Now and then, a study grabs the interest of the editors and readers of Sensible Medicine to such a degree that we seem unable to let it rest. Here, Dr. Blase Polite pushes back against recent critiques of CHALLENGE, a trial examining the effects of exercise on colon cancer.
I struggle with Dr Polite’s critique. If anything the Challenge trial probably shows that highly selected patients ( think here of how long it took to recruit ) are fitter and have a better performance status and hence tolerate current and future Colorectal cancer therapies.
The first thing I noticed is that there needs to be a link between a survival benefit in CRC patients and the proposed impact exercise has on that oncogenic process. Exercise improves cardiovascular health, fitter patients can tolerate treatment better , is that what the study has found ?
It would be great to get Dr Polite’s view on how exercise as described in the study has a specific mechanistic effect that is anti cancer ? What is the pathological mechanism that every other anti cancer treatment that is scrutinised from a scientific perspective must explain , what is the hypothesis ?
Also beware “ rolling in “ previous cohort studies with a RCT , they are completely different things.
If Dr. Polite truly believes that light exercise or for that matter any exercise has any effect on colon cancer progression, I have a bridge to nowhere to sell him. And for sure remind me not to consult Dr. Polite for any oncological advice. Of course exercise is good for one for all sorts of reasons, but even at face value the ~10% improvement is insignificant from any meaningful perspective. There is just no biological mechanism whereby exercise could be of any consequence. Now, if the good doctor is dealing with patients who can't climb up a flight of stairs with ease and are huffing and puffing, perhaps a small degree of exercise might improve their cardiovascular health and hence their overall survival but that has nothing to do with cancer progression. As far as colon cancer is concerned, claiming that exercise has an overall survival benefit is not different from claiming that a sugar pill increases OS, and I doubt even the good Dr would buy that.
"There is just no biological mechanism whereby exercise could be of any consequence."
That's a pretty bold statement, not backed up by evidence.
The authors offer a number of mechanisms: "Exercise may be an effective treatment for colon cancer micrometastases and prevention of second primary cancers through various mechanisms, including increased fluid shear stress, enhanced immune surveillance, reduced inflammation, improved insulin sensitivity, and altered microenvironment of major sites of metastases. In particular, exercise may affect metabolic growth factors such as insulin and insulin-like growth factors that promote cancer-cell proliferation and progression."
Planned analyses of serial blood samples will address questions related to possible mechanisms.
Not a bold statement at all. Just common sense. Why not compare cancer rates in those who exercise and those who don't. The differences are going to be tiny. To think that exercise "may be an effective treatment for colon cancer micrometastases and prevention of secondary cancers" is no different from believing in the tooth fairy. Ineed, it's no different from believing that oral vitamin C is an effective cancer-prevention regimen.
Dr Polite cites “10% improvement in 5 yr OS”. While seemingly “robust”: if 9 of 10 patients receive no OS benefit my guess is that when offered these options many patients may take a negative view and instead remain couch potato- like ??? Especially given the degree of effort/ manpower required to accrue this “robust” benefit.
I think this study is akin to STRONG-HF for heart failure. It is a laborious protocol that will have significant external validity challenges. But if it’s somehow something that the health system can provide (and the pt can stick to), there’s really no downside. In some regards it’s better than “strong hf”, since it’s just encouraging exercise and not a “rush to put 4 drugs on everybody”. This is nowhere near my field, and hence not something I would have much occasion to apply, but I “want” it to be correct.
I would note that a 2mL/kg/min improvement in MVO2 represents less than an increase of 1 MET (metabolic equivalent) which certainly does not portend going from NYHA class 3 to class 2 as suggested in the OP.
Also, the trial suggested an improvement of 25-30m for 6MWT (the threshold for meaningful clinical improvement for cardiopulmonary conditions is generally somewhere btw 25-50m). This would seem to be in that ballpark if the same metric applies in oncology. But I wouldn’t characterize that as being able to walk “1 or 2 more blocks”….at least not in the city I live in.
Get 'em Blase!
I struggle with Dr Polite’s critique. If anything the Challenge trial probably shows that highly selected patients ( think here of how long it took to recruit ) are fitter and have a better performance status and hence tolerate current and future Colorectal cancer therapies.
The first thing I noticed is that there needs to be a link between a survival benefit in CRC patients and the proposed impact exercise has on that oncogenic process. Exercise improves cardiovascular health, fitter patients can tolerate treatment better , is that what the study has found ?
It would be great to get Dr Polite’s view on how exercise as described in the study has a specific mechanistic effect that is anti cancer ? What is the pathological mechanism that every other anti cancer treatment that is scrutinised from a scientific perspective must explain , what is the hypothesis ?
Also beware “ rolling in “ previous cohort studies with a RCT , they are completely different things.
If Dr. Polite truly believes that light exercise or for that matter any exercise has any effect on colon cancer progression, I have a bridge to nowhere to sell him. And for sure remind me not to consult Dr. Polite for any oncological advice. Of course exercise is good for one for all sorts of reasons, but even at face value the ~10% improvement is insignificant from any meaningful perspective. There is just no biological mechanism whereby exercise could be of any consequence. Now, if the good doctor is dealing with patients who can't climb up a flight of stairs with ease and are huffing and puffing, perhaps a small degree of exercise might improve their cardiovascular health and hence their overall survival but that has nothing to do with cancer progression. As far as colon cancer is concerned, claiming that exercise has an overall survival benefit is not different from claiming that a sugar pill increases OS, and I doubt even the good Dr would buy that.
"There is just no biological mechanism whereby exercise could be of any consequence."
That's a pretty bold statement, not backed up by evidence.
The authors offer a number of mechanisms: "Exercise may be an effective treatment for colon cancer micrometastases and prevention of second primary cancers through various mechanisms, including increased fluid shear stress, enhanced immune surveillance, reduced inflammation, improved insulin sensitivity, and altered microenvironment of major sites of metastases. In particular, exercise may affect metabolic growth factors such as insulin and insulin-like growth factors that promote cancer-cell proliferation and progression."
Planned analyses of serial blood samples will address questions related to possible mechanisms.
Not a bold statement at all. Just common sense. Why not compare cancer rates in those who exercise and those who don't. The differences are going to be tiny. To think that exercise "may be an effective treatment for colon cancer micrometastases and prevention of secondary cancers" is no different from believing in the tooth fairy. Ineed, it's no different from believing that oral vitamin C is an effective cancer-prevention regimen.
Dr Polite cites “10% improvement in 5 yr OS”. While seemingly “robust”: if 9 of 10 patients receive no OS benefit my guess is that when offered these options many patients may take a negative view and instead remain couch potato- like ??? Especially given the degree of effort/ manpower required to accrue this “robust” benefit.
I think this study is akin to STRONG-HF for heart failure. It is a laborious protocol that will have significant external validity challenges. But if it’s somehow something that the health system can provide (and the pt can stick to), there’s really no downside. In some regards it’s better than “strong hf”, since it’s just encouraging exercise and not a “rush to put 4 drugs on everybody”. This is nowhere near my field, and hence not something I would have much occasion to apply, but I “want” it to be correct.
I would note that a 2mL/kg/min improvement in MVO2 represents less than an increase of 1 MET (metabolic equivalent) which certainly does not portend going from NYHA class 3 to class 2 as suggested in the OP.
Also, the trial suggested an improvement of 25-30m for 6MWT (the threshold for meaningful clinical improvement for cardiopulmonary conditions is generally somewhere btw 25-50m). This would seem to be in that ballpark if the same metric applies in oncology. But I wouldn’t characterize that as being able to walk “1 or 2 more blocks”….at least not in the city I live in.