64-year-old man with metastatic colon cancer

The patient was in his usual state of health until approximately June 2005 when he started to notice some fatigue. He was evaluated by his primary care physician and was found to have a hemoglobin of 9.3 g/dL and a mean corpuscular volume of 77.9. Subsequent iron studies confirmed iron deficiency with an iron of 11, total iron binding capacity of 448, percent saturation of 2, and ferritin of 6.

Colonoscopy revealed a 4-cm nonobstructing circumferential mass in the ascending colon that was biopsy-proven adenocarcinoma. The patient underwent a right hemicolectomy revealing a moderately differentiated adenomcarcinoma, staged as a T4N0 colon cancer. Eight lymph nodes were removed at the time of surgery and all were negative for metastatic disease. No adjuvant chemotherapy was administered.

Anne H. Blaes

Approximately two years later, the patient was found on routine evaluation to have a rising carcinoembryonic antigen. A PET/CT scan was performed revealing three small lesions within the liver that were PET avid. Biopsy confirmed the presence of metastatic colon cancer. The patient was started on 5-FU and oxaliplatin (Eloxatin, Sanofi Avenitis; FOLFOX) in combination with bevacizumab (Avastin, Genentech).

He was stable on this regimen for approximately 13 months. Follow-up scans revealed new liver metastases and a single isolated pulmonary nodule.

At the time he was found to have progressive colon cancer, his energy level was slightly diminished. He had no fevers or infectious symptoms, and no chest pain or shortness of breath. He had mild neuropathy.

Physical examination shows: blood pressure 106/70 mm Hg, heart rate 88 and regular, temperature 98·C, respirations 16.

General appearance: Alert, pleasant, healthy-appearing gentleman who is in no acute distress.

Lymph nodes: There is no cervical, supraclavicular, infraclavicular, axillary or inguinal lymphadenopathy.

Cardiovascular: Regular rate and rhythm, with a normal S1 and S2.

Lungs: Clear to auscultation and percussion bilaterally.

Abdomen: There is a midline vertical abdominal incision that is well-healed without any erythema. Normoactive bowel sounds. Soft, nontender, nondistended, without any hepatosplenomegaly or appreciable masses.

Neurologic: Grossly normal.

In this patient with metastatic colon cancer that has progressed after treatment with FOLFOX plus bevacizumab, the most appropriate treatment recommendation would be which of the following:

A. Single-agent irinotecan.

B. FOLFIRI with bevacizumab.

C. An irinotecan-based chemotherapy in combination with cetuximab (Erbitux, Imclone).

D. Clinical trial enrollment.

E. Continuation of bevacizumab as a single agent.

Case Discussion

In the United States, colon cancer is the second leading cause of cancer-related death. In 2008, an estimated 108,070 new cases of colon cancer and 40,780 cases of rectal cancer resulted in 49,960 deaths. Although the majority of patients with metastatic colorectal cancer will die of their disease, the overall survival has increased from a few months to approximately 20 months in the last few years with the addition of chemotherapeutic agents such as irinotecan or oxaliplatin. Both irinotecan and oxaliplatin, in combination with 5-FU, appear superior in outcome compared with single agent 5-FU. As a result, initial chemotherapy for metastatic colon cancer consists of 5-FU in combination with oxaliplatin (FOLFOX or XELOX) or with irinotecan (FOLFIRI). Given the results presented by Goldberg et al in which FOLFOX resulted in an improved median survival of 19.5 months, FOLFOX tends to be the favored initial chemotherapy. Irinotecan, used either as a single agent or in combination with 5-FU (FOLFIRI), results in response rates of 4% to 20% as second-line chemotherapy.

The addition of bevacizumab, a recombinant humanized version of a murine antihuman vascular endothelial growth factor monoclonal antibody known to play a key role in the regulation of angiogenesis and tumor growth, to irinotecan or oxaliplatin has also improved the outcomes for patients with metastatic colon cancer. Giantonio et al reported results of 829 patients with metastatic colon cancer previously treated with 5-FU and irinotecan.

These patients were randomly assigned to FOLFOX plus bevacizumab, FOLFOX alone, or bevacizumab alone. The addition of bevacizumab to FOLFOX alone resulted in an improved overall survival of 12.9 months compared with 10.8 months for FOLFOX alone (HR=0.75, P=.0011). However, this improvement in overall survival also resulted in a 14% increased risk of grade-3/4 adverse events, such as hypertension, bleeding and vomiting.

Bevacizumab has also been investigated in combination with irinotecan-based chemotherapy regimens. Fuchs et al reported the results of the BICC-C trial in which patients with untreated metastatic colon cancer were treated with FOLFIRI and bevacizumab. The initial follow-up reported an overall response rate of 58% with a median progression-free survival of 11.2 months (n=61). Subsequently, at a median follow-up of 34 months, those patients treated with FOLFIRI and bevacizumab had a median survival of 28 months.

Preliminary results from the BEAT trial confirm similar results with a median progression-free survival of 11.1 months in 501 patients. Although these studies appear to have favorable outcomes for adding bevacizumab to combination chemotherapy, the exact utilization, schedule and timing of the administration of bevacizumab is still being investigated.

In 2004, when the FDA approved the use of bevacizumab for metastatic colon cancer, the BRiTE (Bevacizumab Regimens: Investigation of Treatment Effects and Safety) trial was developed. This trial was a prospective observational cohort study developed to study the safety and effectiveness of bevacizumab in combination with chemotherapy in the setting of untreated metastatic colon cancer. This observational trial involved 1,953 patients enrolled at 248 sites.

Patients were treated with bevacizumab as first-line treatment for metastatic colon cancer. These patients were then followed on study until death. At a median follow-up of 19.6 months, 1,445 patients (74%) had experienced progressive disease. Of these, 253 (17%) received no postprogressive disease treatment, 531 received additional treatment without the continuation of bevacizumab, and 642 patients were continued on treatment with bevacizumab. The median overall survival for all patients was 25.1 months, whereas overall survival for those with no further treatment was 12.6 months; no bevacizumab, 19.9 months; and bevacizumab, 31.8 months. Bevacizumab was strongly and independently associated with improved survival (HR=0.48, P=.001) compared with no bevacizumab.

This observational trial suggests that the continuation of bevacizumab after disease progression may result in better survival. This hypothesis is currently being investigated in a prospective trial by the Southwestern Oncology Group (SWOG S0600) in which patients who have progressed on first-line FOLFOX with bevacizumab are randomly assigned to an irinotecan- and cetuximab-based chemotherapy in combination with varying doses of bevacizumab.

In this patient, treatment with an irinotecan-based chemotherapy regimen would be the favored approach. In patients who are wild-type for the KRAS mutation, the addition of cetuximab is also reasonable. If at all possible, clinical enrollment in the SWOG S0600, in which the continuation of bevacizumab is being investigated, would be the favored approach.

Anne H. Blaes, MD, is a Fellow at the University of Minnesota and a member of the HemOnc Today Editorial Board.

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