of cetuximab alone or in combination with carboplatin in patients with locally advanced or metastatic cSCC. Overall, clinical response was rated at 21.4 and 64.3% for ORR and DCR after 2 cycles of treatment, therefore with a majority of SD compared with PR. No CR was achieved. Owing to the limited number of assessable patients, no relevant comparison could be carried out between patients receiving CM versus CC, even though ORR appeared slightly better with the combined treatment along with a longer PFS, whereas OS was longer with cetuximab alone. However, disease progression after initial response or control was common, and OS was limited as a consequence. Only 1 patient receiving the combined treatment was still responding at the last report after 8.5 months of continuous treatment, but her disease, although locally advanced, was probably less aggressive (stage II) than the condition of other patients.

Cetuximab has not been specifically developed in cSCC and no RCT has been conducted in this setting, but a number of individual case reports and some series, most often with a retrospective design, have been previously published to date in this indication (Table 4) [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]. The most relevant report is probably a multicenter phase II study of cetuximab in monotherapy for unresectable locally advanced or metastatic cSCC [27] that analyzed 31 finally assessable patients with ORR and DCR of 13 and 81%, respectively, in per-protocol analysis. Overall PFS was 4.1 months in all controlled patients versus 6.8 months in responding patients. Only 1 patient obtained a CR. As in our series, the best overall DCR obtained throughout the study was equal to the DCR at first evaluation set at 6 weeks of treatment. Acneiform rash was associated with a higher PFS, a relationship not clearly observed in our patients. Additionally, a single-center phase II study of cetuximab for unresectable cSCC was more recently published by Preneau et al. [28] with 20 patients accrued between 2009 and 2011 who were treated with cetuximab only or in combination with chemotherapy or radiotherapy. In this series, the authors observed no CR after 2 months of treatment but rather 9 PR, 6 SD, and 4 PD, with overall disease control and response rates of 78 and 47%, respectively. Cetuximab combined with radiotherapy appeared to be associated with a higher response rate (ORR 80%) than cetuximab combined with carboplatin (ORR 44%) or cetuximab alone (ORR 33%). In a slightly different setting, Reigneau et al. [29] prospectively used cetuximab alone or combined with platinum salt and 5-fluorouracil in a neoadjuvant strategy for unresectable, locally advanced cSCC and achieved a response in 85% of 34 patients who could then undergo secondary surgery, including 53% of complete histological response ensured by analysis of the resected tissues. PFS and OS were 8.5 and 26 months, respectively, after surgery.

Table 4

Retrospective and prospective case series (>3 patients) or clinical trials of advanced cSCC treated with cetuximab alone or combined with chemotherapy and/or radiotherapy

/WebMaterial/ShowPic/836277

Although cross-study comparisons should be interpreted with caution, our results are overall in line with these data and especially with the report by Maubec et al. [27] even though the interpretation was based on intention-to-treat and not per-protocol analysis as in this latter trial. Response duration was short, as largely mentioned in previous reports, with relatively close median PFS observed in the 3 series including ours (2.65, 5.2, and 5.7 months); the shorter PFS observed in our series is probably partially related to intention-to-treat analysis. Only few patients displayed a PFS exceeding 9 months (3 patients in the study by Preneau et al. [28] and 2 patients along with an ongoing response at 8.5 months in our series). Interestingly, the results are significantly better in the neoadjuvant setting, but this difference is likely to be partially related to a difference in patient selection favoring less aggressive conditions where radical surgery might still be considered after tumor reduction. Combining cetuximab with chemotherapy seems more effective in other malignancies, and the same tendency was indeed observed in 2 prior series using platinum salt alone or with 5-fluorouracil [28,29] and also in our patients receiving carboplatin, although no statistical analysis could be performed owing to the limited number of patients. As already stated, response rates were higher with cetuximab combined with radiotherapy [28], but the additional benefit of radiotherapy could not be specifically evaluated in our series since it was not included in the initial therapeutic strategy but mostly used as a rescue or palliative option after disease progression.

Our study included a higher percentage of cSCC patients with regional nodal or distant metastases (50%) than most previously reported cases. Similarly, Giacchero et al. [17] treated 8 cSCC patients among whom 4 presented with regional lymph node metastases at initial staging with 3 CR and 1 PR. Conen et al. [24] reported a small series of 6 patients with regional or distant metastases, achieving 1 CR and 3 PR for a DCR of 67%. Taken together with the results in our 5 evaluable patients with nonlocally advanced tumors (PR 20% and DCR 100%), these data highlight the potential interest of cetuximab to treat not only unresectable locally advanced cSCC but also patients with regional nodal or distant metastases. Interestingly, PFS was higher in our series in patients with regional or distant disease than in locally advanced tumors, seemingly paradoxical data that might be related to the higher rate of acute complication of very aggressive localized tumors including sepsis and cataclysmic bleeding secondary to arterial erosion.

There was no clear correlation between tumor response and intensity of EGFR staining in our series since 3 patients with low expression of EGFR nonetheless responded to cetuximab, a result consistent with previous reports in cSCC and in other malignancies [30,31]. Accordingly, EGFR expression by IHC as patient selection criteria for cetuximab treatment is unlikely to be suitable in cSCC.

The safety profile recorded in our study was overall acceptable and similar to that reported in other studies. The most frequent AE was, as expected, acne-like rash observed in 67% of the patients, with no trend toward a relationship between its occurrence during treatment and a more prolonged PFS, a result contrasting with data from Maubec et al. [27] and obtained in other malignancies but based on more restricted figures. In our series, psychiatric disorders of all types were observed in 28.5% of patients, a pattern that has already been observed in metastatic colorectal cancer but not frequently reported in other tumors including previous reports in cSCC.

Overall, all series including the present one tend to show significant DCR with a minority of PR but very few CR. Tumor control is usually rapidly obtained in the large majority of cases (on average after 2 cycles of treatment) but is usually of short duration as summarized in Table 4. Taken altogether, these data suggest that locally advanced or metastatic cSCC can indeed be amenable to therapies targeting the EGFR, either alone or combined with conventional chemotherapy and/or radiotherapy whenever it is possible in these fragile patients, an option that is likely to be extended to penile SCC where cetuximab seems equally efficient in patients with locally advanced or metastatic diseases [32]. The optimal combination is still to be determined, considering that other molecules than platinum salts and 5-fluorouracil have been proposed including capecitabine [33] and docetaxel [34,35].

Key Message

Cetuximab alone or with chemotherapy may control locally advanced or metastatic cutaneous squamous cell carcinoma.

Statement of Ethics

A general written consent was obtained at admittance from all patients included in this study. No formal approval of the study protocol was required by the local ethics committee according to local regulations.

Disclosure Statement

The authors have no conflicts of interest to declare.


References

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  6. Frampton JE: Spotlight on cetuximab in squamous cell carcinoma of the head and neck. Bio Drugs 2011;25:129-133.
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  15. Jalili A1, Pinc A, Pieczkowski F, Karlhofer FM, Stingl G, Wagner SN: Combination of an EGFR blocker and a COX-2 inhibitor for the treatment of advanced cutaneous squamous cell carcinoma. J Dtsch Dermatol Ges 2008;6:1066-1069.
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Author Contacts

Olivier Dereure

Department of Dermatology, University of Montpellier

Hôpital Saint-Eloi, 80 Avenue Augustin Fliche

FR-34295 Montpellier Cedex 5 (France)

E-Mail o-dereure@chu-montpellier.fr


Article / Publication Details

First-Page Preview
Abstract of Skin Cancer - Original Paper

Received: January 18, 2017
Accepted: January 31, 2017
Published online: April 07, 2017
Issue release date: April 2017

Number of Print Pages: 10
Number of Figures: 4
Number of Tables: 4

ISSN: 1018-8665 (Print)
eISSN: 1421-9832 (Online)

For additional information: https://www.karger.com/DRM


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References

  1. Karia PS, Han J, Schmults CD: Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol 2013;68:957-966.
  2. Rogers HW, Weinstock MA, Feldman SR, Coldiron BM: Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the US population, 2012. JAMA Dermatol 2015;151:1081-1086.
  3. Maubec E, Duvillard P, Velasco V, Crickx B, Avril M-F: Immunohistochemical analysis of EGFR and HER-2 in patients with metastatic squamous cell carcinoma of the skin. Anticancer Res 2005;25:1205-1210.
    External Resources
  4. Burtness B, Goldwasser MA, Flood W, et al: Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 2005;23:8646-8654.
  5. Vermorken JB, Trigo J, et al: Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25:2171-2177.
  6. Frampton JE: Spotlight on cetuximab in squamous cell carcinoma of the head and neck. Bio Drugs 2011;25:129-133.
  7. Cohen MH, Chen H, Shord S, Fuchs C, He K, Zhao H, Sickafuse S, Keegan P, Pazdur R: Approval summary: cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer. Oncologist 2013;18:460-466.
  8. Bauman JE, Eaton KD, Martins RG: Treatment of recurrent squamous cell carcinoma of the skin with cetuximab. Arch Dermatol 2007;143:889-892.
  9. Suen JK, Bressler L, Shord SS, Warso M, Villano JL: Cutaneous squamous cell carcinoma responding serially to single-agent cetuximab. Anticancer Drugs 2007;18:827-829.
  10. Arnold AW, Bruckner-Tuderman L, Zuger C, Itin PH: Cetuximab therapy of metastasizing cutaneous squamous cell carcinoma in a patient with severe recessive dystrophic epidermolysis bullosa. Dermatology 2009;219:80-83.
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