Original StudyViews of Australian Medical Oncologists Regarding the Use of Mismatch Repair Status to Assist Adjuvant Chemotherapy Recommendations for Patients With Early-Stage Colon Cancer
Introduction
Australia has among the highest incidence of colorectal cancer (CRC) globally.1 CRC is the second most common cancer in Australia and accounted for an estimated 15,840 new cases and 3960 deaths in 2012.2 The primary treatment for early-stage disease involves surgical resection, followed by adjuvant chemotherapy (AC) in cases in which pathologic staging has revealed a significant risk of relapse.
Stage III disease, based on locoregional nodal involvement, represents the clearest indication for AC, with an absolute improvement of approximately 15% in 5-year overall survival (OS).3 The benefit of AC for patients with stage II disease is less clear. Although no clear OS advantage has been seen to date, 2 large meta-analyses have shown a significant disease-free survival advantage.4, 5 Clinicopathologic variables have classically been used to identify patients with a greater risk of relapse, despite the lack of consensus on which variables should be used6, 7, 8 and whether they can predict a benefit from AC.4, 9, 10 However, microsatellite instability (MSI-H), a biologic marker of DNA mismatch repair (MMR) deficiency, has emerged as a prognostic biomarker in CRC. It is also potentially predictive of response to 5-fluorouracil (5-FU)-based AC and hence has been suggested as a variable upon which treatment decisions can be made.
In addition to being a hallmark of Lynch syndrome, MSI-H is present in approximately 15% of patients with sporadic CRC. Rather than germline mutations in the MMR genes (MLH1, MSH2, MSH6, PMS2) classically seen in Lynch syndrome, MSI-H in sporadic CRCs are secondary to epigenetic silencing of MLH1 through promoter hypermethylation.11 Sporadic tumors exhibiting MSI-H represent a distinct clinicopathologic subset of CRCs with proximal colon predominance, poor differentiation, an increased number of tumor-infiltrating lymphocytes, and a greater prevalence in stage II disease and older women. The lack of expression of MMR proteins by immunohistochemistry is highly concordant with molecular MSI testing12 and represents a more accessible and cost-effective test. Tumors with MSI-H or the loss of MMR protein expression can be jointly classified as MMR deficient (dMMR).13
Retrospective evidence has suggested that dMMR tumors are associated with superior stage-adjusted survival compared to MMR proficient tumors14, 15, 16, 17, 18, 19 and that single-agent 5-FU–based AC confers no benefit.17, 19, 20, 21, 22, 23, 24 The use of MMR status as a predictor of 5-FU efficacy in the adjuvant setting, however, remains controversial, because the lack of benefit could not be confirmed by other studies.25, 26 Prospective evidence supporting the practice is also lacking. Hence, considerable variation could exist in the interpretation of the evidence and resultant practice. We conducted a survey of Australian medical oncologists (MOs) to obtain their views and practices relating to the use of MMR status in the treatment of patients with early-stage colon cancer (ESCC).
Section snippets
Participants
A covering electronic mail letter (e-mail) with an online questionnaire link was sent to all 550 members of the Medical Oncology Group of Australia (MOGA), the peak professional organization representing all MOs in Australia, in February 2013. MOs in training constituted 168 of the 550 members and were included in the survey invitation. Two follow-up e-mails (March and June 2013) were sent to improve the response rates. In addition, the survey was e-mailed to MOs who had attended an Australian
Demographic Data
A total of 190 responses were received by the end of the survey period. This represented 35% of the MOGA membership. Of the 190 responses received, 152 (80%) were from MOs who routinely treat patients with CC, and 38 (20%) were from MOs who opted to end the survey at the first screening question. The MOs who ended the survey at the first screening question were deemed to have completed the survey. Twenty-two MOs did not complete the whole survey, for a total completion rate of 88%. Of 143 MOs,
Discussion
In the present study, we conducted a case-based survey of Australian MOs to obtain the views and practices relating to AC for resected ESCC, in particular, the use of MMR status as a clinical decision tool regarding AC recommendations.
Most MOs in our survey would recommend AC for patients with stage III CC, consistent with the guidelines.6, 8, 28 This was not the case for stage II disease, with our survey indicating that only 52% would routinely discuss AC with their patients. The current
Conclusion
Despite its associated controversies, the use of MMR status as a decision-making tool for patients with early-stage CC appears well embraced by Australian MOs. Whether MMR status has a place in clinical practice in the adjuvant setting of ESCC remains subject to debate and will ultimately depend on the views and interpretation of the available evidence by individual MOs.
Disclosure
The authors have stated that they have no conflicts of interest.
Acknowledgments
The Department of Medical Oncology, Peter MacCallum Cancer Centre funded the survey prize and survey printing.
References (36)
- et al.
ESMO consensus guidelines for management of patients with colon and rectal cancer: a personalized approach to clinical decision making
Ann Oncol
(2012) - et al.
Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients
Gastroenterology
(2006) - et al.
Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer
Gastroenterology
(2004) - et al.
Early colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up
Ann Oncol
(2013) - et al.
Global cancer statistics
CA Cancer J Clin
(2011) Cancer in Australia: actual incidence data from 1991 to 2009 and mortality data from 1991 to 2010 with projections to 2012
Asia Pac J Clin Oncol
(2013)- et al.
Primary colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up
Ann Oncol
(2009) - et al.
Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?
J Clin Oncol
(2004) - et al.
Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer Care Ontario Program in evidence-based care's gastrointestinal cancer disease site group
J Clin Oncol
(2004) - et al.
American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer
J Clin Oncol
(2004)
Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial
J Clin Oncol
Adjuvant chemotherapy for stage II colon cancer with poor prognostic features
J Clin Oncol
CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer
Nat Genet
Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors
J Clin Oncol
DNA mismatch repair and adjuvant chemotherapy in sporadic colon cancer
Nat Rev Clin Oncol
Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability
Cancer
Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers
J Natl Cancer Inst
Cited by (2)
K.W.J. Loh's current affiliation: Department of Medical Oncology, National Cancer Centre Singapore, Singapore.