A New Light in Nonsurgical Rectal Cancer Treatment

In stage 2 and 3 rectal cancer, the accepted standard approach to neoadjuvant (preoperative tumor-shrinking) treatment is radiotherapy with concurrent capecitabine chemotherapy, followed after radiotherapy by dual chemotherapy with capecitabine plus oxaliplatin. When considering "how to further increase the effectiveness of neoadjuvant treatment" in colon and rectal cancer, one thinks of irinotecan chemotherapy, which is highly effective in advanced disease. However, because of irinotecan's side effects, a meaningful benefit in neoadjuvant rectal cancer treatment had not been shown so far. The first comprehensive (phase III) study evaluating UGT1A1 genotype to guide irinotecan dosing was a clinical trial whose results were published on 29 October in Journal of Clinical Oncology, showing that UGT1A1 genotype-based, dose-adjusted irinotecan in neoadjuvant treatment led to a 2-fold increase in pathological complete response rates as a result!

What Is UGT1A1? Its Importance for Cancer and Irinoteken Chemotherapy 

UGT1A1 is the name for UDP-glucuronosyltransferase 1-1, which in humans is encoded by the UGT1A1 gene and is an enzyme. UGT1A1 gene changes are associated with more side effects from certain medicines.

UGT1A1 28 is a genetic change causing more neutropenia(low white blood cells) and diarrhea in patients receiving irinotecan. The United States Food and Drug Administration (FDA) therefore recommends a lower irinotecan dose for patients with the * 28 genetic change.

Understanding the Rectum Better

The human large bowel consists of two parts, the colon and rectum. It averages 1.5 m in length. Shaped like an inverted U, it begins with the cecum in the lower right abdomen, goes upward, turns below the liver and crosses the abdomen horizontally. It reaches below the spleen in the upper left corner, then turns again and descends on the left to join the rectum. The rectum is the final part of the digestive system, formed by widening of the large bowel, and averages 15 cm in length.

The rectum, the last 15 cm of the large bowel, is divided into 3 regions: lower, middle and upper. Rectal tumors are treated differently depending on which region or regions they involve. For a tumor close to the anus, neoadjuvant treatment and rectum-preserving surgeries and approaches become more important.

The Irinotecan Study Based on UGT1A1 in Neoadjuvant Rectal Treatment

An increased irinotecan dose guided by UGT1A1 genotype, combined with capecitabine-based chemoradiation, significantly improved clinical response with acceptable side effects in Chinese patients with locally advanced rectal cancer.

Ji Zhu and colleagues in the Department of Radiation Oncology at Fudan University Shanghai Cancer Center in Shanghai, China, investigated whether adding a second drug to neoadjuvant chemoradiation could improve clinical outcomes. This is the first phase III clinical trial evaluating UGT1A1 genotype to guide irinotecan dosing in neoadjuvant treatment of locally advanced rectal cancer.

The authors explained in the study background that irinotecan had previously been investigated for effectiveness in combination with neoadjuvant chemoradiation, but there were concerns about poor tolerability.

Varying irinotecan dosage by UGT1A1 genotype improves pathological complete response after neoadjuvant treatment. Given routinely, without knowing or considering UGT1A1 genotype, irinotecan causes severe side effects in some patients. Such severe side effects exceed acceptable levels for early-stage cancer treatment. It therefore seems useful to use a biomarker such as UGT1A1 genotype to adjust irinotecan dosage.

Study Details

Chinese researchers conducted a China-based randomized, open-label, multicenter phase III trial investigating irinotecan combined with capecitabine-based chemoradiation for locally advanced rectal cancer (a large tumor or spread to neighboring lymph nodes).

Patients with T3-4 tumors (full-thickness involvement of the rectal wall) and/or node-positive rectal adenocarcinoma and UGT1A1 genotype * 1 * 1 or * 1 * 28 were enrolled.

Below is an image to help explain the "T staging" system for rectal tumors:

Patients randomly divided into 2 groups received radiotherapy to the rectal region, 50 Gy in 25 fractions, concurrently with:

• capecitabine plus disease irinotecan in the experimental arm
• capecitabine alone in the control arm.

After radiotherapy, treatment continued with:

• capecitabine plus irinotecan in the experimental arm,
• capecitabine plus oxaliplatin in the control arm.

Irinotecan Dosing Was Adjusted as Follows:

• 80 mg/m2 for patients with UGT1A1 * 1 * 1 genotype;
• 65 mg/m2 for patients with UGT1A1 * 1 * 28 genotype.

The primary endpoint was pathological complete response.

Study Results

• 356 patients were assigned to one of the two arms, with 178 in each group.
• Surgery was performed in 87% of control-group and 88% of experimental-group patients.
• Pathological complete response was 15% in the control group and 30% in the experimental group.
• Severe (grade 3 and 4) side effects were recorded in 6% of the control group and 38% of the experimental group.
• The most common grade 3 - 4 side effects were leukopenia, neutropenia and diarrhea.
• Surgical complication rates did not differ significantly between the groups (11% vs 15%; p <0.001).

Study Significance and Commentary

As shown, adding irinotecan to neoadjuvant treatment based on UGT1A1 genotype increased pathological complete response by 2-fold compared with standard treatment in Chinese patients. Irinotecan caused more side effects, particularly leukopenia, neutropenia and diarrhea. High-dose irinotecan added to standard chemoradiation under UGT1A1 guidance may become an innovative and more effective strategy for better tumor regression in locally advanced rectal cancer.

Comparison with Earlier Studies

The ongoing phase III ARISTOTLE study in the United Kingdom was also designed to establish irinotecan's benefit in neoadjuvant chemoradiotherapy. The main difference from the Chinese study discussed here is that ARISTOTLE administers a fixed irinotecan dose of 60 mg/m2, which appears to have been too low.

At the ASCO 2020 Annual Meeting, ARISTOTLE investigators reported that patients in the irinotecan group did not achieve a higher pathological complete response. Chinese researchers say the main reason was insufficient irinotecan dosage. However, White and Asian populations differ in genotype prevalence and irinotecan tolerance, and these differences must be fully considered when evaluating generalizability.