Platinum sensitivity in patients with IDH1/2 mutated vs wild-type intrahepatic cholangiocarcinoma: A propensity score-based study.

Isocitrate dehydrogenase (IDH)1/2 mutations are the most frequent druggable alterations in intrahepatic cholangiocarcinoma (iCCA), reported in ~20% of cases. Preclinical evidence indicates that these mutations are associated with homologous recombination deficiency (HRD), which could be exploited as a target for platinum chemotherapy (ChT) and PARP inhibitors. However, the role of IDH1/2 mutations as surrogate biomarkers for platinum efficacy is unknown. We conducted a multicenter, propensity score-matched analysis to investigate the impact of IDH1/2 mutations on progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) in patients with iCCA treated with platinum-based ChT. An exploratory comparison of complex HRD estimates between IDH1/2 mutated and wild-type tumors from TCGA was also performed. A total of 120 cases were matched in a 1:1 ratio (60 IDH1/2 mutant and 60 wild-type). No differences were observed for platinum-based PFS (7.7 vs 7.3 months, P = .970), DCR (66.1% vs 74.1%, P = .361) and ORR (27.8% vs 25.0%, P = .741). IDH1/2 mutations showed mutual exclusivity with genomic alterations in ATM, BRCA2, MST1R, NF1, FGFR2 and CDKN2A/B losses, respectively, with no clear survival and response differences. Among TCGA tumors, IDH1/2 mutated CCA did not show higher HRD compared to wild-type cases. IDH1/2 mutations are not associated with increased sensitivity to platinum-based ChT in iCCA patients. Deeper genomic sequencing is needed to elucidate the HRD phenotype in IDH1/2 mutant iCCA and exploit its therapeutic vulnerabilities.

Impressive response to denosumab in a patient with bone metastatic adenocarcinoma of the stomach after 2 years of zoledronic acid.

Bone is a common site for tumor spread in patients with solid tumors. So far bisphosphonates have been the main pharmacological treatment option for patients with bone metastases. We present a case of bone metastatic gastric cancer treated with zoledronic acid at first and later with denosumab. After 1 year of denosumab treatment, the 18F-fluorodeoxyglucose (18F-FDG)-PET/computed tomography scan reassessment documented a metabolic complete response, even in the absence of specific antiblastic treatment. Whether denosumab can be used directly after pretreatment with bisphosphonates has yet to be addressed.

Clinical outcome and safety profile of metastatic pancreatic cancer patients treated with more than six cycles of nab-paclitaxel plus gemcitabine.

The phase III MPACT trial demonstrated the superiority of gemcitabine plus nab-paclitaxel (NABGEM) versus gemcitabine alone in previously untreated patients with metastatic pancreatic cancer (mPC). The aim of this study was to evaluate the responses in terms of efficacy and safety in patients treated with more than 6 cycles of chemotherapy. From January 2015 to December 2018, patients with mPC receiving first-line treatment with NABGEM were included in a multicentre retrospective observational study. Exploratory analyses of efficacy and safety were performed. The cohort included 153 patients with performance status of 1. The median overall survival and progression-free survival were 20 months (hazard ratio [HR] 0.28, 95% confidence interval [CI]: 0.17-0.44) and 10 months (HR 0.24 95% CI: 0.16-0.38) respectively, in patients who received >6 cycles compared to 9 and 5 months in those treated with ≤6 cycles (p < 0.001). The disease control rate was 100% versus 56% in patients receiving >6 and ≤6 cycles, respectively. No progression of disease was recorded in patients who received >6 cycles. Grade 1 neuropathy and grade 3 neutropenia were more frequent in patients treated with >6 cycles compared to patients receiving ≤6 cycles (p = 0.01; p = 0.03, respectively). Dose reduction was necessary for 70.1% and 53.4% of patients treated with >6 or ≤6 cycles, whereas treatment interruption occurred in 37.1% and 21.6%, respectively. Our results confirmed the efficacy and safety of NABGEM in untreated mPC. In particular, we highlighted significant clinical efficacy in patients who received >6 cycles of chemotherapy compared to those who received ≤6 cycles, with manageable toxicity profile.

Pattern of recurrence and overall survival in esophagogastric cancer after perioperative FLOT and clinical outcomes in MSI-H population: the PROSECCO Study.

BACKGROUND: FLOT regimen is the standard perioperative treatment in Western countries for patients with locally advanced gastric (GC) or gastroesophageal junction cancer (GEJC). High microsatellite instability (MSI-H) and Mismatch Repair deficient (dMMR) demonstrated a favorable prognostic role and a concomitant negative predictive impact on the benefit of perioperative 5-fluorouracil-based doublets; however, its role in pts receiving FLOT chemotherapy is still unclear. METHODS: This is a retrospective, multicenter observational study of 265 pts with GC/GEJC treated with perioperative FLOT regimen in 11 Italian oncology centers between January 2017 to December 2021 and analyzed for microsatellite status. RESULTS: The MSI-H phenotype was found in 27 (10.2%) of 265 analyzed tumors. Compared to microsatellite stable (MSS) and Mismatch Repair proficient (pMMR) cases, MSI-H/dMMR were more frequently female (48.1% vs. 27.3%, p = 0.0424), elderly pts (age > 70 years, 44.4% vs. 13.4%, p = 0.0003), Laurens's intestinal type (62.5% vs. 36.1%, p = 0.02) and pts with a primary location tumor in the antrum (37 vs. 14.3%, p = 0.0004). A statistically significant difference in the rate of pathologically negative lymph node emerged (63% vs 30.7%, p = 0.0018). Compared to the MSS/pMMR tumor population, the MSI-H/dMMR subgroup had a better DFS (median not reached [NR] vs. 19.5 [15.59-23.59] mos, p = 0.031) and OS (median NR vs. 34.84 [26.68-47.60] mos, p = 0.0316). CONCLUSIONS: These real-world data confirm that FLOT treatment is effective in daily clinical practice for locally advanced GC/GEJC, also in the MSI-H/dMMR subgroup. It also showed a higher rate of nodal status downstaging and a better outcome of MSI-H/dMMR pts in comparison to MSS/pMMR.

Clinical Outcomes After Progression on First-Line Therapies in IDH1 Mutated Versus Wild-Type Intrahepatic Cholangiocarcinoma Patients.

BACKGROUND: Isocitrate dehydrogenase-1 (IDH1) mutations occur in a significant proportion of intrahepatic cholangiocarcinomas (iCCAs). No data are available regarding the prognostic impact of IDH1 mutations in advanced iCCA patients after progression on first-line therapies. OBJECTIVE: We investigated the role of IDH1 mutation in advanced iCCA after progression on first-line therapies. PATIENTS AND METHODS: After progression on first-line therapies for advanced iCCA, consecutive patients were retrospectively collected. The IDH1 status was tested at baseline. This analysis aimed to examine the association between the presence of IDH1 missense mutations and survival outcomes in patients with advanced iCCA treated with a second-line therapy. RESULTS: The analysis included 119 patients; 56/119 (47%) were IDH1 mutated (IDH1m) and 63/119 (53%) were IDH1 wild type (IDH1 WT). At univariate analysis for overall survival (OS), the presence of IDH1 mutation was associated with a worse median OS (mOS; 8.2 vs. 14.1 months; hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-3.0, p = 0.0047). Patients harboring IDH1 mutations showed a worse objective response rate (ORR) compared with patients without IDH1 mutation, whereas no significant differences in disease control rate (DCR) were found. Multivariate analysis confirmed IDH1 mutations as an independent negative prognostic factor for OS (HR 1.7, 95% CI 1.1-2.7, p = 0.0256). By evaluating only patients receiving FOLFOX as second-line therapy, no statistically significant differences were found in terms of both OS and PFS between IDH1m and IDH1 WT patients. In this subset of patients, those harboring an IDH1 mutation showed a worse ORR and DCR compared with those without. Finally, at univariate analysis for OS from third-line treatment, the presence of an IDH1 mutation was associated with a trend toward a worse mOS (6.0 vs. 11.9 months; HR 1.6, 95% CI 0.8-3.2, p = 0.25). CONCLUSION: The present analysis constitutes the first evidence of a negative prognostic impact of IDH1 mutations in a cohort of patients treated after progression on first-line therapies in contrast to IDH1 inhibitors.

Colorectal Cancer Heterogeneity and the Impact on Precision Medicine and Therapy Efficacy.

Novel targeted therapies for metastatic colorectal cancer are needed to personalize treatments by guiding specific biomarkers selected on the genetic profile of patients. RAS and BRAF inhibitors have been developed for patients who become unresponsive to standard therapies. Sotorasib and adagrasib showed promising results in phase I/II basket trial and a phase III trial was planned with a combination of these RAS inhibitors and anti-EGFR monoclonal antibodies. Encorafenib and binimetinib were administered in phase II clinical trials for BRAF mutated patients. Pembrolizumab is now recommended in patients exhibiting microsatellite instability. Larotrectinib and entrectinib showed a fast and durable response with few and reversible adverse events in cases with NTRK fusions. Trastuzumab and trastuzumab deruxtecan exhibited promising and durable activity in HER-2-positive patients. In this review, the reasons for an extension of the molecular profile of patients were assessed and placed in the context of the advancements in the understanding of genetics. We highlight the differential effect of new targeted therapies through an ever-deeper characterization of tumor tissue. An overview of ongoing clinical trials is also provided.

Gene mutational profile of BRCAness and clinical implication in predicting response to platinum-based chemotherapy in patients with intrahepatic cholangiocarcinoma.

BACKGROUND AND AIMS: Biliary tract cancers are rare malignancies with a poor prognosis and scarce therapeutic strategies. The significance of BRCAness in this setting is already unknown. METHOD: Tissue specimens of BTC patients treated with platinum-based chemotherapy have been analyzed through the FOUNDATIONPne assay. RESULTS: 72/150 (48%) BRCAness mutated and 78/150 (52.0%) wild type (WT) patients were included. The most commonly mutated genes in the BRCAness mutated group were: ARID1A (N = 32, 44%), CDKN2A (N = 23, 32%), KRAS/NRAS (N = 16, 22%), CDKN2B (N = 13, 18%), BRCA2 (N = 13, 18%), PBRM1 (N = 12, 17%), ATM (N = 11, 15%), FGFR2 (N = 10, 14%), TP53 (N = 8, 11%), IRS2 (N = 7, 10%), CREBBP (N = 7, 10%) (table 3, figure 1). At the univariate analysis BRCAness mutation was associated with longer median Progression Free Survival (mPFS) (HR 0.68; 95% CI 0.49-0.95; p = 0.0254); it was not associated with longer mOS but a trend toward a benefit in survival was found (HR 0.77; 95% CI 0.50-1.19; p = 0.2388). Patients with BRCAness mutation showed a higher percentage of disease control rate (77.8 vs 67.9; p = 0.04) compared to patients WT. Multivariate analysis confirmed BRCAness mutation (HR 0.66; 95% CI: 0.45-0.98; p = 0.0422) as independent favorable prognostic factors for PFS and a positive trend was found for OS (HR 0.84; 95% CI: 0.53-1.33; p = 0.3652). CONCLUSION: BRCAness BTC patients showed a better PFS compared BRCAnessWT patients after exposure to platinum-based chemotherapy. Moreover, the OS curves' trend showed in our analysis suggests that BRCAness mutated patients could benefit from a maintenance therapy with PARPi.

Molecular profile and its clinical impact of IDH1 mutated versus IDH1 wild type intrahepatic cholangiocarcinoma.

IDH1-mutated cholangiocarcinomas (CCAs) are an interesting group of neoplasia with particular behavior and therapeutic implications. The aim of the present work is to highlight the differences characterizing IDH1m and IDH1wt CCAs in terms of genomic landscape. 284 patients with iCCA treated for resectable, locally advanced or metastatic disease were selected and studied with the FOUNDATION Cdx technology. A comparative genomic analysis and survival analyses for the most relevant altered genes were performed between IDH1m and IDH1wt patients. Overall, 125 patients were IDH1m and 122 IDH1wt. IDH1m patients showed higher mutation rates compared to IDH1wt in CDKN2B and lower mutation rates in several genes including TP53, FGFR2, BRCA2, ATM, MAP3K1, NOTCH2, ZNF703, CCND1, NBN, NF1, MAP3KI3, and RAD21. At the survival analysis, IDH1m and IDH1wt patients showed no statistically differences in terms of survival outcomes, but a trend in favor of IDH1wt patients was observed. Differences in prognostic values of the most common altered genes were reported. In surgical setting, in IDH1m group the presence of CDKN2A and CDKN2B mutations negatively impact DFS, whereas the presence of CDKN2A, CDKN2B, and PBRM1 mutations negatively impact OS. In advanced setting, in the IDH1m group, the presence of KRAS/NRAS and TP53 mutations negatively impact PFS, whereas the presence of TP53 and PIK3CA mutations negatively impact OS; in the IDH1wt group, only the presence of MTAP mutation negatively impact PFS, whereas the presence of TP53 mutation negatively impact OS. We highlighted several molecular differences with distinct prognostic implications between IDH1m and IDH1wt patients.

Next-generation sequencing analysis of cholangiocarcinoma identifies distinct IDH1-mutated clusters.

BACKGROUND: IDH1-mutated intrahepatic cholangiocarcinomas (IDH1m iCCAs) could be treated with anti-IDH1 drugs, although the high heterogeneity in this class of tumours could limit treatment efficacy. METHODS: We selected 125 IDH1m iCCAs that were treated as resectable, locally advanced, or metastatic and were screened by the NGS-based FoundationOne gene panel. We conducted a mutation-based clustering of tumours and survival analysis. RESULTS: Three main clusters were identified. The most altered pathways in cluster 1 were cell cycle and apoptosis, RTK/RAS, PI3K, and chromatin modification. Of note, CDKN2A/2B were mutated in 41/44 patients of this cluster. In cluster 2, the most affected pathways were as follows: Chromatin modification, DNA damage control, PI3K, and RTK/RAS. In this cluster, the most frequently mutated genes were ARID1A and PBRM1. The most altered pathways in cluster 3 were as follows: Cell cycle and apoptosis, DNA damage control, TP53, and chromatin modification. Importantly, TP53 was mutated only in cluster 3 patients. In the cohort of patients treated with surgery, cluster 2 showed statistically significant better disease-free survival (DFS) and overall survival (OS) compared with patients in cluster 3 and cluster 1 (p = 0.0014 and p = 0.0003, respectively). In the advanced setting, cluster 2 experienced a statistically significant better PFS (p = 0.0012), a tendency toward a better OS from first-line treatment, and a better OS from first-line progression compared with patients in cluster 1 and cluster 3 (p = 0.0017). We proposed an easy-to-use algorithm able to stratify patients in the three clusters on the basis of the genomic profile. CONCLUSION: We highlighted three different mutation-based clusters with prognostic significance in a cohort of IDH1m iCCAs.

Neoplastic meningitis from solid tumors: new diagnostic and therapeutic approaches.

Neoplastic meningitis is a result of the spread of malignant cells to the leptomeninges and subarachnoid space and their dissemination within the cerebrospinal fluid. This event occurs in 4%-15% of all patients with solid tumors and represents an important prognostic factor for poor survival. Neoplastic meningitis should be diagnosed in the early stages of disease to prevent important neurological deficits and to provide the most appropriate treatment. Despite new diagnostic approaches developed in recent years, such as positron emission tomography-computed tomography and new biological markers, the combination of magnetic resonance imaging without and with gadolinium enhancement and cytology still has the greatest diagnostic sensitivity. Recently, no new randomized studies comparing intrathecal (i.t.) with systemic treatment have been performed, yet there have been a few small phase II studies and case reports about new molecularly targeted substances whose successful i.t. or systemic application has been reported. Trastuzumab, gefitinib, and sorafenib are examples of possible future treatments for neoplastic meningitis, in order to better individualize therapy thus allowing better outcomes. In this review, we analyze the most recent and interesting developments on diagnostic and therapeutic approaches.

State-of-the-Art of Monoclonal Antibodies for the Treatment of Gastric Cancer.

Gastric cancer (GC) is a complex and heterogeneous disease with poor prognosis and limited available treatment options. During recent years, several molecular stratifications have been proposed to optimize the overall treatment strategy for GC patients. Breakthroughs in cancer biology and in molecular profiling through DNA and RNA sequencing are now opening novel landscapes, leading to the personalization of molecular matched therapy. In particular, therapies against HER2, Claudine 18.2, Fibroblast Growth Factor Receptors (FGFR), and other molecular alterations could significantly improve survival outcomes in the advance phase of the disease. Furthermore, immunotherapy with checkpoint inhibitors also represents a promising option in a selected population. Hoping that precision oncology will enter soon in clinical practice, our review describes the state of the art of many novel pathways and the current evidence supporting the use of monoclonal antibodies implicated in GC treatment.

Comparing immunotherapies to other frequently used treatments of gastric cancer.

Introduction: Although standard doublet chemotherapy represents the upfront gold standard to increase survival and improve quality of life of gastric cancer patients, overall improvements in long-term outcomes are modest and novel treatments are urgently needed. Among these, immunotherapy is an increasingly attractive option.Areas covered: A number of clinical trials have shown that checkpoint inhibitors may be of value, but many unclear issues remain controversial and should be promptly untangled. In our short review, we offer the current available data regarding immunotherapies in gastric cancers, discuss potential limits of the reported trials, compare outcomes of checkpoints inhibitor to those of standard chemotherapy or other novel treatments, and present basic principles of immune surveillance and immune escape that may be embraced in the near future with novel drug combinations.Expert opinion: Gastric cancer patients may benefit from immunotherapy, both given alone in advanced lines and upfront in combination with chemotherapy. We believe that appropriate patients' and tumor's selection are crucial issues to maximize its potential efficacy. In addition, we think that assay standardization, biomarker agreement, and translational studies will improve the benefit-to-risk ratio of these agents in the clinical practice.

Positive experience of intraperitoneal chemotherapy followed by intravenous chemotherapy in heavily pretreated patients with suboptimal residual ovarian cancer and primary peritoneal cancer.

AIMS AND BACKGROUND: To assess feasibility and toxicity of intraperitoneal administration of cisplatin and paclitaxel, followed by intravenous chemotherapy in pretreated patients with suboptimal ovarian cancer (residuum >1 cm) or primary peritoneal tumor, and suffering from ascites and/or intestinal obstruction. METHODS: Fourteen relapsed ovarian cancer patients, 5 of whom were platinum sensitive (platinum-free interval >6 mo), 7 platinum-resistant (platinum-free interval <6 mo), and 2 platinum-refractory, received one cycle of intraperitoneal cisplatin, 100 mg/m2 on day 1, and two cycles of intraperitoneal paclitaxel, 120 mg/m2 on days 8 and 14. Intravenous chemotherapy was administrated 4 weeks following the last intraperitoneal paclitaxel instillation. Blood and peritoneal fluid samples were harvested at 0, 1, 4 and 24 h after ending paclitaxel delivery to guarantee proper tumor exposure and patient safety. RESULTS: Intraperitoneal cisplatin determined 6 cases of vomiting grade 1-2 (40% of the morbidity). Intraperitoneal paclitaxel was associated with 6 events of grade 1-2 abdominal pain; the only grade 4 toxicity was one case of neutropenia and one of mucositis. Ascites decreased in 11 patients: the median time to first need for paracentesis was 5 months, compared to a median baseline paracentesis of 4 weeks. Three intestinal normalizations were obtained. The median overall survival was 10 months for our cohort of patients. Intraperitoneal paclitaxel clearance was significantly higher in patients with suboptimal tumor and symptomatic disease than in patients with smaller residual masses and without ascites (P = 0.004). CONCLUSIONS: Intraperitoneal treatment was feasible, and enhanced response to the following intravenous chemotherapy was seen in these patients.

Symptomatic COVID-19 in advanced-cancer patients treated with immune-checkpoint inhibitors: prospective analysis from a multicentre observational trial by FICOG.

BACKGROUND: This prospective, multicentre, observational INVIDIa-2 study is investigating the clinical efficacy of influenza vaccination in advanced-cancer patients receiving immune-checkpoint inhibitors (ICIs), enrolled in 82 Italian centres, from October 2019 to January 2020. The primary endpoint was the incidence of influenza-like illness (ILI) until 30 April 2020. All the ILI episodes, laboratory tests, complications, hospitalizations and pneumonitis were recorded. Therefore, the study prospectively recorded all the COVID-19 ILI events. PATIENTS AND METHODS: Patients were included in this non-prespecified COVID-19 analysis, if alive on 31 January 2020, when the Italian government declared the national emergency. The prevalence of confirmed COVID-19 cases was detected as ILI episode with laboratory confirmation of SARS-CoV-2. Cases with clinical-radiological diagnosis of COVID-19 (COVID-like ILIs), were also reported. RESULTS: Out of 1257 enrolled patients, 955 matched the inclusion criteria for this unplanned analysis. From 31 January to 30 April 2020, 66 patients had ILI: 9 of 955 cases were confirmed COVID-19 ILIs, with prevalence of 0.9% [95% confidence interval (CI): 0.3-2.4], a hospitalization rate of 100% and a mortality rate of 77.8%. Including 5 COVID-like ILIs, the overall COVID-19 prevalence was 1.5% (95% CI: 0.5-3.1), with 100% hospitalization and 64% mortality. The presence of elderly, males and comorbidities was significantly higher among patients vaccinated against influenza versus unvaccinated (p = 0.009, p < 0.0001, p < 0.0001). Overall COVID-19 prevalence was 1.2% for vaccinated (six of 482 cases, all confirmed) and 1.7% for unvaccinated (8 of 473, 3 confirmed COVID-19 and 5 COVID-like), p = 0.52. The difference remained non-significant, considering confirmed COVID-19 only (p = 0.33). CONCLUSION: COVID-19 has a meaningful clinical impact on the cancer-patient population receiving ICIs, with high prevalence, hospitalization and an alarming mortality rate among symptomatic cases. Influenza vaccination does not protect from SARS-CoV-2 infection.

Correlation between magnetic resonance imaging and histopathological tumor response after neoadjuvant chemotherapy in breast cancer.

AIM: To evaluate the accuracy of magnetic resonance imaging in assessing tumor response following neoadjuvant chemotherapy in patients with locally advanced breast cancer. MATERIALS AND METHODS: Twenty-six patients entered a phase II study of neoadjuvant chemotherapy, undergoing bilateral breast magnetic resonance imaging before therapy and before surgery. Tumor response was classified using RECIST criteria, using tumor size at magnetic resonance imaging. The latter was then compared to residue found at histopathological examination. RESULTS: Magnetic resonance imaging showed 6 (23%) complete responses, 17 (65%) partial responses, 3 (11.5%) disease stabilizations and no disease progressions. Twenty-three tumors (88.5%) were considered responsive and 3 (11.5%) unresponsive. Pathological tumor response was: 6 complete responses (23%), 17 partial responses (65%), 2 stable disease (8%), 1 progression (4%). When results of the preoperative magnetic resonance imaging were compared to pathological tumor response, magnetic resonance imaging overestimated tumor size in 12 cases (46%) and underestimated it in 9 (35%). However, preoperative magnetic resonance imaging failed to detect invasive tumor in 2 false-negative cases (8%), 1 of which was multifocal. Mastectomy was performed in 12 cases: 1 case of disease progression even though the neoplasm appeared smaller at magnetic resonance imaging, 3 cases with stable disease, and 4 cases with T3 or T4 disease. The 9th patient was T2N2 with initial retroareolar disease and negative magnetic resonance imaging after chemotherapy. The 10th patient, affected by lobular cancer, was in partial remission but was T3N1. The 11th patient was 57 years old but was not interested in conservative surgery. The 12th patient requested bilateral prophylactic mastectomy due to her positive family history of breast cancer. CONCLUSIONS: Magnetic resonance imaging of the breast allowed conservative surgery in 54% of the patients. This low value is primarily due to overestimation of tumor size, with a negative predictive value of 67% in our population. However, surgeons were able to choose conservative surgery with relative safety in cases of small residual disease.

Intraperitoneal Chemotherapy in Patients Pretreated for Ovarian Cancer Matched with Patients Treated with Parenteral Chemotherapy.

BACKGROUND: Our aim was to analyze the impact of intraperitoneal chemotherapy (IPC), administered with direct peritoneal puncture, on the survival of patients with pretreated ovarian cancer in a real-life setting. PATIENTS AND METHODS: This was a retrospective study comparing patients with advanced ovarian cancer treated with IPC (N=33) and patients treated with standard intravenous (i.v.) chemotherapy matching cases for known prognostic factors (age, platinum sensitivity, histological subgroup and grade). Data were then analyzed for survival with nested Cox multivariate regression. RESULTS: The case matching resulted in two homogeneous cohorts by age, platinum sensitivity, resistance to therapy and histology. When analyzed by hazard ratio (HR), the number of previous treatments and IPC vs. i.v. therapy were significant (HR=1.97 for i.v. and HR=1.90 for each incremental previous treatment line, multivariate p<0.001). When analyzing the patients with fewer than three previous treatment lines, IPC conferred a survival advantage of about 2.2 months (IPC=10.0 vs. i.v.=7.8 months, p=0.011). However, the survival advantage in heavily pre-treated patients (with three or more previous treatments) was not significant. One case, pre-treated with more lines of chemotherapy, with renal failure after intraperitoneal cisplatin was followed by death. None of the patients had bowel sub-occlusions and we recorded a lower incidence of local toxicity, such as cellulite, with IPC (two out of 33 cases). Two patients thereafter refused IPC due to abdominal pain. CONCLUSION: Our findings confirm that IPC is an effective approach compared to systemic chemotherapy for advanced ovarian cancer, even in pre-treated patients, including platinum-resistant cases. The survival benefit appears to be confined to non-heavily treated patients. Overall, direct intraperitoneal drug injection (without permanent devices) appears to be feasible, safe and possibly advantageous.

Advanced gastric cancer (GC) and cancer of the gastro-oesophageal junction (GEJ): focus on targeted therapies.

Despite recent improvements in surgical techniques and chemotherapy treatments, locally advanced/metastatic gastroesophageal junction (GEJ) and gastric cancer (GC) are still associated with poor clinical outcome. However, increased understanding of molecular mechanisms underlying carcinogenesis and its implementation in the treatment of breast, colon, lung, and other cancers in recent years have spurred focus on the development and incorporation of targeted agents in current therapeutic options for this difficult-to-treat disease. Such agents have the ability to target a variety of cancer relevant targets, including epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) and its receptor. In this review, we describe the current status of targeted therapies in the treatment of advanced GC and GEJ cancer, focusing on pre-clinical and clinical data available on monoclonal antibodies and tyrosine kinase inhibitors acting in these pathways, including completed and ongoing phase III studies.

Hepatoid adenocarcinoma of the colon: what should we target?

Hepatoid adenocarcinoma is a rare extra hepatic neoplasm that displays morphological and phenotypic features similar to those of hepatocellular carcinoma. We report a case of a 75-year-old woman, presenting with abdominal pain and complaints of weakness and lost of appetite, who was found to have a mass on her right colon. She underwent right hemicolectomy for a pT3N2M0, stage IIIC colon cancer. The tumor phenotype and immunophenotype, as documented by alpha-fetoprotein immunoreaction positivity, were consistent with adenocarcinoma of hepatoid origin. The patient received FOLFOX-4 regimen as adjuvant treatment, relapsed after six cycles, then was switched to FOLFIRI regimen plus Bevacizumab and progressed after only four cycles. She died 1 month later, eight months after the diagnosis. The lack of any clinical benefit despite an aggressive and multimodal therapeutic strategy, raises a question about what should be targeted when we face this rare disease associated with a very poor prognosis.

Phase II study of neoadjuvant gemcitabine, pegylated liposomal doxorubicin, and docetaxel in locally advanced breast cancer.

AIM: This was a phase II study to assess the activity of a novel neoadjuvant regimen in locally-advanced breast cancer. PATIENTS AND METHODS: Fifty patients with histological confirmation of locally advanced breast cancer received treatment with gemcitabine 1000 mg/m(2) (day 1) followed by gemcitabine 800 mg/m(2) plus docetaxel 75 mg/m(2) plus pegylated liposomal doxorubicin (PLD) 30 mg/m(2) (day 8) every 3 weeks for at least 4 cycles, plus a final 2 additional cycles. Tumour size was T1 (n=2), T2 (n=32), T3 (n=14), T4 (n=2). All 50 patients underwent surgery. RESULTS: Clinical complete, partial and no response were observed in 13 (26%), 24 (48%) and 11 (22%) patients, respectively (overall response rate: 74%). The number of chemotherapy cycles was found to be an independent predictor of a pathologic complete response. CONCLUSION: The combination of gemcitabine-docetaxel-PLD can yield high tumour response rates in patients with locally-advanced breast cancer who undergo a full treatment of 6 cycles.