the current standard of treatment for locally advanced rectal cancer ( uicc stages ii and iii ) includes a 5-fluorouracil ( 5-fu)-based preoperative radiochemotherapy ( rct ) , total mesorectal excision , and postoperative chemotherapy [ 1 , 2 ] .
several randomized clinical trials during the last decades have demonstrated that neoadjuvant 5-fu - based rct significantly improves locoregional control of rectal cancer [ 3 , 4 ] .
today , the limitation of the prognosis of individual patients is mainly determined by the occurrence of distant metastases in 3040% of patients .
this led to the intensification of systemic therapy through integration of platinum derivatives , an approach that not only promises a therapeutic benefit but simultaneously bears the risk of increased toxicity .
subsequently , to avoid unnecessary toxicity , more individualized and risk - adapted treatment approaches are needed and are currently being validated in several ongoing clinical trials . however , in rectal cancer , reliable biomarkers to predict the response to neoadjuvant rct , individual prognosis and occurrence of treatment - associated toxicity have not yet been established as part of the clinical routine . the adjuvant treatment strategy with 5-fu in combination with leucovorin and oxaliplatin
is well established and has been used for nearly 10 years in the adjuvant treatment of uicc iii colon cancer . the neoadjuvant and adjuvant treatment with folfox against locally advanced rectal cancer ( uicc ii and iii ) is integrated in several randomized phase iii multicenter trials such as the cao / aro / aio-04 trial of the german rectal cancer study group .
the cao / aro / aio-04 regimen consists of intravenous oxaliplatin ( 80 mg / m ) combined with leucovorin ( 400 mg / m ) and subsequent 5-fu infusion ( 2,400 mg / m ) , repeated every 14 days over 4 months ( 8 cycles ) .
oxaliplatin is a platinum derivative whose therapeutic effect is based on alkylating effects . the platinum compound binds to dna forming cross - links , which inhibit dna replication and transcription , and so result in cell death [ 9 , 10 ] .
for patients with chronic renal failure ( creatinine clearance < 30 ml / min ) , a dose reduction is necessary ( starting dose of 65 mg / m ) .
common adverse reactions of oxaliplatin ( over 10% ) include central neurological , gastrointestinal , hematologic , and peripheral neuropathic reactions .
typical side effects of oxaliplatin are a grade 34 neutropenia and in rare cases neutropenic fever .
the peripheral neuropathy is very common ; it might affect the patient 's quality of life and might therefore lead to dose reductions .
the acute form is characterized by peripheral , acral and facial paresthesia and pain , commonly being exacerbated by exposure to the cold .
the chronic side effects of neuropathy grade 34 with decreased distal sensation and proprioception affect the extremities and are reversible in most patients . of note ,
we report on 2 cases of oxaliplatin - induced leukocytoclastic vasculitis with kidney involvement , a side effect which  to the best of our knowledge  was only reported in a single case before .
written informed consent was obtained from the patients for the publication of this paper and any accompanying images .
a 75-year - old man presented with a locally advanced adenocarcinoma of the rectum ( 37 cm above the anal verge , endoscopically staged as ut3 un ) . as he had received interstitial brachytherapy ( > 145 gy ) 2 years before as a treatment for prostate cancer ( ct2b , cnx , cm0 , gleason score 6 ) ,
the standard treatment of neoadjuvant rct with 50.4 gy and concomitant 5-fu ( + / oxaliplatin ) was not possible .
an abdomino - perineal rectum exstirpation with implantation of a descendostoma was performed to remove the rectal cancer .
the histopathological work - up revealed a pt3a , pn2b ( 21/31 ) , cm0 , l1 , v0 , g3 , r0 ( uicc iiib ) adenocarcinoma and thus adjuvant chemotherapy was strongly suggested according to the vote of the institutional interdisciplinary tumor board .
eight weeks after surgery , the first cycle of adjuvant chemotherapy with 5-fu , leucovorin and oxaliplatin ( folfox-6 ) was scheduled .
the cycle consisted of a bimonthly regimen with intravenous oxaliplatin ( 80 mg / m ) and leucovorin ( 400 mg / m ) administered on day 1 .
5-fu 2,400 mg / m followed on day 1 as a continuous infusion for 46 h. during the following 3 days , the patient developed fever that resolved spontaneously .
fourteen days later , the patient showed disseminated petechiae with secondary hemorrhage , along with edema on both legs and interdigital ulceration .
he reported that he had experienced arthralgia in his knees and elbows 4 days after the first dose of chemotherapy .
his blood count showed microcytic , hypochromic anemia , leukocytosis of 13,900/l , elevated c - reactive protein of 90.1 mg / l , and an increase in the retention parameters ( urea 25 mg / dl ) , indicating an affliction of the kidneys .
the chemotherapy was interrupted and the patient was admitted to the department of dermatology . on examination , there was palpable purpura with petechial hemorrhage on the lower limb in addition to massive edema on both lower legs ( fig .
1 ) . some petechiae were also found on the lower arms and the abdomen .
the patient did not complain about abdominal pain and 3 tests for occult blood in the stool were negative .
after 2 days , the renal parameters were rising ( creatinine 1.33 mg / dl ; normal range 0.51.0 mg / dl ) and the patient developed proteinuria of 1,200 mg / day in the 24-hour urine collection . because of the putative renal involvement , therapy with a high - dose corticosteroid ( prednisolone 80 mg / day ) , a proton pump inhibitor ( pantoprazole 40 mg / day ) and osteoporosis prophylaxis ( calcium carbonate and cholecalciferol 500 mg and 10 g b.i.d .
in addition , the patient was prescribed an ace - inhibitor ( ramipril 2.5 mg / day ) for renal protection .
an infectious origin of the leukocytoclastic vasculitis was considered implausible because there were no respective clinical symptoms and serological tests were negative for hepatitis a , b and c as well as for an infection with streptococci .
g / l ) , c4 ( 0.25 g / l ) , p - anca - if ( < 1:20 ) , and ana - if ( > 1:80 ) , were not elevated and no circulating immune complexes were detected .
a punch biopsy from the active area of the frontal aspect of the right lower leg showed typical features of leukocytoclastic vasculitis ( fig .
nuclear dust in the higher corium , extravasated erythrocytes , focal small - vessel edema , endothelial cell swelling within the vessels and fibrinoid deposition .
direct immunofluorescence revealed igm , iga , c3 , and fibrinogen deposition in the small vessels of the dermis . in our opinion
, there was strong evidence for drug - induced toxicity as the cause of the vasculitis , so chemotherapy with oxaliplatin was discontinued .
the patient was treated with prednisolone at a decreasing dosage for the next 6 weeks . under the steroid therapy
after 2 weeks , there was evidence of hematuria ( > 20 erythrocytes ) and proteinuria ( 745
the urine analysis showed an increase in renal parameters with creatinine 2.41mg / dl , urea 43 mg / dl , egfr 26.3 , a proteinuria of 1,800 mg / day in a 24-hour urine collection , and a creatinine clearance of 40.1 ml / min .
the patient was admitted to the department of nephrology with the clinical diagnosis of acute renal failure , presumably as a consequence of acute glomerulonephritis .
the percutaneous renal biopsy showed a focal segmental extravascular necrotizing proliferating glomerulonephritis . because gbm - antibodies ( 0.4 u / ml ) or cryoglobulins ( < 0.2% ) were not detectable , the most likely cause of renal failure was a renal manifestation of the leukocytoclastic vasculitis . under high - dose steroid therapy ( prednisolone 250 mg for 3 days followed by tapered doses ) ,
the renal function improved slowly . unfortunately , during further follow - up , the patient had developed tumor progression with pulmonary metastases at the 12-month follow - up visit .
consequently , a palliative regimen with folfiri ( 5-fu , leucovorin and irinotecan ) was scheduled . under this treatment
recent mri and ct scans revealed a progressive disease with new metastasis - like lesions in the thoracic spine and suspect lymph nodes in the retroperitoneal , iliacal and inguinal region .
we also treated a 71-year - old male patient with similar symptoms after chemotherapy with folfox-6 and bevacizumab for colon cancer with hepatic metastases [ pt3 , pn0 ( 0/33 ) , pm1 ( hepatic ) , g2 , r0 ] .
initially , he had received surgical treatment with a right hemicolectomy and an atypical liver resection of some of the lesions .
after the subsequent postoperative chemotherapy with folfox-6 and bevacizumab for 4 cycles , restaging was performed . due to the remaining hepatic metastases , a right hemihepatectomy was performed .
except for increased s - ana - if activity ( 1:320 ) , the rheumatoid factors were negative .
a punch biopsy from an active hemorrhagic lesion again confirmed the diagnosis of a leukocytoclastic vasculitis . shortly after diagnosis ,
the patient showed clinical symptoms of acute renal failure and his renal parameters increased to a serum creatinine of 2.5 mg / dl and an urea of 69 mg / dl , necessitating forced diuresis in addition to systemic corticosteroids for the next 2 months . the nephrotic syndrome with microhematuria persisted for 2 months of continued cortisone therapy .
a renal biopsy was repeated 2 months later and showed an iga nephritis with focal segmental and global glomerulosclerosis . as treatment for the chronic renal failure grade iii ,
assuming that drug toxicity was the cause of the vasculitis , the supporting chemotherapy was prematurely terminated . within the following 12 months ,
the patient regretfully developed new metastases in the right lung segment and also showed bifocal liver metastases in the remaining left liver lobe .
the dose reduction was 75% and he received additional fluids for renal protection . under this treatment
, the patient again suffered from acute or chronic renal failure , which made hemodialysis necessary .
oxaliplatin is a third - generation platinum alkylating agent currently used to treat a great number of malignancies , including both locally advanced and metastatic colorectal cancer .
unfortunately , the use of oxaliplatin is associated with a plethora of adverse effects . while some of these effects , like nausea or thrombocytopenia , are common reactions to many cytostatic drugs
, oxaliplatin has been reported to induce some rather unique side effects . with the report of these 2 cases ,
we have documented a very rare oxaliplatin - induced side effect with a potentially dramatic impact on the affected patients .
physicians should be aware of this rare , yet potentially detrimental adverse effect of oxaliplatin when employing it as a standard chemotherapeutic substance or as a part of novel combination therapies .
to our knowledge , there has been only 1 case report prior to our observations reporting leukocytoclastic vasculitis as an adverse effect of treatment with oxaliplatin .
 leukocytoclastic vasculitis is a multicausal systemic inflammatory disease of the small vessels , histologically characterized by inflammation and deposition of both nuclear debris and fibrin in dermal postcapillary venules . 
 the clinical picture typically involves palpable purpura of the lower legs and may be associated with general symptoms such as fatigue , arthralgia and fever . 
 involvement of the internal organs , most notably the kidneys , the central nervous system or the eyes , is possible and determines the prognosis . 
 oxaliplatin - induced leukocytoclastic vasculitis is a very rare event that limits treatment options in affected patients . 
 we report 2 patients who developed the condition under chemotherapy for advanced rectal and metastatic colon carcinoma , respectively ; a termination of the therapy was therefore necessary . while current therapies for colorectal cancer include the combination of multimodal treatment with new and targeted agents , rare and unusual side effects elicited by established agents also need to be taken into account for the clinical management . 
Background
Case 1
Case 2
Conclusions
Disclosure Statement