Who Benefits the Most From Adjuvant Durvalumab After Chemoradiotherapy for Non-small Cell Lung Cancer? An Exploratory Analysis

PurposeAdjuvant durvalumab is now recommended for most patients with locally advanced non-small cell lung cancer after concurrent chemoradiotherapy. Herein, we explore the clinical factors that may be associated with the benefit from adjuvant durvalumab.Methods and MaterialsPatients with non-small cell lung cancer who were treated with definitive concurrent chemoradiotherapy at our institution between August 2013 and May 2019 were included in this analysis. Clinical and treatment characteristics were tested for associations with progression-free survival (PFS) in Cox models. Interaction terms were added to the PFS Cox models to explore factors that may modulate the effects of adjuvant durvalumab. PFS and overall survival (OS) rates were estimated using the Kaplan-Meier method, and comparisons between patient subgroups were performed using log rank testing.ResultsA total of 105 patients met the eligibility criteria. Thirty-five patients (33%) received adjuvant durvalumab. Treatment with durvalumab was associated with significant improvement in PFS (1-year PFS: 67% vs 39%; log rank P = .006) and OS (1-year OS: 88% vs 76%; log rank P = .041). Exploratory analyses identified the neutrophil-to-lymphocyte ratio (NLR) after radiation therapy (RT) as a factor that may be associated with a benefit from durvalumab. For patients with post-RT NLR exceeding the cohort’s median value of 4.3, receipt of adjuvant durvalumab was not associated with a significant PFS improvement (1-year PFS: 45% vs 36%; log rank P = .702). For patients with post-RT NLR <4.3, durvalumab receipt was associated with improved PFS (69% vs 41%; P = .009). High mean RT doses delivered to the heart and esophagus were associated with high post-RT NLR.ConclusionsWe identified low NLR after chemoradiotherapy as a factor that may be associated with a benefit from adjuvant durvalumab. Validation studies are warranted.     

Patients Treated With Platinum-Doublet Chemotherapy for Advanced Non–Small-Cell Lung Cancer Have Inferior Outcomes If Previously Treated With Platinum-based Chemoradiation

IntroductionThe standard of care for locoregionally advanced non–small-cell lung cancer is concurrent platinum-based chemoradiation. Many patients relapse, and subsequent systemic treatment may involve platinum-doublet chemotherapy. It is not known if prior platinum-based chemoradiation influences the response to platinum-based chemotherapy given subsequently for relapse. Therefore, we compared outcomes in these patients with those in patients without prior treatment.MethodsA retrospective study of patients who had been treated with carboplatin and gemcitabine chemotherapy for de novo metastatic disease or recurrent non–small-cell lung cancer after receiving platinum-based chemoradiation. The primary outcome was progression-free survival (PFS).ResultsA total of 104 patients were analyzed. The median age was 63 years (range, 35-81 years), with 63 (61%) patients with newly diagnosed disease and with 41 (39%) who were previously treated. The response rate was significantly lower for those previously exposed to chemoradiation (10% vs. 29%: P = .001), as was the median PFS (3.6 months vs. 5.7 months; P = .002), and median overall survival (OS) (8.6 months vs. 12.1 months; P = .007). Only the treatment group was a significant predictor (P = .032) of PFS by univariate analysis. In univariate analysis; sex (men; P = .04), histology (squamous cell; P = .04), Eastern Cooperative Oncology Group Performance Status Scale (P = .002), and treatment group (P = .023) predicted significantly inferior OS. Multivariate analysis showed that performance status was the only significant predictor of inferior OS.ConclusionOutcomes were inferior in patients previously exposed to platinum-based chemoradiation. An approach of stratifying such patients in future trials of chemotherapy should be adopted. Alternative options such as non–platinum-based agents or targeted therapies should be considered in this group.     

Prognostic Variables Associated With Improved Outcomes in Patients With Stage III NSCLC Treated With Chemoradiation Followed by Consolidation Pembrolizumab: A Subset Analysis of a Phase II Study From the Hoosier Cancer Research Network LUN 14-179

IntroductionThe Hoosier Cancer Research Network (HCRN) LUN 14-179 is a phase II trial of consolidation pembrolizumab after concurrent chemoradiation for the treatment of patients with stage III non–small-cell lung cancer (NSCLC). Time to metastatic disease or death (TMDD), progression-free survival (PFS), and overall survival (OS) appear to be superior to that in historical controls of chemoradiation alone. Unfortunately, not all patients benefit from consolidation immunotherapy. We performed a univariate analysis to evaluate variables associated with PFS, metastatic disease, and OS.Patients and MethodsWe conducted a retrospective analysis of patients enrolled in HCRN LUN 14-179. Data collected included age, sex, stage, smoking status, programmed death ligand 1 status, Grade (G) ≥ 2 versus G ≤ 1 adverse event, G ≤ 2 versus G ≥ 3 pneumonitis, duration of pembrolizumab (< 4 vs. ≥ 4 cycles), chemotherapy regimen, performance status 0 versus 1, time to start pembrolizumab (4-6 vs. 6-8 weeks from radiation), volume of lung receiving at least 20 Gy of radiation (V₂₀; < 20% vs. ≥ 20%). Univariable Cox regression was performed to determine the variables associated with 3 end points: TMDD, PFS, and OS.ResultsFrom April 2015 to December 2016, 93 patients were enrolled and 92 were included in the efficacy analysis (1 patient was ineligible). For TMDD, improved outcomes might be associated (P < .1) with stage IIIA and ≥ 4 cycles of pembrolizumab. For PFS, improved outcomes (P < .1) might be seen for ≥ 4 cycles of pembrolizumab, stage IIIA and V₂₀ < 20%. For OS, improved outcomes (P < .1) might be seen for stage IIIA and ≥ 4 cycles of pembrolizumab.ConclusionStage IIIA and longer duration of pembrolizumab treatment might be associated with prolonged TMDD, PFS, and OS for patients with stage III NSCLC treated with chemoradiation followed by pembrolizumab.     

Outcomes of Elderly Patients Who Receive Combined Modality Therapy for Locally Advanced Non–Small-Cell Lung Cancer

Background

The objective of this study was to review our institution's experience among patients with locally advanced non–small-cell lung cancer (LA-NSCLC) treated with chemotherapy and radiation and to determine the prognostic significance of age.

Statin Use,Heart Radiation Dose,and Survival in Locally Advanced Lung Cancer

PurposePatients with locally advanced non-small cell lung cancer (LA-NSCLC) have a high prevalence of pre-existing coronary heart disease and face excess cardiac risk after thoracic radiation therapy. We sought to assess whether statin therapy is a predictor of overall survival (OS) after thoracic radiation therapy.Methods and MaterialsWe performed a retrospective analysis of 748 patients with LA-NSCLC treated with thoracic radiation therapy, using Kaplan-Meier OS estimates and Cox regression.ResultsStatin use among high cardiac risk patients (Framingham risk ≥20% or pre-existing coronary heart disease; n = 496) was 51.2%. After adjustment for baseline cardiac risk and other prognostic factors, statin therapy was associated with a significantly increased risk of all-cause mortality (adjusted hazard ratio, 1.39; 95% confidence interval [CI], 1.00-1.91; P = .048) but not major adverse cardiac events (adjusted hazard ratio, 1.18; 95% CI, 0.52-2.68; P = .69). Among statin-naïve patients, mean heart dose ≥10 Gy versus <10 Gy was associated with a significantly increased risk of all-cause mortality (hazard ratio, 1.32; 95% CI, 1.04-1.68; P = .022), with 2-year OS estimates of 46.9% versus 60.0%, respectively. However, OS did not differ by heart dose among patients on statin therapy (hazard ratio, 1.00; 95% CI, 0.76-1.32; P = 1.00; P-interaction = .031), with 2-year OS estimates of 46.9% versus 50.3%, respectively.ConclusionsAmong patients with LA-NSCLC, only half of statin-eligible high cardiac risk patients were on statin therapy, reflecting the highest cardiac risk level of our cohort. Statin use was an independent predictor of all-cause mortality but not major adverse cardiac events. Elevated mean heart dose (≥10 Gy) was associated with increased risk of all-cause mortality in statin-naïve patients but not among those on statin therapy, identifying a group of patients in which early intervention with statins may mitigate the deleterious effects of high heart radiation therapy dose. This warrants evaluation in prospective trials.     

TPX2 as a Novel Prognostic Indicator and Promising Therapeutic Target in Triple-negative Breast Cancer

IntroductionTriple-negative breast cancer (TNBC), which lacks endocrine therapies and targeted therapies, has the worst prognosis of all breast cancers which remain the most common malignancy in women worldwide. Targeting protein for xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein that is strongly correlated with chromosomal instability, resulting in the development of different human tumors. Herein, we investigated the relationship between the clinical outcome of TNBC and the expression level of the TPX2 protein.Materials and MethodsPatients initially treated at Tongji Hospital for confirmed TNBC were evaluated by immunohistochemical staining and retrospectively recruited into our study. The immunohistochemical staining evaluation of TPX2 was based on the staining intensity and extent. STATA was used to analyze all the data.ResultsIn total, 97 patients with TNBC were recruited into our study. The TPX2 protein was overexpressed in almost all patients with TNBC. Our study demonstrated that an elevated TPX2 protein level was significantly associated with worse outcomes in the patients with TNBC, including worse progression-free survival (PFS) and overall survival (OS) (log-rank test, P < .001). Our model also indicated that TPX2 expression was an independent predictor of OS (hazard ratio, 2.20; 95% confidence interval, 1.13-4.28; P = .020) but not of PFS (P = .639).ConclusionIn conclusion, we demonstrated that TPX2 could be a novel prognostic marker of PFS and OS after the initial treatment of TNBC. We also revealed that TPX2 expression could serve as an independent predictor of OS but not of PFS and a promising therapeutic target in patients with TNBC.     

Tumor Infiltrating Lymphocytes Predict Survival in Solid Organ Transplant Recipients With Monomorphic Post-transplant Lymphoproliferative Disorders

IntroductionThe tumor microenvironment (TME) in post-transplant lymphoproliferative disorders (PTLDs) remains unexplored. Tumor infiltrating lymphocytes (TILs) are prognostic in other lymphomas. We assessed the prognostic impact of TILs in monomorphic B-cell PTLD.MethodsTIL density (CD3+ cells/mm²) was determined by CD3 immunohistochemistry in archived diagnostic biopsies from patients diagnosed with monomorphic B-cell PTLD.ResultsAmongst monomorphic PTLDs (N = 107), low TIL-count was associated with inferior 2-year progression-free survival (PFS) (41% versus 86%, P = .003) and 2-year overall survival (OS) (52% versus 93%, P = .003) by Kaplan-Meier analysis. Low TIL-count was significant on Cox univariate regression for inferior PFS (HR 4.5, 95% CI 2.0-9.9, P < .001) and OS (HR 4.6, 95% CI 1.8-11.8, P < .001). Multivariate analysis with clinical variables (age ≥60 years, high LDH, stage III/IV, CNS involvement) and TIL-count showed significance for PFS (HR 3.3, 95% CI 1.3-8.3, P = .010) and a non-significant trend for OS (HR 2.6, 95% CI 0.9-7.3, P = .064). A composite score including TILs and clinical variables (age ≥60 years, high LDH, stage III/IV, CNS involvement) effectively stratified monomorphic PTLD patients by PFS and OS (2-year OS: low-risk 93%, intermediate-risk 61%, high-risk 23%, P < .001).ConclusionsThe TME and TILs are prognostically relevant in monomorphic PTLD. Prognostic models including measures of the TME may improve risk stratification for patients with monomorphic PTLDs.     

Definitive Chemoradiation and Durvalumab Consolidation for Locally Advanced,Unresectable KRAS-mutated Non-Small Cell Lung Cancer

BackgroundConsolidation durvalumab immunotherapy following definitive chemoradiation (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) improves overall survival. As therapeutic options for patients with KRAS-driven disease evolve, more understanding regarding genomic determinants of response and patterns of progression for durvalumab consolidation is needed to optimize outcomes.MethodsWe conducted a single-institutional retrospective analysis of real-world patients with locally advanced, unresectable NSCLC who completed CRT and received durvalumab consolidation. Kaplan-Meier analyses compared progression-free survival (PFS) and overall survival (OS) from start of durvalumab consolidation between patients with KRAS-mutated and non-mutated tumors. Fisher's exact test was used to compare rates of intrathoracic or extrathoracic progression.ResultsOf 74 response-evaluable patients, 39 had clinical genomic profiling performed. 18 patients had tumors with KRAS mutations, 7 patients had tumors with non-KRAS actionable alterations (EGFR, ALK, ERBB2, BRAF, MET, RET, or ROS1), and 14 patients had tumors without actionable alterations. Median PFS for the overall cohort was 16.1 months. PFS for patients with KRAS-mutated NSCLC was 12.6 months versus 12.7 months for patients with non-actionable tumors (P= 0.77, log-rank). Fisher's exact test revealed a statistically significantly higher rate of extrathoracic progression versus intrathoracic-only progression for patients with KRAS-driven disease compared to patients with non-actionable tumors (P= 0.015).ConclusionPatients with KRAS-mutated NSCLC derived similar benefit from durvalumab as patients with non-actionable tumors. A higher rate of extrathoracic progression was also observed among the patients with KRAS-mutated NSCLC compared to patients with non-actionable tumors. This highlights the potential unmet needs for novel systemic therapies and surveillance methods for KRAS-mutated stage III NSCLC.     

Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group

BackgroundTo explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer (mCRC) receiving first-line therapy.Patients and methodsA total of 1239 patients from five randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by the Kaplan–Meier method, log-rank tests and Cox models.ResultsIn 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free survival (PFS) and overall survival (OS) [multivariate hazard ratio (HR) for PFS: 1.20 (1.02–1.42), P = 0.03; multivariate HR for OS: 1.41 (1.17–1.70), P < 0.001]. BRAF mutation was also associated with inferior PFS [multivariate HR: 2.19 (1.59–3.02), P < 0.001] and OS [multivariate HR: 2.99 (2.10–4.25), P < 0.001]. Among specific KRAS mutation variants, the KRAS G12C-variant (n = 28) correlated with inferior OS compared with unmutated tumors [multivariate HR 2.26 (1.25–4.1), P = 0.001]. A similar trend for OS was seen in the KRAS G13D-variant [n = 71, multivariate HR 1.46 (0.96–2.22), P = 0.10]. More frequent KRAS exon 2 variants like G12D [n = 152, multivariate HR 1.17 (0.86–1.6), P = 0.81] and G12V [n = 92, multivariate HR 1.27 (0.87–1.86), P = 0.57] did not have significant impact on OS.ConclusionMutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D (trend) being associated with rather poor survival.     

Expression of Maspin in Non–Small-Cell Lung Cancer: Correlation with Clinical Features

PurposeMaspin is a member of the serpin (serine protease inhibitor) family and has been shown to be a suppressor of tumor growth and metastasis in several types of tumors. The objective of this study was to evaluate whether maspin is a prognostic factor in patients with non–small-cell lung cancer (NSCLC).Patients and MethodsWe investigated maspin expression in 181 patients with curatively resected NSCLC by means of immunohistochemistry. We also determined whether expression of maspin correlates with the microvessel density (MVD) level.ResultsThe incidence of strong maspin expression in patients with squamous cell carcinoma was significantly higher than that in patients with other histology (46 of 70 [65.7%]; P < .0001). There was no significant difference between maspin expression status and MVD. Prognosis was defined as progression-free survival (PFS) and overall survival (OS). There was no difference in PFS or OS between patients with strong and weak maspin expression among all patients. However, for squamous cell carcinoma, the PFS and OS rates for patients with strong maspin expression were significantly higher than those for patients with weak maspin expression (PFS, P = .004; OS, P = .001). In multivariate analysis on squamous cell carcinoma, strong maspin expression was an independent favorable prognostic indicator (PFS, P = .03; OS, P = .01).ConclusionStrong maspin expression was an independent factor in predicting a favorable prognosis in squamous cell carcinoma of lung.     

Prognostic value of baseline total metabolic tumor volume (TMTV0) measured on FDG-PET/CT in patients with peripheral T-cell lymphoma (PTCL)

BackgroundMost peripheral T-cell lymphoma (PTCL) patients have a poor outcome and the identification of prognostic factors at diagnosis is needed.Patients and methodsThe prognostic impact of total metabolic tumor volume (TMTV0), measured on baseline [¹⁸F]2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography, was evaluated in a retrospective study including 108 PTCL patients (27 PTCL not otherwise specified, 43 angioimmunoblastic T-cell lymphomas and 38 anaplastic large-cell lymphomas). All received anthracycline-based chemotherapy. TMTV0 was computed with the 41% maximum standardized uptake value threshold method and an optimal cut-off point for binary outcomes was determined and compared with others prognostic factors.ResultsWith a median follow-up of 23 months, 2-year progression-free survival (PFS) was 49% and 2-year overall survival (OS) was 67%. High TMTV0 was significantly associated with a worse prognosis. At 2 years, PFS was 26% in patients with a high TMTV0 (>230 cm³, n = 53) versus 71% for those with a low TMTV0, [P < 0.0001, hazard ratio (HR) = 4], whereas OS was 50% versus 80%, respectively, (P = 0.0005, HR = 3.1). In multivariate analysis, TMTV0 was the only significant independent parameter for both PFS and OS. TMTV0, combined with PIT, discriminated even better than TMTV0 alone, patients with an adverse outcome (TMTV0 >230 cm³ and PIT >1, n = 33,) from those with good prognosis (TMTV0 ≤230 cm³ and PIT ≤1, n = 40): 19% versus 73% 2-year PFS (P < 0.0001) and 43% versus 81% 2-year OS, respectively (P = 0.0002). Thirty-one patients (other TMTV0–PIT combinations) had an intermediate outcome, 50% 2-year PFS and 68% 2-year OS.ConclusionTMTV0 appears as an independent predictor of PTCL outcome. Combined with PIT, it could identify different risk categories at diagnosis and warrants further validation as a prognostic marker.     

Correlation of progression-free and post-progression survival with overall survival in advanced colorectal cancer

BackgroundPolychemotherapy and biological drugs have increased therapeutic options and outcomes of advanced colorectal cancer (CRC). We examined the relation between progression-free survival (PFS), post-progression survival (PPS) and overall survival (OS) in trials of modern (oxaliplatin- and irinotecan-based) chemotherapy alone or with targeted therapies for advanced CRC. We also evaluated surrogacy of PFS and OS.Patients and methodsA PubMed search identified 34 randomized trials. We split the OS, PFS and PPS and evaluated the correlation between OS and either PFS or PPS.ResultsThe median PPS and PFS were 10.75 and 8.4 months, respectively. For all trials, PPS was strongly associated with OS [regression coefficient (R²) = 0.8; Spearman's rank correlation coefficient (r) = 0.88], whereas PFS was moderately associated with OS (R² = 0.43; r = 0.64). In trials with targeted therapies, the correlation of PPS with OS was 0.88. However, across all trials, correlation between differences in median PFS (ΔPFS) and median OS (ΔOS) is 0.59 (P = 0.0007), confirming PFS/OS surrogacy.ConclusionOur findings indicate that in recent first-line, phase III, trials, OS becomes more associated with PPS than PFS. However, improvements in PFS are strongly associated with improvements in OS. In this setting so, PFS may be an appropriate surrogate for OS.     

Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized,open-label,phase III trial (SAKK 75/08)

BackgroundThis open-label, phase III trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma.Patients and methodsPatients were randomly assigned (1 : 1) to two cycles of chemotherapy (docetaxel 75 mg/m², cisplatin 75 mg/m²) followed by chemoradiation (45 Gy, docetaxel 20 mg/m² and cisplatin 25 mg/m², weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m² weekly and adjuvant cetuximab 500 mg/m² fortnightly for 3 months. The primary end point was progression-free survival (PFS).ResultsIn total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years [95% confidence interval (CI), 2.0 to not reached] with cetuximab and 2.0 years (95% CI, 1.5–2.8) with control [hazard ratio (HR), 0.79; 95% CI, 0.58–1.07; P = 0.13]. Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2–4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52–1.01; P = 0.055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31–0.90; P = 0.017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64–1.59, P = 0.97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings.ConclusionAdding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma.Clinical trial informationNCT01107639     

Induction Chemotherapy and Chemoradiation Therapy for Inoperable Locally Advanced Non–Small-Cell Lung Cancer: A Single-Institution Review of Two Different Regimens

PurposeWe compared 2 different chemotherapeutic agents in combination with cisplatin as induction chemotherapy (ICT) followed by chemoradiation therapy (CHRT) in patients with inoperable locally advanced non–small-cell lung cancer (NSCLC).Patients and MethodsA total of 90 patients with inoperable locally advanced NSCLC received 3 courses of ICT consisting of gemcitabine 1200 mg/m² on day 1 and day 8 every 3 weeks and cisplatin 75 mg/m² on day 1 every 3 weeks (group 1; n = 39) or docetaxel 75 mg/m² on day 1 every 3 weeks and cisplatin 75 mg/m² on day 1 every 3 weeks (group 2; n = 51) followed by CHRT (docetaxel 30 mg/m² every week and cisplatin 20 mg/m² every week with 6600 cGy radiation therapy).ResultsAfter the ICT, the response rate for group 2 (88.2%) was significantly higher than that of the gemcitabine-cisplatin arm (64.1%; P = .017). The response assessment performed on first month after CHRT revealed statistical difference for objective response rate in group 2 when compared with group 1 (P = .04). At the median follow-up of 15.7 months (range, 5-36 months), median overall survival (OS) was 12 months in group 1 (95% CI, 9.1-14.8) and 29.9 months in group 2 (95% CI, 16-43). Median progression-free survival (PFS) was 8 months in group 1 and 15 months in group 2. There was statistically significant difference between the 2 groups regarding OS and PFS (P = .043).ConclusionOur results suggest that OS, PFS, and local control rate are significantly improved with ICT consisting of docetaxel and cisplatin when compared with gemcitabine-cisplatin in inoperable locally advanced NSCLC.     

Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in patients with advanced ovarian cancer: exploratory analysis of the phase 3 OVA-301 study

In this exploratory analysis, patients with recurrent ovarian cancer carrying BRCA1^mut gene had improved outcomes with trabectedin + PLD treatment compared with PLD alone. Prospective evaluation of BRCA status is likely an important evaluation for DNA-damaging agents and may significantly impact interpretation of clinical studies. XPG may be a biomarker of poor outcome in these patients.BackgroundWe investigated the association of BRCA1 and XPG mutations with response rate (RR), progression-free survival (PFS) and overall survival (OS) in a subset of patients from a phase 3 clinical trial comparing the efficacy and safety of trabectedin + pegylated liposomal doxorubicin (PLD) versus PLD alone in patients with recurrent ovarian cancer.Patients and methodsA candidate array was designed based on the Breast Cancer Information Core database for BRCA mutation analyses. An exploratory analysis of BRCA1/XPG mutation status was conducted using a two-sided log-rank test and 0.05 significance in germline DNA samples from 264 women with failed first-line platinum-based chemotherapy, randomized (1 : 1) to trabectedin + PLD or PLD alone.ResultsOverall, 41 (16%) of the 264 women had BRCA1^mut (trabectedin + PLD: n = 24/135, 18%; PLD: n = 17/129; 13%) and 17 (6%) had XPG^mut (trabectedin + PLD: n = 8/135, 6%; PLD: n = 9/129, 7%). A higher RR was observed in BRCA1^mut patients (20/41; 49%) versus BRCA1^wt patients (62/223; 28%). Within the BRCA1^mut group, trabectedin + PLD-treated patients had longer PFS and longer OS than PLD-treated patients (median PFS 13.5 versus 5.5 months, P = 0.0002; median OS 23.8 versus 12.5 months, P = 0.0086), whereas in BRCA1^wt patients, OS was not significantly different (median OS: 19.1 versus 19.3 months; P = 0.9377). There were no differences in OS or PFS of patients with XPG^mut between the two treatment arms. However, trabectedin + PLD-treated patients with XPG^mut had a trend toward shorter PFS (median PFS: 1.9 versus 7.5 months; P = 0.1666) and OS (median OS: 14.5 versus 20.7 months; P = 0.1774) than those with XPG^wt.ConclusionsIn this exploratory analysis, patients with recurrent ovarian cancer carrying the BRCA1^mut had improved outcomes with trabectedin + PLD treatment compared with PLD alone. Prospective evaluation of BRCA status is likely an important evaluation for DNA-damaging agents and may significantly impact interpretation of clinical studies. XPG may be a biomarker of poor outcome in these patients.     

A Prospective Study of Bone Tumor Response Assessment in Metastatic Breast Cancer

BackgroundIn our previous study, new MD Anderson (MDA) bone tumor response criteria (based on computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) predicted progression-free survival (PFS) better than did World Health Organization (WHO) bone tumor response criteria (plain radiography [XR] and SS) among patients with breast cancer and bone-only metastases. In this pilot study, we tested whether MDA criteria could reveal bone metastasis response earlier than WHO criteria in patients with newly diagnosed breast cancer with osseous and measurable nonosseous metastases.MethodsWe prospectively analyzed bone metastasis response using each imaging modality and set of bone response criteria to distinguish progressive disease (PD) from non-PD and their association with PFS and overall survival (OS). We also compared the response of osseous metastases assessed by both criteria with the response of nonosseous measurable lesions.ResultsThe median follow-up period was 26.7 months (range, 6.1-53.3 months) in 29 patients. PFS rates differed at 6 months based on the classification of PD or non-PD using either set of criteria (MDA, P = .002; WHO, P = .014), but these rates, as well as OS, did not differ at 3 months. Response in osseous metastases by either set of criteria did not correlate with the response in nonosseous metastases.ConclusionMDA and WHO criteria predicted PFS of patients with osseous metastases at 6 months but not at an earlier time point. We plan a well-powered study to determine the role of MDA criteria in predicting bone tumor response by incorporating 18-fluorodeoxyglucose (¹⁸F) positron emission tomography (FDG-PET)/CT to see if findings using this modality are earlier than those with WHO criteria.     

Evaluation of predictive variables in locally advanced pancreatic adenocarcinoma patients receiving definitive chemoradiation

PurposeTo analyze a single-center experience with locally advanced pancreatic cancer (LAPC) patients treated with chemoradiation (CRT) and to evaluate predictive variables of outcome.Methods and MaterialsLAPC patients at our institution between 1997 and 2009 were identified (n = 109). Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier analysis. Cox proportional hazard models were used to evaluate predictive factors for survival. Patterns of failure were characterized, and associations between local progression and distant metastasis were explored.ResultsMedian OS was 12.1 months (2.5-34.7 months) and median PFS was 6.7 months (1.1-34.7 months). Poor prognostic factors for OS include Karnofsky performance status ≤80 (P = .0062), treatment interruption (P = .0474), and locally progressive disease at time of first post-therapy imaging (P = .0078). Karnofsky performance status ≤80 (P = .0128), pretreatment CA19-9 >1000 U/mL (P = .0224), and treatment interruption (P = .0009) were poor prognostic factors for PFS. Both local progression (36%) and distant failure (62%) were common. Local progression was associated with a higher incidence of metastasis (P < .0001) and decreased time to metastasis (P < .0001).ConclusionsLAPC patients who suffer local progression following definitive CRT may experience inferior OS and increased risk of metastasis, warranting efforts to improve control of local disease. However, patients with poor pretreatment performance status, elevated CA19-9 levels, and treatment interruptions may experience poor outcomes despite aggressive management with CRT, and may optimally be treated with induction chemotherapy or supportive care. Novel therapies aimed at controlling both local and systemic progression are needed for patients with LAPC.     

Effects of Variant Histology on the Oncologic Outcomes of Patients With Upper Urinary Tract Carcinoma After Radical Nephroureterectomy: A Propensity Score–Matched Analysis

PurposeTo determine the prognostic effect of upper tract urothelial carcinoma (UTUC) with variant histology (VH) after radical nephroureterectomy (RNU).Patients and MethodsThe data of 1173 patients who received RNU for UTUC without neoadjuvant chemotherapy in 11 institutions between 2002 and 2016 were retrospectively reviewed. A matched propensity score analysis was performed. Clinicopathologic variables, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were compared between patients with pure UTUC and patients with UTUC and VH. Univariate and multivariate Cox proportional regression models were used to determine the independent variables associated with oncologic outcomes.ResultsUTUC with VH was observed in 93 patients (7.9%). After propensity score matching, UTUC with VH showed no difference in clinicopathologic features compared to pure UTUC; however, it was associated with shorter RFS, CSS, and OS (log rank, P = .011, P = .002, P = .006, respectively). Additionally, the multivariate analysis revealed that VH was independently associated with a poor RFS [hazard ratio (HR) = 1.92; 95% confidence interval (CI), 1.27-2.89; P = .002], CSS (HR = 4.47; 95% CI, 1.99-10.1; P = .001), and OS (HR = 3.00; 95% CI, 1.55-5.78; P = .001). However, the Kaplan-Meier method revealed that differences in RFS, CSS, and OS were not significant in patients who received adjuvant chemotherapy (log rank, P = .562, P = .060, P = .153, respectively).ConclusionUTUC with VH was independently associated with poor oncologic outcomes in patients with UTUC after RNU. Although patients with UTUC and VH had a poor prognosis compared to patients with pure UTUC, adjuvant chemotherapy would be helpful in improving the survival rates of these patients.     

Updated survival and outcomes for older adults with inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel: analysis of a phase III trial from the Hoosier Oncology Group (HOG) and US Oncology

BackgroundConcurrent chemoradiation with etoposide and cisplatin (EP/XRT) is standard treatment for inoperable stage III locally advanced non-small-cell lung cancer (LA-NSCLC). Consolidation docetaxel (D; Taxotere) after EP/XRT resulted in increased toxicity but no improvement in survival compared with observation (O). We report updated survival for the entire study population and include an analysis of efficacy and tolerability of EP/XRT with or without D in patients aged ≥ 70 years.Patients and methodsHoosier Oncology Group LUN 01-24 enrolled 243 patients with LA-NSCLC and randomized 166 after EP/XRT to three cycles of D versus O. the trial was terminated after an analysis of the first 203 patients demonstrated futility of D.ResultsMedian survival time (MST) for the overall study population was 21.5 months, and 3-, 4-, and 5-year survival rates were 30.7%, 18.0%, and 13.9%, respectively. No differences in MST or 3-year survival were noted between D and O arms. Older patients had similar MST (17.1 versus 22.8 months for younger patients, P = 0.15) but higher rates of grade 3/4 toxicity and hospitalization during induction.ConclusionsConsolidation docetaxel after EP/XRT does not improve survival in LA-NSCLC. Fit older adults with LA-NSCLC benefit from concurrent chemoradiation similarly as younger patients but experience higher rates of hospitalization and toxicity.     

The Value of 18F-FDG PET/CT in Predicting the Response to PD-1 Blocking Immunotherapy in Advanced NSCLC Patients with High-Level PD-L1 Expression

BackgroundThe objective of this study was to evaluate if ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT)-derived parameters are useful in predicting response and survival after programmed cell death protein 1 (PD-1) blocking immunotherapy in patients with advanced NSCLC characterized by a high programmed death-ligand 1 (PD-L1) expression (≥50%) on immunohistochemistry.Patients and MethodsIn 30 patients with advanced stage IV non–small-cell lung cancer (NSCLC) and high PD-L1 expression, ¹⁸F-FDG PET/CT parameters before start of treatment with PD-1 blocking immunotherapy were evaluated retrospectively. In 24 out of the 30 patients, ¹⁸F-FDG PET/CT was available 8 to 9 weeks after start of the treatment. Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and metabolic responses assessed on ¹⁸F-FDG PET/CT were compared.ResultsMedian follow-up was 20 months (range, 4.2-37.6). Median PD-L1 expression was 80%. The objective response rate with RECIST 1.1 was 53.3%. Median progression-free survival (PFS) was 12.4 months (95% confidence interval [CI], 1.0-37.8), and median overall survival (OS) was 14.9 months (95% CI, 2.4-38.2). Baseline ¹⁸F-FDG PET/CT parameters did not differ between responders and non-responders (all P > .05). The maximum standardized uptake value (SUVmax) was the only ¹⁸F-FDG PET/CT parameter associated with PFS (P = .04), with a trend for OS (P = .06). At first evaluation, response according to total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) were associated with PFS and OS (both P < .0001). This was not the case for RECIST 1.1 (P = .29 for PFS and P = .38 for OS).ConclusionClinical response and survival were independent from metabolic tumor volume at baseline. Reduction of metabolic tumor volume after 8 to 9 weeks of treatment was a better predictor for prolonged survival than RECIST 1.1.