Few studies have evaluated the impact of risk factors such as performance status (PS) and comorbidities on overall survival (OS) in patients with metastatic pancreatic cancer (mPC). We investigated ...the influence of comorbidity, PS and age on nab-paclitaxel and gemcitabine (NabGem) effectiveness profile in naive patients with mPC. 153 patients with mPC treated with NabGem upfront was divided in three groups (score 0 to 3) based on the absence or the presence of one or more risk factors among: age ≥ 70 years, PS 1 and comorbidities and the clinical outcomes was compared. Fifty-five patients were elderly (≥ 70 years), 80 patients have PS 1, whereas the other have PS 0. Patients with no risk factors (score 0) had an overall survival higher (20 months) than patients with one or two risk factors (score 1-2) (OS 11 months) and with three risk factors (score 3) (OS 8 months) (p < 0.01). The difference in OS was also statistically significant in patients without comorbidities (OS 15 months) compared to those with ≥ 1 comorbidity (OS 10 months) (p < 0.001). NabGem chemotherapy represent an effective treatment in naive patients. Age, PS, and comorbidities were prognostic factors in patients with metastatic pancreatic cancer.
Gastric cancer is one of the most common malignancy worldwide. In unresectable or metastatic disease, the prognosis is poor and in generally less than a year. HER2 expression remains an important ...biomarker to lead the addition of trastuzumab to first-line systemic chemotherapy in unresectable or metastatic gastroesophageal adenocarcinoma. To date, a major issue is represented by resistance to trastuzumab developed during treatment, considering the not improved outcomes in this molecular subtype of gastroesophageal adenocarcinoma to other HER2 target strategies. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance to HER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Furthermore, we describe the prognostic value of new non-invasive screening methods, under development novel agents (e.g., HER2 antibody-drug conjugates and bispecific antibodies) and strategies with antitumor activity in early studies.
Mucositis is a common complication of chemotherapy, radiotherapy and targeted agents. It often affects compliance to anticancer therapies as it frequently causes schedule delays, interruptions or ...discontinuations of treatment. Moreover, the economic impact related to the management of mucositis is topical and several estimations of additional hospital costs due to this clinical condition have been recently reported. The ability to determine risk factors for mucositis, to early detect its onset, to assess correctly the degree of this toxicity and to plan its multidisciplinary management are all key elements to guarantee the quality of life of patients and to avoid useless dose reduction or interruption of treatment. The pathogenesis of mucositis is multifactorial and it is classily subdivided into oral and gastrointestinal mucositis according to its anatomic presentation. Treatment and patients' related factors might help in predicting the frequency and the potential degree of symptoms onset. Here we discuss about clinical presentation and pathogenesis of mucositis in relation to different kinds of treatments. Moreover, we focus on therapeutic and prevention strategies, describing past and present management according to international guidelines and the most promising new data about agents potentially able to further improve the treatment of mucositis in the next future.
We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrollment in a ...phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2-positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test (N=256) and clinical validation (N=830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in >50% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2-positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.
Summary Background Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line ...treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. Methods ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov , number NCT01041404. Findings 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18·6 months (IQR 11–25) in the trastuzumab plus chemotherapy group and 17·1 months (9–25) in the chemotherapy alone group. Median overall survival was 13·8 months (95% CI 12–16) in those assigned to trastuzumab plus chemotherapy compared with 11·1 months (10–13) in those assigned to chemotherapy alone (hazard ratio 0·74; 95% CI 0·60–0·91; p=0·0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 67% vs chemotherapy alone, 184 63%), vomiting (147 50% vs 134 46%), and neutropenia (157 53% vs 165 57%). Rates of overall grade 3 or 4 adverse events (201 68% vs 198 68%) and cardiac adverse events (17 6% vs 18 6%) did not differ between groups. Interpretation Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. Funding F Hoffmann-La Roche.
Summary Background Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. ...We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. Methods We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24–87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00917384. Findings 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3–9·9) in patients in the ramucirumab group and 3·8 months (1·7–7·1) in those in the placebo group (hazard ratio HR 0·776, 95% CI 0·603–0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605–0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 16% vs nine 8%), whereas rates of other adverse events were mostly similar between groups (223 94% vs 101 88%). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. Interpretation Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer. Funding ImClone Systems.
Malnutrition and muscle wasting are frequently reported in cancer patients, either linked to the tumor itself or caused by oncologic therapies. Understanding the value of nutritional care during ...cancer treatment remains crucial. In fact, cancer-associated sarcopenia plays a key role in determining higher rates of morbidity, mortality, treatment-induced toxicities, prolonged hospitalizations and reduced adherence to anticancer treatment, worsening quality of life and survival. Planning baseline screening to intercept nutritional troubles earlier, organizing timely reassessments, and providing adequate counselling and dietary support, healthcare professional may positively interfere with this process and improve patients' overall outcomes during the whole disease course. Several screening tools have been proposed for this purpose. Nutritional Risk Screening (NRS), Mini Nutritional Assessment (MNA), Patient Generated Subjective Global Assessment (PG-SGA) are the most common studied. Interestingly, second-level tools including skeletal muscle index (SMI) and bioelectric impedance analysis (BIA) provide a more precise assessment of body composition, even if they are more complex. However, nutritional assessment is not currently used in clinical practice and procedures must be standardized in order to improve the efficacy of standard chemotherapy, targeted agents or even checkpoint inhibitors that is potentially linked with the patients' nutritional status. In the present review, we will discuss about malnutrition and the importance of an early nutritional assessment during chemotherapy and treatment with novel checkpoint inhibitors, in order to prevent treatment-induced toxicities and to improve survival outcomes.
Abstract
Background
Tumors with homologous recombination deficiency (HRD) show high sensitivity to platinum salts and poly(ADP-ribose) polymerase–inhibitors in several malignancies. In colorectal ...cancer (CRC), the role of HRD alterations is mostly unknown.
Methods
Next-generation sequencing, whole transcriptome sequencing, and whole exome sequencing were conducted using CRC samples submitted to a commercial Clinical Laboratory Improvement Amendments certified laboratory. Tumors with pathogenic and/or presumed pathogenic mutations in 33 genes involved in the homologous recombination pathway were considered HRD, the others were homologous recombination proficient (HRP). Furthermore, tumor samples from patients enrolled in the phase III TRIBE2 study comparing upfront FOLFOXIRI+bevacizumab vs FOLFOX+bevacizumab were analyzed with next-generation sequencing. The analyses were separately conducted in microsatellite stable or proficient mismatch repair (MSS/pMMR) and microsatellite instable-high or deficient mismatch repair (MSI-H/dMMR) groups. All statistical tests were 2-sided.
Results
Of 9321 CRC tumors, 1270 (13.6%) and 8051 (86.4%) were HRD and HRP, respectively. HRD tumors were more frequent among MSI-H/dMMR than MSS/pMMR tumors (73.4% vs 9.5%; P < .001; q < 0.001). In MSS/pMMR group, HRD tumors were more frequently tumor mutational burden high (8.1% vs 2.2%; P < .001; q < 0.001) and PD-L1 positive (5.0% vs 2.4%; P < .001; q = 0.001), enriched in all immune cell and fibroblast populations and genomic loss of heterozygosity-high (16.2% vs 9.5%; P = .03). In the TRIBE2 study, patients with MSS/pMMR and HRD tumors (10.7%) showed longer overall survival compared with MSS/pMMR and HRP tumors (40.2 vs 23.8 months; hazard ratio HR = 0.66, 95% confidence interval CI = 0.45 to 0.98; P = .04). Consistent results were reported in the multivariable model (HR = 0.67, 95% CI = 0.45 to 1.02; P = .07). No interaction effect was evident between homologous recombination groups and treatment arm.
Conclusions
HRD tumors are a distinctive subgroup of MSS/pMMR CRCs with specific molecular and prognostic characteristics. The potential efficacy of agents targeting the homologous recombination system and immune checkpoint inhibitors in this subgroup is worthy of clinical investigation.
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