TPF sequential therapy: when and for whom?

Concurrent chemoradiation is a standard approach for the treatment of locally advanced squamous cell carcinoma of the head and neck. However, sequentially administered chemotherapy and radiotherapy/chemoradiation may be an effective alternative for some patients. Although chemoradiation is a highly effective treatment approach, it is associated with high incidences of severe acute toxicities, including mucositis. In addition, late toxicities can cause long-term morbidity in a substantial proportion of patients. In a retrospective analysis of three Radiation Therapy Oncology Group trials, pharyngeal dysfunction was seen in 27% of patients and feeding tube dependence and laryngeal dysfunction were each seen in approximately 12% of patients. Sequential administration of chemotherapy and radiotherapy, with a doublet cisplatin and 5-fluorouracil (PF) induction chemotherapy regimen, is associated with less acute severe mucositis than concomitantly administered cisplatin and radiotherapy. The addition of the taxane docetaxel to PF has resulted in the highly active triplet induction regimen TPF. Data from randomized trials indicate that TPF sequential therapy may be an effective alternative to concurrent chemoradiation for some patients. TPF is well tolerated, although it is associated with a higher incidence of hematologic adverse events than with PF, including neutropenia and neutropenia-related complications. This may be managed by the use of prophylactic G-CSF and/or antibiotics. Patients suitable for treatment with a TPF-based sequential administration approach include those with a good performance status, no contraindication to cisplatin or taxanes, and locally advanced oropharyngeal, hypopharyngeal, or laryngeal cancer with a high tumor load.     

Prophylactic cranial irradiation for small-cell lung cancer: how, when and for whom?

Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastases and improves overall survival in both limited disease (LD) and extensive disease (ED) small-cell lung cancer (SCLC), in complete and good responders to initial chemo(radio)therapy. In LD-SCLC, a standard dose of 25 Gy given in ten fractions is recommended, whereas in ED-SCLC a shorter schedule of 20 Gy in five fractions could be used. The issues of acute neurotoxicity (NT) and the potential impact of PCI on quality of life are of particular concern in ED-SCLC patients, as their expected survival is short. In LD-SCLC late neurologic sequelae may worsen quality-adjusted life expectancy for long-term survivors, as the pronounced effect of NT becomes apparent after several years. Some novel potential approaches to reduce the PCI-related late NT have recently been investigated. Despite the growing incidence of lung cancer in elderly people, there are no established standards of treatment for this subset of the population.     

Carfilzomib and the cardiorenal system in myeloma: an endothelial effect?

Carfilzomib (Cfz) has been associated with an ~5% incidence of unexplained and unpredictable cardiovascular toxicity in clinical trials. We therefore implemented a detailed, prospective, clinical cardiac and renal evaluation of 62 Cfz-treated myeloma patients, including serial blood pressure (BP), creatinine, troponin, NT-proBNP and pre- and post-treatment echocardiograms, including ejection fraction (EF), average global longitudinal strain and compliance. Pre-treatment elevations in NT-proBNP and BP, as well as abnormal cardiac strain were common. A rise in NT-proBNP occurred frequently post-treatment often without corresponding cardiopulmonary symptoms. A rise in creatinine was common, lessened with hydration and often reversible. All patients had a normal EF pre-treatment. Five patients experienced a significant cardiac event (four decline in EF and one myocardial infarction), of which 2 (3.2%) were considered probably attributable to Cfz. None were rechallenged with Cfz. The ideal strategy for identifying patients at risk for cardiac events, and parameters by which to monitor for early toxicity have not been established; however, it appears baseline echocardiographic testing is not consistently predictive of toxicity. The toxicities observed suggest an endothelial mechanism and further clinical trials are needed to determine whether or not this represents a class effect or is Cfz specific.     

Hemostatic changes after 1?month of thalidomide and dexamethasone therapy in patients with multiple myeloma

Thromboembolic events (TEE) are a serious clinical problem in multiple myeloma (MM) patients receiving thalidomide (T). Thirty-one MM patients were tested on diagnosis and after 2 and 4?weeks of therapy with T alone, or T in combination with dexamethasone (TD). Closure time (CT) in PFA-100 and P-selectin expression were assessed, as well as plasma levels of thrombin-antithrombin complexes (TAT), D-dimer (DD), soluble thrombomodulin (sTM) and von Willebrand factor antigen (vWF:Ag), along with the activity of coagulation factor VII and factor VIII. The concentration of vascular endothelial growth factor and its type 1 and 2 receptors were also assayed. On diagnosis, significantly prolonged median CT with both used cartridges, elevated P-selectin expression, DD concentration, TAT, vWF:Ag and factor VIII and factor VII activity were seen in the patient group as compared to controls. Therapy with these regimens caused marked shortening of CT with both cartridges. Treatment with TD leads to the significant increase in CD62P expression on platelets. Median TAT value increased significantly in relation to baseline after therapy with both regimens. Factor VIII activity exceeded 150?% in all patients after 2?weeks of TD therapy and was markedly elevated compared to baseline. One month of TD therapy significantly increased sTM concentration. These results demonstrate the enhanced platelet and coagulation system activation already present in MM patients on diagnosis, which is further increased by antimyeloma therapy. These changes are more pronounced after TD therapy and may promote TEE. Tested angiogenesis marker levels are elevated already on diagnosis, do not change after therapy and have no significant impact on the coagulation system in patients with MM.     

Genetics and molecular profiling of multiple myeloma: Novel tools for clinical management?

The understanding of molecular events involved in multiple myeloma (MM) development as well as of mechanisms underlying sensitivity/resistance to anticancer drugs has been dramatically increased by the wide-spread use of modern technologies for genetic analysis, global gene expression and proteomic profiling. Such analytical approaches, which are presently supported by reliable bioinformatic tools, have depicted a new scenario for the development of molecular-based anti-MM agents and for predicting clinical outcome. IgH translocations or a hyperdiploid state are emerging as early genetic signatures of MM which lead to deregulated expression of cyclin D. At present however, the major challenge remains the definition of the potential role of cytogenetic techniques and molecular profiling technologies in individual patient management. Here we will describe the prospective potential and current achievements of such technologies which might produce major advancements in the treatment of this still incurable disease.     

Thalidomide in relapsed or refractory multiple myeloma: how much and for how long?

The optimum dose and duration of treatment with thalidomide for relapsed or refractory multiple myeloma are not known. Long term responses were seen in 5 patients given low doses of thalidomide (100-200 mg) with or without pulsed dexamethasone, for between 48 and 108 weeks. The responses were sustained for between 23 and 67 weeks after stopping treatment. We recommend that the lowest effective dose (LED) and optimum duration of therapy with thalidomide should be determined within the framework of a well conducted clinical trial in order to answer these important questions.     

Systemic lupus Erythematosus and IgA multiple myeloma: a rare association?

The coexistence of systemic lupus Erythematosus (SLE) and multiple myeloma (MM) is uncommon and the pathogenetic mechanisms underlying this association remain unclear. We report the case of a woman who was diagnosed with SLE in 1993 aged 57, then developing IgA lambda type MM in the IIB clinical stage 7 years later. The SLE was treated successfully with methylprednisolone and chloroquine, and low dose maintenance steroid was continued with bisphosphonate protection until December 1994 when she suffered multiple vertebral fractures. She continued to receive 4 mg alternate day methylprednisolone and calcitonin until she decided to discontinue her own treatment 2 years later. In 2000, while still in stable SLE remission, she was diagnosed with MM. Protein electrophoresis revealed the IgA lambda paraprotein (40.5 g/l) and she had a Bence Jones (BJ) proteinuria of the lambda light chain type. Bone marrow trephine biopsy revealed a massive patchy infiltrate of abnormal plasmocytes (70%), while an extensive x-ray skeletal survey did not show any new fractures or osteolysis. The patient was treated according to the VMCP protocol without attaining a plateau phase. There was a similar poor clinical response to second and third line treatments (VAD, Thalidomide, Melphalan, and high dose dexamethasome). After 4 years of refractory disease the patient died from severe bilateral pneumonia. This case is discussed with reference to the literature.     

Viagra, cialis, impase--which of them, to whom, when and how?

The study has been performed of the efficacy in the treatment of erectile dysfunction (ED) of oral drugs affecting nitric oxide: impase and phosphodiesterase-5 (PDE-5) inhibitors--sildenafil citrate (viagra), tadalafil (sialis)--alone and in combination with impase. A total of 218 ED patients aged 21-73 years (mean age 58.1 +/- 13.2 years) were divided into 3 groups comparable by the number of the patients, age, suspected etiology, pathogenesis and ED severity. Group 1 (n = 81) took viagra in the individually adjusted dose for 6 months; group 2 (n = 64) received sialis in a dose 20 mg for 6 months; group 3 (n = 73) took impase 1 tablet each other day sublingually for 6 months. Overall efficacy made up 77.8, 81.3 and 56.2% for viagra, sialis and impase, respectively. In view of different mechanism of action of PDE-5 inhibitors (viagra, sialis) and impase we combined the drugs in those who failed monotherapy or had drastic side effects. The combination raised efficacy of pharmacotherapy from 56.2 to 92.2%. We came to the conclusion that in psychogenic, isolated neurogenic, compensated and subcompensated arteriogenic ED of a mild or moderate degree, the treatment can be started with impase. If it was uneffective, in severe ED or moderate venoocclusive ED it is better to use PDE-5 inhibitors (viagra, sialis). If one of the latter fails, the other should be administered. If the inhibitors have low efficacy or in side effects, it is indicated to use their combination with impase.     

High-risk multiple myeloma: does it still exist?

Major improvement milestones in the treatment of patients with multiple myeloma (MM) include the introduction of the melphalan/prednisone combination in the 1960s, high-dose chemotherapy supported by autologous stem cell transplant in the 1980s, and the more recent introduction of the novel agents thalidomide, lenalidomide, and bortezomib. Historically, age and eligibility for autologous stem cell transplantation were the primary basis for treatment selection, but, from a biologic standpoint, MM therapy was "one size fits all," in that therapy was not tailored based on molecular or other features that define subtypes of MM. Recently, novel therapies have extended overall survival for the broad spectrum of patients with myeloma. Moreover, newer data demonstrate that novel therapies may ameliorate the prognostic impact of predictors of high risk and poor outcome in MM, which suggests that patients with MM and with high-risk disease should receive novel agents. Such approaches may constitute nascent steps toward individualized therapy, ie, the selection of highly effective therapies based on specific features exhibited by an individual patient's MM. However, prospective data that demonstrate the validity of these approaches are lacking. Definitive, multi-institutional clinical trials are required before redefining standards of myeloma care based on this approach.     

“Off-the-shelf” immunotherapies for multiple myeloma

Over the past couple of decades, the life expectancy of patients with multiple myeloma (MM) has progressively increased, however, the disease per se remains incurable. This has resulted in a subset of the patient population who have progressed despite multiple standard treatment options but remain amenable for novel therapies to achieve durable remission. With the discovery of the role of B-Cell Maturation Antigen (BCMA) in the pathogenesis of MM, strategies targeting the BCMA have been the focus of many treatment modalities in development. Although autologous CAR-T cell therapy has shown an overall efficacy of >80% across various phases of studies, it has its own set of limitations and challenges. There is now an increasing focus on identifying novel therapeutic targets for multiple myeloma and developing “off-the-shelf” immunotherapeutic approaches for treatment of MM. This review discusses and highlights the emerging data from various ongoing trials on “off-the-shelf” approaches like antibody-drug conjugates, bispecific antibodies, and allogeneic cellular therapies demonstrating feasibility, acceptable safety, and promising preliminary efficacy. Ongoing and future efforts will need to focus on comparative effectiveness of these different approaches, possible combination strategies, and ensuring equitable and affordable access to these therapies globally.     

Metastasectomy for stage IV melanoma: for whom and how much?

Although the conventional paradigm for treating metastatic melanoma relies on systemic therapies, a surgical approach should be strongly considered in selected patients. A surgical approach may not be appropriate for all patients, but it can offer a rapid clearance of disease without the toxicity of systemic therapy. Patient selection is of paramount importance for surgery to be effective. The rationale for surgical intervention in the management of metastatic melanoma, selection factors to be considered, published results, and future directions are discussed in this article.