Feature

Eric Roeland, MD FAAHPM ; Thomas LeBlanc, MD MA FAAHPM

A New Era in Oncology

Harnessing the immune system to treat cancer has been a game changer for a select group of cancer patients. Unfortunately, predicting who will experience the immunotherapy “Lazarus effect” is challenging for both oncologists and palliative care (PC) clinicians alike (refer to Bill and Cody stories). Approximately 15% of certain cancer patients will achieve durable responses to immunotherapy, but determining who those patients are is like trying to hit a moving target. Multiple challenges exist in using immunotherapy including predicting response, palliating side effects, measuring effect, prognosticating, paying for drugs, integrating PC, and addressing hospice care.

In contrast to traditional cytotoxic chemotherapy, immunotherapy manipulates a patient’s own immune system to ideally strike an equilibrium between attacking cancer cells and not damaging healthy, normal cells. Today, there are multiple immunotherapy drugs in development, but there are three FDA-approved drugs that dominate the field: ipilimumab (Yervoy^®), nivolumab (Opdivo^®), and pembrolizumab (Keytruda^®) (Table 1). This article will focus on the three main immunotherapy drugs in the solid tumor cancer setting including the basics of immunotherapy, management of toxicities, and implications for PC clinicians.

Table 1: FDA-Approved Checkpoint Inhibitors, Indications, and Side Effects

*Can be used in combination for the treatment of melanoma; †Not a comprehensive list

Immunotherapy 101

The multibillion-dollar drugs ipilimumab, nivolumab, and pembrolizumab, used as single agents or in combination, are all classified as immune checkpoint inhibitors (Table 1). Immune checkpoints normally serve as safety measures to protect tissues from damage when the immune system is responding to infection (Figure 1).¹ Unfortunately, cancer can develop specific resistance mechanisms to exploit immune checkpoints and out-maneuver the immune system. Immunotherapy is unique in that it indirectly targets the tumor by harnessing and reinvigorating the host immune system to fight cancer—releasing the pressure on the immune safety brake pedal (Figure 2). In doing so, some patients with otherwise incurable cancer have the potential to have long-term remissions and sometimes cures, even after discontinuing therapy.

Figure 1: Overview of the Immune System and Checkpoint Inhibitors

Reprinted with permission.¹¹

Figure 2: Immune Checkpoints Regulate Different Components in the Immune Response

Reprinted with permission.¹

As a medical oncologist at the UC San Diego Moores Cancer Center who specializes in cancer immunotherapy and early phase clinical trials across all types of cancer, Sandip Patel, MD, routinely discusses the double-edged sword of activating the immune checkpoint blockade while preventing overactivation, resulting in the immune system attacking normal tissues. This is referred to as immune-related adverse events (irAEs). He emphasizes that any gastrointestinal symptoms (diarrhea and abdominal pain) or pulmonary symptoms (cough and shortness of breath) may be signs of autoimmune reactions and reinforces that these side effects can be delayed and may not have a distinct temporal association. Immune checkpoint blockade may have fewer side effects for some cancer patients than their prior chemotherapy, but immune-mediated severe events can be life threatening and require hospitalization.

When collaborating with PC clinicians, Dr. Patel notes that “the hardest thing has been the use of these agents as a last-ditch effort with very advanced cancer patients who are declining and looking for one last option.” Optimally, oncologists need several months to evaluate how each cancer will respond. Yet oncologists can’t be sure exactly when a cancer will respond. “It’s variable, sometimes taking as long as 6 months to see a response, sometimes taking as little as 2–4 weeks,” cautions Dr. Patel. Oncologists often are faced with requests by patients and caregivers who want to get that “one last dose of immunotherapy” to see if their cancer will respond. In combination with the perception that these drugs have fewer side effects compared to older cytotoxic chemotherapy, the allure to try immunotherapy, even for patients in clinical deterioration, remains strong. “If there is even a 2% chance of a long-term remission with an immunologic, many patients and families are willing to take those odds, and I worry that more patients are spending their final moments undergoing aggressive therapy in the hospital and clinical setting rather than focusing on quality of the end of their life at home,” says Dr. Patel. It is not an easy situation and, until we expand the available biomarkers that can better define who will respond best, will continue to be a major challenge in oncology and PC.

There are multiple misconceptions about immunotherapy (Table 2), but the leading misunderstanding by patients is that immunotherapy is a panacea. According to Dr. Patel, “It is not a cure-all. In fact, outside of Hodgkin’s lymphoma, melanoma, cancers with high mutational burden tumors, and acute lymphoblastic leukemia, immunotherapy only benefits anywhere from a fifth to a quarter of patients.” However, when immunotherapy works, it works well. This anecdotal experience of practicing oncologists who observe these super-responders continues to drive the excitement and development of these drugs.

Table 2: Myth Busting: Fiction Versus Fact Regarding the Use of Immunotherapy

Immune-Related Side Effects

Because patients are equally—if not more—excited about the future of immunotherapy, they may not necessarily pay much attention to its related side effects. Immunotherapy does not have fewer side effects, but it does have new ones. Judith Paice, PhD RN, at Northwestern University notes the misconception by patients and caregivers that these drugs are safer than cytotoxic chemotherapy (Table 1). “Patients believe that because this is not chemotherapy, the side effects will be less frequent or less severe. Consequently, patients may not report symptoms as quickly,” she explains. During treatment, a unique set of irAEs may occur. These include rashes, which rarely progress to life-threatening toxic epidermal necrolysis, and colitis, characterized by a mild to moderate but occasionally severe diarrhea. Diarrhea often is overlooked by the patient as simple distress when it may be an early sign of colitis. Hypophysitis, hepatitis, pancreatitis, uveitis, lymphadenopathy, neuropathies, and nephritis also have been reported (Table 1).² In fact, it is now a standard of care to check thyroid function studies, amylase, and cortisol levels prior to receiving each dose of immunotherapy.

Early recognition of immune-mediated side effects and initiation of treatment are critical to reduce the risk of sequelae. These side effects can be exponentially worse when these drugs are used in combination (eg, ipilimumab and nivolumab in the treatment of melanoma) or on clinical trial with novel immunotherapeutic drugs. Dr. Paice points out, “Another challenge is the tension in determining whether a symptom is an adverse effect of the drug, particularly in the face of a clinical trial.” The reluctance can occur on the part of the patient who may not want to give up on this last option, or on the part of the oncologist for the same reason. Consequently, researchers may tend to grade the toxicity as less severe.

Treating these symptoms is not simple, but there is a well-established PC tool that works very well: glucocorticoids. When patients experience grade 2 or 3 immune-mediated side effects, general recommendations are to start oral prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours followed by a taper over the next 4 weeks.² However, the if and when glucocorticoids can be used is a challenge. Interestingly, immune-mediated side effects have correlated with treatment response in some studies.² Therefore, oncologists and patients are equally reluctant to use glucocorticoids to palliate immunotherapy side effects given concerns they also will block their potential therapeutic effects. PC clinicians always should engage patients and their treating oncologists in a conversation when considering the use of glucocorticoids in this setting.

Immunotherapy Cost Implications

For most cancer patients receiving immunotherapy for FDA-approved indications, insurance will cover the treatment. “Still, it’s possible those patients will face high out-of-pocket costs for these drugs in the form of copays or coinsurance,” warns Duke University’s Yousef Zafar, MD, whose research focuses on treatment-related costs and financial toxicity.³ Dr. Zafar adds, “These patients might still benefit from seeking out financial assistance programs to help defray these expenses.” And for those patients receiving immunotherapy for a non-FDA-approved indication, insurance will not cover the drug, but patients typically can receive the drug at no cost from the drug manufacturer. As the indications of immunotherapy continue to expand, drug companies increasingly want their drug to be the preferred go-to agent for oncologists. Therefore, off-label requests are quickly processed.

In the short term, patient-access programs provide considerable benefit for patients through financial relief. Whether the financial assistance comes from a foundation or directly from the manufacturer, patients who qualify can receive coverage for most, if not all, of their out-of-pocket costs. Yet, there are potential long-term harms associated with these programs. Some argue that by decreasing cost-sharing, these programs remove cost barriers to low-value care. “In other words, these programs might bypass the very intent of insurance benefit design,” suggests Dr. Zafar, “and might artificially inflate drug prices by allowing drug manufacturers to set prices as they like, force payers to cover a proportion, then ‘discount’ the rest to patients while still making a considerable profit.” He recommends that PC clinicians inquire about financial concerns and identify institutional resources for them as these may be major stressors for patients and caregivers.

Prognostication in the Era of Immunotherapy

As immunotherapy increasingly becomes more available to cancer patients, clinicians face a major challenge in the evaluation of these drugs—the accurate determination of clinical efficacy and prognostication. Old prognostication algorithms based on cytotoxic chemotherapy no longer apply. For example, even measuring how tumors respond on surveillance imaging is inexact. Historically, oncologists have relied on WHO and RECIST^4,5 criteria to provide standard guidelines to define tumor response to therapy by defining increases in the size of tumor lesions and the development of new lesions as unequivocal evidence of cancer progression.

However, some tumors will respond to immune-targeted treatment with tumor shrinkage or stable disease, while others can have a distinct immune-related pattern of response—called pseudoprogression—that should give PC clinicians pause.⁶ For example, melanoma treated with ipilimumab may show an initial increase in size of tumor lesions and then subsequently demonstrate decreased tumor burden months later. This robust inflammatory response may even lead to delayed clinical responses and tumor regression. The findings of pseudoprogression would have been classified prematurely as progressive disease according to old criteria and have prompted the development of a specific immune-related response criteria that PC clinicians must consider.⁷

“In general, palliative care clinicians need to know that oncologists, patients, and caregivers are feeling a great deal of optimism about immunotherapy,” remarks Jennifer Temel, MD, at Massachusetts General Hospital. This optimism is wonderful when patients respond to immunotherapy and don’t experience significant side effects or toxicities. However, when the drugs do not work, or when patients have significant side effects, the disappointment can feel quite overwhelming. Dr. Temel notes that “palliative care clinicians can play an important role in managing expectations of patients, families, and medical professionals involved in their care and in helping them cope if immunotherapy does not work or when side effects are troubling. Although there has always been prognostic uncertainty for patients with advanced solid tumors, the stakes are now higher because those who do respond can live significantly longer than those who do not.” Ideally, the uncertainty associated with this drug class needs to be discussed prior to administration, and PC should be introduced as a resource for all patients receiving immunotherapy. It also is critical that PC clinicians recognize the perspectives of oncologists who have observed very noteworthy responses to immunotherapy in a minority of their patients. This anecdotal experience with super-responders may occur among patients that PC may not see and, therefore, may further skew the PC clinician perspective of the clinical benefit of immunotherapy. In addition to managing expectations about the efficacy and toxicity of these drugs, PC clinicians can help guide conversations about prognosis when it becomes clear that these medications are or are not working. This is especially important when immunotherapy does not work—when, in addition to the emotional toll, a patient’s health status often declines during the few months they are receiving inadequate treatment. Dr. Temel suggests that PC is well suited to engage and support patients in this uncertainty. She adds, “Palliative care can help patients and their families understand that their life expectancy may not be as long as they had hoped and help them make decisions that are aligned with their goals and preferences.”

Approaching Uncertainty Together

As we venture into the immunotherapy era, PC clinicians and oncologists increasingly must rely on and learn from one another. We also must note that blanket criticisms of immunotherapy are divisive and even insulting to oncologists’ good intentions when prescribing immunotherapy. “Frequent collaboration with the oncologist is essential,” recommends Charles von Gunten, MD PhD, at Ohio Health. Oncologists and PC clinicians must become increasingly more humble and cooperative as we engage in uncertainty together. PC must transform to an even more patient-centered decision-making process that requires a broader skill set—we must be with patients in uncertainty. “I don’t know, but we will figure it out together,” is increasingly becoming the right answer and we must embrace this. “The current generation of immunotherapy represents the new floor, not the ceiling, of where oncology is headed,” Dr. Patel acknowledges. And considering the many recent demonstrations of improved outcomes from earlier-integrated PC in cancer care, PC is ideally suited for this expanded role.

Table 3: Immunotherapy Resources for PC Clinicians

Eric Roeland, MD FAAHPM, is a dual-trained medical oncologist and palliative care clinician at UC San Diego Moores Cancer Center whose research focuses on interventional symptom studies for patients with advanced cancer. Contact him at This email address is being protected from spambots. You need JavaScript enabled to view it. and follow him on Twitter @MDRoeland.

Thomas LeBlanc, MD MA FAAHPM, is a dual-trained medical oncologist and palliative care clinician at Duke University School of Medicine whose work focuses primarily on improving the quality of care for hematologic malignancy patients. Contact him at This email address is being protected from spambots. You need JavaScript enabled to view it. and follow him on Twitter @tomleblancMD.

References

1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264.
2. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.
3. Zafar SY. Financial toxicity of cancer care: it’s time to intervene. J Natl Cancer Inst. 2016;108(5):djv370.
4. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92(3):205-216.
5. Eisenhauer E, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
6. Chiou VL, Burotto M. Pseudoprogression and immune-related response in solid tumors. J Clin Oncol. 2015;33(31):3541-3543.
7. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412-7420.
8. Yervoy (ipilimumab) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2015 Oct.
9. Opdivo (nivolumab) injection package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2017 Feb.
10. Keytruda (pembrolizumab) injection package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.;2017 Mar.
11. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1-10.

To contact interviewees/contributors:
Sandip Patel— This email address is being protected from spambots. You need JavaScript enabled to view it.
Judith Paice— This email address is being protected from spambots. You need JavaScript enabled to view it.
Yousuf Zafar— This email address is being protected from spambots. You need JavaScript enabled to view it.
Jennifer Temel— This email address is being protected from spambots. You need JavaScript enabled to view it.
Charles von Gunten— This email address is being protected from spambots. You need JavaScript enabled to view it.

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