Chemobiotherapy
There have been significant advances in the survival of patients with unresectable mCRC. Kopetz et al[37] reviewed the survival of 2,470 patients with mCRC treated at the Mayo Clinic and The University of Texas M.D. Anderson Cancer Center. They found that the median overall survival time of patients treated from 1990 to 1997 was 14.2 months, compared with a median overall survival time of 29.3 months for patients treated during 2004–2006, when hepatic resection was performed in 20% of the patients and new chemotherapy and biotherapy agents were available, such as oxaliplatin(Drug information on oxaliplatin), bevacizumab(Drug information on bevacizumab), and cetuximab(Drug information on cetuximab). The authors also found that the 5-year overall survival rate increased from 9.1% to 19.2% during the period 2001–2003.
Palliative therapy is the mainstay of treatment, and, as previously discussed, since the mid 1990s, with effective additions to the treatment armamentarium, median survival time following a diagnosis of mCRC has increased from 5 months to 2 years.[4] Treatment is aimed at prolonging life that is of high quality with manageable toxicity. Grothey et al[38] showed that patients who were able to receive all active drugs available at the time of study (irinotecan, 5-FU, oxaliplatin), had the longest overall survival time. Thus, the goal is to help patients tolerate therapy without unacceptable toxicities, and to move from first-line, to second-line, to third-line regimens when the tumor develops resistance and progresses.
Individualized patient treatment plans should start with the regimen most likely to benefit the patient, given his or her individual comorbidities. The patient should continue to be given that regimen until disease progression occurs, with dose reductions as needed to address toxicity, as long as the treatment response continues. Active drugs used alone or in combination, and available today, are 5-FU/leucovorin, capecitabine(Drug information on capecitabine), irinotecan(Drug information on irinotecan), oxaliplatin, bevacizumab, cetuximab, and panitumumab (Vectibix). The leucovorin shortage has led to increased use of levoleucovorin, use of lower doses of leucovorin, or to forgoing treatment with leucovorin.
NCCN Recommendations for Chemobiotherapy in Patients With Advanced or Metastatic Colorectal Cancer
Only about 15% of patients will respond to the epidermal growth factor receptor (EGFR) antagonists cetuximab and panitumumab, biological agents that block EGFR on the outside of the tumor cell, thereby blocking messages for cell proliferation, invasion, survival, and the release of vascular endothelial growth factor (VEGF). Studies have shown that these patient responders have the wildtype (normal) KRAS gene. Therefore, the NCCN recommends that these drugs should only be used in patients who test positive for wildtype KRAS.[16] Some physicians will also test patients who have wildtype KRAS for mutations in the BRAF gene; the BRAF molecule is downstream of KRAS in a signaling pathway involved in cell cycling. Testing is performed because, if KRAS is functional (wildtype) but BRAF is mutated, then the EGFR antagonist will be ineffective. This testing may soon become the standard. BRAF testing is not necessary in patients with KRAS mutations. Unfortunately, patients with BRAF mutations have a worse outcome, as shown in the large phase III CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial.[39] See Table 1 for sequences of therapy recommended by the NCCN.
Because treatment of mCRC will be lifelong, the question of duration of therapy has been studied. In the GERCOR OPTIMOX 1 trial, Tournigand et al[40] compared patients who were randomized to receive FOLFOX6 (with an oxaliplatin dose of 130 mg/m2) every 2 weeks indefinitely, with patients who were randomized to receive 6 cycles of FOLFOX6, followed by 5-FU/leucovorin infusion as maintenance therapy every other week for 12 cycles, and then a switch back to FOLFOX6. Patients receiving FOLFOX6/maintenance therapy were found to have significantly less neurotoxicity compared with the group receiving continuous FOLFOX6, and overall survival was similar between groups. In the GERCOR OPTIMOX2 trial Chibodel et al[41] studied whether modified FOLFOX7 chemotherapy could be discontinued in patients with unresectable metastatic colorectal cancer (and restarted upon tumor progression). They found that patients randomized to a planned cessation of chemotherapy had shorter disease-free and overall survival times than patients in the maintenance chemotherapy group. Median duration of disease control was 13.1 months in patients assigned to the maintenance arm and 9.2 months in patients assigned to the chemotherapy-free interval (CFI) arm (P = .046). Median PFS and OS were 8.6 and 23.8 months, respectively, in the maintenance arm and 6.6 and 19.5 months, respectively, in the CFI arm. Median duration of maintenance therapy was 4.8 months and of the CFIs was 3.9 months.
Another question that has arisen is whether bevacizumab should be continued upon tumor progression and when the chemotherapy regimen is changed. Biologically, Mancuso et al[42] showed that when treatment with an antiangiogenic agent is begun, 50%–60% of tumor blood vessels disappear, but blood vessel sleeves remain in the tumor blood vessel basement membranes. When the antiangiogenic drug was stopped, new blood vessel sprouts appeared in the blood vessel sleeves, followed by blood flow within 24 hours. Within 7 days, the tumor was fully revascularized. This suggests that bevacizumab (or the antiangiogenic agent) should be continued.
Grothey[43] published findings of an observational study which showed that patients whose bevacizumab treatment was continued upon tumor progression while the chemotherapy regimen was changed, had longer survival compared with those who did not. This needs to be confirmed in large, prospective clinical trials.
Zafar et al[44] studied common practices for treatment of mCRC (N = 738 patients) and found that oxaliplatin was used as first-line therapy in 87% of patients, 12% received irinotecan, and 74% received bevacizumab. Gastrointestinal toxicity was most commonly associated with drug discontinuance and hospitalization.
Although intuitively it would seem that combining an EGFR antagonist (eg, cetuximab or panitumumab,) plus a VEGF antagonist (eg, bevacizumab) with chemotherapy could improve treatment outcomes, evidence shows that, in fact, patients do less well (with shorter PFS and an inferior quality of life) when both EGFR-inhibitor and VEGF-inhibitor biologics and chemotherapy are administered together, so they should not be combined.[45] Cetuximab was shown to have a role in conversion therapy in patients refractory to chemotherapy, as it increased the number of patients whose livers could be resected without increasing liver injury or operative mortality.[46] The incidence of cetuximab anaphylaxis appears related to geographical location and exposure to a component of the drug. Chung et al[47] found that the incidence of hypersensitivity reactions to cetuximab was 20.8% in Tennessee, 6.1% in Northern California, and 0.6% in Boston, Mass. Most patients who had a hypersensitivity reaction also had IgE antibodies against cetuximab (specifically against galactose-α-1,3-galactose, present on the cetuximab molecule) in their serum prior to receiving the drug. It is unclear how the patients developed the antibody.
Chemobiotherapy Regimens for Metastatic Colorectal Cancer
Tables 1 and 2 highlight NCCN recommendations for chemotherapy treatment options and chemobiotherapy regimens, respectively. Treatment toxicities from these systemic chemotherapy regimens challenge patients, their families, and the multidisciplinary healthcare team. Primary toxicities are outlined in Table 3. The Oncology Nursing Society offers an easy-to-read educational guide (available at http://www.onsedge.com/patient/mcrc-2/) that can be shared and discussed with patients, describing serious adverse effects of mCRC treatment that patients should watch for (such as headache, mouth sores, and fatigue).
Biomarkers That Predict Response to Biological Agents
The epidermal growth factor receptor is important in many cancers, and its overexpression confers an aggressive tumor behavior with poor prognosis.[48] When EGFR is abnormally activated in a number of CRC tumors, many signals are sent to the tumor cell nucleus telling the cell to divide or proliferate, to invade neighboring tissue, to metastasize, and to make new blood vessels to support the growing tumor. In addition, EGFR helps cancer cells to stay alive (survive). There are three pathways that take the message from EGFR on the outside of the cell, to the cell nucleus, and they involve the Ras pathway (Ras→Raf), the COX2 pathway, and the PI3K pathway, which involves mTOR (mammalian target of rapamycin) and results in angiogenesis.[49]
Common Toxicities Associated With Systemic Treatment for mCRC
When EGFR is blocked by an EGFR antagonist such as cetuximab, and the rest of the ras pathway is normal, with a normal or “wildtype” ras gene, then the message will be blocked and not sent to the cell nucleus. However, about 40% of patients with CRC have a mutated KRAS gene, so even if EGFR is blocked, the mutated KRAS continues to send the message to the cell nucleus; thus, the tumor will not respond to EGFR antagonists cetuximab or panitumumab. This was determined in a number of clinical trials.[50,51]
Today’s standard is that all tumors from patients with mCRC should be tested for mutation of the KRAS gene. Only about 40%–60% of patients with normal or wildtype KRAS respond to EGFR antagonists, so other aspects of the pathway must be explored. The next link in the signaling pathway below KRAS is BRAF. As previously discussed in this article, it has been found that if the BRAF gene is mutated, then the tumor will not respond to EGFR blockade either. While mutations in KRAS and BRAF are associated with a poor prognosis and predict nonresponse to EGFR antagonists, patients with KRAS and BRAF mutations do appear to be able to respond to chemotherapy with oxaliplatin or irinotecan.[52]
While not yet a standard of CRC management, as previously discussed, the tumor also should be tested for a mutation in the BRAF gene. Two other findings are relevant, but unfortunately do not appear to offer practical clinical guidance at this time: First, in patients with a normal KRAS gene, if there were many copies of the EGFR gene (EGFR amplification), then the patient was likely to respond to EGFR-antagonist therapy. Second, normal activity of the tumor-suppressor gene PTEN (phosphatase and tensin homolog) appears to be a predictor for overall survival in mCRC.[53]
Implications for Nurses
Today, the newly diagnosed patient with mCRC is presented with many different treatment choices, and the goal is to have an individualized treatment plan based on the patient’s preference, comorbidites, and tumor extent (metatatic sites) and aggressiveness. The patient and family have many questions, and often are so overwhelmed that they need the assistance of the nurse to help them formulate their questions as well as to provide clarifying information. The nurse caring for the patient with mCRC must be knowledgeable not only about this cancer, but also about its different management options. If the patient is potentially resectable, then the nurse will help to organize care so that the patient is informed and able to safely tolerate neoadjuvant or conversion therapy, with the goal of resection when this procedure is possible and optimal.
The National Cancer Institute’s website offers excellent colorectal cancer informational resources and tools for nurses to use and share with colleagues, along with links to current clinical trials in colon and rectal cancer and educational guides to review with patients (see http://www.cancer.gov/cancertopics/types/colon-and-rectal). It also is essential that nurses are able to understand and communicate information about important emerging individual factors (eg, mutations in EGFR, KRAS, BRAF) to consider when selecting appropriate therapy for a given patient. Indeed, as the role of genetics in determining the choice of therapy expands across the cancer-management continuum, it will be increasingly important for oncology nurses to achieve basic competency in the genetic/genomic underpinnings of treatment, for example, as outlined in the Essential Nursing Competencies and Curricula Guidelines for Genetics and Genomics (available at http://www.genome.gov/17517146).
Patients and their families need to understand in practical terms the potential benefit and possible side effects of the chemobiotherapy drugs, and, if indicated, surgery, so that treatment decisions can be made. In addition, as patients move through treatment, the nurse is ideally situated to empower both patients and their families through education and proactive measures to prevent or manage anticipated side-effects, so that patients can achieve the highest quality of life possible.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
This article contains reference to five drugs approved by the US Food and Drug Administration (FDA) that are used in off-label situations in adjuvant and neoadjuvant treatment of resectable or potentially resectable patients with metastatic colon or rectal cancer: 5-fluorouracil, irinotecan, oxaliplatin, bevacizumab, and cetuximab. No non–FDA-approved investigational agents are mentioned in the context of management of metastatic colorectal cancer.
