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after the introduction of folfox therapy , the prognosis of advanced / recurrent colorectal cancer markedly improved . however , in some patients , even though the antitumor effects of this therapy are observed , its continuation is difficult due to peripheral neuropathy caused by oxaliplatin .
we report a patient in whom bevacizumab ( bv ) + modified folfox6 ( mfolfox6 ) therapy was changed to bv + cape therapy due to peripheral neuropathy , and the peripheral neuropathy decreased with partial response being maintained .
a 69-year - old female with a past history of surgery for choledocholithiasis ( details unknown ) visited a local hospital due to melena .
she was referred to our hospital under a diagnosis of rectosigmoid cancer with multiple hepatic metastases made by colonoscopy and abdominal ultrasonography . at the time of the first consultation at our department , the levels of cea ( 224.3 ng / ml , normal range < 5 ng / ml ) and ca19 - 9 ( 444 u / ml , normal range < 37 u / ml ) as tumor markers were high .
colonoscopy revealed a type 2 lesion ( 2/3 of the circumference ) in the rectosigmoid area ( fig .
the primary lesion was considered to be resectable , and high anterior resection of the rectum with d2 lymph node dissection was performed in december 2008 .
postoperative chemotherapy for the metastatic lesions of the liver , therapy with bv and mfolfox6 was initiated in january 2009 ( chemotherapy consisted of an intravenous injection of oxaliplatin 85 mg / m with isovorin 200 mg / m over 2 h followed by 5-fluorouracil ( 5-fu ) 400 mg / m bolus and 2,400 mg / m continuous infusion over 48 h with bv 5 mg / m , which was repeated every 2 weeks ) ( fig .
3 ) . after 6 courses of this therapy ( april 2009 ) , the levels of cea and ca19 - 9 as tumor markers decreased to 12.3 ng / ml and 48 u / ml , respectively .
a total of 11 courses were performed until july 2009 , and both tumor markers improved to a normal level . however , since grade 3 peripheral neuropathy according to the common terminology criteria for adverse events v. 3.0 ( ctcae v. 3.0 ) developed , the bv + mfolfox6 therapy was discontinued .
regimens involving oxaliplatin were considered difficult , and bv + capecitabine ( cape ) therapy was initiated ( bv 7.5 mg / kg on day 1 plus cape 1,500 mg / m twice daily on days 114 , every 3 weeks . ) . in january 2010 , after 6 courses of bv + cape therapy , the peripheral neuropathy disappeared , and the tumor marker levels ( cea 3.5 ng / ml , ca19 - 9 9 u / ml ) were within the normal range .
folfox therapy , first reported by de gramont et al . in 2000 , is a globally established standard therapy effective against advanced / recurrent colorectal cancer . in addition
, its combination with bv as a molecular targeted drug has markedly prolonged the survival period in patients with colorectal cancer . however , drug accumulation - associated peripheral neuropathy as an adverse event specific to oxaliplatin used in this therapy is a major problem . as its cause ,
abnormality of the na channel of neurons has attracted attention , but its detailed mechanism has not been clarified .
persistent symptoms are defined in the oxaliplatin interview form as symptoms persisting for = 14 days that are accompanied by progressive sensory disturbance , hypesthesia , or the disappearance of somatic sensation , disturbing daily life . in general , when the aggravation of peripheral neuropathy , the delay in recovery , or sensory dysfunction develops , a reduction in the dose of oxaliplatin or suspension / discontinuation of its administration is necessary .
persistent peripheral neuropathy accounts for more than 30% of the causes of therapy discontinuation . in our patient , after 11 courses of bv + mfolfox6 therapy , persistent grade 3 peripheral neuropathy developed , and discontinuation of this therapy was decided upon . about 90% of patients with severe peripheral neuropathy
based on the results of our previous optimox-1 study , the suspension of oxaliplatin was considered to have no influence on the antitumor effects in this patient . in the optimox-1 study , we compared two groups who underwent 6 courses of folfox therapy followed by folfox4 therapy until tumor aggravation or 12 courses of slv5fu2 therapy followed by 6 courses of folfox7 therapy , but observed no significant difference in the median aggravation - free survival period between the two groups .
the results of optimox-1 study demonstrated that a  stop - and - go approach employing oxaliplatin - free interval resulted in decreased neurotoxicity but did not affect overall survival in patients receiving folfox as initial therapy for metastatic colorectal cancer .
the optimox-2 study suggests that chemotherapy - free interval is not recommended for patients with advanced colorectal cancer .
since the antitumor effects of cape used alone on metastatic colorectal cancer has been reported to be similar to that of intravenous 5-fu / leucovorin therapy , we considered that oral cape administration was also appropriate in this patient . in patients who have received primary treatment involving bv , prolongation of the survival period by continuous bv administration
another study on bv + cape therapy showed a response rate of 34% and an aggravation - free period of 10.8 months .
results of the ecog3200 study reported that use of single - agent bv is not recommended since it was shown to have inferior efficacy compared with folfox alone or folfox + bv treatment arms .
finally , the patient made a decision not of chemotherapy - free interval but of bv + cape therapy ( bv 7.5 mg / kg on day 1 plus cape 1,500 mg / m twice daily on days 114 , every 3 weeks ) continuance along with improvement of her general status .
in out patient partial response was observed after 11 courses of bv + mfolfox6 therapy .
after 6 subsequent courses of bv + cape therapy , persistent peripheral neuropathy disappeared and partial response continued , showing successful tumor control . we intend to resume oxaliplatin administration after talking with the patient . to continue treatment using regimens involving oxaliplatin ,
this case suggests that bv + cape therapy can be a maintenance therapy during the suspension of oxaliplatin administration .
a 69-year - old female visited our department with a diagnosis of rectosigmoid cancer and multiple hepatic metastases ( stage iv ) . 
 abdominal ct revealed multiple metastatic lesions in the bilateral lobes of the liver . 
 the primary lesion was considered to be resectable , and high anterior resection of the rectum was performed . after the operation , 6 courses of therapy with bevacizumab ( bv ) and modified folfox6 were performed . 
 ct showed a partial response , and tumor marker levels became normal . 
 after a total of 11 courses of this therapy , grade 3 peripheral neuropathy developed , and the therapy was changed to bv and capecitabine ( cape ) . 
 after 6 courses of this therapy , ct showed the maintenance of partial response , and tumor marker levels were also within the normal range . 
 bv and cape therapy may be useful not only for reducing peripheral neuropathy , but also as a maintenance therapy in patients requiring the suspension of oxaliplatin administration due to peripheral neuropathy .