Case History
W.W., a 66-year-old man, received an unexpected diagnosis of stage IV lung cancer after presenting to the emergency department with intractable, midthoracic back pain. He had been having severe, "deep aching" pain for some time, but the pain level increased dramatically when he was getting into bed and felt a "snap" that caused his back to spasm. The muscle spasms were so severe he could barely breathe, so his wife called emergency medical services. The initial chest X-ray showed a large mass in the right lung and a subsequent MRI of the chest confirmed a 5.2 x 5 cm right lower lobe tumor (the primary site) and another 1.3 cm diameter tumor in the left lower lobe. W.W. was already at one of the leading U.S. cancer hospitals, so the emergency department physician requested consults from the medical, radiation, and surgical oncology teams.
A biopsy of the lung mass confirmed a diagnosis of non-small cell lung cancer (NSCLC) of the adenocarcinoma cell type. An MRI of the thoracic spine showed bone metastasis in the T3 vertebrae of the upper back, and at T6 and T7 in the midthoracic area (Figure 1). A pathological compression fracture at T7 with vertebral collapse caused the sudden-onset, intractable back pain, and breath-taking muscle spasm. When the fracture occurred, the tumor within the vertebrae and bone fragments pressed on the spinal cord and spinal nerves. Multiple lymph nodes were affected in both sides of the chest, and an MRI of the abdomen showed two, metastatic tumors in the liver. A brain scan ruled out central nervous system metastasis. Tumor and blood samples were sent for genetic sequencing and immunohistochemistry testing.
W.W. had smoked one pack per day of cigarettes for over 40 years but had quit approximately 5 years ago. There had been warning signs prior to the acute pain, but he had ascribed increasing shortness of breath to chronic obstructive pulmonary disease, back pain to arthritis, fatigue to long work hours, and the productive cough to smoking. The diagnosis of advanced disease was emotionally devastating for W.W. and his family.
Approximately 237,000 Americans will receive a new lung cancer diagnosis in 2022 and lung cancer is second only to prostate cancer in men and breast cancer in women. Most lung cancers (84%) are NSCLC (American Cancer Society [ACS], 2022) and, as will be discussed below, relatively new options provide the real possibility of positive treatment outcomes, even with advanced, metastatic disease.
Non-Small Cell Lung Cancer
As with other types of cancer, NSCLC begins with a mutation in a single cell that causes uncontrolled cloning. A solid tumor forms within the tissues of a single lobe of one lung and begins to grow larger. As the tumor grows, cancerous cells break free and travel to local and distant sites through the circulatory and lymphatic systems. NSCLC cells tend to metastasize to other areas of the lungs, lymph nodes, visceral and parietal pleura, chest wall, mediastinum, great vessels, pericardium, heart, bone and spine, liver, adrenal gland, nervous system, and brain. It is not unusual for extensive metastasis to be present at diagnosis (Waqar et al., 2018; Zhu et al., 2020). Based on data from the most recent Surveillance, Epidemiology, and End Results (SEER) program, approximately 21.9% of U.S. patients presented with stage IV lung cancer at diagnosis, with an additional 8.7% at stage III (SEER, n.d.). Signs and symptoms of lung cancer may be attributed to other factors, and the patient may not realize the need for medical intervention until the metastatic lesions cause pain or other intolerable problems.
When W.W.'s primary tumor was biopsied, the pathologist studied the stained cells under a microscope (immunohistochemistry testing). The tumor originated in lung tissue (the primary site) and the type of cancer was an adenocarcinoma. Adenocarcinomas originate in cells that produce mucous, in this case, in an alveolar cell (Brown et al., 2018).
Staging for NSCLC
In the United States, the extent of NSCLC is described using the American Joint Committee on Cancer TNM grouping and staging method (American College of Surgeons, n.d.). "T" refers to tumor size in centimeters and describes the extent of local metastasis within the affected side of the chest and into the mediastinum. Values range from TX-cancer cells are present in sputum or lung fluid with no detectable tumor, to T4-tumors of 7 cm or larger, that have grown into specific tissues and structures. Lymph node involvement is described using "N" with values ranging from N0 for no affected lymph nodes to N3, which is used when there is metastasis to lymph nodes on the opposite side of the body. Metastasis ("M") describes the degree to which the cancer spread. M0 is used until there is distant metastasis. Distant metastasis to the opposite lung, malignant pleural effusion, and malignant pericardial infusion are coded M1a. When a single distant lymph node or vital organ is affected by metastasis, M1b is used. Lastly, M1c is used to describe distant metastasis to more than one distant site (ACS, 2019).
The extent of the cancer is then further described with a stage that ranges from stage 0 for cancer in situ-no spread beyond the primary site, to stage IVB, when there is more than one tumor identified at a distant site (American College of Surgeons, n.d.). For W.W., the stage group was T4 N3 M1c, and the stage was IVB given the large tumor, extensive, bilateral chest, spinal, distant lymph node metastasis, and two liver tumors.
Treatment
In the past, such extensive disease would have meant rapid progression toward death and referral to palliative care or hospice. Today, tumor-specific, potentially curative treatment options are available. For individuals diagnosed with adenocarcinoma NSCLC between 2000 and 2018, 25.9% will survive 5 years post diagnosis, and 69.2% of 5-year survivors are expected to live at least 5 additional years. For those 65 years and older diagnosed with distant metastasis, there is still reason to hope. Five-year survival is at 6.1%, and of those who survive to 5 years, 41.9% are likely to be alive 5 years later (National Cancer Institute, n.d.). Development of personalized, holistic, and multidisciplinary home health treatment plans can help cancer survivors transition from acute to chronic disease management with the highest possible quality of life.
Although W.W. was diagnosed at stage IVB and had advanced metastatic disease, he was relatively young, had few comorbidities, and an excellent support system. He also lived in an area with numerous highly qualified specialists, top of the line equipment and treatment options.
Precision Medicine and Personalization of W.W.'s Treatment Plan
Acute Symptom Management
W.W. presented to the emergency department with intractable pain, radiating from the midthoracic spine to the anterior chest on both sides. He described the pain as "being squeezed" and rated it at 10/10. The pain was so severe that he had difficulty breathing and treatment for an acute myocardial infarction was initiated. He was placed on oxygen, a cardiac monitor, and was given intravenous (IV) morphine, aspirin, and sublingual nitroglycerin. The clinical picture clarified when cardiac enzymes were negative, and the large mass was identified on the chest X-ray. Pain control became the primary focus with IV morphine every 2 hours. An MRI of the chest and spine was completed after the pain was controlled enough for him to tolerate the procedure.
Stereotactic Radiosurgery
Pain related to spinal metastasis is neuropathic, frequently intractable, and extremely difficult to treat. Central acting narcotics, like morphine and hydromorphone can cause oversedation with little impact on this type of pain. Stereotactic radiosurgery, a very precise form of radiation, can reduce tumor size in 1 to 3 fractions (treatments) with minimal damage to surrounding tissues (Li et al., 2021). W.W. received spinal stereotactic radiosurgery during the inpatient stay and the baseline pain was reduced from 10/10 to 4-6/10 after the third treatment. Pregabalin (Lyrica) was prescribed at 150 mg oral twice a day to treat the radiculopathy (Pfizer, 2020). Pain continued to spike to 10 with any movement.
The Home Health Plan of Care
W.W. and his family were overwhelmed and unable to process much of the information received in the hospital. The home care nurse, a certified oncology specialist, reviewed the basics. Then she explained: "We are going to work together to develop a holistic home care treatment plan to help you manage symptoms, prevent complications, and meet the goals that are important to you. I am going to make notes in the record as we talk. What has your doctor told you about your illness and treatment plan?"
As W.W. told his story, she made eye contact and paid close attention to his facial expressions and body language. A new diagnosis of advanced, life-limiting cancer is devastating for the patient and their significant others. Telling the story from first symptoms to diagnosis may help the patient begin to process the trauma. It also helps clinicians identify the patient's priorities. An extra 30 to 45 minutes may be needed during the start of care visit for the patient to tell their story, but it is a worthwhile investment. The nurse continued with a thorough physical and psychosocial assessment and then asked W.W. to describe his goal(s) for home care: "I want to get this pain under control and get my strength back."
Although W.W. stated the pain had improved drastically, it was still intractable. He became diaphoretic and cried out in pain several times with even slight movement. When she asked about his last morphine dose, W.W. tearfully described trying to wait until he could no longer tolerate the pain, because the morphine made him too sedated. His daughter and grandchildren were visiting from out of state and his time with them was precious. He also relayed concerns about addiction and his desire to return to work when his condition stabilized.
The nurse discussed the importance of effective pain control to prevent predictable consequences of limited mobility including cancer-related fatigue, weakness, debilitation, and higher risk for respiratory complications. With severe pain spikes, W.W. would not be able to effectively participate in therapy. In addition, she explained how difficult it was for family members to cope with seeing him in severe pain and that his (and their) quality of life would be better if the team found a combination of methods for effective pain management.
To help W.W. visualize how pain management could be improved, the nurse plotted a graph as he described his pain patterns (Figure 2). Pain from the spinal lesions had improved after the spinal stereotactic radiosurgery but was always present, with continuous background pain at 4/10 during the day and at 3/10 during the night after morphine. He woke up every hour or so during the night. He indicated that the pain "goes from zero to ten right away" with movement, and the worst pain occurred with the morning shower and when getting ready for bed. He also had pain related to arthritis in multiple locations.
Care Coordination
The home care nurse started the previously arranged video appointment with the medical oncologist and the oncology nurse navigator so concerns could be addressed immediately. An oncology nurse navigator helps with patient and family education about treatment options and survivorship plans, coordinates care through the acute to postacute continuum, assists with finding medical and community resources to address psychosocial and financial needs, and helps break down barriers to continuity of care (Reed & Rua, 2020). The following changes were made:
* Prednisone 40 mg daily was ordered for 10 days, to be titrated down to a daily dose of 10 mg to reduce inflammation from the fracture and spinal cord compression.
* Pregabalin was increased to 200 mg twice a day to reduce the neuropathic pain.
* A consult with a spinal surgeon/pain specialist was planned to discuss minimally invasive options to remove small bone fragments pressing on the cord and stabilize the vertebrae.
* Extended-release morphine (MS Contin) 15 mg twice a day was prescribed to provide more consistent analgesia with less likelihood of oversedation (Purdue Pharma, 2016).
* A preactivity dose of immediate-release morphine was recommended for 30 minutes before the morning shower, physical and occupational therapy sessions, and bedtime.
* Topical diclofenac sodium (Voltaren) was prescribed four times a day to reduce local inflammation and pain from the T-6 to T-7 site of injury (Novartis, 2016).
* A follow-up radiation oncology appointment was scheduled to discuss the possibility of additional spinal stereotactic radiosurgery treatments.
* A guided imagery meditation app was downloaded to W.W.'s phone to help with relaxation at bedtime.
Medications were reconciled and crucial education was provided. Although not contraindicated, morphine and pregabalin interact to increase the effect of both drugs, so the nurse stressed the importance of watching for adverse effects. Senna, a stimulant laxative and docusate sodium, a stool softener, was prescribed daily. Because severe constipation usually occurs with opioids, polyethylene glycol 3350 (Miralax), an osmotic laxative, was added as needed for constipation. The nurse explained that straining at stool could put pressure on the spine.
W.W. had an elevated blood pressure and heart rate attributed to inadequately controlled pain, so he was instructed to take vital signs four times a day and record pain levels, pharmacological, and nonpharmacologic interventions every 2 hours while awake. The record would be used to help W.W. and the nurse evaluate progress toward goals.
Activity: Physical and Occupational Therapy
Research has shown that physical activity and exercise programs are very helpful in reducing cancer-related fatigue, psychological effects such as anxiety and depression, and pain. Pulmonary and cardiac function, muscle mass, and strength are also better preserved with an exercise program (Avancini et al., 2020). Maintaining cardiopulmonary function is important to reduce the potential impact of adverse cardiac and respiratory effects that can occur with targeted and immunotherapy treatments.
The nurse called the physical and occupational therapists and discussed the current plan and scheduled a follow-up visit to reevaluate pain management in 2 days. When W.W. expressed concern about therapy causing additional pain, both therapists reassured him that pain management would be an important part of the plans.
At the evaluation visit, the occupational therapist recommended a shower bench, handheld shower head, and bedside commode, and introduced energy conservation techniques. The physical therapist initiated a basic maintenance exercise program designed to prevent complications such as foot drop and contractures, as well as bed mobility strategies to prevent shearing and pressure injuries. Both therapists planned to develop more aggressive programs when pain was better controlled.
Pharmacologic Treatment Options
Chemotherapy
Chemotherapy agents are cytotoxic chemical agents that are synthesized or extracted from a variety of sources used to kill the cancer. Chemotherapy agents such as Docetaxel (Taxotere) or Gemcitabine (Gemzar) may be used for NSCLC (National Comprehensive Cancer Network, 2021, October). W.W. and the medical oncologist discussed the option of starting a chemotherapy drug, but W.W. decided to wait for the genetic sequencing and immunohistochemistry tests, as the results were expected within 2 weeks.
Targeted Therapies and Precision Medicine
The pharmacological treatment plan is based on the patient's specific tumor characteristics. The testing identified the type of cell and "driver" genetic mutation(s) that are producing abnormal proteins that "feed" the tumor. Treatments that can inactivate the abnormal protein or attach to and block the receptors that the protein normally binds to can be highly effective (Jiang et al., 2018). Cancer growth may be halted or at least slowed. If the treatment is effective, tumors shrink as cancer cells die. These medications tend to be far more effective than the cytotoxic chemotherapy agents that indiscriminately affect most fast-growing cells.
Identification of Pathological Gene Variants
W.W. and his wife met with the oncologist to review test results and decide on treatment options (Figure 3). Testing identified:
* An EGFR EXON 19 deletion, a pathological gene mutation that produces an epidermal growth factor receptor protein that causes abnormal cell reproduction and survival.
* Excessive tumor cell production of vascular endothelial growth factor, a protein that normally promotes growth of new blood and lymph vessels in response to low tissue oxygen levels in arterial disease.
* Over 40% of tumor cells produced programmed death ligand 1 proteins (PD-L1 > 40%) that bind to the PD-1 receptor on T cells to reduce the risk of auto-immune disease but allow tumor cells to escape detection.
Evidence-based guidelines recommend initial treatment directed at the endothelial growth factor variant and use of the third-generation tyrosine kinase inhibitor Osimertinib (Tagrisso) versus first-generation treatments such as Erlotinib (Tarceva). Osimertinib 80 mg oral daily is recommended to continue for 3 years if follow-up scans are progression free (National Comprehensive Cancer Network, 2021, October). Approximately half of endothelial growth factor driven tumors develop resistance to first-generation tyrosine kinase inhibitors (Jiang et al., 2018).
With cancer, tumor growth tends to stall when the blood supply can no longer support the rapid cellular reproduction. When the endothelial growth factor protein is produced by cancer cells, the tumor grows new blood vessels to supply itself with oxygen and nutrients. There are currently two drugs that target endothelial growth factor, Bevacizumab (Avastin) IV every 3 weeks or Ramucirumab (Cyramza) IV every 2 weeks. The FDA has approved a combination of the first-generation endothelial growth factor targeted therapy, Erlotinib (Tarceva) plus Ramucirumab, but tumors tend to develop resistance to Erlotinib over time (Le et al., 2021), at this time Osimertinib is not approved for use with either endothelial growth factor blocker.
Immunotherapy is not currently approved as a first-line treatment for individuals with an endothelial growth factor mutation but is indicated if the disease progresses. Immunotherapy would provide another potentially curative option for W.W., given the overexpression of PD-L1, if the first-line targeted therapy did not work. His oncologist indicates they will use immunotherapy after the 3 years of Osimertinib is complete.
Monoclonal antibodies that block the PD-1 receptor, such as nivolumab (Opdivo) and pembrolizumab (Keytruda), bind with PD-1 receptors on the T cells so that the T cells can see, attack, and destroy the tumor. T cells that are converted to memory T cells after exposure to the cancer cells will continue to circulate and will recognize the cancer if it reoccurs (Bristol Myers Squibb, 2022a; Merck Sharp & Dohme, 2021).
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a glycoprotein produced by activated T cells. Proliferation of new T cells is decreased when CTLA-4 binds to the CD80/CD86 receptors on the outside of the T cells. This mechanism prevents an overactive, autoimmune response. Ipilimumab (Yervoy), a monoclonal that blocks the CD80/CD86 receptors allows the T cells to readily reproduce and launch a powerful attack on the cancerous cells. Nivolumab and Ipilimumab are often used together (Bristol Myers Squibb, 2022b).
Care Coordination and Follow-up After Oncology Appointments
The nurse assessed for and instructed W.W. and his wife on signs and symptoms of potential adverse effects of Osimertinib, including pneumonitis, cardiomyopathy, and skin reactions (risk of erythema multiforme major or Stevens-Johnson syndrome), visual changes due to keratitis, stomatitis, and infection (American Lung Association, 2021; Astra Zeneca, 2020). The nurse explained the importance of early intervention and instructed on signs and symptoms to report. She asked that W.W. download physician visit and procedure reports from his electronic medical record to improve care coordination and to keep for his own records.
As W.W.'s case manager, the nurse conferences regularly with the therapists and sends a copy of relevant documentation to the oncology nurse navigator and oncologist through the electronic medical record. She also calls when there are changes, as was the case when W.W. developed mouth lesions and symptoms of a respiratory infection.
A Patient-Driven Survivorship Plan
As W.W. and the nurse prepared for discharge, they updated the survivorship plan that was initiated by the oncology nurse navigator (Figure 4). She emphasized how important it was for W.W. to have scans and lab tests as scheduled. She stressed early intervention which is critical if his condition changes. W.W. entered follow-up oncology and primary care visits, scans, and due dates for routine screenings for other types of cancer on his calendar. He was able to teach back on the importance of early intervention if there were changes in pain, shortness of breath, chest pain, fast or irregular heart rate, leg edema/fluid retention, vision, changes in skin texture or red/purple blotches, cognitive status, fatigue, activity tolerance, or adverse effects of the medications.
During the 120 days that W.W. received home healthcare, he responded to the treatment and the chest and liver tumors decreased in size. After a vertebroplasty and additional stereotactic radiosurgery fractions, pain was minimal, and the morphine was gradually reduced to avoid withdrawal symptoms. He made great progress with physical and occupational therapy. He was independent with the home exercise program and ready to return to work. Another 60-day recertification period was not appropriate because he was no longer confined to his home, and did not require the specialized skills of the nurse or therapists.
Five Years Later
"Do you remember me?" the man asked. "You helped me get my life back." As they stood in the aisle at the grocery store, W.W. explained that after he had completed 3 years of the targeted therapy treatments, he had an additional 2 years of immunotherapy. "I am totally in remission, my oncologist said there is absolutely no evidence of active disease! I felt hopeless when I received the diagnosis, but you and your team taught me how to live despite the cancer. I am alive today because you gave me hope for a future. Thank you!"
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REFERENCES