squamous cell carcinoma ( scc ) is one of the most important non - melanoma skin cancers ( nmsc ) because of its frequency and because it has a more aggressive course than basal cell carcinoma ( bcc ) , the most common nmsc . scc development has been linked to chronic uv exposure with an odds ratio of 1.77 . patient related incidence rates for cutaneous scc in germany has been estimated at 9.7 for females and 17.4 for males . higher incidence rates in europe have been reported for scotland ( 34.7 ) and spain . tumor staging is dependent on tumor diameter , invasion into cranial bone , tumor thickness and invasion level , differentiation , perineural invasion and anatomic location . the standard treatment of scc of the head and neck area is mohs surgery or delayed mohs . for advanced scc , radiation therapy is another therapeutic option . since conventional chemotherapy in head and neck scc ( hnscc ) of the mucous membranes is associated with significant toxicity , alternatives for cutaneous scc have emerged . a phase iii trial with bleomycin versus other chemotherapy protocols , and prospective observational studies using bleomycin , cisplatin , doxorubicin or oral 5-fluorouracil ( 5-fu ) , had low rates of complete responses ( 033% ) but significant adverse effects . interferon in combination with capecitabine ( an oral prodrug of 5-fu ) is effective in scc of the head and neck region and in the reduction of scc developing in transplant recipients . advanced scc shows numerical aberrations in the epidermal growth factor - receptor ( egfr ) gene and overexpression of egf / egfr . therefore , targeted therapy against egf - receptor ( egfr ) would be another option . recently , monoclonal antibodies against egfr have become available , including gefitinib , erlotinib , cetuximab and panitumumab . cetuximab is a 152 kda chimeric igg1 monoclonal antibody of 65% human and 35% murine origin . it specifically binds to egfr at an extracellular epitope in the ligand - binding domain . the drug half - life is 70100 h. there are encouraging data from hnscc using cetuximab in the treatment of recurrent or metastatic tumors , either alone or in combination with radiation or chemotherapy . since 2006 , cetuximab is approved for use in combination with radiotherapy in patients with locally advanced hnscc . there are limited data available for cetuximab therapy in advanced cutaneous scc of the head and neck region . we present a patient who was successfully treated by cetuximab combined with radiation for locally advanced cutaneous scc of the scalp . a 77-year old male patient presented with a large tumor of the scalp that had grown over a period of more than 24 months . he suffered from arterial hypertonia , hyperlipidemia , hyperuricemia , and liver cirrhosis . on examination 4 cm in diameter ) with three macroscopically visible satellite metastases in the right temporo - occipital region ( figure 1 ) . the defect was covered by large transposition flaps leaving a central area that was closed with a full thickness skin graft . histological examination of the species revealed a moderately differentiated scc ( t2 , n0 , m0 ; stage ii , american joint committee on cancer ( ajcc ) ) with lymphangiosis carcinomatosa , and perineural infiltration and satellitosis ( figure 3 ) . because of the age of the patient and his co - morbidities , we decided against further surgery but initiated a closer follow up . figure 3histological evaluation demonstrates ( a ) lymphatic and ( b ) perineural invasion ( hematoxylin - eosin , 20 ) . histological evaluation demonstrates ( a ) lymphatic and ( b ) perineural invasion ( hematoxylin - eosin , 20 ) . eight weeks later , the patient presented with ulcerated satellitosis in the frontal and right fronto - temporal area of the scalp . restaging demonstrated a t2 , n1 , m0 profile ( stage iii , ajcc ) . therefore , we decided to use targeted therapy with monoclonal anti - epidermal growth factor receptor ( egfr ) antibody cetuximab ( erbitux ; bristol - meyers sqibb ) in combination with radiotherapy . after the loading dose of 400 mg / m , the patient received 250 mg / m once a week for six weeks . , 4 mg dimetindene maleate i.v . , 50 mg ranitidine i.v . and 8 mg ondansetron p.o . cetuximab was well tolerated except for the loading dose when the patient developed fever chills . there was a fast recovery within a couple of hours . from the second infusion onwards , no further adverse effects of this kind were observed . within the first week of monoclonal antibody treatment , the patient developed rosacea - like pustules on facial and neck skin . these cutaneous lesions were treated with metronidazole gel and there was a marked improvement within two weeks . irradiation was realized by volumetric modulated arc - therapy ( vmat ) . in this irradiation technique , the gantry of the accelerator moves 360 around the patient . due to the use of a dynamic multileaf collimator , variable dose rates and variable gantry speeds , this technique allows the generation of a very complex dose distribution in one or two optimized arcs around the patient . through continuously modulating the applied dose , high doses to the entire tumor volume another major advantage of vmat is the dramatically shorter treatment time compared to all existing methods , including tomotherapy . in the application of this technique , the exact and reproducible set - up of the patient during every treatment session is of crucial importance . we used a custom - formed 1 cm thick thermoplastic head - mask for immobilization and fixation . this mask was lined inside with bolus material to shift the dose maximum in the superficial treatment area . the physical treatment plan was designed according to a proposal of skinner consisting of 3 non - coplanar arcs . this technique provides homogeneous dose distribution and target coverage but still results in a relevant dose to brain ( mean dose 28 gy ) and eyes . we modified this approach in order to improve the protection of brain and eyes : both the non - coplanar arcs were divided into two partial arcs ( figure 4 ) . in summary , the dose deposition in the target volume is built up mainly by tangential irradiation ( figure 5 ) and optimal sparing of all organs at risk is achieved ( table 1 , figure 6 ) . to verify the correct application of this treatment plan , , melbourne / fl , usa ) prior to the patient 's first treatment session . this showed good agreement between calculated and measured dose distributions [ gamma ( 3% , 3 mm ) = 95.4 ] . additional checks were carried out to investigate influences of deviations in daily patient set - up or bolus attachment on the dose distribution , in target volume and organs at risk . all results demonstrated that a safe application of this treatment plan is guaranteed , taking account of the tolerance levels achievable in daily routine clinical practce . to minimize these tolerances , patient set - up was checked and corrected by orthogonal fluoroscopic images recorded daily by the on - board imager ( obi ) used in our varian accelerator . figure 4improved treatment technique is based on 2 coplanar and 4 non - coplanar arcs . improved treatment technique is based on 2 coplanar and 4 non - coplanar arcs . figure 5image of one partial non - coplanar arc demonstrating the dose deposition mainly in a tangential direction to the target volume . image of one partial non - coplanar arc demonstrating the dose deposition mainly in a tangential direction to the target volume . table 1main values characterizing dose distribution in planning target volume and organs of risk.ptvvolume > 95 % dose92%  brainmaximum dose17.2 gyspinal cordmaximum dose34.3 gyoptic nerves ( left / right)maximum dose16.4/22.0 gychiasmamaximum dose7.3 gyeyes ( left / right)maximum dose11.1/28.2 gyeye lenses ( left / right)maximum dose4.1/9.0 gy 
 
 figure 6image of one partial non - coplanar arc demonstrating the dose deposition mainly in a tangential direction to the target volume . image of one partial non - coplanar arc demonstrating the dose deposition mainly in a tangential direction to the target volume . average daily beam time was 6 min ( 6 arcs , 767 monitor units ) . total treatment time , including patient set - up and set - up correction , was less than 20 min . radiotherapy was well tolerated and the patient achieved complete remission ( figure 7 ) . 
 figure 7treatment course with cetuximab and radiotherapy . advanced cutaneous scc has a risk of metastases and relapse . in a prospective analysis of 653 patients , tumor thickness more than 2 mm and tumor size more than 6 mm are the major risk factors for these phenomena . other features characterizing high - risk cutaneous scc include poor differentiation , perineural or lympho - vascular infiltration , and bone invasion . we report a successful treatment of advanced cutaneous scc with regional lymphnode involvement of the scalp with the anti - egfr drug cetuximab and radiation after primary surgery . there are limited data available in this indication for cutaneous scc despite approval for hnscc ( table 2 ) . a single phase ii trial performed in france has only been published as an abstract cetuximab therapy alone was able to control the disease in 69% of patients making this well tolerated treatment of interest for elderly patients with scc . 79 yrs , maleback3 cycles of cetuximabweekly for 4 weekscr for at least26 monthsmiller et al . . 24 yrs , femalearm12 weeks cetuximabpr ; > 3 monthsarnold et al . 200912 . 77 yrs , malescalp6 weeks cetuximaband radiotherapycr , > 3 monthspresent 
  hnscc and cutaneous scc over - express egfr , a 170 kda transmembrane protein , linked to tumor progression and autonomous tumor cell growth . egfr signaling in the cell is mediated by three major pathways : ras - map kinases , pi3k - aktc , and scr - stat . response to cetuximab in these tumors has been associated to overexpression of signal transducers and activators of transcription ( stat ) gene stat5a and ephrin receptor gene epha2 . cetuximab demonstrated in vitro antiproliferative activity , direct cytotoxicity , and the potentiation of chemo- or radiotherapy in hnscc . in vitro studies using cell lines derived from cutaneous xenograft tumor models gave evidence for the anti - angiogenic , apoptotic and anti - proliferative activity of cetuximab . a great advantage of cetuximab compared to traditional chemotherapy is the fact that there is no additional hepatotoxicity . egfr - inhibitors can induce skin reactions like papulopustular rash or periungual inflammation , compromised hair growth , skin dryness and itching . these types of adverse effects have been linked to better outcome in patients with colorectal cancer and targeted therapy against egfr . in a recent investigation , 49% of patients with hnscc developed a grade iii to iv radiation dermatitis with concurrent cetuximab . a possible explanation is the reduction of a major anti - oxidant enzyme , i.e. glucose-6-phosphate dehydrogenase by cetuximab . in the present case , other egfr inhibitors have been developed , such as erlotinib and gefitinib , but there are limited reports of experience with these drugs in cutaneous scc . this , a total dose of at least 60 gy in six weeks based on daily doses of 2.0 gy is necessary when using percutaneous irradiation . traditionally these lesions were treated by two different methods : by afterloaded iridium-192 skin moulds . unfortunately , this technique is very time - consuming in terms of preparation , planning , quality assurance and implementation . additionally , it results in high doses to brain and optical structures , and the actually delivered dose may vary from the planned dose ; most commonly combined photon - electron plans are used . this is technically very complex due to necessary shiftings of match - lines between different fields during the treatment course , and results in less conformal plans with large dose gradients in the target volume . therefore , studies using the application of helical tomotherapy were initiated to overcome these problems . in recent publications , volumetric modulated arc - therapy ( vmat ) has also been demonstrated to be an alternative option ; it is clinically acceptable and comparable to tomotherapy . it provides significantly more homogeneous dose distribution and reduces high - dose regions in the brain to a larger degree than all conventional methods . the present case report and other reports from the literature ( table 2 ) suggest that the combination of monoclonal egfr antibody and radiotherapy is effective in controlling advanced cutaneous scc with or without metastases in analogy to hnscc . the recent advances in radiotherapy offer an effective and well tolerated treatment option . in summary
a 77-year old male patient presented with an ulcerated exophytic tumor ( t2 , n0 , m0 ) with three macroscopically visible satellite metastases in the right temporo - occipital region . 
 mohs surgery could not control the disease due to lymphangiosis carcinomatosa and perineural infiltration , and recurrence of satellite skin metastases . 
 re - staging demonstrated a t2 , n1 , m0 profile ( stage iii , ajcc ) . 
 chemotherapy was limited by the patient 's co - morbidities . 
 therefore , we used targeted therapy with monoclonal anti - epidermal growth factor receptor antibody cetuximab in combination with volumetric modulated arc- radiotherapy ( vmat ) . 
 cetuximab was well tolerated except for the loading dose when the patient developed fever chills . to verify the correct application of vmat 
 , it was applied to a 3-dimensional measuring phantom prior to the patient 's first treatment session . to minimize these tolerances , patient set - up 
 was checked and corrected by orthogonal fluoroscopic images recorded daily by the on - board imager used in our varian accelerator . 
 the average daily beam time was 6 min ( 6 arcs , 767 monitor units ) ; the total treatment time including patient set - up and set - up correction was less than 20 min . 
 combined therapy was well tolerated and complete remission was achieved .