the introduction of imatinib mesylate ( glivec/gleevec , novartis , basel , switzerland ) has improved outcomes for patients with advanced gastrointestinal stromal tumor ( gist ) , and imatinib is now considered the standard first - line treatment in patients with metastatic or unresectable gist ( 1 , 2 ) .
imatinib is generally well tolerated , although some patients have difficulty tolerating the standard dose of 400 mg / day , which may necessitate imatinib dose reductions .
however , patients and physicians are cautious and sometimes reluctant to reduce the dose of imatinib because of concerns about disease progression .
indeed , results from a pharmacokinetic analysis suggested that adequate drug exposure , as determined by imatinib plasma trough concentration , is correlated with clinical benefit ; a low plasma trough concentration of imatinib ( < 1,100 ng / ml ) might contribute to reduced efficacy in patients with advanced gist ( 3 ) .
previous pharmacokinetic studies also showed that imatinib blood levels have high interpatient variability ( 3 - 5 ) and are affected by several covariates , such as albumin concentration , creatinine clearance , white blood cell count , and major gastrectomy ( 3 , 5 ) .
as a result , monitoring imatinib plasma concentration on an individual basis may be important for optimizing clinical outcomes of patients with advanced gist ( 6 , 7 ) .
some patients who take the standard dose of imatinib may have abnormally high plasma levels of imatinib due to their individual predisposition to decreased drug metabolism ( 3 - 5 ) ; it is known that some imatinib - related toxicities may be related to overexposure to the drug ( 6 ) .
the problem becomes even more complicated when these imatinib - related toxicities confound the evaluation of response to imatinib therapy .
for example , when patients do not have tumor size reduction and ascites develops as a toxicity of imatinib , this may be misinterpreted as having disease progression and managed with imatinib dose escalation or switching to second - line sunitinib ( 8) .
therefore , adjusting imatinib dosage by plasma level monitoring may help manage patients who experience intolerable toxicities while also achieving sufficient imatinib trough concentrations to maintain efficacy .
here we describe two patients with advanced gist whose imatinib - related toxicities were successfully managed with dose modifications guided by imatinib plasma level testing .
a 67-yr - old asian man who presented with intermittent melena and significant weight loss was diagnosed with small bowel gist with multiple liver metastases and peritoneal seeding on may 25 , 2010 .
he underwent jejunal resection and anastomosis with palliative intent . the excised jejunal gist measured 7  5  5 cm and had a c - kit exon 9 mutation ( 1,510 - 1,515 duplication ) .
two months later , the patient developed grade 3 edema , grade 3 ascites , and grade 2 vomiting , with chest radiography revealing layering of a moderate amount of pleural fluid .
because the patient had peritoneal seeding , it was hard to determine whether his ascites and pleural effusion were due to imatinib toxicity or the progression of gist .
although the follow - up abdomino - pelvic computed tomography ( ct ) scan showed that the patient 's liver metastases had not changed significantly , disease progression was suspected , which prompted a cessation in imatinib treatment and a commencement of sunitinib treatment .
the patient was transferred to our hospital for a second opinion after he had been taking sunitinib for approximately 2 months .
a thorough review of his previous serial ct scans showed no definitive evidence of disease progression whilst he was on imatinib treatment .
we therefore decided to resume 400 mg / day imatinib and use f - fluorodeoxyglucose ( fdg ) positron emission tomography ( pet)/ct for accurate assessment of response to imatinib treatment .
one month after the patient restarted imatinib , a pet / ct scan revealed a significant decrease in maximum standardized uptake value from 4.2 to 2.9 in one of his liver metastases ( fig .
1a and b ) , suggesting the tumor was responding to imatinib . however , the patient required paracentesis once weekly to control his ascites , and he complained of peripheral edema and dyspnea . because imatinib blood level testing revealed that the patient had very high imatinib trough plasma exposure , 4,120 ng / ml and 4,600 ng / ml on two different days ( fig .
1c ) , we decreased his dose to 300 mg / day , which resulted in a steady - state imatinib plasma trough concentration of 3,220 ng / ml ( fig .
however , the patient still had grade 2 edema , ascites , and dyspnea on exertion due to pleural effusion .
as his imatinib trough plasma exposure was sufficiently high to achieve an adequate tumor response ( 3 ) , we further reduced his dose to 200 mg / day . at this dose , his fluid retention ,
including ascites , edema , and pleural effusion , was greatly improved , and he had no difficulties in daily life ; in addition , his liver metastases remained stable ( fig .
five months later , the patient expressed concerns that 200 mg / day of imatinib may be insufficient to control his tumor , as studies have shown that gist patients with the c - kit exon 9 mutation may benefit from higher than normal exposure to imatinib ( 3 , 9 , 10 ) .
he was able to tolerate ascites and dyspnea with the use of regular diuretics but had some limitation of activities .
follow - up ct scans to date showed the patient 's disease remained stable ( fig . 1b ) . a 69-yr - old asian man presenting with melena was diagnosed with duodenal gist and underwent whipple 's operation on may 6 , 2004 .
the excised mass measured 5.5  4.5  2.0 cm and had a low mitotic rate ( < 5 mitoses per 50 high - powered fields ) .
mutation analysis showed that the tumor had a kit exon 11 deletion at amino acid 552 .
twenty - two months after surgery , a liver metastasis was detected on follow - up ct scans .
the treatment was effective , with a partial response noted after 3 months ( fig .
2a ) ; the treatment was also tolerable , with grade 2 edema the only adverse event experienced by the patient . at 26 months following the commencement of imatinib treatment , the patient developed several small , round , mesenteric lymph node enlargements , which were regarded as a sign of disease progression even though the metastatic lesions in his liver remained stable .
after 7 months at this dosage , the patient experienced grade 3 dyspnea and grade 3 pericardial effusion .
however , an in - depth review of his previous serial ct scans by an experienced gastrointestinal radiologist revealed that the morphology of these enlarged mesenteric lymph nodes suggested reactive changes , instead of lymph node metastases , which are rare in gist ( 11 ) .
ct scans 10 months later showed that the patient 's liver metastasis were stable ( fig .
although his ascites and pleural effusion gradually improved , the patient complained of dyspnea , and diuretics were required for the control of grade 2 generalized edema . because imatinib plasma monitoring revealed that the patient had high imatinib plasma trough concentrations ( 3,850 ng / ml and 4,280 ng / ml on two different days ; fig .
2b ) , we reduced his dose to 300 mg / day , which resulted in imatinib plasma trough concentrations of 2,670 ng / ml and 2,880 ng / ml ( fig .
however , pericardial effusion was persistently observed , even after his imatinib dose was further decreased to 200 mg / day , which resulted in steady - state imatinib plasma trough concentrations of 3,070 ng / ml and 2,710 ng / ml ( fig . 2b ) .
as the patient 's imatinib trough plasma exposure was still sufficiently high ( 3 ) and the follow - up ct scan showed that his liver metastasis remained stable ( fig .
2a ) , we further decreased his dose to 100 mg / day , which resulted in imatinib plasma trough concentrations of 1,660 ng / ml and 1,480 ng / ml ( fig .
to date , the patient has been taking 100 mg / day of imatinib for approximately 1 yr .
a 67-yr - old asian man who presented with intermittent melena and significant weight loss was diagnosed with small bowel gist with multiple liver metastases and peritoneal seeding on may 25 , 2010 .
he underwent jejunal resection and anastomosis with palliative intent . the excised jejunal gist measured 7  5  5 cm and had a c - kit exon 9 mutation ( 1,510 - 1,515 duplication ) .
two months later , the patient developed grade 3 edema , grade 3 ascites , and grade 2 vomiting , with chest radiography revealing layering of a moderate amount of pleural fluid .
because the patient had peritoneal seeding , it was hard to determine whether his ascites and pleural effusion were due to imatinib toxicity or the progression of gist .
although the follow - up abdomino - pelvic computed tomography ( ct ) scan showed that the patient 's liver metastases had not changed significantly , disease progression was suspected , which prompted a cessation in imatinib treatment and a commencement of sunitinib treatment .
the patient was transferred to our hospital for a second opinion after he had been taking sunitinib for approximately 2 months .
a thorough review of his previous serial ct scans showed no definitive evidence of disease progression whilst he was on imatinib treatment .
we therefore decided to resume 400 mg / day imatinib and use f - fluorodeoxyglucose ( fdg ) positron emission tomography ( pet)/ct for accurate assessment of response to imatinib treatment .
one month after the patient restarted imatinib , a pet / ct scan revealed a significant decrease in maximum standardized uptake value from 4.2 to 2.9 in one of his liver metastases ( fig .
1a and b ) , suggesting the tumor was responding to imatinib . however , the patient required paracentesis once weekly to control his ascites , and he complained of peripheral edema and dyspnea . because imatinib blood level testing revealed that the patient had very high imatinib trough plasma exposure , 4,120 ng / ml and 4,600 ng / ml on two different days ( fig .
1c ) , we decreased his dose to 300 mg / day , which resulted in a steady - state imatinib plasma trough concentration of 3,220 ng / ml ( fig .
however , the patient still had grade 2 edema , ascites , and dyspnea on exertion due to pleural effusion .
as his imatinib trough plasma exposure was sufficiently high to achieve an adequate tumor response ( 3 ) , we further reduced his dose to 200 mg / day . at this dose , his fluid retention ,
including ascites , edema , and pleural effusion , was greatly improved , and he had no difficulties in daily life ; in addition , his liver metastases remained stable ( fig .
five months later , the patient expressed concerns that 200 mg / day of imatinib may be insufficient to control his tumor , as studies have shown that gist patients with the c - kit exon 9 mutation may benefit from higher than normal exposure to imatinib ( 3 , 9 , 10 ) .
he was able to tolerate ascites and dyspnea with the use of regular diuretics but had some limitation of activities .
follow - up ct scans to date showed the patient 's disease remained stable ( fig . 1b ) .
a 69-yr - old asian man presenting with melena was diagnosed with duodenal gist and underwent whipple 's operation on may 6 , 2004 . the excised mass measured 5.5  4.5  2.0 cm and had a low mitotic rate ( < 5 mitoses per 50 high - powered fields ) .
mutation analysis showed that the tumor had a kit exon 11 deletion at amino acid 552 .
twenty - two months after surgery , a liver metastasis was detected on follow - up ct scans .
the treatment was effective , with a partial response noted after 3 months ( fig .
2a ) ; the treatment was also tolerable , with grade 2 edema the only adverse event experienced by the patient . at 26 months following the commencement of imatinib treatment , the patient developed several small , round , mesenteric lymph node enlargements , which were regarded as a sign of disease progression even though the metastatic lesions in his liver remained stable .
after 7 months at this dosage , the patient experienced grade 3 dyspnea and grade 3 pericardial effusion .
however , an in - depth review of his previous serial ct scans by an experienced gastrointestinal radiologist revealed that the morphology of these enlarged mesenteric lymph nodes suggested reactive changes , instead of lymph node metastases , which are rare in gist ( 11 ) .
ct scans 10 months later showed that the patient 's liver metastasis were stable ( fig .
although his ascites and pleural effusion gradually improved , the patient complained of dyspnea , and diuretics were required for the control of grade 2 generalized edema . because imatinib plasma monitoring revealed that the patient had high imatinib plasma trough concentrations ( 3,850 ng / ml and 4,280 ng / ml on two different days ; fig .
2b ) , we reduced his dose to 300 mg / day , which resulted in imatinib plasma trough concentrations of 2,670 ng / ml and 2,880 ng / ml ( fig .
however , pericardial effusion was persistently observed , even after his imatinib dose was further decreased to 200 mg / day , which resulted in steady - state imatinib plasma trough concentrations of 3,070 ng / ml and 2,710 ng / ml ( fig . 2b ) .
as the patient 's imatinib trough plasma exposure was still sufficiently high ( 3 ) and the follow - up ct scan showed that his liver metastasis remained stable ( fig .
2a ) , we further decreased his dose to 100 mg / day , which resulted in imatinib plasma trough concentrations of 1,660 ng / ml and 1,480 ng / ml ( fig .
to date , the patient has been taking 100 mg / day of imatinib for approximately 1 yr .
imatinib is metabolized in the liver , predominantly by cytochrome p450 ( cyp ) 3a4 ( 12 ) . as a result
, the plasma concentration of imatinib may be affected by intrinsic variability of cyp enzyme activity and other factors , such as albumin concentration ( 3 , 5 ) .
although studies have assessed the relationship between imatinib plasma concentration and efficacy ( 3 , 4 , 12 ) , less is known about the relationship between imatinib plasma concentration and toxicity ( 6 ) .
one study showed that the occurrence and number of side - effects correlated with imatinib total and free plasma concentration in patients with gist ( 6 ) .
however , the study did not assess imatinib exposure with the grade or type of toxicities , findings that may have been of value in clarifying the dose - dependent toxicities of imatinib .
here we described two patients who experienced intolerable toxicities while on standard - dose imatinib treatment .
both had high imatinib plasma trough concentrations , which appeared to have contributed to the severe fluid retention ( e.g. ascites , edema , and pleural effusion ) observed in these patients . through imatinib plasma monitoring
, we reduced the dose of imatinib , consequently decreasing these toxicities , while maintaining sufficient imatinib exposure for adequate efficacy of the treatment .
another interesting aspect of these two patient cases is that they highlight the difficulties of response evaluation for imatinib therapy in gist patients .
toxicity of imatinib or reaction to imatinib treatment may sometimes be mistaken for disease progression .
for example , in the first patient who had peritoneal metastases , ascites was regarded as a sign of disease progression ; in the second patient , enlarged reactive mesenteric lymph nodes were mistaken for lymph node metastatses . because both patients had no tumor shrinkage in other nodules , which is quite common in patients with advanced gist on imatinib therapy , it was difficult to determine whether imatinib treatment was effective .
fdg - pet / ct scan may be considered for accurate assessment of response to imatinib , especially when rapid readout of activity is necessary . when considering imatinib plasma level monitoring to address intolerable adverse events , it is necessary to also consider covariates that may affect imatinib pharmacokinetics , such as demographics , body weight , and other clinical characteristics .
patients of asian descent , for example , might display different imatinib pharmacokinetics compared with those of caucasian descent as a result of different physical characteristics . whilst there has been no clear elucidation of the influence of race on imatinib pharmacokinetics ,
several reports have suggested a trend towards lower imatinib trough levels in patients with higher body mass index ( 3 , 5 , 13 ) . as such
it might be assumed that asian patients would have a tendency towards lower imatinib trough levels compared to their caucasian counterparts .
however , this assumption should be treated with caution given that the reports were associated with only a weak correlation or tendency towards insignificance .
furthermore , it should also be noted that physical attributes alone are unlikely to explain pharmacokinetic differences between racial backgrounds given potential differences in pharmacogenomics and activity of metabolic enzymes such as cyp3a5 .
therefore , in order to individualize treatment with imatinib in patients with gist , investigation of clinical and demographic covariates correlated with imatinib pharmacokinetics is warranted . the optimal imatinib exposure level in an individual patient maybe defined as the level that is able to sustain maximal tumour response whilst minimizing adverse events .
no reliable evidence exists to define a pharmacokinetic threshold for clinical benefit , though an imatinib plasma trough concentration of less than 1,100 ng / ml has been reported to be related to reduced efficacy in patients with advanced gist ( 3 ) .
the results of these case reports demonstrate that imatinib plasma monitoring - guided dose modification can successfully manage imatinib - related toxicities due to overexposure without compromising the efficacy of the treatment .
our findings suggest that individual imatinib blood level testing may be a promising approach for fine - tuning imatinib dosage for better tolerability and optimal clinical outcomes in patients with advanced gist .
 imatinib , the first - line treatment in patients with advanced gastrointestinal stromal tumors ( gist ) , is generally well tolerated , although some patients have difficulty tolerating the standard dose of 400 mg / day . 
 adjusting imatinib dosage by plasma level monitoring may facilitate management of patients who experience intolerable toxicities due to overexposure to the drug . 
 we present two cases of advanced gist patients in whom we managed imatinib - related toxicities through dose modifications guided by imatinib plasma level monitoring . 
 imatinib blood level testing may be a promising approach for fine - tuning imatinib dosage for better tolerability and optimal clinical outcomes in patients with advanced gist . 
INTRODUCTION
CASE DESCRIPTION
Patient 1
Patient 2
DISCUSSION