A retrospective study of SBRT of metastases in patients with primary sarcoma.

We retrospectively reviewed the results of stereotactic body radiotherapy (SBRT) in 46 patients with a total of 136 metastases from primary sarcoma. The purpose of this study was to evaluate the overall response rate and side effects of SBRT in metastatic sarcoma. The patients were treated at Karolinska University Hospital between 1994 and 2005, using 3D conformal multifield technique and a stereotactic body-frame. Prescribed doses ranged from 4 to 20 Gy per fraction in 1-5 fractions, with total doses of 10-48 Gy. All 46 patients were diagnosed with a primary sarcoma. The treated metastases were localized mainly in the lungs. A total number of 136 metastases were treated (1-14 per patient). Overall response rate (local control = CR, PR and SD) for each tumour was 88 % (119/135). Median follow-up was 21.8 months (range 2.7-112.8 months). Thirteen patients (31 %) were long-term survivors (>36 months), and 5 patients are still alive after last follow-up. Two cases of serious non-lethal side effects were seen, one patient had a colon perforation and another patient had contracture of the hip region. SBRT is a safe, convenient and effective non-invasive treatment with high local control for patients with metastatic sarcoma.

Interferons and osteosarcoma.

In 1970, we initiated studies at the Karolinska hospital to find out whether biologically meaningful doses of interferon (IFN) alpha preparations could be administered systemically to patients with viral and tumour diseases without causing unacceptable side effects. Antiviral and antitumour efficiency was demonstrated. Only a limited number of patients were injected due to shortage of high dose IFN preparations. Osteosarcoma patients participated in these early attempts. Due to clinical observations on one patient and due to lack of meaningful systemic standard treatment for osteosarcoma at the time, we decided to continue to give adjuvant IFN treatment to a consecutive series of osteosarcoma patients attending our hospital . We were encouraged by the preliminary follow up results of the series and continued to use this therapeutic principle up to 1990. The clinical results achieved are briefly summarized in this mini-review as are the results obtained in simultaneously ongoing model experiments in vitro and in vivo. A randomized large scale ongoing trial, involving the use of adjuvant IFN treatment of osteosarcoma patients, has been initiated by the European and American osteosarcoma study group 35 years after the first osteosarcoma patient received IFN. The trial is briefly outlined in this article.

Interferon-alpha as the only adjuvant treatment in high-grade osteosarcoma: long term results of the Karolinska Hospital series.

This experience of single agent interferon-alpha treatment in high-grade osteosarcoma was based on observed anti-osteosarcoma activity in laboratory models and was started before introduction of aggressive combination chemotherapy. From 1971 to 1990, 89 consecutive patients with non-metastatic high-grade osteosarcoma received semi-purified, leukocyte interferon-alpha as adjuvant treatment. From 1971 to 1984, 70 patients were given a dose of 3 MIU daily for one month followed by 3 times weekly for an additional 17 months. For 19 patients treated from 1985 to 1990 the dose was increased to 3 MIU daily and the treatment duration extended to 3-5 years. All patients underwent surgery prior to interferon treatment. The toxicity was mainly constitutional and long-term toxicity was virtually absent. With a median follow-up of 12 years the observed 10-year metastases-free and sarcoma specific survival rates were 39% and 43%, respectively. Only one of seven survivors after relapse received chemotherapy. This work suggests activity of interferon-alpha as adjuvant treatment in high-grade osteosarcoma. The efficacy of interferon in combination with standard therapy should be explored in randomized trials.

A systematic overview of radiation therapy effects in head and neck cancer.

UNLABELLED: A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for head and neck cancer is based on data from 39 randomized trials and 1 meta-analysis. In total, 40 scientific articles are included, involving 20893 patients. The results were compared with those of a similar overview from 1996 including 79 174 patients. The conclusions reached can be summarized as follows: General, non-nasopharynx. Substantial evidence indicates that the tumour effect of radiotherapy can be increased by the concomitant administration of chemotherapeutic agents, particularly cisplatin and 5-fluorouracil. There is moderate evidence of a survival benefit of radiation combined with concomitant chemotherapy compared to radiation alone. However, the results are equivocal. There is substantial evidence in published studies for an increased frequency of severe acute side effects as a result of concomitant chemotherapy and radiotherapy. There are very few studies that allow any estimates of the risk for serious late side effects. There is a weak indication of an increased risk for serious fibrosis. COMMENT: The general quality of studies and the lack of information on serious side effects indicate a need for large, well-designed clinical studies with a reasonable follow-up. Larynx preservation studies. There is strong evidence that larynx preservation is possible in 50% of the patients surviving for 5 years with hypopharyngeal cancers when treated with neoadjuvant chemotherapy and radical radiotherapy There is a non-significant trend for the overall survival being lower in non-surgically treated patients than in those treated with primary surgery and postoperative radiotherapy Nasopharynx. There is moderate evidence that patients with nasopharyngeal carcinomas of the endemic type benefit from therapy with a combination of chemotherapy and radical radiotherapy. However, the results from the reported studies are equivocal. There is some indication that the acute side effects of radiation are more severe in the concomitant setting than in the neoadjuvant. COMMENT: There are no data on serious late toxicity. Dose, fractionation schedules. There is some evidence that certain schedules of altered fractionation improve tumour control without increasing severe late side effects. There is some evidence that nervous tissues are more susceptible to damage by altered fractionation. Solid data shows that altered fractionation increases acute side effects. There is moderate evidence that accelerated hyperfractionation may reduce the frequency of serious late side effects while retaining a similar tumour effect as conventional radiotherapy Hypoxic cell sensitizers. Most reported trials reject the usefulness of nitroimidazole derivatives for sensitization of hypoxic tumour cells. There is some evidence that patients with tumours in the pharynx and larynx may benefit from sensitization by nimorazole. Prophylactic treatment of side effects. There is weak evidence that local antibiotics have a clinically significant effect in preventing acute radiotherapy side effects. There is insufficient evidence that radioprotective agents offer clinically significant protection of parotid glands (one study in two publications). There is insufficient evidence that radioprotective agents do not spare tumour tissue. Since the previous report no randomized studies comparing the effectiveness of external beam radiotherapy and brachytherapy have been performed. Both methods are well established and have independently proved to be effective in the treatment of certain head and neck cancers. No conclusion can be drawn regarding their relative effectiveness. Since the previous report no data to guide the use of intraoperative radiotherapy have been identified.

A systematic overview of radiation therapy effects in soft tissue sarcomas.

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for soft tissue sarcomas (STS) is based on data from five randomized trials. Moreover, data from 6 prospective studies, 25 retrospective studies and 3 other articles were used. In total, 39 scientific articles are included, involving 4 579 patients. The results were compared with those of a similar overview from 1996 which included 3 344 patients. The conclusions reached can be summarized as follows: The well-established prognostic factors for tumour-related death from STS-histological grade, tumour size and age-are well documented. The importance of superficial versus deep site as well as the anatomic site is also reaffirmed to some extent. There is strong evidence that adjuvant radiotherapy improves the local control rate in combination with conservative surgery in the treatment of STS of extremities and trunk in patients with negative, marginal or minimal microscopic positive surgical margins. A local control rate of 90% has been achieved. Improvement is obtained with radiotherapy added in the case of intralesional surgery, but the local control rate is somewhat lower. More studies are needed on this issue. For STS in other anatomic sites, retroperitoneum, head and neck, breast and uterus, there is only weak indication of a benefit for the local control rate, with the use of adjuvant radiotherapy. There is still insufficient data to establish that preoperative radiotherapy is favourable compared to postoperative radiotherapy for local control in patients presenting primarily with large tumours. One small study has shown a possible survival benefit for preoperative radiotherapy. There is fairly good evidence to suggest that the preoperative setting results in more wound complications. There is no randomized study comparing external beam radiotherapy and brachytherapy. The data suggest that external beam radiotherapy and low dose rate brachytherapy result in comparable local control for high-grade tumours. Some patients with low-grade soft tissue sarcomas benefit from external beam radiotherapy in terms of local control. Brachytherapy with low dose rate for low-grade tumours seems to be of no benefit, but data are sparse. The available data are inconclusive concerning the effect of intraoperative high dose rate radiotherapy for retroperitoneal STS. Further studies are needed. Neutron radiotherapy might be beneficial for patients with low- and intermediate-grade tumours considered inoperable and for those operated with intralesional margins. More severe side effects for neutrons have been registered. In two small studies investigating hyperfractionation schedules there was no indication of improvements compared to daily fractions of 2 Gy. Further studies should be encouraged. One small study using preoperative limb perfusion with TNF alpha melphalan and +/- interferon gamma combined with postoperative radiotherapy in the case of marginal or positive surgical margin has shown excellent local control without enhanced morbidity.