Pretreatment Performance Status Research Articles

Targeted Radionuclide Therapy for the Treatment of Metastatic Bone Disease: A Retrospective Analysis in Moscow, Russia

Introduction: Metastatic bone disease (MBD) is a common complication of advanced cancer, causing significant morbidity and negatively impacting patients' quality of life. Targeted radionuclide therapy (TRT) has emerged as a promising treatment modality for MBD, offering targeted delivery of therapeutic radiation to bone metastases while minimizing damage to healthy tissues. Methods: A retrospective cohort study was conducted at leading oncology centers in Moscow, Russia, between 2018 and 2023. Patients with MBD who received TRT with either Strontium-89 or Samarium-153 were included. Data on patient demographics, primary tumor type, number of bone metastases, pre-treatment pain scores, performance status, and survival outcomes were collected. Results: A total of 150 patients were included in the study (mean age 62 years, 55% female). The most common primary tumor types were prostate (35%), breast (25%), and lung (15%). The median number of bone metastases was 5 (range 1-20). Pre-treatment pain scores were high (median 7 on a 0-10 scale). A significant reduction in pain scores was observed post-TRT (median 3, p<0.001). Overall survival at 1 year was 75%, with a median survival of 18 months. Favorable prognostic factors included a lower number of bone metastases, good performance status, and absence of visceral metastases. Conclusion: TRT is a safe and effective treatment option for patients with MBD in Moscow, Russia, offering significant pain palliation and improved quality of life.

Maximum Efficacy of Immune Checkpoint Inhibitors Occurs in Esophageal Cancer Patients With a Low Neutrophil-to-Lymphocyte Ratio and Good Performance Status Prior to Treatment.

Immune checkpoint inhibitors (ICIs) play an important role in the treatment of esophageal cancer (EC). However, few patients achieve long-term survival, and some patients develop serious immune-related adverse events (irAEs). Reliable predictive biomarkers of efficacy and safety need to be established in order to improve efficacy. We retrospectively analyzed the outcomes of nivolumab monotherapy on EC at Showa University, Department of Medicine, to identify biomarkers and characteristics of patients who benefit from ICI monotherapy. Eighty-six patients with EC who received nivolumab monotherapy were included in the present study. Patient characteristics, efficacy, and safety were analyzed. A multivariable analysis evaluated the correlation among overall survival (OS), progression-free survival (PFS), best overall response (BOR), irAEs, and the following variables: sex, age, performance status (PS), neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP) level, albumin level, and body-mass index before treatment. Median PFS was 3.1 months, and median OS was 9.0 months. In multivariable analysis, pretreatment PS, NLR, and sex were significantly correlated with OS and PFS. NLR <3.3 predicted longer survival (median OS 17.5 vs. 6.4 months for NLR ≥3.3; p<0.001). Median OS was 10.6 months for PS 0-1 and 1.3 months for PS 2-3 (p<0.001). NLR remained significantly predictive in the PS 0-1 group. The development of irAEs was significantly associated with increased OS and PFS. Patients with low NLR and good PS before treatment may maximize the benefits of ICIs. A low NLR may be an indicator of higher immunocompetence for anti-tumor immunity, suggesting that NLR may be a convenient predictive biomarker in daily practice.

Comparison of therapeutic outcomes in esophageal squamous cell carcinoma following neoadjuvant chemoradiotherapy: A prospective observational cohort study

Patients with locally advanced esophageal squamous cell carcinoma (ESCC) following neoadjuvant chemoradiotherapy (nCRT) may not always receive resection despite the possible achievement of a pathologic complete response (pCR) being associated with superior survival benefit. We aimed to compare outcomes among ESCC patients with or without pCR and those refusing surgery. In total, 111 medically operable, non-cervical ESCC patients after the same protocol of nCRT (platinum/5-fluorouracil plus radiation 50Gy) were prospectively enrolled between 2011 and 2021. Eighty-three of them underwent esophagectomy comprising pCR (n=32) and non-pCR (n=51), while 28 operable patients declined surgery (refusal-of-surgery group). Predictors and survival data were analyzed. In terms of esophagectomy, 38.5% (32/83) patients achieved pCR. The pCR group exhibited better pretreatment performance status than the non-pCR group (adjusted odds ratio: 0.11, 95% confidence interval: 0.03-0.58; p=0.01). Among pCR, non-pCR, and refusal-of-surgery groups, the 5-year overall survival (OS) rates were 56%, 29% and 50% (p=0.08) and progression-free survival (PFS) rates were 52%, 28% and 36% (p=0.07) respectively. The pCR group had significantly better OS and PFS than the non-PCR group (adjusted hazard ratio: 2.33 and 1.93, p=0.02 and 0.049 respectively) but not the refusal-of-surgery group. Better pretreatment performance status is associated with higher chance of pCR. Consistent with previous studies, we found attainment of pCR confers the best OS and PFS. Suboptimal OS in the refusal-of-surgery group reflects some of them would have residual disease in addition to complete remission. Further studies are needed to identify prognostic factors of pCR to select candidates who could validly decline esophagectomy.

Comorbidities Associated with Early Mortality after CD19 CAR-T Cell Therapy

Objective: CD19 chimeric antigen receptor (CAR) T-cell therapy has changed the standard for treatment of relapsed and/or refractory (r/r) large b-cell lymphoma (LBCL). Currently, pre-treatment evaluation of patients and disease factors do not accurately predict outcomes. This study aims to identify risk factors associated with early mortality prior to day 100 after CAR-T infusion. Methods: We performed a single-centered retrospective adult patients (pts) with r/r LBCL who received CAR-T cell therapy between 2018-2021. CAR-T cell toxicities graded according to either CAR T-Cell Therapy-Associated Toxicity (CARTOX) grading system prior to May, 2019 or American Society of Transplantation and Cellular Therapy (ASTCT) consensus grading thereafter for cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS). Comorbidities defined as per Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). (Sorror et al., 2009). Hepatic dysfunction defined as infection with hepatitis B or C or history of liver cirrhosis or elevated total bilirubin, AST, or ALT on at least two values on two different days from day -24 till day -10 prior to CAR-T. Cardiovascular (CV) comorbidity determined by presence of coronary heart disease, congestive heart failure or reduced ejection fraction detected by echocardiogram. Psychiatric disturbance defined as presence of depression and/or anxiety requiring treatment or consultation. Patient demographics, disease characteristics and clinical outcomes summarized through descriptive statistics. Wilcoxon rank sum test used to evaluate difference in a continuous variable between patient groups. Kaplan-Meier method used to estimate time-to-event endpoints including progression free survival (PFS), and overall survival (OS). Results: Two hundred and fifty patients included in analysis. Median age of 61years (range: 18-89) and 30.8% of patients were female (n=77). Histology was categorized as LBCL (65.9%) and included diffuse LBCL or high grade LBCL, transformed follicular lymphoma (26.9%), primary mediastinal b-cell lymphoma (6.4%) or follicular lymphoma (0.8%). Majority of pts received axicabtagene ciloleucel 95.6% (n=239) while 4.4% (n=11) received tisagenlecleucel and 52% (n=130) of pts received bridging therapy. CRS of any grade was 90.4% ; ICANS any grade was 57.2% while grade 3 CRS/ICANS occurred 6.4% and 38.4% respectively. Median follow-up 24.7 months (mo) (95% CI: 20.7 ~ 26.4 mo). One-hundred twenty-eight pts died during follow-up, 48 pts died within 100 days, and most common cause of death was progression of lymphoma (29.2%; n=73). Early 30-day mortality occurred in 4.8% pts and causes of death due to CAR-T related toxicity in 6 pts, disease progression in 3 pts, and infection in 1 pts. 100-day mortality rate was 24.6% (n=32) for pts >60 years old vs 13.3% (n=16) for <60 (p-value=0.02). 100-day mortality rate was 36.5% for ECOG 2-4 vs 14.9% for ECOG 0-1 (p-value=0.0005). In terms of non-relapsed mortality (NRM), risk stratification according to cumulative HCT-CI score was not associated with higher 100-day NRM (p=0.24). Pts with cardiac score of 1 had a higher NRM (26.9% vs. 8.1%; p-value=0.005). The 100-day NRM rates for hepatic score of 0, 1, and 3 were 8.9%, 14.3%, and 50% (p-value=0.04). Pts with psychiatric disturbance score of 1 had higher 100-day NRM (19.6% vs. 7.8%; p-value=0.03). Conclusion: This single center retrospective study observed an increase in 100-day mortality in correlation with pre-treatment performance status, and older age. Pts with cardiac comorbidity, hepatic dysfunction or psychiatric disturbance had a higher 100-day NRM. Similar to other studies, the combined HCT-CI score was not predictive of NRM, but individual variables were associated with higher non-CART related toxicity. These findings require validation with further studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience.

Up to 30% of patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) never respond or develop resistance to 177Lu-labeled PSMA-targeted radioligand monotherapy. Single-agent PSMA-targeted radioligand therapy (PRLT) with the alpha-emitter 225Ac showed promise against mCRPC but may cause severe and/or persistent xerostomia, which may substantially impair patients' quality-of-life. We hypothesized that when 177Lu-PSMA ligand alone is ineffective, tandem therapy with low-activity 225Ac-PSMA ligand plus full activity of the beta emitter may enhance efficacy while minimizing xerostomia severity. We retrospectively analyzed pilot experience with 1 course of 225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy in our first 20 patients with mCRPC receiving this intervention after insufficiently responding to 177Lu-PSMA-617 monotherapy. This cohort had late-stage/end-stage disease with high baseline prostate-specific antigen (PSA) concentration (median 215 ng/mL), heavy pre-treatment (abiraterone and/or enzalutamide, and 177Lu-PRLT [median cumulative activity, 26.3 GBq] in 20/20 patients, 100%; docetaxel and/or cabazitaxel in 13/20 patients, 65%), and frequent Eastern Cooperative Oncology Group performance status of 2 (8/20 patients, 40%). Median (minimum-maximum) administered activities were 225Ac-PSMA-617, 5.3 (1.5-7.9) MBq, and 177Lu-PSMA-617, 6.9 (5.0-11.6) GBq. Significant responders to tandem therapy received 177Lu-PSMA-617 monotherapy as maintenance (median [minimum-maximum]: 1 [0-5] cycle). After a median (minimum-maximum) 22 (14-63) weeks' follow-up, 13/20 patients (65%) had as best biochemical response a PSA decline > 50%. Median (95% confidence interval) progression-free survival was 19 (12-26) weeks, and overall survival was 48 (4-92) weeks post-tandem therapy administration. Xerostomia was reported as grade 1 (very mild) in 8/20 patients (40%), grade 2 (mild) in 5/20 (25%), and grade 3/4 in 0/20. Our results suggest that a single course of tandem therapy with low-activity 225Ac-PSMA-617/full-activity 177Lu-PSMA-617 may safely enhance response to PRLT in men with late-stage/end-stage mCRPC while minimizing xerostomia severity. Formal study of this combination is warranted.

Survival Benefit With Resection of Brain Metastases From Renal Cell Carcinoma in the Setting of Molecular Targeted Therapy and Immune Therapy

Abstract INTRODUCTION Patient survival with renal cell carcinoma (RCC) has improved with the use of molecular targeted agents and immunotherapy. Given the potential activity of these agents in treating brain metastases (BM), the role of aggressive local management with surgery and/or radiation may diminish. This study evaluated the benefit of aggressive local therapy of RCC BM in the setting of molecular targeted agents and/or immunotherapy. METHODS A retrospective single-center review between 2011 and 2018 identified 1659 patients treated for RCC. The study group included patients that developed BM and received molecular targeted agents and/or immunotherapy during the course of their disease. Data analyzed included demographic information, systemic treatments, and local BM treatment modalities. Kaplan-Meier curves and log-rank values were used to assess progression free survival (PFS) and overall survival (OS) following RCC and BM diagnosis. RESULTS Of 1659 patients, 108 (6.5%) were diagnosed with BM during their clinical course. Mean OS from diagnosis of RCC for these 108 patients was 44.5 ± 40.1 mo, with 1-, 3-, and 5-yr survival of 76.9%, 43.3%, and 38.1%. All patients were treated with molecular targeted agents and/or immunotherapy. OS was analyzed based on three treatment groups: systemic therapy only (26.1 ± 31.2, n = 21), systemic and radiotherapy (41.4 ± 34.9, n = 54), and systemic and radiotherapy plus BM resection (61.4 ± 46.9, n = 33). Survival benefit was seen with surgery compared to systemic therapy alone (P = .002) and the systemic and radiotherapy cohort (P = .038). PFS did not differ significantly between cohorts. Variables such as pre-treatment performance status (ECOG P = .085; KPS P = .231), number of BM (median 2, P = .685) and status of systemic disease at the time of BM diagnosis did not differ significantly. CONCLUSION In the setting of molecular targeted agents and immunotherapy, BM resection maximizes OS in surgical candidates. Prospective clinical trials are needed to elucidate activity of newer molecular targeted agents and immunotherapy in RCC BM treatment.

Prognostic value of performance status in metastatic renal cell carcinoma patients receiving tyrosine kinase inhibitors: a systematic review and meta-analysis

BackgroundThe association between performance status (PS) and the prognosis of metastatic renal cell carcinoma (mRCC) patients receiving tyrosine kinase inhibitors (TKIs) remains controversial. The aim of this study is to evaluate the prognostic value of PS in mRCC patients treated with TKIs.MethodsElectronic databases were searched to identify the studies that had assessed the association between pretreatment PS and prognosis in mRCC patients receiving TKIs. Hazard ratios (HRs) and 95% confidence interval (CI) for overall survival (OS) and progression-free survival (PFS) from eligible studies were used to calculate combined HRs. The heterogeneity across the included studies was assessed by Cochrane’s Q test and I2 statistic. The Begg’s funnel plot and Egger’s linear regression teats were used to evaluate the potential publication bias. The meta-analysis was performed with RevMan 5.3 and Stata SE12.0 according to the PRISMA guidelines.ResultsA total of 6780 patients from 19 studies were included in this meta-analysis. The results showed that a poor PS was an effective prognostic factor of both OS (pooled HR: 2.08, 95% CI: 1.78–2.45) and PFS (pooled HR: 1.51, 95% CI: 1.20–1.91). Subgroup analysis revealed that poor PS significantly associated with poor OS and PFS in studies using Karnofsky PS scale (OS, pooled HR: 2.20, 95% CI: 1.65–2.94; PFS, pooled HR: 1.74, 95% CI: 1.19–2.56), conducted in Asia (OS, pooled HR: 2.25, 95% CI: 1.71–2.95; PFS, pooled HR: 1.73, 95% CI: 1.14–2.64) and Newcastle-Ottawa Scale score of 8 (OS, pooled HR: 2.61, 95% CI: 1.92–3.55; PFS, pooled HR: 2.43, 95% CI: 1.36–4.33).ConclusionsThis study suggests that a poor PS is significantly associated with poor prognosis in mRCC patients receiving TKIs.

An Analysis of Toxicity and Outcomes in Older Versus Younger Rectal Cancer Patients Treated with Trimodality Therapy

Trimodality therapy (TMT), neoadjuvant chemoradiation followed by surgical resection, is standard of care for locally advanced rectal cancer, improving outcomes versus surgery alone. However, older patients are not well represented in studies and data are limited in this population. This study analyzed toxicity patterns and outcomes in older versus younger rectal cancer patients treated with TMT. We included patients at a single institution identified to undergo TMT for histologically confirmed locally advanced rectal adenocarcinoma. Patients receiving upfront surgery or short course radiation were excluded. A classification and regression tree (CART) analysis was used to determine an ideal age cutoff. The primary endpoint was acute toxicity, with secondary endpoints of treatment modification, recurrence free survival (RFS), and pathologic complete response (pCR) rate. Wilcoxon and Fisher’s exact tests were used to determine the association between age group and outcomes. RFS was assessed with the Kaplan-Meier method. A total of 123 patients were included, ages 30-92, with 43 months median follow up. The older (age >=65, n=41) and younger (age<65, n=82) groups were well balanced with respect to gender, race, T and N stage, tumor location, chemotherapy regimen, and radiation technique. However, the older population had worse pretreatment performance status (PS) and higher Charlson Comorbidity Index (CCI) score. Older patients had significantly more hospitalizations (17.1% vs 2.4%, p = 0.006) and more hematologic toxicity (p=0.006). There was no significant difference in non-hematologic toxicity, decrease in PS, or weight loss during treatment. There was a higher rate of chemotherapy deintensification (39.0% vs 8.5%, p=0.0001), but no significant difference in rates of radiation treatment breaks (26.8% vs 18.3%, p=0.35) or rates of surgical resection (95.1% vs 96.3%, p=0.99). There was a significant difference in RFS between the two groups (p=0.012), with 3 year RFS 76% in the older group and 90% in the younger. Even when adjusted for pretreatment PS (p=0.033) or CCI score (p=0.049) the difference in RFS between older and younger patients persisted. There was no significant difference in pCR rates (30.3% vs 35.9%, p=0.68). Older rectal cancer patients treated with TMT experienced more hematologic toxicity and hospitalizations during treatment, with associated increased rates of chemotherapy deintensification but no significant difference in radiation or surgical therapy. These differences may have contributed to decreased RFS in older patients. Decreased RFS persisted after PS and comorbidity adjustments, indicating the strength of age as a predictor of RFS. As this is a novel finding in rectal cancer, additional studies are warranted to evaluate the appropriate approach to older patients with this disease.

Multicenter Clinicopathological Study of High-Grade Serous Carcinoma Presenting as Primary Peritoneal Carcinoma.

We conducted a multicenter clinicopathological study to characterize patients with high-grade serous carcinoma presenting as primary peritoneal carcinoma (clinical PPC). At 9 sites in Japan, patients with clinical PPC diagnosed according to Gynecologic Oncology Group criteria were enrolled retrospectively. The Gynecologic Oncology Group criteria allow for minor ovarian involvement by high-grade serous carcinoma. There was no systematic detailed histopathological review of the fallopian tubes to determine whether they were involved by serous carcinoma. There were 139 patients and 64% were aged 60 years or older. Median pretreatment serum CA-125 was 1653.5 IU/mL. Pretreatment performance status was poor in more than 50%, endometrial cytology was positive in 40.3%, and the preoperative clinical diagnosis was correct in 72.7%. Primary debulking surgery was performed in 36% of patients, whereas 64% underwent neoadjuvant chemotherapy (NAC) with interval debulking surgery (IDS). The main tumor sites were the upper abdomen (greater omentum), extrapelvic peritoneum, mesentery, and diaphragm. Lymph node metastasis was found in 46.8% of patients undergoing systematic retroperitoneal node dissection. The optimal surgery rate was 32.0% with primary debulking surgery versus 53.9% with NAC and IDS (P = 0.0139). The response rate was 82.0% with NAC and 80.6% with postoperative chemotherapy. Median progression-free survival was 19.0 months and median overall survival was 41.0 months. Multivariate analysis showed that prognostic factors for progression-free survival were NAC and residual tumor diameter after debulking surgery, whereas the only prognostic factor for overall survival was the residual tumor diameter. This study identified various characteristics of clinical PPC. Neoadjuvant chemotherapy with IDS is a reasonable treatment strategy, and complete debulking surgery is optimum.

Carcinoembryonic Antigen as a Predictive Biomarker of Response to Nivolumab in Non-small Cell Lung Cancer.

To find new predictive factors for the efficient use of immune checkpoint inhibitors in patients with non-small-cell lung cancer (NSCLC). In this multicenter retrospective cohort study, we evaluated consecutive patients treated with nivolumab between January and October 2016 after second-line systemic chemotherapy. The endpoint was progression-free survival (PFS), as defined by Response Evaluation Criteria in Solid Tumors version 1.1. A total of 189 patients were included in the study. Sixty-four percent had received two or more prior systemic therapies. In Cox proportional hazard analyses, Eastern Cooperative Oncology Group Performance Status of 2 or more, lactate dehydrogenase (LDH) ≥217 mg/dl, and carcinoembryonic antigen ≥13.8 ng/ml were independently associated with inferior PFS. LDH was not associated in the sensitivity analysis. In patients with NSCLC treated with nivolumab, worse pretreatment performance status, and higher carcinoembryonic antigen were associated with inferior PFS.

Pretreatment nutritional risk scores and performance status are prognostic factors in esophageal cancer patients treated with definitive chemoradiotherapy.

This study evaluated the prognostic effects of nutritional risk scores and performance status (PS) on unresectable locally advanced esophageal cancer (LAEC) patients who were treated with definitive concurrent chemoradiotherapy (dCRT). A total of 202 LAEC patients from four different cancer centers were retrospectively reviewed. Nutritional risk and PS were measured using the Nutritional Risk Screening 2002 (NRS-2002) scores and Eastern Cooperative Oncology Group (ECOG) scales. Outcomes were clinical response rate, overall survival (OS) and progression-free survival (PFS). Multivariate analysis of predictive factors of response to dCRT and survival were performed using a logistic regression and a Cox model, respectively. The majority of patients (71.8%) had an ECOG PS score of 0-1, and 52.5% (n=106) of patients were identified as having nutritional risk (NRS-2002 ≥3) upon treatment initiation. There was no correlation between NRS-2002 scores and ECOG PS (Spearman's ρ=0.046; P=0.516). In multivariate analysis, NRS-2002 scores (P=0.002, HR 2.805, 95%CI: 1.445-5.446) and ECOG PS (P=0.015, HR 2.719, 95%CI: 1.218-6.067) were independent prognostic factors for the response to dCRT. NRS-2002 scores (OS: HR 1.530, 95%CI 1.059-2.209; P=0.023; PFS: HR 1.517, 95%CI 1.105-2.082; P=0.010) and ECOG PS (OS: HR 1.729, 95%CI 1.185-2.522; P=0.005; PFS: HR 1.678, 95%CI 1.179-2.387; P=0.004) were both independent prognostic factors for OS and PFS. In conclusions, NRS-2002 scores and ECOG PS scales both have prognostic effects on clinical response and survival in LAEC, but a significant association of NRS-2002 scores and ECOG PS were not observed.

IBRUTINIB FOR RELAPSED / REFRACTORY CLL: AN UPDATE OF THE UK AND IRELAND ANALYSIS OF OUTCOMES IN 315 PATIENTS

Introduction: The UK CLL Forum recently published the largest real-world data set of patients treated with ibrutinib for relapsed/refractory CLL (Haematologica, 2016). We have now updated our database with an additional 14 months median follow-up. Methods: Data were collected retrospectively from 62 centres, and discontinuation free survival (DFS) and overall survival (OS) were analysed and stratified by baseline and treatment-related characteristics. Results: Of the original 315 patients, 103 have now died, 37 are alive but have stopped ibrutinib, and 175 continue to take the drug. With a median 30 months follow-up, 54.4% (95% CI: 48.5–60.0) of patients are still taking ibrutinib and 66.1% (60.4–71.3) are still alive. Despite the additional follow-up, with univariable analysis, we could still not show any deleterious effect of 17p deletion or number of prior lines of therapy on discontinuation-free survival or overall survival (OS) (OS for 17p deleted vs 17p wildtype: 68.6% vs 67.8%; OS for number of prior lines 1 vs 2 vs 3+: 66.0% vs 64.9% vs 66.6%). However, increased age and poorer pre-treatment performance status remain associated with ibrutinib discontinuation and earlier death. With our original publication, we were unable to demonstrate any survival detriment for dose-reduced patients, although patients who had treatment breaks >14 days, had inferior outcomes. Of the 48 patients who had dose-reduced ibrutinib without treatment breaks in the first year, 17 have now stopped the drug, 10 have died, 25 continue on dose-reduced ibrutinib and 6 are back to standard dose. To analyse on-going potential effects of first year dose reductions and treatment breaks, we classified all patients who were alive at 1 year into one of 4 different groups depending on first year treatment, namely, A: standard dosing with no breaks >14 days; B: dose reductions but no breaks >14 days; C1: temporary treatment breaks >14 days (but re-taking ibrutinib by 1 year); C2: permanent discontinuation of ibrutinib within the first year. Figure 1 plots DFS and OS with 18 months median follow-up for these patients beyond one year. There is no statistical difference in DFS and OS between groups A and B (DFS; 76.7% (68.3–83.1) vs 71.1% (53.3–83.1), p = 0.23: OS; 88.1% (81.6–92.5) vs 83.7% (66.8–92.5), p = 0.75). However, patients who had temporary breaks >14 days (C1) or permanently stopped ibrutinib (C2) within the first year have impaired survival over the next 18 months compared with groups A and B (OS C1: 63% (41.4–78.5); OS C2: 40.6% (22.7–57.8).This represents a 3.1-fold and 7.7-fold respective increase risk of death for groups C1 and C2 compared with standard dosed patients. Keywords: chronic lymphocytic leukemia (CLL); ibrutinib.

Lactate dehydrogenase predicts combined progression-free survival after sequential therapy with abiraterone and enzalutamide for patients with castration-resistant prostate cancer.

An array of clinical issues remains to be resolved for castration-resistant prostate cancer (CRPC), including the sequence of drug use and drug cross-resistance. At present, no clear guidelines are available for the optimal sequence of use of novel agents like androgen-receptor axis-targeted (ARAT) agents, particularly enzalutamide, and abiraterone. This study retrospectively analyzed a total of 69 patients with CRPC treated with sequential therapy using enzalutamide followed by abiraterone or vice versa. The primary outcome measure was the comparative combined progression-free survival (PFS) comprising symptomatic and/or radiographic PFS. Patients were also compared for total prostate-specific antigen (PSA)-PFS, overall survival (OS), and PSA response. The predictors of combined PFS and OS were analyzed with a backward-stepwise multivariate Cox model. Of the 69 patients, 46 received enzalutamide first, followed by abiraterone (E-A group), and 23 received abiraterone, followed by enzalutamide (A-E group). The two groups were not significantly different with regard to basic data, except for hemoglobin values. In a comparison with the E-A group, the A-E group was shown to be associated with better combined PFS in Kaplan-Meier analysis (P = 0.043). Similar results were obtained for total PSA-PFS (P = 0.049), while OS did not differ between groups (P = 0.62). Multivariate analysis demonstrated that pretreatment lactate dehydrogenase (LDH) values and age were significant predictors of longer combined PFS (P < 0.05). Likewise, multivariate analysis demonstrated that pretreatment hemoglobin values and performance status were significant predictors of longer OS (P < 0.05). The results of this study suggested the A-E sequence had longer combined PSA and total PSA-PFS compared to the E-A sequence in patients with CRPC. LDH values in sequential therapy may serve as a predictor of longer combined PFS.

Ibrutinib for relapsed/refractory chronic lymphocytic leukemia: a UK and Ireland analysis of outcomes in 315 patients

In 2014, ibrutinib was made available for relapsed/refractory chronic lymphocytic leukemia patients. The UK Chronic Lymphocytic Leukaemia Forum collected data from UK/Ireland patients with a minimum of 1 year follow-up with pre-planned primary endpoints; the number of patients still on therapy at 1 year "discontinuation-free survival" and 1 year overall survival. With a median of 16 months follow up, data on 315 patients demonstrated a 1 year discontinuation-free survival of 73.7% and a 1 year overall survival of 83.8%. Patients with better pre-treatment performance status (0/1 vs. 2+) had superior discontinuation-free survival (77.5% vs. 61.3%; P<0.0001) and overall survival (86.3% vs. 76.0%; P=0.0001). In univariable analysis, overall survival and discontinuation-free survival were not associated with the number of prior lines of therapy or 17p deletion. However, multivariable analysis identified an interaction between prior lines of therapy, age and 17p deletion, suggesting that older patients with 17p deletion did worse when treated with ibrutinib beyond the second line. Overall, 55.6% of patients had no first year dose reductions or treatment breaks of >14 days and had an overall survival rate of 89.7%, while 26% of patients had dose reductions and 13% had temporary treatment breaks of >14 days. We could not demonstrate a detrimental effect of dose reductions alone (1 year overall survival: 91.7%), but patients who had first year treatment breaks of >14 days, particularly permanent cessation of ibrutinib had both reduced 1 year overall survival (68.5%), and also a statistically significant excess mortality rate beyond one year. Although outcomes appear inferior to the RESONATE trial (1 year overall survival; 90%: progression-free survival; 84%), this may partly reflect the inclusion of performance status 2+ patients, and that 17.5% of patients permanently discontinued ibrutinib due to an event other than disease progression.

An Introduction to a Head and Neck Cancer-Specific Frailty Index and Its Clinical Implications in Elderly Patients: A Prospective Observational Study Focusing on Respiratory and Swallowing Functions.

Frailty refers to a decreased physiologic reserve in geriatric patients and its importance in terms of treatment planning and outcome prediction has been emphasized in oncologic practices for older patients with cancer. We investigated the clinical implications of a head and neck cancer (HNC)-specific frailty index suggested by prospective clinical and functional evaluations of HNC patients. We analyzed data on 165 elderly patients with HNC who were prospectively enrolled in our hospital from 2010 to 2013. Pretreatment functional evaluations were performed according to all comprehensive geriatric assessment (CGA) domains. We additionally evaluated the patients' respiratory and swallowing functions using pulmonary function tests, voice handicap index (VHI), MD Anderson Dysphagia Inventory (MDADI), and other associated tests. Factors affecting the 2-year morbidity and mortality were also analyzed. Respiratory and swallowing problems were major causes of 2-year morbidity. Pretreatment performance status, VHI ≥8, MDADI <70, dental problems, and chemotherapy were significantly associated with early morbidity and mortality (all p < .05). CGA-assessed frailty was found in 72 patients (43.6%) and was significantly associated with 2-year mortality (p = .027) but not with morbidity (p = .716). The high-risk group according to our new HNC-specific frailty index that included functional evaluations of respiration and swallowing showed significantly higher 2-year morbidity (p = .043) and mortality (p < .001). Pretreatment functional disabilities related to respiration and swallowing were significantly associated with early morbidity and mortality. The suggested index would be more useful for assessing frailty in elderly HNC patients. This study is the first report in terms of suggesting a new frailty index focusing on respiratory and swallowing functions in elderly patients with head and neck cancer. This study shows that functional disabilities associated with respiration and swallowing significantly affected early morbidity and mortality in these elderly patients. The head and neck cancer-specific frailty index described in this report, which includes functional evaluations of respiration and swallowing, significantly predicted both early morbidity and mortality.

Pretreatment quality of life, performance status and their relation to treatment discontinuation and treatment changes in high-risk breast cancer patients receiving chemotherapy: results from the prospective randomized ADEBAR trial.

Health-related quality of life (QoL) is a self-assessed construct indicating how people feel in regard to aspects of their health. Performance status (PS) is evaluated by the treating physician. We examined whether pretreatment QoL and PS are related to subsequent treatment discontinuation and treatment changes in high-risk breast cancer patients receiving chemotherapy. We conducted a prospective cohort study with data from a randomized phase III trial comparing FEC- and EC-DOC-chemotherapy in patients with primary breast cancer (ADEBAR). We examined the patient's request to discontinue the study, discontinuation due to toxicity, the prolongation of therapy, and dose reduction. Baseline QoL was assessed using the EORTC QLQ-C30. PS was evaluated using the Eastern Cooperative Oncology Group Scale (ECOG). Four QoL scales were selected prior to analysis as outcomes: global health, physical functioning, emotional functioning, and fatigue. Multivariate binary logistic regression analyses were used to test for differences within the independent variables. 1322 patients were included. 1094 (82.8%) patients completed therapy according to protocol. 6.3% stopped therapy due to toxicity and 4.4% refused treatment. Global health was not related to any of the four QoL outcomes. Physical functioning had the strongest impact on QoL, when comparing the fittest group to the lowest quintile [OR 2.14 (95% CI 1.00-4.60)]. ECOG 0 compared to worse than 1 was strongly correlated to therapy discontinuation due to toxicity [OR 20.15 (95% CI 9.48-42.83)] and treatment refusal [OR 8.32 (95% CI 3.81-18.14)]. Pretreatment QoL, especially physical functioning, is associated with subsequent therapy discontinuation due to toxicity and with changes of the treatment protocol. Pretreatment performance status is strongly associated with therapy discontinuation due to toxicity and with treatment refusal.

Stereotactic body radiotherapy (SBRT) for medically inoperable lung metastases—A pooled analysis of the German working group “stereotactic radiotherapy”

ObjectivesThe current literature on stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by small patient cohorts with heterogeneous primary tumors, metastases location and dose regimes. Hence, this study established a multi-institutional database of 700 patients treated with SBRT for pulmonary metastases to identify prognostic factors influencing survival and local control. Materials and methodsAll German radiotherapy departments were contacted and invited to participate in this analysis. A total number of 700 patients with medically inoperable lung metastases treated with SBRT in 20 centers between 1997 and 2014 were included in a database. Primary and metastatic tumor characteristics, treatment characteristics and follow-up data including survival, local control, distant metastases, and toxicity were evaluated. Lung metastases were treated with median PTV-encompassing single doses of 12.5Gy (range 3.0–33.0Gy) in a median number of 3 fractions (range 1–13). ResultsAfter a median follow-up time of 14.3 months, 2-year local control (LC) and overall survival (OS) were 81.2% and 54.4%, respectively. In multivariate analysis, OS was most significantly influenced by pretreatment performance status, maximum metastasis diameter, primary tumor histology, time interval between primary tumor diagnosis and SBRT treatment and number of metastases. For LC, independent prognostic factors were pretreatment performance status, biological effective dose (BED) at PTV isocenter (BEDISO) and single fraction (PTV-encompassing) dose in multivariate analysis. Radiation-induced pneumonitis grade 2 or higher was observed in 6.5% of patients. The only factor significantly influencing toxicity was BEDISO (p=0.006). ConclusionSBRT for medically inoperable patients with pulmonary metastases achieved excellent local control and promising overall survival. Important prognostic factors were identified for selecting patients who might benefit most from this therapy approach.

Gfeller-Waller Concussion Awareness Act.

Aim: To find new predictive factors for the efficient use of immune checkpoint inhibitors in patients with non-small-cell lung cancer (NSCLC). Patients and Methods: In this multicenter retrospective cohort study, we evaluated consecutive patients treated with nivolumab between January and October 2016 after second-line systemic chemotherapy. The endpoint was progression-free survival (PFS), as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Results: A total of 189 patients were included in the study. Sixty-four percent had received two or more prior systemic therapies. In Cox proportional hazard analyses, Eastern Cooperative Oncology Group Performance Status of 2 or more, lactate dehydrogenase (LDH) ≥217 mg/dl, and carcinoembryonic antigen ≥13.8 ng/ml were independently associated with inferior PFS. LDH was not associated in the sensitivity analysis. Conclusion: In patients with NSCLC treated with nivolumab, worse pretreatment performance status, and higher carcinoembryonic antigen were associated with inferior PFS.

Pre-treatment performance status and stage at diagnosis in patients with head and neck cancers.

Performance status (PS) is a key factor in the selection of treatment in head and neck cancer patients (HNC). There is a probability in the development of an unfavorable PS with HNC advancing stages. This retrospective study was done on data of patients registered during the period from January 2010 to December 2012 at a cancer registry in the North Eastern India. PS was recorded according to the WHO scale. Multinomial logistic regression analysis was conducted to assess the probability of poor performance status with advancing stage. Out of 3,593 patients, there were 78.9% (2,836) males and 21.1% (757) females. Average PS0 was seen in 57.4% of all HNCs, less than 1% of all cases in HNCs with poor PS3-4 except in cases with thyroid, parotid and nose and PNS cancers, 0.7% stage IV (±M1) HNC with PS4, favorable PS0-1 was seen in 84% to 100% of cases, RR=57.1 (CI=21.2-154.1) in M1 for PS4 and with advancing stages the probability of worsening of PS0 to PS4 was 3 times (P=0.021, 95% CI= 1.187-8.474). In HNC, the majority of patients presents with a favorable PS0- 1 with different odds of worsening of PS with advancing stages and the presence of metastasis in stage IV is significantly associated with a poor PS.

Prediction Of CR On Reinduction In Patients With Newly Diagnosed Acute Myeloid Leukemia Given Intensive Induction Regimens: A Report From SWOG and Cleveland Clinic

3+7” (3 days of daunorubicin or idarubicin + 7 of cytarabine) is the most frequently used intensive induction regimen for newly diagnosed AML. While it is common practice to reinduce patients (pts) who do not achieve marrow ablation by day 14 with the same agents, it remains unclear whether any particular disease or treatment-related factors can predict for CR with such a strategy, or can identify pts who should more appropriately be considered to have primary refractory disease at day 14 and treated with different agents.This analysis was designed to address this question. MethodsWe analyzed 1505 pts given 3+7 on SWOG studies S8600 (n = 534), S9031 (n= 215), S9333 (n = 161), and S0106 (n = 595) and 235 treated at Cleveland Clinic from 2006-2010 of whom 54 were reinduced with anthracycline-based therapy. In the SWOG cohort, 49% of pts achieved CR on course 1. Of the 734 patients who were alive at day 28 but did not achieve CR on course 1, 336 (53%) had received a reinduction course of 3+7. We used multivariate logistic regression to identify covariates associated with achievement of CR to reinduction in these 336 pts. The area under receiver operating characteristic curves (AUC) were used to quantify the effectiveness of the multivariate models at predicting CR in reinduction (AUC 1.0 = perfect prediction, AUC 0.5 = “coin flip”). Numerical covariates examined were [median (range)]: age (51, 15-83), day the first post-induction marrow was examined (hereafter “day 14”, 15, 7-48), day 14 blasts % (20, 0-95), day 14 % cellularity (37, 1-85), and their product (infiltrate, 5, 0-74), change in % blasts from day 1 (-44, -96,50), change in cellularity from day 1 (-5, -99-80), change in infiltrate from day 1 (-2, 93-41), and days from start of course 1 to start of course 2 (21, 13-67). Categorical covariates examined were: pre-treatment performance status (PS, ECOG scale) and pre-treatment cytogenetics (SWOG criteria). Results40% of the 336 SWOG pts achieved CR to 3+7 reinduction, while 14% died during the first 28 days following reinduction, and 45% neither died during this time nor achieved CR (resistant). Age was associated with reinduction CR rate (median 47 for CR, 56 for no CR, p<0.001), as was day of reinduction (median 24 for CR, 20 for no CR, p=0.005), cytogenetics (CR rates 75% for favorable, 35% for intermediate, 18% for unfavorable, and 9% for unknown, p=0.04), and AML status (CR rate 42% for de novo and 16% for secondary AML). However, the AUC for age was 0.63, day of second induction was 0.59, cytogenetics was 0.60, and AML status was 0.53. Day 14 marrow blast % was similar in pts who did and did not achieve CR to reinduction (medians 20% and 22% respectively, p = 0.8). Similarly, day 14 cellularity, day 14 infiltrate, change in blast %, cellularity, infiltrate from pretreatment, and day when course 2 began were not associated with reinduction CR rate. On multivariate analysis, none of these covariates nor SWOG protocol was associated with second course CR rate, and the AUC for this multivariate model was only 0.70. There was no evidence that the effects of covariates differed in the different protocols. In the Cleveland Clinic cohort, 53% of pts achieved a CR on their reinduction or 3rd induction course, 11% died during the first 28 days of reinduction, and 33% were resistant. In this cohort, no covariates were associated with CR on reinduction or 3rd induction and AUC values were uniformly low and similar to the SWOG cohort. ConclusionIn AML pts treated with 3+7 regimens, our findings indicate that bone marrow parameters, specifically day 14 blasts %, marrow cellularity, and treatment-related changes do not predict for subsequent CR with a reinduction Perhaps too few patients not in CR after a first course of 3+7 receive reinduction with 3+7.ClinicalTrials.gov Identifier: NCT00085709 (others precede registry reporting) FundingThis work was supported by PHS Cooperative Agreement grants awarded by the National Cancer Institute, CA32102 and CA38926 Disclosures:No relevant conflicts of interest to declare.