Neues zur systemischen Therapie des medullären Schilddrüsenkarzinoms

Context

Medullary thyroid cancer (MTC) is a rare form of cancer with an annual incidence of only 2–5 per million inhabitants and has a very variable, often a relatively indolent course of the disease. In recent years substantial new data have been collected on novel therapy options for this neoplasm.

Objective

The aim of this review is to present and evaluate the current therapeutic options for advanced MTC.

Methods

Selective review of the literature, analysis of clinical trials.

Results

As the natural course of disease even with known distant metastases is frequently relatively slow a watchful waiting strategy is justified in many patients. Surgery or local ablative therapy should be considered. If a significant tumor progression is observed systemic treatment options should be discussed with the patient. Based on the observation of a mutated RET protooncogene and increased neoangiogenesis in MTC, many tyrosine kinase inhibitors have been evaluated with very promising results. Vandetanib has been approved in 2012 as the first drug for the treatment of aggressive and symptomatic MTC. Data on cytotoxic chemotherapy regimens are limited; therefore, these drugs should only be used in individual therapeutic concepts.

Conclusion

In order to further improve therapeutic options in this rare cancer all patients should preferentially be treated within clinical trials.     

Management des fortgeschrittenen medullären Schilddrüsenkarzinoms

Background

Medullary thyroid carcinoma (MTC) is a slowly growing tumor of neuroendocrine origin with a good prognosis and patient quality of life, which can be cured by surgery. Patients with persistent postoperative disease, slightly elevated calcitonin (Ct) level, low tumor burden and stable disease are often asymptomatic. A small subset of patients shows aggressive tumor growth.

Objectives

In patients with a significant tumor burden and advanced or progressive metastatic MTC, therapy with tyrosine kinase inhibitors (TKI) is now available.

Material and methods

The clinical impact of the novel TKI therapy in the setting of long-term follow-up management of patients with advanced metastatic MTC was evaluated. Selection criteria for local and systemic treatment based on recent trials and guidelines are discussed.

Results

Patients with rapidly growing MTC, as determined by sequential imaging studies using response evaluation criteria in solid tumors (RECIST), and by documented shortened doubling times of serum Ct and carcinoembryonic antigen (CEA) levels, should be considered for systemic therapy. In this setting, TKIs such as vandetanib and cabozantinib, appear to be the most effective treatment modality. They achieve significant improvement of progression-free survival in patients with progressive metastatic MTC. However, TKIs have a significant toxicity requiring dose reduction or even interruption of treatment.

Conclusion

Treatment with TKIs represents an important new therapeutic option for patients with progressive metastatic MTC; however, there are several unresolved questions, such as continuous or intermittent therapy, combination therapy, second line treatment after progress under TKI treatment and initiation of treatment at an earlier stage?     

Neue Entwicklungen in der Therapie des fortgeschrittenen Hodgkin-Lymphoms

Context

With the current standard of care of the German Hodgkin Study Group (GHSG) consisting of 6 cycles of the BEACOPP_escalated regimen and radiotherapy of residual lymphomas ≥?2.5 cm, the overall survival (OS) of patients with advanced Hodgkin’s lymphoma (HL) is 95?%. However, minimizing acute and late toxicities without compromising the tumor-specific outcome of patients is the major goal of current clinical research. Defining the correct balance between efficacy and toxicity remains the most important challenge in treatment of HL.

Objective

This article presents an evidence-based systematic review of the current status of therapy as well as new developments in the treatment of advanced HL.

Material and methods

A systematic literature search was carried out and relevant publications as well as new developments in the treatment of advanced HL tested in current trials are summarized.

Results

Recent comparisons of the BEACOPP_escalated and ABVD regimens showed a substantial benefit of BEACOPP_escalated in terms of progression-free survival (PFS) and OS. In combination with supportive treatment measures, such as obligatory prephase treatment with dexamethasone for patients older than 40 years and prophylactic antibiotic treatment during the time of aplasia, 6 cycles of BEACOPP_escalated can be considered a safe and feasible therapy. Thus, minimizing acute and late toxicities without compromising the tumor-specific outcome of patients is the major goal of current clinical research. The recruiting GHSG HD18 trial investigates the reduction from 6 to 4 cycles of BEACOPP_escalated for patients with good, early tumor response as defined by positron emission tomography (PET). Another strategy might be the implementation of targeted drugs into the first-line therapy. This approach is currently being evaluated in the GHSG targeted BEACOPP study (NCT01569204) with the implementation of brentuximab vedotin into two modified BEACOPP regimens.

Conclusions

The major goal in the treatment of advanced HL is the implementation of targeted drugs into the first-line therapy. Targeted drugs might replace unspecific cytotoxic drugs, which cause systemic toxicity. Brentuximab vedotin was approved for use in Europe in November 2012 for the treatment of relapsed or refractory HL and is currently being investigated in combination with two modified escalated BEACOPP regimens in advanced stage HL patients in the targeted BEACOPP trial. Hopefully, these new combinations will improve the current standard of care in the treatment of HL regarding both efficacy and tolerability.     

In-vivo monitoring of erythropoietin treatment after myocardial infarction in mice with [68Ga]Annexin A5 and [18F]FDG PET

Background

Several studies substantiate the cardioprotective effects of erythropoietin (EPO). Our goal was to quantify the effects of EPO treatment on the early expression of the apoptosis marker phosphatidylserine as well as on the left ventricular volumes and function by means of small animal PET.

Methods and Results

Myocardial infarction (MI) was induced in C57BL/6 mice. Animals were assigned to saline or EPO groups and underwent Annexin PET (day 2) and gated FDG PET (days 6 and 30). Annexin uptake was significantly higher in the infarction than in remote myocardium, with no differences between treatment groups. Infarct size showed a slight decrease in the EPO group and a slight increase in the controls, which did not reach statistical significance. Follow-up analyses revealed a significant increase of end-diastolic and end-systolic volumes in the EPO group, in which a stable left ventricular ejection fraction (LVEF) was maintained.

Conclusion

We find that deleterious effects of EPO can outweigh cardioprotective effects. The present EPO treatment did not significantly reduce apoptosis after MI, but seemingly provoked significant myocardial dilation while maintaining a stable LVEF. Molecular mechanisms of EPO treatment may need further elucidation to optimize therapy regimens.