Case and Review Received: May 30, 2013 Accepted after revision: August 3, 2013 Published online: November 7, 2013
Dermatology 2013;227:289–294 DOI: 10.1159/000355181
Treatment of Advanced Cutaneous Squamous Cell Carcinomas with Epidermal Growth Factor Receptor Inhibitors M. Alter I. Satzger A. Mattern A. Kapp R. Gutzmer Department of Dermatology and Allergy, Hannover Medical School, Skin Cancer Center Hannover, Hannover, Germany
Abstract In advanced cutaneous squamous cell carcinoma (cSCC), efficient medical treatment options are limited in case surgery and radiotherapy failed, particularly since most patients are of higher age and suffer from comorbidities. In many tumor entities, the epidermal growth factor receptor (EGFR) has been established as an important therapeutic target, and blockade of EGFR signaling by monoclonal antibodies or small molecules achieves a therapeutic benefit. EGFR expression is also often dysregulated in cSCC. We report here two patients with advanced cSCC treated with the EGFR inhibitor cetuximab and summarize the current published experience with the use of EGFR inhibitors in © 2013 S. Karger AG, Basel cSCC.
Introduction
Cutaneous squamous cells carcinoma (cSCC) with a yearly incidence of at least 30/100,000 is the second most common
skin cancer after basal cell carcinoma [1]. Due to its main risk factor ultraviolet lightinduced damage, cSCC predominately occurs in the ultraviolet light-exposed skin of elderly patients. A recent case series of 653 patients demonstrated a median age of 73 years [2]. Treatment is usually performed by surgical excision or radiotherapy. In approximately 7% of patients local recurrence or metastases develop (advanced cSCC) [2]. Thus, there is only a relatively small population that fails local treatments. Local tumor growth often results in greasy ulcers and superinfections, mainly located in visible areas of the head and neck. Thus, patients often suffer from a severe reduction of quality of life due to their cutaneous tumor growth. At the same time, therapeutic options are limited due to patients’ age, comorbidities and the lack of efficient medical therapies [3]. Current guidelines and reviews list methotrexate, platinum, 5-fluorouracil/capecitabine, bleomycin and interferon alpha plus retinoids, which have only been explored in small patient numbers and with limited success considering response rates and duration of response [3–5]. The epidermal growth factor receptor (EGFR) is expressed on the majority of cSCCs [6–10] and appears to be upregulated on advanced or metastatic tumor tissue
© 2013 S. Karger AG, Basel 1018–8665/13/2274–0289$38.00/0 E-Mail [email protected] www.karger.com/drm
[8, 11, 12]. However, the studies are not consistent, some showing a downregulation of EGFR on cSCC with a more malignant phenotype [13] or no correlation of cSCC differentiation and intensity of EGFR expression [14]. These studies used primarily immunohistochemistry to detect EGFR expression. The different results might be explained by different methods and reagents used. Molecular analysis of the EGFR showed only very few mutations in cSCC [15, 16]. At the same time, RAS mutations were also very rarely detected in cSCC [15]. RAS mutations activate the pathway downstream of the EGFR, and EGFR inhibition is largely ineffective in other tumor entities with activating RAS mutations. Thus, advanced cSCC often shows a dysregulated EGFR expression without EGFR or RAS mutation and therefore represents a potential target tumor for therapeutic EGFR blockade. Various strategies have been developed to therapeutically block the EGFR by employing either small molecules (i.e. erlotinib and gefitinib) or antibodies (i.e. cetuximab and panitumumab). These substances have entered the clinics and are approved for the treatment of different types of cancers. Thus, we decided to use the anti-EGFR monoclonal antibody cetuximab (Erbitux®) to treat locally advanced cSCC. We
Mareike Alter Department of Dermatology and Allergy Skin Cancer Center Hannover, Hannover Medical School Carl-Neuberg-Str. 1, DE–30625 Hannover (Germany) E-Mail alter.mareike @ mh-hannover.de
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Key Words Epidermal growth factor receptor · Squamous cell carcinoma · Skin cancer · Medical tumor therapy · Dermatooncology
Color version available online
a
b
c
d
e
f
Fig. 1. Patient 1 with local recurrence of cSCC after operation and irradiation within the radiation field before
treatment with cetuximab (a), after 1 month of cetuximab monotherapy (b), after 3 months of cetuximab monotherapy (c), after 1 month (d) and 3 months (e) of cetuximab plus cisplatin combination therapy and after complete excision (f). Note that there was virtually no granulation during cetuximab therapy.
Case Reports
Case 1 An 80-year-old female patient presented with surgically unresectable cSCC of the scalp. Although wide surgical resection of the tumor was performed, complete resection could not been reached. Thus subsequent radiation therapy was initiated. Three months later the patient developed new subcutaneous tumors near the first resection area and at the border of the radiation field. Histopathology showed recurrence of the cSCC and the patient underwent dose-intensifying radiotherapy. However, the tumor continued to grow within the irradiated area, and additional radiotherapy and surgery were impossible (fig. 1a). Staging procedures including cranial and neck computer tomography, ab-
290
dominal ultrasound and peripheral lymph node and chest X-ray showed no evidence of further metastazation. Thus treatment with cetuximab, an antibody blocking the EGFR, was initiated. Cetuximab was given as a monotherapy, starting with 400 mg/ m2, followed by 250 mg/m2 weekly. Clinically, the tumor rapidly improved (fig. 1b). Histopathologically most of the tumorbearing area had cleared after 2 months, only in one area a well-differentiated cornifying cSCC (instead of the previously undifferentiated cSCC) was seen. Only 1 month later worsening of clinical findings was observed (fig. 1c). Histopathology showed recurrence of the squamous cell carcinoma. Thus we decided to intensify therapy and started a combination of cetuximab 500 mg/m2 and cisplatin 20 mg/m2 every 2 weeks. After two cycles of this regimen a slight improvement had occurred (fig. 1d). After 6 cycles this combination therapy had to be discontinued due to disease progression (fig. 1e). Surgical resection was performed (fig. 1f). At present, secondary wound healing is taking place with good signs of re-epithelization. Interestingly, during EGFR blockade there
Dermatology 2013;227:289–294 DOI: 10.1159/000355181
was virtually no granulation or epithelization of the defects (fig. 1f). During cetuximab therapy only few papules and pustules were observed in the face as a side effect of EGFR blockade. Case 2 A 61-year-old male patient underwent heart transplantation 16 years ago after several cardiac infarctions. He received an immunosuppressive regimen with cyclosporine for the first 10 years after transplantation, then switched to tacrolimus, in addition to mycophenolate mofetil and steroids. Since July 2010, multiple cSCCs on the scalp were diagnosed and treated by complete excision and mesh graft closure. Three months after surgery multiple satellite metastases occurred, and 2 months later radiotherapy around the mesh graft was applied (66 Gy). Six months later, within the mesh graft new metastases occurred, surgical excision was incomplete and again radiotherapy was initiated but was stopped due to rapid progression. Immunosuppression was switched from the calcineurin inhibitor tacrolimus to the mTOR inhibitor everolimus; mycophenolate mofetil and
Alter/Satzger/Mattern/Kapp/Gutzmer
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describe here our experience in two patients and review the current literature on the use of EGFR blockers in cSCC. The literature review was performed by MEDLINE search.
Color version available online
a
b
c
d
Fig. 2. Patient 2 after radiotherapy and switch of immunosuppression to everolimus before initiating first cetuximab therapy (a), after
6 cycles of cetuximab plus radiotherapy (b), at the time point when cetuximab was re-initiated (c) and after 3 months of cetuximab therapy (d).
Discussion
The therapeutic options in advanced cSCC are limited in case surgery and radiotherapy are not possible, in particular since most patients are elderly and suffer from comorbidities. Chronically immunosup-
Treatment of Advanced cSCCs with EGFR Inhibitors
pressed patients such as organ transplant recipients are a good example because they often develop cSCC with an aggressive behavior (patient 2). Since cSCC often shows dysregulation of EFGR expression without RAS mutations, EGFR inhibitors might represent a therapeutic option. They have been licensed for various tumor entities, e.g. cetuximab for head and neck squamous cell carcinoma (HNSCC) and erlotinib and gefitinib for certain subtypes of lung carcinomas. A variety of cases and case series using EGFR inhibitors to treat patients with advanced or metastatic cSCC have been published (table 1). They used mainly cetuximab in the standard dose (initial dose 400 mg/m2, followed by 250 mg/m2 weekly), and less frequently erlotinib and gefitinib, also in their oral standard dose of 150 and 250 mg per day, respectively. Possible reasons might be the availability of cetuximab (that was licensed first) and the registration of cetuximab for the treatment of HNSCC, since most cSCCs are also located in the head and neck area. Cetuximab was also administered in combination with radiotherapy, analogous to the use in HNSCC. In contrast, the combination of cetuximab and chemotherapy such as platinum (as in our first patient) [17] or paclitaxel [18] has rarely been used in these patients thus far, probably due to the comorbidities of the patients (table 1). However, the combination is feasible as demonstrated in our first patient. Another potential combination partner of EGFR blockers are cyclooxygenase-2 inhibitors, since there is an interplay of EGFR
signaling, cyclooxygenase-2 and prostaglandin E2 [19–21]. This combination has also been used in single patients thus far [22]. With regard to response rates, a number of small case series and case reports demonstrate partial (PR) or complete response (CR) with cetuximab, erlotinib and gefitinib. This was often short-lasting, with only a few months of duration, and sometimes long-lasting (table 1). There are only two larger studies with cetuximab and gefitinib, respectively. Cetuximab monotherapy resulted in 36 patients in 5.5% CR, 22.2% PR and 41.7% disease stabilization [11]. Neoadjuvant gefitinib given in 22 patients demonstrated 18.2% CR und 27.3% PR [23]. Erlotinib has been used in single patients thus far [24] (table 1). A recent review summarized reports of 54 cSCC patients undergoing cetuximab therapy, with CR in 10 patients (18.5%) and PR in 16 patients (29.6%). The combination of radiotherapy and cetuximab resulted in complete remission in 4/8 patients (50%) [25]. Thus, combination of cetuximab with radiotherapy appears to lead to higher response rates (table 1). In HNSCC, the combination of cetuximab with radiotherapy was superior to radiotherapy alone [26]. However, in cSCC there might be a ‘publication bias’ in small case series and single cases, publishing only patients with successful treatment. Moreover, many patients (such as our two patients) had received radiotherapy before, and the options for retreatment are limited.
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steroids were continued. Another 6 months later the cSCC progressed again and cetuximab was given (initial dose 400 mg/m2, followed by 5 cycles of 250 mg/m2 weekly) (fig. 2a). In addition radiotherapy (24 Gy) was administered. This resulted in a good clinical response with almost complete remission (fig. 2b). A marked papulopustular exanthema was the only side effect of cetuximab and was well controlled by doxycycline 2 × 50 mg and topical antibiotics. Four months after cetuximab therapy the patient presented again with local recurrence. We initiated acitretin 25 mg once daily. Because of further progression cetuximab was re-initiated 3 months later (initial dose 400 mg/m2, followed by 6 weekly doses of 250 mg/m2 and 17 doses of 500 mg/m2 every other week) (fig. 2c). A further radiotherapy was not possible. This resulted clinically in stable disease (fig. 2d). Since there was no granulation tissue visible on the scalp defects and everolimus is known to inhibit wound healing, everolimus was discontinued again and switched to cyclosporine. Currently, the patient is still on cetuximab; after 4 weeks of discontinuing everolimus there appears to be improved wound healing.
Table 1. Published patients with advanced cSCC treated with EGFR inhibitors Reference
Number of patients
Sex
Age, years
Treatment
Response
Duration of response
Maubec et al. [11]
36 (31 evaluable for tumor response) 2
58% m
median 79 (32 – 95)
2 CR, 8 PR, 15 SD
m
73
CR
disease control rate at 6 weeks 69% 4+ months
f
71
cetuximab first-line monotherapy (initial dose 400 mg/m2, followed by 250 mg/m2 weekly until disease progression or intolerable side effects) cetuximab first-line monotherapy, dose reduction due to severe ‘acneiform rash’ cetuximab first-line monotherapy
PR
5+ months
1
m
88
PR
7 months
1 recessive dystrophic epidermolysis bullosa 1
24 f; EGFR expression ++, wild-type KRAS m 79
‘tumor necrosis’
3+ months
cetuximab first-line monotherapy
CR
26+ months
8
m
67
7 weeks cetuximab + 50 Gy radiotherapy
CR
3 months
f
69
32 weeks cetuximab + 70 Gy radiotherapy
PR
18+ months
m
72
7 weeks cetuximab + 60 Gy radiotherapy
CR
5 months
m
79
16 weeks cetuximab + 70 Gy radiotherapy
CR
21+ months
f
82
46 weeks cetuximab
SD
11 months
m
69
11 weeks cetuximab
PD
m
57
9 weeks cetuximab + 70 Gy radiotherapy
PR
m
78
7 weeks cetuximab + 70 Gy radiotherapy
PR
2 lung transplant m patients
59
3 cetuximab infusions within 4 weeks
m
67
diffuse alveolar damage leading to death within 2 weeks after cetuximab diffuse alveolar damage leading to death within 4 weeks after cetuximab CR 1 month
Bauman et al. [30] Bauman et al. [30] Jalili et al. [22] Arnold et al. [31] Miller et al. [32] Giacchero et al. [33] Giacchero et al. [33] Giacchero et al. [33] Giacchero et al. [33] Giacchero et al. [33] Giacchero et al. [33] Giacchero et al. [33] Giacchero et al. [33] Leard et al. [28] Leard et al. [28] Suen et al. [34]
1
m
Rubio Casadevall et al. [35]
1 xeroderma pigmentosum
m
Kim et al. [36] Kalapurakal et al. [29]
1
m
Engelhardt et al. [24]
Lewis et al. [23]
4 patients, 2 of them renal transplant recipients 1 high expression m of EGFR on tumor cells by immunohistochemistry 22 evaluable 74% m for response
cetuximab 2 cycles (1 cycle: initial dose 400 mg/m2, followed by 250 mg/m2 weekly for 6 weeks); celecoxib 100 mg p.o. daily 12 weeks cetuximab third-line monotherapy after two lines of unsuccessful chemotherapies (cisplatin + 5-fluorouracil and carboplatin + paclitaxel)
first-line therapy with carboplatin + paclitaxel, discontinued after 2 cycles due to thrombocytopenia; second-line therapy with cetuximab (1 infusion) 87 cetuximab initial dose 400 mg/m2, then 250 mg/m2 weekly for 6 weeks resulted in CR that lasted 1 month; re-induction of cetuximab 250 mg/m2 weekly, CR after 7 weeks, but progression after 8 weeks of continuing cetuximab; second-line 5-fluorouracil therapy was unsuccessful 37 first-line therapy with cisplatin + 5-fluorouracil, after 2 months no response and thrombocytopenia, followed by radiotherapy, followed by vinorelbine (stopped after 2 months due to leukopenia); next cetuximab (initial dose 400 mg/m2, followed by 250 mg/m2 weekly for 11 months) 92 cSCC metastatic to the neck; cetuximab initial dose 400 mg/m2, then weekly 250 mg/m2 for 3 months median 71.5 in 3 patients cetuximab starting dose 125 mg/m2 once weekly, in 1 patient 250 mg/m2, in this patient (38 – 89) maintenance treatment for 30 months with 4 weeks cetuximab weekly and 2 weeks off treatment 47 erlotinib therapy resulted in SD for 4 months, then progression despite continuation of erlotinib
median 65 (27 – 93)
250 mg/day gefitinib for 60 days, in case of SD after 15 days dose increase to 500 mg/day; after 60 days of gefitinib, therapy was changed to surgery (in 11.8% of patients), radiation (17.6%), radiation plus gefitinib (11.8%) or surgery, radiation and gefitinib (47%)
6 months
PR
11 months
CR
7+ months
3 CR, 1 PR
2 relapses in a median follow-up of 32.5 months 4 months
SD
after 60 days of gefitinib: 18.2% CR, 27.3% PR, 22.7% SD, 31.8% PD
292
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f = Female; m = male; CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease.
The treatment duration is also not clear yet. While some studies treated until disease progression [11], others terminated treatment after 6–12 weeks (table 1). Reinduction in case of progression after termination of EGFR was performed in our two patients, however, the efficiency is not clear yet. EGFR mutation analysis was only performed in small numbers of cSCC tumors, showing mutations in a minority of patients [15, 16]. Presence of mutations did not correlate with response to therapy [23]. Thus at present there is no evidence for a role of EGFR mutation analysis in cSCC before EGFR inhibitor treatment. The side effects that we saw in our patients and that were reported in the litera-
ture are similar to the side effects of EGFR inhibitors in indications other than cSCC and most frequently target the skin [11, 27]. In two lung transplant recipients, diffuse alveolar damage was seen after one and three cetuximab infusions, pointing towards a possible unusual side effect in this particular patient subgroup [28]. In contrast, two renal transplant recipients [29] and one heart transplant recipient (our second patient) were reported, who received cetuximab for cSCC without unusual side effects. Taken together, the response rates and the favorable side effect profile support the further exploration of EGFR inhibitors in patients with advanced cSCC. Several clinical trials have been initiated investigating
the effect of erlotinib alone (NCT01198028, www.clinicaltrials.gov), neoadjuvant erlotinib before definitive surgery or radiotherapy (NCT01059305, NCT00369512), gefitinib (NCT00054691), gefitinib plus radiotherapy (NCT00126555) and panitumumab (NCT01129154).
10 Toll A, Salgado R, Yebenes M, Martin-Ezquerra G, Gilaberte M, Baro T, et al: Epidermal growth factor receptor gene numerical aberrations are frequent events in actinic keratoses and invasive cutaneous squamous cell carcinomas. Exp Dermatol 2010;19:151–153. 11 Maubec E, Petrow P, Scheer-Senyarich I, Duvillard P, Lacroix L, Gelly J, et al: Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol 2011;29:3419–3426. 12 Ch’ng S, Low I, Ng D, Brasch H, Sullivan M, Davis P, Tan ST: Epidermal growth factor receptor: a novel biomarker for aggressive head and neck cutaneous squamous cell carcinoma. Hum Pathol 2008;39:344–349. 13 Nazmi MN, Dykes PJ, Marks R: Epidermal growth factor receptors in human epidermal tumours. Br J Dermatol 1990;123:153–161. 14 Lavrijsen AP, Tieben LM, Ponec M, van der Schroeff JG, van Muijen GN: Expression of EGF receptor, involucrin, and cytokeratins in basal cell carcinomas and squamous cell carcinomas of the skin. Arch Dermatol Res 1989; 281:83–88. 15 Mauerer A, Herschberger E, Dietmaier W, Landthaler M, Hafner C: Low incidence of EGFR and HRAS mutations in cutaneous squamous cell carcinomas of a German cohort. Exp Dermatol 2011;20:848–850. 16 Ridd K, Bastian BC: Somatic mutation of epidermal growth factor receptor in a small subset of cutaneous squamous cell carcinoma. J Invest Dermatol 2010;130:901–903. 17 Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116– 1127.
18 Hitt R, Irigoyen A, Cortes-Funes H, Grau JJ, Garcia-Saenz JA, Cruz-Hernandez JJ, et al: Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Ann Oncol 2012;23:1016–1022. 19 Buchanan FG, Wang D, Bargiacchi F, DuBois RN: Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 2003; 278:35451–35457. 20 Xu K, Shu HK: EGFR activation results in enhanced cyclooxygenase-2 expression through p38 mitogen-activated protein kinase-dependent activation of the Sp1/Sp3 transcription factors in human gliomas. Cancer Res 2007; 67:6121–6129. 21 Pai R, Soreghan B, Szabo IL, Pavelka M, Baatar D, Tarnawski AS: Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med 2002; 8:289–293. 22 Jalili A, 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. 23 Lewis CM, Glisson BS, Feng L, Wan F, Tang X, Wistuba II, et al: A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res 2012;18:1435–1446. 24 Engelhardt C, Curiel-Lewandrowski C, Warneke J, Cranmer L: Metastatic cutaneous squamous cell carcinoma responding to erlotinib therapy. J Am Acad Dermatol 2011; 65: 237–238.
Disclosure Statement
M. Alter and I. Satzger have received speaker’s honoraria from Roche. R. Gutzmer has served as a consultant and has received speaker’s honoraria from Roche Pharma, Merck Serono and Amgen.
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Treatment of Advanced cSCCs with EGFR Inhibitors
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33 Giacchero D, Barriere J, Benezery K, Guillot B, Dutriaux C, Mortier L, et al: Efficacy of cetuximab for unresectable or advanced cutaneous squamous cell carcinoma – a report of eight cases. Clin Oncol (R Coll Radiol) 2011; 23:716–718. 34 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. 35 Rubio Casadevall J, Grana-Suarez B, Hernandez-Yague X, Vayreda Ribera J, Huc Grasa O, Brunet Vidal J: Xeroderma pigmentosum: neck lymph node metastasis of a squamous cell carcinoma of the skin treated with cetuximab. Eur J Dermatol 2009;19:163–165. 36 Kim S, Eleff M, Nicolaou N: Cetuximab as primary treatment for cutaneous squamous cell carcinoma to the neck. Head Neck 2011; 33: 286–288.
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Dermatology 2013;227:289–294 DOI: 10.1159/000355181
Treatment of Advanced Cutaneous Squamous Cell Carcinomas with Epidermal Growth Factor Receptor Inhibitors M. Alter I. Satzger A. Mattern A. Kapp R. Gutzmer Department of Dermatology and Allergy, Hannover Medical School, Skin Cancer Center Hannover, Hannover, Germany
Abstract In advanced cutaneous squamous cell carcinoma (cSCC), efficient medical treatment options are limited in case surgery and radiotherapy failed, particularly since most patients are of higher age and suffer from comorbidities. In many tumor entities, the epidermal growth factor receptor (EGFR) has been established as an important therapeutic target, and blockade of EGFR signaling by monoclonal antibodies or small molecules achieves a therapeutic benefit. EGFR expression is also often dysregulated in cSCC. We report here two patients with advanced cSCC treated with the EGFR inhibitor cetuximab and summarize the current published experience with the use of EGFR inhibitors in © 2013 S. Karger AG, Basel cSCC.
Introduction
Cutaneous squamous cells carcinoma (cSCC) with a yearly incidence of at least 30/100,000 is the second most common
skin cancer after basal cell carcinoma [1]. Due to its main risk factor ultraviolet lightinduced damage, cSCC predominately occurs in the ultraviolet light-exposed skin of elderly patients. A recent case series of 653 patients demonstrated a median age of 73 years [2]. Treatment is usually performed by surgical excision or radiotherapy. In approximately 7% of patients local recurrence or metastases develop (advanced cSCC) [2]. Thus, there is only a relatively small population that fails local treatments. Local tumor growth often results in greasy ulcers and superinfections, mainly located in visible areas of the head and neck. Thus, patients often suffer from a severe reduction of quality of life due to their cutaneous tumor growth. At the same time, therapeutic options are limited due to patients’ age, comorbidities and the lack of efficient medical therapies [3]. Current guidelines and reviews list methotrexate, platinum, 5-fluorouracil/capecitabine, bleomycin and interferon alpha plus retinoids, which have only been explored in small patient numbers and with limited success considering response rates and duration of response [3–5]. The epidermal growth factor receptor (EGFR) is expressed on the majority of cSCCs [6–10] and appears to be upregulated on advanced or metastatic tumor tissue
© 2013 S. Karger AG, Basel 1018–8665/13/2274–0289$38.00/0 E-Mail [email protected] www.karger.com/drm
[8, 11, 12]. However, the studies are not consistent, some showing a downregulation of EGFR on cSCC with a more malignant phenotype [13] or no correlation of cSCC differentiation and intensity of EGFR expression [14]. These studies used primarily immunohistochemistry to detect EGFR expression. The different results might be explained by different methods and reagents used. Molecular analysis of the EGFR showed only very few mutations in cSCC [15, 16]. At the same time, RAS mutations were also very rarely detected in cSCC [15]. RAS mutations activate the pathway downstream of the EGFR, and EGFR inhibition is largely ineffective in other tumor entities with activating RAS mutations. Thus, advanced cSCC often shows a dysregulated EGFR expression without EGFR or RAS mutation and therefore represents a potential target tumor for therapeutic EGFR blockade. Various strategies have been developed to therapeutically block the EGFR by employing either small molecules (i.e. erlotinib and gefitinib) or antibodies (i.e. cetuximab and panitumumab). These substances have entered the clinics and are approved for the treatment of different types of cancers. Thus, we decided to use the anti-EGFR monoclonal antibody cetuximab (Erbitux®) to treat locally advanced cSCC. We
Mareike Alter Department of Dermatology and Allergy Skin Cancer Center Hannover, Hannover Medical School Carl-Neuberg-Str. 1, DE–30625 Hannover (Germany) E-Mail alter.mareike @ mh-hannover.de
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Key Words Epidermal growth factor receptor · Squamous cell carcinoma · Skin cancer · Medical tumor therapy · Dermatooncology
Color version available online
a
b
c
d
e
f
Fig. 1. Patient 1 with local recurrence of cSCC after operation and irradiation within the radiation field before
treatment with cetuximab (a), after 1 month of cetuximab monotherapy (b), after 3 months of cetuximab monotherapy (c), after 1 month (d) and 3 months (e) of cetuximab plus cisplatin combination therapy and after complete excision (f). Note that there was virtually no granulation during cetuximab therapy.
Case Reports
Case 1 An 80-year-old female patient presented with surgically unresectable cSCC of the scalp. Although wide surgical resection of the tumor was performed, complete resection could not been reached. Thus subsequent radiation therapy was initiated. Three months later the patient developed new subcutaneous tumors near the first resection area and at the border of the radiation field. Histopathology showed recurrence of the cSCC and the patient underwent dose-intensifying radiotherapy. However, the tumor continued to grow within the irradiated area, and additional radiotherapy and surgery were impossible (fig. 1a). Staging procedures including cranial and neck computer tomography, ab-
290
dominal ultrasound and peripheral lymph node and chest X-ray showed no evidence of further metastazation. Thus treatment with cetuximab, an antibody blocking the EGFR, was initiated. Cetuximab was given as a monotherapy, starting with 400 mg/ m2, followed by 250 mg/m2 weekly. Clinically, the tumor rapidly improved (fig. 1b). Histopathologically most of the tumorbearing area had cleared after 2 months, only in one area a well-differentiated cornifying cSCC (instead of the previously undifferentiated cSCC) was seen. Only 1 month later worsening of clinical findings was observed (fig. 1c). Histopathology showed recurrence of the squamous cell carcinoma. Thus we decided to intensify therapy and started a combination of cetuximab 500 mg/m2 and cisplatin 20 mg/m2 every 2 weeks. After two cycles of this regimen a slight improvement had occurred (fig. 1d). After 6 cycles this combination therapy had to be discontinued due to disease progression (fig. 1e). Surgical resection was performed (fig. 1f). At present, secondary wound healing is taking place with good signs of re-epithelization. Interestingly, during EGFR blockade there
Dermatology 2013;227:289–294 DOI: 10.1159/000355181
was virtually no granulation or epithelization of the defects (fig. 1f). During cetuximab therapy only few papules and pustules were observed in the face as a side effect of EGFR blockade. Case 2 A 61-year-old male patient underwent heart transplantation 16 years ago after several cardiac infarctions. He received an immunosuppressive regimen with cyclosporine for the first 10 years after transplantation, then switched to tacrolimus, in addition to mycophenolate mofetil and steroids. Since July 2010, multiple cSCCs on the scalp were diagnosed and treated by complete excision and mesh graft closure. Three months after surgery multiple satellite metastases occurred, and 2 months later radiotherapy around the mesh graft was applied (66 Gy). Six months later, within the mesh graft new metastases occurred, surgical excision was incomplete and again radiotherapy was initiated but was stopped due to rapid progression. Immunosuppression was switched from the calcineurin inhibitor tacrolimus to the mTOR inhibitor everolimus; mycophenolate mofetil and
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describe here our experience in two patients and review the current literature on the use of EGFR blockers in cSCC. The literature review was performed by MEDLINE search.
Color version available online
a
b
c
d
Fig. 2. Patient 2 after radiotherapy and switch of immunosuppression to everolimus before initiating first cetuximab therapy (a), after
6 cycles of cetuximab plus radiotherapy (b), at the time point when cetuximab was re-initiated (c) and after 3 months of cetuximab therapy (d).
Discussion
The therapeutic options in advanced cSCC are limited in case surgery and radiotherapy are not possible, in particular since most patients are elderly and suffer from comorbidities. Chronically immunosup-
Treatment of Advanced cSCCs with EGFR Inhibitors
pressed patients such as organ transplant recipients are a good example because they often develop cSCC with an aggressive behavior (patient 2). Since cSCC often shows dysregulation of EFGR expression without RAS mutations, EGFR inhibitors might represent a therapeutic option. They have been licensed for various tumor entities, e.g. cetuximab for head and neck squamous cell carcinoma (HNSCC) and erlotinib and gefitinib for certain subtypes of lung carcinomas. A variety of cases and case series using EGFR inhibitors to treat patients with advanced or metastatic cSCC have been published (table 1). They used mainly cetuximab in the standard dose (initial dose 400 mg/m2, followed by 250 mg/m2 weekly), and less frequently erlotinib and gefitinib, also in their oral standard dose of 150 and 250 mg per day, respectively. Possible reasons might be the availability of cetuximab (that was licensed first) and the registration of cetuximab for the treatment of HNSCC, since most cSCCs are also located in the head and neck area. Cetuximab was also administered in combination with radiotherapy, analogous to the use in HNSCC. In contrast, the combination of cetuximab and chemotherapy such as platinum (as in our first patient) [17] or paclitaxel [18] has rarely been used in these patients thus far, probably due to the comorbidities of the patients (table 1). However, the combination is feasible as demonstrated in our first patient. Another potential combination partner of EGFR blockers are cyclooxygenase-2 inhibitors, since there is an interplay of EGFR
signaling, cyclooxygenase-2 and prostaglandin E2 [19–21]. This combination has also been used in single patients thus far [22]. With regard to response rates, a number of small case series and case reports demonstrate partial (PR) or complete response (CR) with cetuximab, erlotinib and gefitinib. This was often short-lasting, with only a few months of duration, and sometimes long-lasting (table 1). There are only two larger studies with cetuximab and gefitinib, respectively. Cetuximab monotherapy resulted in 36 patients in 5.5% CR, 22.2% PR and 41.7% disease stabilization [11]. Neoadjuvant gefitinib given in 22 patients demonstrated 18.2% CR und 27.3% PR [23]. Erlotinib has been used in single patients thus far [24] (table 1). A recent review summarized reports of 54 cSCC patients undergoing cetuximab therapy, with CR in 10 patients (18.5%) and PR in 16 patients (29.6%). The combination of radiotherapy and cetuximab resulted in complete remission in 4/8 patients (50%) [25]. Thus, combination of cetuximab with radiotherapy appears to lead to higher response rates (table 1). In HNSCC, the combination of cetuximab with radiotherapy was superior to radiotherapy alone [26]. However, in cSCC there might be a ‘publication bias’ in small case series and single cases, publishing only patients with successful treatment. Moreover, many patients (such as our two patients) had received radiotherapy before, and the options for retreatment are limited.
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steroids were continued. Another 6 months later the cSCC progressed again and cetuximab was given (initial dose 400 mg/m2, followed by 5 cycles of 250 mg/m2 weekly) (fig. 2a). In addition radiotherapy (24 Gy) was administered. This resulted in a good clinical response with almost complete remission (fig. 2b). A marked papulopustular exanthema was the only side effect of cetuximab and was well controlled by doxycycline 2 × 50 mg and topical antibiotics. Four months after cetuximab therapy the patient presented again with local recurrence. We initiated acitretin 25 mg once daily. Because of further progression cetuximab was re-initiated 3 months later (initial dose 400 mg/m2, followed by 6 weekly doses of 250 mg/m2 and 17 doses of 500 mg/m2 every other week) (fig. 2c). A further radiotherapy was not possible. This resulted clinically in stable disease (fig. 2d). Since there was no granulation tissue visible on the scalp defects and everolimus is known to inhibit wound healing, everolimus was discontinued again and switched to cyclosporine. Currently, the patient is still on cetuximab; after 4 weeks of discontinuing everolimus there appears to be improved wound healing.
Table 1. Published patients with advanced cSCC treated with EGFR inhibitors Reference
Number of patients
Sex
Age, years
Treatment
Response
Duration of response
Maubec et al. [11]
36 (31 evaluable for tumor response) 2
58% m
median 79 (32 – 95)
2 CR, 8 PR, 15 SD
m
73
CR
disease control rate at 6 weeks 69% 4+ months
f
71
cetuximab first-line monotherapy (initial dose 400 mg/m2, followed by 250 mg/m2 weekly until disease progression or intolerable side effects) cetuximab first-line monotherapy, dose reduction due to severe ‘acneiform rash’ cetuximab first-line monotherapy
PR
5+ months
1
m
88
PR
7 months
1 recessive dystrophic epidermolysis bullosa 1
24 f; EGFR expression ++, wild-type KRAS m 79
‘tumor necrosis’
3+ months
cetuximab first-line monotherapy
CR
26+ months
8
m
67
7 weeks cetuximab + 50 Gy radiotherapy
CR
3 months
f
69
32 weeks cetuximab + 70 Gy radiotherapy
PR
18+ months
m
72
7 weeks cetuximab + 60 Gy radiotherapy
CR
5 months
m
79
16 weeks cetuximab + 70 Gy radiotherapy
CR
21+ months
f
82
46 weeks cetuximab
SD
11 months
m
69
11 weeks cetuximab
PD
m
57
9 weeks cetuximab + 70 Gy radiotherapy
PR
m
78
7 weeks cetuximab + 70 Gy radiotherapy
PR
2 lung transplant m patients
59
3 cetuximab infusions within 4 weeks
m
67
diffuse alveolar damage leading to death within 2 weeks after cetuximab diffuse alveolar damage leading to death within 4 weeks after cetuximab CR 1 month
Bauman et al. [30] Bauman et al. [30] Jalili et al. [22] Arnold et al. [31] Miller et al. [32] Giacchero et al. [33] Giacchero et al. [33] Giacchero et al. [33] Giacchero et al. [33] Giacchero et al. [33] Giacchero et al. [33] Giacchero et al. [33] Giacchero et al. [33] Leard et al. [28] Leard et al. [28] Suen et al. [34]
1
m
Rubio Casadevall et al. [35]
1 xeroderma pigmentosum
m
Kim et al. [36] Kalapurakal et al. [29]
1
m
Engelhardt et al. [24]
Lewis et al. [23]
4 patients, 2 of them renal transplant recipients 1 high expression m of EGFR on tumor cells by immunohistochemistry 22 evaluable 74% m for response
cetuximab 2 cycles (1 cycle: initial dose 400 mg/m2, followed by 250 mg/m2 weekly for 6 weeks); celecoxib 100 mg p.o. daily 12 weeks cetuximab third-line monotherapy after two lines of unsuccessful chemotherapies (cisplatin + 5-fluorouracil and carboplatin + paclitaxel)
first-line therapy with carboplatin + paclitaxel, discontinued after 2 cycles due to thrombocytopenia; second-line therapy with cetuximab (1 infusion) 87 cetuximab initial dose 400 mg/m2, then 250 mg/m2 weekly for 6 weeks resulted in CR that lasted 1 month; re-induction of cetuximab 250 mg/m2 weekly, CR after 7 weeks, but progression after 8 weeks of continuing cetuximab; second-line 5-fluorouracil therapy was unsuccessful 37 first-line therapy with cisplatin + 5-fluorouracil, after 2 months no response and thrombocytopenia, followed by radiotherapy, followed by vinorelbine (stopped after 2 months due to leukopenia); next cetuximab (initial dose 400 mg/m2, followed by 250 mg/m2 weekly for 11 months) 92 cSCC metastatic to the neck; cetuximab initial dose 400 mg/m2, then weekly 250 mg/m2 for 3 months median 71.5 in 3 patients cetuximab starting dose 125 mg/m2 once weekly, in 1 patient 250 mg/m2, in this patient (38 – 89) maintenance treatment for 30 months with 4 weeks cetuximab weekly and 2 weeks off treatment 47 erlotinib therapy resulted in SD for 4 months, then progression despite continuation of erlotinib
median 65 (27 – 93)
250 mg/day gefitinib for 60 days, in case of SD after 15 days dose increase to 500 mg/day; after 60 days of gefitinib, therapy was changed to surgery (in 11.8% of patients), radiation (17.6%), radiation plus gefitinib (11.8%) or surgery, radiation and gefitinib (47%)
6 months
PR
11 months
CR
7+ months
3 CR, 1 PR
2 relapses in a median follow-up of 32.5 months 4 months
SD
after 60 days of gefitinib: 18.2% CR, 27.3% PR, 22.7% SD, 31.8% PD
292
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f = Female; m = male; CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease.
The treatment duration is also not clear yet. While some studies treated until disease progression [11], others terminated treatment after 6–12 weeks (table 1). Reinduction in case of progression after termination of EGFR was performed in our two patients, however, the efficiency is not clear yet. EGFR mutation analysis was only performed in small numbers of cSCC tumors, showing mutations in a minority of patients [15, 16]. Presence of mutations did not correlate with response to therapy [23]. Thus at present there is no evidence for a role of EGFR mutation analysis in cSCC before EGFR inhibitor treatment. The side effects that we saw in our patients and that were reported in the litera-
ture are similar to the side effects of EGFR inhibitors in indications other than cSCC and most frequently target the skin [11, 27]. In two lung transplant recipients, diffuse alveolar damage was seen after one and three cetuximab infusions, pointing towards a possible unusual side effect in this particular patient subgroup [28]. In contrast, two renal transplant recipients [29] and one heart transplant recipient (our second patient) were reported, who received cetuximab for cSCC without unusual side effects. Taken together, the response rates and the favorable side effect profile support the further exploration of EGFR inhibitors in patients with advanced cSCC. Several clinical trials have been initiated investigating
the effect of erlotinib alone (NCT01198028, www.clinicaltrials.gov), neoadjuvant erlotinib before definitive surgery or radiotherapy (NCT01059305, NCT00369512), gefitinib (NCT00054691), gefitinib plus radiotherapy (NCT00126555) and panitumumab (NCT01129154).
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Disclosure Statement
M. Alter and I. Satzger have received speaker’s honoraria from Roche. R. Gutzmer has served as a consultant and has received speaker’s honoraria from Roche Pharma, Merck Serono and Amgen.
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