Adjuvant Cohort Research Articles

Imaging-based surrogate classification for risk stratification of hepatocellular carcinoma with microvascular invasion to adjuvant hepatic arterial infusion chemotherapy: a multicenter retrospective study.

Patients with microvascular invasion (MVI)-positive hepatocellular carcinoma (HCC) have shown promising results with adjuvant hepatic arterial infusion chemotherapy (HAIC) with FOLFOX after curative resection. We aim to develop an imaging-derived biomarker to depict MVI-positive HCC patients more precisely and promote individualized treatment strategies of adjuvant HAIC. Patients with MVI-positive HCC were identified from five academic centers and utilized for model development (n=470). Validation cohorts were pooled from a previously reported prospective clinical study conducted (control cohort (n=145), adjuvant HAIC cohort (n=143)) (NCT03192618). The primary endpoint was recurrence-free survival (RFS). Imaging features were thoroughly reviewed, and multivariable logistic regression analysis was employed for model development. Transcriptomic sequencing was conducted to identify the associated biological processes. Arterial phase peritumoral enhancement, boundary of the tumor enhancement, tumor necrosis stratification, and boundary of the necrotic area were selected and incorporated into the nomogram for RFS. The imaging-based model successfully stratified patients into two distinct prognostic subgroups in both the training, control, and adjuvant HAIC cohorts (median RFS, 6.00 vs. 66.00mo, 4.86 vs. 24.30mo, 11.46 vs. 39.40mo, all P<0.01). Furthermore, no significant statistical difference was observed between patients at high-risk of adjuvant HAIC and those in the control group (P=0.61). The area under the receiver operating characteristic curve at two years was found to be 0.83, 0.84, and 0.73 for the training, control, and adjuvant HAIC cohorts respectively. Transcriptomic sequencing analyses revealed associations between the radiological features and immune-regulating signal transduction pathways. The utilization of this imaging-based model could help to better characterize MVI-positive HCC patients and facilitate the precise subtyping of patients who genuinely benefit from adjuvant HAIC treatment.

DNA Damage Response in Early Breast Cancer: A Phase III Cohort in the Phobos Study.

We assessed the impact of DNA damage response and repair (DDR) biomarker expressions in 222 node-positive early breast cancer (BC) patients from a previous Phase III GOIM 9902 trial of adjuvant taxanes. At a median follow-up of 64 months, the original study showed no disease-free survival (DFS) or overall survival (OS) differences with the addition of docetaxel (D) to epirubicine-cyclophosphamide (EC). Immunohistochemistry was employed to assess the expression of DDR phosphoproteins (pATM, pATR, pCHK1, γH2AX, pRPA32, and pWEE1) in tumor tissue, and their association with clinical outcomes was evaluated through the Cox elastic net model. Over an extended follow-up of 234 months, we confirmed no significant differences in DFS or OS between patients treated with EC and those receiving D → EC. A DDR risk score, inversely driven by ATM and ATR expression, emerged as an independent prognostic factor for both DFS (HR = 0.41, p < 0.0001) and OS (HR = 0.61, p = 0.046). Further validation in a public adjuvant BC cohort was possible only for ATM, confirming its protective role. Overall, our findings confirm the potential role of the DDR pathway in BC prognostication and in shaping treatment strategies advocating for an integrated approach, combining molecular markers with clinical-pathological factors.

Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers

BackgroundThe long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H).MethodsThis retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable.ResultsIn NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90–100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72–96%) and 93% (85–100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84–100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82–100%) and 96% (88–100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease.ConclusionWith a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Impact of joint peer review with a specialist radiologist in head and neck cancer radiotherapy planning.

e18059 Background: Head and neck oncology is heavily dependent on interpretation of radiology. This raises the question whether input from radiology should be formally scheduled as part of the radiotherapy contouring processes. Our aim was to assess the impact of this practice through qualitative and quantitative analysis. Methods: H &amp; N patients treated with radiotherapy between May-2022 and August-2023 were reviewed by a specialist HN radiologist. Incidence of changes in T, N, M and TNM-stage, change as defined by The RCR guidance: 'major' (change in gross tumour volume and/or high-dose clinical target volume, dose/fractionation) or 'minor' (change in intermediate or elective dose clinical target volumes or organs at risk), was recorded. We evaluated whether any of these changes were time dependent (Time interval between MDT to RT Peer Review). Other clinical variables: age, gender, primary diagnosis, tumour site, significant incidental findings, post-operative pTNM, post-operative disease status in adjuvant setting on planning imaging (NIRADS), need for additional imaging. We also recorded number of scans reviewed per patient, types of imaging studies reviewed, time taken for review and number of radiologist PA’s required. Retrospective analysis of a prospective database was performed. Results: 410 patients (252-definitive, 137-adjuvant, 21-palliative) were reviewed of which 51.5%-oropharynx followed by 26.8%-Larynx &amp; Hypopharynx. Mean age was 66.14 yrs (SD 11.46) and M:F was 4:1. Baseline and Therapy planning imaging was reviewed for 100% patients of which baseline included: MR (91.7%), CT (96.1%), US (34.1%), PETCT (31%) and therapy planning (62%-CECT, 19%-MR&amp;CT, 15%-CT, 4%-PETCT). In all patients (n=410), T/N/M/TNM-stage percentage upstage was 27/36.8/8.3/42.2% and in definitive cohort (n=252), it was 41.7/56.7/7.1/59.5%. Reviewing RT-planning Imaging in adjuvant cohort (n=137), 76.6% were NIRADS-1, 11.7% NIRADS-3/4/loco-regional disease and 11.7% distant metastasis. T/N/M/TNM-stage upstage was time dependent and the mean time interval between MDT to RT was higher in upstaged patients (p &lt;0.001). Overall percentage change in treatment plan: no/minor/major/palliative was 40.5/33.9/17.3/8.3% and in definitive cohort 30.2/42.1/20.6/7.1%. Change in plan was not dependent on mean time interval between MDT to RT. Average 10 patients (4 imaging studies/patient) were reviewed by radiologist in 1PA (time to review and peer review meeting time). Conclusions: Routine head and neck radiologist input in radiotherapy peer review is feasible and resulted in a number of major and minor changes to treatment. Inputs not only eased the contouring for oncologists but also lead to updating of current disease stage just prior to treatment. Overall, our results suggest that this is a practice changing step in the radiotherapy workflow which has a direct impact on patient management.

Pathologic Complete Response, Total Neoadjuvant Therapy and the Survival Paradox in Locally Advanced Rectal Cancer.

Pathologic complete response (pCR) after preoperative chemoradiation (nCRT) correlates with improved overall survival for patients with locally advanced rectal cancers (LARCs). Escalation protocols including total neoadjuvant therapy (TNT), which delivers multi-agent chemotherapy and chemoradiation before surgery, are associated with increased complete response rates. However, TNT is not associated with improved overall survival. The authors hypothesized that the route to pCR may be an important predictor of oncologic outcome. Adults with LARC between 2006 and 2017 were identified in the National Cancer Database. The cohort was limited to those who received neoadjuvant radiation (45-70 Gy) and underwent proctectomy. Of 25,880 patients, 16 % received TNT and 84 % had nCRT followed by either multi-agent (27 %), single-agent (14 %), or no adjuvant chemotherapy (44 %). Overall, 18 % achieved pCR, with higher rates in the TNT cohort than in the nCRT (18 %) or multi-agent (14 %) chemotherapy cohorts. With control for covariates, the OS in the pCR cohort was similar for the patients that received single-agent therapy and those that received multi-agent adjuvant therapy, and superior to the TNT and no adjuvant therapy cohorts. Conversely, among the patients who did not achieve pCR, those who received single-agent chemotherapy had OS comparable with those who had multi-agent adjuvant therapy and TNT, which was better than no adjuvant therapy. Patients achieving pCR after TNT had worse OS than those who had CRT alone, suggesting that the neoadjuvant route by which pCR is achieved is prognostically relevant. Therefore, in the era of neoadjuvant therapy escalation, pCR does not necessarily portend a uniformly favorable prognosis.

Adjuvant and post-recurrent treatment patterns in patients with resectable gastric cancer in Japan: a retrospective database cohort study

BackgroundThis study examined temporal shifts in adjuvant therapy patterns in Japanese patients with resectable gastric cancer (GC) and treatment patterns of first-line and subsequent therapy among those with recurrent disease.MethodsThis retrospective analysis of hospital-based administrative claims data (April 1, 2008 to March 31, 2022) included adults (aged ≥ 20 years) with GC who started adjuvant therapy on or after October 1, 2008 (adjuvant cohort) and patients in the adjuvant cohort with disease recurrence (recurrent cohort), further defined by the time to recurrence (≤ 180 or > 180 days after adjuvant therapy).ResultsIn the adjuvant cohort (n = 17,062), the most common regimen during October 2008–May 2016 was tegafur/gimeracil/oteracil potassium (S-1; 95.7%). As new standard adjuvant regimen options were established, adjuvant S-1 use decreased to 65.0% and fluoropyrimidine plus oxaliplatin or docetaxel plus S-1 use increased to 15.0% and 20.0%, respectively, in September 2019–March 2022. In the recurrent cohort with no history of trastuzumab/trastuzumab deruxtecan treatment (n = 1257), the most common first-line regimens were paclitaxel plus ramucirumab (34.0%), capecitabine plus oxaliplatin (CapeOX; 17.0%), and nab-paclitaxel plus ramucirumab (10.1%) in patients with early recurrence, and S-1 plus oxaliplatin (26.3%), S-1 plus cisplatin (15.3%), CapeOX (14.0%), S-1 (13.2%), and paclitaxel plus ramucirumab (10.8%) in those with late recurrence.ConclusionsThis study demonstrated temporal shifts in adjuvant treatment patterns that followed the establishment of novel regimens, and confirmed that post-recurrent treatment patterns were consistent with the Japanese Gastric Cancer Association guideline recommendations.

Abstract LB113: Immunogenicity of Atezolizumab plus personalized neoantigen vaccination (PGV-001) in patients with urothelial cancer in adjuvant vs metastatic setting

Abstract Background: Urothelial cancer (UC) of the genitourinary tract, most commonly arising from the bladder, has historically been a challenging area for the development of new therapeutics. Immune checkpoint blockade inhibitors (CBIs) induce durable responses only in a subset of patients with UC, potentially due to lack of neoantigen primed T cells. To build on this hypothesis, we designed a study to evaluate safety and immunogenicity of a combination treatment with atezolizumab and PGV-001, a personalized genomic neoantigen vaccine. Having previously reported clinical outcomes, here we describe analysis of immunogenicity induced by the treatment. Methods: In this phase I trial (NCT03359239) UC patients were enrolled to receive PGV-001 with atezolizumab in the adjuvant (undergone radical cystectomy or nephroureterectomy with a high risk of recurrence) or metastatic setting. Each PGV001 vaccine included up to 10 neoantigen (predicted using OpenVax pipeline) synthetic long peptides (SLPs). Each subject received 10 PGV-001 vaccines and 1200 mg i.v. atezolizumab every 3 weeks for up to 12 months (adjuvant) or 24 months (metastatic). To investigate T cell immunity, ex vivo IFNγ ELISPOT and T cell expansion assays were performed using 15mer overlapping peptide (OLP) pools corresponding to each neoantigen SLP. Results: Samples from 9 subjects (3 adjuvant and 6 metastatic) were evaluable for ex vivo ELISPOT analysis. In 100% of the subjects, at least 1 neoantigen was found to elicit an immune response. Overall, out of 87 evaluated neoantigens, 47% were immunogenic, with the immunogenic peptides inducing an average of 16.7 fold increase in ex vivo ELISPOT response over baseline. While 39% (11/28) of the peptides in adjuvant cohort were immunogenic vs 51% (39/50) in metastatic cohort, it is not possible to determine statistically significant difference in response between metastatic and adjuvant cohort. The T cell expansion assay was performed for 6 subjects, 3 each from the adjuvant and metastatic cohorts. Among 57 evaluated neoantigens, 46% and 54% of the peptides elicited a CD8+ and CD4+ T cell targeted immune response, respectively. A greater proportion of neoantigens induced both CD8+ and CD4+ T cell responses in subjects treated in the metastatic setting vs adjuvant setting. Upon epitope mapping, for 5 evaluable subjects, 141 OLPs were analyzed and a similar number of OLPs were found to be immunogenic for CD8+ (31.2%, 44/141) and CD4+ response (30%, 43/141). Conclusions: These data indicate that vaccination with personalized neoantigens in combination with systemic anti-PD-L1 can induce neoantigen-focused T cell responses in both adjuvant and metastatic disease settings. However, the single arm nature of the trial, and sample size, preclude definitive assessment of the contribution of the components of the combination therapy. Future studies will investigate the efficacy of this approach on a larger scale with pre- and on-treatment analyses of treatment-driven immunomodulation. Citation Format: Mansi Saxena, Jonathan Anker, Julia Kodysh, Timothy O'Donnell, Marcia Meseck, Olivia Hapanowicz, Scot Niglio, Hardik Shah, Yayoi Kinoshita, Rachel Brody, Alex Rubinsteyn, Robert Sebra, Nina Bhardwaj, Mathew Galsky. Immunogenicity of Atezolizumab plus personalized neoantigen vaccination (PGV-001) in patients with urothelial cancer in adjuvant vs metastatic setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB113.

Interferon-gamma signature as prognostic and predictive marker in macroscopic stage III melanoma

BackgroundA substantial proportion of patients with macroscopic stage III melanoma do not benefit sufficiently from adjuvant anti-PD-1 therapy, as they either recur despite therapy or would never have recurred. To...

Perioperative Immune Checkpoint Blockade for Muscle-Invasive and Metastatic Bladder Cancer.

Checkpoint inhibitors offer promise in treating muscle-invasive and metastatic bladder cancer, but the optimal timing of their administration-neoadjuvant or adjuvant-remains unclear. To determine the efficacy of combining checkpoint inhibition with standard cisplatin-based chemotherapy, we conducted a phase II trial of neoadjuvant anti-PD-1 (αPD-1) and anti-CTLA-4 (αCTLA-4), in combination with cisplatin-gemcitabine, for patients with muscle-invasive bladder cancer prior to radical cystectomy. In addition, a novel murine model of spontaneous metastatic bladder cancer was used to compare the efficacy of neoadjuvant versus adjuvant anti-PD-L1 (αPD-L1) treatment. The clinical trial was closed prematurely due to the industry's withdrawal of drug provision. Adverse events were observed in all patients; however, serious adverse events were not observed in any patient. A complete pathologic response was observed in 50% of the 4 patients enrolled. Response to treatment was significantly associated with elevated urinary T cells including CD8+ and IFNγ+ CD4+ T cells, suggesting potential reinforcement of immune responses by neoadjuvant αPD-1 and αCTLA-4 against bladder tumor cells. These findings suggest that combining chemotherapy and immunotherapy in the neoadjuvant setting could be safe. However, the complete response rate of this four-drug regimen was modest and emphasizes the need for randomized controlled trials to properly assess immunotherapy efficacy in the neoadjuvant setting. In corresponding murine studies, the MB49-met model consistently displayed widespread metastasis, including tumor growth in the lungs, liver, and bowel mesentery, within 20 days of subcutaneous transplantation. Mice receiving surgery plus neoadjuvant αPD-L1 or adjuvant αPD-L1 exhibited improved survival compared to those receiving only αPD-L1. However, no significant difference in survival was observed between the neoadjuvant and adjuvant αPD-L1 cohorts. Furthermore, the timing of neoadjuvant therapy administration (early vs. late) did not significantly impact survival. This study highlights the potential of perioperative immunotherapy in the treatment of locally advanced and metastatic bladder cancer.

Nomogram to Predict Risk of Early Mortality Following Definitive or Adjuvant Radiation and Systemic Therapy for Head and Neck Cancer

Tools to predict individual patient risk for early mortality in head and neck cancer patients receiving chemoradiation are lacking. We sought to create a nomogram to predict individual risk of early mortality, which may help identify patients who require interventions to prevent early death. We included patients in the National Cancer Database with non-metastatic squamous cell carcinoma of the head and neck who received radiation and systemic therapy between 2004 and 2017 in either the definitive or adjuvant setting. Covariates analyzed in the cohort include race, gender, income, age, T and N category, tumor site, insurance type, facility type, urban or rural environment, radiation modality, and comorbidity. Early mortality was defined as any death less than 90 days after the beginning of radiation. Chi-squared analysis was used for all categorical covariates and t-tests were used for continuous variables to test for associations with early mortality. Multivariable logistic regression was used to assess the relationship between covariates and early mortality. Nomograms to predict the risk of early death were created for both the definitive and adjuvant settings. The final cohorts included 84,563 patients in the definitive group and 18,514 patients in the adjuvant group. Rates of early mortality were 3.5% (95% CI 3.4-3.7%) and 2.2% (95% CI 1.9-2.4%) in the definitive and adjuvant cohorts, respectively. Patients above the age of 70 had an early mortality rate of 7.8% (95% CI 7.3-8.2%) in the definitive group and 4.4% (95% CI 3.6-5.4%) in the adjuvant group. In the multivariable analysis, age, comorbidity, T and N category, and tumor site were associated with early mortality in both cohorts (p<0.05 for all); while in the definitive group, radiation type, year of diagnosis, and insurance status were also statistically significant (p<0.05). In both cohorts, nomograms were created to predict the risk of early mortality that included age, comorbidity, T and N category and tumor site. The nomogram including age, comorbidity, T and N category and tumor site performed better than age alone at predicting early mortality (AUC for definitive group: 0.70 vs 0.66; AUC for adjuvant group: 0.71 vs 0.61). Nomograms including age, comorbidity, T and N category and tumor site were developed to predict the risk of early death following definitive or adjuvant chemoradiation.

Racial and socioeconomic disparities in time to chemotherapy and survival in patients with pancreatic cancer.

4100 Background: Pancreatic cancer is traditionally known to be an aggressive malignancy, requiring timely diagnosis and treatment, including chemotherapy and/or surgery. Prior studies have evaluated variances in overall survival (OS) based on race or income; however, research regarding time to treatment based on racial and socioeconomic disparities is underwhelmingly studied. Our project sought to evaluate the impact of race and income on time to chemotherapy and OS in pancreatic cancer patients receiving neoadjuvant or adjuvant chemotherapy. Methods: The National Cancer Database (NCDB) from 2004-2020 was reviewed for patients with a diagnosis of pancreatic cancer, including all types and stages. Exclusion criteria included: no documented income level, time to first treatment surgery, or time to chemotherapy. Our patient population was then separated into two cohorts: neoadjuvant and adjuvant. Income level was stratified into the following: &lt; $30,000, $30,000-34,999, $35,000-$45,999, and &gt; $46,000. Race was also noted. We utilized a logistic regression to identify factors associated with longer time to chemotherapy (using median time to chemotherapy as a benchmark for early or later initiation of chemotherapy). A Cox proportional hazards model was used to identify factors associated with worse survival. A p-value &lt; 0.05 was deemed significant. Results: Our final sample size included 64,640 patients. 6,887 (10.6%) of patients had an income less than $30,000. 55,340 (85.6%) of patients were Caucasian, 6,379 (9.9%) patients were African American, and 172 (0.002%) were American Indian. 18,679 (28.9%) received neoadjuvant chemotherapy, and 45,961 (71.1%) received adjuvant chemotherapy. Median time to chemotherapy was 27 [0-2048] days and 71 [0-1895] days in the neoadjuvant and adjuvant cohorts, respectively. Within both cohorts, income &gt; $46,000 was noted to have significantly earlier time to chemotherapy compared to lower income levels. Those privately insured had significantly earlier time to chemotherapy compared to uninsured. The African American population was associated with a later time to first chemotherapy in comparison to Caucasians in both subgroups. A significantly less OS in the African American population was appreciated in the neoadjuvant cohort (HR 0.92, p-value 0.02), but not the adjuvant cohort. Conclusions: Our retrospective analysis emphasizes that minorities and/or those with a poor socioeconomic status have significant delay in time to chemotherapy in the neoadjuvant and adjuvant setting. Within the African American neoadjuvant cohort, a significantly worse OS was highlighted. This study emphasizes racial and socioeconomic disparities in our healthcare system. Limitations of our study include its retrospective nature and no information regarding the type of surgery the patients received, which could further account for differences in time to chemotherapy.

Prospective observational study to evaluate lemborexant utility in insomnia among women with breast cancer (WJOG14921B, LUNAR study).

TPS12148 Background: Insomnia occurs in approximately 60% of cancer patients. The importance of early intervention to treat insomnia has been advocated because insomnia may be associated with poor prognosis, early discontinuation of treatment and decreased quality of life. It has been reported that breast cancer patients receiving endocrine therapy have the highest rate of insomnia among all cancer patients due to vasomotor symptoms (ie, hot flashes) and comorbid symptoms associated with fatigue and depression. Insomnia has also been found to occur in patients with metastatic/recurrent breast cancer. Lemborexant (LEM) is a dual orexin receptor antagonist, which has been shown to be effective for insomnia patients without malignancies. In clinical practice, while LEM has been administered to cancer patients with insomnia, there are no prospective data. The aim of this study is to evaluate prospectively whether LEM improves insomnia in patients with breast cancer receiving endocrine therapy. Methods: This is an open-label, prospective, multicenter, observational study to evaluate efficacy and safety of LEM to treat insomnia in patients with breast cancer receiving endocrine therapy [UMIN000047718]. The primary endpoint is change from baseline of total Insomnia Severity Index (ISI) score at 1 month. Secondary endpoints include change from baseline of cancer fatigue scale scores, EORTC QLQ C-30 and BR23 score, and Patient Health Questionnaire-9 score after 1 month and 3 months, change from baseline in total sleep time and sleep efficiency using an electronic sleep diary after 2 weeks, 1 month and 3 months, and safety profile. Exploratory endpoints include biomarker analysis including evaluation of cytokines and orexin A levels, and evaluation of sleep parameters using Oura ring, which is a ring-type wearable device. The primary endpoint will be assessed by the Wilcoxon signed-rank test. Total sample size will be 70 patients (adjuvant cohort: 50 patients, recurrent and/or metastatic cohort: 20 patients). Patients ≥20, meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition for Insomnia Disorder and ISI score ≥10 will be eligible. LEM 5mg will be administrated orally every night. Dosage of LEM will follow clinical practice and the Japanese LEM label. Enrollment began in September 2022; 14 patients have been recruited in adjuvant cohort as of January 2023. Clinical trial information: UMIN000047718 .

Measuring variation in the quality of systemic anti-cancer therapy delivery across hospitals: A national population-based evaluation.

6593 Background: To date, there has been little systematic assessment of the quality of care associated with systemic anti-cancer therapy (SACT) delivery across national healthcare systems. We evaluated hospital-level toxicity rates during SACT treatment as a means of identifying variation in care quality. Methods: All colorectal cancer patients receiving SACT within 106 English National Health Service hospitals between 2016 and 2019 were included. Severe acute toxicity rates were derived from hospital administrative data using a validated coding framework. Variation in hospital-level toxicity rates was assessed separately in the adjuvant and metastatic settings. Toxicity rates were adjusted for age, sex, comorbidity, performance status, tumour site, and TNM staging. Results: Of the 8,173 patients receiving SACT in the adjuvant setting, 2,074 (25%) had a toxicity with adjusted hospital-level rates varying from 11% to 49%. Of the 7,683 patients receiving SACT in the metastatic setting, 3,625 (47%) had a toxicity with adjusted hospital-level rates varying from 25% to 67%. Compared to the national mean toxicity rate in the adjuvant cohort, six hospitals were more than 2 standard deviations (2SD) above, and four hospitals were more than 2SD below. Similarly, in the metastatic cohort, six hospitals were more than 2SD above, and seven hospitals were more than 2SD below the national mean toxicity rate. Conclusions: There is substantial variation in hospital-level severe acute toxicity rates in both the adjuvant and metastatic settings, despite comprehensive risk-adjustment. Ongoing reporting of this performance indicator can be used to focus further investigation of toxicity rates and stimulate quality improvement initiatives to enhance care.

The adjuvant oxaliplatin-irinotecan paradox.

e15655 Background: A pervasive pattern in oncology is that chemotherapeutic agents which achieve acceptance for adjuvant use are the ones that have shown superior efficacy in the treatment of metastatic disease. The greater the efficacy in metastatic disease, the greater the likelihood that adjuvant use will be statistically viable. Oxaliplatin is the exception to this, having paradoxically shown similar outcomes to irinotecan in metastatic colorectal cancer (CRC) but superiority in the adjuvant setting. In this study, the TriNetX research database was used to better evaluate the adjuvant efficacy of oxaliplatin use in real-world patients. Methods: The TriNetX research database was used for this study. The TriNetX platform provides access to anonymized medical record information on more than 91 million patients in 75 large healthcare organizations. Three cohorts of stage III colorectal patients were created for comparison, utilizing International Classification of Disease-10 (ICD-10) codes and medication codes provided in the TriNetX platform. All patients were required to have a diagnosis of colon cancer (C18) and lymph node involvement (C77), with the absence of any liver or lung metastases (C78.7 and C78.0, respectively). Adjuvant oxaliplatin use was identified by the presence of the oxaliplatin medication code within 9 months of CRC diagnosis. The adjuvant oxaliplatin cohort was compared to a cohort with no oxaliplatin exposure, identified by the exclusion of the oxaliplatin medication code for 12 months following CRC diagnosis. The cohorts were balanced for age, race, gender, and ethnicity. The endpoint of the comparisons was all-cause mortality at 5 years. Results: Adjuvant use of oxaliplatin was associated with a 2.3% absolute decrease in the risk of death at 5 years (risk ratio 0.88, 95% CI (0.79,0.97), p-value 0.01). See figure 1. Conclusions: This study shows that adjuvant use of oxaliplatin is associated with a 2.3% absolute survival advantage in stage III colorectal cancer patients. This small absolute benefit is likely why occasional retrospective analyses have been unable to replicate it. A controlled interrupted time series analysis from Huang, et. al. showed no benefit to adjuvant oxaliplatin in the stage III setting for Taiwanese patients. Such a small benefit may also explain why the ACHIEVE trial found three months of adjuvant oxaliplatin to be equivalent to six. When a benefit is very small, a shorter duration of treatment would be more likely to result in statistical equivalency than if the benefit was more substantial. [Table: see text]

FLORA-5/GOG3035: Chemo-immunotherapy (paclitaxel-carboplatin-oregovomab [PCO] vs chemotherapy (paclitaxel-carboplatin-placebo [PCP]) as front-line treatment in patients with advanced epithelial ovarian cancer (EOC)—Phase III, double blind, placebo controlled, global, multinational study.

TPS5625 Background: Oregovomab, a murine IgGκ1 monoclonal antibody with high affinity binding to tumor associated antigen CA125, renders the target antigen CA125 more immunogenic or “neoantigen-like”. The proposed mechanism action is enhanced antigen processing and presentation to specific T cells. This phenomenon is hypothesized to bypass tumor-associated immune suppression when oregovomab is combined with chemotherapy. In a randomized phase II study, oregovomab, in combination with paclitaxel and carboplatin, (PC) induced tumor immunity and demonstrated significant improvement in median PFS (41.8 months(m) PCO vs 12.2 m PC, HR 0.46, p = 0.0027) and median OS (N.E. PCO vs 43.2 m PCP, HR 0.35, p = 0.043) in patients with previously untreated EOC. Patients receiving adjuvant chemotherapy were included. Oregovomab combined with PC had a favorable toxicity profile. FLORA-5/GOG3035, the definitive confirmatory global registration trial, is currently recruiting patients in the front-line setting. Methods: In this phase 3, multicenter, double-blind, placebo-controlled trial, optimally debulked patients with FIGO III/IV EOC and serum CA125 ≥ 50 U/ml receiving adjuvant (Cohort 1) or patients receiving neoadjuvant chemotherapy post-interval cytoreductive surgery (Cohort 2) will be randomized to PC + oregovomab or placebo (PCO vs. PCP). Patients with germline BRCA1/2 mutations are excluded. Chemotherapy will be administered every 3 weeks in both cohorts. Oregovomab/placebo is administered simultaneously at cycles 1, 3, and 5 of chemotherapy with an additional dose at 12 weeks following cycle 5 in Cohort 1. Neoadjuvant patients will be administered oregovomab/placebo after debulking surgery at cycles 4 and 6 with two additional doses at 6- and 18-weeks following cycle 6 in Cohort 2. No other front-line maintenance therapy is permitted. The primary objective is PFS determined by RECIST 1.1. Cohort 1 will recruit 372 patients with a 90% power to detect a difference with an alpha of 0.025 and a hazard ratio of 0.65 when 252 PFS events have been observed. Cohort 2 will be analyzed separately recruiting 232 patients with a 90% power to detect a difference with an alpha of 0.025 and a hazard ratio of 0.60 when 165 PFS events have been observed. An interim futility analysis will be performed. Secondary objectives include OS, frequency and severity of AEs, and QoL. Exploratory objectives include iRECIST, TFST, TSST, PFS2, and evaluation of correlative biomarkers. The study is actively enrolling in the US, Canada, Belgium, Italy, Spain, Czech Republic, Hungary, Poland Korea, Taiwan, Mexico Argentina, India and Chile. 518 of the planned 602 patients were enrolled at the time of submission. Clinical trial information: NCT04498117 .

Primary and adjuvant intensity-modulated radiotherapy in oropharyngeal carcinoma patients from a single institution.

To retrospectively access outcome, adverse events and prognostic factors in oropharyngeal carcinoma (OPC) patients treated with intensity-modulated radiotherapy (IMRT). Ninety-eight OPC patients were treated between 2000 and 2015. Thirty-three patients received definitive and 65 adjuvant radiotherapy. Seventy-one percent had simultaneous chemotherapy. Patients were systematically followed up (mean 114 months, range 19-197 months). Statistical analysis used Kaplan-Meier method, Cox regression analysis, and log-rank test. Adverse events were classified according to common toxicity criteria version (CTCAE) 4.03. The 1-, 5-, and 10-year overall survival rates in the adjuvant vs. definitive cohort were 90.8% vs. 66.7%, 67.4% vs. 33.1%, and 57.7% vs. 16.5%. Survival in the adjuvant cohort was significantly longer than in the definitive cohort (P < 0.00005). Patients <65 years had a significantly longer survival than older patients. Locoregional tumor control rates after 1-, 5-, and 10 years in the adjuvant vs. definitive cohort were 90.2% vs. 66.7%, 82.2% vs 45.4%, and 72.1% vs. 30.3%. Locoregional tumor control in the adjuvant cohort was significantly longer than in the definite cohort (P < 0.005). Distant metastases were diagnosed in 20.4% of all patients. Most patients had mild CTCAE grade 1 and 2 adverse events and mild late adverse events including xerostomia, dysphagia, and lymphedema. Intensity-modulated radiotherapy for OPC is an important part of the treatment algorithm alone and in particular after surgery while the additional benefits of chemotherapy might be age dependent. Despite advanced tumor stages, nearly half of our patients were alive in the long term. The majority of patients had relatively mild chronic adverse events.

Abstract P6-01-09: Efficacy of platinum-based chemotherapy and germline mutational status in early-stage triple-negative breast cancer: a unicenter retrospective analysis with long-term follow-up

Abstract BACKGROUND: In early-stage triple negative breast cancer (TNBC), the addition of carboplatin (CBDCA) to neoadjuvant chemotherapy (CT) increases pathologic complete response (pCR) and relapsed-free survival. However, it is unclear whether CBDCA improves overall survival (OS). In addition, the prognostic and/or predictive role of pathogenic germline variants (PGV) in BRCA1/2 genes and other cancer risk in this setting is not fully understood. Here, we assessed the efficacy of (neo)adjuvant CBDCA and the prognostic and predictive role of a panel of 14 genes in patients (pts) with eTNBC. METHODS: This is a retrospective study on 117 pts diagnosed with early-stage TNBC between 2000-2021 at Hospital Clinic of Barcelona. Eighty-one pts (69%) were candidates for PGV testing. Overall, 14 genes (PGV) (BRCA1, BRCA2, PALB2, BRIP1, CHEK2, TP53, ATM, RAD51C, RAD51D, BARD1, MLH1, MSH2, MSH6 and PMS2) were assessed using the TruSight hereditary cancer panel (Illumina MySeq platform) according to local guidelines. Univariable and multivariable logistic regression and Cox regression analyses were performed to identify clinical and molecular predictors of pCR and relapse-free survival (RFS), respectively. Chi-squared or Fisher’s exact tests were used to assess characteristics’ distribution as appropriate. RESULTS: Of 117 pts, 83 (71%) received CT in the neoadjuvant setting and 28 (24%) in the adjuvant setting. CBDCA was added to standard CT in 68 pts (82%) in the neoadjuvant cohort and 7 pts (6%) in the adjuvant cohort. Among pts with germline testing, 32/81 (39%) harbored PGV. BRCA1 was the most frequently mutated gene (18/32, 56%), followed by BRCA2 (5/32, 16%), PALB2 (4/32, 13%), BRIP1 (2/32, 6%), CHEK2, TP53 and PMS2 (3/32, 6%). Percentages of pts receiving CBDCA were similar between patients with and without PGV (14/16,87% and wild type (53/67,79%)(p=0.120). In the neoadjuvant cohort (n=83), CBDCA was the only variable significantly associated with pCR at both univariate (pCR rates of 58.5% with CBCDA and 14.3% without CBCDA; odds ratio [OR]=8.2 [95% CIs 2.0-55.7], p=0.008) and remained statistically significant after adjusting for PGV, tumor size and nodal status (OR=6.9 [95% CIs 1.4-53.0], p=0.028). pCR rates according to PGV are reported in Table 1. In terms of RFS, addition of CBDCA to neoadjuvant therapy (hazard ratio [HR]=0.2 [0.1-0.45], p&amp;lt; 0.001), PGV (HR=0.2 [0.05-0.9], p=0.048), pCR (HR=0.2 [0.1-0.6], p=0.004) and nodal status (HR=5.1 [1.7-15.2], p&amp;lt; 0.003) were significantly associated with RFS in univariate analyses. In a multivariable model, CBDCA remained an independent predictor of improved RFS along with pCR. When the neoadjuvant and adjuvant cohort were pooled together (n=117), platinum-based CT remained significantly associated with better RFS (HR=0.2 [0.14-0.86], p=0.021) regardless of time of administration (i.e., neoadjuvant or adjuvant). With a median follow-up of 5 years, CBCDA use was not found associated with OS (HR=0.7 [0.3-1.8], p= 0.560). CONCLUSIONS: The addition of CBDCA to standard CT was significantly associated with pCR and RFS but not OS, consistent with the phase III data. The benefit in terms of RFS was independent of the presence and the type of pathogenic germline alterations. Table 1. pCR rates according to PGV Citation Format: Adela Rodríguez Hernández, Benedetta Conte, Laia Fernández, Fara Brasó-Maristany, Belén Pastor, Miriam Potrony, Lorena Moreno, Elia Grau, Joan Antón Puig-Butillé, Aurora Sánchez, Blanca González-Farré, Esther Sanfeliu, Olga Martínez-Sáez, Claudette Falato, Maria Vidal, Nuria Chic, Tomás Pascual, Francesco Schettini, Montserrat Muñoz, Francesc Balaguer, Aleix Prat, Barbara Adamo. Efficacy of platinum-based chemotherapy and germline mutational status in early-stage triple-negative breast cancer: a unicenter retrospective analysis with long-term follow-up [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-09.

Are we delivering high-quality medical oncology care? A national comparison of severe acute toxicity from systemic anti-cancer therapy

BackgroundIn the precision medicine era the complexity of systemic anti-cancer therapy (SACT) delivery and their associated toxicities have also increased. However, there has been little systematic assessment of the quality of care associated with systemic anti-cancer therapy delivery across national healthcare systems. We evaluated hospital-level severe acute toxicity rates during SACT treatment as a means of identifying variation in care quality. MethodsAll colorectal cancer (CRC) patients receiving SACT within 106 English National Health Service (NHS) hospitals between 2016 and 2019 were included.Severe acute toxicity rates were derived from hospital administrative data using a validated coding framework. Toxicity rates were adjusted for age, sex, comorbidity, performance status, tumour site, and TNM staging. Variation in hospital-level toxicity rates was assessed separately in the adjuvant and first-line metastatic settings. Results8,173 patients received SACT in the adjuvant setting, and 7,683 patients in the first-line metastatic setting. Adjusted severe acute toxicity rates varied between hospitals from 11% to 49% for the adjuvant cohort, and from 25% to 67% for the metastatic cohort.Compared to the national mean toxicity rate in the adjuvant cohort, six hospitals were more than 2 standard deviations (2SD) above, and four hospitals were more than 2SD below. In the metastatic cohort, six hospitals were more than 2SD above, and seven hospitals were more than 2SD below the national mean toxicity rate.Overall, 12 hospitals (12%) had toxicity rates more than 2SD above the national mean, and 11 (10%) had rates more than 2SD below. ConclusionThere is substantial variation in hospital-level severe acute toxicity rates in both the adjuvant and metastatic settings, despite risk-adjustment. Ongoing national public reporting of this performance indicator can be used investigate reasons for variation in toxicity rates and stimulate quality improvement initiatives to improve care. This may include increasing centralisation of SACT care delivery to minimise variation. This approach can be applied across different cancer types and in many different countries where similar regional or national clinical and administrative hospital datasets are available.

Efficacy of sequential perioperative FOLFIRNOX plus gemcitabine nab-paclitaxel for resected pancreatic and periampullary cancers.

724 Background: Perioperative chemotherapy with single regimen either FOLFIRINOX (FFX) or gemcitabine/nab-paclitaxel (Gem/NabP) is the current standard of care for pancreatic and periampullary cancers (PC) with overall survival (OS) of 2-3 years without pre-selected CA19-9 level. Sequential chemotherapy with FFX plus Gem/NabP has recently been investigated in metastatic PC and shown to improve OS. We investigated the outcome of patients who received sequential perioperative chemotherapy FFX plus Gem/NabP. Methods: Patients treated with curative intent surgery for PC who received perioperative sequential chemotherapy FFX plus Gem/NabP (each regimen was given at least two months) were identified. OS and recurrence-free survival (RFS) were calculated from the date of initial treatment (neoadjuvant chemotherapy or resection) to the date of last follow-up/death or recurrence via Kaplan-Meier analysis. Results: A total of 29 patients were identified: 24 (83%) patients had pancreatic cancer, 5 (17%) patients had periampullary cancer; 16 (55%) patients received neoadjuvant chemotherapy FFX plus Gem/NabP; 13 (45%) patients underwent upfront surgery and received adjuvant FFX plus Gem/NabP chemotherapy; 22 (76%) patients had resectable disease, the rest 7 (24%) patients had borderline or unresectable disease were all in the neoadjuvant cohort; node positivity was higher in the adjuvant cohort (n=8, 62%) than in the neoadjuvant cohort (n=8, 50%); 5 (17%) patients were found to have homologous recombination deficiency (HRD: BRCA2, CHEK, BARD, ATM) and received PARP inhibitors as part of the perioperative therapy combination. 10 (34%) patients had CA19-9 ≥ 500. Median age was 65 years (range, 45-79 years), 20 (69%) were male. During the study period, 4 (14%) patients died, and 6 (21%) patients had disease recurrence. Median RFS and OS were not reached with a median follow-up of 28 months (range, 10.9–119 months). The longest RFS was 10 years. The 2-years RFS and OS for the entire cohort was 76.7% and 88.8%, respectively. There was no statistical difference in RFS (log rank HR 1.72, 95% CI 0.23-13.15) or OS (log rank HR 0.99, 95% CI 0.20-4.93) for patients in the neoadjuvant cohort versus adjuvant cohort. Conclusions: Sequential perioperative chemotherapy combined FFX plus Gem/NabP for resected PC is effective and potentially prolongs survival, compared to historical controls who received single regimen.[Table: see text]

Cardiovascular risk factor reporting in immune checkpoint inhibitor trials: A systematic review

BackgroundImmune checkpoint inhibitors (ICI) have revolutionized the treatment of numerous cancers but are associated with increased risk of myocardial infarction. The prevalence of traditional cardiovascular risk factors (CVRF) in patients treated with ICIs is unknown. This study sought to describe the frequency of reporting of CVRFs among landmark ICI trials. MethodsA systematic review of all phase 2 or 3 cancer trials employing ICIs that led to United States Food and Drug Administration approval was conducted. ResultsOf the 69 identified trials, only one study reported baseline rates of hypertension, diabetes mellitus, and dyslipidemia. Smoking history was reported in 27 studies (39 %) and three (4 %) reported body mass index. No study reported history of previous cardiovascular disease, although 17 (25 %), six (9 %), and 21 (30 %) studies excluded patients with recent myocardial infarction, revascularization and heart failure respectively. Similarly low rates of cardiovascular risk factor reporting were observed in studies employing concurrent vascular endothelial growth factor inhibitors and recruiting (neo)adjuvant cohorts. ConclusionThe prevalence of CVRFs is poorly described in ICI trials despite increasingly reported risks of myocardial infarction. A systematic approach to collecting and reporting CVRFs should be considered in future trials and real world populations.