Radiotherapy Combined with Raltitrexed and Irinotecan for Treating Unresectable Recurrent Colorectal Cancer

Background:Locally recurrent colorectal cancer is often associated with considerable morbidity and poor quality of life. Moreover, surgical resection is frequently not viable because of tumor fixation in the pelvis. This study aimed to evaluate the effects and safety of intensity-modulated radiotherapy when administered concurrently with raltitrexed and irinotecan to patients with unresectable recurrent colorectal cancer.Methods:Eligible patients had unresectable pelvic recurrence of colorectal cancer, UGT1A1 genotype *1*1 or *1*28, and were refractory to, or intolerant of, chemotherapy with fluoropyrimidine and oxaliplatin. Intensity-modulated radiation therapy (IMRT) was delivered to the pelvis with a total dose of 50–60 Gy in 25–30 fractions, concurrently with irinotecan (200 mg/m2 on days 1 and 22) and raltitrexed (3 mg/m2 on days 1 and 22). After completion of radiation treatment, patients underwent surgery or continued the same regimen of chemotherapy and were assessed by a multidisciplinary team. The primary endpoint was the objective response rate, evaluated using RECIST version 1.1. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), local progression-free survival (LPFS), and safety. Clinical and imaging evaluations were scheduled every month during treatment.Results:Between January 1, 2019, and July 14, 2020, 30 patients were enrolled in this study at the Fudan University Shanghai Cancer Center. All patients completed radiotherapy with a median number of 5 chemotherapy cycles (range, 2–10). Twelve patients (40%) experienced an objective response, including two complete responses and ten partial responses. Seventeen patients exhibited stable disease, leading to a DCR of 96.7%. With a median follow-up of 13 (range, 4–25) months, progression was observed in 20 patients (11 loco-regional failures, 11 distant metastases, and 5 deaths). The median PFS was 13 (95% confidence interval [CI], 9–18) months; the median LPFS was 15 (95% CI, 14 to not reached) months. The incidence of grade 3 or 4 adverse events was 26.7%. The most common grade 3 or 4 adverse event was neutropenia (13.3%).Conclusions:IMRT with concurrent raltitrexed and irinotecan exhibited encouraging efficacy with an acceptable toxicity profile in patients with unresectable recurrent colorectal cancer.Trial registration: ClinicalTrials.gov: NCT04499586, registered on July 31, 2020 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04499586.

A case in which TAS-102 produced disease control without severe adverse events in a patient with recurrent colorectal cancer and dihydropyrimidine dehydrogenase deficiency

Fluoropyrimidine is commonly used to treat unresectable cases of metastatic colorectal cancer or as an adjuvant therapy for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is an enzyme encoded by the DPYD gene, which is responsible for the rate-limiting step in pyrimidine catabolism and breaks down >80% of standard doses of 5-fluorouracil (5-FU). Reductions in DPD activity increase the half-life of 5-FU, resulting in excess 5-FU accumulation and toxicity, which can lead to life-threatening side effects. There have been several published case reports about DPD deficiency in colorectal cancer patients from Western countries. However, case reports of DPD deficiency in Japanese colorectal cancer patients are rare because the measurement of DPD activity is not covered by the public medical insurance system in Japan, and DPD activity is not currently measured in daily clinical practice. Furthermore, there have not been any reports about anticancer drug therapy for Japanese patients with DPD deficiency. In this report, we describe a case in which a Japanese patient with colorectal cancer was diagnosed with DPD deficiency. The DPD deficiency arose as a severe adverse effect of mFOLFOX6/CapOX treatment for recurrent colorectal cancer, and the patient was subsequently treated with TAS-102, without experiencing any severe adverse effects. We report this case along with a review of the literature.

Forkhead Box Q1 Expression Is Associated With Tumor Location of Right-Sided Colon, But Not With Acquisition of Oxaliplatin Resistance in Colorectal Cancer

Oxaliplatin (OHP) is a reagent for the standard treatment of advanced and recurrent colorectal cancer (CRC), although OHP resistance mechanisms are not fully elucidated. We found that OHP-resistant clones derived from HCT116, but not DLD1 were also resistant against the other drugs used for CRC treatment (5-fluorouracil, OHP, and trifluorothymidine) and their xenograft tumors were resistant against OHP treatment. Among the candidate genes derived from microarray analysis using the samples of OHP-resistant cells and their xenografts derived from HCT116, Forkhead box Q1 (FOXQ1) was further assessed for validation of OHP resistance and its association with clinicopathological features. Modification of FOXQ1 via siRNA knockdown and expression vector could not confirm the involvement of FOXQ1 in OHP resistance. In 173 CRC patients, FOXQ1 was upregulated in most CRC tumors compared to normal colonic mucosa. FOXQ1 expression was significantly different by tumor location of the right-sided colon cancer compared with left-sided and rectal cancer. Moreover, expression level was significantly associated with prognosis in advanced and recurrent patients. TCGA data also showed significant association of FOXQ1 expression with tumor location. Our results indicated that FOXQ1 expression is associated with tumor location of right-sided colon, but not with acquisition of OHP resistance in colorectal cancer.

Nivolumab-induced endocrinopathy

Inhibitors of immune control points (ICP) is a new group of drugs used to treat patients with incurable neoplasias, in particular their metastatic forms. However, there is a risk of developing immune-mediated adverse events from a number of organ systems during therapy with these drugs. Immune-mediated adverse events are understood as a side effect due to excessive activation of the immune system with autoimmune damage to normal tissues of various organs and systems, and not the main goal of immunotherapy. In particular, one of these side effects when using ICP is the development of endocrinopathies (thyroiditis, hypophysitis, adrenalitis, type 1 diabetes mellitus). We present a literature review and a clinical case of the development of hypothyroidism, hyponatremia and psychosis in a patient after nivolumab therapy for recurrent colorectal cancer 3 months after immunotherapy.