Time Of First Progression Research Articles

SBRT with ipilimumab and nivolumab to metastatic MSS colorectal and pancreatic cancer: A pooled analysis of four prospective phase II trials.

752 Background: The role of immunotherapy (IO) in microsatellite stable (MSS) pancreatic and colorectal cancer is limited. Stereotactic body radiation therapy (SBRT) is increasingly used in the limited metastatic setting, however its use with IO remains an area of investigation for both target response and overall systemic response. Here we evaluate the local failure rate of irradiated target lesions with and without IO. Methods: We pooled four prospective phase II single-arm studies of patients with metastatic MSS colorectal or pancreatic cancer treated with SBRT alone or with IO. Those in the first study (NCT01239381) received ablative liver SBRT to a maximum biologically effective dose (BED) of 48-100 Gy. Patients in the remaining studies received low dose SBRT to liver, lung, or nodal metastases with 24 Gy in 3 fractions to a BED of 43.2 Gy in combination with Ipilimumab and Nivolumab during the first (NCT04361162, NCT04575922) or second (NCT03104439) cycles. Local failure rates at the time of first progression were estimated by the cumulative incidence with non-target progression only and death as competing risks and compared using Gray’s test. The best response at the target was measured with the RECIST 1.1 criteria using the largest reduction in target size during follow up. Fisher’s exact test was used to compare objective response (ORR) and disease control rates (DCR), while the Wilcoxon rank sum test was performed to compare target size and percentage of tumor reduction. Results: Across all four studies there were 154 evaluable patients including 50 who received ablative SBRT and 104 patients who received low dose SBRT with IO. There were 92 patients with colorectal and 62 with pancreatic cancer. Median target size was 3.7 cm in the ablative SBRT group and 2.8 cm in the IO group (P=0.04). The 6-month, 1-year, and 2-year local failure rates were 10%, 18%, and 20% respectively following ablative SBRT and 24%, 25%, and 26% following low dose SBRT with IO (P=0.32). The ORR was 50.0% with SBRT alone and 23.1% with the addition of IO (P=0.001). There was no significant difference in the DCR (80.0% vs. 68.3%, P=0.18). The percent decrease in size was significantly higher in those with ablative SBRT (median -53.0% vs. -10.6%, p=0.02). There was no difference in the percent tumor response with respect to primary tumor type (P=0.13), KRAS (P=0.11) or TP53 (P=0.27) status. Conclusions: Despite the use of low dose SBRT with immune checkpoint inhibitors, there was no significant difference in local failure rates compared to ablative SBRT. Ablative SBRT dosing yielded a significantly higher depth of response. As clinical and preclinical studies suggest liver metastases are less responsive to IO, understanding dose and fractionation schemas for optimal local control is critical. Further studies are needed to explore the radiation dose with regards to local control when delivered with IO.

Longitudinal study on MRI and neuropathological findings: Neither DSC-perfusion derived rCBVmax nor vessel densities correlate between newly diagnosed and progressive glioblastoma.

When evaluating MRIs for glioblastoma progression, previous scans are usually included into the review. Nowadays dynamic susceptibility contrast (DSC)-perfusion is an essential component in MR-diagnostics of gliomas, since the extent of hyperperfusion upon first diagnosis correlates with gene expression and survival. We aimed to investigate if this initial perfusion signature also characterizes the glioblastoma at time of progression. If so, DSC-perfusion data from the initial diagnosis could be of diagnostic benefit in follow-up assessments. We retrospectively identified 65 patients with isocitrate dehydrogenase wildtype glioblastoma who had received technically identical DSC-perfusion measurements at initial diagnosis and at time of first progression. We determined maximum relative cerebral blood volume values (rCBVmax) by standardized re-evaluation of the data including leakage correction. In addition, the corresponding tissue samples from 24 patients were examined histologically for the maximum vessel density within the tumor. Differences (paired t-test/ Wilcoxon matched pairs test) and correlations (Spearman) between the measurements at both timepoints were calculated. The rCBVmax was consistently lower at time of progression compared to rCBVmax at time of first diagnosis (p < .001). There was no correlation between the rCBVmax values at both timepoints (r = .12). These findings were reflected in the histological examination, with a lower vessel density in progressive glioblastoma (p = .01) and no correlation between the two timepoints (r = -.07). Our results suggest that the extent of hyperperfusion in glioblastoma at first diagnosis is not a sustaining tumor characteristic. Hence, the rCBVmax at initial diagnosis should be disregarded when reviewing MRIs for glioblastoma progression.

External Validation of the FLIPI Risk Score Measured at Initial Diagnosis and POD24 Among Previously Treated Individuals with Progressed Follicular Lymphoma in Alberta, Canada

Introduction: A number of variables have been shown to predict survival outcomes in follicular lymphoma (FL), including the Follicular Lymphoma International Prognostic Index (FLIPI) score measured at initial diagnosis and progression of disease within 24 months (POD24). However, there exists little research aimed at informing prognosis in a cohort comprised exclusively of FL patients whose disease has relapsed after prior therapy. To address this gap, we assessed the FLIPI score measured at diagnosis and POD24 with respect to their ability to stratify survival outcomes measured from the time of first progression in a group of individuals with FL who experienced disease progression after initial treatment. Methods: An external validation of the FLIPI score measured at diagnosis and POD24 was conducted using population-level data from Alberta, Canada. The study cohort was comprised of individuals diagnosed with FL between 2004-2010 who received either systemic therapy and/or radiation within 180 days of diagnosis and who subsequently had disease progression. Individuals were followed until death or last-known contact with the healthcare system. Relevant data were identified through record linkage of the provincial cancer registry and electronic medical records along with a manual chart review conducted by trained medical doctors. Outcomes were examined from the time of first progression and included time to death (OS), time to death after first progression or second progression (PFS2), and time to death or initiation of third line treatment (TTNT2). For each outcome, Kaplan-Meier curves were estimated stratified by FLIPI and by POD24. To quantify the degree of separation of the Kaplan-Meier curves, we estimated hazard ratios (HRs) using a Cox proportional hazards model and Harrell's concordance statistic (c-statistic) for both the FLIPI index and POD24. Results: 910 individuals were diagnosed with FL between 2004-2010, of which 584 received systemic or radiation therapy. 527 individuals initiated front-line therapy within 180 days of diagnosis, of which 216 experienced progression during the follow-up period and were included in these analyses. Among the 216 individuals, 162 (75%) received front-line systemic therapy which was primarily R-CVP (n=57; 35%) or R-CHOP (n=78; 48.1%). From the time of disease progression, median OS was 11.7 years (95% CI: 8.9-NA). POD24 status was available for all 216 individuals, with 90 (42%) individuals having evidence of progression of disease within 24 months of initiating front-line therapy (POD24+). Overall, 129 of the 216 (60%) individuals had complete information required to derive the FLIPI risk score with 43 (33%) being classified as high-risk, 46 (36%) intermediate-risk, and 40 (31%) low-risk. OS estimates stratified by FLIPI score and by POD24 are presented in Table 1. POD24 was not highly predictive of OS from the time of disease progression (c-statistic: 0.55; HR [POD24+ vs. POD24-]: 1.42; 95% CI: 0.93 to 2.15; p = 0.10). Conversely, the FLIPI score measured at diagnosis was highly predictive of OS from the time of disease progression (c-statistic 0.70; HR [High vs. Low]: 7.38; 95% CI: 3.05 to 17.88, p < 0.01; HR [Int. vs. Low]: 3.70; 95% CI: 1.51 to 9.10, p < 0.01; ; HR [High vs. Int.]: 1.99; 95% CI: 1.15 to 3.47, p = 0.01; Figure 1). These findings were similar when examining PFS2 and TTNT2. In sensitivity analysis, findings were similar when restricting to individuals who received front-line systemic therapy. In addition, the classification of individuals by both POD24 and FLIPI did not meaningfully improve discrimination over FLIPI alone. Conclusions: The FLIPI score measured at initial diagnosis can be used for risk stratification at the time of disease progression among previously treated FL patients. In contrast, POD24 was not highly predictive of survival outcomes from the time of disease progression within this population of FL patients who all had disease progression. Future research is needed to determine if the prognostic utility of the FLIPI risk score measured at initial diagnosis can be improved upon by incorporating variables assessed at the time of relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immunotherapy in Hodgkin lymphoma

Classical Hodgkin lymphoma (cHL) is a very curable form of cancer for the majority of patients that receive standard primary therapy. Many patients will have a second opportunity for cure at the time of first progression using approaches that incorporate high dose chemotherapy and autologous stem cell transplant (ASCT). In the non-curative setting, a group of patients (including patients with advanced age and comorbidities precluding standard therapy approaches and those with lymphoma that persists despite these treatments) will be treated with palliative intent. While these patients have had limited options in the past, novel therapies have rapidly become the standard of care in this setting. Antibodies targeting CD30 (the antibody drug conjugate brentuximab vedotin [BV]) and the immune checkpoint through PD1 (nivolumab and pembrolizumab) have now become standard approved treatments for patients beyond second-line treatment. The biology of PD1 appears particularly relevant in cHL, providing a strong clinical rationale for evaluating these agents in this malignancy. Clinicians in Canada now have several choices when making treatment decisions in patients with relapsed or refractory cHL (RR-cHL). Prospective trials are now determining the role of anti-PD1 antibodies in the curative setting.

Prediction of Metastatic Patterns in Bladder Cancer: Spatiotemporal Progression and Development of a Novel, Web-based Platform for Clinical Utility

BackgroundBladder cancer (BCa), the sixth commonest cancer in the USA, is highly lethal when metastatic. Spatial and temporal patterns of patient-specific metastatic spread are deemed random and unpredictable. Whether BCa metastatic patterns can be quantified and predicted more accurately is unknown. ObjectiveTo develop a web-based calculator for forecasting metastatic progression in individual BCa patients. Design, setting, and participantsWe used a prospectively collected longitudinal dataset of 3503 BCa patients who underwent a radical cystectomy following diagnosis and were enrolled continuously. We subdivided patients by their pathologic subgroup stages of organ confined (OC), extravesical (EV), and node positive (N+). We illustrated metastatic pathway progression using color-coded, circular, tree ring diagrams. We created a dynamical, data-visualization, web-based platform that displays temporal, spatial, and Markov modeling figures with predictive capability. Outcome measurements and statistical analysisPatients underwent history and physical examination, serum studies, and liver function tests. Surveillance follow-up included computed tomography scans, chest x-rays, and radiographic evaluation of the reservoir and upper tracts, with bone scans performed only if clinically indicated. Outcomes were measured by time to clinical recurrence and overall or progression-free survival. Results and limitationsMetastases developed in 29% of patients (n = 812; median follow-up 15.3 yr), with 5-yr overall survival of 20.2%, compared with 78.6% in those without metastases (n = 1983; median follow-up 10.9 yr). The three commonest sites of spread at the time of first progression were bone (n = 214; 26.4%), pelvis (n = 194; 23.9%), and lung (n = 194; 23.9%). The order and frequency of these sites vary when divided by pathologic subgroup stages of OC (lung [n = 65; 25.1%], urethra [n = 45; 17.4%], and bone [n = 29; 11.2%]), EV (pelvis [n = 63; 33.0%], bone [n = 45; 23.6%], and lung [n = 29; 15.2%]), and N+ (bone [n = 111; 30.7%], retroperitoneum [n = 70; 19.3%], and pelvis [n = 60; 16.6%]). Markov chain modeling indicated a higher probability of spread from bladder to bone (15.5%), pelvis (14.7%), and lung (14.2%). ConclusionsOur web-based calculator allows real-time analyses in the clinic based on individual patient-specific demographic and cancer data elements. For contrasting subgroups, the models indicated differences in Markov transition probabilities. Spatiotemporal patterns of BCa metastasis and sites of spread indicated underlying organotropic mechanisms in the prediction of response. This recognition opens the possibility of organ site–specific therapeutic targeting in the oligometastatic BCa setting. In the precision medicine era, visualization of complex, time-resolved clinical data will enhance management of postoperative metastatic BCa patients. Patient summaryWe developed a web-based calculator to forecast metastatic progression for individual bladder cancer (BCa) patients, based on the clinical and demographic information obtained at diagnosis. This can help in predicting disease status and survival, and improving management in postoperative metastatic BCa patients. Take Home MessageFuture pathways of metastatic progression for individual bladder cancer patients can be determined based on currently available clinical and demographic information obtained at diagnosis. In focused subgroups of patients, these metastatic spread patterns can also portend disease status and survival.

Morbid Progression Is Common Among Patients with Multiple Myeloma and Is Associated with Shortened Overall Survival: Validation of the Progression-Free Survival Endpoint

INTRODUCTIONThe validity of progression-free survival (PFS) as a clinical endpoint in multiple myeloma (MM) has been debated, largely based on the potential association between PFS and overall survival (OS). However, MM progression can cause morbid end-organ damage. Bone lesions (B) and renal dysfunction (R) may be irreversible, while progressive anemia (A) and hypercalcemia (C), though reversible, can cause severe symptoms, and all are sources of both morbidity and mortality. There is limited research on the rates of progression or on the OS implications associated with morbid progression events compared with asymptomatic biochemical progression. We therefore aimed to characterize the presence of CRAB symptoms at the time of progression and to examine the associations between morbid relapses and OS in 2 large, randomized clinical trials in transplant-ineligible elderly patients (pts) with MM that relapsed after initial therapy.METHODSThis analysis used pooled data from the phase 3, randomized MM-020 and MM-015 trials of pts with newly diagnosed MM (NDMM) aged ≥ 65 years and included pts who progressed on study. Treatment arms in MM-020 were lenalidomide-dexamethasone (Rd) until progressive disease (PD), Rd for 18 cycles, and melphalan-prednisone-thalidomide, and in MM-015 were melphalan-prednisone, melphalan-prednisone-lenalidomide (MPR), and MPR followed by lenalidomide maintenance. CRAB (Calcium > 11.5 mg/dL, Renal insufficiency: creatinine > 2 mg/dL or creatinine clearance [CrCl] decrease by 10 mL/min, Anemia: hemoglobin < 10 g/dL, and Bone lesions) criteria were analyzed within 1 month before or after PD, defined as an increase of 25% from the lowest response value in ≥ 1 of the following: serum M protein, urine M protein, free light chain levels, or bone marrow plasma cell percentage. Pts with PD and meeting ≥ 1 CRAB criterion were considered to have morbid PD; all other pts with PD were categorized as asymptomatic. Demographic and baseline characteristics are reported by relapse group (morbid PD vs asymptomatic PD). The association between morbid PD and PFS from the time of progression (PFS2) as well as OS was examined using an adjusted Cox regression analysis adjusted for baseline pt characteristics, including age, gender, International Staging System (ISS) stage, creatinine, randomized treatment, and anemia. Other covariates were assessed in the window of 1 cycle before or after PD. PFS2 and OS were measured from time of PD. Multivariable Cox regression models estimated the association between morbid PD and PFS and OS. Direct adjusted survival curves based on these models were used to estimate median OS and PFS.RESULTSOf the 2082 pts in the pooled intent-to-treat population of MM-020 (N = 1623) and MM-015 (N = 459), 1243 pts (60%) had PD in first-line treatment for NDMM. At the time of first progression 543 pts (44%) were considered to have morbid (≥ 1 CRAB criterion) PD and 700 pts (56%) had asymptomatic PD. Of the pts with morbid PD, 12 (2%) had hypercalcemia, 271 (50%) had elevated creatinine, 370 (68%) developed anemia, and 79 (15%) developed new bone lesions. Baseline pt characteristics were generally similar between the morbid and asymptomatic PD groups, with a median age of 74.0 yrs for both groups; 51% vs 53% were male and 41% vs 37% had ISS stage III disease, respectively. Hemoglobin < 10 g/dL was less common in the morbid PD group (50% vs 80%), whereas CrCl < 60 mL/min and lactic dehydrogenase > 200 U/L were more frequent in the pts with morbid vs asymptomatic PD (40% vs 26% and 20% vs 13%, respectively).After adjustment for baseline characteristics, median PFS2 was 11.5 vs 20.0 mos in pts with morbid vs asymptomatic PD (HR = 1.56 [95% CI, 1.37-1.79]; P < .0001). Median OS was 23.2 mos in pts with morbid PD and 39.3 mos in pts with asymptomatic PD (HR = 1.51 [95% CI, 1.30-1.76]; P < .0001; Figure).CONCLUSIONSIn this retrospective analysis of 2 large, randomized controlled trials, morbid PD was common, accounting for over 40% of progression events. Moreover, potentially irreversible events, worsening renal function and new bone lesions, occurred in 22% and 15% of pts, respectively. Finally, morbid progression was associated with shortened PFS2 and OS. Additional multivariate analyses examining the relationship between other prognostic factors (including cytogenetics and FISH) and morbid PD are ongoing. [Display omitted] DisclosuresRosenberg:Amgen: Speakers Bureau. Facon:Amgen, Celgene: Speakers Bureau. Abouzaid:Celgene Corporation: Employment, Equity Ownership, Research Funding. Srinivasan:Celgene: Employment. Chung:Celgene Corporation: Employment, Equity Ownership. Parikh:Celgene Corporation: Employment. Tuscano:Takeda: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis Pharmaceuticals: Honoraria, Research Funding.

Evaluation of Definitive Stereotactic Body Radiotherapy and Outcomes in Adults With Extracranial Oligometastasis

The outcomes and factors that influence survival in patients with oligometastasis (OM) are not well understood and have not been well described in large-scale studies. To evaluate overall progression-free survival (PFS), widespread progression (WSP) outcomes, and survival factors from a pooled data set of 1033 patients with OM treated with stereotactic body radiotherapy (SBRT). Case series from January 1, 2008, to December 31, 2016. The dates of analysis were April 2019 to May 2020. The setting was multi-institutional tertiary care hospitals. Participants were consecutive patients with 5 or fewer extracranial OMs whose primary tumor was treated curatively. Definitive SBRT. Overall survival (OS), progression-free survival, rate of WSP, patterns of failure, and factors altering OS. In the largest international OM case series to date (1033 participants) (mean age, 68.0 years [range, 18.0-94.3 years]; 601 [58.2%] men), 1416 SBRT courses were delivered to patients with 1 OM (596 [57.7%]), 2 OMs (245 [23.7%]), 3 OMs (105 [10.2%]), 4 OMs (55 [5.3%]), and 5 OMs (32 [3.1%]). The median follow-up was 24.1 months (range, 0.3-104.7 months), and the median OS was 44.2 months (95% CI, 39.2-48.8 months). The median PFS was 12.9 months (95% CI, 11.6-14.2 months), and the median time to WSP was 42.5 months (95% CI, 36.8-53.5 months). The OS rates were 84.1% (95% CI, 81.7%-86.2%) at 1 year, 56.7% (95% CI, 53.0%-60.2%) at 3 years, and 35.2% (95% CI, 30.1%-40.3%) at 5 years. The 3-year OS, PFS, and WSP rates were 56.7% (95% CI, 53.0%-60.2%), 23.0% (95% CI, 20.2%-25.9%), and 45.2% (95% CI, 41.4%-48.9%), respectively. The 5-year OS, PFS, and WSP rates were 35.2% (95% CI, 30.1%-40.3%), 14.8% (95% CI, 11.9%-17.9%), and 54.5% (95% CI, 49.8%-59.2%), respectively. At the time of first progression, 342 patients (33.1%) had recurrence of OM disease, and 230 patients (22.3%) underwent subsequent ablative therapies to all known metastatic sites. Multivariable analyses identified primary tumor type (hazard ratio [HR], 3.73; 95% CI, 1.75-7.94; P < .001 for breast; 5.75; 95% CI, 2.88-11.46; P < .001 for colorectal; 4.67; 95% CI, 2.12-10.31; P < .001 for kidney; 10.61; 95% CI, 5.36-20.99; P < .001 for lung; and 12.00; 95% CI, 6.06-23.76; P < .001 for other [with prostate being the reference group]), metachronous OM presentation more than 24 months since initial diagnosis (HR, 0.63; 95% CI, 0.49-0.80; P < .001), metastases confined to the lung only (HR, 0.58; 95% CI, 0.48-0.72; P < .001), and nodal or soft-tissue metastases only (HR, 0.49; 95% CI, 0.26-0.90; P = .02) as survival factors. Sixty-six (6.4%) grade 3 or higher toxic effects were observed, including 1 (0.1%) grade 5 event. This study found favorable long-term OS and WSP rates associated with extracranial OM ablated with SBRT; however, modest PFS rates were observed. A substantial proportion of patients with OM developed progressive disease and were treated with local ablation. Factors that can inform clinical decision-making and clinical trial design include primary tumor type, a metachronous presentation more than 24 months since diagnosis, and the site of OM presentation.

A 3-Question Symptom Assessment Score Can Predict Outcomes in Newly Diagnosed Multiple Myeloma (MM)

A 3-Question Symptom Assessment Score Can Predict Outcomes in Newly Diagnosed Multiple Myeloma (MM)

Characteristics and outcome of patients with relapsed/refractory Hodgkin lymphoma following front-line escalated BEACOPP-based chemotherapy: a report from the Australasian Lymphoma Alliance

The optimal management of the small number of patients who experience early failure of eBEACOPP in Hodgkin lymphoma (HL) is unclear. We identified 12 patients with HL who progressed within 12 months of the front-line therapy between January 2010 and July 2019. Median time of first progression following diagnosis was 7 months (range 2.1–13.2). Nine patients proceeded to stem cell therapy following salvage therapy (8 autografts, 1 allograft). Seven patients received novel therapy after relapse, of these, 6 were alive at census, versus 2 out of 5 of those who had standard therapy alone. At the end of follow up (median 22 months), 4 were deceased from progressive disease, 6 were in complete remission and 2 in partial remission on continuing therapy. The outcome of patients with primary refractory HL to eBEACOPP therapy is better than expected and the use of a novel agents after relapse may be a contributing factor.

Enzalutamide (E) re-challenge as second-line in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with first-line enzalutamide + docetaxel (D): Preliminary results of a post-progression analysis of CHEIRON trial.

123 Background: CHEIRON trial was a phase II study which randomized previously untreated mCRPC pts to receive D 75 mg/m2 IV d1 q3w for 8 courses alone or plus E 160 mg PO daily. As per protocol, E was administered in experimental arm for only 24 wks until D conclusion. The study met its primary endpoint since the rate of pts without disease progression at 6 mos was significantly higher in DE arm compared to D arm (89.1% vs 72.8%; p = 0.002). The clinicians were asked to consider an E re-challenge as first post-progression treatment for those pts without disease progression at the chemotherapy end in the experimental arm. We presented the preliminary analysis of E activity in post-progression setting of CHEIRON DE arm. Methods: We evaluated all patients enrolled in the experimental arm, focusing on pts who received E as first post-progression treatment. We collected data concerning the treatment duration and disease control and compared the outcomes of pts treated with E re-challenge with those of pts who received other treatments at the time of first progression after experimental therapy. Results: Among the 120 pts who received DE experimental arm, 101 did not show a disease progression and 82 received a second-line active treatment: 54 (66%) were treated with E, the other received abiraterone (10 pts), cabazitaxel (13 pts), and radium 223 (5 pts). The median interval between the end of DE and the start of E re-challenge was 7.6 mos (range 0.9-18.4 mos). At a median follow-up of 15.5 mos, the median duration of E re-challenge was 9.8 mos (range 1.9-30.9) with 22 pts still on treatment. Pts who received E rechallenge showed a median progression free survival of 11.4 mos which was significantly longer compared to 4.5 mos showed in pts who received other treatments (p &lt; 0.0001). The median overall survival was 20.4 mos and 12.3 mos, respectively (p = NS). Conclusions: In pts who received first-line DE in the CHEIRON trial, the reintroduction of E after a per-protocol discontinuation demonstrated to be feasible, with a prolonged disease control compared to the other post-progression therapeutic options. Clinical trial information: NCT02453009.

Survival outcome of tyrosine kinase inhibitors beyond progression in association to radiotherapy in oligoprogressive EGFR-mutant non-small-cell lung cancer.

Aim: The association of tyrosine kinase inhibitors (TKIs) and local radiotherapy in EGFR-mutated non-small-cell lung cancer patients experiencing disease progression under TKIs could be a valid an option. Patients & methods: We included 131 patients experiencing disease progression during first-line TKI. In group A, patients received TKI beyond progression and site(s) of progression were irradiated; in group B, patients remained on TKI alone beyond progression; and group C stopped TKI at first disease progression. Results: Median overall survival resulted longer in group A versus B and C (p<0.0001). Group A had a trend toward a longer second progression-free survival (measured from the time of first progression until second progression) versus group B (p=0.06). Conclusion: TKI beyond progression in association with local ablative treatment is a valid treatment option in oligoprogressive patients.

Salvage rates after progression of high-risk neuroblastoma with a soft tissue mass

PurposeTreatment of progression in high-risk neuroblastoma remains challenging despite improved survival. We retrospectively evaluated outcomes in children with a first progression that included soft-tissue masses. MethodsWe reviewed records of 903 consecutive children with high-risk neuroblastoma diagnosed between 2004 and 2014, and identified 42 whose first progression included soft-tissue masses. Data on demographics, disease characteristics, treatment, and survival were collected. Primary outcome was 5-year overall survival (OS) from time of first progression. Secondary outcomes were local disease-free progression (LDFR) and progression-free survival (PFS) postprogression. We evaluated the prognostic significance of concomitant bone/bone marrow involvement, MYCN status, and multifocality of soft tissue relapse. ResultsMedian age at diagnosis was 3.0 (range: 1–10.7) years. Median time to first relapse or progression was 1.2 (range: 0.1–4.5) years after complete remission or minimal stable residual disease. Twelve (29%) patients had concomitant bone or marrow involvement at progression/relapse. There were 11 (26%) patients with International Neuroblastoma Staging System stage 3 disease (all with MYCN amplification), and 31 (74%) with stage 4 disease (12 with MYCN amplification). Nine (21%) patients had multifocal soft tissue progression. R1 resection was achieved in 41 children (95%), 38 (95%) of whom also received salvage radiation therapy. Five-year OS postprogression was 35% (95% CI: 19–51%), 5-year LDFS was 52% (95% CI: 32–72%), and 5-year PFS postprogression was 20% (95% CI: 6–34%). ConclusionAmong children with high-risk neuroblastoma who underwent aggressive treatment of a first soft-tissue recurrence, 5-year postprogression overall survival was 34%. Multifocality and MYCN amplification were the predominant prognostic correlates for worse survival.

Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance

Vemurafenib improves survival in advanced BRAFV600(mut) melanoma patients, but tolerance is often poor and resistance frequently occurs, without predictive factor. Our aim was to investigate for the first time a relationship between plasma vemurafenib concentration (PVC) and efficacy or tolerance. Plasma samples from unresectable metastatic BRAFV600(mut) melanoma patients treated with vemurafenib monotherapy were prospectively collected at each tumour response evaluation (RECIST 1.1) or when adverse event occurred (CTCAE 4.0). PVC was measured with liquid chromatography-tandem mass spectrometry. Herein, we report on PVC at steady state (≥14 days after vemurafenib introduction or dose modification). Samples collected after first melanoma progression were excluded from the response analysis. All samples were analysed in the tolerance analysis. We kept the closest collected sample from the onset of each adverse effect or the one with the highest PVC in the absence of this adverse effect. Comparisons of means (Student's t-tests and Wilcoxon rank sum tests) and of frequencies (χ(2) tests) were carried out. A logistic regression analysis identified predictors of progression. We included 105 plasma samples in 23 patients (10M/13F). Initial vemurafenib dose was 960 mg b.i.d., reduced by 25% (8 patients) or 50% (2 patients) for intolerance in 10 patients (44%). PVC displayed high inter-individual variability (13.0-109.8 µg/ml, median 54.0). Mean PVC was lower at time of first progression (38.8 ± 19.7 µg/ml) than mean PVC found when tumour was stable or in partial or complete response (56.4 ± 21.0 µg/ml, P = 0.013, 21 patients). Logistic regression revealed that having a low PVC (P = 0.01) or brain metastasis (P = 0.01) were both significantly and independently associated with tumour progression. High PVC was not statistically significantly associated with the occurrence of adverse effects. PVC at steady state is highly variable and low PVC was associated with tumour progression, suggesting a new path to melanoma resistance to vemurafenib.

Long-term outcomes of rituximab use prior to autologous stem cell transplant (ASCT) in low-grade follicular lymphoma (FL) at the time of first progression.

7036 Background: Some studies suggest that prior use of rituximab is associated with poor outcomes following ASCT in relapsed diffuse large B-cell lymphoma (DLBCL). The effects of rituximab use pri...

Outcome of salvage treatment for recurrent glioblastoma

Most glioblastoma (GBM) cases recur within a year and almost all cases recur at some point. Standard treatment for recurrent GBM has not yet been established. We investigated the outcome of various salvage treatments for recurrent GBM. Retrospective analysis was undertaken in 144 patients who received salvage treatment at the time of first progression after maximum debulking surgery followed by concomitant chemoradiotherapy and adjuvant temozolomide (TMZ) chemotherapy. The median follow-up period was 18.2months. We grouped these patients into five groups according to the salvage modalities: Gamma Knife radiosurgery (GKS) group (n=29), TMZ group (n=31), GKS+TMZ group (n=28), reoperation group (n=38) and “other treatment” group (n=18). The median time to first progression from initial diagnosis was 8.8months. The median overall survival (OS) of the five different treatment groups; GKS, TMZ, GKS+TMZ, reoperation, and “other treatment”, was 9.2, 5.6, 15.5, 13.2, and 8.0months, respectively. Median progression-free survival (PFS) was 3.6, 2.3, 6.0, 4.3, and 2.6months, respectively. Pairwise comparison of OS of the GKS+TMZ group with the other groups showed that the OS of the GKS+TMZ group was significantly better than all others except the reoperation group. Statistically significant prolongation of PFS was observed in the GKS+TMZ group compared with the TMZ group and the “other treatment” group. GKS followed by TMZ salvage treatment was a good prognostic factor for both PFS and OS in multivariate analysis. Retrospectively, GKS+TMZ as a salvage treatment, tended to provide a superior survival benefit at the time of recurrence.

Combination of High Serum Lactate Dehydrogenase Levels at the Time of First Diagnosis and Progression Predicts Early Lymphoma Related Death in Patients with Follicular Lymphoma Receiving R-CHOP Regimen

Background: Rituximab-combined chemotherapy improves survival in patients with follicular lymphoma (FL), however, many patients have a risk of eventual relapse. Recently, early progression of FL within the first 2 years has been reported to be associated with poor outcomes (Casulo C. et al., 55th ASH Annual Meeting abstract # 510). We conducted a retrospective study to analyze clinical features and prognostic factors of patients with FL in early progression.Methods: Among 181 consecutive FL patients newly diagnosed in our institute, data were available for 95 patients who were diagnosed as clinical stage II to IV and received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) based chemotherapy. Early relapse was defined in this study as early progression within the first 2 years after initial diagnosis.Results: With a median follow-up of 6.3 years (range: 0.7-14.0 years), the 6-year overall (OS) and progression-free survival rates (PFS) of the 95 patients were 89% (95%CI: 81 to 94) and 60% (95%CI: 49 to 70), respectively. Cumulative incidence of relapse at 2 and 6 years was 19% (95%CI: 12 to 28) and 36% (95%CI: 25 to 46), respectively. Of the 95 patients, a total of 35 patients experienced relapses, of which 18 patients with 8 male had early relapse. Patients with early relapse demonstrated worse OS compared with that of patients who experienced relapses beyond the first 2 years [the 6-year OS rates: 100% vs. 65% (P = 0.0083, Log-rank)].At initial diagnosis, the median age of the 18 early relapsed cases was 55 years (range: 39 to 72) and 7 patients were more than 60 years of age. Seventeen patients were initially diagnosed as stage III and IV. Serum lactate dehydrogenase (LDH) levels at the time of first diagnosis and progression were elevated in 10 and 7 patients, respectively. Fourteen patients had high tumor burden defined by Groupe d’Etude des Lymphomas Folliculaires (GELF) criteria. According to Follicular lymphoma international prognostic index 2 (FLIPI2), 6 and 9 patients were classified as the groups of intermediate and poor risk, respectively. Pathological diagnosis was performed in 16 of the 18 patients at the time of first progression. Transformation of FL to diffuse large B-cell lymphoma (DLBCL) occurred in two patients and tumor sample from one patient included FL with a component of DLBCL.After progression, salvage chemotherapy was undergone in 18 patients and 3 patients received transplantation. Seven patients, all of whom died of FL, showed disease progression within 13 months after initial diagnosis, while no patients died of FL when diagnosis was made after that. With a median follow-up of 3.7 years (range: 1.1-12.0 years), the 3-year OS rate of the early relapsed patients was 67% (95%CI: 40 to 83). Patients with high levels of serum LDH both at initial diagnosis and at the time of first progression showed worse survival [P = 0.0001, Log-rank (Figure 1)]. Deaths due to FL was not observed in patients with low risk groups defined by FLIPI2 and with low tumor burden defined by GELF criteria at initial diagnosis.Conclusions: Early relapse was observed in 19 % of the patients who were diagnosed as clinical stage II to IV and received first-line R-CHOP therapy. Deaths due to FL occurred in patients who had early progression within 13 months after initial diagnosis. Two factors of high levels of LDH both at initial diagnosis and at the time of first progression might be useful prognostic tool to predict deaths from FL. [Display omitted] Abbreviations: LDH high, patients with high levels of serum LDH both at initial diagnosis and at the time of first progression; LDH low, the remaining patients DisclosuresNo relevant conflicts of interest to declare.

Leptomeningeal metastases in high-grade adult glioma: development, diagnosis, management, and outcomes in a series of 34 patients.

Methods: Leptomeningeal metastases (LM) in the setting of glioma have often been thought to carry a particularly poor prognosis. We sought to better characterize this phenomenon through a review of patients with glioma seen in our institution over the preceding 10 years. We focus here on 34 cases with LM due to grade III or IV glioma. Over the period in question, we estimate a prevalence of almost 4% in those affected by grade IV tumors.Results: Leptomeningeal spread was present at the time of initial diagnosis in 4 patients. Among the others, LM occurred at the time of first progression of disease in 17. The median time to development of LM (excluding those where it was present at initial diagnosis) was 16.4 months [95% confidence interval (CI) 8.2–43.9]. The median time to further progression of disease following LM was 4.9 months (95% CI 3.1–6.9). Twenty-five patients were known to have died at the time of writing. Thus, median overall survival (OS) was 10.2 months (95% CI 8.8–14.7) following LM. At the time of diagnosis of LM, some form of treatment (chemotherapy and/or radiation vs. no treatment) increased OS (median 11.7 vs. 3.3 months, p < 0.001 by log-rank test). Use of radiation therapy (vs. no radiation) also increased OS, although the effect was more modest (7.8 vs. 16.8 months, p = 0.07). Higher Karnofsky Performance Status (KPS) at the time of diagnosis of LM was associated with OS (p = 0.007, median OS for KPS ≥90 19 months vs. 7.8 for KPS <90). In a two-variable model incorporating the use any treatment (vs. none) and KPS, the latter tended to be a more significant predictor of survival (p = 0.22 vs. p = 0.06 by likelihood-ratio test). This was also true for radiation (vs. none) and KPS (p = 0.27 vs. p = 0.02). No significant benefit could be demonstrated for the use of chemotherapy considered alone, either systemic or intrathecal. It should be noted that 4 of 9 patients receiving intrathecal chemotherapy had a ventriculo-peritoneal shunt in place during these injections, which may have reduced its effectiveness.Conclusion: Overall, treatment appears to improve outcomes. We favor maximal treatment, as tolerated, particularly with a KPS of ≥70. Such treatment would typically include radiation to the maximum tolerated dose, concurrent, and adjuvant chemotherapy (preferably with an alkyating agent), in addition to intrathecal treatment.

BM-11 * LEPTOMENINGEAL METASTASES IN HIGH-GRADE ADULT GLIOMA: DEVELOPMENT, DIAGNOSIS, MANAGEMENT AND OUTCOMES IN A SERIES OF 34 PATIENTS

Leptomeningeal metastases (LM) in the setting of glioma have often been thought to carry a particularly poor prognosis. We sought to better characterize this phenomenon through a review of patients with glioma seen in our institution over the preceding 10 years. This series of 34 in grade III or IV glioma is the largest of which we are aware. Leptomeningeal spread was present at the time of initial diagnosis in 4 patients. In the others, LM occurred at the time of first progression of disease in 17. The median time to development of LM (excluding those where it was present at initial diagnosis) was 16.4 months (95% confidence interval (CI) 8.2-43.9). The median time to further progression of disease following LM was 4.9 months (95% CI 3.1-6.9). 25 patients were known to have died at the time of writing. Thus median overall survival (OS) was 10.2 months (95% CI 8.8-14.7) following LM. At the time of diagnosis of LM, some form of treatment (chemotherapy and/or radiation vs. no treatment) increased OS (median 11.7 vs. 3.3 months, p < 0.001 by log-rank test). Use of radiation therapy (vs. no radiation) also increased OS, although the effect was more modest (7.8 vs. 16.8 months, p = 0.07). Higher Karnofsky Performance Status (KPS) at the time of diagnosis of LM was associated with OS (p = 0.007, median OS for KPS <= 90 19 months vs. 7.8 for KPS <90). In a two-variable model incorporating the use any treatment (vs. none) and KPS, KPS tended to be a more significant predictor of survival (p = 0.22 vs. p = 0.06 by likelihood-ratio test). This was also true for radiation (vs. none) and KPS (p = 0.27 vs. p = 0.02). No significant benefit could be demonstrated for the use of chemotherapy considered alone, either systemic or intrathecal. However 4/9 receiving intrathecal chemotherapy had a ventriculoperitoneal shunt in place.

Circulating angiogenic factors as predictors of benefit from bevacizumab (bev) beyond progression in metastatic colorectal cancer (mCRC): Traslational analyses from the phase III BEBYP trial.

3603 Background: TML and BEBYP trials demonstrated that the strategy of prosecuting bev beyond progression is effective in mCRC. Previous analyses from phase II studies showed that a modulation of plasma angiogenic factors occurs during 1st-line treatment with chemotherapy (CT) + bev and a wide variability in soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) levels was observed at the time of progression. Moving from preliminary analyses in murine models we selected a pool of candidate ligands to be tested in the clinical setting. Methods: sVEGFR2, Placental Growth Factor (PlGF), Platelet-Derived Growth Factor-C, basic Fibroblast Growth Factor, Angiopoietin-2 and soluble Tie-2 were assessed by ELISA on plasma samples collected at baseline in a cohort of 59 patients enrolled in phase III BEBYP trial of 2nd-line CT ± bev beyond progression to a bev-containing first-line regimen. Plasma levels were defined high or low adopting the median values as cut-off. Results: A significant interaction between treatment arm and baseline sVEGFR-2 levels was observed (p=0.036). Among 30 patients with high sVEGFR-2 levels, the prosecution of bev was associated with a significant benefit in terms of PFS (median: 10.4 vs 3.4 months, HR 0.37 [95%CI 0.10-0.58], p=0.0015), that was not evident among 29 patients with low sVEGFR-2 levels (5.4 vs 5.0 months, HR 0.98 [95%CI 0.45-2.11], p=0.956). Despite a trend towards a greater benefit from bev among 30 patients with high PlGF levels (HR 0.45 [95%CI 0.13-0.86]), no interaction between treatment arm and baseline PlGF levels was observed (p=0.210). Combined analysis of sVEGFR-2 and PlGF showed that prosecuting bev provided a substantial benefit in PFS in the subgroup with high levels of both ligands (10.5 vs 2.3 months, HR 0.25 [95%CI 0.01-0.45], p=0.043). Conclusions: sVEGFR-2 levels at the time of first progression may predict benefit from prosecuting bev. Interesting results from simultaneous analysis of sVEGFR-2 and PlGF may be affected by a pronounced subgrouping and should be considered cautiously. Given their potential clinical value, these data need prospective confirmation. Clinical trial information: NCT00720512.

Circulating angiogenic factors as predictors of benefit from bevacizumab (bev) beyond progression in metastatic colorectal cancer (mCRC): Translational analyses from the phase III BEBYP trial.

382 Background: TML and BEBYP trials demonstrated that the strategy of prosecuting bev beyond progression is effective in mCRC. Previous analyses from phase II studies showed that a dynamic modulation of plasma angiogenic factors occurs during first-line treatment with chemotherapy (CT) plus bev and a wide variability in soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2) levels was observed at the time of progression. Moving from preliminary analyses in murine models we selected a pool of candidate ligands to be tested in the clinical setting. Methods: sVEGFR2, Placental Growth Factor (PlGF), Platelet-Derived Growth Factor-C, basic Fibroblast Growth Factor, Angiopoietin-2 and sTie-2 were assessed by ELISA on plasma samples collected at baseline in a cohort of 59 patients enrolled in phase III BEBYP trial of 2nd-line CT ± bev beyond progression to a bev-containing first-line regimen. Plasma levels were defined high or low adopting the median as cut-off. Results: A significant interaction between treatment arm and baseline sVEGFR2 levels was observed (p=0.036). Among 30 patients with high sVEGFR2 levels, the prosecution of bev was associated with a significant benefit in terms of PFS (median: 10.4 vs 3.4 months, HR 0.37 [95%CI:0.10-0.58], p=0.0015), that was not evident among 29 patients with low sVEGFR2 levels (5.4 vs 5.0 months, HR 0.98 [95%CI:0.45-2.11], p=0.956). Despite a trend towards a greater benefit from bev among 30 patients with high PlGF levels (HR 0.45 [95%CI: 0.13-0.86]), no interaction between treatment arm and baseline PlGF levels was observed (p=0.210). Combined analysis of sVEGFR2 and PlGF showed that prosecuting bev provided a substantial benefit in PFS in the subgroup with high levels of both ligands (10.5 vs 2.3 months, HR 0.25 [95%CI:0.01-0.45], p=0.043). Conclusions: sVEGFR2 levels at the time of first progression may predict benefit from the prosecution of bev. Impressive results deriving from concomitant testing of sVEGFR2 and PlGF may be affected by excessive subgrouping and should be considered cautiously. Given their potential clinical value these data need prospective confirmation. Clinical trial information: NCT00720512.