Single-agent carboplatin in extensive disease small-cell lung cancer patient with liver failure: a case report within the experience of a single institution.

Until recently, platinum-based chemotherapy has represented the benchmark for the treatment of extensive disease small-cell lung cancer (ED-SCLC). ED-SCLC patients are often diagnosed with poor performance status (PS ≥2) and/or compromised organ functions. In fact, up to 63% of ED-SCLC has extensive liver involvement at diagnosis, which correlates with a poor prognosis. Whether to treat patients with tumor-related organ failure is still debated and the selection of those who could benefit from chemotherapy is crucial. Moreover, severe liver impairment contraindicates the administration of etoposide. Among 74 consecutive ED-SCLC patients followed at our institution from January 2017 to November 2019, three patients received single-agent carboplatin as a first-line treatment due to liver failure. We provide a brief description of a former heavy smoker 70-year-old man who was diagnosed with ED-SCLC and severe liver involvement leading to liver failure. The patient received a first-line treatment with single-agent carboplatin, obtaining a partial response, clinical benefit and the normalization of laboratory test, which documented the complete recovery of liver function. The intent of our work is to highlight the feasibility of single-agent carboplatin in ED-SCLC patients with tumor-related hepatic failure but preserved Eastern Cooperative Oncology Group PS, suggesting that this therapeutic option should not be discouraged a priori. Indeed, the identification of specific tools guiding physicians in the selection of patients who might benefit from the treatment is remarkably needed; meanwhile, the use of available prognostic score (e.g. Manchester score) might be of great value and should be considered in clinical practice.

Hyperammonemic encephalopathy during XELOX regimen. Is it capecitabine or oxaliplatin responsible?

Hyperammonemic encephalopathy represents a rare adverse effect of several chemotherapeutic agents, occurring in about 0.7% of patients treated with fluoropyrimidines, and it is independent from dihydropyrimidine dehydrogenase deficiency. Instead, its physiopathology is linked to the inhibition of Krebs cycle by fluoroacetate, leading to decreased ATP production, and to the inhibition of the urea cycle. Oxaliplatin seems to induce hyperammonemic encephalopathy in a similar way, acting on mitochondria. Here, we report the intriguing case of acute hyperammonemic encephalopathy in a 65-year-old patient with preserved liver function, who was treated with oxaliplatin and capecitabine for a metastatic, G1, atypical lung carcinoid. We reviewed the literature and found very few reports of oxaliplatin or capecitabine-induced hyperammonemic encephalopathy. Out of five cases of capecitabine-related hyperammonemic encephalopathy analyzed (four plus our case), median time to hyperammonemic encephalopathy onset was 6 days, with median serum ammonia levels of 213 µmol/L. Oxaliplatin-related hyperammonemic encephalopathy analyzed cases were three (two plus ours), with a median time to hyperammonemic encephalopathy of 11 days and median serum ammonia levels of 167 µmol/L. Identified predisposing factors for chemotherapy-induced hyperammonemia, such as dehydration, liver and renal impairment, infections, and sarcopenia were absent in our case. We hypothesize that the combination of a platinum-derivative and a fluoropyrimidine multiplies the risk of hyperammonemic encephalopathy, even in the absence of predisposing factors nor impaired liver function. We therefore suggest to always consider the risk of hyperammonemia when starting fluoropyrimidines-based chemotherapy, especially combined with platinum-derivatives, and to timely investigate neurologic symptoms monitoring ammonia serum levels.

Clinical management of a pituitary gland metastasis from clear cell renal cell carcinoma.

In very few years, several treatments have significantly improved the prognosis of patients with metastatic renal cell carcinoma (RCC). Despite this, the clinical outcomes of specific subgroups of patients including those with central nervous metastases still remain poor. In this population, a very infrequent and poorly described site of metastases is the pituitary gland. Because of the important endocrinal function and the anatomic site of this specific organ, clinical management of this complication requires several additional precautions compared with other central nervous metastases. Here, we describe a case of a single pituitary metastasis from clear cell RCC in a patient who showed a surprising progression-free survival and overall survival to sunitinib first-line treatment. Because of the uncommon clinical course of the disease of our patient and the atypical site of metastases, we want also to underline the importance of further investigation of molecular pathways associated with a favorable prognosis in patients with metastatic clear cell RCC.

A case of complete response to nivolumab after long-term progression-free survival with tyrosine kinase inhibitor.

Nivolumab is an effective and tolerable treatment for metastatic renal cell carcinoma, showing longer median overall survival than everolimus and achieving a good percentage of objective response, stable disease, and prolonged responses. However, very few cases have been reported in the literature of a complete response to nivolumab in the metastatic pretreated setting. Here, we report a case of complete response to nivolumab in II line following sunitinib in a metastatic clear cell renal cell carcinoma with favorable risk according to the IMDC criteria. This is also an interesting case on the use of immunotherapy following a long period of antiangiogenetic therapy, underlining the importance of the sequence of treatment to achieve the best possible outcome in terms of prolonged overall survival, progression-free survival, and objective response.

The outcome to axitinib or everolimus after sunitinib in metastatic renal cell carcinoma.

We aimed to investigate the different outcomes in patients with metastatic renal cell carcinoma treated with second-line axitinib or everolimus after sunitinib. Patients treated in 16 oncological centres in Italy were included, and those receiving axitinib or everolimus from January 2013 onwards were analysed for outcomes. Descriptive statistical tests were used to highlight differences between groups. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Data on 634 patients with metastatic renal cell carcinoma treated with first-line sunitinib have been obtained. A total of 182 patients received a second-line therapy with everolimus (79 patients, 43%) or axitinib (103 patients, 57%), respectively. The median PFS was 4.6 [95% confidence (CI): 2.6-6.5] months for patients treated with everolimus and 5.5 (95% CI: 4.3-6.7) months for patients treated with axitinib (P=0.7). The median OS was 13.9 (95% CI: 10.4-17.4) months for patients treated with everolimus and 12.0 (95% CI: 7.9-16.2) months for patients treated with axitinib (P=0.3). No differences were found based on length of first-line treatment. Major limitations are the retrospective nature of the study and the lack of a prospective evaluation of the progression. This study reports no significantly differences between everolimus and axitinib in terms of both PFS and OS. Furthermore, the length of first-line treatment cannot be used as such a predictive factor and cannot suggest the use of a molecule compared with another.

Oxaliplatin-Based Chemotherapy in Advanced Neuroendocrine Tumors: Clinical Outcomes and Preliminary Correlation with Biological Factors.

PURPOSE: The role of chemotherapy in low-/intermediate-grade neuroendocrine tumors (NETs) is still debated. We present the results of an Italian multicenter retrospective study evaluating activity and toxicity of oxaliplatin-based chemotherapy in patients with advanced NETs. METHODS: Clinical records from 5 referral centers were reviewed. Disease control rate (DCR) corresponding to PR + SD (partial response + stable disease) at 6 months, progression-free survival (PFS), overall survival (OS) and toxicity were calculated. Ki67 labeling index, grade of differentiation and excision- repair-cross-complementing group 1 (ERCC-1) were analyzed in tissue tumor samples. RESULTS: Seventy-eight patients entered the study. Primary sites were: pancreas in 46, gastrointestinal in 24, lung in 19 and unknown in 10% of patients. The vast majority were G2 (2010 WHO classification). Eighty-six percent of the patients were metastatic, and 87% were pretreated and progressive to previous therapies. Sixty-five percent of the patients received capecitabine/oxaliplatin (CAPOX), 6% gemcitabine/oxaliplatin (GEMOX), and 29% leucovorin/fluorouracil/oxaliplatin (FOLFOX-6). PR occurred in 26% of the patients, half of them with pancreatic NETs, and SD in 54%. With a median follow-up of 21 months, the median PFS and OS were 8 and 32 months with 70 and 45 events, respectively. The most frequent G3 toxicities were neurological and gastrointestinal. ERCC-1 immunohistochemical overexpression was positive in 4/28 evaluated samples, with no significant correlation with clinical outcome. CONCLUSION: This analysis suggests that oxaliplatin-based chemotherapy can be active with a manageable safety profile in advanced NETs irrespective of the primary sites and tumor grade. The 80% DCR and 8-month PFS could justify a prospective study in NETs with intermediate biological characteristics, especially with pancreatic primary tumors.

Real-world study of everolimus in advanced progressive neuroendocrine tumors.

Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3-4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3-4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs.

Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the XELBEVOCT study.

BACKGROUND: We assessed the activity and toxicity of the XELBEVOCT regimen in patients with metastatic well-to-moderately differentiated neuroendocrine neoplasms (WMD-NEN). Ancillary studies evaluated hypertension, proteinuria, and vascular endothelial growth factor (VEGF) polymorphisms in predicting progression-free survival (PFS) and the predictive role of serum vitamin D in progression-free survival and proteinuria onset. METHODS: This prospective phase 2 study included 45 patients with WMD-NEN arising from various primary sites. The treatment regimen was octreotide long-acting release (LAR), 20 mg monthly, metronomic capecitabine, 2000 mg/daily, and intravenous bevacizumab, 5 mg/kg every 2 weeks, without interruption for 9 months. Bevacizumab was continued until disease progression. RESULTS: Partial response was obtained in 8 patients (17.8%, 95% confidence interval [CI], 6.4%-28.2%); tumor response was more frequent in pancreatic than in non-pancreatic malignancies. The median PFS was 14.9 months; median overall survival was not attained. Biochemical and symptomatic responses were observed in 52.9% and 82.3% of cases, respectively. The treatment was well tolerated. Grade 3 toxicities included hand and foot syndrome (11.1%), proteinuria (4.4%), and renal toxicity (2.2%). Proteinuria (all grades) was correlated with longer PFS (p = 0.017). There was an inverse relationship between proteinuria and vitamin D levels. VEGF polymorphisms were not associated with patient outcome. CONCLUSION: The XELBEVOCT regimen is active and well tolerated in patients with metastatic WMD-NEN. Proteinuria correlated with hypovitaminosis D status and was the best predictive factor of treatment efficacy. TRIAL REGISTRATION: Trial registration number NCT01203306.

Human herpesvirus 6 encephalitis simulating brain metastases in a patient with advanced small-cell lung cancer.

BACKGROUND: The brain is a frequent site of metastases in small-cell lung cancer. Symptoms of cerebral involvement are headache, disorientation, nausea/vomiting and seizures. CASE: A man with small-cell lung cancer developed a human herpesvirus 6 (HHV-6) meningoencephalitis with neurological symptoms that simulated brain involvement from the lung cancer. HHV-6 is a T cell lymphotropic virus which may be pathogenic in the immunocompromised host. HHV-6 remains latent after the first infection, and when the immune system is compromised it can reactivate. The treatment of HHV-6 infection is highly specific and the drugs recommended are the two antivirals, ganciclovir or foscarnet. CONCLUSION: In cancer patients neurologic symptoms are usually due to brain metastases. This case shows that in a cancer patient any aspecific neurologic symptom should be carefully evaluated in order to exclude a non-oncologic cause. This statement is particularly true if the therapies for the oncological and neurological diseases are effective.

Critical diagnostic delay associated with unusual presentation of hepatocellular carcinoma (HCC) with orbital metastases: a case report.

Orbital metastases are an extremely rare finding in patients with hepatocarcinoma (HCC), especially as its first presentation. Therefore, the risk of misdiagnosis is high, as well as that of drastic delays of the therapeutic algorithm. Here we report a 71-year-old man presenting with orbital metastases as the initial sign of HCC, whose initial misdiagnosis led to the impossibility to start life-saving cancer treatment. The patient's history has begun on March 2018 with a growing tumefaction of the right orbit initially treted with antibiotics and corticosteroids without benefit. Subsequently, a facial CT scan showed a voluminous right intra-orbital mass, eroding the orbital roof. Tissue biopsy documented well differentiated malignant epithelial tumor cells. Under the suspect of primitive lachrymal gland tumor, the patient was admitted to the head and neck Unit with surgical intent. However, a subsequent 18F-FDG-PET documented the presence of liver lesions and multiple sites of metastasis. A new biopsy, this time on liver nodules, was carried out and the diagnosis of HCC was finally made. Samples from the first biopsy were then reviewed and judged consistent with HCC metastasis. Unfortunately, the initial misdiagnosis resulted in a six-month delay of the start of a therapeutic approach. During that time, patient's general conditions got extremely worse, making him unable to afford an antiblastic treatment. The patient died three months after the definitive diagnosis. This case suggests that the presence of intraorbital lesion requires a multimodal approach starting from the initial presentation. Performing a complete staging since tumor's clinical onset is mandatory, preferably before carrying out a tissue biopsy. Even though HCC represents a rare cause of intraocular metastasis, it needs to be ruled out when an orbital mass is documented, as the short median survival and the frequently poor conditions of HCC patients make a timely diagnosis crucial.

Venous thromboembolism and port-related thrombosis in metastatic colorectal cancer patients: a monocenter experience.

Venous thromboembolism (VTE) may occur during the natural history of neoplastic disease and is a common cause of mortality and morbidity in cancer patients. Major risk factors for VTE in cancer patients include surgery, immobilization, hospitalization, and the administration of granulopoietic and/or erythropoietic (stimulatory) agents. Chemotherapy is a supplementary independent risk factor for VTE and the use of central venous catheters (CVC) in clinical practice has increased the risk of thromboembolic events. We conducted a retrospective study to evaluate CVC-related thrombosis and the VTE rate in 145 consecutive metastatic colorectal cancer patients. We observed only 2 cases of symptomatic CVC- related thrombotic events (1.38%) and 10 cases of thromboembolic events (6.9%) in our series. Only surgery for metastases was found to be significantly related to the development of VTE, with an incidence of 16.1% vs. 4.4 in patients who did not undergo surgery (p = 0.037). In addition, a history of VTE seems to be a supplementary risk factor for CVC-related thrombosis (p = 0.055).

Durable complete response of hepatocellular carcinoma after metronomic capecitabine.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly vascular tumor which is poorly responsive to standard systemic chemotherapy. Recently, various antiangiogenic targeted agents have shown promising activity at different levels of evidence in patients with advanced HCC, suggesting that such treatments might be effective. CASE REPORT: Since chemotherapy administered with metronomic schedules inhibits angiogenesis, we treated a 64-year-old man with advanced HCC with metronomic capecitabine. After only two months of treatment the HCC nodules disappeared on ultrasonography. This finding was confirmed by a computed tomography scan. After more than three years the patient is still in treatment with minimal toxicity and maintains a complete remission. CONCLUSIONS: Our case report suggests that metronomic capecitabine may be effective in advanced HCC patients while being also well tolerated. This is important, given the frequent comorbidities of HCC patients.

Dual TMPRSS2:ERG Fusion in a Patient with Lung and Prostate Cancers.

The TMPRSS2:ERG fusion is considered prostate specific and has been rarely described in other tumors. We describe the case of a patient who developed lung and prostate cancers, both harboring the TMPRSS2:ERG fusion. The patient developed a cancer of the prostate with lymph node metastases and after two years a nodule of the thoracic wall. The histology and immunohistochemical profile of the two tumors were typical of prostate and lung cancers. The presence of the TMPRSS2:ERG fusion was demonstrated by next-generation sequencing on both malignancies, leading to the assumption that the lung nodule was a metastasis from the prostate cancer. The patient failed to respond to antiandrogen therapy, while chemotherapy for lung cancer led to a significant objective response. To our knowledge, this is the first case of a lung cancer harboring the TMPRSS2:ERG fusion, widening the spectrum of lung cancer-associated molecular alterations.

Improving IMDC Prognostic Prediction Through Evaluation of Initial Site of Metastasis in Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND: Several models are adopted in clinical practice to estimate prognosis of patients with metastatic renal cell carcinoma (mRCC); however, none of these models have evaluated patients treated by immune-checkpoint inhibitors. The aim of this study was to investigate if the site of initial metastasis could be a parameter able to stratified prognosis among patients with mRCC among different risk groups defined by the International Metastatic Renal Cell Database Consortium (IMDC) model. The site of initial metastasis was defined as the primary tissue or organ in which metastasis was diagnosed in the course of the medical history of the disease. PATIENTS AND METHODS: A total of 134 patients treated between January 2010 and December 2018 in our institution were retrospectively evaluated. The primary outcome was overall survival (OS) defined as the time from initiation of first-line therapy to death from any cause. Of note, 26 (19.4%) patients received immune-checkpoint inhibitors. Univariable analysis was performed through the log-rank test to estimate the effect of number of metastatic sites and site of initial metastasis on OS. Subsequently, a Cox regression proportional hazards model was employed in multivariable analysis. RESULTS: Of the 12 variables analyzed, 4 were statistically associated to worse OS in univariable analysis (number of metastases and liver, bone, or central nervous system metastases). Multivariate analysis confirmed that bone (hazard ratio [HR], 1.92; 95% confidence interval [CI], 1.17-3.13), liver (HR, 2.65; 95% CI, 1.59-4.42), and central nervous system (HR, 3.3; 95% CI, 1.62-6.74) initial metastases were independent parameters related to worse OS. The presence of 1 or more of the selected sites recognized specific populations of patients associated to worse prognosis in both good (P = .003) and intermediate (P = .047) risk groups. CONCLUSION: The site of initial metastasis defines specific populations of patients associated with worse prognosis in the good and intermediate IMDC groups.

The safety and efficacy of enzalutamide in the treatment of advanced prostate cancer.

INTRODUCTION: Enzalutamide - a non-steroidal second-generation antiandrogen - represents an active treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC) in both chemotherapy-naïve and docetaxel-pretreated settings, based on the demonstration of improved overall survival over placebo in two large phase III trials. AREAS COVERED: The therapeutic landscape of mCRPC, narrowed to docetaxel until recently, encompasses now several treatments of a different nature (including androgen receptor targeting agents, taxanes, radiometabolic therapy, and immunotherapy), improving considerably the patients prognosis. However, direct comparisons between these agents still lack, raising the question of the optimal sequence of treatment. Expert commentary: We described in detail available data on clinical efficacy and safety of enzalutamide in different clinical settings (chemotherapy-naïve and -pretreated mCRPC patients), analyzing patients characteristics, the effects of enzalutamide on major clinical outcomes and its impact on patients quality of life. Finally, we briefly overviewed ongoing clinical trials evaluating potential active combinations, cross-resistance with other compounds, sequential strategies, and possible prognostic or predictive biomarkers.

Ultrasound-guided Central Venous Catheterization for Home Parenteral Nutrition and Hydratation in Advanced Incurable Cancer Patients: Results of A Prospective Observational Study.

BACKGROUND: Most patients with advanced cancer are frequently malnourished and frequently they develop decreased oral fluid intake and dehidratation. Home parenteral nutrition (HPN) is an increasingly used therapy for patients with advanced cancer. A central venous access device is often an essential component allowing parenteral nutrition and hidratation. However central venous catheter (CVC) insertion represents a risk for pneumothorax or other mechanical complications. This study aimed to determine the reduction of risks related to central venous catheter positionement in the setting of cancer patients with palliative programm. METHODS: Consecutive patients with a variety of cancer in advanced phase requiring palliative care who were undergoing placement of central venous catheter for parenteral nutrition or hydratation have been prospectively studied in a program of ultrasound-guided CVC placement. Four types of possible complications were defined:mechanical, thrombotic, infection and malfunctioning. After sterilization, local anesthesia is applied and a 7.5 MHZ puncturing US probe is placed in the supraclavicular site and a 16-gauge needle is advanced under real-time US guidance, into the last portion of internal jugular vein by experienced physicians. The Seldinger tecnique is used to place the catheter that is advanced into the superior vena cava until insertion to right atrium. Two hours after each procedure a chest X-ray and US scanning are carried out to confirm CVC position and rule out a pneumotorax. RESULTS: From 30 October 2000 to 31 October 2008: 209 CVC insertional procedure were applied in 207 patients with cancer in the palliative phase only. There were 101 women and 106 men with a mean age of 67.68 year (range 22-86). A single needle puncture of the vein was performed on 206 of 209 procedures (98.6%), the technique was efficacious at the first attempt in 98.6% of cases, in 2 patients (0.96%) the CVC was positioned at the second attempt. The procedure failed only one case (0.44%). No cases of pneumothorax, of major bleeding or nerve punctured were reported. Symptomatic vein thrombosis developed in one patient (0.44%). Infection episodes were reported in two cases. Mean time for CVC permanence was 92.5±9.1 days (range 8-158). CONCLUSION: This study indicates that US-guided CVC insertion is a safe, cheap procedure for cancer patients in advanced phase and with palliative program, allowing parenteral nutrition and hydratation.

Metastatic pancreatic cancer: is gemcitabine still the best standard treatment? (Review).

Pancreatic ductal adenocarcinoma is the fourth cause of death in the Western world. Surgery remains the only treatment offering an advantage in terms of overall survival (5-year survival range, 15-25%), but unfortunately only 10-20% of patients present resectable disease at the time of diagnosis. Hence chemotherapy, possibly combined with radiation therapy, remains the only treatment option aimed at palliation of symptoms and ensuring a better quality of life. Notwithstanding the efforts to find more effective therapies for the treatment of pancreatic cancer, significant results have not yet been achieved. Increasing interest has focused on integrated treatments, i.e. chemotherapy combined with targeted therapies, and a better selection of patients. This study examines the principal clinical trials that will help give clinicians an overview of the progress made in the systemic therapy for advanced pancreatic cancer patients in recent years.

To widen the setting of cancer patients who could benefit from metronomic capecitabine.

PURPOSE: We investigated the efficacy and toxicity of metronomic capecitabine administered at a fixed dose of 1,000 mg daily in three elderly or poor performance status patients with advanced colorectal cancer (CRC) and gastric cancer. METHODS: In this study a pretreated advanced CRC patient (patient 1), a not previously treated advanced gastric cancer patient (patient 2), and a not previously treated advanced rectal cancer patient (patient 3) were given metronomic capecitabine administered at a fixed dose of 1,000 mg daily (day 1-28 continuously). The efficacy was evaluated every 3 months by instrumental evaluation and the treatment was continued until progression of disease or toxicity. RESULTS: A stable disease was observed in all three patients. The duration of treatment was above 3 months and no major toxicities occurred. CONCLUSIONS: Our results indicate that metronomic capecitabine may be considered a safe and valid treatment option for advanced CRC and gastric cancer patients, both after failure of previous lines of chemotherapy or in front-line when standard chemotherapy is contraindicated, especially when the aim of medical treatment is to achieve disease control and to arrest tumour growth without affecting the patient's quality of life. Nevertheless, further clinical studies, as well as a greater clinical experience are required in order to better define the role of this strategy in medical oncology.