Paul F. Engstrom, MD, reviewed the recent changes to the National Comprehensive Cancer Network guidelines for colon and rectal cancer.
Paul F. Engstrom, MD, Fox Chase Cancer Center, reviewed the recent changes to the National Comprehensive Cancer Network (NCCN) guidelines for colon and rectal cancer, released as v.2.2010. These updates come only one month after NCCN’s updated January guidelines for colon cancer (version 1.2010). Some provisions in the latest version are based on research data released over the past few months.
Modifications to Therapy Guidelines
NCCN modified several therapy recommendations. Panitumumab (Vectibix) was added as an alternative to cetuximab (Erbitux) in combination with FOLFOX and FOLFIRI to treatment algorithms for metastatic colorectal cancer (mCRC) patients whose tumors are wild-type KRAS; panitumumab has also been included in combination with FOLFIRI as a second-line option for patients who progress on FOLFOX and bevacizumab (Avastin). Panitumumab can now be used with these cytotoxic chemotherapies following colectomy to treat patients with resectable synchronous liver and/or lung metastases, as a primary treatment in patients with advanced mCRC that have received adjuvant FOLFOX in the prior year, and as initial therapy or therapy after first progression in patients with advanced mCRC that are candidates for intensive therapy.
Other updates to treatment guidelines include removal of cetuximab as a recommended agent in combination with chemotherapy regimens containing capecitabine and oxaliplatin, a notation that bevacizumab may be safely administered at a rate of 0.5 mg/kg/minute (5 mg/kg over 10 minutes and 7.5 mg/kg over 15 minutes), and a statement that FOLFOX is superior to fluoropyrimidine alone in patients with stage III disease. In addition, NCCN added a footnote to the adjuvant therapy section advising against treating stage II or III patients with bevacizumab, cetuximab, panitumumab, or irinotecan outside a clinical trial. Engstrom said patients with Tis; T1, N0, M0; or T2, N0, M0 pathologic stage should not receive any adjuvant therapy.
Under “Principles of Risk Assessment for Stage II Disease” and as a footnote on adjuvant therapy recommendations, the committee concludes that the approximately 15% of patients with stage II tumors exhibiting low frequency microsatellite instability (MSI-H) may have a good prognosis and will not benefit from 5-FU. Engstrom said studies show patients with MSI-H actually do worse when they receive adjuvant chemotherapy with 5-FU. Because of this, for the v.1.2010 release, “The committee agreed ‘Any patient aged 50 years or younger should have MSI testing,’” Engstrom said. “This advantage or disadvantage [with 5-FU] does not hold for stage III patients,” he added.
Is It Time to Test for BRAF Mutations?
Just as the NCCN was on the forefront of treatment guidelines for colon cancer in being the first United States organization to release guidelines advising against the use of EGFR inhibitors in patients with KRAS mutations, it appears to be taking a lead in addressing the role of BRAF mutations. The January guidelines broached the topic with the following footnote: “Patients with a known V600E BRAF mutation appear to be unlikely to benefit from monoclonal antibodies.” NCCN modified this in v.2.2010 to say, “Patients with a known BRAF mutation appear unlikely to benefit from anti-EGFR monoclonal antibodies, although the data are somewhat inconsistent.” The NCCN guidelines do not advise routine testing for BRAF mutations but suggest it be considered in patients who are wild-type KRAS. There is no need to test patients with a KRAS mutation for a BRAF mutation because evidence suggests these two mutations are mutually exclusive. Engstrom said approximately 10% of patients have a BRAF mutation, and he would not give cetuximab or panitumumab to these individuals.
This recommendation comes on the heels of updated data from the CRYSTAL trial presented at the ASCO 2010 gastrointestinal meeting by Eric Van Cutsem, MD, PhD, head of the digestive oncology division at University Hospital Gasthuisberg in Leuven, Belgium. Van Cutsem said patients with BRAF mutations did not respond as well to EGFR inhibitors as patients with wild-type BRAF and wild-type KRAS. Van Cutsem concluded that BRAF was an indicator of poor prognosis but said more investigation was needed to determine whether it was also a poor predictor of treatment response.
Engstrom wrapped up his presentation with a discussion of guidelines for treating rectal cancer. The primary treatment for T1-T2 N0 rectal cancer, he said, is generally transanal excision, after which patients should optimally be staged as T1 with negative margins. “Those patients with high-risk features should go on to get chemotherapy,” Engstrom said.
Although transanal excision is typical, Engstrom said an analysis at Memorial Sloan-Kettering Cancer Center showed a significant improvement in life expectancy for patients who received radical resection for a T1 lesion compared with patients who had transanal excision. “Transanal resection should be limited to patients who are not candidates for radical resection,” Engstrom cautioned. He suggested the procedure be reserved for elderly patients with an expected survival of <5 years.
For patients whose tumors are T3, N0 or T any, N1-2, the NCCN guidelines recommend preoperative chemotherapy and radiotherapy, with continuous 5-FU as the preferred cytotoxic agent. This should be followed by transabdominal resection and adjuvant chemotherapy. Engstrom highlighted studies that showed greater patient satisfaction and a lower 5-year recurrence rate associated with preoperative radiotherapy versus postoperative radiotherapy or no radiotherapy. He noted, however, that high response rates do not obviate the need for complete surgical resection. He also emphasized the importance of sphincter preservation to patients quality of life and satisfaction. In patients who present with M1 resectable stage 4 disease, Engstrom said it is generally recommended that they receive chemotherapy up front, after which the patient can be restaged and treated accordingly.