Adjuvant Platinum-based Chemotherapy Research Articles

Nomogram of Combining CT-Based Body Composition Analyses and Prognostic Inflammation Score: Prediction of Survival in Advanced Epithelial Ovarian Cancer Patients

To investigate the value of body composition changes measured by quantitative computer tomography (QCT) in evaluating the prognosis of advanced epithelial ovarian cancer (AEOC) patients who underwent primary debulking surgery (PDS) and adjuvant platinum-based chemotherapy, and constructed a nomogram model for predicting survival in combination with prognostic inflammation score (PIS). Fifty-seven patients with AEOC between 2012 and 2016 were retrospectively enrolled. Pre- and post-treatment CT images were used to analyze the body composition biomarkers. The subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), cross-sectional area of paraspinal skeletal muscle area (PMA), skeletal muscle density (SMD), body mineral density (BMD) were measured from two sets of CT images. In multivariate analyses, VFA gain, PMA loss, BMD loss, and PIS were independent risk factors of overall survival (OS) (HR=3.7, 3.0, 2.8, 1.9, respectively, all p < 0.05). Receiver operating characteristic (ROC) curves showed that the prognostic model combining body composition changes (BCC) and PIS had the highest predictive performance (area under the curve=0.890). The concordance index (C-index) of the prognostic nomogram was 0.779 (95% CI, 0.673-0.886). Decision curve analysis (DCA) demonstrated the prognostic nomogram had a great distinguishing performance. CT-based body composition analyses and PIS were associated with poor OS for AEOC patients who underwent PDS and adjuvant platinum-based chemotherapy. The prognostic nomogram with a combination of BCC and PIS was dependable in predicting survival for AEOC patients during treatment.

Prognostic impact of Schlafen 11 in bladder cancer patients treated with platinum-based chemotherapy.

ABSTRACTThe utility of Schlafen 11 (SLFN11) expression as a predictive biomarker for platinum‐based chemotherapy has been established for cancers from different histologies. However, the therapeutic relevance of SLFN11 in bladder cancer (BC) is unknown. Here, we examined the clinicopathologic significance of SLFN11 expression across 120 BC cases by immunohistochemistry. We divided the cases into two cohorts, one including 50 patients who received adjuvant or neoadjuvant platinum‐based chemotherapy, and the other including 70 BC patients treated by surgical resection without chemotherapy. In the cohort of 50 BC cases treated with platinum‐based chemotherapy, the SLFN11‐positive group (n = 25) showed significantly better overall survival than the SLFN11‐negative group (n = 25, P = .012). Schlafen 11 expression correlated significantly with the expression of luminal subtype marker GATA3. Multivariate analyses identified SLFN11 expression as an independent prognostic predictor (odds ratio, 0.32; 95% confidence interval, 0.11‐0.91; P = .033). Conversely, in the cohort of 70 BC cases not receiving platinum‐based chemotherapy, the SLFN11‐positive group (n = 29) showed significantly worse overall survival than the SLFN11‐negative group (n = 41, P = .034). In vitro analyses using multiple BC cell lines confirmed that SLFN11 KO rendered cells resistant to cisplatin. The epigenetic modifying drugs 5‐azacytidine and entinostat restored SLFN11 expression and resensitized cells to cisplatin and carboplatin in SLFN11‐negative BC cell lines. We conclude that SLFN11 is a predictive biomarker for BC patients who undergo platinum‐based chemotherapy and that the combination of epigenetic modifiers could rescue refractory BC patients to platinum derivatives by reactivating SLFN11 expression.

Options for the Treatment of Mucinous Ovarian Carcinoma.

Complete surgical resection is the gold-standard treatment for all mucinous ovarian carcinoma (MOC) cases. Advanced-stage disease is often additionally treated with adjuvant platinum-based chemotherapy; however, these were developed largely against the more common high-grade serous ovarian carcinoma and have low efficacy in treating MOC. More effective therapeutics are needed to treat late-stage and platinum-resistant tumors; however, traditional drug development and clinical trial paradigms are a major challenge for such a rare disease. New approaches to support evidence-based treatment decisions are required, such as registry trials. Recently, a number of targeted therapies have emerged as viable treatment options in other cancer types, and for some of these, the actionable tumor mutations are also seen in MOC. Thus, a promising alternative approach to provide benefit to current MOC patients involves DNA sequencing to identify a tumor's unique mutational profile and allow matching to available targeted agents. Such a pipeline can involve special approval to administer a drug already approved for clinical use in other cancer types to a given MOC patient, or their inclusion in existing ongoing clinical trials, such as basket trials encompassing patients with tumors from a range of anatomical sites. Implementation of such personalized medicine can be boosted using improved pre-clinical models, where through a clinical research collaboration a patient's own tumor cells can be used to a test a range of putative therapies prior to administration in the clinic, enabling selection of the available pharmaceutical/s that give any given patient the best possible chance of cancer remission.

Thioredoxin reductase-1 levels are associated with NRF2 pathway activation and tumor recurrence in non-small cell lung cancer

Activating mutations in the KEAP1/NRF2 pathway characterize a subset of non-small cell lung cancer (NSCLC) associated with chemoresistance and poor prognosis. We herein evaluated the relationship between 64 oxidative stress-related genes and overall survival data from 35 lung cancer datasets. Thioredoxin reductase-1 (TXNRD1) stood out as the most significant predictor of poor outcome. In a cohort of NSCLC patients, high TXNRD1 protein levels correlated with shorter disease-free survival and distal metastasis-free survival post-surgery, including a subset of individuals treated with platinum-based adjuvant chemotherapy. Bioinformatics analysis revealed that NSCLC tumors harboring genetic alterations in the NRF2 pathway (KEAP1, NFE2L2 and CUL3 mutations, and NFE2L2 amplification) overexpress TXNRD1, while no association with EGFR, KRAS, TP53 and PIK3CA mutations was found. In addition, nuclear accumulation of NRF2 overlapped with upregulated TXNRD1 protein in NSCLC tumors. Functional cell assays and gene dependency analysis revealed that NRF2, but not TXNRD1, has a pivotal role in KEAP1 mutant cells’ survival. KEAP1 mutants overexpress TXNRD1 and are less susceptible to the cytotoxic effects of the TXNRD1 inhibitor auranofin when compared to wild-type cell lines. Inhibition of NRF2 with siRNA or ML-385, and glutathione depletion with buthionine-sulfoximine, sensitized KEAP1 mutant A549 cells to auranofin. NRF2 knockdown and GSH depletion also augmented cisplatin cytotoxicity in A549 cells, whereas auranofin had no effect. In summary, these findings suggest that TXNRD1 is not a key determinant of malignant phenotypes in KEAP1 mutant cells, although this protein can be a surrogate marker of NRF2 pathway activation, predicting tumor recurrence and possibly other aggressive phenotypes associated with NRF2 hyperactivation in NSCLC.

Homologous Recombination Deficiency Assays in Epithelial Ovarian Cancer: Current Status and Future Direction.

Epithelial ovarian cancer (EOC) patients are generally diagnosed at an advanced stage, usually relapse after initial treatments, which include debulking surgery and adjuvant platinum-based chemotherapy, and eventually have poor 5-year survival of less than 50%. In recent years, promising survival benefits from maintenance therapy with poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) has changed the management of EOC in newly diagnosed and recurrent disease. Identification of BRCA mutations and/or homologous recombination deficiency (HRD) is critical for selecting patients for PARPi treatment. However, the currently available HRD assays are not perfect predictors of the clinical response to PARPis in EOC patients. In this review, we introduce the concept of synthetic lethality, the rationale of using PARPi when HRD is present in tumor cells, the clinical trials of PARPi incorporating the HRD assays for EOC, the current HRD assays, and other HRD assays in development.

MA15.05 Rates of Guideline-Concordant Surgery and Adjuvant Chemotherapy Among Patients in The U.S. ALCHEMIST Study (Alliance)

The standard of care for resectable non-small cell lung cancer (NSCLC) includes anatomic surgical resection with adequate lymph node dissection and adjuvant chemotherapy for appropriate patients. Historically, many patients with early-stage NSCLC have not received such guideline-concordant therapy. Longstanding disparities have also existed in the delivery of quality cancer care by sociodemographic factors such as race and ethnicity. This could impact interpretation of adjuvant therapy trials. In this descriptive analysis, we examined rates of guideline-concordant treatment among patients enrolled in ALCHEMIST, a large U.S.-wide screening trial to facilitate enrollment to targeted adjuvant treatment trials for resectable NSCLC, enrolling at 754 sites. Patients who enrolled in ALCHEMIST (Alliance A151216) from August 18, 2014-April 1, 2019 who did not enroll in a therapeutic adjuvant therapy clinical trial were included; these patients had stage IB-IIIA disease (AJCC 7th edition), with tumors at least 4 cm in size and/or positive lymph nodes. Four outcomes are reported: whether patients (1) had adequate lymph node dissection per National Comprehensive Cancer Network criteria (≥ one N1 nodal station plus ≥ three N2 nodal stations); (2) received any adjuvant chemotherapy; (3) received any cisplatin-based adjuvant chemotherapy; and (4) received at least 4 cycles of adjuvant chemotherapy. Associations between these binary outcomes and sociodemographic variables were explored using unadjusted modified Poisson regression models accounting for trial site-level correlation. 2,834 patients were analyzed; 53.4% had adequate lymph node dissection; 57.1% received any adjuvant chemotherapy; 34.1% received any cisplatin-based adjuvant chemotherapy; and 43.7% received at least four cycles of adjuvant platinum-based chemotherapy. The distribution of treatment by key clinical and demographic characteristics is provided in Table 1; adjuvant chemotherapy was delivered more often to patients who were younger, had more advanced stage, had non-squamous NSCLC, and did not have EGFR-mutant tumors. Rates were similar across categories of race and ethnicity. Many patients with early-stage NSCLC did not receive adequate lymph node dissection or adjuvant chemotherapy despite indications for such treatment, even among patients who consented for testing to inform eligibility for an adjuvant therapy clinical trial. No substantial disparities in treatment were observed by race or ethnicity in this clinical trial cohort, contrary to historical patterns in population-based cohorts. Efforts are needed to optimize utilization of therapies with proven benefit for early-stage NSCLC. These results may inform the generalizability of clinical trials of novel therapies in the adjuvant setting. Support: U10CA180821, U10CA180882; U10CA180820 (ECOG-ACRIN); https://acknowledgments.alliancefound.org; Clinicaltrials.gov Identifier: NCT02194738

Immunonutritional Indices in Non-small-cell Lung Cancer Patients Receiving Adjuvant Platinum-based Chemotherapy.

Adjuvant platinum-based chemotherapy (APC) has been the standard of care for patients with non-small-cell lung cancer (NSCLC) who have undergone complete pulmonary resection. This study analyzed the clinical and prognostic significance of immunonutritional indices in NSCLC patients receiving APC. We retrospectively reviewed 110 patients from 2008 to 2016. Three immunonutritional indices were calculated: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI). The median age was 64 years, and 66 patients were males. Each index showed a significant correlation with primary tumor length. NLR and PLR were significantly correlated with vascular invasion. Prognostic analyses revealed that each index was significantly correlated with postoperative recurrence-free survival (RFS) and overall survival (OS). On multivariate analyses, PNI was an independent predictor of RFS and OS. Host immunonutritional status may have a significant effect on the postoperative prognosis of NSCLC in patients receiving APC.

Prediction Models for Complete Resection in Secondary Cytoreductive Surgery of Patients With Recurrent Ovarian Cancer.

The most advanced epithelial ovarian cancer develops recurrent disease despite maximal surgical cytoreduction and adjuvant platinum-based chemotherapy. Treatment with secondary cytoreductive surgery (SCS) combined with chemotherapy or with chemotherapy alone for patients with platinum-sensitive recurrent ovarian cancer (ROC) is currently under heated discussion. Encouragingly, the results of the AGO DESKTOP III Study and the SOC1/SGOG-OV2 trial, which have been published recently, showed a striking advantage in terms of overall survival (OS) and progression-free survival (PFS) of ROC patients undergoing SCS compared to chemotherapy alone; moreover, a benefit of SCS exclusively for patients with complete gross resection (CGR) was particularly highlighted. CGR is considered the ultimate goal of SCS, on condition that the balance between maximal survival gain and minimal operative morbidity is maintained. Several models have been proposed to predict the rate of CGR, such as the MSK criteria, the AGO score, and the Tian model, over the last 15 years. This summary is mainly about the several previously published prediction models for CGR in SCS of ROC patients and discusses the effectiveness and limitations of these prediction models.

Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB–IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial

Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients. IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II-IIIA population, and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting). Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II-IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88; p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%). IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC. F Hoffmann-La Roche and Genentech.

Benefit of adjuvant chemotherapy for patients with stage IB non-small cell lung cancer: a systematic review and meta-analysis.

BackgroundAdjuvant chemotherapy (ACT) is routinely the recommended treatment for patients with advanced non-small cell lung cancer (NSCLC) but remains a controversial option in stage IB patients. We therefore pooled the current evidence to determine the prognostic impact of ACT in stage IB NSCLC patients in the context of the eighth tumor, node, metastasis (TNM) staging system.MethodsFive electronic databases were searched for eligible studies up to December 2020 without language restrictions. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS). Search results were filtered by a set of eligibility criteria and analyzed in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The risk of bias was assessed independently using a modified set. Stata 16.0 was used for general data analysis and meta-analysis, and subgroup analyses were performed to investigate the source of interstudy heterogeneity.ResultsIn all, 12 eligible studies were identified and 15,678 patients included. Our results demonstrated that ACT was associated with improved OS [n=11; hazard ratio (HR) =0.65; 95% confidence interval (CI): 0.60–0.70; P<0.001; I2=33.4%, P=0.131] and DFS (n=9; HR =0.73; 95% CI: 0.63–0.83; P<0.001; I2=66.7%, P=0.002) in stage IB NSCLC patients. Subgroup analysis by histology indicated that administration of ACT conferred more favorable survival to both stage IB squamous cell carcinoma (n=1; HR =0.56; 95% CI: 0.28–0.84; P<0.001) and adenocarcinoma (n=6; HR =0.59; 95% CI: 0.47–0.71; P<0.001; I2=31.0%, P=0.203). Meanwhile, both platinum-based ACT (n=7; HR =0.62; 95% CI: 0.51–0.74; P<0.001; I2=44.8%, P=0.093) and other regimens (n=2; HR =0.66; 95% CI: 0.61–0.72; P<0.001; I2=0.7%, P=0.316) could benefit patients with stage IB disease.DiscussionACT might provide survival benefits to patients with stage IB NSCLC irrespective of histology or regimens. Patient selection and time trend biases were inevitable due to the limitation of retrospective studies. More prospective studies should be initiated to investigate the optimal ACT regimens in different histologic types in stage IB NSCLC patients.

Adjuvant platinum-based chemotherapy in radically resected adrenocortical carcinoma: a cohort study

BackgroundAfter radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy.MethodsIn this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort (n = 268). For both approaches, we accounted for immortal time bias.ResultsOf the 31 patients in the platinum cohort (R0 n = 25, RX n = 4, R1 n = 2; ENSAT Stage II n = 11, III n = 16, IV n = 4, median Ki67 30%, mitotane n = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95% CI 0.09–0.42; P < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29–0.89, P = 0.021) and for OS 0.25 (0.09–0.69; P = 0.007).ConclusionsOur study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.

Platinum-based adjuvant chemotherapy for upper tract urothelial carcinoma: a change of paradigm? A meta-analysis of aggregate data.

We performed a systematic review and meta-analysis to evaluate the role of platinum-based adjuvant chemotherapy (AC) in upper tract urothelial carcinoma. Eligible studies were identified using Pubmed/Medline, Cochrane library, Embase and meeting abstracts. Outcomes of interest included: overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS). Platinum-based AC was associated with improved DFS, while the benefit in OS and CSS was not statistically significant compared to observation. Conversely, platinum-based AC showed a modest OS benefit in an analysis combing multivariable HRs with estimated HRs from Kaplan-Meier curves. Our results suggest that platinum-based AC is associated with improved DFS and a modest OS benefit in patients with locally advanced urothelial carcinomas.

The oncological outcome of the patients with ovarian clear cell cancer: Platinum-based adjuvant chemotherapy is not suitable

Background/Aim: Ovarian clear cell cancer (OCCC) is one of the rare histological subtypes of epithelial ovarian cancer with different tumoral biology and prognosis. This study aimed to evaluate the clinical and pathological data of OCCC and define the prognostic factors. Methods: Sixty-three patients with OCCC were included in this retrospective cross-sectional study. Patients with mixed-type clear cell carcinoma were excluded. Response to chemotherapy was assessed according to the WHO criteria. The survival analysis was performed using the Kaplan-Meier method and survival curves were compared with the log-rank test. Cox proportional hazards model was used in the multivariate analysis. Results: The mean age of patients was 54.6 (10.7) years. Twenty-three (36.5%) patients were stage III&IV. Systematic lymphadenectomy was performed in 55 (87.3%) patients and 13 (23.6%) had lymph node metastasis. Maximal cytoreduction was performed in 57 (90.5%) patients, optimal cytoreduction, in 1 (1.6%) patient, and suboptimal cytoreduction was performed in 2 (3.2%) patients via primary cytoreductive surgery. The complete clinical response rate following adjuvant treatment was 61.1% in stages III&IV. Five-year failure-free survival was 63% in the entire cohort. According to the multivariate analysis, the stage was an independent risk factor for treatment failure. The probability of recurrence increased 24 times in stages III and IV (95% Confidence interval: 5.561-104.421; P<0.001). Conclusion: The stage of the disease is a prognostic factor for OCCC. The response to platinum-based chemotherapy in OCCC is very low.

Role of involved-site radiation in the management of recurrent ovarian malignancies: a single institutional experience

Objectives: Radiation therapy is commonly used to preserve local control in patients with oligometastatic disease. The objective of this study was to evaluate our institutional experience utilizing involved-site radiation (ISRT) in the management of recurrent ovarian cancer. Methods: Twenty-eight patients with recurrent ovarian cancer treated with ISRT between 2008-2019 were identified from our institutional database. A retrospective review of patient charts was performed. ISRT was delivered to sites of gross disease for all the patients who developed localized oligorecurrence following prior lines of chemotherapy to preserve local control. Results: The median age of diagnosis was 53 years range (23-70 years). Serous cystadenocarcinoma was the most common histological type (60.7%), followed by endometroid (14.3%) and clear cell subtypes (10.7%). Most patients had stage 3C (46.4%) at initial diagnosis. Many patients (79%) underwent initial optimal debulking, followed by platinum-based adjuvant chemotherapy. ISRT was considered mostly for patients who had recurrent disease confined to the pelvis (85.7%). The median time from the initial diagnosis to the initiation of ISRT was 49 months, and the median follow-up time after ISRT was 9.5 months (range 0-51 months). Most of the patients had a median of 2 recurrences (range 0-8) before receiving ISRT. The median radiation dose was 48 Gy (range 38-66 Gy). The median time to initiate additional chemotherapy after the ISRT was 2 months (range 0-23 months). The one-year rates of local control and distal progression following ISRT were 78% and 64.7%, respectively. The one-year overall survival rate after completion of ISRT was 72.5%. A majority of patients with recurrent disease following ISRT were treated with additional chemotherapy (10/19), and one patient with an out of field recurrence was managed with complete resection of distal metastases. The median time to initiate additional chemotherapy after the ISRT was 2 months (range 0-23 months). All patients tolerated ISRT well, and no ≥ grade 3 toxicities were observed. Conclusions: ISRT in recurrent ovarian cancer offers reasonable local control in well-selected patients with oligo-recurrences of ovarian cancer. Treatment was well-tolerated and may offer an alternative to interval-debulking surgery or chemotherapy in selected patients.

Loss of muscle mass during cancer therapy is associated with poor oncologic outcomes in epithelial ovarian cancer

<h3>Objectives:</h3> Sarcopenia, a loss of muscle mass and function, is a risk factor for decreased survival in advanced epithelial ovarian cancer (EOC). Little is known about the effect of primary treatment for EOC on sarcopenia and how this relates to patient outcomes. Our aim was to determine the change in sarcopenia measures over the course of primary EOC treatment and if changes are associated with overall survival. <h3>Methods:</h3> We utilized an institutional EOC surgical database to identify patients diagnosed with stage IIIC or IV EOC who received primary debulking surgery (PDS) and adjuvant chemotherapy at our institution. Patients were included if they had pre and post-treatment computerized tomography (CT) scans available. Patient CT scans were analyzed for body composition, including skeletal muscle area and skeletal muscle index (SMI, skeletal muscle area normalized for patient height). Sarcopenia was defined as a SMI <39 cm²/m². Percent change in body composition measures and change in sarcopenia were analyzed for association with death and disease progression based on fitting Cox proportional hazards models. <h3>Results:</h3> We identified 116 patients who underwent PDS followed by adjuvant chemotherapy from 2006-2016 at a large volume single institution. Most patients (73%) had 6 cycles of adjuvant platinum-based chemotherapy. A post-treatment CT scan was obtained at a median of 25 days following the last day of treatment. Overall, there was a decrease in the mean skeletal muscle area and skeletal muscle index, with a percent change of 2.6% from pre- to post-treatment CT scans. Almost half of patients (54/116; 47%) were sarcopenic at some point during their treatment. Of the 116 patients, 62 (53%) were never sarcopenic, 5 (4%) were initially sarcopenic but not at the time of post-treatment scan, 28 (24%) were sarcopenic on both CT scans, and 21 (18%) were only sarcopenic at the time of post-treatment CT scan.The 21 patients who became sarcopenic during the course of treatment were more likely to have an American Society of Anesthesiologists physical status score more than 2 (62% vs 43%), preoperative albumin <3.5 g/dL (24% vs 14%), stage IV disease (48% vs 21%) and to have undergone a high complexity surgery (57% vs 33%). Developing sarcopenia during treatment was associated with both an increased risk of disease progression (HR=1.43; 95% CI 0.85-2.40; p=0.18) and death (HR=1.78; 95% CI 1.00-3.18; p=0.05) when compared to all others (Figure). The development of sarcopenia following treatment was the strongest predictor of death compared to the 4 aforementioned factors. <h3>Conclusions:</h3> We observed that sarcopenia changes during the course of treatment among EOC patients who underwent curative intent PDS and adjuvant chemotherapy. Patients who develop sarcopenia following treatment appear to be at increased risk for poor oncologic outcomes. The cause of sarcopenia in EOC is unclear, and may reflect worse tumor biology or other patient specific factors.

Neuroendocrine Carcinomas of the Digestive Tract: What Is New?

Simple SummaryIn this narrative review, we describe the current data and management of neuroendocrine carcinomas (NEC) of the digestive tract. These tumors are very rare and suffer from a lack of clinical trials which would allow for standardized therapeutic management. To date, most guidelines come from studies in small-cell lung cancer, which is a similar entity in the lung. The incidence of NEC is rising and their prognostic is very low, underlying the urgent need for more trials to help define their best management.Neuroendocrine carcinomas (NEC) are rare tumors with a rising incidence. They show poorly differentiated morphology with a high proliferation rate (Ki-67 index). They frequently arise in the lung (small and large-cell lung cancer) but rarely from the gastrointestinal tract. Due to their rarity, very little is known about digestive NEC and few studies have been conducted. Therefore, most of therapeutic recommendations are issued from work on small-cell lung cancers (SCLC). Recent improvement in pathology and imaging has allowed for better detection and classification of high-grade NEN. The 2019 World Health Organization (WHO) classification has described a new entity of well-differentiated grade 3 neuroendocrine tumors (NET G-3), with better prognosis, that should be managed separately from NEC. NEC are aggressive neoplasms often diagnosed at a metastatic state. In the localized setting, surgery can be performed in selected patients followed by adjuvant platinum-based chemotherapy. Concurrent chemoradiotherapy is also an option for NEC of the lung, rectum, and esophagus. In metastatic NEC, chemotherapy is administered with a classic combination of platinum salts and etoposide in the first-line setting. Peptide receptor radionuclide therapy (PRRT) has shown positive results in high-grade NEN populations and immunotherapy trials are still ongoing. Available therapies have improved the overall survival of NEC but there is still an urgent need for improvement. This narrative review sums up the current data on digestive NEC while exploring future directions for their management.

P0807 - Selecting the best candidates for platinum-based adjuvant chemotherapy after radical cystectomy in pN+ bladder cancer patients

P0807 - Selecting the best candidates for platinum-based adjuvant chemotherapy after radical cystectomy in pN+ bladder cancer patients

IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC).

8500 Background: Adjuvant platinum-based chemotherapy (chemo) provides only a modest 5-year survival benefit in fully resected, high-risk early-stage NSCLC. We report the primary disease-free survival (DFS) results from the pre-planned interim analysis of IMpower010, a randomized phase 3 open-label trial of adjuvant atezolizumab (atezo; anti–PD-L1) vs best supportive care (BSC) after adjuvant chemo in patients (pts) with early-stage resected NSCLC. Methods: Eligible pts had completely resected (4-12 weeks prior to enrollment) Stage IB (≥4 cm)-IIIA NSCLC (AJCC/UICC v7) and ECOG PS 0-1. A total of 1280 pts were enrolled, and 1269 pts received up to four 21-day cycles of cisplatin-based chemo (plus pemetrexed, docetaxel, gemcitabine or vinorelbine). Of these pts (n=1269), 1005 were subsequently randomized 1:1 to 16 cycles of atezo 1200 mg Q3W or BSC. The primary endpoint of investigator-assessed DFS and secondary endpoint of overall survival (OS) were tested hierarchically: first DFS in the PD-L1 TC ≥1% (SP263) subgroup with Stage II-IIIA disease, then DFS in all randomized pts with Stage II-IIIA disease, then DFS in the ITT population (Stage IB-IIIA) and finally OS in the ITT population. Efficacy assessments were based on randomized pts. Safety was assessed in the safety-evaluable population, defined as pts who received ≥1 dose of atezo or who had ≥1 post-baseline safety assessment if randomized to the BSC arm. Results: At data cutoff (January 21, 2021), median follow-up was 32.2 months in the ITT population. Baseline characteristics were generally balanced between arms. Atezo showed statistically significant DFS benefit vs BSC in the PD-L1 TC ≥1% Stage II-IIIA and all randomized Stage II-IIIA populations; the significance boundary was not crossed for DFS in the ITT population (Table). OS data were immature and not formally tested. Pts in the atezo arm received a median of 16 (range, 1-16) atezo doses. Any-grade AEs occurred in 92.7% (atezo) and 70.7% (BSC); events were Grade 3/4 in 21.8% and 11.5%, respectively. Grade 5 treatment-related AEs occurred in 0.8% of pts in the atezo arm. AEs leading to atezo discontinuation occurred in 18.2% of atezo-treated pts. Conclusions: IMpower010 met its primary endpoint, showing DFS benefit with adjuvant atezo vs BSC after adjuvant chemo in pts with resected Stage II-IIIA NSCLC, with pronounced benefit in the PD-L1 TC ≥1% subgroup. The safety profile of atezo was consistent with prior experience of atezo monotherapy across indications and lines of therapy. Funding: F. Hoffmann-La Roche Ltd. Clinical trial information: NCT02486718. [Table: see text]

Efficacy of anti-PD(L)1 therapy for patients (Pts) with advanced urothelial carcinoma (aUC) with primary resistance to platinum-based chemotherapy (PC).

e16515 Background: PC remains standard first-line (1L) therapy for aUC. Approximately 15% of pts exhibit primary resistance (P-R) to PC and ∼25% progress by 4 months. PD(L)1 inhibitors yield objective response rates (ORR) of ∼20% in pts with progression after PC; however, it is unclear if this benefit extends to pts with P-R to PC. We examined the efficacy of anti-PD(L)1 in pts with aUC who experienced P-R to 1L PC. Methods: We conducted a multi-institutional retrospective study of pts with aUC who experienced P-R to PC and were subsequently treated with single-agent anti-PD(L)1 therapy. Eligibility included pts with unresectable or metastatic disease diagnosed after January 1, 2017. P-R to PC was defined as radiographic progression by RECISTv1.1 within 12 weeks from initiation of PC. Pts who developed metastatic disease while receiving (neo)adjuvant PC were eligible. Clinicopathologic variables were collected. ORR to anti-PD(L)1 was the primary endpoint. Secondary endpoints included time to treatment failure (TTF, defined as time from start of anti-PD(L)1 therapy to next line of therapy, hospice or death) and overall survival (OS) were estimated using Kaplan-Meier method. Multivariate (MV) analysis using Cox regression evaluating factors associated with OS was performed. Results: Overall, 42 pts were included: 74% male, median age 65 (28-90); 79% ever smokers; 21% mixed histology; 31% received definitive locoregional therapy. Metastatic sites at diagnosis of aUC included: lymph node only (19%), liver (29%), bone (38%) and lung (33%). At diagnosis of aUC, ECOG PS was 0 in 26%, 1 in 52% and unknown in 21%. 1L PC included cisplatin (76%) and carboplatin (24%) based regimens. Anti-PD(L)1 was received either 2L (98%) or 3L (2%). Overall, ORR to anti-PD(L)1 was 17%: CR (2%), PR (14%), SD (14%), PD (57%) and unknown (12%). Of the 24 pts with PD as best response to anti-PD(L)1, only 9 (38%) received subsequent therapy. Overall, median TTF was 4.2 mo (95% CI 2.8-6.7 mo) and median OS was 7.4 mo (95% CI 4.2-11.1 mo). ORR in patients with a PDL1 combined positive score ≥ 10% (n=6) was 0%: 1 SD and 5 PD. MV analysis for OS from start of anti-PD(L)1 is shown (Table). Conclusions: P-R to PC portends a poor prognosis in pts with aUC. While a subset of patients may respond to anti-PD(L)1 therapy, the majority of pts do not derive benefit. Alternative agents, e.g. antibody drug conjugates and FGFR inhibitors, and combination-therapy should be investigated for this high risk population.[Table: see text]

Prevalence of EGFR mutation testing in early-stage lung cancer: Implications of the ADAURA trial for clinical practice.

e20507 Background: It is reported that about 20% of patients with resected NSCLC adenocarcinoma harbor an EGFR driver mutation in the United States. Up to the recent approval of osimertinib in the adjuvant setting for resected EGFR + NSCLC based on the ADAURA trial, routine molecular profiling of early-stage lung cancer had not been standard of care. We hypothesize that there is a significant proportion of patients with resected adenocarcinoma with unknown EGFR status who could benefit from treatment that are missed with our current testing practices. Methods: We performed a retrospective analysis of Stage IB-IIIA lung adenocarcinomas resected at the University of Miami from 2014 to 2019. Eligible patients were identified from the Cancer Registry and information on EGFR mutation testing and treatment was obtained from chart review. We evaluated the prevalence of EGFR mutation testing in this population and outcomes based on EGFR mutation status. Disease free survival (DFS) and clinico-pathologic characteristics were evaluated. We estimated the number of patients that would have been eligible for EGFR testing and adjuvant osimertinib therapy in the pre-ADAURA era in our patient cohort. Results: A total of 120 patients had resected stage IB-IIIA adenocarcinoma during this five-year period (Stage IB 42.5%; Stage IIA 13.3%; Stage IIB 25%; Stage IIIA 19.2%) with a median age of 66 years. Most were females (59%), NHWs (51.5%), Hispanics (46.9%), and former smokers (66.7%). Out of patients with Stage IB-IIIA NSCLC with adenocarcinoma, 42.5% completed recommended adjuvant platinum-based chemotherapy. Only 40% of patients were referred for EGFR testing during this study period. The prevalence of EGFR mutations in this population was 10.8% (13 /120), but 59% of cases had no available EGFR testing. The most prevalent mutation was L858R (53.8%) followed by exon-19 deletions (30.8%). A total of 6 patients received an EGFR TKI therapy during the follow up period (2 in the adjuvant setting). With a median follow up of 12 mos, the rate of recurrence by stage was: Stage IB (3.9%); Stage IIB (10%); Stage IIIA (13%). Median time to disease progression or death was 13 months in this subgroup. There was no difference in disease free survival for patients with EGFR testing and those without results available in this short follow up period. Conclusions: Based on this retrospective review, up to 60% of patients with early-stage NSCLC with non-squamous histology have no available EGFR testing in the pre-ADAURA era. Of the anticipated 20% of patients with expected EGFR mutations based on historical controls, we have only identified half of patients that would have been eligible for adjuvant osimertinib. This study establishes the importance of upfront EGFR mutation testing in all NSCLC patients, not only to prognosticate, but also to identify the subset of patients who could benefit from adjuvant EGFR therapy.