Amanda Boyer, PharmD Candidate

With the United States in the midst of an opioid abuse crisis, cancer pain remains challenging for patients and their prescribers treating the burden of this disease. Clinicians have many legal restrictions when prescribing opioids, and some patients with cancer are hesitant to use this class of drugs because of the stigma of potential addiction.

Cancer pain is just 1 of the many disease-related issues arising in these patients. An estimated 14 million patients with cancer reside in the United States, and about 40% of those are afflicted with associated pain.

 The treatment paradigm is slowly shifting toward a multimodal approach (ie, anticonvulsants, antidepressants, and nonsteroidal anti-inflammatory drugs [NSAIDs]), but opioids remain the agent of choice for cancer pain treatment.

In the general population, when patients experience pain, it is usually the result of biological processes or injury. However, cancer pain is unique to those who are affected by either its manifestations or treatments. As a tumor enlarges, it can damage or exert pressure on nerve endings within the surrounding affected area. Additionally, certain types of cancer cells and tumors can release damaging or irritating chemicals that result in pain, such as bradykinin, endothelin-1, nerve growth factor, and tumornecrosis factor alpha.

 If cancers or tumors are not solely responsible for inducing pain, many patients experience discomfort related to their cancer treatment (eg, chemotherapy, radiation, and surgery). Patients have reported different types of pain, including mixed, neuropathic, or nociceptive, over the progression of their disease (figure 1).

 Nociceptive pain is pain caused by stimuli or tissue damage that has the potential to cause additional damage, whereas neuropathic pain is characterized by damage or dysfunction of the nervous system.

Pain treatment should be individualized based on causes, characteristics, clinical condition, and patient goals, according to the European Society for Medical Oncology guidelines (figure 2).

 Patients’ pain intensity, signs, and symptoms should dictate treatment decisions.

 Pain may present as somatic pain, which can be related to disease manifestations, such as metastatic bone cancer and skeletal muscle inflammation. Standards for the treatment of somatic pain include acetaminophen, NSAIDs, and skeletal muscle relaxants. Visceral pain is associated with internal organs and can be related to organ compression or tumor infiltration. Neuropathic pain can arise from nerve damage, because of cancer treatment-related complications and tumor infiltration. Based on the suspected pathophysiology and pharmacotherapy, anticonvulsants (gabapentin and pregabalin), antidepressants (duloxetine and tricyclic antidepressants), and NSAIDs, can be used to target and ease disease-related suffering.

Prolonged opioid use causes increased risk and incidence of opioid-induced constipation (OIC) and opioid-induced neurotoxicity (OIN). OIC has been shown to significantly reduce quality of life and has proved challenging to treat.

 Symptoms of OIN include hallucinations, hyperalgesia, and myoclonus, which can be severe but managed via opioid rotation and rehydration as deemed appropriate.

 Concomitant medications during cancer treatment, including possible cytochrome P450 enzyme inhibitors, may complicate treatment by further inducing opioid toxicity or decreasing analgesic effects through drug-drug interactions.

 Some patients at risk of developing opioid use disorders may be asked to participate in regular pain management consults and can be paired with multidisciplinary teams. These teams are formed according to the patient’s specific needs and can aid in psychological and social aspects of OUD to prevent further opioid dependence through education.

Opioids continue to be first-line therapy for moderate to severe pain in patients with cancer, despite their undesirable adverse effects.6 Neuropathic-targeted treatments continue to be at the forefront of cancer pain management and are the focus of new and improved drug regimens. Receptors, such as melatonin receptors type 1 and 2, and newer agents, such as the cannabinoids, may be prospective advances in the treatment of neuropathic pain. Medications such as cannabidiol, melatonin, quetiapine, have had their treatment roles expanded.

Unrelenting cancer pain can be devastating. With the United States in the grips of an opioid crisis, substance abuse must not cloud the needs of patients with cancer who are genuinely seeking relief from pain and suffering. It has been shown that these patients are far less likely to exploit and overdose from opioids than those in the general population.

 The patient and prescriber are often intertwined in challenging clinical and personal battles to manage their pain. Clinicians must optimize pharmacotherapy to improve patients’ quality of life. 

Jerry A. Barbee Jr, PharmD, BCPS, CPh, and Glenn Schulman, PharmD, MS, BCPS, BCACP, BCGP, BCIDP, are clinical pharmacists in Pensacola, Florida. Matthew Bailey and Amanda Boyer are PharmD candidates at Auburn University in Alabama. Meagan Balding is a PharmD candidate at the University of Florida in Gainesville.

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Articles

Some patients are hesitant to use this class of drugs because of the stigma of potential addiction. 

Cancer Pain Treatment Remains a Challenge

The number of individuals diagnosed with cancer steadily increases each year. Data from the National Cancer Institute suggest that 23.6 million new cases will be diagnosed by 2030.

Renal carcinomas account for about 3.5% of cancer diagnoses in the United States (see 

). In 2018, an estimated 65,000 newly diagnosed cases of kidney cancer will result in the death of about 23% of those patients.

 The kidneys are a vital aspect of human homeostasis, producing hormones that stimulate erythropoiesis, filtering the blood’s extraneous materials, maintaining critical electrolyte balances, and regulating blood pressure.

 When abnormal pathologies, such as kidney cancer arise, integrity and organ function are compromised, resulting in detrimental outcomes. Although renal carcinomas can be treated, the level of intervention depends on the complexity of the cellular subtype. Clear cell carcinoma is a histological subtype of kidney cancer considered to encompass 70% of all renal neoplasms.

 However, clear cell carcinoma cases are unresponsive to usual chemotherapeutic regimens, making them increasingly difficult to treat with traditional chemotherapeutics, such as capecitabine, 5-fluorouracil, and gemcitabine.

 Therefore, the need to produce therapies and develop innovative approaches to treating renal neoplasms is critical.

Renal cell carcinomas (RCCs) of all subtypes and variations are dispersed nationwide. The incidence and number of kidney cancer cases is not geographically specific. African Americans, Alaska Natives, and Native Americans are at an increased risk for developing kidney and renal pelvis cancers. Gender-based analysis has produced data indicating that men are twice as likely to develop renal cancers than women.

 The development of renal cancers largely correlates to those with both at-risk ethnic backgrounds and predisposing risk factors to carcinogenesis.

Individuals are predisposed to an increased risk of developing RCCs depending on the number of environmental, hereditary, and personal health-related comorbidities (see 

 Prognosis is related to increased age, overall health, and the stage of disease. Early detection typically increases survival rates. Occupational exposure to chemicals such as asbestos, benzene, cadmium, and trichloroethylene has been associated with an increase in the incidence of RCCs. Individuals who are employed in the agricultural industry, commercial painting, dry cleaning, jewelry production, and welding are frequently exposed to the chemical compounds implicated in renal neoplasms.

 Smoking cigarettes has been found to increase the risk of developing kidney cancer by 50%.

Patients with a history of hypertension may have as much as a two-thirds increased risk of developing renal carcinomas.

 Modifying risk factors, such as blood pressure maintenance, healthy diet adherence, smoking cessation, and weight loss may reduce a patient’s overall lifetime risk.

 However, there are genetic conditions that cannot be modified by patient intervention. Familial diseases, which include Birt-Hogg-Dubé syndrome, tuberous sclerosis complex, and von Hippel-Lindau syndrome, can predispose a patient to developing severe forms of nephrological neoplasms.

Generally, RCC is not detected based on specific signs or symptoms. Most patients tend to be asymptomatic in the early stages.

 This cancer is generally detected when patients present with unrelated complaints or during routine imaging exams. Patients may present with symptoms such as fatigue, fever of unknown origin, flank pain, hematuria, and weight loss (see 

 More subtle signs indicative of disease progression include adenopathy, bone pain, coughing, and shortness of breath.

 Unfortunately, data concerning the frequency of the signs and symptoms are scarce and not well defined. Many of the observable manifestations of disease are specific to each patient.

Most RCCs originate in the epithelial cells of the proximal convoluted tubule.

 The site of origination depends on whether the carcinoma is from hereditary or sporadic causes. Hereditary renal cell tumors are usually associated with bilateral RCCs, whereas nonfamilial causes are usually unilateral. As the tumor progresses, malignant cells have the potential to penetrate through the renal vein and migrate through the vena cava to susceptible tissues. Common sites of metastasis include the adrenal glands, bones, brain, liver, lungs, and lymph nodes (see 

 The lungs and bronchial tissues are the most susceptible to malignant renal cells when establishing a secondary site.

Staging is based on the size of the primary tumor, growth into nearby areas, spread to lymph nodes, and metastasis

to distant organs. Surgical excision is considered the first-line treatment option for RCC in all stages, unless the cancer is surgically unresectable.

 Primary tumor subtype 1a (pT1a) is defined as a stage 1 tumor that is less than or equal to 4 cm and has not metastasized. Tumors between 4 and 7 cm are classified as a primary tumor subtype 1b (pT1b). For pT1a or pT1b tumors, treatment methods rely on either removal of the tumor or ablation therapy in patients who do not qualify for surgery.

 However, as RCC progresses and the cancer metastasizes, a patient’s prognosis becomes increasingly poor and the necessity for chemotherapeutic agents becomes a crucial piece of the treatment algorithm. Because of the highly resistant nature of RCC toward traditional antineoplastic drugs, biologics become first-line agents in advanced-stage and metastatic kidney cancer.

 Clinicians reserve the option to use certain biologics according to patient-based criteria in conjunction with supportive care. Worsened prognoses in the later stages could be attributed to high plasma levels of calcium, lactate dehydrogenase, and anemia.

) outlines renal carcinoma treatment based on staging and ideal procedures to increase survival rates and reduce complications.

Traditional approaches to cancer treatment include a combination of surgery and radiation or monotherapy with biologics based on the stage of disease progression (see 

 When treating kidney cancers and most of its subtypes, the typical treatment begins with either a partial or radical nephrectomy. Radiation therapy is neither desired or used because of its low efficacy and potential to damage healthy renal tissue.

 Most patients can function with a unilateral kidney.

Tyrosine kinase inhibitors / VEGF inhibitors

mTOR indicates mammalian target of rapamycin; VEGF, vascular endothelial growth factor.

The number of individuals diagnosed with cancer steadily increases each year.

Renal Carcinoma: Causes, Symptoms, and Treatments

Cancer is the second-leading cause of death in the United States.

In 2015, cancer shortened the lives of 595,930 people, comprising 22% of all deaths in the United States, according to the CDC.

This number continues to rise, and it is estimated that by the end of 2017, cancer will have taken more than 600,000 lives this year.

 According to the Agency for Healthcare Research and Quality, in 2014 an estimated $87.8 billion was spent in the United States to provide health care services related to cancer.

 Screenings are available to assist patients in the war against cancer, but that is where the conundrum begins. Early detection on occasion leads to early and unnecessary treatments. The medical profession needs to be astute as these test results are interpreted. Early cancer testing is available for multiple types of malignancies.

Screenings for early detection have favorably altered the survival rates from different types of cancer by up to 35%, according to the National Institutes of Health.

Cancer screenings not only increase survival rates but also potentially reduce costs for both the health care system and patients.

A cancer screening test is used to detect a specific type of tissue malignancy.

Each screening is catered toward detecting a different type of cancer, eg, breast, cervical, colorectal, lung, ovarian, prostate, or skin. Common methods of screening for cancer include blood work, diagnostic imaging, genetic testing, and physical examination.

 The rationale behind a cancer screening is that by discovering malignant tissue or changes in tissue early in the disease state, the patient’s rate of survival may be increased by treating cancer in the earlier stages, when it is most responsive to therapy. However, the tests may generate false negatives or false positives, which can result in missed opportunities or trigger unnecessary treatments that may not be in the patient’s best interest.

The primary goal is identification of high-risk populations and early cancer screening of candidates to reduce mortality. Appropriate early screening may not only alter mortality but also offer a chance for a lengthened and improved quality of life for the patient. Breast cancer, for example, is one of the leading causes of death among women with a malignancy. Statistics produced by the National Cancer Institute have shown that those women who underwent a regular mammogram reduced the risk of death by 15% to 20%.

 Generally, overall screening compliance is low, meaning that the number of individuals who should be tested for certain cancers is not optimal. For example, in 2014 the CDC indicated that just 65.7% of patients over 50 were up-to-date with their colon cancer screenings, while an astonishing 27.3% had never been screened.

 Investigators at the University of Michigan in Ann Arbor found that every patient within the appropriate criteria standards who underwent regular colon cancer screenings could prevent 90% of colon cancer diagnoses.

 According to the CDC, 9 of 10 patients who found colon cancer through regular screening procedures were still alive 5 years post diagnosis.

Additionally, individuals participating in cancer prevention programs, such as lifestyle alterations and smoking cessation, can contribute to lower out-of-pocket costs and a reduction in overall health care expenses. In some cancers, early intervention prior to metastasis can improve treatment options and outcomes.

Investigators at Johns Hopkins University in Baltimore, Maryland, conducted a new method of cancer detection known as targeted error correction sequencing. It is used to detect even the lowest levels of circulating tumor DNA, which is commonly found in those with early-stage cancers. In the study, 200 samples were taken from individuals with breast, colorectal, lung, and ovarian cancer, which identified 62% of stage I and II cancers. In addition, no false positives were found in 44 healthy individuals who were tested.

 This has been a drawback of other methods of cancer screenings. Various biomarkers have been identified for a host of cancers, including breast, colorectal, lung, ovarian, and prostate. In 2016, 15,000 patients with 50 different types of cancer underwent liquid biopsy testing, yielding detectable changes in 6 different types of biomarkers, such as the epidermal growth factor receptor

and proto-oncogene B-Raf, which has been linked to an increased incidence of melanoma,

with 94% to 100% specificity of similar tissue biopsies.

This could allow for potential targeted therapies geared toward gene-specific cancers to be personalized and treatment opportunities for those not previously eligible. Liquid biopsies (

) could help reduce the risk of cancer recurrence by detecting circulating DNA after colon cancer surgery. In 2016, a study found that measuring tumor DNA from the blood of patients with stage II colon cancer could predict patients with a high risk of recurrence by detecting any remnants of residual circulating DNA from the tumor. Those who had circulating tumor DNA after surgery were more likely to suffer recurrence, while those who were screened postoperatively with liquid biopsies were 90% less likely to develop recurrence.

The liquid biopsy may help identify those who could benefit from postoperative chemotherapy.

What Is the Role of the Health Care Provider?

Health care providers can play a vital role in the prevention of cancer. Screening tests are sometimes invasive and often will have a cost associated with the diagnostic testing. The health care provider can identify a high-risk population and offer assistance to modify risk factors. According to the American Cancer Society, 45% of cancer deaths could have been prevented. The top contributors were cigarette smoking, obesity, alcohol, ultraviolet radiation, and lack of physical activity.

 As health care providers, we must continue to improve cancer detection protocols and testing. Effectively identifying and educating patients will improve their outcomes. Health care providers must discern what screening needs to be completed and what results need to be treated.

Jerry Barbee Jr, PharmD, BCPS, CPh, and Glenn Schulman, PharmD, MS, BCPS, BCACP, BCGP, are clinical pharmacists at HCA West Florida Hospital in Pensacola, Florida. Matthew Bailey and Amanda Boyer are PharmD candidates at Auburn University in Alabama.

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