Uridine Diphosphate Glucuronosyltransferase 1a1 Improves Response Rate in Advanced CRC

By Michael Vlessides, /alert Contributor
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New research has concluded that using the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype to guide the dose of irinotecan (Camptosar; Pfizer) -- when administered in combination with capecitabine-based neoadjuvant chemoradiotherapy -- can improve the rate of pathologic complete response in patients with locally advanced rectal cancer.

The multicenter Chinese investigation (NCT02605265), one of the first phase-III studies of its kind, demonstrated that UGT1A1 genotype guidance can increase the pathologic complete response rate from 15% to 30% compared with capecitabine-based neoadjuvant chemoradiotherapy. 

Reporting in the Journal of Clinical Oncology, the researchers explained that while the efficacy of irinotecan in combination with neoadjuvant chemoradiotherapy has been well researched, there have been concerns about irinotecan’s poor tolerability. At the same time, the UGT1A1 genotype has become the key determinant of irinotecan dosing. 

Indeed, previous dose-escalation studies have found that the maximum tolerated irinotecan dose decreased with an increasing number of defective UGT1A1 alleles. This, the investigators said, confirms that the irinotecan dose can be guided by the UGT1A1 genotype.

“We hypothesized,” the authors wrote, “that the irinotecan dose administered to patients undergoing neoadjuvant chemotherapy could be guided by the UGT1A1 genotype.”

To help test this idea, the investigators performed the multicenter, prospective randomized, open-label, phase-III trial at 17 radiation oncology centers across China between November 2015 and December 2017. Patients were eligible if they had clinical T3-4 and/or N+ rectal adenocarcinoma and UGT1A1 genotype *1*1 or *1*28. 

Participants were randomly allocated to one of two groups. Controls underwent pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by oxaliplatin and capecitabine. Their counterparts in the treatment group underwent radiation with capecitabine, combined with weekly irinotecan (80 mg/m2 for patients with UGT1A1*1*1 or 65 mg/m2 for patients with UGT1A1*1*28), followed by irinotecan and capecitabine. Surgery was scheduled for eight weeks after chemotherapy completion. 

The study’s primary endpoint was pathologic complete response. Secondary endpoints were several, and included tolerability, quality of life, tumor regression grade, local control, disease-free survival, and overall survival.

According to study lead author Ji Zhu, MD, of Fudan University Shanghai Cancer Center, in Shanghai, China, 360 patients were initially enrolled in the trial, 356 of whom were evaluated as the modified intention-to-treat population (n=178 in each group). Surgery was performed in 87% of patients in the control group, compared with 88% of their counterparts in the experimental group. 

It was found that pathologic complete response was observed in 15% of patients in the control group (27 of 178) and 30% of those in the experimental group (53 of 178), yielding a risk ratio of 1.96 (95% confidence interval: 1.30-2.97; p=0.001). Four controls and six experimental-group patients achieved complete clinical response, respectively. 

With respect to treatment tolerability, grade 3-4 toxicities occurred in 6% of patients in the control group (n=11), significantly less than the 38% of patients (n=68) in the experimental group who experiences such toxicities (p<0.001). The most common grade 3-4 toxicities were leukopenia  (3% controls vs 25% experimental), neutropenia (2% vs 20%), and diarrhea (2% vs 13%).

The overall surgical complication rate (grade 3-4) was not significantly different between the two groups, affecting 11% and 15% of patients in the control and experimental groups, respectively. These included wound infection, anastomotic stenosis, anastomotic leakage, delayed wound healing, and ileus/obstruction. 

The investigators concluded that using UGT1A1 genotype to guide the addition of irinotecan to capecitabine-based neoadjuvant chemoradiotherapy can significantly improve complete tumor response. This approach, they noted, may help improve tumor regression in patients with locally advanced rectal cancer.

“The local control, disease-free survival, and overall survival data reflecting the long-term prognosis are not yet mature;” they wrote, “we plan to report survival outcomes separately in approximately three years.”


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