A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301).

PURPOSE: 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. PATIENTS AND METHODS: NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. RESULTS: Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0-11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. CONCLUSION: NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. TRIAL REGISTRATION: Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240 .

Lag3: From Bench to Bedside.

The introduction of immune checkpoint inhibitors represented a breakthrough treatment for metastatic melanoma, but the effect of these agents is not limited to a single cancer type. Promising results have been reported in various solid tumors, for example, lung cancer. The success of these drugs depends on the activation of tumor-infiltrating lymphocytes and primary and acquired resistance have been reported alongside a high rate of immune-related adverse events when agents targeting different immune checkpoints are given in combination. Numerous other targets have been investigated to overcome the resistance, improve the activity, and reduce the toxicity of checkpoint inhibitor therapy. Among these, the most promising is Lymphocyte-activation gene 3 (LAG-3), a transmembrane protein involved in cytokine release and inhibitory signaling in T cells. Preclinical data showed that LAG-3 is a negative regulator of both CD4+ T cell and CD8+ T cell and the activity on CD8+ T cell is independent of CD4+ activation. On the CD8+ T cell, LAG-3 activation abrogates the antigen presentation whereas on the CD4+ T cell, arrests the S phase of the cell cycle. The blockade of LAG-3 has been tested in several combination therapies, and recent clinical data showed a good safety profile and a synergistic effect with anti-PD-1, suggesting that this combination could become a standard treatment for metastatic melanoma. In this review, we report the available preclinical data and the new clinical data on LAG-3 blockade in different solid tumors, and we discuss LAG-3 as potential prognostic and predictive factor, together with possible future applications.

Long-Term Outcomes of Immune Checkpoint Inhibition in Metastatic Melanoma.

Increasing knowledge about the biology of melanoma and of immunology has led to the development and regulatory approval of the immune checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab, which are indicated for the treatment of melanoma irrespective of the B-Raf proto-oncogene mutation status of the tumour. Only a subset of patients will respond, but those who do can expect long-lasting, previously unheard-of responses. Long-term survival results for the registration trials, including CheckMate 067, Keynote-006, and Keynote-001, have recently been published. In particular, the combination of ipilimumab and nivolumab showed an impressive 5-year overall survival of just over 50%. However, toxicity remains a significant concern, with some of the side effects being life threatening and/or life changing. In this review, we discuss the safety and efficacy data of all the agents currently approved for the first-line treatment of advanced melanoma, identifying factors that influence the choice of a single agent rather than combination therapy. We highlight the potential biomarkers of response, effects of long-term toxicity, and options after progression.

CHK1 inhibition exacerbates replication stress induced by IGF blockade.

We recently reported that genetic or pharmacological inhibition of insulin-like growth factor receptor (IGF-1R) slows DNA replication and induces replication stress by downregulating the regulatory subunit RRM2 of ribonucleotide reductase, perturbing deoxynucleotide triphosphate (dNTP) supply. Aiming to exploit this effect in therapy we performed a compound screen in five breast cancer cell lines with IGF neutralising antibody xentuzumab. Inhibitor of checkpoint kinase CHK1 was identified as a top screen hit. Co-inhibition of IGF and CHK1 caused synergistic suppression of cell viability, cell survival and tumour growth in 2D cell culture, 3D spheroid cultures and in vivo. Investigating the mechanism of synthetic lethality, we reveal that CHK1 inhibition in IGF-1R depleted or inhibited cells further downregulated RRM2, reduced dNTP supply and profoundly delayed replication fork progression. These effects resulted in significant accumulation of unreplicated single-stranded DNA and increased cell death, indicative of replication catastrophe. Similar phenotypes were induced by IGF:WEE1 co-inhibition, also via exacerbation of RRM2 downregulation. Exogenous RRM2 expression rescued hallmarks of replication stress induced by co-inhibiting IGF with CHK1 or WEE1, identifying RRM2 as a critical target of the functional IGF:CHK1 and IGF:WEE1 interactions. These data identify novel therapeutic vulnerabilities and may inform future trials of IGF inhibitory drugs.

Window of opportunity clinical trial designs to study cancer metabolism.

Window of opportunity trials exploit the 'window' of time after cancer diagnosis, typically prior to initiation of cancer therapy. In recent years this study design has become a more regular feature of drug development, as this 'window' provides an opportunity to carry out a thorough pharmacodynamic assessment of a therapy of interest in tumours that are unperturbed by prior treatment. Many of the first window trials interrogated the bioactivity of drugs being repurposed for cancer treatment, in particular the anti-mitochondrial agent, metformin. In this review, we describe examples of window study designs that have been used to assess drugs that target cancer metabolism with a focus on metformin. In addition, we discuss how window studies may aid the development of molecular metabolic cancer imaging.

Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor-positive, advanced breast cancer: A real-world experience.

Data from 423 human epidermal growth factor receptor 2-negative (HER2-), hormone receptor-positive (HR+) advanced breast cancer (aBC) patients treated with palbociclib and endocrine therapy (ET) were provided by 35 Italian cancer centers and analyzed for treatment outcomes. Overall, 158 patients were treated in first line and 265 in second/later lines. We observed 19 complete responses and 112 partial responses. The overall response rate (ORR) was 31% (95% confidence interval [CI], 26.6-35.4) and clinical benefit was 52.7% (95% CI, 48-57.5). ORR was negatively affected by prior exposure to everolimus/exemestane ( p = 0.002) and favorably influenced by early line-treatment ( p < 0.0001). At 6 months, median progression-free survival was 12 months (95% CI, 8-16) and median overall survival was 24 months (95% CI, 17-30). More favorable outcomes were associated with palbociclib in early lines, no visceral metastases and no prior everolimus/exemestane. The main toxicity reported was neutropenia. Our results provide further support to the use of palbociclib with ET in HER2-, HR+ aBC. Differences in outcomes across patients subsets remain largely unexplained.

Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues.

BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

Immunotherapy for pancreatic cancer: present and future.

Despite the identification of some efficient drugs for the treatment of metastatic pancreatic cancer, this tumor remains one of the most lethal cancers and is characterized by a strong resistance to therapies. Pancreatic cancer has some unique features including the presence of a microenvironment filled with immunosuppressive mediators and a dense stroma, which is both a physical barrier to drug penetration and a dynamic entity involved in immune system control. Therefore, the immune system has been hypothesized to play an important role in pancreatic cancer. Thus, therapies acting on innate or adaptive immunity are being investigated. Here, we review the literature, report the most interesting results and hypothesize future treatment directions.

GEMOX: An Active Regimen for the Treatment of Luminal and Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.

BACKGROUND: Pretreated metastatic breast cancer (MBC) remains a formidable challenge with unmet needs both in terms of prolonged survival and quality-of-life-related issues. METHODS: We collected data from 27 MBC patients treated with gemcitabine and oxaliplatin (GEMOX) at our institution between June 2009 and April 2015. The patients were heavily pretreated, and all had previously been exposed to anthracyclines and taxanes. RESULTS: We achieved a complete response in 1 patient (4%), a partial response in 7 patients (26%) and stable disease in 12 patients (44%), while 6 patients (22%) experienced progressive disease. The response of 1 patient (4%) could not be evaluated because she interrupted her treatment during the first cycle due to a major reaction to oxaliplatin. We observed grade 4 hypertransaminasaemia in only 1 patient (4%) and grade 2 neuropathy in 16 patients (59%). Grade 3 leuconeutropenia was observed in 5 patients (18%). The median progression-free survival was 5.9 months and the median overall survival was 9.6 months. CONCLUSIONS: GEMOX is an efficient and well-tolerated salvage regimen for MBC patients.

Parents with cancer: Searching for the right balance between telling the truth and protecting children.

OBJECTIVE: Recent scientific approaches to cancer patients draw attention to the psychological aspects of the disease and the involvement of their families, who are forced to reorganize themselves in order to manage the patient's illness. Functional responses to a stressful event facilitate open communication between family members and empathy for the patient's children, who need to be involved and informed about the illness in a clear and open fashion. The primary goal of this observational study was to explore the communication styles used by cancer-stricken parents with their children and to identify a correlation with the patient's levels of anxiety and depression and their ability to cope. We also sought to understand whether location, severity, and time from diagnosis influenced communication, coping, anxiety, or depression. METHOD: From September of 2011 to July of 2015, 151 questionnaires were given to patients who had received at least one course of chemotherapy. The instruments that we employed were the Openness to Discuss Cancer in the Nuclear Family Scale, the Hospital Anxiety and Depression Scale, and the Mini-Mental Adjustment to Cancer Scale. Our sample included patients with children aged from 3 to 18 years. The patients had different types of cancer, mainly gastrointestinal and breast cancer. Their disease was at the metastatic stage in approximately 20% of patients. RESULTS: Our results showed statistically significant correlations between higher levels of anxiety and depression and more closed communication styles. The coping styles "hopelessness/helplessness," "cognitive avoidance," and "anxious preoccupation" were associated with a closed communication style that is correlated with higher levels of anxiety and depression. Tumor location, time from diagnosis, and stage of disease did not show statistically significant correlations with anxiety, depression, coping mechanisms, or communication styles. SIGNIFICANCE OF RESULTS: Our study confirmed what has been reported in the literature: high levels of anxiety and depression affect communication among family members. Not surprisingly, the "fighting spirit" coping style engenders open communication.

Chemotherapy rechallenge after regorafenib treatment in metastatic colorectal cancer: still hope after the last hope?

INTRODUCTION: The introduction of biological agents in cancer therapy is changing the progression of metastatic colorectal cancer. Currently, resistance to biological agents is an emerging problem; the progression of the disease is caused by the development of resistant clones. According to some authors, these clones can be re-sensitized to traditional and previously utilized chemotherapy agents. The results of the CORRECT study demonstrated the efficacy of regorafenib monotherapy in both KRAS wild type and mutant pretreated patients (pts). Two recent reports showed the potential of reintroduction of chemotherapy, even after treatment with regorafenib. PATIENTS AND METHODS: We performed a retrospective review of clinical data from patients treated with regorafenib at our institution between March 2012 and March 2013. We analysed patient characteristics, KRAS/NRAS status, response to treatment (evaluated by RECIST v1.1 criteria) and survival. RESULTS: Regorafenib was administered to 128 patients, and 11 (8.6%) received post-regorafenib therapy (to our knowledge). Seven (63.6%) patients were wild type for KRAS/NRAS. Post-regorafenib therapy represented for all the patients at least the fourth line: all the pts received both oxaliplatin- and irinotecan-based chemotherapy, all of them were treated with bevacizumab, and 7 patients also received cetuximab. Eight patients (72.7%) were treated with standard chemotherapy after regorafenib (irinotecan monotherapy, capecitabine plus oxaliplatin or irinotecan, dacarbazine or raltitrexed), while 3 patients received an experimental therapy (clinical trial). Nine of the 11 (81.8%) patients had PD and 2 patients had SD. The median progression-free survival was 1.6+ months (range 0.5-3.5), the median OS post-regorafenib was 2.1+ months (range 0.5-10.2) and the 6-month OS was 27.3%. CONCLUSION: Our retrospective analysis showed that after regorafenib therapy, re-introduction of chemotherapy is possible. Unfortunately, we reported a high percentage of disease progression beyond regorafenib, which is likely due to the high percentage of heavily pretreated patients (some received four or five types of therapy before regorafenib). We think that regorafenib could represent a chemotherapy resensitizing agent; however, additional studies are needed in patients who have received less pretreatment.

Current Role of Minimally Invasive Radical Cholecystectomy for Gallbladder Cancer.

Background. For Tis and T1a gallbladder cancer (GbC), laparoscopic cholecystectomy can provide similar survival outcomes compared to open cholecystectomy. However, for patients affected by resectable T1b or more advanced GbC, open approach radical cholecystectomy (RC), consisting in gallbladder liver bed resection or segment 4b-5 bisegmentectomy, with locoregional lymphadenectomy, is considered the gold standard while minimally invasive RC (MiRC) is skeptically considered. Aim. To analyze current literature on perioperative and oncologic outcomes of MiRC for patients affected by GbC. Methods. A Medline review of published articles until June 2016 concerning MiRC for GbC was performed. Results. Data relevant for this review were presented in 13 articles, including 152 patients undergoing an attempt of MiRC for GbC. No randomized clinical trial was found. The approach was laparoscopic in 147 patients and robotic in five. Conversion was required in 15 (10%) patients. Postoperative complications rate was 10% with no mortality. Long-term survival outcomes were reported by 11 studies, two of them showing similar oncologic results when comparing MiRC with matched open RC. Conclusions. Although randomized clinical trials are still lacking and only descriptive studies reporting on limited number of patients are available, current literature seems suggesting that when performed at highly specialized centers, MiRC for GbC is safe and feasible and has oncologic outcomes comparable to open RC.

Pancreatic cancer: New hopes after first line treatment.

Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. Extensive research has yielded advances in first-line treatment strategies, but there is no standardized second-line therapy. In this review, we examine the literature trying to establish a possible therapeutic algorithm.

[Ramucirumab-paclitaxel as second-line therapy for advanced gastric cancer: Poliambulanza experience]. / Ramucirumab-paclitaxel nella seconda linea nel carcinoma gastrico metastatico: esperienza della Fondazione Poliambulanza.

We reported the cases of two patients affected by metastatic gastric cancer exposed to second line therapy with ramucirumab plus paclitaxel after progression. Both obtained a fast marker reduction with a very favourable toxicity profile. In the first case, a woman affected by peritoneal carcinomatosis, the disease had been stable for 8 months despite of the chemotherapy suspension after 3 cycles; whereas in the second case, a highly symptomatic man with a heavy tumor load (gastric tumor and multiple bone, node and peritoneal metastases) obtained an immediate clinical benefit even if of relatively short duration with a good tolerability.

QT Prolongation and Anticancer Drugs: Is it a Cardiologist's Worry? The Oncologist's Point of View.

Currently, many novel therapies are available for physicians treating cancer; some of them are associated with adverse cardiac events. One of the most worrisome cardiac event is QT prolongation, which is a risk factor for developing the potentially fatal torsade de pointe. Many classes of drugs, both anticancer and concomitant agents, are involved in this issue. We report a review of old and new commonly used agents with torsadogenic potential.

Pancreatic Cancer: Promises and Failures of Target Therapies.

Currently, few efficient therapies are available to battle pancreatic cancer. Mechanisms underlying this cancer are not well known and researchers are trying to identify new therapeutic targets. Here, we present a review of new treatments and their results in recent years.

Gemcitabine Plus Nab-Paclitaxel as Second-Line and Beyond Treatment for Metastatic Pancreatic Cancer: a Single Institution Retrospective Analysis.

Metastatic pancreatic cancer still represent one of the most deadly disease for which there are few therapeutic options, especially in second line and beyond setting. Nabpaclitaxel plus gemcitabine activity was demonstrated in first line setting, but there are no clear evidence suggesting its use after that. We report a retrospective data analysis of 23 patients who received nab-paclitaxel plus gemcitabine after first line treatment at our Oncology Department. We observed a significant clinical benefit (43,5%) with a median overall survival of 5 months. In addition, manageable side effects were reported. Our data, despite the small sample, seem to indicate that nab- paclitaxel plus gemcitabine is an active and well tolerated regimen even in pretreated patients.

Oxaliplatin-induced hypersensitivity reaction: underlying mechanisms and management.

Hypersensitivity reactions are rare but feared drugs adverse effect. These reactions are not uncommon with anticancer drugs, such as taxanes, monoclonal antibodies, and platinum compounds. Oxaliplatinum, a third-generation platinum compound, one of the mainstay drugs in the treatment of many gastrointestinal cancers, can give rise to hypersensitivity reactions, sometimes with fatal outcomes. In this paper, we reviewed the incidence and mechanisms underlying the occurrence of this event, highlighting the most recent advances concerning the pathogenesis of the reaction and also reporting possible risk factors identified and the most effective treatment in preventing the onset of this event.

Assessing cancer caregivers' needs for an early targeted psychosocial support project: The experience of the oncology department of the Poliambulanza Foundation.

OBJECTIVE: Caregivers play a key role in the management of patients with cancer. However, some studies have suggested that caregivers have even more unmet needs than the patients. METHOD: To better identify the needs and changes in the lifestyles of the caregivers in our practice and to plan a targeted support project to decrease caregiver burden, we administered the Caregiver's QoL Index-Cancer (CQoLC) to 200 consecutive caregivers. This questionnaire assesses psychological well-being, the relationship with healthcare professionals, administration of finances, lifestyle disruption, and positive adaptation. RESULTS: Our data showed that being a caregiver to a patient with metastatic disease negatively affected females mostly with regard to mental and emotional burden, while men complained more about their sexual life (42.3 vs. 33.6%), although this result was not significant. Some 93.5% of caregivers reported that they were pleased with their role, while 83.4% were concerned about financial difficulties. SIGNIFICANCE OF RESULTS: We strongly believe that early supportive care directed not only at patients but also to caregivers may improve the quality of life (QoL) in this population. We are currently developing a targeted support project to decrease caregiver burden.