Symptom Management and Palliative Care in Hematologic Malignancies

Introduction

Patients with hematologic malignancies experience complex physical and psychosocial symptoms, affecting their quality of life (QOL). Patients may undergo specific high-risk procedures such as hematopoietic cell transplantations (HCTs) and chimeric antigen receptor T-cell (CAR-T-cell) therapies, which further predispose them to toxicities. Therefore it is imperative to screen individuals for risk factors with additional physical and psychologic interventions before initiating treatments. The intensity of symptoms and level of distress are dependent on multiple factors such as the type of therapies, type and dose of chemotherapy and radiation therapy used during conditioning, the degree of cytopenias and associated infections, and other organ dysfunction such as liver and kidneys. In our opinion, certain symptoms are relatively common such as pain, nausea and vomiting, diarrhea, mucositis, and delirium. Graft-versus-host disease (GVHD) is a complication of HCT with high morbidity and mortality. It is a frequent reason for HCT failure. We aim to provide a brief overview of the management of acute and chronic GVHD symptoms from a supportive care standpoint. A small but significant body of literature examining the benefits of early integration of palliative care with standard oncologic care suggests improved physical and psychosocial wellbeing. Despite this evidence, a recent study indicates that patients with hematologic malignancies were most likely to receive first-time palliative care consultation within 24 hours of their death.

Quality-of-Life Measures

MD Anderson Symptom Inventory (MDASI) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT) are the most common QOL measures used in hematologic care. MDASI is a validated multisymptom patient-reported outcome measure for clinical and research used to assess the severity of symptoms experienced by patients with cancer and the interference of daily living. It consists of 13 symptoms based on a 0 to 10 scale (0 = Symptom not present, 10 = Symptom as bad as you can imagine), which can be applied broadly across cancer types and treatments. Specific to bone marrow transplant patients, the FACT-BMT combines the Functional Assessment of Cancer Therapy and the Bone Marrow Transplantation Subscale. It is a 47-item questionnaire that can be used to assess five areas of well-being (physical, social/family, emotional, functional, and doctor-patient relationship) using a 0 to 4 scale (0 = Not at all, 4 = Very much). Edmonton Symptom Assessment Scale (ESAS) can also be used to measure physical and psychologic symptoms. ESAS is a validated tool to assess the patient rating of pain, fatigue, nausea, anxiety, depression, drowsiness, appetite, feeling of wellbeing, shortness of breath, and sleep. The patient is asked to grade the severity of their symptoms from “no symptom” 0 to “worst symptom” 10 in the last 24 hours. ESAS has a high test-retest reliability of (> 0.8) and has been validated in many clinical settings, including the cancer population.

Graft-Versus-Host Disease

GVHD is a complication of HCT with high morbidity and mortality. It is an important reason for HCT failure. In this section, we will briefly discuss the Supportive management of acute and chronic symptoms related to GVHD.

The rash is the most common manifestation of acute GVHD, affecting 81% of patients, followed by gastrointestinal (GI) (54%) and liver dysfunction (50%). Skin is frequently the first organ involved. Common sites, early on, include palms and soles, upper back, lateral neck, cheeks, and the external ear. Treatment includes immunosuppressives such as steroids and psoralen plus ultraviolet A irradiation PUVA or extracorporeal photophoresis for limited skin disease. GI involvement can be diffuse with the comparable diagnostic yield at the rectal, sigmoid, gastric, and duodenal biopsy sites. The symptoms may include nausea, vomiting, anorexia, abdominal pain, and diarrhea; if symptoms are severe, rectal bleeding can also occur. Pain and nausea are discussed separately in this chapter. Abdominal pain related to GVHD can be treated with anticholinergic medications such as dicyclomine or glycopyrrolate. It is crucial to consider infectious causes of diarrhea, with Salmonella , Shigella , Campylobacter , Cryptosporidium , and Clostridium difficile being common culprits along with viral etiologies. Extensive GVHD involving the GI tract can result in up to 10 liters of diarrhea in a day. Therefore it is important to manage metabolic derangements, dehydration, and nutrition. Loperamide and octreotide can be given to help with diarrhea after infectious causes are ruled out. Jaundice from hyperbilirubinemia is commonly seen, especially in the early stages of hepatic involvement. Ursodeoxycholic acid has been shown to decrease the frequency of jaundice, lower acute GVHD incidence, and improve survival.

Symptoms commonly seen in chronic GVHD are related to increased dryness. Artificial tears can palliate sicca symptoms experienced in chronic GVHD, moisture-chamber eyewear, gas-permeable scleral lens, or plugging or ligation of the tear ducts in more severe cases. Patients with xerostomia may find relief from medications, which increase the salivary flow, such as cevimeline. Oral involvement may respond to therapy with topical steroid wash. Genitalia involvement is more common in chronic GVHD and includes vaginal GVHD, which manifests as ulcerated and thickened mucosa, narrowed introitus with scar tissue. Treatment includes topical immunosuppressive medications such as cyclosporine, vaginal dilators, and in severe disease, surgical lysis. Myositis, fasciitis, contractures, and joint stiffness are also seen in chronic disease. Deep tissue massage, frequent weight-bearing exercise, and physical activity help with these symptoms. Other chronic GI manifestations include esophageal webs and strictures. Lung disease includes bronchiolitis obliterans, cryptogenic organizing pneumonia, and restrictive lung disease.

Mucositis

Oral mucositis arising from HCT is common and experienced by 76% of patients undergoing this procedure. Almost 42% of patients have described mucositis as the most significant adverse effect of HCT. In one study, 84% of patients with mucositis thought symptoms were more severe than expected, with 65% reporting poor or no control of symptoms. Patients at increased risk of mucositis after HCT include those who receive total body irradiation, have a body mass index ≥ 25 kg/m ² , do not receive multivitamins before transplantation, and those with the methylenetetrahydrofolate reductase 677TT genotype. Mucositis can result in many complications for the patient. It can stress resources leading to more frequent emergency room visits and hospital admissions, increased reliance on total parenteral nutrition, and a 3.9-fold rise in mortality.

There are several grading scales, which can assist with the clinical diagnosis of mucositis. The World Health Organization (WHO) scale was developed before the National Cancer Institute Common Terminology Criteria for Adverse Events Scale, which uses clinical and functional components to determine the grades ( Table 38.1 ).

The injury occurs at the start of chemotherapy or radiation and becomes evident a few days later. Cellular apoptosis occurs, which leads to the syndrome. Patients may experience a burning sensation on the oral mucosa with erythema and removable white plaques. Desquamation and epithelial sloughing occur, with symptoms peaking at 1 week, eventually leading to ulceration and severe pain. Certain areas of the oral mucosa are prone to mechanical injury from normal activity. Cytokines and interleukins released after chemotherapy and radiotherapy may cause increased vascularity in those areas. Bacterial, viral, and fungal infections may arise and can be complicated by bacteremia, especially in neutropenia. The most common condition seen with mucositis is candidiasis. This is followed by a herpes simplex virus (HSV) infection, most commonly caused by the reactivation of HSV-1. Mucositis is self-limited, and lesions are usually healed 2 weeks after chemotherapy administration. The guidelines for the prevention of mucositis include good oral hygiene and some helpful interventions if needed. Good oral hygiene consists of the use of a soft toothbrush, consulting dental care before and after treatments, drinking plenty of liquids, regular flossing, abstaining from tobacco and alcohol as well as acidic foods, use of mouth lubricants such as artificial saliva or jellies, performing baking soda mouth rinses and good denture care. Interventions for prevention include oral cryotherapy for patients receiving bolus 5-fluorouracil chemotherapy or high-dose melphalan or bolus doses of methotrexate. Recombinant keratinocyte growth factor-1 known as Palifermin could be given to patients with hematologic malignancies receiving high-dose chemotherapy and total body irradiation followed by HCT. Low-level laser therapy can be given to patients receiving HCT conditioned with high-dose chemotherapy and head and neck cancer patients receiving radiotherapy. Of note, chlorhexidine and sucralfate mouthwashes are not recommended for prevention.

Treatment for established oral mucositis is usually aimed at symptom control. This consists of mouth protectants, analgesia, and treatment of infection in addition to good oral hygiene. Mouth protectants include baking soda rinses and denture care, as discussed previously, are important to maintain. For mucositis with mild pain, patients can try bland rinses, which consist of normal saline and sodium bicarbonate. If the pain is moderate, topical analgesia mouthwash options include preparations comprising of the previous ingredients in combinations with lidocaine, hydrocortisone, and diphenhydramine, known as Magic or Miracle mouthwashes . Doxepin, xyloxylin, and morphine sulfate mouthwashes are also available options. Of note, these mouthwashes require frequent swish and swallow use several times per day. For more severe pain with mucositis, systemic opioids are considered. Patients are usually started on oral opioids such as morphine, keeping in mind that because of severe pain, the oral route may not be feasible. If so, clinicians can consider a fentanyl patch or parenteral opioid administration. For infections, certain populations, can be considered for infection prophylaxis. Neutropenic patients often receive hematopoietic growth factors. Treatment with bortezomib is linked with the reactivation of HSV-1, so antiviral prophylaxis is recommended. For patients with established candida infections, nystatin swish and swallow, clotrimazole, or fluconazole can be given. For HSV infections, acyclovir or valacyclovir can be given while cultures are collected. Practice guidelines are available for review with the Infectious Diseases Society of America. Refractory or systemic infections require the use of parenteral medications and consultation with an Infectious Disease specialist.