Influence of proton pump inhibitors on the pathological response of rectal cancer: a multicentre study.

Background: The standard neoadjuvant therapy for rectal cancer involves fluoropyrimidines and radiotherapy and, most recently, total neoadjuvant therapy (TNT). A drug-drug interaction between fluoropyrimidines and proton-pump inhibitors (PPI) was suggested, with a negative impact on oncological outcomes in breast, colon and gastric cancers. Little is known about such an effect on rectal tumours. We aimed to evaluate the impact of PPI utilisation on the pathological response after chemoradiation for rectal cancer. Materials and methods: Retrospective multicentre study of rectal cancer patients treated with neoadjuvant chemoradiotherapy with capecitabine (cohort 1) or 5-fluororuracil (5-FU) (cohort 2); TNT with oxaliplatin-based regimens was allowed. The pathological response was considered a complete (ypCR) or complete + partial (ypCR + ypPR) according to American Joint Committee on Cancer. PPI use was considered at any time during the neoadjuvant period if concomitant to fluoropyrimidines. Results: From January 2007 to November 2020, 251 patients received capecitabine and 196 5-FU. The rates of PPI use in cohorts 1 and 2 were 20.3% and 26.5%, respectively. TNT was offered to 18.3% in cohort 1. PPI use did not influence ypCR in cohort 1 (yes versus no: 29.4% versus 19.5%; p = 0.13) or 2 (yes versus no: 25.0% versus 26.4%; p = 1.0). Similar ypCR + ypPR were observed in both cohorts 1 (76.5% versus 72.0%; p = 0.60) and 2 (86.5% versus 76.4%; p = 0.16). PPI use was not associated with pathological response in multivariable analysis. PPI users experienced more grade 3 or higher diarrhoea and infections. Conclusion: PPI concomitant to capecitabine/5-FU chemoradiation did not influence the pathological response in rectal cancer but was associated with more treatment-related adverse events.

Ibero-American Consensus Review and Incorporation of New Biomarkers for Clinical Practice in Colorectal Cancer.

Advances in genomic technologies have significantly improved the management of colorectal cancer (CRC). Several biomarkers have been identified in CRC that enable personalization in the use of biologic agents that have shown to enhance the clinical outcomes of patients. However, technologies used for their determination generate massive amounts of information that can be difficult for the clinician to interpret and use adequately. Through several discussion meetings, a group of oncology experts from Spain and several Latin American countries reviewed the latest literature to provide practical recommendations on the determination of biomarkers in CRC based on their clinical experience. The article also describes the importance of looking for additional prognostic biomarkers and the use of histopathology to establish an adequate molecular classification. Present and future of immunotherapy biomarkers in CRC patients are also discussed, together with several techniques for marker determination, including liquid biopsy, next-generation sequencing (NGS), polymerase chain reaction (PCR), and fecal immunohistochemical tests. Finally, the role of Molecular Tumor Boards in the diagnosis and treatment of CRC is described. All of this information will allow us to highlight the importance of biomarker determination in CRC.

Short-course radiotherapy for rectal cancer: real-world evidence in Argentina.

Background: Short-course radiotherapy (SCRT) of 25 Gy in five daily fractions is a recommended strategy in the neoadjuvant setting for resectable locally advanced rectal cancer (LARC), as well as in cases of metastatic disease for local control. There is scarce information regarding the use of SCRT for patients who have received nonoperative management. Objectives: To describe the characteristics of patients who received treatment with SCRT for LARC and metastatic rectal cancer, toxicity, and the approach after radiation treatment. Methods: This is a retrospective analysis of all patients who underwent SCRT for rectal cancer at the Alexander Fleming Institute from March 2014 to June 2022. Results: In total, 44 patients were treated with SCRT. The majority were male (29, 66%), with a median age of 59 years (interquartile range 46-73). Most patients had stage IV disease (26, 59.1%), followed by LARC (18, 40.9%). Most lesions were located in the middle rectum (30, 68%). The majority of LARC patients underwent SCRT followed by consolidation chemotherapy (ChT) (16/18, 89%), while most patients with metastatic disease underwent SCRT followed by consolidation ChT (14/26, 53.8%). A clinical complete response (cCR) was documented in 8/44, 18.2% of patients. Most patients with LARC and cCR were managed by a watch and wait approach (5/18, 27.7%). Local recurrence was observed in LARC cases (2/18, 11.1%). Patients who underwent SCRT following consolidation ChT were more likely to have adverse events (AEs) than those undergoing induction ChT following SCRT (11/30, 36.7% versus 3/12, 25%, p = 0.02). Conclusion: In a subgroup of patients diagnosed with LARC and treated with SCRT followed by ChT, surgical treatment could be omitted after they achieved a cCR. Local recurrence was similar to that reported in a previous study. SCRT is a reasonable option for local disease control in stage IV disease, yielding low toxicity rates. Therefore, decisions must be made by a multidisciplinary team. Prospective studies are necessary to reach further conclusions.

Implementation of a virtual multicenter gastrointestinal tumor board to reduce cancer disparities in Argentina.

Given the increasing complexity of cancer care, multidisciplinary tumor boards have become essential in daily clinical oncology practice. The Project Extension for Community Healthcare Outcomes (ECHO) initiative developed an innovative telementoring model using a "hub and spoke" design consisting of a team of experts (hub) that offers a full service to multiple participants (the spokes) during regularly scheduled sessions discussing patients' clinical cases. The Alexander Fleming Cancer Institute in Buenos Aires was the first hub in Latin America to implement Project ECHO for gastrointestinal tumors. In our 3-year experience, 80 patients from 37 centers were evaluated within Project ECHO and a range of three to five cases were discussed in each meeting. From our perspective, the impact of this novel approach was a remarkable strategy to reduce care disparities by equalizing access to high-quality medical knowledge in a multidisciplinary environment for medical discussions. Additionally, it was shown to have a cost-effective impact directly on the patients and the local health system, since relevant costs were saved after unnecessary treatments, studies and travel expenses were avoided.

Implementation of a molecular tumour board in LATAM: the impact on treatment decisions for patients evaluated at Instituto Alexander Fleming, Argentina.

BACKGROUND: The role of the molecular tumour board (MTB) is to recommend personalised therapy for patients with cancer beyond standard-of-care treatment. A comprehensive molecular analysis of the tumour in a molecular pathology laboratory is important for all targeted therapies approaches. Here we report the 1-year experience of the Instituto Alexander Fleming Molecular Tumour Board. PATIENTS AND METHODS: The MTB of the Instituto Alexander Fleming was launched in December 2019 in a monthly meeting. In each interactive monthly session, five cases were presented and discussed by the members. These cases were referred by the treating oncologists. The MTB recommendations were sent to each physician individually, and to the rest of the meeting participants. This was discussed with the patients/families by the treating oncologist. The final decision to choose therapy was left to the treating physicians. Of the 32 patients presented at MTB, 28 (87.5%) had potentially actionable alterations and only 4 (12.5%) had no actionable mutation. Six (19%) patients received a local regulatory agency approved drug recommendation, nine (28%) patients received an off-label approval treatment recommendation and three (9%) patients did not receive the treatment due to access and reimbursement of the drug. CONCLUSION: In most of the cases evaluated, the MTB was able to provide treatment recommendations based on targetable genetic alterations. Molecular-guided extended personalised patient care is effective for a small but clinically significant proportion of patients in challenging clinical situations. We believe that the implementation of a MTB is feasible in the Latin America (LATAM) region.

Opportunistic and Serious Infections in Patients with Neuroendocrine Tumors Treated with Everolimus: A Multicenter Study of Real-World Patients.

INTRODUCTION: The incidence of infections is poorly studied in patients with neuroendocrine tumors (NET) treated with everolimus outside of clinical trials. We aimed to evaluate the frequency of and risk factors for opportunistic infections (Opl) or any serious infection in eligible patients. METHODS: This was a retrospective multicenter study of a Latin American cohort of consecutive patients with advanced NET treated with everolimus. Duration of everolimus, comorbidities, Charlson comorbidity score, type of prior treatment, institution, and concurrent immunosuppressive conditions were tested for possible associations with serious (grade 3-5) infections in univariate and multivariable logistic regression models. RESULTS: One hundred eleven patients from 5 centers were included. The median duration of everolimus was 8.9 months. After a median follow-up of 32.9 months, 34 patients (30.6%; 95% CI 22.2-40.1) experienced infections of any grade, with 24 (21.6%; 95% CI 14.8-30.4) having a serious infection and 7 (6.3%; 95% CI 2.6-12.6) having at least 1 OpI (Candida sp., Toxoplasma gondi, Pneumocystis sp., Herpes sp., and Cryptococcus sp.). Four patients (3.6%) died from infections, but only 2 deaths (1.8%) were deemed to be related to everolimus. The multivariable analysis identified everolimus duration (every 6-month increase; OR = 1.28; 95% CI 1.02-1.60; p = 0.03) as an independent risk factor for serious infection. CONCLUSION: Infections are more frequent in NET patients using everolimus than previously reported in clinical trials. Patients on everolimus should be closely monitored for infections, especially those receiving it for several months.

Retrospective analysis of patients with locally advanced or metastatic gastric cancer in Argentina.

AIM: To assess patient and disease characteristics, treatment patterns and associated costs in patients with locally advanced or metastatic gastric cancer in Argentina, in the public and private sectors. METHODS: A historic cohort of patients who had received first-line chemotherapy treatment (platinum analog and/or a fluoropyrimidine) and were followed-up for at least three months after the last administration of a first-line cytotoxic agent were eligible. Case-report forms were prepared based on medical records from four Argentinian hospitals. Estimates of treatment costs were also calculated using the unit costs of the participating hospitals. RESULTS: Of 101 patients, more than three quarters (79.2%) were male, 41.6% were diagnosed with metastatic stage IV disease (mean age, 57.7years), and 27.7 % had a smoking history. Before locally advanced or metastatic gastric cancer diagnosis, 42.4% of the patients had received total gastrectomy. Ninety-seven percent of the patients received a doublet or triplet therapy, of which epirubicin in combination with oxaliplatin and capecitabine was the most common treatment (38%), followed by capecitabine plus oxaliplatin (29%). Around 36% of the patients responded to first-line treatment (complete and partial response). Out of the 76.2% of the patients who followed a second-line treatment, 37.7% were still administered a platinum analog and/or fluoropyrimidine. During the reported follow-up period, 50% of the patients progressed, and 32.8% had stable disease. The best supportive care consisted mostly of outpatient visits after last-line therapy (16.8%), palliative radiotherapy (16.8%), and surgery (30.7%). We observed significant differences between public and private hospital costs. CONCLUSIONS: Understanding treatment patterns in patients with locally advanced or metastatic gastric cancer may help address unmet medical needs for better patient management and improvement of their clinical outcome in Argentina.

OBJETIVO: Describir las características clínicas, los patrones de tratamiento y los costos asociados en pacientes con cáncer gástrico localmente avanzado o metastásico en Argentina, en los sectores público y privado. MÉTODOS: Una cohorte histórica de pacientes que recibieron tratamiento de quimioterapia de primera línea (análogo de platino y/o una fluoropirimidina) y fueron seguidos durante al menos tres meses después de la última administración de un agente citotóxico de primera línea fueron elegibles. Se extrajeron los datos a través de un cuestionario estructurado a partir de los registros médicos de cuatro hospitales argentinos. Las estimaciones de los costos de tratamiento también se calcularon utilizando los costos unitarios de los hospitales participantes. RESULTADOS: Entre los 101 pacientes, más de tres cuartas partes (79,2%) eran hombres, 41,6% fueron diagnosticados con enfermedad metastásica en estadio IV, la edad media fue de 57,7 años y el 27,7% tenían antecedentes de tabaquismo. Antes del diagnóstico de cáncer gástrico metastásico, el 42,4% de los pacientes habían recibido gastrectomía total. El 97% de los pacientes recibió una terapia doble o triplete, de los cuales el tratamiento más frecuente fue la epirubicina en combinación con oxaliplatino y capecitabina (38%), seguida de capecitabina + oxaliplatino (29%). Alrededor del 36% de los pacientes respondieron al tratamiento de primera línea (respuesta completa y parcial). Del 76,2% de los pacientes que siguieron un tratamiento de segunda línea, al 37,7% todavía se les administró un análogo de platino y/o fluoropirimidina. Durante el período de seguimiento, el 50% de los pacientes progresó y el 32,8% tenía enfermedad estable. La terapia de apoyo consistió principalmente en visitas ambulatorias después de la última línea de quimioterapia (16,8%), radioterapia paliativa (16,8%) y cirugía (30,7%). Se observaron diferencias significativas entre los costos de los hospitales públicos y privado. CONCLUSIONES: Comprender los patrones de tratamiento en pacientes con cáncer gástrico localmente avanzado o metastásico puede ayudar a abordar las necesidades médicas no satisfechas para un mejor manejo del paciente y la mejora de sus resultados clínicos en Argentina.

Phase II Study of Adjuvant Immunotherapy with the CSF-470 Vaccine Plus Bacillus Calmette-Guerin Plus Recombinant Human Granulocyte Macrophage-Colony Stimulating Factor vs Medium-Dose Interferon Alpha 2B in Stages IIB, IIC, and III Cutaneous Melanoma Patients: A Single Institution, Randomized Study.

The irradiated, allogeneic, cellular CSF-470 vaccine plus Bacillus Calmette-Guerin (BCG) and recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) is being tested against medium-dose IFN-α2b in stages IIB-III cutaneous melanoma (CM) patients (pts) after surgery in an open, randomized, Phase II/III study. We present the results of the Phase II part of the ongoing CASVAC-0401 study (ClinicalTrials.gov: NCT01729663). Thirty-one pts were randomized to the CSF-470 vaccine (n = 20) or to the IFN-α2b arm (n = 11). During the 2-year treatment, immunized pts should receive 13 vaccinations. On day 1 of each visit, 1.6 × 107 irradiated CSF-470 cells plus 106 colony-forming units BCG plus 100 µg rhGM-CSF were administered intradermally, followed on days 2-4 by 100 µg rhGM-CSF. IFN-α2b pts should receive 10 million units (MU)/day/5 days a week for 4 weeks; then 5 MU thrice weekly for 23 months. Toxicity and quality of life (QOL) were evaluated at each visit. With a mean and a maximum follow-up of 39.4 and 83 months, respectively, a significant benefit in the distant metastasis-free survival (DMFS) for CSF-470 was observed (p = 0.022). Immune monitoring showed an increase in antitumoral cellular and humoral response in vaccinated pts. CSF-470 was well tolerated; 20/20 pts presented grades 1-2 dermic reactions at the vaccination site; 3/20 pts presented grade 3 allergic reactions. Other adverse events (AEs) were grade 1. Pts in the IFN-α2b arm presented grades 2-3 hematological (7/11), hepatic (2/11), and cardiac (1/11) toxicity; AEs in 9/11 pts forced treatment interruptions. QOL was significantly superior in the vaccine arm (p < 0.0001). Our results suggest that CSF-470 vaccine plus BCG plus GM-CSF can significantly prolong, with lower toxicity, the DMFS of high-risk CM pts with respect to medium-dose IFN-α2b. The continuation of a Phase III part of the CASVAC-0401 study is encouraged.

Recomendaciones sobre el manejo del cáncer de páncreas tipo adenocarcinoma en Latinoamérica: Reunión del Consenso del Simposio Latinoamericano de Gastroenterología Oncológica (SLAGO) y de la Asociación Ibero Latinoamericana de Terapia Radiante (ALATRO), Viña del Mar, Chile 2015 / Recommendations for the management of pancreatic cancer type adenocarcinoma: A consensus statement reached during the 2015 Latin American Symposium on Gastroenterological Oncology

Pancreatic cancer is a malignancy of great impact in developed countries and is having an increasing impact in Latin America. Incidence and mortality rates are similar for this cancer. This is an important reason to offer to the patients the best treatments available. During the Latin American Symposium of Gastroenterology Oncology (SLAGO) held in Viña del Mar, Chile, in April 2015, a multidisciplinary group of specialists in the field met to discuss about this disease. The main conclusions of this meeting, where practitioners from most of Latin American countries participated, are listed in this consensus that seek to serve as a guide for better decision making for patients with pancreatic cancer in Latin America.

Non-surgical management of rectal cancer. Series of 68 cases, long follow up in two leading centres in Argentina.

BACKGROUND: The non-surgical management in a selected group of rectal cancer patients has shown promising results with adequate follow up. AIMS: describing the results of the non-surgical management in patients with complete clinical response, with a close follow up. METHODS: Between 2006 and 2015, patients with rectal cancer, stages I-III, without metastasis, treated with neoadjuvant CRT/CT, who had clinical complete response were included. CCR was defined through digital palpation, endoscopy-based criteria and MRI. Follow up was set according to institutional guidelines. RESULTS: 68 patients were included. Initial stage was assessed with MRI in 55/68 pts and EUS 11/68. Considering the recurrence risk factors 57.6% (29/68) were T2-3ab N0, 3.3% (2/68) were T4N0, 29% (20/68) were T3-4 N1-2, with 39.7% with positive MRC. Mean distance to the anal margin was 3cm. Chemoradiation included radiotherapy at 50.4cGy, and concurrent capecitabine. In 22% a fluoropirimidine and oxaliplatin-based schema was used as induction therapy. Median follow up was 37.5 months and response assessment time 9 weeks (5-19). Eleven patients recurred, 6 endoluminally, 3 developed mesorectal recurrence, and two distant failure. Five years DFS and OS were 76.3% and 93.8%. CONCLUSIONS: conservative management was feasible with close follow up in leading cancer centres. In this series, DFS and OS were comparable to the data already reported in the literature.

[Recommendations for the management of pancreatic cancer type adenocarcinoma: A consensus statement reached during the 2015 Latin American Symposium on Gastroenterological Oncology]. / Recomendaciones sobre el manejo del cáncer de páncreas tipo adenocarcinoma en Latinoamérica: Reunión del Consenso del Simposio Latinoamericano de Gastroenterología Oncológica (SLAGO) y de la Asociación Ibero Latinoamericana de Terapia Radiante (ALATRO), Viña del Mar, Chile 2015.

Pancreatic cancer is a malignancy of great impact in developed countries and is having an increasing impact in Latin America. Incidence and mortality rates are similar for this cancer. This is an important reason to offer to the patients the best treatments available. During the Latin American Symposium of Gastroenterology Oncology (SLAGO) held in Viña del Mar, Chile, in April 2015, a multidisciplinary group of specialists in the field met to discuss about this disease. The main conclusions of this meeting, where practitioners from most of Latin American countries participated, are listed in this consensus that seek to serve as a guide for better decision making for patients with pancreatic cancer in Latin America.

Observational study of patients with gastroenteropancreatic and bronchial neuroendocrine tumors in Argentina: Results from the large database of a multidisciplinary group clinical multicenter study.

Neuroendocrine tumors (NET) include a spectrum of malignancies arising from neuroendocrine cells throughout the body. The objective of this clinical investigation of retrospectively and prospectively collected data was to describe the prevalence, demographic data, clinical symptoms and methods of diagnosis of NET and the treatment and long-term follow-up of patients with NET. Data were provided by the participating centers and assessed for consistency by internal reviewers. All the cases were centrally evaluated (when necessary) by the pathologists in our group. The tissue samples were reviewed by hematoxylin and eosin and immunohistochemical staining techniques to confirm the diagnosis of NET. In total, 532 cases were documented: 461 gastroenteropancreatic-NET (GEP-NET) and 71 bronchial NET (BNET). All the tumors were immunohistochemically defined according to the World Health Organization (WHO) and European Neuroendocrine Tumor Society criteria. The most common initial symptoms in GEP-NET were abdominal pain, diarrhea, bowel obstruction, flushing, gastrointestinal bleeding and weight loss. The most common tumor types were carcinoid (58.0%), non-functional pancreatic tumor (23.0%), metastatic NET of unknown primary (16.0%) and functional pancreatic tumor (3.0%). Of the BNET, 89.0% were typical and 11.0% atypical carcinoids. Of the patients with GEP-NET, 59.2% had distant metastasis at diagnosis. The locations of the primary tumors in GEP-NET were the small bowel (26.9%), pancreas (25.2%), colon-rectum (12.4%), appendix (7.6%), stomach (6.9%), esophagus (2.8%), duodenum (2.0%) and unknown primary (16.3%). The histological subtypes based on the WHO classification were well-differentiated NET (20.1%), well-differentiated neuroendocrine carcinomas (66.5%) and poorly differentiated neuroendocrine carcinomas (10.3%). Overall, 67.3% of the patients underwent surgery, 41.2% with curative intent and 26.1% for palliative purposes. The 5-year survival rates were 65.1% (95% confidence interval, 58.0-71.4%) in GEP-NET and 100.0% in typical carcinoid of the lung. This observational, non-interventional, longitudinal study aimed to accumulate relevant information regarding the epidemiology, clinical presentation and current practices in the treatment of NET patients in Argentina, providing insight into regional differences and patterns of care in this heterogeneous disease.

Chromogranin A as a biochemical marker for the management of neuroendocrine tumors: a multicenter study developed in Argentina.

Elevated circulating levels of chromogranin A (CgA) are found in the neuroendocrine tumors (NETs), but diagnostic usefulness of this marker is still debatable. To assess the role of CgA for the identification and follow up of gastroenteropancreatic neuroendocrine tumors (GEP-NET), a multicenter prospective longitudinal study has been carried out in Argentina. CgA was measured by RIA in 119 histologically proven GEP-NET patients and in 39 healthy controls. A cutoff value of 2.8 nmol/L was established from a receiver-operating characteristic (ROC) curve, as discriminating between controls and patients with active disease (specificity 100% and sensitivity 92.3%). CgA levels were higher in functioning than in no functioning tumors (median 55 nmol/L vs 5 nmol/L, p < 0.05). Metastases were present in 83 patients and their CgA levels were significantly higher than levels in the 36 patients without metastases (median 44 nmol/L vs 64 nmol/L, p < 0.0001). CgA levels are strongly correlated with tumor metastatic spread. Sensitivity differed between patients with localized disease (median 6 nmol/L), extensive disease (median 22 nmol/L) and very extensive disease (median 44 nmol/L) (p < 0.001). In conclusion, due to its high sensitivity and specificity, CgA is useful in a newly discovered GEP-NET especially when no abnormal hormone secretion can be demonstrated. CgA levels were significantly higher in functioning tumors than in non-functioning tumors and increased with metastatic spread. If serial evaluation of CgA levels is sufficient for the detection of tumor growth changes remains to be prospectively demonstrated.