Originally published as JCO Early Release 10.1200/JCO.2006.06.7801 on September 11 2006

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Metabolic Imaging Predicts Response, Survival, and Recurrence in Adenocarcinomas of the Esophagogastric Junction

Katja Ott, Wolfgang A. Weber, Florian Lordick, Karen Becker, Raymonde Busch, Ken Herrmann, Hinrich Wieder, Ulrich Fink, Markus Schwaiger, Jörg-Rüdiger Siewert

From the Departments of Surgery, Nuclear Medicine, Pathology, Internal Medicine III, Medical Statistic, Technische Universität München, Munich, Germany; and the Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA

Address reprint requests to Katja Ott, MD, Department of Surgery, Technische Universitaet Muenchen, Ismaningerstr 22, D-81675, Munich, Germany; e-mail: Katja.Ott{at}lrz.tum.de

	ABSTRACT

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PURPOSE: A previous study suggested that measurement of therapy-induced changes in tumor glucose metabolism by positron emission tomography (PET) with the glucose analog [¹⁸F]fluorodeoxyglucose (FDG) allows to select patients most likely to benefit from preoperative chemotherapy in adenocarcinomas of the esophagogastric junction (AEG). The aim of this study was to prospectively validate these findings by using an a priori definition of metabolic response.

PATIENTS AND METHODS: Sixty-five patients with locally advanced AEGs were included. Tumor glucose utilization was quantitatively assessed by FDG-PET before chemotherapy and 14 days after initiation of therapy. Patients were classified as metabolic responders when the metabolic activity of the primary tumor had decreased by more than 35% at the time of the second PET.

RESULTS: Metabolic responders showed a high histopathologic response rate (44%) with a 3-year survival rate of 70%. In contrast, prognosis was poor for metabolic nonresponders with a histopathologic response rate of 5% (P = .001) and a 3-year survival rate of 35% (P = .01). A multivariate analysis (covariates: ypT-, ypN-category, histopathologic response) demonstrated that metabolic response was the only factor predicting recurrence (P = .018) in the subgroup of completely resected (R0) patients.

CONCLUSION: This study prospectively demonstrates that changes in tumor metabolic activity during chemotherapy predict response, prognosis, and recurrence. These data provide the basis for clinical trials in which preoperative treatment is changed for patients without a metabolic response early in the course of therapy. PET-guided induction therapy may even be applicable to earlier tumor stages because surgery is only minimally delayed in nonresponding patients.

	INTRODUCTION

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It is known from several studies that the outcome of patients with adenocarcinomas of the esophagogastric junction (AEG) treated with preoperative chemotherapy is heterogeneous. Patients with a histopathologic response are characterized by a favorable prognosis.^1,2 Two most recently presented phase III studies indicated that preoperative chemotherapy improves survival in patients with esophageal adenocarcinoma³ and in patients with tumors at the esophagogastric junction.⁴ However, a systematic review did show only marginal effects of preoperative chemotherapy for resectable intrathoracic esophageal cancer.⁵ Of note, in nonresponders survival seems to be similar or even worse than after surgical resection alone.⁶ Therefore, early identification of patients with an unfavorable outcome after preoperative therapy is highly important for the future use of neoadjuvant therapy in patients with tumors of the esophagogastric junction.

We have previously studied early changes in tumor glucose utilization in patients with locally advanced AEG treated with cisplatinum-based chemotherapy followed by surgical resection. We found that a decrease of tumor metabolic activity by more than 35% after 2 weeks of therapy predicts a high histopathologic response rate (53%) and is associated with a favorable prognosis (median survival, > 50 months).⁷ However, this study used a posthoc definition of a metabolic response. Therefore, it might have overestimated the predictive value of early metabolic changes for tumor response and patient outcome. Furthermore, median patient follow-up was only 14 months and the long-term survival of metabolic responders and the patterns of recurrence could not be evaluated.

Thus the aim of this study was to validate an a priori defined metabolic response in [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET) as a predictor for response and patient survival in a larger patient population with longer follow-up. Such a prospective validation is necessary before preoperative treatment is changed for patients without a metabolic response early in the course of therapy.

	PATIENTS AND METHODS

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Study Design
Our previous study⁷ suggested that a metabolic response is achieved in approximately 40% of the treated patients, that the median survival of patients without a metabolic response is 19 months, and that the relative risk of death is approximately three times lower in patients with a metabolic response than in patients without a metabolic response. On the basis of these findings, an accrual time of 36 months and a follow-up time of 24 months, 53 patients have to be evaluated to detect with a power of 80% a three-fold higher risk of death in the group of metabolic nonresponders at a 5% significance level using a log-rank test.⁸ Our previous study has also suggested that in approximately 20% of the patients tumor metabolic activity will be too low for quantitative analysis. Therefore, a total of 65 patients were included in this study.

Patient Population
Eligibility requirements included the presence of biopsy proven adenocarcinoma of the distal esophagus or cardia (AEG I or AEG II)⁹ with or without metastases in local lymph nodes (tumor stage T3, Nx, and M0 in the TNM classification). Staging procedures included endoscopy, endoscopic ultrasound, and computed tomography of the chest and abdomen.^7,10 Exclusion criteria were published recently.^7,10 The study protocol was approved by the institutional review board at the Technische Universität München, Munich, Germany.

Preoperative therapy consisted of two cycles of combination chemotherapy, each 49 days in duration. On day 1 cisplatinum, at a dose of 50 mg/m² body surface area (BSA), was given as intravenous infusion over a period of 1 hour. Thereafter patients received leucovorin (500 mg/m² BSA) over a period of 2 hours, followed by fluorouracil (2 g/m² BSA) over a period of 24 hours. Treatment with cisplatinum was repeated on days 15 and 29. Infusion of leucovorin and fluorouracil was repeated on days 8, 15, 22, 29, and 36.¹¹ AEG I tumors were additionally treated by paclitaxel (80 mg/m² BSA) over a period of 3 hours, one day before infusion of cisplatinum.¹² All patients were treated within ongoing phase II trials at our department. Surgical resection of the tumor was scheduled 3 to 4 weeks after completion of chemotherapy.⁷

Imaging Studies
A baseline FDG-PET was performed during initial staging before initiation of preoperative therapy. Patients were excluded from further analysis when there was insufficient contrast between tumor and surrounding normal tissues. FDG-PET was repeated on day 14 of the first chemotherapy cycle.

Patients fasted at least 6 hours before PET imaging to ensure standardized glucose metabolism. Static emission images of the tumor region of 20 minutes duration were acquired 40 minutes after intravenous injection of 250 to 370 MBq FDG as previously described. Blood glucose levels were measured before each PET study. Patients with a blood glucose level greater than 150 mg/dL were excluded. Images were reconstructed iteratively using an attenuation weighted ordered subset expectation maximization algorithm (eight iterations, four subsets) and then smoothed in 3D using a 4 mm Gauss filter. Image data were normalized for injected dose of FDG and patient's body weight.^7,13 Normalization to body weight was used because this represents the most commonly used way to calculate standardized uptake values for the FDG uptake of tumor tissue. Because only short term changes of tumor metabolic activity were analyzed, other normalization procedures (BSA, lean body mass) yielded identical results (data not shown). Quantitative evaluation of tumor FDG uptake was otherwise performed as previously described.^7,10

Surgical Therapy, Response Evaluation, and Patient Follow-Up
The surgical procedure was an abdominothoracic esophagectomy for patients with AEG I. In patients with AEG II tumors, a transhiatal extended gastrectomy was performed.¹⁴ Conventional methods for evaluation of response (endoscopy with endoluminal ultrasound and computed tomography [CT] scan) were used after the first and second cycle as described previously.⁷ Histopathologic analysis of the resected specimens was performed by a single pathologist (K.B.). Tumor regression was assessed semiquantitatively according to a recently published scoring system.¹⁵ For the purposes of this study, all patients with less than 10% residual tumor cells (regression score 1) were classified as responding. All other patients were classified as histopathologically nonresponding. Patients were also classified as histopathologically nonresponding when they were not operated on because of tumor progression during chemotherapy. Pathologist, radiologists, and endoscopists were blinded to PET response and patient outcome parameters. Patient follow-up included CT of the chest and abdomen and endoscopy at 3-month intervals during the first year after surgery and thereafter at 6-month intervals. Overall survival and recurrence-free survival were calculated from the first day of chemotherapy and the day of surgery, respectively. No patient was lost to follow-up.

Statistical Analysis
All quantitative data are expressed as mean ± one standard deviation. Differences in proportions of patients were analyzed by the Fisher's exact test. Inter- and intraindividual comparisons of quantitative data were made by using a Mann-Whitney U and a Wilcoxon signed rank test, respectively. Survival rates were estimated according to Kaplan-Meier. Statistical comparisons between different groups of patients were performed with a log-rank test and the proportional hazard model. All tests are two sided and are performed at the 5% level of significance by using SPSS for Windows, version 11.50 (SPSS Inc, Chicago, IL).

	RESULTS

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Between January 1999 and July 2002, 65 patients were included in this study and underwent the baseline PET scan. This represents 65% of the patients with locally advanced AEG I and II tumors treated by preoperative chemotherapy at our institution during this time period. Results of 14 of the patients have already been reported previously.⁷ However, the cut off value for definition of a metabolic response (35% decrease of baseline FDG uptake) had already been defined on the basis of the results of the first 26 patients.¹⁶ The clinical stage as determined by endoscopic ultrasound was uT3 in all 65 patients. No significant difference between AEG I and II in the whole patient population could be found regarding Lauren classification (P = .60), grading (P = .30), N category (0 versus +; P = 1.0), overall survival (P = .77), and recurrence-free survival (P = .72). Significant differences could be found for sex (P = .014) and the ypT-category (P = .025) due to the ypT2b classification for proximal gastric cancer (AEG II). Demographic and histopathologic parameters of the AEG I and II tumors were in line with the published data.¹⁷ In eight patients FDG uptake of the tumor was too low for quantitative analysis,^10,18 and in one additional patient the blood glucose level was markedly elevated at the time of the follow-up PET (175 mg/dL). These patients were excluded. Thus a total of 56 patients were assessable for this study. Thirty-five tumors were located above the cardia (AEG I tumors) and 21 tumors were located at the level of the cardia (AEG II tumors). Further patient characteristics are summarized in Table 1.

View larger version (27K): [in this window] [in a new window]   Fig 1. Transaxial positron emission tomography images of two patients at baseline and day 14. (A) In patient A there is a marked decrease in tumor [18F]fluorodeoxyglucose-uptake (quantitatively: –54% corresponding to a metabolic response). (B) In contrast, there is no change in the intensity tumor [18F]fluorodeoxyglucose uptake in patient B (quantitatively: –5% corresponding to a metabolic nonresponse). SUV, standardized uptake values.

In a total of 10 patients, less than 10% viable tumor cells were present in the resected tumor bed. Thus, the overall histopathologic response rate was 10 (18%) of 56. A metabolic response was highly significantly correlated with a subsequent histopathologic response (P = .001; Table 2). A histopathologic response was achieved in 44% (8 of 18; 95% CI, 22% to 69%) of the patients with a metabolic response, but only in 5% of the patients without a metabolic response (2 of 38; 95% CI, 1% to 18%; Table 2). Metabolic response was significantly correlated with conventional methods for response evaluation as well (P < .001; Table 3).

View larger version (12K): [in this window] [in a new window]   Fig 2. (A) Overall survival (56 patients). Median survival of metabolic responders (18 patients) was not reached; median survival for metabolic nonresponders (38 patients) was 18 months (P = .01). (B) Recurrence-free survival after complete tumor resection (41 patients). Median recurrence-free survival for metabolic responders (16 patients) was not reached; median recurrence-free survival for metabolic nonresponders (25 patients) was 10 months (P = .009).

For the R0 patients median recurrence-free survival was 49 months. Recurrence-free survival was significantly better for metabolic responders as compared with metabolic nonresponders (Fig 2B). Median recurrence-free survival of metabolic nonresponders was only 10 months, while median recurrence-free survival has not been reached for metabolic responders (P = .009). The corresponding 3-year recurrence-free survival rates were 38% and 80%. Cox regression revealed metabolic response as the only independent prognostic factor for recurrence-free survival in the subgroup of R0 patients (Table 5).

	DISCUSSION

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Interestingly, the ypN-category was the only prognostic factor in multivariate analysis predicting survival in the group of resected and completely resected patients. This is likely explained by the fact that the ypN-category integrates two important prognostic factors in AEG: the histopathologic response^1,2 in neoadjuvantly treated patients and the nodal category, the strongest prognostic factor in completely resected patients undergoing primary tumor resection.^20-22 However, ypT-, ypN-category, and histopathologic response are determined postoperatively, 3 to 4 months after initiation of preoperative chemotherapy. In contrast the metabolic response can already be assessed on day 14 of the first chemotherapy cycle. Although metabolic response in FDG-PET was not an independent prognostic factor in a multivariate model including ypT-, ypN-category, and histopathologic response as covariates for overall survival in the group of resected or completely resected patients, assessment of the tumor metabolic response may be used to adjust the treatment regimen early in the course of therapy, whereas this is not feasible for postoperative prognostic factors. Furthermore metabolic response was the only independent prognostic factor predicting recurrence after complete resection. Thus metabolic response appears to be the strongest factor predicting short-term outcome, whereas the ypN-category is a stronger predictor for long-term survival. Because metabolic response influences prognosis as well as recurrence in completely resected patients, it should be considered to offer PET-guided induction therapy even to patients with earlier tumor categories (for example, uT2) who have a high probability of complete resection. This consideration is based on the fact that there are subgroups of primary resected patients with early tumor stages, which present with dismal prognosis and early recurrence.²³ The outcome of these patients may also be improved, if those patients are integrated in prospective PET-controlled trials.

It has long been recognized that response to preoperative chemotherapy is a very strong prognostic factor for patients with gastric and esophageal cancer.^1,2 Despite intensive efforts to identify molecular markers, which are predictive for tumor response and prognosis, the value of each of these markers is currently not sufficiently validated to use them for the selection of patients for preoperative chemotherapy.^24-29 Our study indicates that patients, without a metabolic response after 2 weeks of therapy, may undergo salvage therapies after only a brief period of chemotherapy. Potential therapeutic options include the use of different chemotherapy regimens, chemoradiotherapy, or immediate surgical resection. Such an individualized approach could significantly reduce the adverse effects and costs of ineffective therapy in nonresponding patients. Based on the data of this prospective trial, we are currently evaluating such an approach in patients with locally advanced AEG. In this concept (MUNICON trial) patients with metabolic nonresponse are immediately referred to surgery after only 2 weeks of chemotherapy. Because disease progression during ineffective chemotherapy has been discussed as one reason for the poor survival of nonresponders, such a PET-controlled chemotherapy may even improve overall survival by reducing the time during which a patient receives ineffective therapy. However, this hypothesis can only be evaluated in randomized trials, because failure to respond to chemotherapy may also be a marker for a biologically aggressive tumor, which is associated with a poor prognosis irrespective of the applied therapy.

A series of randomized studies will also be necessary to validate PET imaging as a surrogate end point for drug development. As pointed out by Prentice,³⁰ a surrogate end point must correlate with the true clinical outcome and fully capture the net effect of treatment on the clinical outcome. The data presented indicate that a metabolic response in PET closely correlates with patient survival. However, close correlation does not guarantee surrogacy.³¹ It still needs to be established whether a metabolic response fully captures the net effect of treatment on the clinical outcome. For example, some new forms of preoperative therapy may result in a clinical benefit without causing a metabolic response early in the course of therapy, whereas others may cause a metabolic response without a clinical benefit. Only a series of randomized trial will be able to demonstrate whether treatment regimens with a higher metabolic response rate also lead to improved patient survival.

In conclusion, this study confirms prospectively that quantitative assessment of tumor metabolism by FDG-PET is an efficient and clinically useful technique to monitor tumor response to chemotherapy early in the course of treatment. An a priori defined metabolic response predicted tumor response, overall survival, and recurrence-free survival. Furthermore the strong influence of metabolic response on overall survival as well as recurrence-free survival even in completely resected patients might justify the integration of earlier tumor stages in PET-controlled therapy strategies. Therefore we anticipate that FDG-PET will have a significant impact on patient management by allowing individualized therapy strategies in AEGs.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following author or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Markus Schwaiger Siemens (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Katja Ott, Wolfgang A. Weber, Ulrich Fink, Markus Schwaiger, Jörg-Rüdiger Siewert Provision of study materials or patients: Katja Ott, Wolfgang A. Weber, Florian Lordick, Karen Becker, Ken Herrmann, Hinrich Wieder Collection and assembly of data: Katja Ott, Wolfgang A. Weber, Karen Becker, Ken Herrmann, Hinrich Wieder Data analysis and interpretation: Katja Ott, Wolfgang A. Weber, Florian Lordick, Raymonde Busch, Markus Schwaiger, Jörg-Rüdiger Siewert Manuscript writing: Katja Ott, Wolfgang A. Weber, Markus Schwaiger Final approval of manuscript: Katja Ott, Wolfgang A. Weber, Florian Lordick, Karen Becker, Raymonde Busch, Ken Herrmann, Hinrich Wieder, Ulrich Fink, Markus Schwaiger, Jörg-Rüdiger Siewert

 

	GLOSSARY

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AEG (adenocarcinomas of the esophagogastric junction):

Siewert's classification of 1998 defines adenocarcinomas of the esophagogastric junction based on their localization. AEG type I is an adenocarcinoma of the distal esophagus. AEG type II is an adenocarcinoma of the cardia and AEG type III is subcardial gastric cancer.

FDG-PET:

Positron emission tomography with the glucose analog [¹⁸F]fluorodeoxyglucose.

Histopathologic response:

Tumor regression is assessed semiquantitatively according to a recently published scoring system. Histopathologic regression defines the percentage of residual tumor compared to the tumor bed.

Regression score 1a: no residual tumor

Regression score 1b: less than 10% residual tumor

Regression score 2: 10%-50% residual tumor

Regression score 3: more than 50% residual tumor

Regression scores 1a and 1b are defined as histopathologic responders

Regression scores 2 and 3 are defined as histopathologic nonresponders

Metabolic response:

Tumor glucose utilization is quantitatively assessed by FDG-PET prior to chemotherapy and 14 days after initiation of therapy. Patients are classified as metabolic responders, when the metabolic activity of the primary tumor has decreased by more than 35% at the time of the second PET. This cut-off-value is prospectively validated for AEGI, II, III and gastric cancer.

Neoadjuvant therapy:

The administration of chemotherapy prior to surgery. Induction chemotherapy is generally designed to decrease the size of the tumor prior to resection and to increase the rate of complete (R0) resections.

PET-guided induction therapy:

Change of treatment for metabolic nonresponders after only a short period (2 weeks) of neoadjuvant chemotherapy, because these patients are unlikely to benefit from neoadjuvant treatment resulting in no clinical and/or histopathologic response and no improvement of prognosis. Possible treatment regimens after only 2 weeks of neoadjuvant chemotherapy are immediate resection of the tumor or the integration of chemoradiotherapy to improve the local tumor control.

Prognostic factor:

A situation or condition of a patient that can be used to estimate the chance of recovery from a disease or the chance of the disease recurring. Independent prognostic factors are revealed in completely resected (R0) patients by multivariate analysis.

Prentice (Prentice criteria):

Prentice defines criteria that a surrogate marker must satisfy to be useful in clinical trials. Treatment must be prognostic (1) for the true endpoint and (2) the surrogate endpoint, (3) the surrogate must be prognostic for the true endpoint, and (4) the full effect of the treatment on the true endpoint is explained by the surrogate.

	ACKNOWLEDGMENTS

 
We thank the clinical staff for their excellent support and the technologists at the Departments of Nuclear Medicine and Surgery. Furthermore, we appreciate the efforts of the cyclotron and radiochemistry staff. The study was supported by internal funds of the Department of Nuclear Medicine, Technische Universitaet Muenchen.

	NOTES

 
published online ahead of print at www.jco.org on September 11, 2006

K.O. and W.A.W. contributed equally to the article.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted March 26, 2006; accepted June 19, 2006.

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				S. Fischer, G. Darling, A. F. Pierre, A. Sun, N. Leighl, T. K. Waddell, S. Keshavjee, and M. de Perrot Induction chemoradiation therapy followed by surgical resection for non-small cell lung cancer (NSCLC) invading the thoracic inlet Eur. J. Cardiothorac. Surg., June 1, 2008; 33(6): 1129 - 1134. [Abstract] [Full Text] [PDF]

				C. Plathow and W. A. Weber Tumor Cell Metabolism Imaging J. Nucl. Med., June 1, 2008; 49(Suppl_2): 43S - 63S. [Abstract] [Full Text] [PDF]

				K. Ott, K. Herrmann, F. Lordick, H. Wieder, W. A. Weber, K. Becker, A. K. Buck, M. Dobritz, U. Fink, K. Ulm, et al. Early Metabolic Response Evaluation by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Allows In vivo Testing of Chemosensitivity in Gastric Cancer: Long-term Results of a Prospective Study Clin. Cancer Res., April 1, 2008; 14(7): 2012 - 2018. [Abstract] [Full Text] [PDF]

				S.-L. Song, J.-J. Liu, G. Huang, Z.-H. Wang, Y.-Y. Song, X.-G. Sun, and T. Chen Changes in 18F-FDG Uptake Within Minutes After Chemotherapy in a Rabbit VX2 Tumor Model J. Nucl. Med., February 1, 2008; 49(2): 303 - 309. [Abstract] [Full Text] [PDF]

				V. Evilevitch, W. A. Weber, W. D. Tap, M. Allen-Auerbach, K. Chow, S. D. Nelson, F. R. Eilber, J. J. Eckardt, R. M. Elashoff, M. E. Phelps, et al. Reduction of Glucose Metabolic Activity Is More Accurate than Change in Size at Predicting Histopathologic Response to Neoadjuvant Therapy in High-Grade Soft-Tissue Sarcomas Clin. Cancer Res., February 1, 2008; 14(3): 715 - 720. [Abstract] [Full Text] [PDF]

				D. H. Ilson Combined Modality Therapy for Gastric, Esophageal, and Gastroesophageal Junction Cancers ASCO Educational Book, January 1, 2008; 2008(1): 177 - 182. [Abstract] [Full Text] [PDF]

				K. Herrmann, K. Ott, A. K. Buck, F. Lordick, D. Wilhelm, M. Souvatzoglou, K. Becker, T. Schuster, H.-J. Wester, J. R. Siewert, et al. Imaging Gastric Cancer with PET and the Radiotracers 18F-FLT and 18F-FDG: A Comparative Analysis J. Nucl. Med., December 1, 2007; 48(12): 1945 - 1950. [Abstract] [Full Text] [PDF]

				D. A. Mankoff, J. F. Eary, J. M. Link, M. Muzi, J. G. Rajendran, A. M. Spence, and K. A. Krohn Tumor-Specific Positron Emission Tomography Imaging in Patients: [18F] Fluorodeoxyglucose and Beyond Clin. Cancer Res., June 15, 2007; 13(12): 3460 - 3469. [Abstract] [Full Text] [PDF]

				D. H. Ilson Surgery After Primary Chemoradiotherapy in Squamous Cancer of the Esophagus: Is the Photon Mightier Than the Sword? J. Clin. Oncol., April 1, 2007; 25(10): 1155 - 1156. [Full Text] [PDF]

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