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Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab.

ABSTRACT: The primary tumour location is an important prognostic factor for previously untreated metastatic colorectal cancer (mCRC). However, the predictive efficacies of primary tumour location, early tumour shrinkage (ETS), and depth of response (DpR) on mCRC treatment has not been fully evaluated. This study aimed to investigate the predictive efficacies of these traits in mCRC patients treated with first-line 5-fluorouracil-based chemotherapy plus biologic agents, namely, cetuximab and bevacizumab. This was a retrospective analysis of the medical records of 110 patients with pathology-documented unresectable mCRC. Patients with left-sided mCRC receiving any first-line regimen showed better overall survival (OS) than those with right-sided mCRC [33.3 vs 16.3 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.27-0.74; p?

SUBMITTER: Sagawa T

PROVIDER: S-EPMC7666202 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab.

Sagawa Tamotsu T Sato Yasushi Y Hirakawa Masahiro M Hamaguchi Kyoko K Fukuya Akira A Okamoto Koichi K Miyamoto Hiroshi H Muguruma Naoki N Fujikawa Koshi K Takahashi Yasuo Y Takayama Tetsuji T

Scientific reports 20201113 1

The primary tumour location is an important prognostic factor for previously untreated metastatic colorectal cancer (mCRC). However, the predictive efficacies of primary tumour location, early tumour shrinkage (ETS), and depth of response (DpR) on mCRC treatment has not been fully evaluated. This study aimed to investigate the predictive efficacies of these traits in mCRC patients treated with first-line 5-fluorouracil-based chemotherapy plus biologic agents, namely, cetuximab and bevacizumab. T ...[more]

PMID: 33188279

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Project description:ObjectiveData from a trial of first-line panitumumab plus FOLFIRI (folinic acid, infusional 5-fluorouracil and irinotecan) in metastatic colorectal cancer were retrospectively analysed to investigate the effects of primary tumour location and early tumour shrinkage on outcomes.MethodsPatients with RAS wild-type metastatic colorectal cancer from a single-arm, open-label phase II study (NCT00508404) were included. Tumours located from the splenic flexure to rectum and in the caecum to transverse colon were defined as left- and right-sided, respectively. Baseline characteristics were summarised by primary tumour location and the effects of primary tumour location on outcomes-including objective response rate, resection rate, depth of response, duration of response and progression-free survival-were analysed. Progression-free survival and objective response rate were analysed by early tumour shrinkage status.ResultsPrimary tumour location was determined in 52/69 (75%) patients with RAS wild-type metastatic colorectal cancer; 45 (87%) had left-sided disease. Median progression-free survival was longer in patients with left-sided tumours (11.2 vs. 7.2 months for right-sided disease) and more of these patients experienced early tumour shrinkage ≥ 30% (53% vs. 29%). Early tumour shrinkage ≥ 30% was associated with improved progression-free survival irrespective of tumour location. More patients with early tumour shrinkage ≥ 30% achieved a partial or complete response. Objective response rate, duration of response, depth of response and resection rates were similar in patients with left- and right-sided tumours.ConclusionsThis analysis has confirmed a prognostic effect of primary tumour location in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab plus FOLFIRI. Early tumour shrinkage was associated with improved progression-free survival irrespective of tumour location. In right-sided disease, early tumour shrinkage may identify a subgroup of patients who might respond to panitumumab. CLINICALTRIALS.Gov identifierNCT00508404.

Project description:BACKGROUND:No biomarkers exist to predict benefit from antiangiogenic therapy in metastatic colorectal cancer patients. ACVRL1 (activin receptor like-protein 1) encodes for ALK1, a member of the transforming growth factor-? receptor family, which directs pathologic angiogenesis. We examined the intratumoral expression of ACVRL1 and other angiogenesis pathway-related genes to identify molecular markers in the TRIBE study. MATERIALS AND METHODS:Of 503 randomized patients, 228 had sufficient tissue for analysis. Formalin-fixed paraffin-embedded specimens were examined for expression of VEGF-A, VEGF-B, VEGF-C, VEGFR1, VEGFR2, ACVRL1, EphB4, and EGFL7 using reverse transcription polymerase chain reaction. A maximal ?2 approach was used to determine the messenger RNA levels associated with progression-free survival (PFS), overall survival (OS), response rate, early tumor shrinkage, and depth of response. Recursive partitioning trees were constructed to identify composite prognostic biomarker profiles. External validation was conducted in silico using the Oncomine database. RESULTS:High ACVRL1 expression was associated with superior OS in both treatment arms (FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]-bevacizumab, 32.7 vs. 13.5 months, hazard ratio [HR], 0.38, P = .023; FOLFIRI [5-fluorouracil, leucovorin, irinotecan]-bevacizumab, 35.1 vs. 22.0 months, HR, 0.36, P = .006) and prolonged PFS (11.7 vs. 5.9 months, multivariate HR, 0.17; P = .001) for patients receiving FOLFOXIRI-bevacizumab on univariate and multivariate analyses. In recursive partitioning analysis, ACVRL1 was the strongest discriminator of the response rate, PFS, and OS in patients receiving FOLFOXIRI-bevacizumab and of OS in patients receiving FOLFIRI-bevacizumab. In silico validation revealed significant associations between ACVRL1 expression, disease recurrence, and 1-year survival (P < .05) among all colorectal cancer stages. CONCLUSION:ACVRL1 expression could serve as a prognostic biomarker in metastatic colorectal cancer patients receiving chemotherapy and bevacizumab and warrants further evaluation in prospective studies.

Project description:ImportanceSecond-line treatment with chemotherapy plus bevacizumab or cetuximab is a valid option for metastatic colorectal cancer.ObjectiveTo evaluate the progression-free survival (PFS) rate at 4 months with chemotherapy plus bevacizumab vs cetuximab for patients with progression of metastatic colorectal cancer after bevacizumab plus chemotherapy.Design, setting, and participantsA prospective, open-label, multicenter, randomized phase 2 trial was conducted from December 14, 2010, to May 5, 2015. The main eligibility criterion was disease progression after bevacizumab plus fluorouracil with irinotecan or oxaliplatin in patients with wild-type KRAS exon 2 metastatic colorectal cancer. All analyses were performed on the modified intent-to-treat population.InterventionsPatients were randomized to arm A (FOLFIRI [fluorouracil and folinic acid combined with irinotecan] or modified FOLFOX6 [fluorouracil and folinic acid combined with oxaliplatin] plus bevacizumab) or arm B (FOLFIRI or modified FOLFOX6 plus cetuximab); the second-line chemotherapy regimen was chosen according to first-line treatment (crossover).Main outcomes and measuresThe primary end point was the 4-month PFS rate. Secondary end points included safety, objective response rate, overall survival, and PFS.ResultsA total of 132 patients (47 women and 85 men; median age, 63.0 years [range, 33.0-84.0 years]; 74 patients with an Eastern Cooperative Oncology Group performance status of 0, 54 patients with a performance status of 1, and 4 patients with unknown performance status) were included at 25 sites. The 4-month PFS rate was 80.3% (95% CI, 68.0%-88.3%) in arm A and 66.7% (95% CI, 53.6%-76.8%) in arm B. The median PFS was 7.1 months (95% CI, 5.7-8.2 months) in arm A and 5.6 months (95% CI, 4.2-6.5 months) in arm B (hazard ratio, 0.71; 95% CI, 0.50-1.02; P = .06), and the median overall survival was 15.8 months (95% CI, 9.5-22.3 months) in arm A and 10.4 months (95% CI, 7.0-16.2 months) in arm B (hazard ratio, 0.69; 95% CI, 0.46-1.04; P = .08). A central analysis of KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF (V600) was performed for 95 tumor samples. Eighty-one patients had wild-type KRAS and wild-type NRAS tumors.Conclusions and relevanceThe results of the PRODIGE18 (Partenariat de Recherche en Oncologie DIGEstive) study showed a nonsignificant difference but favored continuation of bevacizumab with chemotherapy crossover for patients with wild-type RAS metastatic colorectal cancer that progressed with first-line bevacizumab plus chemotherapy.Trial registrationClinicalTrials.gov identifier: NCT01442649 and clinicaltrialsregister.eu identifier: EUDRACT 2009-012942-22.

Dataset Information

Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab.

Publications

Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab.

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