- Email: [email protected]
Is sidedness prognostically important across all stages of colorectal cancer?
Comment
By contrast, for patients with low PORTOS, doctors could consider a combination of image-guided radiotherapy and short-term androgen deprivation therapy with luteinizing hormone-releasing hormone agonists. This personalised medicine approach could be enriched by the measurement of tumour hypoxia, which plays a major role in tumour radiosensitivity, and the identification of DNA signatures of genomic instability to improve the planning and prediction outcome of external beam radiotherapy.10 Michel Bolla Grenoble-Alpes University, Grenoble University Hospital, 38043 Grenoble, Cedex 9, France [email protected]
3
4 5
6
7
8
9
I declare no competing interests. 1
2
Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 2012; 380: 2018–27. Wiegel T, Bartowiak D, Bottke D, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol 2014; 66: 243–50.
10
Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological TN0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009; 181: 956–62. European Association of Urology. Guidelines on prostate cancer. Arnhem: European Association of Urology, 2015. Zhao SG, Chang SL, Spratt DE, et al. Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. Lancet Oncol 2016; published online Oct 12. http://dx.doi.org/10.1016/S1470-2045(16)30491-0. Sweeney C, Nakabayashi M, Regan M, et al. The development of intermediate clinical endpoints in cancer of the prostate. J Natl Cancer Inst 2015; 107: djv261. Carrie C, Hasbini A, de Laroche G, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol 2016; 17: 747–56. Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004; 291: 2817–26. Goodwin JF, Schiewer MJ, Dean JL, et al. A hormone-DNA repair circuit governs the response of genotoxic insult. Cancer Discov 2013; 3: 1254–71. Lalonde E, Ishkanian AS, Sykes J, et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol 2014; 15: 1521–32.
Is sidedness prognostically important across all stages of colorectal cancer? Traditionally, colorectal cancer has been topographically divided according to position of the primary tumour, either above or below the peritoneal reflection (ie, separated into colon and rectal cancer, respectively). Differences in terms of epidemiology and patterns of metastasis have been described between these two entities1 and there has been a steady evolutionary divergence in terms of their oncological management. Acceptance of this division has frequently led to either a priori exclusion of one geographical entity or the other from a specific therapeutic trial; or at least stratification to achieve balance between these two separate primary subsites across the groups of such studies. Despite this historical distinction, detailed analyses (gene copy number, expression and miRNA profiles, and DNA methylation) have suggested that, in non-hypermutated tumours, rectal and colonic cancers cannot be separated at the genomic level.2,3 Reporting at the recent American Society of Clinical Oncology meeting, Venook and colleagues4 have shown that tumour sidedness (where right-sided is considered 1480
caecum to hepatic flexure and left-sided is splenic flexure to rectum) is clinically important in terms of outcome in patients with metastatic colorectal cancer. Thus, patients whose initial primary tumour was leftsided, compared with those that were right-sided, exhibited superior overall survival (for Kras-wt tumours, 34·2 months vs 19·4 months; hazard ratio [HR] right side vs left side 1·56 [95% CI 1·32–1·84]; p<0·0001) and progression-free survival (for Kras-wt tumours 11·5 months vs 8·9 months; HR right side vs left side 1·25 [1·08–1·46]; p=0·002). The authors concluded that sidedness should be a stratification factor in trials of metastatic colorectal cancer to ensure balance in this important novel prognostic factor. To complement these data taken from the advanced disease setting, we have analysed tumour specimens plus histopathological and outcome data from two of our own large adjuvant trials (VICTOR trial5 and QUASAR2 trial6) using the same definition of sidedness. We have compared overall survival, relapse-free survival, and survival after relapse in 1935 patients www.thelancet.com/oncology Vol 17 November 2016
Comment
www.thelancet.com/oncology Vol 17 November 2016
A
Left Right
100
Overall survival (%)
70
50
20
0 Number at risk Left Right
Univariate HR 1·42 (95% CI 1·13−1·80); p=0·003 Multivariate HR 1·40 (95% CI 1·07−1·82); p=0·013 0
1
2
3
4
5
1041 541
1013 513
961 476
887 425
705 342
385 185
B
Relapse-free or recurrence-free survival (%)
100
70
50
20 Univariate HR 0·96 (95% CI 0·78−1·20); p=0·74 Multivariate HR 1·14 (95% CI 0·90−1·45); p=0·29
0 0 Number at risk Left 1041 Right 540
1
2
3
4
5
949 472
848 423
757 383
606 315
333 167
4
5
16 5
4 2
C
100
Survival after recurrence (%)
with left-sided versus right-sided primary tumours in a multivariate model which was adjusted for trial, sex, age, chemotherapy (yes vs no), radiotherapy (yes vs no), pathological T stage (4 vs 1/2/3), pathological N stage (1/2 vs 0), and a range of molecular markers (MSI, CIN, and mutational status of KRAS and BRAF).7 The KaplanMeier survival curves are shown in the figure with the results of the univariate and multivariate analyses. In the multivariate analysis, we found that overall survival was significantly improved in patients whose primary tumours were left-sided compared with those with right-sided tumours (n=1582; HR right side vs left side 1·40 [95% CI 1·07–1·82]; p=0·013). Interestingly, sidedness had no significant effect on relapse-free survival (n=1581; HR right side vs left side 1·14 [95% CI 0·90–1·45]; p=0·29), suggesting that rates of recurrence were not significantly lower in patients whose tumours were left sided. The difference in overall survival appears to be a consequence of an increased duration of survival after relapse for those patients with left-sided tumours compared with those with right-sided tumours (n=362; HR right side vs left side 1·53 [95% CI 1·14–2·06]; p=0·004). Consequently, we found that the median survival after relapse for patients with an initial primary tumour on the left side was 2·25 years (95% CI 1·88–2·57) compared with 1·12 years (0·88–1·53) for those with primaries on the right side. Our data appear to confirm that tumour sidedness is prognostically relevant for colorectal cancer. Multivariate analysis suggests that this feature is independent of primary stage, adjuvant treatment, and some genomic markers, which have themselves been previously shown to be somewhat prognostic. However, in isolation, sidedness does not appear independently prognostic in terms of determining risk of recurrence or relapse in the adjuvant setting, but rather dictates outcome or survival once recurrent or metastatic disease is established, in keeping with Venook’s observations. This finding could suggest that recurrences arising from right-sided primary tumours might have an inherently more aggressive phenotype or perhaps that they are more resistant to our current therapeutic options for advanced colorectal cancer than metastases arising from left-sided tumours. Hence, this might be partially a predictive rather than a solely prognostic effect.
70
50
20
0 Number at risk Left Right
Univariate HR 1·84 (95% CI 1·42−2·39); p=4·03×10−6 Multivariate HR 1·53 (95% CI 1·14−2·06); p=0·004 0
1
241 121
173 63
2 3 Analysis time (years) 105 34
45 19
Figure: Kaplan-Meier survival curves showing overall survival, relapse-free or recurrence-free survival, and survival after recurrence for patients whose primary tumours are right sided versus left sided
1481
Comment
Embryologically we know that the left colon is derived from the midgut, whereas the right side of the colon and rectum develop from the hindgut, and there are genomic differences between these tissues that might underlie the observed divergence in outcome. Given that survival differences are still seen despite adjusting for MSI, BRAF, KRAS, and CIN,5 implies that we should be actively pursuing new molecular markers that could define clinical outcome. Additionally, we should now consider sidedness as a stratification factor in clinical therapeutic trials in advanced colorectal cancer, but stratification according to primary topography in the adjuvant setting is not justified.
We declare no competing interests. 1 2
3
4
5
6
7
*David J Kerr, Enric Domingo, Rachel Kerr Radcliffe Department of Medicine (DJK) and Department of Oncology (ED, RK), University of Oxford, Oxford OX3 9DU, UK [email protected]
1482
Riihimäki M, Hemminki A, Sundquist J, Hemminki K. Patterns of metastasis in colon and rectal cancer. Sci Rep 2016; 6: 29765. Gawlick U, Lu KC, Douthit MA, et al. Stage III & IV colon and rectal cancers share a similar genetic profile: a review of the Oregon Colorectal Cancer Registry. Am J Surg 2013; 205: 608–12. The Cancer Genome Atlas Network Collaborators. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487: 330–37. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC): analysis of CALGB/ SWOG 80405 (Alliance). Proc Am Soc Clin Oncol 2016; 34 (suppl): abstr 3504. Midgley RS, McConkey C, Kerr DJ, et al. Final results of the VICTOR trial: a phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer. J Clin Oncol 2010; 28: 4575–80. Kerr RS, Love S, Segelov E, et al. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol 2016; 17: 1543–57. Domingo E, Ramamoorthy R, Oukrif D, et al. Use of multivariate analysis to suggest a new molecular classification of colorectal cancer. J Pathol 2013; 229: 441–48.
www.thelancet.com/oncology Vol 17 November 2016
By contrast, for patients with low PORTOS, doctors could consider a combination of image-guided radiotherapy and short-term androgen deprivation therapy with luteinizing hormone-releasing hormone agonists. This personalised medicine approach could be enriched by the measurement of tumour hypoxia, which plays a major role in tumour radiosensitivity, and the identification of DNA signatures of genomic instability to improve the planning and prediction outcome of external beam radiotherapy.10 Michel Bolla Grenoble-Alpes University, Grenoble University Hospital, 38043 Grenoble, Cedex 9, France [email protected]
3
4 5
6
7
8
9
I declare no competing interests. 1
2
Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 2012; 380: 2018–27. Wiegel T, Bartowiak D, Bottke D, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol 2014; 66: 243–50.
10
Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological TN0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009; 181: 956–62. European Association of Urology. Guidelines on prostate cancer. Arnhem: European Association of Urology, 2015. Zhao SG, Chang SL, Spratt DE, et al. Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. Lancet Oncol 2016; published online Oct 12. http://dx.doi.org/10.1016/S1470-2045(16)30491-0. Sweeney C, Nakabayashi M, Regan M, et al. The development of intermediate clinical endpoints in cancer of the prostate. J Natl Cancer Inst 2015; 107: djv261. Carrie C, Hasbini A, de Laroche G, et al. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial. Lancet Oncol 2016; 17: 747–56. Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004; 291: 2817–26. Goodwin JF, Schiewer MJ, Dean JL, et al. A hormone-DNA repair circuit governs the response of genotoxic insult. Cancer Discov 2013; 3: 1254–71. Lalonde E, Ishkanian AS, Sykes J, et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol 2014; 15: 1521–32.
Is sidedness prognostically important across all stages of colorectal cancer? Traditionally, colorectal cancer has been topographically divided according to position of the primary tumour, either above or below the peritoneal reflection (ie, separated into colon and rectal cancer, respectively). Differences in terms of epidemiology and patterns of metastasis have been described between these two entities1 and there has been a steady evolutionary divergence in terms of their oncological management. Acceptance of this division has frequently led to either a priori exclusion of one geographical entity or the other from a specific therapeutic trial; or at least stratification to achieve balance between these two separate primary subsites across the groups of such studies. Despite this historical distinction, detailed analyses (gene copy number, expression and miRNA profiles, and DNA methylation) have suggested that, in non-hypermutated tumours, rectal and colonic cancers cannot be separated at the genomic level.2,3 Reporting at the recent American Society of Clinical Oncology meeting, Venook and colleagues4 have shown that tumour sidedness (where right-sided is considered 1480
caecum to hepatic flexure and left-sided is splenic flexure to rectum) is clinically important in terms of outcome in patients with metastatic colorectal cancer. Thus, patients whose initial primary tumour was leftsided, compared with those that were right-sided, exhibited superior overall survival (for Kras-wt tumours, 34·2 months vs 19·4 months; hazard ratio [HR] right side vs left side 1·56 [95% CI 1·32–1·84]; p<0·0001) and progression-free survival (for Kras-wt tumours 11·5 months vs 8·9 months; HR right side vs left side 1·25 [1·08–1·46]; p=0·002). The authors concluded that sidedness should be a stratification factor in trials of metastatic colorectal cancer to ensure balance in this important novel prognostic factor. To complement these data taken from the advanced disease setting, we have analysed tumour specimens plus histopathological and outcome data from two of our own large adjuvant trials (VICTOR trial5 and QUASAR2 trial6) using the same definition of sidedness. We have compared overall survival, relapse-free survival, and survival after relapse in 1935 patients www.thelancet.com/oncology Vol 17 November 2016
Comment
www.thelancet.com/oncology Vol 17 November 2016
A
Left Right
100
Overall survival (%)
70
50
20
0 Number at risk Left Right
Univariate HR 1·42 (95% CI 1·13−1·80); p=0·003 Multivariate HR 1·40 (95% CI 1·07−1·82); p=0·013 0
1
2
3
4
5
1041 541
1013 513
961 476
887 425
705 342
385 185
B
Relapse-free or recurrence-free survival (%)
100
70
50
20 Univariate HR 0·96 (95% CI 0·78−1·20); p=0·74 Multivariate HR 1·14 (95% CI 0·90−1·45); p=0·29
0 0 Number at risk Left 1041 Right 540
1
2
3
4
5
949 472
848 423
757 383
606 315
333 167
4
5
16 5
4 2
C
100
Survival after recurrence (%)
with left-sided versus right-sided primary tumours in a multivariate model which was adjusted for trial, sex, age, chemotherapy (yes vs no), radiotherapy (yes vs no), pathological T stage (4 vs 1/2/3), pathological N stage (1/2 vs 0), and a range of molecular markers (MSI, CIN, and mutational status of KRAS and BRAF).7 The KaplanMeier survival curves are shown in the figure with the results of the univariate and multivariate analyses. In the multivariate analysis, we found that overall survival was significantly improved in patients whose primary tumours were left-sided compared with those with right-sided tumours (n=1582; HR right side vs left side 1·40 [95% CI 1·07–1·82]; p=0·013). Interestingly, sidedness had no significant effect on relapse-free survival (n=1581; HR right side vs left side 1·14 [95% CI 0·90–1·45]; p=0·29), suggesting that rates of recurrence were not significantly lower in patients whose tumours were left sided. The difference in overall survival appears to be a consequence of an increased duration of survival after relapse for those patients with left-sided tumours compared with those with right-sided tumours (n=362; HR right side vs left side 1·53 [95% CI 1·14–2·06]; p=0·004). Consequently, we found that the median survival after relapse for patients with an initial primary tumour on the left side was 2·25 years (95% CI 1·88–2·57) compared with 1·12 years (0·88–1·53) for those with primaries on the right side. Our data appear to confirm that tumour sidedness is prognostically relevant for colorectal cancer. Multivariate analysis suggests that this feature is independent of primary stage, adjuvant treatment, and some genomic markers, which have themselves been previously shown to be somewhat prognostic. However, in isolation, sidedness does not appear independently prognostic in terms of determining risk of recurrence or relapse in the adjuvant setting, but rather dictates outcome or survival once recurrent or metastatic disease is established, in keeping with Venook’s observations. This finding could suggest that recurrences arising from right-sided primary tumours might have an inherently more aggressive phenotype or perhaps that they are more resistant to our current therapeutic options for advanced colorectal cancer than metastases arising from left-sided tumours. Hence, this might be partially a predictive rather than a solely prognostic effect.
70
50
20
0 Number at risk Left Right
Univariate HR 1·84 (95% CI 1·42−2·39); p=4·03×10−6 Multivariate HR 1·53 (95% CI 1·14−2·06); p=0·004 0
1
241 121
173 63
2 3 Analysis time (years) 105 34
45 19
Figure: Kaplan-Meier survival curves showing overall survival, relapse-free or recurrence-free survival, and survival after recurrence for patients whose primary tumours are right sided versus left sided
1481
Comment
Embryologically we know that the left colon is derived from the midgut, whereas the right side of the colon and rectum develop from the hindgut, and there are genomic differences between these tissues that might underlie the observed divergence in outcome. Given that survival differences are still seen despite adjusting for MSI, BRAF, KRAS, and CIN,5 implies that we should be actively pursuing new molecular markers that could define clinical outcome. Additionally, we should now consider sidedness as a stratification factor in clinical therapeutic trials in advanced colorectal cancer, but stratification according to primary topography in the adjuvant setting is not justified.
We declare no competing interests. 1 2
3
4
5
6
7
*David J Kerr, Enric Domingo, Rachel Kerr Radcliffe Department of Medicine (DJK) and Department of Oncology (ED, RK), University of Oxford, Oxford OX3 9DU, UK [email protected]
1482
Riihimäki M, Hemminki A, Sundquist J, Hemminki K. Patterns of metastasis in colon and rectal cancer. Sci Rep 2016; 6: 29765. Gawlick U, Lu KC, Douthit MA, et al. Stage III & IV colon and rectal cancers share a similar genetic profile: a review of the Oregon Colorectal Cancer Registry. Am J Surg 2013; 205: 608–12. The Cancer Genome Atlas Network Collaborators. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012; 487: 330–37. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC): analysis of CALGB/ SWOG 80405 (Alliance). Proc Am Soc Clin Oncol 2016; 34 (suppl): abstr 3504. Midgley RS, McConkey C, Kerr DJ, et al. Final results of the VICTOR trial: a phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer. J Clin Oncol 2010; 28: 4575–80. Kerr RS, Love S, Segelov E, et al. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol 2016; 17: 1543–57. Domingo E, Ramamoorthy R, Oukrif D, et al. Use of multivariate analysis to suggest a new molecular classification of colorectal cancer. J Pathol 2013; 229: 441–48.
www.thelancet.com/oncology Vol 17 November 2016