MOLECULAR PATHWAYS OF COLORECTAL CANCER DEVELOPMENT: MECHANISMS OF ACTION AND EVOLUTION OF MAIN SYSTEMIC THERAPY COMPOUNDS.

Colorectal cancer is known as one of the "big killers" in oncology given its burden in terms on morbidity and mortality. Since the second half of the last century, similarly to what happened for other solid tumors, a large series of cytotoxic molecules have been developed and tested to treat this disease. Following new discoveries in terms of colorectal cancer pathogenesis and specific pathways involved such as angiogenesis, a new series of drugs have been developed: targeted therapies. In this review we will briefly describe colorectal cancer molecular biology and its main pathways in order to retrace the main stages of oncological treatment development for colorectal cancer from the first available treatments to novel approaches to the disease.

Chromoendoscopy Is Not Superior to White Light Endoscopy in Improving Adenoma Detection in Lynch Syndrome Cohort Undergoing Surveillance with High-Resolution Colonoscopy: A Real-World Evidence Study.

BACKGROUND: Endoscopic surveillance in patients with Lynch syndrome (LS) is crucial due to a genetically based high risk of colorectal cancer (CRC). We aimed to compare the adenoma detection rate (ADR) between high-resolution white light endoscopy (WLE) alone and WLE plus dye chromoendoscopy (CE) in a cohort of LS patients. METHODS: In a context of real-world data, we retrospectively enrolled 50 LS patients who had non-randomly undergone WLE versus CE surveillance examinations from 2007 to 2019. The 2 groups were compared at baseline (BL) in terms of the rate of patients with lesions and the number of lesions, and at follow-up (FU), to evaluate a possible enhanced detection rate. Longitudinal analysis of the effect of the endoscopy type on the main outcomes was performed by generalized linear mixed models. RESULTS: Forty-two patients had undergone at least one diagnostic colonoscopy. At BL and at FU analysis, we found no significant differences in detection rates and clinical-pathological features between WLE and CE groups. At the longitudinal analysis, an increase in the endoscopy rank (i.e., the position of each colonoscopy for all the colonoscopies that a patient had undergone) was associated with an increase in polyp detection rate (p = 0.006) and ADR (p = 0.005), while a trend toward significance (p = 0.069) was found for endoscopy type (CE vs. WLE) in the detection of serrated lesions. CONCLUSIONS: CE is not superior to high-resolution WLE in increasing the ADR. Even under standard WLE, an active and careful endoscopic surveillance of LS patients can prevent CRC.

Seminoma Retroperitoneal Relapse 23 Years After Surgery.

Stage I seminoma is the most frequent tumour in young men. It has a very good prognosis thanks to the use of a multidisciplinary therapeutic approach including surgery, radiotherapy and systemic chemotherapy. Late (after 2 years) and very late (after 5 years) relapses are uncommon, but not impossible, even if standardized follow-up for testicular tumours lasts up to 5 years after the diagnosis. We report a case of a 67-year-old Caucasian man with metachronous bilateral testicular seminoma who developed a retroperitoneal relapse of testicular seminoma 23 years after the first orchiectomy. Based on histological confirmation of testicular relapse, the patient underwent four cycles of systemic chemotherapy with bleomycin, etoposide and cisplatin (PEB), with no adverse reactions. He subsequently achieved complete radiological response at restaging computed tomography imaging, confirmed by the absence of glucose metabolism on positron emission tomography. In conclusion, this case report suggests the importance of longer standardized follow-up for patients treated for testicular tumours in order to detect earlier recurrence, which can be successfully treated.

Irinotecan-Induced Transient Dysarthria: Case Series and Updated Literature Review.

Irinotecan-based regimens are used worldwide for the treatment of several recurrent or advanced gastrointestinal malignancies. In this paper we describe the cases of four patients treated in our institution who developed acute dysarthria while receiving intravenous infusion of irinotecan. In all our cases, dysarthria occurred during the infusion of the first course of irinotecan, and then resolved rapidly without any sequelae. Imaging of the brain was performed, but failed to show any evidence of an acute neurological event. We also reviewed the literature on this very uncommon adverse event. The pathogenesis of irinotecan-induced dysarthria is still unknown and is not completely elucidated by the current pharmacodynamic or kinetic explanations; therefore, we could only hypothesize some assumptions.

Brachytherapy for the palliation of dysphagia owing to esophageal cancer: A systematic review and meta-analysis of prospective studies.

BACKGROUND: The management of dysphagia owing to esophageal cancer is challenging. Brachytherapy has been proposed as an alternative option to stent placement. We performed a systematic review to examine its efficacy and safety in the resolution of dysphagia. METHODS: Prospective studies recruiting at least 20 patients with malignant dysphagia and published up to April 2016 were eligible. The dysphagia-free survival (DFS) and adverse event rates were pooled by means of a random effect model. RESULTS: Six studies for a total of 9 treatment arms (623 patients) were eligible for inclusion. After 1month since treatment, the DFS rate was 86.9% [95%CI: 76.0-93.3%]; after 3months, it was 67.2% [95%CI: 56.1-76.7%]; after 6months, it was 47.4% [95%CI: 38.5-56.5%]; after 9months, it was 37.6% [95%CI:30.0-45.9%]; and, finally, after 12months, it was 29.4% [95%CI: 21.6-38.7%]. The heterogeneity between studies was high at 1-, 3- and 6-month assessment; the values of I2 were 86.3%, 80.0% and 57.8%, respectively. The meta-regression analysis showed total radiation dose and number of fractions as the only positively influencing factors. Severe adverse event rate was 22.6% (95%CI 19.4-26.3). The main reported adverse events were brachytherapy-related stenosis (12.2%) and fistula development (8.3%). Two cases (0.3%) of deaths were reported due to esophageal perforation. CONCLUSION: Brachytherapy is a highly effective and relatively safe treatment option therefore its underuse is no longer justified. Further studies should investigate the optimal radiation dose and number of fractions able to achieve the highest DFS rates.

The tumor-targeting immunocytokine F16-IL2 in combination with doxorubicin: dose escalation in patients with advanced solid tumors and expansion into patients with metastatic breast cancer.

A phase Ib/II trial was performed to evaluate safety, tolerability, recommended dose (RD) and efficacy of F16-IL2, a recombinant antibody-cytokine fusion protein, in combination with doxorubicin in patients with solid tumors (phase Ib) and metastatic breast cancer (phase II). Six patient cohorts with progressive solid tumors (n = 19) received escalating doses of F16-IL2 [5-25 Million International Units (MIU) of IL2 equivalent dose] in combination with escalating doses of doxorubicin (0-25 mg/m(2)) on day 1, 8 and 15 every 4 weeks. Subsequently, patients with metastatic breast cancer (n = 10) received the drug combination at the RD. Clinical data and laboratory findings were analyzed for safety, tolerability, and activity. F16-IL2 could be administered up to 25 MIU, in combination with the RD of doxorubicin (25 mg/m(2)). No human anti-fusion protein antibodies (HAFA) response was detected. Pharmacokinetics of F16-IL2 was dose-dependent over the tested range, with half-lives of ca. 13 and ca. 8 hours for cohorts dosed at lower and higher levels, respectively. Toxicities were controllable and reversible, with no combination treatment-related death. After 8 weeks, 57% and 67% disease control rates were observed for Phase I and II, respectively (decreasing to 43% and 33% after 12 weeks), considering 14 and 9 patients evaluable for efficacy. One patient experienced a long lasting partial response (45 weeks), still on-going at exit of study. F16-IL2 can be safely and repeatedly administered at the RD of 25 MIU in combination with 25 mg/m(2) doxorubicin; its safety and activity are currently being investigated in combination with other chemotherapeutics, in order to establish optimal therapy settings.

Novel small molecule EGFR inhibitors as candidate drugs in non-small cell lung cancer.

In the last decade, better understanding of the role of epidermal growth factor receptor in the pathogenesis and progression of non-small cell lung cancer has led to a revolution in the work-up of these neoplasms. Tyrosine kinase inhibitors, such as erlotinib and gefitinib, have been approved for the treatment of non-small cell lung cancer, demonstrating an improvement in progression-free and overall survival, particularly in patients harboring activating EGFR mutations. Nevertheless, despite initial responses and long-lasting remissions, resistance to tyrosine kinase inhibitors invariably develops, most commonly due to the emergence of secondary T790M mutations or to the amplification of mesenchymal-epithelial transition factor (c-Met), which inevitably leads to treatment failure. Several clinical studies are ongoing (http://www.clinicaltrials.gov), aimed to evaluate the efficacy and toxicity of combined approaches and to develop novel irreversible or multitargeted tyrosine kinase inhibitors and mutant-selective inhibitors to overcome such resistance. This review is an overview of ongoing Phase I, II, and III trials of novel small molecule epidermal growth factor receptor inhibitors and combinations in non-small cell lung cancer patients.

State of the art for cardiotoxicity due to chemotherapy and to targeted therapies: a literature review.

Cardiotoxicity is a common complication of many anti-cancer agents and it remains a major limitation, strongly impacting the quality of life and the overall survival, regardless of the oncologic prognosis. Cardiotoxicity may occur during or shortly after treatment (within days or weeks), or it may become evident months, and sometimes years, after completion of chemotherapy. Cardiotoxicity associated with cancer therapies can range from asymptomatic subclinical abnormalities, including electrocardiographic changes and temporary left ventricular ejection fraction decline, to life-threatening events such as congestive heart failure or acute coronary syndromes. The aim of this review is to summarize potential cancer chemotherapeutics-related cardiovascular toxicities in adult cancer-patients and to suggest monitoring and treatment options for each agent, that can serve as a tool in the clinical practice.

Role of maspin in cancer.

Maspin (mammary serine protease inhibitor), is a member of the serine protease inhibitor/non-inhibitor superfamily. Its expression is down-regulated in breast, prostate, gastric and melanoma cancers but over-expressed in pancreatic, gallbladder, colorectal, and thyroid cancers suggesting that maspin may play different activities in different cell types. However, maspin expression seems to be correlated with better prognosis in prostate, bladder, lung, gastric, colorectal, head and neck, thyroid and melanoma cancer. In breast and ovarian cancer maspin significance is associated with its subcellular localization: nucleus maspin expression correlates with a good prognosis, whilst in pancreatic cancer it predicts a poor prognosis. Since tumor metastasis requires the detachment and invasion of tumor cells through the basement membrane and stroma, a selectively increased adhesion by the presence of maspin may contribute to the inhibition of tumor metastasis. Furthermore the different position of maspin inside the cell or its epigenetic modifications may explain the different behavior of the expression of maspin between tumors. The expression of maspin might be useful as a prognostic and possibly predictive factor for patients with particular types of cancer and data can guide physicians in selecting therapy. Its expression in circulating tumor cells especially in breast cancer, could be also useful in clinical practice along with other factors, such as age, comorbidities, blood examinations in order to select the best therapy to be carried out. Focusing on the malignancies in which maspin showed a positive prognostic value, therapeutic approaches studied so far aimed to re-activate a dormant tumor suppressor gene by designed transcription factors, to hit the system that inhibits the expression of maspin, to identify natural substances that can determine the activation and the expression of maspin or possible "molecules binds" to introduce maspin in cancer cell and gene therapy capable of up-regulating the maspin in an attempt to reduce primarily the risk of metastasis.Further studies in these directions are necessary to better define the therapeutic implication of maspin.

Resected biliary tract cancers: a novel clinical-pathological score correlates with global outcome.

BACKGROUND: Biliary tract cancer presents a poor prognosis. AIMS: The objective of this study is to find clinical-laboratory parameters like prognostic factors to select patients who can benefit from surgery and post-operative treatments. METHODS: Between 2005 and 2010, 41 patients underwent radical surgery at our Institution. A novel score was retrospectively calculated assigning a grade to the clinical-laboratory findings at diagnosis. 0 and 1 point were respectively assigned to the normal or abnormal parameter. Two groups were identified: SCORE 0 and SCORE 1. RESULTS: Patients with cholangiocarcinoma or Klatskin tumours or asymptomatic at diagnosis presented a significantly better overall survival (OS) than patients with different primary sites or who presented pain, jaundice or cholangitis. At univariate analysis, high levels of aspartate aminotransferase, alanine aminotransferase and CA19-9 before surgery, hyperbilirubinemia before and after surgery had a negative correlation with OS. A worse OS was observed in patients with a higher score (median OS in the "score 0" group=30.79 months vs. median OS in the "score 1"=17.98 months). CONCLUSION: Our results suggest that pre and post-surgery clinical-laboratory parameters and the novel score, could be useful, especially for intrahepatic tumours, in predicting the outcome in patients undergoing surgery and in selecting patients to receive adjuvant therapy.

Maspin expression is a favorable prognostic factor in non-small cell lung cancer.

OBJECTIVE: To evaluate prognostic impact of maspin expression in patients with resected non-small cell lung cancer (NSCLC). STUDY DESIGN: From 1996 to 2001, 439 patients underwent radical surgery for NSCLC at the Polytechnic University of the Marche Region. Maspin expression was detected as cytoplasmic and nuclear staining of neoplastic cells. For cytoplasmic staining, cases were classified as negative, low positive, and high positive. In positive cases, intensity of staining was also considered and scored. A similar classification was used for nuclear staining, but intensity was not considered. RESULTS: The analysis showed that smoking history, pathologic stage of disease, N status, histologic grading, sex, and Eastern Cooperative Oncology Group performance status had a prognostic impact on overall survival (OS). Expression of maspin was also found to be an independent prognostic factor. A statistically significant longer OS was seen in patients with higher compared with lower expression of nuclear maspin, and poorer OS was present in patients with a higher intensity of cytoplasmic staining. Nuclear expression of maspin was also found to be an independent prognostic factor at multivariate analysis. CONCLUSION: Results suggest that overexpression of maspin correlates with favorable prognosis in NSCLC. and may be a useful clinical marker.

Nuclear factor-κB predicts outcome in locally advanced rectal cancer patients receiving neoadjuvant radio-chemotherapy.

BACKGROUND: NF-κB expression has been shown to be responsible for resistance to antineoplastic agents. AIMS: The aim of our study was to investigate the importance of NF-κB expression as prognostic factor in locally advanced rectal cancer patients receiving neoadjuvant radiochemotherapy. METHODS: We retrospectively analysed the immunoreactivity for NF-κB in patients with locally advanced rectal cancer who underwent neoadjuvant treatment (chemotherapy and/or radiotherapy) in our Institution between March 2003 and June 2006. RESULTS: Seventy-four consecutive patients were enrolled into this study. Immunohistochemistry analysis for NF-κB was performed both in biopsies and in primary tumour samples. NF-κB was considered positive when at least 1% of the tumour cells showed nuclear positivity. A significant correlation between a positive NF-κB nuclear expression, both in biopsies and in tumour samples, and a worse overall survival was observed. Moreover, median time to progression was significantly shorter in the NF-κB-positive subgroup of patients. CONCLUSION: Globally, our findings seem to suggest that NF-κB could represent an important parameter able to predict the outcome in patients receiving neoadjuvant treatment for rectal cancer. It also could be useful in order to select patients to receive adjuvant chemotherapy, intensifying the adjuvant therapy and, in the next future, obviating the use of drugs involving NF-κB system in their mechanism of action in NF-κB-positive patients.

Phase II study of pharmacogenetic-tailored therapy in elderly colorectal cancer patients.

BACKGROUND: Retrospective analyses suggested that a pharmacogenetic approach may allow a tailored selection of chemotherapy for metastatic colorectal cancer. AIM: We conducted a phase II study of pharmacogenetic-selected first-line chemotherapy in elderly patients with advanced colorectal cancer, with the aim to improve efficacy and to reduce toxicity in this group of patients. METHODS: 24 patients were enrolled in this study. Chemotherapy regimen was prospectively assigned based on TS, DPD, ERCC-1 and UGT1A1 genotyping results. Twelve patients (50%) were treated with modified FOLFIRI, 11 patients (46%) with modified FOLFOX6 and 1 (4%) with De Gramont regimen. RESULTS: A partial remission was obtained in 4 cases (17%), stable disease in 8 cases (33%) and progressive disease in 12 cases (50%). Grade 3-4 neutropenia was observed in 7 patients (29%) and diarrhoea in 3 cases (12%). The trial was then interrupted according to study design requiring 13 partial remissions out of the first 24 patients enrolled as the necessary response rate level in order to continue. CONCLUSION: Prospective selection of chemotherapy based on TS, DPD, ERCC-1 and UGT1A1 expression in elderly advanced colorectal cancer patients failed to confirm previous results. A more accurate validation of retrospective findings is warranted before these molecular markers can be used for treatment selection in the clinical practice.

Epidermal growth factor receptor status in stages of resected non-small cell lung cancer: implications for treatment with epidermal growth factor receptor inhibitors.

OBJECTIVE: To verify whether epidermal growth factor receptor (EGFR) status could be considered a prognostic factor and assessment of it an effective tool for planning therapy in patients with non-small cell lung cancer (NSCLC). STUDY DESIGN: From 1996 to 2001, 439 patients underwent radical surgery for NSCLC at the Polytechnic University of the Marche Region. EGFR expression was detected as membranous and/or cytoplasmic staining of neoplastic cells with various intensity and was considered positive when > or = 1% of the tumor cells had membranous staining. RESULTS: Samples from 423 patients were available for EGFR analysis. EGFR expression and a stronger intensity of staining were associated with a trend for a worse prognosis in the analysis of all of the patients. The subgroup analysis showed no prognostic significance in stages I and II but a significantly longer survival in patients with advanced disease (stage III and particularly N2) overexpressing EGFR. CONCLUSION: The results of our study, showing a significantly longer survival in patients with advanced disease (stage III, particularly N2) overexpressing EGFR, present a new perspective, both for prognostic evaluation of patients with radically resected NSCLC and for the management of adjuvant treatment also employing targeted therapy.

The role of HER-3 expression in the prediction of clinical outcome for advanced colorectal cancer patients receiving irinotecan and cetuximab.

Preclinical data suggested that, in the presence of human epidermal growth factor receptor (HER)-3-altered activation, colorectal cancer cells may escape anti-epidermal growth factor receptor (EGFR)-mediated cell death. HER-3 overexpression may then represent a key factor for resistance to anti-EGFR antibodies in colorectal cancer. The aim of our analysis was to investigate a possible correlation between HER-3 expression and clinical outcome in wild-type K-RAS advanced colorectal cancer patients receiving cetuximab and irinotecan. We retrospectively analyzed immunoreactivity for HER-3 in wild-type K-RAS advanced colorectal cancer patients receiving irinotecan and cetuximab. Eighty-four advanced wild-type K-RAS colorectal cancer patients were available for HER-3 analysis. Forty patients (48%) had a HER-3(-) colorectal tumor, whereas the remaining 44 cases (52%) were deemed HER-3(+). In patients with HER-3(-) and HER-3(+) tumors, we observed a partial response in 17 (42%) and eight (18%) patients respectively; progressive disease occurred in 11 (35%) and 26 (53%) patients with HER-3(-) and HER-3(+) tumors, respectively (p = .003). The median progression-free survival time was 6.3 months in patients with HER-3(-) tumors and 2.8 months for those who had HER-3-overexpressing tumors (p < .0001). The median overall survival time was 13.6 months in patients showing HER-3(-) tumors and 10.5 months for those who had HER-3-expressing tumors (p = .01). HER-3 proved to be a predictive factor for clinical outcome in wild-type K-RAS colorectal cancer patients treated with cetuximab. Combined HER-3 and K-RAS analysis may represent an effective strategy for better selection of responding colorectal cancer patients.

Trans-arterial chemo-embolization (TACE), with either lipiodol (traditional TACE) or drug-eluting microspheres (precision TACE, pTACE) in the treatment of hepatocellular carcinoma: efficacy and safety results from a large mono-institutional analysis.

More data about TACE and pTACE seem necessary to better define the global treatment strategy for HCC. Aim of our analysis was to evaluate the role of TACE, either with lipiodol (traditional) or drug-eluting microspheres in terms of response rate (RR), time to progression (TTP), overall survival (OS) and toxicity in HCC.Patients with HCC undergoing traditional TACE or pTACE (either alone or in combination with other treatment options) were eligibleOne hundred and fifty patients were analyzed. In the global patient population median OS was 46 months for lipiodol TACE and 19 months for pTACE (p < 0.0001), TTP was 30 months versus 16 months for patients receiving TACE or pTACE respectively (p = 0.003). These results were confirmed also among the group of patients who received exclusive TACE or pTACE. Neither RR nor toxicity was different between TACE or pTACE.At multivariate analysis, age, the Okuda stage, type of TACE and number of TACE proved to be independent prognostic factors influencing overall survival.In our experience, lipiodol TACE showed a better OS and TTP over pTACE, without difference in toxicity profile and RR. Among the staging systems analyzed only the Okuda stage seemed able to reliably predict patients outcome.

Panitumumab: the evidence for its use in the treatment of metastatic colorectal cancer.

Panitumumab is the first fully human monoclonal antibody to Epidermal Growth Factor Receptor (EGFR) to enter clinical trials for the treatment of solid tumors. The anti-tumor activity of panitumumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in numerous cancer models, particularly lung, kidney and colorectal (CRC). Preclinical and clinical studies have established a role for panitumumab in metastatic colorectal cancer (mCRC) refractory to multiple chemotherapeutic regimens. Based on these encouraging findings, panitumumab was approved by the US Food and Drug Administration for the treatment of patients with epidermal growth factor receptor-expressing mCRC refractory to fluoropyrimidine-, oxaliplatin-, and/or irinotecan-containing chemotherapeutic regimens. The improvement in progression free survival (PFS) and response rate (RR) produced by panitumumab monotherapy was significantly greater in patients with non mutated (wild-type) K-RAS than in those with mutant K-RAS. Therefore implementing routine K-RAS screening and limiting the use of EGFR inhibitors to patients with wild-type K-RAS appears the better strategy for select only the patients who could benefit from the therapy with panitumumab and also may have the potential for cost savings. The purpose of this review was to evaluate the patient-related, disease-related and economic-related evidence for the use of panitumumab in the treatment of metastatic colorectal cancer in clinical practice.

Insulin-like growth factor 1 expression correlates with clinical outcome in K-RAS wild type colorectal cancer patients treated with cetuximab and irinotecan.

Seventy to 40% of K-RAS wild type colorectal tumors does not seem to benefit from treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies. Recent data suggested that in presence of IGF-1 system, altered activation colorectal cancer cells may escape anti-EGFR mediated cell death. The interaction between IGF-1 expression and K-RAS mutational analysis was tested to verify the ability of IGF-1 to identify a subgroup of patients more likely to benefit from EGFR-targeted antibodies treatment. IGF-1 expression and K-RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab. One hundred twelve patients were analyzed. IGF-1 was negative in 30 patients (27%) and overexpressed in the remaining 82 cases (73%). In IGF-1 negative and IGF-1 positive tumors, we observed progressive disease in 9 (30%) and 55 (67%) patients, respectively (p = 0.001). Median progression-free survival was 7.5 mo in patients showing IGF-1 negative tumors and 3 mo for IGF-1 expressing tumors (p = 0.002). Among K-RAS wild type patients, IGF-1 negative and positive tumors showed a partial response to cetuximab-irinotecan in 13 (65%) and 11 (22%) cases, respectively (p = 0.002). Median progression-free survival in IGF-1 negative tumors was 10 mo and 3.2 mo in IGF-1 positive colorectal cancers (p = 0.02). IGF-1 proved to be a possible predictive factor for resistance to anti-EGFR monoclonal antibodies in K-RAS wild type colorectal cancer. Combined IGF-1 and K-RAS analysis may represent an effective strategy for a better selection of responding colorectal cancer patients.

Locally advanced rectal cancer: from molecular profiling to clinical practice. A literature review: Part 2.

Colorectal cancer is the third most common cause of cancer deaths worldwide. The management of rectal cancer has undergone, and continues to undergo, significant evolutions. In the last two decades, new multimodality strategies have been developed. The ability to predict tumor response before treatment could significantly impact the selection of patients for preoperative combined-modality therapy, as well as potentially modify postoperative treatment plans. The present review analyzes the new molecular targets that could be involved in predicting response and prognosis.