Chemorefractory Gastric Cancer: The Evolving Terrain of Third-Line Therapy and Beyond

Gastric cancer; Molecular approach; Third line of treatmentCáncer gástrico; Enfoque molecular; Tercera línea de tratamientoCàncer gàstric; Enfocament molecular; Tercera línia de tractamentGastric and gastro-oesophageal junction cancer (GC) represent a global healthcare problem being the fifth most common tumour type and the fourth cause of cancer mortality. Extremely poor median survival of approximately 10 months is normally reported within advanced GC patients, mainly secondary to two factors, i.e., the fragility of these patients and the aggressiveness of this disease. In this context, the correct treatment of GC patients requires not only a multidisciplinary team with special attention to palliative and nutritional care but also a close follow-up with regular monitoring of disease symptoms and tumour evaluation. Sequential treatment lines with few toxic adverse events have emerged as the best therapeutic approach, and a third line of therapy could further improve survival and quality of life of GC patients. Chemotherapy, immunotherapy, and targeted agents -when indicated- constitute the treatment armamentarium of these patients. In this review, we discuss treatment options in the refractory setting as well as novel approaches to overcome the poor prognosis of GC

ESMO Congress 2021: highlights from the EORTC gastrointestinal tract cancer group’s perspective

Neuroendocrine tumours; Pancreatic cancer; Stomach cancerTumores neuroendocrinos; Cáncer de páncreas; Cáncer de estómagoTumors neuroendocrins; Càncer de pàncrees; Càncer d'estómacThere has been no major change of practice in gastrointestinal oncology at the European Society for Medical Oncology (ESMO) symposium 2021, but confirmation that immunotherapy in combination with chemotherapy has become standard of care in several indications. The European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Track Cancer Group has selected important phase II and III trials presented during the symposium across all gastrointestinal cancers as well as early reports on new drugs or new combinations that may change practice in the future.This work was supported by a donation from the Swiss Cancer Research Foundation from Switzerland. MC was supported by a grant by EORTC Cancer Research Fund (ECRF) and the Gastrointestinal Tract Cancer Group

Highlights from ASCO-GI 2021 from EORTC Gastrointestinal tract cancer group

Biliary tract cancer; Colorectal cancer; Drug developmentCáncer del tracto biliar; Cáncer colorrectal; Desarrollo de fármacosCàncer del tracte biliar; Càncer colorectal; Desenvolupament de fàrmacsLast year the field of immunotherapy was finally introduced to GI oncology, with several changes in clinical practice such as advanced hepatocellular carcinoma or metastatic colorectal MSI-H. At the virtual ASCO-GI symposium 2021, several large trial results have been reported, some leading to a change of practice. Furthermore, during ASCO-GI 2021, results from early phase trials have been presented, some with potential important implications for future treatments. We provide here an overview of these important results and their integration into routine clinical practice.Open Access funding provided by Université de Genève

Caracterización molecular del cáncer gástrico HER2 positivo; mecanismos de resistencia al tratamiento con anticuerpos monoclonales dirigidos /

El cáncer gástrico (CG) y de la unión gastro-esofágica (CUGE) representa un problema a nivel mundial; si bien es la 5ª causa más frecuente de cáncer, se sitúa la 3ª como causa de muerte por cáncer. El pronóstico de los pacientes con CG metastásico es muy pobre, con una supervivencia a los 5 años inferior al 5%, y la quimioterapia ofrece un beneficio clínico con una duración limitada. Aproximadamente entre un 15-20% de los pacientes presentan sobrexpresión del receptor de crecimiento epidérmico de tipo 2 (HER2). Trastuzumab, un anticuerpo monoclonal humanizado selectivo para HER2, ha sido el primer fármaco dirigido que ha demostrado mejorar el pronóstico de estos pacientes. El estudio TOGA randomizaba a los pacientes HER2 positivo a recibir una primera línea de quimioterapia con o sin trastuzumab. La mediana en la supervivencia global de los pacientes tratados con trastuzumab mejoraba significativamente, de 11.1 a 13.8 meses (Hazard ratio = 0.74, p 0.01). De todas formas, sólo el 50% de los pacientes del grupo experimental se beneficiaba, en términos de respuesta, y que en la mayoría de los pacientes la enfermedad acababa progresando. La resistencia al tratamiento con trastuzumab se podría explicar por alteraciones moleculares a nivel de las proteínas efectoras de las vías de señalización intracelular que activa HER2: la vía de las MAP-quinasas y la vía de PI3K-AKT-mTOR. Esta tesis doctoral analiza posibles alteraciones moleculares en proteínas efectoras de las vías de señalización intracelular de HER2 como posible causa de resistencia primaria a trastuzumab, en una cohorte de 100 pacientes afectos de CG y CUGE HER2 positivo. El análisis molecular se ha realizado sobre las biopsias tumorales de estos pacientes. Se ha analizado el estado de las ciclinas E y D1 (amplificación, sobrexpresión), de PIK3CA (amplificación, secuenciación), de PTEN (expresión), de HER3 (sobrexpresión), y de p95HER2 (sobrexpresión, cuantificación). Además, se han correlacionado los hallazgos moleculares con los datos clínicos de los pacientes. El 25% de los pacientes presenta amplificación de la ciclina E, y este hecho se asocia a un peor pronóstico. La amplificación de la ciclina E es causa de su sobrexpresión. El 15% de los pacientes presenta amplificación de la ciclina D1. Un 4% de los pacientes presentan amplificación a nivel del gen de PIK3CA, mientras que un 3.1% presentan mutaciones a nivel de los dominios helical y catalítico del gen. Un 4% de los pacientes presentan pérdida de la expresión de PTEN, y un 11% presentan baja expresión. Una tercera parte (39%) de los pacientes presentan sobrexpresión de HER3. Un 27% de los pacientes presentan sobrexpresión de p95HER2, y se describe su correlación con una mejor tasa de supervivencia libre de progresión. La investigación translacional integra la investigación básica de laboratorio con la clínica hospitalaria. El conocimiento de los mecanismos moleculares de desarrollo y progresión del cáncer es indispensable para una práctica clínica oncológica como la que entendemos a día de hoy, abordando la enfermedad desde el conocimiento de su biología molecular. El descubrimiento del papel de HER2 y del potencial terapéutico de trastuzumab marcaron el punto de inflexión en el CG, a partir del cual debemos continuar para poder mejorar el pronóstico de nuestros pacientes. Esta tesis sigue la misma línea, e identifica la amplificación de la ciclina E como factor pronóstico negativo de supervivencia, y la sobrexpresión de p95HER2 como factor predictivo positivo de respuesta a terapia basada en trastuzumab, en pacientes afectos de CG y CUGE HER2 positivoGastric cancer (GC) and gastro-esophageal junction cancer (GEJC) is a worldwide problem; although it is the 5th most common cause of cancer, it remains the 3rd cause of death from cancer. The prognosis of patients with metastatic GC is very poor, with 5 year survival rates of less than 5%. Chemotherapy is efficient but with a limited duration. Approximately 15-20% of patients present overexpression of the epidermal growth factor receptor type 2 (HER2). Trastuzumab, a humanized monoclonal antibody that binds HER2, was the first targeted therapy to demonstrate an improvement of the prognosis of these patients. The TOGA trial randomized HER2 positive patients to receive a first-line chemotherapy with or without trastuzumab. The median overall survival of the patients treated with trastuzumab improved significantly, from 11.1 to 13.8 months (Hazard ratio = 0.74, p 0.01). However, only 50% of patients in the experimental group benefit in terms of response and, at the end, the most of them progressed. Resistance to trastuzumab could be explained by molecular alterations at the level of the effector proteins of HER2 intracellular signaling pathways: MAP-kinase and PI3K-AKT-mTOR pathways. This thesis analyzes possible molecular alterations within the effector proteins of the HER2 pathway as the possible cause of primary resistance to trastuzumab, in a cohort of 100 patients with HER2 positive GC and GEJC. The molecular analysis was performed on tumor biopsies from these patients. The status of cycline D1 and E (amplification, overexpression), PIK3CA (amplification, sequencing), PTEN (expression), HER3 (overexpression), and p95HER2 (overexpression, quantification) has been analyzed. Moreover, the results have been correlated with the clinical outcome of the patients. Twenty-five percent of patients present cycline E amplification, and these results are associated with a worse prognosis. Cycline E amplification is the cause of cycline E overexpression. Fifteen percent of patients present cycline D1 amplification. Four percent of patients have PIK3CA amplifications, while 3.1% present mutations in the helical and catalytic domains. Four percent of patients have loss of PTEN, and 11% have low expression. A third (39%) of patients has HER3 overexpression. Twenty-seven percent of patients have p95HER2 overexpression, which is correlated with a better progression-free survival. Translational research integrates basic laboratory research with the clinic. The knowledge of the molecular mechanisms of cancer development and progression is essential for a correct oncologic practice, addressing the disease from their molecular biology. The discovery of the role of HER2 and the therapeutic potential of trastuzumab set the turning point in the GC, from which we should continue in order to improve the prognosis of these patients. This thesis address this point, and identifies the amplification of cycline E as a negative prognostic factor for survival, and the overexpression of p95HER2 as a positive predictor of response to trastuzumab-based therapy in HER2 positive GC and GEJC patients

SEOM-GEMCAD-TTD Clinical Guideline for the diagnosis and treatment of esophageal cancer (2021)

Diagnosis; Esophageal cancer; TreatmentDiagnóstico; Cáncer de esófago; TratamientoDiagnòstic; Càncer d'esòfag; TractamentEsophageal cancer is an aggressive tumor, and is the sixth-leading cause of death from cancer. Incidence is rising in Spain, particularly among men. Two main pathological different subtypes have been described: squamous cell carcinoma and adenocarcinoma. Growing evidence of their epidemiology and molecular differences explains their different response to novel treatments, and they are therefore likely to be treated as two separate entities in the near future. The best results are obtained with a multidisciplinary therapeutic strategy, and the introduction of immunotherapy is a promising new approach that will improve prognosis. In these guidelines, we review the evidence for the different methods of diagnosis and therapeutic strategies that form the basis of our standard of care

External validity of clinical trials with diverse trastuzumab-based chemotherapy regimens in advanced gastroesophageal adenocarcinoma: data from the AGAMENON-SEOM registry

Quimioteràpia; Càncer gàstric; TrastuzumabQuimioterapia; Cáncer gástrico; TrastuzumabChemotherapy; Gastric cancer; TrastuzumabBackground: Trastuzumab combined with cisplatin and fluoropyrimidines, either capecitabine or 5-fluorouracile (XP/FP), is the standard first-line treatment for advanced, HER2-positive, gastric cancer patients based on the ToGA trial. Despite the lack of phase III trials, many clinicians administer trastuzumab with alternative regimens. One meta-analysis suggests that substituting cisplatin for oxaliplatin might lead to greater efficacy and less toxicity. Methods: 594 patients with HER2-positive gastroesophageal adenocarcinoma were recruited from the AGAMENON-SEOM registry. The objective was to evaluate the external validity of clinical trials with chemotherapy and trastuzumab. Results: The regimens used in at least 5% of the patients were XP (27%), oxaliplatin and capecitabine (CAPOX) (26%), oxaliplatin and 5-fluorouracil (FOLFOX) (14%), FP (14%), triplet with anthracycline/docetaxel (7%), and carboplatin-FU (5%). Median exposure to trastuzumab was longer with FOLFOX (11.4 months, 95% CI, 9.1–21.0) versus ToGA regimens (7.5, 6.4–8.5), p < 0.001. Patients with HER2-IHC 3+ cancers had higher response rates than those with IHC 2+/FISH+, odds-ratio 1.97 (95% CI, 1.25–3.09). The results achieved with CAPOX–trastuzumab were comparable to those attained with ToGA regimens. FOLFOX–trastuzumab was superior to ToGA schemes in terms of overall survival (OS), with a greater magnitude of effect in IHC 2+/FISH+ tumors (HR 0.47, 0.24–0.92) compared with IHC 3+ (HR 0.69, 0.49–0.96), and in diffuse (HR 0.37, 0.20–0.69) versus intestinal-type tumors (HR 0.76, 0.54–1.06). Conclusion: We have updated the external validity of clinical trials with trastuzumab in first-line treatment of gastric cancer. Our data confirm the comparable outcomes of ToGA regimens and CAPOX–trastuzumab in clinical practice and point toward a possible benefit of FOLFOX–trastuzumab, contingent on the subtypes typically less sensitive to trastuzumab, to be confirmed in clinical trials.The authors received no financial support for the research, authorship, and/or publication of this article

Efficacy and safety of trifluridine/tipiracil in older and younger patients with metastatic gastric or gastroesophageal junction cancer: subgroup analysis of a randomized phase 3 study (TAGS)

Age groups; Gastrointestinal neoplasms; TrifluridineGrupos de edad; Neoplasias gastrointestinales; TrifluridinaGrups d'edat; Neoplàsies gastrointestinals; TrifluridinaBackground Trifluridine and tipiracil (FTD/TPI) demonstrated survival benefit vs placebo and manageable safety in previously treated patients with metastatic gastric/gastroesophageal junction cancer (mGC/GEJC) in the randomized, placebo-controlled, phase 3 TAGS study. This subgroup analysis of TAGS examined efficacy/safety outcomes by age. Methods In TAGS, patients with mGC/GEJC and ≥ 2 prior therapies were randomized (2:1) to receive FTD/TPI 35 mg/m2 or placebo, plus best supportive care. A preplanned subgroup analysis was performed to evaluate efficacy and safety outcomes in patients aged < 65, ≥ 65, and ≥ 75 years. Results Among 507 randomized patients (n = 337 FTD/TPI; n = 170 placebo), 55%, 45%, and 14% were aged < 65, ≥ 65, and ≥ 75 years, respectively. Overall survival hazard ratios for FTD/TPI vs placebo were 0.67 (95% CI 0.51–0.89), 0.73 (95% CI 0.52–1.02), and 0.67 (95% CI 0.33–1.37) in patients aged < 65, ≥ 65, and ≥ 75 years, respectively. Regardless of age, patients receiving FTD/TPI experienced improved progression-free survival and stayed longer on treatment than those receiving placebo. Among FTD/TPI-treated patients, frequencies of any-cause grade ≥ 3 adverse events (AEs) were similar across age subgroups (80% each), although grade ≥ 3 neutropenia was more frequent in older patients [40% (≥ 65 and ≥ 75 years); 29% (< 65 years)]; AE-related discontinuation rates did not increase with age [14% (< 65 years), 12% (≥ 65 years), and 12% (≥ 75 years)]. Conclusions The results of this subgroup analysis show the efficacy and tolerability of FTD/TPI treatment regardless of age in patients with mGC/GEJC who had received 2 or more prior treatments.This study was sponsored by Taiho Oncology, Inc., and Taiho Pharmaceuticals Co., Ltd. Professional medical writing and editorial assistance were provided by Vasupradha Vethantham, PhD, and Jennifer L. Robertson, PhD, at Ashfield MedComms, an Ashfield Health company, funded by Taiho Oncology, Inc

Trifluridine/tipiracil versus placebo for third or later lines of treatment in metastatic gastric cancer: an exploratory subgroup analysis from the TAGS study

Metastatic gastric cancer; Overall survival; Trifluridine/tipiracilCàncer gàstric metastàtic; Supervivència global; Trifluridina/tipiracilCáncer gástrico metastásico; Supervivencia global; Trifluridina/tipiraciloBackground Metastatic gastric cancer and cancer of the esophagogastric junction (GC/EGJ) is an aggressive disease with poor prognosis. In the TAGS study, trifluridine/tipiracil (FTD/TPI) improved overall survival (OS) compared with placebo in heavily pre-treated patients. This unplanned, exploratory subgroup analysis of the TAGS study aimed to clarify outcomes when FTD/TPI was used as third-line (3L) treatment and fourth- or later-line (4L+) treatment. Patients and methods Patients were divided into a 3L group (126 and 64 in FTD/TPI and placebo arms, respectively) and 4L+ group (211 and 106 in FTD/TPI and placebo arms, respectively). Endpoints included OS, progression-free survival (PFS), time to Eastern Cooperative Oncology Group performance status (ECOG PS) deterioration to ≥2, and safety. Results Baseline characteristics were generally well balanced between FTD/TPI and placebo for 3L and 4L+ treatment. Median OS (mOS) for FTD/TPI versus placebo was: 6.8 versus 3.2 months {hazard ratio (HR) [95% confidence interval (CI)] = 0.68 (0.47-0.97), P = 0.0318} in the 3L group; and 5.2 versus 3.7 months [0.73 (0.55-0.95), P = 0.0192] in the 4L+ group. Median PFS for FTD/TPI versus placebo was 3.1 versus 1.9 months [0.54 (0.38-0.77), P = 0.0004] in the 3L group; and 1.9 versus 1.8 months [0.57 (0.44-0.74), P < 0.0001] in the 4L+ group. Time to deterioration of ECOG PS to ≥2 for FTD/TPI versus placebo was 4.8 versus 2.0 months [HR (95% CI) = 0.60 (0.42-0.86), P = 0.0049] in the 3L group; and 4.0 versus 2.5 months [0.75 (0.57-0.98), P = 0.0329] in the 4L+ group. The safety of FTD/TPI was consistent in all subgroups. Conclusions This analysis confirms the efficacy and safety of FTD/TPI in patients with GC/EGJ in third and later lines with a survival benefit that seems slightly superior in 3L treatment. When FTD/TPI is taken in 3L as recommended in the international guidelines, physicians can expect to provide patients with an mOS of 6.8 months.The TAGS study was funded by Taiho Oncology and Taiho Pharmaceutical (no grant number). This exploratory subgroup analysis was funded by Servier (no grant number)

Definitions and treatment of oligometastatic oesophagogastric cancer according to multidisciplinary tumour boards in Europe

Oesophageal neoplasm; Oligometastasis; RadiosurgeryNeoplàsia esofàgica; Oligometàstasi; RadiocirurgiaNeoplasia esofágica; Oligometástasis; RadiocirugíaBackground Consensus about the definition and treatment of oligometastatic oesophagogastric cancer is lacking. Objective To assess the definition and treatment of oligometastatic oesophagogastric cancer across multidisciplinary tumour boards (MDTs) in Europe. Material and methods European expert centers (n = 49) were requested to discuss 15 real-life cases in their MDT with at least a medical, surgical, and radiation oncologist present. The cases varied in terms of location and number of metastases, histology, timing of detection (i.e. synchronous versus metachronous), primary tumour treatment status, and response to systemic therapy. The primary outcome was the agreement in the definition of oligometastatic disease at diagnosis and after systemic therapy. The secondary outcome was the agreement in treatment strategies. Treatment strategies for oligometastatic disease were categorised into upfront local treatment (i.e. metastasectomy or stereotactic radiotherapy), systemic therapy followed by restaging to consider local treatment or systemic therapy alone. The agreement across MDTs was scored to be either absent/poor (<50%), fair (50%–75%), or consensus (≥75%). Results A total of 47 MDTs across 16 countries fully discussed the cases (96%). Oligometastatic disease was considered in patients with 1–2 metastases in either the liver, lung, retroperitoneal lymph nodes, adrenal gland, soft tissue or bone (consensus). At follow-up, oligometastatic disease was considered after a median of 18 weeks of systemic therapy when no progression or progression in size only of the oligometastatic lesion(s) was seen (consensus). If at restaging after a median of 18 weeks of systemic therapy the number of lesions progressed, this was not considered as oligometastatic disease (fair agreement). There was no consensus on treatment strategies for oligometastatic disease. Conclusion A broad consensus on definitions of oligometastatic oesophagogastric cancer was found among MDTs of oesophagogastric cancer expert centres in Europe. However, high practice variability in treatment strategies exists

Definition, diagnosis and treatment of oligometastatic oesophagogastric cancer: A Delphi consensus study in Europe

Gastric cancer; Metastasectomy; OligometastasisCáncer gástrico; Metastasectomía; OligometástasisCàncer gàstric; Metastasectomia; OligometàstasiBackground Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. Methods In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%–75%) or consensus (≥75%). Results A total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with metastatic oesophagogastric cancer limited to 1 organ with ≤3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without progression at restaging after systemic therapy (consensus). For patients with synchronous or metachronous OMD with a disease-free interval ≤2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). Conclusion The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials