| Part OnePre-treatment 18F-FDG PET/CT Helps Identify patients with Esophageal Cancer at High Risk of Local FailureEsophageal cancer(EC)is the eighth most common cause of cancer and the sixth leading cause of cancer related mortality over the world.Esophageal squamous cell carcinoma(ESCC)still accounts for more than 90%of esophageal cancers in China.Definitive chemoradiotherapy(DCRT)was the standard therapy for inoperable patients.Despite advances in chemotherapy and radiotherapy,the clinical outcome of these patients remains extremely poor,with a local failure rate as high as nearly 50%and a 2-y OS rate of only 30%-40%.A rationale way to solve this is to find patients with a high likelihood of failure.For these patients seclectiv personalized treatment should be adopted.18F-deoxyglucose posiuron emission tomography/computed tomography(18F-FDG PET/CT)provides additional information on the pathophysiological and biological characteristics of a tumor,as a result,may lead to a better assessment of the variability of tumor cell radio-resistant.18F-FDG PET/CT has played an important role in the staging,response assessment,outcome prediction and even radiotherapy planning in EC.But there was rarely study using 18F-FDG PET/CT to identify patients with high risk of local failure.PurposeThe aim of this study was to evaluate the prognostic significance of some metabolic parameters measured by 18F-FDG PET/CT in ESCC patients treated with DCRT and to determine whether 18F-FDG PET parameters can predict local failure in ESCC patients treated with DCRT.Methods1.PatientsWe retrospectively reviewed the medical records of all patients with histologically or cytologically proven ESCC who underwent pre-treatment 18F-FDG PET/CT scanning at our hospital between September 2010 and February 2013.2.TreatmentAll patients had been treated with definitive radiotherapy.Radiation treatments were to be delivered as three-dimensional conformal radiotherapy(3D-CRT)or Intensity Modulated Radiation Therapy(IMRT).The gross tumor volume(GTV)was delineated on the planning CT using all available resources,including endoscopy,conrtrast-enhanced diagnostic CT and PET/CT.The clinical tumor volume(CTV)was defined by adding to the GTV a 3.0-5.0 cm margin superior and inferior,0.8-1.0 cm margin radial and plus the regional draining lymphatics.A 5 mm margin was added in each plane to generate a planning target volume(PTV).Platinum-based chemotherapy was administered to 82 patients.Ten patients received radiotherapy only.Thirty-four patients received concurrent chemotherapy.Fifty patients received Sequential chemoradiotherapy.3.18F-FDG PET/CT imagingAll patients received 18F-FDG PET/CT before treatment.SUVmax was defined the as the maximum SUV.The metabolic tumor volume(MTV)was defined as the volume of hyper-metabolic tissue with an SUV greater than a defined threshold of 2.5.Total lesion glycolysis(TLG)was calculated by multiplying the selected PET volume by the average SUV within that volume.4.Follow upAfter completion of treatment,patients were evaluated with CT seans every 3 months for first year,every 6 month in the following year,and yearly thereafter.OS was defined as the time interval from the date of 18F-FDG PET/CT scanning to the date of death from any cause.LFFS was defined as the time interval from the date of18F-FDG PET/CT scanning to the date of first local disease progression or death from any cause without previous progression.5.Statistical analysisWe used SPSS statistical software,version 17.0,for statistical analyses.Probability values of<0.05 were considered to be statistically significant.Results1.SurvivalThe estimated median OS for the entire cohort was 23.8 months(95%CI,15.0-32.6 months),with 1-year survival of 89.0%,2-year survival of 50.0%and 3-year survival of 34.8%.2.Failure pattern and local controlForty-two patients(45.7%)had local failure in primary tumor during the observation period,33 patients(35.8%)experience distant metastasis.Of the 33 patients with distant metastasis,21 patients(22.8%)had failure without local failure and 12 patients(13.0%)had failure in both primary tumor and distant.Twenty-nine patients(31.5%)had no evidence of treatament failure at last follow-up.The 1-year,2-year and 3-year LFFS was 80%,58.7%and 35.2%respectively.3.PET metabolic parameters and survivalPre-treatment MTV and TLG of primary tumor were significant predictors of OS(p=0.033 and p=0.022 respectively)and LFFS(p=0.035 and p=0.011 respectively).SUVmax was not a significant predictor for OS and LFFS(p=0.095 and p=0.052).Multivariate Cox proportional hazards models showed that MTV,TLG and lymph node metastasis were significant predictors for OS.MTV,TLG,T4 stage and tumor length were were significant predictors LFFS.4.Subgroup analysis by MTV and TLGTo evaluate the optimal cutoff value of tumor length,SUVmax,MTV and TLG for predicting local failure,we employed the ROC and the AUC as the criterion.AUC of tumor length,SUVmax,MTV and TLG are 0.608(p = 0.076),0.597(p = 0.111),0.648(p = 0.015)and 0.701(p = 0.001)respectively.The optimal cut-off values for MTV and TLG are 19.1 cm3 and 130,respectively.Patients within low MTV group had significantly better 3-year LFFS(59.6%vs.11.6%,p = 0.036)and 3-year OS rate(49.6%vs.29.1%,p = 0.013)than patients within high MTV group.Patients within low TLG group(TLG<130)had significantly better 3-year LFFS rate(57.8%%vs.16.4%,p = 0.002)and 3-year OS rate(50.0%vs.27.7%,p = 0.024).ConclusionsPre-treatment 18F-FDG PET/CT metabolic parameters MTV and TLG are valuable tools for predicting OS and LFFS in ESCC patients treated with DCRT.Patients with high MTV and TLG were with high risk of local failure.For these patients,more aggressive treatment should be taken.Part Two18F-FDG PET/CT Predicts Regions with High Risk of Local Failure in Esophageal Squamous Cell Carcinoma Treated with Concurrent ChemoradiotherapyWe have previously proved that 18F-FDG PET/CT can be used to predit patients with high risk of local failure in ESCC.The most commonly used strategy to improve local control is escalating the radiation dose.However,RTOG 94-05 showed that increasing the radiation dose to 64.8Gy did not improve local-regional control or survival.One possible explanation is that inappropriate dose escalation to a large volume using a 2-dimensional radiotherapy may have contributed to increased morbidity.This is the main reason for a significant prolongation of treatment time and treatament breaks in high radiation dose group in the trail.A rationale way to solve this is to escalate the dose selectively to the regions with a high likelihood of failure by intensity modulated radiotherapy(IMRT),which has the ability to dose paint different regions within the target while limiting the radiation dose delivered to the normal tissues.Up to day,it is important and challenging to identify the regions with high risk of local failure.PurposeTo determine whether pre-treatment 18F-FDG PET can identify regions with high risk of local failure in ESCC patients treated with concurrent chemoradiotherapy(CCRT).Methods1.PatientsA total of 56 patients with locally advanced ESCC at our hospital between June 2010 and February 2012 were prospectively enrolled for this study.All patients underwent a baseline,8F-FDG PET/CT scan and had PET-positive tumor.Other eligibility criteria were good performance status ECOG score<1)and adequate hematologic,hepatic and renal function.Exclusion criteria included the presence of multiple primary esophageal lesions or other malignancies,and previous treatment with chest radiotherapy,systemic chemotherapy,targeted therapy,or esophageal surgery.Pretreatment evaluation included physical examination,complete blood count,biochemistry surveys of liver and kidney function,electrocardiography,chest radiography,barium esophagography,esophagogastroscopy with tumor biopsy,endoscopic ultrasonography(EUS),ultrasound evaluation of the neck and abdomen and pulmonary function testing.Patients were considered treatment failure if pathologically proven or documented radiographically though serial progression.When patients were considered failure,a failure 18F-FDG PET/CT was required.2.TreatmentAll patients had been treated with CCRT.Radiation treatments were to be delivered as 3D-CRT.The GTV was defined as any visible esophageal lesion.The lymph nodes over 1.0 cm in the short axis or 1.5 cm in the long axis on CT scan or with a high FDG uptake on PET images were considered to be metastatic.The CTV was defined as the GTV plus a 3.0 cm margin superior and inferior to the primary tumor and a 1.0 cm radial margin plus the regional draining lymphatics,depending on the primary tumor location.A 5 mm margin was added in each plane to generate a PTV.Radiation therapy was administered once daily for 5 days per week for 28 fractions for a total dose of 50.4 Gy in 1.8 Gy fractions.The primary tumor received a cone down of 9.0 Gy to a total dose of 59.4 Gy.The intent of the cone down was to treat the primary tumor only,not the regional primary lymph nodes.The superior and inferior borders of the field were decreased to 2 cm beyond the tumor.The lateral anterior and posterior borders were the same as the initial target volume.Patients received two cycles of concurrent chemotherapy with 75 mg/m2 of cisplatin administered on days 1 and 29 and 700 mg/m2 of 5-FU administered as a continuous intravenous infusion for 96 hours on days 1 to 4 and 29 to 32.3.18F-FDG PET/CT imagingAll patients fasted for at least 6 h before the examination,and blood glucose level was recorded before injection of 5.50 MBq/kg of 18F-FDG.The simulation images were acquired 60 minutes after injection.Scanning was performed in whole-body mode from head to thigh for 5 minutes per field of view,each covering 14.5 cm,at an axial sampling thickness of 4.25 mm per slice.Unenhanced CT scan was performed with an x-ray tube voltage peak of 120 kV,90 mA,a 6:1 pitch,a slice thickness of 4.25 mm,and a rotational speed of 0.8 s per rotation..Both PET and CT scans were performed with patients under normal shallow respiration.PET data sets were reconstructed iteratively using CT data for attenuation correction.The PET images,CT images,and fused PET/CT images displayed as coronal,sagittal,and transaxial slices were viewed on the Philips extended brilliance workspace.To better analyze the PET/CT scans quantitatively,some parameters were used.Standardized uptake value(SUV)was corrected for injected dose of ’8F-FDG and patient body weight.SUVmax was defined as the maximum SUV.The metabolic tumor volume(MTV)was defined as the volume of hyper-metabolic tissue with an SUV greater than a defined treshold of 2.5.Total lesion glycolysis(TLG)was calculated by multiplying the selected PET volume by the average SUV within that volume.4.High risk regions for local failureUsing an automatic rigid registration algorithm based on mutual information of the CT scans,the images of failure scans were fused to the pre-treatment scans on the Philips extended brilliance workspace.If the automatic registration showed a large deformation between the two CT scans,the images were manually registered on the surrounding anatomy of the tumor.By fusing these post-treatment PET/CT scans with the pretreatment PET/CT ones we farther classified local failure as in pre-treatment high uptake regions and out of high uptake regions.Overlap fraction(OF)of the primary tumor was calculated.The OF was defined as the volume of overlap divided by the smallest volume.On pre-treatment 18F-FDG PET/CT,the baseline subvolumes were delineated using a relative threshold method(40,50,60 and 70%of primary tumor SUVmax)as MTV40%,MTV50%,MTV 60%and MTV70%respectively.On failure 18F-FDG PET/CT,threshold of SUV 2.5 was used to delineate the local failure volume.5.Follow upWithin 28-45 days after the completion of all therapy,patients were examined(including barium swallow and thoracic and abdomen CT scan).The following were performed until the time of treatment failure every 3 months for the first year,every 6 months during the next 3 years then annually.For patients with treatment failure,a 18F-FDG PET/CT is required before any salvage treatment.6.Statistics analysisWe used SPSS statistical software,version 17.0(SPSS Inc.,Chicago,IL,USA),for statistical analysis.The survival rate and high uptake region failure free rate were estimated using the Kaplan-Meier method.The difference between groups was tested for significance using the log rank test.For the Kaplan-Meier calculations,patients were censored at the time of last follow-up(or death).Univariate and multivariate Cox proportional hazards models were fit to evaluate potential associations between OS rate,high uptake region failure free survival rate with clinical factors.Receiver operator curves(ROC)were determined to assess the area under curve(AUC)and the optimal cutoff value for predicting failure in pre-treatment high uptake regions.Results1.SurvivalThe estimated median OS for the entire cohort was 26 months(95%CI,18.0-33.9 months),with 1-year survival of 80.4%,2-year survival 54.8%and 3-year survival 34.5%.2.Failure pattern and local controlTwenty-one patients(40.4%)had local failure in primary tumor during the observation period,14 patients(26.9%)experience distant metastasis.Twenty-one patients(40.4%)had no evidence of disease at last follow-up.Of the 21 patients with local failure in primary tumor,14 patients had persistent local disease and 7 patients experience local recurrence.3.18F-FDG PET/CT to identify regions with high risk of local failureFor all patients with local failure in primary tumor,20 patients(95.2%)had failure in the pretreatment high uptake regions and only 1 patient(4.8%)had failure in the esophageal but out of the pretreatment high uptake regions.The high FDG uptake volumes(40-70%SUVmax)on the pre-treatment PET/CT scans were compared to the MTV measured by the threshold of SUV 2.5.The MTV 40%of the local failure patients was 23.09 ± 16.25cm3(71.2%of MTV).The MTV50%,MTV60%and MTV70%was 19.65 ± 11.32cm3(60.6%of MTV),11.34 ± 7.28cm3(34.9%of MTV)and 8.12 ± 4.85cm3(25.0%of MTV)respectively.We correlated volumes of FDG uptake region measured by different threshold(40-70%SUVmax)on pre-treatment PET/CT with the high uptake region measured by SUV 2.5 on the failure PET/CT to calculate the OF.The local-failure areas(with threshold of SUV 2.5)were transposed to the pre-treatment scans.The OF for MTV40%,MTV50%,MTV60%and MTV70%were 78.6 ± 21.7%,66.3 ± 22.4%,54.5 ± 24.2%and 42.8 ± 25.7%,respectively.4.Subgroup analysis by MTV and TLGTumor length(p=0.029),T stage(p = 0.036),pre-treatment MTV(p = 0.007)and TLG(p = 0.006)of primary tumor were significant predictors of high uptake region failure.Multivariate Cox proportional hazards models showed that MTV,TLG and tumor length were significant predictors for high uptake region failure.We employed the ROC to evaluate the optimal cutoff value of tumor length,MTV and TLG for predicting failure in pre-treatment high uptake regions.Area under the curve of tumor length,MTV and TLG are 0.584(p = 0.305),0.743(p = 0.003)and 0.747(p＝0.003)respectively.The optimal cut-off values for MTV and TLG are 21 cm3 and 95,respectively.Patients(n = 36)with MTV<21cm3 had significantly better 2-year high uptake regions failure free survival rate(77.9%vs.50.1%,p = 0.004)and OS rate(70.8%vs.40.7%,p = 0.006)than patients(n = 16)with MTV>21cm3.Patients(n = 19)with TLG<95 had significantly better 2-year high uptake regions failure free survival rate(83.6%vs.47.4%,p 0.007)and OS rate(68.4%vs.46.9%,p = 0.038)than the patients(n = 32)with TLG>95.ConclusionsPre-treatment 18F-FDG PET/CT is valuable for indentifying regions with high risk of local failure for ESCC patients treated with DCRT.50%SUVmax may be a potential threshold for escalated radiation dose. |
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