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INTRODUCTION

Multimodal cancer therapy, a combination of 2 or more pharmaceutical agents targeting pathways that sustain cell growth or induce cancer, is the cornerstone of cancer treatment.¹ Most commonly, cytotoxic chemotherapy, targeted therapy, hormonal therapy, biologic therapy, and immunotherapy are used. Although monotherapy is still common in the treatment of some forms of cancer, it is typically less effective than multimodal therapy. The multimodal approach is more effective because it combines different therapeutic targets, which allows for reducing drug resistance and cancer growth, as well as metastatic potential, by working synergistically or against different pathways. It also reduces toxicity because lower doses are needed in multimodal therapy than in monotherapy.

Combination therapy was first introduced in 1965 as a treatment for pediatric patients with acute lymphoblastic leukemia when several cytotoxic agents were combined (methotrexate, 6-mercaptopurine, vincristine, and prednisone) in a regimen known as POMP.¹ This regimen reduced tumor burden and prolonged remission. Subsequently, this approach became the focus of ongoing cancer research throughout the years, with focus turning eventually to combining drugs that target different pathways and mechanisms of action to improve overall outcomes. The superiority of multimodal therapy results from the ability to minimize drug resistance because cancer cells are incapable of adapting to the simultaneous effects of 2 or more agents. The various pathways targeted in multimodal therapy also can target the heterogeneous nature of tumors, which can contribute to drug resistance and cancer recurrence years later.

Multimodal therapy combines cytotoxic chemotherapy, targeted therapies, and immunotherapies to treat many cancer types. The toxicity profiles of these agents vary, but some overlap occurs, as well. Despite the benefits of multimodal therapy, unwanted adverse effects do occur, and, at times, it is difficult to identify which anticancer agent is producing the adverse effect. This monograph is aimed at describing the emerging combination cancer therapies involving contemporary and conventional therapies, as well as the identification and management of adverse effects arising from the use of these novel combinations.

THE CHANGING LANDSCAPE OF CANCER CARE

Cytotoxic chemotherapy has been a mainstay of anticancer therapy since the 1940s when nitrogen mustard was used to treat lymphoma.² With efforts to improve disease response rates and minimize toxicity, cancer research has focused on the development of novel agents with differing mechanisms of action. Targeted therapies revolutionized the treatment of many cancers, and the number of available agents has risen dramatically since imatinib was first introduced in 2001.³ Unlike cytotoxic chemotherapy, which targets inhibition of DNA and RNA replication and function, targeted agents block alterations in cancer cells that make them malignant. For example, targeted agents may block intracellular signaling pathways, which govern cell responses, movement, and division, eventually leading to apoptosis or stimulation of the immune system to destroy cancer cells. These drugs can either be small-molecular-weight drugs or monoclonal antibodies specifically designed to interact with extracellular receptors or interfere with intracellular signaling pathways and prevent subsequent downstream signaling, with the goal of decreasing cell proliferation and increasing cancer cell death.⁴ The first monoclonal targeted antibody, rituximab, was approved by the United States (U.S.) Food and Drug Administration (FDA) in 1997. Since then, more than 20 have been approved. Since 2001, more than 60 oral targeted agents have been approved by the FDA.

Recently, immunotherapy has again revolutionized cancer treatment.² Although immunotherapy has been used in cancer treatments for many years, the introduction of checkpoint inhibitors, such as those targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1), has been practice changing. Immunotherapy provokes host immunity and induces a systemic response that produces higher and durable response rates with reduced toxicity.

In 2011, the CTLA-4 inhibitor ipilimumab became the first FDA-approved immune checkpoint inhibitor. It prevents T-cell inhibition and promotes activation and proliferation of effector T cells. It was initially approved for treating patients with advanced melanoma. Since then, PD-1 and PD-L1 inhibitors have been approved for use in both solid tumor and hematologic malignancy settings. PD-1 and PD-L1 inhibitors prevent the PD-1/PD-L1 interaction, which is responsible for immune tolerance, and, thus, facilitate a positive immune response.⁵

Once these therapies were shown to be as effective as monotherapy in many solid and hematologic tumors, combination regimens were developed to maximize efficacy. In fact, their use is growing. Targeted therapies have been combined with cytotoxic chemotherapy and immunotherapy, as well as other targeted therapies. Similarly, immunotherapy has been combined with cytotoxic therapy, targeted therapy, and other immunotherapies. See Table 1 for common combination therapies used in many cancer types.^8-14

COMMON ADVERSE EFFECTS OF ANTICANCER THERAPIES

Adverse effects associated with anticancer therapy agents depend on the type of therapy, as well as patient-specific factors. Prevention and monitoring guidelines are available to mitigate adverse effects of therapy as much as possible, and ongoing assessment of patient response to therapy is recommended.

Cytotoxic chemotherapy

Cytotoxic chemotherapy targets rapidly dividing cells at one or more phases of the cell cycle, which causes destruction of both cancer and healthy cells.² Typically, these agents have a very narrow therapeutic index and can have significant organ toxicity. Doses of cytotoxic agents are administered at a frequency that allows the patient to recover from the toxicity before the next dose (i.e., cyclic fashion, such as once every 3 weeks), and doses are often modified if significant toxicity occurs. Adverse effects usually manifest on the most rapidly proliferating cells of the body: bone marrow (myelosuppression), gastrointestinal tract (nausea, vomiting, mucositis, diarrhea), skin (hand-foot syndrome, nail changes, pigmentation changes), and hair follicles (alopecia).

Additional adverse effects may be related to the class of cytotoxic agents, which is typically based on mechanism of action. For example, anthracyclines like doxorubicin have the potential to cause cardiac toxicity, with a risk related to the cumulative dose. Microtubule agents, such as vinca alkaloids and taxanes, can cause neuropathy. Other toxicities can be related to accumulation of drug or toxic metabolites in organs or tissues, such as cisplatin-induced nephrotoxicity or ifosfamide-induced hemorrhagic cystitis or neurotoxicity.

Targeted therapy

Some oral targeted therapies are administered as continuous treatments and others are administered in a cyclic fashion like cytotoxic chemotherapy to allow recovery from toxicity (e.g., 3 weeks on, 1 week off). Targeted monoclonal antibodies are typically administered in a cyclic fashion due to the long half-life of these agents. Although adverse effects that are common with cytotoxic chemotherapy can occur with some targeted therapies (e.g., nausea, myelosuppression, mucositis), they are typically not dose-limiting, as they often are with cytotoxic chemotherapy.³ Instead, targeted therapies typically result in toxicities that are uncommon with cytotoxic chemotherapy and require different management practices. The common toxicities that occur with targeted agents are based on their pharmacologic mechanism, that is, which intracellular pathway they target.

Off-target effects, which is toxicity unrelated to the intracellular pathway but can be a result of modulation of other targets, can occur as well. For example, vascular endothelial growth factor (VEGF)-targeted agents (e.g., axitinib, bevacizumab, cabozantinib, lenvatinib, regorafenib, pazopanib, sunitinib) are all associated with hypertension due to the fact that VEGF is vital for maintenance of blood vessels and nitric oxide production, which is necessary for vasodilation and angiogenesis. When blocking this pathway, an increase in vascular resistance occurs, leading to decreased nitric oxide production, vasoconstriction, and, ultimately, hypertension. Another example includes the epidermal growth factor receptor (EGFR) pathway, which is involved in homeostasis of the epidermis through stimulation of keratinocyte proliferation and maturation. Inhibitors of the EGFR pathway, such as cetuximab, erlotinib, lapatinib, and osimertinib, all cause papulopustular eruption that occurs in a seborrheic distribution (i.e., scalp, face, upper chest, and back). Off-target effects of tyrosine kinase inhibitors include adverse effects such as anorexia, myelosuppression, reductions in laboratory values (e.g., phosphate, glucose), and edema. Some additional examples of on- and off-target toxicities of targeted therapies can be found in Table 2.¹⁵

Table 2. Examples of On-Target and Off-Target Toxicities of Targeted Cancer Therapies15
Drug class	Drugs	On-target adverse effects	Off-target adverse effects
BRAF inhibitors	Dabrafenib Vemurafenib	Arthralgia Cutaneous squamous cell carcinomas Skin rash Keratocanthomas	Hemolytic anemia in patients with G6PD deficiency
EGFR inhibitors	Afatinib Cetuximab Erlotinib	Acneiform rash Diarrhea Mucositis/stomatitis	Anorexia Hypophosphatemia
VEGF inhibitors	Axitinib Bevacizumab Cabozantinib Lenvatinib Pazopanib Sorafenib Sunitinib	Arterial/vascular thrombosis Gastrointestinal perforation Hemorrhage Hypertension Poor wound healing	Hand-foot syndrome Electrolyte disturbances Hyperglycemia Neutropenia
BRAF, proto-oncogene B-Raf and VRaf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; G6PD, glucose-6-phosphate dehydrogenase; VEGF, vascular endothelial growth factor.

Immunotherapy

Immunotherapies are typically better tolerated than cytotoxic chemotherapy.^2,6 In contrast to cytotoxic chemotherapy, immune-related adverse events (irAEs) typically manifest as inflammation and autoimmune symptoms as a result of infiltration of hyperactivated CD4+ and CD8+ T cells into normal tissues and organs.^6,7 irAEs can affect any organ but most commonly affect skin, the gastrointestinal tract, lungs, endocrine glands, and liver. Most are mild to moderate in nature, but they can become severe and life-threatening if not promptly identified and managed. The time to onset of irAEs varies according to the type of AE, type of immunotherapy, and whether the immunotherapy is combined with other agents. Rash, pneumonitis, and colitis are some typical early-onset irAE reactions. Delayed-onset irAEs involve organ-specific reactions, such as enterocolitis, hepatitis, and endocrinopathies.^6,7

ASSESSMENT AND MANAGEMENT OF ADVERSE EFFECTS

For most adverse effects of cancer treatments, no approved mitigating or evidence-based treatment strategies exist.¹⁶ Development of such therapies are often limited by lack of mechanistic insight into adverse effects, difficulty in objectively measuring effects, and lack of good preclinical models and assays to test potential therapies for reducing or preventing adverse effects. Furthermore, funding for symptom and toxicity research is limited. Despite this, some evidence-based guidelines do exist (Table 3). ^6,17-34 These guidelines tend to primarily focus on adverse effects most commonly associated with cytotoxic chemotherapy and immunotherapy, but, if applicable, may apply to targeted therapies. For example, some oral targeted therapies do cause significant nausea and vomiting and should be managed with prophylactic antiemetics. The National Comprehensive Cancer Network (NCCN) antiemesis guidelines provide guidance on which cancer therapies should have prophylactic antiemetics and the best types of antiemetics to use.²⁹ In addition to guidelines, management strategies have been published and adopted by many practitioners. For example, dermatologic toxicities of EGFR inhibitors and metabolic disorders are treated with mammalian target of rapamycin (mTOR) inhibitors.^35-38

The approach to toxicity management in cancer care, however, is similar regardless of the type of cancer therapy. Awareness of potential adverse effects, close monitoring for those adverse effects, employment of prevention strategies if evidenced-based guidance is available, and prompt identification and management of adverse effects that occur are critical to patient care. In fact, overall outcomes are improved when adverse effects are mitigated and managed promptly and appropriately. To that end, it is important to know the potential adverse effects associated with the cancer therapy, as well as recommended monitoring parameters and frequency. This information can often be found in the package inserts of the drugs and in drug databases such as Lexicomp or Micromedex. Additionally, grading of the severity of the adverse event is important, since the management will be based on this severity. The grading system used in clinical trials and in patient care is the National Cancer Institute Common Terminology Criteria for Adverse Events, which grades adverse events from 1 to 5: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening; and grade 5, death.³⁹

The healthcare team should conduct regular assessments of cancer patients that include physical examination and assessment, patient interview, and laboratory monitoring that is specific to the therapy each patient is receiving. Prevention and treatment of adverse effects can be guided by evidence-based guidelines, if they exist (Table 3), existing clinical guidelines related to the condition (e.g., hypertension, hyperlipidemia), or with supportive care therapies that would be used for symptom control regardless of cause (e.g., correction of electrolyte abnormalities).⁴⁰ See Table 4 for examples of assessment, prevention, and treatment strategies for targeted therapies.^40,41 A review by Dy and colleagues also provides some guidance on managing toxicities of targeted therapies.⁴⁰

Assessment and management of irAEs

Generally, mild irAEs can be monitored closely and therapy can be continued. However, moderate to severe adverse effects can result in rapid declines in organ function and quality of life and even death. Therefore, prompt identification of these toxicities and proper management is needed. It is critical to understand that adverse effects can occur at any point during therapy, as well as after therapy has been completed.^6,7 Management can include therapy discontinuation, systemic treatment with corticosteroids and, in some cases, infliximab and organ-specific therapies (e.g., thyroid replacement for hypothyroidism, oral antihistamines or gabapentin for pruritus). The goal for the management of these adverse events is to prevent, treat, and minimize their effects, thereby enabling patients to remain on treatment and improve their quality of life. Proactive management, along with ongoing patient education, can help to effectively manage symptoms, often without the need for dose modification or drug withdrawal. The American Society of Clinical Oncology (ASCO) and the NCCN have developed practice guidelines aimed at monitoring, evaluating, and managing adverse effects of checkpoint inhibitor immunotherapies.⁶

Steroids, specifically corticosteroids, are the main treatment for irAEs: prednisone doses of 0.5 to 1 mg/kg/day (or an equivalent dose), or up to 2 mg/kg/day according to severity, are usually prescribed.⁶ After resolution of irAEs, patients will require tapering of corticosteroid therapy or, in some cases, supportive prophylaxis treatments for long-term steroid use. In addition, utilization of other immunosuppressants may need to be considered on the basis of the severity of grade or lack of response to steroids.

Continued treatment with immunotherapy through grade 1 irAEs is typically recommended; however, in patients with grade 2 or greater irAEs, immunotherapy is often held until resolution of symptoms. In some cases, due to the type of side effect profiles, permanent discontinuation may indeed be warranted. Differences in the treatment and side effect profiles of irAEs are listed in Table 5.⁶ 

Adverse effects with combination therapy

Combined immunotherapies have demonstrated better anti-tumor activity than monotherapy but, not unexpectedly, have a higher incidence of irAEs. These irAEs also tend to be more severe than adverse events seen with monotherapy.⁷ Similar to monotherapy, the most common irAEs related to combined immunotherapy regimens include dermatologic-, gastrointestinal-, hepatic-, pulmonary-, and endocrine-related irAEs. For example, in the CheckMate 067 trial, in which advanced melanoma patients were randomly assigned to nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for 4 doses followed by nivolumab (3 mg/kg) every 2 weeks, nivolumab monotherapy (3 mg/kg) every 2 weeks plus placebo, or ipilimumab monotherapy (3 mg/kg) plus placebo, 96% of patients in the combination group experienced irAEs compared to 86% of those receiving monotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 59% of patients receiving nivolumab plus ipilimumab, in 21% of the nivolumab group, and in 28% of the ipilimumab group. The most common adverse events of any grade within the combination group were diarrhea (45%), fatigue (38%), pruritus (35%), and rash (30%).⁴²

When immunotherapy is combined with chemotherapy or targeted therapy, toxicities may overlap with irAEs but have different underlying causes and, thus, may need to be treated differently.⁷ Because of the complex nature of irAEs, however, it can sometimes be difficult to distinguish which symptoms are related to immunotherapy, which are caused by other drugs used in multimodal treatments, and which are caused by the disease itself.⁷ Adverse effects from cytotoxic chemotherapy tend to occur earlier in treatment than irAEs. With targeted therapies, the onset of adverse effects is variable. Knowledge of the timeline of presentation of adverse effects is an important factor in helping to distinguish irAEs in patients receiving combined therapies. For example, preliminary results of the JAVELIN Renal 100 trial of axitinib 5 mg by mouth twice daily plus avelumab 10 mg/kg intravenously every 2 weeks in patients with advanced renal cell carcinoma showed that the most common adverse events were diarrhea (58%), dysphonia (47%), hypertension (47%), and fatigue (46%).43 Diarrhea and fatigue are common with both of these drugs when used individually, and dysphonia and hypertension are more common with axitinib. Another example is with pembrolizumab and lenvatinib for endometrial cancer. Makker and colleagues⁴⁴ evaluated lenvatinib 20 mg daily plus pembrolizumab 200 mg intravenously every 3 weeks in patients with advanced endometrial carcinoma. In this study, the most common any-grade treatment-related adverse effects were hypertension (58%), fatigue (55%), diarrhea (51%), and hypothyroidism (47%), and the most common grade 3 treatment-related adverse effects were hypertension (34%), diarrhea (8%), fatigue (6%), and palmar-plantar erythrodysesthesia syndrome (6%). Pre-specified irAEs occurred in 57% of patients, with 10% requiring high-dose steroid therapy as treatment. In this study, it was not unexpected that the hypertension and palmar-plantar erythrodysesthesia syndrome was related to lenvatinib, which is a multikinase inhibitor that inhibits VEGF. However, fatigue, diarrhea, and hypothyroidism could occur with either lenvatinib or pembrolizumab. Similar reports have occurred with other combinations. A prudent approach for the toxicities that are most common with the immunotherapy is to promptly identify the toxicity and then assess and accurately diagnose it to allow for appropriate intervention. If an immune-mediated toxicity is suspected, it is important to follow treatment guidance for irAEs because of the potentially life-threatening aspect of those adverse effects.

THE ROLE OF PHARMACISTS IN ADVERSE EVENT MANAGEMENT

Pharmacists should not only be aware of the unique adverse effects associated with cytotoxic, targeted, and immune-related therapies, but they should also know the strategies to prevent, treat, and minimize the effects, so that treatment is not stopped early in patients who may be benefiting.⁶ In fact, supportive care plays a key role in optimizing care for patients with advanced cancer. This is a crucial role of pharmacists, particularly for patients receiving immunotherapy in whom potentially life-threatening irAEs can occur. Prompt identification of irAEs and appropriate referral for accurate diagnosis and intervention can minimize irAE-related morbidity and prevent irAE-related mortality. Early recognition and treatment of irAEs may also allow the patient to continue immunotherapy treatment and, thus, achieve an improved duration of benefit. Additionally, pharmacists should screen patients for predisposing conditions that put them at high risk of irAEs (e.g., autoimmune diseases) and then, if present, monitor them more rigorously in close collaboration with an organ specialist. Early identification and prompt diagnosis and treatment are also important for preventable adverse effects such as nausea and vomiting with cytotoxic chemotherapy or targeted therapy or for those effects with known preventive measures that can mitigate the onset or severity of adverse effects, such as skin care for EGFR or VEGF inhibitors.

Patient education should include information about the adverse effects of the therapy, signs and symptoms of these adverse effects, and how and when to report these adverse effects to the healthcare team.⁶ It is important to provide patients with written information summarizing all of this information, as well as a wallet card that lists current therapy and contact details of the oncology team, as this can be a good tool for communicating with non-oncology healthcare professionals. Patient education should also be a continuous process in which these elements are reinforced several times throughout therapy. As an example, for patients receiving checkpoint inhibitors, patient education should describe irAEs and how they differ from traditional treatment toxicities. Specifically, patients should understand common signs and symptoms of irAEs (e.g., rash, itching, diarrhea, shortness of breath, extreme tiredness, hair loss, feeling cold), the fact that many symptoms can be related and that any new or changing symptoms could be related, and the timeline of development of irAEs (essentially, they can occur any time during or after therapy). The importance of paying attention to symptoms and reporting them immediately should also be emphasized. Finally, patients should be provided information about whom to call both during office hours and outside of office hours for immediate questions or concerns related to therapy.

Monitoring patients for signs and symptoms of adverse effects is also important for early diagnosis and effective management. Regular physical examination, review of pertinent laboratory values, and assessment of patient-reported outcomes will provide information about adverse effects. For immunotherapy, guidelines recommend routine monitoring in 4-to-6-week intervals, with frequency increasing with the onset of adverse effects.⁷ For cytotoxic chemotherapy or targeted therapy, monitoring is typically based on the cycle of the regimen and expected adverse effects. Package inserts and databases often provide this information. Symptom checklists can facilitate identification of adverse effects; some manufacturers provide these, but institutions can develop them, as well. Assessment of toxicity can also be done by phone between visits. By evaluating laboratory values and changes from baseline, as well as distinguishing adverse effects from different types of therapies within multimodal therapy, the pharmacist can assist with the prompt identification of adverse effects.

Pharmacists have the knowledge of pharmacology, pharmacokinetics, safety, and efficacy of anticancer therapies, but also understand supportive care, so they are ideally positioned to evaluate the risks and benefits of therapies and individualize adverse effect management, both preventive measures and treatment.⁶ With immunotherapy, pharmacists can provide recommendations on steroid tapers and the best immunosuppressive regimens for steroid-refractory irAE management. Medina and colleagues⁶ provide recommendations for steroid tapers. For patients receiving an orally administered steroid, they recommend tapering over 4 to 6 weeks by reducing the steroid dose by 10 mg every 3 to 7 days (as toxicity allows) until the dose is 10 mg per day. Once the 10-mg/day threshold is reached, the steroid should be tapered by 5 mg every 5 days and then stopped. During this period, patients should be monitored by telephone twice weekly to assess for the return of symptoms. If symptoms return, the dose should be increased again and tapered more slowly. For patients receiving intravenous steroids, the taper should occur over a minimum of 6 weeks. The 2-mg/kg/day dose should be administered for 5 days, switched to an oral steroid at 1 mg/kg/day for 3 days, and then reduced to 60 mg/day. Upon discharge from the hospital, a reduction in steroid dose of 10 mg every 7 days (as toxicity allows) is recommended until a 10-mg/day dose is achieved. Similar to the oral steroid taper, the dose is then reduced by 5 mg every 7 days and then stopped; again, monitoring the patient by telephone twice weekly during the taper is recommended.

When patients are refractory to steroids, alternative immunosuppressive regimens can be used. Refer to the NCCN/ASCO guidelines for recommendations and select the most appropriate therapy on the basis of individual patient characteristics (e.g., concomitant diseases and medications, organ function, adherence capability). Additionally, pharmacists can ensure care is optimized by following recommendations on monitoring and treatment initiation for endocrinopathies, which are typically not treated with steroids but rather thyroid-related medications. For example, thyroid adverse effects, such as hyperthyroidism or hypothyroidism, are common with checkpoint inhibitors. Pharmacists can optimize care by ensuring thyroid function tests are ordered and monitored, as well as initiating thyroid-regulating medications as needed.

CONCLUSION

Pharmacists are instrumental in the management of adverse effects with multimodal cancer therapy. Monitoring, identifying, and managing adverse effects are critical aspects of patient care, and outcomes can be optimized when adverse effects are mitigated or identified and treated promptly. Pharmacists are well positioned to participate in the management of patients receiving multimodal cancer therapy because of their knowledge, expertise, and skills related to drug therapy. They serve key roles in educating the patient, caregivers, and healthcare team about likely adverse effects, the need to identify and report effects promptly, and appropriate preventive and treatment options that are tailored to the individual patient. As more is learned about emerging multimodal therapies, pharmacists can assist the team by providing guidance about appropriate monitoring and treatment and their role is likely to evolve.

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