Antiangiogenesis in Early-Stage Colon Cancer—Microscopically Busted | Colorectal Cancer | JAMA Network Open | JAMA Network
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Invited Commentary
Oncology
October 19, 2020

Antiangiogenesis in Early-Stage Colon Cancer—Microscopically Busted

Author Affiliations
  • 1Rutgers Cancer Institute and the Robert Wood Johnson School of Medicine, New Brunswick, New Jersey
JAMA Netw Open. 2020;3(10):e2021064. doi:10.1001/jamanetworkopen.2020.21064

The final report by Chibaudel et al1 on the patients with stage II disease in the large, prospective, randomized phase 3 AVANT (Bevacizumab-Avastin Adjuvant) colon adjuvant therapy trial presents more questions than answers. With only 573 patients randomized to 3 groups, this study is underpowered to show disease-free survival or overall survival benefit for patients with stage II colon cancer. This report1 includes a subset of the larger AVANT trial, and because there are fewer than 200 patients in each group, it only has the power to detect approximately 25% improvement in disease-free survival (which is far more improvement than is possible). Furthermore, the negative results agree with the already reported results from the larger, complete AVANT data set2 and the NSABP (National Surgical Adjuvant Breast and Bowel Project) C-08 study,3 both of which studied the specific role of adjuvant bevacizumab, an antibody directed against vascular endothelial growth factor. We know this antibody essentially binds all free circulating vascular endothelial growth factor and is active in advanced colon cancer and other malignant neoplasms.4 According to the proposed mechanisms of angiogenesis, this drug should work in microscopic disease as tumors activate via the angiogenic switch, which is required to grow from microscopic to macroscopic metastases.5 These events should happen with reasonable frequency over the year of adjuvant antiangiogenic therapy in the experimental groups. Chibaudel et al1 have not provided the same time analysis as provided in the NSABP C-08 study.3 These data showed massive effects during the early months of treatment with bevacizumab (with very positive hazard ratios for recurrence) but then gradual loss of effect over the year of treatment. It would be very interesting to see whether this was also the case for AVANT in both stage II and III cancers.

One additional observation here is the improved overall survival in the capecitabine-oxaliplatin (CapeOX) and bevacizumab group compared with the folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab group in the study by Chibaudel et al.1 This is interesting in the context of the IDEA (International Duration Evaluation of Adjuvant Therapy) collaboration report6 of more than 12 000 cases (from 6 phase 3 studies) of stage III colon cancer treated with 6 months vs 3 months of therapy, using either FOLFOX or CapeOX. The overall collaboration did not randomize between FOLFOX or CapeOX, and this choice of regimen was dictated by individual trial design. However, given this very large sample size, it appears that CapeOX performs better than FOLFOX for disease-free survival in both low-risk and high-risk groups. It is postulated that this difference is associated with increased intensity of the fluoropyrimidine therapy.6

Another important observation in the study by Chibaudel et al1 relates to the arbitrary risk factors for recurrence. These were not uniformly predictive and, in this study,1 both age (<50 years) and vascular involvement were not prognostic compared with the other high-risk factors. This risk classification system, however, should soon disappear, as we move toward circulating tumor DNA, which will not show risk but actually identify patients with minimal residual disease. These are the patients who should receive further therapy versus those whom we can clear for no further treatment with a negative test. Individuals with stage IIA colon cancer can contribute to this knowledge base by joining the National Cancer Institute–sponsored COBRA (Phase II/III Study of Circulating Tumor DNA as a Predictive Biomarker in Adjuvant Chemotherapy in Patients With Stage IIA Colon Cancer) trial (ClinicalTrials.gov identifier: NCT04068103).

The main take-home points from the report by Chibaudel et al1 are (1) excellent overall survival for stage II colon cancer, (2) clinical risk factors that are not uniform, and (3) the likely failure of adding an active antiangiogenic antibody (even given the lack of power). This poses important questions for our preclinical models of angiogenesis: are our models incorrect? We need to return to the laboratory to better understand angiogenesis in the microscopic setting.

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Article Information

Published: October 19, 2020. doi:10.1001/jamanetworkopen.2020.21064

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Hochster HS. JAMA Network Open.

Corresponding Author: Howard S. Hochster, MD, Rutgers Cancer Institute and the Robert Wood Johnson School of Medicine, 195 Little Albany St, Room 2004, New Brunswick, NJ 08903 (howard.hochster@rutgers.edu).

Conflict of Interest Disclosures: Dr Hochster reported receiving personal fees from Genentech outside the submitted work.

References
1.
Chibaudel  B, Henriques  J, Rakez  M,  et al.  Association of bevacizumab plus oxaliplatin-based chemotherapy with disease-free survival and overall survival in patients with stage II colon cancer: a secondary analysis of the AVANT trial.   JAMA Netw Open. 2020;3(10):e2020425. doi:10.1001/jamanetworkopen.2020.20425Google Scholar
2.
de Gramont  A, Van Cutsem  E, Schmoll  H-J,  et al.  Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial.   Lancet Oncol. 2012;13(12):1225-1233. doi:10.1016/S1470-2045(12)70509-0PubMedGoogle ScholarCrossref
3.
Allegra  CJ, Yothers  G, O’Connell  MJ,  et al.  Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08.   J Clin Oncol. 2011;29(1):11-16. doi:10.1200/JCO.2010.30.0855PubMedGoogle ScholarCrossref
4.
Krämer  I, Lipp  HP.  Bevacizumab, a humanized anti-angiogenic monoclonal antibody for the treatment of colorectal cancer.   J Clin Pharm Ther. 2007;32(1):1-14. doi:10.1111/j.1365-2710.2007.00800.xPubMedGoogle ScholarCrossref
5.
Ferrara  N, Davis-Smyth  T.  The biology of vascular endothelial growth factor.   Endocr Rev. 1997;18(1):4-25. doi:10.1210/edrv.18.1.0287PubMedGoogle ScholarCrossref
6.
Grothey  A, Sobrero  AF, Shields  AF,  et al.  Duration of adjuvant chemotherapy for stage III colon cancer.   N Engl J Med. 2018;378(13):1177-1188. doi:10.1056/NEJMoa1713709PubMedGoogle ScholarCrossref
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