Javier Gallego

Phase II trial of preoperative irinotecan-cisplatin followed by concurrent irinotecan-cisplatin and radiotherapy for resectable locally advanced gastric and esophagogastric junction adenocarcinoma.

PURPOSE To determine in a Phase II trial whether preoperative irinotecan-cisplatin (IC) followed by concurrent IC therapy and radiotherapy (IC/RT) improved outcome in patients with resectable, locally advanced gastric adenocarcinoma (GC) or esophagogastric junction cancer (EGJC). PATIENTS AND METHODS Patients with resectable Stage II-IV, M0 GC or EGJC made up the study population. The primary endpoint was pathologic complete response (pCR). Two courses of IC (irinotecan, 65 mg/m(2); cisplatin, 30 mg/m(2) on Days 1 and 8 every 21 days) were given. Patients without progression then received IC/RT, consisting of daily radiotherapy (45Gy) with concurrent IC (irinotecan, 65 mg/m(2); cisplatin, 30 mg/m(2) on Days 1, 8, 15, and 22). Surgical resection was performed, if feasible, 5-8 weeks after the end of radiotherapy. RESULTS Twenty-three patients were included in the study: 10 with EGJC and 13 with GC. Two patients (9%) achieved pCR. The incidences of Grade 3-4 toxicities were as follows: IC: neutropenia 35% (febrile 13%), anemia 22%, diarrhea 22%, emesis 8%; IC/RT: neutropenia 52% (febrile 5%), asthenia 19%, anemia 9%, emesis 9%, diarrhea 5%, cardiotoxicity 5%. No patients died during IC or IC/RT. R0 resection was achieved in 15 patients (65%). Median survival was 14.5 months, and the actuarial 2-year survival rate was 35%. CONCLUSIONS Preoperative IC followed by IC/RT resulted in moderate response and resection rates with mild toxicity in patients with GC and EGJC.

Preoperative Chemotherapy in Patients With Intermediate-Risk Rectal Adenocarcinoma Selected by High-Resolution Magnetic Resonance Imaging: The GEMCAD 0801 Phase II Multicenter Trial

BACKGROUND The need for preoperative chemoradiation or short-course radiation in all T3 rectal tumors is a controversial issue. A multicenter phase II trial was undertaken to evaluate the efficacy and safety of neoadjuvant capecitabine and oxaliplatin combined with bevacizumab in patients with intermediate-risk rectal adenocarcinoma. METHODS We recruited 46 patients with T3 rectal adenocarcinoma selected by magnetic resonance imaging (MRI) who were candidates for (R0) resection located in the middle third with clear mesorectal fascia and who were selected by pelvic MRI. Patients received four cycles of neoadjuvant capecitabine and oxaliplatin combined with bevacizumab (final cycle without bevacizumab) before total mesorectal excision (TME). In case of progression, preoperative chemoradiation was planned. The primary endpoint was overall response rate (ORR). RESULTS On an intent-to-treat analysis, the ORR was 78% (n = 36; 95% confidence interval [CI]: 63%-89%) and no progression was detected. Pathologic complete response was observed in nine patients (20%; 95% CI: 9-33), and T downstaging was observed in 48%. Forty-four patients proceeded to TME, and all had R0 resection. During preoperative therapy, two deaths occurred as a result of pulmonary embolism and diarrhea, respectively, and one patient died after surgery as a result of peritonitis secondary to an anastomotic leak (AL). A 13% rate of AL was higher than expected. The 24-month disease-free survival rate was 75% (95% CI: 60%-85%), and the 2-year local relapse rate was 2% (95% CI: 0%-11%). CONCLUSION In this selected population, initial chemotherapy results in promising activity, but the observed toxicity does not support further investigation of this specific regimen. Nevertheless, these early results warrant further testing of this strategy in an enriched population and in randomized trials.

Circulating tumour cell analysis as an early marker for relapse in stage II and III colorectal cancer patients: a pilot study.

IntroductionRecent studies have identified both the prognostic and predictive utility of determining the number of circulating tumour cells (CTC) in patients with solid cancers.Material and methodsIn the present pilot study we evaluated the ability of two different methods to isolate CTC in combination with two strategies to enumerate CTC from patients with stages II and III surgically treated colorectal cancer (CRC). First, we used two systems for tumour cell enrichment (differential centrifugation and immunomagnetic beads), combined with two methods to enumerate CTC (real-time PCR and flow cytometry), to determine the most efficient combination. These experiments were performed in a model system using serial dilutions of HT29 tumour cell lines with lymphocytes. Then, CTC analysis using the technical approach selected before was performed in 109 blood samples from 16 stage II and III CRC patients during chemotherapy treatment and follow-up.ResultsImmunomagnetic beads followed by flow cytometry was the most efficient combination (ED=60.53; p=0.5). Two cases out of 16 patients analysed had clinical tumour relapse. In both, we detected a significant increase of CTC five and six months, respectively, before the relapse was clinically evidenced. An increase of CTC was also observed in another case without clinical evidence of relapse. The remaining cases (13) had very few or no detectable CTC and no clinical evidence of relapse (p=0.029).ConclusionsChanges in CTC numbers during follow-up might predict tumour relapse. Further evaluation of CTC prognostic and predictive value in patients with early CRC is warranted.

Nomogram-based prediction of survival in patients with advanced oesophagogastric adenocarcinoma receiving first-line chemotherapy: a multicenter prospective study in the era of trastuzumab

Background:To develop and validate a nomogram and web-based calculator to predict overall survival (OS) in Caucasian-advanced oesophagogastric adenocarcinoma (AOA) patients undergoing first-line combination chemotherapy.Methods:Nine hundred twenty-four AOA patients treated at 28 Spanish teaching hospitals from January 2008 to September 2014 were used as derivation cohort. The result of an adjusted-Cox proportional hazards regression was represented as a nomogram and web-based calculator. The model was validated in 502 prospectively recruited patients treated between October 2014 and December 2016. Harrells c-index was used to evaluate discrimination.Results:The nomogram includes seven predictors associated with OS: HER2-positive tumours treated with trastuzumab, Eastern Cooperative Oncology Group performance status, number of metastatic sites, bone metastases, ascites, histological grade, and neutrophil-to-lymphocyte ratio. Median OS was 5.8 (95% confidence interval (CI), 4.5–6.6), 9.4 (95% CI, 8.5–10.6), and 14 months (95% CI, 11.8–16) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the derivation set and 4.6 (95% CI, 3.3–8.1), 12.7 (95% CI, 11.3–14.3), and 18.3 months (95% CI, 14.6–24.2) for high-, intermediate-, and low-risk groups, respectively (P<0.001), in the validation set. The nomogram is well-calibrated and reveals acceptable discriminatory capacity, with optimism-corrected c-indices of 0.618 (95% CI, 0.591–0.631) and 0.673 (95% CI, 0.636–0.709) in derivation and validation groups, respectively. The AGAMENON nomogram outperformed the Royal Marsden Hospital (c-index=0.583; P=0.00046) and Japan Clinical Oncology Group prognostic indices (c-index=0.611; P=0.03351).Conclusions:We developed and validated a straightforward model to predict survival in Caucasian AOA patients initiating first-line polychemotherapy. This model can contribute to inform clinical decision-making and optimise clinical trial design.

Consensus guidelines for diagnosis, treatment and follow-up of patients with pancreatic cancer in Spain.

The management of patients with pancreatic cancer has advanced over the last few years. We convey a multidisciplinary group of experts in an attempt to stablish practical guidelines for the diagnoses, staging and management of these patients. This paper summarizes the main conclusions of the working group. Patients with suspected pancreatic ductal adenocarcinoma should be rapidly evaluated and referred to high-volume centers. Multidisciplinary supervision is critical for proper diagnoses, staging and to frame a treatment plan. Surgical resection together with chemotherapy offers the highest chance for cure in early stage disease. Patients with advanced disease should be classified in treatment groups to guide systemic treatment. New chemotherapeutic regimens have resulted in improved survival. Symptomatic management is critical in this disease. Enrollment in a clinical trial is, in general, recommended.

Current controversies in the management of metastatic colorectal cancer

The factors affecting the decisions for the treatment for patients with metastatic colorectal cancer (mCRC) are related to the patient, the tumor, and the treatment itself. Both cetuximab and panitumumab are anti-EGFR monoclonal antibody options for patients with RAS wild-type tumors. Several trials comparing these agents with bevacizumab are analyzed in this paper. The liver is the most common site of metastases in patients with CRC, and perioperative chemotherapy has been shown to yield benefits in this setting. In the second-line treatment for mCRC, maintenance with bevacizumab after progression following first-line treatment is convenient in some groups of patients with mCRC. Also, aflibercept has demonstrated benefits in response rate, progression-free survival, and overall survival in second-line treatment, whereas regorafenib provides benefits to patients progressing on all standard therapies. Several novel therapeutic options for patients with mCRC are under development, and these are discussed.

Biomarkers in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is currently the third most frequent form of malignancy. The role of biomarkers in the diagnostic and therapeutic strategy of cancer is constantly expanding. Translational research is already changing paradigms in tumours encompassing from early diagnosis to precision medicine in advanced disease. Nomenclature for molecular subtypes of tumours is gradually gaining acceptance and there are growing expectations it will further go from the bench to the bedside. However, the clinical relevance of biomarkers in PDAC is still far behind the relevance of biomarkers in other solid tumours. This article is part of a wider project (GALLgo) involving over forty specialists devoted to the multidisciplinary management of PDAC which concluded in recommendations based on scientific evidence. The aim of the present article is to review the diagnostic, prognostic and predictive biomarkers, either in localised or advanced disease, which have been lately subjected to study and analysis and others currently available for PDAC in order to give strength-graded recommendations linked to quality of evidence that can be used as guidelines in routine clinical practice.

Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: real-world data from the AGAMENON National Cancer Registry

Background:The choice of chemotherapy in HER2-negative gastric cancer is based on centre’s preferences and adverse effects profile. No schedule is currently accepted as standard, nor are there any factors to predict response, other than HER2 status. We seek to evaluate whether Lauren type influences the efficacy of various chemotherapies and on patient overall survival (OS).Methods:We have conducted a multicenter study in 31 hospitals. The eligibility criteria include diagnosis of stomach or gastroesophageal junction adenocarcinoma, HER2 negativity, and chemotherapy containing 2–3 drugs. Cox proportional hazards regression adjusted for confounding factors, with tests of ‘treatment-by-histology’ interaction, was used to estimate treatment effect.Results:Our registry contains 1303 tumours analysable for OS end points and 730 evaluable for overall response rate (ORR). A decrease in ORR was detected in the presence of a diffuse component: odds ratio 0.719 (95% confidence interval (CI), 0.525–0.987), P=0.039. Anthracycline- or docetaxel-containing schedules increased ORR only in the intestinal type. The diffuse type displayed increased mortality with hazard ratio (HR) of 1.201 (95% CI, 1.054–1.368), P=0.0056. Patients receiving chemotherapy with docetaxel exhibited increased OS limited to the intestinal type: HR 0.65 (95% CI, 0.49–0.87), P=0.024, with no increment in OS for the subset having a diffuse component. With respect to progression-free survival (PFS), a significant interaction was seen in the effect of docetaxel-containing schedules, with better PFS limited to the intestinal type subgroup, in the comparison against any other schedule: HR 0.65 (95% CI, 0.50–0.85), P=0.015, and against anthracycline-based regimens: HR 0.64 (95% CI, 0.46–0.88), P=0.046.Conclusions:As a conclusion, in this registry, Lauren classification tumour subtypes predicted survival and responded differently to chemotherapy. Future clinical trials should stratify effect estimations based on histology.

Updating controversies on the multidisciplinary management of gastric cancer.

The rates of relapse and death remain high in gastric cancer patients, especially in advanced stages. Local relapses in the tumour bed and regional lymph nodes, peritoneal spread as abdominal carcinomatosis, and distant metastasis are common mechanisms of failure after a R0 resection. To overcome this, a multidisciplinary approach has been prompted. In recent years, multidisciplinary treatment has been strengthened by some randomised controlled trials and it is now considered the standard by most groups, although the improvement in long-term survival rates achieved is still limited. This new therapeutic approach in gastric cancer is rapidly evolving and has led to a series of controversies on the best strategy to follow. Some of these controversies are discussed in this paper.

Author Correction: Exploratory analyses assessing the impact of early tumour shrinkage and depth of response on survival outcomes in patients with RAS wild-type metastatic colorectal cancer receiving treatment in three randomised panitumumab trials

The authors would like to include the following changes in the published article.