Effectiveness of bevacizumab in first- and second-line treatment for metastatic colorectal cancer: ITACa randomized trial

Abstract

Background: Cancer trials involving multiple treatment lines substantially increase our understanding of therapeutic strategies. However, even when the primary end-point of these studies is progression-free survival (PFS), their statistical analysis usually focuses on each line separately, or does not consider repeated events, thus missing potentially relevant information. Consequently, the evaluation of the effectiveness of treatment strategies is highly impaired. Methods: We evaluated the potentially different effect of bevacizumab (B) administered for the first- or second-line treatment of metastatic colorectal cancer (mCRC) in the ITACa (Italian Trial in Advanced Colorectal Cancer) randomized trial. The ITACa trial consisted of two arms: first-line chemotherapy (CT)+B followed by second-line CT alone versus first-line CT alone followed by second-line CT+B or CT+B+cetuximab according to KRAS status. Cox models for repeated disease progression were performed, and potential selection bias was adjusted using the inverse probability of censoring weighting method. Hazard ratios (HR) [95% confidence interval (CI)] for PFS (primary endpoint) were reported. Results: The overall effect of B across the two lines resulted in a HR = 0.80 (95% CI 0.68–0.95, p = 0.008). Evaluating the differential effect of B in first- and second-line, the addition of B to first-line chemotherapy (CT) produced a 10% risk reduction (HR = 0.90, 95% CI 0.72–1.12, p = 0.340) versus CT alone; B added to second-line CT produced a 36% risk reduction (HR = 0.64, 95% CI 0.49–0.84, p = 0.0011) versus CT alone. Conclusion: Our results seem to suggest that B confers a PFS advantage when administered in combination with second-line chemotherapy, which could help to improve current international guidelines on optimal sequential treatment strategies.

Use of Sequential Multiple Assignment Randomized Trials (SMARTs) in oncology: systematic review of published studies

“…Among the included records, there was a match between three trials’ protocols [ 26 – 28 ] and the corresponding trials’ registrations, and between two reports of trials’ results [ 16 , 22 ] and the corresponding trials’ registrations.…”

“…Among trials’ results reports and protocols, nine were published in oncology journals [ 11 , 12 , 14 , 15 , 18 , 19 , 22 – 24 ], three in experimental and research medicine journals [ 25 – 27 ], two in internal and general medicine journals [ 10 , 16 ]. The other five records were published in specialised journals in other areas of medicine, including clinical neurology [ 17 ], respiratory system [ 20 ] and peripheral vascular diseases [ 21 ].…”

Are All Anti-Angiogenic Drugs the Same in the Treatment of Second-Line Metastatic Colorectal Cancer? Expert Opinion on Clinical Practice

“…Other treatment sequencing strategies investigated with bevacizumab include first-line chemotherapy plus bevacizumab followed by second-line chemotherapy alone (Arm A), which was compared with first-line chemotherapy alone followed by second-line chemotherapy plus bevacizumab (with or without cetuximab, according to KRAS status, Arm B) in the ITACa trial ( 49 , 50 ) ( Table 2 ). However, results from this study should be interpreted with caution because of significant study limitations, including slow and poor recruitment, a change in the primary objective (from OS to PFS), the high proportion of patient withdrawals and consequently a lack of patients entering into second-line treatment with or without bevacizumab, thus affecting the treatment duration.…”

Patient profiles as an aim to optimize selection in the second line setting: the role of aflibercept

“…The recently published ITACa study [ 19 ] compared two different sequences of treatment for mCRC. Despite the study itself should be interpreted with caution due to the methodological design and biases, results also support that second line treatment could be an ideal setting for angiogenesis inhibition.…”

“…If it is used exclusively CT (chemotherapy) with FOLFOX scheme as first-line treatment, the most recommended scheme in second-line would be FOLFIRI-aflibercept, as previously commented on the ITACa study [ 19 ] and the E3200 Study with bevacizumab (after having used irinotecan) [ 20 ].…”