Para-aortic lymphadenectomy in surgery for gastric cancer: current indications and future perspectives

Involvement of para-aortic nodes (PAN) has been detected at pathological examination in 10-25% of locally advanced gastric cancer. Based on these data of nodal diffusion, the lymphadenectomy of para-aortic stations would be desirable in locally advanced gastric cancer. However, the debate on the oncological benefit of para-aortic nodes dissection is still not solved. A review of the literature was performed and papers reporting either the rate of para-aortic nodal metastases or the long-term survival outcomes after D2+ para-aortic nodes dissection (PAND) or D3 lymphadenectomy were descriptively reported. The literature survey yielded 14 studies. Most of the papers show the outcome of series of advanced gastric cancer treated with surgery alone, while starting from 2012, 3 articles report the outcomes of D2 + PAND or D3 lymphadenectomy after preoperative chemotherapy. The rate of PAN metastases ranges between 8.5 and 28% in surgical series. Survival outcomes largely improved in series of patients treated with multimodal approach compared to those of surgery alone. In patients with clinically detected para-aortic nodal metastases, preoperative chemotherapy followed by PAND is indicated. More data are needed to clarify the indication to prophylactic PAND in the era of multimodal treatment, anyway super-extended lymphadenectomies have to be performed by experienced surgeons in dedicated centres

Predictors of Local Control for Stereotactic Ablative Radiotherapy (SAbR) in Pulmonary Oligometastases from Gastrointestinal Malignancies

Background/aim: To assess predictors of local control (LC) for stereotactic ablative radiotherapy (SAbR) in pulmonary oligometastatic disease (OMD) from gastrointestinal (GI) malignancies. Patients and methods: Patients with pulmonary OMD treated with SAbR from January 2016 to December 2018 were included in this observational analysis. Primary endpoint was LC. Uni- and multivariate analyses to assess variable correlations were conducted. Results: Thirty-seven patients and 59 lung metastases were evaluated. The delivered dose was 30-60 Gy in 3-8 fractions. After a median follow-up of 23.0 months (range=6.3-50.4 months), LC rate at 1/2 years was 89.7%/85.0%, and increased to 96.0%/91.0% for lesions treated with a biologically effective dose (BED10) ≥100 Gy (p=0.03). RECIST response at 6 months was predictive for LC (p=0.002). Conclusion: SAbR is an effective option for pulmonary OMD from GI malignancies. A BED10 ≥100 Gy and radiological response at 6 months can affect LC

Clinical pathways in gastric cancer care

The diagnostic–therapeutic pathways (DTPs) are emerging as useful instruments for clinical management of complex diseases as gastric cancer, whose treatment is challenging and requires a multidisciplinary approach. However, the DPTs of patients with gastric cancer are still not defined yet. The aim of this study was to define the optimal DPT to be applied for patients with gastric cancer in the Veneto region. Rather than defining the ideal DTPs a priori, we conducted a preliminary research by analyzing the differences in the actual DPTs for patients with gastric cancer among different hospitals (hub and spokes) in Veneto. Then, the final DPT was elaborated based on the current available best clinical evidences; however, also the areas of homogeneity among the actual DPTs of the included centers as well as the critical issues that had emerged by our preliminary analysis were taken into account for pathway design. High heterogeneity in actual DTPs of patients with gastric cancer was observed among the analyzed centres. Moreover, some of the major criticisms have been found at crucial points of the current pathways. Based on these data, a reference path that is applicable to the whole-regional health network was constructed. The reference DTP is focused on multidisciplinary team management of patients with gastric cancer. Clinical pathways are essential tools to properly manage complex diseases such as gastric cancer. As such, more efforts should be done to implement their use

Pretreatment Primary Tumor Stage is a Risk Factor for Recurrence in Patients with Esophageal Squamous Cell Carcinoma Who Achieve Pathological Complete Response After Neoadjuvant Chemoradiotherapy

BACKGROUND: Although pathological complete response (pCR) after multimodal treatment for esophageal cancer is associated to the best prognosis, recurrence may occur in 20-40% of cases. The present study investigated the recurrence pattern and predictive factors of recurrence after pCR in patients with esophageal cancer.METHODS: In this study, 427 patients received preoperative treatment for either esophageal squamous cell carcinoma (SCC) or adenocarcinoma at Verona University Hospital between 2000 and 2018. Of these, 145 patients (34%) achieved a pCR. Long-term prognosis, recurrence pattern, and risk factors for relapse in pCR patients were analysed.RESULTS: During a median follow-up of 52months, 37 relapses (25.5%) occurred, mostly at distant level (n=28). Nearly all locoregional relapses (8/9) were detected in SCC cases. The 5-year overall survival and cancer-related survival were 71.7% (95% confidence interval [CI] 62.6-78.9%) and 77.5% (95% CI 68.5-84.2%) respectively. Male sex, higher body mass index, and cT4 were significant risk factors for recurrence at univariate analysis. The multivariate analysis confirmed the role of cT4 as predictor of recurrence only in SCCs.CONCLUSIONS: Esophageal cancer recurs in about one-fourth of pCR cases. A fair number of local recurrences occurs in SCCs, but the main problem is the systemic disease control. According to our analysis, SCCs patients with cT4 stage have an increased risk to recur, so they should be managed differently by a personalized approach in terms of adjuvant treatment and follow-up

Treatment of EGJ Cancer within or outside clinical trials: Does the setting matter? A monocentric prospective observational study

Introduction: RCTs support neoadjuvant chemoradiotherapy (nCRT) followed by surgery in Locally Advanced Esophago-Gastric Junction (LA-EGJ) adenocarcinoma. However, RCTs are performed in highly controlled settings with limited representativeness of real-life patients (RLS). Aim: To compare the outcomes in RLS and clinical trial settings. Methods: The outcomes of RLS, which comprised 125 patients consequently treated for LA-EGJ adenocarcinoma between 2012 and 2017, were compared with the phase II trial (PIIS), performed on 65 patients from 2003 to 2011. Results: About half of RLS (51.2%) were treated with nCRT according to VR-protocol, 20.8% with standard-CRT according to CROSS/Al-Sarraf, 20% with CT alone. pCR was 36.8%, 28.6% and 9.1% after VR-protocol, standard-CRT, and chemotherapy respectively (p=0.082), while three-year overall survival (OS) was 58.6% (95% CI 43.2-71.1%), 32.8% (14.6-52.4%) and 44.8% (21.3-65.9%) respectively (p=0.030). With respect to PIIS, RLS had a higher proportion of cN+ (94% versus 54%; p<0.001), and a lower proportion of pCR after CT/CRT (23% versus 39%; p=0.041). Three-year OS was slightly higher, although not significantly, in PIIS (58.9%, 45.1-70.2%) than RLS (47.9%, 37.4-57.7%) and nearly identical to 3-year OS in RLS treated with VR-protocol. Discussion/conclusion: Real-life patients with EGJ adenocarcinoma have more advanced cancer at baseline, lower pathologic response to neoadjuvant treatment than patients enrolled in clinical trials, but similar survival

18F-FDG PET/CT Metrics Are Correlated to the Pathological Response in Esophageal Cancer Patients Treated With Induction Chemotherapy Followed by Neoadjuvant Chemo-Radiotherapy

Background and ObjectiveThe aim of this study was to assess the ability of Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (F-18-FDG PET/CT) to provide functional information useful in predicting pathological response to an intensive neoadjuvant chemo-radiotherapy (nCRT) protocol for both esophageal squamous cell carcinoma (SCC) and adenocarcinoma (ADC) patients.Material and MethodsEsophageal carcinoma (EC) patients, treated in our Center between 2014 and 2018, were retrospectively reviewed. The nCRT protocol schedule consisted of an induction phase of weekly administered docetaxel, cisplatin, and 5-fluorouracil (TCF) for 3 weeks, followed by a concomitant phase of weekly TCF for 5 weeks with concurrent radiotherapy (50-50.4 Gy in 25-28 fractions). Three F-18-FDG PET/CT scans were performed: before (PET1) and after (PET2) induction chemotherapy (IC), and prior to surgery (PET3). Correlation between PET parameters [maximum and mean standardized uptake value (SUVmax and SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG)], radiomic features and tumor regression grade (TGR) was investigated.ResultsFifty-four patients (35 ADC, 19 SCC; 48 cT3/4; 52 cN+) were eligible for the analysis. Pathological response to nCRT was classified as major (TRG1-2, 41/54, 75.9%) or non-response (TRG3-4, 13/54, 24.1%). A major response was statistically correlated with SCC subtype (p = 0.02) and smaller tumor length (p = 0.03). MTV and TLG measured prior to IC (PET1) were correlated to TRG1-2 response (p = 0.02 and p = 0.02, respectively). After IC (PET2), SUVmean and TLG correlated with major response (p = 0.03 and p = 0.04, respectively). No significance was detected when relative changes of metabolic parameters between PET1 and PET2 were evaluated. At textural quantitative analysis, three independent radiomic features extracted from PET1 images ([JointEnergy and InverseDifferenceNormalized of GLCM and LowGrayLevelZoneEmphasis of GLSZM) were statistically correlated with major response (p < 0.0002).ConclusionsF-18-FDG PET/CT traditional metrics and textural features seem to predict pathologic response (TRG) in EC patients treated with induction chemotherapy followed by neoadjuvant chemo-radiotherapy. Further investigations are necessary in order to obtain a reliable predictive model to be used in the clinical practice

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) in multimodal therapy for patients with oligometastatic peritoneal gastric cancer: a randomized multicenter phase III trial PIPAC VEROne

Objectives: Peritoneal carcinomatosis is the most frequent site of metastases in patients with gastric cancer. Current standard treatment is palliative systemic chemotherapy with very poor prognosis. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) resulted in long-term benefits in selected patients. Among patients with peritoneal carcinomatosis, a distinctive subset is oligometastatic disease which is characterized by low metastatic burden. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a recent technique of intraperitoneal chemotherapy used in combination with systemic chemotherapy with promising results. Methods: PIPAC VER-One is a prospective, randomized, multicenter phase III clinical trial that aims to evaluate the effectiveness of the use of PIPAC in combination with systemic chemotherapy in patients with gastric cancer and synchronous positive peritoneal cytology and/or limited peritoneal metastases (peritoneal cancer index [PCI] ≤6). Patients will be randomized into two arms: arm A (control) treated with standard systemic chemotherapy and arm B (experimental) treated with a bidirectional scheme including PIPAC and systemic chemotherapy. Results: Primary endpoint is the secondary resectability rate. Secondary endpoints are: overall survival (OS), pregression-free survival (PFS), disease-free survival (DFS), histological response assessed both on primary tumor and peritoneal lesions, quality of life (QoL), complication rate (CTCAE v5), and incremental cost-effectiveness ratios (ICER). Conclusions: The role of PIPAC in multimodal treatment for oligometastatic gastric cancer will be investigated in this trial

Long-Term Outcomes of Induction Chemotherapy Followed by Chemo-Radiotherapy as Intensive Neoadjuvant Protocol in Patients with Esophageal Cancer

BACKGROUND: A phase II intensive neoadjuvant chemo-radiotherapy (nCRT) protocol for esophageal cancer (EC) was previously tested at our Center with promising results. We here present an observational study to evaluate the efficacy of the protocol also in "real life" patients.METHODS: We retrospectively reviewed 122 ECs (45.1% squamous cell (SCC) and 54.9% adenocarcinoma (ADC)) treated with induction docetaxel, cisplatin, and 5-fluorouracil (TCF), followed by concomitant TCF and radiotherapy (50-50.4 Gy/25-28 fractions), between 2008 and 2017. Primary endpoints were overall survival (OS), event-free survival (EFS) and pathological complete response (pCR).RESULTS: With a median follow-up of 62.1 months (95% CI 50-67.6 months), 5-year OS and EFS rates were 54.8% (95% CI 44.7-63.9) and 42.7% (95% CI 33.1-51.9), respectively. A pCR was observed in 71.1% of SCC and 37.1% of ADC patients (p = 0.001). At multivariate analysis, ypN+ was a significant prognostic factor for OS (Hazard Ratios (HR) 4.39 [95% CI 2.36-8.18]; p < 0.0001), while pCR was a strong predictor of EFS (HR 0.38 [95% CI 0.22-0.67]; p < 0.0001).CONCLUSIONS: The nCRT protocol achieved considerable long-term survival and pCR rates also in "real life" patients. Further research is necessary to evaluate this protocol in a watch-and-wait approach

A phase II trial of the FGFR inhibitor pemigatinib in patients with metastatic esophageal-gastric junction/gastric cancer trastuzumab resistant: the FiGhTeR trial

Background: Prognosis of patients affected by metastatic esophageal-gastric junction (EGJ) or gastric cancer (GC) remains dismal. Trastuzumab, an anti-HER2 monoclonal antibody, is the only targeted agent approved for the first-line treatment of patients with HER2-overexpressing advanced EGJ or GC in combination with chemotherapy. However, patients invariably become resistant during this treatment. We recently identified the overexpression of fibroblast growth factor (FGF) receptor 3 (FGFR3) as a molecular mechanism responsible for trastuzumab resistance in GC models, providing the rationale for the inhibition of this receptor as a potential second-line strategy in this disease. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. Methods: The FiGhTeR trial is a phase II, single-arm, open-label study to assess safety and activity of the FGFR inhibitor pemigatinib as second-line treatment strategy in metastatic EGJ/GC patients progressing under trastuzumab-containing therapies. The primary endpoint is the 12-week progression-free survival rate. Plasma and tumor tissue samples will be collected for translational research analyses at baseline, during treatment, and at progression on pemigatinib. Discussion: Co-alterations in genes coding for different tyrosine-kinase receptors are emerging as relevant mechanisms of acquired resistance to anti-HER2 therapeutic strategies in GC. In particular, our group has recently identified that in GC models the overexpression of FGFR3 sustains the acquired resistance to trastuzumab. This trial aims to assess the safety, tolerability and activity of the FGFR inhibitor pemigatinib as a second-line treatment in metastatic EGJ/GC patients refractory to first-line trastuzumab-containing therapies. Furthermore, this study offers the opportunity to prospectively study mechanisms and pathways involved in trastuzumab resistance. Protocol number: CRC2017_02 EudraCT Number: 2017-004522-1