- Email: [email protected]
Cetuximab in metastatic colorectal cancer
Reflection and Reaction
When this trial was planned the importance of HPV was not known, and consequently the HPV status of the patients was not investigated. However, retrospectively, it would have been of great value if the authors had addressed the issue and had tested for HPV status (as has been done more recently in a number of other clinical trials, including the Danish DAHANCA 19). Thus, efforts should be taken to re-collect the pre-treatment tumour material in the trial by Bonner and colleagues to analyse HPV or P16 protein status as an indirect marker of HPV aetiology, just like they did upfront when estimating the EGFR-expression pattern. Doing so will add important new information to their original data, and eventually focus and adjust the indications for the use of cetuximab in advanced head and neck cancer. Furthermore, such data could provide new insight into the relation between HPV status, EGFR expression, and fractionated radiotherapy.
Jesper Grau Eriksen*, Pernille Lassen, Jens Overgaard Department of Oncology, Odense University Hospital, Odense (JGE); Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (PL, JO), Denmark [email protected] The authors declared no conflicts of interest. 1
2
3
4
5
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010; 11: 21–28. Bernier J, Schneider D. Cetuximab combined with radiotherapy: an alternative to chemo-radiotherapy for patients with locally advanced squamous cell carcinomas of the head and neck? Eur J Cancer 2007; 43: 35–45. Pignon JP, le Maître A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009; 92: 4–14. Lassen P, Eriksen JG, Dutoit SH, et al. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck: results from the DAHANCA 5 study. J Clin Oncol 2009; 27: 1992–98. Lassen P, Eriksen JG, Dutoit SH, et al. HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer. Radiother Oncol 2010; 94: 30–35.
Cetuximab in metastatic colorectal cancer
www.thelancet.com/oncology Vol 11 April 2010
Third, an important issue that is not discussed is the association between KRAS status and R0 resection rate. In 2008, Folprecht and colleagues2 reported on resectability rates in the same cohort of patients. R0 resection was achieved in 23 of 67 (34%) patients with wild-type KRAS, and in 13 of 39 (33%) patients with either KRAS (n=29) or BRAF (n=3) mutations or unknown KRAS status (n=7). Assuming a normal KRAS status distribution among the seven patients with unknown KRAS status, the R0 resectability still remains identical in KRAS wild-type or mutated tumours. Thus, compared with patients with KRAS mutations who had a response rate of only 41%, the high response rate of the KRAS wild-type patients (70%) did not translate into a higher rate of R0 resection. Failure of cetuximab to increase the actual resectability rate in KRAS wild-type compared with mutated tumours, lack of increased resectability following treatment compared with pretreatment assessment, and use of theoretical resectability rates do not support the assumption that cetuximab-based therapy improves resectability rate of liver metastases in patients with wild-type KRAS. Therefore this assumption should be tested in a larger prospective trial.
Astrid and Hanns-Frieder Michler/Science Photo Library
In the January 2010 issue of The Lancet Oncology, Folprecht and colleagues1 explored the R0 resectionrate in 106 patients with unresectable colorectal liver metastases treated with cetuximab-based therapy. We have several concerns regarding the interpretation of the study results. First, the authors concluded that chemotherapy with cetuximab leads to significantly increased resectability.1 However, this conclusion was solely based on theoretical resectability deduced from imaging. Theoretical resectability is not a valid endpoint in oncological studies. Indeed, the discrepancy between actual and theoretical resectability observed in this study shows the failure to correctly predict resectability, and emphasises the need to use actual events as the basis for decision making. Despite the small number of patients receiving surgical intervention, the authors should have based their conclusions on actual R0 rates, or a predefined secondary endpoint. Second, although unresectability was defined as an inclusion criteria, preoperative imaging showed that 32% of the patients were potentially resectable. Thus, the observed R0 resectability rates (34%) were not increased after treatment and remained similar to the expected rates based on pretreatment assessment.
Ido Wolf*, Talia Golan, Adi Shani, Dan Aderka 313
Reflection and Reaction
Sheba Medical Center, Ramat-Gan, Israel [email protected] The authors declared no conflicts of interest. 1
2
Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 2010; 11: 38–47. Folprecht G, Gruenberger T, Hartmann JT, et al. Randomized multicenter study of cetuximab plus FOLFOX or plus FOLFIRI in neoadjuvant treatment of non-resectable colorectal liver metastases (celim-study). Ann Oncol 2008; 19: 168.
Authors’ reply For a better understanding of the CELIM (cetuximab and either FOLFOX6 or FOLFIRI in neoadjuvant treatment of unresectable colorectal liver metastases) study1 we would like to distinguish between actual resectability (based on imaging data and additional clinical information, ie, results of previous laparotomy, disease-free interval, liver function) and imaging resectability. Most trials in this setting report actual resectability only. Our study showed an increase in the actual resectability from 0% at baseline to 34% following treatment. Although clinically important, the limitation of actual resectability is that the decision to resect or not is a complex process that cannot be measured simply and objectively at different time points. We therefore used an imaging review to measure potential changes in patient resectability over time. To increase the objectivity of this assessment, surgeons were blinded to all clinical data, and to the time point at which the images were taken. The differences between these two assessments were obvious after treatment, with 34% of patients actually resected compared with 60% of patients who were resectable according to imaging alone. We believe that the changes in imaging resectability are important because they confirm that neoadjuvant treatment helps with, or
even enables, liver resection. As both the actual (0–34%) and imaging (32–60%) resectability were improved after treatment, we concluded that chemotherapy with cetuximab leads to increased resectability. In the absence of a chemotherapy-alone group, we did not draw any conclusions regarding the contribution of cetuximab, but referred to the CRYSTAL trial2 (cetuximab and FOLFIRI or FOLFIRI) which reported increased R0resectability with the cetuximab combination. The number of patients in the CELIM trial limits extensive subgroup analyses. Therefore, we did not report the R0-resection rate according to the KRAS status which was—with wide confidence intervals— slightly higher in patients with KRAS wild-type (22 of 67, 33% [95% CI: 22–45%]) than in KRAS-mutant tumours (eight of 27, 30% [14–50%]) and highest in patients with unknown KRAS status (six of 12, 50% [21–79%]). We think that the wide confidence intervals prevent firm conclusions, particularly regarding the proof or an absence of differences in resection rates between the KRAS subgroups. Gunnar Folprecht*, Claus-Henning Köhne University Hospital Carl Gustav Carus, Medical Department I, University Cancer Center, Dresden, Germany [email protected] GF has received honoraria from MerckSerono, Pfizer, Sanofi-Aventis, Roche, and Amgen, and has provided an advisory role for MerckSerono, Abbott, Genentech and Roche. Both authors have received research funding from MerckSerono, Pfizer, and Sanofi-Aventis. 1
2.
Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 2010; 11: 38–47. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360: 1408–17.
In the interest of full disclosure We read the recent article by Albain and colleagues1 with interest. In this translational study, the 21-gene recurrence assay (Genomic Health, Redwood City, CA, USA) was successfully performed on 601 samples from Southwest Oncology Group-8814, INT-0100. We were surprised that results were not reported for the 234 tissue samples from patients who received cyclophosphamide, doxorubicin, and fluorouracil with concurrent tamoxifen (CAFT). This subset was excluded after the results were 314
obtained despite comprising more than a third of the successful 21-gene assays in the study. Albain and colleagues1 state that they excluded the CAFT subset because of inferior efficacy compared with cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen (CAF-T). However, the original study was powered to compare disease-free survival in the chemotherapy groups (CAF-T plus CAFT) versus the tamoxifen-alone group. The combined chemotherapy www.thelancet.com/oncology Vol 11 April 2010
When this trial was planned the importance of HPV was not known, and consequently the HPV status of the patients was not investigated. However, retrospectively, it would have been of great value if the authors had addressed the issue and had tested for HPV status (as has been done more recently in a number of other clinical trials, including the Danish DAHANCA 19). Thus, efforts should be taken to re-collect the pre-treatment tumour material in the trial by Bonner and colleagues to analyse HPV or P16 protein status as an indirect marker of HPV aetiology, just like they did upfront when estimating the EGFR-expression pattern. Doing so will add important new information to their original data, and eventually focus and adjust the indications for the use of cetuximab in advanced head and neck cancer. Furthermore, such data could provide new insight into the relation between HPV status, EGFR expression, and fractionated radiotherapy.
Jesper Grau Eriksen*, Pernille Lassen, Jens Overgaard Department of Oncology, Odense University Hospital, Odense (JGE); Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (PL, JO), Denmark [email protected] The authors declared no conflicts of interest. 1
2
3
4
5
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010; 11: 21–28. Bernier J, Schneider D. Cetuximab combined with radiotherapy: an alternative to chemo-radiotherapy for patients with locally advanced squamous cell carcinomas of the head and neck? Eur J Cancer 2007; 43: 35–45. Pignon JP, le Maître A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009; 92: 4–14. Lassen P, Eriksen JG, Dutoit SH, et al. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck: results from the DAHANCA 5 study. J Clin Oncol 2009; 27: 1992–98. Lassen P, Eriksen JG, Dutoit SH, et al. HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer. Radiother Oncol 2010; 94: 30–35.
Cetuximab in metastatic colorectal cancer
www.thelancet.com/oncology Vol 11 April 2010
Third, an important issue that is not discussed is the association between KRAS status and R0 resection rate. In 2008, Folprecht and colleagues2 reported on resectability rates in the same cohort of patients. R0 resection was achieved in 23 of 67 (34%) patients with wild-type KRAS, and in 13 of 39 (33%) patients with either KRAS (n=29) or BRAF (n=3) mutations or unknown KRAS status (n=7). Assuming a normal KRAS status distribution among the seven patients with unknown KRAS status, the R0 resectability still remains identical in KRAS wild-type or mutated tumours. Thus, compared with patients with KRAS mutations who had a response rate of only 41%, the high response rate of the KRAS wild-type patients (70%) did not translate into a higher rate of R0 resection. Failure of cetuximab to increase the actual resectability rate in KRAS wild-type compared with mutated tumours, lack of increased resectability following treatment compared with pretreatment assessment, and use of theoretical resectability rates do not support the assumption that cetuximab-based therapy improves resectability rate of liver metastases in patients with wild-type KRAS. Therefore this assumption should be tested in a larger prospective trial.
Astrid and Hanns-Frieder Michler/Science Photo Library
In the January 2010 issue of The Lancet Oncology, Folprecht and colleagues1 explored the R0 resectionrate in 106 patients with unresectable colorectal liver metastases treated with cetuximab-based therapy. We have several concerns regarding the interpretation of the study results. First, the authors concluded that chemotherapy with cetuximab leads to significantly increased resectability.1 However, this conclusion was solely based on theoretical resectability deduced from imaging. Theoretical resectability is not a valid endpoint in oncological studies. Indeed, the discrepancy between actual and theoretical resectability observed in this study shows the failure to correctly predict resectability, and emphasises the need to use actual events as the basis for decision making. Despite the small number of patients receiving surgical intervention, the authors should have based their conclusions on actual R0 rates, or a predefined secondary endpoint. Second, although unresectability was defined as an inclusion criteria, preoperative imaging showed that 32% of the patients were potentially resectable. Thus, the observed R0 resectability rates (34%) were not increased after treatment and remained similar to the expected rates based on pretreatment assessment.
Ido Wolf*, Talia Golan, Adi Shani, Dan Aderka 313
Reflection and Reaction
Sheba Medical Center, Ramat-Gan, Israel [email protected] The authors declared no conflicts of interest. 1
2
Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 2010; 11: 38–47. Folprecht G, Gruenberger T, Hartmann JT, et al. Randomized multicenter study of cetuximab plus FOLFOX or plus FOLFIRI in neoadjuvant treatment of non-resectable colorectal liver metastases (celim-study). Ann Oncol 2008; 19: 168.
Authors’ reply For a better understanding of the CELIM (cetuximab and either FOLFOX6 or FOLFIRI in neoadjuvant treatment of unresectable colorectal liver metastases) study1 we would like to distinguish between actual resectability (based on imaging data and additional clinical information, ie, results of previous laparotomy, disease-free interval, liver function) and imaging resectability. Most trials in this setting report actual resectability only. Our study showed an increase in the actual resectability from 0% at baseline to 34% following treatment. Although clinically important, the limitation of actual resectability is that the decision to resect or not is a complex process that cannot be measured simply and objectively at different time points. We therefore used an imaging review to measure potential changes in patient resectability over time. To increase the objectivity of this assessment, surgeons were blinded to all clinical data, and to the time point at which the images were taken. The differences between these two assessments were obvious after treatment, with 34% of patients actually resected compared with 60% of patients who were resectable according to imaging alone. We believe that the changes in imaging resectability are important because they confirm that neoadjuvant treatment helps with, or
even enables, liver resection. As both the actual (0–34%) and imaging (32–60%) resectability were improved after treatment, we concluded that chemotherapy with cetuximab leads to increased resectability. In the absence of a chemotherapy-alone group, we did not draw any conclusions regarding the contribution of cetuximab, but referred to the CRYSTAL trial2 (cetuximab and FOLFIRI or FOLFIRI) which reported increased R0resectability with the cetuximab combination. The number of patients in the CELIM trial limits extensive subgroup analyses. Therefore, we did not report the R0-resection rate according to the KRAS status which was—with wide confidence intervals— slightly higher in patients with KRAS wild-type (22 of 67, 33% [95% CI: 22–45%]) than in KRAS-mutant tumours (eight of 27, 30% [14–50%]) and highest in patients with unknown KRAS status (six of 12, 50% [21–79%]). We think that the wide confidence intervals prevent firm conclusions, particularly regarding the proof or an absence of differences in resection rates between the KRAS subgroups. Gunnar Folprecht*, Claus-Henning Köhne University Hospital Carl Gustav Carus, Medical Department I, University Cancer Center, Dresden, Germany [email protected] GF has received honoraria from MerckSerono, Pfizer, Sanofi-Aventis, Roche, and Amgen, and has provided an advisory role for MerckSerono, Abbott, Genentech and Roche. Both authors have received research funding from MerckSerono, Pfizer, and Sanofi-Aventis. 1
2.
Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 2010; 11: 38–47. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360: 1408–17.
In the interest of full disclosure We read the recent article by Albain and colleagues1 with interest. In this translational study, the 21-gene recurrence assay (Genomic Health, Redwood City, CA, USA) was successfully performed on 601 samples from Southwest Oncology Group-8814, INT-0100. We were surprised that results were not reported for the 234 tissue samples from patients who received cyclophosphamide, doxorubicin, and fluorouracil with concurrent tamoxifen (CAFT). This subset was excluded after the results were 314
obtained despite comprising more than a third of the successful 21-gene assays in the study. Albain and colleagues1 state that they excluded the CAFT subset because of inferior efficacy compared with cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen (CAF-T). However, the original study was powered to compare disease-free survival in the chemotherapy groups (CAF-T plus CAFT) versus the tamoxifen-alone group. The combined chemotherapy www.thelancet.com/oncology Vol 11 April 2010