Safety and effectiveness of neoadjuvant PD-1 inhibitor (toripalimab) plus chemotherapy in stage II-III NSCLC (LungMate 002): an open-label, single-arm, phase 2 trial.

BACKGROUND: This trial aimed to analyse the safety, effectiveness and transcriptomic characteristics of neoadjuvant toripalimab plus chemotherapy in II-III non-small-cell lung cancer (NSCLC). METHODS: Patient eligibility mainly involved treatment-naive, clinical stage II-III and wild-type EGFR/ALK NSCLC. The patients received 2-4 cycles of toripalimab (240 mg q3w) plus carboplatin-based chemotherapy. After the second treatment cycle, all patients were re-evaluated by a multidisciplinary team. Candidates eligible for surgery underwent surgery; otherwise, patients received the remaining treatment cycles. The primary endpoints were safety and major pathological response (MPR). Secondary endpoints were R0 resection rate, progression-free survival (PFS) and overall survival (OS). RNA sequencing of baseline and post-treatment samples was conducted to explore the transcriptomic characteristics of the therapeutic response. RESULTS: In total, 50 eligible patients were enrolled, including 12 (24.0%) with resectable disease (RD) and 38 (76.0%) with potentially resectable disease (PRD). Treatment-related adverse events (TRAEs) were recorded in 48 cases (96.0%). Severe TRAEs occurred in 3 (6.0%) cases, including myelosuppression, drug-induced liver injury and death related to haemoptysis. The objective response rate (ORR) was 76.0%, with 8 (16.0%) patients having a complete response (CR), 30 (60.0%) partial response (PR), 10 (20.0%) stable disease (SD) and 2 (4.0%) progressive disease (PD). Surgery could be achieved in 12 (100%) patients with RD and 25 (65.8%) with PRD; 1 (2.0%) with PRD refused surgery. Therefore, R0 resection was performed for all 36 (100%) patients who underwent surgery; 20 (55.6%) achieved MPR, including 10 (27.8%) with a complete pathological response (pCR). The CHI3L1 (chitinase-3-like protein 1) immunohistochemistry (IHC) expression of baseline tumour samples could predict the therapeutic response (AUC=0.732), OS (P=0.017) and PFS (P=0.001). Increased PD-1 expression, T cell abundance and immune-related pathway enrichment were observed in post-treatment samples compared to baseline in the response group (CR+PR) but not in the non-response group (SD+PD). CONCLUSIONS: Neoadjuvant toripalimab plus chemotherapy was safe and effective, with a high MPR and manageable TRAEs for II-III NSCLC, even converting initially PRD to RD. Disparate transcriptomic characteristics of therapeutic efficiency were observed, and CHI3L1 expression predicted therapeutic response and survival. TRIAL REGISTRATION: ChiCTR1900024014, June 22, 2019.

Which goals should we pursue in each line of treatment for advanced soft tissue sarcoma?

Treatment goals for advanced soft tissue sarcoma (STS) vary according to disease stage and treatment line. In potentially resectable advanced disease, the goal of treatment is tumor shrinkage to facilitate surgical resection with better margins. Doxorubicin in combination with ifosfamide (or dacarbazine) is first-line therapy of choice in this setting. Tumor shrinkage is relevant not only for surgical rescue but also to obtain rapid symptomatic relief related to tumor volume. Doxorubicin monotherapy can be selected as first-line therapy in cases where disease control with less morbidity is the objective. Second-line therapy for metastatic disease generally aims for disease stabilization with good quality of life although, in some palliative or potentially resectable cases, tumor shrinkage may be relevant. To date, treatment aim has not been a critical factor in the design of clinical trials in advanced STS. In clinical practice, however, treatment is selected according to aim. Future clinical trials in patients with advanced STS should take treatment goals into account. Using illustrative case studies, evidence is examined which supports the current approach to treatment of advanced STS.

Selecting patients for resection after primary chemotherapy for non-metastatic pancreatic adenocarcinoma.

BACKGROUND: Patients with borderline (BL) or locally advanced (LA) pancreatic adenocarcinoma are usually treated with primary chemotherapy (CT), followed by resection when feasible. Scanty data are available about the criteria to candidate patients to resection after CT. PATIENTS AND METHODS: Between 2002 and 2016 overall 223 patients diagnosed with BL or LA pancreatic adenocarcinoma were primarily treated with Gemcitabine combination (4-drugs or nab-paclitaxel-gemcitabine) for 3-6 months followed by surgery and/or chemoradiation. Resection was carried out when radical resection could be predicted by imaging studies and intraoperative findings. The prognostic value of both pre-treatment factors and treatment response was retrospectively evaluated, searching for criteria that could improve the selection of patients for surgery. RESULTS: Median survival (MS) for the whole population was 18.3 months. Surgical resection was carried out in 61 patients; MS in resected patients was significantly longer (30.0 months) as compared with 162 non-resected patients (16.5 months) (P < 0.00001). According to response criteria, 48% had a radiological partial response, 47% a stable disease and 5% a disease progression); CA19.9 response (reduction >50%) was obtained in 77.8% of patients. Among resected patients, neither pre-treatment factors, including BL/LA distinction, nor radiological response, were able to prognosticate survival differences. Survival of resected patients having no CA19.9 response was significantly lower as compared with responders (MS 15.0 versus 31.5 months, P = 0.04), and was similar to non-responders patients that did not undergo resection (MS 10.9 months, P= 0.25). Multivariate analysis carried out on the overall population, showed that Karnofsky performance status, T3-T4 status, resection and CA19.9 response were independent prognostic factors, while radiological response, BL/LA distinction and baseline CA19.9 had not significant influence on survival. CONCLUSIONS: CA19.9 response may allow a better selection of patients who will benefit from resection after primary CT for BL or LA pancreatic adenocarcinoma.

Multimodality Management of "Borderline Resectable" Pancreatic Neuroendocrine Tumors: Report of a Single-Institution Experience.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) constitute approximately 3% of pancreatic neoplasms. Like patients with pancreatic ductal adenocarcinoma (PDAC), some of these patients present with "borderline resectable disease." For these patients, an optimal treatment approach is lacking. We report our institution's experience with borderline resectable PanNETs using multimodality treatment. METHODS: We identified patients with borderline resectable PanNETs who had received neoadjuvant therapy at our institution between 2000 and 2013. The definition of borderline resectability was based on National Comprehensive Cancer Network criteria for PDAC. Neoadjuvant regimen, radiographic response, pathologic response, surgical margins, nodal retrieval, number of positive nodes, and recurrence were documented. Statistics were descriptive. RESULTS: Of 112 patients who underwent surgical resection for PanNETs during the study period, 23 received neoadjuvant therapy, 6 of whom met all inclusion criteria and had borderline resectable disease. These 6 patients received at least 1 cycle of temozolomide and capecitabine, with 3 also receiving radiation. All had radiographic evidence of treatment response. Four (67%) had negative-margin resections. Four patients had histologic evidence of a moderate response. Follow-up (3.0-4.3 years) indicated that all patients were alive, with 5/6 free of disease (1 patient with metastatic disease still on treatment without progression). CONCLUSIONS: A multimodality treatment strategy (neoadjuvant temozolomide and capecitabine ± radiation) can be successfully applied to patients with PanNETs who meet NCCN borderline resectable criteria for PDAC. To our knowledge, this is the first report of the use of a multimodality protocol in the treatment of patients with borderline resectable PanNETs.

Borderline Resectable Pancreatic Cancer: Challenges for Clinical Management.

Background: 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). Objective: To identify the current challenges that exist in the management of BR-PDAC. Methods: A review of the literature was conducted to identify articles discussing the definitions and management of BR-PDAC. Key Findings: 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. Conclusion: 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.

Cytokines and Lymphoid Populations as Potential Biomarkers in Locally and Borderline Pancreatic Adenocarcinoma.

Despite its relative low incidence, PDAC is one of the most aggressive and lethal types of cancer, being currently the seventh leading cause of cancer death worldwide, with a 5-year survival rate of 10.8%. Taking into consideration the necessity to improve the prognosis of these patients, this research has been focused on the discovery of new biomarkers. For this purpose, patients with BL and resectable disease were recruited. Serum cytokines and growth factors were monitored at different time points using protein arrays. Immune cell populations were determined by flow cytometry in peripheral blood as well as by immunohistochemistry (IHC) in tumor tissues. Several cytokines were found to be differentially expressed between the study subgroups. In the BL disease setting, two different scores were proven to be independent prognostic factors for progression-free survival (PFS) (based on IL-10, MDC, MIF, and eotaxin-3) and OS (based on eotaxin-3, NT-3, FGF-9, and IP10). In the same context, CA19-9 was found to play a role as independent prognostic factor for OS. Eotaxin-3 and MDC cytokines for PFS, and eotaxin-3, NT-3, and CKß8-1 for OS, were shown to be predictive biomarkers for nab-paclitaxel and gemcitabine regimen. Similarly, oncostatin, BDNF, and IP10 cytokines were proven to act as predictive biomarkers regarding PFS, for FOLFIRINOX regimen. In the resectable cohort, RANTES, TIMP-1, FGF-4, and IL-10 individually differentiated patients according to their cancer-associated survival. Regarding immune cell populations, baseline high levels of circulating B lymphocytes were related to a significantly longer OS, while these levels significantly decreased as progression occurred. Similarly, baseline high levels of helper lymphocytes (CD4+), low levels of cytotoxic lymphocytes (CD8+), and a high CD4/CD8 ratio, were related to a significantly longer PFS. Finally, high levels of CD4+ and CD8+ intratumoural infiltration was associated with significantly longer PFS. In conclusion, in this study we were able to identify several prognostic and predictive biomarker candidates in patients diagnosed of resectable or BL PDAC.

Advances in neoadjuvant therapy for resectable pancreatic cancer over the past two decades.

In the last two decades, pancreatic cancer has been undergoing important changes in its perioperative management due to the great interest in multidisciplinary management and preoperative multimodal therapy, which in numerous studies have shown promising clinical results. Although the standard of treatment for resectable pancreatic ductal adenocarcinoma (PDAC) today is surgery followed by adjuvant therapy, as it is a biologically aggressive disease, even with complete resection, it has high rates of local and distant relapse. Several retrospective and prospective phase I/II studies have opened the window for neoadjuvant therapy with chemotherapy (CT), chemoradiotherapy (CRT), or both, as an alternative treatment for resectable pancreatic cancer, with promising results. Neoadjuvant therapy could has some advantages, including early administration of systemic treatment, in vivo assessment of response to treatment, increase resectability rate in borderline patients, increase resection rate with negative margin and survival benefit. While it seems clear that even potentially resectable disease would benefit from preoperative multimodal therapy, the optimal neoadjuvant therapeutic strategy is still controversial and currently there are only recommendations for neoadjuvant treatment, in clinical guidelines such as the NCCN and ESMO, for borderline and/or locally advanced PDAC. This review provides an overview of recent studies available and how they relate to systemic treatment of resectable PDAC in the neoadjuvant setting.

The Role of Positron Emission Tomography/Computed Tomography (PET/CT) for Staging and Disease Response Assessment in Localized and Locally Advanced Pancreatic Cancer.

Pancreatic Cancer (PC) has a poor prognosis, with a 5-year survival rate of only 9%. Even after radical surgical procedures, PC patients have poor survival rates, with a high chance of relapse (70-80%). Imaging is involved in all aspects of the clinical management of PC, including detection and characterization of primary tumors and their resectability, assessment of vascular, perineural and lymphatic invasion and detection of distant metastases. The role of Positron Emission Tomography/Computed Tomography (PET/CT) in detecting PC is still controversial, with the international guidelines not recommending its routine use. However, in resectable PC, PET/CT may play a role in assessing PC stage and grade and potential resectability after neoadjuvant treatment. Quantitative image analysis (radiomics) and new PET/CT radiotracers account for future developments in metabolic imaging and may further improve the relevance of this technique in several aspects of PC. In the present review, the current state of the art and future directions of PET/CT in resectable PC are presented.

Induction treatment in patients with stage III non-small cell lung cancer.

Stage III non-small cell lung cancer (NSCLC) comprises a highly heterogeneous group of patients defined according to the extent and localization of disease. Patients with discrete N2 involvement identified preoperatively with resectable disease are candidates for multimodal therapy either with definitive chemoradiation therapy, induction chemotherapy, or chemoradiotherapy (CTRT) followed by surgery. Neoadjuvant chemotherapy has yielded comparable survival benefit to adjuvant chemotherapy in patients with stage II-III disease and may allow for downstaging the tumor or the lymph nodes, an earlier delivery of systemic treatment, and better compliance to systemic therapy. The use of immune checkpoint inhibitors (ICIs) as induction therapy shows encouraging activity and a favorable safety profile in patients with resectable early stage or locally advanced NSCLC. An unprecedented rate of pathological response and downstaging has been reported in single-arm clinical trials, especially when immunotherapy is combined with neoadjuvant chemotherapy. Ongoing randomized phase II/III clinical trials assessing the efficacy and safety of induction with immunotherapy plus chemotherapy have the potential to establish this therapeutic approach as a novel standard of care. These trials aim to validate pathological response as a surrogate marker of survival benefit and to demonstrate that this therapeutic strategy can improve the cure rate in patients with stage II-III NSCLC.

Locally advanced gastro-oesophageal cancer: Recent therapeutic advances and research directions.

Gastric (GC) and gastro-oesophageal (GOJC) adenocarcinomas are often considered as a single entity, even though differences exist in epidemiology, clinical presentation, molecular biology and treatment options. Locally advanced, resectable disease represents a particularly challenging scenario, as many critical issues need to be addressed. In both GC and GOJC among Western countries, systemic chemotherapy demonstrated the greatest benefit when administered before and after surgery and perioperative chemotherapy has been set as a standard in this setting. Nonetheless, multiple chemotherapy regimens have been tested and direct comparisons have been only recently presented. Adjuvant chemoradiotherapy is an option as well, but several trials have questioned its role when more effective combination regimens are used. With regards to GOJC, preoperative chemoradiotherapy is an alternative to perioperative chemotherapy, as it is associated with higher pathologic responses and a different toxicity profile: however, a definitive comparison with chemotherapy is ongoing. Herein, we review the current options for the treatment of resectable GC and GOJC and the main open questions in the management of these patients, trying to depict an update of the available algorithms for everyday practice. Moreover, we summarize the design and preliminary results of the randomized trials in progress that will hopefully give definitive answers to the most debated issues in the field.

A randomised phase 2 trial of nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in locally advanced or borderline resectable pancreatic adenocarcinoma.

BACKGROUND: The current trial assessed whether the addition of cisplatin and capecitabine to the nab-paclitaxel-gemcitabine backbone is feasible and active against borderline and locally advanced pancreatic adenocarcinoma (PDAC). METHOD: Fifty-four chemo-naive patients, aged between 18 and 75 years, with a pathological diagnosis of locally advanced or borderline resectable PDAC were randomised to receive either nab-paclitaxel, gemcitabine, cisplatin and oral capecitabine (PAXG; arm A; N = 26) or nab-paclitaxel followed by gemcitabine (AG; arm B; N = 28). The primary end-point was the tumour resection rate. If at least four such resections were performed, the treatment was considered as active. The secondary end-points were progression-free survival (PFS), overall survival (OS), Response Evaluation Criteria in Solid Tumours response rate, Hartman's pathologic response, carbohydrate antigen 19.9 response rate and toxicity. RESULTS: Eight patients (31%) in the PAXG arm and nine (32%) in the AG arm underwent resection. PFS at 1-year was 58% in arm A and 39% in arm B. OS at 18-month was 69% in arm A and 54% in arm B. CONCLUSIONS: In this phase II study, the addition of cisplatin and capecitabine to the AG backbone was feasible and yielded promising results in terms of disease control without detrimental impact on tolerability. The approach warrants further investigation in a phase III study. TRIAL REGISTRATION: NCT01730222.