Although about 50% of patients can be cured after surgical resection when colorectal cancer (CRC) is detected early, the remaining patients aren’t as fortunate. CRC that metastasizes before detection or recurs following surgery remains a major treatment challenge for patients and providers.

However, several promising new targeted therapies known as antiangiogenic agents have been introduced recently that are prolonging survival for patients with advanced disease. In his article in the October 2015 issue of the Clinical Journal of Oncology Nursing, Keith McIntyre explored those new agents and the nursing considerations for patients who are receiving them.

Antiangiogenic Agents for Metastatic CRC

Antiangiogenic agents work by blocking the growth of blood vessels to tumors, McIntyre explained. Three antiangiogenic targeted agents currently exist for metastatic CRC: bevacizumab, which was approved in 2004, and ziv-afibercept and regorafenib, which were both approved in 2012. McIntyre stressed that creating a nursing plan to assess for adverse events (AEs) is essential to minimizing the occurrence and severity of side effects for patients receiving any of the antiangiogenic agents. By preventing toxicities or intervening early when they occur, patients are better able to complete treatment as intended.

Regorafenib: In clinical trials, as many as 93% of patients experienced treatment-related AEs. Those grade 3 or higher were hand-foot skin reactions, fatigue, diarrhea, hypertension, and rash or desquamation. Common all-grade AEs also included mucositis, hemorrhage, infection, weight loss, increased alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, thrombocytopenia, and lymphopenia. More than three-quarters (76%) of patients required dose modifications.

Patients receiving regorafenib should be instructed on proper adherence to the treatment regimen, as well as to call immediately if they experience any AEs. They should also be informed about the possibility of dose reductions or delays. Finally, regorafenib should be taken with a low-fat breakfast, and patients should not consume grapefruit products while taking the agent.

Ziv-aflibercept: In clinical trials, 83% of patients receiving ziv-aflibercept experienced grade 3 or 4 AEs, including bleeding, hypertension, arterial and venous thrombotic events, diarrhea, asthenic conditions, stomatitis and ulceration infections, and palmar-plantar erythrodysesthesia. Other common side effects were proteinuria, fatigue, headache, abdominal pain, weight loss, hand-foot syndrome, increased ALT or AST levels, thrombocytopenia, leukopenia, and neutropenia. Nurses also need to be aware that treatment with ziv-aflibercept cannot be started for at least 28 days after surgery and must be paused for at least 28 days before any planned surgery.

Management of AEs From Antiangiogenic Agents

Nurses should carefully monitor patients receiving any of the antiangiogenic agents for metastatic CRC, including ensuring that all appropriate lab tests are being ordered, such as urine dipstick, urinary protein creatinine ratio, complete blood count with differential, and serum AST and ALT. Additionally, nurses should watch for signs and symptoms of hypertension, bleeding, and thromboembolic events. 

Hand-foot skin reaction: McIntyre emphasized that hand-foot skin reactions and hand-foot syndrome are two different side effects. “Hand-foot skin reactions are characterized by scaling surrounded by erythema and are found on the pressure-bearing areas of the hands and feet. . . . Patients present with pain, dysesthesia, and palmar and plantar hyperkeratotic plaques with an acral distribution, affecting distal portions of limbs. . . . Hand-foot skin reactions are characterized by more callous formation, blistering, sloughing, and tender reaction” (p. 573). See Figure 1 for an overview of the differences between the two AEs.

Figure 1. Comparison of Hand-Foot Skin Reaction and Hand-Foot Syndrome

Hand-Foot Skin Reaction

  • Located on the ventral digit tips, over the interphalangeal joints, thenar and hypothenar in hands
  • Characterized by acral pain and dysesthesia
  • Located on the ventral surfaces of the feet, heels and forefoot

Hand-Foot Syndrome

  • Located on the palms of the hands and soles of the feet
  • Characterized by a diffuse redness, tenderness, dryness, and cracking
  • Hyperpigmentation in patients with dark complexions

McIntyre noted that patients receiving regorafenib may be at higher risk for hand-foot skin reaction than those receiving other drugs in the same class. Actively preventing the AE is more effective than treating it once it occurs; using a preemptive skin treatment regimen reduced the incidence of skin toxicities by more than 50%.

Hypertension: As many as 28% of patients with metastatic CRC receiving regorafenib develop hypertension, McIntyre reported. The National Cancer Institute convened an expert panel to study cardiovascular issues associated with certain cancer therapies; the panel developed the following recommendations.

  • A formal risk assessment for potential cardiovascular complications should be conducted on all patients who are being considered for these therapies.
  • Preexisting hypertension should be identified and addressed before therapy is started.
  • Blood pressure should be actively assessed throughout treatment, with more frequent assessments during the first treatment cycle.
  • The blood pressure goal for most patients should be lower than 140/90 mmHg, or less than that for patients with preexisting cardiovascular risk factors.

Kidney and liver toxicity: Older adults and those with preexisting renal problems may be at increased risk for renal toxicities. Patients scheduled for antiangiogenic drugs should be monitored for proteinuria as well as liver function tests.

Hemorrhage and wound healing: McIntyre noted that angiogenesis is a necessary part of wound healing, so antiangiogenic agents will naturally slow healing. Patients receiving ziv-aflibercept are at particular risk and should be educated about and monitored for bleeding and any hypertension should be tightly controlled.

Fatigue: Fatigue is a common side effect from regorafenib and ziv-aflibercept, and patients should be monitored for the development or worsening of fatigue during treatment. Nurses should determine whether the symptom can be attributed to treatment, disease recurrence or progression, or other concomitant medications or supplements. Other comorbid conditions, such as anemia, hypothyroidism, cardiomyopathy, chemical imbalances, depression, sleep problems, and dehydration, may also be a factor. Nurses should advise patients to conserve energy, schedule necessary activities for periods of peak energy, and to stay active to improve sleep.

For more information on these and other side effects from antiangiogenic agents for metastatic CRC, refer to the full article by McIntyre.