Fracture after radiation therapy for femoral metastasis: incidence, timing and clinical features.

We analyzed 428 femoral metastases initially treated with radiotherapy between 2002 and 2011 to clarify the clinical details of post-irradiation fractures of femoral metastasis. Patients included 161 men and 167 women, with a mean age of 62 years. Fracture incidence, fracture site, fracture risk based on X-ray images before radiotherapy, and interval from completion of radiotherapy to fracture occurrence were assessed. In addition, 24 pathological specimens obtained during 27 surgeries for these fractures were examined. Fractures occurred in 7.7% of 428 femoral metastases (total 33: 28 actual fractures and five virtual fractures with progressive pain and bone destruction). The fracture rate was 7.8% in the proximal femur and 1.5% in the shaft (P = 0.001). Fractures occurred a median of 4.4 months after radiotherapy, with 39.4% occurring within 3 months and 63.6% within 6 months. Among femurs with high fracture risk according to Harrington's criteria or Mirels' score, the fracture rate was 13.9% and 11.8%, respectively. Viable tumor cells were detected in all five patients with painful virtual fracture, in 85.7% of femurs with actual fractures that occurred within 3 months, and in only 25.0% of actual fractures occurring after 3 months. Post-irradiation fractures of femoral metastasis most frequently occurred within 3 months after radiotherapy, and were more common in the peritrochanteric area than in the shaft. Radiological evidence of impending fracture did not correlate with a high fracture rate. Actual fractures occurring after more than 3 months were likely caused by post-irradiation fragility of the femur, without viable tumor cells.

[Extracorporeal irradiation : Reimplantation of bone segments in the treatment of malignant bone tumours]. / Die extrakorporale Bestrahlung : Replantation von Knochensegmenten bei malignen Knochentumoren.

BACKGROUND: Malignant bone tumors themselves and the wide resection required because of them may cause huge bone defects in the bone segment involved. Autologous bone grafts are a reliable option to cover these defects in many cases but their availability is limited. Besides common alternative reconstruction methods, including the use of allografts and/or prostheses, especially extracoroporeal irradiation (ECI) and reimplantation of the bone segment involved is attracting increasingly more attention nowadays. DISCUSSION: In the following, we report on indications/contraindications, details of the operative technique, as well as the recommended rehabilitation regime of ECI. Furthermore, we compare our own results with those published in the recent literature. Especially the advantages and disadvantages of this method, the risks and the complications are illustrated and critically discussed. CONCLUSION: Extracorporeal irradiation of a tumor bearing bone segment is a valuable alternative reconstruction technique following tumor resections of the pelvis, femur and tibia, with encouraging results with respect to local control, complication risks and functional outcome.

Fluorodeoxyglucose Uptake on Positron Emission Tomography Is a Useful Predictor of Long-Term Pain Control After Palliative Radiation Therapy in Patients With Painful Bone Metastases: Results of a Single-Institute Prospective Study.

PURPOSE: To determine whether fluorodeoxyglucose positron emission tomography (FDG-PET) before and after palliative radiation therapy (RT) can predict long-term pain control in patients with painful bone metastases. METHODS AND MATERIALS: Thirty-one patients with bone metastases who received RT were prospectively included. Forty painful metastatic treatment fields were evaluated. All patients had undergone pre-RT and post-RT PET/CT scanning. We evaluated the relationships between the pre-RT, post-RT, and changes in maximum standardized uptake value (SUVmax) and the pain response, and between SUVmax and pain relapse of the bone metastases in the treatment field. In addition, we compared the SUVmax according to the length of time from the completion of RT to pain relapse of the bone metastases. RESULTS: Regarding the pain response at 4 weeks after the completion of RT, there were 36 lesions of 27 patients in the responder group and 4 lesions of 4 patients in the nonresponder group. Changes in the SUVmax differed significantly between the responder and nonresponder groups in both the early and delayed phases (P=.0292 and P=.0139, respectively), but no relationship was observed between the pre-RT and post-RT SUVmax relative to the pain response. The responder group was evaluated for the rate of relapse. Thirty-five lesions of 26 patients in the responder group were evaluated, because 1 patient died of acute renal failure at 2 months after RT. Twelve lesions (34%) showed pain relapse, and 23 lesions (66%) did not. There were significant differences between the relapse and nonrelapse patients in terms of the pre-RT (early/delayed phases: P<.0001/P<.0001), post-RT (P=.0199/P=.0261), and changes in SUVmax (P=.0004/P=.004). CONCLUSIONS: FDG-PET may help predict the outcome of pain control in the treatment field after palliative RT for painful bone metastases.

Muscle cramping over the diagnosis.

A 44-year-old man with hypogonadism and adrenal insufficiency presented with transient blurred vision and halos around lights. Visual acuity was 20/20 in both eyes, and he had mild bilateral optic disk edema. Brain imaging was unremarkable, and lumbar puncture showed an opening pressure of 28.5 cm H2O with elevated protein. He also complained of muscle cramping, and magnetic resonance imaging of the spine demonstrated a heterogenous bone marrow signal. Bone survey showed a mixed lytic and sclerotic lesion within the left femur that proved to be a plasmacytoma. Serum protein electrophoresis had a small IgA spike, and plasma vascular endothelial growth factor (VEGF) was elevated. He was diagnosed with POEMS syndrome and underwent radiation to the plasmacytoma. Two years later he had a stable neuro-ophthalmologic exam with no signs of multiple myeloma. POEMS syndrome is a rare paraneoplastic syndrome from a plasma cell dyscrasia that may cause optic disk edema.

[Localized primary bone lymphoma: about four cases]. / Lymphome osseux primitif localisé : à propos de quatre cas.

PURPOSE: To study epidemiological, clinical, pathological anatomy and therapeutic results of localized primary bone lymphoma. PATIENTS AND METHODS: Between February 1993 and February 2013, four patients were treated for localized primary bone lymphoma in Sfax's hospitals (Tunisia). Treatment was decided regarding to the age of the patient, his performance status, stage of the disease, lactate dehydrogenase (LDH) and socio-economical conditions of the patient. The therapeutic evaluation was done after chemotherapy and after radiotherapy. There was a clinical, biological and radiological follow-up. RESULTS: The mean age was 59.5 years. The sex-ratio was 3. Bone localizations were clavicula, femur, humerus and mandibula. All patients had stage I large cell B lymphoma. In 3 cases, imaging showed osteolytic lesions with cortical destruction and extension to soft tissues. One patient had a fracture of the humerus. The treatment consisted in chemotherapy followed by radiotherapy. Three patients were alive with complete remission after a mean follow-up of 76 months. CONCLUSION: The treatment of primary bone lymphoma is based on a combination of chemotherapy (with or without anti-CD20) and radiotherapy. The prognosis is excellent when it is localized.

[A rare case of bone metastasis from gastro-intestinal stromal tumour: place of radiotherapy]. / À partir d'un cas rare de métastases osseuses d'une tumeur stromale gastro-intestinale : intérêt de la radiothérapie.

Gastro-intestinal stromal tumours are the most common mesenchymal neoplasms of the gastrointestinal tract. Their usual metastatic sites are the liver and the peritoneum, but gastro-intestinal stromal tumours rarely metastasize to the bones. We report the case of a 56-year-old male presenting with bone lesions six years after initial surgical resection. We discuss through this paper the possibilities of management of these lesions and the place of radiotherapy.

An unusual sarcomatous retroperitoneal metastasis. A rare case report with a brief literature review.

Retroperitoneal sarcomas are rare tumors associated with a high rate of recurrence and very bad prognosis. Their only efficient treatment is a negative- margin surgical resection that is extremely difficult to achieve. Retroperitoneal metastases from extremity sarcomas are considered unusual. In literature, such a metastatic pattern is described extremely rarely. In this paper we report a case of a very aggressive extremity chondrosarcoma, associated with local recurrence, multiple distant metastases, that finally led to a retroperitoneal metastasis. The recurrence and progression of the sarcoma in this localization were impressive, with a fast overcome of therapeutic options. Chemo- and radiotherapy have not proved to be efficacious in this context and they could have had a role in the deterioration of patient state of health. New tumor markers for the detection and follow-up of these tumors should be considered.

Anabolic and antiresorptive drugs improve trabecular microarchitecture and reduce fracture risk following radiation therapy.

Many patients with symptomatic bone metastases receive radiation therapy, even though radiation is known to have potential adverse effects on bone. We hypothesized that the concurrent use of a bisphosphonate drug (zoledronic acid, ZA) or a combination of ZA plus an anabolic agent (parathyroid hormone, PTH) would lead to improvements in the microarchitecture and mechanical properties of irradiated bone. Human breast cancer cells were injected into the distal femur of 56 female nude mice, which were then divided into four groups: no treatment (0 Gy), radiation administered 4 weeks postinjection (20 Gy), radiation plus ZA (12.5 microg/kg weekly from weeks 4 to 12) (20 Gy + ZA), and radiation followed by ZA (25 microg/kg weekly from weeks 4 to 8) and PTH(1-34) (100 microg microg/kg daily from weeks 8 to 12) (20 Gy + ZA + PTH). Left limbs served as normal control bones. Bone loss over the 12-week study was tracked with serial radiography and bone densitometry. At the end of the study, micro-computed tomography and mechanical testing were used to quantify bone microarchitecture and bone strength. Radiation alone failed to prevent tumor-induced decreases in bone mineral density (BMD), trabecular bone volume, and bone strength. Treatment with 20 Gy + ZA or 20 Gy + ZA + PTH as adjuncts to radiation was effective at preserving trabecular bone architecture and bone strength at normal levels. ZA reduced the risk of mechanical fragility following irradiation of a lytic bone lesion. Supplemental use of PTH did not result in further increases in bone strength but was associated with significant increases in BMD and bone mass, suggesting that it may be beneficial in enhancing bone architecture following radiation therapy.

[Radiotherapy for soft tissue sarcomas of extremities. Preliminary comparative dosimetric study of 3D conformal radiotherapy versus helical tomotherapy]. / Radiothérapie postopératoire des sarcomes des tissus mous des extrémités. Etude dosimétrique préliminaire comparative de la radiothérapie conformationnelle avec la tomothérapie hélicoïdale.

PURPOSE: To evaluate dosimetry of helicoidal tomotherapy versus three-dimensional conformal radiotherapy (3D-CRT) with and without IMRT for the treatment of soft tissue sarcoma (STS) of the thigh. METHODS AND PATIENTS: A retrospective study was performed for three patients who received 3D-CRT as adjuvant radiation therapy for STS of the thigh. These three patients had a tumor in posterior, adductor or anterior compartment of the thigh. In each case, three treatments plans were optimised in tomotherapy, without bloc, with directional bloc and complete bloc of controlateral limb, to adequately treat the planning target volume and spare organ at risk. For each patient, we compare the three modalities of tomotherapy or "classical" IMRT from a clinac with the 3D-CRT actually performed for the treatment. RESULTS: Tomotherapy provides improved PTV coverage and dose homogeneity. This benefit was comparable in the three tomotherapy plans. The average D95% for tomotherapy and 3D-CRT were 97.6% and 94.8% respectively and the standard deviation is, at least, divided by two with conformal and is always better than performed with a clinac. The volume of the surrounding soft tissues receiving at least full prescription and hot spots, as evaluated by D2%, were significantly reduced in tomotherapy. Nevertheless, the results concerning the skin, the femur and the gonads were dependent on the tumor site in the thigh and not always improved with tomotherapy dosimetric studies. CONCLUSIONS: For this preliminary study, tomotherapy can provide better coverage and dose uniformity in PTV and minimize the volume of surrounding muscular tissues receiving high doses. However, in this study, there is no benefit for others OAR (skin, femur and gonads) except in particular constraint (for instance for a precise sparing of cutaneous or bony area). Other dosimetric studies, followed by prospective evaluations with long-term follow-up are needed to determine whether tomotherapy can improve outcome for patients with STS of the thigh.

Synovial chondrosarcoma of the hip: report of two cases and literature review.

Synovial chondrosarcoma (SCH) is a rare malignant tumour. The lesion may arise de novo in intra-articular space or, more frequently, it may occur as a malignant degeneration of synovial chondromatosis (SC). The authors report two cases of SCH of the hip joint occurring on a SC diagnosed 23 years earlier in one case and 10 years earlier in another case. In both cases the SCH showed an intermediate grade of malignancy at histology (grade 2). In the first case, the patient underwent an external hemipelvectomy and he was disease-free 10 years after the operation. In the second case, the patient refused the proposed amputation and, after palliative radiation therapy, she was alive with disease 58 months after diagnosis. A review of literature reports on SCH was carried out. The knee was the most affected joint, followed by the hip. An amputation was performed in two thirds of cases. Amputation was done as primary surgery in one fifth of cases and for tumour recurrence after synovectomy in four fifth of cases. Metastatic dissemination was seen in 29% of cases. An early detection of malignant transformation of SC might improve the rate of limb salvage surgery in these patients, although no reliable clinical and imaging signs of malignant degeneration have been identified so far.

The "mini brain" appearance of plasmacytoma in the appendicular skeleton.

We report on the case of a 70-year-old woman presenting with right hip pain. Radiographs of the right hip demonstrated a well-defined large lytic lesion in the proximal right femur, with prominent trabeculae situated peripherally and extending into the lesion in a "spoke-wheel" pattern. Magnetic resonance imaging (MRI) demonstrated solid enhancing marrow-replacing lesion, with intervening linear nonenhancing areas of low T2 signal intensity. The MRI appearance resembled that of a small brain or "mini brain". Biopsy specimen demonstrated predominantly mature plasma cells, with occasional admixed immature forms. A diagnosis of plasmacytosis, consistent with myeloma, was made. This case illustrates a rare but seemingly characteristic "mini brain" appearance of plasmacytoma, which, to date, has only been reported in the spine and has not been observed in other bony lesions.

Concurrent administration of zoledronic acid and irradiation leads to improved bone density, biomechanical strength, and microarchitecture in a mouse model of tumor-induced osteolysis.

BACKGROUND AND OBJECTIVES: Bone metastases are typically treated with bisphosphonates as adjuncts to radiation therapy. The goal of this study was to determine whether radiotherapy combined with a bisphosphonate could restore bone density, microarchitecture, and biomechanical strength of a tumor-burdened bone to normal. MATERIALS AND METHODS: Breast cancer cells were injected into the right femur of 30 female nude mice. Mice were divided into three treatment groups (0 Gy, 20 Gy, and 20 Gy + ZA). Left limbs served as non-operated normal bones. Tumor-bearing femora were irradiated 3 weeks later. ZA (100 microg/kg SC) was administered once weekly for 6 weeks. Mice were euthanized at 9 weeks or earlier if severe lameness or pathology occurred. RESULTS: Mice treated with 20 Gy/ZA exhibited higher bone density, bone volume, fractional trabecular bone volume, and biomechanical strength compared to mice treated with 20 Gy only (P < 0.05). Statistical analysis revealed that mice treated with 20 Gy/ZA were not significantly different from normal bones with respect to bone density and strength. Micro-CT reconstructions showed improved microarchitecture in the 20 Gy/ZA group compared to 20 Gy. CONCLUSIONS: Treatment of an osteolytic bone with radiation therapy plus zoledronic acid restores normal bone qualities with respect to bone density, microarchitecture, and biomechanical strength.

Long-term clinical and functional outcomes after treatment for localized Ewing's tumor of the lower extremity.

PURPOSE: Retrospective review describing the 35-year University of Florida experience with Ewing's tumors of the lower extremity. PATIENTS AND METHODS: Fifty-three patients were treated between 1971 and 2006. Thirty patients were treated with radiotherapy (RT) alone and 23 patients were treated with surgery +/- RT. Larger tumors and tumors of the femur were treated more often with definitive RT. Median potential follow-up was 19.2 years. Functional outcome was assessed using the Toronto Extremity Salvage Score (TESS). RESULTS: Before 1985, 24% of patients were treated with surgery; since then, the rate has increased to 61%. The 15-year actuarial overall survival (OS), cause-specific survival (CSS), freedom from relapse, and limb preservation rates were 68% vs. 47% (p = 0.21), 73% vs. 47% (p = 0.13), 73% vs. 40% (p = 0.03), and 43% vs. 40% (p = 0.52), respectively, for patients treated with surgery +/- RT vs. RT alone. Excluding 8 patients who underwent amputation or rotationplasty, the 15-year actuarial local control rate was 100% for the surgery +/- RT group and 68% for the definitive RT group (p = 0.03). The ranges of the TESS for surgery +/- RT vs. RT alone were 70-100 (mean, 94) and 97-100 (mean, 99), respectively. Twenty-six percent (6/23) of patients had complications related to surgery requiring amputation or reoperation. CONCLUSIONS: Overall survival and CSS were not statistically compromised, but we observed an increased risk of relapse and local failure in patients treated with RT alone, thereby justifying a transition toward primary surgical management in suitable patients. However, despite an adverse risk profile, patients treated with RT alone had similar long-term amputation-free survival and demonstrated comparable functional outcomes. Poor results observed in Ewing's of the femur mandate innovative surgical and RT strategies.

Pathological femur fracture secondary to radiation therapy for soft tissue sarcoma

Bone fracture is a well known possible late complication of radiation treatment. Little has been written about fractures of long bones after irradiation. We present a case of femur bone necrosis secondary to postoperative radiation for a soft tissue sarcoma of the thigh 20 years earlier. Fixation of the diaphyseal fracture and radiological evolution are described (AU)

Proximal femoral replacement for metastatic bone disease.

Between 1994 and 2000, 13 patients (8 women and 5 men; 14 hips) underwent proximal femoral replacement secondary to metastatic disease. Average patient age was 62 years (range: 46-77 years). The most common diagnosis was renal cell carcinoma. Seven pathologic fractures were noted. Patients ambulated with full weight bearing postoperatively and wore an abduction brace for 3-4 months. Ten patients died of their diseases at 0.5-3.5 years postoperatively. No dislocations, infections, or reoperations occurred. Proximal femoral replacement provides excellent pain relief and good restoration of function when more simple reconstructive options are not feasible.

Intercalary femoral reconstruction with extracorporeal irradiated autogenous bone graft in limb-salvage surgery.

Between 1996 and 2003, 16 patients (nine female, seven male) were treated for a primary bone sarcoma of the femur by wide local excision of the tumour, extracorporeal irradiation and re-implantation. An additional vascularised fibular graft was used in 13 patients (81%). All patients were free from disease when reviewed at a minimum of two years postoperatively (mean 49.7 months (24 to 96). There were no cases of infection. Primary union was achieved after a median of nine months (interquartile range 7 to 11). Five host-donor junctions (16%) united only after a second procedure. Primary union recurred faster at metaphyseal junctions (94% (15) at a median of 7.5 months (interquartile range 4 to 12)) than at diaphyseal junctions (75% (12) at a median of 11.1 months (interquartile range 5 to 18)). Post-operatively, the median Musculoskeletal Tumour Society score was 85% (interquartile range 75 to 96) and the median Toronto Extremity Salvage score 94% (interquartile range 82 to 99). The Mankin score gave a good or excellent result in 14 patients (88%). The range of movement of the knee was significantly worse when the extracorporeally irradiated autografts were fixed by plates rather than by nails (p = 0.035). A total of 16 (62%) of the junctions of the vascularised fibular grafts underwent hypertrophy, indicating union and loading. Extracorporeal irradiation autografting with supplementary vascularised fibular grafting is a promising biological alternative for intercalary reconstruction after wide resection of malignant bone tumours of the femur.

Rhemium-186-monoaminemonoamidedithiol-conjugated bisphosphonate derivatives for bone pain palliation.

To develop a radiopharmaceutical for the palliation of painful bone metastases based on the concept of bifunctional radiopharmaceuticals, we synthesized a bisphosphonate derivative labeled with rhenium-186 (186Re) that contains a hydroxyl group at the central carbon of its bisphosphonate structure, we attached a stable 186Re-MAMA chelate to the amino group of a 4-amino butylidene-bisphosphonate derivative [N-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (186Re-MAMA-HBP) and we investigated the effect of a hydroxyl group at the central carbon of its bisphosphonate structure on affinity for hydroxyapatite and on biodistribution by conducting a comparative study with [N-[2-[[3-(3,3-diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (186Re-MAMA-BP). The precursor of 186Re-MAMA-HBP, trityl (Tr)-MAMA-HBP, was obtained by coupling a Tr-MAMA derivative to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. 186Re-MAMA-HBP was prepared by a reaction with 186ReO(4-) and SnCl2 in citrate buffer after the deprotection of the Tr groups of Tr-MAMA-HBP. After reversed-phase high-performance liquid chromatography, 186Re-MAMA-HBP had a radiochemical purity of over 95%. Compared with 186Re-MAMA-BP, 186Re-MAMA-HBP showed a greater affinity for hydroxyapatite beads in vitro and accumulated a significantly higher level in the femur in vivo. Thus, the introduction of a hydroxyl group into 186Re complex-conjugated bisphosphonates would be effective in enhancing accumulation in bones. These findings provide useful information on the design of bone-seeking therapeutic radiopharmaceuticals.

Radiation treatment decreases bone cancer pain through direct effect on tumor cells.

The most used treatment for bone cancer pain is radiation; however, the mechanism responsible for analgesia after irradiation is unknown. The mechanistic influence of a single, localized 10-, 20- or 30-Gy dose of radiation on painful behaviors, osteolysis, histopathology and osteoclast number was evaluated in mice with painful femoral sarcomas. Dramatic reductions in pain behaviors (P < 0.05) and osteolysis (P < 0.0001) were seen in mice irradiated with 20 and 30 Gy. Irradiation reduced the tumor area by more than 75% (P < 0.05) but did not affect osteoclast frequency per mm2 tumor. Treatment with 20 Gy prior to tumor injection had no effect on tumor growth or pain behaviors, suggesting that radiation reduces osteolysis and pain through direct tumor effects. To demonstrate that tumor elimination was responsible for reduction in osteolysis and pain, sarcoma cells containing the suicide gene cytosine deaminase (CD) were inoculated into femora. After onset of bone cancer pain, mice were treated with the prodrug 5-fluorocytosine (5-FC). 5-FC treatment significantly reduced both osteolysis (P < 0.0005) and bone cancer pain (P < 0.05). The findings in this study demonstrate that one mechanism through which radiation decreases bone cancer pain is by direct effects on tumor cells.