Currently, targeted agents are not affordable to many Chinese patients as a first-line treatment. For them, chemotherapy alone can be used as maintenance treatment.
In the XelQuali study, patients with unresectable mCRC who obtained stable disease (76%) after 4 cycles of first-line CapeOx treatment continued to have single-agent capecitabine maintenance . The results showed that the median PFS was 6.7 months, and the median OS was 20.5 months for all recruited patients. In the capecitabine maintenance subgroup, the median PFS and OS were 8.1 and 23.1 months, and the occurrence of AEs of all grades (neuropathy, diarrhea, and lethargy) was significantly reduced. The occurrence rates of grade 1/2 and grade 3 AEs were 77% and 7% in the experimental group and were 47% and 3% in the control group. The results indicated that single capecitabine maintenance for patients obtained CR, PR, or SD after short-term CapeOx provided an effective and tolerable therapeutic option. This protocol minimized accumulated neurotoxicity by reducing repeated injections of oxaliplatin. It is more cost-effective and convenient than continuous treatment to be used for patients and healthcare providers .
The single-agent capecitabine maintenance protocol has been fully verified in Chinese patients with mCRC. Sun Yat-sen University Cancer Center conducted a phase II study of CapeOx as a first-line treatment followed by capecitabine maintenance in patients with mCRC. Among the 124 patients with treatment-naïve mCRC receiving a median 6 cycles of CapeOx, 62 with no disease progression chose discontinuation or continued to receive oral capecitabine (1000 mg/m2, twice daily) until disease progression or intolerable toxicity occurred. Among them, 22 received maintenance treatment. The patients who did or did not have maintenance treatment were similar in baseline characteristics. The results showed that at the end of the study (median follow-up, 20 months), 19 (86.3%) patients in the maintenance group were still alive (range, 8–37 months); therefore, OS could not be calculated. The median duration of disease control was superior in the maintenance group than in the non-maintenance group (14 vs. 9 months, P = 0.041). Among the 22 patients in the maintenance group, only 1 discontinued treatment due to grade 3 hand-foot syndrome after receiving 2 cycles of capecitabine. Four patients (18.2%) had grade 1/2 hand-foot syndrome, and the rest had a mild AE .
Sun Yat-sen University Cancer Center published the results of a phase III multi-center study on continuous capecitabine maintenance after CapeOx or FOLFOX in 2015 . In total, 274 patients with mCRC were enrolled, and they were randomized at a 1:1 ratio into capecitabine maintenance (1000 mg/m2, twice daily for 14 days, then chemo-free interval for 7 days; n = 136) or non-maintenance observation (n = 138) after CapeOx or FOLFOX for 18–24 weeks. The results showed that the maintenance group surpassed the observation group in PFS (10.43 vs. 7.82 months, P < 0.001). Two patients (1.5%) in the maintenance group withdrew from the study due to a toxic reaction, but most patients tolerated the treatment well.
Another similar study on capecitabine maintenance after first-line treatment was performed by Peking University Oncology Hospital, with 85 recruited mCRC patients obtaining controlled disease (CR, PR, or SD) after first-line CapeOx, FOLFOX, or FOLFIRI . Thirty-three patients chose to receive capecitabine maintenance, and the others were observed without maintenance. The results suggested a superior prognosis of the maintenance group compared with the non-maintenance group. The median time to progression (TTP) was 9.0 months in the maintenance group and 6.5 months in the non-maintenance group (P = 0.007); OS was 40.4 and 21.9 months, respectively (P = 0.015). Among the patients on maintenance treatment, 6 (18.2%) had grade 1 hand-foot syndrome, 1 (3.0%) had grade 3 diarrhea, and 1 (3.0%) had grade 3 thrombocytopenia. All of these events were controlled by supportive treatment and did not contribute to early withdrawal .
Maintenance therapy with targeted agents
Maintenance with chemotherapy in combination with targeted agents
For mCRC patients responding to chemotherapy in combination with targeted agents, maintenance with less toxic chemotherapy (5-FU) and targeted agents are recommended. Among these schemes, the bevacizumab plus capecitabine regimen has the most compelling evidence.
In the sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO3) study, a Dutch phase III randomized controlled trial, mCRC patients were randomized to receive bevacizumab plus capecitabine doublet maintenance, or to be observed with no maintenance after 6 cycles of first-line CapeOx plus bevacizumab, and then they were re-inducted with CapeOx plus bevacizumab when disease progression occurred . The results showed that the maintenance group was superior to the suspension group with regard to PFS, but there was no significant difference in QoL scores .
In the German AIO KRK 0207 trial, patients with mCRC were randomized to receive 5-FU plus bevacizumab maintenance, single-agent bevacizumab maintenance, or no maintenance after 24 weeks of 5-FU, oxaliplatin plus bevacizumab triplet therapy . The results showed that the median PFS was 6.2, 4.8, and 3.6 months, respectively. To achieve a longer first TTP, 5-FU plus bevacizumab is a superior maintenance scheme .
Maintenance treatment with a single targeted drug
For patients responding to chemotherapy in combination with targeted drugs, if they cannot tolerate a less toxic chemotherapy regimen, individual targeted agent maintenance is a possible treatment option.
In the First-Line XELOX Plus Bevacizumab Followed by XELOX Plus Bevacizumab or Single-Agent Bevacizumab as Maintenance Therapy in Patients with Metastatic Colorectal Cancer study, the Phase III MACRO TTD study, AEs were significantly reduced in patients with single-agent bevacizumab compared with those with continuous chemotherapy . This study assessed the efficacy on patients with mCRC who switched to single-agent bevacizumab maintenance or continued the scheme after receiving CapeOx plus bevacizumab induction. The results showed that median PFS (9.7 vs. 10.4 months), median OS (20.0 vs. 23.2 months), and response rate (49% vs. 47%) were not significantly different between the two groups. However, the rate of AEs including diarrhea, food-hand reaction, and neuropathy was significantly higher in patients continuing chemotherapy than in patients switching to maintenance treatment .
In the MACRO-2 study, patients received FOLFOX plus cetuximab for 8 cycles, and then they were randomized to receive single-agent cetuximab maintenance or continuous FOLFOX plus cetuximab . The results revealed that the efficacy of single-agent cetuximab maintenance was not inferior to continuous combination therapy (PFS: 8.9 vs. 9.8 months, P = 0.09; OS: 23.6 vs. 22.2 months, P = 0.54; response rate: 47% vs. 39%, P = 0.33) .
The combination maintenance with two or more targeted agents presented an increased degree of AEs instead of improved benefits; therefore, epidermal growth factor receptor (EGFR)- and vascular endothelial growth factor receptor (VEGF)-targeted agent combination was not recommended.
The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study found that for oxaliplatin- or irinotecan-based chemotherapy in combination with bevacizumab, when panitumumab was added, PFS was significantly shortened and toxicity was significantly strengthened, regardless of wild-type or KRAS exon 2 mutations . Similar results were obtained from the CAIRO2 study by adding cetuximab to capecitabine, oxaliplatin, and bevacizumab . Therefore, the community of experts is strongly averse to combining therapies that target EGFR (cetuximab or panitumumab) and VEGF (bevacizumab).