Management guidelines for gastrointestinal irAEs1–3
Common gastrointestinal irAE symptoms
BMS-recommended management guidelines for GI irAEs2
For suspected irAEs, first exclude other causes
| Grade 1 | Grade 2 | Grade 3–4 | |
|---|---|---|---|
| Definition | (Diarrhoea: <4 stools per day over baseline
colitis: asymptomatic) |
(Diarrhoea: 4–6 stools per day over baseline, IV fluids indicated <24 hours, not interfering with ADL
colitis: abdominal pain, blood in stool) |
(Diarrhoea [G3]: ≥7 stools per day over baseline, incontinence, IV fluids ≥24 hours interfering with ADL
colitis [G3]: severe abdominal pain, medical intervention indicated, peritoneal signs [G4] life-threatening, perforation) |
| Dual NIVO + IPI | Continue treatment | Withhold treatment until Grade 0–1
Permanently discontinue for recurrent colitis upon restarting3 |
Permanently discontinue3 |
| NIVO alone | Continue treatment | Withhold treatment
Permanently discontinue1 nivolumab for recurrent colitis upon restarting1 |
Grade 3: Withhold nivolumab until Grade 0–11
Grade 4: Permanently discontinue nivolumab1 |
| Symptomatic treatment | Administer | Administer | – |
| Medication | – | If symptoms persist >5 days or recur
0.5–1 mg/kg/day methylprednisolone equivalent* |
1–2 mg/kg/day methylprednisolone equivalent** |
| GI tests | – | – | Consider lower GI endoscopy |
| Follow-up | Close monitoring for worsening symptoms
Educate patient to report worsening immediately If symptoms worsen or persist Treat as Grade 2 or 3–4 |
If improved to Grade 1:
Resume treatment If steroids have been administered, taper steroids over ≥1 month before resuming treatment If symptoms worsen or persist >3–5 days with oral steroids Treat as Grade 3–4 |
If improved from Grade 3 while administering nivolumab monotherapy
When at Grade 1, taper steroids over ≥1 month before resuming treatment Permanently discontinue for recurrent colitis upon re-initiation of nivolumab or the nivolumab + ipilimumab regimen If symptoms persist 3–5 days or recur after improvement Add non-corticosteroid immunosuppressive medication (e.g. infliximab 5 mg/kg)*** |
*Consider prophylactic antibiotics for opportunistic infections; **Add prophylactic antibiotics; ***Infliximab is not recommended in cases of TB or hepatitis.4 If no response, consider switching to the other biologic, higher-dose infliximab, faecal microbiota transplantation, ustekinumab, tofacitinib, extracorporeal photopheresis, colectomy and repeat testing for infections.5
ADL, activities of daily living; GI, gastrointestinal; IPI, ipilimumab; irAE, immune-related adverse event; IV, intravenous; NIVO, nivolumab; TB, tuberculosis
International guideline (ASCO, ESMO and NCCN) recommendations for GI irAEs4–6^
^ For detailed guidelines, please refer to original publication
| Grade 1 | Grade 2 | Grade 3–4* | |
|---|---|---|---|
| Immunotherapy | Consider holding4,6 | Hold4,6 | Hold/discontinue4–6
Grade 3: (Consider)6 permanent discontinuation of anti-CTLA-4. Consider anti-PD-1/PD-L1 upon resolution4,6 Grade 4: Permanently discontinue responsible agent4,6 |
| Symptomatic treatment | Loperamide4–6 or diphenoxylate/ atropine4
Hydration Advise dietary change5,6 If persistent or progressive, but without infection or negative lactoferrin/ calprotectin, add mesalamine, cholestyramine4 |
– | – |
| Medication | – | Prednisone/(methyl)prednisolone or equivalent**
If no response within 2–3 days,4 consider adding within 2 weeks6:
For infliximab or vedolizumab-refractory colitis, consider4:
|
Prednisone/IV methylprednisolone**
If no response within 1–2 days,4 continue steroids and strongly consider adding4,6:
For infliximab or vedolizumab-refractory colitis, consider4:
|
| Consultation | – | (Consider)4 gastroenterology6 | (Consider)4 gastroenterology5,6 |
| Admission | – | – | Provide inpatient care6 |
*In all cases, increase the urgency of testing and intervention in Grade 4 patients; **Consult steroid dosing table below
IV, intravenous; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1
At Grade 2 or above, work-ups should include blood and stool investigations to assess patient condition and rule out infectious aetiology.5,6 Testing for bacterial, viral and parasitic causes should also be conducted.4–6 Lactoferrin and calprotectin testing can be considered.6 Imaging may be conducted to assess ulceration.5,6
|
ASCO, ESMO, NCCN |
|||
|---|---|---|---|
| Grade 1 | Grade 2 | Grade 3–4 | |
| Increase of <4 stools per day and/or mild increase in ostomy output over baseline, feeling well, no colitis symptoms | Increase of 4–6 stools per day and/or moderate increase in ostomy output over baseline4–6 | Increase of ≥7 stools per day, incontinence, severe increases in ostomy output compared with baseline, limiting self-care ADL.4–6 Colitis symptoms, haemodynamic instability, other serious complications,4 including life-threatening consequences6 | |
ADL, activities of daily living; ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; NCCN, National Comprehensive Cancer Network
| ASCO6 | ESMO5 | NCCN4 | |
|---|---|---|---|
| Grade 1 | – | – | – |
| Grade 2 | Initial dose of 1 mg/kg/day prednisone or equivalent if clinically indicated | Oral corticosteroid 40–60 mg/day. Wean over 4–8 weeks. If refractory to corticosteroids, rapid steroid tapering and:
|
Prednisone/methylprednisolone 1–2 mg/kg/day tapering over 4–6 weeks after achieving Grade 1 (<2–4 weeks if infliximab or vedolizumab were added) |
| Grade 3–4 | Grade 3: Initial dose of 1–2 mg/kg/day prednisone or equivalent; If concern for concurrent upper GI inflammation, consider IV methylprednisolone; consider early infliximab or vedolizumab if persistent symptoms after 3 days
Grade 4: 1–2 mg/kg/day methylprednisolone or equivalent, tapering over 4–6 weeks once Grade 1 is achieved; If symptoms persist after 3 days, start taper over 4–6 weeks and consider infliximab or vedolizumab |
IV (methyl)prednisolone 1 mg/kg/day; assess response at days 3–5;
If response to IV corticosteroids, switch to oral prednisolone 1 mg/kg/day. Wean over 4–8 weeks. If refractory to corticosteroids,
|
IV (methyl)prednisolone 1–2 mg/kg/day tapering over 4–6 weeks after achieving Grade 1 (<2–4 weeks if infliximab or vedolizumab were added) |
ESMO recommends considering infliximab 5 mg/kg (IV in the more severe forms) or vedolizumab 300 mg in the more moderate forms and rapid corticosteroid tapering for Grade 2–4 refractory to corticosteroids. If no response, consider switching to the other biologic, higher-dose infliximab, faecal microbiota transplantation, ustekinumab, extracorporeal photopheresis, colectomy and repeat testing for infections.
ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; GI, gastrointestinal; IV, intravenous; NCCN, National Comprehensive Cancer Network
ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; GI, gastrointestinal; irAE, immune-related adverse event; NCCN, National Comprehensive Cancer Network
References:
- OPDIVO® (nivolumab) Product Information, BMS Hong Kong.
- Bristol-Myers Squibb. Immune-Related Adverse Reaction (irAR) Management Guide. 1506AU2002148-01. April 2020.
- YERVOY® (ipilimumab) Product Information, BMS Hong Kong.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Management of immunotherapy-Related Toxicities. Version 1.2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Accessed February 2023.
- Haanen J, et al. Ann Oncol 2022;33:1217–1238. Available at: https://www.annalsofoncology.org/article/S0923-7534(22)04187-4/fulltext. Accessed March 2023.
- Schneider BJ, et al. J Clin Oncol 2021;39:4073–4126. Available at: https://ascopubs.org/doi/full/10.1200/JCO.21.01440. Accessed March 2023.
