With the rapid development of new, highly efficient anticancer drugs such as checkpoint inhibitors, an expanded spectrum of side effects of oncological therapies inevitably arises. The increasing use of immunotherapy requires knowledge of these potential adverse effects and also strategies for their management. While the overall picture of the range, extent, and frequency of side effects is slowly coming together with wider use outside of trials, methods for their prophylaxis and therapy are being diligently tested.
The immune system functions in a fragile balance of immune response and tolerance. This is the only way to prevent an excessive immune response to autoantigens and thus the destruction of the body’s own cells in the case of a sufficient defense against infection. Several mechanisms exist to maintain the balance, such as positive and negative selection in the thymus or co-inhibitory molecules on the T cell. These co-inhibitory molecules include the well-known targets of immunotherapy PD-1 and CTLA-4. Interfering with such a well-established mechanism is risky and unfortunately often does not remain without negative consequences, even if it enables highly effective cancer therapy.
What are the most common immune-mediated side effects?
The skin, colon and liver are particularly affected by the autoimmunity that can be triggered by therapy with checkpoint inhibitors. Unfortunately, however, adverse effects are not limited to these organs, but can also occur in many other parts of the body (overview 1) . Thus, neurological effects such as muscle weakness or paresthesias are also frequently observed. Furthermore, there are effects on the endocrine system, which, according to Prof. Dr. med. Robert Zeiser of the University Medical Center Freiburg, often manifest themselves non-specifically and occur, for example, in the form of fatigue or headaches. These concomitant effects, such as thyroid or pituitary insufficiency, would have a special position in that they are almost always irreversible, unlike most other effects of immunotherapy.
In the characteristic temporal sequence of adverse effects, colonic involvement with diarrhea and colitis follows dermal effects, which for the ipilimumab example present most frequently five to six weeks after initiation of therapy. Hepatotoxicity and endocrine side effects usually develop later in the course. However, Prof. Zeiser emphasizes the variability of these values.
In a comparison of the drug ipilimumab targeting CTLA-4 and the pembrolizumab targeting PD-1 in melanoma patients, it was shown that especially diarrhea and pruritus occurred significantly more frequently during therapy with ipilimumab [1]. On the other hand, pembrolizumab performed worse in the areas of fatigue, asthenia, and arthralgia. Patients treated with ipilimumab experienced higher-grade toxicity in just under 20%, while those receiving pembrolizumab suffered severe side effects in 10-13%. For both drugs, dermal and gastrointestinal toxicity were most common.
What to do in case of adverse effects?
Early detection of immune-mediated side effects is critical to the success of therapy. Therefore, any suspicion should be investigated. After ruling out other causes, such as infection with C. difficile in colitis or tumor progression, histological detection is useful – if possible and not too risky, says Prof. Zeiser. In colitis, this could be provided by endoscopic biopsy, and in moderate or severe pneumonitis by bronchoscopy and BAL. This is often necessary, he said, because differentiation from lymphangiosis carcinomatosa or fungal pneumonia in CT thorax is sometimes difficult. In the case of dermatitis, histological evidence is recommended only in unclear cases to exclude an infectious cause. For the diagnosis of hepatitis and in the area of the endocrine system, the focus is on laboratory analysis, with this being supplemented, if necessary, by imaging such as an MRI in the case of suspected hypophysitis or sonography in the case of liver involvement.
The therapy of the side effect depends on the severity (Tab. 1) and looks similar for all immune-mediated side effects. In mild cases, oncological treatment can be continued in parallel. Since this is immunosuppressive therapy in patients with active malignant disease, it should be kept as short as possible. Purely symptomatic treatment is also not recommended, especially in the case of gastrointestinal side effects, as this can mask progression and, in the worst case, lead to perforation.
While colitis, dermatitis or pneumonitis usually heal with short-term immunosuppression, lifelong substitution therapy is often required after infestation of an endocrine organ.
Trust is good…
In order to be able to intercept possible side effects of the immunotherapy at an early stage, regular controls are indispensable. This includes interrogation of symptoms such as fatigue or diarrhea, laboratory value determinations (Tab. 2), and imaging for suspected endocrinopathies or pneumonitis. To ensure that immunotherapy can be interrupted in time if necessary, these checks should be carried out in each case before the drug is administered.
Source: Forum for Continuing Medical Education (FOMF), Refresher, Immunoncologics and Targeted Therapies – Presentation on “Side Effects and their Therapy”, Livestream 19.06.2020, Prof. Dr. med. Robert Zeiser, University Hospital Freiburg (D).
Literature:
- Robert C, Schachter J, Long GV, et al: Pembrolizumab versus ipilimumab in advanced melanoma. New England Journal of Medicine. 2015;372(26): 2521-2532.
InFo ONCOLOGY & HEMATOLOGY 2020; 8(4): 20-21 (published 9/22/20, ahead of print).
