A phase II study evaluating neo-/adjuvant EIA chemotherapy, surgical resection and radiotherapy in high-risk soft tissue sarcoma

<p>Abstract</p> <p>Background</p> <p>The role of chemotherapy in high-risk soft tissue sarcoma is controversial. Though many patients undergo initial curative resection, distant metastasis is a frequent event, resulting in 5-year overall survival rates of only 50-60%. Neo-adjuvant and adjuvant chemotherapy (CTX) has been applied to achieve pre-operative cytoreduction, assess chemosensitivity, and to eliminate occult metastasis. Here we report on the results of our non-randomized phase II study on neo-adjuvant treatment for high-risk STS.</p> <p>Method</p> <p>Patients with potentially curative high-risk STS (size ≥ 5 cm, deep/extracompartimental localization, tumor grades II-III [FNCLCC]) were included. The protocol comprised 4 cycles of neo-adjuvant chemotherapy (EIA, etoposide 125 mg/m²iv days 1 and 4, ifosfamide 1500 mg/m²iv days 1 - 4, doxorubicin 50 mg/m²day 1, pegfilgrastim 6 mg sc day 5), definitive surgery with intra-operative radiotherapy, adjuvant radiotherapy and 4 adjuvant cycles of EIA.</p> <p>Result</p> <p>Between 06/2005 and 03/2010 a total of 50 subjects (male = 33, female = 17, median age 50.1 years) were enrolled. Median follow-up was 30.5 months. The majority of primary tumors were located in the extremities or trunk (92%), 6% originated in the abdomen/retroperitoneum. Response by RECIST criteria to neo-adjuvant CTX was 6% CR (n = 3), 24% PR (n = 12), 62% SD (n = 31) and 8% PD (n = 4). Local recurrence occurred in 3 subjects (6%). Distant metastasis was observed in 12 patients (24%). Overall survival (OS) and disease-free survival (DFS) at 2 years was 83% and 68%, respectively. Multivariate analysis failed to prove influence of resection status or grade of histological necrosis on OS or DFS. Severe toxicities included neutropenic fever (4/50), cardiac toxicity (2/50), and CNS toxicity (4/50) leading to CTX dose reductions in 4 subjects. No cases of secondary leukemias were observed so far.</p> <p>Conclusion</p> <p>The current protocol is feasible for achieving local control rates, as well as OS and DFS comparable to previously published data on neo-/adjuvant chemotherapy in this setting. However, the definitive role of chemotherapy remains unclear in the absence of large, randomized trials. Therefore, the current regimen can only be recommended within a clinical study, and a possibly increased risk of secondary leukemias has to be taken into account.</p> <p>Trial registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01382030">NCT01382030</a>, EudraCT 2004-002501-72</p

Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme

Therapy options at the time of recurrence of glioblastoma multiforme are often limited. We investigated whether treatment with a new intratumoral thermotherapy procedure using magnetic nanoparticles improves survival outcome. In a single-arm study in two centers, 66 patients (59 with recurrent glioblastoma) received neuronavigationally controlled intratumoral instillation of an aqueous dispersion of iron-oxide (magnetite) nanoparticles and subsequent heating of the particles in an alternating magnetic field. Treatment was combined with fractionated stereotactic radiotherapy. A median dose of 30 Gy using a fractionation of 5 × 2 Gy/week was applied. The primary study endpoint was overall survival following diagnosis of first tumor recurrence (OS-2), while the secondary endpoint was overall survival after primary tumor diagnosis (OS-1). Survival times were calculated using the Kaplan–Meier method. Analyses were by intention to treat. The median overall survival from diagnosis of the first tumor recurrence among the 59 patients with recurrent glioblastoma was 13.4 months (95% CI: 10.6–16.2 months). Median OS-1 was 23.2 months while the median time interval between primary diagnosis and first tumor recurrence was 8.0 months. Only tumor volume at study entry was significantly correlated with ensuing survival (P < 0.01). No other variables predicting longer survival could be determined. The side effects of the new therapeutic approach were moderate, and no serious complications were observed. Thermotherapy using magnetic nanoparticles in conjunction with a reduced radiation dose is safe and effective and leads to longer OS-2 compared to conventional therapies in the treatment of recurrent glioblastoma

High incidence of metastatic disease in primary high grade and large extremity soft tissue sarcomas treated without chemotherapy

BACKGROUND: The risk of metastasis and the survival in patients with primary extremity soft tissue sarcomas is worse when tumour size is large and the grade of malignancy is high. Such tumours may receive chemotherapy and/or radiation therapy (RTX) for optimising local control. Irradiation can either be applied preoperatively or after tumour resection. The question arises if the kind of RTX in the absence of chemotherapy influences the outcome concerning local control, metastatic disease, survival and complications. METHODS: We retrospectively reviewed the clinical outcome of 233 patients with a primary extremity soft tissue sarcoma treated between 1990 – 2000 with a mean follow-up of 35.8 (4–120) months in our institute. 41 patients had high grade, deep and large tumours (>8 cm), an AJCC stage III (no evidence of metastasis prior to treatment) and were treated with limb salvage surgery and irradiation but stayed without additional chemotherapy. Two groups of patients were compared: the first group received postoperative RTX after tumour resection (n = 33); the second group was treated with preoperative RTX (n = 8). Both groups did not differ concerning clinical parameters. We analysed primary and secondary outcomes. RESULTS: 56% (23/41) of the population developed metastatic disease, 24% (10/41) local recurrence. The risk of metastasis was higher in the group with preoperative irradiation (p = 0.046). The overall (p = 0.0248) and relapse free survival (p = 0.104) were worse in this group. The delay to tumour resection amounted 8 weeks on average in the preoperative group. Local control was not different (p = 0.38) in both study groups. Wound infections and other combined therapy related complications were equally distributed (p = 0.22). CONCLUSION: Without chemotherapy there remains a high risk of metastasis in AJCC grade 3 patients. In high risk patients treated without chemotherapy the elapsed time to tumour resection after preoperative radiation might contribute to the development of metastasis. This outcome may support the thesis that a combination of RTX and offensive multimodal treatment protocols is advantageous in such a subset of patient

Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer

Ultrasound (US) is a non-ionizing pressure wave that can produce mechanical and thermal effects. Bisphosphonates have demonstrated clinical utility in bone metastases treatment. Preclinical studies suggest that bisphosphonates have anticancer activity. However, bisphosphonates exhibit a high affinity for bone mineral, which reduces their bioavailability for tumor cells. Ultrasound has been shown to be effective for drug delivery but in interaction with gas bubbles or encapsulated drugs. We examined the effects of a clinically relevant dose of bisphosphonate zoledronate (ZOL) in combination with US. In a bone metastasis model, mice treated with ZOL+US had osteolytic lesions that were 58% smaller than those of ZOL-treated animals as well as a reduced skeletal tumor burden. In a model of primary tumors, ZOL+US treatment reduced by 42% the tumor volume, compared with ZOL-treated animals. Using a fluorescent bisphosphonate, we demonstrated that US forced the release of bisphosphonate from the bone surface, enabling a continuous impregnation of the bone marrow. Additionally, US forced the penetration of ZOL within tumors, as demonstrated by the intratumoral accumulation of unprenylated Rap1A, a surrogate marker of ZOL antitumor activity. Our findings made US a promising modality to trigger bisphosphonate anticancer activity in bone metastases and in primary tumors