Significant Improvement In Relapse-free Survival Research Articles

Adjuvant chemotherapy combined with immunotherapy in patients with cholangiocarcinoma after radical resection.

The malignancy of cholangiocarcinoma is highly pronounced, and it exhibits a propensity for recurrence and metastasis even in the presence of standard chemotherapy. The efficacy of adjuvant chemotherapy combined with immunotherapy in patients with resected cholangiocarcinoma needs to be substantiated. Data from 101 patients with cholangiocarcinoma treated at the Sun Yat-sen University Cancer Center between 2015 and 2020 were studied. After propensity score matching, there were no significant differences in baseline characteristics between patients in the combined adjuvant chemotherapy and immunotherapy group (AC + IM group) and the adjuvant chemotherapy alone group (AC group) (all p > 0.05). The AC + IM group demonstrated a statistically significant improvement in relapse-free survival (RFS) compared to the AC group (p = 0.032). Likewise, the AC + IM group exhibited a significantly superior overall survival (OS) outcome when compared to the AC group (p = 0.044). Multivariate Cox analysis unveiled perineural invasion (p = 0.041), lymph node metastasis (p = 0.006), and postoperative immunotherapy (p = 0.008) as independent prognostic factors exerting a significant impact on the OS of patients. In the cohort of patients with perineural invasion, the AC + IM group exhibited significantly improved OS compared to the AC group (p = 0.0077). Similarly, within the subset of patients with lymph node metastasis, the AC + IM group exhibited a significantly superior OS outcome when compared to the AC group (p = 0.023). Combining postoperative adjuvant chemotherapy with immunotherapy extends the RFS and OS of patients with cholangiocarcinoma following radical resection.

Outcomes after interruption of targeted therapy in patients with histiocytic neoplasms.

Little is known about outcomes following interruption of targeted therapy in adult patients with histiocytic neoplasms. This is an IRB-approved study of patients with histiocytic neoplasms whose BRAF and MEK inhibitors were interrupted after achieving complete or partial response by 18-fluorodeoxyglucose positron emission tomography (FDG-PET). 17/22 (77%) of patients experienced disease relapse following treatment interruption. Achieving a complete response prior to interruption, having a mutation other than BRAFV600E, and receiving MEK inhibition only were each associated with a statistically significant improvement in relapse-free survival. Relapse is common following treatment interruption however some patients may be suitable for limited-duration treatment.

Prognostic value of postoperative ctDNA detection in patients with early non-small cell lung cancer: a systematic review and meta-analysis.

Circulating tumor DNA (ctDNA) has emerged as a potential biomarker for monitoring early non-small cell lung cancer (ENSCLC), particularly after radical surgery. However, the prognostic value of postoperative ctDNA is still being investigated due to the small sample size and heterogeneity of patients with ENSCLC in current trials. Moreover, the potential clinical utility of ctDNA assessment for administering adjuvant therapy (AT) in patients with ENSCLC is also an important area of active research. We aimed to identify the prognostic value of postoperative ctDNA detection in ENSCLC patients with stages I-III. This study type is a systematic review and meta-analysis. We conducted a search in the Cochrane Library, Embase, PubMed, and ScienceDirect for prospective or retrospective investigations involving patients with ENSCLC, gathering outcomes based on predefined end points. The literature review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the Newcastle-Ottawa scale was employed to carry out a quality evaluation of the included studies. The primary end point of the study was to evaluate the association of ctDNA status in two time points (within 1 month after surgery and long-term postoperative monitoring with more than 3 months) with relapse-free survival (RFS) and overall survival (OS). In addition, the study investigated the role of ctDNA in predicting the response to AT. The secondary end points of the study were to determine the impact of ctDNA on RFS and OS in different subgroups of ENSCLC patients based on pathological subtypes and TNM staging. In total, 2149 studies were screened, and 11 studies met the inclusion criteria for the analysis. The presence of ctDNA within 1 month after surgery as well as long-term postoperative ctDNA were both associated with poorer RFS [hazard ratio (HR) = 4.43; 95% CI: 3.23-6.07 and HR = 7.99; 95% CI: 3.28-19.44, respectively] and worse OS (HR = 5.07; 95% CI: 2.80-9.19 and HR = 7.49; 95% CI: 3.42-16.43, respectively). Most subgroup analyses yielded similar results. Moreover, ctDNA-positive patients could acquire survival benefits from AT (HR = 0.30; 95% CI: 0.16-0.54), while ctDNA-negative patients that received AT did not show significant improvement in RFS (HR = 1.18; 95% CI: 0.67-2.09). The postoperative ctDNA assessment is a promising approach to stratify the risk of relapse and death in ENSCLC patients. Our data suggest that patients with negative ctDNA in the postoperative setting may not benefit from AT, which warrants further investigation. This finding, if validated in prospective trials with a larger sample size, could aid in better-individualized treatment for patients and avoid potential side effects of AT. This study was designed in accordance with PRISMA and registered with PROSPERO (CRD42022311615).

Enhanced immune activation within the tumor microenvironment and circulation of female high-risk melanoma patients and improved survival with adjuvant CTLA4 blockade compared to males

BackgroundWe hypothesized that a gender difference in clinical response may exist to adjuvant CTLA4 blockade with ipilimumab versus high-dose IFNα (HDI). We investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME).Patients and methodsThis gender-based analysis was nested within the E1609 trial that tested adjuvant therapy with ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus HDI in high risk resected melanoma. We investigated gender differences in treatment efficacy with ipi3 and ipi10 versus HDI while adjusting for age, stage, ECOG performance (PS), ulceration, primary tumor status and lymph node number. Forest plots were created to compare overall survival (OS) and relapse free survival (RFS) between ipi and HDI. Gene expression profiling (GEP) was performed on tumors of 718 (454 male, 264 female) patients. Similarly, serum and peripheral blood mononuclear cells (PBMC) samples were tested for soluble and cellular biomarkers (N = 321 patients; 109 female and 212 male).ResultsThe subgroups of female, stage IIIC, PS = 1, ulcerated primary, in-transit metastasis demonstrated significant improvement in RFS and/or OS with ipi3 versus HDI. Female gender was significant for both OS and RFS and was further explored. In the RFS comparison, a multivariate Cox regression model including significant variables indicated a significant interaction between gender and treatment (P = 0.024). In peripheral blood, percentages of CD3+ T cells (P = 0.024) and CD3+ CD4+ helper T cells (P = 0.0001) were higher in females compared to males. Trends toward higher circulating levels of IL1β (P = 0.07) and IL6 (P = 0.06) were also found in females. Males had higher percentages of monocytes (P = 0.03) with trends toward higher percentages of regulatory T cells (T-reg). Tumor GEP analysis supported enhanced infiltration with immune cells including gammadelta T cells (P = 0.005), NK cells (P = 0.01), dendritic cells (P = 0.01), CD4+ T cells (P = 0.03), CD8+ T cells (P = 0.03) and T-reg (P = 0.008) in the tumors of females compared to males and a higher T-effector and IFNγ gene signature score (P = 0.0244).ConclusionFemale gender was associated with adjuvant CTLA4 blockade clinical benefits and female patients were more likely to have evidence of type1 immune activation within the TME and the circulation.Trial registration ClinicalTrials.gov NCT01274338. Registered 11 January 2011, https://www.clinicaltrials.gov/ct2/show/NCT01274338

Individual patient data meta-analysis of adjuvant gemcitabine-based chemotherapy for biliary tract cancer: combined analysis of the BCAT and PRODIGE-12 studies

BackgroundAlthough gemcitabine-based chemotherapy is the standard of care for advanced biliary tract cancers (BTCs), adjuvant phase III studies (BCAT in Japan, PRODIGE 12 in France) failed to show benefit, possibly owing to fewer patients (n = 225 and n = 194) compared with the adjuvant capecitabine BILCAP trial (n = 447). We performed a combined analysis of both gemcitabine-based chemotherapy adjuvant studies. MethodsWe performed individual patient data meta-analysis of all patients included in BCAT and PRODIGE 12. BCAT study randomised patients with extrahepatic cholangiocarcinoma to single-agent gemcitabine or observation. PRODIGE 12 randomised patients with all BTC subtypes to gemcitabine-oxaliplatin combination or observation. Combined analysis was performed using Kaplan–Meier curves and a Cox regression model stratified on the trial. ResultsTwo hundred and twelve versus 207 patients were randomised in the gemcitabine-based chemotherapy versus observation arms. Baseline characteristics were balanced between arms. The median follow-up was 5.5 years. After 258 relapse-free survival (RFS) events, there was no difference in RFS (log-rank p = 0.45; hazard ratio [HR] = 0.91 [95% confidence interval [CI] 0.71–1.16]; p = 0.46). RFS rates at five years were 40.8% (95%CI: 33.9%–47.5%) for gemcitabine-based chemotherapy versus 36.6% (95%CI: 29.8%–43.4%) for observation. After 201 deaths, there was no difference in overall survival (OS) (log-rank p = 0.83; HR = 1.03 [95%CI: 0.78–1.35]; p = 0.85). OS rates at five years were 50.5% (95%CI: 43.1%–57.4%) for gemcitabine-based chemotherapy versus 49.3% (95%CI: 41.6%–56.5%) for observation. ConclusionWith 419 patients included, this analysis did not show significant improvement in RFS and no trend in improvement in OS. Gemcitabine-based chemotherapy should not be used as an adjuvant treatment for BTC.

Systemic adjuvant therapy for high-risk cutaneous melanoma.

Cutaneous melanoma continues to increase in incidence and poses a significant mortality risk. Surgical excision of melanoma in its early stages is often curative. However, patients with resected stages IIB-IV are considered at high risk for relapse and death from melanoma where systemic adjuvant therapy is indicated. The long-studied high-dose interferon-α was shown to improve relapse-free survival (RFS) and overall survival (OS) but is no longer in use. Adjuvant therapy with ipilimumab at 10 mg/kg (ipi10) demonstrated significant RFS and OS improvements but at a high cost in terms of toxicity, while adjuvant ipilimumab 3 mg/kg was shown to be equally effective and less toxic. More recently, the adjuvant therapy for resected stages III-IV melanoma in clinical practice has changed in favor of nivolumab, pembrolizumab, and BRAF-MEK inhibitors dabrafenib plus trametinib (for BRAF mutant melanoma) based on significant improvements in RFS as compared to ipi10 (nivolumab and pembrolizumab) and placebo (dabrafenib plus trametinib). For resected stages IIB-IIC melanoma, pembrolizumab achieved regulatory approval in the United States based on significant RFS benefits. In this article, we review completed and ongoing phase III adjuvant therapy trials. We also briefly discuss neoadjuvant therapy for locoregionally advanced melanoma. Finally, we explore recent studies on predictive and prognostic melanoma biomarkers in the adjuvant setting.

Prognostic Value of Measurable Residual Disease Assessed By Multiparameter Flowcytometry in Patients with NPM1-Mutated Acute Myeloid Leukemia

Prognostic Value of Measurable Residual Disease Assessed By Multiparameter Flowcytometry in Patients with NPM1-Mutated Acute Myeloid Leukemia

Clinical Characteristics and Contemporary Outcomes of Acute Myeloid Leukemia Evolving from Chronic Myelomonocytic Leukemia

Clinical Characteristics and Contemporary Outcomes of Acute Myeloid Leukemia Evolving from Chronic Myelomonocytic Leukemia

Final analysis of overall survival (OS) and relapse-free-survival (RFS) in the intergroup S1404 phase III randomized trial comparing either high-dose interferon (HDI) or ipilimumab to pembrolizumab in patients with high-risk resected melanoma.

9501 Background: We assessed whether or not adjuvant pembrolizumab given over 1 year would improve OS and RFS in comparison to high dose ipilimumab (ipi10) or HDI - the two FDA-approved adjuvant treatments for high risk resected melanoma at the time of study design. Methods: Patients age 18 or greater with resected stages IIIA(N2), B, C and IV were eligible. Patients with CNS metastasis were excluded. At entry, patients must have had complete staging and adequate surgery to render them free of melanoma including completion lymph node dissection for those with sentinel node positive disease. Prior therapy with PD-1 blockade, ipilimumab or interferon was not allowed. Two treatment arms were assigned based on stratification by stage, PD-L1 status (positive vs. negative vs. unknown), and intended control arm (HDI vs. Ipi10). Patients enrolled between 10/2015 and 8/2017 were randomized 1:1 to either the control arm [(1) interferon alfa-2b 20 MU/m2 IV days 1-5, weeks 1-4, followed by 10 MU/m2/d SC days 1, 3, and 5, weeks 5-52 (n=190), or (2) ipilimumab 10 mg/kg IV q3w for 4 doses, then q12w for up to 3 years (n=465)], or the experimental arm [pembrolizumab 200 mg IV q3w for 52 weeks (n=648)]. The study had three primary comparisons: 1) RFS among all patients, 2) OS among all patients, 3) OS among patients with PD-L1+ baseline biopsies. Results: 1,426 patients were screened and 1,345 patients were randomized with 11%, 49%, 34%, and 6% AJCC7 stage IIIA(N2), IIIB, IIIC and IV, respectively. This final analysis was performed per-protocol 3.5 years from the date the last patient was randomized, with 512 RFS and 199 OS events. The pembrolizumab group had a statistically significant improvement in RFS compared to the control group (pooled HDI and ipi10) with HR 0.740 (99.618% CI, 0.571 to 0.958). There was no statistically signifcant improvement in OS in the 1,303 eligible randomized overall patient population with HR 0.837 (96.3% CI, 0.622 to 1.297), or among the 1,070 (82%) patients with PD-L1 positive baseline biopsies with HR 0.883 (97.8% CI, 0.604 to 1.291). Gr 3/4/5 event rates were as follows: HDI 69/9/0%, ipi10 43/5/0.5% and pembrolizumab 17/2/0.3%. Conclusions: Pembrolizumab improves RFS but not OS compared to HDI or ipi10 in the adjuvant treatment of patients with high-risk resected melanoma. Pembrolizumab is a better tolerated adjuvant treatment regimen than HDI or Ipi10. Support: NIH/NCI NCTN grants CA180888, CA180819, CA180820, CA180863; and in part by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Editorial Acknowledgement: With special thanks to Elad Sharon, MD, MPH, and Larissa Korde, MD, MPH. National Cancer Institute, Investigational Drug Branch, for their contributions to this trial, as well as Nageatte Ibrahim, MD, and Sama Ahsan, MD Merck. Clinical trial information: NCT02506153.

Randomised trial of external-beam radiotherapy alone or with high-dose-rate brachytherapy for prostate cancer: Mature 12-year results

Background and purposeA randomised phase-III trial compared external beam radiotherapy (EBRT) alone with EBRT combined with high-dose-rate brachytherapy boost (HDR-BTb) in localised prostate adenocarcinoma. Previous analysis, at median follow up of 85 months, demonstrated improved relapse free survival (RFS) with EBRT + HDR-BTb. This data has now been updated with a median follow up of 131 months. Materials and methodsFrom December 1997 to August 2005, patients were assigned either to EBRT alone delivering 55 Gy in 20 fractions over 4 weeks or EBRT followed by a temporary high-dose-rate implant delivering 2 × 8·5 Gy over 24 h. The primary endpoint was RFS defined by a PSA rise ≥2.0 µg/l above nadir, clinical progression or death. Actuarial survival rates and Hazard Ratios (HRs) were calculated using the Kaplan–Meier method and Cox’s Proportional Hazard Model, respectively. Secondary endpoints were overall survival (OS), urinary and bowel toxicity. ResultsOne hundred and six patients received EBRT alone and 110 EBRT + HDR-BTb. Median time to relapse was 137 months in the HDR-BTb arm compared to 82 months for EBRT alone (p = 0·01). A 27% risk of recurrence with EBRT alone was observed (p = 0·001), resulting in a 21% improvement in RFS at 12 years with EBRT + HDR-BTb. In multivariate analysis treatment arm, risk category and no androgen deprivation therapy were significant covariates for risk of relapse. Differences in overall survival were not significant. ConclusionAt 12 years there remains a significant improvement in RFS after EBRT + HDR-BTb; both treatments were equitoxic for severe late urinary and bowel events and urethral strictures.

Prognostic role of early interim [18F] fluoro-deoxy-glucose positron emission tomography in patients with advanced seminoma undergoing standard treatment.

5055 Background: In patients (pts) with advanced seminoma, efforts are underway to tailor a risk-adapted treatment strategy to the individual pt. Our main objective was to prospectively determine the prognostic value of [18F]fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT2) after two cycles of bleomycin, etoposide and cisplatin (BEP) or EP chemotherapy under standardized treatment and PET evaluation criteria. Methods: Pts with advanced-stage seminoma were treated with BEP or EP according to guidelines. PET/CT examinations were performed at baseline, after two cycles in all pts and after chemotherapy at physician’s choice. PET/CT response was qualitatively evaluated by two independent nuclear medicine physicians. Contrast-enhanced CT scans were also performed according to the guidelines (at baseline, after treatment, during follow-up). The primary endpoint was the relapse-free survival (RFS). Results: From 01/2009 to 01/2017, 75 consecutive pts were enrolled, of whom 70 were evaluable. The clinical stage was IIA-B and IIC-III in 40% and 60% of the pts, respectively. Eight pts (11.4%) received consolidation radiotherapy. By local assessment, 46 PET/CT2 scans (65.7%) were reported as negative, and 46% of these pts presented with stage IIC-III. The median follow-up was 79 months. Five-year RFS of PET/CT2-positive pts was 75% (95%CI: 60-95%) compared with 97.8% (95%CI: 93.7-100%) of PET/CT2-negative pts (p = .002). This significant improvement in RFS was maintained when analyzing only pts with clinical stage IIC-III (p = 0.04) and by excluding those who received consolidation RT (p = 0.02). An increasing linear association was found between the maximum diameter of retroperitoneal lymph nodes and the rate of PET/CT2+. In univariable Cox regression analyses, PET/CT2+ (HR: 12.9, 95%CI: 1.5-106.9, p = 0.02) and elevated HCG levels (HR: 6.3, 95%CI: 1.2-32.3, p = 0.03) were significantly associated with RFS, whereas IGCCCG risk group was not (p = 0.1). PET/CT2 result was also associated with the tumor shrinkage post-BEP (p = 0.009), whereas complete response at CT did not predict the RFS (p = 0.3). Conclusions: No residual FDG-uptake after 2 cycles of conventional chemotherapy is prognostic in advanced seminoma, may outperform the utility of standard prognostic risk groups and may be more accurate to predict the RFS compared to standard response criteria. Benchmark RFS estimates for the design of the next clinical trials of chemotherapy de-escalation are offered.

Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers

Randomized clinical trials of vitamin D supplementation for secondary prevention in patients with cancer are needed, given positive results of observational studies. To determine whether postoperative vitamin D3 supplementation can improve survival of patients with digestive tract cancers overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels. The AMATERASU trial, a randomized, double-blind, placebo-controlled trial conducted at a single university hospital in Japan. Enrollment began in January 2010 and follow-up was completed in February 2018. Patients aged 30 to 90 years with cancers of the digestive tract from the esophagus to the rectum, stages I to III, were recruited. Of 439 eligible patients, 15 declined and 7 were excluded after operation. Patients were randomized to receive oral supplemental capsules of vitamin D (2000 IU/d; n = 251) or placebo (n = 166) from the first postoperative outpatient visit to until the end of the trial. The primary outcome was relapse-free survival time to relapse or death. The secondary outcome was overall survival time to death due to any cause. Subgroups analyzed had baseline serum 25(OH)D levels of 0 to less than 20 ng/mL, 20 to 40 ng/mL, and greater than 40 ng/mL; because of small sample size for the highest-baseline-level group, interactions were tested only between the low- and middle-baseline-level groups. All 417 randomized patients (mean age, 66 years; male, 66%; esophageal cancer, 10%; gastric cancer, 42%; colorectal cancer, 48%) were included in the analyses. There was 99.8% follow-up over a median 3.5 (interquartile range, 2.3-5.3) years, with maximal follow-up of 7.6 years. Relapse or death occurred in 50 patients (20%) randomized to vitamin D and 43 patients (26%) randomized to placebo. Death occurred in 37 (15%) in the vitamin D group and 25 (15%) in the placebo group. The 5-year relapse-free survival was 77% with vitamin D vs 69% with placebo (hazard ratio [HR] for relapse or death, 0.76; 95% CI, 0.50-1.14; P = .18). The 5-year overall survival in the vitamin D vs placebo groups was 82% vs 81% (HR for death, 0.95; 95% CI, 0.57-1.57; P = .83). In the subgroup of patients with baseline serum 25(OH)D levels between 20 and 40 ng/mL, the 5-year relapse-free survival was 85% with vitamin D vs 71% with placebo (HR for relapse or death, 0.46; 95% CI, 0.24-0.86; P = .02; P = .04 for interaction). Fractures occurred in 3 patients (1.3%) in the vitamin D group and 5 (3.4%) in the placebo group. Urinary stones occurred in 2 patients (0.9%) in the vitamin D group and 0 in the placebo group. Among patients with digestive tract cancer, vitamin D supplementation, compared with placebo, did not result in significant improvement in relapse-free survival at 5 years. UMIN Identifier: UMIN000001977.

A systematic review and network meta-analysis of adjuvant therapy for curatively resected biliary tract cancers.

247 Background: Although recently completed randomized controlled trials (RCTs) have added high-quality data regarding adjuvant therapy in curatively resected biliary tract cancer (BTC), there is still no standard approach to manage these patients. We conducted a systematic review and network meta-analysis to compare the efficacy of adjuvant therapy regimens in curatively resected BTC to help guide clinical decision making and the design of future prospective trials. Methods: We conducted a systematic review of published studies and abstracts up to and including June 2018. Studies were included if they were phase III RCTs on patients with histologically proven BTC receiving adjuvant chemotherapy after a complete surgical resection (R0 or R1). BTCs included gallbladder cancer, intrahepatic and extrahepatic cholangiocarcinoma. The endpoints of interest were overall survival (OS) and relapse-free survival (RFS). Network meta-analysis methods were used for indirect comparison between adjuvant therapy regimens. Results: Five RCTs were included in the qualitative synthesis and three RCTs (BILCAP, PRODIGE 12-ACCORD 18 and BCAT) included sufficient data to be included in the meta-analysis. Results from the indirect comparison demonstrated no significant difference in OS between any of the adjuvant therapy regimens, however there was a trend that favoured adjuvant therapy with capecitabine over gemcitabine or gemcitabine plus oxaliplatin (GEMOX), with hazard ratios (HRs) of 0.82 (95% CI, 0.53-1.27) and 0.86 (95% CI, 0.56-1.34), respectively. Similarly there was no significant improvement in RFS with capecitabine compared to gemcitabine or GEMOX with HRs of 0.82 (95% CI, 0.53-1.27) and 0.86 (95% CI, 0.56-1.34), respectively. Conclusions: Although capecitabine is considered to be standard of care in the adjuvant setting based on a single randomized phase III study, in this indirect comparison, we did not find a statistically significant improvement in OS or RFS with capecitabine compared to GEMOX or gemcitabine. Further prospective trials comparing adjuvant therapies to capecitabine are warranted.

Benefit of adjuvant chemotherapy in patients with high-risk UICC II colon cancer T4N0M0: A ten-year population-based analysis of 3544 cases.

628 Background: The benefit of adjuvant chemotherapy in UICC stage III colon carcinoma has been demonstrated in numerous studies. For UICC stage II such an advantage was not shown. However, it remains controversial whether adjuvant chemotherapy might be considered in certain high-risk UICC stage II situations. High-risk factors include T4 tumors, associated with an increased risk of recurrence and poorer prognosis due to their more aggressive biological behavior. Methods: The present population-based, multicenter cohort study investigated the influence of adjuvant chemotherapy on survival and recurrence rates in UICC stage II in the high-risk situation T4N0M0. It is based on an anonymized nationwide ADT dataset and includes 208,030 patients diagnosed with colorectal cancer from 2002 to 2011. A total of 3544 patients with a T4 tumor were identified, of whom 34.3% (1215 patients) received adjuvant chemotherapy and 65.7% (2329 patients) none. Results: Median overall survival was markedly prolonged in subjects who received adjuvant chemotherapy from 4.5 years (SD 0.163, 95% CI 4.1-4.8) to 8.1 years (SD 0.474, 95% CI 7.2 -9.0; p < .001). After 5 years, 69.5% of chemotherapy patients were still alive compared to 45.1% of non-chemotherapy patients. After adjusting for factors in a multivariable Cox regression analysis, the significant benefit of adjuvant chemotherapy for overall survival was maintained (HR = 0.642, 95% CI 0.555-0.743, p < .001). The relative cumulative risk of recurrence in the multivariable analysis was HR = 0.696 (95% CI 0.580-0.843, p < .001) for chemotherapy patients. Furthermore, a highly significant improvement in relapse-free survival through chemotherapy was demonstrated (HR = 0.634, 95% CI 0.555-0.725, p < .001). Conclusions: In this representative study, a significant advantage of adjuvant chemotherapy for UICC stage II colon carcinoma patients with a T4 tumor was demonstrated in terms of overall survival, recurrence rate and relapse-free survival. On the basis of these results, adjuvant chemotherapy is recommended for the high-risk situation T4.

Addition of Cladribine: Improving Standard of Care in Newly Diagnosed Acute Myeloid Leukemia

Acute myeloid leukemia (AML) continues to be one of the most common myeloid malignancies in the United States. Achieving a complete response (CR) after induction with standard daunorubicin and cytarabine (7+3) remains suboptimal, occurring in 55-65% of patients. No significant advances have improved these outcomes in the last decade. A recent phase III randomized clinical trial by the Polish Adult Leukemia Group (PALG), showed that adding cladribine 5mg/m2 to standard 7+3 (Daunorubicin 60mg/m2, Ara-C 200mg/m2) improved CR rates to 68% vs 56% with standard 7+3 alone. Achieving a higher CR is important in the outcome of high-risk patients who require allogeneic stem cell transplantation (Allo-SCT) as a curative measure. At our center, we conducted a retrospective analysis evaluating the addition of cladribine to the current standard of care treatment in newly diagnosed AML. We hypothesized an improvement in CR rates in all-risk patients will allow more patients to proceed to Allo-SCT.Adult patients 18 years of age or older with newly diagnosed AML who received remission induction chemotherapy between May 2012 and May 2018 were included in the study. A total of 118 AML patients were screened and those who did not complete induction or did not have bone marrow biopsy at end of induction chemotherapy were excluded. A total of 100 patients were evaluable of which 26 (26%) received DAC and 74 (74%) received 7+3. Within the 7+3 group, 29 (39%) received a Daunorubicin dose of 60mg/m2 (D60) and 45 (61%) received a dose of 90mg/m2 (D90). A higher absolute CR rate was noted after one induction in the DAC group as compared to the combined 7+3 group (21 [80.7%] vs. 49 [66.2%], respectively). The improvement in CR between DAC and D60 reached statistical significance (p=0.043) but there was no statistically significance difference in CR rates between DAC vs D90 (p=0.48). It is interesting to note that more patients in D60 (39%) and D90 (26%) group required re-induction as compared with DAC (12%) (p=0.067). Median overall survival (OS) for the DAC group was not reached, while median OS for D60 was 10 (DAC vs D60 p=0.076) and for D90 was 28 months (DAC vs D90 p=0.97). In the subgroup of patients who underwent Allo-SCT, median OS in the D90 group was 30 months (DAC vs D90 p=0.43) while not reached in the DAC and D60 group (DAC vs D60 p=0.84). For all patients, the median relapse-free survival (RFS) for the DAC cohort was not reached. Median RFS was 12 months for D60 (DAC vs D60 p=0.047) and 25 months for D90 (DAC vs D90 p=0.166) groups. There was no difference in OS and RFS between all three groups who were transplanted in first CR (CR1).In conclusion CR rates following induction chemotherapy were higher in DAC vs Daunorubicin groups, however only statistically significant with respect to D60. Additionally a statistically significant improvement in RFS and a trend towards improved OS was noted in favour of DAC vs D60. Regardless of the induction chemotherapy, there was no difference in OS and RFS of patients who were transplanted in CR1. These results have encouraged us to perform a prospective comparison of standard 7+3 with Dauno 90mg/m2 and DAC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Advances in Immunotherapy of Malignant Melanoma

Development of immunotherapy has dramatically changed poor prognosis of metastatic malignant melanoma (MM). Inhibition of immune checkpoints represents a new effective treatment. Monoclonal antibodies against CTLA-4 ipilimumab and against PD-1 (programme death 1) nivolumab and pembrolizumab prolong progression free survival and overall survival (OS) in patients with advanced metastatic MM. Both achieved significant improvement in relapse-free survival and OS also in adjuvant setting. It looks like the efficacy of the combined immunotherapy of ipilimumab with anti-PD-1 antibodies is superior to the monotherapy, but combined therapy is accompanied by higher toxicity. Management of adverse events of ipilimumab plus nivolumab combination were solved in several clinical trials. New combinations such as immunotherapy with intralesional oncolytic vaccination are explored. In this review, some results of clinical trials presented at ASCO (American Society of Clinical Oncology) 2017 are mentioned. Interesting data were obtained from the evaluation of long-term efficacy of immunotherapy in patients who had to stop the treatment for adverse events. Other trial (CheckMate 172) evaluated the safety and efficiency of nivolumab in MM patients who failed on or after therapy with ipilimumab. Considerable attention has been paid to the efficacy of immunotherapy in the treatment of brain metastases.Key words: malignant melanoma - immunotherapy - ipilimumab - nivolumab - pembrolizumab - talimogene laherparepvec - brain metastases The author declares she no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 31. 8. 2017Accepted: 24. 10. 2017.

Feasibility of Allogeneic Hematopoietic Cell Transplantation Among High-Risk AML Patients in First Complete Remission: Results of the Transplant Objective from the SWOG (S1203) Randomized Phase III Study of Induction Therapy Using Standard 7+3 Therapy or Idarubicin with High-Dose Cytarabine (IA) Versus IA Plus Vorinostat

Background: Adult acute myeloid leukemia (AML) patients with high-risk cytogenetics have a significantly worse survival compared to similarly treated intermediate- or favorable-risk patients. Although prior studies suggest better outcome in high-risk AML patients in first complete remission (CR1) who undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy, only 40% of patients proceed to HCT. The lack of a matched sibling donor (available in about 33%) should not be a barrier to HCT since alternative donors are available for the large majority of high-risk AMLpatients and recent data suggest outcomes after allogeneic HCT from fully matched unrelated donors are similar to those following matched related donor transplantation. We sought to determine if a prospective organized effort could rapidly identify alternative donors to improve the historical 40% allogeneic HCT rate in high-risk CR1 AML patients ≤ age 61. Secondly, we hypothesized that transplanting significantly more adults with high-risk AML in CR1 would lead to an improved outcome compared with the historical relapse-free survival (RFS) of 22%. Patients and Methods: Adult patients between ages 18 and 60 years with untreated AML were randomized to receive induction therapy with standard cytarabine plus daunorubicin (7+3; n=261), idarubicin with high-dose cytarabine (IA; n=261), or IA with vorinostat (IA+V; n=216). Conventional cytogenetics were obtained at time of enrollment and used to determine risk classification by standard criteria. All patients with high-risk cytogenetics underwent expedited HLA-typing. High-risk patientswere encouraged tobe referred for consultation with a transplant team with the goal of conducting an allogeneic HCT in CR1. Results: Of 738 eligible patients (median age, 49 years; range, 18-60), 159 (22%) had high-risk cytogenetics, of whom 60 (38%), 61 (38%), and 38 (24%) received induction with 7+3, IA, or IA+V, respectively. A total of 107 of the 159 high-risk patients achieved CR/CRi (67%). HCT was performed in 317 of all 738 patients (43%) and 68 (64%) of the high-risk patients received a transplant in CR1 (p Conclusions: In newly diagnosed adults with AML age 18-60, early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donorled to a CR1 transplant rate of 64% in the high-risk group, which in turn led to a significant improvement in RFS over historical controls. Better outcomes in poor prognosis AML patients may be achieved simply by rapidly finding unrelated donors and performing allogeneic HCT in CR1 as soon as possible. Clinical Trials Registry: NCT #0180233; Support: NIH/NCI grants: CA180888, CA180819, CA18020, CA180821, CA180863, CA077202; CCSRI #021039 Disclosures Othus:Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Other: laboratory contract; ARIAD: Consultancy; Pfizer: Consultancy; TwinStrand: Consultancy; Bristol-MyersSquibb: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:AbbVie: Consultancy; Lundbeck: Consultancy; BMS: Consultancy, Honoraria; Velgene: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Jazz: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees. Stone:Amgen: Consultancy; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Agios: Consultancy; Novartis: Consultancy; Celator: Consultancy; Karyopharm: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Research Funding.

A Randomized Phase II Trial of Short-Course Androgen Deprivation Therapy With or Without Bevacizumab for Patients With Recurrent Prostate Cancer After Definitive Local Therapy

Patients with recurrent prostate cancer after local treatment make up a heterogeneous population for whom androgen deprivation therapy (ADT) is the usual treatment. The purpose of this randomized phase II trial was to investigate the efficacy and toxicity of short-course ADT with or without bevacizumab in men with hormone-sensitive prostate cancer. Eligible patients had an increasing prostate-specific antigen (PSA) of ≤ 50 ng/mL and PSA doubling time of less than 18 months. Patients had either no metastases or low burden, asymptomatic metastases (lymph nodes < 3 cm and five or fewer bone metastases). Patients were randomly assigned 2:1 to a luteinizing hormone-releasing hormone agonist, bicalutamide and bevacizumab or ADT alone, for 6 months. The primary end point was PSA relapse-free survival (RFS). Relapse was defined as a PSA of more than 0.2 ng/mL for prostatectomy patients or PSA of more than 2.0 ng/mL for primary radiation therapy patients. Sixty-six patients received ADT + bevacizumab and 36 received ADT alone. Patients receiving ADT + bevacizumab had a statistically significant improvement in RFS compared with patients treated with ADT alone (13.3 months for ADT + bevacizumab v 10.2 months for ADT alone; hazard ratio, 0.47; 95% CI, 0.29 to 0.77; log-rank P = .002). Hypertension was the most common adverse event in patients receiving ADT + bevacizumab (36%). ADT combined with bevacizumab resulted in an improved RFS for patients with hormone-sensitive prostate cancer. Long-term follow-up is needed to determine whether some patients have a durable PSA response and are able to remain off ADT for prolonged periods. Our data provide rationale for combining vascular endothelial growth factor-targeting therapy with ADT in hormone-sensitive prostate cancer.

Multi-Center US Intergroup Study of Intensive Chemotherapy Plus Dasatinib Followed By Allogeneic Stem Cell Transplant in Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Younger Than 60

▪Background- Introduction of tyrosine kinase inhibitors in the treatment of patients with Philadelphia (Ph) chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) has led to a significant improvement in the long term outcome of patients, in particular those who are unsuitable to undergo allogeneic stem cell transplant (alloSCT) in first complete remission (CR1).Design- This multicenter, phase II, clinical trial was conducted in 37 centers across the US to determine whether the addition of dasatinib to chemotherapy followed by an alloSCT in the eligible patients would lead to a significant improvement in relapse-free survival. The study also examined the duration of CR in patients unable to receive an alloSCT and the potential value of detection of minimal residual disease (MRD) using quantitative PCR for BCR-ABL fusion transcripts at defined intervals. Patients ≥ 18 and ≤ 60 years of age with newly diagnosed Ph+ ALL with an ECOG performance status of 0-2 and adequate organ function were enrolled to receive 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate chemotherapy in addition to dasatinib 100 mg daily for the first 14 days of each cycle. Later the protocol was amended and patients received dasatinib 70 mg daily continuously from cycle 2 onwards. Central nervous system prophylaxis was in the form of alternating doses of cytarabine and methotrexate administered intrathecally twice per cycle for 8 doses. Patients who had received one cycle of induction therapy before the Ph abnormality was identified were allowed to participate in the study. All patients with an available matched sibling or unrelated donor were encouraged to undergo an alloSCT in CR1. Others received maintenance therapy with continuous dasatinib 100 mg daily as well as monthly vincristine and prednisone for 2 years and followed by dasatinib indefinitely. Patients receiving alloSCT would receive dasatinib 100 mg daily starting from day 100 for up to 5 years, with dose adjustments as necessary.Results- The study has accrued 97 patients, 94 of whom were eligible and evaluable. Their median age is 44 years (range, 20-60 years) and median WBC at presentation 10 x 109/L (range, 1 - 410 x 109/L). Among 93 patients with available data, 82 (88%) achieved CR or CR with incomplete count recovery (CRi). 34 patients were enrolled having received prior therapy, 16 in CR/CRi, 7 with unknown response status (5 achieved CR on the study), and 11 with refractory disease after 1 course of prior therapy (9 achieved CR on the study). Among the 60 untreated patients, 51 achieved CR, 2 achieved CRi, 2 had unconfirmed CR, 2 died early, 2 were refractory and 1 had missing data. 41 patients underwent study-related alloSCT in CR1 including 35 with TBI-based regimens and 4 with busulfan-based regimens; 2 had missing data. 8 patients had non-prescribed alloSCT off study. Median follow-up among all patients known to be alive is 26 months (range 9 - 57 months). For the overall population, overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) at 12 months were 88%, 74%, and 85%, respectively (Figure 1). The 12-month RFS and OS after transplant were 71% and 87%, respectively. Landmark analysis at 131 days from the time of CR/CRi (time to alloSCT in 75% of transplanted patients), showed a statistically superior advantage for RFS (p=0.03) but no difference in survival (p=0.07) for the transplanted patients (Figures 2a and 2b, respectively). MRD status at CR1 is available in 19 patients, 13 were positive (MRD+) and 6 were negative (MRD-). There is no difference in RFS by the MRD status at CR (p=0.52).Conclusion- The addition of dasatinib to the treatment in younger patients with Ph+ ALL significantly improves the 12-month RFS for those who undergo alloSCT in CR1 and is associated with an improved OS compared to historical data prior to the introduction of TKIs.Acknowledgments: Dr. Meir Wetzler is posthumously recognized for his important contributions to this study. Support from NIH/NCI/NCTN grants CA180888, CA180819, CA180821, CA180820; and in part by Bristol-Myers Squibb Company. Dasatinib was distributed by the NCI/DCTD/CTEP. [Display omitted] [Display omitted] DisclosuresUy:Novartis: Research Funding. Borate:Genoptix: Consultancy; Gilead: Speakers Bureau; Seattle Genetics: Research Funding; Novartis: Speakers Bureau; Alexion: Speakers Bureau; Amgen: Speakers Bureau. Erba:Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celator: Research Funding; Astellas: Research Funding; Celator: Research Funding; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy; Sunesis: Consultancy; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Millennium/Takeda: Research Funding; Millennium/Takeda: Research Funding; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Astellas: Research Funding; Daiichi Sankyo: Consultancy; Ariad: Consultancy; Sunesis: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees ; Pfizer: Consultancy; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Daiichi Sankyo: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees.

Early Allogeneic Stem Cell Transplantation and Use of Asparaginase during Induction Chemotherapy Appear to Improve Otherwise Poor Outcomes in Adult T-Cell Acute Lymphoblastic Leukemia/Lymphoma (T-ALL/T-LBL) Patients: A Multi-Institutional Review

Background: AdultT-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) is a rare, aggressive bone marrow malignancy with a historically poor prognosis despite use of various chemotherapies.Methods: After institutional review board approval, we compiled a database of all adult T-ALL/T-LBL cases at three large cancer centers between the years 2005-2015, treated at the physician's discretion. Data collected included patient demographics, tumor characteristics (white cell count at diagnosis, blast phenotype, FISH, cytogenetics, bone marrow involvement), treatment regimens and patient outcomes. Relapse-free survival (RFS) and overall survival (OS) were examined looking at medians and interquartile ranges of times to events. Kaplan Meier curves provided a graphical representation of the survival probability. Moreover, we provided estimates of the 50th percentile along with corresponding 95% confidence intervals (CIs). We also used Univariate and Multivariable Cox Regression to estimate unadjusted and adjusted Hazard Ratios (HRs) and their 95% CIs. Stratified analysis was also performed using the Mann-Whitney U-test to compare median survival times, and the Log-rank to compare survival curses for RFS and OS.Results: The final analysis included 95 adult patients. Median age at diagnosis was 32 (range 17-75). 71.6% of patients were male. 49.5% of patients were white, 14.7% were black, 6.3% were Hispanic, 7.4% were Asian and in 22.1% of patients the race was unknown. Multiple frontline treatment regimens were used with 60% of patients treated with Hyper-CVAD, an additional 5.3% of patients received Hyper-CVAD with asparaginase, 24.2% of patients were treated on a pediatric-based protocol, 4.2% on a clinical trial, and 6.3% received other regimens. In total, 40 patients (42.1%) received asparaginase at some point during treatment regimen with 27 patients (28.4%) receiving it in the initial treatment regimen. After induction therapy, 65 patients (68.4%) achieved remission. Twenty-eight patients (29.5%) underwent transplant (8 matched-related donors, 10 matched unrelated donors, 5 mismatched unrelated donor, 2 cord transplants, 2 autologous, and 1 haplo-identical transplant). Ten patients (10.5%) underwent transplant in first complete remission (CR1) while two patients (2.1%) proceeded to transplant with minimal residual disease following induction. Despite therapy, 59 patients (62.1%) had known disease relapse or progressive disease. 16 patients (16.8%) underwent transplant after disease relapse. At time of analysis, 57 patients (60.6%) died. In the entire cohort, median RFS was 12.9 months and median OS was 19 months. In patients with a very high white count (>100 x 103/cmm at presentation) there was a trend toward earlier relapse when compared to patients presenting with white counts in the normal range (HR 2.27, p-value 0.085). Patients who received asparaginase in their initial treatment regimen have statistically improved RFS (HR 2.65, p-value = 0.014) and OS (HR 2.3, p-value=0.017). When adjusting for the presence of the covariates of age, sex, and WBC, patients who received initial asparaginase still had significant improvement in RFS (HR 3.18, p-value 0.033). In overall survival, significant benefit was seen in the addition of asparaginase in patients under 40 (HR 3.4, CI 1.22-9.5), however in patients greater than 40, asparaginase use seemed to decrease survival (HR 0.24, CI 0.03-1), although this did not reach statistical significance. All patients who underwent transplant had an improvement in OS, with median survival in the transplant group of 27 months compared to 18.2 months in the non-transplanted patients (log-rank test p-value = 0.048). Patients who received a transplant in CR1 had a trend towards improvement in RFS of 6.3 months (17.8 months versus 11.5 months in non-transplanted patients; log-rank test p-value = 0.03).Conclusion: Overall, adult T-ALL/T-LBL has a poor prognosis. Our multi-institutional retrospective review showed that OS and RFS may be improved by incorporating asparaginase use in front line therapy and by transplanting patients in first CR. Our data is limited in that actual dosing of asparaginase was not examined and that relatively few patients > 40 yrs old received asparaginase (4 pts) or SCT (5 pts). More prospective studies are needed in older adult T-ALL/LBL patients using these approaches to possibly improve their outcomes. DisclosuresBorate:Gilead: Speakers Bureau; Genoptix: Consultancy; Seattle Genetics: Research Funding; Novartis: Speakers Bureau; Amgen: Speakers Bureau; Alexion: Speakers Bureau. Hathaway:OnQ Health: Research Funding. Kota:Pfizer: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding. Shah:DeBartolo Institute for Personlaized Medicine: Research Funding; Rosetta Genomics: Research Funding; Acetylon Pharmaceuticals, INC: Membership on an entity's Board of Directors or advisory committees; Plexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Spectrum: Speakers Bureau; Bayer: Honoraria; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Research Funding; SWOG: Consultancy; NCCN: Consultancy. Jillella:Leukemia Lymphoma Society: Research Funding. Heffner:Amgen: Consultancy. Erba:Novartis; Incyte; Celgene: Consultancy, Patents & Royalties; GlycoMimetics; Janssen: Other: Data Safety & Monitoring Committees; Seattle Genetics; Amgen: Consultancy, Research Funding; Millennium/Takeda; Celator; Astellas: Research Funding; Sunesis;Pfizer; Daiichi Sankyo; Ariad: Consultancy.