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Distinct metastatic patterns in colorectal cancer patients based on primary tumour location
European Journal of Cancer 75 (2017) 3e4
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Letter to the Editor
Distinct metastatic patterns in colorectal cancer patients based on primary tumour location Niek Hugen a,*, Iris D. Nagtegaal b a b
Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
Received 19 December 2016; accepted 2 January 2017
To the Editor:
We read with interest the meta-analysis by Holch et al. regarding the importance of primary tumour location in patients with metastatic colorectal cancer for prognostic and predictive purposes [1]. The authors have performed a thorough analysis in order to summarise the available evidence from clinical studies on this issue. In an era in which genetic and molecular subtyping is rapidly evolving, there is an increasing interest of the oncology community in the relevance of primary tumour location in metastatic colorectal cancer [2]. The authors report that patients with a left-sided tumour (LC) are associated with a better outcome than patients with a right-sided tumour (RC). A recent systematic review even seems to confirm these findings for nonmetastatic patients [3]. However, a satisfactory explanation for the difference in survival is still lacking. It has been suggested that RCs have a distinct molecular profile, and that the improved survival in LCs may be related to a better response to anti-epidermal growth factor receptor (EGFR) therapy, caused by an EGFR inhibitor-sensitive phenotype [1,2]. We think that findings from our previously published autopsy study, in
* Corresponding author: Radboud University Medical Center, Department of Surgery, P.O. Box 9101, HP690, 6500 HB Nijmegen, The Netherlands. Fax: þ31 (0) 24 3540501. E-mail address: [email protected] (N. Hugen). http://dx.doi.org/10.1016/j.ejca.2017.01.003 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
which over 1500 patients with metastatic colorectal cancer were analysed, may support another hypothesis for the differences in survival [4]. In this nationwide autopsy study, a review of pathological and autopsy records of 5817 patients diagnosed with colorectal cancer and who were autopsied between 1991 and 2010 was performed. The study showed differences in patterns of metastatic spread between colon and rectal cancer patients. We reanalysed the data from this study applying the definitions of LC and RC. Tumours were classified as LC if they were found in the splenic flexure up to the rectum and were classified as RC if they were found in the caecum, ascending or transverse colon. A total of 1519 patients with metastatic disease was selected. When applying the definitions of LC and RC it appeared that primary tumour location was associated with differences in metastatic pattern. In LC patients a higher rate of liver metastases (71.2% versus 63.6%, p < 0.002) and lung metastases (36.6% versus 28.6%, p < 0.002) was found when compared with RC, whereas RC was associated with a higher rate of peritoneal metastases (33.6% versus 20.6%, p < 0.0001) and metastases at other sites (37.5% versus 27.9%, p < 0.0001), Table 1. We believe that this should be taken into account when analysing the prognostic and predictive relevance of primary tumour location for targeted therapy in metastatic colorectal cancer patients. Autopsy studies generate insight into the distribution of metastases and may be considered the gold standard
4
N. Hugen, I.D. Nagtegaal / European Journal of Cancer 75 (2017) 3e4
Table 1 Distribution of metastases according to the primary tumour location. Metastatic site
Liver Lung Peritoneum Distant lymph nodes Bone Other sites Brain Kidney Adrenal gland Ovary Heart Omentum Pleura Pancreas Spleen Skin/subcutaneous tissue Mesentery Other
RC
LC
p-Value
N
(%)
N
(%)
342 154 181 120 25 202 10 23 33 19 10 65 34 17 17 22 27 44
63.6 28.6 33.6 22.3 4.6 37.5 1.9 4.3 6.1 3.5 1.9 12.1 6.3 3.2 3.2 4.1 5.0 8.2
698 359 202 203 64 274 39 23 71 22 20 48 42 10 13 34 10 60
71.2 36.6 20.6 20.7 6.5 27.9 4.0 2.3 7.2 2.2 2.0 4.9 4.3 1.0 1.3 3.5 1.0 6.1
0.002 0.002 <0.0001 n.s. n.s. <0.0001 0.026 0.036 n.s. n.s. n.s. <0.0001 n.s. 0.003 0.014 n.s. <0.0001 n.s.
RC, right-sided colon cancer (caecum, ascending and transverse colon); LC, left-sided colon cancer (splenic flexure up to rectum); n.s., not significant.
in the study of cancer metastases. The clinical relevance of findings from autopsy studies has previously been validated [4,5]. Liver and lung metastases, which are potentially curable, are more commonly found in LC patients. Peritoneal metastases, which are associated with poor survival, even after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC), are more commonly found in RC patients. Moreover, palliative chemotherapy for patients with peritoneal metastases has a worse outcome than for patients without peritoneal metastases [6]. We suggest that the differences in metastatic pattern based on primary tumour location may at least partially explain the differences in survival between LC and RC. Interestingly, metastatic patterns differ between colon and rectal cancer patients as well [4,7]. Rectal cancers are less like to metastasise to the peritoneum, but have a higher rate of lung metastases than colon cancers. This can be explained by the anatomical location within the mesorectum and the aberrant venous drainage that bypasses
the liver. It may also explain the better survival for rectal cancer patients compared with colon cancer patients [7]. Based on the differences in metastatic pattern according to location of the primary tumour, we strongly support the inclusion of tumour location as a stratification criterion in future trial designs. We encourage to stratify according to RC, LC (without rectal cancer) and rectal cancer and emphasise that it is crucial to report the metastatic patterns in trials for metastatic cancer. Conflict of interest statement None declared.
References [1] Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials. Eur J Cancer 2016;70:87e98. [2] Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS Wild-metastatic Colorectal Cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol 2016 Oct 10. http://dx.doi.org/10.1001/jamaoncol.2016.3797 [Epub ahead of print]. [3] Petrelli F, Tomasello G, Borgonovo K, Ghidini M, Turati L, Dallera P, et al. Prognostic survival associated with left-sided vs rightsided Colon Cancer: a systematic review and meta-analysis. JAMA Oncol 2016 Oct 27. http://dx.doi.org/10.1001/jamaoncol.2016.4227 [Epub ahead of print]. [4] Hugen N, van de Velde CJ, de Wilt JH, Nagtegaal ID. Metastatic pattern in colorectal cancer is strongly influenced by histological subtype. Ann Oncol 2014;25(3):651e7. [5] Knijn N, van Erning FN, Overbeek LI, Punt CJ, Lemmens VE, Hugen N, et al. Limited effect of lymph node status on the metastatic pattern in colorectal cancer. Oncotarget 2016;7(22): 31699e707. [6] Franko J, Shi Q, Meyers JP, Maughan TS, Adams RA, Seymour MT, et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database. Lancet Oncol 2016 Dec;17(12):1709e19. http: //dx.doi.org/10.1016/S1470-2045(16)30500-9 [Epub 2016 Oct 12]. [7] Riihimaki M, Hemminki A, Sundquist J, Hemminki K. Patterns of metastasis in colon and rectal cancer. Sci Rep 2016;6:29765.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Letter to the Editor
Distinct metastatic patterns in colorectal cancer patients based on primary tumour location Niek Hugen a,*, Iris D. Nagtegaal b a b
Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
Received 19 December 2016; accepted 2 January 2017
To the Editor:
We read with interest the meta-analysis by Holch et al. regarding the importance of primary tumour location in patients with metastatic colorectal cancer for prognostic and predictive purposes [1]. The authors have performed a thorough analysis in order to summarise the available evidence from clinical studies on this issue. In an era in which genetic and molecular subtyping is rapidly evolving, there is an increasing interest of the oncology community in the relevance of primary tumour location in metastatic colorectal cancer [2]. The authors report that patients with a left-sided tumour (LC) are associated with a better outcome than patients with a right-sided tumour (RC). A recent systematic review even seems to confirm these findings for nonmetastatic patients [3]. However, a satisfactory explanation for the difference in survival is still lacking. It has been suggested that RCs have a distinct molecular profile, and that the improved survival in LCs may be related to a better response to anti-epidermal growth factor receptor (EGFR) therapy, caused by an EGFR inhibitor-sensitive phenotype [1,2]. We think that findings from our previously published autopsy study, in
* Corresponding author: Radboud University Medical Center, Department of Surgery, P.O. Box 9101, HP690, 6500 HB Nijmegen, The Netherlands. Fax: þ31 (0) 24 3540501. E-mail address: [email protected] (N. Hugen). http://dx.doi.org/10.1016/j.ejca.2017.01.003 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
which over 1500 patients with metastatic colorectal cancer were analysed, may support another hypothesis for the differences in survival [4]. In this nationwide autopsy study, a review of pathological and autopsy records of 5817 patients diagnosed with colorectal cancer and who were autopsied between 1991 and 2010 was performed. The study showed differences in patterns of metastatic spread between colon and rectal cancer patients. We reanalysed the data from this study applying the definitions of LC and RC. Tumours were classified as LC if they were found in the splenic flexure up to the rectum and were classified as RC if they were found in the caecum, ascending or transverse colon. A total of 1519 patients with metastatic disease was selected. When applying the definitions of LC and RC it appeared that primary tumour location was associated with differences in metastatic pattern. In LC patients a higher rate of liver metastases (71.2% versus 63.6%, p < 0.002) and lung metastases (36.6% versus 28.6%, p < 0.002) was found when compared with RC, whereas RC was associated with a higher rate of peritoneal metastases (33.6% versus 20.6%, p < 0.0001) and metastases at other sites (37.5% versus 27.9%, p < 0.0001), Table 1. We believe that this should be taken into account when analysing the prognostic and predictive relevance of primary tumour location for targeted therapy in metastatic colorectal cancer patients. Autopsy studies generate insight into the distribution of metastases and may be considered the gold standard
4
N. Hugen, I.D. Nagtegaal / European Journal of Cancer 75 (2017) 3e4
Table 1 Distribution of metastases according to the primary tumour location. Metastatic site
Liver Lung Peritoneum Distant lymph nodes Bone Other sites Brain Kidney Adrenal gland Ovary Heart Omentum Pleura Pancreas Spleen Skin/subcutaneous tissue Mesentery Other
RC
LC
p-Value
N
(%)
N
(%)
342 154 181 120 25 202 10 23 33 19 10 65 34 17 17 22 27 44
63.6 28.6 33.6 22.3 4.6 37.5 1.9 4.3 6.1 3.5 1.9 12.1 6.3 3.2 3.2 4.1 5.0 8.2
698 359 202 203 64 274 39 23 71 22 20 48 42 10 13 34 10 60
71.2 36.6 20.6 20.7 6.5 27.9 4.0 2.3 7.2 2.2 2.0 4.9 4.3 1.0 1.3 3.5 1.0 6.1
0.002 0.002 <0.0001 n.s. n.s. <0.0001 0.026 0.036 n.s. n.s. n.s. <0.0001 n.s. 0.003 0.014 n.s. <0.0001 n.s.
RC, right-sided colon cancer (caecum, ascending and transverse colon); LC, left-sided colon cancer (splenic flexure up to rectum); n.s., not significant.
in the study of cancer metastases. The clinical relevance of findings from autopsy studies has previously been validated [4,5]. Liver and lung metastases, which are potentially curable, are more commonly found in LC patients. Peritoneal metastases, which are associated with poor survival, even after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC), are more commonly found in RC patients. Moreover, palliative chemotherapy for patients with peritoneal metastases has a worse outcome than for patients without peritoneal metastases [6]. We suggest that the differences in metastatic pattern based on primary tumour location may at least partially explain the differences in survival between LC and RC. Interestingly, metastatic patterns differ between colon and rectal cancer patients as well [4,7]. Rectal cancers are less like to metastasise to the peritoneum, but have a higher rate of lung metastases than colon cancers. This can be explained by the anatomical location within the mesorectum and the aberrant venous drainage that bypasses
the liver. It may also explain the better survival for rectal cancer patients compared with colon cancer patients [7]. Based on the differences in metastatic pattern according to location of the primary tumour, we strongly support the inclusion of tumour location as a stratification criterion in future trial designs. We encourage to stratify according to RC, LC (without rectal cancer) and rectal cancer and emphasise that it is crucial to report the metastatic patterns in trials for metastatic cancer. Conflict of interest statement None declared.
References [1] Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials. Eur J Cancer 2016;70:87e98. [2] Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS Wild-metastatic Colorectal Cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol 2016 Oct 10. http://dx.doi.org/10.1001/jamaoncol.2016.3797 [Epub ahead of print]. [3] Petrelli F, Tomasello G, Borgonovo K, Ghidini M, Turati L, Dallera P, et al. Prognostic survival associated with left-sided vs rightsided Colon Cancer: a systematic review and meta-analysis. JAMA Oncol 2016 Oct 27. http://dx.doi.org/10.1001/jamaoncol.2016.4227 [Epub ahead of print]. [4] Hugen N, van de Velde CJ, de Wilt JH, Nagtegaal ID. Metastatic pattern in colorectal cancer is strongly influenced by histological subtype. Ann Oncol 2014;25(3):651e7. [5] Knijn N, van Erning FN, Overbeek LI, Punt CJ, Lemmens VE, Hugen N, et al. Limited effect of lymph node status on the metastatic pattern in colorectal cancer. Oncotarget 2016;7(22): 31699e707. [6] Franko J, Shi Q, Meyers JP, Maughan TS, Adams RA, Seymour MT, et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database. Lancet Oncol 2016 Dec;17(12):1709e19. http: //dx.doi.org/10.1016/S1470-2045(16)30500-9 [Epub 2016 Oct 12]. [7] Riihimaki M, Hemminki A, Sundquist J, Hemminki K. Patterns of metastasis in colon and rectal cancer. Sci Rep 2016;6:29765.