Left-sided Primary Tumor Location Research Articles

Yttrium-90 Hepatic Radioembolization for Advanced Chemorefractory Metastatic Colorectal Cancer: Survival Outcomes Based on Right- Versus Left-Sided Primary Tumor Location.

BACKGROUND. Primary colon cancer location affects survival of patients with metastatic colorectal cancer (mCRC). Outcomes based on primary tumor location after salvage hepatic radioembolization with 90Y resin microspheres are not well studied. OBJECTIVE. The objectives of this study are to assess the survival outcomes of patients with advanced chemorefractory mCRC treated with 90Y radioembolization, as stratified by primary tumor location, and to explore potential factors that are predictive of survival. METHODS. A total of 99 patients who had progressive mCRC liver metastases while receiving systemic therapy and who were treated with 90Y radioembolization at a single center were retrospectively analyzed. For 89 patients, tumor response on the first imaging follow-up examination (CT or MRI performed at a mean [± SD] of 1.9 ± 0.9 months after 90Y radioembolization) was evaluated using RECIST. Overall survival (OS), OS after 90Y radioembolization, and hepatic progression-free survival (PFS) were calculated using the Kaplan-Meier method. Outcomes and associations of outcomes with tumor response were compared between patients with left- and right-sided tumors. RESULTS. A total of 74 patients had left-sided colon cancer, and 25 patients had right-sided colon cancer. Median OS from the time of mCRC diagnosis was 37.2 months, median OS after 90Y radioembolization was 5.8 months, and median hepatic PFS was 3.3 months. Based on RECIST, progressive disease on first imaging follow-up was observed in 38 patients (43%) after 90Y radioembolization and was associated with shorter OS after 90Y radioembolization compared with observation of disease control on first imaging follow-up (4.0 vs 10.5 months; p < .001). Patients with right-sided primary tumors showed decreased median OS after 90Y radioembolization compared with patients with left-sided primary tumors (5.4 vs 6.2 months; p = .03). Right- and left-sided primary tumors showed no significant difference in RECIST tumor response, hepatic PFS, or extrahepatic disease progression (p > .05). Median survival after 90Y radioembolization was significantly lower among patients with progressive disease than among those with disease control in the group with left-sided primary tumors (4.2 vs 13.9 months; p < .001); however, this finding was not observed in the group with right-sided primary tumors (3.3 vs 7.2 months; p = .05). CONCLUSION. Right-sided primary tumors were independently associated with decreased survival among patients with chemorefractory mCRC after 90Y radioembolization, despite these patients having a similar RECIST tumor response, hepatic PFS, and extrahepatic disease progression compared with patients with left-sided primary tumors. CLINICAL IMPACT. Primary colon cancer location impacts outcomes after salvage 90Y radioembolization and may help guide patient selection.

168O Right-sided versus left-sided primary tumor location in patients with KRASmut metastatic colorectal cancer (mCRC) treated with 1st-line anti-VEGF plus chemotherapy (CTx) - Data from the National Czech Registry

168O Right-sided versus left-sided primary tumor location in patients with KRASmut metastatic colorectal cancer (mCRC) treated with 1st-line anti-VEGF plus chemotherapy (CTx) - Data from the National Czech Registry

Primary tumor location and survival in colorectal cancer: A retrospective cohort study.

BACKGROUNDPrimary tumor location is a prognostic factor for metastatic colorectal cancer (mCRC). Post hoc analyses of mCRC clinical trials, including FIRE-3, CALGB/SWOG 80405, suggest that primary tumor location is also predictive of survival benefit with cetuximab or bevacizumab in combination with 5-fluorouracil-based chemotherapy.AIMEvaluate prognostic/predictive roles of primary tumor location in real-world mCRC patients treated with cetuximab or bevacizumab plus 5-fluorouracil-based chemotherapy.METHODSThis retrospective cohort study selected patients with KRAS wild-type mCRC who initiated first-line therapy with cetuximab or bevacizumab in combination with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) or 5-fluorouracil/ leucovorin/oxaliplatin (FOLFOX) between January 2013 and April 2017 from the Flatiron Health electronic health record-derived database of de-identified patient-level data in the United States. Primary tumor location was abstracted from patients’ charts. Left-sided primary tumor location (LPTL) was defined as tumors that originated in the splenic flexure, descending colon, sigmoid colon, or rectum; right-sided primary tumor location (RPTL) was defined as tumors that originated from the appendix, cecum, ascending colon, hepatic flexure, or transverse colon. Propensity score matching was used to balance the baseline demographic and clinical characteristics between patients treated with cetuximab and patients treated with bevacizumab. Kaplan-Meier and Cox regression methods were used for survival analyses.RESULTSA total of 1312 patients met the selection criteria. Of 248 cetuximab plus FOLFIRI or FOLFOX patients, 164 had LPTL and 84 had RPTL; of 1064 bevacizumab plus FOLFIRI or FOLFOX patients, 679 had LPTL and 385 had RPTL. Cetuximab LPTL and RPTL patients were more likely to receive FOLFIRI vs bevacizumab patients (LPTL: 64.0% vs 24.3%; RPTL: 76.2% vs 24.9%, P < 0.001). Stage at initial diagnosis was different between cetuximab RPTL vs bevacizumab RPTL patients (P < 0.001); cetuximab RPTL patients were more likely to have stage III disease (44.0% vs 22.6%), while bevacizumab RPTL patients were more likely to have stage IV disease (65.7% vs 48.8%). Cetuximab RPTL patients were more likely to have a documented history of adjuvant chemotherapy vs bevacizumab RPTL patients (47.6% vs 22.3%, P < 0.001). In the propensity score-matched sample, median overall survival (OS) was 29.7 mo (95%CI: 26.9-35.2) for LPTL patients vs 18.3 mo (95%CI: 15.8-21.3) for RPTL patients (P < 0.001). Median OS was 29.7 mo (95%CI: 27.4-NA) for cetuximab LPTL patients vs 29.1 mo (95%CI: 26.6-35.6) for bevacizumab LPTL patients (HR = 0.87; 95%CI: 0.63-1.19; P = 0.378) and 17.0 mo (95%CI: 12.0-32.6) for cetuximab RPTL patients vs 18.8 mo (95%CI: 15.8-22.3) for bevacizumab RPTL patients (HR = 1.00; 95%CI: 0.68-1.46; P = 0.996). The interaction of treatment and primary tumor location was not significant in the Cox regression.CONCLUSIONIn this real-world mCRC cohort, the prognostic role of primary tumor location was substantiated, but not the predictive role for treatment with cetuximab vs bevacizumab in combination with 5-fluorouracil-based chemotherapy.

Cost-effectiveness of FOLFIRI + cetuximab vs FOLFIRI + bevacizumab in the first-line treatment of RAS wild-type metastatic colorectal cancer in Germany: data from the FIRE-3 (AIO KRK-0306) study

Aims: This analysis evaluates the cost-effectiveness of first-line treatment with FOLFIRI + cetuximab vs FOLFIRI + bevacizumab for patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in Germany based on the randomized phase 3 FIRE-3 trial. For patients with RAS wt mCRC, FOLFIRI + cetuximab yielded statistically significant median overall survival gains over FOLFIRI + bevacizumab.Materials and methods: A standard 3-state partitioned survival cost-utility model was developed to compare the health benefits and costs of treatment from a German social health insurance perspective using individual patient–level trial data. Health outcomes were reported in life-years (LYs) and quality-adjusted life-years (QALYs) gained. Survival was estimated based on Kaplan-Meier (KM) curves supplemented with best-fitting parametric survival model extrapolations. Subgroup analyses of patients with a left-sided primary tumor location or patients with metastases confined to the liver were performed.Results: In the modified intention-to-treat analysis, FOLFIRI + cetuximab, providing 0.68 additional LYs (0.53 QALYs), yielded incremental cost-effectiveness ratios (ICERs) of €36,360/LY and €47,250/QALY. In subgroup analyses, patients experienced improved survival gains without a corresponding increase in costs, resulting in lower ICERs. Our model was most sensitive to changes in treatment duration across all lines of therapy, utility of progressive disease, as well as patients’ weight and body surface area.Limitations: This cost-effectiveness analysis was based on patient-level data from the FIRE-3 trial. Trial outcomes may not adequately reflect those in the real-world setting. Additionally, resource use and costs were obtained from tariff lists, which do not account for differences in treatment practice. These considerations limit generalizability of outcomes to other countries, or within the German healthcare setting.Conclusions: Based on our analyses, FOLFIRI + cetuximab is cost-effective compared with FOLFIRI + bevacizumab in patients with RAS wt mCRC, with ICERs well below willingness-to-pay thresholds for diseases with a high burden.

Non-V600E BRAF mutations and EGFR signaling pathway in colorectal cancer.

The Raf murine sarcoma viral oncogene homolog B (BRAFV600E ) mutation (MT) in metastatic colorectal cancer (CRC) is a well-known prognostic indicator and a negative predictive biomarker for antiepidermal growth factor receptor (EGFR) treatment. However, the clinical characteristics and significance of BRAFnon-V600E MTs remain unclear. Here, we evaluated the clinical characteristics of BRAFnon-V600E MTs vs. those of other MTs in the EGFR signaling pathway, including BRAFV600E . Consecutive CRC patients in our institute from June 2012 to November 2013 were enrolled in our study. Multiplex genotyping of the EGFR pathway was performed with archival samples using a Luminex Assay for BRAFV600E /BRAFnon-V600E , KRAS/NRAS exons 2-4, and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA). We analyzed correlations among the MT profiles, clinical data and primary tumor locations in CRC. All statistical analyses were performed using R software. CRC samples (824) from 374 (45.4%) male and 450 (54.6%) female patients were analyzed, of which 154 (18.7%), 202 (24.5%), 270 (32.8%) or 198 (24.0%) had Stages I, II, III or IV or recurrent CRC, respectively. The frequencies of BRAFV600E /BRAFnon-V600E , KRAS (including exons 2-4), NRAS and PIK3CA MTs were 5.3/1.7, 41.4, 3.3 and 9.6%, respectively. The characteristics of patients with the BRAFV600E MT were an age of ≥65 years old, a right-sided primary tumor location, poorly differentiated histology and an advanced disease stage. In contrast, the characteristics of patients with BRAFnon-V600E MTs were a left-sided primary tumor location and well-differentiated histology. BRAFnon-V600E MTs were relatively rare and showed different characteristics compared to the BRAFV600E MT. These results may contribute to future precision medicine.

HSR19-077: Primary Tumor Location (PTL) and Survival Outcomes in a Real World Cohort of KRAS Wild-Type (WT) Metastatic Colorectal Cancer (mCRC) Patients in the United States

Background: PTL is a prognostic factor for mCRC. Recent data suggest PTL is also predictive of survival benefit with cetuximab (CET) and bevacizumab (BEV). This study evaluated the prognostic and predictive effect of PTL in patients with KRAS WT mCRC who initiated first-line (1L) therapy with CET vs BEV in the real world. Methods: This retrospective study selected patients with KRAS WT mCRC who initiated 1L therapy with CET or BEV + FOLFIRI or FOLFOX between January 2013 and April 2017 from Flatiron Health’s electronic health record-derived database. PTL was abstracted from patients’ charts. Left-sided PTL (LPTL): splenic flexure to rectum; right-sided PTL (RPTL): cecum to splenic flexure. Propensity score matching was used to balance treatment cohorts on baseline characteristics. Kaplan Meier and Cox regression methods were used for survival analyses. Results: 1,312 patients met the selection criteria. Of 248 CET + FOLFIRI or FOLFOX patients, 164 had LPTL and 84 had RPTL; of 1,064 BEV + FOLFIRI or FOLFOX patients, 679 had LPTL and 385 had RPTL. CET LPTL and RPTL patients were more likely to receive FOLFIRI vs BEV patients (LPTL: 64.0% vs 24.3%; P&lt;.001; RPTL: 76.2% vs 24.9%; P&lt;.001). Stage at initial diagnosis was different between CET RPTL vs BEV RPTL patients (P&lt;.001). CET RPTL patients were more likely to be stage III (44.0% vs 22.6%) while BEV RPTL patients were more likely to be stage IV (48.8% vs 65.7%) at initial diagnosis. CET RPTL patients were more likely to have a history of adjuvant chemotherapy vs BEV RPTL patients (47.6% vs 22.3%; P&lt;.001). In the matched sample, median overall survival (OS) was 29.7 months (95% CI, 26.9–35.2) for LPTL patients vs 18.3 months (95% CI, 15.8–21.3) for RPTL patients (P&lt;.001). Median OS was 29.7 months (95% CI, 27.4–NA) for CET LPTL vs 29.1 months (95% CI, 26.6–35.6) for BEV LPTL patients (HR, 0.87; 95% CI, 0.63–1.19; P=.378), and 17.0 months (95% CI, 12.0–32.6) for CET RPTL vs 18.8 months (95% CI, 15.8–22.3) for BEV RPTL patients (HR, 1.00; 95% CI, 0.68–1.46; P=.996). The interaction of treatment and PTL was not significant in the Cox regression. Conclusions: This study found a prognostic effect of PTL but not a predictive effect. LPTL patients had significantly longer OS vs RPTL patients. However, the treatment effect for CET vs BEV by PTL was not significantly different. Future research is needed to examine differences between real-world and clinical trial populations that may have contributed to divergent results.

Association between Primary Tumor Location and Prognostic Survival in Synchronous Colorectal Liver Metastases after Surgical Treatment: A Retrospective Analysis of SEER Data.

The prognostic and predictive role of primary tumor location (PTL) in localized and metastatic colorectal cancer (CRC) is a hotspot issue in recent years. However, its prognostic role is still unclear in synchronous colorectal liver metastases (sCRLM), especially in those receiving surgical treatment of primary tumor and liver metastases. Here, a retrospective survival analysis was performed using the Surveillance, Epidemiology, and End Results Program (SEER) database between 2010 and 2014, on patients who were pathologically confirmed sCRLM, and received surgical treatment of both primary tumor and liver metastases. After stringent exclusive procedure, a total of 1508 patients with sCRLM (872 men [57.8%] and 636 women [42.2%]; mean age, 60.9 years) were eligible for the final study. Compared with sCRLM with left-sided PTL, cases with right-sided PTL were more likely to be T4 (31.3% vs. 20.1%, p<0.001), N2 (42.5% vs. 31.8%, p<0.001) and poorly differentiated (30.5% vs. 15.1%, p<0.001). Furthermore, right-sided sCRLM showed significantly shorter cancer specific survival (CSS) than those from left-side (p<0.001). After Cox hazard regression analysis, right-sided PTL still remained to be a strong independent predictor for poor prognosis in this cohort of sCRLM patients (OS, HR=1.75, 95% CI 1.34-2.29; CSS, HR=1.76, 95% CI 1.33-2.35). In conclusion, according to this population-based cohort from the SEER database, PTL was a critical prognostic factor that affect long-term OS and CSS in patients with sCRLM after surgical treatment of primary tumor and liver metastases.

Prognostic relevance of primary tumor location in stage III and II colon cancer: Experience at University Hospital Ramon y Cajal (HURyC) Madrid.

703 Background: Primary tumor location of colon cancer (CC) is emerging as an important prognostic factor owing to distinct biological features. However, this factor still does not represent a prognostic parameter when deciding for adyuvant or palliative chemotherapy. In a meta-analysis of 66 studies including patients with all stages of disease, left-sided primary tumor location was associated with a significantly reduced risk of death and this was independent of other prognostic factors. Methods: We retrospectively included patients with stage II and III CC that underwent surgical resection between 2009 and 2014 HURyC. We performed a multivariate Cox model analysis to estimate if tumor location is an independent prognostic factor for overall survival (OS). The model was further adjusted by including the following confounders: ECOG-PS, number of removed nodes ( &lt; 12 or ≥ 12), perforation, grade, use of adyuvant chemotherapy and age. A covariate was considered a confounder factor if the difference between the adjusted and unadjusted coefficient of chemotherapy varied &gt; 10%. Stata 13.1 was used to analyze the data. Results: 564 patients were identified (267 left sided and 297 right sided). The median follow-up of the entire cohort was 49 months. Globally, right sided CC was not significantly associated with better DFS or OS in comparison with left sided CC (HR: 0.74, p: 0.128; HR: 0.94, p: 0.75, respectively). By stages, stage II right sided CC seemed to show better DFS (HR: 0.45, p: 0.02), although no significant differences were found in OS (HR: 1.004, p: 0.98). Stage III right sided CC was not significantly associated with better DFS or OS in comparison with left sided CC (HR: 0.87, p: 0.585; HR: 0.66, p: 0.19, respectively). Conclusions: The multivariate analysis did not show significant differences in terms of prognostic relevance of primary tumor location in the adyuvant setting.

Prognostic survival associated with left-sided vs. right-sided Colon cancer: a systematic review and meta-analysis Petrelli F, et al (2017) JAMA Oncol 3:211–9

Primary tumor location is emerging as an important prognostic factor owing to distinct biological features. However, the side of origin of colon cancer (CC) still does not represent a prognostic parameter when deciding for adjuvant or palliative chemotherapy. To determine the prognostic role of left vs. rightsidedness of primary tumor location in patients with CC. PubMed, Embase, the Cochrane Library,Web of Science, LILACS, CINAHL, and SCOPUS for prospective or retrospective studies reporting data on overall survival for left-sided colon cancer (LCC) compared with rightsided colon cancer (RCC). Studies were selected if: 1) side of CC was reported among variables entered into survival analysis; 2) survival information was available (overall survival [OS] was reported in the article as hazard ratio [HR] according to multivariate analysis); 3) articles were published in the English language. Data were pooled using HRs for OS of LCC vs. RCC according to fixed or random effects models. Subgroup analysis and multivariate random-effects model meta-regression was also implemented adjusting for stage distribution, sample size, race, year of publication, type and quality of studies, and adjuvant chemotherapy. HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. In this analysis, all HRs with 95 %CIs (confidence intervals) were pooled to obtain prognostic information on the location of the primary tumor (left vs. right location site of CC) independent of other common clinicopathological covariates. An analysis was made from the 66 studies conducted. It included 1 437 846 patients with a median follow-up of 65 months. Left-sided primary tumor location was associated with a significantly reduced risk of death (HR: 0.82; 95% CI: 0.79–0.84; P < 0.001) and this was independent of stage, race, adjuvant chemotherapy, year of study, number of participants, and quality of included studies. Based on these results, CC side should be acknowledged as a criterion for establishing prognosis in all stages of disease. It should be considered when deciding treatment intensity in metastatic settings, and should represent a stratification factor for future adjuvant studies.

Primary tumor location as a prognostic and predictive factor in metastatic colorectal cancer (mCRC) treated with chemotherapy plus cetuximab: A retrospective analysis.

711 Background: Left- and right-sided colon cancers are significantly different in epidemiologic, clinicopathological and molecular characteristics. However, the impact of primary tumor location in mCRC treated biological targeted agent in combination with chemotherapy is unclear. We therefore investigated the prognostic and predictive impact of primary tumor location in mCRC. Methods: Single-institution, retrospective, case-control study was reviewed. A total of 96 patients with mCRC were enrolled between January 2011 and December 2015. We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy plus cetuximab or bevacizumab. The impact of primary tumor location for cetuximab and bevacizumab groups was analyzed, respectively. Left-sided primary tumors were defined as tumors from rectum to splenic flexure, while right-sided primary tumors were defined as tumors from cecum to the distal part of the transverse colon. Results: 68 patients presented left-sided tumors and 28 patients right-sided primary tumors. In the cetuximab group, left-sided tumors were significantly superior to right-sided tumors in terms of the progression-free survival (PFS) and Overall survival (OS) (PFS, left vs right, 18.3 vs 6.8 M, p = 0.0415; OS, 50.6 vs10.5 M, p = 0.0004). Likewise, in the bevacizumab group, OS showed differences between the left- and right-sided tumors (PFS, left vs right, 11.6 vs 7.3 M, p = 0.1904; OS, 25.7 vs 16.2 M, p = 0.0389). In left-sided tumors, cetuximab group were significantly superior to bevacizumab group in terms of the OS (PFS, cetuximab vs bevacizumab, 18.0 vs 11.6 M, p = 0.1088; OS, 50.6 vs 25.7 m p = 0.0354). Conversely, in right-sided, the survival times showed no differences between cetuximab- and bevacizumab group (PFS, cetuximab vs bevacizumab, 6.8 vs 7.3 M, p = 0.7816; OS, 10.5 vs 16.2 M, p = 0.1088). Conclusions: Our study demonstrates that primary tumor location is an important prognostic factor in previously untreated mCRC. Furthermore, left-sided primary tumor location might be a strong predictor of PFS and OS in cetuximab therapy.

168O Right-sided versus left-sided primary tumor location in patients with KRASmut metastatic colorectal cancer (mCRC) treated with 1st-line anti-VEGF plus chemotherapy (CTx) - Data from the National Czech Registry

168O Right-sided versus left-sided primary tumor location in patients with KRASmut metastatic colorectal cancer (mCRC) treated with 1st-line anti-VEGF plus chemotherapy (CTx) - Data from the National Czech Registry