An update on current and future treatment options for chondrosarcoma.

Introduction: Human chondrosarcomas (CS; a malignant cartilage-forming bone tumor) respond poorly to chemotherapy and radiation treatment, resulting in high morbidity and mortality rates. Expanded treatment options are urgently needed. Areas covered: This article updates our 2014 review, in which we evaluated the CS treatments available at that time and potential treatment options under investigation. Since then, advances in research findings, particularly from Chinese herbal medicines, may be bringing us closer to more effective therapies for CS. In particular, promising findings have been reported from research targeting platelet-derived growth factor receptor. Expert opinion: Few treatment options exist for CS; chemotherapy is not even an option for unresectable disease, in which 5-year survival rates are just 2%. New information about the multitude of genes and signaling pathways that encourage CS growth, invasion and metastasis are clarifying how certain signaling pathways and plant-derived active compounds, especially molecularly-targeted therapies that inhibit the PDGF receptor, interfering with these biological processes. This review summarizes discoveries from the last 5 years and discusses how these findings are fueling ongoing work into effectively dealing with the disease process and improving the treatment of CS.

An approach for cure: PEI-chemotherapy and regional deep hyperthermia in children and adolescents with unresectable malignant tumors.

BACKGROUND: Elevated temperatures of 40 - 44 degrees C increase the actions of various anticancer drugs including N-lost derivatives, cytotoxic antibiotics and platinum analoga. In clinical usage thermochemotherapy (TCH) should facilitate surgical resection and ameliorate local tumor control. PATIENTS AND METHODS: From 07/1993 to 12/2002 a total of 39 patients have been enrolled onto a phase-II study (female = 24, male = 15, age 1 - 37.5 years, median 5.2). Among these, 24 patients had extracranial non-testicular germ cell tumors and 15 patients soft tissue or chondrosarcomas. INDICATION: locoregional relapse (n = 29) or unresectable tumor after neoadjuvant chemotherapy (n = 10). Among these two groups, there were ten patients with poor response or progressive disease under primary or relapse chemotherapy. Ten out of the 29 relapse patients had more than one relapse. Tumor site: pelvis (30), abdomen (4), head and neck (2), proximal leg (2) and lumbar spine (1). Thermochemotherapy (TCH): 1800 - 2000 mg ifosfamide/m (2) and 100 mg etoposide/m (2) on days 1 - 4 and 40 mg cisplatin/m (2) on days 1 + 4 combined with regional deep hyperthermia (42 - 44 degrees C, 1 h) on days 1 + 4. RESULTS: In 39 protocol patients a total of 166 TCH courses (332 heat sessions) were applied. 20 patients achieved complete response, and 10 patients achieved partial response. TCH was followed by surgical tumor resection in 28/39 patients and/or radiotherapy in 13/39 patients. At a median follow-up of 27 months, outcome in this high-risk patient population was 22 NED, 3 AWD, 12 DOD, 2 DOC. Five year event free (EFS) and overall survival (OS) for the whole study cohort was 0.39 +/- 0.11 (20/39 patients) and 0.52 +/- 0.11 (25/39 patients), respectively. CONCLUSION: TCH shows substantial therapeutic efficacy and facilitates complete tumor resection in 14 out of 28 operated patients. Multimodal treatment including TCH, surgical resection and/or radiotherapy leads to sustained remission in the majority of patients with locoregional tumor recurrence. The therapeutic effect is most pronounced, if TCH is administered at first relapse. Due to the clinical and histologic heterogeneity the number of patients eligible for TCH is limited. Therefore, a more valid assessment of treatment efficacy can only be made by a matched-pair comparison in cooperation with the clinical registers.

Electrochemotherapy for digital chondrosarcoma.

Electrochemotherapy (ECT) delivers nonpermeable anticancer drugs to cell interiors by temporally increasing the permeability of the cytoplasmic membrane under locally applied pulsating electrical stimuli. This treatment results in consistent and enhanced pharmacological effects of drugs on the targeted tissue. ECT has been used for surface skin cancer but never for musculoskeletal tumors. This report describes a clinical trial of ECT for digital chondrosarcoma. A 74-year-old woman with a digital chondrosarcoma was administered electric stimulation with two surface electrodes 10 min after intratumoral multiple injection of bleomycin sulfate and 15 s after intraarterial perfusion of bleomycin sulfate. Biopsy performed after ECT showed 90% tumor necrosis. Marginal resection of the tumor was followed by autologous bone grafting to fill the bone defect. Although the follow-up period was short (3 years), the patient remained disease-free after ECT and was satisfied that amputation of the affected finger could be avoided. This preliminary result suggests that ECT is a viable modality for limb-preserving treatment of patients with sarcoma of the extremities.

Bone tumors of the extremities or pelvis treated by microwave-induced hyperthermia.

From July 1992 through March 1999, 213 patients with malignant bone tumors of the extremities (176 patients) and pelvis (37 patients) were treated by microwave-induced hyperthermia. Osteosarcoma and chondrosarcoma were the most common diagnoses. The limb-salvage procedure was done as follows: After separating the tumor-bearing bone and the extraosseous mass from surrounding normal tissues with a proper margin, microwave energy was delivered into the tumor while the healthy tissues were protected carefully from overheating. Restrengthening of the devitalized bone was necessary in many cases. The eschar resulting from the heat necrosis was curettaged. Most patients can walk early with a partial weightbearing brace for support. The survival rate was 73.9%. Fracture, local recurrence, and infection were the main complications although the majority of complications occurred early in the study. Thermotherapy is a novel and effective way to treat bone tumors in selected patients.

Hyperthermia increases the susceptibility of chondro- and osteosarcoma cells to natural killer cell-mediated lysis.

As an adjuvant to chemotherapy hyperthermia has proven to be successful as a treatment for osteo- and chondrosarcoma patients. The aim of this study was to investigate whether hyperthermia could increase cellular expression of heat-shock-protein 72 in human osteo- and chondrosarcoma cells and how heat treatment would affect their susceptibility to natural killer cell (NK-cell)-mediated lysis. About 5-10% of the peripheral mononuclear blood cells (PBMC) in the human peripheral blood are natural killer cells (NK-cells). Natural cytotoxicity, mediated by NK-cells, is believed to play an important role in host defense against cancer. The exact mechanisms of recognition of target cells and subsequent NK-cell activation are not yet known. NK-cells, isolated from the peripheral blood of healthy donors, were enriched by magnetic cell-separation to a purity of 85-97%, assessed by FACS-analysis. The susceptibility of heat-treated (42.5 degrees C, 90 minutes) and untreated osteosarcoma (MG63) and chondrosarcoma (HTB94) cell lines to NK-killing was determined by a release assay of lactate dehydrogenase (LDH). Lysis by NK-cells was increased by heat treatment of the target cells from 16.6% + 4.5% to 33% + 15%, p=0.035, for osteosarcoma cells, (E/T ratio of 5:1) and from 13.7% + 3.1% to 27.9% + 16.9%, p=0.021, (E/T ratio of 20:1) for chondrosarcoma cells. An increased expression of HSP72 of chondro- and osteosarcoma cells after heat treatment was detected by the Western blot technique. The results of this study show that hyperthermia increases HSP72 expression in osteo- and chondrosarcoma cells and their susceptibility to NK-cell-mediated lysis. These findings may lead to new therapeutic strategies, using hyperthermia to improve immunological defense against chondro- and osteosarcoma cells.

MR-guided laser-induced thermotherapy of the infratemporal fossa and orbit in malignant chondrosarcoma via a modified technique.

A 76-year-old patient presented with a recurrent mass of a malignant chondrosarcoma in the right infratemporal fossa and in the left maxillary sinus with orbital invasion. The patient was treated with a palliative intention with MR-guided laser-induced thermotherapy using a modified applicator technique. Following treatment clinical symptoms improved and MRI revealed complete laser-induced tumor necrosis.

[Treatment of malignant or aggressive bone tumors with microwave induced hyperthermia].

Limb-sparing procedures have been well established for dealing with malignant bone tumors. Unfortunately, these procedures have different problems. We used an alternative operation combined with microwave-induced hyperthemia to modify the surgical methods. Thermotherapy with microwave intracorporeal irradiation was used to treat 112 patients with bone tumors. In this series, 79 had malignant tumors and 33 aggressive benigh tumors. Postoperatively, immune therapy was carried out regularly. The patients immunologic functions were monitored by assay of the subpopulation of T cells, IL-2 and sIL-2R (soluble IL-2 receptor). Follow-up varied from 3 to 50 months (mean 23 month) s. Excluding 5 patients with malignancy in the vertebrae treated for palliation, 107 were evaluated by oncological and orthopedic criteria. 10 patients had local recurrence and required amputation. The remaining 97 had excellent local control. In 12 of the 74 patients with malignancy of the extremities, lung metastasis occurred 4 months to 2 years after surgery. Pathological fracture occurred at devitalized bone in 8 patients. In 29 out of 40 tumor-free cases followed for more than 2 years, the knee joints functioned properly with almost full range of motion. Single photon emission computered tomography (SPECT) study revealed revascularization of the devitalized tumor bearing bone segment could accomplish in one year or more. The immune state was improved after thermotherapy plus immunotherapy in the majority of patients. These results indicated that the use of microwave hyperthermia and adjuvant immunotherapy in the surgical treatment of bone tumors can be considered a definitive procedure, which is safe and well-tolerated.

[Microwave heating and neoadjuvant chemotherapy for malignant bone tumor].

Limb salvage is widely used but has different disadvantages. Attempting to establish a new limb conservative procedure, we treate patients with malignant bone tumor by intraoperative microwave heating on tumor bearing bone in place and neoadjvant chemotherapy. The tumors were localized at distal femur in 16, proximal tibia in 5, femur shaft in 2, and illia in 2. Pathological diagnosis showed osteosarcoma in 16 patents, parosteoal osteosarcoma in 4, chondrosarcoma in 3, and leiomyosarcoma in 2. The stage of tumor was II b in 18 patients, II a in 6, and III b in 3. Operative technique was wide resection for tumor in soft tissue, protecting the surrounding tissue from heat injury by copper net, and cheating tumor bone at 50 C for 15 minutes. Follow-up varied from 4 to 180 months (mean 57 months). The 5-, 10-years surviral rates were 70.19% and 54.83% respectively. Functional results of 21 patients were > 15 points by Enneking system. The advantages of the method and keeping the shape and continuity of the tumor bearing bone without osteotomy and internal fixation, controlling the time and temperature of heating treatment easily, benefiting for bone remodeling of heated bone. The indications, complications, and surgical procedure of this method were discussed in detail.

Capacitive heating of phantom and human tumors with an 8 MHz radiofrequency applicator (Thermotron RF-8).

The thermal profile was investigated in agar phantoms and in human tumors heated capacitively with 8 MHz RF. Deep and homogeneous heating could be achieved in a large homogeneous phantom of 25 cm diameter and 24 cm thick when heated with a pair of 25 cm diameter electrodes, coupled to both bases of the phantom. When the size of the two electrodes was not the same, the region near the smaller electrode was preferentially heated. It was, therefore, possible to control the depth of heating by choosing properly sized electrodes. Therapeutic temperature (greater than 42 degrees C) could be obtained in 7 out of 9 small, as well as, bulky superficial human tumors as large as 8 X 8 X 10 cm. Indications are that heating of some deep-seated human tumors might be achieved by the capacitive method, provided that subcutaneous fat layer is cooled by temperature controlled bolus and large electrodes are used. The effect of the anatomical structure on the power deposition in the human body during capacitive heating should be further investigated.

Palliation of advanced head and neck cancer with radiofrequency hyperthermia and cytotoxic chemotherapy.

Fourteen patients with recurrent malignant tumours of the head and neck were treated with radiofrequency hyperthermia and chemotherapy after conventional therapy had failed. After 2 to 11 treatment courses and a follow-up of 30 weeks, the neoplasms in three patients had completely regressed and one had a partial response. Of eight patients who died, two had partial responses initially; a third patient died of complications relating to surgical resection of the tumour after a partial response. Three of five patients whose tumours were unresponsive to methotrexate responded when this drug was given with radiofrequency hyperthermia. There were seven minor skin burns in six patients. Further studies of radiofrequency hyperthermia and chemotherapy for palliation of head and neck cancer are planned.