Adjuvant therapy (and Avastin) for stage II colon cancer and OncotypeDx Colon – pro

Lay Summary: Adjuvant chemotherapy for Stage II colon cancer is controversial but the field until recently was moving away from it. A recent study is reporting again that it may be beneficial.

Adjuvant chemotherapy for Stage II colon cancer is controversial but the field until recently was moving away from it. A recent study is reporting again that it may be beneficial.

Recent guidelines make it optional rather than recommended. An ASCO panel collaborating with the Cancer Care Ontario Practice Guideline Initiative reviewed randomized controlled trials and other relevant studies from the literature through May 2003. This meta-analysis found no evidence in stage II patients of statistically significant improvement in survival with adjuvant chemotherapy.

“The routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer is not recommended,” the panel writes. “However, there are populations of patients with stage II disease that could be considered for adjuvant therapy, including patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology.”

Limitations of the literature reviewed include insufficient number of patients in previously reported trials, the relatively good prognosis of patients with stage II disease, competing noncancer-related deaths in this population, the lack of consistent information provided on the stage II subsets in the trials analyzed, and the relatively small percentage of patients with stage II disease in each trial.

The guidelines acknowledge that the same relative benefit probably results from adjuvant therapy for patients at both stages II and III, but that the number of patients studied in most trials is too small to detect and quantify absolute survival benefits from adjuvant therapy in stage II disease. To detect a survival difference of 2% between treatment and control groups of a trial, a sample size of 9,680 per group would be needed (90% power with a significance level of .05).

R Zeiser, A Burchert, C Lengerke, M Verbeek, K Maas-Bauer, S K Metzelder, S Spoerl, M Ditschkowski, M Ecsedi, K Sockel, F Ayuk, S Ajib, F S de Fontbrune, I-K Na, L Penter, U Holtick, D Wolf, E Schuler, E Meyer, P Apostolova, H Bertz, R Marks, M Lübbert, R Wäsch, C Scheid, F Stölzel, R Ordemann, G Bug, G Kobbe, R Negrin, M Brune, A Spyridonidis, A Schmitt-Gräff, W van der Velden, G Huls, S Mielke, G U Grigoleit, J Kuball, R Flynn, G Ihorst, J Du, B R Blazar, R Arnold, N Kröger, J Passweg, J Halter, G Socié, D Beelen, C Peschel, A Neubauer, J Finke, J Duyster and N von Bubnoff, Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia (31 July 2015) | doi:10.1038/leu.2015.212

“Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease,” the authors write. “The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. Patients with stage II disease should be encouraged to participate in randomized trials.” This is also the conclusion of the NCCN and other guidelines.

Researchers recently conducted a clinical study to further evaluate adjuvant chemotherapy in the treatment of Stage II colorectal cancer. The study, referred to as the QUASAR study, included 3,239 patients with Stage II colorectal cancer who were treated with surgery followed by adjuvant chemotherapy (consisting of a 5-fluorouracil-based regimen) or with no further treatment. Median follow-up was five and a half years.

The five-year survival was improved by 3.5% among patients who received adjuvant chemotherapy compared with those who did not receive adjuvant therapy.
The risk of recurrences was reduced by approximately 22% among patients treated with adjuvant chemotherapy. The researchers concluded that adjuvant chemotherapy in Stage II colorectal cancer is associated with a modest though significant improvement in survival.

Patients diagnosed with Stage II colorectal cancer may wish to speak with their physician regarding their individual risks and benefits of chemotherapy. However, once a decision is made to use standard chemo, such as Folfox or Xeloda, it should not be considered investigational or not medically necessary.

One way to individualize adjuvant chemotherapy is through an assessment of risk factors. The QUASAR study data was used to validate Oncotype DX test, which became avalilble in early 2010. Based on data from the nearly 3,300 patients in development and validation studies, the Oncotype DX Colon Cancer Assay was thought to deliver information that can be used to help make decisions about adjuvant therapy. The assay provides an individualized Recurrence Score, which gives the oncologist the patient-specific information to help decide which of stage II colon cancer patients should be most appropriately considered for post-surgical chemotherapy. Supporting the original QUASAR study, additional results from a second clinical validation study of stage II colon cancer patients enrolled in CALGB 9581 further confirmed that the Recurrence Score result improves the ability to differentiate higher from lower recurrence risk beyond conventional factors, such as tumor grade, number of nodes examined, and lymphovascular invasion. There is also support from several smaller restrospective analyses.

The Recurrence Score is based upon the quantitative expression of the 7 cancer genes, normalized to the 5 reference genes. The Recurrence Score includes 7 genes identified as consistently and significantly associated with recurrence free interval (RFI) in the 1,851 patients from the development studies. These genes include the cell cycle group (Ki-67, MYBL2, C-MYC), the stromal group (FAP, INHBA, BGN) and GADD45B. The pre-specified Recurrence Score gene panel was validated in 1,436 stage II colon cancer patients with tissue from the QUASAR trial. To my knowledge, no professional group or guideline has yet recommended OncotypeDx.

QUASAR Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomized study. Lancet Oncology. 2007;370:2020-2029.

Benson AB 3rd, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, Krzyzanowska MK, Maroun J, McAllister P, Van Cutsem E, Brouwers M, Charette M, Haller DG. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004 Aug 15;22(16):3408-19. [45 references]

Deborah Schrag, Sheryl Rifas-Shiman, Leonard Saltz, Peter B. Bach, Colin B. Begg
Adjuvant Chemotherapy Use for Medicare Beneficiaries With Stage II Colon Cancer Journal of Clinical Oncology, Vol 20, Issue 19 (October), 2002: 3999-4005

NCCN.ORG, Colon Cancer 2012

Lisa Baddi, Al Benson, III Adjuvant Therapy in Stage II Colon Cancer: Current Approaches The Oncologist, Vol. 10, No. 5, 325-331, May 2005;

Kerr D, Gray P, Quirke P, et al. A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study. Journal of Clinical Oncology 2009;27:15s, Abstract #4000.

Figueredo A, Coombes ME, Mukherjee S. Adjuvant Therapy for completely resected Stage II Colon Cancer. Cochrane Database of Systematic Reviews 2008, Issue 3.

Sargent D, Sobrero A, Grothey A, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2009;27(6):872-7

Venook A, Niedzwiecki D, Lopatin M, et al. Validation of a 12-gene colon cancer recurrence score (RS) in patients (pts) with stage II colon cancer (CC) from CALGB 9581. Presented at: American Society of Clinical Oncology; June 2011; Chicago, IL.

Meropol N, Lyman GH, Chien R. Use of a multigene prognostic assay for selection of adjuvant chemotherapy in patients with stage II colon cancer: Impact on quality-adjusted life expectancy and costs. Poster presented at the American Society Clinical Oncology Gastrointestinal Cancers Symposium; San Francisco, CA; January 2011.


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