scholarly journals RADI-13. IMPACT OF CITV AND BRAF MUTATION ON MELANOMA METASTASIS RESPONSE TO STEREOTACTIC RADIOSURGERY

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i24-i24
Author(s):  
Ali Alattar ◽  
Rushikesh Joshi ◽  
Brian HIrshman ◽  
Kate Carroll ◽  
Osamu Nagano ◽  
...  
Keyword(s):  
Stereotactic Radiosurgery ◽  
Braf Mutation ◽  
Proportional Hazards ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Cox Proportional Hazards ◽  
Melanoma Metastasis ◽  
Mutation Status ◽  
Prognostic Assessment ◽  
Independent Cohort

Abstract INTRODUCTION: Survival prognostication is an important aspect of personalizing oncologic care for patients with melanoma brain metastasis (BM). We previous demonstrated the utility of a cumulative intracranial tumor volume modified diagnosis-specific graded prognostic assessment scale (CITV-dsGPA) for SRS-treated melanoma BM patients. Pertinent prognostic variables in this model included age, Karnofsky performance status (KPS), and CITV. Here we determined whether the incorporation of BRAF mutation status into this CITV-modified scale further enhanced its prognostic accuracy. METHODS: We collated the survival pattern of 331 melanoma BM patients with known BRAF mutation status treated with stereotactic radiosurgery (SRS) and validated our findings in an independent cohort of 174 patients. All patients with BRAF mutation were treated with BRAF inhibitors. The prognostic utility of the model with and without BRAF mutation information was compared using the net reclassification index (NRI > 0) and integrated discrimination improvement (IDI) metric. RESULTS: Presence of the BRAF mutation was associated with a reduced hazard of death in univariate Cox proportional hazards survival analysis (hazard ratio (HR) 0.74, p< 0.001). This effect persisted in a multivariate model that controlled for age, KPS, and CITV (HR 0.72, p< 0.001). Addition of BRAF mutation status to the CITV-ds-GPA model for melanoma significantly improved its prognostic value, with NRI >0 of 0.294 (p=0.01) and IDI of 0.017 (p=0.02). We validated these findings in an independent cohort of 174 melanoma patients. CONCLUSIONS: Optimal survival prognostication for SRS-treated patients with melanoma BM requires an integrated assessment of age, KPS, CITV, and BRAF mutation status.

scholarly journals Cumulative Intracranial Tumor Volume Augments the Prognostic Value of Diagnosis-Specific Graded Prognostic Assessment Model for Survival in Patients with Melanoma Cerebral Metastases

Neurosurgery ◽  
2017 ◽  
Vol 83 (2) ◽  
pp. 237-244 ◽  
Author(s):  
Brian R Hirshman ◽  
Bayard R Wilson ◽  
Mir Amaan Ali ◽  
Alexander J Schupper ◽  
James A Proudfoot ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Tumor Volume ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Intracranial Tumor ◽  
Assessment Model ◽  
Prognostic Assessment ◽  
Prognostic Accuracy ◽  
Graded Prognostic Assessment ◽  
Independent Cohort

Abstract BACKGROUND The diagnosis-specific graded prognostic assessment scale (ds-GPA) for patients with melanoma brain metastasis (BM) utilizes only 2 key prognostic variables: Karnofsky performance status and the number of intracranial metastases. We wished to determine whether inclusion of cumulative intracranial tumor volume (CITV) into the ds-GPA model for melanoma augmented its prognostic value. OBJECTIVE To determine whether or not CITV augments the ds-GPA prognostic scale for melanoma. METHODS We analyzed the survival pattern of 344 melanoma patients with BM treated with stereotactic radiosurgery (SRS) at separate institutions and validated our findings in an independent cohort of 201 patients. The prognostic value of ds-GPA for melanoma was quantitatively compared with and without the addition of CITV using the net reclassification index (NRI > 0) and integrated discrimination improvement (IDI) metrics. RESULTS The incorporation of CITV into the melanoma-specific ds-GPA model enhanced its prognostic accuracy. Addition of CITV to the ds-GPA model significantly improved its prognostic value, with NRI > 0 of 0.366 (95% CI: 0.125-0.607, P = .002) and IDI of 0.024 (95% CI: 0.008-0.040, P = .004). We validated these findings that CITV improves the prognostic utility of melanoma ds-GPA in an independent cohort of 201 melanoma cohort. CONCLUSION The prognostic value of the ds-GPA scale for melanoma BM is enhanced by the incorporation of CITV.

Association of Surgical Resection, Disability, and Survival in Patients with Glioblastoma

2019 ◽  
Vol 80 (04) ◽  
pp. 262-268 ◽  
Author(s):  
Yahya Ahmadipour ◽  
Monika Kaur ◽  
Daniela Pierscianek ◽  
Oliver Gembruch ◽  
Marvin Darkwah Oppong ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Extent Of Resection ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Hazards Model ◽  
Surgical Modality ◽  
Supratotal Resection

Objective Extent of resection (EOR) and Karnofsky Performance Status (KPS) are at odds in glioblastoma (GBM) surgery, that is, the anticipated postoperative disability limits the EOR. This study analyzes the correlation of different surgical modalities with the resulting physical status and survival of patients with GBM. Methods A total of 565 patients with primary GBM were operated on in a single institution between 2006 and 2014. Possible surgical modalities comprised supratotal resection (SLR), gross total resection (GTR; ≥ 95% by volume), tumor debulking (TDB; ≤ 95% by volume), and stereotactic biopsy (SB). Pre- and postoperative KPS before and up to 4 weeks after surgery as well as overall survival (OS) rate were determined retrospectively. Hazard ratio (HR) and 95% confidence intervals were calculated using a Cox proportional hazards model. Results Median postoperative KPS was ≥ 70, irrespective of surgical modality. Mean OS was 12.5 months. Multivariate analysis revealed age ≥ 70 years (HR: 1.93), preoperative KPS < 70 (HR: 2.15), and unmethylation in MGMT promoter (HR: 1.27) as independent factors for worse OS. Regarding surgical modality, SB was associated with the worst survival (HR: 2.3) followed by TDB (HR: 1.36). SLR was inferior to GTR (HR: 1.27). Conclusion Higher EOR in patients with GBM does not seem inevitably correlated with increasing functional impairment, but better survival, provided there is a balanced preoperative indication. Nevertheless, SLR does not seem to be superior to GTR. Whenever possible, maximal safe resection should be considered in patients with GBM, even if an EOR ≥ 95% is not possible.

scholarly journals Butterfly Tumor of the Corpus Callosum: Clinical Characteristics, Diagnosis, and Survival Analysis

2017 ◽  
Vol 08 (S 01) ◽  
pp. S57-S65 ◽  
Author(s):  
Thara Tunthanathip ◽  
Sanguansin Ratanalert ◽  
Sakchai Sae-heng ◽  
Thakul Oearsakul
Keyword(s):  
Corpus Callosum ◽  
Clinical Characteristics ◽  
Proportional Hazards ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Descriptive Analysis ◽  
Clinical Manifestations ◽  
B Cell Lymphoma ◽  
Cox Proportional Hazards ◽  
Karnofsky Performance Status Score

ABSTRACT Background: The pathologies implicate the bilateral corpus callosum that builds the butterfly pattern on axial view. These tumors have seldom been investigated for both clinical manifestations and outcome. Objective: The objective of this study was to describe the clinical characteristics and outcomes of the butterfly tumor and to identify the predictive factors associated with survival outcome. Methods: A retrospective study of 50 butterfly tumor was conducted between 2003 and 2016. The clinical characteristics, imaging, and outcome were assessed for the purpose of descriptive analysis. Using the Kaplan–Meier method, the median overall survival of the butterfly tumor was determined. Furthermore, the Cox proportional hazard regression was the estimated hazard ratio for death. Results: Diffuse large B-cell lymphoma was common of butterfly lesions. The mortality rate was 78% and overall median survival time was 16.03 months (95% confidence interval: 14.0–19.8). Using Cox proportional hazards regression, the independent prognostic factors were Karnofsky Performance Status score ≤70, splenium involvement, and butterfly glioblastoma. Conclusions: The butterfly tumor is a poor prognostic disease compared with each histology subgroup. Further molecular investigation is preferable to explore genetic variations associated with these tumors.

scholarly journals Cyberknife® hypofractionated stereotactic radiosurgery (CK-hSRS) as salvage treatment for brain metastases

2021 ◽  
Author(s):  
Sergej Telentschak ◽  
Daniel Ruess ◽  
Stefan Grau ◽  
Roland Goldbrunner ◽  
Niklas von Spreckelsen ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Stereotactic Radiosurgery ◽  
Poor Prognosis ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Salvage Treatment ◽  
Treatment Modalities ◽  
Large Tumor ◽  
Fractionated Radiotherapy ◽  
Hypofractionated Stereotactic Radiosurgery

Abstract Purpose The introduction of hypofractionated stereotactic radiosurgery (hSRS) extended the treatment modalities beyond the well-established single-fraction stereotactic radiosurgery and fractionated radiotherapy. Here, we report the efficacy and side effects of hSRS using Cyberknife® (CK-hSRS) for the treatment of patients with critical brain metastases (BM) and a very poor prognosis. We discuss our experience in light of current literature. Methods All patients who underwent CK-hSRS over 3 years were retrospectively included. We applied a surface dose of 27 Gy in 3 fractions. Rates of local control (LC), systemic progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan–Meier method. Treatment-related complications were rated using the Common Terminology Criteria for Adverse Events (CTCAE). Results We analyzed 34 patients with 75 BM. 53% of the patients had a large tumor, tumor location was eloquent in 32%, and deep seated in 15%. 36% of tumors were recurrent after previous irradiation. The median Karnofsky Performance Status was 65%. The actuarial rates of LC at 3, 6, and 12 months were 98%, 98%, and 78.6%, respectively. Three, 6, and 12 months PFS was 38%, 32%, and 15%, and OS was 65%, 47%, and 28%, respectively. Median OS was significantly associated with higher KPS, which was the only significant factor for survival. Complications CTCAE grade 1–3 were observed in 12%. Conclusion Our radiation schedule showed a reasonable treatment effectiveness and tolerance. Representing an optimal salvage treatment for critical BM in patients with a very poor prognosis and clinical performance state, CK-hSRS may close the gap between surgery, stereotactic radiosurgery, conventional radiotherapy, and palliative care.

scholarly journals Glioblastoma Multiforme: an Advanced Analysis of 153 Patients and Review of the Literature

2017 ◽  
Vol 36 (02) ◽  
pp. 080-090 ◽  
Author(s):  
Mohammad Nikdad ◽  
Farshid Farhan ◽  
Milad Shafizadeh ◽  
Atefeh Mirmohseni ◽  
Mohsen Afarideh ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Local Recurrence ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Tertiary Care ◽  
Cox Proportional Hazards ◽  
Recurrence Rates ◽  
Operative Method ◽  
Factors Associated ◽  
Advanced Analysis

Objective Glioblastoma multiforme (GBM) is an aggressive primary tumor with frequent recurrences that leaves patients with a short survival time and a low quality of life. The aim of this study was to review the prognostic factors in patients with glioblastoma multiforme. Material and Methods The focus of this retrospective study was a group of 153 patients with supratentorial GBM tumors, who were admitted to a tertiary-care referral academic center from 2005 to 2013. The factors associated with survival and local recurrence were assessed using the hazard ratio (HR) function of Cox proportional hazards regression and neural network analysis. Results Out of the 153 patients, 99 (64.7%) were male. The average age of the patients was 55.69 ± 15.10 years. The median overall survival (OS) and progression-free survival (PFS) rates were 14.0 and 7.10 months respectively. In the multivariate analysis, age (HR = 2.939, p < 0.001), operative method (HR = 7.416, p < 0.001), temozolomide (TMZ, HR = 11.723, p < 0.001), lomustine (CCNU, HR = 8.139, p < 0.001), occipital lobe involvement (HR = 3.088, p < 0.001) and Karnofsky Performance Status (KPS, HR = 4.831, p < 0.001) scores were shown to be significantly associated with a higher OS rate. Furthermore, higher KPS (HR = 7.292, p < 0.001) readings, the operative method (HR = 0.493, p = 0.005), the use of CCNU (HR = 2.047, p = 0.003) and resection versus chemotherapy (HR = 0.171, p < 0.001) were the significant factors associated with the local recurrence of the tumor. Conclusion Our findings suggest that the use of CCNU and TMZ, the operative method and higher KPS readings are associated with both higher survival and lower local recurrence rates.

Differential response rates in early-phase cancer clinical trials (EPCCT).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3133-3133
Author(s):  
Rozana Abdul Rahman ◽  
Neethu Billy Graham Mariam ◽  
Hitesh Mistry ◽  
Sreeja Aruketty ◽  
Matt Church ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Response Rates ◽  
Primary Objective ◽  
Cox Proportional Hazards ◽  
Sustained Response ◽  
Phase Ii Trials ◽  
Significant Difference

3133 Background: The primary objective of EPCCT (phase I and non-randomised phase II trials) is to determine the safety and tolerability of new therapeutic agents. Response rates (RR) in these trials have typically been reported at around 10-15%. Increasingly RR and survival outcomes are now investigated in EPCCT as primary or secondary objectives. Methods: Retrospective data analysis was performed on patients (pts) enrolled onto an EPCCT between January 2018 and December 2019 at The Christie NHS Foundation Trust, UK. Data on demographics, prior systemic treatment, sites of disease, performance status, comorbidities, types of therapy, RR, progression free survival (PFS), and overall survival (OS) were collected. Statistical analyses were performed with univariable and multivariable models. Objective response rate (ORR) was defined as the proportion of pts with complete response (CR) and partial response (PR). Duration of response (DOR) was from initial response to progressive disease (PD). Disease control rate (DCR) was defined as CR+PR+ stable disease (SD). Results: A total of 247 pts were treated across 46 EPCCTs. Median age 61 years; 57% female. Sixty-six percent of pts had ≥2 lines of treatment and the majority were ECOG PS 0/1 (98%). Eighty-one percent of pts had ≥2 sites of metastatic disease, and 13 major tumour types were included. Monotherapy trials (159 pts) were predominantly targeted therapies (TT; 60%), or immunotherapies (IO; 20%). Combination therapy trials (88 pts) were TT-based (68%) or IO-based (32%). Data for RR analyses was available for 231 pts. ORR across all trials was 15% (CR 2%) and DCR was 63%. The median DOR was 8.3 months (mos) (95% CI: 7.0 – 9.7) with 28% of pts responding for >6 mos and 7% for >12 mos. ORR in pooled IO treated pts was 27%, DCR was 65% with sustained response >6 mos seen in 37% of these pts. ORR in pooled TT treated pts was 9.4%, DCR was 60% and sustained response > 6 mos seen in 25% of pts. ORR for IO v TT treated pts was significantly different, p=0.007 (pearson chi square), but no significant difference was seen for DCR. Median PFS for all patients was 5.0 mos (95% CI: 4.1 – 6.0) and OS was 10.4 mos (95% CI: 8.4 – 13.0). OS for those with a PR is not reached (HR for PR v PD, 0.006 (95% CI: 0.002 – 0.18). Pts with SD appear to have significantly better OS compared to those with PD (14.6 v 4.2 mos, HR 0.2 (95% CI: 0.1 – 0.3). Multivariable Cox proportional hazards analysis for OS was significant for male gender (HR 1.9, p=0.002), presence of liver metastasis (HR 2.0, p=0.001), low Hb (HR 0.8, p=0.03) and log (LDH) (HR 1.9, p<0.001). Conclusions: Two-thirds of pts enrolled on EPCCTs benefitted in terms of DCR with significant OS improvement in those with PR and SD. Higher ORR were seen in pts receiving IO-based treatments however DCR was similar in IO and TT pts. Gender, presence of liver metastases, Hb count and LDH level contributed significantly to survival differences.

scholarly journals Factors influencing the outcome of stereotactic radiosurgery in patients with five or more brain metastases

2019 ◽  
Vol 26 (1) ◽  
Author(s):  
E. Hamel-Perreault ◽  
D. Mathieu ◽  
L. Masson-Cote
Keyword(s):  
Brain Metastases ◽  
Stereotactic Radiosurgery ◽  
Karnofsky Performance Status ◽  
Systemic Disease ◽  
Performance Status ◽  
Recursive Partitioning ◽  
Nonsmall Cell Lung Cancer ◽  
Factors Influencing ◽  
Treatment Volume ◽  
Extracranial Disease

Background Stereotactic radiosurgery (srs) for patients with 5 or more brain metastases (bmets) is a matter of debate. We report our results with that approach and the factors influencing outcome.Methods In the 103 patients who underwent srs for the treatment of 5 or more bmets, primary histology was nonsmall- cell lung cancer (57% of patients). All patients were grouped by Karnofsky performance status and recursive partitioning analysis (rpa) classification. In our cohort, 72% of patients had uncontrolled extracranial disease, and 28% had stable or responding systemic disease. Previous irradiation for 1–4 bmets had been given to 56 patients (54%). The mean number of treated bmets was 7 (range: 5–19), and the median cumulative bmets volume was 2 cm3 (range: 0.06–28 cm3).Results Multivariate analyses showed that stable extracranial disease (p < 0.001) and rpa (p = 0.022) were independent prognostic factors for overall survival (os). Moreover, a cumulative treated bmets volume of less than 6 cm3 (adjusted hazard ratio: 2.54; p = 0.006; 95% confidence interval: 1.30 to 4.99) was associated with better os. The total number of bmets had no effect on survival (p = 0.206). No variable was found to be predictive of local control. The rpa was significant (p = 0.027) in terms of distant recurrence.Conclusions Our study suggests that srs is a reasonable option for the management of patients with 5 or more bmets, especially with a cumulative treatment volume of less than 6 cm3.

Evaluation of Prognostic Factors for Early Mortality After Stereotactic Radiosurgery for Brain Metastases: a Single Institutional Retrospective Review

Neurosurgery ◽  
2017 ◽  
Vol 83 (1) ◽  
pp. 128-136 ◽  
Author(s):  
E Emily Bennett ◽  
Michael A Vogelbaum ◽  
Gene H Barnett ◽  
Lilyana Angelov ◽  
Samuel Chao ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Brain Metastases ◽  
Stereotactic Radiosurgery ◽  
Karnofsky Performance Status ◽  
Systemic Disease ◽  
Performance Status ◽  
Early Death ◽  
Tumor Type ◽  
Prognostic Groups ◽  
Prior Surgery

Abstract BACKGROUND Stereotactic radiosurgery (SRS) is used commonly for patients with brain metastases (BM) to improve intracranial disease control. However, survival of these patients is often dictated by their systemic disease course. The value of SRS becomes less clear in patients with anticipated short survival. OBJECTIVE To evaluate prognostic factors, which may predict early death (within 90 d) after SRS. METHODS A total of 1427 patients with BM were treated with SRS at our institution (2000-2012). There were 1385 cases included in this study; 1057 patients underwent upfront SRS and 328 underwent salvage SRS. The primary endpoint of the study was all-cause mortality within 90 d after first SRS. Multivariate analyses were performed to develop prognostic indices. RESULTS Two hundred sixty-six patients (19%, 95% confidence interval 17%-21%) died within 90 d after SRS. Multivariate analysis of upfront SRS patients showed that Karnofsky Performance Status, primary tumor type, extracranial metastases, age at SRS, boost treatment, total tumor volume, prior surgery, and interval from primary to BM were independent prognostic factors for 90-d mortality. The first 4 factors were also independent predictors in patients treated with salvage SRS. Based on these factors, an index was defined for each group that categorized patients into 3 and 2 prognostic groups, respectively. Ninety-day mortality was 5% to 7% in the most favorable cohort and 36% to 39% in the least favorable. CONCLUSION Indices based on readily available patient, clinical, and treatment factors that are highly predictive of early death in patients treated with upfront or salvage SRS can be calculated and used to define well-separated prognostic groups.

Quantitative Gene Expression Analysis of Surrogate Markers for Genetic Risk Groups and Survival in CLL

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4170-4170
Author(s):  
Dirk Kienle ◽  
Axel Benner ◽  
Dirk Winkler ◽  
Manfred Hensel ◽  
Riccardo Dalla-Favera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Survival Analysis ◽  
Genetic Risk ◽  
Proportional Hazards ◽  
Risk Groups ◽  
Cox Proportional Hazards ◽  
Surrogate Markers ◽  
Mutation Status ◽  
Binet Stage

Abstract In CLL, a variety of surrogate markers for individual genetic features, mostly the VH mutation status, were proposed from gene expression analyses. However, their detailed relation to specific genetic subsets such as V3-21 usage, del11q22-q23 (11q−), and del17p13 (17p−), and their prognostic value in relation to established factors is not elucidated yet. Gene expression markers (ADAM29, ATM, CLLU1, DMD, GLO1, HS1, KIAA0977, LPL, MGC9913, PCDH9, PEG10, SEPT10, TCF7, TP53, Vimentin, ZAP-70, ZNF2) were evaluated using real-time quantitative RT-PCR (RQ-PCR) in purified samples of 151 patients. VH sequencing and FISH screening for genomic aberrations were carried out for all cases, survival information was available for 133 cases. Logistic regression was performed to test the predictive value of gene expression for genetic risk groups, Cox proportional hazards statistics for survival analysis. VH mutation status was best assigned by LPL and ZAP70, followed by TCF7, a marker with a characteristic overexpression in VH mutated CLL patients (correct VH prediction in 83%, 83%, and 75% of the patients, respectively). A similar rate of correct VH assignments was achieved in the subgroup of patients with 11q− or 17p− when using these markers (88%, 86%, and 79%, respectively). In contrast to LPL and TCF7, most of the patients with V3-21 usage were recognized as risk patients by ZAP70 independently of the VH status. Therefore, ZAP70 yielded the best results for the overall recognition of patients with a genetic risk constellation (VH unmutated or V3-21 usage or 11q− or 17p−). Comparison of ZAP-70 determination by RQPCR and flow cytometry was performed for 72 patients and revealed 30% of discordant cases. Thereof, the majority was VH unmutated (including several cases with 11q− or 17p−) showing ZAP-70 negativity by FACS and positivity by RQ-PCR. In multivariate analysis of time to first treatment (TFT), ADAM29 was an independent prognostic factor besides the VH status and Binet stage. In overall survival analysis including the gene expression variables only, LPL was the strongest predictor for overall survival. When genetic and clinical factors were added to this analysis, V3-21 usage, 17p−, age, binet stage, and expression of ATM, ADAM29, SEPT10, and TCL1 were identified as significant prognostic factors. In conclusion, novel gene expression markers allow screening for patients at risk but can not fully substitute for the genetic factors, which should therefore at present remain the basis for risk stratification approaches. Some of the novel markers appear to have a prognostic relevance independently of the established factors, which points to relevant biologic and clinical implications demanding further investigation.

Pharmacogenetic analysis in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line irinotecan (IR)+/− cetuximab (CB): The EPIC experience

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4022-4022
Author(s):  
D. Yang ◽  
A. Pohl ◽  
W. Zhang ◽  
G. Lurje ◽  
Y. Ning ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Rank Test ◽  
Second Line ◽  
Ca Repeat ◽  
Ras Mutation ◽  
Mutation Status ◽  
Log Rank Test

4022 Background: EPIC, a multinational phase III clinical trial with IR + CB vs IR alone in mCRC pts in the second-line setting after failure of FOLFOX demonstrated a benefit for IR+CB in progression-free survival (PFS) and response rate (RR). We evaluated functional germline polymorphisms involved in the EGFR- (EGF, EGFR), angiogenesis- (VEGF, IL-8, CXCR-2) - and drug- metabolism related genes (UGT1A1, MTHFR) for their potential role as molecular predictors for clinical outcome in pts treated with CB/IR vs. IR alone. Methods: DNA was extracted from all available formalin-fixed paraffin-embedded tumor samples from the phase III EPIC trial (US sites only). Genotyping was performed using PCR-RFLP assays and 5’ -end [g-33P] ATP’ labeled PCR-protocols. Results: 186 pts were treated either with IR/CB (arm A, 84 pts) or IR (arm B, 102 pts) only. In arm A, 11/84 pts (13%) showed CR or PR, whereas 73/84 (87%) pts had SD or PD. For arm B, 6/102 pts (6%) showed CR or PR, whereas 96/102 pts (94%) had SD or PD. Median PFS in arm A was 3.0 months (95%CI: 2.4- 4.1 months) vs 2.7 months (95%CI: 2.2–2.9 months) in arm B; median overall survival (OS) was 9.3 months (95%CI: 7.1–12.1 months) in arm A vs. 12.3 months (95%CI: 10.4- 17.9 months) in arm B. K-ras mutation status was not significantly associated with PFS or response to CB/IR in the subgroup of 186 patients. We found an EGFR-CA- repeat in intron 1 in arm A to be associated with PFS (p=0.031, log-rank test). In arm B, we found a significant association with RR (p=0.0103, Fisher's exact test) for MTHFR1298. Furthermore, MTHFR 677 (p =0.0048, log-rank test) and MTHFR 1298 (p=0.038, log-rank test) were also found to be associated with OS in arm B. In multivariate analysis, EGFR-CA-repeat was significantly associated with PFS (adjusted p= 0.023). Furthermore, MTHFR 677 and MTHFR 1298 was associated with OS (adjusted p=0.028 and 0.026, respectively, Cox-proportional hazards models), independent from K-ras mutation status, race and number of disease sites. Conclusions: Our study demonstrates the potential predictive value of polymorphisms in the EGFR- and MTHFR- gene in mCRC pts treated with IR+ CB. Further validation in additional clinical trials is necessary. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document