Understanding and treating solid tumor-related disseminated intravascular coagulation in the "era" of targeted cancer therapies.

A systemic activation of blood coagulation is usually present in many clinical conditions including the infectious or inflammatory ones and malignant disease as well. Depending upon circumstances, patients suffering from acute decompensated disseminated intravascular coagulation may be managed by a medical oncologist and either an internist or a physician working in an emergency and/or intensive care unit. In some cases, for example, the indolent ones, the activation of coagulation might not be easily detected by routine laboratory tests and not lead to clinical manifestations. Such a chronically activated intravascular coagulation can progress toward an overt decompensated disseminated intravascular coagulation. Traditional therapy of decompensated disseminated intravascular coagulation is based on reversing the underlying triggering disease and providing patients with adequate supportive treatment. The dilemma for the oncologist is whether or not the trigger cause can be treated and amended with a specific antineoplastic treatment, without worsening the consumption of platelets and the risk of bleeding. In light of the availability of new targeted therapies, the main criteria that should drive the strategy against solid cancer-related disseminated intravascular coagulation will be discussed.

Molecular-targeted therapy for elderly patients with advanced non-small cell lung cancer.

Lung cancer is the most common cause of cancer-related mortality in men and women. Non-small cell lung cancer (NSCLC) represents close to 90% of all lung cancers. When diagnosed, >50% of patients are >65 years old. Through an improved understanding of the molecular mechanisms involved in lung oncogenesis, molecular-targeted approaches have become an essential element for the treatment of patients with NSCLC. As the toxicity profiles of the techniques are definitely more favorable compared with chemotherapy, they are particularly attractive for use in elderly patients, who are potentially more susceptible to the toxicity of systemic oncological therapies. However, studies on the activity of molecular-targeted agents in this aged patient setting are much more limited compared with those in their younger counterparts. In the present review, the literature on molecular-targeted therapy for elderly patients with advanced NSCLC is discussed. It is concluded that bevacizumab should be reserved only for highly select elderly patients with advanced NSCLC when the clinician deems it useful in the face of acceptable toxicities. In elderly patients with advanced epidermal growth factor receptor mutation-positive NSCLC, erlotinib and gefitinib appear to repeat the same favorable performance as that documented on a larger scale in the overall population of patients with activating mutations. A good toxicity profile is also confirmed for active molecules on different pathways, such as crizotinib.

Neoadjuvant therapy for locally advanced melanoma: new strategies with targeted therapies.

Neoadjuvant chemotherapy has been successfully tested in several bulky solid tumors, but it has not been utilized in advanced cutaneous melanoma, primarily because effective medical treatments for this disease have been lacking. However, with the development of new immunotherapies (monoclonal antibodies specific for cytotoxic T lymphocyte-associated antigen 4 [anti-CTLA-4] and programmed death protein-1 [anti-PD1]) and small molecules interfering with intracellular pathways (anti-BRAF and mitogen-activated protein kinase kinase [anti- MEK]) the use of this approach is becoming a viable treatment strategy for locally advanced melanoma. The neoadjuvant setting provides a double opportunity for a better knowledge of these drugs: a short-term evaluation of their intrinsic activity, and a deeper analysis of their action and resistance-induction mechanisms. BRAF inhibitors seem to be ideal candidates for the neoadjuvant setting, because of their prompt, repeatedly confirmed response in V600E BRAF-mutant metastatic melanoma. In this report we summarize studies focused on the neoadjuvant use of traditional medical treatments in advanced melanoma and anecdotal cases of this approach with the use of biologic therapies. Moreover, we discuss our experience with neoadjuvant targeted therapy as a priming for radical surgery in a patient with BRAF V600E mutation-positive advanced melanoma.

Low molecular weight heparin administration in cancer patients with hypercoagulability-related complications and carrying brain metastases: a case series study.

BACKGROUND: Venous thromboembolism (VTE) and brain metastases (MTS) are significant clinical problems in the cancer patient population. Brain MTS and deep vein thrombosis are life-threatening conditions because of the risk of fatal endocranic hypertension and pulmonary embolism. Low molecular weight heparin (LMWH) is a major treatment for cancer patients suffering from VTE with regard to the management of the acute phase and subsequent secondary prophylaxis. Treatment with anticoagulants is feared because of the risk of triggering a massive intracranial hemorrhage. METHODS: The medical records of patients with hypercoagulability-related complications and carrying brain MTS treated with LMWH, in a 10-year period, were scrutinized. The authors aimed to focus on the occurrence of intracranial hemorrhage in anticoagulated patients; furthermore, data were collected with regard to the characteristics of the administered LMWHs along with the duration and dosing of the anticoagulative treatment. RESULTS: A total of 38 patients (pts) carrying an intracranial metastatic tumor were administered LMWHs: calcium nadroparin (32 pts); enoxaparin (2 pts); reviparin (2 pts); parnaparin (2 pts). Reason for LMWH therapy: deep vein thrombosis and/or pulmonary embolism (15 pts); superficial thrombophlebitis (15 pts); intracardiac thrombus (1 pt); mild DIC (5 pts); acute DIC (1 pt); Raynaud phenomenon (1 pt); atrial fibrillation (1 pt). Median duration of LMWH therapy: 13 weeks (range 1-52). None of the patients developed clinical and/or radiographic findings imputable to intracranial hemorrhage. CONCLUSION: There is no standard medical approach for the management of patients who require anticoagulant treatment and are suffering from brain MTS. These patients as necessary, might be anticoagulated with LMWH and its dose reduction is to be considered.

Initial experience with hepatic intraarterial fotemustine and interferon alpha 2b combination for treatment of liver tumors.

BACKGROUND: Locoregional treatments represent a good option for patients suffering from hepatocellular carcinoma (HCC) not eligible for resection or transplantation. Locoregional approaches include a wide spectrum of therapeutic methods and hepatic intra-arterial drug infusion is also considered. Fotemustine is a chemotherapy drug usually administered intravenously according to standard administration schedules. Interferon alpha 2b (IFNα2b), a biological response modifier conventionally administered by a systemic route, has been employed in the treatment of both virus-related hepatitis and HCC. Nonetheless, both drugs can also be infused into the hepatic artery. PATIENTS AND METHODS: We report on five patients with liver cancer, not suitable for conventional therapies, treated with hepatic intra-arterial administration of fotemustine in combination with IFNα2b. They received fotemustine at a dose of 30 mg/m(2) and IFNα2b at a starting dose of 2,000,000 IU (increasing up to 3,000,000 IU for subsequent administrations) weekly for three consecutive weeks, followed by two weeks of rest. RESULTS: Among the patients suffering from HCC, the first patient showed a partial response, two patients had almost stable disease and one patient was not assessable. A patient with an intrahepatic biliary tract cancer experienced disease progression. CONCLUSION: The therapeutic regimen used showed acceptable tolerability profiles and lack of life-threatening side-effects. Further evaluation with a larger patient cohort will be required to clarify if fotemustine and IFNα2b administered into the hepatic artery could be beneficial in treating patients with HCC.

Successful administration of a low dose of calcium nadroparin in patients suffering from pulmonary embolism and brain metastases: a report of two cases.

OBJECTIVE: To focus on the optimal management of thromboembolic complication in patients who have undergone chemotherapy with concomitant brain metastases and referred to a Division of Clinical Oncology. BACKGROUND: Thromboembolic diseases are common events in cancer patients due to clotting activation by tumor cells. On the other hand, brain metastases are common complication of systemic cancers. Postmortem studies show that a quarter of patients dying from cancer have intracranial metastases. Brain metastases and pulmonary embolism are life-threatening conditions because of the risk of fatal endocranic hypertension and severe dyspnea. Calcium nadroparin is a low molecular weight heparin usually administered in patient with venous thromboembolism at a dose level of 180 IU/kg/daily. CASE SUMMARIES: The authors report the cases of two patients with intracranial metastases and pulmonary embolism-related dyspnea successfully treated with low dose of calcium nadroparin. A patient suffering from metastatic breast cancer and another one with metastatic nonsmall cell lung cancer were recently referred to our department because of severe dyspnea occurring during chemotherapy treatment. Both patients had cerebellar intracranial metastases. Massive pulmonary embolisms were shown by means of the computerized tomography. Despite the administration of a lower heparin dose than the usual one, around three-quarters of the calcium nadroparin daily conventional dose, quickly regressed dyspnea. Significant pulmonary embolism regression was revealed with computerized tomography scan within 8 weeks from the beginning of the thromboembolic complications. None of the patients showed any heparin treatment-related complications. CONCLUSION: The authors conclude that, with regard to cancer patients carrying brain metastases who require anti-coagulant therapy, increased risk of intracranial hemorrhage should be kept in mind. An initial low molecular weight heparin dose reduction could be effective, and safely administered, also in case of pulmonary embolism with severe dyspnea.

Hepatic intra-arterial interferon alpha 2b-based immunotherapy combined with 5-fluorouracil (5-FU)-based systemic chemotherapy for patients with hepatocellular carcinoma (HCC) not responsive and/or not eligible for conventional treatments: a pilot study.

BACKGROUND: Surgery (partial hepatic resection or orthotopic liver transplantation) remains the mainstay for treatment of hepatocellular carcinoma (HCC). Unfortunately, most patients have HCC that cannot be removed either as a result of its size, multiple tumors, location, proximity to major vessels or ducts within the liver, and comorbidity, such as a not well-compensated cirrhosis. For patients who cannot be treated surgically, systemic chemotherapy is frequently limited by unacceptable toxicity, poor response and low survival rates, so that locoregional approaches may be considered as alternatives. PATIENTS AND METHODS: Nine patients with HCC, not eligible for conventional treatments, were treated with interferon alpha 2b-based locoregional, hepatic intra-arterial, immunotherapy and concomitant 5-fluorouracil (5-FU)-based systemic chemotherapy. Interferon was administered at a starting dose of 2,000,000 IU, which could be escalated to 9,000,000 IU, adding 1,000,000 IU weekly, depending on toxicity. 5-Fluorouracil was infused continuously over 28 days, administered as an endovenous protracted infusion weekly at a dose of 250 mg/m2/day for 4 weeks followed by a 2-week break. Eight out of nine patients were evaluable for response and toxicity. The median patient age was 68 years (range 51-77 years). All patients were suffering from cirrhosis. RESULTS: A total of 29 cycles of treatment were administered with a median of 3.6 per patient (range 1-11 per patients). A partial response was observed in 3 out of 8 patients; 1 had stable and 4 progressive disease. The main toxicities were: grade 3 hepatic toxicity (1 patient), grade 3 flu-like syndrome (1 patient) and grade 3 abdominal pain (1 patient). Moreover, one patient developed fatal ischemic stroke and another a fatal central venous catheter infection. CONCLUSION: The preliminary data, show that an interferon-based hepatic intra-arterial immunotherapy combined with low doses of 5-fluorouracil (5-FU)-based systemic chemotherapy, can represent a tolerable combination to apply in the palliative treatment of patients with hepatocellular carcinoma.