VOLUME
33
䡠
NUMBER
9
䡠
MARCH
20
2015
JOURNAL OF CLINICAL ONCOLOGY
C O R R E S P O N D E N C E
Clinical Tumor Staging of Adenocarcinoma of the Esophagus and Esophagogastric Junction TO THE EDITOR: We congratulate Davies et al1 on the retrospective analysis of 400 patients treated with neoadjuvant chemotherapy followed by surgery at two high-volume London centers over the course of a decade. Rather than examining the prognostic effect of tumor regression, the authors focused on the downstaging effect of neoadjuvant chemotherapy as a predictor of recurrence-free and overall survival. Following adjustment for known clinicopathologic variables, tumor downstaging was associated with a reduction in the risk of recurrence and death, suggesting that major clinical decisions should be based on postchemotherapy staging. As mentioned by the authors, advanced diagnostic staging procedures, such as positron emission tomography-computed tomography (PET-CT), are important for detecting nodal disease and distant metastases. To classify a tumor as downstaged, it is essential to not only accurately define the pathologic stage following surgical resection but also to define the clinical stage before chemotherapy. Although much work has been carried out to standardize the reporting of pathologic stage, the use of clinical staging methodologies has varied over time and between centers.2,3 Staging that uses PET-CT can detect occult metastatic disease in up to 13% of patients, and in one study, it led to a change in treatment intent in 38% of the patients.4,5 Considering that the patient cohort in this study was compiled between 2000 and 2010, earlier patients were most likely staged with CT and possibly endoscopic ultrasound, and the authors comment that PET-CT was introduced only “latterly.” The authors did not provide a clear breakdown of the proportion of patients staged with PET-CT,asrecommendedbycurrentguidelines.6-8 Whateffectcouldthis have had on the study results? Without clinical staging that incorporates PET-CT,itislikelythatupto13%ofpatientshadoccultmetastaticdisease and so were incurable by surgical resection at presentation. The T3/T4 node-positive patients were used as the reference group in the KaplanMeier graphs, and their 3-year survival was unexpectedly low, at approximately 20%, suggesting understaging. In a comparable group of patients withpoorprognosiswhowereclinicallystagedbyusingPET-CTandwho showed no evidence of a metabolic response to therapy on a repeat PET-CT scan carried out 14 days later, the 3-year survival rate was 35%.9 The T3/T4 node-positive patients who were not downstaged represented 35% of the patients in the study and the majority of the 56% of patients in the reference group who were used in the multivariable analysis and who were not downstaged. This would lead to an overestimate of the benefit of tumor downstaging because the reference group could contain a subset of patients with resistant metastatic disease. In addition, the R1 resection rate for all patients receiving chemotherapy was 44.8%, markedly above the rate of 31.1% reported in the recent United Kingdom’s National Oesophago-GastricCancerAudit,whichemphasizestheimprovementin surgical outcomes over the last decade and the importance of accurate
clinical staging.10 Although the presence of tumor downstaging is undoubtedly an important prognostic factor, its significance may have been overestimated in this study by clinical understaging in the first instance. These comments are not intended to diminish the significant efforts by this group in compiling this retrospective data set but rather to ask, Do these results reflect modern practice? If postchemotherapy imaging and tumor downstaging is to be used to more accurately predict outcome and eligibility for surgery, it is important to (1) exclude occult metastatic disease before chemotherapy and (2) to use advanced imaging techniques after neoadjuvant chemotherapy. In our institution, we perform PET-CT before and after chemotherapy, which enable precise staging, assessment of metabolic response, and selection of patients for surgical resection. Accurate staging throughout the treatment pathway is essential to avoid inappropriate therapy and provide the information necessary for developing individualized therapy.
Richard C. Turkington, Eileen Parkes, and Richard D. Kennedy Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, United Kingdom
Martin M. Eatock, Claire Harrison, Paula McCloskey, and Colin Purcell Northern Ireland Cancer Centre, Belfast City Hospital, Belfast, United Kingdom
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org. REFERENCES 1. Davies AR, Gossage JA, Zylstra J, et al: Tumor stage after neoadjuvant chemotherapy determines survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction. J Clin Oncol 32:2983-2990, 2014 2. Palser TR, Cromwell DA, Hardwick RH, et al: Re-organisation of oesophago-gastric cancer care in England: Progress and remaining challenges. BMC Health Serv Res 9:204, 2009 3. Homs MY, van Oijen MG, Wijnhoven BP, et al: Changes in diagnostic and treatment strategies of oesophageal cancer in the period from 2001 to 2009: A survey in the Netherlands. Eur J Gastroenterol Hepatol 24:126-133, 2012 4. Noble F, Bailey D, SWCIS Upper Gastrointestinal Tumour Panel, et al: Impact of integrated PET/CT in the staging of oesophageal cancer: A UK population-based cohort study. Clin Radiol 64:699-705, 2009 5. Knight ZA, Shokat KM: Chemical genetics: Where genetics and pharmacology meet. Cell 128:425-430, 2007 6. Allum WH, Blazeby JM, Griffin SM, et al: Guidelines for the management of oesophageal and gastric cancer. Gut 60:1449-1472, 2011 7. Stahl M, Mariette C, Haustermans K, et al: Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 24:vi51-vi56, 2013 8. National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers, 2014 9. Lordick F, Ott K, Krause B, et al: PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: The MUNICON phase II trial. Lancet Oncol 8:797-805, 2007 10. The Royal College of Surgeons of England: National Oesophago-Gastric Cancer Audit, 2013
DOI: 10.1200/JCO.2014.59.2402; published online ahead of print at www.jco.org on February 2, 2015
■ ■ ■
1088
© 2015 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 33, No 9 (March 20), 2015: pp 1088-1089
Information downloaded from jco.ascopubs.org and provided by at Buddhist Dalin Hospital on March 20, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 203.64.11.45
Correspondence
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Clinical Tumor Staging of Adenocarcinoma of the Esophagus and Esophagogastric Junction The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Richard C. Turkington No relationship to disclose Eileen Parkes Travel, Accommodations, Expenses: Boehringer Ingelheim Colin Purcell Travel, Accommodations, Expenses: Merck Serono, Pfizer Paula McCloskey No relationship to disclose
Martin M. Eatock Honoraria: Celgene Consulting or Advisory Role: Eli Lilly Research Funding: Amgen (Inst), Eli Lilly (Inst), Boston Biomedical (Inst) Richard D. Kennedy Employment: Almac Diagnostics Patents, Royalties, Other Intellectual Property: Patent for molecular diagnostic test in cancer
Claire Harrison No relationship to disclose
www.jco.org
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Buddhist Dalin Hospital on March 20, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 203.64.11.45
33
䡠
NUMBER
9
䡠
MARCH
20
2015
JOURNAL OF CLINICAL ONCOLOGY
C O R R E S P O N D E N C E
Clinical Tumor Staging of Adenocarcinoma of the Esophagus and Esophagogastric Junction TO THE EDITOR: We congratulate Davies et al1 on the retrospective analysis of 400 patients treated with neoadjuvant chemotherapy followed by surgery at two high-volume London centers over the course of a decade. Rather than examining the prognostic effect of tumor regression, the authors focused on the downstaging effect of neoadjuvant chemotherapy as a predictor of recurrence-free and overall survival. Following adjustment for known clinicopathologic variables, tumor downstaging was associated with a reduction in the risk of recurrence and death, suggesting that major clinical decisions should be based on postchemotherapy staging. As mentioned by the authors, advanced diagnostic staging procedures, such as positron emission tomography-computed tomography (PET-CT), are important for detecting nodal disease and distant metastases. To classify a tumor as downstaged, it is essential to not only accurately define the pathologic stage following surgical resection but also to define the clinical stage before chemotherapy. Although much work has been carried out to standardize the reporting of pathologic stage, the use of clinical staging methodologies has varied over time and between centers.2,3 Staging that uses PET-CT can detect occult metastatic disease in up to 13% of patients, and in one study, it led to a change in treatment intent in 38% of the patients.4,5 Considering that the patient cohort in this study was compiled between 2000 and 2010, earlier patients were most likely staged with CT and possibly endoscopic ultrasound, and the authors comment that PET-CT was introduced only “latterly.” The authors did not provide a clear breakdown of the proportion of patients staged with PET-CT,asrecommendedbycurrentguidelines.6-8 Whateffectcouldthis have had on the study results? Without clinical staging that incorporates PET-CT,itislikelythatupto13%ofpatientshadoccultmetastaticdisease and so were incurable by surgical resection at presentation. The T3/T4 node-positive patients were used as the reference group in the KaplanMeier graphs, and their 3-year survival was unexpectedly low, at approximately 20%, suggesting understaging. In a comparable group of patients withpoorprognosiswhowereclinicallystagedbyusingPET-CTandwho showed no evidence of a metabolic response to therapy on a repeat PET-CT scan carried out 14 days later, the 3-year survival rate was 35%.9 The T3/T4 node-positive patients who were not downstaged represented 35% of the patients in the study and the majority of the 56% of patients in the reference group who were used in the multivariable analysis and who were not downstaged. This would lead to an overestimate of the benefit of tumor downstaging because the reference group could contain a subset of patients with resistant metastatic disease. In addition, the R1 resection rate for all patients receiving chemotherapy was 44.8%, markedly above the rate of 31.1% reported in the recent United Kingdom’s National Oesophago-GastricCancerAudit,whichemphasizestheimprovementin surgical outcomes over the last decade and the importance of accurate
clinical staging.10 Although the presence of tumor downstaging is undoubtedly an important prognostic factor, its significance may have been overestimated in this study by clinical understaging in the first instance. These comments are not intended to diminish the significant efforts by this group in compiling this retrospective data set but rather to ask, Do these results reflect modern practice? If postchemotherapy imaging and tumor downstaging is to be used to more accurately predict outcome and eligibility for surgery, it is important to (1) exclude occult metastatic disease before chemotherapy and (2) to use advanced imaging techniques after neoadjuvant chemotherapy. In our institution, we perform PET-CT before and after chemotherapy, which enable precise staging, assessment of metabolic response, and selection of patients for surgical resection. Accurate staging throughout the treatment pathway is essential to avoid inappropriate therapy and provide the information necessary for developing individualized therapy.
Richard C. Turkington, Eileen Parkes, and Richard D. Kennedy Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, United Kingdom
Martin M. Eatock, Claire Harrison, Paula McCloskey, and Colin Purcell Northern Ireland Cancer Centre, Belfast City Hospital, Belfast, United Kingdom
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org. REFERENCES 1. Davies AR, Gossage JA, Zylstra J, et al: Tumor stage after neoadjuvant chemotherapy determines survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction. J Clin Oncol 32:2983-2990, 2014 2. Palser TR, Cromwell DA, Hardwick RH, et al: Re-organisation of oesophago-gastric cancer care in England: Progress and remaining challenges. BMC Health Serv Res 9:204, 2009 3. Homs MY, van Oijen MG, Wijnhoven BP, et al: Changes in diagnostic and treatment strategies of oesophageal cancer in the period from 2001 to 2009: A survey in the Netherlands. Eur J Gastroenterol Hepatol 24:126-133, 2012 4. Noble F, Bailey D, SWCIS Upper Gastrointestinal Tumour Panel, et al: Impact of integrated PET/CT in the staging of oesophageal cancer: A UK population-based cohort study. Clin Radiol 64:699-705, 2009 5. Knight ZA, Shokat KM: Chemical genetics: Where genetics and pharmacology meet. Cell 128:425-430, 2007 6. Allum WH, Blazeby JM, Griffin SM, et al: Guidelines for the management of oesophageal and gastric cancer. Gut 60:1449-1472, 2011 7. Stahl M, Mariette C, Haustermans K, et al: Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 24:vi51-vi56, 2013 8. National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers, 2014 9. Lordick F, Ott K, Krause B, et al: PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: The MUNICON phase II trial. Lancet Oncol 8:797-805, 2007 10. The Royal College of Surgeons of England: National Oesophago-Gastric Cancer Audit, 2013
DOI: 10.1200/JCO.2014.59.2402; published online ahead of print at www.jco.org on February 2, 2015
■ ■ ■
1088
© 2015 by American Society of Clinical Oncology
Journal of Clinical Oncology, Vol 33, No 9 (March 20), 2015: pp 1088-1089
Information downloaded from jco.ascopubs.org and provided by at Buddhist Dalin Hospital on March 20, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 203.64.11.45
Correspondence
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Clinical Tumor Staging of Adenocarcinoma of the Esophagus and Esophagogastric Junction The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Richard C. Turkington No relationship to disclose Eileen Parkes Travel, Accommodations, Expenses: Boehringer Ingelheim Colin Purcell Travel, Accommodations, Expenses: Merck Serono, Pfizer Paula McCloskey No relationship to disclose
Martin M. Eatock Honoraria: Celgene Consulting or Advisory Role: Eli Lilly Research Funding: Amgen (Inst), Eli Lilly (Inst), Boston Biomedical (Inst) Richard D. Kennedy Employment: Almac Diagnostics Patents, Royalties, Other Intellectual Property: Patent for molecular diagnostic test in cancer
Claire Harrison No relationship to disclose
www.jco.org
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Buddhist Dalin Hospital on March 20, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 203.64.11.45
