New Study Reports Neurotoxic Side Effects Are Less with the Use of Immunotherapy Compared To Chemotherapy

UH Seidman Update | June 2022

Neurological side effects are very rare with the use of immunotherapy. However, they are one of the most debilitating side effects of immunotherapy. In this meta-analysis led by Ankit Mangla, MD, 2876 articles were collected and analyzed for relevance, and 39 clinical trials, including 23,705 patients, reported neurological side effects in the participants qualified to be included in the final analysis. The team first analyzed the data from the entire group and found that overall neurologic side effects were more with non-immunotherapy regimens than immunotherapy only regimens. Peripheral neuropathy was the most common side effect reported by 23 clinical trials and was significantly higher in the non-immunotherapy group. Likewise, dysgeusia was reported by fewer subjects in the immunotherapy group.

Ankit Mangla, MD

Since the clinical trials included in the overall analysis included a variety of therapies (including chemotherapy, vaccines, placebo, and targeted therapy), a subgroup analysis was done to better understand the differences in the neurological adverse events. The first subgroup analysis included 15 trials where immunotherapy was used in one arm, and only cytotoxic chemotherapy was used in the other. This subgroup analysis was more decisive in terms of understanding the frequency of adverse events with the use of immunotherapy versus cytotoxic chemotherapy. Even in this group, the overall incidence of all neurological side effects was higher with chemotherapy compared to immunotherapy. However, compared to chemotherapy, peripheral neuropathy, dysgeusia, and paresthesia were much lower with the use of immunotherapy. At the request of reviewers, the team also analyzed overall neurotoxicity after excluding peripheral neuropathy events. The final analysis continued to show a lower incidence of overall neurotoxicity with immunotherapy compared to chemotherapy.

The second subgroup analysis included five trials where immunotherapy was compared with placebo. This analysis showed that the overall risk of neurologic side effects is higher with immunotherapy compared to placebo. Dr. Mangla says that these results show that, although rare, neurological side effects are still an important part of the profile of adverse events related to immunotherapy. In addition, the team also reported that headaches are more common with immunotherapy compared to placebo.

Advantages/unique points of this study:

1. This project is the first comprehensive meta-analysis of neurologic side effects from immunotherapy ever to be published. Furthermore, no such research has been published prior to this report, analyzing the clinical trial data on such a massive scale.
2. The data helps us counsel patients regarding immunotherapy's potential side effects. In addition, the oncologist practicing in the community can draw favorable conclusions regarding neurological adverse events from immunotherapy, especially regarding a common adverse event like peripheral neuropathy.
3. Dysgeusia is a very common issue with chemotherapy. As a result, patients lose the taste of food and often cannot eat as many calories as needed to sustain the energy requirements during the treatment. So it is reassuring to know that it is not as common with immunotherapy compared to chemotherapy.
4. The comparison of immunotherapy with placebo does caution the provider that the risk of neuropathy is still real. Hence, symptoms of neurologic side effects should never be disregarded.

Future directions:

Although this is a comprehensive and the largest collection of trials reporting neurologic adverse events, it is impossible to determine the risk of very rare adverse events like myasthenia gravis or Guillain barre syndrome in such studies. The number of subjects reporting such rare adverse events is so few that the numbers cannot fit into mathematical calculations. Hence, comprehensive databases made possible by cooperation between various groups need to be built and accessible to clinicians and statisticians to help understand rarer adverse events.

Dr. Mangla says it is still unclear what the real impact of neurologic side effects on patients who actually develop these side effects is unclear. This data is not reflective of the impact of immunotherapy-related neurologic adverse events on a patient’s survival, ability to take further treatments, enroll in clinical trials, etc. Again, comprehensive databases tracking such patients' evolution will help understand the real impact of neurological adverse events from immunotherapy.

Take away message:

The incidence of neurologic adverse events is lower with immunotherapy compared to chemotherapy and other non-immunotherapy-based regimens; however, it still needs to be watched for by the treating clinicians.

Contributing Expert:
Ankit Mangla, MD
UH Seidman Cancer Center
Hematology/Oncology
Assistant Professor
Case Western Reserve University School of Medicine

Read the full article online at JAMA Network Open.