Neoadjuvant Treatment Approach Research Articles

Prospective screening and proposed treatment algorithm for immune checkpoint inhibitor induced myositis in neoadjuvant-treated rectal cancer patients: data from the phase II CHINOREC trial

Abstract Background Myositis is an infrequent (<1%) but potentially life-threatening (case fatality rate 40-50%) immune-related adverse event (irAEs) of immune checkpoint inhibitors (ICI), such as ipilimumab (IPI) and nivolumab (NIVO). The true incidence is likely to be underestimated and may not be representative for curative neoadjuvant treatment approaches in gastrointestinal (GI) cancers, especially in combination with chemoradiotherapy (CRT). Currently, the summary of product characteristics (SmPC) does not suggest any pre-emptive screening or surveillance. Methods The CHINOREC study is an ongoing prospective, randomized, open-label, multicenter, phase II investigator-initiated trial (IIT). Patients with intermediate to locally advanced rectal cancer (LARC) receive either neoadjuvant CRT alone or in combination with a single dose of IPI and 3 cycles of NIVO, following surgical resection. Patients are monitored at baseline and throughout the whole study period for myotoxicity biomarkers, including cardiac troponin T (cTnT) and cardiac troponin I (cTnI). Findings From 06/2020 to 11/2023, 80 patients have been enrolled of whom 50 patients were randomized to the CRT+IPI/NIVO arm. Six patients (12%) developed biopsy-verified myositis. Myositis treatment was promptly implemented using a pragmatic step-up approach. Patients received glucocorticoids (GC) with concomitant intravenous immunoglobulin (IVIG). If myotoxicity biomarkers did not improve, patients received infliximab (INFLIXI) and/or plasma exchange (PLEX). Although all patients had strikingly elevated cTnT (median peak 284 ng/L, 95% CI 39-3097), cTnI levels remained largely normal, correlating with a negative cardiac magnetic resonance (CMR). All patients underwent successful tumor surgery without any major surgical complication. As of today, all patients' creatine kinase (CK) and myoglobin (MB) levels have normalized and they are tumor free without any major sequela. Interpretation Longitudinal biomarker screening (cTnT/cTnI) for ICI-induced myotoxicities is pivotal in curative neoadjuvant-treated cancer patients to initiate an early counter treatment in a holistic step-up approach, without compromising oncological principles.

Update on HPV-associated head and neck cancers-highlights of the 2024 ASCO Annual Meeting

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is becoming increasingly important in head and neck oncology. At this year's conference of the American Society of Clinical Oncology (ASCO), alarge number of papers were presented on the topic of HPV-associated HNSCC, particularly with regard to neoadjuvant treatment approaches, radiation de-escalation strategies, therapeutic vaccines, and treatment monitoring. In this context, study results on the treatment of HPV-related recurrent respiratory papillomatosis (RRP) were also presented. Based on contributions to the 2024 ASCO Annual Meeting, an insight into the latest developments in HPV-associated diseases of the head and neck is provided. The papers were reviewed for clinical relevance and contextualized based on current therapeutic concepts. Alarge number of studies on liquid biopsies (LB) were presented. It was shown that although the methods for analyzing LBs for HPV-positive patients are well developed and can be used for diagnostics, risk classification, treatment management, or tumor follow-up, the methods vary considerably, and their clinical application has not yet been sufficiently validated. With regard to therapeutic HPV vaccination, three large studies were presented for the treatment of recurrent/metastatic HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). The only randomized study was on the vaccine ISA101b (peltopepimut-S) and did not reach its primary endpoint; however, the vaccine seemed to be highly effective in patients with a combined positive score (CPS) ≥ 20. Furthermore, data from aphaseIstudy on PRGN2012, an adenovirus-based immunotherapy used therapeutically for the treatment of recurrent respiratory papillomatosis (RRP), were presented. PRGN2012 led to areduction in surgical interventions for RRP, and the US Food and Drug Administration (FDA) designated PRGN2012 as abreakthrough therapy and orphan drug. However, the vaccine is not yet approved for the treatment of RRP.

Comparison of neoadjuvant chemoradiotherapy versus chemoradiotherapy plus immunotherapy for esophageal squamous cell carcinoma in a real-world multicenter cohort: a propensity score matching study.

Neoadjuvant chemoradiotherapy combined with immunotherapy (NICRT) is a new neoadjuvant treatment approach that has raised concerns regarding potential challenges in surgery and postoperative complications. This study aimed to compare the efficacy and safety of neoadjuvant chemoradiotherapy (NCRT) and NICRT for the treatment of resectable locally advanced esophageal squamous cell carcinoma (ESCC). We retrospectively analyzed 291 patients with locally advanced ESCC who underwent neoadjuvant therapy and esophagectomy at three centers between January 2019 and September 2023 and added the data from PALACE-1 for the analysis, Among these patients, 248 and 61 patients received NCRT and NICRT, respectively. Propensity score matching (PSM) was used to balance the potential bias. After the PSM,the rate of a pathological complete response (pCR) in the NCRT group was not significantly different from that in the NICRT group (46.90% vs 36.36%, P = 0.180). There were no significant differences in the tumor regression grade (TRG) and positive lymph node pCR rates between the two groups (P = 0.233 and P = 0.354, respectively). Treatment-related toxicities and postoperative complications were not significantly different between the NCRT group and the NICRT group (P = 0.199, P = 0.284). Compared with NCRT, NICRT did not lead to the better treatment efficacy. There were no significant differences was observed in the incidence of treatment-related toxicities and postoperative complications.

Advancing Pancreatic Cancer Surgical Treatments and Proposal of New Approaches.

Pancreatic cancer is a significant challenge in oncology due to its aggressive nature and complex management, leading to high mortality rates and a dismally low 5-year survival rate. Approximately 85% of cases manifest as adenocarcinoma, while endocrine tumors constitute less than 5%. Borderline resectable and locally advanced pancreatic cancers are particularly difficult to treat due to vascular involvement, which complicates complete resections and increases morbidity. Various therapeutic modalities aim to overcome these challenges and improve patient outcomes. Traditionally, upfront surgery was the standard for resectable tumors, with multimodal chemotherapy being central to treatment. Understanding surgical anatomy is pivotal in enhancing surgical outcomes and patient survival. Resectability challenges are several when seeking to achieve R0 resections, particularly for borderline resectable tumors. Various classification systems-the MD Anderson criteria, the NCCN criteria, the AHPA/SSAT/SSO consensus statement, and the Alliance definition-assess tumor involvement with major blood vessels, with the first of these systems being broadly accepted. Vascular staging integration is also important, with the Ishikawa staging system using preoperative imaging to assess venous involvement. Furthermore, neoadjuvant therapy enhances treatment effectiveness by addressing micro-metastatic disease early, increasing R0 resection chances, and downstaging tumors for optimal surgery. Insights from the Fox Chase Cancer Center's neoadjuvant treatment approach highlight the importance of a multidisciplinary strategy when advancing therapy and improving patient prognosis. This commentary, inspired by Dr. Sanjay S. Reddy's Keynote Conference during MedNews week, highlights current advancements and ongoing challenges in the treatment of pancreatic cancer, emphasizing the need for a comprehensive, multidisciplinary approach to improve outcomes.

Comparison of the efficacy of immunotherapy at different time points during the perioperative period for stage II-III NSCLC.

e20009 Background: The application of immune checkpoint inhibitors (ICIs) in early-stage lung cancer is fraught with unresolved issues, and there are no clinical studies directly comparing the efficacy of ICIs used in neoadjuvant, adjuvant, and neoadjuvant followed by adjuvant therapy across different perioperative time points in non-small cell lung cancer (NSCLC). Consequently, the optimal timing for immunotherapy in surgically resectable NSCLC remains uncertain. Methods: This study encompassed 536 patients with stage II-III NSCLC, diagnosed and treated across multiple centers from January 2019 to December 2022. Clinical data for all patients ultimately included in the study were retrospectively collected. The primary endpoints evaluated were event-free survival (EFS)/disease-free survival (DFS) and overall survival (OS) . Secondary endpoints included pathological complete response (pCR) and major pathological response (MPR). Propensity score matching was utilized to mitigate confounding factors, comparing the efficacy of ICIs across different treatment modalities and time dimensions during the perioperative period of lung cancer. Results: The integration of neoadjuvant ICIs with chemotherapy was observed to significantly enhance pCR ( p < 0.001), MPR ( p < 0.001), EFS ( p = 0.002), and OS ( p < 0.001) in comparison to neoadjuvant chemotherapy alone. Similarly, the combination of adjuvant ICIs with chemotherapy markedly improved DFS ( p = 0.034) and OS ( p = 0.021) relative to adjuvant chemotherapy alone. Building on these insights, we further delineated the efficacy of ICIs across distinct temporal dimensions within the perioperative interval, categorizing patients into three groups: neoadjuvant ICIs plus chemotherapy, adjuvant ICIs plus chemotherapy, and a sequential regimen of neoadjuvant followed by adjuvant ICIs plus chemotherapy. The analysis revealed no significant differences in DFS and OS among the three patient groups for stage II NSCLC. In contrast, for stage III NSCLC, both neoadjuvant ( p = 0.015) and sequential treatment approaches ( p = 0.047) demonstrated significantly improved DFS outcomes compared to the adjuvant protocol, with no substantial statistical difference noted between the neoadjuvant and sequential treatments ( p = 0.274). Furthermore, the sequential regimen outperformed the adjuvant strategy in OS ( p = 0.020). However, when comparing the neoadjuvant strategy with either the adjuvant ( p = 0.054) or sequential approaches ( p = 0.717), there were no statistically significant variances detected. Conclusions: For individuals with resectable stage III NSCLC, perioperative administration of neoadjuvant and sequential adjuvant ICIs appears to confer enhanced survival advantages. Future efforts should focus on refining treatment strategies for early-stage NSCLC, aiming to deliver enhanced survival benefits to patients.

A single-institution experience of acute toxicities in patients treated with short course hypofractionated radiotherapy in locally advanced rectal cancer.

92 Background: Hypofractionated short course radiation treatment (SCRT) as part of a total neoadjuvant treatment (TNT) approach to treat rectal cancer has increased in popularity since the publication of the RAPIDO trial. However, the literature on SCRT for rectal cancer has not reported significant acute toxicities in the weeks immediately following the completion of treatment. This study examines the acute toxicities in patients treated with hypofractionated radiation therapy as part of their definitive treatment for rectal cancer. Methods: At our institution, we retrospectively analyzed 71 patients with locally advanced rectal cancer treated between 2016-2022 with SCRT (25 Gy in 5 fractions) as part of definitive treatment. Acute toxicity caused by radiation was defined as that occurring from the start of radiation treatment to either 30 days post radiation completion, the start of chemotherapy, or date of surgery, whichever occurred first. Acute neuropathic lumbosacral (LSN) pain was defined as bilateral radiating pain down the lower extremities. Matched patients without reported LSN pain were identified and matched on N stage, location of tumor, and treatment position. Organs at risk were contoured on the CT planning scan and dosimetric analysis was conducted on the patient’s treatment plan. Results: In 71 patients treated with SCRT, we identified diarrhea (n=34, 47.9%), rectal pain (n=15, 21.1%), rectal urgency (n=15, 21.1%) nausea (n=14, 19.7%), and rectal bleeding (n=12, 16.9%) as frequent acute toxicities in the setting of SCRT. For patients with rectal pain, 31.2% required steroids. We also identified an acute toxicity of LSN pain in 10 patients (14.1%). Patients rated this LSN pain between moderate and severe; median time to LSN pain was 2 days (range 1-6 days). For LSN pain, management was conservative for 3 (30%) patients and symptoms self-resolved. The other 7 patients required ibuprofen and acetaminophen treatment; 2 of these patients had persistent symptoms and one was treated with topical hydrocortisone and gabapentin and the other with a burst of methylprednisolone. Dosimetric analysis of the lumbosacral nerve plexus area did not detect a statistically significant difference in dose parameters between symptomatic and asymptomatic patients. Conclusions: We have identified acute toxicities in patients treated with short course hypofractionated radiation, including diarrhea, rectal pain requiring steroid treatment, and previously underappreciated neuropathic lumbosacral pain. Toxicities mainly occurred within one week of treatment and resolved. Further analysis will seek to identify predictive factors of these acute toxicities and to determine whether there is a correlation between these observed acute toxicities and long-term outcomes.

Oncological results in primary and secondary malignant chest wall tumors.

This study aims to evaluate the oncological results of primary and secondary chest wall tumors treated with curative resections and to investigate possible prognostic factors. Between January 2010 and December 2021, a total of 77 patients (53 males, 24 females; median age: 59 years; range, 3 to 87 years) who underwent curative resection for malignant chest wall tumors were retrospectively analyzed. Each tumor was staged according to its histological type. Age, sex, tumor diameter, tumor type (primary/secondary), histological tumor type, grade, stage, complete resection, rib resection, reconstruction, neoadjuvant and adjuvant therapy, recurrence, and survival data were recorded. Of the chest wall tumors, 33 (42.9%) were primary and 44 (57.1%) were secondary (local invasion, metastasis). Nine (11.7%) patients had positive surgical margins. Chest wall resection was most commonly performed due to lung cancer invasion (46.8%), followed by Ewing sarcoma (13%). Recurrence was observed in 34 (44.2%) patients. The five-year recurrence-free survival rate was 42.7% and the five-year overall survival rate was 58.6%. There was no significant difference between the primary and secondary tumors in terms of recurrence-free and overall survival (p=0.663 and p=0.313, respectively). In the multivariate analysis, tumor grade and rib resection were found to be independent prognostic factors for both recurrence-free survival (p=0.005 and p<0.001, respectively) and overall survival (p=0.048 and p=0.007, respectively). Successful oncological results can be achieved in wellselected patients with primary and secondary chest wall tumors. The grade of the tumor should be taken into account while determining the neoadjuvant or adjuvant treatment approach and surgical margin width. Rib resection should not be avoided when necessary.

Correlation between Baseline Conventional Ultrasounds, Shear-Wave Elastography Indicators, and Neoadjuvant Therapy Efficacy in Triple-Negative Breast Cancer.

In patients with triple-negative breast cancer (TNBC)-the subtype with the poorest prognosis among breast cancers-it is crucial to assess the response to the currently widely employed neoadjuvant treatment (NAT) approaches. This study investigates the correlation between baseline conventional ultrasound (US) and shear-wave elastography (SWE) indicators and the pathological response of TNBC following NAT, with a specific focus on assessing predictive capability in the baseline state. This retrospective analysis was conducted by extracting baseline US features and SWE parameters, categorizing patients based on postoperative pathological grading. A univariate analysis was employed to determine the relationship between ultrasound indicators and pathological reactions. Additionally, we employed a receiver operating characteristic (ROC) curve analysis and multivariate logistic regression methods to evaluate the predictive potential of the baseline US indicators. This study comprised 106 TNBC patients, with 30 (28.30%) in a nonmajor histological response (NMHR) group and 76 (71.70%) in a major histological response (MHR) group. Following the univariate analysis, we found that T staging, dmax values, volumes, margin changes, skin alterations (i.e., thickening and invasion), retromammary space invasions, and supraclavicular lymph node abnormalities were significantly associated with pathological efficacy (p < 0.05). Combining clinical information with either US or SWE independently yielded baseline predictive abilities, with AUCs of 0.816 and 0.734, respectively. Notably, the combined model demonstrated an improved AUC of 0.827, with an accuracy of 76.41%, a sensitivity of 90.47%, a specificity of 55.81%, and statistical significance (p < 0.01). The baseline US and SWE indicators for TNBC exhibited a strong relationship with NAT response, offering predictive insights before treatment initiation, to a considerable extent.

Targeting Tri-Methyl-Histone H3 (Lys27) in Rectal Cancer: A Novel Strategy to Enhance Radiosensitivity and Predict Response to Neoadjuvant Therapy

Tri-Methyl-Histone H3 (Lys27) is a modification of histone H3 involved in gene regulation and chromatin organization. It plays a crucial role in cell response to ionizing radiation and affects DNA damage repair, with altered levels being linked to decreased radiation sensitivity. Our hypothesis is that high levels of Tri-Methyl-Histone H3 (Lys27) in rectal tumors can predict response to neoadjuvant chemoradiation, and targeting SETD2, the histone methyltransferase responsible for adding the tri-methyl group to Lys27 of histone H3, may enhance radiosensitivity in rectal cancer cells. Biopsy samples from 25 patients with locally advanced rectal adenocarcinoma (Stage II-III) were obtained for analysis. Immunohistochemistry (IHC) was used to evaluate Tri-Methyl-Histone H3 (Lys27) expression levels in the tumor biopsies. The staining intensity was scored semi-quantitatively. Samples with 100% positive staining were grouped as "Tri-Methyl-High," and all others were grouped as "Tri-Methyl-Low." Fisher's exact test was used to analyze the data to determine the correlation between Tri-Methyl-Histone H3 (Lys27) levels and response to neoadjuvant chemoradiation. The primary endpoint was either a sustained clinical complete response (cCR) at one year or a pathological complete response (pCR). To further understand the role of Tri-Methyl-Histone H3 (Lys27) in response to ionizing radiation (IR), clonogenic assays, γH2aX foci staining, and western blot analysis of DNA damage response proteins and histones were performed on two established human rectal cancer cell lines following either RNA inhibition (RNAi) or drug targeting of SETD2. Twenty-five patients with rectal cancer had pre-treatment biopsies analyzed for Tri-Methyl-Histone H3 (Lys27) levels, 11 were classified as Tri-Methyl-High and 14 as Tri-Methyl-Low. The groups were well balanced in terms of age, sex, clinical T/N stage, and neoadjuvant treatment approach. The overall combined complete response (cCR/pCR) rate was 36%, while the rate for Tri-Methyl-High patients was 9% (1/11) compared to 57% (8/14) in Tri-Methyl-Low patients (p = 0.03). After treating two colorectal cancer cell lines (SW837 and HCT116) with IR (5 Gy) in vitro, Tri-Methyl-Histone H3 (Lys27) levels increased 3-fold. SETD2 RNAi reduced Tri-Methyl-Histone H3 (Lys27) and increased cell death when combined with IR. In vitro treatment with a novel SETD2 inhibitor, EZM0414, led to a 2-fold increase in DNA damage following IR (5 Gy) as measured by γH2aX foci staining. EZM0414 treatment showed a 37% improvement in the dose enhancement ratio. Our study uncovers a new biomarker, Tri-Methyl-Histone H3 (Lys27), that could be used to predict response to neoadjuvant chemoradiation in rectal cancer patients. Our preclinical data indicates that targeting SETD2 to reduce Tri-Methyl-Histone H3 (Lys27) mediated DNA repair could improve the efficacy of radiation therapy for rectal cancer patients.

A Single-Institution Experience of Acute Neuropathic Lumbosacral Pain in Patients Treated with Short Course Hypofractionated Radiotherapy in Locally Advanced Rectal Cancer

There has been increased interest in the use of short course hypofractionated radiotherapy as part of a total neoadjuvant treatment (TNT) approach in the management of rectal cancer since publication of the RAPIDO trial. However, the literature on short course radiation for rectal cancer has not reported significant acute toxicities in the weeks immediately following the completion of treatment. Anecdotally, a subset of patients has experienced acute neuropathic pain characterized in a lumbosacral distribution. This study investigates acute lumbosacral toxicity for patients receiving hypofractionated short course radiation as part of their definitive treatment for rectal cancer. We retrospectively analyzed 75 patients with locally advanced rectal adenocarcinoma treated with hypofractionated short course radiation (25 Gy in 5 fractions) at our institution between 2016 and 2022. Acute toxicity caused by radiation was defined as that occurring from the start of radiation treatment to either 30 days post radiation completion, the start of chemotherapy, or date of surgery, whichever occurred first. Among 75 patients treated with hypofractionated short course preoperative radiation with definitive intent, we identified 10 patients (13.3%) who experienced significant lumbosacral neuropathic pain and initiated a report to their medical providers during the acute toxicity time frame. Commonly, this was described as an achy pain in the bilateral buttocks radiating down to the knees or posterior claves. Patients rated this pain between moderate to extreme and management included steroids after failure of improvement with conservative measures, gabapentin, and conservative treatment with NSAIDs and Tylenol. Average time to onset of acute lumbosacral neuropathic pain was 3.7 days (SD 2.05) from start of RT. We have identified a previously underappreciated acute toxicity of neuropathic lumbosacral pain in short course hypofractionated radiation therapy, which may be due to a lumbosacral plexus toxicity. Further analysis will seek to identify predictive factors such as comorbidities and dose to the lumbosacral plexus, and to determine whether there is a correlation between these observed acute toxicities and long-term outcomes.

Adjuvant and neoadjuvant approaches in pancreatic cancer.

Pancreatic cancer treatment remains a challenging problem for surgeons and oncologists. This review aims to summarize the current advances on adjuvant and neoadjuvant treatment approaches for resectable pancreatic cancer. Recent phase III randomized trials of adjuvant therapy showed improvement of overall survival in both experimental and control groups. Effectiveness of adjuvant therapy in specific subgroups as elderly patients, intraductal papillary mucinous neoplasms, stage I, and DNA damage repair gene germline variants has been reported. Completion of all cycles of planned adjuvant chemotherapy is confirmed as an independent prognostic factor. Adjuvant chemotherapy remains underutilized, mainly because of early recurrence, prolonged recovery, or older age older than 75 years. So, neoadjuvant treatment is a logical approach to administer systemic treatment to more patients. Meta-analysis did not demonstrate an overall survival benefit of neoadjuvant treatments in resectable pancreatic cancer, and definitive conclusions cannot be drawn from available randomized controlled trials. Upfront surgery and adjuvant chemotherapy should still be considered a standard approach in resectable pancreatic cancer. Adjuvant chemotherapy with mFOLFIRINOX remains the standard of care in fit patients with resected pancreatic cancer, and limited high-level evidence support the use of neoadjuvant therapy in upfront resectable pancreatic cancer.

Personalizing neoadjuvant immune-checkpoint inhibition in patients with melanoma.

Neoadjuvant immune-checkpoint inhibition is a promising emerging treatment approach for patients with surgically resectable macroscopic stage III melanoma. The neoadjuvant setting provides an ideal platform for personalized therapy owing to the very homogeneous nature of the patient population and the opportunity for pathological response assessments within several weeks of starting treatment, thereby facilitating the efficient identification of novel biomarkers. A pathological response to immune-checkpoint inhibitors has been shown to be a strong surrogate marker of both recurrence-free survival and overall survival, enabling timely analyses of the efficacy of novel therapies in patients with earlystage disease. Patients with a major pathological response (defined as the presence of ≤10% viable tumour cells) have a very low risk of recurrence, which offers an opportunity to adjust the extent of surgery and any subsequent adjuvant therapy and follow-up monitoring. Conversely, patients who have only a partial pathological response or who do not respond to neoadjuvant therapy still might benefit from therapy escalation and/or class switch during adjuvant therapy. In this Review, we outline the concept of a fully personalized neoadjuvant treatment approach exemplified by the current developments in neoadjuvant therapy for patients with resectable melanoma, which could provide a template for the development of similar approaches for patients with other immune-responsive cancers in the near future.

Neoadjuvant Treatment Approaches for Stage II–III Rectal Cancer

Excellent long-term outcomes are being achieved with contemporary treatment strategies for localized rectal cancer. A “watch-and-wait” nonoperative strategy seems to be a safe option for patients experiencing a complete clinical response. Total neoadjuvant therapy (TNT) has shown many advantages over standard chemoradiotherapy, although the optimal sequencing—with induction or consolidation chemotherapy—is still debated. The use of FOLFIRINOX can boost the benefit of TNT. Of note, in the small subset of patients whose tumors have mismatch repair deficiency, checkpoint inhibition has led to responses in most patients, eliminating the need for further treatment.

NeoAdjuvant pembrolizumab and STEreotactic radiotherapy prior to nephrectomy for renal cell carcinoma (NAPSTER): A phase II randomised clinical trial

BackgroundSurgery remains the standard of care for localised renal cell carcinoma (RCC). Nevertheless, nearly 50% of patients with high-risk disease experience relapse after surgery, with distant sites being common. Considering improved outcomes in terms of disease-free survival with adjuvant immunotherapy with pembrolizumab, we hypothesise that neoadjuvant SABR with or without the addition of pembrolizumab before nephrectomy will lead to improved disease outcomes by evoking better immune response in the presence of an extensive reserve of tumor-associated antigens. Methods and analysisThis prospective, open-label, phase II, randomised, non-comparative, clinical trial will investigate the use of neoadjuvant stereotactic ablative body radiotherapy (SABR) with or without pembrolizumab prior to nephrectomy. The trial will be conducted at two centres in Australia that are well established for delivering SABR to primary RCC patients. Twenty-six patients with biopsy-proven clear cell RCC will be recruited over two years. Patients will be randomised to either SABR or SABR/pembrolizumab. Patients in both arms will undergo surgery at 9 weeks after completion of experimental treatment. The primary objectives are to describe major pathological response and changes in tumour-responsive T-cells from baseline pre-treatment biopsy in each arm. Patients will be followed for sixty days post-surgery. Outcomes and significanceWe hypothesize that SABR alone or SABR plus pembrolizumab will induce significant tumor-specific immune response and major pathological response. In that case, either one or both arms could justifiably be used as a neoadjuvant treatment approach in future randomized trials in the high-risk patient population.

Impact of Professional Seniority on Total Neoadjuvant Treatment Approach for Locally Advanced Rectal Cancer

Impact of Professional Seniority on Total Neoadjuvant Treatment Approach for Locally Advanced Rectal Cancer

Borderline Resectable Pancreatic Cancer: Challenges for Clinical Management.

Pancreatic ductal adenocarcinoma (PDAC) remains a significant worldwide health problem with a poor prognosis. A borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) is a tumor with limited vascular involvement that is technically resectable but with a high risk of positive margins (R1 resection). To identify the current challenges that exist in the management of BR-PDAC. A review of the literature was conducted to identify articles discussing the definitions and management of BR-PDAC. Several anatomic definitions of BR-PDAC exist, and there is significant heterogeneity in their utilization across published trials. To improve the odds of a margin negative (R0) resection, a neoadjuvant treatment approach involving chemotherapy with or without radiation is currently preferred. While supporting the efficacy of a neoadjuvant approach in BR-PDAC, the largest published randomized trials have utilized older gemcitabine-based regimens. Recently published Phase II evidence and meta-analyses have supported the use of modern multi-agent regimens such as FOLFIRINOX. The utility of adding radiation to a chemotherapy backbone remains in question. Due to remnant fibrosis and edema following neoadjuvant therapy, accurately selecting patients for resection based on a restaging CT scan is challenging. Furthermore, the role of adjuvant therapy in BR-PDAC patients receiving neoadjuvant therapy needs to be defined. Though progress has been made, the optimal management of BR-PDAC is uncertain. Phase III trials utilizing modern chemotherapeutic regimens are needed to establish a standard of care.

Surgical Management of Melanoma: Advances and Updates.

To review and update surgeons about the evolving complexities in the surgical management of melanoma including lymph node staging and treatment. Primary resection with adequate margins continues to be the standard of care for localized cutaneous melanoma. Sentinel lymph node biopsy is confirmed to be a powerful tool due to its prognostic value and informative guidance for adjuvant treatments and surveillance. Due to the lack of benefit in melanoma-specific survival and distant metastasis-free survival, completion lymph node dissection is not performed routinely after a positive sentinel lymph node biopsy. Neoadjuvant systemic treatment approaches for advanced loco-regional disease show promise in phase I and II clinical trial data, and phase III studies. The surgical management of cutaneous melanoma continues to evolve with further de-escalation of the extent of excision of primary melanomas and the management of lymph node disease.

The professional seniority affects the clinical application of total neoadjuvant therapy for locally advanced rectal cancer.

e15590 Background: Total neoadjuvant therapy (TNT) integrates whole planned systemic chemotherapy within standard neoadjuvant protocols either before or after radiotherapy for locally advanced rectal cancer (LARC). Preference of neoadjuvant treatment type may vary among the medical oncologists. This study aimed to evaluate impact of professional seniority on TNT approach for LARC. Methods: A 20-item questionnaire was presented to medical oncologists as a cross-sectional survey during a national oncology congress via tablets. The evaluation was stratified by position; early-career oncologists (ECOs) and seniors. 2 questions were about experience regarding rectal cancer treatment. 5 questions were about physicians’ choice of screening and treatment in LARC and the factors affecting their treatment choices. 13 questions were about TNT approach (the sequencing of treatment, denominators of sequencing, chemotherapy choice, treatment response evaluation, operation preferences, adjuvant treatment and its denominators). Results: 189 medical oncologists were included (62.4% (n = 118) ECOs). An endorectal ultrasound was significantly preferred by the seniors (p = 0.039) in addition to conventional staging tools. 65.6% (n = 124) of the participants preferred long-course chemoradiation as their favorite neoadjuvant treatment approach. External sphincter invasion, threatened circumferential resection margin (CRM) and clinical stage were the most common denominators of TNT regardless of experience. ECOs favored short-course RT (p = 0.009) while the seniors chose long-course chemoradiotherapy (p = 0.041) as the index step of TNT. 57% (n = 108) of the physicians preferred to monitor treatment response for TNT at 8-weeks periods. Almost half of the participants (47.1%) reported pathological complete response (pCR) rates between 25-50% with TNT in their clinical practice. The physicians who prefer to give adjuvant treatment after completion of TNT make individualized decisions when surgical pathology reveals non-pCR, CRM and lymph node involvement. There was a significant difference between the ECOs and seniors (63.6 vs 45.1%, p = 0.013) in terms of choosing the adjuvant chemotherapy based on CRM positivity. Majority of the senior medical oncologists (88%) and ECOs (76.3%) agree that TNT should be the standardized neoadjuvant treatment approach for LARC. The preferred adjuvant chemotherapy after TNT was capecitabine-oxaliplatin (51.1%) or capecitabine alone (46%). Conclusions: TNT for LARC is well accepted among the medical oncologists and the professional seniority seems to affect its clinical application.

Total neoadjuvant treatment approach and carcinoembryonic antigen level in locally advanced rectal cancer.

e15595 Background: Total Neoadjuvant therapy (TNT) has gained acceptance in the treatment of locally advanced rectal cancer, although the optimal sequencing of therapy chemoradiation (CRT) followed by consolidation chemotherapy (cChT) or induction chemotherapy followed by chemoradiation (iChT), remains a subject of ongoing debate. The effect of TNT sequencing and carcinoembryonic antigen (CEA) level on progression free survival (PFS) is uncertain. We conducted a retrospective analysis to examine these issues. Methods: Patients (n = 44) with locally advanced rectal cancer from June 2016 to December 2020 were reviewed. CEA level was compared against the primary outcome of response to TNT approaches. We categorized patients into 3 groups based on pre-TNT and post-TNT (i.e. pre-surgical) CEA: normal CEAPRE/normal CEAPOST, elevated CEA PRE/normal CEA POST, elevated CEA PRE/elevated CEA POST. 3-Year PFS was calculated using Kaplan-Meier method. Univariable and multivariable logistic regression analyses identified characteristics predictive of PFS and clinicopathologic variables associated with TNT sequencing. Results: The study cohort had a median age of 61 years and was predominantly male (70%) and Caucasian (94%). Pre-treatment stage was either II (27%) or III (72%), with the majority (65%) undergoing iChT. Downstaging occurred in 42/44 (95%). Baseline CEA was elevated in 40.9% of patients. On multivariable, logistic regression variable associated with receipt of CRT followed by cChT included: Age &gt; 61 years clinical T4 disease and lack of T downstaging (p &lt; 0.05 for all).There was no difference in 3-year PFS between patients receiving iChT versus patients receiving cChT (p = 0.53). When patients were stratified according to pretreatment CEA level, no difference in 3 year PFS were noted (p = 0.46). On multivariable analysis, lack of nodal downstaging following neoadjuvant treatment was associated with higher likelihood of progression (p = 0.02). Similarly, pretreatment CEA &gt; 4.25 ng/ml (p = 0.08) and failure of CEA to decrease by &gt;2 ng/ml following TNT (p = 0.07) trended toward higher likelihood of progression. Conclusions: Neither TNT sequencing, nor baseline CEA predicted the PFS although the power of our study was limited. Lack of nodal downstaging was identified as a predictor of worse PFS. Further areas of study should include plasma-based assays to quantitate circulating tumor DNA and next generation sequencing to assess prognosis with different sequencing of TNT.

Clinical outcomes of neoadjuvant treatment strategies in localized mismatch repair-deficient rectal cancer.

192 Background: Rectal cancer treatment paradigm has been evolving over time. Historically, for locally advanced rectal cancer, standard therapy (ST) consisted of neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy. Recently, total neoadjuvant treatment (TNT) approach that delivers both neoadjuvant chemotherapy (CAPOX or FOLFOX) and chemoradiation (or radiation only) prior to surgery is increasingly being utilized. The prognostic and predictive values of mismatch repair deficient (dMMR) in rectal cancer is not well characterized. Most dMMR patients receive the same treatment as MMR proficient (pMMR) patients although there is limited data that dMMR rectal cancer patients may not have the same level of benefits from neoadjuvant treatment. This retrospective study aims to evaluate the clinicopathological/molecular characteristics, disease response, and clinical outcomes in dMMR localized rectal cancer patients. Methods: A retrospective analysis was conducted on consecutive adult patients with a diagnosis of dMMR rectal cancer who were treated at Mayo Clinic between January 2000 to September 2021. Patients who presented with concurrent primary non-colorectal malignancies were excluded. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were collected. Survival was assessed using Kaplan-Meier curves and Cox models were stratified by treatment arms to determine significance of treatment strategies. Results: Forty-one patients were identified with a median age of 45.3 years. Thirty (73.2%) pts were male. The most common MMR were loss of MSH2 and MSH6 (12/42; 29.3%) followed by loss of MLH1 and PMS2 (10/42; 24.4%) and solitary loss of MSH2 (4/42; 9.8%). The treatment, pathological response, and clinical outcomes are listed in table. With a median follow up of 101 months, only 6 patients (14.3%) died and median overall survival was not reached. Conclusions: Our findings showed dMMR localized rectal cancer responded to both ST and TNT with good clinical outcomes.[Table: see text]