Effect of Chemotherapy on Overall Survival in Contemporary Metastatic Prostate Cancer Patients

IntroductionRandomized clinical trials demonstrated improved overall survival in chemotherapy exposed metastatic prostate cancer patients. However, real-world data validating this effect with large scale epidemiological data sets are scarce and might not agree with trials. We tested this hypothesis.Materials and MethodsWe identified de novo metastatic prostate cancer patients within the Surveillance, Epidemiology, and End Results (SEER) database (2014-2015). Kaplan-Meier plots and Cox regression models tested for overall survival differences between chemotherapy-exposed patients vs chemotherapy-naïve patients. All analyses were repeated in propensity-score matched cohorts. Additionally, landmark analyses were applied to account for potential immortal time bias.ResultsOverall, 4295 de novo metastatic prostate cancer patients were identified. Of those, 905 (21.1%) patients received chemotherapy vs 3390 (78.9%) did not. Median overall survival was not reached at 30 months follow-up. Chemotherapy-exposed patients exhibited significantly better overall survival (61.6 vs 54.3%, multivariable HR:0.82, CI: 0.72-0.96, p=0.01) at 30 months compared to their chemotherapy-naïve counterparts. These findings were confirmed in propensity score matched analyses (multivariable HR: 0.77, CI:0.66-0.90, p<0.001). Results remained unchanged after landmark analyses were applied in propensity score matched population.ConclusionsIn this contemporary real-world population-based cohort, chemotherapy for metastatic prostate cancer patients was associated with better overall survival. However, the magnitude of overall survival benefit was not comparable to phase 3 trials.

Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma

Multiple myeloma (MM) patients frequently attain a bone marrow (BM) minimal residual disease (MRD) negativity status in response to treatment. We identified 568 patients who achieved BM MRD negativity following autologous stem cell transplantation (ASCT) and maintenance combination therapy with an immunomodulatory agent and a proteasome inhibitor. BM MRD was evaluated by next generation flow cytometry (sensitivity of 10-5 cells) at 3 to 6 months intervals. With a median follow up of 9.9 years from diagnosis (range, 0.4 - 30.9), 61% of patients maintained MRD negativity, while 39% experienced MRD conversion at a median of 6.3 years (range, 1.4 - 25). The highest risk of MRD conversion occurred within the first 5 years after treatment and was observed more often in patients with abnormal metaphase cytogenetic abnormalities (95%vs. 84%; P = 0.001). MRD conversion was associated with a high risk of relapse and preceded it by a median of 1.0 year (range, 0 - 4.9). However, 27% of MRD conversion positive patients had not yet experienced a clinical relapse with a median follow-up of 9.3 years (range, 2.2 - 21.2). Landmark analyses using time from ASCT revealed patients with MRD conversion during the first 3 years had an inferior overall and progression-free survival compared to patients with sustained MRD negativity. MRD conversion correctly predicted relapse in 70%, demonstrating the utility of serial BM MRD assessment to complement standard laboratory and imaging to make informed salvage therapy decisions.

Long-term Risk of Heart Failure and Other Adverse Cardiovascular Outcomes in Granulomatosis With Polyangiitis: a Nationwide Cohort Study

Objective To examine the long-term rates of heart failure and other adverse cardiovascular outcomes in a nationwide cohort of patients diagnosed with granulomatosis with polyangiitis (GPA) compared with the background population. Methods Using Danish nationwide registries, patients with first-time diagnosed GPA were identified and matched 1:4 by age, sex, and comorbidities with subjects from background population. Outcomes were compared using Cox regression. Due to violation of the proportional hazard assumption, landmark analyses for the first year and from one year were performed. Results Of the 1,923 patients with GPA, 1,781 patients (median age 59 years, 47.9% men) were matched with 7,124 subjects from the background population. The median follow-up was 6.4 years. The absolute 10-year risk of HF was 6.8% (95%CI, 5.5-8.2%) for GPA patients and 5.9% (5.3-6.6%) for the background population. During the first year after diagnosis, GPA was associated with a significantly higher rate of HF (HR 3.60 [95%CI, 2.28-5.67]) and other adverse outcomes, including atrial fibrillation/flutter (HR 6.50 [4.43-9.55]) and ischemic stroke (HR 3.24 [1.92-5.48]), compared with the background population. After the first year, GPA was not associated with higher rates of HF or other cardiovascular outcomes than the background population, except atrial fibrillation/flutter (HR 1.38 [1.12-1.70]). Conclusion During the first year after diagnosis, the rates of HF and other cardiovascular outcomes were higher in patients with GPA compared with the background population. However, after the first year, the rates of HF and other cardiovascular outcomes, except atrial fibrillation/flutter, were similar to those in the background population.

NIMG-11. VOLUMETRIC ENDPOINTS IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): COMPARISON TO CROSS-SECTIONAL MEASURES AND CORRELATION WITH OUTCOMES

INTRODUCTION Cross-sectional tumor measures are used as endpoints in clinical trials of DIPG, but may not capture meaningful changes in disease burden. Volumetric measures may provide a more accurate assessment of tumor growth. We measured the correlation between cross-sectional and volumetric measures and compared their prognostic impact to better understand response evaluation in DIPG. METHODS Patients from the International DIPG Registry with diagnostic and post-radiation MRIs were included. Utilizing mint LesionTM software, tumors were manually contoured by an experienced pediatric neuro-radiologist to extrapolate cross-sectional product (CP) and volume measures. Correlation between CP and volume was assessed by linear regression. Landmark analyses were performed to determine differences in overall survival (OS) (via log-rank) between patients classified as progressive disease (PD) versus non-PD according to CP and volumetric measurements at one-, three-, and five-months post-radiation. Imaging consistent with pseudoprogression was designated non-PD. Hazard ratios (HR) for survival after these timepoints were calculated by Cox regression. RESULTS A total of 317 MRIs from 46 patients were analyzed. When comparing change from smallest previous tumor size, CP increase of 25% (PD by RAPNO) correlated with volume increase of 28% (R2=0.685). There was no difference in OS between patients classified as PD versus non-PD by CP at one-month, three-months, or five-months post-radiation (p >0.05). However, significant differences in OS were observed between patients classified as PD versus non-PD by volume (28% increase) at one-month (2.7 vs. 12.8 months, p=0.005), three-months (1.9 vs. 10.7 months, p=0.036), and five-months post-radiation (3.7 vs. 9.1 months, p=0.023). PD by volume, but not by CP, was predictive of survival at all timepoints (HR: 5.0, 2.4, 2.4). CONCLUSIONS Volumetric assessments of PD correlated better with survival than CP at all post-radiation timepoints. Tumor volume likely represents a more accurate, prognostically-relevant measure of disease burden that deserves investigation in future DIPG trials.

On the morphospace of eurypterine sea scorpions

ABSTRACT Eurypterids (sea scorpions) are a group of extinct, marine euchelicerates that have an extensive Palaeozoic record. Despite lacking a biomineralised exoskeleton, eurypterids are abundantly preserved within select deposits. These collections make statistical analyses comparing the morphology of different genera possible. However, eurypterid shape has not yet been documented with modern geometric morphometric tools. Here, we summarise the previous statistical assessments of eurypterid morphology and expand this research by presenting landmark and semi-landmark analyses of 115 eurypterid specimens within the suborder Eurypterina. We illustrate that lateral compound eye morphology and position drives specimen placement in morphospace and separates proposed apex predators from more generalist forms. Additionally, evidence for size clusters in Eurypterus that may reflect ontogeny is uncovered. We highlight the use of geometric morphometric analyses in supporting the naming of new taxa and demonstrate that these shape data represent a novel means of understanding inter-generic ontogenetic trajectories and uncovering developmental changes within the diverse euarthropod group.

Landmark analysis of overall survival (OS) by objective response (OR) in previously treated patients (pts) with advanced hepatocellular carcinoma (aHCC): Post hoc analysis of the randomized, phase 3 KEYNOTE-240 study.

e16122 Background: Studies have shown that OR is prognostic of OS in pts with HCC. KEYNOTE-224 (NCT02702414) evaluated pembrolizumab (pembro; anti–PD-1) in sorafenib (sora)-treated pts with aHCC and showed an ORR of 17% that was durable in responders receiving pembro, ultimately leading to FDA approval. In KEYNOTE-224, a landmark analysis showed that OR in pembro-treated pts was prognostic of longer OS. The KEYNOTE-240 (NCT02702401) study evaluated pembro + best supportive care (BSC) vs placebo (pbo) + BSC in sora-treated pts with aHCC. Although clinical benefit was observed in KEYNOTE-240 with pembro vs pbo, prespecified statistical significance criteria for OS and PFS were not met. This post hoc analysis of KEYNOTE-240 was performed to determine whether OR at landmark is prognostic of longer survival after landmark time. Methods: Eligible pts were aged ≥18 y, had confirmed aHCC, and experienced progression during or after sora treatment or intolerance to sora. Landmark analyses of OS according to OR at 6, 12, and 18 wk after randomization were performed on the pembro arm to evaluate the association between survival after the landmark with response achieved before the landmark. OR was assessed by blinded independent central review per RECIST v1.1. Responders at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders. HR and 95% CI for survival after the landmark were calculated from the Cox proportional hazards model using Efron method of tie handling, with responder status as a single covariate. Analysis was performed on the ITT population. Results: As of Jan 2, 2019, median time from randomization to data cutoff was 21.2 mo (range 13.4-30.4) for pembro. In the pembro arm, 51 pts (18.3%) had a best OR of CR or PR and 6 pts (4.4%) in the pbo arm had a best OR of PR (no CR) (excluded from landmark analyses). OS after landmark time was longer for responders than nonresponders at the wk 6, 12, and 18 time points (Table). The HR for OS after landmark time for responders vs nonresponders was 0.37 (95% CI 0.18-0.75), 0.39 (95% CI 0.23-0.66), and 0.37 (95% CI 0.21-0.63) at wk 6, 12, and 18, respectively. Conclusions: This post hoc analysis showed that pts with sora-treated aHCC who achieved OR by landmark time with pembro have longer OS after the landmark time, confirming the prognostic association between OR with pembro and OS observed in KEYNOTE-224. Clinical trial information: NCT02702401. [Table: see text]

Pooled analyses of immune-related adverse events (irAEs) and efficacy from the phase 3 trials IMpower130, IMpower132, and IMpower150.

9002 Background: PD-L1/PD-1 inhibitors have transformed the treatment (tx) of advanced NSCLC. Evidence suggests that the occurrence of irAEs with these agents may predict improved outcomes in cancers such as NSCLC. Atezolizumab (atezo; anti–PD-L1) has shown efficacy and tolerability in NSCLC and is currently approved in the 1L and 2L+ settings. The Ph 3 IMpower130, IMpower132 and IMpower150 trials evaluated atezo + chemo ± bevacizumab (bev) as 1L tx of NSCLC. We explore the association between irAEs and efficacy in these trials. Methods: Each trial enrolled tx-naive patients (pts) with nonsquamous stage IV NSCLC. Pts were randomized to: carboplatin (carbo) + nab-paclitaxel alone or with atezo in IMpower130; carbo or cisplatin alone or with atezo in IMpower132; atezo (A) + bev (B) + carbo + paclitaxel (CP), ACP or BCP in IMpower150. Data were pooled (data cutoffs: Mar 15 2018 [IMpower130]; May 22 2018 [IMpower132]; Sep 13 2019 [IMpower150]) and analyzed by tx (atezo-containing vs control) and irAE status. A time-dependent Cox model and landmark analyses at 1, 3, 6 and 12 mo were used to control for immortal bias. Study protocols required atezo tx interruption/discontinuation for grade (Gr) ≥3 irAEs. Results: 2503 pts were included in the analysis (atezo, n = 1577; control, n = 926). In both arms, baseline characteristics were generally balanced between pts with irAEs (atezo, n = 753; control, n = 289) and without irAEs (atezo, n = 824; control, n = 637). Any-Gr irAEs occurred in 48% (atezo) and 32% (control) of pts; Gr 3-5 irAEs occurred in 11% (atezo) and 5% (control). The most common irAEs (atezo vs control) were rash (28% vs 18%), hepatitis (lab abnormalities; 15% vs 10%) and hypothyroidism (12% vs 4%). Median time to onset of first irAE was 1.7 (atezo) vs 1.4 mo (control). OS HRs (95% CI) from the time-dependent Cox model between pts with vs without irAEs were 0.69 (0.60, 0.78) in the atezo arm and 0.82 (0.68, 0.99) in the control arm; after excluding rash (perceived as the least specific irAE), OS HRs (95% CI) were 0.75 (0.65, 0.87) and 0.90 (0.71, 1.12), respectively. OS landmark data are in the Table. Conclusions: In this exploratory pooled analysis, pts with irAEs had longer OS vs pts without irAEs in the atezo-containing and control arms per the time-dependent Cox model and landmark analyses; this trend remained for the atezo arm after excluding rash. Landmark analyses suggest that in the atezo arm, pts with Gr 1/2 irAEs had the longest OS and pts with Gr ≥3 irAEs had the shortest OS, potentially due to tx interruption/discontinuation. Clinical trial information: NCT02367781; NCT02657434; NCT02366143. [Table: see text]

Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial

PURPOSE Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen. METHODS From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses. RESULTS The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent ( P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13). CONCLUSION The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years.

Non-maintenance intravesical Bacillus Calmette–Guérin induction therapy with eight doses in patients with high- or highest-risk non-muscle invasive bladder cancer: a retrospective non-randomized comparative study

Background To explore possible solutions to overcome chronic Bacillus Calmette–Guérin (BCG) shortage affecting seriously the management of non-muscle invasive bladder cancer (NMIBC) in Europe and throughout the world, we investigated whether non-maintenance eight-dose induction BCG (iBCG) was comparable to six-dose iBCG plus maintenance BCG (mBCG). Methods This observational study evaluated 2669 patients with high- or highest-risk NMIBC who treated with iBCG with or without mBCG during 2000–2019. The patients were classified into five groups according to treatment pattern: 874 (33%) received non-maintenance six-dose iBCG (Group A), 405 (15%) received six-dose iBCG plus mBCG (Group B), 1189 (44%) received non-maintenance seven−/eight-dose iBCG (Group C), 60 (2.2%) received seven−/eight-dose iBCG plus mBCG, and 141 (5.3%) received only ≤5-dose iBCG. Recurrence-free survival (RFS), progression-free survival, and cancer-specific survival were estimated and compared using Kaplan–Meier analysis and the log-rank test, respectively. Propensity score-based one-to-one matching was performed using a multivariable logistic regression model based on covariates to obtain balanced groups. To eliminate possible immortal bias, 6-, 12-, 18-, and 24-month conditional landmark analyses of RFS were performed. Results RFS comparison confirmed that mBCG yielded significant benefit following six-dose iBCG (Group B) in recurrence risk reduction compared to iBCG alone (groups A and C) before (P < 0.001 and P = 0.0016, respectively) and after propensity score matching (P = 0.001 and P = 0.0074, respectively). Propensity score-matched sequential landmark analyses revealed no significant differences between groups B and C at 12, 18, and 24 months, whereas landmark analyses at 6 and 12 months showed a benefit of mBCG following six-dose iBCG compared to non-maintenance six-dose iBCG (P = 0.0055 and P = 0.032, respectively). There were no significant differences in the risks of progression and cancer-specific death in all comparisons of the matched cohorts. Conclusions Although non-maintenance eight-dose iBCG was inferior to six-dose iBCG plus mBCG, the former might be an alternative remedy in the BCG shortage era. To overcome this challenge, further investigation is warranted to confirm the real clinical value of non-maintenance eight-dose iBCG.