Thomas Abrams, MD

As usual, several provocative additions to the colorectal cancer literature were published last month, but I will review only one today: the NordICC trial. This trial evaluated the use of screening colonoscopy to reduce the incidence of colorectal cancer, death from colorectal cancer, and all-cause mortality.

We have long accepted that colonoscopy is the gold standard for detection of colorectal cancer, but until the publication of this study there has never been a prospective, randomized controlled clinical trial to evaluate the efficacy of the test. Nearly 85,000 men and women from Nordic nations were randomly assigned to receive an invitation for either screening colonoscopy or usual care (ie, no colonoscopy). In the intention-to-screen analysis, colonoscopy reduced the risk for colorectal cancer over a period of 10 years by 18% (relative risk [RR] 0.82; 95% CI 0.70-0.93). However, the reduction in risk for death from colorectal cancer failed to reach statistical significance (RR 0.90; 95% CI 0.64-1.16).

These results were especially disappointing because sigmoidoscopy, a test that evaluates only the rectum and left colon, has been shown in multiple studies to reduce risk for colorectal cancer death and all-cause mortality. It is difficult for me to think of a biologically plausible explanation for colonoscopy to be less effective than sigmoidoscopy in the prevention of cause-specific and all-cause death. However, potential explanations are hidden in the study data. Most glaringly, only 42% of the colonoscopy invitees received a colonoscopy as compared with a much larger percentage of patients (58%-87%) in the sigmoidoscopy trials. While this might be an important real-world data point, it is far less than the estimated 60% of patients in the United States who adhere to the recommendation for screening colonoscopy from ages 45 to 55. Additionally, the study had only 10 years of follow-up. It is possible that this is just not long enough for the benefits of screening colonoscopy to be fully realized. Finally, 29% of endoscopists had an adenoma detection below the recommended threshold of 25%, suggesting that poor colonoscopic technique may have played a role in the limited efficacy of colonoscopy found in the study.

Regardless of what we think of these results, the study was generally well designed and, therefore, very important. Studies like this give us critical information that we, as a nation, need to determine how best to allot our limited healthcare resources. While this study does not change my perception of the efficacy of colonoscopy, it makes me think twice about its societal utility.

As usual, several provocative additions to the colorectal cancer literature were published last month, but I will review only one today: the NordICC trial. This trial evaluated the use of screening colonoscopy to reduce the incidence of colorectal cancer, death from colorectal cancer, and all-cause mortality.

We have long accepted that colonoscopy is the gold standard for detection of colorectal cancer, but until the publication of this study there has never been a prospective, randomized controlled clinical trial to evaluate the efficacy of the test. Nearly 85,000 men and women from Nordic nations were randomly assigned to receive an invitation for either screening colonoscopy or usual care (ie, no colonoscopy). In the intention-to-screen analysis, colonoscopy reduced the risk for colorectal cancer over a period of 10 years by 18% (relative risk [RR] 0.82; 95% CI 0.70-0.93). However, the reduction in risk for death from colorectal cancer failed to reach statistical significance (RR 0.90; 95% CI 0.64-1.16).

These results were especially disappointing because sigmoidoscopy, a test that evaluates only the rectum and left colon, has been shown in multiple studies to reduce risk for colorectal cancer death and all-cause mortality. It is difficult for me to think of a biologically plausible explanation for colonoscopy to be less effective than sigmoidoscopy in the prevention of cause-specific and all-cause death. However, potential explanations are hidden in the study data. Most glaringly, only 42% of the colonoscopy invitees received a colonoscopy as compared with a much larger percentage of patients (58%-87%) in the sigmoidoscopy trials. While this might be an important real-world data point, it is far less than the estimated 60% of patients in the United States who adhere to the recommendation for screening colonoscopy from ages 45 to 55. Additionally, the study had only 10 years of follow-up. It is possible that this is just not long enough for the benefits of screening colonoscopy to be fully realized. Finally, 29% of endoscopists had an adenoma detection below the recommended threshold of 25%, suggesting that poor colonoscopic technique may have played a role in the limited efficacy of colonoscopy found in the study.

Regardless of what we think of these results, the study was generally well designed and, therefore, very important. Studies like this give us critical information that we, as a nation, need to determine how best to allot our limited healthcare resources. While this study does not change my perception of the efficacy of colonoscopy, it makes me think twice about its societal utility.

As usual, several provocative additions to the colorectal cancer literature were published last month, but I will review only one today: the NordICC trial. This trial evaluated the use of screening colonoscopy to reduce the incidence of colorectal cancer, death from colorectal cancer, and all-cause mortality.

We have long accepted that colonoscopy is the gold standard for detection of colorectal cancer, but until the publication of this study there has never been a prospective, randomized controlled clinical trial to evaluate the efficacy of the test. Nearly 85,000 men and women from Nordic nations were randomly assigned to receive an invitation for either screening colonoscopy or usual care (ie, no colonoscopy). In the intention-to-screen analysis, colonoscopy reduced the risk for colorectal cancer over a period of 10 years by 18% (relative risk [RR] 0.82; 95% CI 0.70-0.93). However, the reduction in risk for death from colorectal cancer failed to reach statistical significance (RR 0.90; 95% CI 0.64-1.16).

These results were especially disappointing because sigmoidoscopy, a test that evaluates only the rectum and left colon, has been shown in multiple studies to reduce risk for colorectal cancer death and all-cause mortality. It is difficult for me to think of a biologically plausible explanation for colonoscopy to be less effective than sigmoidoscopy in the prevention of cause-specific and all-cause death. However, potential explanations are hidden in the study data. Most glaringly, only 42% of the colonoscopy invitees received a colonoscopy as compared with a much larger percentage of patients (58%-87%) in the sigmoidoscopy trials. While this might be an important real-world data point, it is far less than the estimated 60% of patients in the United States who adhere to the recommendation for screening colonoscopy from ages 45 to 55. Additionally, the study had only 10 years of follow-up. It is possible that this is just not long enough for the benefits of screening colonoscopy to be fully realized. Finally, 29% of endoscopists had an adenoma detection below the recommended threshold of 25%, suggesting that poor colonoscopic technique may have played a role in the limited efficacy of colonoscopy found in the study.

Regardless of what we think of these results, the study was generally well designed and, therefore, very important. Studies like this give us critical information that we, as a nation, need to determine how best to allot our limited healthcare resources. While this study does not change my perception of the efficacy of colonoscopy, it makes me think twice about its societal utility.

Once again, I have been given the distinct honor of analyzing two of the most provocative studies in colorectal cancer this month for Clinical Edge. The first study I will examine was done by Khamzina and colleagues and attempts to define the optimal time to perform surgery after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. In this retrospective analysis, 770 patients who received long-course chemoradiotherapy for rectal cancer followed by total mesorectal excision (TME) were analyzed by how long the interval was between completion of radiation and surgery. Patients were separated into two groups: 6-8 weeks (n = 502) vs >8 weeks (n = 268). Though the pathologic complete response rates and 5-year disease-free survival rates were not significantly different between the two groups, tumor regression grade was significantly better in the >8 weeks arm (P = .004). This result confirms many previous studies that demonstrate continued tumor shrinkage months after completion of chemoradiotherapy and may provide an explanation of why the OPRA trial demonstrated a higher TME-free rate in the chemoradiotherapy-then-chemotherapy arm than it did in the induction chemotherapy-then-chemoradiotherapy arm (53% vs 41%).

Schaefer and colleagues looked at the potential prognostic markers for efficacy of transarterial radioembolization (TARE) with ⁹⁰Y resin microspheres in the treatment of liver-dominant metastatic colorectal cancer (mCRC). Their study evaluated 237 patients with liver-dominant mCRC from the prospective observational CIRSE Registry for SIR-Spheres Therapy (CIRT) study who were scheduled to receive TARE with ⁹⁰Y resin microspheres. For these patients, the aspartate transaminase-to-platelet ratio index (APRI), international normalized ratio (INR), and albumin-bilirubin (ALBI) grade were measured prior to treatment to potentially detect values that might be associated with differential outcomes from TARE. An APRI > 0.40 independently predicted worse overall survival (OS) (hazard ratio [HR] 2.25; P < .0001), progression-free survival (PFS) (HR 1.42; P = .0416), and hepatic PFS (HR 1.50; P = .0207). The other independent predictors for worse OS and hepatic PFS were an INR value of < 1 (HR 1.66; P = .0091) and ALBI grade 3 (HR 5.29; P = .0075), respectively. It is very difficult to make much out of this study save to say that poorer liver function at baseline (at least with respect to APRI and ALBI) predicts worse outcomes after TARE, which is none too controversial an opinion. That said, APRI and ALBI may be able to provide an extra measure of granularity to determine who might be more of a marginal candidate for TARE than would categorization according to Child-Pugh score alone. Saving these patients from a potentially morbid procedure would be a significant benefit.

Once again, I have been given the distinct honor of analyzing two of the most provocative studies in colorectal cancer this month for Clinical Edge. The first study I will examine was done by Khamzina and colleagues and attempts to define the optimal time to perform surgery after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. In this retrospective analysis, 770 patients who received long-course chemoradiotherapy for rectal cancer followed by total mesorectal excision (TME) were analyzed by how long the interval was between completion of radiation and surgery. Patients were separated into two groups: 6-8 weeks (n = 502) vs >8 weeks (n = 268). Though the pathologic complete response rates and 5-year disease-free survival rates were not significantly different between the two groups, tumor regression grade was significantly better in the >8 weeks arm (P = .004). This result confirms many previous studies that demonstrate continued tumor shrinkage months after completion of chemoradiotherapy and may provide an explanation of why the OPRA trial demonstrated a higher TME-free rate in the chemoradiotherapy-then-chemotherapy arm than it did in the induction chemotherapy-then-chemoradiotherapy arm (53% vs 41%).

Schaefer and colleagues looked at the potential prognostic markers for efficacy of transarterial radioembolization (TARE) with ⁹⁰Y resin microspheres in the treatment of liver-dominant metastatic colorectal cancer (mCRC). Their study evaluated 237 patients with liver-dominant mCRC from the prospective observational CIRSE Registry for SIR-Spheres Therapy (CIRT) study who were scheduled to receive TARE with ⁹⁰Y resin microspheres. For these patients, the aspartate transaminase-to-platelet ratio index (APRI), international normalized ratio (INR), and albumin-bilirubin (ALBI) grade were measured prior to treatment to potentially detect values that might be associated with differential outcomes from TARE. An APRI > 0.40 independently predicted worse overall survival (OS) (hazard ratio [HR] 2.25; P < .0001), progression-free survival (PFS) (HR 1.42; P = .0416), and hepatic PFS (HR 1.50; P = .0207). The other independent predictors for worse OS and hepatic PFS were an INR value of < 1 (HR 1.66; P = .0091) and ALBI grade 3 (HR 5.29; P = .0075), respectively. It is very difficult to make much out of this study save to say that poorer liver function at baseline (at least with respect to APRI and ALBI) predicts worse outcomes after TARE, which is none too controversial an opinion. That said, APRI and ALBI may be able to provide an extra measure of granularity to determine who might be more of a marginal candidate for TARE than would categorization according to Child-Pugh score alone. Saving these patients from a potentially morbid procedure would be a significant benefit.

Once again, I have been given the distinct honor of analyzing two of the most provocative studies in colorectal cancer this month for Clinical Edge. The first study I will examine was done by Khamzina and colleagues and attempts to define the optimal time to perform surgery after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. In this retrospective analysis, 770 patients who received long-course chemoradiotherapy for rectal cancer followed by total mesorectal excision (TME) were analyzed by how long the interval was between completion of radiation and surgery. Patients were separated into two groups: 6-8 weeks (n = 502) vs >8 weeks (n = 268). Though the pathologic complete response rates and 5-year disease-free survival rates were not significantly different between the two groups, tumor regression grade was significantly better in the >8 weeks arm (P = .004). This result confirms many previous studies that demonstrate continued tumor shrinkage months after completion of chemoradiotherapy and may provide an explanation of why the OPRA trial demonstrated a higher TME-free rate in the chemoradiotherapy-then-chemotherapy arm than it did in the induction chemotherapy-then-chemoradiotherapy arm (53% vs 41%).

Schaefer and colleagues looked at the potential prognostic markers for efficacy of transarterial radioembolization (TARE) with ⁹⁰Y resin microspheres in the treatment of liver-dominant metastatic colorectal cancer (mCRC). Their study evaluated 237 patients with liver-dominant mCRC from the prospective observational CIRSE Registry for SIR-Spheres Therapy (CIRT) study who were scheduled to receive TARE with ⁹⁰Y resin microspheres. For these patients, the aspartate transaminase-to-platelet ratio index (APRI), international normalized ratio (INR), and albumin-bilirubin (ALBI) grade were measured prior to treatment to potentially detect values that might be associated with differential outcomes from TARE. An APRI > 0.40 independently predicted worse overall survival (OS) (hazard ratio [HR] 2.25; P < .0001), progression-free survival (PFS) (HR 1.42; P = .0416), and hepatic PFS (HR 1.50; P = .0207). The other independent predictors for worse OS and hepatic PFS were an INR value of < 1 (HR 1.66; P = .0091) and ALBI grade 3 (HR 5.29; P = .0075), respectively. It is very difficult to make much out of this study save to say that poorer liver function at baseline (at least with respect to APRI and ALBI) predicts worse outcomes after TARE, which is none too controversial an opinion. That said, APRI and ALBI may be able to provide an extra measure of granularity to determine who might be more of a marginal candidate for TARE than would categorization according to Child-Pugh score alone. Saving these patients from a potentially morbid procedure would be a significant benefit.

As always, several provocative publications on colorectal cancer (CRC) have found their way into the medical literature. I will be discussing two of these in my Clinical Edge Journal Scan commentary for the month of October.

The first article, by Kennecke and colleagues, examines the role of neoadjuvant chemotherapy for early rectal cancer. We have been inundated with data showing that organ preservation is achievable in cases of node-positive rectal cancer with neoadjuvant chemoradiotherapy and chemotherapy (total neoadjuvant treatment [TNT] approach). As such, it stands to reason that organ preservation should also be achievable in cases of early, node-negative rectal cancer.

NEO was a single-arm, phase 2 trial examining the role of neoadjuvant chemotherapy only in early rectal cancer. In it, 58 patients with clinical T1-T3ab N0 low-to-mid rectal adenocarcinoma (proficient mismatch repair status) eligible for endoscopic resection were treated with 3 months of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin). Those with evidence of tumor regression proceeded to transanal resection.

The primary endpoint was a protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1 N0/X and who avoided radical surgery. Thirty-three (33) of the 58 patients were successfully downstaged, resulting in a protocol-specified organ preservation rate of 57% (90% CI 45-68). Of note, this treatment had no radiation at all and only used chemotherapy. Of the remaining 23 patients, 13 declined total mesorectal excision (TME) and went into observation. Of the 10 patients who underwent TME, seven had no histopathologic evidence of residual disease. The 1- and 2-year locoregional relapse-free survival rates were 98% (95% CI 86-100) and 90% (95% CI 58-98), respectively, and there were no metastatic recurrences or deaths. Although this is a small study, the results are enormously encouraging, suggesting that organ preservation not only can be achieved in early-stage rectal cancer, but also can be accomplished using only chemotherapy, further reducing morbidity to patients.

The second study I want to discuss was conducted by Ciardiello and colleagues and concerns the KRAS^G12C mutation in colorectal cancer. This mutation is targetable in lung cancer and has led to the approval of sotorasib for the treatment of advanced KRAS^G12C non–small-cell lung cancer . Unfortunately, previous studies of these inhibitors in advanced KRAS^G12C colorectal cancer have yielded disappointing results.

This study looked retrospectively at 6952 cases of metastatic colorectal cancer across Italy. A total of 256 cases (3.7%) demonstrated the KRAS^G12C mutation. Of those, 111 met inclusion criteria and were included in the analysis. Of note, this mutation was associated with a poor response to first-line chemotherapy (38.7%), with a median progression-free survival of 9 months (95% CI 7.5-10.5 months). Median overall survival was 21 months (95% CI 17.4-24.6 months). There was little difference between first-line oxaliplatin-containing regimens compared with those containing irinotecan. Triplet therapy (folinic acid, fluorouracil, oxaliplatin, and irinotecan; FOLFOXIRI) was associated with an objective response rate of 56.3% with a progression-free survival of 13 months and median overall survival of 32 months, suggesting that triplet therapy might be a better approach for these patients when they are identified. This study is important because it corroborates and builds upon data reported in smaller studies demonstrating the general resistance of KRAS^G12C metastatic colorectal cancer to chemotherapeutic treatments.

As always, several provocative publications on colorectal cancer (CRC) have found their way into the medical literature. I will be discussing two of these in my Clinical Edge Journal Scan commentary for the month of October.

The first article, by Kennecke and colleagues, examines the role of neoadjuvant chemotherapy for early rectal cancer. We have been inundated with data showing that organ preservation is achievable in cases of node-positive rectal cancer with neoadjuvant chemoradiotherapy and chemotherapy (total neoadjuvant treatment [TNT] approach). As such, it stands to reason that organ preservation should also be achievable in cases of early, node-negative rectal cancer.

NEO was a single-arm, phase 2 trial examining the role of neoadjuvant chemotherapy only in early rectal cancer. In it, 58 patients with clinical T1-T3ab N0 low-to-mid rectal adenocarcinoma (proficient mismatch repair status) eligible for endoscopic resection were treated with 3 months of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin). Those with evidence of tumor regression proceeded to transanal resection.

The primary endpoint was a protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1 N0/X and who avoided radical surgery. Thirty-three (33) of the 58 patients were successfully downstaged, resulting in a protocol-specified organ preservation rate of 57% (90% CI 45-68). Of note, this treatment had no radiation at all and only used chemotherapy. Of the remaining 23 patients, 13 declined total mesorectal excision (TME) and went into observation. Of the 10 patients who underwent TME, seven had no histopathologic evidence of residual disease. The 1- and 2-year locoregional relapse-free survival rates were 98% (95% CI 86-100) and 90% (95% CI 58-98), respectively, and there were no metastatic recurrences or deaths. Although this is a small study, the results are enormously encouraging, suggesting that organ preservation not only can be achieved in early-stage rectal cancer, but also can be accomplished using only chemotherapy, further reducing morbidity to patients.

The second study I want to discuss was conducted by Ciardiello and colleagues and concerns the KRAS^G12C mutation in colorectal cancer. This mutation is targetable in lung cancer and has led to the approval of sotorasib for the treatment of advanced KRAS^G12C non–small-cell lung cancer . Unfortunately, previous studies of these inhibitors in advanced KRAS^G12C colorectal cancer have yielded disappointing results.

This study looked retrospectively at 6952 cases of metastatic colorectal cancer across Italy. A total of 256 cases (3.7%) demonstrated the KRAS^G12C mutation. Of those, 111 met inclusion criteria and were included in the analysis. Of note, this mutation was associated with a poor response to first-line chemotherapy (38.7%), with a median progression-free survival of 9 months (95% CI 7.5-10.5 months). Median overall survival was 21 months (95% CI 17.4-24.6 months). There was little difference between first-line oxaliplatin-containing regimens compared with those containing irinotecan. Triplet therapy (folinic acid, fluorouracil, oxaliplatin, and irinotecan; FOLFOXIRI) was associated with an objective response rate of 56.3% with a progression-free survival of 13 months and median overall survival of 32 months, suggesting that triplet therapy might be a better approach for these patients when they are identified. This study is important because it corroborates and builds upon data reported in smaller studies demonstrating the general resistance of KRAS^G12C metastatic colorectal cancer to chemotherapeutic treatments.

As always, several provocative publications on colorectal cancer (CRC) have found their way into the medical literature. I will be discussing two of these in my Clinical Edge Journal Scan commentary for the month of October.

The first article, by Kennecke and colleagues, examines the role of neoadjuvant chemotherapy for early rectal cancer. We have been inundated with data showing that organ preservation is achievable in cases of node-positive rectal cancer with neoadjuvant chemoradiotherapy and chemotherapy (total neoadjuvant treatment [TNT] approach). As such, it stands to reason that organ preservation should also be achievable in cases of early, node-negative rectal cancer.

NEO was a single-arm, phase 2 trial examining the role of neoadjuvant chemotherapy only in early rectal cancer. In it, 58 patients with clinical T1-T3ab N0 low-to-mid rectal adenocarcinoma (proficient mismatch repair status) eligible for endoscopic resection were treated with 3 months of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin). Those with evidence of tumor regression proceeded to transanal resection.

The primary endpoint was a protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1 N0/X and who avoided radical surgery. Thirty-three (33) of the 58 patients were successfully downstaged, resulting in a protocol-specified organ preservation rate of 57% (90% CI 45-68). Of note, this treatment had no radiation at all and only used chemotherapy. Of the remaining 23 patients, 13 declined total mesorectal excision (TME) and went into observation. Of the 10 patients who underwent TME, seven had no histopathologic evidence of residual disease. The 1- and 2-year locoregional relapse-free survival rates were 98% (95% CI 86-100) and 90% (95% CI 58-98), respectively, and there were no metastatic recurrences or deaths. Although this is a small study, the results are enormously encouraging, suggesting that organ preservation not only can be achieved in early-stage rectal cancer, but also can be accomplished using only chemotherapy, further reducing morbidity to patients.

The second study I want to discuss was conducted by Ciardiello and colleagues and concerns the KRAS^G12C mutation in colorectal cancer. This mutation is targetable in lung cancer and has led to the approval of sotorasib for the treatment of advanced KRAS^G12C non–small-cell lung cancer . Unfortunately, previous studies of these inhibitors in advanced KRAS^G12C colorectal cancer have yielded disappointing results.

This study looked retrospectively at 6952 cases of metastatic colorectal cancer across Italy. A total of 256 cases (3.7%) demonstrated the KRAS^G12C mutation. Of those, 111 met inclusion criteria and were included in the analysis. Of note, this mutation was associated with a poor response to first-line chemotherapy (38.7%), with a median progression-free survival of 9 months (95% CI 7.5-10.5 months). Median overall survival was 21 months (95% CI 17.4-24.6 months). There was little difference between first-line oxaliplatin-containing regimens compared with those containing irinotecan. Triplet therapy (folinic acid, fluorouracil, oxaliplatin, and irinotecan; FOLFOXIRI) was associated with an objective response rate of 56.3% with a progression-free survival of 13 months and median overall survival of 32 months, suggesting that triplet therapy might be a better approach for these patients when they are identified. This study is important because it corroborates and builds upon data reported in smaller studies demonstrating the general resistance of KRAS^G12C metastatic colorectal cancer to chemotherapeutic treatments.

This month's journal articles in the field of colorectal cancer research lack the cachet of some of the high-profile dispatches we discussed in previous editions of Clinical Edge. Nonetheless, there are several interesting reports this month.

The first is a clinical trial report that came out of China investigating the possible synergistic effect of high-dose vitamin C with chemotherapy in the first-line treatment of metastatic colorectal cancer (mCRC). The study was based on preclinical data that showed a synergistic increase in cancer cell death with chemotherapy plus high-dose vitamin C in in vitro models. Wang and colleagues randomly assigned 442 treatment-naive patients with mCRC to receive folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab with or without 1.5 g/kg vitamin C intravenously on days 1-3 of each chemotherapy cycle.

The study's primary endpoint was progression-free survival (PFS), and patients were stratified on the basis of tumor sidedness and use of bevacizumab. PFS for the intention-to-treat group was unaffected by use of vitamin C (hazard ratio [HR] 0.86; 95% CI 0.70-1.05; P = .1). However, patients whose tumors harbored RAS mutations had a PFS that was significantly improved in the vitamin C arm (9.2 vs 7.8 months; HR 0.67; 95% CI 0.50-0.91; P = .01). Additionally, treatment-related adverse events were no more common in the treatment arm than in the control arm. Although I seldom draw clinical conclusions from subgroup analyses, I find it comforting to know that high-dose vitamin C is at least safe and potentially helpful for some patients. Many of my patients through the years have asked me about the utility of high-dose vitamin C. At least I can now inform them that the treatment is unlikely to cause physical harm or substantially decrease the efficacy of chemotherapy.

The second article I will discuss focuses on dietary fat intake and its potential effects on mortality and cancer progression in patients with mCRC. Using a food-frequency questionnaire, the authors of the study assessed the diets of 1194 patients who had been part of a previous cooperative group study for patients with treatment-naive mCRC (Van Blarigan et al). Over a median follow-up of 6.1 years, patients with the highest median intake of vegetable fats (23.5% kcal/d; interquartile range [IQR] 21.6%-25.7% kcal/d) vs the lowest intake (11.6% kcal/d; IQR 10.1%-12.7% kcal/d) showed a lower risk for all-cause mortality (adjusted HR 0.79; 95% CI 0.63-1.00) and cancer progression or death (adjusted HR 0.71; 95% CI 0.57-0.88). Although this study's results were not unexpected given data that have been published in the past, it builds on previous work as it shows the specific benefits of vegetable fats vis-à-vis animal fats, which are detrimental to survival. Oncologists continue to benefit from these studies because they allow us to give more specific dietary recommendations for high fat-containing vegan foods, such as avocados, olives, and nuts.

This month's journal articles in the field of colorectal cancer research lack the cachet of some of the high-profile dispatches we discussed in previous editions of Clinical Edge. Nonetheless, there are several interesting reports this month.

The first is a clinical trial report that came out of China investigating the possible synergistic effect of high-dose vitamin C with chemotherapy in the first-line treatment of metastatic colorectal cancer (mCRC). The study was based on preclinical data that showed a synergistic increase in cancer cell death with chemotherapy plus high-dose vitamin C in in vitro models. Wang and colleagues randomly assigned 442 treatment-naive patients with mCRC to receive folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab with or without 1.5 g/kg vitamin C intravenously on days 1-3 of each chemotherapy cycle.

The study's primary endpoint was progression-free survival (PFS), and patients were stratified on the basis of tumor sidedness and use of bevacizumab. PFS for the intention-to-treat group was unaffected by use of vitamin C (hazard ratio [HR] 0.86; 95% CI 0.70-1.05; P = .1). However, patients whose tumors harbored RAS mutations had a PFS that was significantly improved in the vitamin C arm (9.2 vs 7.8 months; HR 0.67; 95% CI 0.50-0.91; P = .01). Additionally, treatment-related adverse events were no more common in the treatment arm than in the control arm. Although I seldom draw clinical conclusions from subgroup analyses, I find it comforting to know that high-dose vitamin C is at least safe and potentially helpful for some patients. Many of my patients through the years have asked me about the utility of high-dose vitamin C. At least I can now inform them that the treatment is unlikely to cause physical harm or substantially decrease the efficacy of chemotherapy.

The second article I will discuss focuses on dietary fat intake and its potential effects on mortality and cancer progression in patients with mCRC. Using a food-frequency questionnaire, the authors of the study assessed the diets of 1194 patients who had been part of a previous cooperative group study for patients with treatment-naive mCRC (Van Blarigan et al). Over a median follow-up of 6.1 years, patients with the highest median intake of vegetable fats (23.5% kcal/d; interquartile range [IQR] 21.6%-25.7% kcal/d) vs the lowest intake (11.6% kcal/d; IQR 10.1%-12.7% kcal/d) showed a lower risk for all-cause mortality (adjusted HR 0.79; 95% CI 0.63-1.00) and cancer progression or death (adjusted HR 0.71; 95% CI 0.57-0.88). Although this study's results were not unexpected given data that have been published in the past, it builds on previous work as it shows the specific benefits of vegetable fats vis-à-vis animal fats, which are detrimental to survival. Oncologists continue to benefit from these studies because they allow us to give more specific dietary recommendations for high fat-containing vegan foods, such as avocados, olives, and nuts.

This month's journal articles in the field of colorectal cancer research lack the cachet of some of the high-profile dispatches we discussed in previous editions of Clinical Edge. Nonetheless, there are several interesting reports this month.

The first is a clinical trial report that came out of China investigating the possible synergistic effect of high-dose vitamin C with chemotherapy in the first-line treatment of metastatic colorectal cancer (mCRC). The study was based on preclinical data that showed a synergistic increase in cancer cell death with chemotherapy plus high-dose vitamin C in in vitro models. Wang and colleagues randomly assigned 442 treatment-naive patients with mCRC to receive folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab with or without 1.5 g/kg vitamin C intravenously on days 1-3 of each chemotherapy cycle.

The study's primary endpoint was progression-free survival (PFS), and patients were stratified on the basis of tumor sidedness and use of bevacizumab. PFS for the intention-to-treat group was unaffected by use of vitamin C (hazard ratio [HR] 0.86; 95% CI 0.70-1.05; P = .1). However, patients whose tumors harbored RAS mutations had a PFS that was significantly improved in the vitamin C arm (9.2 vs 7.8 months; HR 0.67; 95% CI 0.50-0.91; P = .01). Additionally, treatment-related adverse events were no more common in the treatment arm than in the control arm. Although I seldom draw clinical conclusions from subgroup analyses, I find it comforting to know that high-dose vitamin C is at least safe and potentially helpful for some patients. Many of my patients through the years have asked me about the utility of high-dose vitamin C. At least I can now inform them that the treatment is unlikely to cause physical harm or substantially decrease the efficacy of chemotherapy.

The second article I will discuss focuses on dietary fat intake and its potential effects on mortality and cancer progression in patients with mCRC. Using a food-frequency questionnaire, the authors of the study assessed the diets of 1194 patients who had been part of a previous cooperative group study for patients with treatment-naive mCRC (Van Blarigan et al). Over a median follow-up of 6.1 years, patients with the highest median intake of vegetable fats (23.5% kcal/d; interquartile range [IQR] 21.6%-25.7% kcal/d) vs the lowest intake (11.6% kcal/d; IQR 10.1%-12.7% kcal/d) showed a lower risk for all-cause mortality (adjusted HR 0.79; 95% CI 0.63-1.00) and cancer progression or death (adjusted HR 0.71; 95% CI 0.57-0.88). Although this study's results were not unexpected given data that have been published in the past, it builds on previous work as it shows the specific benefits of vegetable fats vis-à-vis animal fats, which are detrimental to survival. Oncologists continue to benefit from these studies because they allow us to give more specific dietary recommendations for high fat-containing vegan foods, such as avocados, olives, and nuts.

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.

The TRIPLETE study from Italy is a simply designed phase 3 clinical trial in which 435 patients with newly diagnosed RAS and BRAF wild-type metastatic colorectal cancer were randomized in a 1:1 fashionto receive either modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) plus panitumumab or fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) plus panitumumab. In both arms, over 90% of patients were aged ≤70 years old, and 12% had right-sided disease. These factors are critical because older patients are less likely to benefit from multidrug chemotherapy, and patients with right-sided disease would not be expected to respond to epidermal growth factor receptor inhibitors, irrespective of RAS status. The study's primary endpoint was objective response rate (ORR) according to the revised Response Evaluation Criteria in Solid Tumours guidelines (RECIST 1.1). Secondary endpoints included safety and progression-free survival (PFS). ORR was 73% in the experimental arm and 76% in the control arm (odds ratio [OR] 0.87; P = .526). There were no differences in PFS, early tumor shrinkage rate, R0 resection rate, or depth of response either.

Though I would have liked to have seen a leucovorin calcium (folinic acid), fluorouracil,and irinotecan hydrochloride (FOLFIRI) arm as well, I believe that these results are enough to cast significant doubt on the burgeoning belief that in metastatic colorectal cancer, more chemotherapy is better for those who can tolerate it.

AtezoTRIBE, also out of Italy, is a randomized, phase 2 study that randomly selected patients with newly diagnosed metastatic colorectal cancer to receive FOLFOXIRI and bevacizumab with or without atezolizumab. I am less sanguine about this study design, vis-à-vis the TRIPLETE study, as patients in AtezoTRIBE were randomized in a 2:1 fashion, with two thirds therefore receiving treatment on the experimental arm. The 2:1 randomization was rationalized on the basis of the supposition that patients are more likely to enroll on a study if they know they have a greater chance of receiving a novel treatment. However, I have never seen a study supporting that hypothesis with data, and a 2:1 randomization significantly reduces statistical power. Patients were stratified on the basis of tumor mutational burden (TMB) and Immunoscore IC (high or low as determined by CD8 cell density, programmed death ligand 1 cell density, as well as proximity and clustering of the two cell groups). There were similar rates of high TMB (7% control and 8% experimental) and high Immunoscore IC (25% control and 22% experimental) in both arms. The primary endpoint was PFS. At a median follow-up of 19.9 months, the experimental arm had astatistically improved median PFS (13.1 vs 11.5 months; adjusted hazard ratio 0.70; P = .018). Serious adverse events were reported in 27% vs 26% of patients, respectively. Of note, the subgroup analysis shows that PFS improvement was accrued in the experimental arm by patients with either high TMB, high Immunoscore IC, or both. Further studies will be needed in patients prospectively selected for high Immunoscore IC to see whether these observations hold. If so, Immunoscore IC could eventually replace TMB as a marker of potential immune therapy responsiveness in microsatellite-stable metastatic colorectal cancer.

The TRIPLETE study from Italy is a simply designed phase 3 clinical trial in which 435 patients with newly diagnosed RAS and BRAF wild-type metastatic colorectal cancer were randomized in a 1:1 fashionto receive either modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) plus panitumumab or fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) plus panitumumab. In both arms, over 90% of patients were aged ≤70 years old, and 12% had right-sided disease. These factors are critical because older patients are less likely to benefit from multidrug chemotherapy, and patients with right-sided disease would not be expected to respond to epidermal growth factor receptor inhibitors, irrespective of RAS status. The study's primary endpoint was objective response rate (ORR) according to the revised Response Evaluation Criteria in Solid Tumours guidelines (RECIST 1.1). Secondary endpoints included safety and progression-free survival (PFS). ORR was 73% in the experimental arm and 76% in the control arm (odds ratio [OR] 0.87; P = .526). There were no differences in PFS, early tumor shrinkage rate, R0 resection rate, or depth of response either.

Though I would have liked to have seen a leucovorin calcium (folinic acid), fluorouracil,and irinotecan hydrochloride (FOLFIRI) arm as well, I believe that these results are enough to cast significant doubt on the burgeoning belief that in metastatic colorectal cancer, more chemotherapy is better for those who can tolerate it.

AtezoTRIBE, also out of Italy, is a randomized, phase 2 study that randomly selected patients with newly diagnosed metastatic colorectal cancer to receive FOLFOXIRI and bevacizumab with or without atezolizumab. I am less sanguine about this study design, vis-à-vis the TRIPLETE study, as patients in AtezoTRIBE were randomized in a 2:1 fashion, with two thirds therefore receiving treatment on the experimental arm. The 2:1 randomization was rationalized on the basis of the supposition that patients are more likely to enroll on a study if they know they have a greater chance of receiving a novel treatment. However, I have never seen a study supporting that hypothesis with data, and a 2:1 randomization significantly reduces statistical power. Patients were stratified on the basis of tumor mutational burden (TMB) and Immunoscore IC (high or low as determined by CD8 cell density, programmed death ligand 1 cell density, as well as proximity and clustering of the two cell groups). There were similar rates of high TMB (7% control and 8% experimental) and high Immunoscore IC (25% control and 22% experimental) in both arms. The primary endpoint was PFS. At a median follow-up of 19.9 months, the experimental arm had astatistically improved median PFS (13.1 vs 11.5 months; adjusted hazard ratio 0.70; P = .018). Serious adverse events were reported in 27% vs 26% of patients, respectively. Of note, the subgroup analysis shows that PFS improvement was accrued in the experimental arm by patients with either high TMB, high Immunoscore IC, or both. Further studies will be needed in patients prospectively selected for high Immunoscore IC to see whether these observations hold. If so, Immunoscore IC could eventually replace TMB as a marker of potential immune therapy responsiveness in microsatellite-stable metastatic colorectal cancer.

The TRIPLETE study from Italy is a simply designed phase 3 clinical trial in which 435 patients with newly diagnosed RAS and BRAF wild-type metastatic colorectal cancer were randomized in a 1:1 fashionto receive either modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) plus panitumumab or fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) plus panitumumab. In both arms, over 90% of patients were aged ≤70 years old, and 12% had right-sided disease. These factors are critical because older patients are less likely to benefit from multidrug chemotherapy, and patients with right-sided disease would not be expected to respond to epidermal growth factor receptor inhibitors, irrespective of RAS status. The study's primary endpoint was objective response rate (ORR) according to the revised Response Evaluation Criteria in Solid Tumours guidelines (RECIST 1.1). Secondary endpoints included safety and progression-free survival (PFS). ORR was 73% in the experimental arm and 76% in the control arm (odds ratio [OR] 0.87; P = .526). There were no differences in PFS, early tumor shrinkage rate, R0 resection rate, or depth of response either.

Though I would have liked to have seen a leucovorin calcium (folinic acid), fluorouracil,and irinotecan hydrochloride (FOLFIRI) arm as well, I believe that these results are enough to cast significant doubt on the burgeoning belief that in metastatic colorectal cancer, more chemotherapy is better for those who can tolerate it.

AtezoTRIBE, also out of Italy, is a randomized, phase 2 study that randomly selected patients with newly diagnosed metastatic colorectal cancer to receive FOLFOXIRI and bevacizumab with or without atezolizumab. I am less sanguine about this study design, vis-à-vis the TRIPLETE study, as patients in AtezoTRIBE were randomized in a 2:1 fashion, with two thirds therefore receiving treatment on the experimental arm. The 2:1 randomization was rationalized on the basis of the supposition that patients are more likely to enroll on a study if they know they have a greater chance of receiving a novel treatment. However, I have never seen a study supporting that hypothesis with data, and a 2:1 randomization significantly reduces statistical power. Patients were stratified on the basis of tumor mutational burden (TMB) and Immunoscore IC (high or low as determined by CD8 cell density, programmed death ligand 1 cell density, as well as proximity and clustering of the two cell groups). There were similar rates of high TMB (7% control and 8% experimental) and high Immunoscore IC (25% control and 22% experimental) in both arms. The primary endpoint was PFS. At a median follow-up of 19.9 months, the experimental arm had astatistically improved median PFS (13.1 vs 11.5 months; adjusted hazard ratio 0.70; P = .018). Serious adverse events were reported in 27% vs 26% of patients, respectively. Of note, the subgroup analysis shows that PFS improvement was accrued in the experimental arm by patients with either high TMB, high Immunoscore IC, or both. Further studies will be needed in patients prospectively selected for high Immunoscore IC to see whether these observations hold. If so, Immunoscore IC could eventually replace TMB as a marker of potential immune therapy responsiveness in microsatellite-stable metastatic colorectal cancer.

Next, a retrospective analysis compared adjuvant capecitabine or capecitabine + oxaliplatin (CapeOX) for resected stage II-III colorectal cancer in 606 patients. Fifty-four of these patients were taking a proton pump inhibitor (PPI) as well. The authors found that concomitant use of a PPI with capecitabine monotherapy led to shorter relapse-free survival (adjusted hazard ratio, 2.48; P = .013) compared with those not taking a PPI. Interestingly, the effect on RFS was not observed in patients receiving CapeOX. A proposed mechanism for this finding is that the increased pH in PPI-treated stomachs decreases dissolution of the capecitabine tablet. Certainly, direct observation would be required to prove this, but these data alone may be enough for oncologists to think twice before prescribing capecitabine to patients who must remain on a PPI.

Lastly, a well-done analysis from the Nurses' Health Study found that higher intake of sugar-sweetened beverages and total fructose was associated with increased incidence of and mortality from proximal colon cancer, but interestingly not distal colon or rectal cancers. The hazard ratios for both the incremental incidence of proximal colon cancer for intake of one serving of sugar-sweetened beverage per day and for 25 g/day of fructose were 1.18 (P_trend = .02), and the hazard ratios for mortality were 1.39 (P_trend = .002) and 1.42 (P_trend = .003), respectively. I am often asked by my patients what, if any, utility there might be in limiting sugar intake when undergoing cancer treatment. This study provides the basis for an answer that is more than just hand-waving.

Next, a retrospective analysis compared adjuvant capecitabine or capecitabine + oxaliplatin (CapeOX) for resected stage II-III colorectal cancer in 606 patients. Fifty-four of these patients were taking a proton pump inhibitor (PPI) as well. The authors found that concomitant use of a PPI with capecitabine monotherapy led to shorter relapse-free survival (adjusted hazard ratio, 2.48; P = .013) compared with those not taking a PPI. Interestingly, the effect on RFS was not observed in patients receiving CapeOX. A proposed mechanism for this finding is that the increased pH in PPI-treated stomachs decreases dissolution of the capecitabine tablet. Certainly, direct observation would be required to prove this, but these data alone may be enough for oncologists to think twice before prescribing capecitabine to patients who must remain on a PPI.

Lastly, a well-done analysis from the Nurses' Health Study found that higher intake of sugar-sweetened beverages and total fructose was associated with increased incidence of and mortality from proximal colon cancer, but interestingly not distal colon or rectal cancers. The hazard ratios for both the incremental incidence of proximal colon cancer for intake of one serving of sugar-sweetened beverage per day and for 25 g/day of fructose were 1.18 (P_trend = .02), and the hazard ratios for mortality were 1.39 (P_trend = .002) and 1.42 (P_trend = .003), respectively. I am often asked by my patients what, if any, utility there might be in limiting sugar intake when undergoing cancer treatment. This study provides the basis for an answer that is more than just hand-waving.

Next, a retrospective analysis compared adjuvant capecitabine or capecitabine + oxaliplatin (CapeOX) for resected stage II-III colorectal cancer in 606 patients. Fifty-four of these patients were taking a proton pump inhibitor (PPI) as well. The authors found that concomitant use of a PPI with capecitabine monotherapy led to shorter relapse-free survival (adjusted hazard ratio, 2.48; P = .013) compared with those not taking a PPI. Interestingly, the effect on RFS was not observed in patients receiving CapeOX. A proposed mechanism for this finding is that the increased pH in PPI-treated stomachs decreases dissolution of the capecitabine tablet. Certainly, direct observation would be required to prove this, but these data alone may be enough for oncologists to think twice before prescribing capecitabine to patients who must remain on a PPI.

Lastly, a well-done analysis from the Nurses' Health Study found that higher intake of sugar-sweetened beverages and total fructose was associated with increased incidence of and mortality from proximal colon cancer, but interestingly not distal colon or rectal cancers. The hazard ratios for both the incremental incidence of proximal colon cancer for intake of one serving of sugar-sweetened beverage per day and for 25 g/day of fructose were 1.18 (P_trend = .02), and the hazard ratios for mortality were 1.39 (P_trend = .002) and 1.42 (P_trend = .003), respectively. I am often asked by my patients what, if any, utility there might be in limiting sugar intake when undergoing cancer treatment. This study provides the basis for an answer that is more than just hand-waving.