Toxic serum metabolomic characteristics of adjuvant chemoradiotherapy for rectal cancer

The team of researcher Zhu Zhengjiang of the Interdisciplinary Research Center of Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and the team of Professor Zhu Ji of Zhejiang Cancer Hospital published an online report entitled “Serum Metabolic Traits Reveal Therapeutic Toxicities and Responses of Neoadjuvant” in the journal Nature Communications Chemoradiotherapy in Patients with Rectal Cancer” (Nature Communications, 2022, 13: 7802). This work revealed changes in metabolic characteristics during chemoradiotherapy and discovered a series of metabolic characteristics related to toxicity and efficacy of chemoradiotherapy through serum metabolomics analysis of multiple time points during radiotherapy and chemotherapy in rectal cancer patients receiving neoadjuvant Chemoradiotherapy (nCRT). Wang Hongmiao, a doctoral student in Zhu Zhengjiang’s group, and Dr. Jia Huixun from Shanghai Jiao Tong University School of Medicine are co-first authors of the paper, and the Interdisciplinary Research Center for Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences is the first unit.

Colorectal cancer is the third most common gastrointestinal malignancy worldwide, and about 15% of colorectal cancer patients are diagnosed with locally advanced rectal cancer at the time of presentation, and this part of patients is often associated with a higher risk of postoperative recurrence and metastasis. At present, neoadjuvant chemoradiotherapy is gradually becoming the standard therapy for locally advanced rectal cancer. However, there is significant individual heterogeneity in the efficacy of chemoradiotherapy among patients, and only some patients can achieve pathopathologic complete remission (pCR) after treatment. In the previous study, Dr. Zhu’s team conducted a multicenter randomized Phase III clinical study (CliClare, J. Clin. Oncol. 2020, 38: 4231-4239)。 This clinical study showed that the proportion of complete pathological response (pCR) in patients could be increased from 10% to 35% by adding the UGT1A1 genotype-guided dose of ilitecan to the traditional capecitabine chemoradiotherapy regimen. However, due to the influence of drug toxicity and other factors during radiotherapy and chemotherapy, patients may have a variety of adverse reactions including diarrhea, leukopenia, neutropenia, etc. These adverse reactions are not conducive to the subsequent treatment of patients, which greatly limits the clinical application of neoadjuvant chemoradiotherapy.

Figure 1 Schematic diagram of experimental design, the type and number of metabolic species identified by non-targeted metabolomics, and the principal component analysis score of metabolome changes during radiotherapy and chemotherapy (Image source: Nature Communications)

In order to explore the metabolic characteristics associated with chemoradiotherapy in rectal cancer patients, the authors used the large-scale non-targeted metabolomics precision measurement and analysis technology developed by Zhu Zhengjiang’s group to systematically characterize the metabolomes of 743 serum samples from 165 rectal cancer patients at five time points in the process of neoadjuvant chemoradiotherapy, and used the MetDNA software independently developed by the group to accurately identify 557 small molecule metabolites to depict the metabolic changes in the process of radiotherapy and chemotherapy. The study found that chemoradiotherapy caused overall changes in the serum metabolome, and a variety of related metabolites, including tryptophan, were significantly downregulated after chemoradiotherapy. Furthermore, this study studied adverse reactions such as diarrhea caused by radiotherapy and chemotherapy, and constructed a metabolite prediction model that predicted the risk of diarrhea and the lowest point of blood count before treatment. The predictive model can assess the risk of adverse reactions in patients before chemoradiotherapy, so as to achieve precise diagnosis and treatment of patients to avoid adverse reactions caused by chemoradiotherapy. This study also showed that female patients have a higher risk of diarrhea during treatment than men, and acetylcarnitine metabolites are strongly associated with this gender heterogeneity.

Figure 2 3-phenylpropanoic acid and phenylacetylglutamine are associated with the efficacy of neoadjuvant chemoradiotherapy during chemoradiotherapy (Image: Nature Communications)

The authors also conducted metabolomic studies on the difference in efficacy of pathologic complete remission after radiochemotherapy treatment. Through two-factor screening of metabolites related to the dose and efficacy of chemoradiotherapy and chemotherapy, two derived metabolites of the intestinal flora, 3-phenylpropanoic acid and phenylacetylglutamine, were closely related to the efficacy of neoadjuvant chemoradiotherapy. Both metabolites remained low in serum of patients who achieved complete pathological remission throughout chemoradiotherapy. This means that lower serum levels of 3-phenylpropionic acid and phenylacetyl glutamine may contribute to tumor retraction during chemoradiotherapy, suggesting that the intestinal flora may play an important regulatory role in chemoradiotherapy. In addition, after chemoradiotherapy, patients with complete pathologic response had higher levels of essential amino acids than those who did not develop pathologically complete remission, and there was no difference between the two groups before chemoradiotherapy. This suggests that serum essential amino acid levels can reflect the efficacy of neoadjuvant chemoradiotherapy, which may indicate a strong correlation between the patient’s nutritional level during treatment and efficacy. In this study, a multi-level systematic study of serum metabolomic changes in the process of neoadjuvant chemoradiotherapy was carried out, revealing the dynamic metabolic changes in the process of neoadjuvant chemoradiotherapy, and providing potential guidelines for individualized neoadjuvant chemoradiotherapy.

This work has been funded by the National Natural Science Foundation of China, the Ministry of Science and Technology, the Chinese Academy of Sciences, the Shanghai Municipal Science and Technology Commission and other funds. (Source: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences)

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