Given the rapid expansion of the number of patients receiving immune checkpoint inhibitors
(ICIs), including special patient groups (with autoimmune disease or transplant patients),
as well as increasing use of combination treatments involving ICIs (either together
or with other cancer treatments), the knowledge base on incidence, management and
outcome of side-effects needs to be addressed to first document and then reduce therapy-associated
morbidity and mortality. Because all organ systems can be affected, some with permanent
sequelae and occasionally even after cessation of therapy, it reemphasises the need
for standardised reporting of side-effects in trials and beyond. Furthermore, ICIs
are being used in earlier tumour stages, including the adjuvant and neoadjuvant setting.
Because in these settings the risk–benefit ratio is less clear, it is particularly
important to optimally document immune-related toxicity, especially when permanent
sequelae or fatalities occur. There is evidence that toxicity reporting could be improved
in immunotherapy trials [
[1]
], and as a community, we need to best leverage our resources to acquire knowledge
on the unique side-effects induced by ICIs, the risk factors for their occurrence and
the best management. A working group of oncologists developed the Side Effect Reporting
in Immuno-Oncology (SERIO) recommendations to increase knowledge on immune-related
adverse events (irAEs) with the following issues:
- 1Document life-changing AEs
-
Reporting of toxicity within clinical trials needs to include the frequency of therapy-induced permanent sequelae. These numbers are crucial for patients when choosing between a generally well-tolerated checkpoint inhibitor therapy with rare permanent impairment and a less well-tolerated therapy, which has nearly no risk of permanent sequelae (for example, combined BRAF/MEK inhibitor treatment in melanoma). This is particularly important for patients with a low risk of recurrence and, thus, death due to tumour progression as even very rare permanent treatment-induced disabilities, such as type-1 diabetes mellitus or neurologic toxicities with permanent disabilities, become much more relevant.
- 2Analyse rare and fatal AEs
-
Rare and fatal treatment-related AEs need to be prominently represented and analysed in clinical trial reports. So far, these events may not be represented in publications if they do not reach a frequency above a threshold of 5%, e.g., cardiac toxicity. Subsequently, there was inconsistent mention of the increased rate of cardiovascular side at international conferences, despite the very high fatality rate [1,2,3]. Importantly, frequency does not necessarily correspond to the severity of a given side-effect [[4]]. A non-standardised format for reporting AEs is insufficient, an issue already raised in the ‘trial reporting in immune-oncology’ initiative [[5]]. Furthermore, rare AEs might only become apparent with treatment of larger cohorts; thus, a registry is necessary.
- 3Acquire prospective data on toxicity
-
Data on side-effects need to be gathered prospectively because side-effect management critically determines morbidity and mortality in patients receiving ICIs. However, there are only scarce assessments with regard to risk factors, incidence, pathogenic characterisation and management of side-effects included in the clinical studies. Investigating side-effects is crucial, especially in severe, rare and steroid-, infliximab- or mycophenolate-refractory cases. Funding for studies on side-effects remains a challenge. Thus, we rely on retrospective data with all the known limitations of such approaches. Japan has shown the way forward with a prospective postmarketing survey including examinations of more than 10,000 patients treated with ICIs [[6]], resulting in important clues on immune-related neurological side-effects.
- 4Attend patients at special risk
-
Data on patient groups at special risk who were excluded from clinical trials, such as patients with autoimmune disease, HIV or hepatitis B/C infection or patients with solid organ transplants, need to be gathered. Many initiatives try to gain insights because these cases represent a conundrum for the treating physician [7,8,9,10]. Being able to anticipate the exacerbation of autoimmunity or transplant rejection would greatly alleviate these situations. Here, a register could help.
- 5Report long-term outcomes
-
Finally, the long-term follow-up of side-effects and quality of life in patients enrolling for clinical trials is needed. Immunotherapy has opened a new era of ‘survivorship’, particularly in malignancies such as advanced melanoma for which this is new. However, side-effects may occur long after completion of checkpoint inhibitor therapy, especially as the immunotherapies are applied in earlier settings.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- A systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors.Ann Oncol. 2015; 26: 1824-1829
- Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis.Lancet. 2018; 391: 933
- Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy.J Immunother Cancer. 2016; 4: 50
- Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis.JAMA Oncol. 2018; 4: 1721-1728
- Trial Reporting in Immuno-Oncology (TRIO): an American society of clinical oncology-society for immunotherapy of cancer statement.J Immunother Cancer. 2019; 37: 72-80
- Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan.Neurology. 2017; 89: 1127-1134
- Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity.Eur J Cancer. 2017; 75: 24-32
- Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.Ann Oncol. 2017; 28: 368-376
- Use of checkpoint inhibitors in liver transplant recipients.Unit Eur Gastroenterol J. 2018; 6: 970-973
- Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection.Eur J Cancer. 2018; 104: 137-144
Article info
Publication history
Published online: March 20, 2019
Accepted:
January 17,
2019
Received:
January 16,
2019
Identification
Copyright
© 2019 Elsevier Ltd. All rights reserved.
