Tumor Sidedness Research Articles

Comparison of UGT1A1 Polymorphism as Guidance of Irinotecan Dose Escalation in RAS Wild-Type Metastatic Colorectal Cancer Patients Treated With Cetuximab or Bevacizumab Plus FOLFIRI as the First-Line Therapy.

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility and toxicity of patients to irinotecan. This retrospective, observational study compared the clinical outcomes and adverse events (AEs) in RAS wild-type metastatic colorectal cancer (mCRC) patients treated with cetuximab or bevacizumab plus FOLFIRI with UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. In total, 173 patients with mCRC with RAS wild-type were enrolled. Among them, 98 patients were treated with cetuximab, whereas 75 patients were treated with bevacizumab. All patients received irinotecan dose escalation based on UGT1A1 genotyping. We compared the progression-free survival (PFS), overall survival (OS), objective response rates (ORRs), disease control rates (DCRs), metastatectomy, and severe adverse events (SAEs) between the two groups. The clinical effects of primary tumor sidedness and target therapy crossover were further analyzed. Over a median follow-up of 23.0 months [interquartile range (IQR), 15.0–32.5 months], no significant differences were observed between the cetuximab and bevacizumab groups in PFS [18.0 months vs. 14.0 months; 95% confidence interval (CI), 0.517–1.027; hazard ratio (HR), 0.729; p = 0.071], OS (40.0 months vs. 30.0 months; 95% CI, 0.410–1.008; HR, 0.643; p = 0.054), ORR (65.3% vs. 62.7%; p = 0.720), DCR (92.8% vs. 86.7%; p = 0.175), metastatectomy (36.7% vs. 29.3%; p = 0.307), and SAEs (p = 0.685). Regardless of primary tumor sidedness and target therapy crossover, no significant differences were noted in efficacy and safety between the two groups (all p > 0.05). Our results revealed that patients with wild-type RAS mCRC, regardless of biologics, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favorable clinical outcome without significantly increased toxicity.

Clinical impact of primary tumor sidedness and sex on unresectable post-recurrence survival in resected pathological stage II-III colorectal cancers: a nationwide multicenter retrospective study

BackgroundSeveral studies have demonstrated that right-sided tumors have poorer prognosis than left-sided tumors in patients with unresectable colorectal cancer (CRC). The predictive ability of the tumor sidedness in CRC treated with chemotherapy in each sex is unclear.MethodsSubjects were 964 unresectable recurrent patients treated with chemotherapy with stage II-III CRC after curative resection between 2004 and 2012. Post-recurrence cancer-specific survival (CSS) for each sex was examined.ResultsPatients were 603 males (222 right-side tumors (cecum to transverse colon) and 381 left-sided tumors (descending colon to rectum)), and 361 females (167 right-side tumors and 194 left-sided tumors). Right-sided tumors developed peritoneal recurrences in males and females. Left-sided tumors were associated with locoregional recurrences in males and with lung recurrences in females. Right-sided tumors were associated with shorter post-recurrence CSS in both sexes. In males, multivariate analyses showed that right-sided tumors were associated with shorter post-recurrence CSS (HR: 1.53, P < 0.0001) together with the presence of regional lymph node metastasis histopathological type of other than differentiated adenocarcinoma, the recurrence of liver only, the recurrence of peritoneal dissemination only, and relapse-free interval less than one-year. In females, multivariate analyses showed that right-sided tumors were associated with shorter post-recurrence CSS (HR: 1.50, P = 0.0019) together with advanced depth of invasion, the presence of regional lymph node metastasis, and recurrence of liver only.ConclusionsPrimary tumor sidedness in both sexes in unresectable recurrent CRC patients treated with chemotherapy may have prognostic implications for post-recurrence CSS.

Early-onset non-metastatic colon cancers do not portend worse prognosis - implications for adjuvant chemotherapy.

Early-onset colon cancers are increasing and the independent influence of age on prognosis and therapeutic efficacy of adjuvant therapy is unclear. The primary aim of the present study was to determine if young age was an independent prognostic factor for survival. Secondarily, age would be used in the context of known factors that predict benefit with adjuvant chemotherapy in stages II and III. Retrospective, single centre study of operated, non-metastatic colon cancer (> 15cm from anal verge) without pre-operative therapy. Early onset cancers were defined as age ≤ 45years. Primary endpoint was disease-free survival (DFS). Six-hundred thirty-three patients were included with 206 (32.5%) early-onset cancers. With a median follow-up of 48months, 5-year DFS was 79.5% and 76.2% for early and late-onset cancers, respectively (p - 0.585). In multivariate analysis, only tumour sidedness, family history, T4 stage, node positivity and microsatellite instability status influenced DFS and not the age of onset (HR - 0.969; 95% - 0.63-1.49). These results were consistent with different models and with stage-wise distribution. Early-onset colon cancers treated with curative intent had survivals similar to older cohorts. Age was not an independent prognostic factor for recurrences. Age did not influence disease-free survival when stage-wise predictive variables for therapeutic benefit with adjuvant chemotherapy were considered.

Effect of Primary Tumor Location on Second- or Later-Line Treatment With Anti-Epidermal Growth Factor Receptor Antibodies in Patients With Metastatic Colorectal Cancer: A Retrospective Multi-Center Study.

BackgroundCurrent guidelines recommend anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR Ab) as first-line treatment only in patients with left-sided RAS wild type (RASwt) metastatic colorectal cancer (mCRC). However, there are no guideline recommendations specific to tumor sidedness in subsequent-line treatment. This study aimed to investigate the effect of primary tumor location on second- or later-line treatment outcomes in patients with KRASwt mCRC.MethodsMedical records of patients diagnosed with mCRC at 3 academic centers in Thailand (Siriraj, Chulalongkorn, and Ramathibodi hospital) between 2008 and 2019 were retrospectively reviewed. Patients with KRASwt mCRC who received anti-EGFR Ab in second- or later-line treatment were included. The impact of tumor sidedness on progression-free survival (PFS) was determined using Kaplan-Meier method, and those results were compared using log-rank test.ResultsAmong the 2,102 patients who had KRAS analysis data, 1,130 (54%) patients had KRASwt. Of those, 413 patients received anti-EGFR Ab in second- or later-line treatment. One hundred and sixty-two of 413 (39%) patients had extended RAS analysis. Seventy (17%) patients had right-sided tumors. Two hundred and thirty-eight (58%) patients received anti-EGFR Ab in the third line, and 132 (32%) patients and 43 (10%) patients were treated in the second and more than third line, respectively. Single-agent irinotecan was the most commonly used backbone chemotherapy (303/413, 73%). Patients with right-sided tumors had non-significantly inferior PFS compared to patients with left-sided tumors (median PFS: 5.7 months (mo), 95% confidence interval [CI]: 3.9-7.5 vs. 7.5 mo, 95% CI 6.5-8.5; p=0.17). Subgroup analysis showed no difference in PFS when stratified by treatment lines. Patient with right-sided tumors had significantly inferior OS compared to patients with left-sided tumors (median OS: 23.3 mo vs. 29.9 mo; p=0.005).ConclusionsTo date, this is the largest real world data of the effect of primary tumor location on anti-EGFR Ab which demonstrated that tumor sidedness has no significant impact on treatment outcomes in KRASwt mCRC patients receiving second- or later-line therapy. Our findings do not support the utility of tumor sidedness for treatment selection in these settings. We confirmed that patients with right-sided tumors had significantly worse survival.

The impact of adjuvant oxaliplatin and tumor sidedness on the overall survival of stage IIB colon cancer patients: a multicentre study

The aim of this multicentre retrospective study was to compare the efficacy of adjuvant chemotherapy regimens both with and without oxaliplatin and tumor sidedness in stage IIB (pT4aN0) colon cancer patients. This study included patients with stage IIB colon cancer who underwent curative surgery and received adjuvant chemotherapy. The patients were divided into two groups (one with and one without oxaliplatin) to compare the overall survival (OS) in right- and left-sided tumors. The study population included 298 patients with stage IIB colon cancer (median age: 57) of whom 69.1% were male. Forty-four per cent of these patients (n = 131) were diagnosed with right-sided colon cancer. The median follow-up duration was 35.9 months. In the entire population, a median OS was not reached, and the five-year OS was 83%. The median disease-free survival (DFS) was 12 months. There was no significant difference in terms of the five-year OS between right- (82%) and left-sided (84%) colon tumors (p = 0.67). In addition, the five-year OS of patients treated with and without oxaliplatin were 76% and 89%, respectively, and there was no statistically significant difference (p = 0.23). The five-year OS of the patients treated with and without oxaliplatin were 83% and 96.5%, respectively, (p = 0.8) in right-sided colon tumors, while it was 75% and 93% (p = 0.06), respectively, in left-sided colon tumors. Tumor sidedness and the addition of oxaliplatin to adjuvant chemotherapy were not found to be associated with the OS in stage IIB colon cancer patients in our study. Further large prospective studies that also include MSI, RAS and BRAF status data are warranted in colon cancer patients.

Evaluating the effect of tumor size and sidedness on prognosis in stage 2 colon cancer: a retrospective population study.

In this study, we aimed to evaluate the effect of tumor size and tumor sidedness on prognosis in patients with stage 2 colon cancer. Data of 501 patients diagnosed with stage 2 colon cancer were evaluated retrospectively. It was evaluated whether the patients' age, gender, tumor differentiation, tumor node metastasis (TNM) stage, overall survival rate, and disease-free survival rate had any correlation with horizontal tumor diameter and tumor sidedness. In the ROC analysis performed to determine the cut-off value for the tumor diameter, which we think will predict survival, no significant results were obtained with maximum sensitivity and specificity. Therefore, the median value of the tumor diameter, which is 5 cm, was accepted as the cut-off value. Kaplan-Meier method and Cox regression analysis were used for survival analysis and determination of prognostic factors. When the patients were evaluated in terms of tumor localization, 189 (37.7%) patients had right colon tumors and 312 (62.3%) patients had left colon tumors. There was no statistically significant difference in terms of disease-free survival and overall survival according to tumor localization. When the patients were analyzed by dividing them into two groups according to the horizontal tumor size (<5 cm and ≥5 cm), no statistically significant difference was found between the groups in terms of disease-free survival (DFS) and overall survival (OS) p=0.085, p=0.699, respectively. Our results suggest that the management of patients with stage 2 colon cancer requires a better understanding of tumor biology rather than features such as tumor size and localization.

The association between tumour sidedness, clinicopathological characteristics and outcomes in patients undergoing curative resection for colon cancer.

148 Background: Right-sided colon cancer is associated with worse outcomes than left-sided disease, likely due to an association between tumour/host factors and tumour sidedness. The present study analyses the association between tumour sidedness, clinicopathological features and common mutations to better understand this discrepancy in outcomes. Methods: The association between tumour sidedness, clinicopathological characteristics and survival was examined within a cohort of patients undergoing curative surgery for TNM I-III colon cancer. Results: 3,419 patients were identified. 54% of cases were right-sided and associated with worse 3-year OS/CSS. On multivariate analysis for clinical factors: sex (OR 0.63), Systemic Inflammatory Grade (SIG), anaemia and differentiation (OR 0.80/0.31/0.57) were associated with T3 cancer sidedness and: sex, anaemia and differentiation (OR 0.61/0.46/0.57) were associated with T4 cancer sidedness. On further MVA including mutational factors anaemia/BRAF status remained significant in T3/T4 cancer respectively (OR 0.08/0.09). BRAF mutant status was associated with SIG in all patients/T3 disease (p=0.046/0.016). Conclusions: Worse outcomes seen in right-sided colon cancer are likely explained predominantly by factors including tumour stage, SIG, anaemia and BRAF mutational status. BRAF mutations are associated with the Systemic Inflammatory Response and further research is required to better understand this relationship taking into the tumour microenvironment, microsatellite instability.[Table: see text]

Tumor response of FOLFOXIRI plus cetuximab versus bevacizumab in RAS wild-type metastatic colorectal cancer: The subgroup-analysis of DEEPER trial (JACCRO CC-13).

109 Background: Triplet regimen, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab has been shown to be superior in terms of early tumor shrinkage and depth of response (DpR) compared to doublet combinations in patients with RAS wild-type metastatic colorectal cancer (mCRC). We performed a randomized phase II study, DEEPER trial (JACCRO CC-13)[NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) in previously untreated mCRC patients with RAS wild-type tumors (Tsuji A, et al. ASCO 2021). Methods: The primary endpoint was DpR during the entire course. Secondary endpoints included overall response rate (ORR), disease control rate, R0 resection rate, progression-free survival, and overall survival. A post-hoc subgroup analysis by PS, tumor sidedness, age, and location of metastases was performed to evaluate the efficacy of triplet plus cet vs. bev regimen. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the full analysis set (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively. Median DpR was 57.4% vs. 46.0% ( p = 0.001), and the ORR was 69.1% vs. 71.7% ( p = 0.60), in cet vs. bev, respectively. The subgroup analysis was present in the table. There was no significant difference in terms of ORR and R0 resection rate between groups according to PS, tumor sidedness, age, and liver metastases (LM). In patients with only LM, the R0 resection rate of cet vs. bev was 25.0% vs. 14.8% ( p = 0.21). Conclusions: The m-FOLFOXIRI plus cet showed to be significantly superior to the m-FOLFOXIRI plus bev in terms of DpR in first-line treatment for RAS wild-type mCRC. The better DpR of m-FOLFOXIRI plus cet was evident for RAS wild-type mCRC patients with left-sided tumors, LM or under 70 years old. Clinical trial information: UMIN000018217.[Table: see text]

Effect of primary tumor location on second- or later-line treatment with anti-epidermal growth factor receptor antibodies in patients with metastatic colorectal cancer: A retrospective multicenter study.

195 Background: Currently, there are no guideline recommendations of anti-EGFR Ab specific to tumor sidedness in subsequent-line treatment in patients with metastatic colorectal cancer (mCRC). We previously reported the effect of primary tumor location on subsequent-line treatment with anti-EGFR Ab from a single center. Here we presented the outcome from a multi-center study. Methods: Medical records of patients diagnosed with mCRC at 3 academic centers in Thailand (Siriraj, Chulalongkorn, and Ramathibodi hospital) between 2008 and 2019 were retrospectively reviewed. Patients with KRASwt mCRC who received anti-EGFR Ab in second- or later-line treatment were included. The impact of tumor sidedness on progression-free survival (PFS) was determined using Kaplan-Meier method, and those results were compared using log-rank test. Results: Among the 2,102 patients who had KRAS analysis data, 1,130 (54%) patients had KRASwt. Of those, 413 patients received anti-EGFR Ab in second- or later-line treatment. One hundred and sixty-two of 413 (39%) patients had extended RAS analysis. Seventy (17%) patients had right-sided tumors. Two hundred and thirty-eight (58%) patients received anti-EGFR Ab in the third line, and 132 (32%) patients and 43 (10%) patients were treated in the second and more than third line, respectively. Single-agent irinotecan was the most commonly used backbone chemotherapy (303/413, 73%). Patients with right-sided tumors had non-significantly inferior PFS compared to patients with left-sided tumors (median PFS: 5.7 months (mo), 95% confidence interval [CI]: 3.9-7.5 vs. 7.5 mo, 95% CI 6.5-8.5; p =0.17). Subgroup analysis showed no difference in PFS when stratified by treatment lines. Patient with right-sided tumors had significantly inferior OS compared to patients with left-sided tumors (median OS: 23.3 mo vs. 29.9 mo; p =0.005). Conclusions: To date, this is the largest real world data of the effect of primary tumor location on anti-EGFR Ab which demonstrated that tumor sidedness has no significant impact on treatment outcomes in KRASwt mCRC patients receiving second- or later-line therapy. Our findings do not support the utility of tumor sidedness for treatment selection in these settings. We confirmed that patients with right-sided tumors had significantly worse survival.

Comparison of comprehensive genomic profiles between young-onset and average-onset colorectal cancer.

167 Retraction The abstract by Torrejon et al entitled, “Comparison of comprehensive genomic profiles between young-onset and average-onset colorectal cancer.,” ( Journal of Clinical Oncology 40, no. 4, suppl 167) published on January 19, 2022, has been retracted due to calculation errors. Current age was used for the analysis instead of age at diagnosis. This error significantly changed the results and conclusion of the abstract. Background: The incidence of young-onset colorectal cancer (yoCRC) is rising for unknown reasons. This study assessed for differences in comprehensive genomic profiles between yoCRC and average-onset colorectal cancer (aoCRC). Methods: All patients with CRC seen at Cleveland Clinic that had tumor-based next generation sequencing (NGS) performed as part of their care with a clinically available assay between January 2017 and September 2020 were included. The cohort was divided based on age of diagnosis, with yoCRC defined as age of CRC diagnosis &lt;50 years old. All clinical data and genomic alterations were included for analysis. We assessed for differences in clinical data and NGS findings between yoCRC and aoCRC using Fisher’s exact test, adjusted for primary tumor sidedness. Overall survival (OS) by genomic alteration was estimated by Kaplan-Meier methods and compared using log rank test. Results: The study population comprised of 51 yoCRC patients and 211 aoCRC patients. There were no significant differences in sex, race or ethnicity between yoCRC and aoCRC patients. Compared to aoCRC patients, yoCRC patients were more likely to present at diagnosis with stage IV disease (81% vs. 56%, p = 0.02) and have left-sided primary tumors (69% vs. 60%, p = 0.26). YoCRC tumors were more likely to have mutations in APC, KRAS, TP53 and FLT3 compared to aoCRC tumors, independent of tumor sidedness. These data are summarized in Table. Compared to left-sided tumors, right-sided tumors had significantly higher frequency of KRAS (67.7% vs. 48.8%, p = 0.003), BRAF (15.2% vs. 3.1%, p = 0.0006) and PTEN (16.2% vs. 3.1%, p value = 0.0003) alterations. AoCRC patients had significantly longer OS compared to yoCRC patients (median OS: 70.0 months vs. 36.3 months, p=0.004). Black (37.2 months, n=35) and Asian (37.8 months, n=7) patients had significantly worse median OS compared to White patients (67.8 months, n=199), p-value 0.005. In the overall population, patients with APC mutations had significantly better OS compared to those with APC wildtype tumors (median OS: 92.6 months vs. 54.4 months, p=0.001). Patients with FLT3 mutations had worse median OS compared to those with FLT3 wildtype tumors (median OS: 42.0 months vs. 64.8 months, p=0.007). There were no survival differences based on MSI status. Conclusions: In this series, yoCRC patients were more likely to present with stage IV disease and experienced worse OS compared to aoCRC patients. YoCRC patients were more likely to have mutations in APC, KRAS, TP53 and FLT3, independent of tumor sidedness. Mutations in FLT3 correlated with worse OS.[Table: see text]

Primary Tumor Sidedness, RAS and BRAF Mutations and MSI Status as Prognostic Factors in Patients with Colorectal Liver Metastases Treated with Surgery and Thermal Ablation: Results from AmCORE

Background: The aim of this study was to assess primary tumor sidedness of colorectal cancer (CRC), rat sarcoma viral oncogene homolog (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations and microsatellite instability (MSI) status as prognostic factors predicting complications, survival outcomes and local tumor progression (LTP) following surgery and thermal ablation in patients with colorectal liver metastases (CRLM).

Efficacy of bevacizumab-based treatment in early-onset treatment-naïve metastatic colorectal cancer patients: An ARCAD database analysis.

101 Background: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (20-49 years, named early-onset CRC, eoCRC) has been increasing. eoCRC patients with metastatic disease are treated with the same standard regimens as late-onset CRC (loCRC, age ≥ 50 years) although detailed response data for eoCRC are largely missing. Methods: Individual patient data on 7,604 subjects with metastatic eoCRC from 11 first line randomized bevacizumab studies between 2000 and 2012 in the ARCAD advanced colorectal cancer database were pooled. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were summarized by age groups. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables. Results: Female eoCRC are more commonly seen compared to loCRC (46.8% vs. 38.7%, p&lt;0.0001). Patients with eoCRC (n=1,289) were significantly more likely to have had prior metastasectomy (17.5% vs. 13.5%, p=0.043) and lung metastatic disease (67% vs. 59.8%, p&lt;0.001), but less likely to have distant lymph node metastatic disease (58.8 vs. 62.9%, p=0.036) or KRAS mutation (29.2% vs. 34.4%, p=0.042) compared to those with loCRC (n=6,315). eoCRC and loCRC patients had similar distributions according to PS, primary tumor sidedness, prior primary tumor resection, liver involvement, peritoneal involvement, number of metastatic sites, NRAS and BRAF. Age of disease onset was not a statistically significant prognostic factor for PFS in univariate and multivariate analysis (seen in table). Bevacizumab in addition to chemo improved PFS in eoCRC population (9.9 vs. 6.8 months, HR = 0.66, p&lt;0.001), which was similar to the findings in loCRC population (9.4 vs. 7.3 months, HR= 0.73, p&lt;0.001, interaction p=0.54). By multivariate analysis, a greater improvement in PFS was noted for the addition of bevacizumab in eoCRC relative to LoCRC patients (HR = 0.62 vs. HR = 0.82). Conclusions: Treatment naive eoCRC patients with metastatic disease derive similar benefit from bevacizumab relative to their average age counterparts.[Table: see text]

Trajectories of body weight change and survival among mCRC patients treated with systemic therapy: Pooled analysis from the ARCAD database.

80 Background: Higher baseline body mass index is associated with improved survival in metastatic CRC (mCRC). Whether weight gain or loss after mCRC diagnosis is associated with survival remains largely unknown. Methods: We analyzed individual patient data from 3504 patients with previously untreated mCRC enrolled in five phase III randomized trials (AVF2017g, AVF2192g, CRYSTAL, N9741, OPUS) conducted between 2000 and 2006. Weight measurements were prospectively collected at 3 months after diagnosis and then up to 5 years. Patients were categorized into three groups based on the percent weight change at 3 months: stable weight or gain, weight loss up to 5% of baseline weight, and ≥5% weight loss of baseline weight. Cox models were used to assess the prognostic associations of weight change at 3 months with overall survival (OS) and progression-free survival (PFS), adjusting for baseline BMI, age, sex, performance score, chemotherapy backbone (oxaliplatin vs. irinotecan), and biologics type (cetuximab vs. bevacizumab). Sub-analyses included Cox models adjusted for additional clinical-pathological factors (primary tumor sidedness [right colon vs. left colon-rectum], and BRAF status; N=1,511). Results: Median percent weight change at 3 months was -0.5% (IQR -4.0 to+1.6%). OS was better in patients with weight stability or gain than in those with weight loss (up to 5% or ≥5%; (Table). Results were consistent for PFS for patients with ≥5% weight loss of baseline weight, as well as for sub-analyses. Conclusions: Patients losing weight during the first 3 months of systemic therapy for metastatic colorectal cancer have significantly shorter overall survival than those with stable or increasing weight. Degree of weight loss is proportional to the observed increased risk of death and remains evident among underweight, normal weight and obese individuals. Further studies examining possible usefulness of on-treatment early weight loss as a novel intermediary end-point are needed.[Table: see text]

Exact Primary Tumor Location in mCRC: Prognostic Value and Predictive Impact on Anti-EGFR mAb Efficacy.

Simple SummarySidedness of primary tumor is a well-established prognostic marker and is predictive for anti-EGFR efficacy in RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. As molecular markers change rather continuously throughout the colon, we ask whether the exact primary tumor location (PTL) is a better prognostic marker than sidedness and predictive for anti-EGFR efficacy in RAS/BRAF wild-type mCRC. We retrospectively analyzed five studies containing various therapy protocols concerning primary tumor location, dividing the colorectal frame into six segments. In our cohort, PTL has a prognostic impact on disease spread and overall survival. Only distal segments benefitted when receiving anti-EGFR containing therapy regarding overall survival. Intermediate segments were indifferent and caecal primaries had a detrimental effect receiving anti-EGFR based therapy. Being a retrospective analysis and challenging the standard of basing anti-EGFR treatment on sidedness in RAS/BRAF wild-type mCRC, future studies are necessary to confirm and further investigate our hypothesis-generating results.Primary tumor sidedness (left vs. right) has prognostic and predictive impact on anti-EGFR agent efficacy and thus management of metastatic colorectal cancer (mCRC). This analysis evaluates the relevance of primary tumor location (PTL) in RAS/BRAF wild-type mCRC patients, when dividing the colorectal frame into six segments. This pooled analysis, performed on a single-patient basis of five randomized first-line therapy trials, evaluates the impact of exact PTL classification on baseline characteristics, prognosis and prediction of anti-EGFR antibody efficacy by chi-square and log-rank tests, the Kaplan–Meier method, Cox and logistic regressions. The PTL was significantly associated with metastatic spread: liver (p = 0.001), lung (p = 0.047), peritoneal (p < 0.001) and lymph nodes (p = 0.048). A multivariate analysis indicated an impact on anti-EGFR agent efficacy in terms of overall survival depending on the exact primary tumor location: from detrimental in caecal (HR 2.63), rather neutral effects in the ascending colon (HR 1.24), right flexure/transverse colon (HR 0.99) and left flexure/descending colon (HR 0.91) to clear benefit in sigmoid (HR 0.71) and rectal (HR 0.58) primaries. Exact primary tumor location affects anti-EGFR antibody efficacy in a rather continuous than a dichotomous fashion in RAS/BRAF wild-type mCRC patients. This perspective might help to support clinical decisions when anti-EGFR antibodies are considered.

Tumour Sidedness and KRAS Mutation Status in the Management of Colorectal Cancer with Synchronous Liver Metastases: A Subgroup Analysis of the Cosmic Cohort

Introduction: The aim of this study was to explore the association of KRAS mutational status and primary tumour sidedness on survival for patients presenting with colorectal cancer and synchronous liver-limited metastatic disease.

Tumor Sidedness in T2 Staged Carcinoma Gall Bladder: A Determinant of Tumor Biology and Prognosis

Introduction: Patients with carcinoma gall bladder infrequently present in early stage. In such early localized gall bladder cancers, location of T2 lesion on liver or peritoneal side may determine disease biology and hence, prognosis.

Primary Colorectal Cancer Histopathology Predicts the Histopathological Growth Pattern of Corresponding Liver Metastasis

Introduction: Histopathological growth patterns (HGPs) are a prognostic and predictive biomarker in the surgical management of colorectal cancer liver metastasis (CRLM); the desmoplastic HGP marks good prognosis whereas the non-desmoplastic HGP predicts favourable chemotherapy response. Clinical applicability is however limited as determination requires resection. This study investigates whether primary colorectal cancer (CRC) histopathology may predict the HGP of corresponding CRLM. Method: A retrospective cohort study was performed in treatment-naive patients undergoing CRLM resection. Thirteen distinct histopathology features were determined on H&E sections of resected CRC and compared between desmoplastic and non-desmoplastic CRLM; tumour sidedness, pT & pN stage, tumour grade, tumour deposits, perineural- (lympho-)vascular- and extramural venous invasion, peritumoural budding, stroma type, CRC growth pattern, Crohn’s-like lymphoid reaction, and tumour-infiltrating lymphocyte (TIL) density. A point-based score (table) was calculated, assigning a point for each unfavourable feature. Multivariable logistic regression was performed using this score and TIL density as predictors. Results: 180 patients were included, of which 150 (83%) had non-desmoplastic CRLM. Unfavourable histopathology was more frequent in non-desmoplastic CRLM for all individual CRC features evaluated (figure), and significantly so for a lower TIL density and a “non-mature” stroma (both p<0.03). This was confirmed by the point-based score, which revealed a significant association between unfavourable CRC histopathology and non-desmoplastic CRLM (median [IQR]: 4 [2;5] vs 1 [1;3] unfavourable features, p<0.001). Multivariable logistic regression achieved good discriminatory performance to predict the HGP (AUC=0.74). Conclusions: The current study observes an association in treatment-naive patients between CRC histopathology and the HGP of corresponding CRLM.Tabled 1CRC histopathology featurePointsCRC histopathology featurePointsRight-sided tumour+1Perineural invasion+1Poorly differentuiated+1(Lympho-)vascular invasion+1pT4 tumour+1Extramural venous invasion+1Positive lymph node(s)+1Peritumoural buddig (II or III)+1Tumour deposit(s)+1Non-mature stroma type+1Absent Chron's-like lymphoid reaction+1Infiltrative CRC growth pattern+1 Open table in a new tab

Bevacizumab in metastatic colorectal cancer in a real-life setting - toxicity profile, survival outcomes, and impact of tumor sidedness.

IntroductionTargeting angiogenesis in metastatic colorectal cancer (mCRC) using bevacizumab is a standard of care. The addition of this targeted biological agent to first-line infusional fluoropyrimidine-based chemotherapy was associated with superior overall survival (OS) in several randomized and controlled studies for CRC patients in the metastatic setting. However, access to this therapy in countries with limited resources is challenging. In Morocco, bevacizumab was introduced for this indication after considerable efforts of the Ministry of Health and Lalla Salma Foundation to support cancer patients with a limited income. In this report, the real-world efficacy and safety of the combination of bevacizumab with chemotherapy in mCRC are reported based on a retrospective cohort in Eastern Morocco.Material and methodsThe archives of the medical records of 98 mCRC patients treated with first-line bevacizumab at the Hassan II Regional Cancer Center (Oujda, Morocco) were sampled from 1st January 2014 to 31st December 2019 and analyzed using descriptive statistics, Kaplan-Meier estimation, and a multivariable Cox regression model for a time-to-event study.ResultsThe toxicity profile was dominated by grade I–II proteinuria (10%), bleeding events (10%), thromboembolic events (9%), grade I–III hypertension (3%), and other rare events such as delayed healing of the stoma, scar dehiscence, intestinal perforation, and heart failure deterioration. In terms of survival, median OS and progression-free survival in the whole cohort were 22 and 13 months respectively. Patients who benefited from a metastasectomy after bevacizumab treatment had 31 months of median OS as compared to 14 months in the matched cohort with non-resectable liver metastasis. Notably, we demonstrated that tumor sidedness is a predictive factor of OS [hazard ratio (HR) = 2.452; 95% CI: 1.434–4.191, p = 0.001]. Moreover, the median OS for patients who received between 10 and 20 or more than 20 bevacizumab administrations was 24 and 33 months respectively as compared to those who received less than 10 cures (17 months) (log rank p < 0.0001). These markedly improved outcomes were also confirmed in multivariate Cox regression. A highly significant association of bevacizumab use and OS was found after adjusting for covariates (HR = 0.518, 95% CI: 0.374–0.717; p < 0.0001).ConclusionsThe current study confirmed the important place of this therapeutic strategy in mCRC. Additional studies with prospective enrollment are awaited to validate these findings.

Exploring the prognostic impact of tumor sidedness in ovarian cancer: A population-based survival analysis of over 10,000 patients

Very recently, emerging evidence demonstrated that laterality might be an independent prognostic factor in patients with advanced ovarian cancer (OC). Based on preliminary provocative observations, our study aimed to investigate the prognostic impact of sidedness in a large cohort of women with OC. Survival was estimated based on Kaplan-Meier method and survival curves were compared using Log-rank test. Cox proportional-hazards model was used to study the association between survival and covariates. A total of 10,177 women with OC were included. Mean age at diagnosis was 59.58 years (±13.5); 36.7% OC right-sided, 36.9% were left- sided, and 26.4% had bilateral OC. The median overall survival (OS) for the entire population was 77 months, with the lowest median OS observed in bilateral OC (median OS: 34 months). The prognostic value of OC sidedness was not confirmed at the univariable analysis (HR = 0.958; 95% CI: 0.888–1.033, p = 0.268). However, women with bilateral OC has a 45% higher risk of death as compared with unilateral diagnosis (HR = 1.453; 95% CI: 1.410–1.497; p< 0.001). The independent prognostic value was further confirmed on multivarible analysis after adjusting for covariates including age, marital status, histological type, CA-125 at diagnosis, grade, stage, chemotherapy and surgery (HR = 1.087; 95% CI: 1.043–1.136, p = 0.02). However, the ultimate prognostic significance appeared less prominent, with bilateral OC conferring a relative increase of 8.7% of mortality. Our real-world study demonstrated that impact of tumor sidedness has no prognostic implication (right vs left OC) but bilateral OCs might be marginally more prognostically unfavorable. Prospective validation might be warranted, to confirm the prognostic significance of OC sidedness, including for the presence of key genetic alterations and lymph nodes asymmetry, to better stratify patients with OC and predict outcomes according to tumor sidedness at diagnosis.

Long-term Oncological Outcomes after Resection and Thermal Ablation of Colorectal Liver Metastases: A Propensity Score Matched Analysis

Introduction: Thermal ablation of colorectal liver metastases is mostly used where resection is not possible, but has recently emerged as a parenchyma-sparing alternative to resection. High-quality data comparing oncological outcomes after resection and ablation of colorectal liver metastases are wanting. Method: Data for patient with colorectal liver metastases treated with laparoscopic resection at Oslo University Hospital between 2007 and 2020 was extracted from a prospectively maintained database and compared to patients undergoing ablation (radiofrequency or microwave). The primary endpoint was overall survival (OS). An average treatment effect (ATE) and potential-outcome means analysis using inverse-probability assignment and censoring using prognostic variables (CEA, largest tumor size, synchronous disease, primary tumor nodal status and sidedness, chemotherapy, previous liver surgery and others). Results: We identified 223 ablation sessions and 765 resection sessions available for comparison. The 5-year OS was 53% in the ablation group and 51% in the resection group. Median OS was 62,4 months (ablation) and 61,6 months (resection). The ATE for ablation versus resection was estimated to be 0,47 months (95% CI -8,1 to 9,9; P=0,92), meaning if every patient was treated with ablation, the average time to death would be 0,47 months longer than if every patient was treated with resection. A complete dataset including local recurrence will be presented at the meeting. Conclusion: Thermal ablation in patients with colorectal liver metastases was associated with rates of OS similar to surgical resection. Our results indicate adequate equipoise for a randomized trial to overcome selection bias.