Surg Today DOI 10.1007/s00595-014-0869-5
ORIGINAL ARTICLE
Evaluation of the necessity of primary tumor resection for synchronous metastatic colorectal cancer Yuji Miyamoto • Masayuki Watanabe • Yasuo Sakamoto • Hironobu Shigaki • Asuka Murata • Hidetaka Sugihara • Kojiro Etoh • Takatsugu Ishimoto • Masaaki Iwatsuki • Yoshifumi Baba • Shiro Iwagami • Naoya Yoshida • Hideo Baba
Received: 4 February 2013 / Accepted: 16 December 2013 Ó Springer Japan 2014
Abstract Purpose We evaluated the need for primary tumor resection in patients with colorectal cancer (CRC) and synchronous unresectable metastases who underwent chemotherapy, and identified the associations between the primary tumor characteristics and risk of intestinal obstruction or perforation. Methods We retrospectively analyzed the survival and complication rates of patients with synchronous metastatic CRC treated between April 2005 and December 2011. Results Of 131 patients, 68 underwent primary tumor resection before chemotherapy, and 63 were treated without resection before chemotherapy. The overall survival (OS) did not significantly differ between the two groups (log-rank P = 0.53). In the resection group, 12 patients (17.6 %) developed postoperative complications. In the non-resection group, 16 patients (25.4 %) required surgical intervention owing to obstruction or perforation during their treatment. Surgical intervention did not affect the OS. A circumferential tumor was a risk factor for obstruction or perforation of the colorectum in non-resected patients (odds ratio = 11.163; P = 0.006). Conclusion Resection of primary tumors before chemotherapy is unnecessary in selected patients with synchronous metastatic colorectal cancer. A circumferential tumor Y. Miyamoto M. Watanabe Y. Sakamoto H. Shigaki A. Murata H. Sugihara K. Etoh T. Ishimoto M. Iwatsuki Y. Baba S. Iwagami N. Yoshida H. Baba (&) Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan e-mail: [email protected] Y. Miyamoto e-mail: [email protected]
is a risk factor for obstruction or perforation during chemotherapy in cases without primary tumor resection. Keywords
Colorectal cancer Chemotherapy Surgery
Introduction Between 20 and 25 % of patients with colorectal cancer (CRC) present with distant metastases at their initial diagnosis [1]. The treatment outcomes for unresectable CRC have been improved with the introduction of newer chemotherapies and targeted agents. Combinations of infusional fluorouracil/leucovorin with oxaliplatin or irinotecan have brought about better tumor shrinkage effects and improved prognoses [2–4]. Furthermore, the addition of anti-angiogenic agents or anti-EGFR antibodies to the above combinations has provided clinically meaningful improvement in the response rates and survival for these patients [5–8]. Efficacious local control can now be expected for both metastatic and primary tumors. The need for resection of the primary tumor for patients with unresectable distant metastasis remains controversial. Although initial primary tumor resection is thought to help prevent intestinal obstruction or perforation [9–11], the development of any postoperative complications would obviously delay the start of chemotherapy. The Japanese guidelines for CRC treatment do not mention the prophylactic resection of asymptomatic primary tumors in such cases [12]. The aims of this study were to evaluate the need for primary tumor resection in CRC patients with synchronous unresectable metastases who are undergoing chemotherapy, and to determine the associations between the primary tumor characteristics and the risk of intestinal obstruction or perforation.
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Patients and methods
Table 1 Characteristics of 131 colorectal cancer patients with unresectable metastases
Patients
Factors
Resection (n = 68)
Non-resection (n = 63)
Mean age (SD), years
61.6 (12.8)
64.4 (9.9)
From April 2005 to December 2011, 131 consecutive patients with unresectable stage IV CRC treated at Kumamoto University Hospital were analyzed retrospectively. These patients were stratified into two groups; patients who underwent primary tumor resection were included in the resection group, while those treated with chemotherapy without initial primary tumor resection were included in the non-resection group. The resection group included patients who had no or moderate primary tumor-related symptoms at diagnosis. Patients who had evidence of manifestations that required urgent surgical treatment were excluded from this analysis. All of the patients who did not undergo primary tumor resection had no or minimal symptoms due to CRC. All patients received up-front chemotherapy, using fluorouracil, leucovorin and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), with or without bevacizumab or anti-EGFR antibodies, as initial chemotherapy. The data collected from inpatient and outpatient records included the demographic data (age, gender), location of the tumor, comorbidities, number of metastatic sites, carcinoembryonic antigen (CEA) levels at diagnosis, data on the primary tumor (size, Borrmann classification, histology, presence of a circumferential lesion), therapeutic management (chemotherapy, complications, overall response), the surgical procedure, postoperative morbidity and mortality and clinical outcomes (overall survival). The patients in the non-resection group were followed for subsequent tumor-related complications and underwent surgical intervention if required. The tumor site was classified as the right colon for tumors from the cecum through the transverse colon, and as the left colon for tumors from the splenic flexure to the sigmoid colon and rectum. Statistical analysis The data are expressed as the mean ± standard deviation (SD). A univariate analysis was conducted using the v2 test and Mann–Whitney U test. Actuarial survival was calculated using the Kaplan–Meier method, and was analyzed using the logrank test. All statistical analyses were performed using the StatView for Windows software program, version 5.0 (SAS Institute Inc., Cary, NC, USA). A multivariate Cox regression analysis was performed with the six statistically significant variables. A value of P \ 0.05 was considered to be significant.
Results The clinical characteristics of the 131 patients with unresectable metastases are summarized in Table 1. The two
123
Gender Male Female
42 (62) 26 (38)
43 (67) 20 (33)
18 (28)
20 (34)
0.441
Left colon
21 (31)
25 (36)
Rectum
29 (42)
18 (30)
Comorbidity
0.471
Yes
31 (46)
36 (53)
No
37 (54)
27 (47)
100 %
44 (65)
34 (54)
\100 %
24 (35)
29 (46)
47 (71)
31 (51)
Circumferential rate
0.211
No. of metastatic sites 1 2 C3 CEA level (SD), (ng/mL)
0.088 13 (20)
21 (34)
8 (9) 196.9 (783.9)
11 (15) 488.1 (1182.0)
First-line chemotherapy cytotoxic agents
0.026 0.101
Oxaliplatin based
52 (76)
57 (90)
Irinotecan based
7 (10)
2 (3)
5-FU based
6 (9)
4 (6)
HAI
3 (4)
0 (0)
Combination with targeted therapy
0.217
Anti-VEGF
13 (19)
17 (27)
Anti-EGFR
2 (3)
6 (10)
None
53 (78)
40 (63)
42.7
49.2
Response rate (%)
0.156 0.904
Location of the tumor Right colon
P value
Overall response
0.452 0.600
CR
1 (1)
PR
28 (41)
0 (0) 31 (49)
SD
32 (47)
24 (38)
PD NE
3 (4) 4 (6)
5 (8) 3 (5)
SD standard deviation, M male, F female, CEA carcinoembryonic antigen, HAI hepatic arterial infusion, VEGF vascular endothelial growth factor, EGFR epidermal growth factor receptor, CR complete response, PR partial response, SD stable disease, PD progressive disease, NE not evaluable
groups did not differ significantly with respect to the patient age, gender, tumor site or comorbidities, first-line chemotherapy regimen, response rate or overall response, but the serum CEA level was significantly higher in the non-resection group than in the resection group. In the resection group, 38 (56 %) patients underwent laparoscopic surgery.
Surg Today 1.0
Table 3 The need for subsequent surgical intervention for complications during chemotherapy in the non-resection group
Resection group Nonresection group
Overall survival
0.8 0.6 0.4
Factor
Number of cases (%)
Overall complications
16 (25.4)
Obstruction
13 (20.6)
Perforation
3 (4.8)
Surgical procedure 0.2
Resection
8 (50.0)
Colectomy
8 (50.0)
0.0 0
12
24
36
48
60
Time after treatment (M)
1.0
Surgical intervention
number at risk 53 42
31 25
15 11
6 7
2 4
Fig. 1 The Kaplan–Meier overall survival curves of 131 patients with stage IV colorectal cancer and unresectable distant metastases who did (resection group; n = 68) or did not (non-resection group; n = 63) undergo primary tumor resection. No significant difference in survival was found between the two groups (log-rank test; P = 0.530)
Nonsurgical intervention
0.8
Overall survival
68 63
0.6 0.4 0.2 0.0 0
Table 2 The postoperative complications and mortality in 68 patients who underwent primary tumor resection Complication
Number of cases (%)
Overall
12 (17.6)
Wound infection
6 (8.8)
Anastomotic leakage
2 (2.9)
Hemorrhage
1 (1.5)
Urination disorder
1 (1.5)
Pulmonary infection
1 (1.5)
Pleural effusion Ileus
1 (1.5) 1 (1.5)
Mortality
0 (0)
The Kaplan–Meier survival curves for the resection and non-resection groups are depicted in Fig. 1. The median survival period was 30.4 months in the resection group, and 24.1 months in the non-resection group, which was not significantly different (log-rank P = 0.530). The overall incidence of postoperative complications was 17.6 % (12/68 patients) in the resection group (Table 2). The incidence rates for the most common complications were 8.8 % for wound infections, followed by 2.9 % for anastomotic leakage. There was no postoperative mortality. The median interval between resection and chemotherapy was significantly longer in patients with postoperative complications than in patients without (45 vs. 29 days; P = 0.035).
number at risk 16 47
12
24
36
Time after treatment (M) 13 31
10 16
6 6
Fig. 2 The Kaplan–Meier overall survival curves of 63 non-resection patients who required surgical intervention (surgical intervention group; n = 16) or who did not require surgical intervention (nonsurgical intervention group; n = 47). No significant difference in survival was found between the two groups (log-rank test; P = 0.326)
Table 3 summarizes the information about the nonresection patients who required surgical intervention for complications during chemotherapy; 13 patients required surgical intervention for intestinal obstruction, and three patients required intervention for intestinal perforation related to the primary tumor. The overall incidence of surgical intervention in this group was 25.4 % (16/63 patients). Half of the patients who needed surgical intervention underwent urgent colostomies (8 of 16 patients). Kaplan–Meier survival curves of non-resection patients were made comparing patients who required surgical intervention with those who did not (Fig. 2). There was no significant difference in the survival between the two groups (log-rank P = 0.326). Finally, we analyzed the risk factors for obstruction or perforation of the colorectum in the non-resection group. Both univariate and multivariate analyses were performed to determine the associations between the primary tumor
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Surg Today Table 4 The results of the univariate and multivariate analyses of risk factors for surgical intervention
Variables
Univariate analysis Surgical intervention
Other
12
25
0.446
4
22
1
8
22
0.848
8
25
1
12
31
2.227
4
16
1
100
14
20
\100
2
27
0.314
0.214–3.368
0.815
0.517–9.601
0.283
2.020–61.676
0.006
13
40
0.278–15.153
0.481
3
7
0.270–7.998
0.656
0.002
Borrmann classification Other
0.093–2.149
0.502
Circumferential rate (%)
Borrmann 2
P value
0.848
Over 100
Right colon
95 % CI
0.446
\100 Tumor site Left colon and rectum
11.16 1 0.715
Tumor size (mm)
2.052 1 0.152
Larger than 40
3
18
1.470
Smaller than 40
13
29
1
characteristics and risk of obstruction or perforation. Six variables were included; the histology, pretreatment serum CEA level, tumor site, rate of circumferential primary tumors, the tumor morphology and the tumor size. Only the presence of a circumferential tumor was identified as an independent risk factor for obstruction or perforation (HR = 11.2; 95 % CI: 2.02–61.68; P = 0.006; Table 4).
Discussion In this study, we showed that the resection of primary tumors before chemotherapy is unnecessary in selected patients with synchronous metastatic colorectal cancer. We also determined that the major risk factor for obstruction or perforation during chemotherapy without primary tumor resection is the presence of a circumferential tumor. Although initial resection of asymptomatic primary tumors for stage IV CRC patients has been advocated to prevent complications such as obstruction, perforation or bleeding [13, 14], the primary tumor resection of stage IV CRC has a 20–30 % risk of causing postoperative morbidity, and a 1–6 % risk of perioperative mortality [15–17]. Of the 63 patients whose primary tumors were not resected, 25.4 % eventually required surgical intervention during chemotherapy. However, their survival rate was unaffected by the surgical intervention, even though many of these patients required emergency procedures.
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OR
(-)
CEA level (ng/mL)
OR odds ratio, CI confidence interval, CEA carcinoembryonic antigen
P value
(?) Histology Well differentiated
Multivariate analysis
Recent reports have indicated that resection of the primary tumor is a prognostic factor for survival in stage IV CRC patients. Ferrand et al. [18] and Venderbosch, et al. [19] reported that the resection of primary tumors may be associated with a survival benefit in patients with stage IV CRC prospectively enrolled in multicenter, randomized trials (the FFCD 9601 trial and CAIRO/CAIRO2). However, in these prospective trials, patients were enrolled either at the time of diagnosis or after recovery from resection of the primary lesion, and thus, some patients who recovered insufficiently to receive chemotherapy after primary tumor resection might have been excluded. Further, patients who underwent resections had a lighter disease burden, with a lower serum LDH level, fewer metastatic lesions and less extrahepatic disease. Prospective randomized trials are needed to accurately determine the survival benefit conferred by primary tumor resection. Verhoef et al. [20] also concluded that the resection of the primary tumors in patients with synchronous metastasized CRC is controversial, although data from the literature suggest that resection is a positive prognostic factor for survival. In the present study, we found that circumferential lesions were a risk factor for obstruction or perforation during chemotherapy in cases without primary tumor resection. There are currently no guidelines for identifying patients with primary tumors who are likely to suffer complications and require surgery during systemic therapy.
Surg Today
Poultsides et al. [21] examined several markers for tumor burden (i.e., C2 metastatic sites, or elevated CEA, alkaline phosphatase, lactate hydrogenase or albumin) and found no statistically significant associations with late primary tumor complications. We focused more on the morphological findings of the primary tumor, including the tumor size, presence of a circumferential tumor and the Borrmann’s classification. The only risk factor for obstruction or perforation was the presence of a circumferential tumor. Since circumferential tumors are relatively common, the decision whether to perform prophylactic surgery may depend on whether there are symptoms related to a patient’s primary tumor. In this study, 16 patients (25.4 %) required late surgical intervention. Other studies reported morbidity in 14–19 % of patients related to the primary tumor [22, 23]. Soon after we began to use bevacizumab, we experienced three cases of intestinal perforation related to the primary tumor, and therefore monitored associated symptoms much more stringently in our patients. For this reason, we believe our series showed more frequent morbidity during chemotherapy, but no mortality in the postoperative period. Furthermore, we were able to identify patients who needed surgical intervention at earlier stages. For these reasons, the survival of patients with and without surgical intervention in the non-resection group did not significantly differ. There are some limitations associated with this study that should be addressed. First, this was a single-institution, retrospective study. In Japan, a randomized controlled trial comparing the resection of the primary tumor followed by chemotherapy, with chemotherapy alone in incurable Stage IV CRC (JCOG 1007) is currently ongoing. Second, we experienced no cases that required the use of a colonic stent for obstruction during chemotherapy, which is less invasive than surgery [24, 25]. Our experience using expandable metal stents for obstruction is limited, so we should evaluate this effective procedure in the future. In conclusion, we have shown that the resection of primary tumors before chemotherapy is unnecessary in selected patients with synchronous metastatic colorectal cancer. We also found that the presence of a circumferential tumor is a risk factor for obstruction or perforation during chemotherapy in patients without primary tumor resection. Conflict of interest
The authors report no conflicts of interest.
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2. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, MeryMignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229–37. 3. Douillard JY, Hoff PM, Skillings JR, Eisenberg P, Davidson N, Harper P, et al. Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2002;20:3605–16. 4. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18:2938–47. 5. Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005;23:3502–8. 6. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern cooperative oncology group study E3200. J Clin Oncol. 2007;25:1539–44. 7. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9. 8. Saeki H, Emi Y, Kumashiro R, Otsu H, Kawano H, Ando K, et al. Impact of second-line and later cetuximab-containing therapy and KRAS genotypes in patients with metastatic colorectal cancer: a multicenter study in Japan. Surg Today. 2013;. doi:10.1007/ S00595-013-0716-0. 9. Sarela AI, Guthrie JA, Seymour MT, Ride E, Guillou PJ, O’Riordain DS. Non-operative management of the primary tumour in patients with incurable stage IV colorectal cancer. Br J Surg. 2001;88:1352–6. 10. 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. 11. Costi R, Di Mauro D, Veronesi L, Ardizzoni A, Salcuni P, Roncoroni L, et al. Elective palliative resection of incurable stage IV colorectal cancer: who really benefits from it? Surg Today. 2011;41:222–9. 12. Watanabe T, Itabashi M, Shimada Y, Tanaka S, Ito Y, Ajioka Y, et al. Japanese Society for cancer of the colon and rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer. Int J Clin Oncol. 2012;17:1–29. 13. Bacon HE, Martin PV. The rationale of palliative resection for primary cancer of the colon and rectum complicated by liver and lung metastasis. Dis Colon Rectum. 1964;7:211–7. 14. Oxley EM, Ellis H. Prognosis of carcinoma of the large bowel in the presence of liver metastases. Br J Surg. 1969;56:149–52. 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. Ruo L, Gougoutas C, Paty PB, Guillem JG, Cohen AM, Wong WD. Elective bowel resection for incurable stage IV colorectal cancer: prognostic variables for asymptomatic patients. J Am Coll Surg. 2003;196:722–8. 17. 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. 18. Ferrand F, Malka D, Bourredjem A, Allonier C, Bouche O, Louafi S, et al. Impact of primary tumour resection on survival of
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patients with colorectal cancer and synchronous metastases treated by chemotherapy: results from the multicenter, randomised trial Federation Francophone de Cancerologie Digestive 9601. Eur J Cancer. 2013;49:90–7. 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. Verhoef C, de Wilt JH, Burger JW, Verheul HM, Koopman M. Surgery of the primary in stage IV colorectal cancer with unresectable metastases. Eur J Cancer. 2011;3(47 Suppl):S61–6. Poultsides GA, Servais EL, Saltz LB, Patil S, Kemeny NE, Guillem JG, et al. Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment. J Clin Oncol. 2009;27:3379–84. McCahill LE, Yothers G, Sharif S, Petrelli NJ, Lai LL, Bechar N, et al. Primary mFOLFOX6 plus bevacizumab without resection
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of the primary tumor for patients presenting with surgically unresectable metastatic colon cancer and an intact asymptomatic colon cancer: definitive analysis of NSABP trial C-10. J Clin Oncol. 2012;30:3223–8. 23. Cheynel N, Cortet M, Lepage C, Benoit L, Faivre J, Bouvier AM. Trends in frequency and management of obstructing colorectal cancers in a well-defined population. Dis Colon Rectum. 2007;50:1568–75. 24. Tilney HS, Lovegrove RE, Purkayastha S, Sains PS, WestonPetrides GK, Darzi AW, et al. Comparison of colonic stenting and open surgery for malignant large bowel obstruction. Surg Endosc. 2007;21:225–33. 25. Karoui M, Charachon A, Delbaldo C, Loriau J, Laurent A, Sobhani I, et al. Stents for palliation of obstructive metastatic colon cancer: impact on management and chemotherapy administration. Arch Surg. 2007;142:619–23.
ORIGINAL ARTICLE
Evaluation of the necessity of primary tumor resection for synchronous metastatic colorectal cancer Yuji Miyamoto • Masayuki Watanabe • Yasuo Sakamoto • Hironobu Shigaki • Asuka Murata • Hidetaka Sugihara • Kojiro Etoh • Takatsugu Ishimoto • Masaaki Iwatsuki • Yoshifumi Baba • Shiro Iwagami • Naoya Yoshida • Hideo Baba
Received: 4 February 2013 / Accepted: 16 December 2013 Ó Springer Japan 2014
Abstract Purpose We evaluated the need for primary tumor resection in patients with colorectal cancer (CRC) and synchronous unresectable metastases who underwent chemotherapy, and identified the associations between the primary tumor characteristics and risk of intestinal obstruction or perforation. Methods We retrospectively analyzed the survival and complication rates of patients with synchronous metastatic CRC treated between April 2005 and December 2011. Results Of 131 patients, 68 underwent primary tumor resection before chemotherapy, and 63 were treated without resection before chemotherapy. The overall survival (OS) did not significantly differ between the two groups (log-rank P = 0.53). In the resection group, 12 patients (17.6 %) developed postoperative complications. In the non-resection group, 16 patients (25.4 %) required surgical intervention owing to obstruction or perforation during their treatment. Surgical intervention did not affect the OS. A circumferential tumor was a risk factor for obstruction or perforation of the colorectum in non-resected patients (odds ratio = 11.163; P = 0.006). Conclusion Resection of primary tumors before chemotherapy is unnecessary in selected patients with synchronous metastatic colorectal cancer. A circumferential tumor Y. Miyamoto M. Watanabe Y. Sakamoto H. Shigaki A. Murata H. Sugihara K. Etoh T. Ishimoto M. Iwatsuki Y. Baba S. Iwagami N. Yoshida H. Baba (&) Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan e-mail: [email protected] Y. Miyamoto e-mail: [email protected]
is a risk factor for obstruction or perforation during chemotherapy in cases without primary tumor resection. Keywords
Colorectal cancer Chemotherapy Surgery
Introduction Between 20 and 25 % of patients with colorectal cancer (CRC) present with distant metastases at their initial diagnosis [1]. The treatment outcomes for unresectable CRC have been improved with the introduction of newer chemotherapies and targeted agents. Combinations of infusional fluorouracil/leucovorin with oxaliplatin or irinotecan have brought about better tumor shrinkage effects and improved prognoses [2–4]. Furthermore, the addition of anti-angiogenic agents or anti-EGFR antibodies to the above combinations has provided clinically meaningful improvement in the response rates and survival for these patients [5–8]. Efficacious local control can now be expected for both metastatic and primary tumors. The need for resection of the primary tumor for patients with unresectable distant metastasis remains controversial. Although initial primary tumor resection is thought to help prevent intestinal obstruction or perforation [9–11], the development of any postoperative complications would obviously delay the start of chemotherapy. The Japanese guidelines for CRC treatment do not mention the prophylactic resection of asymptomatic primary tumors in such cases [12]. The aims of this study were to evaluate the need for primary tumor resection in CRC patients with synchronous unresectable metastases who are undergoing chemotherapy, and to determine the associations between the primary tumor characteristics and the risk of intestinal obstruction or perforation.
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Patients and methods
Table 1 Characteristics of 131 colorectal cancer patients with unresectable metastases
Patients
Factors
Resection (n = 68)
Non-resection (n = 63)
Mean age (SD), years
61.6 (12.8)
64.4 (9.9)
From April 2005 to December 2011, 131 consecutive patients with unresectable stage IV CRC treated at Kumamoto University Hospital were analyzed retrospectively. These patients were stratified into two groups; patients who underwent primary tumor resection were included in the resection group, while those treated with chemotherapy without initial primary tumor resection were included in the non-resection group. The resection group included patients who had no or moderate primary tumor-related symptoms at diagnosis. Patients who had evidence of manifestations that required urgent surgical treatment were excluded from this analysis. All of the patients who did not undergo primary tumor resection had no or minimal symptoms due to CRC. All patients received up-front chemotherapy, using fluorouracil, leucovorin and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), with or without bevacizumab or anti-EGFR antibodies, as initial chemotherapy. The data collected from inpatient and outpatient records included the demographic data (age, gender), location of the tumor, comorbidities, number of metastatic sites, carcinoembryonic antigen (CEA) levels at diagnosis, data on the primary tumor (size, Borrmann classification, histology, presence of a circumferential lesion), therapeutic management (chemotherapy, complications, overall response), the surgical procedure, postoperative morbidity and mortality and clinical outcomes (overall survival). The patients in the non-resection group were followed for subsequent tumor-related complications and underwent surgical intervention if required. The tumor site was classified as the right colon for tumors from the cecum through the transverse colon, and as the left colon for tumors from the splenic flexure to the sigmoid colon and rectum. Statistical analysis The data are expressed as the mean ± standard deviation (SD). A univariate analysis was conducted using the v2 test and Mann–Whitney U test. Actuarial survival was calculated using the Kaplan–Meier method, and was analyzed using the logrank test. All statistical analyses were performed using the StatView for Windows software program, version 5.0 (SAS Institute Inc., Cary, NC, USA). A multivariate Cox regression analysis was performed with the six statistically significant variables. A value of P \ 0.05 was considered to be significant.
Results The clinical characteristics of the 131 patients with unresectable metastases are summarized in Table 1. The two
123
Gender Male Female
42 (62) 26 (38)
43 (67) 20 (33)
18 (28)
20 (34)
0.441
Left colon
21 (31)
25 (36)
Rectum
29 (42)
18 (30)
Comorbidity
0.471
Yes
31 (46)
36 (53)
No
37 (54)
27 (47)
100 %
44 (65)
34 (54)
\100 %
24 (35)
29 (46)
47 (71)
31 (51)
Circumferential rate
0.211
No. of metastatic sites 1 2 C3 CEA level (SD), (ng/mL)
0.088 13 (20)
21 (34)
8 (9) 196.9 (783.9)
11 (15) 488.1 (1182.0)
First-line chemotherapy cytotoxic agents
0.026 0.101
Oxaliplatin based
52 (76)
57 (90)
Irinotecan based
7 (10)
2 (3)
5-FU based
6 (9)
4 (6)
HAI
3 (4)
0 (0)
Combination with targeted therapy
0.217
Anti-VEGF
13 (19)
17 (27)
Anti-EGFR
2 (3)
6 (10)
None
53 (78)
40 (63)
42.7
49.2
Response rate (%)
0.156 0.904
Location of the tumor Right colon
P value
Overall response
0.452 0.600
CR
1 (1)
PR
28 (41)
0 (0) 31 (49)
SD
32 (47)
24 (38)
PD NE
3 (4) 4 (6)
5 (8) 3 (5)
SD standard deviation, M male, F female, CEA carcinoembryonic antigen, HAI hepatic arterial infusion, VEGF vascular endothelial growth factor, EGFR epidermal growth factor receptor, CR complete response, PR partial response, SD stable disease, PD progressive disease, NE not evaluable
groups did not differ significantly with respect to the patient age, gender, tumor site or comorbidities, first-line chemotherapy regimen, response rate or overall response, but the serum CEA level was significantly higher in the non-resection group than in the resection group. In the resection group, 38 (56 %) patients underwent laparoscopic surgery.
Surg Today 1.0
Table 3 The need for subsequent surgical intervention for complications during chemotherapy in the non-resection group
Resection group Nonresection group
Overall survival
0.8 0.6 0.4
Factor
Number of cases (%)
Overall complications
16 (25.4)
Obstruction
13 (20.6)
Perforation
3 (4.8)
Surgical procedure 0.2
Resection
8 (50.0)
Colectomy
8 (50.0)
0.0 0
12
24
36
48
60
Time after treatment (M)
1.0
Surgical intervention
number at risk 53 42
31 25
15 11
6 7
2 4
Fig. 1 The Kaplan–Meier overall survival curves of 131 patients with stage IV colorectal cancer and unresectable distant metastases who did (resection group; n = 68) or did not (non-resection group; n = 63) undergo primary tumor resection. No significant difference in survival was found between the two groups (log-rank test; P = 0.530)
Nonsurgical intervention
0.8
Overall survival
68 63
0.6 0.4 0.2 0.0 0
Table 2 The postoperative complications and mortality in 68 patients who underwent primary tumor resection Complication
Number of cases (%)
Overall
12 (17.6)
Wound infection
6 (8.8)
Anastomotic leakage
2 (2.9)
Hemorrhage
1 (1.5)
Urination disorder
1 (1.5)
Pulmonary infection
1 (1.5)
Pleural effusion Ileus
1 (1.5) 1 (1.5)
Mortality
0 (0)
The Kaplan–Meier survival curves for the resection and non-resection groups are depicted in Fig. 1. The median survival period was 30.4 months in the resection group, and 24.1 months in the non-resection group, which was not significantly different (log-rank P = 0.530). The overall incidence of postoperative complications was 17.6 % (12/68 patients) in the resection group (Table 2). The incidence rates for the most common complications were 8.8 % for wound infections, followed by 2.9 % for anastomotic leakage. There was no postoperative mortality. The median interval between resection and chemotherapy was significantly longer in patients with postoperative complications than in patients without (45 vs. 29 days; P = 0.035).
number at risk 16 47
12
24
36
Time after treatment (M) 13 31
10 16
6 6
Fig. 2 The Kaplan–Meier overall survival curves of 63 non-resection patients who required surgical intervention (surgical intervention group; n = 16) or who did not require surgical intervention (nonsurgical intervention group; n = 47). No significant difference in survival was found between the two groups (log-rank test; P = 0.326)
Table 3 summarizes the information about the nonresection patients who required surgical intervention for complications during chemotherapy; 13 patients required surgical intervention for intestinal obstruction, and three patients required intervention for intestinal perforation related to the primary tumor. The overall incidence of surgical intervention in this group was 25.4 % (16/63 patients). Half of the patients who needed surgical intervention underwent urgent colostomies (8 of 16 patients). Kaplan–Meier survival curves of non-resection patients were made comparing patients who required surgical intervention with those who did not (Fig. 2). There was no significant difference in the survival between the two groups (log-rank P = 0.326). Finally, we analyzed the risk factors for obstruction or perforation of the colorectum in the non-resection group. Both univariate and multivariate analyses were performed to determine the associations between the primary tumor
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Surg Today Table 4 The results of the univariate and multivariate analyses of risk factors for surgical intervention
Variables
Univariate analysis Surgical intervention
Other
12
25
0.446
4
22
1
8
22
0.848
8
25
1
12
31
2.227
4
16
1
100
14
20
\100
2
27
0.314
0.214–3.368
0.815
0.517–9.601
0.283
2.020–61.676
0.006
13
40
0.278–15.153
0.481
3
7
0.270–7.998
0.656
0.002
Borrmann classification Other
0.093–2.149
0.502
Circumferential rate (%)
Borrmann 2
P value
0.848
Over 100
Right colon
95 % CI
0.446
\100 Tumor site Left colon and rectum
11.16 1 0.715
Tumor size (mm)
2.052 1 0.152
Larger than 40
3
18
1.470
Smaller than 40
13
29
1
characteristics and risk of obstruction or perforation. Six variables were included; the histology, pretreatment serum CEA level, tumor site, rate of circumferential primary tumors, the tumor morphology and the tumor size. Only the presence of a circumferential tumor was identified as an independent risk factor for obstruction or perforation (HR = 11.2; 95 % CI: 2.02–61.68; P = 0.006; Table 4).
Discussion In this study, we showed that the resection of primary tumors before chemotherapy is unnecessary in selected patients with synchronous metastatic colorectal cancer. We also determined that the major risk factor for obstruction or perforation during chemotherapy without primary tumor resection is the presence of a circumferential tumor. Although initial resection of asymptomatic primary tumors for stage IV CRC patients has been advocated to prevent complications such as obstruction, perforation or bleeding [13, 14], the primary tumor resection of stage IV CRC has a 20–30 % risk of causing postoperative morbidity, and a 1–6 % risk of perioperative mortality [15–17]. Of the 63 patients whose primary tumors were not resected, 25.4 % eventually required surgical intervention during chemotherapy. However, their survival rate was unaffected by the surgical intervention, even though many of these patients required emergency procedures.
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OR
(-)
CEA level (ng/mL)
OR odds ratio, CI confidence interval, CEA carcinoembryonic antigen
P value
(?) Histology Well differentiated
Multivariate analysis
Recent reports have indicated that resection of the primary tumor is a prognostic factor for survival in stage IV CRC patients. Ferrand et al. [18] and Venderbosch, et al. [19] reported that the resection of primary tumors may be associated with a survival benefit in patients with stage IV CRC prospectively enrolled in multicenter, randomized trials (the FFCD 9601 trial and CAIRO/CAIRO2). However, in these prospective trials, patients were enrolled either at the time of diagnosis or after recovery from resection of the primary lesion, and thus, some patients who recovered insufficiently to receive chemotherapy after primary tumor resection might have been excluded. Further, patients who underwent resections had a lighter disease burden, with a lower serum LDH level, fewer metastatic lesions and less extrahepatic disease. Prospective randomized trials are needed to accurately determine the survival benefit conferred by primary tumor resection. Verhoef et al. [20] also concluded that the resection of the primary tumors in patients with synchronous metastasized CRC is controversial, although data from the literature suggest that resection is a positive prognostic factor for survival. In the present study, we found that circumferential lesions were a risk factor for obstruction or perforation during chemotherapy in cases without primary tumor resection. There are currently no guidelines for identifying patients with primary tumors who are likely to suffer complications and require surgery during systemic therapy.
Surg Today
Poultsides et al. [21] examined several markers for tumor burden (i.e., C2 metastatic sites, or elevated CEA, alkaline phosphatase, lactate hydrogenase or albumin) and found no statistically significant associations with late primary tumor complications. We focused more on the morphological findings of the primary tumor, including the tumor size, presence of a circumferential tumor and the Borrmann’s classification. The only risk factor for obstruction or perforation was the presence of a circumferential tumor. Since circumferential tumors are relatively common, the decision whether to perform prophylactic surgery may depend on whether there are symptoms related to a patient’s primary tumor. In this study, 16 patients (25.4 %) required late surgical intervention. Other studies reported morbidity in 14–19 % of patients related to the primary tumor [22, 23]. Soon after we began to use bevacizumab, we experienced three cases of intestinal perforation related to the primary tumor, and therefore monitored associated symptoms much more stringently in our patients. For this reason, we believe our series showed more frequent morbidity during chemotherapy, but no mortality in the postoperative period. Furthermore, we were able to identify patients who needed surgical intervention at earlier stages. For these reasons, the survival of patients with and without surgical intervention in the non-resection group did not significantly differ. There are some limitations associated with this study that should be addressed. First, this was a single-institution, retrospective study. In Japan, a randomized controlled trial comparing the resection of the primary tumor followed by chemotherapy, with chemotherapy alone in incurable Stage IV CRC (JCOG 1007) is currently ongoing. Second, we experienced no cases that required the use of a colonic stent for obstruction during chemotherapy, which is less invasive than surgery [24, 25]. Our experience using expandable metal stents for obstruction is limited, so we should evaluate this effective procedure in the future. In conclusion, we have shown that the resection of primary tumors before chemotherapy is unnecessary in selected patients with synchronous metastatic colorectal cancer. We also found that the presence of a circumferential tumor is a risk factor for obstruction or perforation during chemotherapy in patients without primary tumor resection. Conflict of interest
The authors report no conflicts of interest.
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