Ann Surg Oncol DOI 10.1245/s10434-014-3805-4
ORIGINAL ARTICLE – COLORECTAL CANCER
A Meta-Analysis to Determine the Effect of Primary Tumor Resection for Stage IV Colorectal Cancer with Unresectable Metastases on Patient Survival Cillian Clancy, MB BCh, MRCSI1, John P. Burke, PhD MRCSI1, Mitchel Barry, MD, FRCSI3, Matthew F. Kalady, MD FASCRS4, and J. Calvin Coffey, PhD FRCSI1,2 Department of Colorectal Surgery, University Hospital Limerick, Limerick, Ireland; 24i Centre for Interventions in Infection, Inflammation and Immunity (4i), Graduate Entry Medical School, University of Limerick, Limerick, Ireland; 3 Department of Surgery, Mater Misericordiae University Hospital, Dublin, Ireland; 4Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 1
ABSTRACT Background. Approximately 20 % of patients diagnosed with colorectal cancer will have distant metastases at first presentation (stage IV disease). The effect of removing the primary tumor on survival for patients with stage IV disease with unresectable metastases remains unclear. To address this a meta-analysis of all studies comparing primary tumor resection with chemotherapy alone in cases of stage IV colorectal cancer with unresectable metastases was performed. Methods. A comprehensive search for published studies examining the effect of primary tumor resection in the setting of colorectal cancer with unresectable metastases was performed. Each study was reviewed and data extracted. Random-effects methods were used to combine data. Results. There were 21 studies including a total of 44,226 patients that met the inclusion criteria. Resection of the primary tumor in patients with unresectable metastases compared with chemotherapy alone was associated with a lower mortality risk (OR 0.28; 95 % CI 0.165–0.474; P \ 0.001), translating into a difference in mean survival of 6.4 months in favor of resection (95 % CI 5.025–7.858,
This study was presented at the Association of Surgeons in Great Britain and Ireland 2014. Ó Society of Surgical Oncology 2014 First Received: 4 March 2014 C. Clancy, MB BCh, MRCSI e-mail: [email protected]
P \ 0.001). Patients who underwent resection of the primary tumor were more likely to have liver metastasis only (OR 1.551; 95 % CI 1.247–1.929; P \ 0.001), were less likely to have C2 metastasis (OR 0.653; 95 % CI 0.508–0.839; P = 0.001), and were less likely to have rectal cancer (OR 0.495; 95 % CI 0.390–0.629; P \ 0.001). There was significant cross-study heterogeneity. Conclusions. Resection of the primary tumor may confer a survival advantage in stage IV colorectal cancer with unresectable metastases but significant selection bias exists in current studies. Randomized controlled trials are essential to validate these findings.
Colorectal cancer is the fourth most common cause of cancer-related mortality worldwide. Approximately 20–25 % of patients newly diagnosed with colorectal cancer will have distant metastases at first presentation, termed stage IV according to TNM criteria.1 In select cases surgical resection of isolated metastases is possible. However, many of these patients (75–90 %) have metastatic disease that is not amenable to resection.2 Emergency presentation with symptoms associated with the primary tumor such as bleeding, obstruction, or perforation necessitates either resection or palliative intervention. There are, however, a large proportion of patients with stage IV colorectal cancer who are asymptomatic. The potential morbidity and mortality associated with surgery and the potential of developing tumor-associated complications requiring emergency resection must be considered. Elective resection of the primary tumor in this patient group remains controversial, and survival benefit is unclear.
C. Clancy et al.
Metastatic colorectal cancer patients are a heterogeneous group, and many different management strategies are available. Palliative surgery such as stoma formation and bypass can be performed, but resection and chemotherapy remain the mainstay of treatment where possible. In the American Surveillance, Epidemiology, and End Results database, 66 % of stage IV colorectal cancer patients underwent resection of the primary tumor over a 12-year period from 1988 to 2000.3 However, with continuous improvement in the efficacy of chemotherapeutic regimens there is an increasing trend toward nonoperative management as this may spare significant surgery-related morbidity. Some studies report the number of patients undergoing chemotherapy without any surgical intervention to be as high as 40 %.4,5 With the majority of metastatic colorectal cancer patients undergoing resection or chemotherapy alone, a clearer understanding of survival benefit is required to achieve optimal outcomes. As there are no randomized controlled trials, it is also important to determine the patient demographics and tumor characteristics of those undergoing resection compared with those receiving only chemotherapy in order to adequately assess differences in survival and preexisting selection bias in currently available studies. To address this, a meta-analysis of all studies comparing primary tumor resection with chemotherapy alone in stage IV colorectal cancer was performed.
MATERIALS AND METHODS Literature Search and Study Selection A systematic search of Pubmed and Embase was performed for all studies published relating to stage IV colorectal cancer with unresectable metastases and surgical resection by using the following in the search algorithm: (colon OR rectal OR colorectal) AND (cancer) AND (stage IV OR metastatic) AND (surgery OR resection) AND (primary). The Cochrane Central Register of Controlled Trials was also searched for articles that investigated surgical resection and stage IV colorectal cancer. The latest search was performed on January 3, 2014. Two authors (C.C. and J.P.B.) independently examined the title and abstract of citations, and the full texts of potentially eligible trials were obtained; disagreements were resolved by discussion. The reference lists of retrieved papers were further screened for additional eligible publications. When data were unclear or incomplete, the corresponding author was contacted to clarify data extraction.
Eligibility Criteria Studies including data on survival comparing resection and chemotherapy in stage IV colorectal cancer with unresectable metastases were eligible for inclusion. The primary end point of the study was the comparative median survival of resection of the primary tumor and chemotherapy alone groups. The secondary end points included patient demographics, tumor location, and metastatic burden in patients undergoing resection of the primary tumor compared with those receiving only chemotherapy. All studies relating to nonstage IV colorectal cancer were excluded. All studies with no comparative data for resection and chemotherapy were excluded. Studies that included patients undergoing nonresection surgery or metastectomy were excluded. There were no language restrictions. Data Extraction and Outcomes The following information regarding each eligible trial was recorded: author’s names, journal, year of publication, study type, enrollment dates, median follow-up, patient demographics, American Society of Anesthesiology (ASA) grade, tumor location, number and location of metastases, and total number of patients included. Timing and type of chemotherapeutic regimens were recorded for each study where available. In addition, the proportion of symptomatic patients included in each study was recorded. From each eligible study the overall survival in the number of patients with stage IV colorectal cancer undergoing resection and undergoing chemotherapy alone was recorded. Statistical Analysis All pooled outcome measures were determined using a random-effects model as described by DerSimonian and Laird, and the odds ratio (OR) was estimated with its variance and 95 % confidence interval (95 % CI).6 The random-effects analysis weighted the natural logarithm of each study’s OR by the inverse of its variance plus an estimate of the between-study variance in the presence of between-study heterogeneity. As previously described, heterogeneity between ORs for the same outcome between different studies was assessed.7,8 This was through the use of the I2 inconsistency test and Chi square-based Cochran’s Q statistic test in which P \ 0.05 is taken to indicate the presence of significant heterogeneity.9 Analyses were conducted using Comprehensive Meta-analysis version 2 (Biostat Inc., Englewood, NJ).
17
14
21
22
10
26
12
29
28
Ahmed
Tsang
Boselli
Verberne 11 Ferrand 27
Kim
Venderbosch
Karoui
Seo
Cellini
4
20
Aslam
Chan
18
19
13
Kaufman
Galizia
Benoist
Cook
3
Cummins
Michel
Tebbutt Ruo 5
15
16
Scoggins
First author
23
2014
2014
2013
2012 2013
Retrospective review
Retrospective review
Retrospective review
Retrospective review Cohort study
Retrospective review
Cohort study
2011
2012
Cohort study
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review Retrospective review
Retrospective review
Study type
2011
2011
2010
2010
2010
2010
2008
2008
2005
2005
2004
2004
2003 2003
1999
Year
TABLE 1 Characteristics of included trials
1992–2005
1996–2007
2010–2011
2002–2006 1997–2001
2000–2009
2005–2006
2003–2004
1998–2007
2001–2008
2002–2008
1998–2007
2000–2002
1998–2003
1995–2005
1997–2002
1988–2000
1989–2003
1996–1999
1990–2000 1996–1999
1985–1997
Enrollment interval
1,180
11,716
48
88 294
201
448
399
208
227
74
647
411
185
65
59
26,754
74
77
362 422
89
Total N of patients
761
8,599
17
26 156
105
289
258
85
144
22
366
286
115
42
32
17657
36
31
280 127
66
N, resection
419
3,117
31
21 60
96
159
141
123
83
9
281
125
70
23
27
9097
25
23
82 103
23
N, no resection
15.2
21
4
26 16.3
14
20.7
16.7
30.7
22
32
14.5
14
30
36
22
11
11.5
21
14 16
14.5
Median survival resection (months)
8.3
10
5
17 19.5
8
13.4
11.4
21.9
14
37
5.8
6
15
17
23
2
4.8
14
8.2 9
16.6
Median survival, no resection (months)
Surgery in Stage IV Colorectal Cancer
C. Clancy et al.
no resection, 79.8 versus 93.3 %; OR 0.280; 95 % CI 0.165–0.474; P \ 0.001), but significant heterogeneity existed (Fig. 2). Also, 20 studies describing 43,720 patients included assessable data on stage IV colorectal cancer and mean survival times according to treatment.3–5,10,11,13–16, 18–29 Resection of the primary tumor was associated with longer survival when compared with chemotherapy only (standard mean difference 6.441 months; 95 % CI 5.025–7.858; P \ 0.001)
Records identified through database searching n = 9,404 Pubmed (4,861) Cochrane (11) Embase (4,535)
Records after duplicates removed (n = 6,514)
Full-text articles assessed for eligibility (n = 43)
Publications included in meta-analysis (n = 21) n = 44,226 patients
Articles excluded by title & abstract (n = 6,471). Reasons: -Management of metastases (1,259) -Irrelevant (5,190) -No comparative data (22)
Full text articles excluded (n =22) Reasons: -Resection vs Palliative Surgery (7) -Metastectomy included (3) -Systematic Review (4) -No comparative data (8)
FIG. 1 PRISMA diagram. Preferred reporting items in systematic reviews and meta-analyses
Metastatic Burden There were 7 studies with a total of 1749 patients that included data on treatment type and patients with metastatic disease located only in the liver.5,11,22–27 Patients undergoing resection of the primary tumor were more likely to have metastatic disease confined to the liver (resection vs no resection, 60.5 versus 50.6 %; OR 1.551; 95 % CI 1.247–1.929; P \ 0.001) (Fig. 3a). Also, 7 studies with a total of 2132 patients included data on treatment type and the number of metastases present.5,20,21,23–27 Patients undergoing resection were less likely to have 2 or more metastases (resection vs no resection, 37.1 versus 47.5 %; OR 0.653; 95 % CI 0.508–0.839; P = 0.001) (Fig. 3b).
RESULTS Patient Characteristics Eligible Studies A total of 21 published studies containing data comparing resection of the primary tumor to chemotherapy alone were identified describing 22 patient cohorts (Table 1).3–5,10–29 The initial search identified 6,514 articles. There were 43 fulltext studies assessed for eligibility, 22 of which were excluded (Fig. 1). Some studies included symptomatic patients and those undergoing emergency surgery (Table 2).4,10,17,18,20,26,29 Studies differed in chemotherapeutic regimens and timing of treatment (Table 2). There were 4 studies that included only patients with hepatic metastases.10,12–14 All studies were published within the last 15 years, and the spectrum of patients was reflective of modern clinical practice. Overall, a total of 44,226 patients were included in the final analysis; 66.7 % of patients underwent resection of the primary tumor, and 33.3 % received only chemotherapy. Survival A total of 19 studies describing 16,295 patients included assessable data on stage IV colorectal cancer and mortality risk according to treatment with a mean patient follow-up of 31.6 ± 15.4 months.4,5,10–15,17–20, 22–29 Resection of the primary tumor resulted in a lower mortality risk (resection vs
There were 6 studies describing a total of 27,915 patients that included data on treatment type and patient age.3,11,20,21,26,27 There was no association between age over 65 and treatment type (resection vs no resection, 59.2 versus 67.2 %; OR 0.846; 95 % CI 0.529–1.353; P = 0.48). Also, 3 studies describing a total of 896 patients included data on treatment type and ASA grade.4,12,26 There was no association between ASA grade [ 2 and treatment type (resection vs no resection, 18.6 versus 27.0 %; OR 0.868; 95 % CI 0.223–3.384; P = 0.84).
Tumor Location There were 15 studies with a total of 42,079 patients that included data on treatment type and rectal tumors.3–5,13–16,20–28 Patients undergoing resection of the primary tumor were less likely to have rectal tumors (resection vs no resection, 12.7 versus 28.5 %; OR 0.495; 95 % CI 0.390–0.629; P \ 0.001). Also, 13 studies describing a total of 41,185 patients included data on treatment type and colon tumors.3–5,13–16,20–22,26–28 Patients undergoing resection of the primary tumor were more likely to have colon tumors (resection vs no resection, 85.2 versus 58.1 %; OR 1.728; 95 % CI 1.231–2.424; P = 0.002).
5
17
3
14
21
22
10
26
11
27
12
23
20.1
19.6
0
19.9
100
39.8
NA
NA
0
NA
1
0
NA
NA
26
NA
0
27
30.6
NA
NA
0
0
NA
0
21.7
0
NA
0
Emergency surgery (%)
18.7
0
44
100
35
24
28
18.5
22
15.6
2.7
20
32
36
28
Rectal cancer (%)
neoadj neoadjuvant, 5-FU 5-fluorouracil
29
28
Ahmed
Tsang
Boselli
Ferrand
Verberne
Kim
Venderbosch
Karoui
Seo
Cellini
4
20
Aslam
Chan
18
19
13
Kaufman
Galizia
Benoist
Cook
Cummins
Michel
Ruo
Tebbutt
15
16
Scoggins
First author
39.5
NA
0
NA
7
93.7
NA
NA
NA
0
27
NA
47
NA
0
0
NA
98.4
0
0
NA
0
Symptomatic resections (%)
TABLE 2 Treatment regimens of included trials
5-FU ± oxaliplatin/irinotecan
NA
5-FU ? leucovorin ? oxaliplatin/ irinotecan ± bevacizumab
5-FU ? leucovorin ± raltitrexed
NA
NA
Capecitabine ? oxaliplatin ? becacizumab ± cetuximab
Capecitabine ? irinotecan ? oxaliplatin
5-FU ? leucovorin oxaliplatin/irinotecan
5-FU ± oxaliplatin/irinotecan
5-FU ? leucovorin oxaliplatin/irinotecan
NA
5-FU ± irinotecan
NA
5-FU ± oxaliplatin/irinotecan
5-FU ± leucovorin ± irinotecan
NA
NA
Oxaliplatin/irinotecan
5-FU ± leucovorin
5-FU/raltitrexed ? capecitabine ? uracil tegafur
NA
No resection, chemotherapy type
Adjuvant
NA
Adjuvant
Adjuvant
Adjuvant
Adjuvant/none
Adjuvant
Adjuvant
Adjuvant
Adjuvant
Neoadj ? adjuvant
Adjuvant/none
Adjuvant/none
Neoadj/adjuvant/none
Adjuvant
Adjuvant
NA
NA
Adjuvant
NA
Adjuvant
NA
Resection, chemotherapy timing
5-FU ± oxaliplatin/irinotecan
NA
5-FU ? leucovorin ? oxaliplatin/ irinotecan ± bevacizumab
5-FU ? leucovorin ± raltitrexed
NA
NA
Capecitabine ? oxaliplatin ? becacizumab ± cetuximab
Capecitabine ? irinotecan ? oxaliplatin
5-FU ? leucovorin oxaliplatin/irinotecan
5-FU ± oxaliplatin/irinotecan
5-FU ? leucovorin oxaliplatin/irinotecan
NA
5-FU ± irinotecan
NA
5-FU ± oxaliplatin/irinotecan
5-FU ± leucovorin ± irinotecan
NA
NA
Oxaliplatin/irinotecan
NA
5-FU/raltitrexed ? capecitabine
NA
Resection, chemotherapy type
Surgery in Stage IV Colorectal Cancer
C. Clancy et al. FIG. 2 Meta-analysis of resection vs nonresection and overall survival. Each study is shown by the point estimate of the odds ratio (OR; square proportional to the weight of each study) and 95 % confidence interval (95 % CI) for the OR (extending lines); the combined ORs and 95 % CIs by random-effects calculations are shown by diamonds. Resection vs nonresection and risk of mortality (n = 16,295; P \ 0.001; test for heterogeneity, Cochran Q = 152.6 (df = 18); P \ 0.001; I2 (inconsistency) = 88.2 %)
Statistics for each study
Study name Odds ratio Scoggins C Ruo L Tsang W Michel P Cummins E Benoist P Galizia G Kaufman M Chan T Aslam M Cellini C Karoui M Venderbosch S1 Venderbosch S2 Kim S Verberne C Ferrand F Boselli C Ahmed S
1.012 0.038 0.369 0.667 0.444 1.000 0.375 0.167 0.259 0.007 1.000 0.645 0.094 0.504 1.000 0.296 0.250 1.000 0.002 0.280
Odds ratio and 95% Cl
Lower Upper limit limit Z-value p-value 0.339 0.005 0.310 0.224 0.095 0.352 0.114 0.070 0.137 0.000 0.205 0.361 0.017 0.328 0.398 0.056 0.123 0.275 0.001 0.165
0.021 3.020 0.286 -3.177 0.438 -11.288 1.986 -0.728 2.075 -1.032 0.000 2.845 1.237 -1.610 0.396 -4.058 0.490 -4.155 0.113 -3.493 4.870 -0.000 1.153 -1.479 0.524 -2.698 0.774 -3.131 2.516 -0.000 1.566 -1.433 0.507 -3.848 0.000 3.636 0.005 -12.443 0.474 -4.737
0.983 0.001 0.000 0.467 0.302 1.000 0.107 0.000 0.000 0.000 1.000 0.139 0.007 0.002 1.000 0.152 0.000 1.000 0.000 0.000 0.01
FIG. 3 a Resection vs nonresection and only liver metastasis (n = 1749; P \ 0.001; test for heterogeneity, Cochran Q = 6.3 (df = 6); P = 0.394; I2 = 4.3 %). b Resection vs nonresection and C 2 metastasis (n = 2132; P = 0.001; test for heterogeneity, Cochran Q = 9.4 (df = 6); P = 0.160; I2 = 35.0 %)
0.1 Resection
1
10 100 No Resection
A Study name
Ruo L Karoui M Venderbosch S1 Venderbosch S2 Kim S Verberne C Ferrand F
Statistics for each study Odds ratio
Lower limit
Upper limit
1.841 0.928 2.309 1.379 1.818 2.078 1.439 1.551
1.088 0.527 1.288 0.917 1.027 0.640 0.788 1.247
3.117 1.634 4.142 2.075 3.220 6.744 2.625 1.929
Odds ratio and 95% Cl
Z-Value p-Value 2.273 -0.260 2.808 1.545 2.050 1.217 1.185 3.946
0.023 0.795 0.005 0.122 0.040 0.223 0.236 0.000 0.01 0.1 1 No Resection
10 100 Resection
B Study name
Statistics for each study Odds ratio
Ruo L Seo G Chan T Venderbosch S1 Venderbosch S2 Kim S Ferrand F
0.527 0.563 0.337 0.642 0.629 1.329 0.704 0.653
Lower Upper ratio ratio 0.307 0.326 0.136 0.421 0.422 0.760 0.385 0.508
0.903 0.971 0.834 0.978 0.936 2.324 1.287 0.839
Odds ratio and 95% Cl
Z-Value
p-Value
-2.332 -2.064 -2.351 -2.063 -2.286 0.996 -1.140 -3.329
0.020 0.039 0.019 0.039 0.022 0.319 0.254 0.001 0.01
0.1 Resection
1
10 100 No Resection
Surgery in Stage IV Colorectal Cancer
DISCUSSION In this study, resection of the primary tumor in stage IV colorectal cancer was associated with longer survival when compared with chemotherapy only. There is a difference of 6.4 months in survival of patients undergoing resection. Palliative chemotherapy alone compared with supportive care has previously shown an increase in survival of 3.7 months.30 Further assessment according to treatment type, however, reveals those undergoing resection have lower metastatic burden that may significantly influence survival. To date this is the largest meta-analysis of studies comparing resection to chemotherapy alone in stage IV disease. Previous systematic reviews have questioned selection bias in patients undergoing resection compared with those receiving chemotherapy alone.2,31 In this study we have identified some of the factors influencing the decision to resect the primary tumor. Patients undergoing resection were more likely to have metastatic disease confined to the liver, single metastases, and tumors located in the colon. As would be expected, those with multiple metastases in locations other than the liver are more likely to receive only chemotherapy. It is likely those with advanced rectal tumors more commonly undergo palliative surgical procedures such as stoma formation rather than resection. There was no association with surgery and age or ASA grade, which suggests selection bias may be confined to metastatic burden. It is noteworthy that the 2 studies including data from patients enrolled in arms of prospective, randomized controlled trials both published in the last 3 years show a difference in survival of 5–7 months associated with resection compared with palliative chemotherapy alone.11,27 Selection bias, however, cannot be disregarded as the decision to resect the primary tumor was taken prior to randomization. Ferrand et al. 27 showed primary tumor resection to be associated with an overall survival benefit in stage IV colorectal cancer when compared with patients starting first-line, single-agent palliative chemotherapy (16.3 vs 9.5 months). Chemotherapeutic agents used were leucovorin, 5-fluorouracil, and raltitrexed. They reported resection of the primary tumor to be an independent prognostic factor compared with other well-established factors. Unfortunately, no tumor-specific mutation data (BRAF/KRAS) was available, which the authors suggested may have explained the poor median survival in the chemotherapy group. Venderbosch et al. showed in their analysis of patients enrolled in single arms of the CAIRO and CAIRO2 studies that there was a survival difference associated with resection compared with nonresection with respective differences of 16.7 versus 11.4 months and 20.7 versus
13.4 months.23–25 Chemotherapy agents in the CAIRO trial included capecitabine, irinotecan, and oxaliplatin.24 The CAIRO2 trial included both anti-angiogenic therapy bevacizumab and anti-EGFR therapy cetuximab in their treatment regimens.25 Resection of the primary tumor was again identified as a prognostic factor for overall survival. A major limitation of this study is that the decision to resect the primary tumor was made prior to study entry and no reason for nonresection was provided. However, in a multivariate analysis that included these variables, resection of the primary remained a significant prognostic factor. Further studies such as the GRECCAR-8 randomized multicenter trial exploring the impact on survival of primary tumor resection in rectal cancer with unresectable metastasis are ongoing. In a previous systematic review by Verhoef et al.31 studies that included symptomatic patients were clearly in favor of resection. In asymptomatic patients overall survival is improved, but because of the nonrandomized, single-center, retrospective nature of studies, patient selection is called into question. A Cochrane review by Cirocchi et al. 32 looking specifically at resection of the primary tumor in asymptomatic patients also concluded that although there was no significant survival difference associated with resection, current literature was insufficient to demonstrate this. Cirocchi et al. included 7 studies, all of which are included in this current study. Several retrospective studies and 1 analysis of patients in a single-arm of a randomized controlled trial have since been published and are included in this current study.11,12 In addition, several studies that did not assess survival in resection versus chemotherapy alone as the primary endpoint, but which had assessable data, were included in this study.10,22,23 A recently published study by Harris et al.33 has shown a survival benefit associated with primary tumor resection in stage IV breast cancer. A similar effect seen in colorectal cancer suggests an underlying molecular mechanism by which removal of the primary tumor influences survival. Chemotactic cytokines such as chemokines 5 and 25 are produced by colorectal cancers and regulate tumor cell metastasis.34,35 The removal of the primary tumor may reduce the circulating concentration of such protumorigenic mediators. This is only 1 of many mechanisms described in the literature by which resection may provide a survival benefit. The contrary argument is that surgery itself may induce a permissive environment for tumor growth.36,37 Current literature does not give a clear conclusion as to whether or not there is a survival difference associated with resection as there are no large, prospective, randomized controlled trials. There are several limitations to our study. All studies included in this meta-analysis are retrospective in nature. Significant heterogeneity is seen in the results as
C. Clancy et al.
study populations differ in the inclusion of rectal and colonic primaries and site and extent of metastases. Chemotherapeutic regimens vary widely as the enrollment intervals of studies span a significant time period in which advancements in individualized therapies have been made. In addition, the timing of chemotherapy differed in some studies, and in a minority of studies a proportion of the patients undergoing resection surgery were not treated with chemotherapy. This study describes a large international dataset and shows that while current literature suggests a survival difference associated with primary tumor resection, there is significant selection bias present. Patients undergoing resection are more likely to have a lower metastatic burden that may significantly influence survival. All studies are retrospective in nature, and the decision to resect the primary tumor has never been subject to randomization in the setting of stage IV colorectal cancer with unresectable metastases. In all cases, the risk of surgical morbidity and mortality must be balanced against any potential survival advantage. Randomized controlled trials to determine the optimal treatment for patients with stage IV colorectal cancer are urgently required. DISCLOSURE the authors.
No funding or financial assistance was received by
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10. Cellini C, Hunt S, Fleshman J, Birnbaum EH, Bierhals AJ, Mutvh MG. Stage IV rectal cancer with liver metastases: is there a benefit to resection of the primary tumor? World J Surg. 2010;34:1102–8. 11. Verberne C, de Bock G, Pijl M, Baas PC, Sieling S, Wiggers T. Palliative resection of the primary tumor in stage IV rectal cancer. Colorectal Dis. 2012;14:314–9. 12. Boselli C, Renzi C, Gemini A, Castellani E, Trastulli S, Desiderio J, et al. Surgery in asymptomatic patients with colorectal cancer and unresectable liver metastases: the authors’ experience. Onco Targets Ther. 2013;6:267–72. 13. Benoist S, Pautrat K, Mitry E, Rougier P, Penna C, Nordlinger B. Treatment strategy for patients with colorectal cancer and synchronous irresectable liver metastases. Br J Surg. 2005;92:1155–60. 14. Galizia G, Lieto E, Orditura M, Castellano P, Imperatore V, Pinto M, et al. First-line chemotherapy vs. Bowel tumor resection plus chemotherapy for patients with unresectable synchronous colorectal hepatic metastases. Arch Surg. 2008;143:352–8. 15. Scoggins CR, Meszoely IM, Blanke CD, Beauchamp RD, Leach SD. Nonoperative management of primary colorectal cancer in patients with stage IV disease. Ann Surg Oncol. 1999;6:651–7. 16. Tebbutt NC, Norman AR, Cunningham D, Hill ME, Tait D, Oates J, et al. Intestinal complications after chemotherapy for patients with unresected primary colorectal cancer and synchronous metastases. Gut. 2003;52:568–73. 17. Michel P, Roque L, Di Fiore F, Langlois S, Scotte M, Tenie`re P, et al. Colorectal cancer with non-resectable synchronous metastases: should the primary tumor be resected? Gastroenterol Clin Biol. 2004;28:434–7. 18. Cummins ER, Vicky KD, Poole GV. Incurable colorectal carcinoma: the role of surgical palliation. Am Surg. 2004;70:433–7. 19. Kaufman MS, Radhakrishnan N, Roy R, Gecelter G, Tsang J, Thomas A, et al. Influence of palliative surgical resection on overall survival in patients with advanced colorectal cancer: a retrospective single institutional study. Colorectal Dis. 2008;10:498–502. 20. Chan TW, Brown C, Ho CC, Gill S. Primary tumor resection in patients presenting with metastatic colorectal cancer: analysis of a provincial population based cohort. Am J Clin Oncol. 2010;33:52–5. 21. Seo GJ, Park JW, Yoo SB, Kim SY, Choi HS, Chang HJ, et al. Intestinal complications after palliative treatment for asymptomatic patients with unresectable stage IV colorectal cancer. J Surg Oncol. 2010;102:94–9. 22. Karoui M, Roudot-Thoroval F, Mesli F, Mitry E, Aparicio T, Des Guetz G, et al. Primary colectomy in patients with stage IV colon cancer and unresectable distant metastases improves overall survival: results of a multicentric study. Dis Colon Rectum. 2011;54:930–8. 23. Venderbosch S, de Wilt JH, Teerenstra S, Loosveld OJ, van Bochove A, Sinnige HA, et al. Prognostic value of resection of primary tumor in patients with stage IV colorectal cancer: retrospective analysis of two randomized studies and a review of the literature. Ann Surg Oncol. 2011;18:3252–60. 24. Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007;370:135–42. 25. Tol J, Koopman M, Rodenburg CJ, Cats A, Creemers GJ, Schrama JG, et al. A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in firstline advanced colorectal cancer: the CAIRO 2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Ann Oncol. 2008;19:734–8.
Surgery in Stage IV Colorectal Cancer 26. Kim SK, Lee CH, Lee MR, Kim JH. Multivariate analysis of the survival rate for treatment modalities in incurable stage IV colorectal cancer. J Korean Soc Coloproctol. 2012;28:35–41. 27. Ferrand F, Malka D, Bourredjem A, Allonier C, Bouche´ O, Louafi S, et al. Impact of primary tumor resection on survival of patients with colorectal cancer and synchronous metastases treated by chemotherapy: results from the multicentre, randomized trial Fe´de´ration Francophone de Cance´rologie Digestive 9601. Eur J Cancer. 2013;49:90–7. 28. Tsang WY, Ziogas A, Lin BS, Seery TE, Karnes W, Stamos MJ, et al. Role of primary tumor resection among chemotherapy treated patients with synchronous stage IV colorectal cancer: a survival analysis. J Gastrointest Surg. 2014;18:592–8. 29. Ahmed S, Leis A, Fields A, Chandra-Kanthan S, Haider K, Alvi R, et al. Survival impact of surgical resection of primary tumor in patients with stage IV colorectal cancer: Results from a large population-based cohort study. Cancer. 2014;120:683–91. 30. Simmonds PC. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. Colorectal Cancer Collaborative Group. BMJ. 2000;321:531–5. 31. Verhoef C, de Wilt J, Burger JW, Verheul HM, Koopman M. Surgery of the primary in stage IV colorectal cancer with unresectable metastases. Eur J Cancer. 2011;47 Suppl 3:S61–6.
32. Cirocchi R, Trastulli S, Abraha I, Vettoretto N, Boselli C, Montedori A, et al. Non-resection versus resection for an asymptomatic primary tumor in patients with unresectable stage IV colorectal cancer. Cochrane Database Syst Rev. 2012; 8:CD008997. 33. Harris E, Barry M, Kell MR. Meta-analysis to determine if surgical resection of the primary tumour in the setting of stage IV breast cancer impacts survival. Ann Surg Oncol. 2013; 20:2828–34. 34. Cambien B, Richard-Fiardo P, Karimdjee BF, Martini V, Ferrua B, Pitard B, et al. CCL5 neutralization restricts cancer growth and potentiates the targeting of PDGFRb in colorectal carcinoma. PLoS One. 2011;6:e28842. 35. Chen HJ, Edwards R, Tucci S, Bu P, Milsom J, Lee S, et al. Chemokine 25-induced signalling suppresses colon cancer invasion and metastasis. J Clin Invest. 2012;122:3184–96. 36. Coffey JC, Wang JH, Smith MJ, Bouchier-Hayes D, Cotter TG, Redmond HP. Excisional surgery for cancer cure: therapy at a cost. Lancet Oncol. 2003;4:760–8. 37. Coffey JC, Wang JH, Bouchier-Hayes D, Cotter TG, Redmond HP. The targeting of phosphoinositide-3 kinase attenuates pulmonary metastatic tumor growth following laparotomy. Ann Surg. 2006;243:250–6.
ORIGINAL ARTICLE – COLORECTAL CANCER
A Meta-Analysis to Determine the Effect of Primary Tumor Resection for Stage IV Colorectal Cancer with Unresectable Metastases on Patient Survival Cillian Clancy, MB BCh, MRCSI1, John P. Burke, PhD MRCSI1, Mitchel Barry, MD, FRCSI3, Matthew F. Kalady, MD FASCRS4, and J. Calvin Coffey, PhD FRCSI1,2 Department of Colorectal Surgery, University Hospital Limerick, Limerick, Ireland; 24i Centre for Interventions in Infection, Inflammation and Immunity (4i), Graduate Entry Medical School, University of Limerick, Limerick, Ireland; 3 Department of Surgery, Mater Misericordiae University Hospital, Dublin, Ireland; 4Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 1
ABSTRACT Background. Approximately 20 % of patients diagnosed with colorectal cancer will have distant metastases at first presentation (stage IV disease). The effect of removing the primary tumor on survival for patients with stage IV disease with unresectable metastases remains unclear. To address this a meta-analysis of all studies comparing primary tumor resection with chemotherapy alone in cases of stage IV colorectal cancer with unresectable metastases was performed. Methods. A comprehensive search for published studies examining the effect of primary tumor resection in the setting of colorectal cancer with unresectable metastases was performed. Each study was reviewed and data extracted. Random-effects methods were used to combine data. Results. There were 21 studies including a total of 44,226 patients that met the inclusion criteria. Resection of the primary tumor in patients with unresectable metastases compared with chemotherapy alone was associated with a lower mortality risk (OR 0.28; 95 % CI 0.165–0.474; P \ 0.001), translating into a difference in mean survival of 6.4 months in favor of resection (95 % CI 5.025–7.858,
This study was presented at the Association of Surgeons in Great Britain and Ireland 2014. Ó Society of Surgical Oncology 2014 First Received: 4 March 2014 C. Clancy, MB BCh, MRCSI e-mail: [email protected]
P \ 0.001). Patients who underwent resection of the primary tumor were more likely to have liver metastasis only (OR 1.551; 95 % CI 1.247–1.929; P \ 0.001), were less likely to have C2 metastasis (OR 0.653; 95 % CI 0.508–0.839; P = 0.001), and were less likely to have rectal cancer (OR 0.495; 95 % CI 0.390–0.629; P \ 0.001). There was significant cross-study heterogeneity. Conclusions. Resection of the primary tumor may confer a survival advantage in stage IV colorectal cancer with unresectable metastases but significant selection bias exists in current studies. Randomized controlled trials are essential to validate these findings.
Colorectal cancer is the fourth most common cause of cancer-related mortality worldwide. Approximately 20–25 % of patients newly diagnosed with colorectal cancer will have distant metastases at first presentation, termed stage IV according to TNM criteria.1 In select cases surgical resection of isolated metastases is possible. However, many of these patients (75–90 %) have metastatic disease that is not amenable to resection.2 Emergency presentation with symptoms associated with the primary tumor such as bleeding, obstruction, or perforation necessitates either resection or palliative intervention. There are, however, a large proportion of patients with stage IV colorectal cancer who are asymptomatic. The potential morbidity and mortality associated with surgery and the potential of developing tumor-associated complications requiring emergency resection must be considered. Elective resection of the primary tumor in this patient group remains controversial, and survival benefit is unclear.
C. Clancy et al.
Metastatic colorectal cancer patients are a heterogeneous group, and many different management strategies are available. Palliative surgery such as stoma formation and bypass can be performed, but resection and chemotherapy remain the mainstay of treatment where possible. In the American Surveillance, Epidemiology, and End Results database, 66 % of stage IV colorectal cancer patients underwent resection of the primary tumor over a 12-year period from 1988 to 2000.3 However, with continuous improvement in the efficacy of chemotherapeutic regimens there is an increasing trend toward nonoperative management as this may spare significant surgery-related morbidity. Some studies report the number of patients undergoing chemotherapy without any surgical intervention to be as high as 40 %.4,5 With the majority of metastatic colorectal cancer patients undergoing resection or chemotherapy alone, a clearer understanding of survival benefit is required to achieve optimal outcomes. As there are no randomized controlled trials, it is also important to determine the patient demographics and tumor characteristics of those undergoing resection compared with those receiving only chemotherapy in order to adequately assess differences in survival and preexisting selection bias in currently available studies. To address this, a meta-analysis of all studies comparing primary tumor resection with chemotherapy alone in stage IV colorectal cancer was performed.
MATERIALS AND METHODS Literature Search and Study Selection A systematic search of Pubmed and Embase was performed for all studies published relating to stage IV colorectal cancer with unresectable metastases and surgical resection by using the following in the search algorithm: (colon OR rectal OR colorectal) AND (cancer) AND (stage IV OR metastatic) AND (surgery OR resection) AND (primary). The Cochrane Central Register of Controlled Trials was also searched for articles that investigated surgical resection and stage IV colorectal cancer. The latest search was performed on January 3, 2014. Two authors (C.C. and J.P.B.) independently examined the title and abstract of citations, and the full texts of potentially eligible trials were obtained; disagreements were resolved by discussion. The reference lists of retrieved papers were further screened for additional eligible publications. When data were unclear or incomplete, the corresponding author was contacted to clarify data extraction.
Eligibility Criteria Studies including data on survival comparing resection and chemotherapy in stage IV colorectal cancer with unresectable metastases were eligible for inclusion. The primary end point of the study was the comparative median survival of resection of the primary tumor and chemotherapy alone groups. The secondary end points included patient demographics, tumor location, and metastatic burden in patients undergoing resection of the primary tumor compared with those receiving only chemotherapy. All studies relating to nonstage IV colorectal cancer were excluded. All studies with no comparative data for resection and chemotherapy were excluded. Studies that included patients undergoing nonresection surgery or metastectomy were excluded. There were no language restrictions. Data Extraction and Outcomes The following information regarding each eligible trial was recorded: author’s names, journal, year of publication, study type, enrollment dates, median follow-up, patient demographics, American Society of Anesthesiology (ASA) grade, tumor location, number and location of metastases, and total number of patients included. Timing and type of chemotherapeutic regimens were recorded for each study where available. In addition, the proportion of symptomatic patients included in each study was recorded. From each eligible study the overall survival in the number of patients with stage IV colorectal cancer undergoing resection and undergoing chemotherapy alone was recorded. Statistical Analysis All pooled outcome measures were determined using a random-effects model as described by DerSimonian and Laird, and the odds ratio (OR) was estimated with its variance and 95 % confidence interval (95 % CI).6 The random-effects analysis weighted the natural logarithm of each study’s OR by the inverse of its variance plus an estimate of the between-study variance in the presence of between-study heterogeneity. As previously described, heterogeneity between ORs for the same outcome between different studies was assessed.7,8 This was through the use of the I2 inconsistency test and Chi square-based Cochran’s Q statistic test in which P \ 0.05 is taken to indicate the presence of significant heterogeneity.9 Analyses were conducted using Comprehensive Meta-analysis version 2 (Biostat Inc., Englewood, NJ).
17
14
21
22
10
26
12
29
28
Ahmed
Tsang
Boselli
Verberne 11 Ferrand 27
Kim
Venderbosch
Karoui
Seo
Cellini
4
20
Aslam
Chan
18
19
13
Kaufman
Galizia
Benoist
Cook
3
Cummins
Michel
Tebbutt Ruo 5
15
16
Scoggins
First author
23
2014
2014
2013
2012 2013
Retrospective review
Retrospective review
Retrospective review
Retrospective review Cohort study
Retrospective review
Cohort study
2011
2012
Cohort study
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review
Retrospective review Retrospective review
Retrospective review
Study type
2011
2011
2010
2010
2010
2010
2008
2008
2005
2005
2004
2004
2003 2003
1999
Year
TABLE 1 Characteristics of included trials
1992–2005
1996–2007
2010–2011
2002–2006 1997–2001
2000–2009
2005–2006
2003–2004
1998–2007
2001–2008
2002–2008
1998–2007
2000–2002
1998–2003
1995–2005
1997–2002
1988–2000
1989–2003
1996–1999
1990–2000 1996–1999
1985–1997
Enrollment interval
1,180
11,716
48
88 294
201
448
399
208
227
74
647
411
185
65
59
26,754
74
77
362 422
89
Total N of patients
761
8,599
17
26 156
105
289
258
85
144
22
366
286
115
42
32
17657
36
31
280 127
66
N, resection
419
3,117
31
21 60
96
159
141
123
83
9
281
125
70
23
27
9097
25
23
82 103
23
N, no resection
15.2
21
4
26 16.3
14
20.7
16.7
30.7
22
32
14.5
14
30
36
22
11
11.5
21
14 16
14.5
Median survival resection (months)
8.3
10
5
17 19.5
8
13.4
11.4
21.9
14
37
5.8
6
15
17
23
2
4.8
14
8.2 9
16.6
Median survival, no resection (months)
Surgery in Stage IV Colorectal Cancer
C. Clancy et al.
no resection, 79.8 versus 93.3 %; OR 0.280; 95 % CI 0.165–0.474; P \ 0.001), but significant heterogeneity existed (Fig. 2). Also, 20 studies describing 43,720 patients included assessable data on stage IV colorectal cancer and mean survival times according to treatment.3–5,10,11,13–16, 18–29 Resection of the primary tumor was associated with longer survival when compared with chemotherapy only (standard mean difference 6.441 months; 95 % CI 5.025–7.858; P \ 0.001)
Records identified through database searching n = 9,404 Pubmed (4,861) Cochrane (11) Embase (4,535)
Records after duplicates removed (n = 6,514)
Full-text articles assessed for eligibility (n = 43)
Publications included in meta-analysis (n = 21) n = 44,226 patients
Articles excluded by title & abstract (n = 6,471). Reasons: -Management of metastases (1,259) -Irrelevant (5,190) -No comparative data (22)
Full text articles excluded (n =22) Reasons: -Resection vs Palliative Surgery (7) -Metastectomy included (3) -Systematic Review (4) -No comparative data (8)
FIG. 1 PRISMA diagram. Preferred reporting items in systematic reviews and meta-analyses
Metastatic Burden There were 7 studies with a total of 1749 patients that included data on treatment type and patients with metastatic disease located only in the liver.5,11,22–27 Patients undergoing resection of the primary tumor were more likely to have metastatic disease confined to the liver (resection vs no resection, 60.5 versus 50.6 %; OR 1.551; 95 % CI 1.247–1.929; P \ 0.001) (Fig. 3a). Also, 7 studies with a total of 2132 patients included data on treatment type and the number of metastases present.5,20,21,23–27 Patients undergoing resection were less likely to have 2 or more metastases (resection vs no resection, 37.1 versus 47.5 %; OR 0.653; 95 % CI 0.508–0.839; P = 0.001) (Fig. 3b).
RESULTS Patient Characteristics Eligible Studies A total of 21 published studies containing data comparing resection of the primary tumor to chemotherapy alone were identified describing 22 patient cohorts (Table 1).3–5,10–29 The initial search identified 6,514 articles. There were 43 fulltext studies assessed for eligibility, 22 of which were excluded (Fig. 1). Some studies included symptomatic patients and those undergoing emergency surgery (Table 2).4,10,17,18,20,26,29 Studies differed in chemotherapeutic regimens and timing of treatment (Table 2). There were 4 studies that included only patients with hepatic metastases.10,12–14 All studies were published within the last 15 years, and the spectrum of patients was reflective of modern clinical practice. Overall, a total of 44,226 patients were included in the final analysis; 66.7 % of patients underwent resection of the primary tumor, and 33.3 % received only chemotherapy. Survival A total of 19 studies describing 16,295 patients included assessable data on stage IV colorectal cancer and mortality risk according to treatment with a mean patient follow-up of 31.6 ± 15.4 months.4,5,10–15,17–20, 22–29 Resection of the primary tumor resulted in a lower mortality risk (resection vs
There were 6 studies describing a total of 27,915 patients that included data on treatment type and patient age.3,11,20,21,26,27 There was no association between age over 65 and treatment type (resection vs no resection, 59.2 versus 67.2 %; OR 0.846; 95 % CI 0.529–1.353; P = 0.48). Also, 3 studies describing a total of 896 patients included data on treatment type and ASA grade.4,12,26 There was no association between ASA grade [ 2 and treatment type (resection vs no resection, 18.6 versus 27.0 %; OR 0.868; 95 % CI 0.223–3.384; P = 0.84).
Tumor Location There were 15 studies with a total of 42,079 patients that included data on treatment type and rectal tumors.3–5,13–16,20–28 Patients undergoing resection of the primary tumor were less likely to have rectal tumors (resection vs no resection, 12.7 versus 28.5 %; OR 0.495; 95 % CI 0.390–0.629; P \ 0.001). Also, 13 studies describing a total of 41,185 patients included data on treatment type and colon tumors.3–5,13–16,20–22,26–28 Patients undergoing resection of the primary tumor were more likely to have colon tumors (resection vs no resection, 85.2 versus 58.1 %; OR 1.728; 95 % CI 1.231–2.424; P = 0.002).
5
17
3
14
21
22
10
26
11
27
12
23
20.1
19.6
0
19.9
100
39.8
NA
NA
0
NA
1
0
NA
NA
26
NA
0
27
30.6
NA
NA
0
0
NA
0
21.7
0
NA
0
Emergency surgery (%)
18.7
0
44
100
35
24
28
18.5
22
15.6
2.7
20
32
36
28
Rectal cancer (%)
neoadj neoadjuvant, 5-FU 5-fluorouracil
29
28
Ahmed
Tsang
Boselli
Ferrand
Verberne
Kim
Venderbosch
Karoui
Seo
Cellini
4
20
Aslam
Chan
18
19
13
Kaufman
Galizia
Benoist
Cook
Cummins
Michel
Ruo
Tebbutt
15
16
Scoggins
First author
39.5
NA
0
NA
7
93.7
NA
NA
NA
0
27
NA
47
NA
0
0
NA
98.4
0
0
NA
0
Symptomatic resections (%)
TABLE 2 Treatment regimens of included trials
5-FU ± oxaliplatin/irinotecan
NA
5-FU ? leucovorin ? oxaliplatin/ irinotecan ± bevacizumab
5-FU ? leucovorin ± raltitrexed
NA
NA
Capecitabine ? oxaliplatin ? becacizumab ± cetuximab
Capecitabine ? irinotecan ? oxaliplatin
5-FU ? leucovorin oxaliplatin/irinotecan
5-FU ± oxaliplatin/irinotecan
5-FU ? leucovorin oxaliplatin/irinotecan
NA
5-FU ± irinotecan
NA
5-FU ± oxaliplatin/irinotecan
5-FU ± leucovorin ± irinotecan
NA
NA
Oxaliplatin/irinotecan
5-FU ± leucovorin
5-FU/raltitrexed ? capecitabine ? uracil tegafur
NA
No resection, chemotherapy type
Adjuvant
NA
Adjuvant
Adjuvant
Adjuvant
Adjuvant/none
Adjuvant
Adjuvant
Adjuvant
Adjuvant
Neoadj ? adjuvant
Adjuvant/none
Adjuvant/none
Neoadj/adjuvant/none
Adjuvant
Adjuvant
NA
NA
Adjuvant
NA
Adjuvant
NA
Resection, chemotherapy timing
5-FU ± oxaliplatin/irinotecan
NA
5-FU ? leucovorin ? oxaliplatin/ irinotecan ± bevacizumab
5-FU ? leucovorin ± raltitrexed
NA
NA
Capecitabine ? oxaliplatin ? becacizumab ± cetuximab
Capecitabine ? irinotecan ? oxaliplatin
5-FU ? leucovorin oxaliplatin/irinotecan
5-FU ± oxaliplatin/irinotecan
5-FU ? leucovorin oxaliplatin/irinotecan
NA
5-FU ± irinotecan
NA
5-FU ± oxaliplatin/irinotecan
5-FU ± leucovorin ± irinotecan
NA
NA
Oxaliplatin/irinotecan
NA
5-FU/raltitrexed ? capecitabine
NA
Resection, chemotherapy type
Surgery in Stage IV Colorectal Cancer
C. Clancy et al. FIG. 2 Meta-analysis of resection vs nonresection and overall survival. Each study is shown by the point estimate of the odds ratio (OR; square proportional to the weight of each study) and 95 % confidence interval (95 % CI) for the OR (extending lines); the combined ORs and 95 % CIs by random-effects calculations are shown by diamonds. Resection vs nonresection and risk of mortality (n = 16,295; P \ 0.001; test for heterogeneity, Cochran Q = 152.6 (df = 18); P \ 0.001; I2 (inconsistency) = 88.2 %)
Statistics for each study
Study name Odds ratio Scoggins C Ruo L Tsang W Michel P Cummins E Benoist P Galizia G Kaufman M Chan T Aslam M Cellini C Karoui M Venderbosch S1 Venderbosch S2 Kim S Verberne C Ferrand F Boselli C Ahmed S
1.012 0.038 0.369 0.667 0.444 1.000 0.375 0.167 0.259 0.007 1.000 0.645 0.094 0.504 1.000 0.296 0.250 1.000 0.002 0.280
Odds ratio and 95% Cl
Lower Upper limit limit Z-value p-value 0.339 0.005 0.310 0.224 0.095 0.352 0.114 0.070 0.137 0.000 0.205 0.361 0.017 0.328 0.398 0.056 0.123 0.275 0.001 0.165
0.021 3.020 0.286 -3.177 0.438 -11.288 1.986 -0.728 2.075 -1.032 0.000 2.845 1.237 -1.610 0.396 -4.058 0.490 -4.155 0.113 -3.493 4.870 -0.000 1.153 -1.479 0.524 -2.698 0.774 -3.131 2.516 -0.000 1.566 -1.433 0.507 -3.848 0.000 3.636 0.005 -12.443 0.474 -4.737
0.983 0.001 0.000 0.467 0.302 1.000 0.107 0.000 0.000 0.000 1.000 0.139 0.007 0.002 1.000 0.152 0.000 1.000 0.000 0.000 0.01
FIG. 3 a Resection vs nonresection and only liver metastasis (n = 1749; P \ 0.001; test for heterogeneity, Cochran Q = 6.3 (df = 6); P = 0.394; I2 = 4.3 %). b Resection vs nonresection and C 2 metastasis (n = 2132; P = 0.001; test for heterogeneity, Cochran Q = 9.4 (df = 6); P = 0.160; I2 = 35.0 %)
0.1 Resection
1
10 100 No Resection
A Study name
Ruo L Karoui M Venderbosch S1 Venderbosch S2 Kim S Verberne C Ferrand F
Statistics for each study Odds ratio
Lower limit
Upper limit
1.841 0.928 2.309 1.379 1.818 2.078 1.439 1.551
1.088 0.527 1.288 0.917 1.027 0.640 0.788 1.247
3.117 1.634 4.142 2.075 3.220 6.744 2.625 1.929
Odds ratio and 95% Cl
Z-Value p-Value 2.273 -0.260 2.808 1.545 2.050 1.217 1.185 3.946
0.023 0.795 0.005 0.122 0.040 0.223 0.236 0.000 0.01 0.1 1 No Resection
10 100 Resection
B Study name
Statistics for each study Odds ratio
Ruo L Seo G Chan T Venderbosch S1 Venderbosch S2 Kim S Ferrand F
0.527 0.563 0.337 0.642 0.629 1.329 0.704 0.653
Lower Upper ratio ratio 0.307 0.326 0.136 0.421 0.422 0.760 0.385 0.508
0.903 0.971 0.834 0.978 0.936 2.324 1.287 0.839
Odds ratio and 95% Cl
Z-Value
p-Value
-2.332 -2.064 -2.351 -2.063 -2.286 0.996 -1.140 -3.329
0.020 0.039 0.019 0.039 0.022 0.319 0.254 0.001 0.01
0.1 Resection
1
10 100 No Resection
Surgery in Stage IV Colorectal Cancer
DISCUSSION In this study, resection of the primary tumor in stage IV colorectal cancer was associated with longer survival when compared with chemotherapy only. There is a difference of 6.4 months in survival of patients undergoing resection. Palliative chemotherapy alone compared with supportive care has previously shown an increase in survival of 3.7 months.30 Further assessment according to treatment type, however, reveals those undergoing resection have lower metastatic burden that may significantly influence survival. To date this is the largest meta-analysis of studies comparing resection to chemotherapy alone in stage IV disease. Previous systematic reviews have questioned selection bias in patients undergoing resection compared with those receiving chemotherapy alone.2,31 In this study we have identified some of the factors influencing the decision to resect the primary tumor. Patients undergoing resection were more likely to have metastatic disease confined to the liver, single metastases, and tumors located in the colon. As would be expected, those with multiple metastases in locations other than the liver are more likely to receive only chemotherapy. It is likely those with advanced rectal tumors more commonly undergo palliative surgical procedures such as stoma formation rather than resection. There was no association with surgery and age or ASA grade, which suggests selection bias may be confined to metastatic burden. It is noteworthy that the 2 studies including data from patients enrolled in arms of prospective, randomized controlled trials both published in the last 3 years show a difference in survival of 5–7 months associated with resection compared with palliative chemotherapy alone.11,27 Selection bias, however, cannot be disregarded as the decision to resect the primary tumor was taken prior to randomization. Ferrand et al. 27 showed primary tumor resection to be associated with an overall survival benefit in stage IV colorectal cancer when compared with patients starting first-line, single-agent palliative chemotherapy (16.3 vs 9.5 months). Chemotherapeutic agents used were leucovorin, 5-fluorouracil, and raltitrexed. They reported resection of the primary tumor to be an independent prognostic factor compared with other well-established factors. Unfortunately, no tumor-specific mutation data (BRAF/KRAS) was available, which the authors suggested may have explained the poor median survival in the chemotherapy group. Venderbosch et al. showed in their analysis of patients enrolled in single arms of the CAIRO and CAIRO2 studies that there was a survival difference associated with resection compared with nonresection with respective differences of 16.7 versus 11.4 months and 20.7 versus
13.4 months.23–25 Chemotherapy agents in the CAIRO trial included capecitabine, irinotecan, and oxaliplatin.24 The CAIRO2 trial included both anti-angiogenic therapy bevacizumab and anti-EGFR therapy cetuximab in their treatment regimens.25 Resection of the primary tumor was again identified as a prognostic factor for overall survival. A major limitation of this study is that the decision to resect the primary tumor was made prior to study entry and no reason for nonresection was provided. However, in a multivariate analysis that included these variables, resection of the primary remained a significant prognostic factor. Further studies such as the GRECCAR-8 randomized multicenter trial exploring the impact on survival of primary tumor resection in rectal cancer with unresectable metastasis are ongoing. In a previous systematic review by Verhoef et al.31 studies that included symptomatic patients were clearly in favor of resection. In asymptomatic patients overall survival is improved, but because of the nonrandomized, single-center, retrospective nature of studies, patient selection is called into question. A Cochrane review by Cirocchi et al. 32 looking specifically at resection of the primary tumor in asymptomatic patients also concluded that although there was no significant survival difference associated with resection, current literature was insufficient to demonstrate this. Cirocchi et al. included 7 studies, all of which are included in this current study. Several retrospective studies and 1 analysis of patients in a single-arm of a randomized controlled trial have since been published and are included in this current study.11,12 In addition, several studies that did not assess survival in resection versus chemotherapy alone as the primary endpoint, but which had assessable data, were included in this study.10,22,23 A recently published study by Harris et al.33 has shown a survival benefit associated with primary tumor resection in stage IV breast cancer. A similar effect seen in colorectal cancer suggests an underlying molecular mechanism by which removal of the primary tumor influences survival. Chemotactic cytokines such as chemokines 5 and 25 are produced by colorectal cancers and regulate tumor cell metastasis.34,35 The removal of the primary tumor may reduce the circulating concentration of such protumorigenic mediators. This is only 1 of many mechanisms described in the literature by which resection may provide a survival benefit. The contrary argument is that surgery itself may induce a permissive environment for tumor growth.36,37 Current literature does not give a clear conclusion as to whether or not there is a survival difference associated with resection as there are no large, prospective, randomized controlled trials. There are several limitations to our study. All studies included in this meta-analysis are retrospective in nature. Significant heterogeneity is seen in the results as
C. Clancy et al.
study populations differ in the inclusion of rectal and colonic primaries and site and extent of metastases. Chemotherapeutic regimens vary widely as the enrollment intervals of studies span a significant time period in which advancements in individualized therapies have been made. In addition, the timing of chemotherapy differed in some studies, and in a minority of studies a proportion of the patients undergoing resection surgery were not treated with chemotherapy. This study describes a large international dataset and shows that while current literature suggests a survival difference associated with primary tumor resection, there is significant selection bias present. Patients undergoing resection are more likely to have a lower metastatic burden that may significantly influence survival. All studies are retrospective in nature, and the decision to resect the primary tumor has never been subject to randomization in the setting of stage IV colorectal cancer with unresectable metastases. In all cases, the risk of surgical morbidity and mortality must be balanced against any potential survival advantage. Randomized controlled trials to determine the optimal treatment for patients with stage IV colorectal cancer are urgently required. DISCLOSURE the authors.
No funding or financial assistance was received by
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