Today’s Immunotherapy Combinations
Immunotherapy has revolutionized cancer treatment, especially for patients with diseases considered otherwise incurable. Since May 2017, the U.S. Food and Drug Administration (FDA) has approved 27 immunotherapy combinations, including (https://jhoonline.biomedcentral.com/articles/10.1186/s13045-021-01164-5) chemoimmunotherapy and regimens with targeted therapies, and researchers are reporting (https://www.mdpi.com/1422-0067/21/14/5009) highly promising data from clinical trials of its combination with radiation.
For oncology nurses, managing patients receiving two types of therapy instead of just one adds layers to their care considerations. From sequencing to side effects, combination modalities have implications for oncology nursing practice—especially when new combinations are constantly emerging.
“I work in thoracic radiation oncology, where many patients receive immunotherapy before or after radiation, or more recently concurrently with radiation in clinical trials,” ONS member Cynthia Bowes, MSN, ANP-BC, thoracic nurse practitioner in the Massachusetts General Hospital department of radiation oncology in Boston and member of the Boston ONS Chapter, said. “I have worked in this specialty for four years now, and treatment options are constantly improving and expanding.”
“I have 20 years of oncology nursing experience, with the past 12 in outpatient infusion. In the past several years, the use of immunotherapy has radically expanded to include many cancer indications,” ONS member Tiffany Kurtz, MSN, RN, OCN®, RN manager of outpatient oncology at Summa Health in Akron, OH, and member of the Cleveland ONS Chapter, said.
Immunotherapy is most commonly combined (https://jhoonline.biomedcentral.com/articles/10.1186/s13045-021-01164-5) with chemotherapy and targeted therapies, and the treatments work synergistically. Numerous studies suggest that cytotoxic chemotherapy decreases tumor cell mass, reduces the tumor burden, then induces immunogenic cell death, thereby reducing the volume of tumor cells that immune cells must kill. The two treatments also mutually increase (https://www.cell.com/immunity/fulltext/S1074-7613(18)30083-9) each other’s effect.
As with chemotherapy, targeted therapy has been shown to enhance the immunologic activity of immunotherapy, and multiple targeted gene expressions have profound impacts on immune cells. To date, almost every approved targeted therapy has been shown to strengthen immune response when paired (https://jhoonline.biomedcentral.com/articles/10.1186/s13045-021-01164-5) with an immunotherapy agent.
Radiation and Immunotherapy
But the next power couple may be combination radiation and immunotherapy, Kurtz and Bowes said.
“Concurrent regimens are limited to clinical trials at this time, but researchers are exploring the combination in many populations,” Bowes said, including early-stage and locally advanced lung cancer. Kurtz added that researchers (https://www.astro.org/News-and-Publications/News-and-Media-Center/News-Releases/2020/Radiation-immunotherapy-combination-shows-promise) have also found benefit (https://www.frontiersin.org/articles/10.3389/fphar.2018.00185/full) for diagnoses, including brain metastases, head and neck squamous cell carcinoma, melanoma, and pancreatic cancer.
Most notably, Kurtz said, immunotherapy may increase radiation’s abscopal effect (i.e., shrinking tumors beyond the targeted field of treatment), and researchers (https://www.frontiersin.org/articles/10.3389/fphar.2018.00185/full) have found that combining the modalities promotes synergy and efficacy. Also, damage to cells caused by radiation may make tumors more visible to the immune system, increasing immunotherapy’s ability to stimulate the body’s immune system (https://www.ons.org/books/manual-radiation-oncology-nursing-practice-and-education-fifth-edition) to attack cancer cells.
Bowes added that it can take up to two months to see immunotherapy’s effects, and radiation can be used to slow rapidly progressive disease, potentially preventing complications like airway obstruction while waiting for an immunotherapy response.
“The infusion and radiation departments at my institution work closely together to coordinate care and treat concurrent patients,” Kurtz said. “We are participating in several clinical trials enrolling patients in studies to determine the effectiveness and side effects of concurrent immunotherapy plus radiation,” including:
- Chemoradiation with or without atezolizumab in treating patients with limited stage small cell lung cancer (https://www.clinicaltrials.gov/ct2/show/NCT03811002)
- Testing the addition of an antibody to standard chemoradiation followed by the antibody for one year to standard chemoradiation followed by one year of the antibody in patients with unresectable stage III non-small cell lung cancer (https://clinicaltrials.gov/ct2/show/NCT04092283) (NSCLC)
- Durvalumab vs placebo with stereotactic body radiation therapy in early stage unresected NSCLC patients (https://clinicaltrials.gov/ct2/show/NCT03833154)
“The primary outcome measures of these clinical trials are to determine overall survival, progression-free survival, and incidence of adverse events between the different arms of the studies,” Kurtz said. “Further clinical trials will be fundamental in determining the benefit and potential increased side effects of administering concurrent immunotherapy plus radiation for certain patient populations.”
Immune-related adverse events (irAEs) associated (https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/side-effects) with immunotherapy agents resemble those of autoimmune diseases and other cancer treatments, including diarrhea, flu-like symptoms, and skin reactions. Bowes and Kurtz both emphasized the necessity of patient assessment, education, and prompt symptom management throughout combination treatments.
“The most important thing a nurse can teach a patient is to notify their healthcare team immediately of side effects that could be indicative of irAEs. Prompt patient reporting of symptoms is critical for the early initiation of treatment and successful management of irAEs,” Kurtz said. “Healthcare professionals need to also be careful not to label immunotherapy as chemo, which can be confusing for patients and clinicians outside oncology.”
Although immunotherapy side effects may mimic those of chemotherapy, understanding the mechanism of action of the drugs and the timing at which the side effects usually present can help clinicians determine (https://www.verywellhealth.com/chemoimmunotherapy-4782366) the causative agent and the appropriate symptom management strategies.
Targeted therapy combinations can alter (https://www.nature.com/articles/nrc3237) immune response that could increase (https://www.frontiersin.org/articles/10.3389/fimmu.2019.00990/full) the likelihood of irAEs, including serious events like hepatotoxicity. Clinicians will tailor the proper dose, sequence, and timing of targeted therapies when used in combination with immunotherapy on an individual basis.
“In general, immunotherapy administration following radiation has been well tolerated,” Kurtz said. “Additional or unexpected side effects have not been largely observed in ongoing studies compared to receiving immunotherapy or radiation alone.”
With any treatment combination, nurses must carefully identify which therapy is causing a side effect so they can manage it correctly, but it may be a little easier with radiation combinations than with chemotherapy or targeted agent combinations. Both radiation and immunotherapy can cause fatigue, and patients can expect exacerbated fatigue when the therapies are combined, Bowes said. However, immunotherapy side effects are usually caused by the immune system attacking normal cells of the body, the same way it attacks cancer cells, and can present anywhere in the body. Most of radiation therapy’s other side effects are limited to the treatment field.
“On the skin, radiation-related changes will appear as an area of faint erythema with dry desquamation a few weeks into the course of treatment and can progress to moist desquamation,” Bowes advised. “Immunotherapy-related skin changes typically present as a maculopapular rash, which is more diffuse, appears weeks to months after immunotherapy is given, and can even develop months after therapy is stopped.
“The same goes for pneumonitis, with radiation-induced inflammation appearing one to six months post-treatment,” she added. “Pneumonitis caused by immunotherapy can appear from weeks to months after starting therapy and is typically more diffuse.”
Biosignatures can help predict symptom severity and appropriateness of treatment, Bowes said. “Some patients with targetable variants may think they could benefit from combination treatment, but it may actually put them at risk for increased toxicity if given with targeted therapy. Others may expect to have no side effects since they won’t be receiving chemotherapy and should be educated appropriately.”
Kurtz encouraged oncology nurses to immediately report any symptom or change in lab value that could indicate an irAE to the provider. Early reporting is important so the care team can begin management strategies while symptoms are mild, Bowes explained. Obtaining baseline assessments can help nurses identify even small changes in a patient’s status to allow for earlier detection and intervention.
“Many immunotherapy effects can be treated effectively with high-dose steroids and a slow taper. Note the timing of symptom appearance relative to therapies they’ve received, and with combination radiation, pay close attention to any skin changes, ranging from local erythema to blisters, cracking, or more diffuse rash,” Bowes said. “Patients may casually mention bowel changes, but it is important to get detailed descriptions of frequency and consistency of bowel movements. Vision changes could indicate uveitis and require timely evaluation by a specialist, so prompt reporting is especially crucial with this side effect.”
Bowes also pointed out that care coordination is essential for both patients and providers.
“Combination immunotherapy requires additional coordination, which can be stressful for patients. Some days may be quite long if patients have both treatments scheduled for the same day,” Bowes said. “Patients should be informed to bring questions to their care teams because treatment combinations are very specialized, and their providers need to know of any changes in their conditions. For example, local emergency room providers may not have experience with the complications associated with immunotherapy combinations and should be advised to reach out to the patient’s oncology team to discuss any findings or interventions.”
Kurtz’s institution implemented a solution in 2020 after her colleague, Elizabeth Hoover, BSN, RN, OCN®, completed a clinical ladder project introducing immunotherapy wallet cards in all outpatient infusion centers. The wallet cards are scanned into the patient’s electronic medical record and help non-oncology clinicians understand that immunotherapy differs from antineoplastic therapies and that their side effects are managed differently, too.
“At Summa Health, the wallet card records the name of the immunotherapy that the patient is receiving and communicates to non-oncology providers potential irAEs and the contact information of the patient’s oncologist,” Kurtz said. “Wallet cards are presented to each patient at their first immunotherapy infusion appointment, and the infusion RN educates the patient on side effects and to show the wallet card to other clinicians, such as their primary care physician and emergency department. This has become an integral part of our immunotherapy patients’ treatment plan.”
ONS has immunotherapy patient education wallet cards (https://www.ons.org/clinical-practice-resources/immunotherapy-patient-wallet-card) on the ONS website that any provider may download to print and give to their patients.
“This is an exciting time for oncology as we learn more about how immunotherapy combinations can synergize to improve patients’ quality of life and survival,” Bowes said.