End Of First-line Chemotherapy Research Articles

High-dose chemotherapy and autologous stem cell transplant as first salvage treatment for relapsed or refractory Hodgkin Lymphoma in the era of PET-adapted strategies

Data on the efficacy of high-dose chemotherapy and autologous stem cell transplantation (ASCT) for classical Hodgkin lymphoma (cHL) patients who failed a PET-driven first-line therapy are limited. We retrospectively evaluated 220 adult cHL patients who underwent ASCT from 2009 to 2021 at 11 centers in Italy. Overall, 49.5% had refractory disease, 23.2% relapsed < 12 and 27.3% ≥12 months from the end of first-line chemotherapy. The 3-year progression-free survival (PFS) and overall survival (OS) were 73.8% and 89.4%. In univariable analysis for PFS events PET-2+ (HR 2.69, p = .001), anemia (HR 2.22, p = .019), refractory disease (HR 1.76, p = .045), less than CR before ASCT (HR 3.24, p < .001) and >2 lines of salvage therapy (HR 2.52; p = .004) were associated with a higher risk of failure after ASCT. In multivariable analysis, >2 lines of salvage therapy (HR 3.28, p = .004) and RT before ASCT (HR 3.00, p = 0.041) retained significance. ASCT is an effective salvage approach for cHL patients treated in the era of PET-adapted therapies.

Significance of the Rhoa G17V Mutation Detected By Ddpcr in Diagnostic and Monitor of Angioimmunoblastic T-Cell Lymphoma

Introduction Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL) that originates from T follicular helper cells (TFH). RHOA G17V mutation is the most common hotspot locus which could be detected in 50%-70% of cases, showing its potential value for the diagnosis and clinical monitor of this disease. Methods RHOA G17V mutation were detected by Droplet digital PCR (ddPCR) in available samples from PTCL patients, at baseline and before every cycle. Response assessments were done by PET/CT and evaluated according to Lugano criteria after 3 cycles and end of first line chemotherapy(EOT), or at suspicious of disease progression. All data analyses were performed using SPSS 20.0 software (SPSS, Inc.) and GraphPad Prism 9.0 software (GraphPad software). p-Value &amp;lt; 0.05 was considered statistically significant. Results 30 patients with PTCL were included in our center from 2021-01-01 to 2023-07-01,21 were confirmed as AITL and 9 were PTCL-NOS by pathologist review. In whole cohort, RHOA G17V mutation could be detected in 46.7%(14/30) of all patients, also was positive in 61.9%(13/21) and negative in 38.1% (9/21) of patients with AITL. The sensitivity and specificity of RHOA G17V mutation in AITL by ddPCR is 61.9% and 88.9%, with a positive predictive value of 92.9%, and a negative predictive value of 50%. Hyperglobulinemia, positive direct Coombs test, elevated LDH, elevated β2-MG were founded in 76.9%(10/13),61.5%(8/13) ,61.5%(8/13) and 76.9% (10/13) of AITL patients with RHOA G17V mutation, which were significantly higher than those without RHOA G17V mutation(P=0.002,0.019,0.019,0.026). Furthermore, all of the of RHOA G17V mutated AITL patients were in clinical stage III or IV(100%, 13/13), 76.9%(10/13) of them with detectable whole-blood EBV-DNA(≥500 copies/mL) and all have three or more TFH markers(100%,13/13). We next evaluated the baseline and dynamical changes in RHOA G17V VAF-positive patients with AITL. Pretreatment VAF was significantly lower for patients who achieved complete remission or partial remission at EOT compared with that of patients with progressive disease or stable disease (mean VAF, 20.75% vs. 4.31%, p = 0.0028). (Figure 1). In addition, the median PFS in AITL patients with and without RHOA G17V mutation was 9.157 months and 15.154 months respectively(P=0.32).Finally, in 10 AITL patients with dynamic results of RHOA G17V mutation (Figure 2) , a good correlation was found in between dynamic changes of VAF of RHOA G17V mutation and response assessment by PET/CT, rerise of RHOA G17V mutation VAF could be detected prior to clinical progression in two patients，showing for the its protentional value for disease monitor. Conclusions Our study first reported the diagnostic value of single hotspot detection of G17V RHOA mutation by ddPCR in PTCL. Monitoring of G17V RHOA mutation in AITL has predictive value of assess tumor burden and response, also can complement the longitudinal supervise of disease.

Using Deauville Scoring to Guide Consolidative Radiotherapy in Diffuse Large B-Cell Lymphoma

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma in adults. Although consolidative radiotherapy (RT) is often administered in DLBCL, guidelines concerning its usage remain unclear. International guidelines recommend using positron emission tomography (PET) with 18F-fluorodeoxyglucose to stage and assess remission in DLBCL patients. We aimed to assess the value of end-of-treatment PET scans, interpreted using the Deauville score (DV), in guiding the utilization of consolidative RT. This approach may help spare low-risk DLBCL patients from unnecessary RT. Methods All DLBCL patients diagnosed from 2010-2022 at National Cancer Centre Singapore with DV measured at the end of first line chemotherapy were included. DV 1-3 patients were classified as low-DV risk and DV 4-5 patients as high-DV risk. Primary endpoint was time-to-progression (TTP), defined as the time from diagnosis to progression or relapse of DLBCL, or death due to DLBCL or treatment-related factors. Patients without these events were censored at their last follow-up. Cox proportional hazards regression was used to assess the association of TTP with various covariates. The predictive value of DV risk group was analyzed by including an interaction term between receipt of RT and DV risk group in the Cox model. Effect estimates were summarized using hazard ratios (HRs) and 95%-confidence intervals (95%CI). Results A total of 349 patients were analyzed, of which 80 were treated with RT (RT-treated) and 269 without RT (RT-omitted). The mean age of the whole cohort was 59.8 years (standard deviation 15.9 years). Compared with RT-omitted patients, there were higher percentages of RT-treated patients with stage 1-2 disease (61% vs 43%, p=0.007), elevated lactate dehydrogenase (85% vs 71%, p=0.039) and bulky disease (25% vs 10%, p=0.003). On average, RT-treated patients also had lower baseline hemoglobin levels compared to RT-omitted patients (11.7 g/dL vs 12.2 g/dL, p=0.038). The median follow-up time was 38.1 months (interquartile range 34.0-42.3 months). As a higher proportion of RT-treated patients was diagnosed later than RT-omitted patients, median follow-up times were significantly different between the two groups (RT-treated: 25.4 months vs RT-omitted: 42.3 months, p&amp;lt;0.001). TTP was comparable between RT-treated and RT-omitted patients (HR 0.81; 95%CI 0.45-1.48; p=0.492) (Table 1). When sub-grouped by DV risk group, RT was associated with a significant improvement in TTP amongst the high-DV risk patients (HR 0.33; 95%CI 0.13-0.88; p=0.027), but not the low-DV risk patients (HR 0.85; 95%CI 0.40-1.81; p=0.670; interaction's p=0.133) (Figure 1). This subgroup analysis result remained the same after adjusting for International Prognostic Index, presence of B symptoms, bone marrow involvement and hemoglobin levels on multivariable analysis (high-DV risk: adjusted HR 0.29; 95%CI 0.11-0.80; p=0.017 vs low-DV risk: HR 0.86; 95%CI 0.40-1.86; p=0.707; interaction's p=0.087). To examine the impact of the different follow-up durations between the RT-treated and RT-omitted patients on the subgroup analysis, we performed a sensitivity analysis censoring TTP at 24 months. In this sensitivity analysis, RT was again associated with a significant improvement in TTP amongst the high-DV risk patients (adjusted HR 0.29; 95%CI 0.10-0.82; p=0.019), but not those with low-DV risk (adjusted HR 0.70; 95%CI 0.27-1.86; p=0.477; interaction's p=0.217). Conclusion Our study suggests that DLBCL patients who received first line chemotherapy with end-of-treatment PET-CT DV 1-3 may not require consolidative RT. This observation will need longer follow-up duration to ascertain the use of DV as a potential marker to guide patient selection for consolidative RT. We will continue to follow these patients up for overall survival.

Pet-2 Positive during Frontline Therapy: An Early Unfavorable Predictor for Subsequent Salvage High-Dose Chemotherapy (HD-CT) and Autologous Stem Cell Transplant in Relapsed or Refractory Classical Hodgkin Lymphoma

Background: Interim PET (PET-2), performed after two cycles of chemotherapy (CT), is widely adopted to select patients (pt) with classical Hodgkin lymphoma (cHL), who might benefit from omitting radiotherapy (RT) or reducing the number of CT cycles in early stages, as well as intensifying or de-escalating first-line therapy in advanced stages. Furthermore, PET-2 has prognostic value in the front-line and in the salvage treatment. In a retrospective multicenter Italian study on patients experiencing failure of first-line treatment, we recently observed that PET-2 seems to be an early unfavorable predictor for subsequent salvage high-dose (HD) CT and autologous stem cell transplant (ASCT). Aims of Study and Methods: To evaluate the impact of the prognostic factor PET-2, we performed a retrospective observational multicenter study on individual data of 184 pt with relapsed or refractory (R/R) cHL after first-line CT given according to a PET-adapted strategy. R/R pt were treated at 11 Italian centers with one or more lines of salvage CT followed by HD-CT and ASCT from 2009 to 2021. We compared characteristics and outcomes of 125 PET-2 negative with those of 59 PET-2 positive (PET-2+) R/R pt. Study endpoints included Progression-free survival (PFS) (defined as the time from the date of ASCT to progression or death after ASCT, whichever occurred first), Overall Survival (OS) (defined as the time from the date of ASCT to death from any cause or the last date for which information was available), and factors associated with ASCT outcome evaluated by univariate and multivariate analysis. Results Main pt characteristics at relapse or progression among 125 PET-2 negative and 59 PET-2+ pt were as follows: median age 34 vs 32 years, M/F 64/61 vs 28/31, refractory disease 38% vs 76%, early relapse (within 12 months from end of first-line CT) 27% vs 19%, late relapse 35% vs 5%, stage III or IV 43% vs 44%, B symptoms 24% vs 27%, extranodal involvement 26% vs 24% bulky disease 12% each, anemia 9% vs 22%, ECOG PS &amp;gt;1 11% vs 8%. First salvage treatment regimen was BeGEV in 34% vs 14%, IGEV in 34% each, Brentuximab Vedotin +/- Bendamustine in 6% vs 24%, DHAP or DHAOX in 17% vs 24% and other regimens in 10% vs 5% of pt, respectively. Before ASCT, 95 (76%) in the PET-2 negative and 32 (54%) in the PET-2+ group achieved a complete metabolic remission (mCR). After a median follow-up of 36 months, the 3-year PFS and OS were 73.8% (95% CI: 66.2-80.0%) and 89.3% (95% CI: 83.0-93.3%), respectively. Figure 1 shows PFS by PET-2 status. A total of 99 patients underwent ASCT after one line of salvage therapy. At 3 years PFS and OS in patients who underwent ASCT after one line of salvage therapy were 80.6% (95% CI: 68.9-88.3) and 92.2% (95% CI: 82.2-96.7) in the PET-2 negative group, and 56.2% (95% CI: 33.6-73.7) and 90.9% (95% CI: 68.1-97.6) in the PET-2+ group. Thirty-six patients required two and 14 more than two lines of salvage therapy in the PET-2 negative group; the same figures in the PET-2+ group were 21 and 14. There was no significant difference in PFS or OS by type of salvage therapy received in the two groups. In univariate analysis PET-2+ during frontline treatment (HR 2.68, P=0.001), anemia (HR 2.18, P=0.038), &amp;gt;2 lines of salvage therapy to enter a response (HR 3.68, P&amp;lt;0.001), achieving less than mCR prior to ASCT (HR 3.19, P&amp;lt;0.001) and RT performed before ASCT (HR 3.11, P=0.017) were associated with inferior PFS. Achieving less than mCR prior to ASCT (HR 2.86, P= 0.026), &amp;gt;2 lines of salvage therapy needed to enter a response prior to ASCT (HR 4.93, P=0.002), anemia (HR 2.96, P=0.040) and checkpoint inhibitors before ASCT (HR=5.10, P=0.032) were adverse prognostic factors for OS, whereas transplant performed after 2012 was associated with improved OS (HR 0.20, P&amp;lt;0.001). Cox regression multivariable analysis led to the identification of more than two lines of salvage therapy needed before ASCT (HR 3.14, P=0.008) as an independent adverse prognostic factor for PFS. PET-2+ at front-line treatment (HR 1.94, P=0.052), anemia at relapse or progression (HR 2.07, P=0.080) and RT before ASCT (HR=2.52, P=0.086) were associated with increased risk of failing ASCT, although they did not reach statistical significance Conclusions: PET-2+ during frontline CT may represent an early marker of chemo-refractoriness. Nevertheless, PET-2+ patients experiencing failure of a PET-guided treatment intensification can benefit from a prolonged OS after HDCT and ASCT.

Differential Regulation of Genes by the Glucogenic Hormone Asprosin in Ovarian Cancer.

Background: Ovarian cancer (OvCa) is one of the most lethal forms of gynaecological malignancy. Altered energy metabolism and increased aerobic glycolysis in OvCa are hallmarks that demand attention. The glucogenic hormone asprosin is often dysregulated in metabolic disorders such as insulin resistance, diabetes (type 2 and gestational), and preeclampsia. Despite association with metabolic disorders, its role in energy metabolism within the tumour microenvironment is yet to be explored. Here, we study the role of asprosin in OvCa using transcriptomics and expand on functional studies with clinical samples. Methods: RNA sequencing, functional gene enrichment analysis, Western blotting and ImageStream. Results: Following treatment with 100 nM of asprosin, the serous OvCa cell line, SKOV-3, displayed 160 and 173 gene regulatory changes, at 4 and 12 h respectively, when compared with control samples (p < 0.05 and Log2FC > 1). In addition to energy metabolism and glucose-related pathways, asprosin was shown to alter pathways associated with cell communication, TGF-β signalling, and cell proliferation. Moreover, asprosin was shown to induce phosphorylation of ERK1/2 in the same in vitro model. Using liquid biopsies, we also report for novel expression of asprosin’s predicted receptors OR4M1 and TLR4 in cancer-associated circulating cells; with significant reduction seen between pre-chemotherapy and end of first line chemotherapy, in addition to patients under maintenance with bevacizumab +/− olaparib for OR4M1. Conclusions: In relation to OvCa, asprosin appears to regulate numerous signalling pathways in-vitro. The prognostic potential of OR4M1 in liquid biopsies should also be explored further.

Early dynamics of circulating tumor DNA predict chemotherapy responses for patients with esophageal cancer.

We investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC). We compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses was evaluated by the ratio of the variant allele frequency of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50 or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy. Mutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1-3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 20 patients with post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 versus 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03). Early ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients.

Outcome of Postchemotherapy Residual Disease in Extracranial Germ Cell Tumor in Children: Experience of a Tertiary Care Center.

The aim was to review outcome with residual disease at the end of first line chemotherapy in patients with extracranial germ cell tumor (GCT) in our resource limited setting. A retrospective analysis of 196 patients with GCT recruited at Shaukat Khanum Memorial Cancer Hospital (SKMCH) from January 2008 to December 2016. Data fields included site, histopathology, stage, risk groups, baseline alpha fetoprotein, beta human chorionic gonadotropin levels, residuum after primary treatment, completeness of surgical excision and outcomes. Data analysis involved quantitative analysis, mean and median calculations, event free survival (EFS) and overall survival (OS) calculations using Kaplan-Meier curves. In 196 included patients, M:F ratio was 1. There were 81 (41.3%) adolescents. Alpha fetoprotein was >10,000 IU/L in 56 (28.6%) patients. Sixty-two (31.6%) patients had extragonadal disease. Most patients (n=137, 69.9%) presented with advanced stage (III/IV). Seventy-six patients had postchemotherapy residual disease (n=59 [78%] with partial response (PR) and 17 [22%] with no response [NR]). Five-year OS was 83% and EFS was 67%. Five-year EFS of patients with complete remission after primary chemotherapy was 85% versus 70% in patients with PR and 6% in those with NR (P=0.001). OS in patients with complete remission, PR and NR was 94%, 87%, and 46%, respectively. All patients with NR progressed or relapsed and 8/17 died. Four patients with normalized tumor marker response were found to have active tumor on resection of postchemotherapy residuum. Patients with postchemotherapy residual disease in pediatric extracranial GCTs, fare better if their residuum is resected compared with those who do not undergo resection.

A continuous responder algorithm to optimize clinical management of small-cell lung cancer with progastrin-releasing peptide as a simple blood test.

This study aimed to investigate whether changes in progastrin-releasing peptide (ProGRP) levels correlate with treatment response and can be used to optimize clinical management of patients with small-cell lung cancer. Patients with small-cell lung cancer (any stage) receiving chemotherapy were eligible. ProGRP was measured in serum/plasma at baseline and after each chemotherapy cycle using the Elecsys® ProGRP assay (Roche Diagnostics). Treatment response was assessed by computed tomography scan. The primary objective was to examine whether changes in ProGRP levels correlated with computed tomography scan results after two cycles of chemotherapy. The prognostic value of ProGRP among patients receiving first-line chemotherapy was also assessed. Overall, 261 patients from six centers were eligible. Among patients with elevated baseline ProGRP (>100 pg/mL), a ProGRP decline after Cycle 2 was associated with nonprogression (area under the curve: 84%; 95% confidence interval: 72.8-95.1; n = 141). ProGRP changes from baseline to end of Cycle 1 were predictive of response, as determined by computed tomography scan 3 weeks later (area under the curve: 87%; 95% confidence interval: 74.1-99.2; n = 137). This was enhanced by repeat measurements, with a 92% area under the curve (95% confidence interval: 85.3-97.8) among patients with ProGRP data after both Cycles 1 and 2 (n = 123); if a patient experienced a ≥25% decline in ProGRP after Cycle 1, and ProGRP remained stable or decreased after Cycle 2, the probability of finding progression on the interim computed tomography scan at the end of Cycle 2 was almost zero (sensitivity: 100%, specificity: 71%). Both ProGRP levels at baseline and at the end of first-line chemotherapy were prognostic; the latter provided a moderately improved hazard ratio of 2.43 (95% confidence interval: 1.33-4.46; n = 110) versus 1.87 (95% confidence interval: 1.04-3.37; n = 216). In summary, for patients with small-cell lung cancer and elevated baseline ProGRP levels, ProGRP may be a simple, reliable, and repeatable tool for monitoring response to chemotherapy and provide valuable prognostic information.

Choice of second-line systemic therapy in stage IV small cell lung cancer (SCLC) – A decision-making analysis amongst European lung cancer experts

ObjectivesStage IV small cell lung cancer (SCLC) is associated with short survival and progression after first-line systemic therapy frequently occurs within months. Although topotecan is approved for second-line treatment, its efficacy is limited, and treatment heterogeneity exists. Material and methodsThe decision-making patterns for second line treatment of 13 European medical oncologists with expertise in SCLC were analyzed. ResultsThe two criteria most relevant to decision-making were the performance status and the interval of recurrence since first-line treatment.With an interval of less than 3 months since the end of first-line chemotherapy, 62 % of the experts recommended cyclophosphamide, doxorubicin and vincristine (CAV) for fit patients and 54 % recommended topotecan for unfit patients. For an interval of more than 6 months, a clear consensus for a re-challenge with a platinum doublet was achieved (92 %). However, there was no consensus on the second-line therapy with an interval of 3–6 months since the end of first-line therapy. ConclusionReal world practice may differ from recommendations in general guidelines and cannot always be directly derived from trial results as other factor such as habits, patient’s preference, convenience or costs have to be factored in.

Occurrence and Characteristics of Hospitalizations During First-Line Chemotherapy Among Individuals with Metastatic Colorectal Cancer.

ObjectiveChoosing chemotherapy for metastatic colorectal cancer (mCRC) requires balancing clinical effectiveness and risk of complications. This study characterized real-world inpatient/emergency department (ED) hospitalizations during first-line chemotherapy among individuals with mCRC.MethodsThis retrospective cohort study used data from medical and pharmacy claims. All patients had mCRC with ≥1 claim for ≥1 of the 5 most frequently utilized first-line chemotherapy agents (fluorouracil, oxaliplatin, bevacizumab, irinotecan, capecitabine). The main outcome was all-cause hospitalizations (inpatient or ED setting) identified from claims via ICD-9/10-CM coding from index date until 30 days after the end of first-line chemotherapy or last available data.ResultsA total of 717 individuals (mean age 55 years; 58% male; ECOG 0/1/2+/missing in 44%/39%/6%/11%; median follow-up 116 days) met study criteria. Thirty-four distinct chemotherapy regimens were used. Overall, 40% of patients had ≥1 hospitalization (n=285; total 415 hospitalizations); 12% (n=85) had ≥2 hospitalizations. The median time to first hospitalization was 52 days; median inpatient length of stay was 4 days; infections/neutropenia (21%) and bowel-related complications (17%) were the most common issues associated with inpatient hospitalizations. In univariate analyses, insurance plan type, geographical location, ECOG, and renal disease were associated with hospitalization. In multivariable analyses, ECOG ≥1 was associated with a 67% increase (p<0.01) in the odds of hospitalization vs ECOG= 0.ConclusionApproximately 40% of patients with mCRC were hospitalized during the study period. Hospital stays were typically short. Further research is needed to determine how many of these hospitalizations may be avoidable. We also observed a large amount of variation in regimens used in the first-line setting.

1568P - Post progression survival for patients treated with docetaxel/nintedanib in the SENECA trial

BackgroundThe SENECA trial showed similar progression free survival (PFS) and overall survival (OS) in non-squamous non-small cell lung cancer (nsNSCLC) patients (pts) treated with second-line docetaxel/nintedanib, regardless relapsing-time from end of first-line chemotherapy and docetaxel schedule employed (weekly or q3wks) [presented at AIOM 2018]. Because of the lack of data about optimal therapeutic algorithms for nsNSCLC pts and the evidence of a strong biologic rationale for using both antiangiogenic drugs and immunotherapy (IT), aim of the present analysis is to investigate post progression survival of SENECA pts, exploring if third-line IT may be positively influenced from prior nintedanib use. MethodsSENECA enrolled 212 nsNSCLC pts treated with docetaxel and oral nintedanib, with the possibility of maintenance in case of stabilization or response. This evaluation focus on those 64 pts receiving a third-line treatment and aims to compare who underwent IT with the remaining ones. PFS2 and OS2 (time from start of docetaxel/nintedanib to progression during third-line or death, respectively) are investigated. Comparisons between Kaplan Meier curves of the two groups are made with Log Rank test. Hazard Ratios (HR) with 95% Confidence Interval (95%CI) are also reported. ResultsPts treated with third-line (39 with IT, 25 with other agents) correspond to 30.2% of the entire study population; they were 40 males and 24 females, mainly current or former-smokers, with ECOG-performance status 0 in 79.7% of cases and average age of 62.2 years. At the cut-off date (April 29th, 2019), after 39.5 months follow-up, no significant differences appear between pts who received IT after SENECA progression and the other ones in terms of PFS2 (10.78 vs 7.91 months; HR 0.602 [95% CI 0.342-1.058], p-value=0.0821), while there are in terms of OS2 (14.33 vs 11.32 months; HR 0.537 [95% CI 0.292-0.987], p-value=0.0161). ConclusionsDespite the small sample size, this analysis shows a higher post progression survival for nsNSCLC pts treated with docetaxel/nintedanib and third-line IT, postulating a synergism between the two regimens. Being this topic extremely attractive for development of new therapeutic algorithms, this report could be the basis for further investigations. Clinical trial identificationEudraCT: 2014-005016-42. Legal entity responsible for the studyThe authors. FundingBoehringer Ingelheim. DisclosureE. Capelletto: Advisory / Consultancy: Boehringer Ingelheim ; Advisory / Consultancy: AstraZeneca. A. Morabito: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): BMS. F. Grossi: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Amgen. V. Scotti: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre. D. Galetta: Honoraria (self): Boehringer Ingelheim ; Honoraria (self): Roche; Honoraria (self): MSD. S. Novello: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AbbVie. All other authors have declared no conflicts of interest.

Final results of the SENECA (SEcond line NintEdanib in non-small cell lung CAncer) trial

ObjectivesDespite the scant docetaxel's tolerability, second-line association with nintedanib still represents a standard-of-care for non-squamous non-small cell lung cancer (nsNSCLC), giving to rapidly-progressing patients the greatest survival advantage. The SENECA trial is a phase IIb, open-label, study evaluating whether nintedanib/docetaxel can be equally effective and safe regardless docetaxel schedule. Materials and MethodsRecurrent nsNSCLC patients were stratified into cohort 1 and 2, according to relapse-time (within or over 3 months) from end of first-line chemotherapy. They were treated with docetaxel (T1: 33 mg/mq on days 1 and 8 in a 21-days cycle; T2: 75 mg/mq q3wks) plus nintedanib, allowing maintenance in case of disease-control. Primary endpoint was progression-free survival (PFS) by investigator’s assessment; secondary endpoints: overall survival (OS), safety and quality-of-life. ResultsBetween January 2016-April 2018, 212 patients were evaluated: 30 resulted screening-failures, 12 were excluded for lack of compliance. According to investigator’s choice, 85 patients received T1 docetaxel and 85 T2; 138 (81.2%) were stratified in C1, 32 (18.8%) in C2, with a median relapse-time of 0.54 and 9.29 months, respectively. Baseline characteristics were balanced between groups. After 35.5 months follow-up, no survival differences appear between cohorts and treatments; toxicity seems to be slightly higher in T2, especially for chemotherapy-related events. Perception of quality-of-life remains stable and docetaxel schedule doesn’t modify patients’ load. ConclusionThe SENECA trial confirms efficacy of second-line nintedanib/docetaxel for nsNSCLC, regardless time of recurrence and docetaxel schedule; higher toxicities for q3wks docetaxel, without alterations in quality-of-life, have been described, underling the possibility, adopting the weekly schedule, to maintain efficacy with better tolerability.

Vascular endothelial growth factor receptor 2 (VEGFR2) correlates with long-term survival in patients with advanced high-grade serous ovarian cancer (HGSOC): a study from the Tumor Bank Ovarian Cancer (TOC) Consortium

The impact of angiogenesis on long-term survival of high-grade serous ovarian cancer (HGSOC) patients remains unclear. This study investigated whether angiogenic markers correlated with 5-year progression-free survival (PFS) in a large cohort of matched advanced HGSOC tissue samples. Tumor samples from 124 primary HGSOC patients were retrospectively collected within the Tumor Bank Ovarian Cancer ( http://www.toc-network.de ). All patients were in advanced stages (FIGO stage III-IV). No patient had received anti-angiogenesis therapy. The cohort contains 62 long-term survivors and 62 controls matched by age and post-surgical tumor residuals. Long-term survivors were defined as patients with no relapse within 5years after the end of first-line chemotherapy. Controls were patients who suffered from first relapse within 6-36months after primary treatment. Samples were assessed for immunohistochemical expression of vascular endothelial growth factor (VEGF) A and VEGF receptor 2 (VEGFR2). Expression profiles of VEGFA and VEGFR2 were compared between the two groups. Significant correlation between VEGFA and VEGFR2 expression was observed (p < 0.0001, Spearman coefficient 0.347). A high expression of VEGFR2 (VEGFR2high) was found more frequently in long-term survivors (77.4%, 48/62) than in controls (51.6%, 30/62, p = 0.001), independent of FIGO stage and VEGFA expression in multivariate analysis (p = 0.005). Also, VEGFR2high was found the most frequently in women with PFS ≥ 10years (p = 0.001) among all 124 patients. However, no significant association was detected between VEGFA expression and 5-year PFS (p = 0.075). VEGFR2 overexpression significantly correlated with long-term PFS in HGSOC patients, independent of age, FIGO stage, tumor residual and VEGFA expression.

Occurrence and characteristics of hospitalizations during first-line chemotherapy among individuals with metastatic colorectal cancer.

691 Background: Choosing chemotherapy for metastatic colorectal cancer (mCRC) requires balancing clinical effectiveness and risk of complications. This study characterized real-world inpatient/ER hospitalizations (HOSP) during first-line chemotherapy among individuals with mCRC. Methods: We conducted a retrospective cohort study of adults with mCRC identified using claims data from the HealthCore Integrated Research Environment as initiating first-line chemotherapy from 12/23/2013 to 06/30/2016 (no minimum follow-up). Cohorts were analyzed in aggregate and for the most frequently observed first-line agents (5 overlapping subcohorts). HOSPs were identified from initiation of first-line chemotherapy to 30 days after the end of first-line chemotherapy or last available data. Results: A total of 717 individuals (mean age 55y; 58% male; 44%/39%/6%/12% with ECOG = 0/1/2+/missing; median follow-up 116 days) met study criteria. Metastasis was most commonly to the liver (51%) and 53% of patients had cancer-attributable morbidities. Chemotherapies included 5-FU (79%), oxaliplatin (67%), bevacizumab (58%), irinotecan (21%), and capecitabine (19%). Overall, 40% of patients had ≥1 HOSP [n = 285; total 415 events], ranging from 38% to 49% across the 5 chemotherapy-based subcohorts; 12% (n = 85) had &gt; 1 HOSP. The median time to first HOSP for patients with an event was 52 days. The median length of inpatient stays was 4 days; Infections/neutropenia (21%), bowel-related complications (17%), cardiac and circulatory disorders (9%), malnutrition (5%), pain (5%) and renal disease (2%) were the most common issues associated with inpatient HOSPs. An increase in HOSPs was observed with worsening ECOG status: 0 (34%), 1 (46%), and 2+ (65%). In regression analyses, ECOG≥1 was associated with a 64%-72% increase (p &lt; 0.01) in the odds of HOSPs compared to patients with ECOG = 0. Conclusions: Approximately 40% of mCRC patients had hospitalizations during the study period. Hospital stays were typically short and associated with infections, neutropenia, or bowel-related complications. Further research is needed to determine how many of these hospitalizations may be avoidable.

Quality of life across chemotherapy lines in patients with advanced colorectal cancer: a prospective single-center observational study.

Palliative chemotherapy in patients with nonresectable advanced colorectal carcinoma is performed to prolong survival, alleviate tumor-associated symptoms, and maintain or improve health-related quality of life (HRQOL). In this prospective single-center observational study, we assessed HRQOL across the various lines of palliative chemotherapy. HRQOL data were acquired using the EORTC Quality of Life Questionnaire-C30 (QLQ-C30) questionnaire. The first assessment was performed at the beginning of each chemotherapy line, the second after three cycles, and the third at the end of chemotherapy. Further assessments were conducted during checkups every 3 months in our outpatient unit. In total, 100 consecutive patients with colorectal carcinoma (mean age 66.4 years; 60 % men) treated with palliative chemotherapy were recruited. Generally, QOL deteriorated constantly across time. Physical functioning, fatigue, pain, dyspnea, and appetite worsened steadily from first-line chemotherapy to the later treatment phase. Global QOL, emotional functioning, and role functioning improved slightly after the end of first-line chemotherapy, deteriorated during second-line chemotherapy to the level of first-line chemotherapy, and further deteriorated in the later treatment phases. In additional analyses, we found the largest differences between patients with and without a treatment response for pain (19.0 vs. 37.2 points) and appetite loss (17.4 vs. 32.7 points). The individual QOL domains deteriorated constantly across time. Our data indicate that patients undergoing first- and second-line palliative chemotherapy experience stabilization of global QOL and psychosocial symptoms. We also found that unselected patients who achieved a treatment response had a lower symptom burden and better QOL than did patients with progressive disease.

Comparison of metabolic and anatomic response to chemotherapy based on PERCIST and RECIST in patients with advanced stage non-small cell lung cancer.

The aim of this study was to explore the prognostic role of metabolic response to chemotherapy, determined by FDG-PET, in patients with metastatic non-small-cell lung cancer (NSCLC). Thirty patients with metastatic NSCLC were analyzed for prognostic factors related to overall survival (OS) and progression free survival (PFS). Disease evaluation was conducted with FDG-PET/CT and contrast-enhanced CT prior to and at the end of first-line chemotherapy. Response evaluation of 19 of 30 patients was also performed after 2-3 cycles of chemotherapy. Morphological and metabolic responses were assessed according to RECIST and PERCIST, respectively. The median OS and PFS were 11 months and 6.2 months, respectively. At the end of first-line chemotherapy, 10 patients achieved metabolic and anatomic responses. Of the 19 patients who had an interim response analysis after 2-3 cycles of chemotherapy, 3 achieved an anatomic response, while 9 achieved a metabolic response. In univariate analyses, favorable prognostic factors for OS were number of cycles of first-line chemotherapy, and achieving a response to chemotherapy at completion of therapy according to the PERCIST and RECIST. The OS of patients with a metabolic response after 2-3 cycles of chemotherapy was also significantly extended. Anatomic response at interim analysis did not predict OS, probably due to few patients with anatomic response. In multivariate analyses, metabolic response after completion of therapy was an independent prognostic factor for OS. Metabolic response is at least as effective as anatomic response in predicting survival. Metabolic response may be an earlier predictive factor for treatment response and OS in NSCLC patients.

42P THE PREDICTIVE SIGNIFICANCE OF LEPTIN, ADIPONECTIN, RESISTIN AND GHRELIN SERUM LEVELS AT DIAGNOSIS OF PATIENTS WITH SMALL CELL LUNG CANCER

Introduction: Adipose tissue secretes cytokines with pro-inflammatory and anti-inflammatory properties. Cancer is associated with a state of chronic inflammation, characterized by abnormal cytokine production which might affect both tumor initiation and tumor progression. Ghrelin, an orexigenic peptide is also expressed in malignant conditions and, therefore, may exert such variable autocrine and/or paracrine function in cancer. Our aim was to assess the role of adipose tissue in generalized inflammatory state of small cell lung cancer patients and the possible use of leptin, adiponectin, resistin and ghrelin as prognostic markers. Correlation of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha was also studied. Methods: Serum levels of leptin, adiponectin, resistin, ghrelin, interleukin-6 and tumor necrosis factor-alpha were determined in 50 patients with small cell lung cancer using commercially available ELISA at diagnosis and at the end of first-line chemotherapy. Epidemiological, anthropometrical and laboratory data were assessed. Results: Multivariate analysis showed a close relationship between serum leptin, resistin, ghrelin and interleukin-6 with the overall survival. Worse clinical outcome was associated with an increase of leptin and resistin levels. However, higher serum ghrelin and interleukin-6 levels were correlated with longer overall survival. No statistically significant relationships between investigated serum levels of adiponectin and tumor necrosis factor-alpha with overall survival were found. Conclusions: Despite no direct involvement of adiponectin and tumor necrosis factor-alpha, leptin, resistin, ghrelin and interleukin-6 may play a role in the pathogenesis of small cell lung cancer and further studies are necessary in order to determine their potential role as prognostic markers. Disclosure: All authors have declared no conflicts of interest.

Post-treatment prognostic model for patients (pts) with metastatic urothelial cancer (UC) treated with first-line chemotherapy.

256 Background: Models to predict the outcome of pts with metastatic UC, based on pre-treatment variables, have previously been developed. However, pts often request “updated” prognostic estimates based on their response to treatment. This is particularly relevant in first-line treatment of metastatic UC, a disease state for which a fixed number of cycles of chemotherapy are typically administered. Methods: Data were pooled from 317 pts enrolled on eight trials evaluating first-line cisplatin-based chemotherapy in metastatic UC. Variables were combined in a Cox proportional hazards model to produce a nomogram to predict survival from end of treatment. The nomogram was validated externally using data from a trial of MVAC versus docetaxel plus cisplatin (n=148). Results: The median survival from end of treatment was 10.65 months [95% CI 9.20 – 13.24]; 69% of patients had died. Baseline (white blood count, ECOG performance status, number of visceral metastatic sites) and post-treatment (treatment response, duration of treatment, reason for treatment discontinuation) variables were evaluated. The Cox proportional hazard model is shown in the Table. The duration of treatment and reason for treatment discontinuation were not significantly associated with survival. The four significant variables were included in a nomogram. The nomogram achieved a bootstrap-corrected concordance index of 0.68. Upon external validation, the nomogram achieved a concordance index of 0.67. Conclusions: A model derived from pre- and post-treatment variables was constructed to predict survival from the end of first-line chemotherapy in pts with metastatic UC. This model may be useful for pt counseling and for stratification of trials exploring “maintenance” treatment. [Table: see text]

Abstract P2-01-13: Prognostic value of Circulating Tumor Cells count at progressive disease after first line chemotherapy metastatic breast patients in a large prospective multicenter trial including serum tumor markers (IC 2006–04 study)

Abstract Background: The IC 2006–04 study included prospectively 267 metastatic breast cancer patients before the start of first line chemotherapy. We previously reported and confirmed the prognostic and predictive of CTC counts before the start of treatment and after 3–4 &amp; 6–9 weeks of treatment (Pierga, JY SABCS 2010, Ann Oncol 2012). We report here the results of the last CTC count performed at tumor progression (i.e. end of first line chemotherapy). Methods: Patients were included in the study from 06/07 to 9/09. CTC were counted by the CellSearch® system at tumor progression (clinical and/or radiological progression). Results: 211 patients experienced a tumor progression at time of final data analysis and the planned CTC count has been performed in 61 patients. High CTC count (≥5 CTC/7.5ml) at progression was observed in 22 patients (36%) and was associated with elevated Cyfra 21–1 and ALP and was not associated with elevated CEA, CA 15–3, LDH, the elapsed progression-free survival, the onset of new metastasis. No CTC was detected at tumor progression in the 5 patients with HER2+ disease, in line with our previous results. The prognostic markers for overall survival at tumor progression were high CTC count (median overall survival 8 vs 19 months, p = .0006) and elevated Cyfra 21–1 (p = .001). Other serum markers (CEA, CA15-3, ALP, LDH) and tumor subtypes had no prognostic value at univariate analysis. At multivariate analysis, the two prognostic factors for overall survival were high CTC count (RR = 2.3 p = 0.03) and elevated Cyfra 21–1 (RR = 3.6 p = 0.02). Conclusion: In the prospective IC 2006–04 study, among the different markers tested at tumor progression during the first line chemotherapy for metastatic breast cancer, high CTC count and elevated Cyfra 21–1 levels were the only two independent prognostic markers for overall survival. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-13.

Les traitements de maintenance dans les cancers bronchiques non à petites cellules métastatiques en 2012

Treatment of advanced non-smallcell lung cancer is usually based on several lines of therapy separated by treatment-free intervals, in which each new line is started when tumor progression is detected. The maintenance strategy consists of continuing an appropriate, well-tolerated treatment immediately after the end of first-line chemotherapy, in order to maintain the initial therapeutic benefit and to avoid rapid clinical deterioration that would rule out further treatment. Maintenance can use either a non-platinum component of induction chemotherapy defining ‘continuation maintenance’ or initiation of a new agent consisting in ‘switch maintenance’. Clinical trials show that maintenance therapy with pemetrexed or erlotinib provides a significant clinical benefit in terms of disease control and survival. Maintenance therapy is an important option in first-line treatment of non-small cell lung cancer but more reliable criteria is needed to identify the patientsmost likely to benefit from either continuation or switch maintenance.