Journal of Thoracic Oncology:
Predictive Value of Initial PET-SUVmax in Patients with Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma
Rizk, Nabil P. MD; Tang, Laura MD, PhD; Adusumilli, Prasad S. MD; Bains, Manjit S. MD; Akhurst, Timothy J. MD; Ilson, David MD, PhD; Goodman, Karyn MD; Rusch, Valerie W. MD
Memorial Sloan-Kettering Cancer Center, New York City, New York.
Disclosure: The authors declare no conflicts of interest.
Address for correspondence: Nabil P. Rizk, MD, Memorial Sloan-Kettering Cancer Center, New York City, NY 10021. E-mail: firstname.lastname@example.org
Introduction: We have previously shown that in early clinical stage esophageal adenocarcinoma, a positron emission tomography standardized uptake values (PET SUVmax) of <4.5 is associated with earlier pathologic stage and predicts better survival. In this study, we analyze the impact of the pretreatment PET SUVmax in patients with locally advanced esophageal adenocarcinoma who undergo preoperative chemoradiotherapy.
Methods: We performed a retrospective analysis, selecting patients with adenocarcinoma of the esophagus who had a pretreatment PET scan and who received chemoradiotherapy before esophagectomy. Data recorded included demographics, PET SUVmax, treatment details, pathologic details, and survival data. Comparison of categorical variables was done by χ2 analysis, continuous variables by t test, survival analysis by the Kaplan-Meier method, and comparisons of survival using the log-rank test.
Results: Between January 1996 and September 2007, 189 patients were appropriate for this analysis. The initial PET SUVmax was <4.5 in 28 patients and ≥4.5 in 161 patients. The two groups were similar with regards to demographics and treatment details. Patients in the low SUV group were less likely to show evidence of treatment response after chemoradiotherapy, including a higher likelihood of residual nodal disease and a lower likelihood of a pathologic complete response and estimated treatment response. However, both groups had similar survival.
Conclusions: Although the initial PET SUVmax does not predict survival in patients with locally advanced esophageal adenocarcinoma who receive preoperative chemoradiotherapy, patients with a high initial SUVmax respond better to preoperative therapy. These results can be used to better select esophageal cancer patients for combined modality treatment.
Positron emission tomography (PET) using [18F]-fluorodeoxyglucose is commonly used in the workup of patients with esophageal cancer. The most established indication for its use is to determine the presence of otherwise undetected metastatic disease.1 Other indications include monitoring response to induction chemotherapy,2,3 postneoadjuvant chemoradiotherapy prognostication, and staging.4–6 We recently published our results on an additional use of PET scan in surgically treated patients with esophageal cancer, namely to identify early clinical stage patients who might be at a higher risk for a poor prognosis.7 In that study, we showed that using a maximal standardized uptake values (SUV) of 4.5 (the median SUVmax of the study group) in patients with adenocarcinoma of the distal esophagus and gastroesophageal (GE) junction segregated patients into high-risk and low-risk groups, independent of clinical and pathologic stage.7 In this current study, we investigated whether a SUVmax greater or less than 4.5 could also stratify prognostically patients with locally advanced adenocarcinoma and GE junction adenocarcinoma who receive preoperative chemoradiotherapy.
We reviewed the medical records of all patients identified in a database maintained by the Thoracic Surgery Service who underwent an esophagogastrectomy for adenocarcinoma of the distal esophagus or gastroesophageal junction (Siewert types 1 and 2) between January 1996 and September 2007. January 1996 was the date when an institutional electronic medical record system was initiated and therefore represents the date at which highly reliable information became available. Patients were eligible for inclusion in the study if they had histologically proven adenocarcinoma of the distal esophagus and gastroesophageal junction, and if they underwent planned preoperative treatment with chemoradiotherapy. The indication to receive preoperative therapy was clinical evidence of locally advanced disease (American Joint Committee on Cancer stage II–IVa), confirmed by computed tomography (CT), PET scan, or an endoscopic ultrasound (EUS) T3 or N1 lesion. When gross full thickness involvement of the esophageal wall was evident by CT, patients did not always undergo a confirmatory EUS. All patients had a PET scan performed with an SUVmax reported before the initiation of chemoradiotherapy. Using our previously published cutoff, patients with an SUVmax <4.5 were termed “low SUV,” and patients with an SUVmax ≥4.5 were termed “high SUV.” All patients must have survived their perioperative course and received adequate follow-up for survival analysis. The data collected included patient demographics, PET scan data (including the primary tumor SUV as well evidence of Fluorodeoxyglucose [FDG] avid lymph nodes), CT scan evidence of adenopathy, EUS assessment of primary tumor T and N stages (morphologic assessment by endoscopist), and preoperative treatment details (chemotherapy type, radiation dose, time from completion of radiation to surgery). Additional data collected included pathologic findings, nodal status, estimated percent treatment response, pathologic complete response (pCR, defined as no residual local or nodal disease), and survival. All pathologic data were reviewed by a single pathologist (LT). This review was performed after approval had been obtained from the Memorial Sloan-Kettering Cancer Center Institutional Review Board and in accordance with an assurance filed with and approved by the Department of Health and Human Services.
Technique of 18FDG Whole-Body PET
Over 80% of the PET scans were done at two facilities and were documented as performed on a dedicated conventional full ring high resolution dedicated position emission tomographs, with either the GE Advance (GEMS Milwaukee, WI) or the CTI Biograph (CTI Knoxville, TN). Patients were injected with pyrogen free F-18 FG 10–15 mCi having been previously instructed to fast for at least 6 hour before scanning. All images were reconstructed using postemission transmission attenuation corrected data sets. Region of interest analysis tools, shipped with the scanners were used to calculate the maximal FDG concentration within the primary tumor mass. Standardized uptake values (SUVmax) were obtained by correcting for the injected dose and the patient's weight, again using the standard software tools provided with the scanners. For the purposes of this study, only 18FDG uptake in the primary site of disease was analyzed. The remaining PET scans were done at various other facilities, and the documented primary tumor SUVmax was recorded based on the outside report without the possibility of further documentation.
Estimation of Treatment Effect and Pathologic Complete Response
The gross appearance of treated tumors varied from a mucosal ulceration, to a fibrous scar, or a prominent mass lesion in the case of a less than profound tumor regression. Photographs of the gross specimen were taken on all cases. The ulcerated or the scarred gross lesion at the gastroesophageal junction was blocked, sequentially and entirely submitted for histopathological evaluation. When the tumor was large in size (>5.0 cm), only representative sections of the tumor were examined microscopically. At the microscopic level, a positive treatment-related effect was observed as the malignant epithelium was destroyed and replaced by reactive fibrosis or fibro-inflammation within the mucosa or the gastroesophageal wall. Ultimately, the pathologic response to treatment was determined by the amount of residual viable carcinoma that remained in relation to areas of fibrosis or fibro-inflammation within the gross lesion. The inverse of this number was then expressed as a percentage (%). Thus, a 100% treatment response indicated fibrosis or fibro-inflammation within an entire gross lesion without microscopic evidence of carcinoma, and a 0% treatment response represented an entirely viable tumor in the absence of any fibrosis of fibro-inflammation, respectively. Acellular mucin was regarded as a form of positive treatment response, not as a residual/viable tumor. A pCR was assigned when there was a 100% local treatment response.
The outcome evaluated was overall survival which was calculated from the time of operation, and the date of death was confirmed from the Social Security Death Index. Follow-up was tracked through February 2008, constituting our censoring date for survival.
Patient characteristics are described using tables for categorical data, and medians and range for continuous variables. Comparison of categorical variables was done by χ2 analysis and continuous variables by t test. Survival analysis was done using the Kaplan-Meier method, with comparison of survival using the log-rank test.
During the study period, 995 esophagectomies for cancer were performed, and 189 patients were appropriate for this analysis. Five hundred and twenty-eight patients were excluded because they did not receive chemoradiation. Of the remaining 467 patients, patients were excluded for the following reasons: 105 patients had squamous cell carcinoma, 83 patients did not have a PET scan, 46 patients had a PET scan but no SUVmax recorded, 42 patients had a Siewert 3 tumor, and 2 patients did not have survival data available. Of the 189 patients available for analysis, 28 patients (14.8%) were in the low SUV group, and 161 patients (85.2%) were in the high SUV group (Figure 1). As shown in Table 1, there were no significant differences in patient characteristics such as age and sex. Although there was a trend toward a more advanced clinical stage in the high SUVmax group, especially with regards to EUS N1 disease (p = 0.14) and PET adenopathy (p = 0.12), these differences were not statistically significant. The type of preoperative chemotherapy administered, the dose of radiation, and the time from radiation completion to surgery was the same in both groups.
Survival of Low SUV and High SUVmax Groups
As seen in Figure 2, the overall survival of the 2 patient groups was not significantly different (p = 0.40). At 3 years, 49.0% of the low SUV group was alive, and 57.9% of the high SUV group was alive.
Pathologic Findings of Low SUV and High SUVmax Groups
There was a significant difference in the findings on final pathologic examination between the two groups of patients. As shown in Table 2, the low SUV group was less likely to experience a pCR (p = 0.02), had less evidence of a treatment response (p = 0.02), and was more likely to have persistent node positive disease (p = 0.03).
The results from this study show that differences in the pretreatment PET SUVmax do not predict overall survival in patients receiving combined modality therapy. However, a high SUVmax is associated with a significantly better response to induction therapy at the time of resection, as evidenced by a higher pCR rate, a greater estimated treatment response, and a lower incidence of nodal disease. Our hypothesis before initiating this study was that patients in the low SUVmax group would have a better survival than patients in the high SUVmax group. Supporting this expectation were several studies, including findings in lung cancer8–10 and esophageal cancer,7,11 which have shown that a high SUVmax in patients undergoing surgery is a predictor of a more advanced clinical and pathologic stage and thereby a worse outcome. For instance, our previous study on patients with esophageal cancer who underwent surgery without preoperative chemotherapy or chemo-radiotherapy showed that a low PET SUVmax predicted a lower pathologic and clinical stage and was associated with a better overall survival compared with a high PET SUVmax.7 An additional expectation regarding postchemoradiotherapy outcomes is that survival is primarily associated with posttreatment nodal status and secondarily with the pathologic treatment response.12 In our study, however, the high SUVmax group had more favorable postchemoradiotherapy pathologic characteristics, yet survival was no different than in the low SUVmax group. To reconcile these discrepant findings, a reasonable interpretation of the results is that high SUVmax tumors have an inherently worse outcome but are also more responsive to chemoradiation, on balance resulting in a similar survival between the two groups. Thus, while PET SUVmax ultimately does not predict overall prognosis, it identifies which patients are most likely to benefit from therapy.
PET scan is increasingly being used in patients undergoing neoadjuvant therapy for esophageal cancer to monitor their response to therapy.2,3 In general, the findings from these studies have shown that patients who have a larger change in SUVmax during treatment also show evidence of a better treatment response and improved survival.2,3 For example, In the MUNICON trial, Lordick et al.2 showed that a 35% or more decrease in SUVmax after 2 weeks of chemotherapy was associated with a greater histologic response as well as improved survival in patients with esophageal adenocarcinoma. Similar findings have also been reported in other tumor types, including lung cancer.13,14 Interestingly, in the MUNICON trial,2 an additional noteworthy finding was that the median initial SUVmax of the nonresponders was lower than in the responders (6.8 versus 8.3, respectively). This finding was noted even though the trial excluded patients with a very low initial SUVmax (cutoff not provided). Similar findings that a high initial SUV was associated with a better treatment response have also been reported by Wieder et al.3 in esophageal squamous cell cancer. In this study, the patients who were found to have a major histopathologic response after chemoradiotherapy had a mean initial SUVmax of 9.6, whereas those without a major response had a an initial SUVmax of 3.5. Similar findings have been noted by Dimtrakopoulou Strauss et al.15 in colorectal cancer, Cremerius et al.16 in lymphoma, and by Lee et al.17 in lung cancer.
Underlying mechanisms, which might not only explain why high SUV tumors would have a worse initial prognosis but also respond better to preoperative therapy, are not well defined. Among proposed reasons is that a low SUV might be associated with hypoxic tumors, that when left untreated may be less aggressive, but paradoxically may make the tumor more resistant to chemoradiotherapy.18 Other possible mechanisms include higher tumor proliferation indices in high SUV tumors19 which in turn makes them more sensitive to preoperative therapy,17 in vitro evidence of chemo resistance is associated with high rates of membrane glucose transport,20 and disruption of the membrane glucose transporter which is associated with decreased FDG uptake and multiresistant cell lines.21
The major limitation of this analysis is that it is retrospective and as such the PET SUV results are subject to both methodological and analytical variability. In addition, given the strong association between high SUVmax and advanced clinical stage and the fact that our institution treats patients with locally advanced disease with preoperative chemoradiotherapy, the number of patients in the low SUV group was small. However, the strengths of this study include the large number of patients studied over a short time period, uniformity of induction therapy, and the homogeneity of the patient population with respect to the tumor type and location. In addition, a meticulous pathologic assessment of the resected tumor was possible in every patient.
In conclusion, this study shows that in patients with adenocarcinoma of the distal esophagus and GE junction who undergo chemoradiotherapy before surgery, while a low pretreatment SUV likely provides an inherent survival advantage over a high SUV, this advantage is negated because of the more dramatic response of high SUV tumors to the preoperative chemoradiotherapy. This finding has implications for the design of future clinical trials, and significant implications for a more appropriate selection of patients for preoperative chemoradiotherapy.
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