Neoadjuvant Treatment In Patients Research Articles

Complete Primary Pathological Response Following Neoadjuvant Treatment and Radical Resection for Pancreatic Ductal Adenocarcinoma.

Neoadjuvant treatment (NAT) for borderline (BD) or locally advanced (LA) primary pancreatic cancer (PDAC) is now a widely adopted approach. We present a case series of patients who have achieved a complete pathological response of the primary tumour on final histology following neoadjuvant chemotherapy +/- chemoradiation and radical surgery. Patients who underwent radical pancreatic resection following neoadjuvant treatment between March 2006 and March 2023 at a single institution were identified by retrospective case note review of a prospectively maintained database. Ten patients were identified to have a complete primary pathological response (ypT0) on postoperative histology. Before treatment, five patients were considered BD and five were LA according to National Comprehensive Cancer Network guidelines. All patients underwent staging Computed Tomography (CT) and nine underwent 18Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET/CT) imaging, with a mean maximum standardized uptake value (SUVmax) of the primary lesion at 6.14 ± 1.98 units. All patients received neoadjuvant chemotherapy, and eight received further chemoradiotherapy prior to resection. Mean pre- and post-neoadjuvant treatment serum Ca19-9 was 148.0 ± 146.3 IU/L and 18.0 ± 18.7 IU/L, respectively (p = 0.01). The mean duration of NAT was 5.6 ± 1.7 months. The mean time from completion of NAT to surgery was 13.1 ± 8.3 weeks. The mean lymph node yield was 21.1 ± 10.4 nodes, with one patient found to have 1 lymph node involved. All resections were reported to be R0. The mean length of stay was 11.8 ± 6.2 days. At the time of analysis, one death was reported at 35 months postoperatively. Two cases of recurrence were reported at 16 months (surgical bed) and 33 months (pulmonary). All other patients remain alive and under active surveillance. The current overall survival is 26.6 ± 20.7 months and counting. Complete primary pathological response is uncommon but possible following neoadjuvant treatment in patients with PDAC. Further work to identify the common denominator within this unique cohort may lead to advances in the therapeutic approach and offer hope for patients diagnosed with borderline or locally advanced pancreatic ductal adenocarcinoma.

RC48-ADC combined with tislelizumab as neoadjuvant treatment in patients with HER2-positive locally advanced muscle-invasive urothelial bladder cancer: a multi-center phase Ib/II study (HOPE-03).

Bladder cancer with high expression of human epidermal growth factor receptor-2 (HER2) is related to pathological malignancy and poor prognosis. The standard care for muscle-invasive urothelial bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) with pelvic lymph node dissection. For HER2-positive MIBC, the efficacy of cisplatin-based NAC is unsatisfactory, and adverse reactions are inevitable or even intolerable. New regimens with higher efficiency and lower toxicity need to be explored in the neoadjuvant setting for this population. HOPE-03 is a multi-center, open-label, single-arm, phase Ib/II study aiming to evaluate the safety and efficacy of RC48-ADC (disitamab vedotin (DV)), a humanized anti-HER2 antibody conjugated with monomethyl auristatin E, and tislelizumab (PD-1 antibody) as a novel neoadjuvant treatment combination in patients with HER2-positive locally advanced urothelial MIBC. Fifty-one patients with cT2-4bN0-3M0-1a pathology- and imaging-diagnosed HER2 positive (immunohistochemistry status 3+ or 2+ or 1+) MIBC were recruited. Of these patients, six were enrolled in the dose-escalation phase (three patients in the RC48-ADC 1.5 mg/kg group and three patients in the 2.0 mg/kg group), and 45 patients were enrolled in the phase II study (the expected recommended phase II dose for RC48-ADC was 2.0 mg/kg). Patients without disease progression received radical cystectomy or bladder-sparing therapies as their preference after neoadjuvant treatment. The primary endpoints were clinical complete remission rate (cCR rate; T0/Ta/Tis), pathological complete remission rate (pCR rate), and safety. The secondary endpoints were overall survival (OS), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and quality of life. The HOPE-03 trial provides a description of the safety profile of RC-48 and tislelizumab combination in the neoadjuvant treatment of HER2-positive locally advanced urothelial MIBC, and the efficacy is explored as well in this population. https://www.chictr.org.cn/showproj.html?proj=137111, identifier ChiCTR2200060153.

The role of FDG PET/CT radiomics in the prediction of pathological response to neoadjuvant treatment in patients with esophageal cancer.

Attainment of a complete histopathological response following neoadjuvant therapy has been associated with favorable long-term survival outcomes in esophageal cancer patients. We investigated the ability of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) radiomic features to predict the pathological response to neoadjuvant treatment in patients with esophageal cancer. A retrospective review of medical records of patients with locally advanced resectable esophageal or esophagogastric junctional cancers. Included patients had a baseline FDG PET/CT scan and underwent Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) protocol followed by surgery. Four demographic variables and 107 PET radiomic features were extracted and analyzed using univariate and multivariate analyses to predict response to neoadjuvant therapy. Overall, 53 FDG-avid primary esophageal cancer lesions were segmented and radiomic features were extracted. Seventeen radiomic features and 2 non-radiomics variables were found to exhibit significant differences between neoadjuvant therapy responders and non-responders. An unsupervised hierarchical clustering analysis using these 19 variables classified patients in a manner significantly associated with response to neoadjuvant treatment (p < 0.01). Our findings highlight the potential of FDG PET/CT radiomic features as a predictor for the response to neoadjuvant therapy in esophageal cancer patients. The combination of these radiomic features with select non-radiomic variables provides a model for stratifying patients based on their likelihood to respond to neoadjuvant treatment.

Efficacy and outcome analysis: Combination of Endostar and chemotherapy as a neoadjuvant treatment of stageIIIA/IIIB squamous cell lung cancer.

Patients with stage IIIA/IIIB squamous non-small cell lung cancer (SqCLC) are particularly challenging to treat with a poor 5-year survival rate and new treatment strategies are needed. In the present study, a retrospective, single-center study was conducted to explore the efficacy and safety of Endostar combined with chemotherapy as the neoadjuvant treatment in patients with stage IIIA/IIIB SqCLC. A total of 27 patients with locally advanced SqCLC treated with Endostar combined with chemotherapy as neoadjuvant therapy from January 1, 2017 to December 31, 2019 at the Zhejiang Cancer Hospital (Hangzhou, China) were included. Short-term efficacy, rate of surgical resection, long-term outcome and adverse events were analyzed. After treatment with Endostar combined with chemotherapy, 37% of the patients underwent surgery and the radical resection rate was 90%. The objective response rate was 63% for the total population and 80% for patients who received surgery. Of note, 100% of the patients achieved disease control after treatment with Endostar combined with chemotherapy. In patients who underwent surgical resection, postoperative pathology showed that 100% of the patients achieved pathological downstaging. Furthermore, 1 (10%) patient showed a pathological complete response after surgery. The median progression-free survival was 13.5 months and overall survival was 27.9 months for the total cohort. The most common adverse events (AEs) were anemia (69.4% of patients), followed by hypertension (29.6% of patients). Most of the AEs were grade 1-2 and only 4 patients (14.8%) developed grade 3-4 AEs. Endostar combined with chemotherapy was well-tolerated and showed promising efficacy in patients with stage IIIA/IIIB SqCLC. Further prospective studies are warranted to explore its value as a neoadjuvant therapy.

2364MO Durvalumab (D) +/- tremelimumab (T) in combination with dose-dense MVAC (ddMVAC) as neoadjuvant treatment in patients with muscle-invasive bladder carcinoma (MIBC): Results of NEMIO, a randomized phase I-II trial

2364MO Durvalumab (D) +/- tremelimumab (T) in combination with dose-dense MVAC (ddMVAC) as neoadjuvant treatment in patients with muscle-invasive bladder carcinoma (MIBC): Results of NEMIO, a randomized phase I-II trial

LBA59 Associations of ctDNA clearance and pathological response with neoadjuvant treatment in patients with resectable NSCLC from the phase III AEGEAN trial

LBA59 Associations of ctDNA clearance and pathological response with neoadjuvant treatment in patients with resectable NSCLC from the phase III AEGEAN trial

1987TiP Pembrolizumab in combination with eftilagimod alpha and radiotherapy in neoadjuvant treatment of patients with soft tissue sarcomas: EFTISARC-NEO trial

1987TiP Pembrolizumab in combination with eftilagimod alpha and radiotherapy in neoadjuvant treatment of patients with soft tissue sarcomas: EFTISARC-NEO trial

Patterns of Locoregional Pancreatic Cancer Recurrence after Total Neoadjuvant Therapy and Implications on Optimal Neoadjuvant Radiation Treatment Volumes

Neoadjuvant treatment for patients with localized pancreatic adenocarcinoma (PDAC) has improved survival duration. As survival increases, local disease control becomes even more important. We sought to understand the patterns of locoregional recurrence following total neoadjuvant therapy (TNT) and determine the impact of treatment volumes on recurrence. Patients with PDAC managed with neoadjuvant chemotherapy and chemoradiation (TNT) followed by surgery who developed an isolated locoregional or simultaneously locoregional and distant recurrence were identified. Locoregional recurrences were individually contoured utilizing commercially available software. When available, original neoadjuvant dose distributions were registered to the scans on which the locoregional recurrences were contoured. Recurrences where then classified as in-field (> 95% of prescription dose), marginal (50-95% of prescription dose), or out of field (< 50% of prescription dose). Target volumes were created using four commonly utilized PDAC contouring guidelines to characterize the relationship of the local recurrence to the RT dose distribution. Of 474 patients treated with TNT and surgery, 80 (17%) patients developed a locoregional recurrence with or without distant recurrence, visible on diagnostic imaging. Of the 80 patients, 56 (70%) had tumors in the pancreatic head; 46 (57.5%) were borderline resectable, 23 (28.8%) locally advanced, and 11 (13.6%) resectable. The most common initial neoadjuvant therapies were FOLFIRINOX (57.5%) and gemcitabine/nab-paclitaxel (18.8%). Chemoradiation included concurrent gemcitabine (47.5%) or 5-fluorouracil (26.3%). RT dose distributions were available for 38 patients; 22 (57.9%) had in-field failures, 9 (23.7%) marginal failures, and 7 (18.4%) out of field failures. Each published contouring atlas covered a relatively low percentage of recurrences, which are summarized in Table 1. Regions at particularly high likelihood of recurrence that were under covered on existing atlases included: aortic-diaphragmic junction, retro-pancreatic duodenal nodal basin, and the region to the right of the superior mesenteric artery (SMA). We present the largest series (to our knowledge) of mapped locoregional recurrences for patients being treated with TNT in PDAC. These recurrences differ substantially from established atlases and highlight anatomical regions of highest priority for RT coverage. A novel visual contouring volume highlighting these regions will be presented which will strive to advance the use of RT in the TNT setting.

Oncological recurrence following pathological complete response after neoadjuvant treatment in patients with esophageal cancer — a retrospective cohort study

BackgroundTo evaluate recurrence in patients with post-neoadjuvant pathological complete response (pCR) and in patients with complete response of primary tumor but persisting lymphatic spread of disease (non-pCR, ypT0ypN +) of esophageal cancer.MethodsSeventy-five patients (63 pCR, 12 non-pCR) were analyzed retrospectively. Pattern and incidence of local and distant recurrence as well as the impact on overall (OS) and disease-free survival (DFS) were evaluated. The efficacy of neoadjuvant chemotherapy according to FLOT protocol was compared to neoadjuvant chemoradiation according to CROSS protocol.ResultsIn the pCR group, isolated local recurrence was diagnosed in 3%, while no isolated local recurrence was observed in the non-pCR group due to the high incidence of distant recurrence. Distant recurrence was most common in both cohorts (isolated distant recurrence: pCR group 10% to non-pCR group 55%; simultaneous distant and local recurrence: pCR group 3% to non-pCR group 18%). Median time to distant recurrence was 5.5 months, and median time to local recurrence was 8.0 months. Cumulative incidence of distant recurrence (with and without simultaneous local recurrence) was 16% (± 6%) in pCR patients and 79% (± 13%) in non-pCR patients (hazard ratio (HR) 0.123) estimated by Kaplan–Meier method. OS (HR 0.231) and DFS (HR 0.226) were significantly improved in patients with pCR compared to patients with non-pCR. Advantages for FLOT protocol compared to CROSS protocol, especially with regard to distant control of disease (HR 0.278), were observed (OS (HR 0.361), DFS (HR 0.226)).ConclusionDistant recurrence is the predominant site of treatment failure in patients with pCR and non-pCR grade 1a regression, whereby recurrence rates are much higher in patients with non-pCR.

Abstract PR02: Tumor sequestered, neoantigen specific T cells are dynamically increased in circulation following neoadjuvant immunotherapy

Abstract Improved recurrence free survival is observed following neoadjuvant immune checkpoint blockade (ICB), but the mechanisms underlying this clinical benefit are incompletely understood. To gain insights into changes in the tumor microenvironment (TME) that occur following ICB, we performed paired single-cell transcriptomic and T cell receptor (TCR) RNA sequencing on sorted tumor infiltrating T-lymphocytes before and after neoadjuvant treatment of patients with newly diagnosed oral carcinoma with bintrafusp alfa, a bifunctional PD-L1 mAb and TGF-b neutralizing construct. Analysis of pre- and post-treatment TIL with identical TCRs allowed characterization of changes within individual clonotypes after treatment. The addition of deep TCRb complimentary determining region 3 (CDR3) sequencing of peripheral T cells allowed assessment of dynamic changes in individual T cell clonotypes between the tumor and peripheral blood. Within the TME, multiple clearly defined clusters of CD8+ and CD4+ T cells with distinct transcriptional profiles were observed, including T cells expressing activation, exhaustion, and tissue-resident markers (exhausted) as well as T cells expressing progenitor and memory markers (memory). Multiple TCRs from clonotypes observed to be present in the exhausted and memory compartments were cloned for study of their antigen specificity. Putative neoepitopes were synthesized following in silico prediction of putative mutation derived neoantigens. Several TCRs from the exhausted compartment were specific for mutation-derived neoantigens. Conversely, TCRs from the memory compartment were specific for common viral antigens. With treatment, exhausted tumor-specific T cells transitioned between different exhausted clusters and some transitioned into a proliferating cluster and expanded in number. Expression of genes associated with TCR signaling and glycolysis increased in exhausted clonotypes that expanded with treatment. Expression of GLS, a key gene associated with glutaminolysis, associated with clonotypes that did not expand with treatment. Study of the peripheral blood revealed that CDR3 sequences matching exhausted, tumor specific TCRs from the TME were not detected or detected at very low frequencies prior to treatment. However, detected of CDR3 sequences matching exhausted, tumor specific TCRs from the TME significantly increased after treatment. CDR3 sequences matching memory, viral specific TCRs from the TME were detected at high levels in the peripheral blood prior to treatment, did not significantly change with treatment. Thus, neoadjuvant immunotherapy appears to expand exhausted, tumor specific T cells in the TME and results in increased frequency of these T cells in circulation. These data imply that tumor specific T cells may be largely sequestered into tissues, such as the tumor and possibly draining lymph nodes, in patients with newly diagnosed oral carcinoma and that surgical removal of disease without the use of neoadjuvant immunotherapy may remove a significant proportion of the patient’s anti-tumor T cell immunity. Citation Format: Cem Sievers, Marco Craveiro, Jason Redman, Clint T. Allen. Tumor sequestered, neoantigen specific T cells are dynamically increased in circulation following neoadjuvant immunotherapy [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PR02.

Smoking impairs the effect of neoadjuvant FOLFIRINOX on postresection survival in pancreatic cancer

IntroductionSmoking plays an important role in carcinogenesis, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the association between smoking status and prognosis in resected PDAC. MethodsAll patients who underwent resection for PDAC were identified from two prospective institutional databases. Clinicopathologic data as well as demographics including smoking status were extracted. Survival analysis and multivariable Cox regression modelling was performed. Restricted cubic splines were used for linear data to define cut-off points. ResultsOut of 848 patients, 357 (42.1%) received neoadjuvant treatment (NAT), 491 upfront resection (57.9%), and 475 (56%) adjuvant therapy. The median overall survival (OS) was 27.8 months, 36.1 months, and 23.0 months for the entire cohort, after NAT and upfront resection. 464 patients were never smokers (54.7%), 250 former smokers (29.5%), and 134 active smokers (15.8%). In the multivariable model, the interaction of neoadjuvant FOLFIRINOX and active smoking was associated with the highest risk for decreased OS (harzard ratio (HR) 2.35; 95% confidence interval 1.13–4.90) and strongly mitigated the benefit of FOLFIRNOX (HR 0.40; 95% CI 0.25–0.63). Adjusted median OS in NAT patients with FOLFIRINOX was not reached for never and former smokers, compared to 26.2 months in active smokers. Based on the model, a nomogram was generated to illustrate the probability of 5-year survival after PDAC resection. ConclusionThe present study confirms that neoadjuvant FOLFIRINOX is associated with excellent survival and demonstrates that active smoking reduces its benefit. The nomogram can assist in daily clinical practice and emphasises the importance of smoking cessation in patients with PDAC, especially prior to NAT with FOLFIRINOX.

Complete response rates in rectal cancer: Temporal changes over a decade in a population-based nationwide cohort

IntroductionIn the past decade many changes in neoadjuvant treatment for patients with rectal cancer have taken place and are expected to impact complete response rates. The aim of this study was to investigate the impact on pathological, and overall, complete response rates in a nationwide population-based cohort, in relation to changes in neoadjuvant treatment and the start of a Watch & Wait (WoW) study. Materials and methodsA nationwide register study using prospectively collected data from the Swedish Colorectal Cancer Register between 2009 and 2020. Patients with rectal cancer stage I-III with a ypT0N0 in the resected specimen after neoadjuvant treatment and clinical complete responders from the yearly inclusion data of the national WoW study were included. Temporal changes in pathological and overall complete response rates were analysed, and differences in neoadjuvant treatment regimens over time and per region were studied. ResultsBetween 2009 and 2020 the pathological complete response rate for rectal cancer remained similar (Mann-Kendall tau of 0.091, p = 0.68) while the overall complete response rate increased significantly from 3.0% to 9.6% (Mann-Kendall tau of 0.818, p < 0.001). The pathological complete response rate for patients receiving short course radiotherapy followed by chemotherapy was reduced by 50% after the introduction of the WoW study. ConclusionsDuring the studied time period the overall complete response rate increased significantly presumably due to changes in national neoadjuvant treatment regimens. Since the start of the national WoW study clinical complete response seem to partly replace pathological complete response.

Predictive value of baseline serum carbohydrate antigen 19-9 level on treatment effect of neoadjuvant chemoradiotherapy in patients with resectable and borderline resectable pancreatic cancer in two randomized trials.

Guidelines suggest that the serum carbohydrate antigen (CA19-9) level should be used when deciding on neoadjuvant treatment in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer). In patients with resectable pancreatic cancer, neoadjuvant therapy is advised when the CA19-9 level is 'markedly elevated'. This study investigated the impact of baseline CA19-9 concentration on the treatment effect of neoadjuvant chemoradiotherapy (CRT) in patients with resectable and borderline resectable pancreatic cancers. In this post hoc analysis, data were obtained from two RCTs that compared neoadjuvant CRT with upfront surgery in patients with resectable and borderline resectable pancreatic cancers. The effect of neoadjuvant treatment on overall survival was compared between patients with a serum CA19-9 level above or below 500 units/ml using the interaction test. Of 296 patients, 179 were eligible for analysis, 90 in the neoadjuvant CRT group and 89 in the upfront surgery group. Neoadjuvant CRT was associated with superior overall survival (HR 0.67, 95 per cent c.i. 0.48 to 0.94; P = 0.019). Among 127 patients (70, 9 per cent) with a low CA19-9 level, median overall survival was 23.5 months with neoadjuvant CRT and 16.3 months with upfront surgery (HR 0.63, 0.42 to 0.93). For 52 patients (29 per cent) with a high CA19-9 level, median overall survival was 15.5 months with neoadjuvant CRT and 12.9 months with upfront surgery (HR 0.82, 0.45 to 1.49). The interaction test for CA19-9 level exceeding 500 units/ml on the treatment effect of neoadjuvant CRT was not significant (P = 0.501). Baseline serum CA19-9 level defined as either high or low has prognostic value, but was not associated with the treatment effect of neoadjuvant CRT in patients with resectable and borderline resectable pancreatic cancers, in contrast with current guideline advice.

18F-FDG-PET/CT to Detect Pathological Complete Response After Neoadjuvant Treatment in Patients with Cancer of the Esophagus or Gastroesophageal Junction: Accuracy and Long-Term Implications

Purpose The curative strategy for patients with esophageal cancer without distant metastases consists of esophagectomy with preceding chemo(radio)therapy (CRT). In 10–40% of patients treated with CRT, no viable tumor is detectable in the resection specimen (pathological complete response (pCR)). This study aims to define the clinical outcomes of patients with a pCR and to assess the accuracy of post-CRT FDG-PET/CT in the detection of a pCR.MethodsFour hundred sixty-three patients with cancer of the esophagus or gastroesophageal junction who underwent esophageal resection after CRT between 1994 and 2013 were included. Patients were categorized as pathological complete responders or noncomplete responders. Standardized uptake value (SUV) ratios of 135 post-CRT FDG-PET/CTs were calculated and compared with the pathological findings in the corresponding resection specimens.ResultsOf the 463 included patients, 85 (18.4%) patients had a pCR. During follow-up, 25 (29.4%) of these 85 patients developed recurrent disease. Both 5-year disease-free survival (5y-DFS) and 5-year overall survival (5y-OS) were significantly higher in complete responders compared to noncomplete responders (5y-DFS 69.6% vs. 44.2%; P = 0.001 and 5y-OS 66.5% vs. 43.7%; P = 0.001). Not pCR, but only pN0 was identified as an independent predictor of (disease-free) survival.ConclusionPatients with a pCR have a higher probability of survival compared to noncomplete responders. One third of patients with a pCR do develop recurrent disease, and pCR can therefore not be equated with cure. FDG-PET/CT was inaccurate to predict pCR and therefore cannot be used as a sole diagnostic tool to predict pCR after CRT for esophageal cancer.

Safety and efficacy of immunotherapy plus chemotherapy as neoadjuvant treatment for patients with locally advanced gastric cancer: a retrospective cohort study.

The combined use of programmed death receptor-1 (PD-1) inhibitors and chemotherapy has reshaped the treatment landscape of advanced or metastatic gastric cancer (GC). This study aimed to assess the efficacy and safety of PD-1 inhibitors combined with chemotherapy in a neoadjuvant setting for locally advanced GC (LAGC). Patients diagnosed with clinical stage II-III GC undergoing neoadjuvant PD-1 inhibitors plus chemotherapy were enrolled from December 2019 to July 2022. Clinicopathological characteristics, pathological information, and survival data were recorded and analyzed. A total of 42 eligible patients were enrolled, of whom 37 (88.1%) had clinical stage III disease. All the patients underwent surgery, and the R0 resection rate was 90.5%. Major pathological response (MPR) and pathological complete response (pCR) rates were 42.9% and 26.2%, respectively. The overall TNM downstaging rate was 76.2%. A total of 36 (85.7%) patients received adjuvant chemotherapy. With a median follow-up of 23.1 months, four patients died after tumor recurrence, and three were alive with recurrence. The 1-year overall survival (OS) and disease-free survival (DFS) rates were 94.4% and 89.5%, respectively, and the median OS and DFS were not reached. Neoadjuvant treatment was well tolerated with no grade 4-5 treatment-related adverse events (TRAEs) observed. The most common grade 3 TRAEs were anemia and alanine aminotransferase increase (n = 2 each, 9.6%). PD-1 inhibitors plus chemotherapy demonstrated promising efficacy, with encouraging pCR and survival outcomes in a neoadjuvant setting for patients with LAGC. The combined therapy also showed a good safety profile.

P-233 Modified FOLFIRINOX as neoadjuvant treatment in patients with borderline resectable and locally advanced pancreatic adenocarcinoma: A single-center study, updated with new data

P-233 Modified FOLFIRINOX as neoadjuvant treatment in patients with borderline resectable and locally advanced pancreatic adenocarcinoma: A single-center study, updated with new data

A phase 2 study of neoadjuvant lenvatinib in locally advanced invasive thyroid cancer.

TPS6105 Background: Lenvatinib is a multiple receptor tyrosine kinase (RTK) inhibitor that has demonstrated meaningful benefit in radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). In SELECT, lenvatinib significantly prolonged progression-free survival (PFS) and was associated with an overall response rate (ORR) of 65% in patients with RAI-refractory DTC, with the greatest degree of tumor shrinkage occurring in the first 2 cycles. The robust activity of lenvatinib in DTC suggests that neoadjuvant treatment in patients presenting with bulky neck disease may make surgery more feasible, allows for optimal surgical outcomes and less aggressive surgical management. Neoadjuvant lenvatinib to improve surgical outcomes in locally advanced DTC has not been studied to date. This phase 2 study will examine the efficacy and safety of lenvatinib prior to thyroidectomy, with the goal of achieving more favorable surgical outcomes. Methods: This is a Simon two-stage Phase 2 open-label multicenter clinical trial for adult patients who meet the following criteria: have been diagnosed with locally advanced or persistent/recurrent thyroid and/or cervical nodal DTC, deemed at risk for R2 resection (surgical margins with macroscopic tumor) (as evident by vocal cord paralysis by laryngoscopic exam, imaging documenting extrathyroidal/extranodal extension, or major vessels involvement), have measurable disease per RECIST v1.1, have an ECOG performance status ≤ 1, and no contraindication to surgery. A total of 28 patients will be enrolled from three centers (Massachusetts General Hospital/Massachusetts Eye &amp; Ear Infirmary (MGH/MEEI), Memorial Sloan-Kettering Cancer Center (MSKCC), and MD Anderson Cancer Center (MDACC)). Participants will receive up to 6 cycles of lenvatinib prior to surgery depending on response. Participants will undergo restaging at the end of cycle 2, 4, and 6. Participants with sufficient response to treatment who projected to achieve an R0 or R1 resection will stop lenvatinib and proceed to surgery within 7-10 days from the last dose. Participants who do not have a sufficient response who are tolerating treatment, will receive an additional 2-4 cycles of lenvatinib, followed by surgery. The primary objective is the R0 (surgical margins free from tumor)/R1 (surgical margins free from macroscopic tumor) resection rate. Secondary outcome measures include R0/R1 resection rates in each of 5 pre-specified anatomic target interfaces (perithyroid muscles, cartilage, esophagus, recurrent laryngeal nerve, major vessels), evaluation of the change in surgical morbidity complexity MGH/MEEI-MSKCC-MDACC (MMM) score and the Invasive Thyroid Class, ORR prior to surgery per RECIST v1.1, and the safety of lenvatinib in this patient population. The study is currently accruing with 11 patients enrolled at time of submission. Clinical trial information: NCT04321954 .

Comment on "Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial" by Mei et al.: Two Overtreatments Compared.

Mei et al. published in Annals of Surgery1 the initial results of the CONVERT trial, comparing neoadjuvant chemotherapy with CAPOX versus standard chemoradiation for rectal cancer with uninvolved mesorectal fascia. The design of the study, reported results and conclusions raise concerns. It seems that a vast majority of the cohort did experience an overtreatment, as their tumors could be adequately treated with surgery alone.2,3 The authors do not discuss these limitations, nor have they reported, whether surgery alone was one of the options given to patients during the consent process. It is not clear, what was the benefit of neoadjuvant treatment in patients with primary operable tumors. The price of this treatment is mentioned. Despite relatively young (median age of 60 years, age limit 75 years) and healthy cohort (ECOG performance status ≤1, adequate hematologic, liver, and renal function), 70.3% in the neoadjuvant chemotherapy group and 64.7% in the neoadjuvant chemoradiotherapy group experienced toxicities. The postoperative morbidity was 18.8% and 25.7%, respectively. Nearly 10% in both groups did not receive surgery at all, and 13% refused postoperative therapy. The authors describe the downstaging of the tumors, but without admitting that the reliability of comparison between MRI and pathological findings is low.4–6 Post-treatment functional impairment, frequency, and severity of low anterior syndrome are also not reported. A statistical comparison of 2 overtreatments does not make the treatment appropriate. All treatment modalities in rectal cancer: surgery, radiotherapy, and chemotherapy do have a significant risk of complication. The combination of these treatment options could possibly potentiate their risks and adverse effects; therefore, selecting the therapy course is a difficult and careful process. The goal is to find a minimal therapy sufficient for success, not a maximal therapy applicable to the patient.

Fruquintinib plus oxaliplatin combined with S-1 (SOX) as neoadjuvant therapy for locally advanced gastric adenocarcinoma (FRUTINEOGA): A multicenter, phase II study.

e16063 Background: Neoadjuvant chemotherapy (NCT) has become the standard treatment for patients (pts) with locally advanced GC, and SOX is the most common neoadjuvant regimen in China. Fruquintinib is a VEGFR inhibitor that blocks new blood vessel growth associated with tumor proliferation. It is a potent, highly selective small-molecule inhibitor of VEGFR-1,-2, and -3. The generally good tolerability in pts and fruquintinib’s low potential for drug-drug interaction suggest that it may be highly suitable for combinations with other antineoplastic therapies. We aimed to investigate the efficacy and toxicity of fruquintinib plus SOX as neoadjuvant treatment for locally advanced GC. Methods: It was a prospective, multicenter, phase II study in pts with stage III (cT3/4aN+M0) GC. Pts received 2 to 4 cycles of fruquintinib (5mg qd D1-14, Q3W) plus SOX (oxaliplatin 130mg/m2 D1, S-1 40-60mg bid D1-14 depending on body surface area (BSA), Q3W). Pts underwent D2 gastrectomy after neoadjuvant treatment. The primary endpoint was pathological response rate (pRR), and the secondary endpoints were disease-free survival (DFS), overall survival (OS), objective response rate (ORR), major pathological response rate (MPR), and R0 resection rate. Results: Up to February 3, 2023, 19 pts were eligible for the study. Median age was 62 years (29-73), 68.4% were male, and 21.1% were ECOG 1. Seven pts dropped out of clinical trial for AEs (2 pts), violation of treatment protocol (1 pt), staging error (2 pts), and refusal of surgery (2 pts). Twelve pts underwent surgery, 1 patient was found with peritoneal implantation, 11 patients underwent gastrectomy. Among the 11 pts, 9 pts achieved pRR (81.8%) and 3 pts achieved MPR (27.3%). The pathologic CR rate was 27.3% (3 of 11 pts). Moreover, 11 pts had curative intended operations and R0 resection rate was 90.9%. Among all the 19 pts, 16 pts received at least one dose of the combination treatment. A total of 2 pts had target lesions, 1 patient had complete response and 1 had partial response. Among the other 14 pts without target lesions, 1 (7.1%) had progressive disease with peritoneal implantation metastasis, and none had complete response. Furthermore, the most common TEAEs of grade ≥ 3 occurred in 19 pts were decreased appetite (21.1%), hypertension (21.1%), nausea (15.8%), vomiting (10.5%), oral mucositis (10.5%), fatigue (5.3%), diarrhea (5.3%) and respiratory infections (5.3%). There were neither new safety signals nor AEs inducing treatment deaths. Conclusions: The combination of fruquintinib and SOX as neoadjuvant treatment in patients with locally advanced GC is safe. The combination demonstrates promising evidence of anti-tumor efficacy in terms of pathological response. Clinical trial information: NCT05122091 .

A phase ll study on the neoadjuvant treatment of resectable high-risk soft tissue sarcoma with anlotinib and doxorubicin.

e23542 Background: Anthracycline and ifosfomide-based chemotherapy is the main neoadjuvant treatment option for resectable high-risk STS with severe myelosuppression and other side effects. Anlotinib has been approved as second-line treatment for most of advanced STS by the Chinese agency. This study was conducted to evaluate the efficacy and safety of anlotinib in combination with doxorubicin in the neoadjuvant treatment of patients with resectable high-risk STS to reduce the toxicity of chemotherapy. Methods: This is a single-center, prospective study. Eligible patients were those ≥18years old, ECOG performance state of 0-1, with histologically confirmed locally resectable high-risk STS. All patients received a preoperative combination of anlotinib (12mg once daily, on for 2 weeks, off for 1 week) and doxorubicin (75mg /m2, IV, D1-2, every 3 weeks) .The combination treatment was repeated 2 to 3 cycles before operation. The primary endpoint was objective response rate (ORR), and the second endpoints were Disease control rate (DCR), and side effects. Results: Between December 2020 and December 2022, 13 patients were evaluated, including 4 synovial sarcoma, 3 undifferentiated sarcoma, 3 spindle cell sarcoma, 2 liposarcoma, 1 angiosarcoma. The median age was 35 years. 1 patients (7.69%) achieved a confirmed partial response (PR) and 7 (53.85%) had stable disease (SD). The ORR and DCR were 7.69% and 61.54% respectively. All patients underwent marginal or extensive excision of the tumor and none underwent amputation. Most of Treatment-related adverse events included neutropenia 5 (38.46%), hypothyroidism 3 (23.08%), anemia 2(15.38%). Three patients experienced grade 3 or 4 adverse events, neutropenia (1/13, 7.69%) and tumor hemorrhage (2/13, 15.38%). No wound complications such as infection, delayed healing or haematoma occurred. Conclusions: This study suggested that the combination of anlotinib and doxorubicin might be a option for neoadjuvant therapy for patients with resectable high-risk STS due to the anti-tumor activity and acceptable toxicity.