anal cancers represent rare gastrointestinal tumors with an estimated annual incidence of about 5,820 new cases in the united states in 2011 . fortunately , only 1020% of patients present extrapelvic metastases at the beginning or during their illness . the most frequently seen metastatic sites are liver , lung , and extrapelvic lymph nodes . there is some evidence that fluorouracil ( 5-fu)-based chemotherapy plus cisplatin has some benefit with a response rate of about 50% and a median overall survival of 1355 months [ 3 , 4 , 5 ] . in selected patients , an aggressive multimodality approach including resection of metastases , irradiation of para - aortic lymph nodes or intra - arterial chemotherapy results in long - term survival [ 6 , 7 ] . in this article , we report about a 64-year - old male patient with metastatic anal cancer who failed first - line palliative therapy with cisplatin and 5-fu but who showed a good response to second - line therapy with irinotecan , leucovorin , 5-fu and cetuximab , a monoclonal antibody against the epidermal growth factor receptor ( egfr ) . a 64-year - old previously healthy man underwent routine colonoscopy . an incidental tumor in the anal canal two lesions in the right lobe of the liver were detected by ct scan ( fig . the histological result of the biopsy of these liver lesions was identical with the primary tumor . considering the fact that the primary anal lesion was very small ( ct1 ) and the patient was in an excellent physical shape ( ecog 0 ) , we discussed at our interdisciplinary tumor board a potentially curative approach with a local excision of the small tumor in the anal canal followed by neoadjuvant chemotherapy with 5-fu and cisplatin and subsequent resection of the liver metastases . six weeks after the r0 transanal tumor resection without rectal amputation , chemotherapy containing cisplatin ( 70 mg / m on days 1 and 2 ) and 5-fu ( 1,000 mg / m on days 14 , repeated every 4 weeks ) was started . in contrast to the previous study there were now metastases on both lobes of the liver , making a curative liver resection quite challenging . however , there was no evidence of a relapse at the primary tumor side . based on the report of lukan et al . , who published quite promising results about metastatic anal cancer patients treated with cetuximab , a monoclonal antibody against egfr , in combination with irinotecan , we excluded a kras mutation by dna sequencing in the tumor material of our patient . second - line therapy with cetuximab ( 500 mg / m every other week after a loading dose of 400 mg / m one week before ) in combination with irinotecan ( 180 mg / m ) , leucovorin ( 200 mg / m ) and 5-fu ( 400 mg / m ) as bolus injection followed by a continuous infusion ( 2.4 g / m ) during 48 h every 2 weeks ( folfiri ) was initiated . after 6 cycles , the ct scan showed a partial remission of the liver lesions according the recist 1.1 criteria ( fig . six weeks later , the ct scan was repeated and showed a clear progression of the known liver lesions as well as several new liver lesions . fortunately , the patient tolerated the therapy extremely well and did not suffer from any severe side effects . after additional 7 cycles , a mixed response based on ct scan could be demonstrated . given the patient 's wish for a new treatment break for spending four weeks in an ayurveda clinic in india we stopped the therapy again . two months later , the images again showed already a progressive disease with an increase in the size of the known liver metastases . selective internal radiation therapy ( sirt ) for treating the liver metastases was evaluated ; however , this was not an option in his case because of a distinctive shunt between the liver and the lung . in the meantime the patient was already in a reduced physical shape ( ecog score 12 ) . nevertheless , he wanted to be treated and his liver values were still in the normal range so that we offered him a reduced therapy regimen containing irinotecan and cetuximab , but no leucovorin and 5-fu . the dosages of cetuximab and irinotecan were unchanged ; the treatment interval was stretched to 3 weeks on the patient 's preference . unfortunately the patient did worse quite soon and therefore treatment was stopped after 8 weeks . he died because of liver failure a few weeks after therapy cessation and 21 months after diagnosis . 1020% of all these patients develop metastatic disease . based on the low incidence and the low metastatic risk very limited data about treatment options for patients with metastatic anal cancer are available . these few data indicate that 5-fu - based chemotherapy in combination with cisplatin may have some benefit [ 3 , 4 , 5 ] . however , this observation has not yet been proven by a statistically powered , prospectively conducted , placebo - controlled study . nevertheless , most physicians consider the combination of cisplatin and 5-fu as a standard of care for their patients with metastatic anal cancer . after failure of this therapy , the literature is quite disappointing with respect to effective chemotherapy protocols blocking of this receptor by a monoclonal antibody such as cetuximab is of clinical benefit in the metastatic setting of several tumors such as head and neck , lung   and colorectal cancer . anal canal cancer tissue expresses nearly universal egfr [ 12 , 13 , 14 ] , as also demonstrated in our patient . based on these findings , cetuximab might be an ideal candidate for the improvement of the therapy in anal cancer patients . however , not all of the anal cancer patients described in the literature showed a response to cetuximab . in a retrospective analysis of anal cancer patients could show partial remission or at least tumor stabilization in kras wild - type patients , whereas patients harboring kras mutations had progressive disease . in analogy to colorectal patients one could speculate that kras might be a predictive factor for cetuximab therapy in metastatic anal cancer patients . however , this hypothesis has to be confirmed by a prospectively designed study . in the case of our patient the administration of cetuximab depended on the result of kras mutation status , which is in accordance with actual retrospective data . nevertheless , our case report further supports the necessity of a prospective , randomized , placebo - controlled study . the fact that the majority of anal cancers harbor no kras mutation [ 12 , 13 ] makes cetuximab an interesting option for the treatment of anal canal patients in order to improve their clinical outcome . however , it might be absolutely possible that there are further predictive factors with respect to the cetuximab therapy in anal cancer patients . a recently published study showed that cetuximab in lung cancer was just beneficial in patients with egfr tumor expression level above a specific threshold   and egfr gene amplification might therefore be another potential predictive factor . besides cetuximab , the chemotherapeutic partners might also be important for the response rate of the immunotherapy . our patient was treated with cetuximab in combination with folfiri ( scheme see above ) . this combination has been extensively described in colorectal but not in anal cancer patients . to our knowledge , this is the first report in the literature about this combination in metastatic anal cancer patients . in contrast to other published combinations of cetuximab , irinotecan , 5-fu and leucovorin as 5-fu modulator were added . this statement is supported by the fact that 5-fu is incorporated in adjuvant as well as in palliative standard chemotherapy protocols for anal cancer patients . therefore we believe that adding 5-fu in combination with leucovorin increases the efficiency of our therapy . in addition , we know that multi - agent chemotherapy has in general a higher risk of toxicity than single - agent chemotherapy . the higher toxicity might overcome the benefit of the multi - agent therapy . fortunately our patient did not suffer from severe side effects despite our multi - agent approach . as single grade ii toxicity , he developed a skin rush about two weeks after the start of cetuximab as a typical side effect of this antibody . it would be very surprising if there would be a big difference with respect to toxicity in these two patient populations . therefore we believe that folfiri might be an effective chemotherapeutic regimen in combination with cetuximab ; probably even more effective than irinotecan alone . in summary , the combination of cetuximab with folfiri showed a promising response in our kras wild - type anal cancer patient .
anal canal cancer is a rare tumor without clear treatment evidence in the metastatic setting . in terms of the bad prognosis of patients with metastatic anal cancer , further therapeutic options 
 are urgently needed . in this paper 
 we present the case of a 64-year - old man suffering from undifferentiated squamous cell carcinoma with liver metastases . 
 after progression on cisplatin and fluorouracil , tumor tissue was analyzed with respect to anti - egfr therapy with cetuximab . 
 there was no kras mutation and the egfr expression level in the tumor tissue was 2 + ; ideal conditions for the immunotherapy . 
 encouraged by these results we started a therapy using folfiri in combination with cetuximab . 
 fortunately the patient showed a partial response after 6 cycles . on patient 's preference 
 we did a therapy break of 6 weeks . within this time period 
 the disease was progressive indicating its aggressiveness . 
 however , the same immunotherapy was able to stabilize the disease for a further 3 months . 
 the patient died 21 months after diagnosis because of liver failure . 
 nevertheless , from our perspective the combination of folfiri and cetuximab is quite a promising therapeutic option for patients with metastatic anal cancer . 
 potential predictive factors of the immunochemotherapy are discussed in this paper .