Early tumour shrinkage (ETS) and its impact on tumour-related symptoms in patients with previously untreated RAS wild-type metastatic colorectal cancer (mCRC): A retrospective analysis of three panitumumab studies
Authors: J. Taieb, M. Geissler, F. Rivera, M. Karthaus, R. Wilson, F. Loupakis, T. Price, M. Tracy, P. Burdon, M. Peeters
Journal: Annals of Oncology (2018)

Introduction: Systemic therapy with epidermal growth factor receptor (EGFR) inhibitors ± chemotherapy can result in tumour shrinkage in patients with wild-type (WT) RAS mCRC, potentially facilitating curative surgery. Treatment decisions should be guided in part by patients' disease symptoms, yet there is no standardised assessment of symptomatic events. This retrospective analysis aimed to investigate whether ETS is related to the time to occurrence of new tumour-related symptoms during first-line treatment of mCRC. Methods: Three studies of patients with previously untreated mCRC were retrospectively analysed: PRIME (NCT00364013; phase III; FOLFOX4 ± panitumumab 6mg/kg Q2W); PEAK (NCT00819780; phase II; mFOLFOX6 ± either panitumumab 6mg/kg Q2W or bevacizumab 5mg/kg Q2W); and '314 (NCT00508404; phase II; panitumumab 6mg/kg Q2W + FOLFIRI). The current analyses included WT RAS mCRC patients only. The proportion of patients who developed the following symptoms during study treatment was calculated: Eastern Cooperative Oncology Group (ECOG) performance decline; new opiate use; first weight-loss event; new anaemia-type event; and new asthenia-type event. Due to their low clinical relevance, grade 1 events were excluded from the analysis. ETS was defined as a reduction of ≥ 30% in the sum-of-the-longest-diameters of measurable target lesions at 8 weeks after initiation of study treatment. Time to occurrence of new symptomatic events pooled across all 3 studies was analysed by ETS status using the Kaplan-Meier method. A composite symptomatic endpoint was also analysed; this included any symptom listed above except ECOG (as any symptom can impact on ECOG performance status). KM medians and adjusted HRs (calculated by Cox proportional hazard model) are presented with 95% confidence intervals (CI) and HR pvalues. Results: 659 patients were included in the analyses and categorised by ETS<30% (n = 330 [PRIME: n = 227; PEAK: n = 70; '314: n = 33]) and ETS≥30% (n = 329; 49.9% [PRIME: n = 213; PEAK: n = 84; '314: n = 32]). In pooled analysis, median time (95% CI) to ECOG decline was numerically longer for patients with ETS≥30% (13.9 [8.6–non-estimable (NE)] vs. 7.9 months [6.3–14.3] for ETS<30%, HR [95% CI]: 0.87 [0.69–1.08], p = 0.204). ETS≥30% was significantly associated with delayed time-to-onset of new opiate use (HR: 0.71 [0.55–0.92], p = 0.009), first weight-loss event (HR: 0.64 [0.48–0.85], p = 0.002), new anaemia-type event (HR: 0.60 [0.41–0.88], p = 0.008) and new asthenia-type event (HR: 0.77 [0.60–1.00], p = 0.049); median time to all these symptoms was not reached except for time to new opiate use in patients with ETS<30% (27.4 [10.8–NE] months). For the composite endpoint, ETS≥30% was associated with delayed median time to onset of any of the assessed symptoms (5.0 [3.9–7.0] vs. 3.4 [2.8–4.6] months for ETS<30%, HR: 0.80 [0.66–0.97], p = 0.021). More patients with ETS≥30% than ETS<30% had not experienced any new symptom at both 6 (46.1% vs. 39.6%) and 12 months (35.0% vs. 28.6%). Conclusion: The onset of new tumour-related symptoms was delayed in patients with RAS WT mCRC who achieved ETS ≥30% relative to those who did not. These data are consistent with an early response to treatment and tumour shrinkage leading to better symptomatic control and improved quality of life. Regimens with high cytoreductive potential may delay the onset of symptoms.