Treatment sequences of patients with advanced colorectal cancer and use of second-line FOLFIRI with antiangiogenic drugs in Japan: A retrospective observational study using an administrative database

Abstract

The objectives were to describe treatment sequences for advanced colorectal cancer (CRC), use of second-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) plus antiangiogenic drug (bevacizumab, ramucirumab, aflibercept beta) therapy, and the factors associated with the duration of antitumor drug treatment from second-line antiangiogenic therapy in Japan. This retrospective observational study was conducted using a Japanese hospital-based administrative database. Patients were enrolled if they started adjuvant therapy (and presumably experienced early recurrence) or first-line treatment for advanced CRC between May 2016 and July 2019, and were analysed until September 2019. Factors associated with overall treatment duration from second-line treatment with FOLFIRI plus antiangiogenic drugs were explored with multivariate Cox regression analysis. The most common first-line treatments were FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin) or CAPOX (capecitabine, oxaliplatin) with bevacizumab (presumed RAS-mutant CRC) and FOLFOX with panitumumab (presumed RAS-wild type CRC). The most common second-line treatments were FOLFIRI-based. Many patients did not transition to subsequent lines of therapy. For second-line treatment, antiangiogenic drugs were prescribed more often for patients with presumed RAS-mutant CRC, right-sided CRC, and independent activities of daily living (ADL). The median duration of second-line FOLFIRI plus antiangiogenic drug treatment was 4.5 months; 66.2% of patients transitioned to third-line therapy. Low body mass index and not fully independent ADL were significantly associated with shorter overall duration of antitumor drug treatment from second-line therapy. Left-sided CRC, presumed RAS-wild type CRC, previous use of oral fluoropyrimidines and use of proteinuria qualitative tests, antihypertensives, or anticholinergics during second-line therapy were significantly associated with longer treatment. Treatment of advanced CRC in Japan is consistent with both international and Japanese guidelines, but transition rates to subsequent therapies need improvement. In addition to antitumor drug treatment, better ADL, higher body mass index, management of hypertension, and proteinuria tests were associated with continuation of sequential therapy that included antiangiogenic drugs.

Real-World Data Analysis of Second-Line Antiangiogenic Targeted Treatments Following Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies and First-Line FOLFOX for Patients with Metastatic Colorectal Cancer

“…Although new treatment options have become available for patients with CRC in recent years, CRC-related deaths in Japan have not decreased [ 2 , 4 , 5 ]. Previously, we showed that treatment patterns of advanced CRC in real-world clinical practice in Japan are consistent with international and Japanese guidelines (Japanese Society for Cancer of the Colon and Rectum [JSCCR]) [ 6 ]. For patients with left-sided RAS wild-type metastatic CRC (mCRC), the standard first-line treatment is chemotherapy with an anti-epidermal growth factor receptor (EGFR) monoclonal antibody [ 5 , 7 ].…”

“…Increased survival has been demonstrated in clinical trials for second-line use of bevacizumab [ 21 ], ramucirumab [ 13 ], and aflibercept beta [ 12 , 22 ], and these antiangiogenic drugs are currently recommended in second-line therapy for patients with unresectable advanced or recurrent CRC [ 5 , 7 ]. Consistent with these recommendations, our previous study, with a September 2019 cutoff, showed that these antiangiogenic drugs were used commonly as second-line therapy for patients with advanced CRC, regardless of first-line treatment choices [ 5 , 6 ]. Despite this, information on the optimal treatment sequences for these patients, especially after first-line anti-EGFR therapy, is lacking.…”

“…However, use of ramucirumab and aflibercept beta is largely informed on the basis of clinical trials that did not include patients who received first-line anti-EGFR therapy [ 12 , 13 ]. Consistent with treatment recommendations [ 5 ], findings from our previous analysis that described treatment patterns for patients with advanced CRC (the overall population, cutoff September 2019) using a Japanese hospital-based administrative database showed that FOLFOX (leucovorin + 5-FU + oxaliplatin) with anti-EGFR antibodies was the most commonly prescribed first-line treatment for Japanese patients with presumed RAS wild-type CRC, followed by second-line irinotecan-based chemotherapy [ 6 ]. In the current study, we used more recent information from this database (cutoff July 2021) to further extend our understanding of the real-world use of prescription medication in Japan, focusing on patients who received first-line anti-EGFR therapy only.…”

“…Although there is consensus that second-line antiangiogenic drugs in combination with chemotherapy should be considered for patients with RAS wild-type CRC who have previously received first-line anti-EGFR therapy [ 5 , 11 ], there is very little evidence from clinical trials to guide clinicians on the most appropriate second- and third-line treatment sequences for these patients [ 11 ]. In Japan, bevacizumab became available for use in combination with various chemotherapy regimens for patients with CRC in April 2007, followed by ramucirumab (in May 2016) and aflibercept beta (in March 2017) for combination with second-line FOLFIRI (leucovorin + 5-fluorouracil [5-FU] + irinotecan) [ 5 , 6 ]. However, use of ramucirumab and aflibercept beta is largely informed on the basis of clinical trials that did not include patients who received first-line anti-EGFR therapy [ 12 , 13 ].…”

Auranofin and its analogs as prospective agents for the treatment of colorectal cancer

“…At variance, the second-line approach also relies on compounds such as irinotecan and raltitrexed now entered in the clinical practice with encouraging results. For instance, FOLFIRI-based (leucovorin, 5-fluorouracil, and irinotecan) regimens are a common clinical practice, even in combination with antiangiogenic agents [ 14 ] .…”