COMMENTARY

Cancer Immunotherapy: Kinder but Not Harmless

John B. Haanen, MD, PhD

Disclosures

February 22, 2018

Knowledge of the long-term impact of cancer immunotherapies on the body is still incomplete. Nevertheless, immunotherapy is increasingly becoming the standard of care for many types of cancer—melanoma, non–small cell lung cancer, and bladder cancer, for example—meaning that the number of patients exposed to these treatments is growing, as is the chance of developing toxicities from these drugs.[1]

Commonly regarded as "kinder" on the body than chemotherapy, immunotherapy drugs still have side effects and toxicities. Awareness about the specific toxicities of immunotherapy drugs is crucial. Physicians and patients alike need to understand and manage the side effects of these treatments.

The European Society for Medical Oncology (ESMO) recently published clinical practice guidelines on the management of toxicities from immunotherapy[2] and has just launched a patient guide on the management of immunotherapy side effects.[3] It contains information on how immunotherapy works, the most common toxicities associated with checkpoint inhibitors, how the oncology team can manage these symptoms, and a few strategies that patients can use to minimize side effects. ESMO's guide provides this information in clear and easy-to-understand language, including helpful illustrations, tables, and a glossary so that patients and caregivers can identify potential side effects.

Chemotherapy Versus Immunotherapy: 'What's the Difference?'

Unlike chemotherapy, which "kills" cancer cells by damaging them so that they cannot reproduce and spread, immune checkpoint inhibitors, a type of immunotherapy, work differently, by enhancing the body's own immune response. T cells, a type of white blood cell, are immune cells that turn the immune response on or off, which is typically used to protect us from disease—by killing viruses, for example. However, some cancer cells make proteins that turn off T cells so that they don't attack cancer. Checkpoint inhibitors target and activate T cells, enabling them to recognize, attack, and destroy cancer cells.

Because immunotherapy with checkpoint inhibitors blocks the body's natural safeguards that prevent immune overactivation, it can also affect healthy cells and normal tissues and cause autoimmune side effects. These are different from those associated with chemotherapy and tumor-targeting drugs, and require different management strategies.

Common Side Effects and Toxicities for Immunotherapies

Checkpoint inhibitors are among the most promising treatments for cancer, but like any other medicine, they are associated with toxicities. Because immune checkpoint molecules play an important role in maintaining the balance between an effective immune response and autoimmune disease, blocking them may lead to severe autoimmune reactions such as diarrhea or hepatitis, or milder reactions such as rashes or thyroid gland disorders.

Depending on the immune checkpoint that is targeted, the type and severity of toxicities vary. Most frequently, they affect the skin, colon, endocrine organs, liver, and lungs. Others are infrequent but may be very serious—even lethal—such as neurologic disorders and myocarditis.

The ESMO Clinical Practice Guidelines on the Management of Toxicities from Immunotherapy contain lists of immuno-oncology drugs approved in Europe and the United States and provide an overview of the main immune-related adverse events, including the grading of symptoms and recommendations for their management.

Immuno-oncology drugs do not always work on their own, so combinations are increasingly being used and have proven effective for certain types of cancer. Nevertheless, combinations may bring with them more toxicities than does treatment with a single agent.

An interesting study[4] presented at the 2017 ESMO Immuno-Oncology Congress provided a real-world analysis of immune-related side effects in 3000 patients. The study explored side effects of single-agent and combination therapies, and criticized the lack of standardized terminology to report and describe them.

If patients experience severe reactions, treatment will be discontinued. The question, then, is whether treatment can be continued once the side effects disappear, as well as what options are available for patients. This depends on the severity of the adverse events. Most physicians will be reluctant to put patients back on checkpoint inhibitors, but cancer can be a lethal disease, so certain patients may want to take the risk. This calls for shared decision-making.

We could call immunotherapy "kinder" than chemotherapy because patients on PD-1/PD-L1 inhibitors generally do well on them and have fewer side effects than with chemotherapy, but around 15% of patients will experience severe side effects. This can rise to 50% of patients on combined immunotherapies, so we need to be careful in selecting patients for these treatments. For example, patients with a history of autoimmune disease, or who are being actively treated for an autoimmune disease, are at risk for worsening of these diseases while on immune checkpoint blockade.

Long-term Dangers of Turning the Immune System On and Off?<

Immuno-oncology is a recent development; we have not followed patients for much longer than 10 years, but we do have data on long-term survival of patients, some of whom we consider cured (no signs of cancer for 10 years).

Most are living normal lives, although some need hormonal replacement therapy for life—but they can live with that. Arthritis can also be a lifelong side effect, but for most patients, side effects will disappear forever. In fact, most adverse events will occur early on in treatment, but some damage, such as endocrine side effects, may be irreversible.

Certain lasting side effects are complex, however. Fatigue is one of them. Patients often report fatigue, but we do not yet know whether this is a neurologic or metabolic side effect. Is there a psychological element or is fatigue purely physical? Or a combination? We don't know yet, but we do know that fatigue can last a long time.

Need for Informed Patients

There is an increased need to educate patients so that they recognize and report potential side effects early, allowing physicians to intervene and find solutions. Thus, it is very important for patients to understand the mechanisms of immuno-oncology in order to recognize side effects. Many general physicians and hospitals where these treatments are not given don't know how to recognize and treat the side effects, so it is vital that patients and their caretakers are able to identify and report new health issues as early as possible to their oncology team of doctors and nurses. Informed patients know how to react.

Financial Toxicity

Immunotherapy medicines come at a high cost today. We use immunotherapy because it is beneficial to patients and can even cure them, but there is currently a big imbalance. There is the excessive financial cost, but there is also a big difference in approvals, which means that these medicines are only available to a limited number of patients. Everyone has a part to play in improving the situation; governments as well as national oncology societies have a role in negotiating with pharmaceutical companies to reduce prices and guarantee access to every patient who needs treatment.

Focus on the Benefits

The introduction of immunotherapy in oncology has produced a profound change in the way we deal with cancer. We never knew that cancer was so visible to the immune system. Now we understand more about the "blocking molecules" that hamper the immune system and we know how to target them. Patients have benefited enormously from these treatments. Most important, we know that the immune system has a memory for dealing with cancer (as it does for viruses), which means that response can be durable and patients may even be cured.

Of course, there are side effects, but the benefits from immuno-oncology far exceed the problems. As long as patients report problems early, in 99% of cases symptoms can be managed, so patients should focus on the benefits that these drugs can provide, including prolonged survival and long-lasting remission.

John B. Haanen, MD, PhD, is head of the Division of Medical Oncology and a staff scientist in the Division of Immunology, and a professor of Translational Immunotherapy of Cancer at Leiden University Medical Centre in the Netherlands. He serves as faculty chair for Tumour Immunology and Immunotherapy for the European Society for Medical Oncology (ESMO) and as principal author of the ESMO Clinical Practice Guidelines on the Management of Toxicities from Immunotherapy.

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