What is the role of arginine (amino acid) in patients with malignancy (cancer)?

Role of Arginine in Malignancy

In cancer patients undergoing surgery, arginine-enriched immunonutrition (combined with omega-3 fatty acids and nucleotides) should be administered perioperatively or postoperatively to malnourished patients undergoing major cancer surgery, as this reduces infectious complications and hospital length of stay. 1

Context-Dependent Dual Role

Arginine plays a paradoxical role in cancer that depends critically on the clinical context:

In Surgical Cancer Patients (Recommended Use)

Perioperative immunonutrition containing arginine is strongly recommended for malnourished patients undergoing major cancer surgery, particularly upper GI malignancies. 1

• ESPEN guidelines (2017,2021) provide Grade B recommendation for peri- or postoperative administration of formulas enriched with arginine, omega-3 fatty acids, and ribonucleotides in malnourished patients undergoing major cancer surgery 1

• Meta-analyses demonstrate arginine-supplemented diets reduce perioperative infectious complications (risk ratio: 0.59, P < 0.00001) and hospital length of stay (weighted mean difference: 2.38 days, P < 0.00001) 1

• In head and neck cancer surgery specifically, arginine supplementation reduced fistulas (OR = 0.36,95% CI: 0.14-0.95) and hospital stay by 6.8 days 1

• A 10-year observational study in head and neck cancer patients showed significantly longer overall survival, better disease-specific survival, and less locoregional tumor recurrence with perioperative arginine-enriched nutrition 1, 2

In Cancer Cachexia (Not Recommended)

Arginine supplementation cannot be recommended for cancer cachexia or weight loss outside the surgical context. 1

• A large RCT in 472 cachectic cancer patients comparing oral mixture of HMB, glutamine, and arginine versus control failed due to compliance problems (only 37% completed protocol), with no statistically significant differences observed 1

• ESPEN guidelines (2017) state there are insufficient consistent clinical data to recommend supplementation with amino acids or metabolites to improve fat-free mass in cancer cachexia 1

Critical Distinction: Arginine Alone vs. Immunonutrition Formula

Important caveat: Evidence does not support arginine supplementation as a single substance. 1

• ESPEN guidelines explicitly state "no clear recommendation can be given regarding the intravenous or enteral supplementation of arginine as a single substance" 1

• The benefits observed are from combination formulas containing arginine plus omega-3 fatty acids and nucleotides, not arginine in isolation 1

• The synergistic effect of these immunonutrients together appears necessary for clinical benefit 1

Timing and Duration

For surgical patients, immunonutrition should be given for 5-7 days perioperatively (preoperatively and/or postoperatively), with at least 250 ml daily 1

• Benefits are similar whether given preoperatively only, pre- and postoperatively combined, or postoperatively only 1

• The most recent guidelines (2025) emphasize this applies particularly to patients with upper GI cancers 1

Theoretical Concerns About Tumor Growth

While preclinical studies show arginine can both stimulate and inhibit tumor growth depending on context 3, 4, 5, 6, clinical evidence in surgical cancer patients demonstrates net benefit on survival and recurrence 1, 2

• Over 70% of tumors suppress ASS1 (argininosuccinate synthase 1), making them dependent on external arginine, which forms the basis for arginine-deprivation therapy in some contexts 4

• However, arginine is also necessary for immune destruction of malignant cells 3

• The long-term survival benefit observed in head and neck cancer patients receiving perioperative arginine-enriched nutrition (10-year follow-up) suggests the immune-enhancing effects outweigh any theoretical tumor-promoting effects in the surgical setting 1, 2

Practical Implementation

For malnourished cancer patients undergoing major surgery (especially upper GI, head and neck):

• Screen all patients for malnutrition risk preoperatively 1
• Administer oral/enteral immunonutrition formula (containing arginine 12.5-18.7 g/L plus omega-3 fatty acids and nucleotides) 1
• Continue for 5-7 days perioperatively, minimum 250 ml daily 1
• Manage within Enhanced Recovery After Surgery (ERAS) protocol 1

Do not use arginine supplementation for:

• Cancer cachexia or weight loss outside surgical context 1
• Arginine as a single supplement (only use combination immunonutrition formulas) 1