oxaliplatin ( l - ohp ) is a third - generation platinum anticancer drug , and l - ohp - containing regimens , including folfox4 and mfolfox6 , are currently standard treatments for colorectal cancer 1 - 5 .
the dose - limiting toxicities of l - ohp were shown to be cumulative sensory neurotoxicity and neutropenia 1 - 3,5 , whereas hypersensitivity reactions have been recognized as problematic with the increasing use of l - ohp in clinical practice 6 - 13 .
hypersensitivity reactions are an important adverse effect that may determine whether the treatment can be continued .
we previously demonstrated that l - ohp - related grade 3/4 hypersensitivity reactions occurred immediately after the initiation of infusion , whereas grade 1/2 reactions did not 14 .
a total of 20 laboratory test data obtained prior to the treatments were analyzed 15 . a lower serum level of lactate dehydrogenase ( ldh )
was found to be a risk factor for grade 1/2 reactions , while a lower monocyte count was a risk factor for grade 3/4 reactions 15 .
these pretreatment markers may contribute to the better management of l - ohp - induced hypersensitivity reactions ; however , the treatment has to be repeated several times if it is to be tolerated by patients .
the cycle number , i.e. , number of repetitions , averaged 7.14.2 ( sd , range : 1 - 19 ) in these studies .
laboratory test data were continuously obtained to assess the condition of the patient before and after each cycle of the treatment .
these values often fluctuate and are used for decision - making regarding the postponement of the next cycle of the treatment
. a more detailed assessment of laboratory test data from the first to last cycle of the treatment may provide a better predictor of hypersensitivity reactions , and an additional analysis was performed herein .
laboratory test data were obtained from 108 patients treated with the folfox4 and/or mfolfox6 regimens at either of the labor health and welfare organization kobe rosai hospital , national hospital organization kobe medical center , kobe university hospital , kobe red cross hospital , or shinko hospital , japan , between april 2005 and march 2009 .
patients had received no prior chemotherapy or only one regimen with a washout period of more than 4 weeks after the final day of the previous treatment .
further eligibility criteria included : 1 ) age of 20 - 75 years ; 2 ) eastern cooperative oncology group ( ecog ) performance status of 0 or 1 ; 3 ) life expectancy of 3 months or more ; 4 ) adequate hematological ( leukocyte count : 4,000/mm-12,000/mm , neutrophil count : 2,000/mmor more , platelets : 100,000/mmor more ) , hepatic ( transaminases : 2.5 times or less the upper limit of normal , total bilirubin : 2.0 mg / dl or less ) , and renal ( serum creatinine : less than the upper limit of normal ) function ; and 5 ) the ability to take oral medication .
depending on the clinical situation , patients who did not meet the criteria could be treated with l - ohp under the careful supervision of medical doctors .
patients were excluded if they had either brain metastases , a history of other neoplasms ( except for cured nonmelanoma skin carcinoma or cured carcinoma in situ ) , a history of severe drug allergies , interstitial pneumonitis or pulmonary fibrosis , severe pleural effusion or ascites , active infection , bowel obstruction , diarrhea , and serious uncontrolled comorbidity or medical conditions .
hypersensitivity reactions were assessed and classified according to the national cancer institute common criteria ( nci - ctcae v3.0 ) .
a total of 20 laboratory test data were compared between patients who exhibited hypersensitivity reactions and those who did not , including hematological parameters ( erythrocyte count , hemoglobin , hematocrit , leukocyte count , neutrophil count , lymphocyte count , eosinophil count , basophil count , monocyte count , and platelet count ) , hepatic parameters ( aspartate aminotransferase , alanine aminotransferase , gamma - glutamyl transpeptidase , total bilirubin , and alkaline phosphatase ) , serum ldh , renal parameters ( blood urea nitrogen and serum creatinine ) , carcinoembryonic antigen , and ca19 - 9 antigen .
this retrospective study was approved by the institutional review board of each of the 5 hospitals .
it should be noted that laboratory test data obtained prior to the first cycle of the treatment were analyzed in terms of susceptibility to hypersensitivity reactions 15 . in this study
, the time course from the first to last cycle of the treatment was additionally analyzed to identify a better predictor of hypersensitivity reactions .
laboratory test data at the n - th cycle represented those from initiation of the n - th cycle to just before the initiation of ( n+1)-th cycle of the treatment , and worst ones were adopted when they were measured more than 2 times .
the averages and variation coefficients ( cv% ) of the data until the last cycle of the treatment were used for comparisons .
the unpaired student 's t - test / welch 's test or mann - whitney 's u test was used for group comparisons , and after a bonferroni correction , p values of less than 0.05 were considered significant .
the cycle number in patients with no , grade 1/2 , and 3/4 hypersensitivity reactions is summarized in table 1 .
the cycle number at which grade 1/2 reactions occurred was 7.54.6 ( range : 2 - 17 ) , whereas it was 9.33.9 ( range : 5 - 16 ) for grade 3/4 reactions .
an additional cycle of the treatment was not performed when grade 3/4 reactions occurred , whereas it was possible for grade 1/2 reactions .
the average values of hematological parameters and serum ldh levels are summarized in table 2 .
serum ldh levels were lower in patients with grade 1/2 reactions than in those with no reactions ( p=0.016 , mann - whitney 's ) ; however , no significant differences were observed in hematological parameters between patients with no and grade 1/2 reactions , or between those with no and grade 3/4 reactions .
no significant differences were noted in the other parameters examined in this study between patients ( data not shown ) .
cv% values are summarized in table 3 . among the 20 laboratory test data analyzed herein , the cv% value was the highest for the basophil count , followed by the eosinophil count , and neutrophil count .
the cv% value of serum ldh levels was relatively low , and a correlation was observed with hypersensitivity reactions ; the cv% value was higher in patients with grade 3/4 reactions than in those with no reactions ( p=0.005 , mann - whitney 's ) .
the difference between the maximum and minimum values was also higher in patients with grade 3/4 reactions ( p=0.017 , mann - whitney 's ) , while no such relationship was found for the maximum values ( p=0.060 , mann - whitney 's ) .
the time courses of serum ldh levels in patients with grade 3/4 are shown in figure 1 , and are from all 10 patients and expressed as a function of the cycle number .
serum ldh levels were increased in 4 of 10 patients as the cycle number increased until grade 3/4 reactions manifested , and these phenomena reflected the higher value of cv% in table 3 .
an increase in serum ldh levels before the manifestation of hypersensitivity reactions was not observed for grade 1/2 reactions .
glycolysis , the transformation of glucose to pyruvate , is a key step for energy acquisition in all mammalian cells , including cancer cells .
pyruvate is further transformed to acetyl - coa under normoxic conditions ; however , suboptimal oxygen availability switches the metabolic pathway , resulting in the transformation to lactate via ldh-5 , one of the 5 isoenzymes of ldh 16 .
immunochemical studies have shown that ldh-5 is overexpressed in non - small - cell lung cancer 17 and advanced metastatic colorectal cancer 18 , 19 .
removal of the primary tumor was shown to result in a significant reduction in serum ldh levels in patients with non - small cell lung cancer 17 ; however , serum ldh levels have not always reflected the presence of a tumor 20 . in spite of the lack of information on the relationships between serum ldh levels and presence of tumors , serum ldh levels have been investigated in terms of the response to treatment and prognosis of cancer patients 17 , 21 - 25 , and higher serum levels
we previously demonstrated that a lower serum ldh level prior to the treatments was a risk factor for grade 1/2 reactions 15 . in this study , we analyzed laboratory test data from the first to last cycle of the treatment , and serum ldh levels were shown to be maintained at lower levels in patients with grade 1/2 reactions than those with no reactions ( tables 2 and 3 ) .
our results suggest that patients without the exacerbation of tumors are susceptible to grade 1/2 reactions . in our previous study ,
a lower monocyte count prior to the treatments was identified as a risk factor for grade 3/4 reactions 15 ; however , no significant differences were observed in the average values between patients with no and grade 3/4 reactions ( table 2 ) .
in contrast , patients with grade 3/4 reactions could be characterized by larger variations in serum ldh levels ( table 3 ) . as shown in figure 1
, serum ldh levels increased as the cycle number increased in some patients , and thereafter grade 3/4 reactions occurred ( figure 1 ) .
this phenomenon was not observed in patients with grade 1/2 reactions . if an increase in serum ldh levels suggests the exacerbation of a tumor , it is accompanied by grade 3/4 reactions .
hypersensitivity reactions are a well - established complication of platinum agents ; however , the mechanisms responsible remain unclear 26 - 29 .
reactions are thought to be mainly caused by the type i ige - mediated system because they occur after multiple infusions ; however , recent studies have suggested the contribution of the type iv t - cell - mediated system 26 - 29 . regarding l - ohp ,
most reactions are thought to be of type i , while reports of hemolysis and thrombocytopenia suggest a type ii reaction , and chronic urticaria , joint pain , and proteinuria can be attributed to a type iii reaction 26 - 29 . in the present study ,
the cv% values of the eosinophil count were slightly higher in patients with grade 1/2 reactions ( p=0.082 ) , whereas those of the basophil count were higher for grade 3/4 reactions ( p=0.089 ) .
eosinophils and basophils express many of the same receptors , whereas the cytokines produced differ 30 .
the eosinophil and basophil counts may be predictive markers of l - ohp - induced hypersensitivity reactions . in conclusion
, a total of 20 laboratory test data were obtained from patients with advanced colorectal cancer who were treated with the l - ohp - containing regimens , folfox4 and/or mfolfox6 .
the time course until the last cycle of the treatment was compared between patients with hypersensitivity reactions and those without .
we demonstrated that the average value of serum ldh levels was lower in patients with grade 1/2 reactions , whereas its cv% value was higher in patients with grade 3/4 reactions than in those without reactions .
these results suggested that the serum ldh levels may be a predictive marker of l - ohp - induced hypersensitivity reactions .
 objective : clinical laboratory test data obtained prior to treatments were previously analyzed from the standpoint of susceptibility to hypersensitivity reactions in patients treated with the platimun anticancer agent , oxaliplatin ( l - ohp ) . in the present study , the time course from the first to last cycle of the treatment was additionally analyzed to determine a better predictor of these reactions.methods : a total of 20 laboratory test data were obtained from 108 japanese patients with advanced colorectal cancer who were treated with the l - ohp - containing regimens , folfox4 and/or mfolfox6 . 
 the averages and variation coefficients ( cv% ) of the data until the last cycle of the treatment were compared between patients with hypersensitivity reactions and those without.results : the average serum lactate dehydrogenase ( ldh ) level was lower in patients with grade 1/2 reactions ( p=0.016 ) , whereas its cv% value was higher in patients with grade 3/4 reactions ( p=0.005 ) than in those without reactions . 
 an increase in serum ldh levels was observed in some patients with grade 3/4 reactions as the cycle number increased , and thereafter hypersensitivity reactions occurred . 
 this phenomenon was not always observed , but was never detected in patients with grade 1/2 reactions.conclusions : serum ldh levels may be a predictive marker of hypersensitivity reactions in patients treated with l - ohp . further extensive examinations with a larger number of patients are needed to establish a patient management strategy . 
Introduction
Methods
Results
Discussion