Elsevier

Clinical Colorectal Cancer

Volume 14, Issue 3, September 2015, Pages 192-197
Clinical Colorectal Cancer

Original Study
Views of Australian Medical Oncologists Regarding the Use of Mismatch Repair Status to Assist Adjuvant Chemotherapy Recommendations for Patients With Early-Stage Colon Cancer

https://doi.org/10.1016/j.clcc.2015.03.001Get rights and content

Abstract

Background

Mismatch repair deficiency (dMMR) has been shown to confer a superior prognosis and is possibly predictive of a lack of benefit from fluoropyrimidine adjuvant chemotherapy (AC) for early-stage colon cancer (ESCC). We conducted a survey to assess medical oncologists' views regarding ESCC AC, with an emphasis on the use of MMR status to guide their recommendations.

Materials and Methods

The survey was distributed to all members of the Medical Oncology Group of Australia. Their demographic data, practice information, and views on the use of MMR status in ESCC and in 3 case scenarios were collected. The 3 case scenarios were a 68-year-old woman with moderate-risk stage II disease, who was eager to undergo AC (case 1); a 43-year-old woman with high-risk stage II disease, who was ambivalent regarding AC (case 2); and a 78-year-old woman with multiple comorbidities and high-risk stage II disease, who was eager to undergo AC.

Results

The survey response rate was 35% (190 of 550). Of the 190 responders, 152 (80%) routinely treated patients with colon cancer (CC) and completed the survey. For patients with stage II CC, 112 of 141 (79%) would use MMR status to assist AC recommendations, and 97 (69%) thought it changed their practice. In the case scenarios, 81% (case 1, 110 of 136), 67% (case 2, 92 of 137), and 43% (case 3, 57 of 133) used MMR status to assist AC recommendations. If dMMR was present, 78% (case 1, 86 of 110), 53% (case 2, 49 of 92), and 53% (case 3, 30 of 57) changed their initial recommendations by advising against AC.

Conclusion

The use of MMR status to assist AC recommendations for patients with stage II CC is an accepted practice for most Australian medical oncologists who responded to our survey.

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.

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