Response to Recommendations to Increase Dietary Protein Intake During Chemotherapy

Articles supplied:

  1. Arends J, Bachmann P, Baracos V et al. ESPEN guidelines on nutrition in cancer patients. Clin Nutr. 2017;36:11-48.
  2. Stobäus N, Müller MJ, Küpferling S, Schulzke JD, Norman K. Low Recent Protein Intake Predicts Cancer-Related Fatigue and Increased Mortality in Patients with Advanced Tumor Disease Undergoing Chemotherapy. Nutr Cancer. 2015;67:818-824.

In my opinion, the recommendations for cancer patients to increase protein intakes are based on bad science, typically referring to journal articles that clearly were not even read, given the mistaken inferences that are drawn. For example, the ESPEN article (1) states (p11): “metabolic investigations showed that an elevated protein intake promoted muscle protein anabolism in patients with cancer (72). Reference 72 (2) does not, however, refer to dietary protein intake; rather, it comments “Muscle protein synthesis is evidently not shut down in patients with cancer, because several studies suggest that this process is unimpaired and responsive to the dietary supply of aminoacids, albeit a somewhat higher quantity than in younger, healthy individuals.(9,10)”. Reference 9 here (3), does not so much comment on the process of muscle protein synthesis, as show that in weight-losing cancer patients, muscle protein synthesis is actually increased compared to normals, suggesting that muscle degradation must be increased in these patients. The experiment in reference 10 (4) did not show response to dietary aminoacids, as the amino acid mixture used was administered intravenously.

Returning to the ESPEN article, it goes on to say “The optimal nitrogen supply for cancer patients has not been determined and the recommendations of experts range between a minimum protein supply of 1 g/kg/day and a target supply of 1.2-2 g/kg/day (73-75). Reference 73 (5) says, “In practice, the optimal nitrogen supply for cancer patients cannot be determined at present. A nitrogen supply of 200–300 mg/kg/day, i.e. 1.2–2 g of protein/ kg/day, appears to be sufficient.” but gives no references to support this. It does say, though, “Correctly adapted supplies can, however, reduce myofibrillar breakdown (108) and, above all, stimulate protein synthesis, generally without upsetting the balance in hypercatabolic cancer patients (109).” Unfortunately for the ESPEN group, references 108 and 109 refer to parenteral (ie, intravenous) nutrition, not dietary.

ESPEN reference 75 (6) is to a book chapter, which points out (p632) “Dietary protein and amino acid requirements of cancer patients have never been formally determined” which is probably as true today as it was in 2006. Baracos goes on to recommend a formula for calculating recommended protein intakes. This formula suggests 150 g protein per day, about 2.5 times the average protein consumption of typical cancer patients. While this had not been tested, Baracos refers to an article (her reference 15) reporting on “targeted amino acid supplementation” (7) which Baracos describes as “31 g of a mixture of arginine, glutamine and a metabolite of leucine” daily. While the test group gained 2.5 kg of lean body mass (LBM) over 12 weeks, compared to a loss of LBM in the control group, it needs to be pointed out that the “metabolite of leucine” in the mixture is actually 3 g of beta-hydroxy-beta-methylbutyrate (HMB), a dietary supplement which has been shown in a number of studies to promote muscle synthesis and reduce muscle breakdown, and is apparently in widespread use by athletes. In fact, the mixture used in the May et al study was a commercial product called “Juven”. I find it misleading to imply that LBM increases due to using this product would translate into LBM increases from increasing dietary protein intake.

A bit further on in the ESPEN article, we find the interesting sentence “Muscle protein synthesis is evidently not shut off completely in patients with cancer, because several studies suggest that this process is not impaired and remains responsive to the dietary supply of amino acids, albeit a somewhat higher quantity than in younger, healthy individuals (84).” If this reads suspiciously like the quotation from Baracos that I provided above, it’s because it’s the same with a couple of minor word changes; however, the ESPEN authors failed to attribute it to Baracos, instead referring (their reference 84; (3)) directly to a paper cited by Baracos.

It is possible to go on, parsing the articles and following the chains of references, but when I do so, I repeatedly find evidence of badly written papers, papers that I would not want to have my name on as an author.

The Stobaus article (8) is interesting, however. This was a prospective observational study which concluded that in patients undergoing chemotherapy, low protein intake (as determined by 24h recall questionnaire) was the “strongest contributor” to cancer-related fatigue, and was also a significant predictor for increased 6-month mortality. As it was an observational study, it can tell us nothing about cause-and-effect or the directionality of the associations. For example, the patients with low protein intakes were older, more likely to be overweight, had experienced more weight loss in the previous 6 months, and were eating much less overall than the high-protein group. Clearly, they were either more ill to begin with, or were having more side effects from their chemotherapy, or both; perhaps these factors influenced their protein intake.

References

1 Arends J, Bachmann P, Baracos V et al. ESPEN guidelines on nutrition in cancer patients. Clin Nutr. 2017;36:11-48. PubMed

2 Baracos VE. Skeletal muscle anabolism in patients with advanced cancer. Lancet Oncol. 2015;16:13-14. PubMed

3 MacDonald AJ, Johns N, Stephens N et al. Habitual Myofibrillar Protein Synthesis Is Normal in Patients with Upper GI Cancer Cachexia. Clin Cancer Res. 2015;21:1734-1740. PubMed

4 Winter A, MacAdams J, Chevalier S. Normal protein anabolic response to hyperaminoacidemia in insulin-resistant patients with lung cancer cachexia. Clin Nutr. 2012;31:765-773. PubMed

5 Nitenberg G, Raynard B. Nutritional support of the cancer patient: issues and dilemmas. Crit Rev Oncol Hematol. 2000;34:137-168. PubMed

Baracos VE. Meeting the aminoacid requirements for protein anabolism in cancer cachexia. In: Mantovani G, editor. Cachexia and wasting: a modern approach. Milan: Springer; 2006. p. 631-634.

7 May PE, Barber A, D’Olimpio JT, Hourihane A, Abumrad NN. Reversal of cancer-related wasting using oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine. Am J Surg. 2002;183:471-479. PubMed

8 Stobäus N, Müller MJ, Küpferling S, Schulzke JD, Norman K. Low Recent Protein Intake Predicts Cancer-Related Fatigue and Increased Mortality in Patients with Advanced Tumor Disease Undergoing Chemotherapy. Nutr Cancer. 2015;67:818-824. PubMed

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