Standard diametric versus volumetric early tumor shrinkage as a predictor of survival in metastatic colorectal cancer: subgroup findings of the randomized, open-label phase III trial FIRE-3 / AIO KRK-0306.

OBJECTIVES: Early tumor shrinkage (ETS) quantifies the objective response at the first assessment during systemic treatment. In metastatic colorectal cancer (mCRC), ETS gains relevance as an early available surrogate for patient survival. The aim of this study was to increase the predictive accuracy of ETS by using semi-automated volumetry instead of standard diametric measurements. METHODS: Diametric and volumetric ETS were retrospectively calculated in 253 mCRC patients who received 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) combined with either cetuximab or bevacizumab. The association of diametric and volumetric ETS with overall survival (OS) and progression-free survival (PFS) was compared. RESULTS: Continuous diametric and volumetric ETS predicted survival similarly regarding concordance indices (p > .05). In receiver operating characteristics, a volumetric threshold of 45% optimally identified short-term survivors. For patients with volumetric ETS ≥ 45% (vs < 45%), median OS was longer (32.5 vs 19.0 months, p < .001) and the risk of death reduced for the first and second year (hazard ratio [HR] = 0.25, p < .001, and HR = 0.39, p < .001). Patients with ETS ≥ 45% had a reduced risk of progressive disease only for the first 6 months (HR = 0.26, p < .001). These survival times and risks were comparable to those of diametric ETS ≥ 20% (vs < 20%). CONCLUSIONS: The accuracy of ETS in predicting survival was not increased by volumetric instead of diametric measurements. Continuous diametric and volumetric ETS similarly predicted survival, regardless of whether patients received cetuximab or bevacizumab. A volumetric ETS threshold of 45% and a diametric ETS threshold of 20% equally identified short-term survivors. KEY POINTS: • ETS based on volumetric measurements did not predict survival more accurately than ETS based on standard diametric measurements. • Continuous diametric and volumetric ETS predicted survival similarly in patients receiving FOLFIRI with cetuximab or bevacizumab. • A volumetric ETS threshold of 45% and a diametric ETS threshold of 20% equally identified short-term survivors.

Early weight loss is an independent risk factor for shorter survival and increased side effects in patients with metastatic colorectal cancer undergoing first-line treatment within the randomized Phase III trial FIRE-3 (AIO KRK-0306).

Body weight loss is frequently regarded as negatively related to outcomes in patients with malignancies. This retrospective analysis of the FIRE-3 study evaluated the evolution of body weight in patients with metastatic colorectal cancer (mCRC). FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab or bevacizumab in mCRC patients with RAS-WT tumors (ie, wild-type in KRAS and NRAS exons 2-4). The prognostic and predictive relevance of early weight loss (EWL) regarding patient outcomes and treatment side effects were evaluated. Retrospective data on body weight during first 6 months of treatment were evaluated (N = 326). To correlate with efficacy endpoints and treatment side effects, patients were grouped according to clinically significant EWL ≥5% and <5% at Month 3. Age constituted the only significant predictor of EWL following a linear relationship with the corresponding log odds ratio (P = .016). EWL was significantly associated with the incident frequencies of diarrhea, edema, fatigue, nausea and vomiting. Further, a multivariate analysis revealed EWL to be an independent negative prognostic factor for overall survival (32.4 vs 21.1 months; hazard ratio [HR]: 1.64; 95% confidence interval [CI] = 1.13-2.38; P = .0098) and progression-free survival (11.8 vs 9.0 months; HR: 1.72; 95% CI = 1.18-2.5; P = .0048). In conclusion, EWL during systemic treatment against mCRC is significantly associated with patient age. Patients exhibiting EWL had worse survival and higher frequencies of adverse events. Early preventative measures targeted at weight maintenance should be evaluated, especially in elderly patients being at highest risk of EWL.

Development and Evaluation of 3D-Printed Cardiovascular Phantoms for Interventional Planning and Training.

Catheter-based interventions are standard treatment options for cardiovascular pathologies. Therefore, patient-specific models could help training physicians' wire-skills as well as improving planning of interventional procedures. The aim of this study was to develop a manufacturing process of patient-specific 3D-printed models for cardiovascular interventions. To create a 3D-printed elastic phantom, different 3D-printing materials were compared to porcine biological tissues (i.e., aortic tissue) in terms of mechanical characteristics. A fitting material was selected based on comparative tensile tests and specific material thicknesses were defined. Anonymized contrast-enhanced CT-datasets were collected retrospectively. Patient-specific volumetric models were extracted from these datasets and subsequently 3D-printed. A pulsatile flow loop was constructed to simulate the intraluminal blood flow during interventions. Models' suitability for clinical imaging was assessed by x-ray imaging, CT, 4D-MRI and (Doppler) ultrasonography. Contrast medium was used to enhance visibility in x-ray-based imaging. Different catheterization techniques were applied to evaluate the 3D-printed phantoms in physicians' training as well as for pre-interventional therapy planning. Printed models showed a high printing resolution (~30 µm) and mechanical properties of the chosen material were comparable to physiological biomechanics. Physical and digital models showed high anatomical accuracy when compared to the underlying radiological dataset. Printed models were suitable for ultrasonic imaging as well as standard x-rays. Doppler ultrasonography and 4D-MRI displayed flow patterns and landmark characteristics (i.e., turbulence, wall shear stress) matching native data. In a catheter-based laboratory setting, patient-specific phantoms were easy to catheterize. Therapy planning and training of interventional procedures on challenging anatomies (e.g., congenital heart disease (CHD)) was possible. Flexible patient-specific cardiovascular phantoms were 3D-printed, and the application of common clinical imaging techniques was possible. This new process is ideal as a training tool for catheter-based (electrophysiological) interventions and can be used in patient-specific therapy planning.

Impact of Size and Location of Metastases on Early Tumor Shrinkage and Depth of Response in Patients With Metastatic Colorectal Cancer: Subgroup Findings of the Randomized, Open-Label Phase 3 Trial FIRE-3/AIO KRK-0306.

BACKGROUND: The Response Evaluation Criteria in Solid Tumors (RECIST) are used to define degrees of response to chemotherapy. For accelerated response evaluation, early tumor shrinkage (ETS) of ≥ 20% has been suggested as a predictor for outcome in metastatic colorectal cancer (mCRC). Together with depth of response (DpR), new alternative metrics have been provided, yielding promising outcome parameters. In this analysis, we aimed to further characterize ETS and DpR. PATIENTS AND METHODS: This analysis was based on FIRE-3, a randomized phase 3 trial comparing first-line FOLFIRI plus either cetuximab or bevacizumab in KRAS exon 2 wild-type mCRC. ETS and DpR were determined on the basis of RECIST 1.1 in a blinded radiologic review. ETS was evaluated as a categorized (≥ 20% shrinkage) and continuous parameter. The impact of baseline location and size of metastases on ETS and DpR were evaluated by univariate and multivariate analyses. RESULTS: Of 592 patients, 395 (66.7%) had data available for radiologic review. Median continuous ETS for lung, liver, and suspected lymph node metastases was 20%, 23%, and 30%, respectively. The median DpR was -32%, -44%, and -50%, respectively (all P < .01). In multivariate analysis, lung metastases were significantly associated with inferior DpR (P = .021), whereas hepatic metastases led to higher DpR (P = .024). Large metastases were associated with favorable ETS, whereas small metastases were correlated with higher DpR (P < .001). CONCLUSION: ETS and DpR depend on the location and size of metastases in mCRC. These associations may establish the basis for further research to optimize the predictive accuracy of both parameters. This may help basing treatment decisions on ETS and DpR.