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Journal of Clinical Oncology, Vol 26, No 27 (September 20), 2008: pp. 4521-4522 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.18.5066
Treatment Considerations for Gallbladder Cancer Should Include Extent of SurgeryDivision of General Surgery, University of Toronto, Toronto, Ontario, Canada To the Editor: We read with interest, "Prediction Model for Estimating the Survival Benefit of Adjuvant Radiotherapy for Gallbladder Cancer" by Wang et al.1 The authors correctly state that surgery remains the only definitively curative therapy for resectable gallbladder cancer. There is a growing body of literature that demonstrates improved overall and disease-free survival for patients who undergo aggressive resections of the liver, bile duct, and portal lymph nodes for their gallbladder cancer, even as salvage surgery after a simple cholecystectomy.2-9 We therefore find it concerning that extent of surgical treatment was not considered in the analysis by Wang et al and suggest caution in the interpretation of this model. In our analysis of gallbladder cancer patients in the Surveillance, Epidemiology, and End Results (SEER) database,10 a small minority of patients (< 10%) underwent en bloc resection (gallbladder plus one adjacent organ) or lymphadenectomy (three or more lymph nodes assessed). Despite this, we found a survival benefit associated with en bloc resection for stage T1 tumors, with trends for improved survival for en bloc resection and lymphadenectomy for stage T2 tumors and lymphadenectomy for stage T3 tumors, on adjusted analysis. From our examination of the data, the majority of stage T3 patients in the Wang et al1 series were likely treated with a simple cholecystectomy (86.4% of stage T3 in our series). A simple cholecystectomy for a stage T3 cancer suggests a noncurative resection (R1 or R2 resection) due to the subserosal plane of dissection, and thus a significant burden of residual disease in these patients. In addition, 21% of their series had stage M1 disease. Due to the high number of noncurative surgical resections in this series, we suggest that the analysis by Wang et al may describe the benefit of palliative, rather than adjuvant, radiation. Despite the incomplete resections, the authors demonstrated a benefit of postoperative radiation in stage T3 and stage M1 disease. We consider this finding to be intriguing given that we would not normally expect local therapy to the liver and gallbladder fossa to be of benefit in these patients, and it is worthy of additional explanation or study. Because of the intriguing results shown by Wang et al,1 we asked, was the benefit of radiation observed due to treatment of residual disease or is there an additive benefit for radiation after an aggressive en bloc surgical resection? Given that we had already performed a similar analysis using the SEER database, we modified our strategy to incorporate surgical resections and postoperative radiation using SEER data for patients resected of gallbladder adenocarcinoma between 1988 and 2003. Resections were classified as en bloc (cholecystectomy plus at least one adjacent organ) or simple (cholecystectomy only); lymphadenectomy was defined as three or more lymph nodes assessed, as required by current American Joint Committee on Cancer staging. Cox proportional hazards survival analysis was limited to 60 months after diagnosis and was adjusted for type of resection, lymphadenectomy, receipt of postoperative radiation, patient age, sex, race, marital status, tumor grade, nodal status, and year of resection. Given the differential effects of surgery and radiation by T stage, the analysis was stratified by T stage. In examining the effect of surgery and postoperative radiation in multivariate analysis for stage T1 cancers, only en bloc resection was associated with improved survival (hazard ratio [HR], 0.46; 95% CI, 0.24 to 0.91); whereas for stage T3 cancers, lymphadenectomy (HR, 0.64; 95% CI, 0.44 to 0.92) and radiation (HR, 0.7; 95% CI, 0.6 to 0.8) were associated with improved survival. Importantly, survival improved significantly for all T-stage tumors with year of diagnosis. A limiting factor in analyses of SEER data is the lack of surgical margin status and specifics of the extent of surgical resection. This is a large and heterogeneous group of patients with respect to surgical margin status. Observations of potential survival benefit may be more strongly influenced by the presence of residual disease than stage or treatment. Furthermore, the extent of the liver resection is not clear in the SEER data. Some series suggest that a formal hepatectomy is necessary to confer benefit,4,5,11 and in this series of patients, a limited wedge resection may have been performed. In summary, we believe that more in-depth assessments of patient selection (including comorbidity) and details of the surgery (ie, margins, extent of liver resection, and inclusion of a bile duct resection) are necessary to define optimal treatments and predict survival for gallbladder cancers. Without these important details, results from a nomogram may not reliably predict the clinical utility of any intervention. The nomogram may be improved by several changes. The inclusion of surgical treatment variables such as en bloc resection and lymphadenectomy are highly relevant in decision making for adjuvant therapy. The likely burden of unresected disease should be included as well (ie, a stage M1 or T3 cancer treated with a simple cholecystectomy as the only surgical therapy v an en bloc liver, bile duct, and lymphadenectomy for a stage T2N0 cancer). Future work should attempt to include American Joint Committee on Cancer stage, as well as resection status, extent of hepatectomy, and comorbidity as potentially important predictors of survival. Furthermore, given that few patients had three or more lymph nodes assessed, clinicians should be careful about making treatment decisions based on an N0 status. We hope that inclusion of these variables will lead to an improved assessment of the true benefit of radiation in patients who undergo an aggressive, curative-intent resection for gallbladder cancer, as well as those who present with advanced disease that can not be cured with surgery. In conclusion, we suggest caution in applying the nomogram proposed by Wang et al1 when making decisions regarding patient treatment. Actual clinical decision making should be influenced by the surgical results of negative margins versus an R1/R2 resection. It should be kept in mind that many series show a survival benefit for a liver and bile duct resection after a cholecystectomy for gallbladder cancer,12-16 and this may be a preferred treatment to postoperative radiation of an incomplete resection by simple cholecystectomy. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS S.P.C. is supported by a Fellowship grant from the Canadian Institutes of Health Research. C.H.L.L. is supported through a Health Research Personnel Development—Career Scientist Award from the Ontario Ministry of Health and Long Term Care. REFERENCES
1. Wang SJ, Fuller CD, Kim JS, et al: Prediction model for estimating the survival benefit of adjuvant radiotherapy for gallbladder cancer. J Clin Oncol 26:2112-2117, 2008 2. Nimura Y, Hayakawa N, Kamiya J, et al: Hepatopancreatoduodenectomy for advanced carcinoma of the biliary tract. Hepatogastroenterology 38:170-175, 1991[Medline] 3. Nakamura S, Sakaguchi S, Suzuki S, et al: Aggressive surgery for carcinoma of the gallbladder. Surgery 106:467-473, 1989[Medline] 4. Todoroki T, Kawamoto T, Takahashi H, et al: Treatment of gallbladder cancer by radical resection. Br J Surg 86:622-627, 1999[CrossRef][Medline] 5. Kondo S, Nimura Y, Hayakawa N, et al: Extensive surgery for carcinoma of the gallbladder. Br J Surg 89:179-184, 2002[Medline] 6. Dixon E, Vollmer CM Jr, Sahajpal A, et al: An aggressive surgical approach leads to improved survival in patients with gallbladder cancer: A 12-year study at a North American Center. Ann Surg 241:385-394, 2005[CrossRef][Medline] 7. Nakeeb A, Tran KQ, Black MJ, et al: Improved survival in resected biliary malignancies. Surgery 132:555-563, 2002[CrossRef][Medline] 8. Bartlett DL, Fong Y, Fortner JG, et al: Long-term results after resection for gallbladder cancer: Implications for staging and management. Ann Surg 224:639-646, 1996[CrossRef][Medline] 9. Cleary SP, Dawson LA, Knox JJ, et al: Cancer of the gallbladder and extrahepatic bile ducts. Curr Probl Surg 44:396-482, 2007[CrossRef][Medline] 10. Coburn NG, Cleary SP, Tan JCC, et al: Surgery for gallbladder cancer: A population-based analysis. J Am Coll Surg 207:371-382, 2008[CrossRef][Medline] 11. Yamaguchi K, Chijiiwa K, Shimizu S, et al: Anatomical limit of extended cholecystectomy for gallbladder carcinoma involving the neck of the gallbladder. Int Surg 83:21-23, 1998[Medline] 12. Shirai Y, Yoshida K, Tsukada K, et al: Inapparent carcinoma of the gallbladder. An appraisal of a radical second operation after simple cholecystectomy. Ann Surg 215:326-331, 1992[Medline] 13. de Aretxabala XA, Roa IS, Burgos LA, et al: Curative resection in potentially resectable tumours of the gallbladder. Eur J Surg 163:419-426, 1997[Medline] 14. Fong Y, Heffernan N, Blumgart LH: Gallbladder carcinoma discovered during laparoscopic cholecystectomy: Aggressive reresection is beneficial. Cancer 83:423-427, 1998[CrossRef][Medline] 15. Chijiiwa K, Nakano K, Ueda J, et al: Surgical treatment of patients with T2 gallbladder carcinoma invading the subserosal layer. J Am Coll Surg 192:600-607, 2001[CrossRef][Medline] 16. Wakai T, Shirai Y, Hatakeyama K: Radical second resection provides survival benefit for patients with T2 gallbladder carcinoma first discovered after laparoscopic cholecystectomy. World J Surg 26:867-871, 2002[CrossRef][Medline] Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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