Adjuvant Treatment Regimens Research Articles

Esophageal cancer: new developments in prevention and therapy

Esophageal carcinomas comprise 2 entities, squamous cell carcinoma and adenocarcinoma, which differ in pathogenesis and treatment. Elimination of inflammatory influences and risk factors, such as obesity and gastroesophageal reflux that contribute to a rising incidence of adenocarcinoma, is crucial for tumor prevention. In Germany, general endoscopic screening for upper GI tumors is not recommended, whereas endoscopic surveillance is applied in the presence of Barrett's metaplasia. In the future, better prediction models will be needed to identify patients at risk who will benefit from endoscopic surveillance. Precancerous lesions and early tumor stages can be removed endoscopically using modern resection methods. In recent years, therapeutic strategies for advanced esophageal tumors have undergone significant changes. In the multimodal treatment of locally advanced stages, radiochemotherapy remains to play a key role for squamous cell carcinoma, whereas new evidence highlights the importance of perioperative chemotherapy for the optimal management of adenocarcinoma. Systemic treatment options for both tumor entities have been significantly expanded due to the successful use of immune checkpoint inhibitors in adjuvant and palliative treatment regimen. Determination of PD-L1 and MSI status has therefore become decisive for the choice of therapy. In metastatic stages of adenocarcinoma, chemotherapy can now be supplemented by multiple antibodies directed against Her2, PD1, or claudin 18.2, and the antibody-drug conjugate trastuzumab deruxtecan has become a Her2-targeted option in second line treatment.

A real-world retrospective study to assess efficacy and safety of alectinib as adjuvant therapy in IB-IIIB NSCLC patients harboring ALK rearrangement.

Alectinib has demonstrated promising disease-free survival (DFS) benefit for early-stage non-small cell lung cancer (NSCLC) patients with ALK rearrangement positive in phase 3 ALINA trial. However, real-world evidence for the efficacy and safety of alectinib in early-stage ALK-positive NSCLC is limited. We retrospectively reviewed 68 patients with stage IB-IIIB ALK-positive NSCLC who underwent complete pulmonary resections from April 2010 to July 2023 at a single institution. 38 (55.9%) enrolled patients had N2 lymph node metastasis, and 17 (24.9%) patients had multi-station N2 metastasis. Patients were stratified into two groups according to the adjuvant treatment regimen, with 19 patients in the alectinib group and 49 patients in the chemotherapy group. There were no significant differences in clinicopathological characteristics between the two groups. After curative resection surgery, patients in alectinib group received oral alectinib at a dose of 600 mg twice daily and patients in chemotherapy group received platinum-based doublet chemotherapy regimen every 3 weeks for 4 cycles. The primary endpoint was 3-year DFS. The Kaplan-Meier method was used to estimate DFS and overall survival (OS). Safety analyses were conducted by comparing the incidence of adverse events between the two groups. At the last follow-up date (January 22th, 2024), A total of 1 (5.3%) and 28 (57.1%) DFS events were observed in alectinib group and chemotherapy group respectively. The 3-year DFS showed significant improvement in the alectinib group compared with chemotherapy group (91.7% vs 60.7%, P=0.051). In the IIIAN2 subgroup, the 3-year DFS rate in the alectinib group reached a satisfactory 87.5%. In both groups, the majority of AEs were graded as level 1 or 2, No grade 3-4 AEs were observed in alectinib group. Alectinib, as adjuvant therapy, demonstrated favorable efficacy and manageable safety in patients with completely resected ALK-positive stage I B-IIIB non-small cell lung cancer. A limitation of this study is the small sample size, and a larger-scale real-world sample study is needed to further evaluate the efficacy and safety of alectinib as adjuvant therapy.

L’immunothérapie péri-opératoire des cancers bronchiques non à petites cellules (CBNPC) : standards actuels et perspectives

Surgery is the cornerstone of the treatment for stage I to IIIA NSCLC. Perioperative platinum-based chemotherapy has long been combined with surgery for patients with resectable stage II-IIIA disease, although the benefits are modest, with an increase in overall survival of approximately 5 %. Recently, immunotherapy has been integrated into neo-adjuvant, adjuvant, and perioperative treatment regimens based on data demonstrating improved event-free survival (EFS) and disease-free survival (DFS), respectively, for localized or locally advanced resectable NSCLC, without activating mutation. Two phase 3 trials have shown an adjuvant benefit and have been approved in Europe but are not supported in France. Four phase III trials Checkmate-816, Checkmate-77T, AEGEAN and KEYNOTE-671 showed a benefit from the combination of an immune checkpoint inhibitor with chemotherapy in the neoadjuvant or in perioperative setting. The results of Checkmate-816 enabled the early access authorization of Nivolumab, in combination with platinum-based chemotherapy in the neoadjuvant treatment of adult patients with resectable NSCLC at high risk of recurrence, including tumors express PD-L1 at the threshold ≥ 1 %, not EGFR mutated, nor ALK translocated.1877-1203/© 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Drug sensitivity tumor cell clusters in malignant peritoneal mesothelioma.

To explore the most effective adjuvant chemotherapy regimen for malignant peritoneal mesothelioma (MPM) through patient derived tumor-like cell clusters (PTC) drug sensitivity test. PTC were cultured in vitro with intraoperative specimens, and drug sensitivity test was performed to calculate the most effective chemotherapy regimen for MPM. The patients were divided into conventional and individualized chemotherapy group according to whether they received PTC drug testing. Univariate and multivariate analyses were conducted to identify independent prognostic factors. Among 186 MPM patients included, 63 underwent PTC culture and drug sensitivity test. The results showed that the most effective chemotherapy regimen was oxaliplatin + gemcitabine. After propensity score matching, a total of 64 patients were enrolled in the following study, including 32 patients receiving individualized chemotherapy guided by PTC drug results as group 1 and 32 patients receiving conventional chemotherapy as group 2. Survival analysis showed that the median OS of group 1 was not reached, significantly longer than that of group 2 (23.5 months) (p < 0.05). Compared with conventional chemotherapy, individualized chemotherapy guided by PTC drug sensitivity tests can prolong patient survival, and oxaliplatin + gemcitabine + apatinib could be the optimal adjuvant treatment regimen for MPM.

The surgical management of axillary lymph node disease in breast cancer patients

The precise assessment and management of the axillary lymph nodes in breast cancer is crucial for regional control, disease staging, selection of adjuvant chemotherapy strategies, and prediction of prognosis, with a general downward trend in surgical management. For early breast cancer with negative axillary lymph node metastases, sentinel lymph node biopsy (SLNB) has replaced axillary lymph node dissection (ALND) as the criterion for axillary status measurement. Patients can be exempted from ALND if they have negative SLNB results. However, it remains to be carefully decided in China whether patients with one or two positive nodes in SLNB can be spared from ALND. However, consensus has been met that patients who meet the criteria of the Z0011 study can be exempted from ALND. For breast cancer patients with positive axillary lymph nodes metastases at the beginning of treatment, the clearance of lymph node disease can be achieved by neoadjuvant therapy, with a reduced rate of complications related to ALND. In particular, there are still many debates associated with SLNB after neoadjuvant therapy, such as whether patients who remain axillary lymph node positive can be spared from ALND. Exploratory and validation studies related to the SLNB avoidance criteria are still controversial. In the future, clinicians should consider the characteristics of patients, the risk of recurrence, and adjuvant treatment regimens to develop individualized axillary lymph node management.

Investigating the Efficacy and Safety of a Dose-Dense Paclitaxel, Cyclophosphamide With Trastuzumab in Stage I-II Human Epidermal Growth Factor Receptor 2 (HER2) Positive Breast Cancer

BackgroundThe evolution of systemic therapies has improved outcomes for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer. Nonetheless, the tolerability and safety profile of systemic therapies represent an area for further improvement. Here we report the results of a phase 2 trial evaluating a nonanthracycline, nonplatinum adjuvant treatment regimen for patients following initial surgical resection. MethodsWe enrolled patients with stage I or II HER2+ breast cancer who underwent upfront surgery to receive adjuvant treatment with 6 cycles of dose-dense Paclitaxel, cyclophosphamide and Trastuzumab (PC-H) every 2 weeks, followed by 13 cycles of maintenance trastuzumab every 3 weeks to complete 52 weeks of treatment (compromising 19 cycles). The primary objective was to determine the safety and feasibility of adjuvant PC-H, measured by the completion rate frequency and the grade of adverse events, using National Cancer Institute Common Terminology Criteria. The secondary objective was to estimate relapse-free survival and overall survival. ResultsBetween 2010 and 2019, a total of 39 patients were enrolled. Of those, 34 patients (87.18%) completed the planned treatment. Severe adverse events of grade 3 or 4 occurred in 27 patients (69.23%), including 3 patients (7.69%) with grade 3-4 decrease in ejection fraction. At median follow up of 5.6 years, all 39 patients were alive. The 5-year relapse-free survival was 94.30% (95% CI: 75.3-100). ConclusionsPC-H demonstrated overall safety and efficacy, yielding high rates of relapse-free survival among patients with early stage (HER2+) breast cancer.

Efficacy and safety of neoadjuvant chemoradiotherapy combined with tislelizumab and thymalfasin in the treatment of locally advanced lower rectal cancer.

e15612 Background: Thymalfasin, as an immunomodulator, can enhance the anti-tumor effects of T cells, NK cells, and macrophages. This study explored the efficacy and safety of a new adjuvant treatment regimen for rectal cancer, combining thymalfasin with chemoradiotherapy and the PD-1 inhibitor tislelizumab, and its impact on the immune microenvironment. Methods: This retrospective study enrolled 26 patients with locally advanced rectal cancer from March 2021 to December 2022. Thirteen patients received long-course concurrent chemoradiotherapy combined with concurrent tislelizumab treatment, and thirteen received thymalfasin combined with long-course chemoradiotherapy and concurrent tislelizumab treatment (radiotherapy: 50 Gy/25 f; capecitabine, 1000mg/m2, bid; tislelizumab: 200mg, every 21 days, 3 cycles; Thymalfasin: 1.6mg, biw). The postoperative pathological complete response rate (ypT0N0M0), tumor regression grade (AJCC 8th Version), and adverse event (CTCAE 4.0) incidence were assessed, along with changes in the immune microenvironment before and after treatment using multiplex immunofluorescence staining. Results: The pathological complete response rates observed postoperatively were 61.5% in the treatment group, compared to 38.5% in the control group. The distribution of tumor regression grades 0, 1, 2, and 3 was 69.2%, 15.4%, 15.4%, 0% in the treatment group respectively, and 38.5%, 38.5%, 7.7%, 15.4%, in the control group respectively. The adverse event rates reached 84.6% in the treatment group and 76.9% in the control group, with all events classified as either grade 1 or 2 according to the CTCAE 4.0. Significant reductions in CD4+PD1+ cell density (p &lt; 0.001), CD8+PD1+ cell density (p = 0.024), CD68+ cell density (p = 0.007), the CD4/CD8 ratio (p &lt; 0.001), and the CD68+CD86+/CD68+CD163+ ratio (p = 0.012) were demonstrated through multiplex immunofluorescence following neoadjuvant treatment. The treatment group exhibited significant decreases in CD8+PD1+ cell density (p = 0.025) and CD68+CD163+ cell density (p = 0.021) when compared to the control group. Conclusions: Thymalfasin combined with chemoradiotherapy and tislelizumab as a neoadjuvant treatment regimen for patients with locally advanced lower rectal cancer has shown favorable efficacy and safety. Neoadjuvant chemoradiotherapy combined with immunotherapy restored T cell function and reduced the proportion of tumor-associated macrophages, but macrophages polarized towards an M2-like phenotype. Thymalfasin may play a role by synergizing with the PD-1 inhibitor to restore cytotoxic T cell function and block macrophage polarization towards M2 cells. Clinical trial information: NCT06024356 .

A randomized controlled study on perioperative treatment of esophageal squamous cell carcinoma with camrelizumab combined with nab-paclitaxel and cisplatin.

e16122 Background: Neoadjuvant immunochemotherapy for esophageal squamous cell carcinoma (ESCC) has received increasing acceptance due to its effectiveness being confirmed by several phase II studies. CheckMate 577 has determined the efficacy of adjuvant immunotherapy in ESCC patients (pts) with R0 resection after neoadjuvant chemoradiotherapy. However, in the era of neoadjuvant immunotherapy, the optimal adjuvant treatment regimen for pts with ESCC warrant further research. This study aims to explore the efficacy and safety of perioperative treatment with camrelizumab combined with nab-paclitaxel and cisplatin for potentially resectable ESCC. Methods: This study planned to enroll 190 pts with potentially resectable stage II/III/IVa (cT1b-4aN0-3M0) ESCC. Eligible pts received 2-cycle of neoadjuvant camrelizumab (200mg, d1, q3w) combined with nab-paclitaxel (125mg/m2, d1,8, q3w) and cisplatin (75mg/m2, d1, q3w). Pts who reached pathologic complete remission (pCR) were randomly assigned to the immunotherapy group (camrelizumab for 16 cycles) and the best supportive care (BSC) group. Pts who did not reach pCR were randomly assigned to the immunochemotherapy group (camrelizumab combined with nab-paclitaxel and cisplatin for 2-4 cycles and camrelizumab for 12-14 cycles) and the immunotherapy group. Primary endpoints were pCR rate and 3-year DFS rate. Secondary endpoints were major pathologic response (MPR) rate, objective response rate (ORR), disease free survival (DFS), overall survival (OS). Results: As of Jan. 9th 2024, 121 pts (83 males and 38 females) with a median age of 65 years were enrolled in the study. One hundred and thirteen pts completed neoadjuvant treatment and 102 pts were available for imaging evaluation, the ORR was 91.9% and the DCR was 98.9%. Ninety six pts underwent surgery, 95 (98.9%) pts had a R0 resection, 32 (33.3%) pts reached pCR, 33 (34.3%) pts reached MPR. TNM down-staging was observed in 74 (77%) pts. Of 81 pts who underwent randomization, 30 pts reached pCR, 14 pts were randomly assigned to immunotherapy group, and 16 were assigned to BSC group. For 51 pts who did not reach pCR, 26 were randomized to the immunochemotherapy group and 25 were assigned to the immunotherapy group. At date cutoff, 5 pts (distant recurrence) relapsed in the immunochemotherapy group and 2 pts (distant recurrence) relapsed in the immunotherapy group who did not reach pCR. One hundred and twtety-one of 123 pts had AEs, and 33 pts had grade ≥3 AEs. The most common grade ≥3 AEs were anemia (9.9%), decreased lymphocyte count (7.4%), leukopenia (4.1%). Conclusions: This ongoing study again confirmed the safety and efficacy of neoadjuvant immunochemotherapy for resectable ESCC. Further data on optimal adjuvant treatment regimen for pts with or without residual disease will be reported in the future. Clinical trial information: NCT05182944 .

Escalation of adjuvant endocrine therapy for early hormone-dependent HER2-negative breast cancer: to whom, when and why?

This review presents the evolution of adjuvant endocrine therapy for early hormone-dependent HER2-negative breast cancer, describes late relapse phenomenon, provides clinical rationale for escalation of treatment, analyzes the key stages of the metastatic cascade, and provides a scientific rationale for the introduction of CDK4/6 inhibitors into adjuvant treatment regimens. The main results of two large randomized studies of therapy including abemaciclib (MonarchE) and ribociclib (NATALEE) in patients with early stages of hormone-dependent HER2-negative breast cancer are presented; the oncological results of escalation of treatment and the safety of therapy are assessed.

O152: Prognostic value of receptor positivity loss following neoadjuvant chemotherapy in breast cancer patients: a systematic review and meta-analysis

Abstract Introduction Receptor status of breast cancer (BC) has been reported to change after neoadjuvant treatment leading to discordance between diagnostic biopsy and surgical specimens. This meta-analysis aims to investigate the prognostic significance of a loss of human epidermal growth factor receptor 2 (HER2) and hormone receptor positivity in residual disease after neoadjuvant therapy. Methods A systematic search of electronic databases was conducted to identify studies that investigated the impact loss of receptor status had on prognosis. Studies reporting disease free survival (DFS) and/or overall survival (OS) hazard ratios (HRs) for loss of HER2 or hormone receptor positivity following neoadjuvant treatment for BC were included. A meta-analysis was undertaken for relevant studies. Pooled hazard ratios were calculated using 95% confidence intervals (CIs). Results Eight studies with a total of 2673 patients were included in the meta-analysis. Patients who lost HER2 positivity had significantly worse OS (pooled HR 1.80, 95% CI 1.01-3.22, p=0.05) and DFS (pooled HR 2.03, 95% CI 1.47-2.82, p&amp;lt;0.001), compared to those who maintained positivity. Similarly, patients with a loss of hormone receptor positivity had significantly worse OS (pooled HR 2.49, 95% CI 1.65-3.77, p&amp;lt;0.001) and DFS (pooled HR 3.71, 95% CI 1.79-7.69, p&amp;lt;0.001) than those who remained hormone receptor positive after neoadjuvant therapy. Conclusion This meta-analysis found that a loss of either HER2 or hormone receptor positivity following neoadjuvant therapy negatively impacted survival outcomes. These findings suggest that retesting of receptor status may offer prognostic information, in addition to potentially altering adjuvant treatment regimens.

Adjuvant TACE plus lenvatinib as compared with TACE alone in patients with hepatocellular carcinoma at high risk of recurrence after surgery: A prospective controlled study.

505 Background: Hepatocellular carcinoma (HCC) remains the fourth leading cause of cancer related deaths globally. Radical resection is still the main curative approach for patients with resectable HCC in China. However, the high 5-year postoperative recurrence rate of about 40% to 70% had become the main negative factor affecting the long-term survival benefit. Although transarterial chemoembolisation (TACE) can effectively reduce the recurrence rate and improve disease-free survival (DFS) and overall survival (OS), the outcomes of patients at high risk of recurrence are still not satisfactory. Thus, there is an urgent need for new adjuvant treatment regimen to further improve the survival outcomes. In this study, we compared the efficacy and safety of the lenvatinib plus TACE with TACE alone for postoperative patients with HCC who were at high risk of recurrence. Methods: The factors associated with high risk of recurrence were defined as pathological suggested vascular invasion (including vascular embolus, cholangiocarcinoma embolus and microvascular invasion), suspicious positive surgical margin or surgical margin &lt; 1cm, satellite lesion with cancer, positive lymph nodes, low differentiation and incomplete envelope. Eligible patients were those who had received radical resection for HCC and had risk factors above. Patients were assigned in a 1:1 ratio to receive the combination of lenvatinib and TACE or TACE alone. Results: From September 2019 to May 2023, 119 patients were enrolled in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine. Sixty received TACE + lenvatinib and 59 received TACE only. The baseline characteristics were similar between two groups. The median duration of follow-up was 22.5 months (rang: 3 to 47) in TACE + lenvatinib group and 23 months (rang: 5 to 48) in TACE group. The 1-year DFS rate was 81.2% (95% CI: 70.8%-93.1%) in lenvatinib + TACE group, which was significantly higher than that of TACE group (58.3% [95% CI: 46.8%-72.7%], p = 0.0087; HR = 0.44 [95% CI: 0.23-0.83]). The median DFS was not reached (95% CI: 28-NR) in lenvatinib + TACE group, and was 20.0 months (95% CI: 12.0-NR) in TACE group. Patients' liver function after treatment with TACE + lenvatinib was comparable to that in the baseline. Conclusions: The preliminary results of this study suggested that adjuvant lenvatinib in combination with TACE can significantly improve DFS compared with TACE alone in patients with HCC at high risk of recurrence after surgery. The toxicity of combined treatment was tolerable and manageable. The follow up is still ongoing to observe the long-term benefit of this treatment regimen.

Postoperative Carbohydrate Antigen 19-9 Level as a Good Indicator of Ineffective Response to the Currently Recommended S-1 Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma: A Single-Center, Retrospective Study.

The intensity of adjuvant treatment for pancreatic ductal adenocarcinomas (PDACs) has not been stratified according to the risk after resection. This study was designed to identify patients with PDACs in whom the current S-1 adjuvant treatment is ineffective. This single-center, retrospective study included patients who underwent pancreatectomy for PDACs from 2009 to 2020 at Sendai Open Hospital and were receiving S-1 adjuvant treatment. The independent risk factors for recurrence and survival were determined by using a Cox proportional hazards regression model. The effects of S-1 adjuvant treatment and detailed patterns of recurrence were evaluated in patients with high-risk factors. Overall, 118 patients with PDAC received S-1 adjuvant treatment. Postoperative nonnormalized carbohydrate antigen (CA19-9) was a predictive risk factor for recurrence (p < 0.010; hazard ratio [HR], 3.87; 95% confidence interval [CI], 2.26-6.62) and survival (p = 0.008; HR, 2.25; 95% CI, 1.24-4.11) after S-1 adjuvant treatment. In 24 patients with nonnormalized postoperative CA19-9, S-1 monotherapy was ineffective in preventing recurrence, even during the treatment period, compared with that noted in patients who did not receive adjuvant treatment. The recurrence rate during adjuvant treatment was 41.7%; in all cases, recurrence was caused by distant metastasis. The total recurrence rate was up to 95.8%, and distant recurrence was especially frequent. The current S-1 adjuvant treatment regimen is ineffective for patients with postoperative nonnormalized CA19-9. The postoperative CA19-9 level may be a good indicator for further aggressive treatment. This study may lead to further discussions on intensity stratification of adjuvant treatments for PDAC.

Changes in Prescribing Patterns in Stage III Colon Cancer.

For patients with resected stage III colon cancer, 6 months of adjuvant fluoropyrimidine-based chemotherapy has been the standard of care. The IDEA collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy was noninferior to 6 months. Despite failing to meet its primary endpoint, the subgroup analyses demonstrated noninferiority based on regimen and treatment duration when a risk-stratified approach was used. To evaluate the impact of the results of the IDEA collaboration, we evaluated adjuvant chemotherapy prescribing practice patterns, including planned adjuvant treatment regimen and duration from January 1, 2016, to January 31, 2021. The time period was selected to evaluate chemotherapy prescribing patterns prior to the abstract presentation of the IDEA collaboration in June 2017 and after full manuscript publication in March 2018. A total of 399 patients with stage III colon cancer who received adjuvant chemotherapy were included in the analysis. A significant increasing trend for use of 3 months of adjuvant chemotherapy was observed after presentation of the IDEA abstract (P<.001). A significant change in CAPOX (capecitabine/oxaliplatin) prescribing was also observed, increasing from 14% of patients prior to presentation of the IDEA abstract to 48% after presentation (P<.001). Comparing 3 months of CAPOX with 6 months of FOLFOX (fluorouracil/leucovorin/oxaliplatin), 3 months of CAPOX use also steadily increased over time (adjusted odds ratio [aOR], 1.28; 95% CI, 1.20-1.37; P<.001). Among subgroups of interest, no differences in adoption of CAPOX were observed. The adoption of 3 months of CAPOX was similar in patients with low-risk cancer (aOR, 1.27; 95% CI, 1.17-1.37) and those with high-risk cancer (aOR, 1.31; 95% CI, 1.16-1.47). Despite the IDEA collaboration failing to demonstrate noninferiority of 3 months' duration of adjuvant therapy compared with 6 months, the findings have influenced practice prescribing patterns, favoring CAPOX and a shorter duration of planned adjuvant treatment.

Neoadjuvant Versus Adjuvant Systemic Therapy for Early-Stage Non-Small Cell Lung Cancer: The Changing Landscape Due to Immunotherapy.

Non-small cell lung cancer (NSCLC) remains a major cause of morbidity and mortality worldwide. One-third of NSCLC patients present with surgically resectable, non-metastatic disease; however, many of these patients will recur despite curative surgery and adjuvant therapy. The recent publication of randomized trials incorporating immune check-point inhibitors (ICI) to the standard neo-adjuvant and adjuvant treatment regimens has reported improved survival with manageable toxicity profiles. The IMpower 010 studied the use of adjuvant atezolizumab after standard surgery and adjuvant chemotherapy. They demonstrated an improvement in 3-year disease-free survival (DFS) prompting a change in treatment guidelines. The Checkmate 816 and NADIM II studies evaluated the addition of pembrolizumab and nivolumab, respectively, to standard neo-adjuvant chemotherapy. The results from both trials showed an improvement in 2-year event-free survival (EFS) and 2-year PFS (PFS), respectively. In this review, we summarize the prior data regarding adjuvant and neo-adjuvant chemotherapy in NSCLC and elaborate on results from the newer trials incorporating ICIs. We briefly discuss the pros and cons of each treatment approach along with areas that need further clarity to inform clinical practice and future directions for research in this disease.

R1 pancreatic cancer patients benefit from chemoradiation when initiation of adjuvant therapy is delayed

BackgroundAdjuvant chemotherapy (AC) following pancreaticoduodenectomy (PD) for pancreas cancer (PDAC) has been demonstrated to improve survival. However, the optimal adjuvant treatment (AT) regimen for R1-margin patients remains unclear. This retrospective study investigates the impact of AC vs. adjuvant chemoradiotherapy (ACRT) on survival (OS). Material and methodsThe NCDB was queried for patients with PDAC who underwent PD between 2010 and 2018. Patients were divided into, (A) AC<60 days, (B) ACRT<60 days, (C) AC≥60 days, and (D) ACRT≥60 days. Kaplan-Meier survival analyses and Cox multivariable regression analyses were performed. ResultsAmong 13 740 patients, median OS was 23.7 months. For R1 patients, median OS for timely AC and ACRT, and delayed AC and ACRT was 19.91, 19.19, 15.24, 18.96 months, respectively. While time of AC initiation was an insignificant factor for R0 patients (p = 0.263, CI 0.957–1.173), a survival benefit was found for R1 patients who received AC<60 vs. ≥60 days (p = 0.041, CI 1.002–1.42). Among R1 patients, administration of delayed ACRT achieves the same survival benefit of timely AC initiation (p = 0.074, CI 0.703–1.077). ConclusionThe study suggests value in ACRT for patients with R1 margins when delay of AT≥60 days cannot be avoided. Hence, ACRT may mitigate the negative impact of delayed AT initiation for R1-patients.

The impact of emotional distress on pathologic response and survival after neoadjuvant combination immune checkpoint blockade (ICB) in high-risk stage III melanoma.

9558 Background: Neoadjuvant ICB has been shown to induce high pathologic response rates in high-risk stage III melanoma, outperforming adjuvant ICB with respect to survival benefit. Biomarkers that have been shown to predict ICB efficacy, including the interferon-gamma (IFN-γ) signature and tumor mutational burden (TMB), do not completely explain why some patients (pts) fail to benefit from neoadjuvant ICB. Emerging evidence in preclinical and clinical studies suggests that emotional distress (ED) negatively affects tumor progression and anti-tumor immune responses, mediated by β-adrenergic and glucocorticoid signaling. Here, we investigate the association between ED prior to neoadjuvant ICB and pathologic response and survival in pts with stage III melanoma treated in the PRADO trial. Methods: PRADO tested neoadjuvant ipilimumab + nivolumab followed by a response-directed surgical and adjuvant treatment regimen in stage III melanoma pts. The European Organization for Research and Treatment of Cancer (EORTC) scale for emotional functioning was used to identify pts with ED, based on established clinically relevant thresholds. Association between ED and pathologic response or survival was assessed using multivariable logistic or Cox regression analysis. Potential effects of ED on the tumor and its microenvironment were examined in baseline tumor biopsies using RNA sequencing. Results: Pts who completed the baseline EORTC questionnaire were included and defined as pts with ED (n = 28) or without ED (n = 60). Baseline characteristics, IFN-γ signature expression and TMB were comparable. Pts with ED showed a trend towards achieving less major pathologic responses (MPR; ≤10% viable tumor) compared to pts without ED (46% vs 65%, p = 0.099). Multivariable analysis showed a significant association between ED and MPR (OR 0.20, p = 0.043) when adjusted for age, sex, IFN-γ signature (OR 9.36, p = 0.002) and TMB (OR 13.21, p = 0.003). Pts with ED also had a significantly lower relapse-free survival (RFS) compared to pts without ED (2-year RFS 74% vs 91%, p = 0.011), and ED at baseline remained associated with relapse in multivariable regression (HR 3.81, p = 0.034) when adjusting for IFN-γ signature (OR 0.34, p = 0.109) and TMB (OR 1.02, p = 0.972). Analyses investigating the relation between ED with β-adrenergic and glucocorticoid signaling and factors representing anti-tumor immune responses are ongoing and will be presented at ASCO. Conclusions: Emotional distress was identified as baseline marker associated with impaired clinical outcomes after neoadjuvant combination ICB in pts with high-risk stage III melanoma. This data warrants further investigation in independent cohorts and into the potential effect of pharmacological and psychosocial interventions, e.g. adrenergic receptor blockade, on the anti-tumor immune response and patient outcomes. Clinical trial information: NCT02977052 .

A randomized controlled study on perioperative treatment of esophageal squamous cell carcinoma with camrelizumab combined with nab-paclitaxel and cisplatin.

e16075 Background: Neoadjuvant immunochemotherapy for esophageal squamous cell carcinoma (ESCC) has received increasing acceptance due to its effectiveness being confirmed by several phase II studies. CheckMate 577 has determined the efficacy of adjuvant immunotherapy in ESCC patients (pts) with R0 resection after neoadjuvant chemoradiotherapy. However, in the era of neoadjuvant immunotherapy, the optimal adjuvant treatment regimen for pts with ESCC warrant further research. This study aims to explore the efficacy and safety of perioperative treatment with camrelizumab combined with nab-paclitaxel and cisplatin for potentially resectable ESCC. Methods: This study planned to enroll 130 pts with potentially resectable stage II/III/IVa (cT1b-4aN0-3M0) ESCC. Eligible pts received 2-cycle of neoadjuvant camrelizumab (200mg, d1, q3w) combined with nab-paclitaxel (125mg/m2, d1,8, q3w) and cisplatin (75mg/m2, d1, q3w). Pts who reached pathologic complete remission (pCR) were randomly assigned to the immunotherapy group (camrelizumab for 16 cycles) and the best supportive care (BSC) group. Pts who did not reach pCR were randomly assigned to the immunochemotherapy group (camrelizumab combined with nab-paclitaxel and cisplatin for 2-4 cycles and camrelizumab for 12-14 cycles) and the immunotherapy group. Primary endpoints were pCR rate and 3-year DFS rate. Secondary endpoints were major pathologic response (MPR) rate, objective response rate (ORR), disease free survival (DFS), overall survival (OS). Results: As of Feb. 9th 2023, 72 pts (52 males and 20 females) with a median age of 64 years were enrolled in the study. Sixty-three pts completed neoadjuvant treatment and 54 pts were available for imaging evaluation, the ORR was 92.5% and the DCR was 98.1%. Fifty-three pts underwent surgery, 52 (98.1%) pts had a R0 resection, 19 (35.8%) pts reached pCR, 15 (28.3%) pts reached MPR. TNM down-staging was observed in 41 (77.3%) pts. Of 44 patients who underwent randomization, 16 pts reached pCR, 8 pts were randomly assigned to immunotherapy group and BSC group respectively. For pts who did not reach pCR, 15 were randomized to the immunochemotherapy group, and 13 were assigned to the immunotherapy group. The median follow-up was 6.1 months, and the median DFS had not yet reached. Sixty-eight out of 72 pts had AEs, and 25 pts had grade ≥3 AEs. The most common grade ≥ 3 AEs were anemia (9.7%), leukopenia (8.3%), hypokalemia (5.5%). There were 2 treatment-related deaths, one was due to postoperative complication and one due to bone marrow suppression, diarrhea and immunotherapy-related myocarditis. Conclusions: This ongoing study again confirmed the safety and efficacy of neoadjuvant immunochemotherapy for resectable ESCC. Further data on optimal adjuvant treatment regimen for pts with or without residual disease will be reported in the future. Clinical trial information: NCT05182944 .

Correlation between recurrence-free survival and overall survival after upfront surgery for resected colorectal liver metastases.

The role of recurrence-free survival (RFS) as a valid surrogate endpoint for overall survival (OS) in patients who underwent upfront surgery for colorectal liver metastases remains uncertain. The aim of the study was to compare the two survival measures in a nationwide cohort of upfront resected colorectal liver metastasis. Data from patients with colorectal liver metastases without extrahepatic metastases who underwent curative surgery for liver metastases were retrieved from the Japanese nationwide database (data collection 2005-2007 and 2013-2014). RFS, OS, and survival after recurrence were estimated using the Kaplan-Meier method. The correlation (ρ) between RFS and OS was assessed using the rank correlation method combined with iterative multiple imputation, to account for censoring. As a secondary analysis, the correlation was evaluated according to adjuvant chemotherapy regimen. In sensitivity analysis, the pairwise correlation between RFS and OS was calculated. A total of 2385 patients with colorectal liver metastases were included. In the primary analysis, there was a moderately strong correlation between RFS and OS (ρ = 0.73, 95 per cent c.i. 0.70 to 0.76). The strength of the correlation was similar regardless of the adjuvant treatment regimen (oxaliplatin plus 5-fluorouracil: ρ = 0.72, 0.67 to 0.77; 5-fluorouracil alone: ρ = 0.72, 0.66 to 0.76; observation: ρ = 0.74, 0.69 to 0.78). The mean(s.d.) pairwise correlation coefficient between 3-year RFS and 5-year OS was 0.87(0.06). In surgically treated patients with colorectal liver metastases, there was a moderately strong correlation between RFS and OS, which was unaffected by the treatment regimen. Further validation using a trial-level analysis is required.

Prognostic effect of CD73 in pancreatic ductal adenocarcinoma for disease-free survival after radical surgery.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a high potency of metastasis or recurrence after radical resection. Effective predictors for metastasis and recurrence postoperatively were dominant for the development of systemic adjuvant treatment regimens. The ATP hydrolase correlated gene CD73 was described as a promoter in tumor growth and immune escape of PDAC. However, there lacked research focused on the role of CD73 in PDAC metastasis. This study aimed to investigate the expression of CD73 in PDAC patients with different outcomes as well as the prognostic effect of CD73 for disease-free survival (DFS). The expression level of CD73 in cancerous samples from 301 PDAC patients was evaluated by immunohistochemistry (IHC) and translated into a histochemistry score (H-score) by the HALO analysis system. Then, the CD73 H-score was involved in multivariate Cox regression along with other clinicopathological characteristics to find independent prognostic factors for DFS. Finally, a nomogram was constructed based on those independent prognostic factors for DFS prediction. Higher CD73 expression was found in PDAC patients with tumor metastasis postoperatively. Meanwhile, higher CD73 expressions were also investigated in PDAC patients diagnosed with advanced N stage and T stage. Furthermore, CD73 H-score along with tumor margin status, CA19-9, 8th N stage, and adjuvant chemotherapy was indicated as independent prognostic factors for DFS in PDAC patients. The nomogram based on these factors predicted DFS in a good manner. CD73 was associated with PDAC metastasis and served as an effective prognostic factor for DFS in PDAC patients after radical surgery.

ALTER-H006: A phase II study of TQB2450 plus anlotinib as adjuvant therapy in hepatocellular carcinoma (HCC) with high risk of recurrence after surgical resection.

TPS632 Background: Recurrence rate at 5 years for patients with early-stage HCC undergoing resection is between 50% and 70%. The optimal adjuvant treatment strategy for patients with resected HCC has not been proved and there is limited evidence to support a standard regimen for adjuvant treatment. Anlotinib, an oral small molecule antiangiogenic inhibitor, has shown promising anti-tumor activity and manageable toxicity as first or second-line treatment for patients with advanced HCC in an open-label phase II trial (NCT02809534). Anlotinib plus TQB2450, an anti-PD-L1 mAb, has shown anti-tumor activity in some solid tumors, such as biliary tract cancer (NCT03996408) and non-small cell lung cancer (NCT03910127). Here we investigate the efficacy and safety of this regimen as an adjuvant treatment for HCC with a high risk of recurrence after surgical resection. Methods: This is a single-arm, multicenter phase II trial. A total number of 37 patients with histologically or cytologically confirmed HCC will be enrolled. Eligible patients are aged 18-75, ECOG 0-1, Child-Pugh class A, 4~8 weeks after R0 resection with any of the following high-risk factors for recurrence: a) tumor nodules ≥4; b)portal vein tumor thrombus (PVTT): vp1 or vp2; c) hepatic vein tumor thrombus (HVTT): vv1 or vv2. Patients enrolled receive anlotinib (12 mg, p.o., qd, d1-14, q3w) plus TQB2450 (1200 mg, i.v., d1, q3w) until disease recurrence or unacceptable toxicity or up to 18 cycles (~1 year), whichever occurs first. Tumor assessment is performed at the end of the second cycle and every four cycles since that, according to RECIST v1.1. The primary endpoint is 1-year recurrence-free survival (RFS) rate. Secondary endpoints include RFS, 1-year overall survival (OS) rate, and safety. Recruitment for this study began in January 2022. Clinical trial information: NCT05111366 .