Glenn Schulman, PharmD, MS, BCPS, BCGP, BCACP, BCIDP

IN 2019, ABOUT 145,600 new cases of colorectal cancer (CRC) were diagnosed in the United States.

CRC is the fourth-most-common malignancy in the United States, with an estimated 64.4% 5-year survival rate.

 The past 20 years have seen an overall decline in CRC-related deaths,1 and for patients with early detection or localized CRC, the survival rate is almost 90%. However, this percentage drastically plummets to 14% in patients with metastatic disease (Figure 1).

CRC rates are about 30% higher in men, with higher mortality and incidence rates in African Americans and the lowest mortality incidence in Asian-Pacific Islanders, according to the National Cancer Institute.

The highest percentage of deaths is among patients between ages 75 and 84. CRC occurs when polyps or tumors form in the lining of the large intestine, which can occur gradually over 10 to 15 years.

Earlier screening is associated with a substantial decrease in CRC morbidity and mortality, thus controlling the costs of CRC treatments.

 This is the result of a significant increase in the number of individuals who undergo screenings. Data from 2000 to 2015 were associated with an increase in the number of screenings from 38.9% to 82.7%, respectively. This increase was associated with a 25.5% reduction in annual CRC incidences and a 52.4% reduction in cancer mortality rates (Figure 2). Most screening strategies have led to cost savings relative to increasing costs associated with chemotherapy for advanced CRC.

 Online Table 1 shows the reasons for screening for patients below age 50 who are at an increased risk of developing CRC.

The 2 types of diagnostic screenings for CRC are stool testing and visual testing. The stool exams comprise the fecal immunochemical test, the guaiac-based fecal blood test, and the stool DNA, which, like the preceding 2 tests, screens for blood but also has the ability to detect DNA shed from tumors.

 Colonoscopy is the gold standard diagnostic screening for CRC. Colonoscopy allows for the direct visual examination of the entire colon and rectum, as well as the ability to excise polyps and suspicious lesions for biopsy.

 A new, noninvasive alternative is also available. The patient ingests a capsule containing on either end 2 miniature cameras, which capture images to allow direct visualization of the colon.

 Screenings are typically recommended for individuals at age 50 and repeated every 10 years. A cross-sectional analysis of CRC screenings across the United States has indicated a higher incidence in invasive procedures in patients aged 50 to 54 years compared with those aged 45 to 49 years. The evidence from this analysis suggests an overall underestimation of CRC and that early screening at age 45 may provide a cost-effective benefit for some individuals who later present with more extensive CRC when screened at age 50.

Treatment of CRC is based on the progression of cancer, with curative intent in early stages of diagnosis.

 Figure 3 provides a general algorithm for recommended treatment.

 Patients with localized CRC undergo surgery to remove the cancerous polyps or a partial colectomy to remove the cancer of the large intestine completely. CRC of stage II and beyond may require adjuvant chemotherapy because of the higher chance of recurrence or the extensiveness of metastasis. Common chemotherapy regimens include a combination of different agents, such as capecitabine with oxaliplatin, as well as fluorouracil, leucovorin, and oxaliplatin. Radiation therapy is considered for stage III and beyond to help relieve pain or for patients for whom surgery may not be an option.

For patients with recurrence despite chemotherapy, immunotherapy may be an option if their cancer cell tests are positive for genetic changes. Options include a class of medications referred to PD-1 inhibitors, such as nivolumab and pembrolizumab, as well as CTLA-4 inhibitors, such as ipilimumab. Clinical trials and treatments using targeted therapy are still emerging (Table 2).

Results from a 2019 research article showed promise of a clinical trial involving a vaccine targeting guanylyl cyclase C, a receptor that has been linked to CRC recurrence. Current testing in phase 1 demonstrated no major adverse events from the vaccine in 10 patients with stage I and II CRC diagnoses. Animal testing in mice has shown promise, but further phase 2 and 3 trials are needed to validate CRC remission.

 Also, clinical trials and emerging therapies are beginning to focus on the use of next-generation sequencing to create effective individualized treatments of immunotherapy with or without chemotherapy.

Early diagnosis of CRC has shown optimal prognosis for survival, yet many barriers to screening still exist. Clinicians should provide risk stratifications in patients to determine who would benefit from early screenings before age 50. Although data indicate that early screening may be the key to reduce mortality rates of CRC, new treatments with biological agents and vaccines are creating a pathway to treat patients with metastatic CRC.

Glenn Schulman, PharmD, MS, BCPS, BCACP, BCGP, BCIDP

, are clinical pharmacists in Pensacola, Florida.

 are PharmD candidates at the University of South Florida’s Taneja College of Pharmacy in Tampa. 

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Articles

New treatments with biological agents and vaccines are creating a pathway for patients with metastatic CRC.

Early Screening Is Key in Colorectal Cancer

An estimated 96,000 cases of melanoma were diagnosed in 2019, and 7230 deaths were attributed to this type of cancer, based on statistics from the National Cancer Institute.

The 5-year overall survival rate for melanoma is high, because 83.6% of cases are diagnosed early, at the local stage (Figure 1).

 However, this percentage drastically decreases once the cancer has metastasized (Figure 2).

Melanoma arises when melanocytes, the cells responsible for producing melanin that provides pigmentation of the skin, become cancerous and create a malignant tumor.

Advanced melanoma is classified as melanoma that has escalated beyond the point of the primary tumor in the body, according to the Skin Cancer Foundation.

This classification encompasses stage III and IV cancers, which are diagnosed by physicians based on the tumor, node, and metastasis system.

 Typically, these advanced stages of melanoma involve the tumor spreading regionally to the lymph nodes (stage III) or metastasizing to other organs (stage IV) and can be further classified within each stage based on the characteristics of the tumor(s).

There are 5 standard treatment options for melanoma: chemotherapy, immunotherapy, radiation therapy, surgery, and targeted therapy.

 Most patients will receive a combination of these treatment modalities. 

As melanoma advances in stage, the treatment approaches will usually involve systemic therapy to target cells in various locations of the body.

Targeted therapy involves BRAF and MEK inhibitors, which are personalized treatment options designed to aim for a specific defective gene in the body contributing to melanoma. BRAF is a gene that when functioning normally, regulates cell multiplication.

 Mutations affecting this gene can lead to continuous cell growth. BRAF mutations are found in about 50% of advanced melanoma cases and should be tested for in all patients with a confirmed diagnosis of advanced melanoma.

 BRAF and MEK inhibitors work by interrupting abnormal cell growth. When used alone, BRAF inhibitors are initially very effective in blocking the overproduction of cells, but then the tumor(s) typically develops resistance to the treatment. To combat this issue, an MEK inhibitor should also be administered in combination with a BRAF inhibitor to prevent the disease from advancing.

for personalized cancer treatment to be effective, the patient’s melanoma must carry the BRAF mutation targeted by these medications (Table 1).

Used in combination, BRAF and MEK inhibitors are first-line therapy when the BRAF mutation is present, according to the National Comprehensive Cancer Network guidelines for

Systemic immunotherapy is also considered first-line therapy in the treatment of patients with advanced melanoma

 because of its significant progress in treatment outcomes

 and is a continuously evolving therapeutic option at the center of ongoing research. Immunotherapy, also referred to as biological therapy, harnesses the body’s natural defenses within the immune system to fight the cancer via the use of synthetic substances acting as either proteins of the immune system or signaling molecules.

There are 4 main classifications of immunotherapy, each with diverse mechanisms of action employed to fight cancer cells (Table 2).

Over the past decade, the use of a single or combination of checkpoint inhibitors, a specific class of immunotherapy, has been at the core of numerous clinical research trials. The 2 categories of checkpoint inhibitor therapies are listed below with their specific mechanisms.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors block the CTLA-4 proteins from protecting cancer cells being destroyed by T cells.

Programmed cell death protein 1 (PD-1) inhibitors attach to another protein, programmed death-ligand 1, to prevent PD-1 from binding and stopping T cells from killing cancer cells.

Ipilimumab is a CTLA-4 inhibitor and also inhibits nivolumab and pembrolizumab PD-1.

 All of these medications are monoclonal antibodies, created by fusing human antibody-producing cells with an immortalized cell line and designed to bind to antigens in order to exert a desired effect within the immune system.

In a randomized, controlled trial published in 2010, ipilimumab was compared alone and with glycoprotein 100 (gp100) versus gp100 alone.

 Gp100 is a well-studied cancer vaccine designed to decrease tumor growth.

 The results of this study indicated that ipilimumab, with or without gp100, led to longer overall survival in patients with metastatic melanoma compared with gp100 alone.

 The KEYNOTE-006 trial, published in 2015, then compared ipilimumab with pembrolizumab in patients with advanced melanoma. Pembrolizumab improved both progression-free survival as well as overall survival more significantly than ipilimumab and caused fewer high-grade adverse events related to toxicity.

 Later in 2015, the Check-Mate 067 trial compared nivolumab with ipilimumab alone and combined in patients with unresectable stage III or IV melanoma. The median progression-free survival for ipilimumab in combination with nivolumab was 11.5 months compared with 2.9 months with only ipilimumab only and 6.9 months for nivolumab alone.

CheckMate 067 therefore sparked interest for further research regarding combination therapy compared with monotherapy. In October 2019, the CheckMate 067 trial provided additional follow-up to the study involving ipilimumab and nivolumab. This update followed patients for a minimum of 5 years, elaborating on the 12-month follow-up from 2015. Overall 5-year survival outcomes were clearly superior in the nivolumab-containing treatment groups compared with ipilimumab alone (Figure 3).

Quality of life (QOL) was measured, and the authors concluded no deterioration in health-related QOL in both groups receiving nivolumab but did note clinically meaningful decreases in QOL for the ipilimumab group.

Survival rates for patients with advanced melanoma were quite dismal in the past. New advances in research and the use of immunotherapy have led to major breakthroughs

regarding biologics such as ipilimumab and nivolumab. Identification of the BRAF mutation is the first step in choosing appropriate therapy, and if present, targeted therapy should be used.

 Because of the significantly greater outcomes with combined immunotherapy, 

 this treatment approach should be used in patients with stage III or IV melanoma without the BRAF mutation, to optimize treatment outcomes. 

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Advances in research and immunotherapy have led to breakthroughs regarding biologics targeting melanoma.