Unfavorable-risk Patients Research Articles

Comparison of Standard vs. Relative Risk Models to Define Candidates for Deintensification in Locoregionally Advanced P16+ Oropharyngeal Cancer

Various methods to identify candidates for treatment deintensification with p16+ oropharyngeal squamous cell carcinoma (OPSCC) have been used, but the optimal approach is unknown. Multi-institutional cohort study of 385 patients with previously untreated p16+ OPSCC undergoing definitive radiotherapy (RT) with or without systemic therapy between 2009-2020. Chemotherapy intensity was categorized as high (bolus cisplatin and/or induction chemotherapy), medium (weekly cisplatin), or low (non-cisplatin or RT alone). Standard favorable vs. unfavorable risk was defined using NRG HN005 eligibility criteria. High vs. low relative risk (RR) group was defined using the HNCIG omega score (≥ 0.80 vs. < 0.80), which quantifies the proportion of a patient's overall event risk due to cancer. We used multivariable ordinal logistic regression to estimate effects of age (yrs), sex, performance status (PS), Charlson comorbidity index (CCI), T/N (AJCC 8th), current smoking, and pack-years (> 10 vs. ≤ 10) on treatment allocation. Effects on relative event hazards were estimated using generalized competing event regression. Median follow-up time was 44.2 months. Chemotherapy intensity was high in 206 (54%), medium in 108 (28%), and low in 71 (18%). 280 patients (73%) were unfavorable risk and 197 (51%) were high RR. 178 patients (46%) had discordant risk classification. On univariable analysis, significant predictors of higher intensity chemotherapy (normalized odds ratio (OR)) were CCI 0-1 (OR 1.49, 95% CI: 1.23-1.79), high omega score (OR 1.46; 1.20-1.77), decreased age (OR 1.43; 1.18-1.74), and PS 0 (OR 1.22; 1.01-1.48). Controlling for CCI, higher omega score was associated with significantly higher odds of intensive chemotherapy (OR 1.35; 1.10-1.65, but unfavorable risk (HN005 ineligibility) was not (OR 1.19; 0.98-1.44). Higher omega score was also associated with significantly higher RR for cancer recurrence (Rec) vs. competing mortality (CM) events (relative HR (rHR) 1.76; 1.12-2.75), but unfavorable risk was not (rHR 1.05; 0.63-1.75). Among patients receiving cisplatin, 50 favorable risk patients (58%) had high RR; all of their event risk was due to cancer recurrence (Table). The 110 unfavorable risk patients (48%) with low omega score had significantly lower RR for cancer events compared to the high omega score group (rHR 0.49; 0.29-0.84). Many patients with favorable risk p16+ OPSCC have high relative risk for cancer events, which correlates with a benefit of intensive treatment. The HNCIG omega score is a strong predictor of allocation to intensive chemotherapy and may help identify candidates for deintensification.

Prognostic Factors for Survival in Patients Undergoing Surveillance After Cytoreductive Nephrectomy.

The clinical course of patients being placed on surveillance in a cohort of systemic therapy-naïve patients who undergo cytoreductive nephrectomy is not well documented. Thus, we evaluated the clinical course of patients placed on surveillance following cytoreductive nephrectomy and identified predictors of survival. In this large single-institution study, we retrospectively analyzed metastatic renal cell carcinoma patients who underwent cytoreductive nephrectomy followed by surveillance. Predictors of survival were evaluated using the Kaplan-Meier method with a log-rank test. Patients were risk stratified based on IMDC (International mRCC Database Consortium) and number of metastatic sites (Rini score), with IMDC score ≤1 and ≤2 metastatic organ sites considered favorable risk. Primary end point was systemic therapy-free survival. Secondary end points included intervention-free survival, cancer-specific survival, and overall survival. Median systemic therapy-free survival was 23.6 months (95% CI: 15.1-40.6), intervention-free survival was 11.8 months (95% CI: 8.0-18.4), cancer-specific survival was 54.2 months (95% CI: 46.2-71.4), and overall survival 52.4 months (95% CI: 40.3-66.8). Favorable-risk patients compared to unfavorable-risk patients had longer systemic therapy-free survival (50.6 vs 11.1 months, P < .01), survival (25.2 vs 7.3, P < .01), and cancer-specific survival (71.4 vs 46.2 months, P = .02). Using risk stratification based on IMDC and number of metastatic sites, surveillance in favorable-risk patients can be utilized for a period without the initiation of systemic therapy. This approach can delay patients' exposure to the side effects of systemic therapy.

Molecular pathological insights reveal a high number of unfavorable risk patients among children treated for medulloblastoma and CNS‐PNET in Oslo 2005–2017

An unexplained regional difference in survival was observed in previous publications on outcome for children treated for medulloblastoma and supratentorial primitive neuroectodermal tumor (CNS-PNET) in Norway. We aimed now to reevaluate and perform a retrospective molecular-based risk stratification of all embryonal brain tumors (excluding atypical teratoid rhabdoid tumors [ATRT]) in pediatric patients, who underwent surgery and treatment at Oslo University Hospital between 2005 and 2017. Specimens from all patients<20 years of age with initial diagnosis of medulloblastoma or CNS-PNET were reviewed. Molecular analyses comprised NanoString gene expression, molecular inversion probe profiling, Sanger sequencing, and 850K-methylation analysis. Whole chromosomal aberration signatures were assessed in standard-risk non-WNT/non-SHH medullobastomas for molecular risk stratification. We identified 53 non-ATRT embryonal tumors among which 33 were medulloblastomas. Molecular genetic parameters including whole chromosomal aberration signatures allowed classification of 17 medulloblastomas as molecular high risk. These patients had a significantly worse 5-year overall survival than the remaining 16 medulloblastoma patients (52.9%vs. 87.1% p=0.036). Five patients in our cohort had tumors that are considered as new entities in the 2021 classification of tumors of the central nervous system. Five tumors were re-classified as nonembryonal tumors after review. Molecular-based risk stratification of standard-risk non-WNT/non-SHH medulloblastoma enabled superior identification of medulloblastomas with dismal prognosis. Our cohort demonstrated a significantly increased fraction of standard-risk non-WNT/non-SHH medulloblastoma with molecular high-risk profile compared to other studies, which might have contributed to previously reported unfavorable outcome data.

Prostate-specific antigen nadir and testosterone level at prostate-specific antigen failure following radiation and androgen suppression therapy for unfavorable-risk prostate cancer and the risk of all-cause and prostate cancer-specific mortality.

Although both PSA nadir (PSAn) and testosterone levels at PSA failure are known prognostic factors in men undergoing radiation therapy (RT) and androgen deprivation therapy (ADT) for unfavorable-risk prostate cancer (PC), it is unclear whether their prognostic significance is independent or overlapping. Seventy-five men treated with RT with or without 6months of ADT for unfavorable-risk nonmetastatic PC enrolled in 2 prospective clinical trials between 1986 and 2001 formed the study cohort. Competing risks and Cox multivariable regression were used to assess whether low versus normal serum testosterone at the time of PSA failure and higher PSAn after initial therapy were independently associated with the risk of PC-specific (PCSM) and all-cause mortality (ACM) adjusting for PC prognostic factors. After a median follow-up of 15.34years (interquartile range, 6.66-16.88years), there were 53 deaths (73.3%): 30 (56.6%) were from PC. Low testosterone at PSA failure was significantly associated with an increased risk of PCSM (adjusted HR [AHR], 7.77; 95% CI, 1.14-52.99; P=.04) and ACM (AHR, 3.01; 95% CI, 1.01-8.96; P=.05), as was higher PSAn (PCSM AHR, 1.03; 95% CI, 1.01-1.05; P<.01; ACM AHR, 1.04; 95% CI, 1.02-1.07; P<.01), although the prognostic significance of PSAn was only noted in men with a normal testosterone at PSA failure. Low testosterone level at PSA failure in high-risk patients with PC treated with RT is associated with increased PCSM and ACM risk. In men with normal testosterone levels at the time of PSA failure, an elevated PSAn was associated with worse PCSM and ACM risk. This study investigates whether the prostate-specific antigen (PSA) nadir and normal versus low testosterone at the time of PSA failure provide mutually exclusive or overlapping prognostic information following treatment with radiation and androgen deprivation therapy for unfavorable-risk patients with prostate cancer using data from 2 prospective clinical trials. It was found that both provided prognostic information; however, higher PSA nadir was only found to be of prognostic significance in men with normal testosterone levels at PSA failure.

Low-/high-dose-rate brachytherapy boost in patients with intermediate-risk prostate cancer treated with radiotherapy: long-term results from a single institution team experience.

PurposeTo compare brachytherapy (BT) boost of low-dose-rate (LDR) and high-dose-rate (HDR) techniques in patients diagnosed with intermediate-risk prostate cancer.Material and methodsBetween January 2005 and February 2018, 142 patients (50 LDR and 92 HDR) with intermediate-risk prostate cancer were treated with a BT boost, and retrospectively analyzed. Prescribed dose was 45 Gy with external beam radiotherapy (EBRT) plus 100-108 Gy with LDR-BT, and 60 Gy with EBRT plus one fraction of 10 Gy with HDR-BT. 99% of patients received androgen deprivation therapy (ADT) for 6 months. Primary endpoint was to compare LDR and HDR boosts in terms of biochemical progression-free survival (bPFS). Secondary endpoint, after re-classifying patients into “favorable” and “unfavorable” sub-groups, was to analyze differences with a similar treatment intensity.ResultsMedian overall follow-up for the total cohort was 66.5 months (range, 16-185 months). There were no significant differences in bPFS, overall survival, cause specific survival, local failure, lymph node failure, or distant failure when LDR or HDR was employed. bPFS at 90 months was 100% for favorable, and 89% and 85% for unfavorable patients at 60 months and 90 months, respectively (log-rank test, p = 0.017). The crude incidence of genitourinary acute and chronic toxicity grade 3 was 0.7% and 4%, respectively. Twelve patients (8%) had chronic rectal hemorrhage grade 2, in whom argon was applied (4 LDR and 8 HDR).ConclusionsCombined treatment is an excellent therapeutic option in patients with intermediate-risk prostate carcinoma, with similar results in both LDR and HDR approaches and very low toxicities. Importantly, the current literature has indicated that unfavorable-risk patients belong to a different category, and should be treated as patients with high-risk factors. Therefore, the stratification and identification of both risk groups is extremely relevant.

Evaluating Acute Myeloid Leukemia Induction Regimens in Elderly Patients with Unfavorable Risk Cytogenetics That Are Candidates for Intensive Remission Therapy

Background/purpose: Standard acute myeloid leukemia (AML) induction regimens have reduced response in elderly patients. As an alternative, hypomethylating agents have better tolerability, but poorer response rates. Venetoclax, an oral anti-apoptotic protein BCL-2 inhibitor, was approved in combination for the treatment of newly-diagnosed AML adults 75 years or older and is supported by NCCN guidelines in combination with hypomethylating agents or low dose cytarabine for special patient populations. This study evaluated the outcomes of AML induction regimens in unfavorable risk patients 60 years old or older that were candidates for intensive remission induction therapy. Methodology: This was an IRB-approved retrospective chart review of AML patients with unfavorable risk cytogenetics aged 60 or older admitted to the Baptist Hospital of Miami Oncology Unit between February 1st, 2018 and August 1st, 2019, an 18-month period. Patients were included if they received one of the following AML induction regimens: daunorubicin + cytarabine (7+3), liposomal daunorubicin/cytarabine (CPX-351), venetoclax + decitabine (VEN +DEC), venetoclax + azacitidine (VEN+ AZA), or venetoclax + low dose cytarabine (VEN + LoDAC). For the purpose of the study, the 7+3 and CPX-351 regimens were classified as high intensity, while the VEN+ DEC, VEN+AZA, and VEN+LoDAC regimens were classified as low intensity. The primary outcome assessed was the rate of complete morphologic remission (CR) and complete morphologic remission with incomplete count recovery (CRi). Additional secondary outcomes included rate of induction failure, relapse free survival (RFS), time to complete remission, transplant status and eligibility, length of stay (LOS), and incidence of any-grade treatment-related toxicities. Results: A total of 20 patients were identified. Of the 20 patients, 9 (45%) received induction with 7+3, 3 (15%) received CPX-351, 5 (20%) received VEN+DEC, and 3 (15%) received VEN +AZA, thus 12 (60%) received high intensity regimens, while 8 (40%) received low intensity. The primary outcome of CR/CRi rate was 75% in the high intensity group vs. 63% in the low intensity group (P=0.0922). Furthermore, the rate of induction failure, median time to CR/CRi, median LOS, and transplant eligibility were similar between the high and low intensity groups. The median RFS was 272 days in the high intensity groups vs. 223 days in the low intensity groups (P=0.1496). The median duration of neutropenia was 30 days in the high intensity group vs. 34 days in the low intensity group while the median duration of thrombocytopenia was 31 days in the high intensity groups vs. 32 days in the low intensity group. Finally, the rate of grade 3 and 4 toxicities was 100% in the high intensity group vs. 88% in the low intensity group (P=0.0003), with higher incidences of grade 3 febrile neutropenia, grade 4 thrombocytopenia, and grade 1 and 2 liver enzyme elevations noted in the high intensity group. Conclusion: There were no statistically significant differences between the CR/CRi rates and median RFS of the high and low intensity groups, while there were significantly less grade 3 and 4 toxicities noted in the low intensity group. Venetoclax-based regimens are an acceptable alternative to intensive induction therapy in unfavorable risk patients over the age of 60 due to similar outcomes and less toxicity. Disclosures No relevant conflicts of interest to declare.

Clinical Outcomes of Postoperative Radiotherapy Following Radical Prostatectomy in Patients with Localized Prostate Cancer: A Multicenter Retrospective Study (KROG 18-01) of a Korean Population.

PurposeThe purpose of this study was to investigate the clinical outcomes of postoperative radiotherapy (PORT) patients who underwent radical prostatectomy for localized prostate cancer.Materials and MethodsLocalized prostate cancer patients who received PORT after radical prostatectomy between 2001 and 2012 were identified retrospectively in a multi-institutional database. In total, 1,117 patients in 19 institutions were included. Biochemical failure after PORT was defined as prostate-specific antigen (PSA) ≥ nadir+2 after PORT or initiation of androgen deprivation therapy (ADT) for increasing PSA regardless of its value.ResultsTen-year biochemical failure-free survival, clinical failure-free survival, distant metastasis-free survival, overall survival (OS), and cause-specific survival were 60.5%, 76.2%, 84.4%, 91.1%, and 96.6%, respectively, at a median of 84 months after PORT. Pre-PORT PSA ≤ 0.5 ng/ml and Gleason’s score ≤ 7 predicted favorable clinical outcomes, with 10-year OS rates of 92.5% and 94.1%, respectively. The 10-year OS rate was 82.7% for patients with a PSA > 1.0 ng/mL and 86.0% for patients with a Gleason score of 8-10. The addition of long-term ADT (≥ 12 months) to PORT improved OS, particularly in those with a Gleason score of 8-10 or ≥ T3b.ConclusionClinical outcomes of PORT in a Korean prostate cancer population were very similar to those in Western countries. Lower Gleason score and serum PSA level at the time of PORT were significantly associated with favorable outcomes. Addition of long-term ADT (≥ 12 months) to PORT should be considered, particularly in unfavorable risk patients with Gleason scores of 8-10 or ≥ T3b.

Risk-based treatment for patients with first relapse or progression of rhabdomyosarcoma: A report from the Children's Oncology Group.

The purpose of this study was to evaluate risk and response-based multi-agent therapy for patients with rhabdomyosarcoma (RMS) at first relapse. Patients with RMS and measurable disease at first relapse with unfavorable-risk (UR) features were randomized to a 6-week phase 2 window with 1 of 2 treatment schedules of irinotecan with vincristine (VI) (previously reported). Those with at least a partial response to VI continued to receive 44weeks of multi-agent chemotherapy including the assigned VI regimen. UR patients who did not have measurable disease at study entry, did not have a radiographic response after the VI window, or declined VI window therapy received 31weeks of multi-agent chemotherapy including tirapazamine (TPZ) at weeks 1, 4, 10, 19, and 28. Favorable-risk (FR) patients received 31weeks of the same multi-agent chemotherapy without VI and TPZ. One hundred thirty-six eligible patients were enrolled. For 61 patients not responding to VI, the 3-year failure-free survival (FFS) and overall survival (OS) rates were 17% (95% confidence interval [CI], 8%-29%) and 24% (13%-37%), respectively. For 30 UR patients not treated with VI, the 3-year FFS and OS rates were 21% (8%-37%) and 39% (20%-57%), respectively. FR patients had 3-year FFS and OS rates of 79% (47%-93%) and 84% (50%-96%), respectively. There were no unexpected toxicities. Patients with UR RMS at first relapse or disease progression have a poor prognosis when they are treated with this multi-agent therapy, whereas FR patients have a higher chance of being cured with second-line therapy.

Impact of unfavorable factors on outcomes among inoperable stage II-IV Nonsmall cell lung cancer patients treated with proton therapy

Purpose: To investigate the impact of unfavorable risk factors among patients with locally advanced nonsmall cell lung cancer (LA-NSCLC) treated with proton therapy (PT).Material and Methods: From May 2008 through July 2015, 90 consecutive patients with unresectable stage II-IV (oligometastatic) NSCLC were treated with PT. Unfavorable factors including age ≥80 years, stage IV, weight loss >10% in 3 months, performance status (PS) ≥2, FEV1 < 1.0 or O2 dependency, prior lung cancer, prior lung surgery, prior 2nd cancer in the past 3 years, and prior chest irradiation were evaluated. All patients received standard fractionation of 1.8–2 Gy(RBE) (median dose, 70 Gy[RBE]). Overall survival (OS) and progression-free survival (PFS) were calculated with the Kaplan-Meier method. The impact of unfavorable factors was analyzed in Cox regression models.Results: Twenty-six percent were favorable-risk, while 42%, 22%, and 10% had 1-, 2-, or ≥3 unfavorable factors. The 2-year OS was 52% and 45% (p = .8522), and 2-year PFS was 21% and 44% (p = .0207), for favorable and unfavorable risk patients, respectively. Among patients with stage III-IV, only PS ≥2 adversely impacted OS (p = .0015).Conclusion: Most patients treated with PT for LA-NSCLC have unfavorable risk factors. These patients had similar outcomes to favorable-risk patients. Enrollment in future clinical trials may improve if eligibility is less restrictive.

Whole-Pelvic Versus Prostate-Only Radiation Therapy in Unfavorable Intermediate-Risk and High-Risk Prostate Cancer Treated with Androgen Deprivation Therapy and Brachytherapy Boost

The ASCENDE-RT randomized controlled trial showed that brachytherapy boost significantly reduces biochemical recurrence in unfavorable intermediate-risk and high-risk prostate cancer treated with whole-pelvic radiation therapy (WPRT) and androgen deprivation therapy (ADT). However, previous level 1 data have not shown an oncologic benefit for WPRT compared to prostate-only radiation therapy (PORT) in patients who did not receive brachytherapy boost. Therefore, we examined the association between WPRT, compared to PORT, and overall survival in patients with unfavorable intermediate-risk or high-risk prostate cancer treated with brachytherapy boost and ADT. Using the National Cancer Database, we identified 7,292 men diagnosed with unfavorable intermediate-risk disease (Gleason 4+3 or ≥2 intermediate-risk factors [Gleason 3+4, prostate-specific antigen (PSA) 10-20 ng/mL, or cT2b-T2c stage]) or high-risk disease (Gleason 8-10, PSA >20 ng/mL, or cT3-T4 stage) from 2004 through 2014 who were treated with brachytherapy boost, ADT, and either WPRT or PORT to 39.6-50.4 Gy. Patients with nodal or metastatic disease were excluded. Risk of lymph node metastases was estimated using the Roach formula ([2/3] × PSA + 10 × [Gleason score - 6]). Cox proportional hazards regression was used to examine the association between WPRT, versus PORT, and overall survival. Median follow-up was 6.3 years. The study cohort consisted of 35.1% unfavorable intermediate-risk patients and 64.9% high-risk patients. Overall, 52.5% of patients received WPRT. On multivariable analysis, WPRT, compared to PORT, was not associated with a significant improvement in overall survival for the entire cohort (adjusted hazard ratio [AHR] 1.02, 95% confidence interval [CI] 0.91-1.14, P =0.702). This lack of overall survival benefit was observed for subgroups of unfavorable intermediate-risk patients (AHR 1.12, 95% CI 0.93-1.35, P =0.246), high-risk patients (AHR 0.98, 95% CI 0.85-1.12, P =0.726), and patients with >15% risk of lymph node metastases (AHR 1.00, 95% CI 0.89-1.13, P =0.985). These results suggest that patients with unfavorable intermediate-risk or high-risk prostate cancer treated with brachytherapy boost and ADT may not benefit from receiving WPRT. Providers should thoughtfully weigh the risks and benefits of WPRT compared to PORT when planning to treat unfavorable-risk patients with brachytherapy boost and ADT.

Prognostic Testing Patterns and Outcomes of Chronic Lymphocytic Leukemia Patients Stratified by Fluorescence In Situ Hybridization/Cytogenetics: A Real-world Clinical Experience in the Connect CLL Registry

IntroductionPrognostic genetic testing is recommended for patients with chronic lymphocytic leukemia (CLL) to guide clinical management. Specific abnormalities, such as del(17p), del(11q), and unmutated IgHV, can predict the depth and durability of the response to CLL therapy. Patients and MethodsIn the present analysis of the Connect CLL Registry (ClinicalTrials.gov identifier, NCT01081015), a prospective observational cohort study of patients treated across 199 centers, the patterns of prognostic testing and outcomes of patients with unfavorable-risk genetics were analyzed. From 2010 to 2014, 1494 treated patients were enrolled in the registry by line of therapy (LOT), and stratified by the results of cytogenetic/fluorescence in situ hybridization (FISH) testing into 3 risk levels: unfavorable (presence of del[17p] or del[11q]), favorable (absence of del[17p] and del[11q]), and unknown. ResultsCytogenetic/FISH testing was performed in 861 patients (58%) at enrollment; only 40% of these patients were retested before starting a subsequent LOT. Of those enrolled at the first LOT, unfavorable-risk patients had inferior event-free survival compared with favorable-risk patients (hazard ratio, 1.60; P = .001). Event-free survival was inferior with bendamustine-containing regimens (P < .0001). Event-free survival did not differ significantly between risk groups for patients treated with ibrutinib or idelalisib in the relapse/refractory setting. The predictors of reduced event-free survival included unfavorable-risk genetics, age ≥ 75 years, race, and treatment choice at enrollment. ConclusionThe present study has shown that prognostic cytogenetic/FISH testing is infrequently performed and that patients with unfavorable-risk genetics treated with immunochemotherapy combinations have worse outcomes. This underscores the importance of performing prognostic genetic testing for all CLL patients to guide treatment.

Impact of Unfavorable Factors on Outcomes Among Inoperable Stage II-IV Non–Small Cell Lung Cancer Patients Treated with Proton Therapy

Clinical trials evaluating proton therapy (PT) for locally advanced non–small cell lung cancer (LA-NSCLC) have been slow to accrue despite the many patients on registry PT studies. We investigated patients with LA-NSCLC treated at a single proton center to better understand who is being treated with PT and describe their outcomes. From May 2008 through September 2016, 101 patients with unresectable stage II-IV (oligometastatic) NSCLC were treated on an IRB-approved outcomes tracking protocol and/or clinical trials with PT. Unfavorable factors including age ≥80 yrs, stage IV, weight loss >5% in 1 month, Performance Status (PS) ≥2, FEV1 <1.0 or O2 dependency, prior lung cancer, prior lung surgery, prior second cancer in the past 3 years, prior chest irradiation, and other severe comorbidities listed as clinical trial ineligibility criteria were evaluated. Ninety-one patients received standard fractionation of 1.8-2 Gy(RBE) (median dose, 70 Gy[RBE]), while 10 others were treated with hypofractionation (≥ 2.5 Gy[RBE]/fraction). Overall survival (OS) and progress-free survival (PFS) were calculated with the Kaplan-Meier method. The impact of unfavorable factors was analyzed in univariate and multivariate Cox regression models. Median follow-up for living patients was 27.7 months. Of the 101 patients, 27% were favorable-risk (0 factors), 40% had 1 unfavorable factor, 20% had 2 factors, and 13% had ≥3 factors; 59% (n=16) of favorable-risk and 9% (n=7) of unfavorable-risk patients were enrolled in clinical trials (P <.001). Seventy-seven percent of patients were ≥age 65 years qualifying for Medicare, only 19% of whom were favorable-risk (P =.003). More favorable- than unfavorable-risk patients received concurrent chemotherapy (96% vs 75.7%; P=.02). Restricted to 91 patients treated with standard fractionation, the 2- and 5-year OS rates were 52% and 13% for favorable-risk patients compared to 43% and 25% for unfavorable-risk patients (P=.84). There was a trend toward a better 2-year PFS rate for unfavorable-risk patients (44% vs 21%; P=.053). None of the unfavorable factors had a significant impact on OS. In a subset analysis for only stage III-IV patients, PS≥2 adversely impacted OS (P=.002). Of the favorable-risk patients, 19% (n=4) developed grade 3 or higher toxicities including 3 GI-related and 1 pulmonary. For unfavorable-risk patients, 11.4% (n=8) had grade 3 or higher toxicities including 4 GI-related and 7 pulmonary. Most patients treated with PT for LA-NSCLC have unfavorable risk factors. These patients had similar outcomes to favorable-risk patients. Enrollment in future clinical trials may improve if eligibility is less restrictive.

PD04-10 IDENTIFYING MRCC PATIENTS WITH VENOUS THROMBUS WHO ARE LIKELY TO BENEFIT FROM CYTOREDUCTIVE SURGERY

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II1 Apr 2016PD04-10 IDENTIFYING MRCC PATIENTS WITH VENOUS THROMBUS WHO ARE LIKELY TO BENEFIT FROM CYTOREDUCTIVE SURGERY E. Jason Abel, Kamran Zargar, Vitaly Margulis, Michael A. Mann, Philippe E. Spiess, Kenan Ashouri, Leonardo Borregales, Ahmed Haddad, Charles Rew, Gong Chen, Fangfang Shi, Surena Matin, Christopher G. Wood, and Jose A. Karam E. Jason AbelE. Jason Abel More articles by this author , Kamran ZargarKamran Zargar More articles by this author , Vitaly MargulisVitaly Margulis More articles by this author , Michael A. MannMichael A. Mann More articles by this author , Philippe E. SpiessPhilippe E. Spiess More articles by this author , Kenan AshouriKenan Ashouri More articles by this author , Leonardo BorregalesLeonardo Borregales More articles by this author , Ahmed HaddadAhmed Haddad More articles by this author , Charles RewCharles Rew More articles by this author , Gong ChenGong Chen More articles by this author , Fangfang ShiFangfang Shi More articles by this author , Surena MatinSurena Matin More articles by this author , Christopher G. WoodChristopher G. Wood More articles by this author , and Jose A. KaramJose A. Karam More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2415AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Nephrectomy with tumor thrombectomy is associated with increased risk for morbidity especially when IVC thrombus extends above the hepatic veins. Some patients with metastatic RCC are less likely to benefit from cytoreductive surgery if their expected survival is short. The purpose of this study was to identify risk factors for poor overall survival in metastatic RCC patients with tumor thrombus. METHODS Data was collected from 4 centers for patients with mRCC and venous thrombus at presentation treated surgically from 2000-2014. MSKCC, IMDC, or MDACC (Cancer 2010) prognostic systems were used to classify patients and Kaplan Meier analysis was used to estimate OS. Univariate and multivariate Cox proportional hazard models were used to evaluate the association of individual variables with OS. RESULTS A total of 293 patients were evaluated and median OS (IQR) was 17.2 (6.4-41.0) months for the entire cohort. Venous thrombus level (Neves system) was 0,1,2,3, and 4 for 77, 38, 104, 45, and 29 patients. Median OS was worse (p=0.03) for patients with IVC thrombus above the diaphragm 6.8 (IQR 2.2-19.1) months compared to renal vein only thrombus 18.8(IQR 8.1-37.8) months or IVC thrombus below the diaphragm 18.9 (IQR 6.7-44.5) months (figure). Risk groups stratification was used to compare the ability of systems to predict short OS. MSKCC poor risk patients had median OS 13.4 (IQR 4.4-28.2) months, IMDC risk poor risk patients had median OS 12.5 (IQR 5.0-35) months and MDACC unfavorable risk patients had median OS 6 (IQR 4.4-28.2) months. Preoperative variables that were independent predictors of OS included: IVC thrombus above diaphragm HR 5.2 (95%CI 2.4-11.3); p<0.001, serum lactate dehydrogenase> ULN HR 1.7 (95%CI 1.1-2.6); p=0.01, and systemic symptoms (fatigue, weight loss, etc.) HR 2.2 (95%CI 1.4-3.3); p=0.0002. CONCLUSIONS Metastatic RCC patients with IVC thrombus above the diaphragm or patients classified as unfavorable using MDACC criteria have poor OS and may not benefit from cytoreductive nephrectomy with thrombectomy. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e123-e124 Advertisement Copyright & Permissions© 2016MetricsAuthor Information E. Jason Abel More articles by this author Kamran Zargar More articles by this author Vitaly Margulis More articles by this author Michael A. Mann More articles by this author Philippe E. Spiess More articles by this author Kenan Ashouri More articles by this author Leonardo Borregales More articles by this author Ahmed Haddad More articles by this author Charles Rew More articles by this author Gong Chen More articles by this author Fangfang Shi More articles by this author Surena Matin More articles by this author Christopher G. Wood More articles by this author Jose A. Karam More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The Prognostic Relevance of Comprehensive Risk Score Is Modulated By Therapy: Analysis of 292 Acute Myeloid Leukemia Patients Registered at the Genova Acute Leukemia Registry (REGAL)

Background, methods and aims of the study.It is widely established that the prognosis of patients with acute myeloid leukemia (AML) is related to clinical (age, denovo or secondary leukemia, presence of comorbidities), cytogenetic and molecular (e.g. FLT3-ITD, NPM1 gene mutation.) factors. We have developed a Comprehensive Risk Score (CRS) identifying three prognostic subgroups with favorable (low risk karyotype or intermediate karyotype + mutations of NPM1 gene without FLT3-ITD), unfavorable (high risk cytogenetics or FLT3-ITD without NPM1 mutation or secondary AML) and intermediate (including all the other patients not belonging to previous groups) prognosis. The clinical utility of CRS was tested on a cohort of 292 AML patients included in the REGAL registry, a regional Italian registry that was established in October 2010 at the University of Genoa.Results.Analysis of age distribution confirmed the increased incidence of AML in patients older than 60 years (n. 182, 62.4%). Patients with de novo or secondary AML were 210 (71.9%) and 82, (28.1%) respectively. Patients with significant and often multiple comorbidities at diagnosis were 131 (44.8%). Seventeen patients (6%) received only supportive therapy, 217 (74.3%) intensive induction regimens (mainly FLAG-Ida and 3+7), including 96% of patients with age below 60 years and 61% of those over the age of 60 years. Therapy with hypomethylating agents (azacitidine and decitabine) was given to 31 patients (10.6%).In the whole cohort of patients 24 months projected survival (OS) was 66% among 62 patients defined as low risk according CRS (median not reached), 37,9% among 118 intermediate risk patients (median 13.8 months) and 12,7% in 112 patients included in the unfavorable risk group (median survival 4.8 months) (p =0.000, Fig. 1).In patients aged younger than 60 years, OS of favorable and intermediate risk groups were similar (77% and 72% in 39 low risk and in 44 intermediate risk patients, respectively), whereas the outcome of 27 high risk patients was worse (OS 28.2%, median survival of 10,3 months, p 0.0001). In the group of elderly patients (> 60 years) the outcome of the intermediate group was rather similar to that observed in the poor risk group (OS 16% and 7% in 74 intermediate and in 85 poor risk patients, respectively, p n.s). On the contrary OS of 23 favorable risk patients was good (49%, p = 0.0015).Twenty-nine patients have actually received an allogeneic bone marrow transplant (BMT) during first CR (66% of 44 with indication) and 14 in second or third CR. The sources of stem cells have been HLA-identical and haploidentical sibling in 45% and 50% of patients, respectively.Discussion and conclusions.Our study suggests that the predictive value of CRS is clearly affected by the therapeutic strategy. Whereas the score allows the stratification of the whole cohort of patients in three groups with different outcome, in younger fit patients a more intensive therapeutic approach, such as the FLAG-IDA regimen and a wider use of allogeneic bone marrow transplantation made possible by the use of haploidentical donors, results in the super-imposable prognosis between favorable risk and intermediate risk patients.However, the same intensive approach cannot overcome the unfavorable features of the majority of high risk patients.In the elderly group median age and comorbidities prevent patients from receiving intensive induction therapy. Therefore, intermediate and unfavorable risk patients show a similar poor outcome. In elderly patients the achievement of a good outcome is related to disease status (denovo AML), favorable cytogenetic and molecular features, good performance status and administration of intensive induction and consolidation treatment, including BMT in selected cases. [Display omitted] DisclosuresCarella:Seattle Genetics Inc.: Research Funding.

Hodgkin Lymphoma: the Changing Role of Radiation Therapy in Early-Stage Disease—the Role of Functional Imaging.

Early-stage classical Hodgkin lymphoma (CHL) is a highly curable malignancy. Historically, extended-field radiotherapy (EFRT) alone showed excellent cure rates, but the risk of radiotherapy (RT)-associated toxicities led to combined modality therapy (CMT) replacing RT alone. RT has subsequently evolved further with significant reductions of dose and field size, and is currently restricted to involved sites only (ISRT). Contemporary CMT yields cure rates in excess of 85%, and most studies do not have adequate follow-up required to evaluate the risk reduction in late effects. In an effort to avoid RT altogether, response-adapted treatment approaches utilizing results of interim [(18)F]fluorodeoxyglucose (FDG) positron emission tomography with fused computed tomography (PET/CT) imaging have been studied. Results from two studies in favorable-risk (UK RAPID and EORTC H10F) and one in unfavorable-risk patients (EORTC H10U) suggest that omission of RT in patients with a negative interim PET/CT response (Deauville score ≤2) yields slightly inferior progression-free survival (PFS) compared to conventional CMT, but with no difference in overall survival (OS) albeit with short-term follow-up. In order to extrapolate results to daily practice, it is critical to understand the selection of patients entered on trials since definitions of favorable and unfavorable disease vary between study groups. Currently, CMT continues to be the standard of care for the vast majority of patients with early-stage CHL and RT is an integral part of therapy in patients with bulky disease. However, for selected patients with favorable characteristics, emerging data suggest that a chemotherapy-alone approach is reasonable.

Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): Phase 2 study results.

BackgroundAGS-003 is an autologous immunotherapy prepared from fully matured and optimized monocyte-derived dendritic cells, which are co-electroporated with amplified tumor RNA plus synthetic CD40L RNA. AGS-003 was evaluated in combination with sunitinib in an open label phase 2 study in intermediate and poor risk, treatment naïve patients with metastatic clear cell renal cell carcinoma (mRCC).MethodsTwenty-one intermediate and poor risk patients were treated continuously with sunitinib (4 weeks on, 2 weeks off per 6 week cycle). After completion of the first cycle of sunitinib, patients were treated with AGS-003 every 3 weeks for 5 doses, then every 12 weeks until progression or end of study. The primary endpoint was to determine the complete response rate. Secondary endpoints included clinical benefit, safety, progression free survival (PFS) and overall survival (OS). Immunologic response was also monitored.ResultsThirteen patients (62%) experienced clinical benefit (9 partial responses, 4 with stable disease); however there were no complete responses in this group of intermediate and poor risk mRCC patients and enrollment was terminated early. Median PFS from registration was 11.2 months (95% CI 6.0, 19.4) and the median OS from registration was 30.2 months (95% CI 9.4, 57.1) for all patients. Seven (33%) patients survived for at least 4.5 years, while five (24%) survived for more than 5 years, including 2 patients who remain progression-free with durable responses for more than 5 years at the time of this report. AGS-003 was well tolerated with only mild injection-site reactions. The most common adverse events were related to expected toxicity from sunitinib therapy. In patients who had sequential samples available for immune monitoring, the magnitude of the increase in the absolute number of CD8+ CD28+ CD45RA− effector/memory T cells (CTLs) after 5 doses of AGS-003 relative to baseline, correlated with overall survival.ConclusionsAGS-003 in combination with sunitinib was well tolerated and yielded supportive immunologic responses coupled with extension of median and long-term survival in an unselected, intermediate and poor risk prognosis mRCC population.Clinical Trial Registry#NCT00678119

Risk-stratified treatment of patients with metastatic germ cell tumor with progression after first-line therapy.

398 Background: The optimal management of patients with metastatic germ cell tumor (GCT) who experience progression after first-line (FL) therapy is controversial. A risk-stratified approach was introduced in 2005. Favorable risk patients received 4 cycles of paclitaxel, ifosfamide, cisplatin (TIP); unfavorable risk patients received 2 cycles of TIP followed by 2 cycles of high-dose chemotherapy [(HDCT); carboplatin and etoposide with autologous stem cell support]. Favorable risk was generally defined as gonadal primary and relapse &gt; 6 months after CR or marker negative PR to FL therapy; all others were unfavorable risk. The aim of this study is to present survival outcome of this risk-stratified approach at a single institution. Methods: A chart-based retrospective review was conducted on all patients with metastatic GCT who experienced progression after FL therapy from 2005 to 2013. Data were collected on baseline demographics and disease characteristics. Progression-free survival (PFS) and overall survival (OS) were calculated for favorable and unfavorable risk patients. Results: 37 patients were identified and included for analysis. Patients characteristics: Caucasian 92%; median age 27 years; gonadal primary 84%; non-seminoma, 81%. 16 (43%) favorable risk patients received TIP x 4; 21 (57%) unfavorable risk patients received TIP x 2 followed by HDCT x 2. The median time for follow-up was 16 months. Favorable risk patients: 2- and 4-year PFS of 60% and 45%; 2- and 4-year OS of 74%. Unfavorable risk patients: 2- and 4-year PFS of 41% and 27%; 2- and 4-year OS of 55% and 34%. Both IGCCCG risk classification at initial diagnosis and IPFSG risk classification at relapse had prognostic validity for OS (log rank p ≤ 0.05) but not PFS (log rank p = 0.065–0.080). Conclusions: Risk-stratified treatment of patients with metastatic GCT with progression after FL therapy may result in the best risk/benefit ratio. However, the optimal management of these patients is still not known and prospective randomized comparisons are needed.

Minimal Residual Disease Assessment By Flow Cytometry in AML Is an Independant Prognostic Factor Even after Adjusting for Cytogenetic/Molecular Abnormalities

Minimal residual disease (MRD) assessment provides early evaluation of the efficacy of anti-leukemic therapy. Previous studies suggested that MRD status serves as a prognostic tool in AML. By contrast to pediatric ALL, where assessment of MRD routinely informs prognosis and guides therapeutic decisions, MRD in adult AML is not routinely used in the clinical context. Moreover, the relationship of MRD status to state-of-the-art molecular prognostic algorithms has not been investigated; it is unknown whether integrating MRD data with molecular profiling allows investigators to better identify patients at increased risk of relapse. In order to investigate the clinical relevance of MRD and its relationship with molecular-based prognostic schema, we performed flow cytometric MRD profiling on AML patients enrolled in the ECOG-led intergroup phase 3 trial, E1900, which randomized patients to induction with cytarabine plus 45 or 90mg/m2 daunorubicin.189 patients (29.3% of the original cohort) had MRD analyzed at morphologic and hematologic complete remission (CR). MRD was evaluated by 4-color flow cytometry (FC) and positivity defined as 0.1% of leukemic cells in bone marrow. There was no association between MRD status and daunorubicin dose (p=1.0), suggesting that dose-intensification, which significantly improving overall survival (OS) (Fernandez et al, NEJM 2010), did not reduce the frequency of MRD positivity. We found a highly significant relationship between MRD positivity and OS (p=0.0002). Of note, the relevance of MRD status to OS was significant in univariate (p=0.0002) and multivariate analyses, after adjusting for age, gender, Hb, WBC/platelet count and cytogenetic risk profile, with a hazard ratio (HR) of MRD positivity vs. MRD negativity of 2.12 (95% CI, 1.31 to 3.41; p=0.0022). The impact of MRD status after consolidation on disease-free survival (DFS) and OS was assessed in 140 patients with evaluable samples at completion of consolidation. Both univariate and multivariate analyses showed strong association between MRD positivity and DFS (p<0.0001 in both analyses) and OS (p<0.0001 in both analyses); the HR for multivariate analysis was 4.16. Notably, using different cut-off thresholds for defining MRD positivity (0.01% and 0.05%) did not change the results of these analyses, confirming that the clinically relevant MRD level in adult AML is 10-times higher than in pediatric ALL.We next investigated whether MRD status provided prognostic information independent of integrated molecular profiling. We assessed the prognostic relevance of MRD status in each of our previously reported molecularly defined risk categories (Patel et al, NEJM 2012). The frequency of MRD positivity increased with increasing risk of relapse as assessed by integrated molecular profiling (p=0.017), with 51% of favorable patients, 76% of intermediate patients, and 73% of unfavorable risk patients having evidence of MRD at the time of CR. Multivariate analysis demonstrated that MRD status had a powerful impact on OS independent of molecularly defined risk (p=0.003), demonstrating that molecular analysis of pre-therapy leukemic cells and post-induction analysis of MRD status independently predict outcome in AML. Notably, the impact of MRD status on outcome was most dramatic in favorable and intermediate risk patients; in each of these subgroups MRD positive patients had an absolute reduction in survival by 28-30% compared to MRD negative patients. By contrast, MRD positive patients with molecularly defined adverse risk did not fare worse than MRD negative patients of this risk class, suggesting that patients with high risk genetic lesions have poor OS regardless of MRD status post induction therapy.The presence of MRD, assessed by flow cytometry, was an independent prognostic factor in newly diagnosed AML patients, both at time of CR and following consolidation. MRD had a strong association with OS even after adjusting for cytogenetic and molecular abnormalities with a most powerful impact on outcome in patients with molecularly defined favorable and intermediate risk disease. Subsequent studies are waranted to delineate the molecular basis for MRD in different AML subsets, and to investigate if MRD-directed therapies can improve outcomes by reducing disease relapse. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcomes Of Allogeneic Hematopoietic Stem Cell Transplantation In AML Patients Registered In Prospective Studies: The JALSG Experience

Background The current guidelines for acute myeloid leukemia (AML) issued by the Japan Society for Hematopoietic Cell Transplantation were updated in 2009 to reflect that AML in intermediate-risk or unfavorable-risk patients younger than 55 years of age should be treated with allogeneic stem cell transplantation (allo-SCT) at the first complete remission (1CR). However, most of the eevidence' for this recommendation was based on the results of either prospective studies with randomization according to donor availability or retrospective studies. Therefore, the influence of eselection bias' is inevitable. On the other hands, physicians sometimes have difficulty deciding whether a patient should receive upfront allo-SCT or final treatment with chemotherapy, as the outcomes of patients with 1CR at allo-SCT and 2nd CR (2CR) at allo-SCT are comparable. Aims We conducted a subgroup analysis to verify the validity of allo-SCT in AML patients in 1CR using the dataset of patients registered in prospective studies. [Methods] We examined the disease status and outcomes of the AML patients registered in the AML97 and AML201 studies conducted by the Japan Adult Leukemia Study Group (823 patients and 1,064 patients, respectively) who underwent allo-SCT. Results A total of 752 patients with AML were registered in the JALSG study and underwent allo-SCT. Their estimated 5-year overall survival (OS) was 44%. The number of patients according to the disease status at allo-SCT was 262 in 1CR, 130 in 1st relapse (1rel), 192 in 2CR and 98 with primary induction failure to CR (PIF). The estimated 5-year OS of the patients with intermediate-risk or unfavorable-risk cytogenetics in 1CR was significantly superior to that of the patients with 1rel or 2CR (57% vs. 41%, p&lt;0.0001). The allo-SCT outcomes of the patients with relapse revealed that the estimated 5-year survival after relapse (SAR) in the patients who achieved 2CR was acceptable at 62%, while that of the patients with 1rel who underwent allo-SCT was significantly superior to that of the patients who did not receive allo-SCT (5-year SAR: 17% vs. 8%, p&lt;0.0001). The outcomes of the patients with relapse and PIF were better among the patients who underwent allo-SCT than among the patients who did not, regardless of the cytogenetic risk category. Conclusions The use of upfront allo-SCT in AML patients with 1CR is recommended, as the allo-SCT outcomes of patients with 1CR are superior to those observed after relapse, although the 5-year OS of patients with 2CR is not inferior to that of patients with 1CR. Disclosures: No relevant conflicts of interest to declare.

Specific Features Identify Patients with Relapsed or Refractory Mantle Cell Lymphoma Benefitting from Autologous Hematopoietic Cell Transplantation

Outcomes with autologous hematopoietic cell transplantation (auto HCT) for relapsed and/or refractory mantle cell lymphoma (MCL) are typically poor. We hypothesized that certain factors could predict which patients experience a favorable outcome with this approach. We thus developed a predictive score from a cohort of 67 such patients using 3 factors independently associated with progression-free survival (PFS): (1) simplified Mantle Cell Lymphoma International Prognostic Index score before auto HCT (hazard ratio [HR], 2.9; P = .002); (2) B symptoms at diagnosis (HR, 2.7; P = .005); and (3) remission quotient, calculated by dividing the time, in months, from diagnosis to auto HCT by the number of prior treatments (HR, 1.4; P = .02). The estimated 5-year PFS for favorable-risk patients (n = 23) and unfavorable-risk patients (n = 44) were 58% (95% confidence interval [CI], 34% to 75%) and 15% (95% CI, 6% to 28%), respectively. These factors also independently predicted overall survival. In summary, we have defined 3 simple factors that can identify patients with relapsed/refractory MCL who derive a durable benefit from salvage auto HCT.