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Management of patients with asymptomatic colorectal cancer and synchronous irresectable metastases
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Annals of Oncology 19: 1829–1835, 2008 doi:10.1093/annonc/mdn398 Published online 28 July 2008
Management of patients with asymptomatic colorectal cancer and synchronous irresectable metastases M. G. W. Scheer1*, C. E. J. Sloots1, G. J. van der Wilt2 & T. J. M. Ruers3 1 3
Department of Surgery; 2Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Center, Nijmegen; Department of Surgery, The Netherlands Cancer Institute/Anthoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Received 15 May 2008; accepted 21 May 2008
introduction About 25% of patients with colorectal cancer present with liver metastasis at the time of diagnosis [1]. Only a selected group (20%–30%) of these patients is suitable for resection of hepatic metastases. Occasionally, administration of systemic chemotherapy may convert irresectable into resectable disease. Nevertheless, for most patients with stage IV colorectal cancer, the principal goal of treatment is palliation in terms of prolonged survival and quality of life [2]. The most common treatment of stage IV colorectal cancer is to perform a palliative colon resection in order to prevent complications of the primary tumor such as intestinal obstruction, perforation or hemorrhage. After resection of the primary tumor, systemic chemotherapy is administered for further treatment of metastatic disease. Resection of the primary colorectal tumor, however, is associated with a high overall morbidity up to 21% [3]. Due to tumor load, patients suffer from weight loss, malnutrition and a deteriorated overall condition. If postoperative complications arise, systemic
*Correspondence to: Dr M. G. W. Scheer, Department of Surgery, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands; Tel: +31-243617365; Fax: +31-24-3610368; E-mail: [email protected]
chemotherapy needs to be postponed, compromising its beneficial effects. For this reason, there is a tendency to a more conservative approach, especially in asymptomatic patients. In such patients, systemic chemotherapy may be the treatment of choice, reserving tumor resection for patients who develop symptomatic disease. In these patients with metastatic colorectal cancer, novel chemotherapy regimens may result in response rates of up to 50% [4, 5]. Besides the effect of this systemic therapy on the liver metastases, this treatment may also affect the growth rate of the primary tumor, reducing the probability of complications such as bleeding, obstruction and perforation. Moreover, it has been suggested that patients with stage IV colorectal cancer and minimal symptoms from the primary tumor are likely to die of progressive systemic disease before the development of complications related to the primary tumor [6]. At present, both strategies, e.g. initial resection of the primary tumor and initial systemic chemotherapy, are practiced. It is unclear which approach is currently evidence based. It is the aim of this systematic review to compare the complication rate of the two strategies. For this purpose, complication rates after resection of the primary tumor were compared with the rate of complications that occurred when initial treatment consisted of chemotherapy.
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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treatment strategy remains controversial. Resection of the primary tumor followed by chemotherapy when possible versus systemic chemotherapy followed by resection of the primary tumor when necessary are compared in this systematic review. Patients and methods: Seven studies reported series of patients with asymptomatic stage IV colorectal cancer and compared first-line chemotherapy with surgery for the primary tumor (n = 850 patients). Primary outcome measure was the complication rate related to the primary tumor in situ in patients receiving first-line systemic chemotherapy. Results: When leaving the primary tumor in situ, the mean complications were intestinal obstruction in 13.9% [95% confidence interval (CI) 9.6% to 18.8%] and hemorrhage in only 3.0% (95% CI 0.95% to 6.0%) of the patients. After resection, the overall postoperative morbidity ranged from 18.8% to 47.0%. Conclusions: For patients with stage IV colorectal cancer, resection of the asymptomatic primary tumor provides only minimal palliative benefit, can give rise to major morbidity and mortality and therefore potentially delays beneficial systemic chemotherapy. When presenting with asymptomatic disease, initial chemotherapy should be started and resection of the primary tumor should be reserved for the small portion of patients who develop major complications from the primary tumor. Key words: chemotherapy, colorectal cancer, metastases, surgery
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Background: In patients with asymptomatic colorectal cancer with irresectable metastatic disease, the optimal
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patients and methods
statistical analysis
search strategy
inclusion and exclusion criteria Studies were eligible for inclusion when they reported a series of patients presenting with stage IV colorectal cancer (adenocarcinoma) and underwent surgery for the primary colorectal tumor or were treated with systematic chemotherapy. Studies were included if they reported on complications, response and/or survival data. In the case of duplicate publications, only the most recent publication was used.
results study selection Figure 1 shows the flow chart of the search procedure for the publications. Seven publications were identified describing a series of patients with metastatic disease in stadium IV colorectal carcinoma [3, 8–13] (Table 1). No studies were found describing randomization between surgical and nonsurgical treatment of the primary tumor in patients with stage IV colorectal cancer. Of the seven articles included, four studies were retrospective case series [3, 8, 10, 11], two were prospective case series [12, 13] and one article described a retrospective case–control study [13]. Two of the seven articles [8, 13] only described results of initial chemotherapy; the other studies compared both treatments. A total of 850 patients were described in the included studies. Of these 850 patients, 536 patients underwent surgery as initial treatment and 314 patients were initially treated with chemotherapy. Outcome measures are listed for each article included (Tables 2 and 3). The median follow-up of patients initially treated with chemotherapy was reported in four
quality assessment We assessed the quality of trials by using a checklist for the assessment of quality as proposed by Downs (Table 1) [7]. Studies were classified as prospective case studies, retrospective case studies or case–control studies.
data extraction Two investigators independently extracted the data from the literature and collected this information using preformed tables. The extracted data concerned study design, study population, follow-up, interventions, survival, complications, morbidity and mortality. The primary outcome measure was the rate of primary tumor-related complications in patients with stage IV colorectal cancer not undergoing surgery. Secondary outcome measures were complications of patients undergoing surgery of the primary tumor or patients receiving systemic chemotherapy, survival of all patients and rate of curative surgery after treatment with systemic chemotherapy.
Figure 1. Flow chart for selection of relevant publications.
Table 1. Included relevant publications Author
Journal of publication
Year
Study qualitya
Methods
n
Scoggins Sarela Tebbutt Ruo Michel Benoist Muratore
Ann Surg Oncol Br J Surg Gut J Am Coll Surg Gastroenterol Clin Biol Br J Surg Ann Surg Oncol
1999 2001 2003 2003 2004 2005 2006
19 12 20 16 18 21 15
Retrospective case series Retrospective case series Prospective case series Retrospective case series Retrospective case series Retrospective case–control study Prospective case series
66 surgery; 23 chemotherapy/radiotherapy 21 chemotherapy 280 surgery; 82 chemotherapy 127 surgery; 103 chemotherapy 31 surgery; 23 chemotherapy 32 surgery; 27 chemotherapy 35 chemotherapy
a
Study quality as measured by the checklist provided by Downs et al. (maximum score of 32 for the optimal study quality).
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A systematic literature search was conducted using the PubMed database and Cochrane Library. The Pubmed database was searched using the Medical Subjects Heading (MeSH) Terms: [‘‘Colorectal Neoplasms/complications’’ (MeSH) OR Colorectal Neoplasms/drug therapy’’ (MeSH) OR ‘‘Colorectal Neoplasms/mortality’’ (MeSH) OR ‘‘Colorectal Neoplasms/pathology’’ (MeSH) OR ‘‘Colorectal Neoplasms/radiotherapy’’ (MeSH) OR ‘‘Colorectal Neoplasms/surgery’’ (MeSH) OR ‘‘Colorectal Neoplasms/ therapy’’ (MeSH)] AND [‘‘Liver Neoplasms/secondary’’ (MeSH)] with the limits English, Publication Date from 1980/01/01, Humans. Furthermore, the Cochrane Library was searched using the terms colorectal cancer. We augmented this computerized literature search by manually reviewing the reference lists of included studies to identify additional relevant articles. From the initial search results, two investigators (MGWS and CEJS) independently evaluated the abstracts and selected relevant articles matching the selection criteria. Disagreements were resolved by discussion.
Statistical pooling was done using the DerSimonian and Laird randomeffects model of meta-analysis. Results are presented as percentage of all patients in the analyzed studies; 95% confidence intervals for outcomes are reported.
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Table 2. Outcome measures of treatment with chemotherapy as primary therapy Author
No. of patients
First-line chemotherapy
n a
23
Unknown chemotherapy Radiotherapy
– –
Sarela
21
5-FU 5-FU + irinotecan 5-FU + oxaliplatin
15 3 3
Tebbutt
82
5-FU based Other
680% 620%
103
5-FU + leucovorin Radiotherapy
86 23
Michel
23
Oxaliplatin based Irinothecan-based Radiotherapy
19 9 –
Benoist
27
5-FU + leucovorin 5-FU + oxaliplatin 5-FU + irinotecan
9 10 8
Muratore
35
5-FU + oxaliplatin
35
Ruo
%
Median survival (months)
Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula
– 8.7 3 – 29 19 – – 23.2 13.4 3.7 6.1 29 – – – – 21.7 – – – 14.8 0 0 – 5.6 2.9 –
16.6 (4–84)
10.3 (6–18)
8.2
9
14
22 (1–38)
Mean survival 17.7 (95% CI 14–21.5)
5-FU, 5-fluorouracil; CI, confidence interval. a Not reported.
Table 3. Outcome measures of resection of the primary tumor as initial therapy Author Scoggins Tebbutt Ruo Michel Benoist
No. of patients 66 280 127 31 32
Morbidity Majora
Minorb
%
Total
%
Mortality %
Median survival (months)
%
12/66 54/280 5/127 – 2/32
18.2 19.3 3.9 – 6.3
19/66 – 23/127 – 4/32
28.8 – 18.1 – 12.5
31/66 54/280 28/127 – 6/32
47.0 19.3 22.0 – 18.8
4.6 – 1.6 3 0
14.5 (0.3–60) 14 16 21 23 (3–42)
a
Major complications: sepsis, peritonitis, bleeding, anastomotic leakage, kidney failure, obstruction, fistula, pulmonary embolism and intra-abdominal abscess. b Minor complications: wound infection, urinary tract infection, pneumonia, bleeding ulcer, arritmia, ileus, thrombosis, pleural effusion and miscellaneous.
studies [8, 9, 12, 13] and ranged from 18 to 26 months. The follow-up of patients who underwent surgery was reported in two studies and was 23 and 30 months [10, 12]. Postoperative mortality and morbidity were reported in all five studies describing patients who underwent initial resection. However, only two studies reported the period of postoperative follow-up (30 days) [10, 11] Except for the studies of Tebbutt and Muratore, all studies included patients retrospectively. Therefore, no information was available on the criteria to either resect the primary tumor or to start chemotherapy.
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Moreover, comparison of both groups was limited due to differences in the extent of liver involvement, the presence of extra hepatic metastatic disease and the rate of left-sided tumors. Although not statistically significant, larger percentages of liver involvement were reported for the group initially treated with chemotherapy in four of five studies [3, 9–11]. (Table 4). Furthermore, three of five studies reported a higher percentage of extra hepatic disease for the group treated with chemotherapy [9–11], of which one study reported significant differences [11]. In two studies, location of the
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Scoggins
Complications
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Table 4. Extent of metastatic disease en differentiation tumor localization Author
Extent liver involvement Chemo
Scoggins
<25% >25% <25% >25% –
Sarela Tebbutt Ruo Michel
Muratore
<25% >25% –
45% 55% Tumor surface area 88.2 cm2 11% 89% –
Resection
P
67.8% 32.2% –
ns –
–
–
Resection
P
34.8% 4.0% 41.7% 25.0% – 13.0% 59.0%
3% 12% –
– –
20% 44%
0.18 0.02
59% 41% 59.6 cm2
0.1
Pulmb Per/Omc Pulm Per/Om Pulm Per/Om Extrahepd
ns
Pulm
13.0%
16.1%
ns
15.6% 84.4% –
ns
Extrahep
7.4%
6.3%
0.63
–
Pulm Per/Om LNe
11.4% 2.9% 5.7%
–
–
Right-sided versus left-sided tumorsa Chemo Resection Right Left Right Left Colon Rectum Right Left Colon Rectum Right Left Right Left
26.1% 73.9% 35.0% 65.0% 54.0% 46.0% 28.0% 72.0% 65.3% 34.7% 33.3% 66.7% 22.9% 77.1%
47% 53% – 67% 33% 46% 54% 90.3% 9.7% 28.1% 71.9% –
P – –
0.06 0.02 0.03 ns –
a
Left sided: ascending colon, colon transversum; right sided: descending colon, sigmoid, rectum Pulm: pulmonary metastases c Per/Om: peritoneal and/or omental metastases d Extrahep: Extra hepatic disease: pulmonary, peritoneal and/or omental disease e LN: Para-aortic lymph nodes b
primary tumor differed significantly between both treatment groups [3, 11].
outcome measures of initial treatment with chemotherapy In patients initially treated with chemotherapy, the most important tumor-related complication was intestinal obstruction. Intestinal obstruction was described in six of seven studies [3, 8–10, 12, 13] (Table 2). The rate of this complication ranged from 5.6% in the study of Muratore to 29% in the study of Ruo. In the latter study, a high percentage (72%) of left-sided or rectal carcinoma was included. The pooled proportion of patients developing bowel obstruction was 13.9% (95% CI 9.6% to 18.8%, Figure 2A). The proportion of patients with hemorrhage due to the primary tumor was reported in four of seven studies [9–13], ranging from 0% to 3.7%. The pooled proportion of patients who experienced bleeding from the primary tumor across these studies was 3.0% [95% confidence interval (CI) 0.95% to 6.0%]. Peritonitis and fistula due to the unresected tumor were reported in two studies. None of the patients who received chemotherapy as primary treatment developed peritonitis or fistulae. In the study of Tebbutt, 6.1% of the patients initially treated with chemotherapy developed peritonitis or fistulae. effect of chemotherapy Three of seven studies reported on patients in whom curative resection of the primary tumor and its metastases was attempted after downstaging by chemotherapy [8, 9, 13]. Sarela reports one patient (4%), while Benoist and Muratore mention an attempt at curative resection for 48% (13 patients)
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and 43% of the patients, respectively. In the study by Benoist, the attempt was successful in 6 of 13 patients. Three patients underwent one-stage resection of the primary tumor and synchronous resection of the liver metastases. The other three patients underwent a two-stage resection, with resection of the primary tumor in the first stage and treatment of the liver metastases in the second stage. In the study of Muratore, the rate of successful resection was not reported. Complications of chemotherapy were reported in only one study [9], with 37% grades 3–4 toxicity in the group of patients initially treated with chemotherapy.
outcome measures of resection of the primary tumor as initial therapy Five of seven studies described the results of primary tumor resection (Table 3) [3, 9–12]. Of these, postoperative morbidity and mortality were described in four studies [9–12]. Postoperative mortality ranged from 0% in the study of Benoist to 4.6% in the study of Scoggins. Meta-analysis of these four studies showed a mortality of 2.7% (95% CI 1.1% to 5.0%, Figure 2B). Postoperative morbidity ranged from 18.8% to 47.0%. These results included complications of variable severity. Major complications included obstruction (13.2%), hemorrhage (1.5%–3.9%) and sepsis (2.3%–10.6%, Table 3). Pooling of these data resulted in 11.8% (95% CI 4.4% to 22.0%) of patients who experienced major complications after surgery of the primary tumor (Figure 2C). Minor complications were reported in three studies [9–11]. Most common complications were wound infections (5.5%–10.6%) and urinary tract infection (2.4%–6.1%, Table 3). Pooling these data resulted in an overall 20.6%
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Benoist
<25% >25% –
60% 40% 27% 73% –
Extra hepatic disease Chemo
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compared with 14 months in the group initially treated with resection. However, a multivariate analysis revealed that performance status and presence of peritoneal or omental metastases were significant factors affecting survival and that resection status of the primary tumor was not significantly associated with survival. The study of Ruo also reported a significant difference in median survival between the two groups, 16 versus 9 months for the resection and nonresection group, respectively. From a univariate analysis, it was concluded that the number of distant sites involved, metastatic disease confined to the liver and volume of hepatic replacement by the tumor were significant prognostic variables. Also in this study, resection status was not significantly associated with survival.
(95% CI 15.6% to 26.0%) of patients who had minor complications following surgery of the primary tumor.
survival Median survival was described in six of seven included studies (Table 2) [3, 8–12]. For patients who underwent resection of the primary tumor as initial treatment, median survival ranged from 14 to 23 months. For patients with chemotherapy as the first treatment, median survival ranged from 8.2 to 22 months. Two studies reported statistically significant differences in survival between resected and nonresected patients. Tebbutt described a median survival of 8.2 months in the group initially treated with chemotherapy
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discussion The optimal treatment of asymptomatic stage IV colorectal cancer is a challenge. The main goal of therapy is to prolong survival and to maintain quality of life. This systematic review was carried out to investigate the best method of palliation for patients with incurable metastatic colorectal cancer. Special focus was directed to determine the value of primary tumor resection before administration of chemotherapy. No randomized controlled trials were available for analysis. A total of seven studies were included comparing patients who initially underwent resection of the primary tumor with patients who were initially treated with chemotherapy. The retrospective approach in these studies may have resulted in confounding. Patients with more extensive disease and less suitable for primary resection were relatively over-represented
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Figure 2. Forest plots showing (A) proportion of intestinal obstruction in patients treated with chemotherapy as initial therapy; (B) proportion of mortality after resection of the primary tumor and (C) proportion of major complications after resection of the primary tumor.
the influence of the primary colonic tumor localization Carcinomas located in the rectum and sigmoid are known to cause symptoms earlier than carcinomas located on the right side. Four of five studies [3, 10–12] reported higher percentages of left-sided tumors in the group of patients treated with chemotherapy; in two studies, this difference was statistically significant between the two groups (Table 4) [3, 11]. Although all studies reported on the localization of the primary tumor for each group, only four studies mention the location of the tumor that caused symptoms [3, 8, 9, 11]. The study of Michel et al. reported two tumors on the right side (13% of all right-sided lesions) that caused symptoms versus three tumors on the left side (38% of all left-sided tumors). Sarela reported three patients with obstruction: all tumors were located in the sigmoid. These symptomatic tumors comprised 21% of all left-sided tumors included in the study. Identical observations were made by Benoist, who reported that three of four patients who developed symptoms showed a primary tumor located in the sigmoid, comprising 17% of all left-sided tumors versus 11% of all right-sided tumors. Moreover, Ruo reported that of the 30 patients with obstruction caused by the primary tumor, 15 patients had a tumor located in the rectum. So in conclusion, left-sided tumors seem to lead more often to significant symptoms than right-sided lesions (median 21% versus 12%, respectively).
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involvement of liver tissue in metastatic disease is the best predictor for survival, outweighing other factors in multivariate analysis [14, 21, 22]. It is claimed in several studies that initially irresectable metastases can be downsized with chemotherapy to such an extent that they become eligible for one- or two-staged resection of both primary tumor and metastases [23]. An attempt at curative surgery was mentioned in three of seven articles and ranged from 4% to 48% [8, 9, 13]. Thirteen patients (48%) eligible for potentially curative surgery were described in more detail by Benoist. Of these 13 patients, resection was successful in six (22%). In these patients, all metastases were confined to the liver. These results are in agreement with a review carried out by Folprecht, in which the resection rate of patients with metastatic disease confined to the liver was reported to be 33%–54% with microscopically tumor-free margins in 29%–43%. However, in patients with initial extra hepatic metastatic disease, the resection rate was significantly lower, ranging from 1% to 26% [24]. The results from our meta-analysis suggest that for patients with stage IV incurable colorectal cancer, resection of the asymptomatic primary tumor provides only minimal palliative benefit, can give rise to major morbidity and mortality and may potentially delay the administration of systemic chemotherapy. Providing asymptomatic disease initial resection should only be carried out after careful consideration and should mainly be reserved for the small proportion of patients who may develop complications due to the presence of primary tumor. On the other hand, when initial chemotherapy is started and incurable stage IV disease is converted into potentially curative disease, combined resection of both the primary tumor and its metastases should certainly be considered.
references 1. Mella J, Biffin A, Radcliffe AG et al. Population-based audit of colorectal cancer management in two UK health regions. Colorectal Cancer Working Group, Royal College of Surgeons of England Clinical Epidemiology and Audit Unit. Br J Surg 1997; 84: 1731–1736. 2. Millikan KW, Staren ED, Doolas A. Invasive therapy of metastatic colorectal cancer to the liver. Surg Clin North Am 1997; 77: 27–48. 3. Michel P, Roque I, Di FF et al. Colorectal cancer with non-resectable synchronous metastases: should the primary tumor be resected? Gastroenterol Clin Biol 2004; 28: 434–437. 4. de GA, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–2947. 5. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355: 1041–1047. 6. Sarela A, O’Riordain DS. Rectal adenocarcinoma with liver metastases: management of the primary tumour. Br J Surg 2001; 88: 163–164. 7. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998; 52: 377–384. 8. Sarela AI, Guthrie JA, Seymour MT et al. Non-operative management of the primary tumour in patients with incurable stage IV colorectal cancer. Br J Surg 2001; 88: 1352–1356. 9. Benoist S, Pautrat K, Mitry E et al. Treatment strategy for patients with colorectal cancer and synchronous irresectable liver metastases. Br J Surg 2005; 92: 1155–1160.
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in the group treated with chemotherapy, implying a poorer prognosis at the onset for this group (confounding by indication). The main outcome measure was the risk of complications such as obstruction, bleeding and perforation when patients were initially treated with chemotherapy and the primary tumor was left in situ. Meta-analysis revealed that obstruction occurred in 13.9% of the patients. In patients with a left-sided colonic tumor, obstruction occurred more frequently: median percentage of 21% versus 12% in patients with right-sided tumor obstruction. Remarkably, Tebbutt et al. reported a comparable percentage (13.2%) of obstruction in a group of patients after resection of the primary tumor. Major complications like bleeding, peritonitis and fistula were reported to occur occasionally. These data suggest that the majority of patients with incurable stage IV colorectal cancer, who present with only minimal symptoms of the primary tumor, may die of progressive systemic disease before development of any primary tumor-specific complication [6]. In patients with advanced disease, an increased mortality rate has been reported after resection of the primary tumor. Our meta-analysis of the available studies showed a 2.7% mortality rate. However, in related articles concerning patients with stage IV colorectal carcinoma who initially underwent resection of the primary tumor, mortality rates ranged from 5.6% to 10% [14–18]. In the series of Matheme, the perioperative mortality rate after resection of the colorectal primary tumor was 10% in patients with distant metastases versus 3% in patients without distant metastases. Compromised nutritional and immunologic factors in patients with significant systemic disease burden may account for these higher figures [19, 20]. In the studies included, morbidity rates ranged from 18.8% to 47%. These results are comparable with the morbidity rates reported in other studies, ranging from 8.8% to 50% [14–18, 21]. Wide variations in morbidity rates in these studies can possibly be explained by differences in definition of complications. Therefore, a differentiation between major and minor complications was made. Meta-analysis showed that 11.8% of the patients had major complications like hemorrhage, sepsis or anastomotic leakage after resection of the primary tumor. Minor complications, such as wound infection or urinary tract infection, were observed in 20.6% of the patients by metaanalysis. In addition to the reported complications, surgery for the primary tumor can result in a reduction of performance status and may therefore in some cases delay or prevent the initiation of systemic chemotherapy; however, data on this subject are lacking [22]. Median survival was reported in six studies [3, 8–12]. Although the median survival was slightly longer in patients who underwent resection of the primary tumor, these results were statistically significant in only two studies [11, 12]. These same studies revealed in multi-and univariated analysis that the performance status, the presence of peritoneal or omental metastases, the number of distant sites involved or the volume of hepatic replacement by the metastases were significant factors predicting survival. After correcting for this imbalance, resection status of the primary tumor was no longer significantly associated with survival. These results are comparable with other series, indicating that the extent of
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18. Kuo LJ, Leu SY, Liu MC et al. How aggressive should we be in patients with stage IV colorectal cancer? Dis Colon Rectum 2003; 46: 1646–1652. 19. Okuyama K, Onoda S, Tohnosu N et al. The prognostic significance of resection of primary tumor in gastric and colorectal cancer patients with synchronous liver metastasis. Jpn J Surg 1988; 18: 7–17. 20. Mahteme H, Pahlman L, Glimelius B et al. Prognosis after surgery in patients with incurable rectal cancer: a population-based study. Br J Surg 1996; 83: 1116–1120. 21. Rosen SA, Buell JF, Yoshida A et al. Initial presentation with stage IV colorectal cancer: how aggressive should we be? Arch Surg 2000; 135: 530–534. 22. Nash GM, Saltz LB, Kemeny NE et al. Radical resection of rectal cancer primary tumor provides effective local therapy in patients with stage IV disease. Ann Surg Oncol 2002; 9: 954–960. 23. Adam R, Delvart V, Pascal G et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004; 240: 644–657. 24. Folprecht G, Grothey A, Alberts S et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 2005; 16: 1311–1319.
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10. Scoggins CR, Meszoely IM, Blanke CD et al. Nonoperative management of primary colorectal cancer in patients with stage IV disease. Ann Surg Oncol 1999; 6: 651–657. 11. Ruo L, Gougoutas C, Paty PB et al. Elective bowel resection for incurable stage IV colorectal cancer: prognostic variables for asymptomatic patients. J Am Coll Surg 2003; 196: 722–728. 12. Tebbutt NC, Norman AR, Cunningham D et al. Intestinal complications after chemotherapy for patients with unresected primary colorectal cancer and synchronous metastases. Gut 2003; 52: 568–573. 13. Muratore A, Zorzi D, Bouzari H et al. Asymptomatic colorectal cancer with unresectable liver metastases: immediate colorectal resection or up-front systemic chemotherapy? Ann Surg Oncol 2007; 14: 766–770. 14. Liu SK, Church JM, Lavery IC et al. Operation in patients with incurable colon cancer—is it worthwhile? Dis Colon Rectum 1997; 40: 11–14. 15. Makela J, Haukipuro K, Laitinen S et al. Palliative operations for colorectal cancer. Dis Colon Rectum 1990; 33: 846–850. 16. Joffe J, Gordon PH. Palliative resection for colorectal carcinoma. Dis Colon Rectum 1981; 24: 355–360. 17. Law WL, Chan WF, Lee YM et al. Non-curative surgery for colorectal cancer: critical appraisal of outcomes. Int J Colorectal Dis 2004; 19: 197–202.
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Annals of Oncology 19: 1829–1835, 2008 doi:10.1093/annonc/mdn398 Published online 28 July 2008
Management of patients with asymptomatic colorectal cancer and synchronous irresectable metastases M. G. W. Scheer1*, C. E. J. Sloots1, G. J. van der Wilt2 & T. J. M. Ruers3 1 3
Department of Surgery; 2Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Center, Nijmegen; Department of Surgery, The Netherlands Cancer Institute/Anthoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Received 15 May 2008; accepted 21 May 2008
introduction About 25% of patients with colorectal cancer present with liver metastasis at the time of diagnosis [1]. Only a selected group (20%–30%) of these patients is suitable for resection of hepatic metastases. Occasionally, administration of systemic chemotherapy may convert irresectable into resectable disease. Nevertheless, for most patients with stage IV colorectal cancer, the principal goal of treatment is palliation in terms of prolonged survival and quality of life [2]. The most common treatment of stage IV colorectal cancer is to perform a palliative colon resection in order to prevent complications of the primary tumor such as intestinal obstruction, perforation or hemorrhage. After resection of the primary tumor, systemic chemotherapy is administered for further treatment of metastatic disease. Resection of the primary colorectal tumor, however, is associated with a high overall morbidity up to 21% [3]. Due to tumor load, patients suffer from weight loss, malnutrition and a deteriorated overall condition. If postoperative complications arise, systemic
*Correspondence to: Dr M. G. W. Scheer, Department of Surgery, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands; Tel: +31-243617365; Fax: +31-24-3610368; E-mail: [email protected]
chemotherapy needs to be postponed, compromising its beneficial effects. For this reason, there is a tendency to a more conservative approach, especially in asymptomatic patients. In such patients, systemic chemotherapy may be the treatment of choice, reserving tumor resection for patients who develop symptomatic disease. In these patients with metastatic colorectal cancer, novel chemotherapy regimens may result in response rates of up to 50% [4, 5]. Besides the effect of this systemic therapy on the liver metastases, this treatment may also affect the growth rate of the primary tumor, reducing the probability of complications such as bleeding, obstruction and perforation. Moreover, it has been suggested that patients with stage IV colorectal cancer and minimal symptoms from the primary tumor are likely to die of progressive systemic disease before the development of complications related to the primary tumor [6]. At present, both strategies, e.g. initial resection of the primary tumor and initial systemic chemotherapy, are practiced. It is unclear which approach is currently evidence based. It is the aim of this systematic review to compare the complication rate of the two strategies. For this purpose, complication rates after resection of the primary tumor were compared with the rate of complications that occurred when initial treatment consisted of chemotherapy.
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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treatment strategy remains controversial. Resection of the primary tumor followed by chemotherapy when possible versus systemic chemotherapy followed by resection of the primary tumor when necessary are compared in this systematic review. Patients and methods: Seven studies reported series of patients with asymptomatic stage IV colorectal cancer and compared first-line chemotherapy with surgery for the primary tumor (n = 850 patients). Primary outcome measure was the complication rate related to the primary tumor in situ in patients receiving first-line systemic chemotherapy. Results: When leaving the primary tumor in situ, the mean complications were intestinal obstruction in 13.9% [95% confidence interval (CI) 9.6% to 18.8%] and hemorrhage in only 3.0% (95% CI 0.95% to 6.0%) of the patients. After resection, the overall postoperative morbidity ranged from 18.8% to 47.0%. Conclusions: For patients with stage IV colorectal cancer, resection of the asymptomatic primary tumor provides only minimal palliative benefit, can give rise to major morbidity and mortality and therefore potentially delays beneficial systemic chemotherapy. When presenting with asymptomatic disease, initial chemotherapy should be started and resection of the primary tumor should be reserved for the small portion of patients who develop major complications from the primary tumor. Key words: chemotherapy, colorectal cancer, metastases, surgery
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Background: In patients with asymptomatic colorectal cancer with irresectable metastatic disease, the optimal
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patients and methods
statistical analysis
search strategy
inclusion and exclusion criteria Studies were eligible for inclusion when they reported a series of patients presenting with stage IV colorectal cancer (adenocarcinoma) and underwent surgery for the primary colorectal tumor or were treated with systematic chemotherapy. Studies were included if they reported on complications, response and/or survival data. In the case of duplicate publications, only the most recent publication was used.
results study selection Figure 1 shows the flow chart of the search procedure for the publications. Seven publications were identified describing a series of patients with metastatic disease in stadium IV colorectal carcinoma [3, 8–13] (Table 1). No studies were found describing randomization between surgical and nonsurgical treatment of the primary tumor in patients with stage IV colorectal cancer. Of the seven articles included, four studies were retrospective case series [3, 8, 10, 11], two were prospective case series [12, 13] and one article described a retrospective case–control study [13]. Two of the seven articles [8, 13] only described results of initial chemotherapy; the other studies compared both treatments. A total of 850 patients were described in the included studies. Of these 850 patients, 536 patients underwent surgery as initial treatment and 314 patients were initially treated with chemotherapy. Outcome measures are listed for each article included (Tables 2 and 3). The median follow-up of patients initially treated with chemotherapy was reported in four
quality assessment We assessed the quality of trials by using a checklist for the assessment of quality as proposed by Downs (Table 1) [7]. Studies were classified as prospective case studies, retrospective case studies or case–control studies.
data extraction Two investigators independently extracted the data from the literature and collected this information using preformed tables. The extracted data concerned study design, study population, follow-up, interventions, survival, complications, morbidity and mortality. The primary outcome measure was the rate of primary tumor-related complications in patients with stage IV colorectal cancer not undergoing surgery. Secondary outcome measures were complications of patients undergoing surgery of the primary tumor or patients receiving systemic chemotherapy, survival of all patients and rate of curative surgery after treatment with systemic chemotherapy.
Figure 1. Flow chart for selection of relevant publications.
Table 1. Included relevant publications Author
Journal of publication
Year
Study qualitya
Methods
n
Scoggins Sarela Tebbutt Ruo Michel Benoist Muratore
Ann Surg Oncol Br J Surg Gut J Am Coll Surg Gastroenterol Clin Biol Br J Surg Ann Surg Oncol
1999 2001 2003 2003 2004 2005 2006
19 12 20 16 18 21 15
Retrospective case series Retrospective case series Prospective case series Retrospective case series Retrospective case series Retrospective case–control study Prospective case series
66 surgery; 23 chemotherapy/radiotherapy 21 chemotherapy 280 surgery; 82 chemotherapy 127 surgery; 103 chemotherapy 31 surgery; 23 chemotherapy 32 surgery; 27 chemotherapy 35 chemotherapy
a
Study quality as measured by the checklist provided by Downs et al. (maximum score of 32 for the optimal study quality).
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A systematic literature search was conducted using the PubMed database and Cochrane Library. The Pubmed database was searched using the Medical Subjects Heading (MeSH) Terms: [‘‘Colorectal Neoplasms/complications’’ (MeSH) OR Colorectal Neoplasms/drug therapy’’ (MeSH) OR ‘‘Colorectal Neoplasms/mortality’’ (MeSH) OR ‘‘Colorectal Neoplasms/pathology’’ (MeSH) OR ‘‘Colorectal Neoplasms/radiotherapy’’ (MeSH) OR ‘‘Colorectal Neoplasms/surgery’’ (MeSH) OR ‘‘Colorectal Neoplasms/ therapy’’ (MeSH)] AND [‘‘Liver Neoplasms/secondary’’ (MeSH)] with the limits English, Publication Date from 1980/01/01, Humans. Furthermore, the Cochrane Library was searched using the terms colorectal cancer. We augmented this computerized literature search by manually reviewing the reference lists of included studies to identify additional relevant articles. From the initial search results, two investigators (MGWS and CEJS) independently evaluated the abstracts and selected relevant articles matching the selection criteria. Disagreements were resolved by discussion.
Statistical pooling was done using the DerSimonian and Laird randomeffects model of meta-analysis. Results are presented as percentage of all patients in the analyzed studies; 95% confidence intervals for outcomes are reported.
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Table 2. Outcome measures of treatment with chemotherapy as primary therapy Author
No. of patients
First-line chemotherapy
n a
23
Unknown chemotherapy Radiotherapy
– –
Sarela
21
5-FU 5-FU + irinotecan 5-FU + oxaliplatin
15 3 3
Tebbutt
82
5-FU based Other
680% 620%
103
5-FU + leucovorin Radiotherapy
86 23
Michel
23
Oxaliplatin based Irinothecan-based Radiotherapy
19 9 –
Benoist
27
5-FU + leucovorin 5-FU + oxaliplatin 5-FU + irinotecan
9 10 8
Muratore
35
5-FU + oxaliplatin
35
Ruo
%
Median survival (months)
Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula Total of complications Intestinal obstruction Hemorrhage Peritonitis/fistula
– 8.7 3 – 29 19 – – 23.2 13.4 3.7 6.1 29 – – – – 21.7 – – – 14.8 0 0 – 5.6 2.9 –
16.6 (4–84)
10.3 (6–18)
8.2
9
14
22 (1–38)
Mean survival 17.7 (95% CI 14–21.5)
5-FU, 5-fluorouracil; CI, confidence interval. a Not reported.
Table 3. Outcome measures of resection of the primary tumor as initial therapy Author Scoggins Tebbutt Ruo Michel Benoist
No. of patients 66 280 127 31 32
Morbidity Majora
Minorb
%
Total
%
Mortality %
Median survival (months)
%
12/66 54/280 5/127 – 2/32
18.2 19.3 3.9 – 6.3
19/66 – 23/127 – 4/32
28.8 – 18.1 – 12.5
31/66 54/280 28/127 – 6/32
47.0 19.3 22.0 – 18.8
4.6 – 1.6 3 0
14.5 (0.3–60) 14 16 21 23 (3–42)
a
Major complications: sepsis, peritonitis, bleeding, anastomotic leakage, kidney failure, obstruction, fistula, pulmonary embolism and intra-abdominal abscess. b Minor complications: wound infection, urinary tract infection, pneumonia, bleeding ulcer, arritmia, ileus, thrombosis, pleural effusion and miscellaneous.
studies [8, 9, 12, 13] and ranged from 18 to 26 months. The follow-up of patients who underwent surgery was reported in two studies and was 23 and 30 months [10, 12]. Postoperative mortality and morbidity were reported in all five studies describing patients who underwent initial resection. However, only two studies reported the period of postoperative follow-up (30 days) [10, 11] Except for the studies of Tebbutt and Muratore, all studies included patients retrospectively. Therefore, no information was available on the criteria to either resect the primary tumor or to start chemotherapy.
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Moreover, comparison of both groups was limited due to differences in the extent of liver involvement, the presence of extra hepatic metastatic disease and the rate of left-sided tumors. Although not statistically significant, larger percentages of liver involvement were reported for the group initially treated with chemotherapy in four of five studies [3, 9–11]. (Table 4). Furthermore, three of five studies reported a higher percentage of extra hepatic disease for the group treated with chemotherapy [9–11], of which one study reported significant differences [11]. In two studies, location of the
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Scoggins
Complications
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Table 4. Extent of metastatic disease en differentiation tumor localization Author
Extent liver involvement Chemo
Scoggins
<25% >25% <25% >25% –
Sarela Tebbutt Ruo Michel
Muratore
<25% >25% –
45% 55% Tumor surface area 88.2 cm2 11% 89% –
Resection
P
67.8% 32.2% –
ns –
–
–
Resection
P
34.8% 4.0% 41.7% 25.0% – 13.0% 59.0%
3% 12% –
– –
20% 44%
0.18 0.02
59% 41% 59.6 cm2
0.1
Pulmb Per/Omc Pulm Per/Om Pulm Per/Om Extrahepd
ns
Pulm
13.0%
16.1%
ns
15.6% 84.4% –
ns
Extrahep
7.4%
6.3%
0.63
–
Pulm Per/Om LNe
11.4% 2.9% 5.7%
–
–
Right-sided versus left-sided tumorsa Chemo Resection Right Left Right Left Colon Rectum Right Left Colon Rectum Right Left Right Left
26.1% 73.9% 35.0% 65.0% 54.0% 46.0% 28.0% 72.0% 65.3% 34.7% 33.3% 66.7% 22.9% 77.1%
47% 53% – 67% 33% 46% 54% 90.3% 9.7% 28.1% 71.9% –
P – –
0.06 0.02 0.03 ns –
a
Left sided: ascending colon, colon transversum; right sided: descending colon, sigmoid, rectum Pulm: pulmonary metastases c Per/Om: peritoneal and/or omental metastases d Extrahep: Extra hepatic disease: pulmonary, peritoneal and/or omental disease e LN: Para-aortic lymph nodes b
primary tumor differed significantly between both treatment groups [3, 11].
outcome measures of initial treatment with chemotherapy In patients initially treated with chemotherapy, the most important tumor-related complication was intestinal obstruction. Intestinal obstruction was described in six of seven studies [3, 8–10, 12, 13] (Table 2). The rate of this complication ranged from 5.6% in the study of Muratore to 29% in the study of Ruo. In the latter study, a high percentage (72%) of left-sided or rectal carcinoma was included. The pooled proportion of patients developing bowel obstruction was 13.9% (95% CI 9.6% to 18.8%, Figure 2A). The proportion of patients with hemorrhage due to the primary tumor was reported in four of seven studies [9–13], ranging from 0% to 3.7%. The pooled proportion of patients who experienced bleeding from the primary tumor across these studies was 3.0% [95% confidence interval (CI) 0.95% to 6.0%]. Peritonitis and fistula due to the unresected tumor were reported in two studies. None of the patients who received chemotherapy as primary treatment developed peritonitis or fistulae. In the study of Tebbutt, 6.1% of the patients initially treated with chemotherapy developed peritonitis or fistulae. effect of chemotherapy Three of seven studies reported on patients in whom curative resection of the primary tumor and its metastases was attempted after downstaging by chemotherapy [8, 9, 13]. Sarela reports one patient (4%), while Benoist and Muratore mention an attempt at curative resection for 48% (13 patients)
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and 43% of the patients, respectively. In the study by Benoist, the attempt was successful in 6 of 13 patients. Three patients underwent one-stage resection of the primary tumor and synchronous resection of the liver metastases. The other three patients underwent a two-stage resection, with resection of the primary tumor in the first stage and treatment of the liver metastases in the second stage. In the study of Muratore, the rate of successful resection was not reported. Complications of chemotherapy were reported in only one study [9], with 37% grades 3–4 toxicity in the group of patients initially treated with chemotherapy.
outcome measures of resection of the primary tumor as initial therapy Five of seven studies described the results of primary tumor resection (Table 3) [3, 9–12]. Of these, postoperative morbidity and mortality were described in four studies [9–12]. Postoperative mortality ranged from 0% in the study of Benoist to 4.6% in the study of Scoggins. Meta-analysis of these four studies showed a mortality of 2.7% (95% CI 1.1% to 5.0%, Figure 2B). Postoperative morbidity ranged from 18.8% to 47.0%. These results included complications of variable severity. Major complications included obstruction (13.2%), hemorrhage (1.5%–3.9%) and sepsis (2.3%–10.6%, Table 3). Pooling of these data resulted in 11.8% (95% CI 4.4% to 22.0%) of patients who experienced major complications after surgery of the primary tumor (Figure 2C). Minor complications were reported in three studies [9–11]. Most common complications were wound infections (5.5%–10.6%) and urinary tract infection (2.4%–6.1%, Table 3). Pooling these data resulted in an overall 20.6%
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Benoist
<25% >25% –
60% 40% 27% 73% –
Extra hepatic disease Chemo
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compared with 14 months in the group initially treated with resection. However, a multivariate analysis revealed that performance status and presence of peritoneal or omental metastases were significant factors affecting survival and that resection status of the primary tumor was not significantly associated with survival. The study of Ruo also reported a significant difference in median survival between the two groups, 16 versus 9 months for the resection and nonresection group, respectively. From a univariate analysis, it was concluded that the number of distant sites involved, metastatic disease confined to the liver and volume of hepatic replacement by the tumor were significant prognostic variables. Also in this study, resection status was not significantly associated with survival.
(95% CI 15.6% to 26.0%) of patients who had minor complications following surgery of the primary tumor.
survival Median survival was described in six of seven included studies (Table 2) [3, 8–12]. For patients who underwent resection of the primary tumor as initial treatment, median survival ranged from 14 to 23 months. For patients with chemotherapy as the first treatment, median survival ranged from 8.2 to 22 months. Two studies reported statistically significant differences in survival between resected and nonresected patients. Tebbutt described a median survival of 8.2 months in the group initially treated with chemotherapy
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discussion The optimal treatment of asymptomatic stage IV colorectal cancer is a challenge. The main goal of therapy is to prolong survival and to maintain quality of life. This systematic review was carried out to investigate the best method of palliation for patients with incurable metastatic colorectal cancer. Special focus was directed to determine the value of primary tumor resection before administration of chemotherapy. No randomized controlled trials were available for analysis. A total of seven studies were included comparing patients who initially underwent resection of the primary tumor with patients who were initially treated with chemotherapy. The retrospective approach in these studies may have resulted in confounding. Patients with more extensive disease and less suitable for primary resection were relatively over-represented
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Figure 2. Forest plots showing (A) proportion of intestinal obstruction in patients treated with chemotherapy as initial therapy; (B) proportion of mortality after resection of the primary tumor and (C) proportion of major complications after resection of the primary tumor.
the influence of the primary colonic tumor localization Carcinomas located in the rectum and sigmoid are known to cause symptoms earlier than carcinomas located on the right side. Four of five studies [3, 10–12] reported higher percentages of left-sided tumors in the group of patients treated with chemotherapy; in two studies, this difference was statistically significant between the two groups (Table 4) [3, 11]. Although all studies reported on the localization of the primary tumor for each group, only four studies mention the location of the tumor that caused symptoms [3, 8, 9, 11]. The study of Michel et al. reported two tumors on the right side (13% of all right-sided lesions) that caused symptoms versus three tumors on the left side (38% of all left-sided tumors). Sarela reported three patients with obstruction: all tumors were located in the sigmoid. These symptomatic tumors comprised 21% of all left-sided tumors included in the study. Identical observations were made by Benoist, who reported that three of four patients who developed symptoms showed a primary tumor located in the sigmoid, comprising 17% of all left-sided tumors versus 11% of all right-sided tumors. Moreover, Ruo reported that of the 30 patients with obstruction caused by the primary tumor, 15 patients had a tumor located in the rectum. So in conclusion, left-sided tumors seem to lead more often to significant symptoms than right-sided lesions (median 21% versus 12%, respectively).
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involvement of liver tissue in metastatic disease is the best predictor for survival, outweighing other factors in multivariate analysis [14, 21, 22]. It is claimed in several studies that initially irresectable metastases can be downsized with chemotherapy to such an extent that they become eligible for one- or two-staged resection of both primary tumor and metastases [23]. An attempt at curative surgery was mentioned in three of seven articles and ranged from 4% to 48% [8, 9, 13]. Thirteen patients (48%) eligible for potentially curative surgery were described in more detail by Benoist. Of these 13 patients, resection was successful in six (22%). In these patients, all metastases were confined to the liver. These results are in agreement with a review carried out by Folprecht, in which the resection rate of patients with metastatic disease confined to the liver was reported to be 33%–54% with microscopically tumor-free margins in 29%–43%. However, in patients with initial extra hepatic metastatic disease, the resection rate was significantly lower, ranging from 1% to 26% [24]. The results from our meta-analysis suggest that for patients with stage IV incurable colorectal cancer, resection of the asymptomatic primary tumor provides only minimal palliative benefit, can give rise to major morbidity and mortality and may potentially delay the administration of systemic chemotherapy. Providing asymptomatic disease initial resection should only be carried out after careful consideration and should mainly be reserved for the small proportion of patients who may develop complications due to the presence of primary tumor. On the other hand, when initial chemotherapy is started and incurable stage IV disease is converted into potentially curative disease, combined resection of both the primary tumor and its metastases should certainly be considered.
references 1. Mella J, Biffin A, Radcliffe AG et al. Population-based audit of colorectal cancer management in two UK health regions. Colorectal Cancer Working Group, Royal College of Surgeons of England Clinical Epidemiology and Audit Unit. Br J Surg 1997; 84: 1731–1736. 2. Millikan KW, Staren ED, Doolas A. Invasive therapy of metastatic colorectal cancer to the liver. Surg Clin North Am 1997; 77: 27–48. 3. Michel P, Roque I, Di FF et al. Colorectal cancer with non-resectable synchronous metastases: should the primary tumor be resected? Gastroenterol Clin Biol 2004; 28: 434–437. 4. de GA, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–2947. 5. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355: 1041–1047. 6. Sarela A, O’Riordain DS. Rectal adenocarcinoma with liver metastases: management of the primary tumour. Br J Surg 2001; 88: 163–164. 7. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998; 52: 377–384. 8. Sarela AI, Guthrie JA, Seymour MT et al. Non-operative management of the primary tumour in patients with incurable stage IV colorectal cancer. Br J Surg 2001; 88: 1352–1356. 9. Benoist S, Pautrat K, Mitry E et al. Treatment strategy for patients with colorectal cancer and synchronous irresectable liver metastases. Br J Surg 2005; 92: 1155–1160.
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in the group treated with chemotherapy, implying a poorer prognosis at the onset for this group (confounding by indication). The main outcome measure was the risk of complications such as obstruction, bleeding and perforation when patients were initially treated with chemotherapy and the primary tumor was left in situ. Meta-analysis revealed that obstruction occurred in 13.9% of the patients. In patients with a left-sided colonic tumor, obstruction occurred more frequently: median percentage of 21% versus 12% in patients with right-sided tumor obstruction. Remarkably, Tebbutt et al. reported a comparable percentage (13.2%) of obstruction in a group of patients after resection of the primary tumor. Major complications like bleeding, peritonitis and fistula were reported to occur occasionally. These data suggest that the majority of patients with incurable stage IV colorectal cancer, who present with only minimal symptoms of the primary tumor, may die of progressive systemic disease before development of any primary tumor-specific complication [6]. In patients with advanced disease, an increased mortality rate has been reported after resection of the primary tumor. Our meta-analysis of the available studies showed a 2.7% mortality rate. However, in related articles concerning patients with stage IV colorectal carcinoma who initially underwent resection of the primary tumor, mortality rates ranged from 5.6% to 10% [14–18]. In the series of Matheme, the perioperative mortality rate after resection of the colorectal primary tumor was 10% in patients with distant metastases versus 3% in patients without distant metastases. Compromised nutritional and immunologic factors in patients with significant systemic disease burden may account for these higher figures [19, 20]. In the studies included, morbidity rates ranged from 18.8% to 47%. These results are comparable with the morbidity rates reported in other studies, ranging from 8.8% to 50% [14–18, 21]. Wide variations in morbidity rates in these studies can possibly be explained by differences in definition of complications. Therefore, a differentiation between major and minor complications was made. Meta-analysis showed that 11.8% of the patients had major complications like hemorrhage, sepsis or anastomotic leakage after resection of the primary tumor. Minor complications, such as wound infection or urinary tract infection, were observed in 20.6% of the patients by metaanalysis. In addition to the reported complications, surgery for the primary tumor can result in a reduction of performance status and may therefore in some cases delay or prevent the initiation of systemic chemotherapy; however, data on this subject are lacking [22]. Median survival was reported in six studies [3, 8–12]. Although the median survival was slightly longer in patients who underwent resection of the primary tumor, these results were statistically significant in only two studies [11, 12]. These same studies revealed in multi-and univariated analysis that the performance status, the presence of peritoneal or omental metastases, the number of distant sites involved or the volume of hepatic replacement by the metastases were significant factors predicting survival. After correcting for this imbalance, resection status of the primary tumor was no longer significantly associated with survival. These results are comparable with other series, indicating that the extent of
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18. Kuo LJ, Leu SY, Liu MC et al. How aggressive should we be in patients with stage IV colorectal cancer? Dis Colon Rectum 2003; 46: 1646–1652. 19. Okuyama K, Onoda S, Tohnosu N et al. The prognostic significance of resection of primary tumor in gastric and colorectal cancer patients with synchronous liver metastasis. Jpn J Surg 1988; 18: 7–17. 20. Mahteme H, Pahlman L, Glimelius B et al. Prognosis after surgery in patients with incurable rectal cancer: a population-based study. Br J Surg 1996; 83: 1116–1120. 21. Rosen SA, Buell JF, Yoshida A et al. Initial presentation with stage IV colorectal cancer: how aggressive should we be? Arch Surg 2000; 135: 530–534. 22. Nash GM, Saltz LB, Kemeny NE et al. Radical resection of rectal cancer primary tumor provides effective local therapy in patients with stage IV disease. Ann Surg Oncol 2002; 9: 954–960. 23. Adam R, Delvart V, Pascal G et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004; 240: 644–657. 24. Folprecht G, Grothey A, Alberts S et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 2005; 16: 1311–1319.
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10. Scoggins CR, Meszoely IM, Blanke CD et al. Nonoperative management of primary colorectal cancer in patients with stage IV disease. Ann Surg Oncol 1999; 6: 651–657. 11. Ruo L, Gougoutas C, Paty PB et al. Elective bowel resection for incurable stage IV colorectal cancer: prognostic variables for asymptomatic patients. J Am Coll Surg 2003; 196: 722–728. 12. Tebbutt NC, Norman AR, Cunningham D et al. Intestinal complications after chemotherapy for patients with unresected primary colorectal cancer and synchronous metastases. Gut 2003; 52: 568–573. 13. Muratore A, Zorzi D, Bouzari H et al. Asymptomatic colorectal cancer with unresectable liver metastases: immediate colorectal resection or up-front systemic chemotherapy? Ann Surg Oncol 2007; 14: 766–770. 14. Liu SK, Church JM, Lavery IC et al. Operation in patients with incurable colon cancer—is it worthwhile? Dis Colon Rectum 1997; 40: 11–14. 15. Makela J, Haukipuro K, Laitinen S et al. Palliative operations for colorectal cancer. Dis Colon Rectum 1990; 33: 846–850. 16. Joffe J, Gordon PH. Palliative resection for colorectal carcinoma. Dis Colon Rectum 1981; 24: 355–360. 17. Law WL, Chan WF, Lee YM et al. Non-curative surgery for colorectal cancer: critical appraisal of outcomes. Int J Colorectal Dis 2004; 19: 197–202.
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