Predictors of Survival in Patients with Resectable Gastric Cancer Treated with Preoperative Chemoradiation Therapy and Gastrectomy Brian Badgwell, MD, MS, FACS, Mariela Blum, MD, Jeannelyn Estrella, MD, Yi-Ju Chiang, MSPH, Prajnan Das, MD, Aurelio Matamoros, MD, Keith Fournier, MD, Paul Mansfield, MD, FACS, Jaffer Ajani, MD The purpose of this study was to determine the overall survival (OS) of patients with resectable gastric cancer treated with preoperative chemoradiation therapy and gastrectomy. STUDY DESIGN: The medical records of patients with gastric adenocarcinoma presenting to our institution (January 1995 to August 2012) were reviewed to identify patients who underwent diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy. Associations between various clinicopathologic factors and OS were examined with Cox proportional hazards models. RESULTS: Of 192 patients who met inclusion criteria, 103 (54%) required total gastrectomy. One hundred sixty-eight patients (88%) had an extended lymph node dissection, 26 (14%) had resection of adjacent organs, and 178 (93%) had an R0 resection. Median follow-up time for surviving patients was 4.2 years. Median OS for all patients was 5.8 years, and 5-year OS rate was 56%. Multivariable Cox regression model results identified variables associated with diminished OS including age 65 years (hazard ratio [HR] 1.62; 95% CI 1.05 to 2.51), male sex (HR 1.76; 95% CI 1.13 to 2.74), adjacent organ resection (HR 1.97; 95% CI 1.16 to 3.35), R1 status (HR 2.29; 95% CI 1.17 to 4.48), pathologic N1 stage (HR 1.92; 95% CI 1.24 to 2.98), N2 stage (HR 2.58; 95% CI 1.01 to 6.58), and N3 stage (HR 6.54; 95% CI 2.69 to 15.93). Five-year OS rates for patients with pathologic N0, N1, N2, and N3 disease were 67%, 42%, 43%, and 0%, respectively. CONCLUSIONS: Patients with gastric cancer who undergo diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy have a high frequency of obtaining an R0 resection and excellent OS rates. Nodal status after surgery remains an important determinant of OS. (J Am Coll Surg 2015;-:1e8. 2015 by the American College of Surgeons)
BACKGROUND:
Helicobacter pylori treatment and advances in food preservation.1 Estimated new cases of gastric cancer and associated deaths in the United States in 2014 were 22,000 and 11,000, respectively, highlighting the poor survival associated with gastric cancer diagnosis despite an overall decrease in incidence.1 Although surgery offers the best chance of long-term survival in patients with localized disease, systemic therapy and radiation can offer additional improvement in survival.2 Regimens considered standard of care based on randomized controlled trials from Western centers include a perioperative chemotherapy approach or postoperative chemotherapy plus chemoradiotherapy.3-5 Adjuvant chemotherapy after a D2 lymph node dissection is also acceptable based on studies from Eastern centers.6,7 Our
Gastric cancer resulted in 20% to 30% of cancer deaths in the 1930s in the United States, but currently accounts for only 2% of cancer deaths, due to improvements in Disclosure Information: Nothing to disclose. Recipient of 2014 J Bradley Aust Award. Presented at the Western Surgical Association 122nd Scientific Session, Indian Wells, CA, November 2014. Received November 26, 2014; Revised February 19, 2015; Accepted April 6, 2015. From the Departments of Surgical Oncology (Badgwell, Chiang, Fournier, Mansfield), Medical Oncology (Blum, Ajani), Pathology (Estrella), Radiation Oncology (Das), and Radiology (Matamoros), The University of Texas MD Anderson Cancer Center, Houston, TX. Correspondence address: Brian Badgwell, MD, MS, FACS, Department of Surgical Oncology, Unit 1484, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. email: [email protected]
ª 2015 by the American College of Surgeons Published by Elsevier Inc.
1
http://dx.doi.org/10.1016/j.jamcollsurg.2015.04.004 ISSN 1072-7515/15
2
Badgwell et al
Preoperative Chemoradiation for Gastric Cancer
Abbreviations and Acronyms
AJCC ¼ American Joint Committee on Cancer HR ¼ hazard ratio OS ¼ overall survival
approach, based on phase II clinical trials and the wellestablished difficulty in completing postoperative therapy, has involved preoperative chemotherapy and chemoradiation therapy.8-10 However, there are no randomized controlled trials or large series of patients with localized gastric cancer receiving preoperative chemoradiation therapy. Therefore, the purpose of this study was to determine the overall survival (OS) in patients with resectable gastric cancer treated with preoperative chemoradiation therapy and gastrectomy. In addition, we sought to identify clinicopathologic variables associated with survival.
METHODS The medical records of 7,404 patients with histologically confirmed gastric and gastroesophageal adenocarcinoma presenting to our institution (January 1995 to August 2012) were reviewed to identify patients who underwent diagnostic laparoscopy with no evidence of metastatic disease, preoperative chemoradiation (with or without induction chemotherapy), and gastrectomy. Patients with cytology demonstrating adenocarcinoma were excluded; patients with cytology results defined as suspicious or atypical were included. Patients with imaging demonstrating metastatic disease at initial diagnosis were excluded. The study was approved by the MD Anderson Cancer Center Institutional Review Board. Demographic and clinicopathologic variables obtained from the medical record included age, sex, tumor grade, and signet ring cell status. Gastric tumors extending to the gastroesophageal junction were noted as having junction involvement. Imaging extent of disease (based on CT, MRI, or PET/CT scans) at the time of diagnosis was classified according to the presence of a gastric mass or gastric thickening, regional lymphadenopathy, and extraregional (D2) lymphadenopathy. Endoscopic ultrasound T (tumor) and N (nodal) stages at diagnosis were extracted from the endoscopic records. Partial or total completion of the preoperative chemoradiation regimen was also recorded. Gastric resection type (total vs subtotal), extent of lymph node dissection (regional [D1] vs extended [D1þ/D2]), and resection of adjacent organs were identified.11 Pathologic stage was classified according to the American Joint Committee on Cancer (AJCC) 7th
J Am Coll Surg
edition manual for stomach cancer.12 Patients with a primary tumor complete pathologic response (T0) after preoperative therapy and surgery, but with residual N1 disease were classified as stage I (T1N1) because there is not a stage group for the pathologic finding of T0N1 disease. The number of lymph nodes examined was categorized as 15 because National Comprehensive Cancer Network Guidelines recommend examining at least 15 lymph nodes.2 Overall survival was calculated from date of gastric cancer diagnosis until death or date of last follow-up. Median follow-up was calculated from the date of diagnosis until last follow-up for all patients and also for surviving patients. Associations between various clinicopathologic factors and OS were examined with Cox proportional hazards models. Variables with a p value 0.25 on univariate analysis were included in the multivariable Cox regression model analysis. Kaplan-Meier curves were created to compare OS between groups. All reported p values are 2-sided, and statistical significance was defined as p < 0.05. All analyses were performed using SAS version 9.3.
RESULTS Our search identified 192 patients with gastric adenocarcinoma treated with diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy. During the study period, 30 patients were treated with preoperative therapy and developed progressive disease, 7 patients declined surgery after treatment completion, and 12 patients developed treatment toxicity that contributed to the decision to not pursue gastrectomy. In addition, 13 patients during the study period were treated while having comorbid conditions that prevented gastrectomy (7 due to medical conditions such as cirrhosis and 6 due to synchronous cancers). Clinicopathologic features of the study population are summarized in Table 1. Median age was 62 years (range 26 to 84 years) and only 7 patients were age 80 or older. Fifty patients (26%) had gastric cancers that extended to the gastroesophageal junction; 102 patients (53%) were noted to have signet ring cell histology. Imaging extent of disease at initial diagnosis and evaluation was classified as the presence of a gastric mass or gastric thickening in 82%, regional lymphadenopathy in 41%, and extraregional (D2) lymphadenopathy in 14%. Endoscopic ultrasound evaluation identified T3 lesions in the majority of patients (72%) and nodal involvement (N1 or greater) in approximately half (53%) of the study population. Most patients were treated with induction chemotherapy plus chemoradiation therapy (79%); 21% were
Vol.
-,
No.
-, -
2015
Badgwell et al
Table 1. Demographic and Clinicopathologic Variables for 192 Patients Who Met Study Criteria for Treatment With Preoperative Chemoradiotherapy and Gastrectomy Variable
Age, y
BACKGROUND:
Helicobacter pylori treatment and advances in food preservation.1 Estimated new cases of gastric cancer and associated deaths in the United States in 2014 were 22,000 and 11,000, respectively, highlighting the poor survival associated with gastric cancer diagnosis despite an overall decrease in incidence.1 Although surgery offers the best chance of long-term survival in patients with localized disease, systemic therapy and radiation can offer additional improvement in survival.2 Regimens considered standard of care based on randomized controlled trials from Western centers include a perioperative chemotherapy approach or postoperative chemotherapy plus chemoradiotherapy.3-5 Adjuvant chemotherapy after a D2 lymph node dissection is also acceptable based on studies from Eastern centers.6,7 Our
Gastric cancer resulted in 20% to 30% of cancer deaths in the 1930s in the United States, but currently accounts for only 2% of cancer deaths, due to improvements in Disclosure Information: Nothing to disclose. Recipient of 2014 J Bradley Aust Award. Presented at the Western Surgical Association 122nd Scientific Session, Indian Wells, CA, November 2014. Received November 26, 2014; Revised February 19, 2015; Accepted April 6, 2015. From the Departments of Surgical Oncology (Badgwell, Chiang, Fournier, Mansfield), Medical Oncology (Blum, Ajani), Pathology (Estrella), Radiation Oncology (Das), and Radiology (Matamoros), The University of Texas MD Anderson Cancer Center, Houston, TX. Correspondence address: Brian Badgwell, MD, MS, FACS, Department of Surgical Oncology, Unit 1484, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. email: [email protected]
ª 2015 by the American College of Surgeons Published by Elsevier Inc.
1
http://dx.doi.org/10.1016/j.jamcollsurg.2015.04.004 ISSN 1072-7515/15
2
Badgwell et al
Preoperative Chemoradiation for Gastric Cancer
Abbreviations and Acronyms
AJCC ¼ American Joint Committee on Cancer HR ¼ hazard ratio OS ¼ overall survival
approach, based on phase II clinical trials and the wellestablished difficulty in completing postoperative therapy, has involved preoperative chemotherapy and chemoradiation therapy.8-10 However, there are no randomized controlled trials or large series of patients with localized gastric cancer receiving preoperative chemoradiation therapy. Therefore, the purpose of this study was to determine the overall survival (OS) in patients with resectable gastric cancer treated with preoperative chemoradiation therapy and gastrectomy. In addition, we sought to identify clinicopathologic variables associated with survival.
METHODS The medical records of 7,404 patients with histologically confirmed gastric and gastroesophageal adenocarcinoma presenting to our institution (January 1995 to August 2012) were reviewed to identify patients who underwent diagnostic laparoscopy with no evidence of metastatic disease, preoperative chemoradiation (with or without induction chemotherapy), and gastrectomy. Patients with cytology demonstrating adenocarcinoma were excluded; patients with cytology results defined as suspicious or atypical were included. Patients with imaging demonstrating metastatic disease at initial diagnosis were excluded. The study was approved by the MD Anderson Cancer Center Institutional Review Board. Demographic and clinicopathologic variables obtained from the medical record included age, sex, tumor grade, and signet ring cell status. Gastric tumors extending to the gastroesophageal junction were noted as having junction involvement. Imaging extent of disease (based on CT, MRI, or PET/CT scans) at the time of diagnosis was classified according to the presence of a gastric mass or gastric thickening, regional lymphadenopathy, and extraregional (D2) lymphadenopathy. Endoscopic ultrasound T (tumor) and N (nodal) stages at diagnosis were extracted from the endoscopic records. Partial or total completion of the preoperative chemoradiation regimen was also recorded. Gastric resection type (total vs subtotal), extent of lymph node dissection (regional [D1] vs extended [D1þ/D2]), and resection of adjacent organs were identified.11 Pathologic stage was classified according to the American Joint Committee on Cancer (AJCC) 7th
J Am Coll Surg
edition manual for stomach cancer.12 Patients with a primary tumor complete pathologic response (T0) after preoperative therapy and surgery, but with residual N1 disease were classified as stage I (T1N1) because there is not a stage group for the pathologic finding of T0N1 disease. The number of lymph nodes examined was categorized as 15 because National Comprehensive Cancer Network Guidelines recommend examining at least 15 lymph nodes.2 Overall survival was calculated from date of gastric cancer diagnosis until death or date of last follow-up. Median follow-up was calculated from the date of diagnosis until last follow-up for all patients and also for surviving patients. Associations between various clinicopathologic factors and OS were examined with Cox proportional hazards models. Variables with a p value 0.25 on univariate analysis were included in the multivariable Cox regression model analysis. Kaplan-Meier curves were created to compare OS between groups. All reported p values are 2-sided, and statistical significance was defined as p < 0.05. All analyses were performed using SAS version 9.3.
RESULTS Our search identified 192 patients with gastric adenocarcinoma treated with diagnostic laparoscopy, preoperative chemoradiation, and gastrectomy. During the study period, 30 patients were treated with preoperative therapy and developed progressive disease, 7 patients declined surgery after treatment completion, and 12 patients developed treatment toxicity that contributed to the decision to not pursue gastrectomy. In addition, 13 patients during the study period were treated while having comorbid conditions that prevented gastrectomy (7 due to medical conditions such as cirrhosis and 6 due to synchronous cancers). Clinicopathologic features of the study population are summarized in Table 1. Median age was 62 years (range 26 to 84 years) and only 7 patients were age 80 or older. Fifty patients (26%) had gastric cancers that extended to the gastroesophageal junction; 102 patients (53%) were noted to have signet ring cell histology. Imaging extent of disease at initial diagnosis and evaluation was classified as the presence of a gastric mass or gastric thickening in 82%, regional lymphadenopathy in 41%, and extraregional (D2) lymphadenopathy in 14%. Endoscopic ultrasound evaluation identified T3 lesions in the majority of patients (72%) and nodal involvement (N1 or greater) in approximately half (53%) of the study population. Most patients were treated with induction chemotherapy plus chemoradiation therapy (79%); 21% were
Vol.
-,
No.
-, -
2015
Badgwell et al
Table 1. Demographic and Clinicopathologic Variables for 192 Patients Who Met Study Criteria for Treatment With Preoperative Chemoradiotherapy and Gastrectomy Variable
Age, y
