Positron emission tomography and pathological evidence of response to neoadjuvant therapy in adenocarcinoma of the esophagus

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1 Diseases of the Esophagus (2008) 21, DOI: /j x Blackwell Publishing Asia Original article Positron emission tomography and pathological evidence of response to neoadjuvant therapy in adenocarcinoma of the esophagus B. M. Smithers, 1,2 G. C. Couper, 1 J. M. Thomas, 1 D. Wong, 5 D. C. Gotley, 1,2 I. Martin, 1,2 J. A. Harvey, 3 D. B. Thomson, 4 E. T. Walpole, 4 N. Watts, 5 B. H. Burmeister 3 1 Upper Gastrointestinal and Soft Tissue Unit, 2 Departments of Surgery, 3 Radiation Oncology and 4 Medical Oncology, University of Queensland, Princess Alexandra Hospital and 5 Southern X-ray, Wesley Private Hospital, Brisbane, Queensland, Australia SUMMARY. Our aim was to determine if fluorodeoxyglucose positron emission tomography (FDG-PET) could be correlated with a pathological response in patients with esophageal adenocarcinoma receiving neoadjuvant chemotherapy and/or chemoradiation therapy. Patients with resectable, histologically proven adenocarcinoma of the esophagus were entered in the study. Preoperative chemotherapy comprised two cycles of cisplatin and 5-fluorouracil. Radiation therapy commenced with the second cycle on day 22. FDG-PET images were obtained pre-treatment and on completion of intended neo-adjuvant treatment. Quantification was achieved by the calculation of both standardized uptake values (SUV) and tumor/liver ratios (TLR). Evidence of histopathological response was identified according to the Mandard tumor regression scoring system. There were 45 patients, 22 receiving neoadjuvant chemotherapy and 23 chemoradiation therapy. Forty patients underwent surgical resection. Seven patients (16%) had a histopathological response. The mean percentage change in SUV in the histological responders group was 56.8% (SD 29) and in the non-responders 27.8% (SD 32.1) (P = 0.035). The mean percentage change in TLR was 49.1% (SD 44.8) in the responders and in the nonresponders 27.3% (SD 31.3) (P = 0.128). There was no difference between the two methods of assessment, however there was less variation with SUV. There was no correlation between the FDG-PET response and the histopathological response. Presently an FDG-PET scan performed 3 6 weeks after neoadjuvant therapy for adenocarcinoma of the esophagus should not be used as a marker of the potential result of the treatment. The optimal timing of a second FDG-PET remains unclear. KEY WORDS: esophageal adenocarcinoma, neoadjuvant therapy, positron emission tomography, tumor response. INTRODUCTION The incidence of adenocarcinomas (AC) of the esophagus is increasing at a rate that outstrips that of all other solid tumors in developed countries. 1 Esophageal carcinomas continue to have a poor prognosis, with overall 5-year survival rates of 9 15%. 2,3 Most patients who present with advanced disease are unsuitable for curative resection. 4 For patients undergoing esophagectomy, 5-year survival rates have improved over the past few decades to around 20%, but this may be attributable to improved patient selection and postoperative care. 5,6 Address correspondence to: Associate Professor B. M. Smithers, Department of Surgery, University of Queensland, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland 4102, Australia. m.smithers@.uq.edu.au The failure to improve survival by surgery alone has led to increasing interest in the role of neoadjuvant therapy. The rational is to treat potential micrometastatic disease while downstaging the primary tumor and increasing the chance of curative resection. Patients who have a significant histopathological response to neoadjuvant therapy have improved survival when compared with patients having surgery alone. 7 Those who do not respond to neoadjuvant therapy have significantly inferior outcomes The largest trial of neoadjuvant chemotherapy in patients with esophageal cancer demonstrated a significant survival advantage at 2 years. 12 A recent meta-analysis of neoadjuvant therapy reported an absolute 2-year survival advantage of 7% with neoadjuvant chemotherapy and 13% with neoadjuvant chemoradiation therapy in patients with esophageal carcinomas, 151

2 152 Diseases of the Esophagus compared to those treated by surgery alone. 13 In these trials the overall results show that the benefit to responders is partially negated by the detrimental effects on non-responders. Detection of response to neoadjuvant therapy may allow continuation of effective treatment in responders and a change of strategy in non-responders. In assessing response the accuracy of computer tomography (CT) scanning is poor, with better results from the use of endoscopic ultrasound, fluorodeoxyglucose positron emission tomography (FDG-PET) scanning, or a combination of both. 14 Squamous cell carcinomas (SCC) and AC of the esophagus characteristically demonstrate a high fluorodeoxyglucose (FDG) uptake The utility of PET in the primary staging of esophageal cancer, particularly in detecting metastatic disease, has been widely reported. 15,18 21 The potential of FDG- PET to detect the response to neoadjuvant therapy in a series of patients with upper gastrointestinal (GI) malignancy was first reported in Subsequent reports on the ability of FDG-PET to identify pathological responders have reached conflicting conclusions However, for patients with SCC of the esophagus there appears to be a correlation between a significant reduction in the FDG- PET uptake in the primary lesion and a significant pathological reduction in the disease. 23,25 27 The method of assessment of the FDG uptake is either the standardized uptake value (SUV) in the primary tumor or a ratio between the maximum SUV in the primary tumor and the maximum value in the liver, that is, the tumor to liver ratio (TLR). 32 The latter has been used to try to overcome the potential issue of the timing of the scan in relation to the injection of the FDG, as there may be a variation in tissue uptake related to the time of injection. It has been postulated that the use of the TLR may potentially overcome this variation. The aim of this study was to determine, in a group of patients with AC of the lower esophagus or gastroesophageal junction, who have had preoperative chemotherapy or chemoradiation therapy, the optimum method of measuring the FDG-PET response, that is, the SUV or TLR, and to assess whether the post-treatment FDG-PET scan would correlate with the pathological response, as assessed following a complete resection of the disease. METHODS From 2002 to 2005 there have been 45 patients with a biopsy-proven AC of the esophagus or esophagogastric junction who were considered fit for a complete resection of the disease and had a FDG-PET scan prior to and following neoadjuvant therapy. These were entered into the study. Patients with junctional tumors with greater than a 2-cm extension into the gastric cardia (Seiwert type III) were excluded. All patients were assessed by members of a multidisciplinary upper GI oncology clinic and were staged preoperatively using endoscopy, CT and FDG-PET imaging. Endoscopy and the FDG-PET scan were repeated 3 6 weeks after completion of the neoadjuvant treatment. A laparoscopy was used selectively for tumors at the esophagogastric junction. None of the patients had previously been treated for esophageal carcinoma or received previous therapy for a major cancer. Neoadjuvant therapy Most patients receiving neoadjuvant therapy were part of a randomized trial comparing preoperative chemotherapy and preoperative chemoradiation therapy. Patients not consenting to be part of the trial were offered preoperative chemotherapy or surgery alone. The preoperative chemotherapy comprised cisplatin (80 mg/m 2 i.v. on days 1 and 22) and 5- fluorouracil (1000 mg/m 2 /day i.v. on days 1 4, 22 26). The patients receiving chemoradiation therapy had the first cycle of cisplatin and 5-flurouracil with the doses mentioned above, commencing on day 1. The concurrent radiation therapy commenced on day 22 with the second cycle of chemotherapy and consisted of 35 Gy in 15 fractions over the following 3 weeks. The dose of cisplatin was the same as the first cycle but the dose of 5-fluorouracil was reduced to 800 mg/m 2 /day with delivery on days in this group of patients. PET studies The PET studies were all performed in a single center using a Philips Allegro GSO dedicated PET scanner (Philips Medical Systems, Best, The Netherlands BV). Following a 6-h fast, patients were imaged 45 min after Mq of 18F-FDG. Whole body transmission scanning was performed and attenuation-corrected images were produced by iterative reconstructed using 3D row action maximum likelihood algorithm. A radiologist (DW) experienced in nuclear medicine reviewed all FDG- PET images. Quantification of PET images was performed by the calculation of both SUV and TLR to enable identification of changes in FDG uptake. The maximal voxel activity in the tumor was used for both methods of quantification. To obtain the TLR the maximal SUV for the tumor and the liver were measured. The resection was performed 4 to 6 weeks after the completion of the neoadjuvant therapy. It was planned that the FDG-PET scan was performed within a week of the scheduled surgery. Patients had either a two-phase esophagogastrectomy

3 Assessment of response to neoadjuvant therapy 153 Table 1 Mandard classification of tumor regression grade (TRG) after preoperative chemoradiation therapy in oesophageal tumors 27 TRG 1 TRG 2 TRG 3 TRG 4 TRG 5 Absence of residual cancer with fibrosis extending through different layers of oesophageal wall Rare residual cancer cells scattered through fibrosis An increase in the number of residual cancer cells but fibrosis predominates Residual cancer cells outgrowing fibrosis Absence of regressive changes with abdominal and thoracic approaches or a thoracoscopic-assisted three-phase resection with a cervical anastomosis. A resection of the primary lesion was performed, and surrounding tissue along with the lymphatic tissue around the celiac axis, inferior mediastinum and subcarinal region was removed. Evidence of histopathological response in the resected specimen was measured according to the Mandard tumor regression grade (TRG) scoring system (Table 1). 33 Patients with a Mandard TRG score of 1 or 2, that is, absence of residual cancer or only rare residual cells scattered through fibrosis, were considered to have had a significant response. Those with scores between 3 and 5 were considered non-responders. This assessment was made from the histology report and in consultation with the reporting pathologist when it was considered the patients had had a significant response. The response of the FDG-PET to the therapy was measured in absolute terms and as a percentage reduction in SUV and TLR. In correlating the histological response to the FDG-PET response an analysis was made assessing reductions of greater than 50% as a point of analysis, as this was one level used in reports previously, 23,25 and our mean reduction in SUV was 50%. Statistical analysis was performed with SPSS software (SPSS, Chicago, IL, USA). PET and histological evidence of response were compared using the Mann Whitney test. Methods of PET scan quantification were compared by Spearman s rank correlation (r). RESULTS Of the 45 patients included in this study, 22 received neoadjuvant chemotherapy and 23 received neoadjuvant chemoradiation therapy. Forty patients underwent a curative resection. Four patients, two from each group, had unresectable disease on restaging or at laparoscopy/laparotomy. Two patients had peritoneal disease on laparoscopy and one patient had peritoneal involvement at laparotomy for the intended resection. One patient had a new liver lesion on the post-therapy FDG-PET scan which was Fig. 1 Correlation of percentage change in standardized uptake values (SUV) and tumor/liver ratios (TLR) (n = 21). Spearman s rank correlation r = (P < ). confirmed as a metastasis by its appearance on a repeated abdominal CT scan. One patient developed cardiac ischemia whilst on chemotherapy and was deemed unfit to undergo a resection. The median time from completion of therapy to the second FDG-PET scan was 24 days (range 15 46) in the chemotherapy group and 32 days (range 21 42) in the chemoradiation therapy group. The median time from the PET scan to surgery was 4 days (range 2 32) in the chemotherapy group and 4.5 days (range 1 39) in the chemoradiation therapy group. The preoperative Spearman s rank correlation between SUV and TLR comparing percentage changes in FDG activity for quantification purposes was r = (P < , two-tailed) (Fig. 1). This close correlation was also the case for the posttherapy assessments (data not shown) confirming equivalence for either method of assessment. The analysis of the FDG uptake pre- and post-therapy was available for the 40 patients who underwent an FDG-PET scan pre- and post-therapy and who had undergone a resection (Table 2). This includes the assessment using both SUV alone and the TLR assessment. Histologically, one patient (5%) in the chemotherapy group had a significant tumor response (TRG 2) to the preoperative therapy and in the chemoradiation therapy patients a significant histopathological response (TRG 1 or 2) was assessed to have occurred in six patients (30%). Two patients had a complete pathological response (10%). Five of the 13 patients (38%) who had an SUV reduction greater than 50% were amongst the histological responders. Table 3 shows the percentage change in SUV and TLR for the responders and the non-responders. In the whole group of patients following resection,

4 154 Diseases of the Esophagus Table 2 Characteristics of patients pre- and post-therapy with histological response Patient number SUV baseline SUV posttherapy SUV % change TLR baseline TLR posttherapy TLR % change Histopathological response (TRG) Chemotherapy Chemoradiation therapy SUV, standardized uptake values; TLR, tumor/liver ratios; TRG, tumor regression grade. the mean percentage change in SUV in the significantly responding group was 56.8% (SD 29) and 27.9% (SD 32.1) in the non-responders group (P = 0.03). The mean percentage change in TLR was 49.8% (SD 44.8) in the responders and 27.3% (SD 31.3) in the non-responders (P = 0.128). When examined for each treatment modality (Table 4) the results using SUV and TLR were similar, with no difference between the reductions in response for the group who had chemoradiation therapy. In the chemotherapy group, where there was only one responder, there was a trend to a difference in SUV and a significant change in TLR. There was no difference between the reductions when the chemotherapy and chemoradiation therapy groups were compared whether there was a response or not. In the chemotherapy group there was an overall mean SUV reduction in the post-therapy FDG-PET of 24.2% (SD 36.4) with an absolute reduction in 15 patients (75%) by an average of 41.5% (SD 21), with five patients being more than 50%. The overall TLR was reduced by 23.2% (SD 33.2) with an absolute reduction in 13 patients by an average of 43.8% (SD 19.1) with five patients by more than 50%. In the chemoradiation therapy group there was an overall mean SUV reduction in the post-therapy FDG-PET of 41.6% (SD 27.8) with an absolute reduction in 19 patients (95%) by an average reduction of 45.1% (SD 23.6) and eight patients had a reduction of more than 50%. The overall TLR was reduced by 38.9% (SD 34.6) with an absolute reduction in 17 patients by an average of 40% (SD 24.4) with 10 patients having a reduction of more than 50%. Despite the similar percentage reduction using SUV or TLR, in the whole group, there were four patients where the change was negative using one

5 Assessment of response to neoadjuvant therapy 155 Table 3 Comparison of changes in fluorodeoxyglucose (FDG) activity in pathological responders and non-responders Pathological non-responders (TRG 3 5) Pathological responders (TRG 1 2) Patient no. Change in SUV (%) Change in TLR (%) Patient no. Change in SUV (%) Change in TLR (%) Mean 27.9 (SD 32.1) 27.3 (SD 31.3) 56.8 (SD 29) 49.8 (SD 44.8) SD, standard deviation; UV, standardized uptake values; TLR, tumor/liver ratios. Table 4 Mean percentage reduction of FDG uptake comparing neoadjuvant therapy and histological response Responders % (SD) Non-responders % (SD) P value Chemoradiation therapy SUV 52.1 (28.8) 37.0 (27.1) TLR 42.8 (45.6) 37.3 (30.2) Chemotherapy SUV (34.4) 0.09 TLR (30.5) 0.05 No standard deviation because only one patient. SD = Standard deviation. SUV, standardized uptake values; TLR, tumor/liver ratios. and positive in the other, with one patient who had a significant response, having a rise in the TLR in the post-therapy scan. Overall, two of the 27 non-responders (7%) also had a reduction of > 50%. This difference was statistically significant (P = 0.027). Five of the patients who had a TLR reduction greater than 50% had a histological response and there was one who had an increase in the TLR but was a TRG grade 2 responder. When a response greater than a 50% reduction in the uptake of FDG-PET was assessed separately in the chemotherapy and chemoradiation groups there was no significant difference in SUV reduction between the responders and the non-responders. When assessing the sensitivity and specificity of a reduction in FDG-PET uptake greater than 50% to predict a significant response, there was little to separate SUV from TLR. For patients having chemotherapy, sensitivity and specificity for SUV and TLR were the same, being 100% and 79%, respectively. For patients who had chemoradiation therapy, sensitivity and specificity for SUV was 66.7% and 71%, respectively, and for TLR, 66.7% and 57%, respectively. DISCUSSION With respect to the assessment of FDG uptake, we have confirmed a previous report 22 that there appears

6 156 Diseases of the Esophagus to be no benefit in using the TLR over the more simply attained SUV when assessing the FDG-PET measurements for an AC in the baseline scan. When assessing the response to neoadjuvant therapy we have also shown there is no benefit in using the TLR to assess FDG-PET uptake over SUV when the second scan is performed 3 6 weeks after completing neoadjuvant therapy. There was one patient where the change in the TLR was misleading with respect to the histological response. The overall pathological response rates reported for our group of patients having neoadjuvant therapy prior to esophageal resection for AC are low, using the Mandard definition. The chemotherapy regimen was based on the UK s Medical Research Council trial, which reported a survival benefit for patients with both AC and SCC. 12 When a similar regimen has been used in trials of patients with SCC of the esophagus, pathological response rates of 40 50% have been reported The lack of a significant response (TRG 1 or 2) in our group of patients with AC suggests that primary AC of the esophagus may not be as responsive to the neoadjuvant chemotherapy that is presently used for this disease. For patients who had chemoradiation therapy, the pathological complete response rate of 5% in this series was similar to that reported in a recent multi-centered study of neoadjuvant chemoradiation therapy where patients received a single cycle of the same drugs and the same radiation dose. 34 If we include patients who have had a significant reduction in disease (TRG 2) with the complete histopathologic responders (TRG 1) our response rate was 45%. Thus, in our group of patients, radiation therapy was the dominant factor in producing a significant local pathological response. That the response rate may be increased with higher doses of radiation is supported by complete response rates of up to 25% being reported in trials using doses up to 40 Gy, 35,36 and other studies assessing FDG-PET response where higher radiation doses were used ,37 Despite the low histological response rates in the whole series, a significant difference existed between the mean percentage reduction in the SUV in the pathological responders compared with the nonresponders. When our two treatment regimens were examined separately there was a significant difference in TLR and a trend with SUV in the preoperative chemotherapy group. However with only one responder in the neoadjuvant chemotherapy group, few conclusions can be drawn from this. In the chemoradiation therapy group there was no difference between the groups. The influence of the small numbers and the low histological response rate is uncertain. In other studies with a predominance of AC, assessing response to chemoradiation with higher doses of radiation than we used all showed a significant reduction in FDG uptake, but there was no association between the percentage FDG-PET response reduction and the histological response The ranges within the responder and nonresponder groups were large and did not enable analysis of a cut-off to be determined to allow an accurate prediction of response. This problem has been shown in previous studies where the FDG reduction cut-off of 50%, 25 52%, 23 60% 27 and 35% 24 were used. In assessing the response to chemoradiation therapy in patients with esophageal SCC, a cut-off of > 52% FDG reduction has been reported to predict response. 23 However in that study, they showed a wide range of FDG reductions occurring within both the responder and non-responder groups. When we assessed SUV reduction > 50% in the total group of patients with AC, we did reveal a difference between the histopathologic responders and the non-responders. This did not occur when the two treatment regimens were analyzed separately. There has been a study where the major response was classified as a reduction of the TLR of greater than 80%. 26 This group had a mixed population of patients with SCC (27 patients) and AC (nine patients), who had a similar chemotherapy regimen to our group of patients but had concurrent radiation to 40 Gy. The FDG-PET scan was performed 4 5 weeks following the completion of the neoadjuvant therapy. A major histological response occurred in 44% of the patients with SCC and in 22% of the AC group. Using the TLR they reported the sensitivity of a serial FDG-PET to confirm a major histological response was 71% and the specificity 82%. There was no difference in the accuracy of the scans assessment of the histologic response for patients with AC (67%) compared those with with SCC (81%). In this study a TLR reduction greater than 80% occurred in 71% of the major histologic responders and in 18% of the-non-responders, with no difference relating to histologic type. In our study with a focus on patients with AC, using the TLR to assess FDG- PET response in the patients who had chemoradiation therapy, there was one patient with a reduction greater than 80% in the histological responder group (16.7%) and one in the non-responder group (7%). The different outcome between the studies may relate to the dose of radiation therapy because the chemotherapy regimen and the timing of the serial scans were similar. We do not have enough patients in this study to draw conclusions about the relevant reduction that may give clinically valuable information. Reductions between 52% and 80% may be of value, but larger studies assessing AC are required to determine whether the use of percentage reduction of FDG uptake is a reproducible method to assess FDG uptake. Others have correlated a positive pathological response with a high metabolic response of the

7 Assessment of response to neoadjuvant therapy 157 initial FDG-PET scan. 28,31 The levels of measured SUV were different in one study presumably due to the scan correcting for lean body mass. 31 However, the opposite was found in a larger study with non-responders having a high initial scan and the conclusion was that patients with an initial SUV greater than four were likely to be non-responders. 29 These different results confirm the lack of standardization of interpretation of SUV reduction in association with the spectrum of disease, different methods of therapy and timing of evaluation of therapy. 14 If there is to be relevant clinical information from serial FDG-PET scans after neoadjuvant therapy the optimal timing of the follow-up scan needs to be determined. Forastiere et al. 38 have suggested that the full effect of therapy may not occur until 12 weeks following the completion of treatment, the hypothesis being that a significant delay may be required to utilize the full potential of the post-therapy scan. We performed the FDG- PET scan later in the chemoradiation group than in the chemotherapy group to minimize the acute effects of radiation. It is possible that in both of our treatment regimens, the maximum PET response may occur much later than the 3 6 week interval that we chose and that the cessation of biological activity from an AC may be much slower than previously thought. If a FDG-PET scan delayed beyond 6 weeks was confirmed to be optimal, the clinical value would be limited, as presently a resection is generally recommended to occur within 4 to 6 weeks after completion of the treatment, as occurred in our study and with most other groups. There is a report suggesting response may be predicted 14 days after commencing the neoadjuvant chemoradiation therapy in patients with SCC. 39 Further supporting this hypothesis, using a cut-off of > 35% reduction in FDG as an indicator of response, Weber et al. reported a sensitivity of 93% and a specificity of 95% in 40 patients with AC of the esophagogastric junction undergoing chemotherapy. 24 FDG-PET images were performed pre-treatment and at 14 days after commencement of treatment, in contrast to the preoperative FDG-PET performed some weeks after the conclusion of the treatment in the current study. Thus the timing of the scan may be critical, with earlier scans during therapy providing a clinical guide in patients with AC. In conclusion, there was no advantage in using TLR over SUV to assess the FDG uptake either prior to or after receiving neoadjuvant therapy in this group of patients with AC when the scans were performed 3 6 weeks after neoadjuvant therapy. In contrast to the reports of patients with SCC of the esophagus, we have not shown a robust correlation between the histopathological response and the reduction in FDG-PET response in patients with AC of the esophagus. This correlation did exist for the whole group that received neoadjuvant therapy, but not when the different treatment regimens were assessed. However, in common with previous studies, the limited numbers hamper definitive conclusions. A clear need exists for closer cooperation among interested units, allowing standardization of imaging protocols and quantification methods and timing of scans to determine optimal cut-off values. Presently, for AC of the esophagus major treatment decisions should not be made in relation to the FDG-PET scan response at the primary lesion from scans performed 3 6 weeks after preoperative therapy. 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