The largest study to date to focus on patients with colorectal cancer (CRC) with deficient DNA mismatch repair (dMMR) has found that adjuvant therapy with fluoropyrimidine combined with oxaliplatin (Eloxatin, Sanofi-Aventis), but not fluoropyrimidine alone, significantly improved disease-free survival when compared with surgery alone in patients with stage III disease. There was also a trend toward benefit in patients with stage II disease, but it did not reach significance.
The finding comes from the French AGEO study, and it confirms preliminary observations from other studies, say the authors.
The data may have implications for the clinical management of these patients ― microsatellite instability (MSI), which results from dMMR, occurs in approximately 15% of all CRC patients.
"The results provided by our study may be of great interest to clinicians as they could help with decision-making regarding adjuvant treatment for [these] patients," the study authors write.
The results are published in the July issue of the Journal of the National Cancer Institute. The corresponding author is David Tougeron, MD, PhD, from the Department of Gastroenterology, Poitiers University Hospital, Poitiers Cedex, France.
Howard S. Hochster, MD, of the Yale Cancer Center and School of Medicine, New Haven, Connecticut, and Daniel J. Sargent, PhD, of Mayo Clinic, Rochester, Minnesota, who authored an accompanying editorial, agree with this conclusion.
The editorialists discuss the limitations of sample size and also the advent of new immunotherapies acting on the programmed cell death (PD) pathway. These agents appear to be very active in dMMR cases.
"[E]ven with these limitations of the sample surveyed and an eye to the future, the data of Tougeron and colleagues is helpful to current practice as we are unlikely to see a true prospective randomized trial of adjuvant chemotherapy for patients with dMMR tumors, and adjuvant data for anti PD-1 or PDL-1 therapy remains years away," the editorialists write.
They explain that MMR deficiency "provides a therapeutic 'Achilles Heel' in colon cancer," adding that "oxaliplatin can make use of this defect to provide more than the usual benefit in the adjuvant setting."
Adjuvant Oxaliplatin vs Surgery
Why did the investigators evaluate the efficacy of oxaliplatin-based therapy in stage II and stage III dMMR CRC?
Although randomized trials have shown that adjuvant oxaliplatin-based chemotherapy improves disease-free survival (DFS) in patients with stage III CRC, the prognostic value of the MMR phenotype in patients with stage III disease with respect to oxaliplatin-based therapy is limited. In addition, the use of adjuvant therapy in patients with stage II disease is controversial, they explain.
"Because dMMR tumors are associated with a low risk of recurrence, some clinicians consider that patients with stage II dMMR colorectal cancer should not receive adjuvant chemotherapy," Dr Tougeron and colleagues write.
"However, adjuvant chemotherapy has not been specifically evaluated in patients with high-risk stage II dMMR colorectal cancer," they add.
AGEO Study Results
The study was conducted in 433 patients with dMMR CRC (median age, 73.1 years). More than half the patients (56.8%) had stage II disease; 43.2% had stage III disease. Overall, 31.3% (n = 125) of patients were identified as having confirmed or suspected Lynch syndrome.
Adjuvant chemotherapy was used in 39.3% patients (n = 170), with 27.5% (n = 119) receiving oxaliplatin-based therapy and 11.8% (n = 51) receiving 5-FU alone.
Of patients receiving adjuvant therapy, 16.7% had stage II disease, and 69.0% had stage III disease.
The median age of the patients receiving adjuvant chemotherapy was 64.3 years; for patients treated with surgery alone, it was 78.6 years.
For the entire cohort, 3-year DFS rates were highest for patients receiving oxaliplatin-based adjuvant chemotherapy — 84.2% vs 75.2% for the surgery-only group and 66.4% for the 5-FU group. In comparison with patients undergoing surgery alone, patients receicing oxaliplatin-based adjuvant chemotherapy had a 65% reduced risk for recurrence and significantly longer DFS (P < .001). Adjuvant 5-FU provided no such benefit (P = .38).
For patients with stage III disease, DFS was significantly longer with oxaliplatin-based adjuvant chemotherapy and was associated with a statistically significant 59% reduced risk for recurrence or death (P = .02). Adjuvant 5-FU therapy was associated with a nonsignificant 34% reduced risk for recurrence or death (P = .32).
In the 246 patients with stage II disease, 41 patients were treated with adjuvant chemotherapy. These included 33 patients at high risk for recurrence; of these, 24 were treated with oxaliplatin-based therapy, and nine with 5-FU. For the patients treated with oxaliplatin-based therapy, there was a trend toward significantly longer DFS, although it was nonsignificant (hazard ratio, 0.13; 95% confidence interval, 0.02 - 1.05; P = .06). Longer DFS was not seen with patients receiving 5-FU (P = 0.83).
Subgroup Analysis
In patients with Lynch syndrome (n = 125), adjuvant chemotherapy with 5-FU alone (n = 20) or in combination (n = 48) with oxaliplatin was not associated with significantly longer DFS compared with surgery alone (n = 57).
In sporadic dMMR CRC (n = 274), patients receiving oxaliplatin-based adjuvant chemotherapy (n = 59) were at a statistically significant 55% reduced risk for recurrence or death (P = 0.02) compared with patents who underwent surgery alone (n = 189). Again, this was not true for patients receiving adjuvant 5-FU (n = 26).
In a subanalysis of patients with stage III CRC, only those with sporadic dMMR stood to benefit from oxaliplatin-based adjuvant chemotherapy.
Immunotherapy in the Future
The editorialists note that the relatively low prevalence of MSI tumors in stage II and stage III disease has made it difficult to assess whether oxaliplatin-based chemotherapy could reverse the resistance seen with 5-FU in dMMR tumors. "This retrospective study...is an impressive achievement," they write.
However, they point to several limitations of the study. Although the retrospective design is considered a limitation, they note that a true prospective, randomized study in this setting is unlikely.
They also note that treatment of dMMR is changing significantly, with immune checkpoint inhibitors leading the way after showing remarkable activity in patients with stage IV dMMR CRC.
"If these observations are confirmed in advanced disease randomized trials, MMR status will become relevant as a predictive marker for patients of all disease stages, and adjuvant treatment of dMMR stage II patients may re-emerge through immuneo rather than chemotherapy," they opine.
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