(Stereotactic) radiosurgery XIX: spinal radiosurgery--two year experience in a UK centre.

INTRODUCTION: Modern radiotherapy image guidance enables the treatment of extracranial targets with the required accuracy for safe delivery of radiosurgical treatments. The first two years' experience of spinal radiosurgery in a UK radiotherapy centre is reported. MATERIALS AND METHODS: Patients with primary or metastatic spinal lesions were treated using the CyberKnife stereotactic radiotherapy system. Xsight Spine (fiducial-free) tumour tracking software was used in all cases. Treatment was delivered using either a single or a three-fraction schedule, between February 2009 and March 2011. RESULTS: Fifty-three spinal lesions were treated, comprising 14 primary lesions in 12 patients, and 39 metastases in 29 patients. The prescription dose ranged from 8 to 30 Gy in 1-3 fractions. Fifty-nine percent of patients experienced no acute side effects from treatment. There were three cases of acute grade 3 back or nerve root pain, all of which responded to a short course of oral corticosteroids. At a median follow-up of 11.1 months, local control and overall survival were 91 and 65%, respectively. Pain improvement was seen in 75% of symptomatic metastases at 6 months post treatment. CONCLUSIONS: Early UK experience confirms that radiosurgery is well tolerated with excellent local control rates. Longer-term prospective data are needed to clarify the role of spinal radiosurgery for patients in this country.

Single center experience of a new intensive induction therapy for ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties.

PURPOSE: To examine the feasibility, tolerability, and toxicity of an intensified induction regimen (vincristine, ifosfamide, doxorubicin, and etoposide [VIDE]) in patients with newly diagnosed Ewing's family of tumors (EFT); to assess ability to maintain dose-intensity, and predictability of peripheral-blood stem cell mobilization. PATIENTS AND METHODS: Thirty patients were treated with vincristine 1.4 mg/m2 (maximum 2 mg) on day 1, doxorubicin 20 mg/m2, ifosfamide 3 g/m2 plus mesna and etoposide 150 mg/m2 on days 1 to 3. Cycles were given every 21 days for up to six cycles. RESULTS: One-hundred and seventy cycles of VIDE were given. The median treatment interval was 21 days (21 to 42) and nadir count: hemoglobin 8.3 (6.3 to 11.9), neutrophils 0.045 (0.0 to 2.1), and platelets 45 (3 to 343). There were 96 episodes of infection requiring hospitalization (56%). Growth factor support reduced infectious complications by 34%. Etoposide dose was reduced, or omitted, in 24% of cycles. Four patients did not complete six cycles due to unacceptable toxicity and one patient progressed on treatment. Twenty patients underwent peripheral-blood stem cell harvesting, 15 after cycle 3, and five after cycle 4. Median CD34+ yield was 4.6 x 106/kg per patient (1.8 to 14.5). Overall response to treatment, measured in 24 patients, was 88%. Seven of 11 patients undergoing surgery achieved greater than 90% necrosis of tumor (64%). CONCLUSION: VIDE is an effective induction regimen with substantial but acceptable toxicity that allows predictable mobilization of stem cells. Maintenance of dose-intensity is feasible in the majority of patients. Growth factors play a role in maintaining dose-intensity and reduce infectious complications.

Fatal radiation myelopathy after high-dose busulfan and melphalan chemotherapy and radiotherapy for Ewing's sarcoma: a review of the literature and implications for practice.

Radiation myelopathy is a rare, devastating, late effect of radiotherapy to the spinal cord. Spinal cord tolerance is currently accepted as about 50 Gy in 1.8-2 Gy fractions. However, the effect of chemotherapy on cord tolerance is unclear. This issue is important, given the increasing use of chemotherapy in combination with radiotherapy. We describe the case of a 17-year-old boy with a right apical paraspinal Ewing's tumour in the neck treated with induction chemotherapy, high-dose chemotherapy (busulfan and melphalan) with peripheral stem-cell rescue and, 4 months later, radiotherapy to the primary tumour site (cervical cord received 50 Gy in 30 fractions). After a latent period of 4 months, he developed a progressive, severe and ultimately fatal radiation myelopathy, which we suggest was due to a synergistic interaction between the high-dose chemotherapy and the radiotherapy. The use of such chemotherapy regimens in Ewing's tumours should be carefully considered, particularly when radiotherapy encompassing the spinal cord is an essential component of management.

Intrinsic radiosensitivity of adult and cord blood lymphocytes as determined by the micronucleus assay.

Predictive radiosensitivity testing necessitates rapid and reliable assays of radiosensitivity. We assessed the lymphocyte micronucleus assay as such an assay. We performed repeated experiments on lymphocytes from 10 healthy donors. Levels of radiation-induced micronuclei were measured following exposures of up to 4 Gy X-rays. When measuring the slope of the dose-response, we have found more variation between individuals than between repeated experiments on the same individual (F value 12.31, P < 0.001). There is also greater interindividual variation in the data following a single dose of X-rays of 2 Gy (F value 3.54, P < 0.01) and of 4 Gy (F value 7.55, P < 0.005). We performed the micronucleus assay on five different samples of cord blood lymphocytes (CBLs). Their radiosensitivities were compared with the mean radiosensitivity of the lymphocytes from the normal group of donors. Comparing the level of micronuclei induced by 2 Gy, only CBL1 (P < 0.01) and CBL2 (P < 0.02) were more radiosensitive than the mean of the adult lymphocytes. At 4 Gy, CBL1 (P < 0.001), CBL2 (P < 0.05), CBL3 (P < 0.01) and CBL5 (P < 0.01) were more radiosensitive than the mean radiosensitivity of the adult lymphocytes. This was also shown when the slope of the dose-response curves were measured. We conclude that the lymphocyte micronucleus assay shows more variability when applied to lymphocytes from different individuals than when repeatedly applied to lymphocytes from the same individual, a requirement for the determination of individual radiosensitivity.

Differences in the level of DNA double-strand breaks in human tumour cell lines following low dose-rate irradiation.

It is now well accepted that differences exist in the intrinsic radiosensitivity of human tumour cells although the molecular basis of this is still unclear. Current evidence suggests that of the lesions induced in DNA by ionising radiation, double-strand breaks (DSB) are the most closely linked to cell death. In this study, levels of DSB were measured by neutral filter elution under conditions of both repair inhibition and maximum recovery and compared with clonogenic survival curves for high (HDR) and low dose-rate (LDR) irradiation in human carcinoma lines of differing radiosensitivity. Four human lung carcinoma lines were used, two small-cell (SCLC; HC12 and HX149) and two non-small cell lines (NSCLC; HX147A7 and HX148G7). Cell survival was measured by soft agar and monolayer colony-forming assays as appropriate and a large variation in sensitivity of the cell lines was seen (alpha values of 0.06 to 0.56 Gy-1). We have previously reported that the damage induced at high dose rate does vary in these cell lines but not in a way which correlates with their cell survival response [5]. Following irradiation to 15 Gy at low dose rate essentially no DSBs were detected in any of the four lines but at 70 Gy the more sensitive SCLC showed more residual damage than in the more radioresistant NSCLC lines. The prime determinant of the difference between the LDR and HDR damage curves is likely to be repair occurring during irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiotherapy and conservative surgery in the management of musculo-aponeurotic fibromatosis.

Fifty-four patients with musculo-aponeurotic fibromatosis treated with surgery, surgery and planned post-operative radiotherapy, or radiotherapy alone between 1936 and 1982 have been retrospectively reviewed. Twenty-seven patients had a previous excision before definitive treatment. All patients in whom surgery was known to be incomplete and who had no further treatment relapsed. Nine patients had a complete surgical excision alone and 1 relapsed. Twenty-nine patients were treated with surgery and post-operative radiotherapy and 7 relapsed. Relapse was associated with small field size, orthovoltage irradiation, and doses less than 50 Gy. Radiotherapy was effective in preventing relapse in 6 of 8 cases incompletely excised and in all of these cases the total dose was more than 50 Gy. In 13 assessable patients with clinically evident disease, 14 fields were treated with radiotherapy. Complete response was achieved in 9 fields (although one subsequently relapsed and 2 had a marginal relapse), partial response in 4, and disease stasis in one. Complete resolution took up to 21 months and total doses ranged from 35.2 Gy to 64 Gy. Radiotherapy is indicated in cases of incomplete excision and inoperable disease. Doses should be radical and fields should be sufficiently generous to encompass the anatomical limits of the infiltrated tissues.

The functional results following primary treatment of breast cancer with breast conservation.

Forty-seven patients who had local excision ('lumpectomy') and radical radiotherapy for carcinoma of the breast in 1982 were assessed at 1 year for the functional result. The appearance of both breast was identical in 34%, while in 10% serious distortion had occurred. No matchline effect or severe telangiectasia were seen, and no patient had arm oedema, restricted arm movements or severe pain. The results were not significantly better (1) following iridium implantation than external boost, (2) after periareolar rather than other incisions, and (3) in patients with small and medium rather than large breasts.

Radiosensitive human tumour cell lines may not be recovery deficient.

Split-dose studies have been performed on four human tumour cell lines of widely differing radiosensitivity in order to characterize the relationship between cellular recovery and radiation dose. Previous studies using the split-dose experiment have usually measured recovery at a single dose level and assumed an underlying multi-target model of radiation effect. This predicts that the recovery ratio should reach a plateau when the dose used per fraction is beyond the shoulder of the acute survival curve. In contrast, the linear-quadratic model predicts that the recovery ratio will increase steeply as a function of dose and will never reach a plateau. Our results show that recovery increases with increasing dose and therefore no single value of the recovery ratio can be used for comparative purposes. Using these data, we have derived a value for the beta-component of the linear-quadratic model that is independent of alpha. In addition we propose that the beta-parameter derived in this way provides the most satisfactory basis for intercomparison of cellular recovery between cell lines of differing radiosensitivity. Cellular recovery at any given dose was greatest in the most radiosensitive cell line, suggesting that increased radiosensitivity does not result from decreased recovery capacity. The results suggest that cells with steep acute radiation survival curves and which show little split-dose recovery may not be recovery deficient. Consequently, using such cells in attempts to correlate recovery with the underlying molecular processes of radiation damage repair could lead to misleading results.

The relationship of DNA double-strand break induction to radiosensitivity in human tumour cell lines.

Recent data suggest that the differences in radiosensitivity between cell lines can be related to differences in dsb induction (Radford 1986a). In the light of this we have set out to assess the extent to which differences in radiation survival between human tumour cell lines can be attributed to differences in dsb induction. For nine human tumour lines survival was assayed by clonogenic assay and compared with dsb induction by irradiation at ice-bath temperature as measured by neutral filter elution. The lines varied widely in their sensitivity, ranging from a sensitive neuroblastoma (surviving fraction at 2 Gy, SF2 = 0.13) to a resistant bladder carcinoma (SF2 = 0.62). Dsb induction was found to vary between the cell lines, such that resistant cells generally suffered less damage than sensitive ones. However, the relationship between damage induction and cellular sensitivity was not a simple one, and other factors which may influence sensitivity need to be invoked. These data suggest that, in human tumour cell lines, differences in radiosensitivity may at least in part be due to different levels of damage induction, but that some lines may vary in their tolerance of damage due to differences in biological characteristics such as repair capacity.

Rhenium-186 HEDP as a boost to external beam irradiation in osteosarcoma.

In this case report we demonstrate the usefulness of targeted radiotherapy in the form of rhenium-186 HEDP as a method for dose escalation in the treatment of osteosarcoma.

A pilot study to evaluate the cost-effectiveness of ondansetron and granisetron in fractionated total body irradiation.

The duration of the antiemetic effect of granisetron was examined in a pilot study of patients (n = 26) undergoing a standard emetogenic stimulus in the form of total body irradiation fractionated over 3-4 days, in a randomized comparison with twice-daily ondansetron. A single intravenous dose of granisetron at the onset of therapy was effective over the entire follow-up period in 50% (6/12) of patients, compared with 77% (10/13) prescribed twice-daily oral ondansetron for 3 or 4 days. The response rate within the first 24 hours from the start of irradiation was 67% (8/12) for granisetron and 77% (10/13) for ondansetron. Granisetron and ondansetron were therefore of similar efficacy within the first 24-hour period, but granisetron was less efficaceous more than 24 hours after the onset of therapy. Patients who required a second dose of granisetron did so at intervals of 12, 42, 47 and 48 hours following the first fraction of radiotherapy. The cost per patient in this study was pound 48 for granisetron and pound 54 for ondansetron, but the dose scheduling we used cannot be recommended in view of the lower effectiveness of granisetron.

Pseudo-Meigs' syndrome due to broad ligament leiomyoma: a mimic of metastatic ovarian carcinoma.

Pseudo-Meigs' syndrome is a rare complication of benign leiomyomas of the female genital tract. We report a patient with pseudo-Meigs' syndrome due to a large broad ligament leiomyoma, which also caused bilateral reversible hydronephrosis. This unusual combination of pseudo-Meigs' syndrome, broad ligament leiomyoma and hydronephrosis requiring ureteric stenting does not appear to have been reported previously. Features of the syndrome that led to a diagnostic problem, the mimicking of metastatic ovarian carcinoma, are presented. The little that is known of the pathogenesis of the pleural and ascitic fluids is discussed. An elevated level of serum CA 125 antigen is reported, we believe for the first time in association with pseudo-Meigs' syndrome.

Tumour volume changes following pre-operative radiotherapy in borderline resectable limb and trunk soft tissue sarcoma.

AIMS: To evaluate tumour volume changes after preoperative radiotherapy (PRT) for borderline operable soft tissue sarcomas (STS). MATERIALS AND METHODS: A retrospective review was performed of 68 patients who received PRT between December 2004 and July 2011. Endpoints were radiological response, surgical margins, local control and survival. RESULTS: Median tumour size was 12.5 cm. Tumour location was extremity (87%), trunk (12%), and neck (1%). Commonest histological subtypes were myxoid liposarcoma (32%) and myxofibrosarcoma (16%). The majority of patients (88%) received 50 Gy in 25 fractions. Post-radiotherapy imaging was available in 55 cases. By RECIST there was stable disease in 89%, partial response in 7% and progressive disease in 4%. Tumour volumes reduced in 80%. Median change in maximal tumour dimension was -13.6%; median change in volume was greater, at -33.3%. Tumour volumes increased in 11 cases (20%). However, surgical margins were clear in all 11 cases, with no local recurrences in this group. For the entire group, surgical margins were clear in 93%, and microscopically positive in 7%. Eight patients (12%) had local relapse at 2-24.8 months after surgery. Two year local relapse free survival was 87.5%; 2 year overall survival was 74.7%. CONCLUSION: The majority of tumours showed reduction in volume. A small number of tumours increased in volume, but there was no definite relationship between volume increase and poor surgical outcomes or lower local control rates. Local control was equivalent to published series' of PRT. PRT is a reasonable approach in patients with borderline resectable tumours.

A systematic review of the role of pulmonary irradiation in the management of primary bone tumours.

INTRODUCTION: Adjuvant therapy in osteosarcoma (OS) and Ewing's sarcoma (ES) is primarily directed towards treatment of subclinical lung disease. Before the advent of modern intensive chemotherapy, lung irradiation was the only available adjuvant treatment. It has proven biological activity and low morbidity. There is, however, a wide variation in its application between centres. This systematic review aims to define the evidence to support the use of lung irradiation in these diseases. DESIGN: A review of trials published between 1966 and 2000 was undertaken to determine the evidence for the use of pulmonary irradiation in OS and ES. RESULTS: Several small series of prophylactic lung irradiation (PLI) have been reported, most from over 20 years ago. These studies support the theoretical basis for the use of PLI in both OS and ES. Few randomised studies have been performed which include PLI. In OS, studies demonstrated a trend in favour of PLI compared with no adjuvant treatment and, subsequently, a level of benefit similar to that achieved with chemotherapy, but no additive effect. No studies have used PLI in addition to current standard chemotherapy regimens, or evaluated its use after successful metastatectomy. In ES, only one randomised study has addressed the role of PLI, in a comparison with vincristine, actinomycin D and cyclophosphamide combination chemotherapy with or without doxorubicin. Prolonged follow-up favoured four-drug chemotherapy. Retrospective reports from large cooperative groups suggest that the addition of whole-lung radiotherapy (WLRT) improves outcome in ES patients presenting with pulmonary metastases. However, there are no randomised study data to support this. CONCLUSIONS: Further randomised studies are necessary to clarify the role of PLI in addition to current standard chemotherapy regimens, or its use after successful metastasectomy in patients with OS. In patients with localised ES adjuvant chemotherapy appears to be superior to PLI alone, while there is little evidence to support treatment with WLRT in patients who present with pulmonary metastases.

A pilot study of short-course intensive multiagent chemotherapy in metastatic and axial skeletal osteosarcoma.

BACKGROUND: This pilot study was undertaken to assess the feasibility, toxicity and response to short-course multiagent chemotherapy followed by high-dose chemotherapy (HDC) in patients with poor prognosis osteosarcoma. PATIENTS AND METHODS: A total of 30 patients entered the study. Chemotherapy consisted of four blocks of multiagent chemotherapy administered sequentially over a short period in a dose-intensive manner. This therapy was followed by HDC which consisted of carboplatin at an AUC8 x 3 days, etoposide 400 mg/m(2) x 3 days and cyclophosphamide 60 mg/kg x 2 days. RESULTS: A total of 227 cycles of chemotherapy were administered. The main toxicity (for blocks 1-4) was haematological. There were two treatment-related deaths: one post HDC due to sepsis and one during surgery. High-dose chemotherapy was administered to 11 patients (10 with extremity tumours and only one with a pelvic tumour). Twenty-seven patients underwent surgery to the primary. Histological response was assessed in 23 patients. Seven patients (30%) had >90% necrosis. Eight patients underwent pulmonary metastatectomy. The median survival time for the whole group was 16 months. The 2- and 3-year survival rates were 50% and 21% for those with extremity tumours and 19% and 13% for those with axial skeletal tumours. CONCLUSIONS: Dose-intensive multiagent chemotherapy though feasible in the group of patients with extremity tumours did not significantly improve the treatment outcome compared with conventional relapse therapy. Inferior survival rates in the axial skeletal group are attributed to less intensive treatment and poor local tumour control.