Commentary: Adjuvant Chemotherapy in Stage II Colon Cancer, August 2022

This month brought us findings from DYNAMIC, a randomized trial of circulating tumor DNA (ctDNA), which aimed to provide guidance on the use of adjuvant chemotherapy in stage II colon cancer. This study has already been touted on oncology Twitter as a massive breakthrough for identifying patients with stage II colon cancer who would benefit from adjuvant chemotherapy. Does the reality live up to the hype? Let's break it down.

Patients with resected stage II colon cancer were eligible for enrollment. Two thirds of patients were randomly assigned to the ctDNA guidance arm, whereas the remaining third had chemotherapy guidance based on clinicopathologic high-risk features (T4, poor differentiation, < 12 lymph nodes in surgical sample, lymphovascular invasion, tumor perforation, or bowel obstruction). Chemotherapy choice was left up to the clinician and could be an oxaliplatin-based doublet or a single-agent fluoropyrimidine. The primary endpoint was recurrence-free survival at 2 years. A key secondary endpoint was chemotherapy treatment frequency by arm. A total of 459 patients were enrolled from 23 Australian centers over 4 years. Approximately 40% of patients were considered to be at high risk for recurrence on the basis of their tumors' clinicopathologic features. Approximately 20% of patients had tumors that were mismatch repair deficient.

There was no difference in 2-year recurrence-free survival between the two arms (93.5% vs 92.4%; 95% CI -4.1 to 6.2). This met criteria for noninferiority. However, chemotherapy administration in the two arms was markedly different. A significantly greater proportion of patients randomly assigned to the standard management arm received chemotherapy (28% vs 15%; relative risk [RR] 1.82; 95% CI 1.25-2.65). However, a significantly greater proportion of patients guided by ctDNA received an oxaliplatin-based doublet (62% vs 10%; RR 2.39; 95% CI 1.62-3.52). Clearly, when clinicians were presented with a positive ctDNA test, they overwhelmingly opted to give an oxaliplatin-based doublet rather than a single-agent fluoropyrimidine. Oxaliplatin's use in stage II colon cancer remains very controversial; it is oxaliplatin that causes most of the long-term toxicity associated with adjuvant chemotherapy for colorectal cancer. Although ctDNA testing might lower the total proportion of patients who received adjuvant treatment, it significantly raised the proportion who received oxaliplatin. I doubt this is a worthy trade-off.

Furthermore, clinicopathologic factors were still highly relevant in patients with ctDNA-negative results. Among ctDNA-negative patients, 3-year recurrence-free survival was higher in patients with clinicopathologic low-risk cancers than in those with high-risk cancers (96.7% vs 85.1%; hazard ratio 3.04; 95% CI 1.26-7.34). This strongly suggests that ctDNA testing is unlikely to replace clinicopathologic high-risk features in the real-world practice of clinical oncology. Rather, ctDNA testing will probably be added to the list of high-risk features, prompting use of more chemotherapy, not less, for stage II colon cancer.

A more useful study, in my opinion, should be performed in stage III colon cancer. Patients with stage III colon cancer receive chemotherapy without exception, although we know from MOSAIC that the absolute benefit of chemotherapy in stage III colon cancer is modest. What proportion of these patients who have a negative ctDNA test might be able to either forgo treatment completely or have treatment with a fluoropyrimidine only? That's something I would be very interested to find out.

This month brought us findings from DYNAMIC, a randomized trial of circulating tumor DNA (ctDNA), which aimed to provide guidance on the use of adjuvant chemotherapy in stage II colon cancer. This study has already been touted on oncology Twitter as a massive breakthrough for identifying patients with stage II colon cancer who would benefit from adjuvant chemotherapy. Does the reality live up to the hype? Let's break it down.

Patients with resected stage II colon cancer were eligible for enrollment. Two thirds of patients were randomly assigned to the ctDNA guidance arm, whereas the remaining third had chemotherapy guidance based on clinicopathologic high-risk features (T4, poor differentiation, < 12 lymph nodes in surgical sample, lymphovascular invasion, tumor perforation, or bowel obstruction). Chemotherapy choice was left up to the clinician and could be an oxaliplatin-based doublet or a single-agent fluoropyrimidine. The primary endpoint was recurrence-free survival at 2 years. A key secondary endpoint was chemotherapy treatment frequency by arm. A total of 459 patients were enrolled from 23 Australian centers over 4 years. Approximately 40% of patients were considered to be at high risk for recurrence on the basis of their tumors' clinicopathologic features. Approximately 20% of patients had tumors that were mismatch repair deficient.

There was no difference in 2-year recurrence-free survival between the two arms (93.5% vs 92.4%; 95% CI -4.1 to 6.2). This met criteria for noninferiority. However, chemotherapy administration in the two arms was markedly different. A significantly greater proportion of patients randomly assigned to the standard management arm received chemotherapy (28% vs 15%; relative risk [RR] 1.82; 95% CI 1.25-2.65). However, a significantly greater proportion of patients guided by ctDNA received an oxaliplatin-based doublet (62% vs 10%; RR 2.39; 95% CI 1.62-3.52). Clearly, when clinicians were presented with a positive ctDNA test, they overwhelmingly opted to give an oxaliplatin-based doublet rather than a single-agent fluoropyrimidine. Oxaliplatin's use in stage II colon cancer remains very controversial; it is oxaliplatin that causes most of the long-term toxicity associated with adjuvant chemotherapy for colorectal cancer. Although ctDNA testing might lower the total proportion of patients who received adjuvant treatment, it significantly raised the proportion who received oxaliplatin. I doubt this is a worthy trade-off.

Furthermore, clinicopathologic factors were still highly relevant in patients with ctDNA-negative results. Among ctDNA-negative patients, 3-year recurrence-free survival was higher in patients with clinicopathologic low-risk cancers than in those with high-risk cancers (96.7% vs 85.1%; hazard ratio 3.04; 95% CI 1.26-7.34). This strongly suggests that ctDNA testing is unlikely to replace clinicopathologic high-risk features in the real-world practice of clinical oncology. Rather, ctDNA testing will probably be added to the list of high-risk features, prompting use of more chemotherapy, not less, for stage II colon cancer.

A more useful study, in my opinion, should be performed in stage III colon cancer. Patients with stage III colon cancer receive chemotherapy without exception, although we know from MOSAIC that the absolute benefit of chemotherapy in stage III colon cancer is modest. What proportion of these patients who have a negative ctDNA test might be able to either forgo treatment completely or have treatment with a fluoropyrimidine only? That's something I would be very interested to find out.

This month brought us findings from DYNAMIC, a randomized trial of circulating tumor DNA (ctDNA), which aimed to provide guidance on the use of adjuvant chemotherapy in stage II colon cancer. This study has already been touted on oncology Twitter as a massive breakthrough for identifying patients with stage II colon cancer who would benefit from adjuvant chemotherapy. Does the reality live up to the hype? Let's break it down.

Patients with resected stage II colon cancer were eligible for enrollment. Two thirds of patients were randomly assigned to the ctDNA guidance arm, whereas the remaining third had chemotherapy guidance based on clinicopathologic high-risk features (T4, poor differentiation, < 12 lymph nodes in surgical sample, lymphovascular invasion, tumor perforation, or bowel obstruction). Chemotherapy choice was left up to the clinician and could be an oxaliplatin-based doublet or a single-agent fluoropyrimidine. The primary endpoint was recurrence-free survival at 2 years. A key secondary endpoint was chemotherapy treatment frequency by arm. A total of 459 patients were enrolled from 23 Australian centers over 4 years. Approximately 40% of patients were considered to be at high risk for recurrence on the basis of their tumors' clinicopathologic features. Approximately 20% of patients had tumors that were mismatch repair deficient.

There was no difference in 2-year recurrence-free survival between the two arms (93.5% vs 92.4%; 95% CI -4.1 to 6.2). This met criteria for noninferiority. However, chemotherapy administration in the two arms was markedly different. A significantly greater proportion of patients randomly assigned to the standard management arm received chemotherapy (28% vs 15%; relative risk [RR] 1.82; 95% CI 1.25-2.65). However, a significantly greater proportion of patients guided by ctDNA received an oxaliplatin-based doublet (62% vs 10%; RR 2.39; 95% CI 1.62-3.52). Clearly, when clinicians were presented with a positive ctDNA test, they overwhelmingly opted to give an oxaliplatin-based doublet rather than a single-agent fluoropyrimidine. Oxaliplatin's use in stage II colon cancer remains very controversial; it is oxaliplatin that causes most of the long-term toxicity associated with adjuvant chemotherapy for colorectal cancer. Although ctDNA testing might lower the total proportion of patients who received adjuvant treatment, it significantly raised the proportion who received oxaliplatin. I doubt this is a worthy trade-off.

Furthermore, clinicopathologic factors were still highly relevant in patients with ctDNA-negative results. Among ctDNA-negative patients, 3-year recurrence-free survival was higher in patients with clinicopathologic low-risk cancers than in those with high-risk cancers (96.7% vs 85.1%; hazard ratio 3.04; 95% CI 1.26-7.34). This strongly suggests that ctDNA testing is unlikely to replace clinicopathologic high-risk features in the real-world practice of clinical oncology. Rather, ctDNA testing will probably be added to the list of high-risk features, prompting use of more chemotherapy, not less, for stage II colon cancer.

A more useful study, in my opinion, should be performed in stage III colon cancer. Patients with stage III colon cancer receive chemotherapy without exception, although we know from MOSAIC that the absolute benefit of chemotherapy in stage III colon cancer is modest. What proportion of these patients who have a negative ctDNA test might be able to either forgo treatment completely or have treatment with a fluoropyrimidine only? That's something I would be very interested to find out.