Giovanni Schinzari

Final analysis of colorectal cancer patients treated with irinotecan and 5-fluorouracil plus folinic acid neoadjuvant chemotherapy for unresectable liver metastases

We have previously reported that neoadjuvant therapy with modified FOLFIRI enabled nearly a third of patients with metastatic colorectal cancer (mCRC) to undergo surgical resection of liver metastases. Here, we present data from the long-term follow-up of these patients. Forty patients received modified FOLFIRI: irinotecan 180 mg m−2, day 1; folinic acid, 200 mg m−2; and 5-fluorouracil: as a 400 mg m−2 bolus, days 1 and 2, and a 48-h continuous infusion 1200 mg m−2, from day 1. Treatment was repeated every 2 weeks, with response assessed every six cycles. Resected patients received six further cycles of chemotherapy postoperatively. Nineteen (47.5%) of 40 patients achieved an objective response; 13 (33%) underwent resection. After a median follow-up of 56 months, median survival for all patients was 31.5 months: for non-resected patients, median survival was 24 months and was not reached for resected patients. Median time to progression was 14.3 and 5.2 months for all and non-resected patients, respectively. Median disease-free (DF) survival in resected patients was 52.5 months. At 2 years, all patients were alive (8 DF), and at last follow-up, eight were alive (6 DF). Surgical resection of liver metastases after neoadjuvant treatment with modified FOLFIRI in CRC patients achieved favourable survival times.

Targeted Therapy in Advanced Gastric Carcinoma:the Future is Beginning

Gastric cancer represents one of the most common cancer worldwide. Unfortunately, the majority of patients present in advanced stage and outcome still remains poor with high mortality rate despite decreasing incidence and new diagnostic and therapeutic strategies. Although utility of classical chemotherapy agents has been widely explored, advances have been slow and the efficacy of these agents has reached a plateau of median overall survival not higher than 12 months. Therefore, researchers focused their attention on better understanding molecular biology of carcinogenesis and deeper knowledge of the cancer cell phenotype, as well on development of rationally designed drugs that would target specific molecular aberrancies in signal transduction pathways. These targets include cell surface receptors, circulating growth and angiogenic factors and other molecules involved in downstream intracellular signaling pathways, including receptor tyrosine kinases. However, therapeutic advances in gastric cancer are not so encouraging when compared to other solid organ malignancies such as breast and colorectal cancer. This article reviews the role of targeted agents in gastric cancer as single-agent therapy or in combination regimens, including their rational and emerging mechanism of action, current and emerging data. We focused our attention mainly on published phase III studies, therefore cornerstone clinical trials with trastuzumab and bevacizumab have been largely discussed. Phase III studies presented in important international meetings are also reviewed as well phase II published studies and promising new therapies investigated in preclinical or phase I studies. Today, in first-line treatment only trastuzumab has shown significantly increased survival in combination with chemotherapy, whereas ramucirumab as single agent resulted effective in progressing patients, but - despite several disappointing results - these are the proof of principle that targeting the proper molecular aberration is the best way for implementing outcome of therapy.

ERCC1 expression affects outcome in metastatic pancreatic carcinoma treated with FOLFIRINOX: A single institution analysis

Introduction No clinically useful predictive factor has been yet identified for treatment of metastatic pancreatic cancer (mPC). It is noteworthy that FOLFIRINOX, despite its high toxicity, is effective only in some patients. We retrospectively analyzed expression of excision repair cross-complementing group-1 (ERCC1) - involved in the repair of platinum induced damage - in patients affected by mPC treated with FOLFIRINOX in order to evaluate its predictive role. Results FOLFIRINOX resulted more effective in patients with normal ERCC1 levels than in those with ERCC1 hyper-expression. Median progression free survival (PFS) was 11 vs. 4 months (HR 0.26; 95% CI 0.14-0.50; p<.0001), median overall survival (OS) 16 vs. 8 months (HR 0.23; 95% CI 0.12-0.46; p<.0001) and disease control rate (DCR) 93% vs. 50% (p=0.00006). The advantage was confirmed at univariate and multivariate analysis. Patients and Methods 71 patients with histologically proven mPC and treated with FOLFIRINOX as first-line therapy were considered eligible. mRNA ERCC1 expression was determined using RT-PCR analysis. Discussion ERCC1 might be an effective predictor of response to FOLFIRINOX in mPC. Patients overexpressing ERCC1 should be excluded by this often toxic therapy and referred to an alternative treatment.

Are TKIs favourable for the elderly with non-small-cell lung cancer?

Background Epidermal Growth Factor Receptor (EGFR) tyrosine-kinase inhibitors (TKIs) have changed treatment strategies for patients with advanced non-small-cell lung cancer (NSCLC) harbouring mutations in EGFR gene. This retrospective analysis assessed efficacy and safety of TKIs in elderly compared to younger patients. Patients and methods 49 patients with advanced NSCLC and mutations in exon 19 or 21 receiving a first-line therapy with TKIs were included and divided into patients aged <70 years and patients aged ≥ 70 years. Primary endpoints were progression free survival (PFS), response rate (RR) and clinical benefit in terms of quality of life; secondary endpoint was overall survival (OS). Results Median PFS was significantly longer in elderly in comparison to younger patients (12.6 and 5.6 months, respectively; p=.008). RR was 64% in younger patients and 75% in elderly population. Eighteen out of 20(90%) elderly patients treated with gefitinib experienced symptoms relief and upgrading of performance status. No difference in terms of OS was found (p= .34). Conclusion TKIs seem more effective in elderly than in younger patients affected by NSCLC with an EGFR gene mutation. We hypothesize that the main difference between the two populations is the number of medications related to concomitant comorbidities that cause an increased plasma level of TKIs.

Real Benefit of Anthracycline-Based Chemotherapy in Elderly and Impaired Patients: a Retrospective Analysis

Non-Hodgkin Lymphoma (NHL) is a frequent cancer in elderly population. Comorbidities often influence the choice among different treatment options; particularly, concern about anthracyclines’ cardiotoxicity induces to select less effective chemotherapy regimens. The present retrospective study includes NHL patients treated in a single institution with and without antracyclines; clinical results have been analysed comparing both elderly (> 70 years) and not-elderly and impaired and not impaired population. 68 patients affected by NHL, diagnosed between 1996 and 2011, have been included. Median OS of whole population was 34 months; there was no significative difference in OS related to age or comorbidities among patients treated with anthracyclines-based regimens. Median OS of elderly patients not treated with anthracyclines resulted significantly lower, irrespectively of comorbidities (20 months); 94% of elderly patients who undergone anthracyclines-based regimen reported symptoms relief and performance status improvement, compared to 75% of elderly not treated with anthracyclines. Results of this retrospective analysis suggest that anthracyclines-based chemotherapy produces a significant improvement in OS and QoL,even in elderly or impaired patients. Comorbidities and age don’t seem absolute contraindications to anthracycline-based chemotherapy.

TK inhibitor pazopanib primes DCs by downregulation of the β-catenin pathway

Pazopanib, a kinase inhibitor that targets angiogenesis, primed dendritic cells from patients with metastatic renal cell carcinoma and healthy donors. The resultant immune response indicates that this could be exploited to improve outcomes for patients undergoing combination immunotherapy. Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting, for example, the VEGF receptors in tumors and have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have also been proposed for treatment of mRCC with encouraging results. A better understanding of the activity of immune cells in mRCC, the immunomodulatory effects of TKIs, and the characteristics defining patients most likely to benefit from various therapies will help optimize immunotherapeutic approaches. In this study, we investigated the influence of the TKI pazopanib on dendritic cell (DC) performance and immune priming. Pazopanib improved DC differentiation and performance by promoting upregulation of the maturation markers HLA-DR, CD40, and CCR7; decreasing IL10 production and endocytosis; and increasing T-cell proliferation. PD-L1 expression was also downregulated. Our results demonstrate that pazopanib inhibits the Erk/β-catenin pathway, suggesting this pathway might be involved in increased DC activation. Similar results were confirmed in DCs differentiated from mRCC patients during pazopanib treatment. In treated patients pazopanib appeared to enhance a circulating CD4+ T-cell population that expresses CD137 (4-1BB). These results suggest that a potentially exploitable immunomodulatory effect induced by pazopanib could improve responses of patients with mRCC in customized protocols combining TKIs with ICI immunotherapy. Cancer Immunol Res; 6(6); 711–22. ©2018 AACR.

Unexpected side effect in mcrc: A care-compliant case report of regorafenib-induced hyperammonemic encephalopathy

Rationale: Regorafenib represents a treatment option in heavily pretreated patients affected by metastatic colorectal cancer (mCRC). Its safety profile is typical of small-molecule tyrosine-kinase inhibitors (TKIs) and most adverse events are manageable. Patient concerns: A 56 years-old Caucasian man affected by mCRC with normal hepatic reserve was treated with regorafenib as second-line treatment. After only 2 days of therapy, the patient presented to the emergency department due to impairment of both spatial and temporal orientation and motor function with bradylalia. Interventions: Serum ammonia level was 191 mmol/L, liver function tests and complete blood count were normal. Regorafenib was withheld and branched chain amino acids and lactulose were administered. Outcomes: Serum ammonia level returned within the normal range, but when regorafenib was restarted at a lower dose level, a new episode of acute confusion arised. Main lesson: Discontinuation of regorafenib after confirmation of hyperammonemia is strongly recommended; reintroduction of the therapy at lower doses after resolution of symptoms related to hyperammonemic encephalopathy has to be discouraged.

COMPETITIVE TESTING THE WHO 2010 VS THE WHO 2017 GRADING OF PANCREAS NEUROENDOCRINE NEOPLASIA: DATA FROM A LARGE INTERNATIONAL COHORT STUDY

Background: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). Objectives: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. Method: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell’s C statistics, and Royston’s explained variation in univariable and multivariable analyses. Results: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. Conclusions: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.

Cisplatin, dacarbazine and vinblastine as first line chemotherapy for liver metastatic uveal melanoma in the era of immunotherapy: a single institution phase II study

No standard therapy is established for metastatic uveal melanoma. Liver involvement in uveal melanoma may lead to organ impairment, which represents a common cause of death. Tumor shrinkage might improve survival by delaying hepatic failure. Since the combination of cisplatin, vinblastine, dacarbazine allowed a high response rate in metastatic cutaneous melanoma, we explored efficacy and safety of this regimen in unresectable liver metastases of uveal melanoma. In the present phase II study we administered intravenously cisplatin (80 mg/mq, day 1), dacarbazine (250 mg/mq/day, days 1–3), vinblastine (2 mg maximum, day 1) every 21 days as first line treatment for patients with unresectable metastases of uveal melanoma and BRAF wild type. Primary endpoint was objective response rate; overall survival (OS), progression-free survival and toxicity were secondary endpoints. Partial responses were observed in five (20%) patients, stable disease in 12 (48%) patients; disease control rate was 68%. Median OS of all the patients was 13 months, median progression free survival was 5.5 months. OS of responding patients was 21 months; OS of patients with disease control was 18 months, significantly longer than survival of progressing patients (7 months, P=0.0003). Five (20%) patients experienced grade 3–4 toxicity. Combination of cisplatin, vinblastine and dacarbazine was feasible and demonstrate both an interesting objective response rate and a survival benefit for patients achieving a disease control. This regimen could be considered for patients with good performance status and unresectable liver limited disease.

Prognostic and predictive factors of eribulin efficacy in heavily pretreated patients affected by metastatic breast cancer: correlation with tumor biology and previous therapies

Background Eribulin mesylate is currently approved in the United States and Europe for the treatment of metastatic breast cancer (MBC). Scope The objective of this retrospective study is to find specific predictive criteria related to patient or tumor characteristics in order to select patients that might benefit the most from eribulin and define the correct treatment sequence. Findings Forty-four patients with MBC who received eribulin in third or subsequent lines of therapy in a single Italian center were considered eligible. Patients were stratified by body mass index, hormonal/HER2 status, and previous therapies. Primary endpoint was progression free survival (PFS), whereas secondary endpoint was disease control rate (DCR). A longer PFS was found in patients with hormone-positive tumors (p=0.0051), in HER2-negative cases (p=0.037), and in overweight patients (p=0.0015). No difference in efficacy was observed when eribulin was administered in third or subsequent lines of therapy. Significantly longer PFS (p<0.0001) and higher DCR (p=0.035) were achieved by patients previously treated with paclitaxel-bevacizumab in comparison to those pretreated with other drug combinations or with anthracyclines. Prior treatment with nab-paclitaxel seems to have a detrimental effect on PFS (p=0.0008). Conclusion Hormone and HER2 status seems a good predictive and prognostic indicator of response to eribulin. Efficacy seems independent from the number of prior therapies, and it is not influenced by prior endocrine treatments and anthracyclines-containing regimens. On the other hand, sensitivity to a prior treatment with paclitaxel-bevacizumab might be predictive of response to eribulin.