An update article on cancer immunotherapy for the family physicians

Wai-man Yeung 楊偉民，Conrad CY Lee 李智仁

HK Pract 2020;42:15-22

Summary

Immunotherapy, in particular immune checkpoint inhibition, is a new mode of cancer treatment. The aim of this article is to provide an update on this topic with practical information for family physicians. The article will start with a brief introduction of different types of cancer immunotherapy as a whole, followed by a more detailed discussion on immune checkpoint inhibitor, including its mechanism of action, indications, side effects and the corresponding management. In the final section of the article, we will talk about the clinical implications of this newer therapeutic agent for the family physicians including the related physical and psychosocial care.

摘要

免疫治療，尤其是免疫檢查點抑制，是癌症治療新模式。這文章是提供這課題的更新和家庭醫生實用資訊。本文首先簡介不同種類的癌症免疫治療，然後深入討論免疫檢查點抑制劑的行動原理、用藥指引、副作用和處理方法。文章最後會討論這新藥對家庭醫生處理病人生理和心理的臨床含義。

Introduction

Cancer is a very prevalent condition. In 2018, there were 17 million new cases of cancer worldwide, 43% of which were lung, female breast, bowel or prostate cancer. It was expected that there will be a 62% projected increase in cancer incidence rates from 2018 to 2040. ¹ In Hong Kong, the incidence of cancer was also increasing. In 2016, a total of 31,468 new cancer cases were diagnosed in Hong Kong. Compared to a decade earlier, new cancer cases had jumped by about 33% or at an average annual rate of 2.9%. In addition, there were 14,209 deaths due to cancer in 2016. Lung cancer had the highest mortality rate and the second highest incidence rate (just next to colorectal cancer) among all cancer types. ²

With the advent of many new cancer treatments, the many patients with advanced cancers can now live longer with active life-prolonging treatments. ³ This, along with an increased incidence of new cases diagnosed means that it is not uncommon for family physicians to see cancer patients in the community who are actively receiving anti-cancer treatments. Although cancer treatments are usually provided by oncologists or specialists from various disciplines according to the cancer types, family physicians do have their special role in cancer patient care. A family doctor, as the first point of contact, may be the first one to diagnose the cancer and make referral to the corresponding specialty. Later on, cancer patients may still see their family doctors for physical or psychosocial problems which may or may not be related to the cancer itself or its treatment side effects. Sometimes, complaints from patients may arise from the cancer or the cancer treatment but misunderstood by the patients to be something else. As a result, family physicians should update themselves in terms of knowledge and skills to answer the questions raised by patients, and be able to recognise the different clinical conditions mentioned above and take action accordingly.

Apart from conventional surgery, radiotherapy and chemotherapy, newer treatment approaches over the past decade include target therapies and, more recently, immunotherapy. Immunotherapy, in particular immune checkpoint inhibition , has made major breakthroughs in many types of advanced cancers in recent years, and is now a very hot topic in oncology. This article does not intend to cover everything related to cancer immunotherapy, but aims to provide updated information on this topic, especially the immune checkpoint inhibitors, which we hope will be helpful for family physicians in their practice.

What is cancer immunotherapy

Immunotherapy is base on the concept of harnessing a patient’s own immune system to fight diverse cancer types. ⁴ In other words, the goals of cancer immunotherapy are to kill or control cancer cells by activating, or reactivating the immune system of the host. The fields of immunology and oncology have been linked since the late 19 ^th century, when the surgeon William Coley reported that an injection of killed bacteria into sites of sarcoma could lead to tumour shrinkage. ⁵ Since that time, advances in the understanding of the intersection between immune surveillance and tumour growth and development have led to broad therapeutic advances that are now being studied for all cancer types.

Bacillus Calmette-Guerin (BCG) is a classical example and one of the most commonly used and earliest discovered cancer immune therapies, whereby attenuated mycobacterium bovis induces a non-specific robust inflammatory response when injected in the urinary bladder. Intravesical BCG is used for the treatment and secondary prevention of superficial bladder cancer. ⁶ It is also because of this non-specific inflammatory response that BCG may lead to side effects including dysuria and other lower urinary tract symptoms.

Since the use of BCG for bladder cancer, many new immunotherapeutic agents had been discovered. In general cancer immunotherapies can be categorised into whether: 1) they actively stimulate the immune system, or passively alter immune system signalling or cell populations, and, 2) the treatment is targeted at a specific, known antigenic target, or is non-specifically stimulating the immune system. The four main categories of cancer immunotherapies with their corresponding examples are shown in Figure 1. Thus, BCG, as discussed above, can be considered to be an active non-specific immunotherapy. A discussion on each immunotherapeutic approach is beyond the scope of this article. Rather, this article will focus on immune checkpoint inhibitors, as this mode of treatment has already become a primary treatment modality for patients with a broad diversity of cancers, resulting in significantly prolonged survival in some patients. It is currently a very hot topic in the field.

Immune checkpoint inhibitors

In a healthy body, the immune system has internal regulatory mechanisms that enable immune cells to identify abnormal cells that need to be attacked while protecting normal tissue. The activity of the immune system is modulated and carefully controlled by immune checkpoints which are protein molecules on the surface of cells. When antigen recognition occurs, the outcome depends on the balance of the signals from the interaction between the immune cell (T lymphocyte) and the target cell. If the signals are largely positive, the T lymphocyte is activated and is primed to attack the antigen presented by the target cell. However if the balance of signals is negative, then the T lymphocyte can become inactivated, sometimes permanently, and the antigen is accepted as a normal / self antigen.

Cancer cells often take advantage of this natural inactivation mechanism. By activating the immune checkpoint systems on T-cells (namely the PD-1 & CTLA-4 pathways), the T lymphocyte is inactivated and the tumour effectively switches off the ability of the host’s immune system to recognise it. Thus by evading the immune system, the cancer cells can continue to multiply and survive, like cloaking themselves in a disguise. ⁸

Therapeutic monoclonal antibodies that reverse the ability of cancer cells to use these pathways are called checkpoint inhibitors and are among the newest agents used to treat cancer. ⁸ They are antibodies that will block the interaction between the checkpoint receptor and its binding partner, re-activate the lymphocyte, and allow the immune system to re-establish recognition and control of the cancer (see Figure 2). In other words, this class of drug unmasks the disguise of the tumour, allowing the immune system to once again recognise and attack it. Immune checkpoints of relevance to cancer include the programmed cell death protein 1 (PD-1/PD-L1) pathway and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway, and these are the targets where the current checkpoint inhibitors will act. ⁹ These checkpoint inhibitors are typically given as a short intravenous infusion in an outpatient setting once every 2-3 weeks. In the setting of advanced metastatic cancers, these treatments are very often continued indefinitely until treatment failure, which could mean, for some patients, very long duration of ongoing treatment.

Efficacy of checkpoint inhibitors in certain cancers

Checkpoint inhibitors can be used to treat a variety of cancers including lung cancer which is known to have the highest mortality rate in Hong Kong. Some examples of checkpoint inhibitors and the types of cancer they are used to treat are shown in Table 1.

In some cancers , the improvements have been rather impressive. For example, in metastatic melanomas, a large study found 1-year survival to be 73% vs. only 42%, when comparing nivolumab vs. conventional chemotherapy. Importantly, the response is often very durable. In other words, although only a proportion of patients derived tumour shrinkage (40% in this study), those tumours which do respond to the treatment often continued to remain quiescent for prolonged periods. ¹³ Similarly, in advanced non-small cell lung cancers in which initial chemotherapy has failed, checkpoint inhibitor appears to be more effective than giving further chemotherapy; achieving a median survival of 9.2 months vs 6 months for squamous cell cancers in a large study. ¹⁴Since then, the indications of immunotherapy in non-small cell lung cancer has expanded to the first line setting either as a single agent (high PD-L1 expression subset) or in combination with chemotherapy for both squamous and non-squamous types. However, it should be noted that for those patient with specific gene aberrations such as EGFR mutations or ALK translocations, target therapies remain the treatment of choice.

Active research is ongoing to help predict which individual patients will derive benefit, but there is still a lot of uncertainty – certain markers (such as positive tumour staining for PD-L1) appear to correlate with treatment response in some tumours but not in others. The list of approved indications for checkpoint inhibitors is still continually expanding and is outside the scope of this article.

Side effects of checkpoint inhibitors

The side effects of immune checkpoint antibodies are due to autoimmune over-activation. Any organ or tissue can be affected, but the skin, colon, lungs, liver and endocrine organs (such as the pituitary gland or thyroid gland) are the most commonly affected (Table 2). Overall, the most common side effects for both CTLA-4 inhibitors and PD-1/PD-L1 inhibitors are skin symptoms, while gastrointestinal symptoms seem to be more common with CTLA-4 inhibitors and lung or thyroid symptoms seem to be more common with PD-1 inhibitors. Liver side effects are less common and occur with roughly similar frequencies across both types of drugs. If patients are treated with a combination of a CTLA-4 inhibitor and a PD-1 inhibitor, the patients will be more likely to get one or more side effects (Table 3). Rarely, checkpoint inhibitors may also lead to neurological, cardiac, rheumatological, renal, ocular or haematological toxicities.

Side-effects of checkpoint inhibitor treatment typically appear within a few weeks or months of starting treatment, but they can arise at any time during treatment – as early as days after the first infusion, but sometimes as long as 1 year after treatment has finished.

Managing side effects of checkpoint inhibitors immunotherapy

Most of these side effects are mild to moderate and reversible if detected early and addressed appropriately. However, side effects can sometimes be life-threatening. Thus checkpoint immunotherapy must be managed with caution and diligence. A robust and routine communication channel between patients and their healthcare workers is of utmost importance.

Side effects are graded from 1 to 4 with increasing severity. However, the precise criteria used to assign a grade to a specific side effect varies, depending on which side effect is being considered. The general principles of management according to the severity of side effects are illustrated in Table 4. Although most toxicities are mild and can be managed easily with a course of steroids, some can require urgent management and hospitalisation. For toxicities that are refractory to initial steroid treatment, antitumor necrosis factor agents may be required. ^9,11 These patients may require specialist consultations to assist with the management of these toxicities. ¹¹ Most importantly, the aim of management is always to identify and address any side effect before it becomes severe.

Two examples of how common side effects of checkpoint inhibitor therapy are graded and the corresponding management are shown in Table 5.

Implications for family physicians

The advance in cancer immunotherapy, especially checkpoint inhibitor agents, has given cancer patients new hope, but also entails some more complicated clinical conditions that family physicians need to consider.

For physical conditions, cancer patients may be suffering from side effects of checkpoint inhibitor therapy, but may present to family physicians with cough or other respiratory symptoms similar to that of an upper respiratory tract infection or pneumonia; or with diarrhoea similar to that experienced with a simple viral gastroenteritis. Patient may also present with a mood condition or sleep disorder, which in fact may be secondary to drug-induced hypothyroidism or hyperthyroidism. For patients presenting with fatigue, it is important to exclude thyroid, pituitary, and other endocrine disorders.

In these situations, if the patients are not given the appropriate remedial treatment, they may further deteriorate with potentially serious consequences. Thus, the primary care physician needs to be vigilant in ruling out autoimmune side effects when dealing with any illness in a cancer patient who has been given checkpoint inhibitors. It is therefore important to conduct a detailed past medical and drug history.

Patients with diarrhoea especially containing blood or mucus, severe abdominal pain, breathlessness, chest symptoms, weight loss, nausea / vomiting, excessive thirst or appetite, excessive and/or frequent urination, headache, confusion, muscle weakness or pain, numbness, painful or swollen joints, unexplained fever, tendency to bruise easily or loss of vision must warrant special attention. ¹⁵ In these situations, attending family physician must be aware of the possibility of immunotherapy complications and include this as an important differential diagnosis when assessing and managing these patients. Appropriate treatment, and possibly referring back to the oncologist for further management should be considered.

For psychosocial conditions, family physicians can act as a companion with the patient on their journey to fight the cancer. Some patients may have good response to immunotherapy, and they would like to share their joy with you. However, checkpoint immunotherapy is active only in certain types of cancers, and even in those cancers, it is effective only in a small subset of patients. Also, as checkpoint inhibitors are not direct anti-cancer agents in themselves, but rather work through activating the immune system, the time to treatment response can be highly variable. This can be a very stressful and difficult time for patients and their families, waiting and hoping. Managing patient and family expectations is an important skill in dealing with advanced cancer cases on treatment - while many patients do see shrinkage of their cancers it is more common that the cancer becomes stable in size. This is not necessarily a bad thing and patients can still enjoy long survival and good quality of life as the cancer becomes a chronic condition. But measuring success in terms of “response rate” will lead to disappointment. So, depending on their own ‘expectations’, 2 patients achieving the same ‘stable outcome’ can have very different psychological responses – one may be satisfied, whilst another may be disappointed. It is a bit like the typical example of how different people feel about a half empty cup of water.

Apart from being able to diagnose psychological conditions in cancer patients, family physicians should adopt a holistic approach in managing cancer patients - listening to their patients and finding out their needs, providing realistic hope, support and advice, and to share their grief – tending to their emotional, social and spiritual needs in addition to their physical conditions. Relevant medication and counselling should be offered. Patients should be encouraged to stay connected with their families and relatives. Patients with significant psychiatric conditions such as psychotic features or suicidal tendency should be referred to a psychiatrist for further assessment. The primary care physician can act as an important hub to connect the cancer patient to the relevant members of various allied health teams e.g. patients with social difficulties should be referred to the social worker, those with nutritional problems may be referred to the dietician, and those requiring nursing assistance may be referred to the community nurses.

Conclusion

With advances in cancer treatment, longer survival than before can now be achieved in many cancers, with implications that can somewhat parallel typical “chronic” diseases. In this article, we have discussed the different physical and psychosocial aspects in patients receiving checkpoint inhibitors immunotherapy. Family physicians should take advantages of their special role and provide a holistic, continual, comprehensive and coordinated care to their cancer patients, and be vigilant to possible unusual treatment side effects and be prepared to liaise or refer back to the oncologist whenever necessary.