Roberto Filippi

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

Biliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the epidermal growth factor receptor (EGFR) pathway could be involved in its progression.

Fluoropyrimidine-induced cardiotoxicity

Fluoropyrimidines (5-fluorouracil and capecitabine) are antimetabolite drugs, widely used for the treatment of a variety of cancers, both in adjuvant and in metastatic setting. Although the most common toxicities of these drugs have been extensively studied, robust data and comprehensive characterization still lack concerning fluoropyrimidine-induced cardiotoxicity (FIC), an infrequent but potentially life-threatening toxicity. This review summarizes the current state of knowledge of FIC with special regard to proposed pathogenetic models (coronary vasospasm, endothelium and cardiomyocytes damage, toxic metabolites, dihydropyrimidine dehydrogenase deficiency); risk and predictive factors; efficacy and usefulness in detection of laboratory markers, electrocardiographic changes and cardiac imaging; and specific treatment, including a novel agent, uridine triacetate. The role of alternative chemotherapeutic options, namely raltitrexed and TAS-102, is discussed, and, lastly, we overview the most promising future directions in the research on FIC and development of diagnostic tools, including microRNA technology.

Rationale for the use of metronomic chemotherapy in gastrointestinal cancer

ABSTRACT Introduction: Metronomic chemotherapy (mCT) is endowed with various properties, ranging from antiangiogenic to immunomodulation, and may revert tumor resistance to conventional drug administration. A variety of antineoplastic agents displayed activity when administered with metronomic schedules in preclinical models of gastrointestinal cancers. However, most of the field is still unexplored. Areas covered: Herein, the authors review the existing literature from PubMed, concerning the use of mCT in gastrointestinal oncology. Expert opinion: A mounting body of evidence is emerging in support of mCT as a treatment option for gastrointestinal tumors, but the frequent signs of clinical activity inconsistently translate into a benefit for survival. Research in this field should focus on providing high-quality evidence on the safety and efficacy of mCT, with more prospective, comparative trials; identifying the subgroups of patients for whom mCT would be the best approach; establishing standardized protocols based on mCT pharmacokinetics and pharmacodynamics; developing drug activity biomarkers. mCT is also potentially suitable for combinations with targeted antiangiogenic drugs and may be incorporated with conventional administration into dual regimens.

Outcomes of Advanced Gastric Cancer Patients Treated with at Least Three Lines of Systemic Chemotherapy

BACKGROUND Second-line therapy has consistently demonstrated survival benefit if compared with best supportive care; however, there is limited evidence whether further lines of treatment may improve the prognosis of advanced gastric cancer (AGC) patients. MATERIALS AND METHODS Starting from a real-world cohort of 868 AGC patients, we retrospectively analyzed baseline parameters, tumor characteristics, and treatment data of those treated with at least three lines. Categorical features were described through cross-tables and chi-square test. We explored the impact of treatment intensity and progression-free survival (PFS) experienced in previous lines on PFS and overall survival in third-line by uni- and multivariate Cox regression models and described by Kaplan-Meier estimator plot with log-rank test. RESULTS Overall, 300 patients were included in the analysis. The most common site of primary tumor was gastric body; 45.3% of cancers had an intestinal histotype, 14% were human epidermal growth receptor 2 positive. In third-line, 45.7% of patients received a single-agent chemotherapy, 49.7% a combination regimen. Patients who had experienced a first-line PFS ≥6.9 months had a better prognosis compared with those who had achieved a shorter one. Consistently, a second-line PFS ≥3.5 months positively influenced the prognosis. Patients receiving a third-line combination regimen had better outcomes compared with those treated with a single-agent chemotherapy. CONCLUSION Our real-world study confirms that selected AGC patients may receive third-line treatment. Longer PFS in previous lines or a more intense third-line treatment positively influenced prognosis. Further efforts are warranted to define the best therapeutic sequences, and to identify the optimal candidate for treatment beyond second-line. IMPLICATIONS FOR PRACTICE The benefit of third-line treatment to advanced gastric cancer patients is controversial. This study depicts a real scenario of the clinical practice in Italy, confirming that a non-negligible proportion of patients receive a third-line therapy. Longer progression-free survival in previous treatment lines or higher third-line treatment intensity positively influenced prognosis. Including a large number of real-world patients, this study provides information on third-line treatment from the daily clinical practice; moreover, its results help in defining the best therapeutic sequence and offer some hints to select the optimal candidate for treatment beyond second-line.

Changing paradigms in the treatment of hormone-receptor positive advanced breast cancer.

The concept that expression of the estrogen and/or the progesterone receptor (ER, PgR) is a necessary, yet not sufficient condition, for the antitumor activity of endocrine manipulation in breast cancer has been extensively studied for decades. [1] The formidable research efforts focusing on primary and acquired mechanisms of resistance to endocrine therapy have resulted in newer treatment paradigms. In particular, the rationale of combining endocrine therapy with a pharmacological ‘antidote’ of the putative biological mechanism of resistance has been tested in randomized clinical trials. Notable examples are combinations of endocrine therapy with epidermal growth factor receptor(s) family (EGFR-HER) targeting agents, and with inhibitors of the PI3K/Akt/mTOR pathway, of angiogenesis, and of the cyclin-dependent kinases (CDK) 4/6. The preclinical and clinical development of palbociclib, the first CDK 4/6 inhibitor approved for clinical use, has been elegantly summarized in a review article in this issue of Expert Opinion on Pharmacotherapy by Guenther Steger and colleagues.[2] Abnormal and dysregulated cell proliferation has long been identified as a hallmark of cancer.[3] In this context, biology suggests that Cyclin D1/CDK4/6/pRb protein interaction is important in sustaining a proliferative and possibly endocrine-resistant phenotype in luminal tumors.[4] As described in the review, the preclinical potentialities of this compound in the treatment of hormone-receptor positive breast cancer have been tested in the clinic, with results that have raised enthusiasm and hopes. Furthermore, considering the rapidity of enrolment in other randomized clinical trials with palbociclib and two other CDK 4/6 inhibitors (ribociclib and abemaciclib),[4] additional data on the clinical activity, safety, and efficacy will become available shortly. As it occurred with the mTOR inhibitor everolimus a few years ago, results with palbociclib suggest another treatment paradigm shift in the treatment of women with hormone-receptor positive metastatic breast cancer. At the present time, endocrine therapy is synonymous with a low-toxic, effective and not demanding therapy both for the patient and the health-care system. For these reasons, guidelines recommend to consider endocrine therapy as a default option in a hormone-receptor positive metastatic breast cancer patient when there is ‘no concern or proof of endocrine resistance or there is disease needing a fast response’.[5] In general, adding a biologic to all patients with hormone-receptor positive disease will add substantial toxicity and costs and would likely change the general perception of ‘endocrine therapy’. Therefore, the authors of the review point out a series of open questions that need addressing to correctly estimate the positioning and impact of this novel therapeutic strategy. In our opinion, the first and foremost would be whether adding CDK 4/6 inhibitors to endocrine therapy prolongs overall survival (OS) in these patients. Paloma 1 and 3 show impressive prolongation of progression-free survival (PFS), which was the primary end point for both studies.[6,7] Similar improvements in PFS have been observed with mTOR inhibitors and angiogenesis inhibitors (Table 1).[8–11] Common to these studies are also a marginal to moderate overall response rate gain (with the exception of studies with bevacizumab) and a substantial increase in the clinical benefit rate, resulting from more patients achieving long-lasting disease stabilizations with the combined treatment. At this stage, with the exception of one Phase II randomized trial with tamoxifen and everolimus,[9] no advantage in OS has been reported in favor of any of the combination tested. Mature follow up of the Paloma 1 and 3 clinical trial and the results of large randomized clinical trials using the three CDK 4/6 inhibitors in late stage of clinical development will hopefully provide solid OS data. A clear OS advantage would undoubtedly confirm that this therapeutic strategy is a major advancement in the treatment of hormone-receptor positive metastatic breast cancer. Waiting for OS results, the question is whether a significant PFS advantage would support the widespread use of these compounds in the clinic. As the authors of this review correctly point out, PFS prolongation has positive effects for the individual patient because, for example, it ‘delays the time until the need for cytotoxic chemotherapy with its associated toxicity, side effects, and psychological distress’. The concept of delaying the use of chemotherapy by fully exploiting the potentiality of endocrine therapy has been postulated before the availability for clinical testing of biologics added to endocrine therapy.[12] In that