ORIGINAL CONTRIBUTION
The Role of Palliative Resection for Asymptomatic Primary Tumor in Patients With Unresectable Stage IV Colorectal Cancer Jung-A Yun, M.D.1 • Jung Wook Huh, M.D., Ph.D.1 • Yoon Ah Park, M.D.1 Yong Beom Cho, M.D., Ph.D.1 • Seong Hyeon Yun, M.D., Ph.D.1 Hee Cheol Kim, M.D., Ph.D.1 • Woo Yong Lee, M.D., Ph.D.1 Ho-Kyung Chun, M.D., Ph.D.2 1 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 2 Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
BACKGROUND: The prognostic role of surgical resection of primary tumors is not well established in patients with asymptomatic unresectable stage IV colorectal cancer. OBJECTIVE: The aims of this study were to reveal the prognostic role of surgical resection of primary tumors and to define prognostic factors affecting long-term oncological outcomes in patients with asymptomatic unresectable synchronous metastases. DESIGN: This study was a retrospective analysis of prospectively collected data. PATIENTS: Between 2000 and 2008, a total of 416 patients with asymptomatic unresectable stage IV colorectal cancer were analyzed with propensity score matching. MAIN OUTCOME MEASURES: Prematching baseline characteristics were compared by bivariate analysis, and 113 pairs were selected after 1:1 matching with propensity scores estimated from logistic regression. The primary end point was overall survival. RESULTS: Among 416 patients, 218 (52.4%) underwent palliative resection of the primary tumor. Before propensity score matching, palliative resection resulted in a better survival rate than nonresection in univariate analysis (p < 0.001), but not in multivariate analysis Financial Disclosures: None reported. Correspondence to: Jung Wook Huh, M.D., Ph.D., Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea, E-mail: [email protected] Dis Colon Rectum 2014; 57: 1049–1058 DOI: 10.1097/DCR.0000000000000193 © The ASCRS 2014 Diseases of the Colon & Rectum Volume 57: 9 (2014)
(p = 0.08). After matching, the 5-year overall survival rate was significantly lower for patients with peritoneal metastasis and clinical M1b stage tumors in univariate analysis (p = 0.004 and p = 0.02). However, neither peritoneal metastasis nor clinical M1b stage showed any prognostic significance in multivariate analysis. The overall 5-year survival rate of the postmatching group was 4.9% and 3.5% in the palliative resection and nonresection groups. Consequently, palliative resection was not associated with a significant increase in survival compared with nonresection (p = 0.27). A subgroup analysis performed according to the site of metastasis also did not show any significant survival benefit of palliative resection after matching. LIMITATIONS: Selection bias and potential confounders were limitations of this study. CONCLUSIONS: Resection of the primary tumor
in patients with asymptomatic unresectable stage IV colorectal cancer was not associated with an improvement in overall survival after propensity score matching. KEYWORDS: Colorectal cancer; Unresectable metastases; Resection; Chemotherapy; Primary tumor.
C
olorectal cancer is one of the most common types of cancer in the United States. Approximately 143,000 patients were newly diagnosed with colorectal cancer in 2012, and approximately one-third of these patients are estimated to have died of the disease.1 In Korea, colorectal cancer was the fourth leading cause of death in 2009, and the incidence rate has steadily increased since 1999.2 Approximately 20% to 25% of patients with 1049
1050
colorectal cancer have distant metastasis at the initial diagnosis; in addition, metastasis is predicted to occur in approximately 50% of patients.3 Therefore, the appropriate treatment of patients who present with metastatic colorectal cancer is a significant oncological issue. Palliative resection of symptomatic primary tumors is often required to treat perforation, obstruction, and intractable bleeding. Tenesmus and pain are also sometimes considered appropriate indications for resection. However, the necessity for primary tumor resection in patients with asymptomatic primary tumors and unresectable metastatic disease is controversial.4 In some cases, palliative resection of asymptomatic primary tumors in patients with resectable stage IV colorectal cancer is performed to potentially increase survival or to prevent later tumor-associated symptoms or emergent surgeries, which are often associated with higher operative complications and mortality rates than elective surgeries.5–9 Also, tumor staging is more accurate when metastatic lesions are confirmed in the abdominal cavity. Furthermore, decreasing the tumor burden maximizes the benefits of chemotherapy.8,10 However, some researchers do not recommend resection of the primary tumor, because it is not clear that resection improves survival rate or quality of life.11 Moreover, the incidence of major intestinal complications in patients with unresected colorectal cancer and synchronous metastases who receive initial treatment with chemotherapy may be low.12 Therefore, the primary purpose of this study was to compare the prognostic role of surgical resection of asymptomatic primary tumors in patients with unresectable synchronous metastases with nonresection. In addition, this study aimed to define prognostic factors affecting long-term oncological outcomes in these patients.
MATERIALS AND METHODS Patient Selection and Follow-up
From January 2000 to December 2008, 657 patients were initially diagnosed with unresectable stage IV colorectal cancer at the Samsung Medical Center (Sungkyunkwan University School of Medicine) in Seoul, Korea. Asymptomatic disease was defined as the absence of obstruction, perforation, or bleeding. We excluded 203 patients from the study who did not exhibit asymptomatic disease. The remaining 454 patients with asymptomatic primary tumors underwent various methods of treatment. We further excluded patients who underwent bypass surgery without resection of the primary tumor (n = 14), diverting enterostomy (n = 23), and open and closure (n = 1). Finally, 416 patients were included in this analysis: 218 with palliative resection and 198 with no resection (Fig. 1). The Institutional Review Board at Samsung Medical Center approved this study.
Yun et al: Palliative Surgery in Stage IV Cancer
January 2000 ~ December 2008 Initially diagnosed as unresectable stage IV colorectal cancer (n = 657) • Symptomatic patients (n = 203) Asymptomatic patients (n = 454) • Diverting enterostomy (n = 23) • Bypass surgery (n = 14) • Diagnostic laparotomy (n = 1)
Palliative resection of primary tumor (n = 218)
Palliative chemotherapy with or without radiotherapy (n = 198)
FIGURE 1. Flowchart of patient selection.
All patients were preoperatively assessed with the use of physical examination, laboratory tests, colonoscopy with biopsy, abdominopelvic CT, and chest CT. Magnetic resonance imaging, positron emission tomography (PET), and bone scans were often performed, depending on the extent of the disease, to accurately determine preoperative staging. The distribution of extrahepatic disease included lung metastases and miscellaneous intra-abdominal locations, including the porta hepatis lymph node, subclavicular lymph node, inguinal lymph node, and peritoneal carcinomatosis. A multidisciplinary team consisting of a surgeon, oncologist, radiation oncologist, radiologist, and endoscopist made the final determination regarding palliative resection after considering the potential for tumor growth, the possibility of emergent operation, and chemosensitivity in patients with unresectable metastases. Comprehensive chart reviews were performed to obtain clinicopathologic information, and follow-up data were obtained from the medical records and the National Bureau of Statistics. The included variables were sex, age, tumor location, BMI, histopathologic type (tumor differentiation), preoperative CEA level, clinical tumor and nodal stage, metastasis status, site of metastases, treatment-related morbidity, and mortality rate. The clinical stage was determined by using several imaging modalities. Treatment-related mortality was defined as death within 30 days of initial treatment. Patients were monitored every 3 months with serum CEA level testing and CT of the chest and abdominopelvic region to assess disease status. Other examinations such as MRI or PET were performed as needed for further evaluation. For patients who did not return for observation after 1 year, information was obtained by letter or telephone. Matching
Prematching baseline characteristics were compared by bivariate analysis, and then 1:1 propensity score matching was performed to minimize selection bias. Propensity scores were estimated by using logistic regression. Age, sex, BMI, ASA score, tumor location, type of operation, preop-
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Diseases of the Colon & Rectum Volume 57: 9 (2014)
TABLE 1. Patient demographics Total cohort
Sex Female Male Age, y , median (range) BMI, kg/m2, median (range) Location of tumor Right colon Left colon Rectum Site of metastasis Liver Lung Distant LN Peritoneum Bone Others Clinical T stage T2 T3 T4 Clinical N stage N0 N1 N2 M stage M1a M1b Pretreatment CEA, >5 ng/mL Cell type WD + MD PD + MUC + SRC Treatment-related morbidity
PR (N = 218)
NR (N = 198)
77 (35.3) 141 (64.7) 58 (23–87) 23.4 (16.9–33.6)
68 (34.3) 130 (65.7) 59 (25–77) 23.3 (17.1–35.2)
Matched cohort p
PR (N = 113)
NR (N = 113)
0.83
54 (24.8) 97 (44.5) 67 (30.7)
50 (26.0) 74 (38.5) 68 (35.4)
152 (69.7) 61 (28.0) 13 (6.0) 48 (22.0) 2 (0.9) 19 (8.7)
161 (81.3) 77 (38.9) 86 (43.4) 25 (12.6) 13 (6.6) 13 (6.6)
4 (1.8) 193 (88.5) 21 (9.6)
11 (5.6) 171 (86.4) 16 (8.1)
37 (17.0) 80 (36.7) 101 (46.3)
26 (13.1) 70 (35.4) 102 (51.5)
130 (59.6) 88 (40.4) 183 (83.9)
72 (36.4) 126 (63.6) 183 (92.4)
172 (78.9) 46 (21.1) 21 (9.6)
179 (90.4) 19 (9.6) 4 (2.0)
0.89 0.56 0.45
0.006 0.02
The Role of Palliative Resection for Asymptomatic Primary Tumor in Patients With Unresectable Stage IV Colorectal Cancer Jung-A Yun, M.D.1 • Jung Wook Huh, M.D., Ph.D.1 • Yoon Ah Park, M.D.1 Yong Beom Cho, M.D., Ph.D.1 • Seong Hyeon Yun, M.D., Ph.D.1 Hee Cheol Kim, M.D., Ph.D.1 • Woo Yong Lee, M.D., Ph.D.1 Ho-Kyung Chun, M.D., Ph.D.2 1 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 2 Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
BACKGROUND: The prognostic role of surgical resection of primary tumors is not well established in patients with asymptomatic unresectable stage IV colorectal cancer. OBJECTIVE: The aims of this study were to reveal the prognostic role of surgical resection of primary tumors and to define prognostic factors affecting long-term oncological outcomes in patients with asymptomatic unresectable synchronous metastases. DESIGN: This study was a retrospective analysis of prospectively collected data. PATIENTS: Between 2000 and 2008, a total of 416 patients with asymptomatic unresectable stage IV colorectal cancer were analyzed with propensity score matching. MAIN OUTCOME MEASURES: Prematching baseline characteristics were compared by bivariate analysis, and 113 pairs were selected after 1:1 matching with propensity scores estimated from logistic regression. The primary end point was overall survival. RESULTS: Among 416 patients, 218 (52.4%) underwent palliative resection of the primary tumor. Before propensity score matching, palliative resection resulted in a better survival rate than nonresection in univariate analysis (p < 0.001), but not in multivariate analysis Financial Disclosures: None reported. Correspondence to: Jung Wook Huh, M.D., Ph.D., Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea, E-mail: [email protected] Dis Colon Rectum 2014; 57: 1049–1058 DOI: 10.1097/DCR.0000000000000193 © The ASCRS 2014 Diseases of the Colon & Rectum Volume 57: 9 (2014)
(p = 0.08). After matching, the 5-year overall survival rate was significantly lower for patients with peritoneal metastasis and clinical M1b stage tumors in univariate analysis (p = 0.004 and p = 0.02). However, neither peritoneal metastasis nor clinical M1b stage showed any prognostic significance in multivariate analysis. The overall 5-year survival rate of the postmatching group was 4.9% and 3.5% in the palliative resection and nonresection groups. Consequently, palliative resection was not associated with a significant increase in survival compared with nonresection (p = 0.27). A subgroup analysis performed according to the site of metastasis also did not show any significant survival benefit of palliative resection after matching. LIMITATIONS: Selection bias and potential confounders were limitations of this study. CONCLUSIONS: Resection of the primary tumor
in patients with asymptomatic unresectable stage IV colorectal cancer was not associated with an improvement in overall survival after propensity score matching. KEYWORDS: Colorectal cancer; Unresectable metastases; Resection; Chemotherapy; Primary tumor.
C
olorectal cancer is one of the most common types of cancer in the United States. Approximately 143,000 patients were newly diagnosed with colorectal cancer in 2012, and approximately one-third of these patients are estimated to have died of the disease.1 In Korea, colorectal cancer was the fourth leading cause of death in 2009, and the incidence rate has steadily increased since 1999.2 Approximately 20% to 25% of patients with 1049
1050
colorectal cancer have distant metastasis at the initial diagnosis; in addition, metastasis is predicted to occur in approximately 50% of patients.3 Therefore, the appropriate treatment of patients who present with metastatic colorectal cancer is a significant oncological issue. Palliative resection of symptomatic primary tumors is often required to treat perforation, obstruction, and intractable bleeding. Tenesmus and pain are also sometimes considered appropriate indications for resection. However, the necessity for primary tumor resection in patients with asymptomatic primary tumors and unresectable metastatic disease is controversial.4 In some cases, palliative resection of asymptomatic primary tumors in patients with resectable stage IV colorectal cancer is performed to potentially increase survival or to prevent later tumor-associated symptoms or emergent surgeries, which are often associated with higher operative complications and mortality rates than elective surgeries.5–9 Also, tumor staging is more accurate when metastatic lesions are confirmed in the abdominal cavity. Furthermore, decreasing the tumor burden maximizes the benefits of chemotherapy.8,10 However, some researchers do not recommend resection of the primary tumor, because it is not clear that resection improves survival rate or quality of life.11 Moreover, the incidence of major intestinal complications in patients with unresected colorectal cancer and synchronous metastases who receive initial treatment with chemotherapy may be low.12 Therefore, the primary purpose of this study was to compare the prognostic role of surgical resection of asymptomatic primary tumors in patients with unresectable synchronous metastases with nonresection. In addition, this study aimed to define prognostic factors affecting long-term oncological outcomes in these patients.
MATERIALS AND METHODS Patient Selection and Follow-up
From January 2000 to December 2008, 657 patients were initially diagnosed with unresectable stage IV colorectal cancer at the Samsung Medical Center (Sungkyunkwan University School of Medicine) in Seoul, Korea. Asymptomatic disease was defined as the absence of obstruction, perforation, or bleeding. We excluded 203 patients from the study who did not exhibit asymptomatic disease. The remaining 454 patients with asymptomatic primary tumors underwent various methods of treatment. We further excluded patients who underwent bypass surgery without resection of the primary tumor (n = 14), diverting enterostomy (n = 23), and open and closure (n = 1). Finally, 416 patients were included in this analysis: 218 with palliative resection and 198 with no resection (Fig. 1). The Institutional Review Board at Samsung Medical Center approved this study.
Yun et al: Palliative Surgery in Stage IV Cancer
January 2000 ~ December 2008 Initially diagnosed as unresectable stage IV colorectal cancer (n = 657) • Symptomatic patients (n = 203) Asymptomatic patients (n = 454) • Diverting enterostomy (n = 23) • Bypass surgery (n = 14) • Diagnostic laparotomy (n = 1)
Palliative resection of primary tumor (n = 218)
Palliative chemotherapy with or without radiotherapy (n = 198)
FIGURE 1. Flowchart of patient selection.
All patients were preoperatively assessed with the use of physical examination, laboratory tests, colonoscopy with biopsy, abdominopelvic CT, and chest CT. Magnetic resonance imaging, positron emission tomography (PET), and bone scans were often performed, depending on the extent of the disease, to accurately determine preoperative staging. The distribution of extrahepatic disease included lung metastases and miscellaneous intra-abdominal locations, including the porta hepatis lymph node, subclavicular lymph node, inguinal lymph node, and peritoneal carcinomatosis. A multidisciplinary team consisting of a surgeon, oncologist, radiation oncologist, radiologist, and endoscopist made the final determination regarding palliative resection after considering the potential for tumor growth, the possibility of emergent operation, and chemosensitivity in patients with unresectable metastases. Comprehensive chart reviews were performed to obtain clinicopathologic information, and follow-up data were obtained from the medical records and the National Bureau of Statistics. The included variables were sex, age, tumor location, BMI, histopathologic type (tumor differentiation), preoperative CEA level, clinical tumor and nodal stage, metastasis status, site of metastases, treatment-related morbidity, and mortality rate. The clinical stage was determined by using several imaging modalities. Treatment-related mortality was defined as death within 30 days of initial treatment. Patients were monitored every 3 months with serum CEA level testing and CT of the chest and abdominopelvic region to assess disease status. Other examinations such as MRI or PET were performed as needed for further evaluation. For patients who did not return for observation after 1 year, information was obtained by letter or telephone. Matching
Prematching baseline characteristics were compared by bivariate analysis, and then 1:1 propensity score matching was performed to minimize selection bias. Propensity scores were estimated by using logistic regression. Age, sex, BMI, ASA score, tumor location, type of operation, preop-
1051
Diseases of the Colon & Rectum Volume 57: 9 (2014)
TABLE 1. Patient demographics Total cohort
Sex Female Male Age, y , median (range) BMI, kg/m2, median (range) Location of tumor Right colon Left colon Rectum Site of metastasis Liver Lung Distant LN Peritoneum Bone Others Clinical T stage T2 T3 T4 Clinical N stage N0 N1 N2 M stage M1a M1b Pretreatment CEA, >5 ng/mL Cell type WD + MD PD + MUC + SRC Treatment-related morbidity
PR (N = 218)
NR (N = 198)
77 (35.3) 141 (64.7) 58 (23–87) 23.4 (16.9–33.6)
68 (34.3) 130 (65.7) 59 (25–77) 23.3 (17.1–35.2)
Matched cohort p
PR (N = 113)
NR (N = 113)
0.83
54 (24.8) 97 (44.5) 67 (30.7)
50 (26.0) 74 (38.5) 68 (35.4)
152 (69.7) 61 (28.0) 13 (6.0) 48 (22.0) 2 (0.9) 19 (8.7)
161 (81.3) 77 (38.9) 86 (43.4) 25 (12.6) 13 (6.6) 13 (6.6)
4 (1.8) 193 (88.5) 21 (9.6)
11 (5.6) 171 (86.4) 16 (8.1)
37 (17.0) 80 (36.7) 101 (46.3)
26 (13.1) 70 (35.4) 102 (51.5)
130 (59.6) 88 (40.4) 183 (83.9)
72 (36.4) 126 (63.6) 183 (92.4)
172 (78.9) 46 (21.1) 21 (9.6)
179 (90.4) 19 (9.6) 4 (2.0)
0.89 0.56 0.45
0.006 0.02
