Mark N. Gaze

Pain relief and quality of life following radiotherapy for bone metastases: a randomised trial of two fractionation schedules

BACKGROUND The optimum dose and fractionation schedule for the palliative irradiation of painful bone metastases is controversial. PURPOSE To compare the efficacy, side-effects and effect on quality of life of two commonly used radiotherapy schedules in the management of painful bone metastases. MATERIALS AND METHODS In a prospective trial, 280 patients were randomised to receive either a single 10 Gy treatment or a course of 22.5 Gy in five daily fractions for the relief of localised metastatic bone pain. RESULTS Response rates have been calculated from 240 assessable treated sites of pain. The overall response rates were 83.7% (single treatment) and 89.2% (five fractions). The complete response rates were 38.8% (single treatment) and 42.3% (five fractions). The median duration of pain control was 13.5 weeks (single treatment) and 14.0 weeks (five fractions). None of these differences was statistically significant. There were no differences between the groups in the effect of treatment on a variety of quality of life parameters. CONCLUSIONS It is concluded that a single 10 Gy treatment is as effective as a course of 22.5 Gy in five fractions in the management of painful bone metastases.

Superior vena cava obstruction: A modern management strategy

Superior vena cava obstruction (SVCO) is a distressing syndrome. The condition may present to specialists in many branches of medicine, but patients have traditionally been referred on to clinical oncologists for management, as malignancy is the main aetiological factor. Treatment without a histological diagnosis is no longer justified, because management needs to be tailored to the underlying disease. This article reviews the causes, symptoms, methods of diagnosis and therapy options. The role of stenting in SVCO is discussed and a management algorithm is proposed.

177Lu-DOTATATE Molecular Radiotherapy for Childhood Neuroblastoma

This study tested the principle that 68Ga-DOTATATE PET/CT may be used to select children with primary refractory or relapsed high-risk neuroblastoma for treatment with 177Lu-DOTATATE and evaluated whether this is a viable therapeutic option for those children. Methods: Between 2008 and 2010, 8 children with relapsed or refractory high-risk neuroblastoma were studied with 68Ga-DOTATATE PET/CT. The criterion of eligibility for 177Lu-DOTATATE therapy was uptake on the diagnostic scan equal to or higher than that of the liver. Results: Of the 8 children imaged, 6 had abnormally high uptake on the 68Ga-DOTATATE PET/CT scan and proceeded to treatment. Patients received 2 or 3 administrations of 177Lu-DOTATATE at a median interval of 9 wk and a median administered activity of 7.3 GBq. Of the 6 children treated, 5 had stable disease by the response evaluation criteria in solid tumors (RECIST). Of these 5 children, 2 had an initial metabolic response and reduction in the size of their lesions, and 1 patient had a persistent partial metabolic response and reduction in size of the lesions on CT, although the disease was stable by RECIST. One had progressive disease. Three children had grade 3 and 1 child had grade 4 thrombocytopenia. No significant renal toxicity has been seen. Conclusion: 68Ga-DOTATATE can be used to image children with neuroblastoma and identify those suitable for molecular radiotherapy with 177Lu-DOTATATE. We have shown, for what is to our knowledge the first time, that treatment with 177Lu-DOTATATE is safe and feasible in children with relapsed or primary refractory high-risk neuroblastoma. We plan to evaluate this approach formally in a phase I–II clinical trial.

[131I]meta-iodobenzylguanidine and topotecan combination treatment of tumors expressing the noradrenaline transporter.

Purpose: Both [131I]meta-iodobenzylguanidine ([131I]MIBG) and the topoisomerase I inhibitor topotecan are effective as single-agent treatments of neuroblastoma. The aim of this study was to investigate the efficacy of [131I]MIBG in combination with topotecan in vitro and in vivo. Experimental Design: The cell lines used were SK-N-BE(2c) (human neuroblastoma) and UVW/NAT (glioma cell line transfected with the noradrenaline transporter gene). Three different treatment schedules were assessed: topotecan given before (schedule 1), after (schedule 2), or simultaneously (schedule 3) with [131I]MIBG. DNA strand breakage was evaluated by comet assay, and cytotoxicity was determined by clonogenic survival. Efficacy was also measured by growth delay of tumor xenografts in nude mice. Results: Combination schedules 2 and 3 caused more cytotoxicity than schedule 1. Similarly, significant DNA damage was observed following treatment schedules 2 and 3 (P < 0.005) but not schedule 1. The mean number of days for a doubling in volume of SK-N-BE(2c) tumors and a 10-fold increase in volume of UVW/NAT tumors were 10.4 and 18.6 (untreated), 19.7 and 25.3 (topotecan alone), 22.8 and 31.9 ([131I]MIBG alone), 26.3 and 37.1 (combination schedule 1), 34.3 and 49.7 (combination schedule 2), and 53.2 and >71 (combination schedule 3), respectively. The highest rate of cure of both xenografts was observed following treatment with combination schedule 3. Conclusions: The combination of topotecan and [131I]MIBG compared with either treatment alone gave rise to greater than additive DNA damage, clonogenic cell kill, and tumor growth delay. These effects were dependent on the scheduling of the two agents.

18F-FDG PET/CT and 123I-Metaiodobenzylguanidine Imaging in High-Risk Neuroblastoma: Diagnostic Comparison and Survival Analysis

The aim of our study was to evaluate prospectively the diagnostic performance and prognostic significance of 18F-FDG PET/CT in comparison with 123I-metaiodobenzylguanidine (123I-MIBG) imaging in patients with high-risk neuroblastoma. Methods: Twenty-eight patients with refractory or relapsed high-risk neuroblastoma (16 male and 12 female patients; age range, 2–45 y; median age, 7.5 y) were simultaneously evaluated with 18F-FDG PET/CT and 123I-MIBG imaging before treatment with high-dose 131I-MIBG. We compared the 2 methods in mapping tumor load, according to the extent of disease and intensity of positive lesions identified in each patient. Separate comparisons were performed for the soft-tissue and bone–bone marrow components of tumor burden. Survival analysis was performed to assess the prognostic significance of 18F-FDG and 123I-MIBG imaging parameters. Results: 18F-FDG PET/CT results were positive in 24 of 28 (86%) patients, whereas 123I-MIBG imaging results were positive in all patients. 18F-FDG was superior in mapping tumor load in 4 of 28 (14%) patients, whereas 123I-MIBG was better in 12 of 28 (43%) patients. In the remaining 12 (43%) patients, no major differences were noted between the 2 modalities. 18F-FDG PET/CT missed 5 cases of bone–bone marrow disease, 4 cases of soft-tissue disease, and 6 cases of skull involvement that were positive on 123I-MIBG scans. Cox regression and Kaplan–Meier survival curves showed that the group of patients (4/28) in whom 18F-FDG was superior to 123I-MIBG had a significantly lower survival rate than the others. Tumoral avidity for 18F-FDG (maximum standardized uptake value) and extent of 18F-FDG–avid bone–bone marrow disease were identified as adverse prognostic factors. Conclusion: 123I-MIBG imaging is superior to 18F-FDG PET/CT in the assessment of disease extent in high-risk neuroblastoma. However, 18F-FDG PET/CT has significant prognostic implications in these patients.

Prediction of accumulation of 131I-labelled meta-iodobenzylguanidine in neuroblastoma cell lines by means of reverse transcription and polymerase chain reaction.

Radiolabelled meta-iodobenzylguanidine (mIBG) currently provides one of the most promising options for targeted radiotherapy of neuroblastoma. No means currently exists for prediction of mIBG uptake in tumour cells of individual patients other than semiquantitative inferences from diagnostic scanning which depend on the continued existence of a macroscopic tumour mass. A biological rapid assay which could be applied at initial biopsy would be invaluable in selecting patients for therapeutic strategies which incorporate radiolabelled mIBG. We have assessed the expression of the noradrenaline transporter gene in six human neuroblastoma cell lines and in three non-neural crest-derived cell lines using reverse transcription followed by the polymerase chain reaction. Transcription of this gene was observed in five out of six neuroblastoma cell lines but in none of the control cells. A highly significant correlation was established (P < 0.01) between gene expression and active cellular accumulation of mIBG. It is suggested that semiquantitative evaluation of noradrenaline transporter gene transcripts may be predictive of mIBG uptake by tumours in vivo.

A systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma.

The optimal use and effectiveness of (131)I-meta iodobenzylguanidine ((131)I-mIBG) molecular radiotherapy for neuroblastoma remain unclear despite extensive clinical experience. This systematic review aimed to improve understanding of the current data and define uncertainties for future clinical trials. Bibliographic databases were searched for neuroblastoma and (131)I-mIBG. Clinical trials and non-comparative case series of (131)I-mIBG therapy for neuroblastoma were included. Two reviewers assessed papers for inclusion using the title and abstract with consensus achieved by discussion. Data were extracted by one reviewer and checked by a second. Studies with multiple publications were reported as a single study. The searches yielded 1216 citations, of which 51 publications reporting 30 studies met our inclusion criteria. No randomised controlled trials (RCTs) were identified. In two studies (131)I-mIBG had been used as induction therapy and in one study it had been used as consolidation therapy. Twenty-seven studies for relapsed and refractory disease were identified. Publication dates ranged from 1987 to 2012. Total number of patients was 1121 with study sizes ranging from 10 to 164. There was a large amount of heterogeneity between the studies with regard to patient population, treatment schedule and response assessment. Study quality was highly variable. The objective tumour response rate reported in 25 studies ranged from 0% to 75%, mean 32%. We conclude that (131)I-mIBG is an active treatment for neuroblastoma, but its place in the management of neuroblastoma remains unclear. Prospective randomised trials are essential to strengthen the evidence base.

Treatment of Neuroendocrine Tumours in Adults with 131I-MIBG Therapy

This is a retrospective review of 131I-MIBG therapy for metastatic neuroendocrine tumours in 25 adult patients. The tumours comprised 17 carcinoids, six paragangliomas, one somatostatinoma and one intestinal smooth muscle sarcoma. All patients (age range 28-84 years) had stage IV disease and a positive diagnostic 123I-MIBG scan. Patients received 11.1 GBq (300 mCi) of 131I-MIBG given in three cycles at 3-monthly intervals. The mean cumulative dose was 27.7 GBq (751 mCi). Symptomatic response was observed in 80%, hormonal response in 55% and tumour response in 48% (WHO criteria). Of the 25 patients, 40% are still under follow-up. Death was due to disease progression in all except one. The median survival time was 48 months from diagnosis of metastatic disease, and 17 months from the last 131I-MIBG therapy. The 5-year survival rate was 59% (95% confidence interval, 34%-78%). There was no statistical difference in survival between previously treated (chemo/radiotherapy) and treatment-naive patients. Side-effects were minimal and commonly include nausea (in the first 24 h) and a transient fall in platelet count. 131I-MIBG provides a good therapeutic response in patients with metastatic neuro-endocrine tumours.

The response of adenoid cystic carcinoma to tamoxifen

Adenoid cystic carcinoma of the parotid gland often recurs locally, or metastases develop, after initial treatment with surgery and radiotherapy. We report a patient with an inoperable local recurrence of previously irradiated adenoid cystic carcinoma, who was treated with tamoxifen, an oestrogen receptor antagonist. After 18 months of treatment with tamoxifen, MRI showed a partial response, and further clinical progression of the disease was halted.

The effect of cisplatin pretreatment on the accumulation of MIBG by neuroblastoma cells in vitro

[131I]meta-iodobenzylguanidine ([131I]MIBG) provides a means of selectively delivering radiation to neuroblastoma cells and is a promising addition to the range of agents used to treat neuroblastoma. As MIBG is now being incorporated into multimodal approaches to therapy, important questions arise about the appropriate scheduling and sequencing of the various agents employed. As the ability of neuroblastoma cells to actively accumulate MIBG is crucial to the success of this therapy, the effect of chemotherapeutic agents on this uptake capacity needs to be investigated. We report here our initial findings on the effect of cisplatin pretreatment on the neuroblastoma cell line SK-N-BE (2c). After treating these cells with therapeutically relevant concentrations of cisplatin (2 microM and 20 microM), a stimulation in uptake of [131I]MIBG was observed. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that this effect was due to increased expression of the noradrenaline transporter. These results suggest that appropriate scheduling of cisplatin and [131I]MIBG may lead to an increase in tumour uptake of this radiopharmaceutical with consequent increases in radiation dose to the tumour.