Median On Overall Survival Research Articles

Implementing CT tumor volume and CT pleural thickness into future staging systems for malignant pleural mesothelioma

ObjectivesTumor thickness and tumor volume measured by computed tomography (CT) were suggested as valuable prognosticator for patients’ survival diagnosed with malignant pleural mesothelioma (MPM). The purpose was to assess the accuracy of CT scan based preoperatively measured tumor volume and thickness compared to actual tumor weight of resected MPM specimen and pathologically assessed tumor thickness, as well as an analysis of their impact on overall survival (OS).MethodsBetween 09/2013–08/2018, 74 patients were treated with induction chemotherapy followed by (extended) pleurectomy/decortication ((E)PD). In 53 patients, correlations were made between CT-measured volume and -tumor thickness (cTV and cTT) and actual tumor weight (pTW) based on the available values. Further cTV and pT/IMIG stage were correlated using Pearson correlation. Overall survival (OS) was calculated with Kaplan Meier analysis and tested with log rank test. For correlation with OS Kaplan-Meier curves were made and log rank test was performed for all measurements dichotomized at the median.ResultsMedian pathological tumor volume (pTV) and pTW were 530 ml [130 ml – 1000 ml] and 485 mg [95 g – 982 g] respectively. Median (IQR) cTV was 77.2 ml (35.0–238.0), median cTT was 9.0 mm (6.2–13.7). Significant association was found between cTV and pTV (R = 0.47, p < 0.001) and between cTT and IMIG stage (p = 0,001) at univariate analysis. Multivariate regression analysis revealed, that only cTV correlates with pTV. Median follow-up time was 36.3 months with 30 patients dead at the time of the analysis. Median OS was 23.7 months. 1-year and 3-year survival were 90 and 26% respectively and only the cTV remained statistically associated with OS.ConclusionPreoperatively assessed CT tumor volume and actual tumor volume showed a significant correlation. CT tumor volume may predict pathological tumor volume as a reflection of tumor burden, which supports the integration of CT tumor volume into future staging systems.

Comparative effectiveness of second-line immune checkpoint inhibitor therapy versus chemotherapy for malignant pleural mesothelioma

ObjectivesSecond-line immune checkpoint inhibition (ICI) was recently shown to have a survival advantage over placebo in malignant pleural mesothelioma (MPM), but the survival comparison to chemotherapy in patients with MPM receiving routine clinical care is unknown. Our objective was to examine the effectiveness of second-line ICI versus chemotherapy on overall survival (OS) outcomes in real-world patients with advanced MPM. Materials and MethodsWe performed a multicenter retrospective cohort study of real-world adult patients with advanced MPM who received first-line platinum-based chemotherapy and at least two total lines of systemic therapy. Patients received either second-line chemotherapy (gemcitabine and/or vinorelbine) or ICI therapy (pembrolizumab or nivolumab ± ipilimumab). The primary outcome was OS, defined as the time from second-line therapy initiation to death or end of the observation period. We used Kaplan-Meier methods and Cox proportional hazards modeling with adjustment for relevant patient demographic and clinical variables to compare OS between the two second-line treatment groups. ResultsOf the 176 patients with MPM, the median age was 75 years (IQR: 69–79.5 years), and most were white (77%), male (74%), and had epithelioid histology (67%). Thirty-five percent (61) received second-line chemotherapy and 65% (115) ICI therapy (80 pembrolizumab, 31 nivolumab, and 4 nivolumab + ipilimumab). Treatment with ICI was associated with significantly longer median OS compared to chemotherapy (8.7 vs 5.0 months, p=0.001; adjusted hazard ratio: 0.52, 95% CI: 0.34–0.81). The estimated 12-month OS probability was 36.7% (95% CI: 27.6%-45.8%) and 15.6% (95% CI: 7.7%-26.1%) in the ICI and chemotherapy groups, respectively. ConclusionIn this “real-world” population of patients with MPM, treatment with ICI was associated with improved OS outcomes compared to chemotherapy in the second-line setting, in contrast with a recent clinical trial. Our findings suggest that ICI may benefit patients with advanced MPM and progression after initial platinum-based chemotherapy.

Abstract 2620: Ignoring left truncation in overall survival within real-world genomic-phenomic data leads to inflated survival estimates

Abstract Studies linking genomic and phenomic data are subject to selection biases, including delayed entry or immortal time bias. Delayed entry can be problematic for time-to-event analyses, but utilization of appropriate statistical methods to account for delayed entry are underutilized. Delayed entry commonly occurs when genomic sequencing results are obtained after the start time for survival estimation. To evaluate the impact of left truncation on overall survival (OS) estimates, we explored outcomes in patients with de novo stage IV non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) from the AACR GENIE Biopharma Collaborative, who had genomic sequencing within a specified timeframe. We analyzed OS from diagnosis and from start of the most common first-line regimen, carboplatin/pemetrexed for NSCLC (N = 212 patients) and FOLFOX for CRC (N = 369 patients). We compared median OS using standard Kaplan-Meier methods to median OS using left truncation methods to account for delayed entry. All NSCLC and CRC patients underwent genomic sequencing after their diagnosis date. Among NSCLC patients on carboplatin/pemetrexed, 41% and among CRC patients on FOLFOX, 14% had sequencing determined after starting first-line regimen. The survfit function in R package survival was used, and the absolute differences and percent differences in median OS estimates were calculated. Failure to account for delayed entry leads to an overestimation of OS, regardless of cohort and start date. Adjusting survival outcomes using left truncation methods reduces the influence of some aspects of selection bias and results in better estimates of time to event outcomes. Analyses from these cohorts can provide meaningful insights about survival outcomes outside the clinical trial setting and may support trial design and reliable selection of control arms. As such, it is imperative that analytic methods to account for the inflated survival estimates are incorporated. EstimateCRC Stage IV (N = 658)NSCLC Stage IV (N = 722)Unadjusted Median (IQR) Overall Survival from Diagnosis (Years)3.2 (2.9, 3.4)2.3 (2.0, 2.5)Median (IQR) Overall Survival from Diagnosis in Years, Adjusting for Delayed Entry2.1 (1.9, 2.4)1.3 (1.1, 1.6)Difference in Medians (Years)1.11.0% Difference in Medians34%44%EstimateCRC Stage IV (N = 369)NSCLC Stage IV (N = 212)Unadjusted Median (IQR) Overall Survival from Most Common First-Line Regimen (Years)2.9 (2.6, 3.4)1.3 (1.0, 1.6)Median (IQR) Overall Survival from Most Common First-Line Regimen in Years, Adjusting for Delayed Entry2.1 (1.8, 2.5)0.9 (0.7, 1.2)Difference in Medians (Years)0.80.4% Difference in Medians28%31% Citation Format: Samantha Brown, Jessica A. Lavery, Eva M. Lepisto, Caroline McCarthy, Hira Rizvi, Celeste Yu, Kenneth L. Kehl, Shawn M. Sweeney, Julia E. Rudolph, Nikolaus Schultz, Ritika Kundra, Brooke Mastrogiacomo, Phillipe Bedard, Jeremy L. Warner, Gregory J. Riely, Deborah Schrag, Katherine S. Panageas, The AACR Project GENIE Consortium. Ignoring left truncation in overall survival within real-world genomic-phenomic data leads to inflated survival estimates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2620.

Abstract 111: Colorectal Cancer Presentation and Survival Outcomes in Nigeria: A Prospective Multi-Centre Cohort Study of 543 Patients

Abstract Purpose: Prospective data on colorectal cancer (CRC) presentation and outcomes in Nigeria is limited, however emergency presentation with advanced disease is thought to be common. Using the African Research Group for Oncology's prospective, multisite database of CRC patients in Southwest Nigeria, we evaluated risk factors for emergency CRC presentation and effects on overall survival (OS). Methods: Consecutive CRC patients presenting between 2013 and May 2020 to five referral sites were included. Demographic, socioeconomic and disease-related risk factors for emergency presentation were evaluated using univariate and multivariable logistic regression methods. We compared OS between emergency and elective patients, stratified for clinical stage, using Kaplan-Meier survival and Cox proportional hazards methods. Results: Of 543 CRC patients, 168 (30.9%) presented emergently. Median age at diagnosis was 55 years, 53% were male, and 4.8% reported a family history of cancer. Patients presenting emergently were more likely to have cancers proximal to the splenic flexure (41.1% vs 24.6%, p&amp;lt;0.001), stage IV disease (62.7% vs 43.4%, p&amp;lt;0.001) use non-motorized transport (54.4% vs 37.7%, p=0.001), have a lower median household income (USD$65/month vs $USD79/month, p&amp;lt;0.04), and lower education level than those presenting electively. On multivariable regression analysis, only low BMI, stage IV disease, mode of transport and hospital site were significantly associated with emergency presentation. Median OS was 5.4 months (IQR 0.9-14.5; n=146) in the emergency group compared to 10.7 months (IQR 3/8-22.5; n=375) among elective patients. After adjustment for clinical stage at diagnosis, emergency presentation was still associated with significantly worse OS (HR 1.52; 95% C.I. 1.36-1.63, p&amp;lt;0.001). Conclusion: A high proportion of CRC patients in Nigeria present emergently, with advanced disease. Even after adjusting for clinical stage, these patients have worse overall survival. Earlier detection of cancers, including removing barriers to timely presentation and diagnosis, should be a focus of cancer control efforts. Citation Format: Adeniyi Aderibigbe, Anna Dare, Gregory Knapp, Olusegan Alatise, T. Peter Kingham. Colorectal Cancer Presentation and Survival Outcomes in Nigeria: A Prospective Multi-Centre Cohort Study of 543 Patients [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 111.

First Report on Overall Survival (OS) and Improved Progression Free Survival (PFS) in a Completed Phase 2a Study of Melflufen in Advanced Relapsed Refractory Multiple Myeloma (RRMM)

First Report on Overall Survival (OS) and Improved Progression Free Survival (PFS) in a Completed Phase 2a Study of Melflufen in Advanced Relapsed Refractory Multiple Myeloma (RRMM)

Conventional Karyotyping Is Still an Important Prognostic Marker for Myeloma in the Era of R-ISS Staging

Introduction: The Revised International Staging System (R-ISS) has been widely adopted to prognosticate Multiple Myeloma (MM). As a result, the continued utility of conventional karyotyping, has been called into question.Methods: A multi-centre study for newly diagnosed MM patients who received novel agent/s at induction from year 1999 at the National University Hospital Singapore, Singapore General Hospital, Alfred Hospital, Melbourne, Australia, was conducted. Conventional karyotype information was categorized based on ploidy as follows: normal, hyperdiploid (48-74 chromosome numbers), non-hyperdiploid (other abnormal karyotype). We evaluated the impact of ploidy on Overall Survival (OS) including a multivariate analysis, taking into account the R-ISS stages, transplant status, age, and novel agent/s used at induction. We also evaluated if it is possible to substitute FISH with conventional karyotyping in identifying high-risk patients. Results were validated in an independent cohort from China.Results: There were 303 patients evaluable. Ploidy significantly affected OS of patients with R-ISS stage II (N=212; p=0.026), with non-hyperdiploid patients doing worst. For R-ISS stage I patients (N=20), the number of patients in each cytogenetic group was too small to draw any conclusion. Non-hyperdiploid karyotype had no prognostic impact on patients with R-ISS stage III (N=71; p=0.990). In the multivariate analysis, ploidy was significantly associated with OS (p=0.018).Based on our results, we divided the R-ISS stage II patients into groups with or without non-hyperdiploid karyotype. The R-ISS stage I group and the R-ISS stage II group without non-hyperdiploid karyotype had similar median OS (median OS of 92.1 and 96.0 months respectively; p=0.001). They were grouped together into a standard-risk group. The R-ISS stage II group with non-hyperdiploid karyotype and the R-ISS stage III group had similar OS and were categorized together as a high-risk group (median OS of 45.0 months and 45.1 months respectively; p=0.001). As high-risk myeloma are of most clinical significance, we proposed a new prognostic staging system that incorporates ploidy into the R-ISS. In this R-ISS+K(Karyotype) staging system, patients were divided into standard and high-risk groups.. Patients in the 2 groups had significantly different OS (median OS of 92.1 versus 45.0 months, p=0.000).We replaced FISH with conventional karyotyping in the K(Karyotype)-ISS staging system, where stage I consisted of patients with ISS stage I with normal LDH and cytogenetics, stage III consisted of patients with ISS stage III with raised LDH or abnormal cytogenetics, and stage II consisted of all others. Of the R-ISS stage III patients, 83.0% were also K-ISS stage III. R-ISS stage II patients who were K-ISS Stage III had median OS of 45.0 months, shorter than K-ISS stage II patients that were R-ISS stage III (median OS of 60.0 months). In this K-ISS staging system, K-ISS stage III patients had median OS of 38.0 months, shorter than the median OS (45.1 months) of the R-ISS stage III group.These results were validated with an independent cohort of 382 patients from the Institute of Hematology, Peking University, China. The median OS in the R-ISS+K standard risk group was 127.1 months compared to 43.0 months for the high risk group (p=0.000). Similarly, K-ISS stage III patients had median OS of 43.1 months, compared to 46.1 months for the R-ISS stage III patients (p=0.000).Conclusion: Ploidy by conventional karyotyping is an independent prognostic factor even in the setting of R-ISS. Ploidy can be incorporated into R-ISS staging system to better identify high-risk patients (R-ISS+K). In countries where FISH is not available, conventional cytogenetics can be used instead of FISH (K-ISS) to identify high-risk patients. [Display omitted] DisclosuresSpencer:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Chng:Janssen China R&D: Research Funding.

The Survival Impact of Lenalidomide Maintenance Chemotherapy in Multiple Myeloma Patients Treated with Autologous Stem Cell Transplant and Bortezomib-Based Induction: An Analysis of Real World Data

IntroductionMultiple myeloma (MM) represents an incurable plasma cell malignancy. Success in the management of this disease requires a focus on prolonging disease control to positively impact survival. This is the rationale behind maintenance chemotherapy after frontline autologous stem cell transplant (ASCT). Recent large-scale phase 3 randomized trials have shown daily low dose lenalidomide, an oral immunomodulator (IMID), has led to markedly improved progression free survival (PFS) and an evolving benefit on overall survival (OS). We sought to evaluate the effect of lenalidomide maintenance in patients with MM undergoing bortezomib-based induction chemotherapy and ASCT in a real world setting.MethodsRetrospective review of patients with MM undergoing initial bortezomib-based induction chemotherapy and ASCT was completed in patients at our institution. Patients who began therapy up until June 30th, 2015 were included to ensure a minimum of 2-yrs follow-up. Patients were analyzed on an intention-to-treat basis. Maintenance chemotherapy included those on lenalidomide alone or lenalidomide plus bortezomib, the latter being a treatment option at our centre for high-risk patients. OS was measured from the time induction therapy was started until death or last follow-up. PFS was measured from the time of induction therapy initiation to relapse, death or last follow-up. Maximal response to treatment was assessed according to the IMWG consensus criteria although an additional endpoint of near CR (nCR) was included to account for patients where the monoclonal protein on electrophoresis disappeared and light chains normalized but where CR was not confirmed with immunofixation and a bone marrow biopsy was not done.Results198 patients were included in the analysis. 121 received lenalidomide based maintenance and 77 received no maintenance between December 2004 to June 30th, 2015. Median ISS score was 2 in both groups without significant difference between them (p=0.98) . In the maintenance and no maintenance groups respectively 32% and 36% had ISS stage 3 disease. The mean number of maintenance cycles received was 25 cycles (0.5 - 84). Sixty percent of patients required dose reductions or discontinuation due to adverse effects excluding relapse. Most commonly this was due to cytopenias (29.8%), rash (10.7%), infection (9.1%) and fatigue (5.8%). 15% discontinued therapy before relapse occurred. Though venous thromboembolism and second primary malignancies (SPMs) are a worry in patients treated long term with IMIDs these were only seen in 3.3% and 1.7% of patients respectively. Median follow-up in the maintenance group was 44 months and 60 months in the no maintenance group. Survival data is shown in figure 1. The median OS was not reached in the maintenance cohort and was 89 months in the no maintenance group (p = 0.01). Estimated 3-year OS was superior in the maintenance group at 88.4% versus 80.5% in the no maintenance cohort. A statistically significant difference in median PFS was also noted favouring the lenalidomide maintenance (55.0 months versus 32.9 months, p=0.002). Of patients treated with lenalidomide-based maintenance 95.0% achieved ≥ VGPR (53.7% ≥ nCR) while 77.9% (29.1% ≥ nCR) of those who did not receive maintenance therapy achieved these endpoints (p=0.03). Further characterization of therapy for relapsed disease as well as PFS after 1st relapse (2nd PFS) and time to second relapse (PFS2) will be presented at the meeting.ConclusionsOur retrospective analysis of lenalidomide maintenance therapy in MM patients treated with bortezomib-based induction chemotherapy and ASCT illustrates the positive impact lenalidomide has had on both PFS and OS. Patients treated with lenalidomide at our centre experienced a more prolonged and profound remission of their disease. The treatment was well tolerated with no unexpected adverse effects. Rates of thromboembolic disease and SPMs were low. Most importantly, the superior OS in the maintenance arm suggests that second line therapy for those not receiving maintenance could not overcome the negative impact of an earlier relapse. This data supports our ongoing approach incorporating lenalidomide-based maintenance continued until progression for all patients who have undergone an ASCT. Importantly, these real world results validate the phase 3 trial experience, helping to further establish this approach as a standard of care. [Display omitted] DisclosuresBelch:Amgen, Celgene, Takeda: Honoraria.

Evaluation of the Impact of Minimal Residual Disease, FLT3 Allelic Ratio, and FLT3 Mutation Status on Overall Survival in FLT3 Mutation-Positive Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) in the Chrysalis Phase 1/2 Study

Evaluation of the Impact of Minimal Residual Disease, FLT3 Allelic Ratio, and FLT3 Mutation Status on Overall Survival in FLT3 Mutation-Positive Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) in the Chrysalis Phase 1/2 Study

The Role of Upfront Autologous Hematopoietic Cell Transplantation in the Treatment of Mantle Cell Lymphoma, a Population Based Study Using the National Cancer Data Base (NCDB)

Introduction: There are no prospective randomized data supporting the use of upfront consolidative autologous stem cell transplant (ASCT) in newly diagnosed mantle cell lymphoma (MCL) patients (pts). The aim of this population-based study in MCL pts is to better define the impact of frontline ASCT on overall survival (OS), and to identify factors influencing treatment selection.Methods: Using the National Cancer Data Base (NCDB), we identified pts with newly diagnosed MCL treated from 2004-2012 with multi-agent chemo alone or in combination with consolidative ASCT as part of first line treatment. Univariable and multivariable Cox proportional hazards regression analyses were used to identify predictors for treatment selection and OS, including age, gender, race, stage, Charlson-Deyo comorbidity index (CDCI), income, education, insurance, treatment facility type, distance to treatment facility and year of diagnosis. Income was recorded as quartiles of median annual household income and education as percentage of persons with less than high school education in pts' residence census. Including these same factors, a propensity score matched analysis (PSMA) was performed to further account for confounding variables.Results: We identified 16,035 MCL pts with known survival times. The following groups were excluded: no chemo (n=3,193), chemo status/type unknown (n=1,056), chemo contraindicated (n=199), single-agent chemo (n=983), received allogeneic SCT (n=79) or ASCT data missing (n=235). The final analysis included 10,290 pts. Median age was 65 years (range 20-90); 66% were > 60 years, 73% male, 93% Caucasian, and 78% had stage III-IV. CDCI was 0 in 79%, 1 in 16% and ≥2 in 5%. Forty percent of pts were treated at academic institutions and 49% travelled >11.5 miles to receive treatment. Medicare was the most common insurance type (48%), followed by private (43%) and Medicaid (4%). Median follow up was 34 months (interquartile range (IQR) 16-60). Median OS for the entire cohort was 64 months; 5- and 10-year OS rates were 52% and 33%, respectively. Seventeen percent of the pts (n=1774) underwent upfront ASCT, and there was a trend of increased use from 2004-2012 (11.9% in 2004 and 21.2% in 2012) that resulted in an annual increase of 1.2% (p<0.001). 31% of pts ≤60 and 25% of pts ≤70 years received ASCT. For the ASCT group, median age was 58 years (IQR 52-64; range 23-77); 89 pts (5%) were ≥70 years of age. Predictors for ASCT use included (p<0.001 for each): stage III-IV (odds ratio (OR) 2.4), having private insurance (OR 2.71), higher education (OR 2.1), no transition of care (diagnosis and treatment done at the same facility) (OR 3.15), longer distance (> 11.5 miles) to treatment facility (OR 1.73) and year of diagnosis ≥2009 (OR 1.62) (Figure 1). Median follow up was 44 months (IQR 28-69) for ASCT group and 31 months (IQR 14-58) for chemo only group. Five and 10-year OS rates for ASCT and chemo group were 77%, 57%, 47% and 28%, respectively. After adjusting for other covariates, the use of ASCT was associated with superior OS (HR: 0.46; 95% CI 0.41-0.52; p<0.001). Other factors associated with superior OS were: female gender (HR 0.92, p=0.01), income (HR 0.92, p<0.001), private insurance (HR 0.71, p<0.001), no transition of care (HR 0.82, p<0.001) and diagnosis year ≥2009 (HR 0.91, p=0.005). Predictors for inferior OS were: age >60 (HR 1.62, p<0.001), African American race (HR 1.23, p=0.009), stage III-IV (HR 1.58, p<0.001) and CDCI ≥2 (HR 2.0, p<0.001). Using a subset of 1582 pts treated with ASCT and 1582 matched controls treated with chemo only, PSMA confirmed the OS benefit associated with ASCT (HR 0.5; CI 0.44-0.57, p<0.001). This OS benefit was observed in both younger (≤60 years: HR 0.44, CI 0.37-0.53, p<0.001) and older pts (>60 years: HR 0.59, CI 0.46-0.68; p<0.001) (Figure 2).Conclusion: In this large MCL cohort, the use of upfront consolidative ASCT was associated with superior OS when compared to chemo alone. Less than one third of young MCL pts treated with multi-agent chemo received consolidative ASCT, and this was influenced by sociodemographic factors with patterns favoring pts with higher education and private insurance. While one caveat in interpreting this retrospective study is that ASCT may have been preferentially applied to pts who responded to induction therapy, these data suggest clinical efficacy of ASCT in MCL. Prospective randomized trials are needed for further validation. [Display omitted] DisclosuresMajhail:Sanofi: Honoraria; Anthem, Inc.: Consultancy.

Survival impact of C-Arm cone-beam computed tomography on hepatocellular carcinoma patients undergoing chemoembolization

Objectives: The objectives of the study were to evaluate the use of C-arm cone-beam computed tomography (CBCT) for tumor targeting for transarterial chemoembolization (TACE) and its impact on overall survival (OS) in hepatocellular carcinoma patients. Material and Methods: Two groups were retrospectively evaluated according to the date of the first TACE session before and after C-arm CBCT installation in late 2005 (group A [n = 34], 2004–2005; group B [n = 104], 2008+). The years 2006 and 2007 were excluded to allow for the incorporation of this new imaging technology into clinical practice. The vessel selection order was recorded for all TACE sessions. Univariate and multivariate analyses were performed to assess the impact on and predictors of survival. Results: The average TACE selection order for each patient was significantly higher in group B than in group A (P &lt; 0.0001). The median OS was significantly longer in group B (29.34 months) than in group A (19.65 months; P = 0.0088), and the difference in duration was most pronounced in patients with tumor burdens &lt; 25% (n = 93; P = 0.0075), in whom the 3-year survival rate was 56.1% in group B and 15.3% in group A. In these 93 patients, the OS was significant longer (P = 0.018) for high (41.07 months) versus low (19.65 months) vessel selection order across both groups. In multivariate analyses, both the period in which TACE was performed (P = 0.022) and the use of C-arm CBCT (P = 0.0075) were significant predictors of improved OS. Conclusion: Use of advanced C-arm CBCT during TACE enhances the operating physician’s ability to deliver targeted, effective therapy for hepatocellular carcinoma, an aggressive approach that favorably impacts survival.

The prognostic impact of resection margin status varies according to the genetic and morphological evaluation (GAME) score for colorectal liver metastasis.

Surgical margin status remains a controversial factor in predicting the outcome of colorectal liver metastases (CRLM) resection. Our study aims to evaluate the effects of surgical margins on oncologic outcomes with regard to the genetic and morphological evaluation (GAME) score. R1 resection was defined as having a less than 1 mm margin width. Patients who underwent surgery for CRLM from January 2005 to December 2018 were recruited. The patients were divided into two risk subgroups, namely, the low or medium risk (GAME 0-3) and high-risk (GAME score 4 or more) groups. The effects of margin status on overall survival (OS) and recurrence-free survival rate (RFS) were examined. In total, 661 patients were recruited, among which 159 (24.1%) had R1 resection. Before hepatectomy, 514 patients showed a low or medium risk (R1 resection: n = 124), while 147 patients demonstrated a high risk (R1 resection: n = 35). In the whole cohort, multivariable analysis did show that R1 resection was associated with worse RFS and OS. While further research only found that in the low or medium risk group, R1 resection was related to poor OS and RFS. Meanwhile, in the high risk group, no significant difference was found in the median OS and RFS among patients with R0 or R1 resection. The prognostic role of margin status varied according to the GAME score. Margin clearance only improved survival rates in patients with low or medium GAME score. In contrast, R1 resection demonstrated similar oncologic outcomes with R0 resection in patients with high GAME score.

High risk of recurrence for grade II meningioma: a 10-year multicenter analysis of prognosis factors.

Atypical meningioma is a variant of meningioma with a high risk of recurrence. Gross total resection is the standard of treatment, while no consensus on optimal adjuvant management has been found. Between 2008 and 2018, a retrospective search identified 216 grade II meningiomas treated in six centers. Clinical, histological, and therapeutic data were analyzed to determine the prognostic factors of recurrence and survival. In total, 216 patients underwent surgical resection. Among these, 122 patients (56%) underwent gross total resection, and 21% of the patients received adjuvant radiotherapy. Univariate analysis reported subtotal resection, high Ki-67, negative progesterone receptor (PR) and histological grade evolution as unfavorable prognosis factors. According to multivariate analysis, the Ki-67 proliferative index (cut-off value of 17.5%) was the only prognostic factor of recurrence (HR 1.1; 95% CI, 1.0-1.2, P=0.048). Gross total resection improved progression-free survival (PFS) (P=0.03) but without impact on overall survival (OS) (P=0.2). Median PFS and OS times were longer for patients receiving adjuvant radiotherapy than those who did not receive adjuvant radiotherapy. PFS (P=0.3) and OS (P=0.7) were associated with adjuvant RT by trend only. After a median follow-up time of 6.7 years, 99 (46%) patients relapsed. Median progression-free and OS rates were 4.5 (95% CI, 3.5-5.5) and 14.7 years (11.4-NA), respectively. In this study, Ki-67 proliferative index was significantly associated with recurrence. Gross total resection significantly improved PFS without impacting OS. Adjuvant radiotherapy delayed recurrence and improved OS, but a longer follow-up time is needed to distinguish a statistically significant difference. Large prospective studies are needed to determine postoperative treatment guidelines.

The Role of Surgery in IDH-Wild-Type Lower-Grade Gliomas: Threshold at a High Extent of Resection Should be Pursued.

While maximizing extent of resection (EOR) is associated with longer survival in lower-grade glioma (LGG) patients, the number of cases remains insufficient in determining a EOR threshold to elucidate the clinical benefits, especially in IDH-wild-type LGG patients. To identify the effects of EOR on the survival outcomes of IDH-wild-type LGG patients. IDH-wild-type LGG patients were retrospectively reviewed. The effect of EOR and other predictor variables on overall survival (OS) and progression-free survival (PFS) was analyzed using Cox regression models and the Kaplan-Meier method. A total of 94 patients (median OS: 48.9 mo; median follow-up: 30.6 mo) were included in this study. In the multivariable Cox regression analysis, postoperative residual volume was associated with prolonged OS (HR=2.238; 95% confidence interval [CI], 1.130-4.435; P=.021) and PFS (HR=2.075; 95% CI, 1.113-3.869; P=.022). Thresholds at a minimum EOR of 97.0% or a maximum residue of 3.0 cm3 were necessary to impact OS positively. For the telomerase reverse transcriptase (TERT)p-wild-type group, such an association was absent. Significant differences in survival existed between the TERTp-wild-type and mutant patients who underwent relatively incomplete resections (residual ≥2.0 cm3+TERTp wild type: median OS of 62.6 mo [95% CI: 39.7-85.5 mo]; residual ≥2.0 cm3+TERTp mutant: median OS of 20.0 mo [95% CI:14.6-25.4 mo]). Our results support the core role of maximal safe resection in the treatment of IDH-wild-type LGGs, especially for IDH-wild-type+TERTp-mutant LGGs. Importantly, the survival benefits of surgery could only be elucidated at a high EOR cut-off point.

Shorter Diagnosis-to-Treatment Interval in Diffuse Large B-Cell Lymphoma is Associated With Inferior Overall Survival in a Large, Population-Based Registry.

Because of prolonged screening requirements, patient and time-dependent selection have been proposed as potential biases in clinical trials. The screening process may exclude patients with a need for emergent treatment (and a short period from diagnosis to treatment initiation [DTI]). We explored the impact of DTI on overall survival (OS) in a population-based cohort of patients with diffuse large B-cell lymphoma (DLBCL). Using population-based administrative databases in Ontario, Canada, we identified adults aged ≥18 years with DLBCL treated with rituximab-based chemotherapy for curative intent between January 2005 and December 2015. Cox regression and multivariable analyses were presented to evaluate the impact of time from DTI on OS, controlling for relevant covariates. We identified 9,441 patients with DLBCL in Ontario; median age was 66 years, 53.6% were male, median number of comorbidities (Johns Hopkins aggregated diagnosis groups) was 10 (interquartile range [IQR], 8-13), and median DTI was 37 days (IQR, 22-61). Between treatment initiation and study end, 43% of patients died (median OS, 1 year; IQR, 0.4-2.8 years). Shorter DTI was a significant predictor of mortality (P<.001). Compared with the shortest DTI period of 0-18 days, those who commenced therapy at 19-29 days (hazard ratio [HR], 0.75; 95% CI, 0.68-0.84), 30-41 days (HR, 0.70; 95% CI, 0.63-0.78), 42-57 days (HR, 0.52; 95% CI, 0.46-0.58), and 58-180 days (HR, 0.52; 95% CI, 0.47-0.58) had improved survival. Increasing age (HR, 1.03; 95% CI, 1.03-1.04), male sex (HR, 1.23; 95% CI, 1.14-1.32), and increasing number of comorbidities (HR, 1.12; 95% CI, 1.11-1.13) were associated with inferior survival. Among patients with DLBCL, shorter DTI was associated with inferior OS. Therefore, DTI may represent a surrogate marker for aggressive biology. Clinical trials with lengthy screening periods are likely creating a time-dependent patient selection bias.

The role of site of metastatic resection (MR) in metastatic colorectal cancer (mCRC) patients (PTS): A mono-institutional cohort study.

e15558 Background: Approximately 50%-60% of CRC pts develop metastases, usually to liver and lung. When feasible, MR is the only potentially curative option in the multimodal management of mCRC pts. Few studies have compared survival outcomes based on different surgical sites with contrasting data. Hence, we retrospectively analyzed mCRC pts, underwent radical lung and/or liver resection at our Institution, investigating the impact of resection site on overall survival (OS). Methods: mCRC pts underwent radical liver (group 1), lung (group 2) or liver and lung (group 3) resection were included. The following variables were collected: age ( &gt; vs ≤ 65 years); gender (male vs female); primary tumor site (right vs left); synchronous vs metachronous; RAS/BRAF status; number (N) of MR (1, 2 or ≥3); chemotherapy treatment (No treatment vs Post-operative vs Peri-operative/pre-operative treatment) and chemotherapy regimen (5FU monotherapy, Oxaliplatin-based, Irinotecan-based regimen, FOLFOXIRI, Bevacizumab, Anti-EGFR). The association of MR site and OS was evaluated. Univariate and multivariate analyses for OS were performed. Results: A total of 191 mCRC pts underwent radical MR were included in the analysis: 112 (59%) pts in group 1, 38 pts (20 %) in group 2, 41 pts (21 %) in group 3. 145 (76%) pts had a left-sided tumor and 46 (24%) a right-sided tumor. Out of 156 evaluable pts, 73 (47%) pts harbored a RAS mutation, while out of 136 evaluable pts, 4 (3%) pts had a BRAF mutation. Regarding the N of MR, 125 pts (65%) underwent 1 radical MR, 43 (23%) pts 2 MR and 23 (12%) ≥3 MR. In the overall population, median OS was 77.2 months. According to MR site, median OS was 59.4, not reached (NR) and 99.1 months, in group 1, 2 and 3, respectively (p = 0.075). At the multivariate analysis no significant association with OS was shown for MR site, while the N of MR and RAS status were indipendently associated with OS. Median OS was 58.5, 97.7 months and NR in pts underwent 1, 2 and ≥3 MR, respectively (p = 0.02). Median OS was 58.5 and 83.1 months in RAS mutated and RAS wild-type pts, respectively (p = 0.12). Conclusions: Despite the limited number of pts and the retrospective nature of our study, these results confirmed that surgery represents the only option with curative intent for mCRC pts, independently of metastatic site (liver vs lung vs liver and lung). Based on our analysis, a higher number of MR is associated to a better outcome, and this could be explained with an accurate selection of patients that could benefit from multiple radical resections. Thus, a multidisciplinary approach is essential for the management of mCRC pts and surgery should be evaluated case by case and always performed when possible, even several times, independently of site of MR.

Update on overall survival (OS) of RESCUE: An open-label, phase 2 trial of camrelizumab (C) in combination with apatinib (A) in patients with advanced hepatocellular carcinoma (HCC).

4076 Background: C+A combination therapy displayed high objective response rate, disease control rate, and durable response with a manageable safety profile in patients (pts) with advanced HCC. Here we performed an updated analysis of OS to characterize the OS benefit of C+A in HCC pts. Methods: 70 pts in first-line cohort and 120 pts in second-line cohort were enrolled. Median OS and 2-year OS rate were evaluated via updated data (data cutoff, 3 January, 2021). Median time from enrollment to data cutoff of the total population (N = 190) was 29.1 months (range, 24.0-33.7). Results: OS events had occurred in 58.6% pts in first-line cohort and 60.0% pts in second-line cohort. The median OS was 20.1 months (95% CI, 14.9-NR) and 2-year OS rate was 43.3% (95% CI, 31.3-54.7) in first-line cohort. The median OS was 21.8 months (95% CI, 17.3-26.8) and 2-year OS rate was 44.6% (95% CI, 35.5-53.3) in second-line cohort. Conclusions: Long-term follow-up of C+A demonstrated remarkable survival benefit in advanced HCC pts, which further suggested that C+A is a promising combination therapy in advanced HCC pts. Clinical trial information: NCT03463876.

Effect of time to relapse on overall survival (OS) in mantle cell lymphoma (MCL) patients (pts) following frontline high-dose therapy and autologous hematopoietic cell transplantation (autoHCT).

7521 Background: In MCL, outcomes are heterogeneous and the clinical significance of the timing of relapse following autoHCT and its impact on OS is not well defined. Using the CIBMTR database, we evaluate the effect of post-autoHCT time to relapse on OS over time. Methods: Adult MCL pts treated with up to two lines of rituximab-based induction therapy followed by first autoHCT within 1-year of diagnosis were identified between 2000-2018. Primary outcomes included OS and post-relapse OS. A dynamic landmark analysis was performed at 6-month intervals following autoHCT to evaluate the impact of relapse on OS while adjusting for significant patient- and disease-related variables. Post-relapse OS was evaluated in pts who experienced relapse. Results: Of the 461 pts included in the analysis, the median age was 60 years (range 29-78), 57% had a KPS of ≥ 90, 83% had stage III-IV disease at diagnosis, and 76% had extranodal involvement. BEAM was the most common conditioning regimen (58%) and 23% of pts received post-autoHCT maintenance rituximab. With a median follow-up of 67 months, the 5-year progression-free survival was 45.8% with a 5-year OS of 69.6%. On multivariate analysis, age ≥60 years was associated with worse OS (HR= 1.55, 95% CI 1.08-2.24, p=0.0191) at all landmark timepoints. Additionally, the impact of relapse on OS varied with time (p=0.006) and was greatest at the 6-month (HR=7.68), 12-month (HR=6.68), and 18-month (HR=5.81) landmark timepoints. The risk of death for relapsing pts decreased with time and was mirrored by an improvement in adjusted OS for both relapsing and non-relapsing pts. In total, 9.3% of patients relapsed prior to the 18-month landmark timepoint. Relapse at the 6-month, 12-month, and 18-month landmark timepoints correlated with a poor median post-relapse OS of 9 months, 24 months, and 34 months, respectively (Table). Conversely, patients relapsing after the 18-month landmark timepoint experienced a median post-relapse OS ranging from 44-67 months. Conclusions: In MCL, early relapse (&lt; 18-months) following autoHCT defines a high-risk group with inferior post-relapse OS. This population should be considered for clinical trials or novel therapeutic approaches including early utilization of chimeric antigen receptor T-cell therapy.[Table: see text]

Analysis of DNA damage repair pathway genes as a predictive biomarker for HAIC in hepatocellular carcinoma.

e16159 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide.Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil, and leucovorin (FOLFOX) is one of the effective treatment for advanced HCC patients. DNA damage repaired (DDR) pathway has been widely researched in many cancers recent years, which was a promising predictive biomarker for the response to platinum-based chemotherapy and Immunotherapy. But the DDR characteristics of different subset pathways in HCC, and its correlation with HAIC efficacy were unknown. Methods: Whole exome sequencing (WES) data of 366 HCC patients was obtained from the Cancer Genome Altas (TCGA). Next generation sequencing (NGS, panel on 381/733-gene) was performed on FFPE tumor samples from 2092 Chinese HCC patients (Chinese cohort). Germ-line or somatic mutations of 32 DDR pathway genes (including Mismatch Repair and Homologous Recombination) were classified as DDR gene mutations. TMB was defined as total number of somatic non-synonymous mutations in coding region. Whole exome sequencing (WES) data and clinical data of 21 HCC advanced patients treated with HAIC were obtained to survival analysis. Results: In total, 59.84% (219/366) of HCC patients in TCGA harboring DDR mutation and 67.38% (1316/2092) in Chinese cohort. In Chinese HCC cohort, the mean TMB level of DDR mutant group was significant higher than wild-type group (mean TMB, mutation vs wild-type = 8.12 vs 6.42 Muts/Mb, P &lt; 0.0001). The top three mutation frequency DDR genes were BRCA2 (17%), ATM (13%) and BARD1 (12%), respectively. The highest mutation frequency DDR subset pathways were Fanconi anemia (FA, 44.14%, 862/2092), homologous recombination repair (HRR, 38.71%, 756/2092) and check point factors (CHP, 17.31%, 338/2092) come in second and third, respectively. Next we compared the TMB level between different DDR subset pathways, the mutant of nucleotide excision repair (NER) pathway harbored the highest medium TMB level (7.26 Muts/Mb). The survival analysis was performed on HCC patients treated with HAIC with FOLFOX. There was no difference in clinical baseline information between DDR mutation group (n = 6) and wild-type group (n = 15). The progression-free survival (PFS) of DDR mutation group were significantly longer than wild-type group (median PFS, mutation vs. wild-type = 8.9 vs. 4.5 months; HR 0.34[95% CI 0.13-0.85]; P = 0.0349), and an extending trend on overall survival (OS) without significant difference (median OS, 15.7 vs 8.9 months; HR 0.37[95% CI 0.13-1.00]; P = 0.0921). Conclusions: The DDR pathways was associated with higher TMB level. Preliminary data from clinical cohorts suggested better treatment outcomes of HAIC with FOLFOX in DDR mutation HCC patients.

Prognostic impact of inflammatory profiling during and after multimodal treatment for stage III NSCLC.

e20559 Background: Immune cells have a broad impact on tumor initiation, growth, and progression, and many of these effects are mediated by proinflammatory cytokines. The prognostic impact of dynamic changes of inflammatory cytokines in non-operable stage III NSCLC patients treated with (chemo)-radiotherapy ± immune checkpoint inhibition is unknown. In a prospective analysis, pro-inflammatory cytokines including interleukin 2, 6, and 8 from peripheral blood samples were evaluated 5-10 days before treatment start (T1), on the last day of thoracic radiotherapy (T2), and 3 weeks after radiation (T3) for their impact on overall survival (OS) and progression-free survival (PFS). Methods: Twenty patients, 85% male, at a median age of 65.5 (range 33-77) years were prospectively enrolled in this study. Eighteen (90%) patients received platinum-based concurrent chemoradiotherapy (CRT); seven (35%) patients additional concurrent and/or sequential immune checkpoint inhibition (four patients nivolumab and three durvalumab); patients treated with nivolumab received induction chemotherapy. Thoracic irradiation (TRT) was applied in all patients with a median cumulative dose in equivalent 2Gy fractions (EQD2) of 64Gy (range: 52-65Gy). Results: Median follow-up achieved 25 (range 14-30) months, median OS was not reached and median PFS was 11.8 (95%CI 5.2-18.4) months. To analyze pre-treatment data, median values were used as cut-off for dichotomization. Higher IL6 levels (≥9.75pg/ml) before irradiation (T1) were associated with impaired OS (median 11 months vs. not reached; p &lt; 0.001) and PFS (median 7.0 months vs. not reached; p = 0.041). Higher IL8 levels (≥4.62pg/ml) were also associated with shorter OS (median 16 months vs. not reached; p = 0.009) and PFS (median 7 months vs. not reached p = 0.040). Patients with a decline of ≥10% of IL8 level between T1 and T2 had a significantly shorter PFS (11.8 months vs. not reached; p = 0.028). Conclusions: High proinflammatory cytokine levels were significantly associated with deterioration of outcome regarding OS and PFS in patients enrolled in multimodal treatment for stage III NSCLC. A decline of ≥10% of IL8 level during TRT was associated with impaired PFS.

Phase I/II study of LDE225 in combination with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer.

e16239 Background: In pancreatic ductal adenocarcinoma (PDAC) desmoplasia is a central feature of the tumor microenvironment. By targeting both tumor cells and tumor stoma, treatment efficacy can be increased. LDE225 is a pharmacological Hedgehog signaling pathway inhibitor and is thought to specifically target tumor stroma. We investigated the combined use of LDE225 and chemotherapy in PDAC patients. Methods: The objective of phase I of the study was to established the maximum tolerated dose (MTD) of LDE225 co-administered with gemcitabine and nab-paclitaxel (ESMO 2017). The objective of phase II was to evaluate efficacy and safety of the treatment combination after prior fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX; ESMO 2019). Tumor response evaluation was performed using CT scan. Tumor microenvironment was assessed with functional MRI using intra-voxel incoherent motion diffusion weighted MRI (IVIM-DWI) and dynamic contrast enhanced (DCE) MRI. Also, the predictive value of IVIM-DWI and DCE MRI parameters on overall survival (OS) using ROC curves was determined. Results: The MTD of LDE225 was 200 mg once daily co-administered with gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 of a 4-week cycle. We combined the outcomes of the five patients of phase I that received 200mg LDE225 and had prior treatment with FOLFIRINOX (n = 25 patients in total) in phase II. Most patients had WHO performance status of 0-1 (93%) and 57% were male. Patients were treated with a median number of two cycles (IQR 2-6). Six therapy related grade 4 adverse events (AE) were observed: sepsis (2), neutropenia (2), elevated gamma GT (1) and thromboembolic event (1), and three grade 5 (sepsis, pneumonia and progressive disease). Most common grade 3 therapy related AEs were neutropenia (37%) and diarrhea (14.8%). Patients discontinued treatment because of progressive disease (22), bacterial infection (1), sepsis (1) and diminished quality of life (1). In 24 patients target lesion response was evaluable. Three patients had partial response (13%), 14 patients showed stable disease (58%) and 7 patients had progressive disease (29%). The median OS was 6 months (IQR 3.9-8.1). Blood plasma fraction (DCE) and diffusion coefficient (IVIM-DWI) significantly increased during treatment. Baseline perfusion fraction can predict OS ( &gt; 222 days) with 80% sensitivity and 85% specificity. Conclusions: This study shows that LDE225 in combination with gemcitabine and nab-paclitaxel is well-tolerated in patients with metastatic PDAC and has promising efficacy after prior treatment with FOLFIRINOX. Functional MRI suggested that LDE225 causes increased tumor diffusion and works particularly well in patients with poor baseline perfusion. Clinical trial information: NCT02358161.