Background

Safety and efficacy of trans-arterial Yttrium-90 radioembolization (TARE) in combination with systemic chemotherapy in the second-line setting for colorectal liver metastases is unknown.

Methods

In this phase 3 trial, patients with colorectal liver metastases who progressed on first-line therapy were randomized 1:1 to receive second-line chemotherapy with or without glass microsphere TARE. The two primary endpoints were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded-independent central review. Randomization was stratified by unilobar/bilobar disease, oxaliplatin/irinotecan-based first-line chemotherapy, and KRAS mutation status.

Results

428 patients from 94 centers were randomized to chemotherapy +/- TARE. The hazard ratio (HR) for PFS was 0.69 (95% confidence interval [CI], 0.54-0.88; 1-sided p=0.0013), with a median PFS of 8.0 (CI, 7.2-9.2) and 7.2 (CI, 5.7-7.6) months, respectively. The HR for hPFS was 0.59 (CI, 0.46-0.77; 1-sided p<0.0001), with a median hPFS of 9.1 (CI, 7.8-9.7) and 7.2 (CI, 5.7-7.6) months, respectively. Objective response rates were 34.0% (CI, 28.0-40.5%) and 21.1% (CI, 16.2-27.1%; 1-sided p=0.0019) for TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (CI, 11.8-15.5) and 14.4 months (CI, 12.8-16.4; 1-sided p=0.7229) with a HR of 1.07 (CI, 0.86-1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently in the TARE group (68.4 vs 49.3%). The PFS benefit of TARE was observed for tumors with KRAS mutation (HR 0.57, CI: 0.40-0.80), left-side primary tumor (HR 0.65, CI: 0.48-0.88), hepatic tumor burden 10-25% (HR 0.43, CI: 0.26-0.72), ≤3 lesions (HR 0.33, CI: 0.14-0.76), addition of a biologic agent (HR 0.58, CI: 0.40-0.84), and resected primary (HR 0.63, CI: 0.46-0.85).

Conclusions

EPOCH study met both primary endpoints, demonstrating the addition of TARE to systemic therapy for second-line colorectal liver metastases leads to significantly longer PFS and hPFS. Further subset analyses will better define the ideal patient population benefitting from TARE.

Clinical trial identification

NCT01483027.

Legal entity responsible for the study

Boston Scientific Corporation.

Funding

Boston Scientific Corporation.

Disclosure

M.F. Mulcahy: Financial Interests, Personal, Research Grant: Boston Scientific. R. Salem: Financial Interests, Personal, Advisory Role: Boston Scientific Corporation; Financial Interests, Personal, Advisory Role: Cook; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Advisory Role: Genentech; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Becton Dickinson; Financial Interests, Personal, Advisory Role: Sirtex; Financial Interests, Personal, Advisory Role: QED Therapeutics; Financial Interests, Institutional, Funding: Boston Scientific; Financial Interests, Personal, Advisory Role: Siemens. A. Mahvash: Financial Interests, Personal, Advisory Role: Sirtex Medical; Financial Interests, Personal, Advisory Role: Boston Scientific; Financial Interests, Personal, Advisory Role: ABK Biomedical; Financial Interests, Institutional, Funding: Sirtex Medical; Financial Interests, Institutional, Funding: Boston Scientific; Financial Interests, Institutional, Funding: ABK Biomedical. M. Pracht: Financial Interests, Personal, Other, Travel: Boston Scientific . K. Hermann: Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Sofie Biosciences; Financial Interests, Personal, Advisory Role: Sirtex; Non-Financial Interests, Personal, Advisory Role: ABX; Financial Interests, Personal, Advisory Role: Adacap; Financial Interests, Personal, Advisory Role: Curium; Financial Interests, Personal, Advisory Role: Endocyte; Financial Interests, Personal, Research Grant: Boston Scientific; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Siemens Healthineers; Financial Interests, Personal, Advisory Role: GE Healthcare; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: ymabs; Financial Interests, Personal, Advisory Role: Aktis Oncology; Financial Interests, Personal, Advisory Role: Theragnostics; Financial Interests, Personal, Advisory Role: Pharma15. P. Ross: Financial Interests, Institutional, Funding: Sanofi; Financial Interests, Institutional, Funding: Bayer; Financial Interests, Personal, Advisory Board: SIRTEX; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Speaker’s Bureau: Servier; Financial Interests, Personal, Speaker’s Bureau: Boston Scientific; Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Other, Travel/Conference: Bayer; Financial Interests, Personal, Other, Travel/Conference: Servier; Financial Interests, Personal, Other, Travel/Conference: Roche; Financial Interests, Personal, Other, Travel/Conference: Ipsen. W.P. Harris: Financial Interests, Personal, Advisory Role: QED Therapeutics; Financial Interests, Personal, Advisory Role: Zymeworks; Financial Interests, Personal, Advisory Role: BD Medical; Financial Interests, Institutional, Funding: Merck; Financial Interests, Personal, Member of the Board of Directors: GI Cancers Alliance; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Personal, Advisory Role: Neotherma; Financial Interests, Institutional, Funding: Agios; Financial Interests, Institutional, Funding: Basilea; Financial Interests, Institutional, Funding: Bayer; Financial Interests, Institutional, Funding: Boston Scientific; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: Exelixis; Financial Interests, Institutional, Funding: Koo Foundation; Financial Interests, Institutional, Funding: MedImmune. M.S. Johnson: Financial Interests, Personal, Advisory Role: Boston Scientific; Financial Interests, Institutional, Funding: Boston Scientific. C.T. Sofocleous: Financial Interests, Institutional, Funding: Ethicon J&J; Financial Interests, Institutional, Funding: Sirtex; Financial Interests, Institutional, Funding: Boston Scientific; Financial Interests, Personal, Advisory Role: Ethicon J&J; Financial Interests, Personal, Advisory Role: Terumo; Financial Interests, Personal, Advisory Role: Boston Scientific; Financial Interests, Personal, Advisory Role: Sirtex; Financial Interests, Personal, Advisory Role: Varian. S.A. Padia: Financial Interests, Personal, Advisory Role: Boston Scientific; Financial Interests, Personal, Advisory Role: Varian Medical Systems; Financial Interests, Personal, Advisory Role: Guerbet; Financial Interests, Personal, Advisory Role: Teleflex Medical; Financial Interests, Personal, Advisory Role: Bristol Meyer Squibb. R.J. Lewandowski: Financial Interests, Personal, Invited Speaker: Boston Scientific; Financial Interests, Personal, Advisory Role: Boston Scientific. E. Garin: Financial Interests, Personal, Advisory Role: Boston Scientific; Financial Interests, Institutional, Funding: Boston Scientific. P. Sinclair: Financial Interests, Personal, Full or part-time Employment: Boston Scientific; Financial Interests, Personal, Stocks/Shares: Boston Scientific; Financial Interests, Personal, Sponsor/Funding: Boston Scientific. All other authors have declared no conflicts of interest.

Background

Surgical resection forms the mainstay of curative treatment for cancers involving the liver. The laparoscopic approach to major liver resections is increasingly being performed. Randomized evidence to show superiority of laparoscopic (LH) compared to open hemihepatectomy (OH) for perioperative and oncological outcomes is lacking.

Methods

Patients undergoing hemihepatectomy for accepted indications (principally known or suspected cancer) were randomized 1:1 to either LH or OH in 16 European centers. Patients and ward personnel were blinded until postoperative day 4. The primary endpoint was time to functional recovery (TFR). The definition included being independently mobile with adequate oral intake and normalizing liver function. Secondary outcomes included length of hospital stay (LOS), postoperative 90-day morbidity, 90-day mortality, resection margin status and 3-year survival. All analyses were by intention to treat (ITT).

Results

179 eligible patients were randomly assigned to LH and 173 to OH between October 2013 and January 2019. 135 (75%) of 179 patients in the LH group and 142 (82%) of 173 patients in the OH group had cancer: 162 colorectal liver metastases (CRLM), 47 hepatoma, 47 cholangiocarcinoma, 21 other metastases. Primary ITT analysis included 327 patients (LH 164 vs OH 163) and demonstrated a significant reduction in TFR: LH 4 days (IQR 2-6) vs OH 5 days (IQR 3-7), P< 0.001. LOS was similarly different: LH 5 days (IQR 2-8) vs OH 6 days (IQR 4-8), P= 0.002. In the LH group 15% (24/164) of patients experienced complications > Clavien-Dindo IIIa within 90 days of surgery vs 18% (30/163) in the OH group, P= 0.36. There were 5 deaths (3.0%) within 90 days of surgery in the LH group vs 5 (3.1%) in the OH group, P= 0.99. For all cancers, resection margins ≥1 mm were attained for 107/133 (81%) patients in the LH group vs 121/138 (88%) patients in the OH group (OR 1.73, 99% CI 0.72-4.14, P= 0.11). At a median follow-up of 37 months (IQR 24-50 months) 3-year survival rate was 58% for LH vs 65% for OH (HR 1.16, 99% CI 0.68-1.98, P=0.49).

Conclusions

LH is superior to OH in terms of TFR and LOS. No significant differences in oncological outcomes were observed but follow-up continues to permit a mature survival analysis.

Clinical trial identification

NCT01441856.

Legal entity responsible for the study

Maastricht University Medical Center.

Funding

Maastricht University Medical Center+ Cancer Research United Kingdom European Association of Endoscopic Surgery Paticipating centers.

Disclosure

All authors have declared no conflicts of interest.

Background

Combined chemoradiation therapy is currently the standard practice for locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). The CONVERT study compares neoadjuvant chemotherapy with CapeOx alone to standard chemoradiotherapy (CRT) with Capecitabine for these patients.

Methods

Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to receive 4 cycles of CapeOx chemotherapy alone (nCT arm) or CRT with concurrent Capecitabine (nCRT arm). Primary endpoint is local regional failure free survival.

Results

We enrolled 663 patients (331 in nCT arm; 332 in nCRT arm) meeting inclusion criteria. 86.3% of patients accomplished full dose of neoadjuvant therapy in nCT arm compared to 91.0% in nCRT arm (P= 0.074). 52.8% of patients accomplished full dose of adjuvant chemotherapy in nCT arm compared to 44.1% in nCRT arm (P= 0.065). The pCR rate and good downstaging (ypStage 0 to 1) rate in nCT arm and nCRT arm was 11.0% vs. 13.8% (P= 0.333), and 40.8% vs. 45.6% (P= 0.265), respectively. nCT significantly reduced perioperative distant metastases compared with nCRT (0.7% vs. 3.1%, P= 0.034). Two patients in nCT arm and 5 patients in nCRT arm achieved complete clinical response and were treated with a non-operative approach. Less preventive ileostomy were observed in nCT arm (52.2 vs. 63.6, P= 0.008). The two arms had similar short-term toxicity and postoperative complications. Similar results were observed in subgroup analysis.

Conclusions

nCT achieved similar pCR and good downstaging rate with less peri-operative distance metastasis and preventive colostomy compared to nCRT. This regimen could serve as a potential alternative to CRT in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results. Table: LBA22

Clinical trial identification

NCT02288195, last update time: 05/09/2021.

Editorial acknowledgement

We thank Prof. Scott R Steele and Prof. Ji-Bin Li for providing the necessary writing assistance and editorial support during the development of the abstract.

Legal entity responsible for the study

The authors.

Funding

Sun Yat-sen University Clinical Research 5010 Program (grant number 2014013).

Disclosure

All authors have declared no conflicts of interest.

Background

Label-free Quantum Cascade Laser (QCL) based IR imaging combined with AI provides spatially and molecularly resolved alterations in unstained cancer tissue thin sections. For example, molecular alterations such as the microsatellite status (MS) can be classified. To verify the method exemplarily for MS classification, tissue samples from the prospective multicentre AIO CPP registry study were analysed (Nöpel-Dünnebacke et al., ESMO 2020).

Methods

IR images of tissue thin sections taken in 30 min with QCL IR microscopes are classified by AI (convolutional neural networks, CNN). An in-house developed segmenting CNN (U-Net) localizes tumour regions and a second CNN (VGG-Net) classifies the MS. Endpoints were area under curve of receiver operating characteristic (AUC-ROC) and area under precision recall curve (AUPRC).

Results

The multicentre clinical cohort includes 491 pts. (tumour-free 100 / tumour 391). Baseline characteristics including BRAF mutation were equally distributed among test cohorts (Table). The U-Net was verified on 491 pts. (train n=294, test n=100, validation n=97) resulting in an AUC-ROC of 0.99 for the validation dataset. The MS classifier was verified on 391 pts. (train n=245, test n=73, validation n=73) presently reaching an AUC-ROC of 0.83 and an AUPRC of 0.64. Further significant improvement is expected during longer training phase. Table: 385O

Cohort details

Conclusions

QCL IR imaging combined with AI can automatically classify unstained tumour tissue accurately in 30 min with an AUC-ROC of 0.99. Further, it provides concurrently molecular tumour classification, as shown here for the MS. Based on the morphological and molecular alterations encoded in the IR images, AI models will be extended to issues such as prognosis and response prediction to facilitate precision oncology.

Legal entity responsible for the study

The authors.

Funding

Ministry of Culture and Science (MKW) of the State of North-Rhine Westphalia, Germany.

Disclosure

H. Jütte: Financial Interests, Personal, Invited Speaker: Roche; BMS; MSD; Ipsen; Merck. A. Reinacher-Schick: Financial Interests, Personal, Invited Speaker: Amgen; AstraZeneca; Aurikamed; BMS; Celgene; iomedico; Lilly; Merck Serono; MCI Global; med publico; MSD; Pfizer; promedicis; Roche; Sanofi-Aventis; Servier; Financial Interests, Personal, Advisory Board: Amgen; AstraZeneca; Baxalta; BMS; Celgene; Merck Serono; MSD; Onkowissen.de; Pierre Fabre; Pfizer; Roche; Servier; Financial Interests, Personal, Advisory Role: Onkowissen.de; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: AstraZeneca; Celgene; Ipsen; MCI Global; Merck; MSD; Onkowissen.de; Pierre Fabre; Roche; Servier; Financial Interests, Institutional, Funding: Roche; Ipsen; Financial Interests, Institutional, Research Grant: Amgen; Alexion; AstraZeneca; Celgene; Ipsen; Lilly; Roche; Servier; AIO Studien GmbH; Agricola; PPD Global Limited UK; Mologen Berlin; Universität München; Universität Erlangen; Universität Köln; Pharma Consulting Group AB Schweden; Syneed medidata GmbH; RafaelPharmaceutics. A. Tannapfel: Financial Interests, Personal, Invited Speaker: AstraZeneca; BMS; Amgen; Falk; Merck; Roche; Celgen. All other authors have declared no conflicts of interest.