Improvements in Systemic Therapies for Advanced Malignant Mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy associated with poor prognosis and a 5-year survival rate of 12%. Many drugs have been tested over the years with conflicting results. The aim of this review is to provide an overview of current therapies in MPM and how to best interpret the data available on these drugs. Furthermore, we focused on promising treatments under investigation, such as immunotherapy with targets different from anti-PD-1/PD-L1 inhibitors, vaccines, target therapies, and metabolism-based strategies.

Baseline total metabolic tumour volume on 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography-computed tomography as a promising biomarker in patients with advanced non-small cell lung cancer treated with first-line pembrolizumab.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become the standard of care in the management of advanced non-small cell lung cancer (NSCLC). Nevertheless, only a small proportion of patients benefit from ICIs. The aim of the present study is to assess whether 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography-computed tomography ([18F]FDG-PET/CT)-derived parameters may be used as biomarkers in patients with advanced NSCLC receiving first-line pembrolizumab. MATERIALS AND METHODS: This is a monocentric retrospective cohort study including patients with advanced NSCLC (stage IV) and Programmed death-ligand 1 (PD-L1) expression ≥50% treated with pembrolizumab. A control group of patients treated with epidermal growth factor receptor (EGFR) inhibitors for EGFR-mutated NSCLC was also enrolled. Only patients with a positive [18F]18F-FDG PET/CT result within 60 days from treatment initiation were included.Total metabolic tumour volume (tMTV) was calculated for each lesion using a dedicated software (PET VCAR; GE Healthcare), which semiautomatically delineates the tumour's contours with a maximum standardised uptake value (SUVmax) threshold of 42% within the lesion. tMTV was obtained summing each lesion's MTV. Potential prognostic parameters for overall survival (OS) were analysed (tMTV, SUVmax, bone/liver metastasis, neutrophil:lymphocyte ratio ≥4, Eastern Cooperative Oncology Group performance status ≥2, lactate dehydrogenase above the upper limit of normal). RESULTS: Overall, 34 patients treated with first line-pembrolizumab and 40 patients treated with EGFR tyrosine kinase inhibitors were included. In the pembrolizumab group, the median follow-up was 20.3, while the median OS was 4.7 months (95% confidence interval [CI] = 0.3-9.1) for patients with tMTV ≥75 cm3 vs not reached (NR) for patients with tMTV <75 cm3 (95% CI = NR-NR; hazard ratio [HR] = 5.37; 95% CI = 1.72-16.77; p = 0.004). No difference was found in the control group (HR = 1.43; 95% CI = 0.61-3.34; p = 0.411). CONCLUSION: Our data suggest that tMTV ≥75cm3 can be used as a prognostic biomarker of poor outcomes in patients with PD-L1-high advanced NSCLC treated with first-line pembrolizumab. This information could be useful for the selection of patients who may require the addition of chemotherapy to pembrolizumab.

How Many Cancer Clinical Trials Can a Clinical Research Coordinator Manage? The Clinical Research Coordinator Workload Assessment Tool.

PURPOSE: Cancer clinical trials (CTs) are now more complex than ever before and require dedicated personnel (clinical research coordinators [CRCs]) to perform regulatory and administrative activities and protocol- and patient-related procedures. We developed a simple tool to measure the workload (WL) of CRCs involved in cancer research and to estimate personnel requirements within a Clinical Trial Center. METHODS: A literature review and 2-month period in which CRCs recorded their activities in a diary provided valuable information that led to the Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Workload Assessment Tool (IWAT) being divided into three sections: Protocol, On-Treatment Patients, and Follow-Up Patients. Twelve full-time senior CRCs from three sites of the Network measured their monthly WL for 30 months to evaluate IWAT reproducibility and accuracy. RESULTS: The IWAT proved to be a user-friendly tool (3-6 minutes required for each CT), with high reproducibility (interobserver reproducibility ranged from 82% to 100% for each IWAT item). In December 2017, the Network had 185 ongoing CTs, with a median of 2.5 active centers for each CT. On the basis of 448 total IWAT measures by CRCs, the majority of trials were academic (57%) or dealt with advanced disease (77%). The median IWAT WL score for each study was 20.98 ± 22.90 (range, 2-188) and 475 ± 229 (range, 150 [junior staff] - 930 [extreme heavy WL]) for each CRC. On the basis of our experience, a monthly WL score of 500-600 was considered an appropriate value for a full-time CRC. CONCLUSION: The IWAT could prove useful in evaluating CT complexity, estimating appropriate CRC WLs, and defining personnel requirements. Independent validation by other CRCs working in different organizational contexts and in different countries is needed.

Early prediction of resistance to tyrosine kinase inhibitors by plasma monitoring of EGFR mutations in NSCLC: a new algorithm for patient selection and personalized treatment.

In Non-Small-Cell Lung Cancer (NSCLC) patients treated with Tyrosine Kinase-Inhibitors (TKIs) therapy, the emergence of acquired resistance can be investigated by plasma monitoring of circulating tumor DNA (ctDNA). A series of 116 patients with EGFR-positive lung adenocarcinomas were treated with first/second generation EGFR TKIs. At clinical progression, 64 (55%) EGFR T790M plasma positive patients were subjected to second line-treatment with osimertinib and strictly monitored during the first month of therapy. Plasma analysis by the EGFR Cobas test showed in 57 (89%) cases a substantial decrease in the levels of the sensitizing EGFR mutant allele (sEGFRma), down to a not detectable value. These patients were defined as plasmatic good responders (PGR). In 7 (11%) patients, the sEGFRma did not drop to zero (plasmatic poor responders, PPR). In these latter cases, Massive Parallel Sequencing (MPS) analysis at the end of the first month and at clinical progression showed the presence of resistant-inducing mutations, including MET and HER2 gene amplification, KRAS and PIK3CA gene mutations. PPR showed disease progression in 5 (71%) cases, stable disease in 2 (29%) cases, and a shorter median Progression-free survival (PFS) (4.3 ± 1.1 months) than that observed in PGR (13.3 ± 1.2 months) (P < 0.0001). Our data indicate that plasma monitoring by a simple RT-PCR-based EGFR mutation test in the first month of treatment may be useful for a rapid identification of patients to be subjected to further characterization by MPS. A diagnostic algorithm for an early detection of resistance-inducing mutations and patient management is reported.

The metronomic all-oral DEVEC is an effective schedule in elderly patients with diffuse large b-cell lymphoma.

Metronomic-chemotherapy (M-CHT) has been rarely assessed in non-Hodgkin-lymphoma (NHL). Therefore, in 2011 we started experimenting a new all-oral M-CHT schedule termed DEVEC (Deltacortene®, etoposide, vinorelbine, cyclophosphamide, +/-Rituximab) in diffuse-large-B-cell lymphoma (DLBCL) patients. Methods Patients with stage Ib-IV were enrolled as follows: 1) treatment-naïve, frail ≥65y, or unfit ≥85y; and 2) relapsed/refractory (R/R) ≥55y. Data were prospectively collected from six Italian centres and compared for efficacy to two reference groups, treated with established iv Rituximab-CHT in 1st and 2nd line respectively. Results from April-2011 to March-2018, 17/51(33%) naïve, 21/51(41%) refractory and 13/51(25.5%) relapsed patients started DEVEC; 39/51(76.5%) were de-novo DLBCL; 10/51(19.6%) transformed-DLBCL and 2/51(3.9%) unclassifiable-DLBCL/classical-Hodgkin-lymphoma. The median age was 85y (range=77-93) and 78y (range=57-91) in naïve and R/R respectively and overall the DEVEC patients had very poor features compared to the reference. The rate of grade≥3 haematological-AEs was 43%(95CI=29-58%): G3-neutropenia was the most frequent; grade≥3 extra-haematological-AEs was 13.7% (95%CI=5.4-25.9%), the most frequent was infection. One-year OS and PFS were 67% and 61% for naive, 60% and 50% for reference-naïve respectively; Cox proportional hazard ratio (Cox-PH-ratio) for OS and PFS were 0.69 (95%CI=0.27-1.76;p=.441) and 0.68 (95%CI=0.28-1.62;p=.381) respectively. One-year OS and PFS were 48% and 39% in the R/R, 36% and 17% in the reference-R/R respectively; Cox-PH-ratio for OS and PFS, were 0.76 (95%CI=0.42-1.40; p=.386) and 0.48 (95%CI=0.28-0.82; p=.007) respectively. Conclusion The favourable activity of DEVEC compared to a real-life series and the convenience of an oral administration, may possibly lay the groundwork for a paradigm-shift in the treatment of elderly DLBCL.

A phase II study of a dose-density regimen with fluorouracil, epirubicin, and cyclophosphamide on days 1 and 4 every 14 days with filgrastim support followed by weekly paclitaxel in women with primary breast cancer.

BACKGROUND: Recent evidence shows that use of anthracycline and taxane adjuvant chemotherapy and dose-dense regimens, consisting of more frequent administration of the drugs, have improved outcomes for breast cancer patients. In this study, we evaluated administration of an epirubicin-based regimen with paclitaxel in a sequential, dose-dense schedule as adjuvant treatment for patients with high-risk primary breast cancer. METHODS: In a phase II Simon two-stage design study, we evaluated the feasibility of a modified fluorouracil, epirubicin, and cyclophosphamide (FEC) regimen at high dose intensity (fluorouracil 500 mg/m(2) i.v. on days 1 and 4, epirubicin 60 mg/m(2) i.v. on days 1 and 4, and cyclophosphamide 500 mg/m(2) i.v. on days 1 and 4; all drugs were administered every 14 days for 3 cycles) with granulocyte colony-stimulating factor support followed by dose-intense weekly paclitaxel 100 mg/m(2) for 8 cycles. In 11 patients with breast cancer following quadrantectomy (n = 8) or modified radical mastectomy (n = 3), any grade 3 (G3) or higher nonhematologic toxicity (excluding alopecia, nausea or vomiting, and bone pain, which might be a consequence of the administration of filgrastim) and adherence to the scheduled dose-dense treatment (deliverability) were monitored with the purpose of enrolling an additional 27 patients in the case of a satisfying toxicity profile and deliverability of the planned treatment (at least 7 patients completing the treatment). RESULTS: Five of 11 patients experienced G3 or higher nonhematologic toxicity during the FEC regimen. We did not observe G3 or higher nonhematologic toxicity related to paclitaxel treatment. In particular, three patients experienced G3 fatigue, one patient had G3 oral mucositis, three patients had G3 hypokalemia, one patient had G3 syncope, one patient had G3 transaminitis (alanine aminotransferase), one patient experienced G4 pulmonary thromboembolism, and 1 patient had a G3 breast infection. Four of 11 patients received the regimen with a 25% dose reduction of day 1 and 4 administrations of FEC. Seven of 11 patients required FEC delay ≥7 days in at least 1 cycle, regardless of dose intensity. Two patients failed to complete the FEC regimen. Two of the remaining 9 patients were treated with paclitaxel delay ≥7 days in at least one cycle. After a median follow-up of 28 months, 9 patients were continuously disease free. CONCLUSION: The tolerability rate of a dose-density regimen with FEC followed by weekly paclitaxel was considered not promising for completing the accrual of this study.

Early outcome prediction on 18F-fluorocholine PET/CT in metastatic castration-resistant prostate cancer patients treated with abiraterone.

OBJECTIVE: We investigated the role of 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) in the early evaluation of abiraterone and outcome prediction in patients with metastatic castration-resistant prostate cancer (CRPC). PATIENT AND METHODS: Forty-three patients with metastatic CRPC progressing after docetaxel received abiraterone 1,000 mg daily with prednisone 5 mg twice daily. Patients were evaluated monthly for serological PSA response and safety. FCH-PET/CT was done at baseline and after 3 to 6 weeks. Univariate and multivariate Cox regression models addressed potential predictors of progression-free survival (PFS) and overall survival (OS). RESULTS: Declines in PSA level of ≥50% were seen in 21 of 43 (49%) patients. Forty-two patients were evaluable for FCH-PET/CT response. FCH-PET/CT bone flare was observed in 4 of 42 (10%) evaluable patients. In univariate analysis, PSA decline and FCH-PET/CT response predicted PFS, while PSA decline and FCH-PET/CT (progression vs non progression) predicted OS. In multivariate analysis, only FCH-PET/CT (progression vs nonprogression) remained significant for PFS and OS (p = 0.022 and p = 0.027, respectively). CONCLUSION: Early FCH-PET/CT can predict clinical outcome in CRPC beyond PSA response. These data support further studies on FCH-PET/CT for abiraterone monitoring and outcome prediction in patients with CRPC.

Chromogranin A predicts outcome in prostate cancer patients treated with abiraterone.

In this retrospective study, we evaluated the chromogranin A (CgA) baseline value as a predictor of clinical outcome in patients with metastatic castration-resistant prostate cancer (CRPC) treated with abiraterone 1000 mg per day, whose disease progressed after docetaxel chemotherapy. In the 48 evaluable patients, serum CgA level was normal when <120  ng/ml (group A, n=16), within three times the upper normal value (UNV) when between 120 and 360 (group B, n=16), more than three times the UNV when ≥360  ng/ml (group C, n=16). Decline in PSA level ≥50% or more (PSA RR) was observed in 26 of 48 (54%) patients. PSA response rate did not correlate with the CgA groups. CgA levels more than three times the UNV predicted an early radiological progressive disease in eight of 11 cases (73%). The median progression-free survival (PFS) among the CgA groups A, B, and C was 9.2, 9.2, and 4.8 months respectively, P=0.0459. The median overall survival (OS) among the CgA groups was 19.0, 18.8, and 10.8 months respectively, P=0.2092. In the multivariate analysis, PSA RR (nonresponsive vs responsive) and CgA levels (group 3 vs groups 1+2) were predictors of PFS (P=0.0002 and P=0.0047 respectively), whereas PSA RR only was significantly associated with OS (P=0.0024), while CgA levels remained of borderline significance (P=0.0919). A serum CGA level more than three times the UNV predicted PFS and showed a trend vs OS prediction, independently from PSA response, in CRPC patients treated with abiraterone.

RANK/RANK-L/OPG in patients with bone metastases treated with anticancer agents and zoledronic acid: a prospective study.

Patients with solid cancer frequently develop bone metastases (BM). Zoledronic acid (Zometa®, ZA), routinely used to treat patients with BM, acts on osteoclasts and also has antitumor properties. We aimed to assess the effect of ZA over time in novel bone turnover markers (RANK/receptor activator of nuclear factor-k B ligand (RANK-L)/ Osteoprotegerin (OPG)) and to correlate these with serum N-terminal telopeptide (NTX). The study prospectively evaluated levels of RANK, RANK-L and OPG transcripts by real-time PCR and NTX expression by ELISA in the peripheral blood of 49 consecutive patients with advanced breast, lung or prostate cancer. All patients received the standard ZA schedule and were monitored for 12 months. Median baseline values of RANK, RANK-L and OPG were 78.28 (range 7.34-620.64), 319.06 (21.42-1884.41) and 1.52 (0.10-58.02), respectively. At 12 months, the median RANK-L value had decreased by 22% with respect to the baseline, whereas median OPG levels had increased by about 96%. Consequently, the RANK-L/OPG ratio decreased by 56% from the baseline. Median serum NTX levels decreased over the 12-month period, reaching statistical significance (p < 0.0001). Our results would seem to indicate that ZA modulates RANK, RANK-L and OPG expression, thus decreasing osteoclast activity.