ESTRO ACROP guidelines for external beam radiotherapy of patients with complicated bone metastases.

This is the second part of the guidelines on the management of bone metastases. In the first part, the diagnosis and management of uncomplicated bone metastases have been addressed. Bone metastases may significantly reduce quality of life due to related symptoms and possible complications. The most common symptoms include pain and neurologic deficits. The most serious complications of bone metastases are skeletal-related events (SRE), defined as pathologic fracture, spinal cord compression, pain, or other symptoms requiring an urgent intervention such as surgery or radiotherapy. Diffuse bone metastases may lead to hypercalcaemia that can be fatal if untreated. The growing access to modern diagnostic tools allows early detection of asymptomatic bone metastases that could be successfully managed with local treatment if oligometastatic or systemic treatment for diffuse bone metastases to try to avoid the development of SRE.

ESTRO ACROP guidelines for external beam radiotherapy of patients with uncomplicated bone metastases.

After liver and lungs, bone is the third most common metastatic site (Nystrom et al., 1977). Almost all malignancies can metastasize to the skeleton but 80% of bone metastases originate from breast, prostate, lung, kidney and thyroid cancer (Mundy, 2002). Introduction of effective systemic treatment in many cancers has prolonged patients' survival, including those with bone metastases. Bone metastases may significantly reduce quality of life due to related symptoms and possible complications, such as pain and neurologic compromise. The most serious complications of bone metastases are skeletal-related events (SRE), defined as pathologic fracture, spinal cord compression, pain, or other symptoms requiring an urgent intervention such as surgery or radiotherapy. In turn, growing access to modern diagnostic tools allows early detection of asymptomatic bone metastases that could be successfully managed with local treatment avoiding development of SRE. The treatment for bone metastases should focus on relieving existing symptoms and preventing new ones. Radiotherapy is the standard of care for patients with symptomatic bone metastases, providing durable pain relief with minimal toxicity and reasonable cost-effectiveness. Historically, the dose was prescribed in one to five fractions and delivered using simple planning techniques. While 3D-conformal radiotherapy is still widely used for treating bone metastases, introduction of highlyconformal radiotherapy techniques such as stereotactic body radiotherapy (SBRT) have opened new therapeutic possibilities that should be considered in selected patients with bone metastases.

Stability and survival analysis of elderly patients with osteolytic spinal bone metastases after palliative radiotherapy : Results from a large multicenter cohort.

PURPOSE: This retrospective study aimed to evaluate the stability and fracture rates of osteolytic spinal bone metastases (SBM) in elderly patients following palliative radiotherapy (RT) and to derive prognostic factors for stability and survival. METHODS: A total of 322 patients aged at least 70 years received palliative RT at two major German academic medical centers or at the German Cancer Research Center. Stability assessment was based on the validated Taneichi score prior to RT and at 3 and 6 months after RT. The survival time following RT was assessed, and prognostic factors for stability and survival were analyzed. RESULTS: Prior to RT, 183 patients (57%) exhibited unstable SBM and 68 patients (21%) pathological fractures. At 3 and 6 months after RT, significant recalcification and stabilization were evident in 19% (23/118) and 40% (31/78) of surviving patients, respectively. Only 17 patients (5%) experienced new pathological fractures following RT. Tumor histology was found to significantly influence stabilization rates with only breast cancer patients exhibiting increased stabilization compared to patients with other histologies. The median survival time and 6­month survival rates following RT were 5.4 months (95% confidence interval 4.4-7.2 months) and 48%, respectively. The patients' performance status was found to be the strongest predictor for survival after RT in this patient cohort; further factors demonstrating a significant association with survival were the application of systemic treatment, the number of SBM and the primary tumor histology. To analyze the influence of age on survival after RT, study patients were stratified into 3 age groups (i.e., 70-74 years, 75-79 years, and ≥80 years). The subgroup of patients aged at least 80 years showed a strong trend towards a worse survival time following RT compared to younger patients (i.e., 6­month survival rate 39% vs. 51%; p = 0.06, log-rank test). CONCLUSIONS: Prognostic factors influencing overall survival such as performance status and histology should guide the choice for palliative RT for SBM. Strongly hypofractionated RT regimes may be advisable for most elderly patients considering the overall poor prognosis in order to reduce hospitalization times.

Functional recovery after surgical stabilization and postoperative radiotherapy due to metastases of long bones.

PURPOSE: To reinvestigate the functional recovery after combined treatment with surgery and postoperative irradiation of complete or impending pathologic fractures of long bones. METHODS: We retrospectively evaluated the results of external beam radiation therapy (EBRT) carried out after 68 orthopedic stabilization procedures (femur, n = 55, 80.8%; humerus, n = 13, 19.2%) for actual or impending pathological fracture of long bone in 61 patients with skeletal metastases. The mean normalized total dose was 34.7 ± 7.8 Gy. Endpoints were patient's functional status (FS; 1 = normal pain free status; 2 = normal use with pain; 3 = significantly limited used; 4 = nonfunctional status), a need for a secondary procedure to the same site and overall survival following surgery. RESULTS: Overall, 75% of patients achieved normal functional status (FS 1-2) within 12 weeks after surgery. Functional recovery in surviving patients reached 93%. Median survival was 17 months (95% confidence interval 13.7-20.2). Secondary surgical intervention at the same location was necessary in 3 patients (4.4%). On multivariate analysis, only general status (p = 0.011) and growing potential of primary tumor (p = 0.049) were associated with achieving normal functional status within 12 weeks after surgery and radiotherapy. The applied radiation schemes demonstrated a comparable impact on functional recovery. CONCLUSIONS: Our results confirm the effectiveness of stabilizing surgery and fractionated postoperative radiotherapy in terms of functional recovery, supporting prior results assessing postsurgical radiotherapy versus follow-up. The patient's general status is a strong prognostic factor for functional recovery. Rapidly growing tumors may hinder achievement of a normal functional status.

Analysis of orthopedic surgery of patients with metastatic bone tumors and pathological fractures.

Objective This study was performed to determine the most common causes, locations, and treatments of metastasizing primary tumors through evaluation of patients with metastatic bone tumors who were admitted to our clinic. Methods In total, 96 patients with metastatic bone tumors who were admitted to our clinic from 2000 to 2016 were included in the study. Results The breast (30 patients, 31.3%) and lung (18 patients, 18.8%) were the most commonly metastasized primary organs. The femur was the most commonly metastasized bone. Conclusions Bone tumors in patients of advanced age are, unless otherwise proven, considered to be metastatic, and the development of specific diagnostic and treatment algorithms is needed. Clinicians should attempt to improve the general condition of patients with tumors exhibiting bone metastasis to increase the patients' quality of life by providing early mobilization. Thus, appropriate patient selection and proper internal fixation are essential.

Lack of clinical evidence for postoperative radiotherapy after surgical fixation of impending or actual pathologic fractures in the long bones in patients with cancer; a systematic review.

Patients with disseminated cancer and bone metastases have a limited life expectancy and therefore any treatment should have a clear beneficial effect, outweighing all possible downsides. This systematic review aims to identify and evaluate available evidence regarding function, pain, quality of life, survival and complications of postoperative radiotherapy (RT) after surgical stabilization of impending or actual pathologic fractures of the long bones due to bone metastases. A literature search resulted in two articles reporting on 64 and 110 patients of whom 55% and 28% received postoperative RT, respectively. Both studies were retrospective cohort studies and postoperative RT had been administered depending on the surgeons' choice. The first study reported better outcomes regarding function, re-interventions and survival in patients receiving postoperative RT. The second study reported no significant difference regarding complications between the two groups. The quality of the evidence was very low due to the observational character of both studies, risk of indication bias, small study sizes, use of non-standardized outcome measures, and limited statistical analyses. The current available literature is insufficient to conclude whether postoperative RT after surgical stabilization should be standard care. It is important to realize this lack of clear evidence when calling upon RT as adjuvant palliative treatment.

[Radiosensitization induced by vemurafenib]. / Radiosensibilisation induite par le vémurafénib.

The recent use of vemurafenib, a specific inhibitor of BRAF, has led to a significant improvement in disease-free survival and overall survival of patients treated for a BRAF-mutated metastatic melanoma. This new class of drugs is not devoid of side effects, including skin effects. In particular, its association with concomitant radiotherapy should be taken into consideration, vemurafenib appearing to be radiosensitizer. The radiation oncologist must be aware of this potential toxicity, which is not uncommon in clinical practice.

Bone metastases, general and clinical issues.

The skeleton is the most common organ for metastasis from solid tumours. Bone metastases pose significant diagnostic and clinical challenges and represent an important cause of cancer-related morbidity. Without appropriate bone-directed therapy, many patients will be at high risk for potentially debilitating skeletal-related events (SREs), such as pain, bone fractures, neurologic deficits and hypercalcemia, severely impacting on the patient's quality of life. Because of their high incidence, bone metastases impose significant demands on health care resources. The optimal management of skeletal metastases depends on the underlying biology of the disease, the extent of bone involvement, the presence and severity of symptoms, the availability of effective systemic therapies and life expectancy of the patient. This article discusses clinical issues concerning diagnosis and available treatment approaches based on the presentation of skeletal involvement. Emphasis is placed on the role of external beam-radiotherapy as a local mode of treatment for palliation of bone pain, decompression of epidural compression and as potential ablative approach through high-dose image-guided irradiation (IGRT) in patients presenting with oligometastatic disease.

DEGRO practice guidelines for palliative radiotherapy of metastatic breast cancer: bone metastases and metastatic spinal cord compression (MSCC).

PURPOSE: To provide practice guidelines and clinical recommendations on preferred standard palliative radiation therapy of bone metastases as well as metastatic spinal cord compression (MSCC) for metastatic breast cancer patients. METHODS: The breast cancer expert panel of the German Society of Radiation Oncology (DEGRO) performed a comprehensive survey of the literature comprising recently published data from clinical controlled trials. The literature search encompassed the period 1995-2008 using databases of PubMed and Guidelines International Network (G-I-N). Search terms were "breast cancer", "bone metastasis", "osseous metastasis", "metastatic spinal cord compression" as well as "radiotherapy" and "radiation therapy". Clinical recommendations were formulated based on the panel's interpretation of the level of evidence referring to the criteria of evidence-based medicine. RESULTS: Different therapeutic goals (pain relief, local tumor control, prevention or improvement of motor deficits, stabilization of the spine or other bones) require complex approaches considering individual factors (i.e., life expectancy, tumor progression at other sites). Best results are achieved by close interdisciplinary cooperation minimizing the interval between diagnosis and onset of treatment. Most important criteria for prognosis and choice of treatment (mostly combined multimodal therapy) are neurologic status at diagnosis of MSCC, time course of duration and progression of the neurologic symptoms. Radiation therapy is effective and regarded as treatment of choice for MSCC with or without motor deficits and/or bone metastases, which do not need immediate surgical intervention. It may be used either postoperatively or as primary treatment in case of inoperability. An optimal dose fractionation schedule or optimal standard dose for treatment of bone metastases has not been established. With regard to different therapeutic goals, different dose concepts and fractionation schedules, single- versus multifraction palliative radiation therapy (1 x 8, 5 x 4, 10 x 3, 15 x 2.5, 20 x 2 Gy), should be adapted individually. CONCLUSION: Bone metastases as well as MSCC should be managed in an interdisciplinary approach mostly as combined-modality treatment according to the specific clinical situation. The present practice guidelines offer criteria and recommendations for different radiooncologic treatment schedules based on the best available levels of evidence. Preferred technique, targeting and different dose schedules are described in detail.

General principles of external beam radiation therapy for skeletal metastases.

Radiation therapy plays a major role in the treatment of patients with bone metastases. The primary goals of treatment include pain relief and relief of neurologic symptoms, if present. Approximately 70% of patients will achieve pain relief with palliative external beam radiotherapy. Improvement in the severity of pain may occur within as few as 48 to 72 hours of initiation of therapy, but in some patients significant relief of pain may not occur for 4 weeks after completion of therapy. Treatment schemes ranging from 800 cGy in a single treatment to 3000 cGy in 10 treatments have not been shown to result in major differences in outcome. Treatment decisions must be individualized based on factors such as the patient's performance status, life expectancy, location of the lesion, and size of area to be treated. External beam radiotherapy is recommended after surgical treatment of pathologic fractures or impending fractures to decrease the need for a second surgical procedure and improve the patient's functional outcome. External beam radiotherapy continues to be an important component of the palliative treatment of bone metastases. Its integration with newer therapeutic modalities such as vertebroplasty and radiofrequency ablation currently is being studied.

[(Impending) pathological fracture]. / (Drohende) pathologische Fraktur.

Pathological fractures will be encountered in increasing frequency due to more patients with cancer, surviving a longer period. The skeleton is the third most frequent localization for metastases. Breast cancer is still the most common primary tumor, but bone metastases from lung cancer seem to be diagnosed more and more. Despite of finding metastases most often in the spinal column, fractures are seen mostly at the femoral site. A pathological fracture and, in almost all cases, an impending fracture are absolute indication for operation. An exact definition of an "impending fracture" is still lacking; it is widely accepted, that 50 per cent of bone mass must be destroyed before visualization in X-ray is possible, thus defining an impending fracture. The score system by Mirels estimates the fracture risk by means of four parameters (localization, per cent of destructed bone mass, type of metastasis, pain). Improving quality of life, relieving pain, preferably with a single operation and a short length of stay are the goals of (operative) treatment. For fractures of the proximal femur, prosthetic replacement, for fractures of the subtrochanteric region or the shaft, intramedullary nails are recommended. Postoperative radiation therapy possibly avoids tumor progression. In patient with a good long term prognosis, tumor should be removed locally aggressive.

[Role of palliative and symptomatic radiotherapy in bone metastasis]. / Il ruolo della radioterapia palliativa e sintomatica delle metastasi ossee.

INTRODUCTION: The presence of bone metastases is a common event in the natural history of nearly all neoplasms which often affects the patient's quality of life greatly. Bone metastases may cause pain and pathologic fractures, or even a cord compression syndrome with severe neurologic symptoms. We tried to assess the optimal irradiation schedule for these patients and to discuss the use of radiopharmaceuticals. MATERIALS AND METHODS: We reviewed the literature focusing on studies investigating the efficacy of hypofractionated radiotherapy for bone metastases. We also addressed the problem of treating multiple skeletal lesions with half-body irradiation and radionuclides. RESULTS: External beam irradiation achieves pain palliation in more than 75% of patients with bone metastases, even with hypofractionation down to a single-dose administration. The results of exclusive radiotherapy in the cord compression syndrome depend on a prompt diagnosis, patient presentation and the intrinsic radiosensitivity of tumor cells. Palsy can always be avoided in these patients. Half-body irradiation can achieve complete pain relief in over 20% of patients and decrease pain markedly in the remaining cases with only a single-dose fraction (6-10 Gy), within 48 hours of irradiation and with little side-effects. Better results in terms of pain relief (80% complete responses) and duration of palliation come from fractionated half-body irradiation (up to 17.5 Gy in 7 fractions), which however has a more delayed response (1-2 weeks) and higher toxicity. The use of radiopharmaceuticals has been recently reevaluated after the introduction of new nuclides: results are similar to those of external beam irradiation (up to 80% responses), but cost and hematologic toxicity are both high. Radiopharmaceuticals can be used within an integrated treatment with external beam irradiation, chemotherapy and biphosphonates. DISCUSSION: The efficacy of external beam irradiation in the palliation of bone metastasis-related symptoms is confirmed by this literature review, even with short treatments and single-dose administrations. This is important for both patient expectations and the necessity for improved resource allocation with reference to the territorial distribution and waiting lists of radiotherapy centers. Finally, as for the role of radiopharmaceuticals, the best nuclides are not widely used yet for the high cost of the treatment, even though they provide similar results to external beam irradiation. The issue of their efficacy in combination with antiblastic drugs and/or external beam irradiation remains open and will be clarified only with further randomized clinical trials.

[Surgical management of bone metastases of the lower extremity with AO interlocking nail]. / Zur operativen Versorgung von Skelettmetastasen der unteren Extremität mittels AO-Verriegelungsmarknagel.

Between January 1991 and June 1995 we have operated on 19 patients (9 male, 10 female) with 22 skeletal metastases of the lower limb (19 femora, 3 tibiae) using a static interlocking nail. Closed intramedullary nailing without resection of the metastasis has been established as our standard procedure. We have stabilized 15 patients with advanced osteolysis and seven pathological fractures. Sixteen patients underwent postoperative local radiation therapy with 40 Gy. As intraoperative complications we have observed one fracture of an osteolysis and one death due to fat embolism. Postoperatively there were observed one seroma, one haematoma and one patient with non fatal pulmonary embolism following DVT. Two patients died within the first 30 postoperative days because of tumor progression. All patients surviving longer than 30 days could be mobilized under full weight-bearing. Morphine like analgetics for metastasis related pain were no longer needed. A secondary instability has not been observed within a mean survival time of 199 days (811 longest follow up). Closed intramedullary nailing in combination with postoperative local radiation therapy seems to be an appropriate and technically non demanding procedure to stabilize skeletal metastases of the lower limb in patients with a short or medium-term expectation of life.

Radiotherapy in the management of bone pain.

Radiotherapy may be indicated for the management of bone metastases because of associated pain, fracture, or neurologic complications. For metastatic bone pain, simple low-dose radiation treatment is usually effective for local problems. When there are multiple sites of bone pain, external beam irradiation using wide-field hemibody techniques is highly effective. An alternative to this approach is the administration of radioisotopes that may localize to the sites of bone metastases, either because they are tumor specific (radioiodine for thyroid cancer) or bone seeking (radioactive phosphorus [32P] and strontium [89Sr]). The primary treatment of pathologic fracture is surgery where possible, but radiotherapy has a major role in postoperative treatment and in treatment of fractures that are inoperable either because of their site, such as a rib or pelvis, or because of the general poor condition of the patient. For neurologic complications such as spinal cord compression or nerve root compression, radiotherapy appears to be as beneficial as decompressive surgery in most situations, except where there is bony instability. The role of radiotherapy in the prophylactic setting is discussed. Prevention of pathologic fracture and spinal cord compression may be possible in high-risk patients.

[Value of local radiotherapy in treatment of osseous metastases, pathological fractures and spinal cord compression]. / Stellenwert der lokalen Strahlentherapie in der Behandlung ossärer Metastasen, pathologischer Frakturen und Myelonkompressionen.

Local radiotherapy plays an important and responsible role in the management of bone metastases. The valence will be described according to the different treatment objectives in the sense of pain relief, remineralization and cord decompression. Radiotherapy schedules, aimed at the relief pain, need to take into consideration life expectancy. Patients with a reduced life expectancy could have a good high chance of achieving pain relief with a single dose of 8 Gy. Patients with a solitary metastasis, patients with a longer life expectancy and patients with a pathological fracture should be treated with 'curative' irradiation doses, aimed at killing the maximum number of tumor cells. In addition to pain relief, remineralization is also an important treatment goal. Conventional radiotherapy with doses of 40-50 Gy resulted in pain relief in 70-100% and in remineralization in 60-80% of the patients. Remineralization could not be accelerated by short-course fractionation courses, but resulted in faster pain relief. Short-course fractionation schedules are not indicated as a 'standard' treatment in the vertebral column. Surgery is the treatment of choice for immediate cord decompression and stabilization of a pathological vertebral fracture. Radiotherapy alone could decrease neurological impairment and is suitable for patients with gradual onset and progression of symptoms, no spinal instability and lesions of the cauda equina.

Clinical expressions of the expansion of the bone marrow in the chronic anemias: the role of radiotherapy.

PURPOSE: In the chronic anemias and particularly in the hemoglobinopathies and in the myeloproliferative disorders there is compensatory hypertrophy and expansion of the bone marrow. This results in severe rarefaction of the bone and in extramedullary hemopoiesis. METHODS AND MATERIALS: Morbid clinical expressions of the osseous changes are spontaneous fractures and osteoarthropathy, while extramedullary hemopoiesis presenting in the form of tumor-like masses may cause pressure symptoms on adjacent organs, particularly on the spinal cord. RESULTS AND CONCLUSION: Extramedullary hemopoiesis masses can be easily diagnosed since they present typical radiological appearance. Radiotherapy has been used for the treatment of these conditions.

Pedicle fixation: an adjuvant for the treatment of thoracolumbar metastases.

For a long time, radiotherapy was considered as the best treatment for spinal metastases. However, radiotherapy alone could not resolve the problem of pathological fracture which is an important complication of spinal metastases. In this paper, we introduce pedicle fixation system as an adjuvant to radiotherapy to treat eight patients with thoracolumbar metastases. The result was encouraging that all the patients achieved spinal stabilisation and all but one had immediate postoperative relief of back pain. The operation time was short and none of the patients required a blood transfusion. Tissue diagnosis was possible through this approach.

Pathological fracture in haemoglobinopathy: treatment by irradiation.

A patient suffering from thalassaemia, with extreme osteoporosis, coarse trabeculation and cortical thinning of the bones, developed a pathological fracture of the left hip. This was treated by a single dose of radiotherapy. It is suggested that the radiotherapy facilitated the healing process by eliminating the causative factor of the fracture, which was the expanding and over-proliferating bone marrow.