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Elderly patients with mCRC may benefit from reduced-dose S-1 + oxaliplatin over full-dose S-1 monotherapy

Roshini Claire Anthony
18 Mar 2019

Elderly, vulnerable patients with metastatic colorectal cancer (CRC) experienced longer progression-free survival (PFS) and fewer toxicities with a reduced-dose combination chemotherapy regimen of S-1 and oxaliplatin compared with full-dose S-1 monotherapy, the phase II NORDIC9* trial showed.

Participants were 160 patients aged 70 years (median age, 78 years) with previously untreated metastatic colorectal adenocarcinoma and ineligible for full-dose combination chemotherapy. They were randomized to receive full-dose oral S-1 (30 mg/m2 BID on days 1–14 every 3 weeks) and at progression, intravenous irinotecan (250 mg/m2 on day 1 every 3 weeks or 180 mg/m2 on day 1 every 2 weeks; n=83) or reduced-dose oral S-1 (20 mg/m2 BID on days 1–14) plus intravenous oxaliplatin (100 mg/m2 on day 1 every 3 weeks) and at progression, oral S-1 (20 mg/m2 BID on days 1–14) plus intravenous irinotecan (180 mg/m2 on day 1 every 3 weeks; n=77).

Patients were followed up for a median 23.8 months. Intravenous bevacizumab at a dose of 7.5 mg/kg on day 1 every 3 weeks (first-line) was allowed. Gradual dose escalation of irinotecan was recommended (to 350 mg/m2 on day 1 every 3 weeks or 250 mg/m2 on day 1 every 2 weeks) in patients who tolerated full-dose monotherapy with only grade 1 toxicities.

Patients who received reduced-dose combination therapy had longer PFS compared with those who received full-dose monotherapy (median, 6.2 vs 5.3 months, hazard ratio [HR], 0.72, 95 percent confidence interval [CI], 0.52–0.99; p=0.047). [Lancet Gastroenterol Hepatol 2019; doi:10.1016/S2468-1253(19)30041-X]

Median time to failure of first-line therapy – after accounting for treatment breaks – was comparable between full-dose monotherapy and reduced-dose combination therapy recipients (6.0 vs 7.4 months, HR, 0.77; p=0.110), as was overall survival (OS; median, 11.5 vs 14.5 months, HR, 0.82, 95 percent CI, 0.57–1.19; p=0.302).

In a post hoc analysis, patients who received bevacizumab (n=22 in each group) demonstrated greater PFS than those who did not (median, 8.2 vs 4.7 months, HR, 0.65; p=0.018), while OS was numerically but not significantly greater in bevacizumab recipients (20.5 vs 12.6 months, HR, 0.64; p=0.051). However, the researchers advised caution when interpreting these findings due to potential confounding. 

“Future studies should explore whether fluoropyrimidine-based monotherapy plus bevacizumab is as effective as reduced-dose combination therapy, and whether bevacizumab adds further benefit when used alongside reduced-dose combination therapy,” they advised.

Of the 157 patients who received treatment, grade 3–4 adverse events (AEs) occurred more frequently among full-dose monotherapy compared with reduced-dose combination therapy recipients (62 percent vs 43 percent; p=0.014), specifically diarrhoea (15 percent vs 3 percent; p=0.018), fatigue (12 percent vs 4 percent; p=0.083), and dehydration (6 percent vs 0; p=0.060). Hospitalization was more common among full-dose monotherapy compared with reduced-dose combination therapy recipients (61 percent vs 39 percent; p=0.0052). Six deaths were deemed treatment-related, four and two in the full-dose monotherapy and reduced-dose combination therapy groups, respectively.

“Hospitalization is associated with irreversible decline in functional status and increased risk of institutionalization in older patients, and the risk of hospitalization is therefore an important aspect when deciding treatment strategies,” the researchers said.

“[R]educed-dose combination chemotherapy with S-1 and oxaliplatin for older and vulnerable patients with metastatic CRC was more effective, had less toxicity, and resulted in fewer hospitalizations than full-dose monotherapy with S-1 [and] could therefore be the preferred treatment [in this population],” they concluded.

 

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Most Read Articles
27 Nov 2017
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