Does Invitation to Screening Colonoscopy Save Lives? Beyond Journal Club with NEJM Group on the NordICC Trial

Core IM Podcast

Time Stamps

• 00:00 Introduction
• 02:28 Pathophysiology of Colorectal Cancer & Why Screening Makes Sense
• 06:15 General Cancer Screening – Observational Studies
• 09:17 General Cancer Screening – Randomized Controlled Trials
• 14:40 NordICC Trial
• 22:36 Implications for Patient Care

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Show Notes

• Why is this topic important?
  • Screening colonoscopy has NOT been studied in a randomized control trial.
• Why hasn’t screening colonoscopy been studied before in a trial?
  • Colon cancer takes a LONG time to develop!
    • Most colon cancers develop through a preceding adenoma.
    • BUT, the timeline of progression is variable…
      • Examples:
        • 26 years for diminutive adenoma (smaller than 5mm)
        • 9 years for tubulovillous adenoma
        • 8 years for small adenoma
        • 5 years for large adenoma
        • 4 years for villous adenoma
    • Screening modalities (sigmoidoscopy or colonoscopy) both detect and treat precancerous lesions by identifying and removing polyps.
    • Colon cancer is usually described as “common,” but…
      • Only about 4% of individuals will develop colon cancer in their lifetime!
        • So 96% of people in a screening study will never be dealing with this disease.

• Which outcome should be used when evaluating the benefit of cancer screening?
  • All-cause mortality vs. Cancer-specific mortality vs. Diagnosis of cancer in question?
    • Argument for all-cause mortality:
      • Patients don’t care what they die from, but they don’t want to die!
    • Argument for cancer-specific mortality:
      • Colonoscopies are done to prevent colon cancer, so looking at mortality from colon cancer is the more relevant endpoint to evaluate the benefit of this intervention
      • Looking at cancer-specific mortality rather than an all-cause mortality may make trials more feasible because you will need fewer patients to demonstrate a difference

• What were the most important papers that informed colonoscopy recommendations before NordICC Trial?
  • NOTABLE LARGE, PROSPECTIVE OBSERVATIONAL STUDIES: Cannot prove causation, due to unmeasured confounders…
    • May overestimate or underestimate the impact of an intervention
      • Examples of confounders:
        • Healthier people tend to seek preventive care
        • People with a strong family history of CRC may be more likely to seek care
    • STUDY 1: “Long Term Colorectal Cancer Incidence and Mortality after Lower Endoscopy” NEJM September 2013
      • Participants: 88,902 participants
      • Duration: 22 years
      • Data Source(s): Nurses’ Health Study (121,700 U.S female nurses; 30 to 55 years of age) and Health Professionals Follow Up study(51,529 U.S. male health professionals; 40 to 75 years of age)
      • Results:
        • For participants who underwent colonoscopy…
          • Lower incidence of colorectal cancer
            • Hazard Ratio of 0.48 (95% CI 0.33 to 0.68)
          • Lower mortality from colorectal cancer
            • azard ratio of 0.32 (95% CI 0.24 to 0.45)
        • For participants who underwent sigmoidoscopy…
          • Lower mortality from colorectal cancer
            • Hazard ratio of 0.59 (95% CI 0.45 to 0.76)
    • STUDY 2: “Effectiveness of Screening Colonoscopy to Prevent Colorectal Cancer Among Medicare Beneficiaries Aged 70 to 79 Years” Annals of Internal Medicine January 2017
      • Participants: 1,355,692 medicare beneficiaries
        • Aged 70 to 79 years
        • Average risk of colorectal cancer
        • Used medicare preventive services
        • Had no prior diagnostic colonoscopy
      • Duration: 8 years
      • Results:
        • Colorectal cancer incidence
          • Screening colonoscopy group: 2.19% (95% CI, 2.00% to 2.37%)
          • No screening colonoscopy group: 2.62% (CI, 2.56% to 2.67%)
          • Absolute Risk Difference: −0.42% (CI, −0.24% to −0.63%)
            • Modest reduction!
        • NOTE: CRC- specific and overall mortality data was not available
  • RANDOMIZED CONTROLLED TRIALS: Four key RCTs looking at sigmoidoscopy
    • INCIDENCE:
      • Demonstrated a lower incidence of CRC in those invited to be screened compared to those not invited to be screened!
    • MORTALITY:
      • Two studies showed NO reduction in CRC-related mortality rate while the other two studies found significant reduction in CRC-related mortality.
    • NOTE: Analysis was “intention to screen analysis,” meaning it included everyone “invited” for screening acknowledging that not all “invited” individuals actually do it.
      • HOWEVER, separate per-protocol analyses have shown significant mortality benefit!
        • Includes only people who actually screened
    • Remember…Sigmoidoscopy studies may under-estimate the effect of colonoscopy screening because it only looks at PART of the colon

• What is the history of screening recommendations?
  • Mid-1990s: First screening recommendation for sigmoidoscopy (USPSTF)
  • 2000: Screening colonoscopy recommended over sigmoidoscopy (by American College of Gastroenterology)
  • 2002: Screening colonoscopy recommended by USPSTF

• What was the NordICC Trial?
  • Question: Does offering screening colonoscopy reduce incidence and mortality of colon cancer?
  • Participants: All men and women aged 55 to 64 years living in Norway, Poland, Sweden and the Netherlands
  • Duration: 10 years
  • Randomization:Invited to colonoscopy screening vs. Usual care (no invitation to screening)
    • NOTE: 31,420 participants who were invited to colonoscopy, BUTonly 40% actually underwent the procedure.
  • Results:
    • Colorectal cancer risk at 10 years
      • Invited colonoscopy Group: 0.98%; Usual Care: 1.2%
        • Percent Reduction = 20%
        • Absolute Risk Reduction = Only 0.2%
          • The number we care more about!
        • Number-needed-to-invite = 455 people
          • To prevent one case of colorectal cancer in 10 years
    • Mortality at 10 years
      • No difference in between invited vs usual care
    • Per-protocol analysis (a per-protocol analysis nullifies the benefit of randomization and introduces potential for bias)
      • Bigger reduction in colon cancer incidence
        • Risk of colorectal cancer at 10 years decreased from 1.2% to .84% in those who actually had colonoscopy,
          • 33% relative risk reduction of colon cancer with under 0.4% absolute risk reduction
      • Decrease in colorectal cancer-related deaths
        • Risk of death from colorectal cancer was 0.30% in the usual care group compared to 0.15% in those who actually got colonoscopy
          • Screening cut the risk of dying from colon cancer by 50% (or half) but very small absolute numbers
  • How do we interpret data from NordICC Trial?
    • Potential Confounder 1: Only followed people for 10 years!
      • Colon cancer takes LONG to develop → Maybe this trial underestimated true effect of screening
    • Potential Confounder 2: Trial took place in location where colonoscopy NOT widely accepted
      • Theoretically, if the RCT were conducted where the rates of colonoscopy are higher, we may see a greater decrease in the rate of colorectal cancer
    • Potential Confounder 3: Inter-endoscopist variation in adenoma detection rates (ADR)
      • 29% of the endoscopists had an ADR less than the recommended 25% (American Standards); In 2018, the average ADR in the US was actually 40.0%, significantly higher than in this study
    • Potential Confounder 4: Unmeasured differences between people who accepted screening versus those who declined
      
      • For example, socioeconomic status in patients who accepted vs declined invitation to colonoscopy
  • What does this all mean for our patients?
    • Inviting individuals to undergo colonoscopy prevents colorectal cancer
      • Based on per-protocol analyses, actually undergoing the procedure may save lives
  • What about FIT testing or Cologuard testing instead?
    • Stool-based testing is much less likely to detect adenomas.
      • It CAN catch cancer, but the point of screening is to prevent colon cancer, not find it when it is already there
        • COLONPREV trial – one-time colonoscopy compared to annual FIT testing are similar in terms of cancer detection but not detection of adenomas; FIT testing was only about half as good as detecting advanced adenomas
      • Stool-based testing does come with a very real world benefit – people are more likely to do it!
    • Cologuard combines FIT testing with DNA markers that are often found in CRC and precancerous adenomas, so it is going to have higher sensitivity.
  • What are current recommendations?
    • USPSTF and ACG have recently lowered the recommended age to initiate screening to 45 in average risk individuals
      • Due to the rising rates of CRC in younger populations!
  • Some policy questions arise from NordICC:
    • Is the cost of colonoscopy financially reasonable?
    • Are other cheaper screening modalities good enough for most patients?
    • Even if we ignore cost, is the added risk and inconvenience of colonoscopy worth it?
    • Who should cover the cost of colonoscopy?
      • These questions are really hard to answer…

Transcript

Dr. Shreya Trivedi: Welcome to the 6th installment of Beyond Journal Club, a collaboration between Core IM and NEJM Group.

Dr. Greg Katz: The goal of Beyond Journal Club is to take landmark clinical trials and put them into context, telling the story of how we got to where we are and what it means for how we take care of our patients.

Dr. Shreya Trivedi: So today, we’re talking about the widely publicized colonoscopy study – the NordICC trial. I’m Dr. Shreya Trivedi, internist at BIDMC.

Dr. Greg Katz: I’m Dr. Greg Katz, a cardiologist at NYU.

Dr. Abby Schubach: And I’m Dr. Abby Schubach, a NEJM Editorial Fellow and Hospitalist at Brigham and Women’s Hospital. And today we are talking about the NordICC trial, published in the October 27th issue of the New England Journal of Medicine in 2022.

Dr. Shreya Trivedi: So Abby, I know you are pretty passionate about this topic and its just not just because you are going to be a gastroenterologist.

Dr. Abby Schubach: Yeah, I am, you know over 50,000 people die in in the USA from colon cancer every year, and I wish that number was lower. If we can get colon cancer screening right, we can save many lives.

Dr. Greg Katz: This is where NordICC can come in. It asked the question: does offering colonoscopy screening reduce the incidence of colorectal cancer, and does it prevent death related to colorectal cancer or death overall?

Dr. Shreya Trivedi: Yeah, good questions. Nordicc made a pretty big splash in the news, but with mixed messages. CNN described the study as “the benefits of colon cancer screening may be overestimated,” while the Washington Post published an article entitled “Don’t Cancel Your Colonoscopy Just Yet.”

Dr. Greg Katz: And it wasn’t just the media. Even tons of smart doctors I was surprised had strong opinions on both sides. I’m talking about serious doctors who are making real decisions taking care of patients who had strong opinions about both positive and negative interpretations of this trial.

Dr. Abby Schubach: Whenever a study gets a lot of press, it can be hard to figure out what the true message really is, and so I really wanted to figure out, how this trial changes our thinking about the value of colonoscopy?

Dr. Greg Katz: So first, we’ll discuss the pathophysiology of colorectal cancer and the theory of why screening makes sense.

Dr. Abby Schubach: Then, we’ll take a step back to look at the big picture on general cancer screening to help understand why it’s so hard to show a benefit in a screening trial.

Dr. Shreya Trivedi: Yeah and then we’ll get into a bit of past story of colorectal cancer clinical trials.

Dr. Greg Katz: And finally we’ll do a deep dive into NordICC to help bring some clarity to the mixed message chaos.

Pathophysiology of Colorectal Cancer & Why Screening Makes Sense

Dr. Shreya Trivedi: In prepping for this episode I was so surprised to hear that a procedure like a colonoscopy that is recommended for everyone in the US has never been studied in a randomized controlled trial.

Dr. Abby Schubach: I’m was shocked, as well. It made more sense to me though when i delved into how hard it is to study the benefit of a screening test and how long it actually takes colon cancer to develop.

Dr. Shreya Trivedi: Yeah, good stuff, so let’s get into just that – what’s the life cycle of colon cancer?

Dr. Abby Schubach: So colon cancer often follows a pretty clear progression, which starts at adenoma and then finally carcinoma. The caveat, of course, is that some cancers can develop without a proceeding polyp. Like a de novo cancer, but most colorectal cancers move through the adenoma pathway.

Dr. Shreya Trivedi: So thinking of cancers down that typical pathway, and what kind of timeframe are we looking at for an adenoma to progress to cancer?

Dr. Abby Schubach: The timeline varies a lot, depending on the type of adenoma. It can be as long as 26 years for diminutive adenoma (smaller than 5mm), 9 years for tubulovillous adenoma, 8 years for small adenoma, 5 years for large adenoma, and actually only 4 years for villous adenoma to develop into cancer.

Dr. Shreya Trivedi: So we are talking anywhere from over two decades to a little less than 10 years except for more scary large adenomas or villous adenomas which is more or less on average 4-5 years.

Dr. Abby Schubach: Yeah, so that timeline makes the impact of colorectal cancer screening *really* hard to study – after an adenoma is removed, the potential cancer would likely not develop for an average of 8 to 10 years after that!!

Dr. Shreya Trivedi: Yeah! That’s a lot of years of follow up, and that’s only for development of cancer. To show a reduction in cancer death will take even longer – as many people go through treatments after diagnosed with colon cancer so many more years after.

Dr. Greg Katz: And it gets even more complicate in showing a benefit in mortality in a screening study is tough. Colon cancer is usually described as common, but it isn’t all *that* common. Only about 4% of individuals will develop colon cancer in their lifetime, so that means that 96% of people in a screening study will never be dealing with this disease.

Dr. Shreya Trivedi: Yeah, man, I don’t do stats for a living, but I’m having anxiety imagining the power calculations to show a mortality benefit and just overall, trying to design a study to demonstrate a benefit in screening seems pretty intimidating!

Dr. Greg Katz: And beyond the statistical questions, there’s also a bit of a controversy about what outcomes matter most for a study like this. Some folks think the most importance metric in a screening test should be all-cause mortality, some think it should be cancer-specific mortality, and some even think it should just be a diagnosis of the specific cancer in question.

Dr. Abby Schubach: Yeah, Greg, for first one, the all-cause mortality argument is that our patients don’t care what they die from, but they don’t want to die!

Dr. Greg Katz:: The counterpoint to arguing all-cause mortality as an endpoint. Screening trials take all-comer and the vast majority won’t be getting that specific cancer. W e need to think about how many people we would need to enroll just to see the difference in all cause mortality when so many people are not effected by the cancer in question.

Dr. Abby Schubach: You know, even though all cause mortality is important, I do like the colorectal cancer-specific metric because after all colonoscopies just look at the colon and rectum and so thats what we should target.

Dr. Shreya Trivedi: I like that! There are benefits and drawbacks with each strategy, but one takeaway is clear – proving that screening is effective requires studying a lot of people for a long time!

Dr. Greg Katz: Let’s get to the back story on colorectal cancer screening before we circle back to NordICC.

General Cancer Screening: Observational Studies

Dr. Abby Schubach: So before the NordICC Trial, the story to support screening for colorectal cancer came from randomized trials looking at sigmoidoscopy and large observational studies looking at both sigmoidoscopy and colonoscopy.

Dr. Greg Katz: Let’s start with observational studies. Whenever I look at observational studies, I keep in mind that observational studies are more hypothesis generating than hypothesis testing. These studies can overestimate or underestimate the impact of an intervention, sometimes because of confounders that we know, but sometimes because of confounders that we don’t realize or can’t measure.

Dr. Abby Schubach: Observational studies can either over or underestimate the benefit of a colonoscopy because of the inability to adjust for important factors such as tendency of healthier people to generally seek preventive care, but also could also have a strong family history of coloreactal cancer prompting them to seek the screening.

Dr. Shreya Trivedi: And to add to that, you mentioned some of these studies were using sigmoidsoscopies. I feel like sigmoidoscopy studies probably under-estimate the effect of colonoscopy screening because of the sheer anatomical perspective that we are not looking at the whole colon and just a part of the colon.

Dr. Greg Katz: Keeping in mind the limitations of observational studies, there were two large prospective observational studies. One published in NEJM in 2013 looking at screening colonoscopy and sigmoidoscopy, and the other published in Annals of Internal Medicine in 2017 looking at just colonoscopy.The two studies consisted of 88,902 patients followed for 22 years, and 1,355,692 patients followed for 8 years, respectively.

Dr. Abby Schubach: And both observed a lower rate of colorectal cancer in screened patients compared to unscreened patients.

Dr. Greg Katz: The NEJM study also observed that fewer people died related to colorectal cancer in the colonoscopy screened patients with a hazard ratio there was o.32, which is pretty impressive. And it’s worth noting, only colonoscopy was associated with lower mortality from proximal colon cancer.

Dr. Shreya Trivedi: And of course, we did NOT see this with the sigmoidoscopy cohort and it makes sense because the sigmoidoscopy doesn’t get the proximal colon.

Dr. Abby Schubach: Yes, let’s take a second to review the anatomy. So sigmoidoscopy is just going to show you the area from the rectum to the sigmoid, but a colonoscopy will go past this, then up the descending colon on left side, over the transverse, down the ascending on the right side, and then all the way to the cecum, that then attaches to the small bowel.

Dr. Shreya Trivedi: Oh, so that’s why all those new GI fellows have cecum celebrations!

Dr. Abby Schubach: Haha, yes because they made it to the end, or I guess really the beginning of the colon!

Dr. Shreya Trivedi: And now that we’ve made it to the end, or should we say the cecum, of the major observational studies, let’s move on to the randomized trials that we’ve seen of sigmoidoscopy!

General Cancer Screening: Randomized Controlled Trials

Dr. Abby Schubach: So there have been four key RCTs looking at sigmoidoscopy, all of which demonstrated a lower incidence of CRC in those invited to be screened compared to those not invited to be screened.

Dr. Greg Katz: So its worth nothing that all of the studies here are always going to be “invited to screen with scoping” versus “not invited to screen with scoping” because you ethically can’t offer someone a sham cancer screening. It would be wrong to tell someone you screened them for cancer, and didn’t actually screen them for cancer.

Dr. Shreya Trivedi: It sounds all great in terms of lowering incidence of colorectal cancer, and then its terms of mortality benefit, so two of those four studies found that offering screening sigmoidoscopies DID NOT reduce colorectal cancer-related mortality rate, BUT in the other two studies found that mortality was significantly reduced.

Dr. Abby Schubach: Yeah, Shreya, so it was half and half. Half showed a mortality benefit and half didn’t. The analysis in those trials were an “intention to screen analysis,” meaning that they are looking at everyone who was invited to undergo screening knowing that a lot of these people who were invited didn’t actually do it. A lot of these studies also do separate analyses called a per protocol analysis only looking at patients who actually completed the screening. These did show a significant mortality benefit in all four studies.

Dr. Shreya Trivedi: And this may be a good time to pause just because I always seem to mix up which one is per protocol and intention to treat (which I know here is technically intention to screen but bare with me). One way that has stuck for me is thinking that T in intention-to-treat is also like the T for trial so ITT is by the books what the trial randomized you to and what outcome whether you did or didn’t undergo the treatment. And then, the P in per protocol reminds me of the P in patients and so per protocol is stratifying what the patient actually get.

Dr. Greg Katz: Keeping those two lines straight is important, not just for understanding the trial, but for understanding the arguments for which of these analyses are better for a screening trial. There’s a line of argument in the world of cancer screening that really believes we should be doing these analyses as “per protocol” rather than “intention to screen” so that we can better capture the true impact of that screening test itself. But it’s hard for me to find that argument truly persuasive if we think about using these trials to make policy since when we lose the ability to evaluate the impact of inviting people to be screened for cancer.

Dr. Abby Schubach: Right, to put this more simply, you can analyze it based on what people were assigned to or what people did. If you analyze it in any other way than what people were invited or assigned to, unfortunately, you lose the benefit of randomization.

Dr. Shreya Trivedi: Either way, I think it’s fair to say that mortality and the colorectal incidence are going to differ significantly when looking at the group of people invited to be screened versus who are actually got the screening scope!

Dr. Abby Schubach: And that is exactly what happened with the SCORE trial (one of 4 RCTs on sigmoidoscopy), in the intention to treat analysis, the mortality rate was not statistically different compared to the control group. But the per protocol analysis told a different story – in this analysis that was a drop in both incidence and death.

Dr. Greg Katz: So, as we will see later in our discussion of NordICC, there seems to be a theme that inviting people to screen may not save lives, but actually undergoing screening probably does. It’s almost like it’s not good enough to have the idea – you actually need to be able to execute a plan to make things work in the real world. And so all this data is where the recommendations in the US for colonoscopy came from, even before RCT data on colonoscopy. Because we do have data that looking at the colon and taking out polyps in sigmoidoscopy saves lives in colorectal cancer.

Dr. Abby Schubach: Yeah! Looking at these recommendations, it surprised me that it wasn’t until the mid-90swhen the first screening recommendations for sigmoidoscopy published by the USPSTF. And then it wasn’t until 2000, when the American College of Gastroenterology (ACG) became the first organization to recommend screening colonoscopy instead of sigmoidoscopy.

Dr. Shreya Trivedi: Haha its so hard for me to not think twice, of course the gastroenterology society the first to recommend the colonoscopy. And it didnt dawn on me that these recommendations were so recent in grand scheme of things! I thought colonoscopies was something we had recommended to patients for decades.

Dr. Greg Katz: The USPSTF waited a couple of years after that ACG recommendation for colonoscopy in 2002, and their recommendations were basically an extrapolation from sigmoidoscopy data, even qualifying their recommendation with the statement: “It is not certain whether the potential added benefits of colonoscopy relative to screening alternatives are large enough to justify the added risks and inconvenience for all patients.”

Dr. Shreya Trivedi:And with all that context, let’s move on to the NordICC trial.

NordICC Trial

Dr. Greg Katz: So, NordICC asked the question: does offering screening colonoscopy reduce incidence and mortality from colorectal cancer?

Dr. Abby Schubach: And as we alluded to earlier, this the first RCT to ask this Q about colonoscopies.

Dr. Shreya Trivedi: So who was enrolled in the NordICC Trial?

Dr. Greg Katz: Eligible individuals were all men and women aged 55 to 64 years living in Norway, Poland, Sweden and the Netherlands. And of these countries, Poland was the only country with an ongoing colorectal cancer screening program.

Dr. Shreya Trivedi: Really? Poland was the only one who had a robust colon cancer screening program? I hadn’t realized they don’t routinely do screening colonoscopies in much of Europe.

Dr. Greg Katz: Does that mean that GI fellowships are less competitive to get into in European countries?

Dr. Shreya Trivedi: Haha that’s a really great point! I don’t know! Someone write in and let us know. But I guess if the salary is still much higher then all bets are off.

Dr. Abby Schubach: Very funny! But in all seriousness European leaders are still trying to use this trial to figure out whether implementing a nationwide screening program with colonoscopy makes sense.

Dr. Shreya Trivedi: So this was an example of study that could have policy implications since sounds like colonoscopy is much less widely accepted in Europe compared to the United States.

Dr. Abby Schubach: Yeah and a part of the reason why colonoscopy is less common is that sedation is much less common as well.

Dr. Shreya Trivedi: Ouch! That does not sound like fun. Without sedation, I would also hard pass on the colonoscopy!

Dr. Greg Katz: Me too! Unless I could bring my own anesthesiologist. Let’s get back to Nordicc, individuals in this trial were randomly assigned to either being offered colonoscopy screening vs. no invitation to screening, termed “usual care.”

Dr. Shreya Trivedi: And to clarify what exactly the invitation to screen meant, it was a letter was sent to invited to screen group with a date and time for their colonoscopy and in one country, only after a response call was done a date and time was given (but that was 10% of the invited to screen group).

Dr. Abby Schubach: And, interestingly, among the 31,420 participants who were assigned to colonoscopy, only 40% accepted the invitation and actually underwent the procedure.

Dr. Shreya Trivedi: Only 40%? Man that really does confirm how unpopular colonoscopies are in Europe.

Dr. Abby Schubach: Yes, in the US it’s a lot higher than that, about 60% of adults meeting screening criteria undergo colonoscopy, so quite a bit of a difference.

Dr. Greg Katz: It’s hard to imagine 60% of U.S. adults agreeing on anything, let alone agreeing to have a colonoscopy. But it’s great the numbers are so high.

Dr. Shreya Trivedi: Ok, so on to results! What differences did we see between the groups that were invited to get the screening colonoscopy versus those who weren’t invited?

Dr. Greg Katz: So colorectal cancer risk at 10 years for the invited group was 0.98%, compared to 1.2% in the usual care group, which is about a 20% reduction in colon cancer risk from being offered screening.

Dr. Abby Schubach: And while a 20% relative risk reduction sounds impressive, but the number we care more about, the absolute risk reduction, was only 0.2%. Based off of this, the number needed to invite to prevent one case of colorectal cancer within 10 years was pretty large at 455 people.

Dr. Shreya Trivedi: Wow, that is a very large amount of people to invite, but I guess when the numbers are that low in terms of incidence of colorectal cancer that Greg mentioned earlier, I think 4%, it makes sense that the number needed to invite is pretty high.

Dr. Greg Katz: And when you look at death from colorectal cancer or all cause mortality, NordICC didn’t show any difference between the invited to screen versus not invited groups at 10 years.

Dr. Shreya Trivedi: I guess that’s not that surprising either, just inviting people to a colonoscopy did not have a mortality benefit. But you guys mentioned there was a per-protocol analysis so I’m curious what that one showed?

Dr. Abby Schubach: The per protocol analysis unsurprisingly had a much bigger reduction in colon cancer and even showed a drop in the number of deaths, as well.

Dr. Greg Katz: And so by using that per protocol analysis, the risk of colorectal cancer at 10 years decreased from 1.2% to .84% in those who actually had colonoscopy, and so that is about a 33% relative risk reduction of colon cancer.

Dr. Shreya Trivedi: And what about the mortality reduction in that per protocol group?

Dr. Greg Katz: And risk of death from colorectal cancer was 0.30% in usual care group compared to 0.15% in those who actually got colonoscopy, so you could look at this and say getting screened cuts your risk of dying from colon cancer by 50% or in half.

Dr. Shreya Trivedi: Wow! So, the mortality reduction actually became significant if you analyze the results based on who actually got scoped.

Dr. Abby Schubach: Yes! Exactly.

Dr. Greg Katz: And if we go back to the intention to screen numbers, we know that there’s a 20% risk reduction in colorectal cancer incidence and no mortality benefit, but I was kind of surprised that colonoscopy didn’t show a more impressive risk reduction. Abby, what do you make of those numbers?

Dr. Abby Schubach: Yeah, Greg, I was surprised too. We have to keep in mind NordICC only followed people for 10 years and we mentioned that sometimes it can take a decade or two for a polyp to progress to cancer, and then dying from that potential cancer takes even longer. So, again, I try to remind myself that when we look 10 years down the road this is likely an underestimation of the true effect.

Dr. Shreya Trivedi: Right. And I think there are some other reasons why this is an underestimation of the true effect. It was likely influenced by where it was conducted in an area where colonoscopy is not widely accepted. Theoretically, if the randomized controlled trial were conducted in the United States, where the rates of colonoscopy are higher, maybe more people would have accepted the invitation to screen and it’s plausible that we would see a greater decrease in the rate of colorectal cancer.

Dr. Greg Katz: And another really important limitation in looking at the impact of colonoscopy was the inter-endoscopist variation in adenoma detection rates (or ADR). ADR is the percentage of colonoscopies performed where at least one adenoma was detected. And remember, if you don’t detect an adenoma you can’t get rid of it. In this study, 29% of the endoscopists had an ADR less than the recommended 25% compared to American standards of endoscopy. Interestingly, in 2018, the average ADR in the US was actually 40.0%, significantly higher than in NordICC.

Dr. Shreya Trivedi: So, coming at this from the perspective of an internist, I hadn’t appreciated the extent in which endoscopist variation could make a difference in the utility of screening.

Dr. Abby Schubach: Yes, and Shreya, it also makes a difference in cancer-related deaths. So one study showed that every 1 percentage point increase in the adenoma detection rates is associated with a 3% reduction in future incidence of colorectal cancer and a 5% reduction in colon cancer related death.

Dr. Greg Katz: One last point that the authors don’t really address, even in the supplementary appendix, is whether there’s a difference in socioeconomic status among patients in the group offered screening between those who accept screening and those who decline it. It makes me wonder what was different between the people in NordICC who received screening versus those who declined it even when offered it.

Dr. Shreya Trivedi: Yes, so many factors that play a role in how to interpret the study results, which I think is one of the most interesting parts of research. And I am glad we are able to discuss it.

Dr. Abby Schubach: Yeah, Shreya, as you know we do our best to control things that often are so out of our control, but ultimately, there ALWAYS ends up being parts of the study that bias the results one way or the another!

Dr. Shreya Trivedi: Totally and we are the detectives trying to figure those out! But this may be a good place to pause and summarize, NordICC found that inviting people to colonoscopy did have reduction in incidence of colorectal cancer, but no survival benefit at 10 years. A few reasons why we may have not seen the mortality decrease we may have wanted to see was (1) the follow-up period being only 10 years (2) there was a lower incidence of adenoma detection than we might see in the US, and lastly, the lower rate of ppl accepting the screening colonoscopy after being invited.

Implications for Patient Care

Dr. Greg Katz: So, we can definitely keep getting into the weeds, picking things apart but let’s dive into what these results actually mean for our patients.

Dr. Abby Schubach: Yes, Greg, thanks for bringing us back to what really matters – at the end of the day what do we tell our patients when they ask us “so what’s with this colonoscopy – do I really have to do it?”

Dr. Shreya Trivedi: Yeah, my perfectionist passive aggressive judgmental father in law asked me this exact question during the pandemic and I didn’t know what to say, the one they had 5-10 years ago was fine, they wanted to know if they can just do stool testing and then just kind of garbled something about pandemic precautions.

Dr. Greg Katz: Shreya, I am not touching your familial challenges with a ten foot pole. But hopefully we can help you and likely a lot of people listening feel more confident with what we know and what we don’t know about colorectal screening based on the NordICC Trial.

Dr. Abby Schubach: Yeah, there are a few important questions to discuss.

Dr. Greg Katz: One is can you make the argument that inviting people to colonoscopy saves lives from colon cancer? The second is a reduction in incidence of a specific type of cancer enough for you to recommend an invasive test like a colonoscopy to your patients?

Dr. Abby Schubach: My take home from this study is that inviting individuals to undergo colonoscopy pretty clearly prevents colorectal cancer. And I find the story that we’ve told pretty compelling to persuade me that actually undergoing the procedure is going to save lives.

Dr. Greg Katz: I feel similarly here – after all the controversy on the headlines about colonoscopy being overrated when we actually dig into the details and reviewed the data, and then you take into account all of the things that we talked about – low adenoma detection rates and low number of people accepted colon cancer screening and then you take per protocol analysis, to me that answers the question I am trying to answer with a high degree of confidence, which is does this procedure prevent colon cancer and the answer is very likely yes.

Dr. Shreya Trivedi: Ok, so thumbs up to colonoscopy. But what about when our patients ask if they can forgo the colonoscopy and get FIT tested or Cologuard instead?

Dr. Greg Katz: It’s a reasonable question, and you can argue that FIT testing is a reasonable alternative to colonoscopy, however, it is much less likely to detect adenomas. It can catch cancer, but the point of screening is to prevent colon cancer – not find it when it is already there. Look at COLONPREV trial – one time colonoscopy compared to annual FIT testing are similar in terms of cancer detection but not detection of adenomas, FIT testing was only about half as good.

Dr. Abby Schubach: But then again FIT testing does come with a very real world benefit – people are more likely to do it.

Dr. Greg Katz: And of course if the FIT or Cologuard is positive than you still need to get a colonoscopy. So you can’t get away with not doing it.

Dr. Shreya Trivedi: For those wondering like me what’s the difference is between the two: turns out that FIT testing just looks for hemoglobin in the stool so is more likely to have false negatives if there is intermittent bleeding. Cologuard, on the other hand, combines FIT testing with DNA markers that are often found in CRC and precancerous adenomas, cologuard is going to give us the bigger bang for our buck with higher sensitivity but at the cost of possibly more false positives.

Dr. Abby Schubach: For a patient who is skeptical about a scope but willing to get a stool test, it’s wonderful we have these other viable options.

Dr. Shreya Trivedi: Yes, and just as a reminder most societies, many societies like the USPSTF and ACG have recently lowered the recommended screening age to 45 in average risk individuals due to the rising rates of colorectal cancer in younger populations.

Dr. Greg Katz: Yes, that is such an important point to note, while it’s not the focus of this podcast, there are younger and younger people being affected by colorectal cancer and so it is a major societal issue. So understanding how we’re going to frame our perspective on the benefits and drawbacks of colonoscopy impacts a lot of conversations that we have, not just with our patients, but with our families, friends, and colleagues.

Dr. Shreya Trivedi: Yeah, I’m one speed dial away from all of my friends and family questions. Yeah so Greg, Abby, let’s talk about then how we would frame this now that we have done such a deep dive. What if my father-in-law had called you up, expecting this perfect answer of what they should do?

Dr. Greg Katz: I would tell him that Dr. Shreya Trivedi is a wonderful doctor. But I would also tell him a colonoscopy is a low risk test that is inconvenient for about 24 hours of your life, and it drastically lowers the chance we are going to die of colon cancer. And since we are all going to die from something, wouldn’t it be nice to remove the third most common cancer and put it way lower down on that list of things that cause us problems?

Dr. Abby Schubach: Definitely. And so as we’re wrapping up, I want to come back to the controversy generated by this trial. A lot of the noise in the media was inflammatory and ultimately confusing for our patients.

Dr. Greg Katz: And so hopefully we clarified some of that. The policy questions that come up after NordICC – like is the cost of colonoscopy financially reasonable? Are other, cheaper screening modalities good enough for most of us? Who should cover the cost of colonoscopy? Those are questions are really hard to answer and I’m not going to pretend that there’s a single clear or unimpeachable conclusion you can take from NordICC to answer of those questions public health questions.

Dr. Abby Schubach: Yes, the policy questions are so hard to answer, but I am going to leave those to the experts. At the end of the day, from a clinical perspective, I think we can all agree that in addition to what we’ve discussed today, counseling patients on staying away from processed meats, tobacco cessation, obesity management, and consumption of less than three alcoholic drinks per day, are probably useful to decrease the risk of colon cancer.

Dr. Shreya Trivedi: Yes! All good stuff. So on that note, so what do we think? Are we excited for our upcoming colonoscopies in less than 10-15 years?

Dr. Abby Schubach: Hm, Shreya, I don’t know if I would use the “e” word, but am I excited to prevent colon cancer with one relatively painless procedure? YOU BET I AM!

Dr. Greg Katz: So there you have it – the sixth edition of Beyond Journal Club with NEJM Group.

Dr. Shreya Trivedi: And that is a wrap for today! If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us!

Dr. Abby Schubach: And if you have any feedback, please email us at [e-mail]. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

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