Advanced melanoma has re-mained an intractable malignancy for decades, with dacarbazine the only approved therapy and high-dose interleukin-2 limited by significant toxicity. Survival has not improved in more than 30 years.1 Melanoma cure rates are high for localized, thin primary lesions; however, once the tumor has spread, only around 15% of patients survive 5 years.2 Although the clinical utility of melanoma vaccines has been disappointing, melanoma is inherently a highly immunogenic tumor, and the fact that some patients with metastatic melanoma can survive for many years after treatment with interleukin-2 has kept the prospect of successful immunotherapy as an option.3
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is the main negative regulator of the T-cell–mediated immune response, designed to prevent unwanted autoimmunity and turn the response off when no longer needed.4 Cells known as antigen-presenting cells use specialized cellular equipment to present the tumor antigen to the T-cell receptor. These structures bind together, triggering a first or “priming” signal (Figure 1).5 To become fully activated, however, a second or “activation” signal is needed. The activation signal is triggered when a specific receptor on the surface of the T cell binds with a ligand on the antigen-presenting cell. The resulting dual signaling leads to a fully functional T cell capable of killing tumor cells, but it also prompts the cell to start producing a negative regulator molecule, CTLA-4.
CTLA-4, which is manufactured within the T cell in direct response to antigen exposure, migrates to the cell surface where it triggers a third delayed signal that switches off T-cell activity to prevent it from causing unwanted damage to healthy tissues. Such “switched off” T cells remain primed (that is, capable of recognizing the target tumor antigen), but are inactive because of the negative signaling of CTLA-4. In the context of cancer, especially advanced disease where antigen exposure is continuous, this homeostatic mechanism is a disadvantage and hinders antitumor immunity. In essence, CTLA-4 acts like an “immunologic brake”; thus, blocking CTLA-4 should release this brake and intensify the antitumor immune response.
Ipilimumab (Yervoy, Bristol-Myers Squibb Company), a fully human monoclonal antibody, is a novel T-cell potentiator that blocks CTLA-4 and has demonstrated improved survival in two phase 3 randomized trials in previously treated patients with advanced melanoma.6,7 In the first trial, up to 46% of patients were still alive at 1 year after starting ipilimumab therapy, and up to 24% were still alive at
2 years.6 More recently, a second phase 3 trial demonstrated significantly higher overall survival in patients who received ipilimumab in combination with dacarbazine compared with those receiving dacarbazine alone.7 Because of its unique immunologic mechanism of action, ipilimumab produces some specific and unusual response patterns and mechanism-related adverse events, which differ from those seen after chemotherapy or older immunotherapies.8 For example, responses can evolve over differing time periods in different patients, depending on the individual functionality of each patient’s immune system.8 Sometimes responses are preceded by apparent tumor growth, and prolonged disease stabilization can occur.9,10
Alongside potentiation of the antitumor T-cell response, however, ipilim- umab’s removal of the “immunologic brake” by blocking CTLA-4 also diminishes the patient’s tolerance to his/her own healthy tissues, thereby producing a characteristic spectrum of immune-related adverse events (irAEs).9,11-16 For ipilimumab to be effective, nurses must become familiar with differences in response patterns and toxicities and learn how to communicate them to patients and fellow healthcare professionals.
Ipilimumab Response Patterns and Assessment
Following chemotherapy, which directly attacks tumor tissue, either responses occur within a few weeks or treatment failure is recorded. Both the Response Evaluation Criteria In Solid Tumors and the World Health Organization criteria were developed with chemotherapy in mind and have been tailored to define responses based on a drug having a cytotoxic mode of action.17 However, because ipilimumab’s mechanism of action works by harnessing the patient’s own immune system, these conventional response criteria may not pick up responses to this agent.17,18 For example, responses may be delayed and can occur even after apparent disease progression.8,9 Some of the response patterns seen in studies with ipilimumab, several of which are different from responses to traditional therapies, are shown in Table 1.9,10 Survival benefits have been associated with all of these response patterns, even for patients with apparent disease progression by conventional criteria.9 A relatively high proportion of patients receiving ipilimumab achieve stable disease and appear to survive as long as those achieving an objective response (Table 2).6,9,19-21 This represents a new response paradigm, since prolonged stable disease is not generally achieved after chemotherapy.10
This variability in response is consistent with not only the time necessary to mount an adequate immune response but also interpatient variability in immune activity. Moreover, tumor enlargement during treatment with ipilimumab may not necessarily represent tumor growth, as would be associated with disease progression, but may be a result of the accumulation of activated lymphocytes, producing a localized inflammatory response and edema at the tumor site.17,22 Such infiltration would reflect antitumor activity and not tumor tissue growth. Therefore, later assessment and repeat assessment are necessary to confirm whether the disease has progressed.
Nurses are uniquely positioned to educate patients and caregivers on the difference between ipilimumab treatment and conventional chemotherapy and to explain that delayed response or apparent disease progression does not necessarily mean that ipilimumab treatment has failed, as might be the case with chemotherapy. Because responses typically evolve gradually and can pass through stages of apparent progression, stability, and, ultimately, sometimes partial or complete response,8,10,18 this has important implications for managing patient expectations and concerns.
For these reasons, the recommended response monitoring for ipilimumab therapy states that the first assessment should be performed no sooner than 12 weeks after treatment starts (ie, at the end of the induction period), compared with chemotherapy response assessment, which is typically done after 6 to 8 weeks of treatment.10 If, at this first assessment, the patient’s cancer seems to be progressing, it is important to emphasize that repeat radiologic assessment after at least 4 weeks is needed to confirm that progression is “true” and ongoing before declaring that treatment has failed. These key differences in timing must be explained to the patient and caregiver, especially if they are familiar with chemotherapy. This approach ensures continuation of therapy to allow enough time for a response to occur, unless there are other reasons why the patient cannot receive further dosing—such as clinical deterioration or serious adverse events (see next section). Patients who have been treated with ipilimumab should continue regular assessment of their disease status, since it is not uncommon for responses to occur several months after therapy has stopped.23
Ipilimumab Adverse Events
Overview and General Principles of Care
Ipilimumab produces irAEs associated directly with its mechanism of action (Figure 1).5 As with responses, symptoms do not always develop early in treatment but may occur after several months have passed since completion of ipilimumab treatment. It is important to communicate to patients that these irAEs are predictable and manageable as long as they are detected early and are not allowed to worsen unchecked; although these irAEs may appear to be similar to those experienced with chemotherapy, they are different and require prompt attention from a healthcare team. It is also important to stress the need to report irAEs early so they do not progress to the point of needing to discontinue therapy.
Ipilimumab irAEs most commonly include grade 1 and 2 toxicities, which usually resolve after symptomatic treatment with over-the-counter treatments (ie, hydroxyzine or diphenhydramine for rash, or loperamide for diarrhea). Less common but nonetheless significant toxicities include hepatitis and hypophysitis, and more rarely, uveitis, pancreatitis, and leukopenia. Persistent or more severe toxicities need prompt intervention, usually with oral or systemic corticosteroids, which would not be used for chemotherapy-related toxicities4,23,24; if patients experience irAEs that require corticosteroid treatment, reassure them that this will not affect clinical response to ipilimumab.9
Even higher-grade toxicities can be managed successfully on an outpatient basis, but ipilimumab should be withheld until symptoms resolve if the patient has grade 2 diarrhea or be permanently discontinued for any grade 3 or 4 toxicity. Immune-related colitis is the most common serious toxicity; if left untreated, it may lead to fatal bowel perforation, which is why any signs of cramping with or without diarrhea should be reported immediately. These symptoms require grading and proactive monitoring by the oncology nurse to ensure that any deterioration is spotted and promptly treated with corticosteroids. Other potentially life-threatening irAEs include hepatitis and hypopituitarism leading to acute adrenal crisis.
Some patients may not report irAEs for fear of being taken off treatment. To manage this, it is advisable that nurses mention the possibility that more severe symptoms may require permanent treatment cessation. It helps to stress that the more quickly any symptoms are reported and managed, the greater the likelihood of being able to continue treatment.
Approved Management Guidelines
Recommended pathways (algorithms) for managing more severe toxicities with ipilimumab (grade 3 and 4) appear in Figure 2.25,26 This management information comes from both the author’s own clinical experience and the Risk Evaluation and Mitigation Strategy (REMS) program established by Bristol-Myers Squibb in coordination with the US Food and Drug Administration.25
Gastrointestinal toxicity. Grade 1 gastrointestinal irAEs usually respond to dietary modifications and treatment with loperamide, but grade 2 symptoms may require oral corticosteroid therapy (eg, prednisone 1 mg/kg once daily). If symptoms persist, ipilimumab treatment should be stopped until symptoms resolve. For grade 3 or 4 gastrointestinal symptoms, the patient should be treated with high-dose steroids; if symptoms do not resolve, consider alternative immunosuppressive therapy such as infliximab at 5 mg/kg (Figure 2).25,26
Liver toxicity. Blood work should include liver function tests prior to each dose of ipilimumab, including the first dose. For grade 1 or 2 liver toxicity, liver enzymes should be monitored and symptomatic treatment provided as needed. If liver function tests normalize but symptoms persist, corticosteroids are given and tapered over at least 1 month, and ipilimumab can be discontinued until symptoms resolve. Grade 3 and 4 symptoms require permanent discontinuation of ipilimumab therapy and high-dose intravenous (IV) corticosteroid treatment (eg, methylprednisolone 2 mg/kg once or twice daily), with the addition of immunosuppressive therapy (eg, mycophenolate mofetil) if symptoms persist (Figure 2).25
Skin toxicity. Although usually mild, serious toxicities, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur. Mild or moderate itching or rash can be managed symptomatically with antihistamines or topical corticosteroids, but persistent or grade 3 or 4 symptoms require permanent discontinuation of ipilimumab therapy and oral or systemic corticosteroids, tapered over ≥1 month once dermatitis is controlled (Figure 2).
Endocrine toxicity. Of these toxicities, thyroid abnormalities (hypo and hyper) and adrenal insufficiency are more commonly observed, but are usually manageable with hormone therapy (ie, levothyroxine, hydrocortisone); ipilimumab should be held until toxicity resolves to grade 1. For symptoms that persist to grade 3 or 4, treatment with high-dose steroids in addition to hormonal therapy may be required, and ipilimumab should be permanently discontinued in this case. Less frequently, cases of hypopituitary (adrenal crisis) are observed; these cases require immediate medical attention with high-dose steroids and hormonal replacement. Typically these patients require ongoing hormone therapy since the pituitary may not completely recover function.25
Efficacy and irAEs
There are many reports in the literature of irAEs serving as potential surrogate markers for clinical response to ipilimumab.9,11-16 Although patients who develop irAEs, especially severe ones, are more likely to experience disease control and tend to survive longer, these outcomes can also occur in patients who do not develop irAEs or who have only mild symptoms.27 This phenomenon represents a delicate balancing act for the oncology nurse—between reassuring patients that irAEs are not necessarily a “bad thing” and avoiding raising expectations unrealistically or disheartening those patients who do not develop irAEs.
To achieve this balance, it is best not to elaborate on the possible significance of irAEs until after they develop. If the patient reports symptoms of an irAE, it can be explained that these are a sign of a hyperstimulated immune system that may mean that he or she will be more likely to respond to treatment. As irAEs do arise, sharing information on how ipilimumab works may help to encourage patients. One example at our clinic is when patients experience vitiligo, we educate them on the fact that depigmentation is possibly due to the immune system attacking their melanocytes. Patients who have read or heard about a potential link between irAEs and better responses can be reassured that not all responders get these side effects. In our clinic, we have seen increased lymphocyte counts in responders as early as the second induction dose of ipilimumab; sharing these results with patients can reduce any anxiety and encourage them that the immune system appears to be overactive, even if there are no irAEs.
Role of Nurses
It is vital to recognize, monitor, and manage irAEs promptly to prevent more serious consequences; establishing protocols based on the guidelines (Figure 2), which are reviewed regularly based on clinical experience, will help optimize irAE management in your facility and across others. Nurses play a key role because they are in regular contact with patients and can be most proactive in inquiring about any irAEs the patients may be experiencing. It is important to remember that even if some symptoms of irAEs are similar to those seen with chemotherapy, the underlying reasons are different, and because ipilimumab side effects have an immune-related etiology, they need to be managed very differently from side effects of chemotherapy. Nurses must understand these differences and communicate them effectively to patients (Table 3).
Oncology nurses play a pivotal role in supporting the successful implementation of ipilimumab therapy in the clinic. By the time they are prescribed ipilimumab, patients with advanced melanoma may well have received chemotherapy and/or other immunotherapies, so their experience and expectations will be based on those treatments. Education on all aspects of ipilimumab therapy will be a vital component of each patient’s treatment plan, and oncology nurses are best placed to provide it.
The REMS program packet provided to patients and physicians includes a checklist of items that can act as prompts for both nurse and patient to make sure that irAEs are recognized and reported as soon as they appear. There is also a medication guidelines handout to give to patients and a patient wallet card, which can be particularly useful in an emergency department situation. The most common questions asked by patients and caregivers as well as the appropriate responses are presented in Table 4.9,28 These basic principles can be tailored according to the audience (patient, caregiver, or peer education), as well as modified to allow for different patients’ abilities and/or willingness to take on this information (eg, kept to the main points only or expanded to include some background explanation). There is no “one size fits all,” and individually tailored education programs have been shown to improve outcomes in cancer patients.29 Consistency of messages is important.
Issues That May Arise
Patients who are already familiar with other forms of therapy and/or who are receiving their ipilimumab treatment in an oncology suite alongside patients receiving other treatments may express concerns that their treatment is not working if they do not achieve a response soon after treatment has started or if they experience disease progression at first assessment. This is especially difficult for patients with palpable or visible tumors. These patients require reassurance and an explanation of why this may be happening. At our clinic, we treated a 45-year-old man with lung metastases and palpable axillary nodal metastases whose disease progressed through biochemotherapy. He became very depressed after starting ipilimumab because his axillary nodes got larger, by his account, at an even faster rate. Later, when he came for his third induction dose, his spirits had lifted because he reported that the nodes had stopped growing. By the fourth induction dose, the nodes had regressed and, after another 3 to 4 weeks, had disappeared. His scans at 12 weeks showed a dramatic decrease in his lung metastases as well. He achieved a complete response at 18 months, and currently, he continues in a complete response almost 4 years later. Other than vitiligo, he has not experienced any other significant adverse events.
The approved ipilimumab administration and dosing is via IV at 3 mg/kg every 3 weeks (weeks 1, 4, 7, and 10).6 This means that the patient’s visits to your center may be relatively infrequent, and if the patient is not local, it may be impractical for him or her to attend more often, for example, if irAEs develop. Patients who live a long way from your treatment center, attending only for dosing and assessment, need additional support from their local community doctor or nurse. You can establish a relationship with these professionals and supply them with educational materials and symptom checklists for their own use and for them to use with patients.
Good sources of educational information can be found at the following websites:
AIM at Melanoma Foundation (www.aimatmelanoma.org)
Melanoma Research Foundation (www.melanoma.org)
Nurses play a pivotal role in ensuring the successful use of ipilimumab in the clinic. Since this agent has a novel mechanism of action, produces unique response patterns, and has characteristic irAEs, which are manageable with prompt recognition and treatment, appropriate education of patients and other healthcare professionals is important.
With regular, ongoing nurse in- volvement in the patient’s treatment plan, ipilimumab can be given optimally to allow immune responses a chance to develop, while minimizing the impact of any irAEs. Ipilimumab is the first agent to show a survival benefit in previously treated patients with advanced melanoma, and it is vital to give optimal support to patients prescribed this drug so that they can benefit from it. The relationship and communication between nurses and their patients will be vital to achieving this goal.
The author takes full responsibility for the content of this publication and confirms that it reflects her viewpoint and medical expertise. The author also wishes to acknowledge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editorial support. Neither Bristol-Myers Squibb nor StemScientific influenced the content of the manuscript, nor did the author receive financial compensation for authoring the manuscript.
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25. YERVOY (ipilimumab) immune-mediated adverse reaction management guide. Bristol-Myers Squibb; 2011. https://www.hcp.yervoy.com/pdf/rems-manage ment-guide.pdf. Accessed April 23, 2013.
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