Patient Flow
Data of 8,246 CRC patients identified from the selected hospitals during the study period were extracted and screened. Among them, 39 patients had missing values or were under 18 years old at primary diagnosis, and 71 patients started third-line palliative chemotherapy after January 1, 2016. After excluding these 110 patients, 8,136 CRC patients were included (Figure 1). Over one-third (2,963/8,136, 36%) of these patients were at TNM stage IV at primary diagnosis, and an additional 915 (11%) patients metastasized during the observation period. Thus, 3,878 (47% of 8,246) mCRC patients were identified.
Baseline Characteristics for CRC Patients
The mean age of CRC patients was 59 (SD 13) years old and 60% of them were males. Most of the patients (87%) presented in internal medicine departments. The size of primary tumor was only available among 36% (2,926/8,136) patients with a mean of 4.48 centimeters (SD 2.05). The KRAS mutation status testing rate was only 25%. The majority of CRC patients had left-sided primary tumor sites (71%) and were physically well (98%) at baseline with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) scoring of 0 or 1 (Table 1). Of the 8,136 CRC patients, 6,764 (83%) had TNM classification records at primary diagnosis. Among them, 7.2%, 19%, 30% and 44% were at stages I, II, III and IV, respectively. Liver was the most common metastatic site (52%), followed by lung (27%) (Figure 2).
Disease Recurrent Risks for CRC Patients with Radical Surgeries
For patients who underwent radical surgeries, the cumulative recurrence rate at year 1, 2, and 3 was 8.9%, 16% and 30%, respectively. By different baseline TNM stage, an upward trend could be seen from baseline stage I to stage III for all 1-, 2- and 3-year recurrence rates (p<0.001, Table S1). Recurrence rates did not differ significantly between left- and right-sided primary tumor sites (Table S2). The log-rank test showed that differences across TNM stage-specific, disease-free survival curves were of statistical significance (p<0.001, Figure 3).
Baseline Characteristics for mCRC Patients
The mean age of mCRC patients at the primary diagnosis date were 57 years old (SD 12). There were more males in mCRC patients (62%) and most (92%) presented in internal medicine departments. The mean size of the primary tumor was 4.52 centimeters (SD 2.09). The KRAS mutation status testing rate was 35%. The majority of CRC patients had left-sided primary tumor sites (69%) and were physically well (98%) at baseline (Table 1).
Treatment Patterns for mCRC Patients with Palliative Chemotherapy
Among the 3,878 mCRC patients, 79% (3,063) had records on first-line treatment of palliative chemotherapy, 1,281 had records on second-line treatment, and 404 had records on third-line treatment. Fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and other oxaliplatin-based regimens were the most frequently administered (1,275/3,063, 42%) in first-line, followed by fluorouracil, leucovorin, and irinotecan (FOLFIRI) and other irinotecan-based regimens (25%) (Figure 4A). Usage of FOLFIRI and other irinotecan-based regimens increased remarkably to 40% in second-line, which dominated treatment of this line (Figure 4B). Correspondingly, FOLFOX and other oxaliplatin-based regimens decreased to 21% in second-line. Less than one-sixth of patients received targeted biologics in combination with chemotherapy (16% and 13% in first- and second-line, respectively). Among these patients, the majority received bevacizumab (312/418, 75% and 124/162, 77% in first- and second-line, respectively). The proportion of patients receiving combination therapy with targeted biologics increased dramatically to 34% in third-line treatment (137/404), and bevacizumab was still the dominant choice (79/137, 58%) (Figure 4C).
Treatment duration decreased in later lines of treatment. Median cycles were 5 in first-line, 3 in second-line and reduced to 2 in third-line treatment. In addition, patients receiving combination therapy with targeted biologics had longer median cycles than chemotherapy alone in all three lines of treatment (6 vs. 4, 6 vs. 3 and 3 vs. 2 in the first-, second- and third-line, respectively) (Figure 4D).
Treatment Sequences for mCRC Patients with Palliative Chemotherapy
In total, 1,200 patients had records on both first- and second-line of treatments, of whom 404 patients had records on third-line of treatments.
Four hundred and ninety-five patients who received FOLFOX and other oxaliplatin-based regimens in first-line treatment changed to second-line, accounting for 39% (495/1,275) of all patients starting treatment with this type of regimen. Among them, the majority (286/495, 58%) changed to FOLFIRI and other irinotecan-based regimens, which was also the most common sequence between first- and second-line treatments (286/1,200, 24%). FOLFOX and other oxaliplatin-based regimens were somehow re-introduced to a small proportion of these patients (65/495, 13%) in second-line treatment.
The second most common sequence between first- and second-line treatments was moving from FOLFIRI and other irinotecan-based regimens to FOLFOX and other oxaliplatin-based regimens (128 out of 1,200, 11%).
A total of 994 patients receiving chemotherapy alone in first-line treatment proceeded to second-line, accounting for 39% of all those received chemotherapy alone. One in ten of them (101/994, 10%) received targeted biologics in combination with chemotherapy as their second-line treatment.
Among the 275 patients receiving the dominant treatment choice in second-line, i.e., FOLFIRI and other irinotecan-based regimens, 151 (55%) proceeded to third-line. The most common sequence from the second-line was to FOLFOX and other oxaliplatin-based regimens (36/151, 24%), followed by to other chemotherapy alone (34/151, 23%). A total of 354 patients receiving chemotherapy alone in second-line proceeded to third-line, accounting for 32% of all those received chemotherapy alone. Among these 354 patients, over a quarter (105/354, 30%) added targeted biologics on top of chemotherapy, which also constituted a large proportion of total patients receiving combination therapy in this line of treatment (105/137, 77%). Figure 5 demonstrates treatment sequences of palliative chemotherapy from first- to third-line treatments.