gynecologic malignancies , including cervical and vaginal cancers , often require a multidisciplinary approach that combines radiation , chemotherapy and/or surgery .
imaging modalities that can accurately assess the extent of the disease and the effect of treatments have become an integral component in evaluating the success of therapy .
radiation therapy is an essential component in the management of unresectable locally advanced disease . more specifically , external beam radiation therapy ( ebrt ) and brachytherapy ( bt ) are the two radiation modalities that are used sequentially to reduce the risk of local recurrence and improve survival . at diagnosis , positron emission tomography / computed tomography ( pet / ct ) with the tracer 2-[fluorine-18]fluoro-2-deoxy - d - glucose ( fdg )
however , studies have indicated that , when fdg - pet is used immediately after ebrt to assess treatment response , it may be difficult to differentiate between residual or recurrent active tumor and inflammation in the area treated with radiation using this tracer ( choi et al . , 2014 ) .
therefore , fdg - pet is not a reliable assessment tool to monitor residual tumor and to direct bt doses immediately after ebrt .
another available pet tracer used for tumor assessment , f-18-fluorothymidine ( flt ) , has the potential to improve detection of metabolically active tumors ( wang et al . , 2015 , hoshikawa et al . , 2015 ) .
this relatively new radiotracer has attracted attention for evaluation of post - radiation response in , head / neck , esophageal , breast , lung , and rectal cancers though its role in the evaluation of gynecologic cancers after ebrt is unknown ( yue et al . , 2010 ,
, 2012 , wieder et al . , 2007 , kahraman et al . , 2011 , menda et al . , 2009 ) .
the fact that only proliferating cells ( i.e. malignant tissues ) enable thymidine incorporation in dna synthesis makes flt imaging a particularly attractive tool when differentiating between residual / recurrent malignancy and inflammation ( rasey et al . , 2002 ,
the goals of this study were to compare metabolic parameter standard uptake values ( suvs ) of flt with fdg pet in patients with gynecologic cancer at diagnosis and to determine if flt suvs are affected by inflammation immediately following ebrt .
between august 2012 and april 2014 , six patients with newly diagnosed gynecologic cancers treated with concurrent chemoradiotherapy ( chemort ) were enrolled on a prospective clinical trial for image - guided brachytherapy .
all tumors were staged according to the international federation of gynecology and obstetrics ( figo ) 2009 staging system ( pecorelli , 2009).the eligibility requirements included : histopathologically confirmed primary lesions ( five were cervical cancers and one was vaginal cancer ) ; mri and/or pet - ct scan within 4  months before registration ; age   18 ; ecog performance status   2 ; and no uncontrolled illness that would limit compliance with study requirements .
the study was approved by the institutional review board , and all participants signed an informed consent form .
the bwh cyclotron and radiopharmacy produced flt in a nucleophilic synthesis box using in - process controls such as high - purity solvents to synthesize the radiopharmaceutical and automated software that controls the temperature and timing parameters and records the information from the production run .
an integrity test was performed on the sterilizing filter in addition to a sterility test on the final drug product ; the process achieved a radiochemical purity of more than 95% .
for both fdg and flt imaging , pet / ct was performed after at least 4  h of fasting and 60    10  min after the intravenous administration of 370480 megabecquerels of fdg or 296370 megabecquerels of flt .
pet imaging was performed in 3-dimensional mode on a discovery st pet / ct scanner ( general electric , milwaukee , wi ) from the skull base through the mid thighs .
non - contrast helical ct imaging was performed over the same range without breath - hold for attenuation correction of pet images and anatomic correlation .
the review of fdg- and flt - pet / ct images and measurements of the tumor suvmax were performed on hermes workstation ( hermes medical solutions ab , stockholm , sweden ) .
the wilcoxon rank sum test was used to compare the suvs of flt and fdg at diagnosis .
between august 2012 and april 2014 , six patients with newly diagnosed gynecologic cancers treated with concurrent chemoradiotherapy ( chemort ) were enrolled on a prospective clinical trial for image - guided brachytherapy .
all tumors were staged according to the international federation of gynecology and obstetrics ( figo ) 2009 staging system ( pecorelli , 2009).the eligibility requirements included : histopathologically confirmed primary lesions ( five were cervical cancers and one was vaginal cancer ) ; mri and/or pet - ct scan within 4  months before registration ; age   18 ; ecog performance status   2 ; and no uncontrolled illness that would limit compliance with study requirements .
the study was approved by the institutional review board , and all participants signed an informed consent form .
the bwh cyclotron and radiopharmacy produced flt in a nucleophilic synthesis box using in - process controls such as high - purity solvents to synthesize the radiopharmaceutical and automated software that controls the temperature and timing parameters and records the information from the production run .
an integrity test was performed on the sterilizing filter in addition to a sterility test on the final drug product ; the process achieved a radiochemical purity of more than 95% .
for both fdg and flt imaging , pet / ct was performed after at least 4  h of fasting and 60    10  min after the intravenous administration of 370480 megabecquerels of fdg or 296370 megabecquerels of flt .
pet imaging was performed in 3-dimensional mode on a discovery st pet / ct scanner ( general electric , milwaukee , wi ) from the skull base through the mid thighs .
non - contrast helical ct imaging was performed over the same range without breath - hold for attenuation correction of pet images and anatomic correlation .
the review of fdg- and flt - pet / ct images and measurements of the tumor suvmax were performed on hermes workstation ( hermes medical solutions ab , stockholm , sweden ) .
the wilcoxon rank sum test was used to compare the suvs of flt and fdg at diagnosis .
the median age at diagnosis for the six patients was 61  years ( range , 3372 ) .
the five cervical cancers were staged as ib2 ( n  =  1 , 20% ) , iib ( n  =  1 , 20% ) , iiib ( n  =  1 , 20% ) and iva ( n  =  2 , 40% ) and the one vaginal cancer was stage iiib ( n  =  1 ) .
the most common histology was squamous cell carcinoma ( n  =  3 , 50% ) followed by adenocarcinoma ( n  =  2 , 33% ) and clear cell adenosquamous carcinoma ( n  =  1 , 17% ) .
median follow - up time was 24  months ( range , 630 months ) .
all six patients received concurrent weekly chemotherapy ( cisplatin for 5 and carboplatin for 1 ) with radiation therapy ( table 1 ) . all received a total radiation dose of 45 gy in 25 fractions of 1.8 gy to the pelvis and para - aortic nodes .
patient a received an additional 6 gy boost to the right inguinal nodes , and patient b received an additional 10 gy boost to the right iliac nodes .
all patients underwent flt - pet and fdg - pet scanning at diagnosis ; these scans were performed 13  weeks before chemort .
all patients also had post - chemort flt - pet / ct scans before receiving brachytherapy , except patient c due to scanner malfunction ( table 2 ) .
all patients had post - chemort fdg - pet , but are not reported due to diffuse uptake . at last follow - up , five patients were alive and one had died with the most recent mri exam showing significant tumor shrinkage 3-months prior to death but the cause was undeterminable .
two patients with primary cervical cancer were known to have had recurrence : 1 in the vaginal cuff ( patient c ) and 1 with metastatic disease to the lung ( patient d ) . at diagnosis ,
fdg uptake was visually more vivid in the primary tumor in all patients than flt uptake ( fig .
the median suvmax at diagnosis was 6.9 ( range , 3.914.2 ) for flt - pet and 11.6 ( range , 5.923.2 ) for fdg - pet .
suvs were 1.53.5 times higher for fdg than for flt in 4 patients ; the other two patients only had minor differences between the suvs of the two tracers .
the difference between the medians was not statistically significant ( p  =  0.15 by wilcoxon rank sum test ) , which may be due to the small sample size .
overall , flt accumulation in primary showed significant decrease after chemort both visually and quantitatively . in 4 of the 5 patients who underwent flt pet after chemort , suvmax of flt declined moderately to markedly .
these declines measured 54% ( patient a , from suvmax of 6.9 to 3.2 ) , 70% ( patient d , from 3.9 to 1.2 ) , 81% ( patient b , from 8.7 to 1.7 ) , and 85% ( patient e , from 6.0 to 0.9 ) ( fig .
the remaining patient f was assessed to have complete resolution of all tumors on both ct and flt pet , and therefore suvmax was not measured .
the median age at diagnosis for the six patients was 61  years ( range , 3372 ) .
the five cervical cancers were staged as ib2 ( n  =  1 , 20% ) , iib ( n  =  1 , 20% ) , iiib ( n  =  1 , 20% ) and iva ( n  =  2 , 40% ) and the one vaginal cancer was stage iiib ( n  =  1 ) .
the most common histology was squamous cell carcinoma ( n  =  3 , 50% ) followed by adenocarcinoma ( n  =  2 , 33% ) and clear cell adenosquamous carcinoma ( n  =  1 , 17% ) .
median follow - up time was 24  months ( range , 630 months ) .
all six patients received concurrent weekly chemotherapy ( cisplatin for 5 and carboplatin for 1 ) with radiation therapy ( table 1 ) . all received a total radiation dose of 45 gy in 25 fractions of 1.8 gy to the pelvis and para - aortic nodes .
patient a received an additional 6 gy boost to the right inguinal nodes , and patient b received an additional 10 gy boost to the right iliac nodes .
all patients underwent flt - pet and fdg - pet scanning at diagnosis ; these scans were performed 13  weeks before chemort .
all patients also had post - chemort flt - pet / ct scans before receiving brachytherapy , except patient c due to scanner malfunction ( table 2 ) .
all patients had post - chemort fdg - pet , but are not reported due to diffuse uptake . at last follow - up , five patients were alive and one had died with the most recent mri exam showing significant tumor shrinkage 3-months prior to death but the cause was undeterminable .
two patients with primary cervical cancer were known to have had recurrence : 1 in the vaginal cuff ( patient c ) and 1 with metastatic disease to the lung ( patient d ) .
at diagnosis , fdg uptake was visually more vivid in the primary tumor in all patients than flt uptake ( fig .
the median suvmax at diagnosis was 6.9 ( range , 3.914.2 ) for flt - pet and 11.6 ( range , 5.923.2 ) for fdg - pet .
suvs were 1.53.5 times higher for fdg than for flt in 4 patients ; the other two patients only had minor differences between the suvs of the two tracers .
the difference between the medians was not statistically significant ( p  =  0.15 by wilcoxon rank sum test ) , which may be due to the small sample size .
overall , flt accumulation in primary showed significant decrease after chemort both visually and quantitatively . in 4 of the 5 patients who underwent flt pet after chemort , suvmax of flt declined moderately to markedly .
these declines measured 54% ( patient a , from suvmax of 6.9 to 3.2 ) , 70% ( patient d , from 3.9 to 1.2 ) , 81% ( patient b , from 8.7 to 1.7 ) , and 85% ( patient e , from 6.0 to 0.9 ) ( fig .
the remaining patient f was assessed to have complete resolution of all tumors on both ct and flt pet , and therefore suvmax was not measured .
in this small pilot evaluation of the role of flt - pet in imaging gynecologic tumors , we found that flt uptake in gynecologic cancers before treatment was slightly lower than that of fdg but high enough to be detected and assessed visually and quantitatively .
furthermore , there was a considerable decrease in flt uptake after chemort in all patients who had post - chemort scans , suggesting no significant influence of radiation - induced inflammation on flt uptake .
greatly increased cell proliferation is a characteristic of many malignant lesions and this cancer - specific process has been exploited in tracer imaging .
retention of flt , an analog of thymidine , has been shown to correlate with thymidine uptake and thymidine kinase-1 ( tk1 ) activity in cancer cells ( rasey et al . , 2002 , toyohara et al . , 2002 ) .
the fact that only proliferating cells enable thymidine incorporation in dna synthesis ( as opposed to glucose utilization , which is increased in both malignant tissue and inflammatory tissue ) makes flt imaging a particularly attractive tool when differentiating between residual / recurrent malignancy and inflammation .
flt has previously been shown to be not as significantly affected by post - radiation inflammation and a more specific tracer than fdg when assessing response to radiation therapy , whereas fdg uptake is higher than flt uptake at diagnosis in most tumors ( chen et al . ,
for example , in laryngeal cancers , fdg uptake was higher than flt uptake at diagnosis both visually and quantitatively ( been et al . , 2009 ) .
on the other hand , kishino et al . found on their mid - treatment scans performed after 40 gy of radiation therapy that abnormal flt uptake disappeared in 63% of head - and - neck squamous cell carcinoma lesions whereas fdg uptake disappeared in only 16% of the lesions ; specificity was 72% for flt compared to 19% for fdg .
the specificity of flt - pet ( 80% ) performed after completion of chemoradiation was also higher than that of fdg - pet ( 48% ) .
however , the sensitivities of mid - treatment and post - rt flt - pet scans ( 87.5% and 89% , respectively ) were both lower than those of the equivalent fdg - pet scans ( 100% for both ) ( kishino et al . , 2012 ) .
van waarde et al . found similar results in an animal study ; using an acute - inflammation model in rats , they demonstrated that flt is a more cancer - specific pet tracer than fdg , showing no uptake in inflammatory tissues ( van waarde et al . , 2004 ) .
however , the usefulness of flt imaging in gynecologic cancers has not been evaluated to date in the setting of post - radiation inflammation .
our results show similar trends when compared to those in other malignancies reported in the literature , such as those for laryngeal and head - and - neck cancer cited above ( been et al .
, 2009 , kishino et al . , 2012 , van waarde et al . , 2004 ) .
although there was a visually significant difference between flt and fdg uptake by tumors at diagnosis in 4 of 6 patients , the overall difference in suv did not reach statistical significance , likely due to the small sample size .
also , although our results indicate the feasibility of flt and its potential usefulness in assessing chemort response in gynecologic cancer , exact sensitivity and specificity of post - rt flt - pet / ct will need to be evaluated in future studies .
furthermore , larger samples are needed to confirm the validity of our findings and to determine the diagnostic accuracy of flt in this patient population , with the goal of developing quantitative imaging tools that will provide feasible method for triaging treatment and a reliable measurement of the changes after radiation therapy .
overall , flt uptake in gynecologic cancers was lower than that of fdg at initial diagnosis but was high enough to be detected visually and to be quantifiable in all patients .
flt may be a useful tool when assessing the effects of chemort on gynecologic cancers and for optimizing post - chemort brachytherapy planning .
 objectivethe role of f-18-fluorothymidine ( flt ) pet - ct imaging in the evaluation of gynecologic cancers has not been established . 
 we sought to evaluate ( flt ) pet - ct imaging in gynecologic cancers by comparing standard uptake values ( suvs ) of flt with f-18-fluorodeoxyglucose ( fdg ) pet in the primary tumor at diagnosis , and assess flt uptake immediately following concurrent chemoradiotherapy ( chemort).methodsin this pilot study , patients treated for cervical ( 5 ) or vaginal ( 1 ) cancer underwent flt - pet and fdg - pet scanning at diagnosis ( flt1 and fdg1 ) . 
 five patients ( 4 cervical and 1 vaginal ) also underwent flt - pet within 13 weeks after chemort before brachytherapy ( flt2 ) . 
 wilcoxon rank - sum test was used to compare the flt1 and fdg1 parameters.resultsmedian age at diagnosis was 61-years ( range , 3372 ) . 
 cervical cancers were staged as ib2 ( n  =  1 , 20% ) , iib ( n  =  1 , 20% ) , iiib ( n  =  1 , 20% ) and iva ( n  =  2 , 40% ) and the single vaginal cancer was staged iiib . 
 the most common histology was squamous cell carcinoma ( n  =  3 , 50% ) followed by adenocarcinoma ( n  =  2 , 33% ) and clear - cell adenosquamous carcinoma ( n  =  1 , 17% ) . median tumor suvmax at diagnosis was 7.8 on flt1-pet ( 3.914.2 ) versus 11.6 ( 5.923.2 ) on fdg1-pet ( p  =  0.15 ) . 
 tumor suvmax of flt declined 54%100% after chemort.conclusionthe tumor suv of flt at diagnosis was lower than that of fdg - pet . 
 flt uptake was markedly decreased after chemort . 
 results indicate that there may not be a significant effect of inflammation on flt uptake in gynecologic cancers . 
 flt may be a useful tool when assessing the effects of chemort on gynecologic malignancies and planning for postchemort brachytherapy treatments . 
Introduction
Material and methods
Patients
FLT synthesis
PET/CT acquisition
Statistical analysis
Results
Patient and tumor characteristics
Comparison of FLT and FDG uptake at diagnosis
Changes in FLT uptake after chemoRT
Discussion
Conclusion
Disclosure