Every year in the United States, approximately 160,000 cases of colorectal cancer (CRC) are diagnosed, and about 57,000 patients die of the disease, making it the second leading cause of death from cancer among adults. Over the past decade we have made significant progress in the development of highly effective treatment modalities for colorectal cancer. The availability of combination cytotoxic agents along with the advent of targeted biologic agents has dramatically expanded treatment options for patients with metastatic colorectal cancer. Moreover, our increasing knowledge of the molecular biology of this disease has increased our ability to deliver patient-specific value to our clinical decision making. This year's annual American Society of Clinical Oncology meeting featured a host of clinically relevant sessions and abstracts dealing with challenges of metastatic CRC.
Oral abstract session
Some of the ongoing challenges in the treatment of metastatic colorectal cancer include defining the optimal role of targeted agents and whether there are substantive differences between sequential and combination chemotherapy regimens. To that end, there were several relevant presentations at this year's oral abstract and educational sessions.
Lead investigator J. Tabernero, MD, presented results from the MACRO Trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD], a multicenter, phase III study in which 480 patients were randomized on either first-line XELOX (capecitabine + oxaliplatin) plus bevacizumab for 6 cycles followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer (mCRC).
Dr. Tabernero stated that the rationale for the study centered on the debate over optimal duration of therapy in mCRC. Some physicians maintain therapy until unacceptable toxicity or disease progression occurs; others discontinue all or partial treatment after 4 to 6 months. However, previous studies have shown that bevacizumab has a good safety profile and the MACRO trial sought to demonstrate that maintenance therapy with single-agent bevacizumab after 6 cycles of induction chemotherapy plus bevacizumab could be a reasonable option. The goal of this approach is to avoid accumulated toxicity without decreasing overall efficacy.
The study's primary endpoint was progression-free survival, with secondary endpoints listed as overall survival, objective tumor response (by RECIST), time to response, duration of response, and number of treatment cycles. Dr. Tabernero noted that the most important finding was progression-free survival; there were no measurable differences between the two arms.
Preliminary safety analysis indicates acceptable tolerability in both arms, with grade 3/4 diarrhea in 11% and 13%, HFS in 12% and 6%, and neuropathy in 24% and 7% in Arms A and B, respectively. Dr. Tabernero concluded that results from the MACRO trial show that bevacizumab as maintenance therapy following induction XELOX/bevacizumab was not inferior to continuation XELOX/ bevacizumab, suggesting that maintenance therapy with single-arm bevacizumab is an appropriate option following induction XELOX/bevacizumab in patients with mCRC. Further studies evaluating this finding are warranted.
On behalf of my colleagues, I, presented results from the NCCTG Intergroup phase III trial N0147. When the study began, we had a rather elementary notion of the mechanism of action of cetuximab. We understood that the epidermal growth factor (EGF) receptor was the ligand that bound to its cell-surface receptor and that binding activates a pathway with multiple downstream mediators, which include a variety of effects on malignant cells. These results ranged from increased proliferation, resistance to chemotherapy and radiation, promotion of angiogenesis, as well as invasion and metastasis, and evasion of apoptosis. At the time of the study we believed that cetuximab bound to the EGF receptor and, like a light switch in the off position, simply enacted the pathways. However, as the study progressed we discovered that the nature of the pathways and the effects of cetuximab were not as simple as first thought.
This study enrolled patients with stage III colon cancer to post-operative adjuvant treatment with modified FOLFOX6 with or without cetuximab. When public data from the CRYSTAL and OPUS studies in patients with advanced colorectal cancer suggested that KRAS mutations rendered tumors resistant to cetuximab this trail was amended to require KRAS testing prior to patient enrollment and only those with KRAS wild-type tumors were randomized. However, the current analysis focuses on the patients enrolled prior to that restriction was implemented.
Patients were randomized to 12 biweekly courses of oxaliplatin 85 mg/m2 day 1, with leucovorin 400 mg/m2, 5-FU 400 mg/m2 bolus IV, then 46-hr IV 5-FU 2,400 mg/m2 on days 1-2 (mFOLFOX6), without (arm A) or with cetuximab (arm D) 250 mg/m2 days 1 and 8, with cetuximab 400 mg/m2, cycle 1, day 1. Tumors were centrally tested for KRAS mutation.
We concluded that the addition of cetuximab to mFOLFOX6 resulted in impaired disease-free survival and a trend toward impaired overall survival in mutated KRAS resected stage III colorectal patients. While some between-arm difference in toxicity and ability to complete the full course of FOLFOX were observed, it is unlikely these factors could account in whole for the poorer outcome with cetuximab added to mFOLFOX6 in pts with mutated KRAS colorectal cancer.
This study posed a clinically important question: Why did patients with KRAS mutation treated with cetuximab do worse than the wild-type population and those treated with FOLFOX alone? We believe that treatment with an EGF antibody somehow drives chemotherapy resistance in the tumors with the KRAS mutation. We believe that the explanation is somehow related to tumor biology. The outcomes of this trial are surprising, challenging us to engage in further studies in order to better understand the interactions of tumor genotype and patient biology - the key to individualizing treatments in this population lies in that understanding.
Selected Educational Sessions
Is There an Optimal Treatment Strategy for Treating Advanced Colorectal Cancer?
Axel Grothey, MD, Chair, led off the session by giving his perspective on recent data in the management of metastatic colorectal cancer (mCRC), noting that:
• Some patients with stage IV disease can be cured with an interdisciplinary approach
• Most patients tolerate a chemo doublet, but not all need it
• Biologics have improved outcomes, but not as much as we hoped for
• We are on the verge of therapy based on molecular predictive factors
Dr. Grothey centered his presentation on how to integrate targeted agents into treatment algorithms for mCRC. He noted that the effectiveness of EGFR inhibitors is dependent on KRAS mutational status in colorectal cancer left no doubt that the future role of genetics in selecting patient therapy is inevitable and will undoubtedly change the way in which mCRC patients are managed.
He concluded with a simplified analysis of bevacizumab vs EGF-receptor in mCRC, pointing out the major strengths and weaknesses of each strategy. Bevacizumab's major strengths are delay of progression; a favorable toxicity profile and on the weakness side, no single-agent activity and a weak response rate. EGF-receptors demonstrated better activity as a single-line therapy, more consistent response rates, plus an activity that is independent of the line of therapy, and finally EGF-receptors can be used as a predictive marker that can guide further treatments down-line in this patient population.
Dr. Grothey's take-home message was straight forward: Clinicians should first analyze and identify the goal of therapy when treating a patient with mCRC. He stressed that response rate is important only for conversion therapy or if the patient is symptomatic from tumor burden. For most patients, however, gain of time and maintaining good quality of life is the primary goal.
Biomarker-driven Treatment in Stage II Colon Cancer: When to Hold and When to Fold
Although advances in systemic chemotherapy have improved overall survival in stage III colon cancer, the use of adjuvant therapy in stage II disease remains a subject of debate. In this session, Drs. Al b. Benson III, Sabine Tejpar, and Neal J. Meropol, reviewed data from several seminal adjuvant clinical trials and discussed the current evidence in the use of molecular biomarkers and the potential directions of this exciting tool in patient treatment decision making.
Citing results from the MOSAIC study, the QUASAR collaborative group study, and NSAPB C-08 trial, the authors gave a mixed bag of results for adjuvant therapy in stage II colon cancer, pointing out that more recent studies, systematic reviews, and meta-analyses in average-risk patients with stage II disease have failed to demonstrate an increase in overall survival with the addition of adjuvant chemotherapy. To that end, ongoing investigations are being directed toward using molecular markers in order to individualize therapy decisions based on tumor biology. This is an emerging field and having strong data from studies that identify biomarkers in stage II colon cancer is a vital step in advancing therapies that promote better survival outcomes in this group of patients. However, as this session demonstrates, in most cases of stage II colon cancer, there is modest benefit of adjuvant therapy, and the decision to initiate treatment requires thoughtful input from physician and patient.