Neoadjuvant Approach Research Articles

Neoadjuvant or perioperative immunotherapy for resectable melanoma: The need for biomarkers.

Groundbreaking studies have reshaped the treatment landscape for patients with resectable stage ≥IIIB melanoma by demonstrating the benefits of neoadjuvant therapy. Data from the NADINA and SWOG S1801 trials reveal substantial improvements in event-free survival compared to adjuvant therapy alone. These studies employed distinct neoadjuvant immunotherapy approaches -ipilimumab plus nivolumab in NADINA and anti-PD-1 monotherapy in SWOG S1801-highlighting potential differences in efficacy and toxicity. The integration of biomarkers may improve the risk/benefit ratio by enabling personalized treatment selection between ipilimumab plus nivolumab versus anti-PD-1 monotherapy. In metastatic melanoma, molecular biomarkers such as BRAF mutational status and intratumoral PD-L1 expression can help guide treatment decisions; however, their, and other biomarkers', role in the neoadjuvant context has yet to be fully investigated. This commentary underscores the need to investigate whether these molecular markers, along with other biomarkers and clinical parameters, can inform neoadjuvant therapy in resectable stage ≥IIIB melanoma. We propose a coordinated effort involving retrospective analyses of current trials and prospective clinical studies, to define the role of biomarkers. A biomarker-guided approach could optimize efficacy and reduce toxicity, offering personalized treatment options for patients with resectable melanoma. As implementation of neoadjuvant therapy rapidly gains global adoption, we advocate for robust research to ensure that each patient receives the most effective and least toxic therapeutic option.

Therapeutic Approaches for Advanced Basal Cell Carcinoma: A Comprehensive Review

Basal cell carcinoma (BCC) accounts for 80% of skin cancer cases. Although mostly curable by simple excision, the treatment of advanced disease can be challenging, as curative surgery or radiotherapy may not always be feasible. The scope of this review is to summarize current knowledge on molecular mechanisms in BCC pathogenesis, to elaborate on the definition of advanced/difficult-to-treat BCC, and to outline systemic treatment options. Particularly, pivotal trial data of the approved hedgehog inhibitors (HHI) sonidegib and vismodegib are compared. Concluding, we provide an overview of novel, particularly neoadjuvant and combined treatment approaches, both with hedgehog and immune-checkpoint inhibitors.

Development and validation of a radiomics nomogram for preoperative prediction of BRAFV600E mutation status in adult patients with craniopharyngioma.

Although craniopharyngiomas are rare benign brain tumors primarily managed by surgery, they are often burdened by a poor prognosis due to tumor recurrence and long-term morbidity. In recent years, BRAFV600E-targeted therapy has been promising, showing potential as an adjuvant or neoadjuvant approach. Therefore, we aim to develop and validate a radiomics nomogram for preoperative prediction of BRAFV600E mutation in craniopharyngiomas. A total of 398 patients with craniopharyngioma (training cohort: n = 278; validation cohort: n = 120) were retrospectively reviewed. We extracted 851 radiomic features from MRI images and adopted a support vector machine (SVM) classifier to develop a radiomic model. Also, a clinical-radiomics nomogram was constructed based on a multivariable logistic regression analysis. The performance of the nomogram was evaluated by its discrimination, calibration, and clinical utility. The radiomic model using the SVM based on three selected features showed good discrimination in the training and validation cohorts (area under the curve [AUC], 0.941 and 0.945, respectively). A higher Rad-score, smaller tumor volume, and homogenous enhancement were demonstrated as independent predictors of BRAFV600E mutation in craniopharyngioma. The nomogram incorporating the Rad-score and clinical-radiological factors exhibited AUCs of 0.958 (95% CI, 0.936-0.980) and 0.956 (95% CI, 0.921-0.991) in the training and validation cohorts, respectively, showing good clinical benefit and calibration. The radiomics nomogram could provide an accurate, non-invasive preoperative prediction of BRAFV600E mutation in craniopharyngioma and may provide potential guidance for the preoperative administration of BRAF V600E mutation inhibitors and promote personalized treatment. Further prospective validation is still needed.

Localized Microrobotic Delivery of Enzyme-Responsive Hydrogel-Immobilized Therapeutics to Suppress Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), characterized by its aggressive metastatic propensity and lack of effective targeted therapeutic options, poses a major challenge in oncological management. A proof-of-concept neoadjuvant strategy aimed at inhibiting TNBC tumor growth and mitigating metastasis through a localized delivery of chemotherapeutics is reported in this paper. This approach addresses the limitations in payload capacity and stimuli responsiveness commonly associated with microrobotics in oncology. A hydrogel-based system is developed for the immobilization of chemotherapeutic agents, subsequently encapsulated within magnetically responsive microrobots. This design leverages external magnetic fields to facilitate the precise navigation and localization of the therapeutic agents directly to the tumor site. The efficacy of this approach is demonstrated in an animal model, in which a significant 14-fold reduction in tumor size and suppression of metastasis to critical organs such as the liver and lungs are observed. Crucially, the drug release mechanism is engineered to be responsive to the tumor microenvironment and is regulated by the overexpression of the enzymatic activity of matrix metalloproteinases (MMP2 and MMP9) in TNBC tumors, triggering the degradation of the hydrogel matrix, leading to controlled release of the immobilized therapeutic drug. This ensures that the therapeutic action is localized, reducing systemic toxicity and enhancing treatment efficacy. These findings suggest that this neoadjuvant approach holds promise for broader applications in other cancer types.

A randomized phase 3 trial of total neoadjuvant therapy (induction chemotherapy, neoadjuvant chemoradiation, neoadjuvant chemotherapy, and surgery) vs. standard long-term chemoradiation therapy (neoadjuvant chemoradiation, surgery, and adjuvant chemotherapy) in locally advanced rectal cancer.

The management of rectal adenocarcinoma has evolved during the last decade, shifting from a conventional neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy in all cases to a total neoadjuvant approach, especially in locally advanced tumors when a sphincter-sparing surgery has been planned. However, the exact indications and the neoadjuvant regimen with the highest response remain unresolved. We aimed to assess whether administering neoadjuvant chemotherapy before and after preoperative chemoradiotherapy could increase the pathological complete response (pCR) rates. We conducted a phase 3, multicenter, randomized trial at four hospitals in Iran. Adult patients with a newly diagnosed, biopsy-proven, locally advanced non-metastatic rectal adenocarcinoma with an ECOG performance status of 0-2 were randomly assigned (2:2) to either the total neoadjuvant treatment (TNT) or the standard-of-care groups using a block randomized design. Investigators and participants were not masked to treatment allocation and groups. The TNT group received neoadjuvant chemotherapy with FOLFOX6 (intravenous 85 mg/m2 oxaliplatin and 400 mg/m2 leucovorin, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2,400 mg/m2 over 46h every 14 days for four cycles before and four cycles after chemoradiotherapy), chemoradiotherapy (50.4 Gy during 28 fractions and 800 mg/m2 concurrent oral capecitabine twice daily 5 days per week), and total mesorectal excision. The standard-of-care group received neoadjuvant chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (eight cycles). The primary endpoint was the pathological complete response. Safety analyses were conducted on treated patients. Overall, 25 and 27 patients were enrolled in the TNT and standard-of-care groups, respectively. Both groups were similar in terms of gender, age, and tumor differentiation. The tumors in the standard-of-care group were significantly located closer to the anal verge compared with those in the TNT group (9.4 ± 3.7cm in TNT vs. 6.8 ± 4cm in standard, p = 0.02). A pCR was reached in 48% (12/25) and 25.9% (7/27) of patients in the TNT and standard-of-care groups, respectively (p = 0.4). The R0 resection rates were identical between the two groups (92% vs. 88.9%, p = 0.3). Moreover, the toxicity rates were similar between the two groups. Our results showed that TNT is a safe and feasible treatment approach in patients with rectal cancer and may improve the overall pCR rate compared with standard treatment. https://irct.behdasht.gov.ir/trial/65666, identifier IRCT20220723055527N1.

Adjuvant Immunotherapy Does Not Improve Survival in Non-small Cell Lung Cancer with Major/Complete Pathological Response after Induction Immunotherapy

In patients with resectable non-small cell lung cancer (NSCLC), immune checkpoint inhibitor (ICI)-based regimens in both neoadjuvant and perioperative settings demonstrate survival benefit. To date, no study has compared the efficacy between pure neoadjuvant and perioperative approaches, especially in patients who achieve substantial pathological responses. In this retrospective study, patients with clinical stage II-IIIB NSCLC who achieved either major (MPR) or complete (pCR) pathological response after induction ICI plus chemotherapy followed by resection between 2019 and 2023 were identified from multicenter databases. Inverse probability of treatment weighting-adjusted Cox regression was performed to compare disease-free survival (DFS) and overall survival (OS) between patients who did and did not receive ICIs postoperatively. One hundred thirty-six patients who achieved pCR and seventy-two patients who achieved MPR were enrolled. Three-quarters of them had squamous cell cancer. The inverse probability-weighted cohort represented 208 weighted patient cases (adjuvant ICI, 117; control, 91). The weighted DFS/OS rates did not differ between the adjuvant-ICI group and the control group (3-year DFS rates: 90.2% vs. 93.2%, hazard ratio [HR]= 2.47, 95% confidence interval [CI]: 0.74 to 8.22; 3-year OS rates: 89.1% vs. 93.9%, HR=2.44, 95% CI: 0.71 to 8.34). Adverse events during the postoperative ICI treatment were found in 19 of 120 patients (15.8%) and led to adjuvant ICI termination in 18 patients (15.0%). Adjuvant ICI does not improve survival in NSCLC patients who achieve pCR/MPR following neoadjuvant immunochemotherapy. A de-escalation strategy could be considered given the adverse events associated with postoperative ICI treatment.

Impact of personalized response-directed surgery and adjuvant therapy on survival after neoadjuvant immunotherapy in stage III melanoma: Comparison of 3-year data from PRADO and OpACIN-neo

BackgroundPathologic response following neoadjuvant immune checkpoint blockade (ICB) in stage III melanoma serves as a surrogate marker for long-term outcomes. This may support more personalized, response-directed treatment strategies. MethodsThe OpACIN-neo and PRADO trials were phase 2 studies evaluating neoadjuvant treatment with ipilimumab and nivolumab in stage III melanoma. In OpACIN-neo, all patients underwent therapeutic lymph node dissection (TLND) without subsequent adjuvant therapy. In contrast, PRADO explored a response- directed strategy, where patients achieving a major pathologic response (MPR) omitted TLND and adjuvant therapy, while those without a pathologic response (pNR) received TLND and adjuvant therapy. Here, we provide a descriptive post-hoc comparison of 3-year survival outcomes between the non-personalized approach in OpACIN-neo and the response-directed approach in PRADO. ResultsFor patients who achieved an MPR, the 3-year recurrence-free survival (RFS) was 93 % for those without TLND versus 96 % for those with TLND (log-rank p = 0.47), and distant metastasis-free survival (DMFS) was 98 % compared to 96 % (log-rank p = 0.49), respectively. For patients with pNR, 3-year RFS rates were 64 % for those receiving adjuvant systemic therapy and 35 % for patients without (log-rank p = 0.10). DMFS rates were 70 % versus 52 % (log-rank p = 0.24), respectively. ConclusionsThese data suggest that TLND and adjuvant therapy may be safely omitted in most patients achieving an MPR, while adjuvant systemic therapy following TLND appears to improve RFS and DMFS in patients with pNR. Although these results are hypothesis-generating and require further validation, they offer a potential foundation for developing personalized neoadjuvant immunotherapy approaches.

Abstract C044: Single cell RNA-sequencing coupled with lineage tracing identifies novel clonal populations associated with immunotherapy resistance

Abstract Although immune checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, many individuals either show no response or eventually develop acquired resistance. This variability could be linked to differences in the tumor immune microenvironment, pre-existing drug-resistant cells or treatment induced changes in melanoma cell states. Using single cell RNA sequencing (scRNA-seq) coupled with heritable barcodes, this study aims to lineage trace changes in melanoma transcriptional cell states and map changes in the tumor immune microenvironment to uncover if preexisting and/or therapy-induced melanoma transcriptional cell states lead to resistance to ICIs. In this study, we used YUMMER1.7 mouse melanoma cells which were transduced with barcodes under conditions that allow delivery of a single unique barcode to each cell, this served as a cell lineage tag. Each barcode is heritable and stably transcribed into RNA molecules so that individual barcoded cells can be matched with a gene expression profile from scRNA-seq outputs. The barcoded cells were subcutaneously injected into C57BL/6 mice, and once tumors were established, mice were treated with 3 cycles of anti-PD-1 and anti-CTLA-4 therapy. Lineage tracing and scRNA-seq analyses were performed on tumors harvested prior to treatment, early on treatment (Day 6), during minimal residual disease (Day 13) and upon relapse. Early on treatment (Day 6)- two tumour groups were harvested, those that responded well and others that only partially responded. Our results showed that during the early on treatment phase (Day 6) tumors that responded well and those that only partially responded displayed distinct barcodes. Additionally, prevalent barcoded cells identified at the minimal residual disease phase were also dominant upon relapse. Analysis of the transcriptional states is underway to determine if ICI therapy induces transcriptional heterogeneity in sensitive and tolerant cells and if a particular or several transcriptional states lead to relapse. This study will potentially identify predictive response biomarkers and vulnerabilities of ICI naïve and resistant cells that could be targeted to improve outcomes for melanoma patients. We will also identify neoadjuvant approaches, to remove the inherent heterogeneity within the tumor cell population, facilitating a more uniform sensitivity to ICIs. Citation Format: Reem Saleh, Riyaben Patel, Dane Vassiliadis, Fayrouz Hammal, Benjamin Blyth, Xin Du, Katie Fennell, Mark A. Dawson, Grant A. McArthur, Karen Sheppard. Single cell RNA-sequencing coupled with lineage tracing identifies novel clonal populations associated with immunotherapy resistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C044.

Systemic therapy for head and neck cancer-highlights of the 2024 ASCO Annual Meeting

Systemic therapy of head and neck squamous cell carcinoma (HNSCC), in contrast to local therapy, is avery general term for the use of drugs that affect the entire organism. Immunotherapy is asubtype of systemic therapy, although the boundaries are hard to define, since the immune system is likely to play an essential role in all treatments. This article focuses on systemic therapy. All abstracts and presentations on systemic therapy of HNSCC from the American Society of Clinical Oncology (ASCO) 2024 annual congress were assessed for relevance. The main contributions were reviewed and summarized. For the first time, arandomized trial demonstrated asurvival advantage for systemic therapy in patients with apoor performance status over best supportive care (BSC). Clinical studies using antibody-drug conjugates (ADCs) show apromising response. In addition, the neoadjuvant approach was resumed through various study approaches. Even in patients with areduced general condition, systemic therapy can lead to asubstantial improvement in overall survival. The systemic therapy approach remains exciting for HNSCC, with new substances and areas of application not only in the palliative situation.

Surgery for Patients With cT3/4N2M0, Stage IIIB NSCLC. Is It Time to Redefine Resectability?

IntroductionChemoradiation followed by durvalumab is considered a standard approach for patients with locally advanced NSCLC. With improvements in perioperative and neoadjuvant approaches, there is renewed interest in offering surgery to carefully selected patients with cT3/4N2 stage IIIB cancer. We sought to assess survival outcomes after surgery as part of a multimodality treatment regimen for these patients. MethodsPatients with cT3/T4N2M0 NSCLC who received surgery (S) as part of a multimodality approach and patients receiving multimodality treatment without surgery (chemoradiation [CRT] or systemic therapy only) were identified in the National Cancer Database (2010–2019). We evaluated factors associated with the receipt of S (logistic regression). After propensity matching, we estimated the overall survival (OS) of patients who received S and compared with those who received CRT (Kaplan-Meier and Cox regression). ResultsA total of 44,756 patients were identified, of whom 3928 (8.8%) underwent S, 29,798 (66.6%) CRT, and 11,030 (24.6%) systemic therapy only. Fewer comorbidities (Charlson-Deyo index 0 or 1, adjusted OR [aOR]: 1.22, 95% confidence interval [CI]: 1.05–1.42), treatment at an academic facility (aOR: 1.70, 95% CI: 1.52–1.89), private insurance (aOR: 2.44, 95% CI: 1.61–3.69), adenocarcinoma histology (aOR: 1.48, 95% CI: 1.22–1.79), and clinical T3 stage (<7 cm, aOR: 1.70, 95% CI: 1.53–1.89) were associated with S. In well-balanced, propensity-matched cohorts, patients selected for S had better OS compared with those who underwent CRT (hazard ratio 0.59, 95% CI: 0.56–0.63, p < 0.001) (median OS 49.7 versus 25.0 mo). ConclusionsIn this retrospective cohort analysis, patients with cT3/4N2, stage IIIB NSCLC who underwent surgical resection had better OS compared with those patients treated with CRT. Careful patient selection is undoubtedly critical, but stage IIIB designation alone should not exclude patients from surgical consideration.

Cross-Sectional National Survey of Practice Patterns in Radiotherapy for Rectal Cancer: A Snapshot of India.

The information on the practice of radiotherapy, including intensity-modulated radiotherapy (IMRT) use for rectal cancer in India, is lacking. This national survey was planned to understand the current status of knowledge, attitudes, and practice among radiation oncologists, specifically concerning the practice of IMRT for rectal cancers. A national survey was sent to radiation oncologists through e-mail or a WhatsApp message, where feasible, with a request letter containing the link to the survey questionnaire. The survey questionnaire was adapted from the UK IMRT survey with permission from the authors. It explored rectal cancer management, IMRT use, reasons for nonadoption, total neoadjuvant therapy (TNT), dose fractionation schedules and radiotherapy processes like radiotherapy simulation, target volume/organ at risk definition, and treatment planning, evaluation, and verification. Descriptive statistics is used to present the results. Over 300 radiation oncologists were approached, and 182 (60.6%) of the 153 institutes responded. Around 88% (160 of 182) indicated using IMRT or volumetric modulated arc therapy (VMAT) to treat rectal cancer, of whom 32% used exclusively IMRT/VMAT in all their patients. The reasons for not adopting IMRT were affordability/lack of insurance, resource constraints, and lack of guidelines. Long-course chemoradiation (capecitabine-based) followed by surgery was the most common neoadjuvant approach, with short course and TNT in less than a third of patients. Daily verification feasibility was reported by 60%. Seventy-three percent emphasized the need for a national IMRT guidance document. This national survey from India indicates a scope of routine implementation of IMRT in rectal cancer, highlighting the urgent need for a national IMRT guidance document, which could significantly enhance the quality of care for patients with rectal cancer in India.

Tumor Response and Its Impact on Treatment Failure in Rectal Cancer: Does Intensity of Neoadjuvant Treatment Matter?

Objectives: Additional adjuvant treatment in patients with rectal cancer with limited response to neoadjuvant treatment to mitigate their higher risk of treatment failure remains controversial. Methods: This is a post hoc analysis of a cohort study of 3 randomized phase 2 or 3 trials (CAO/ARO/AIO-94, -04, and -12 trial) that included 1948 patients with locally advanced rectal adenocarcinoma. After excluding patients with missing information, 1788 patients (1254 men and 524 women; median age: 62.6 years, age range: 19-84 years) were eligible. We analyzed the extent of tumor response and its association with the incidence of treatment failure after different neoadjuvant treatment approaches. Results: Tumor response was significantly enhanced with more intensive neoadjuvant treatment. After a median follow-up of 55 months for the entire cohort (IQR: 37 months-62 months), the incidence of treatment failure (TF) stratified by tumor response or post-neoadjuvant pathological outcome was not significantly affected by the intensity of neoadjuvant treatment, whereas the ypTNM stage was significantly associated with the risk of treatment failure. Conclusions: In this cohort study, we provide evidence that limited or no response to intensified neoadjuvant treatment protocols is not likely to be more strongly associated with an extensive risk of TF after 5-FU CRT+/- adjuvant chemotherapy.

Neoadjuvant Chemotherapy With the Angiogenesis Inhibitor Bevacizumab for Locally Advanced Cervical Cancer.

We hypothesized that adding bevacizumab to platinum-based neoadjuvant chemotherapy - whose efficacy for patients with recurrent or metastatic cervical cancer has already been proven - could optimize the therapy regimen, leading to improved response rates and survival outcomes. Forty patients with histologically confirmed cervical cancer with FIGO stage IB3-IVA who received platinum-based neoadjuvant treatment between March 2008 and January 2019 in the Department of Obstetrics and Gynecology of University Hospital Cologne were analyzed. Twenty patients were treated with additional bevacizumab. The comparative cohort consisted of 18 patients treated with neoadjuvant chemotherapy alone. The response rates and clinical outcomes, including progression-free survival and overall survival, were evaluated. Neoadjuvant chemotherapy combined with bevacizumab significantly improved the response rate (p=0.046). The survival analysis showed that patients treated without bevacizumab had better progression-free survival up to FIGO stage IVA than patients treated with bevacizumab. However, overall survival was similar for both cohorts. For patients with advanced tumor stage, including FIGO IVB, progression-free survival and overall survival improved with the addition of bevacizumab. Pathological complete remission was a statistically significant prognostic factor for progression-free survival (p=0.039) but did not significantly affect overall survival (p=0.098). While bevacizumab did not demonstrate a significant improvement in overall survival rates, it was associated with a notable reduction in tumor size and showed a trend towards improved clinical response rates. These findings suggest that bevacizumab may have potential in optimizing the neoadjuvant treatment approach.

Tailored Approaches and Patient-centered Care: The Current Landscape of Neoadjuvant Therapy in Rectal Cancer

Colorectal cancer (CRC) is the third most diagnosed cancer in Canada and worldwide. Although mortality rates have declined, it remains the second most lethal malignancy worldwide. For patients with locally advanced rectal cancer (LARC), several new concepts have been introduced in recent years for treatment sequencing and de-escalation. The use of pelvic magnetic resonance imaging (MRI) for initial staging and neoadjuvant therapy response assessment has become a key part of the workup for LARC, utilizing the expertise of specialist radiologists. High-volume rectal cancer centers have adopted total neoadjuvant therapy (TNT) as a preferred approach for many patients with LARC. There is rising interest in shortening the duration of chemotherapy or radiation, or even omitting radiation altogether for select patients, to reduce the burden of long-term toxicities. For patients who achieve clinical complete or near-complete responses (cCR or nCR) to neoadjuvant therapies, nonoperative management (NOM) has emerged as an option to avoid the complications of a total mesorectal excision (TME). This paradigm shift has resulted in numerous treatment options for many patients with rectal cancer, enabling a more individualized, multidisciplinary approach to care. Clinicians must understand how to interpret the evidence around these new concepts to successfully implement them into clinical practice. This review summarizes the recent evidence for neoadjuvant therapy approaches in rectal cancer to provide a context for this paradigm shift to a tailored therapeutic strategy.

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 (&amp;lt;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.

What do we know about the role of neoadjuvant targeted therapy in early-stage EGFR-mutant and ALK-fused non-small cell lung cancer?-a narrative review of the current literature.

The standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions is targeted therapy using tyrosine kinase inhibitors (TKIs). However, data are still lacking on the use of TKIs as a neoadjuvant or induction approach. Therefore, this narrative review aims to summarize the current knowledge on resectable EGFR-mutant and ALK-fused NSCLC regarding available perioperative treatment regimens and off-label neoadjuvant use of targeted therapy. The relevant literature was identified by using PubMed and ClinicalTrials.gov (last search phase June 2024) and was restricted to English language. Peer-reviewed manuscripts but also conference abstracts that did not undergo peer-review were included. Patients with EGFR-mutations and ALK-fusions have typically been excluded from available phase III perioperative immunotherapy trials due to lower efficacy and higher toxicity of immunotherapy in those patients. In the adjuvant setting, recent evidence from the phase III ALINA and ADAURA trials demonstrated efficacy and safety of targeted therapy in resected ALK-fused and EGFR-mutant NSCLC. However, to date there is no approval for the use of TKIs as neoadjuvant or induction therapy in those patients. We have therefore identified a number of case series and phase II trials using targeted therapy in resectable EGFR-mutant and ALK-fused NSCLC. Current evidence suggests that targeted therapies might be effective in patients with resectable EGFR-mutant and ALK-positive NSCLC, but ongoing trials will need to provide further evidence on the safety and efficacy of perioperative TKI therapy.

Datopotamab-deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial.

Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes. Here we tested datopotamab-deruxtecan (Dato-DXd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin-cyclophosphamide (block C). Patients are randomized into arms consisting of different investigational block A treatments. Algorithms based on magnetic resonance imaging and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response, the primary endpoint. There are two primary efficacy analyses: after block A and across all blocks for the six prespecified breast cancer subtypes (defined by clinical hormone receptor/human epidermal growth factor receptor 2 (HER2) status and/or the response-predictive subtypes). We report results of 103 patients treated with Dato-DXd. While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype, the treatment strategy across all blocks graduated in the hormone receptor-negative HER2-Immune-DNA repair deficiency- subtype with an estimated pathological complete response rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato-DXd was particularly active in the hormone receptor-negative/HER2-Immune-DNA repair deficiency- signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379 .

Re-evaluation and operative indications after induction therapy for thymic epithelial tumors.

Thymic epithelial tumors (TETs), encompassing thymoma and thymic carcinoma, represent a rare and heterogeneous group of thoracic malignancies with varying prognoses and treatment strategies. Surgical resection is the cornerstone of therapy for localized stages, but the management of locally advanced or unresectable TETs often involves induction therapy, including chemotherapy and/or radiation therapy, as a neoadjuvant approach aimed at downstaging the tumor to facilitate subsequent resection. This review synthesizes current knowledge on the re-evaluation process and operative indications following induction therapy for TETs, highlighting the pivotal role of accurate assessment in guiding surgical decisions and optimizing patient outcomes. Induction therapy's efficacy is contingent upon precise re-evaluation methods to accurately gauge treatment response and assess resectability post-therapy. This review discusses the various modalities employed in re-evaluation, including computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography-CT (PET-CT), and the significance of tumor markers, underlining their strengths and limitations. The adoption of modified RECIST criteria for TETs by the International Thymic Malignancy Interest Group (ITMIG) underscores the necessity for standardized assessment guidelines to ensure consistency and reliability across studies and clinical practices. Furthermore, we explore the implications of induction therapy on surgical decision-making, emphasizing the criteria for determining the suitability of patients for surgical intervention post-therapy. The review addresses the challenges and future perspectives associated with the re-evaluation process, including the potential for advanced imaging techniques and the integration of molecular and genetic markers to enhance the precision of treatment response assessment. In conclusion, the re-evaluation of TETs post-induction therapy is a complex but critical component of the multidisciplinary management approach for these patients. Standardizing re-evaluation methodologies and incorporating novel diagnostic tools could significantly improve the prognostication and treatment stratification, ultimately enhancing the therapeutic outcomes for patients with advanced TETs.

National Landscape of Neoadjuvant Therapy in Potentially Resectable Colon Cancer

IntroductionSurgery followed by pathology-guided adjuvant therapy is standard treatment for colon cancer. Data from the FOxTROT clinical trial showed potential benefit of a 6-wk neoadjuvant chemotherapy (NACT) in T3/T4 patients. The present study evaluated real-world outcomes of neoadjuvant therapy in a national cohort of patients with resectable colon cancer. Methods169,120 patients with clinical stage I, II, or III colon cancer from the National Cancer Database registry were included. Patients were categorized as having received neoadjuvant therapy followed by surgery (NACT), surgery then adjuvant chemotherapy (AC), or surgery alone. Factors associated with treatment sequencing and outcomes were assessed. ResultsOf identified patients, 1.4% received NACT including 0.5% of stage I, 1.8% of stage II, and 3.0% of stage III. For stage I, 5-y overall survival (OS) was 74.7% after AC, 62.2% after NACT, and 76.4% after SA. For stage II, 5-y OS was 73.2% after AC, 66.8% after NACT, and 64.3% after SA. For stage III, 5-y OS was 67.3% after AC, 67.7% after NACT, and 42.4% after SA. Cox proportional-hazards model suggested NACT had worse outcomes versus AC in clinical stages I (hazard ratio [HR] = 1.59, 95% confidence interval [CI] 1.39-1.85, P < 0.01) and II (HR = 1.37, 95% CI 1.23-1.52, P < 0.01). In stage III, there was no difference in OS between NACT and AC (HR = 1.1, 95% CI 0.99-1.22, P = 0.05). ConclusionsIn a real-world national cohort of patients with resectable colon cancer, NACT had no OS benefit over AC. Future studies should examine which subset of patients might benefit from neoadjuvant approaches.