Neoplasms

Symptoms and General Pathology

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Nervous System Diseases

Musculoskeletal Diseases

Rare Diseases

Neoplasm Metastasis

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Disease Progression

Spinal Cord Neoplasms

Ependymoma

Spinal Neoplasms

Brain Neoplasms

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Spinal Cord Diseases

Bone Neoplasms

Bone Diseases

Spinal Diseases

Neuroepithelioma

According to the site to irradiate and to local constraints, SBRT consist in 1 to 8 fractions of 5 to 18 Gy

For Brain metastasis the SBRT treatment consists on 3 fractions of 8 Gy or 5 fractions of 7 Gy or 1 fraction of 18 Gy for a single metastasis which is less than 20 mm.

For primary or secondary pulmonary tumors the SBRT treatment consists on 3 fractions of 15 Gy or 5 fractions of 10 Gy for peripheral lesions and on 5 fractions of 8 Gy for proximal lesions.

For primary or secondary spinal or para-spinal tumors the SBRT treatment consists on 3 fractions of 9 Gy or 5 fractions of 7 Gy.

For previously irradiated tumors (same locations) the SBRT treatment consists on 5 to 8 fractions of 5 Gy.

For relapsed Ependymoma previously irradiated the SBRT treatment will be allocated by surgical stratified randomization and consists on either 3 fractions of 8 Gy or 5 fractions of 5 Gy.

SBRT treatment

Line CLAUDE, Doctor

The purpose of this study is to evaluate the efficacy of hypofractionated stereotactic radiation treatments (SBRT) on children, teenagers and young adults malignant tumors.

SBRT (Stereotactic Body Radiation Therapy) is a radiotherapy treatment which involves the delivery of a single high dose radiation treatment or a few fractionated radiation treatments (usually up to 5). A high potent biological dose of radiation is delivered to the tumor improving the cure rates for the tumor, in a manner previously not achievable by standard conventional radiation therapy.

For adult patients, the "Haute Authorité de Santé" (HAS) validates some indications for this treatment which are the followings :

* Few primary or secondary brain tumors, which cannot be surgically removed
* Spinal tumors
* Primary bronchopulmonary tumors T1 T2 N0 M0 and pulmonary metastasis with slow growth and controled primary tumor.

For pediatrics patients, no indication is now validated by HAS. Indications validated for adults are rare in pediatrics but not exceptional, and in such cases efficient alternative treatments does not exist.

In consequence, and regarding the good results obtained in adult patients, it seems very important to validate the efficacy of this treatment on pediatrics population

Study of SBRT Efficacy on Intra and Extra -Cranial Tumors or Metastasis in Pediatrics Population (SBRT Pediatrics)

Hypofractionated Stereotactic Radiation Treatments (SBRT) on Children, Teenagers and Young Adults Malignant Tumors

The SBRT treatment related costs will be evaluated by a "microcosting" method which take into account, in particular, the irradiation duration seance, the time for the mobilized staff, the kind of equipment required, the duration of related AE hospitalizations.

2 modalities of SBRT are compared in patients with an ependymoma (3 fractions of 8 Gy versus 5 fractions of 5 Gy). It will be calculated the cost/efficacity ratio for the avoided toxicity 6 months after SBRT.

The costs will be evaluated by the data from french social security system, from homogeneous group of patients and from general classification of professional acts

2 modalities of SBRT are compared in patients with an ependymoma (3 fractions of 8 Gy versus 5 fractions of 5 Gy). It will be calculated :

* the cost/efficacity per gained year of life without relapse after 12 months after SBRT
* the cost/efficacity per gained year of life without disease after 12 months after SBRT.

The costs will be evaluated by the data from french social security system, from homogeneous group of patients and from general classification of professional acts

2 modalities of SBRT are compared in patients with an ependymoma (3 fractions of 8 Gy versus 5 fractions of 5 Gy). It will be calculated :

* the cost/efficacity per gained year of life without relapse after 24 months after SBRT
* the cost/efficacity per gained year of life without disease after 24 months after SBRT.

The costs will be evaluated by the data from french social security system, from homogeneous group of patients and from general classification of professional acts

The treatment efficacy is assessed by calculation of local control rate of irradiated locations according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria (complete response + partial response + stable disease)

The treatment efficacy is assessed by calculation of local control rate of irradiated locations according to RECIST version 1.1 criteria (complete response + partial response + stable disease) between 1,5 and 3 months after treatment

Calculated from the date of inclusion to the date defined as the first documented disease progression, or second cancer appearance, or death from any cause (Up to 5 years since the first inclusion)

Calculated from the date of inclusion to the date of death from any cause (Up to 5 years since the first inclusion)

Toxicities appeared during SBRT treatment and up to 3 months after SBRT. Toxicities will be assessed by the evaluation of intensity and incidence of the Adverse Events (AE) displayed by patients. The intensity of each AE will be classified according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Toxicities appeared after 24 months after inclusion. The outcome measure concerns toxicities appeared after the study following period. Toxicities will be assessed by the evaluation of intensity and incidence of the Adverse Events (AE) displayed by patients. The intensity of each AE will be classified according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

The treatment efficacy is assessed by calculation of local control rate of irradiated locations according to RECIST version 1.1 criteria (complete response + partial response + stable disease) at 12 months after treatment

The treatment efficacy is assessed by calculation of local control rate of irradiated locations according to RECIST version 1.1 criteria (complete response + partial response + stable disease) at 24 months after treatment

Toxicities appeared between 3 months and 24 months after treatment. Toxicities will be assessed by the evaluation of intensity and incidence of the Adverse Events (AE) displayed by patients. The intensity of each AE will be classified according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Centre Leon Berard

IORT with Kyphoplasty IORT Device: Intrabeam®

IORT with kyphoplasty is give concurrently for the treatment of spinal metastases

IORT with Kyphoplasty

Intrabeam®

Beth Chiappetta, BSN

William Small, MD

The primary objective is to evaluate the tolerability (side effects) of the intraoperative radio therapy (IORT) (e.g., wound healing, infections, bone necrosis, nerve, spinal cord damage, and pathological fracture), and the secondary objective is to evaluate the effectiveness of IORT (i.e., pain relief, quality of life, narcotic use, and tumor response).

Disease Background:

Bone metastases are the third most common site of metastatic spread, affecting 10% - 30% of all cancer patients. The spine remains the most common site of bone metastases, with incidence ranging from 30-70% depending on the primary tumour.

Spinal metastases can be a significant cause of morbidity for cancer patients: severe pain, bone fracture, nerve root or spinal cord compression, hypercalcemia, and limited mobility. Symptomatic spinal metastases are most frequently located in the thoracic spine (70%), followed by lumbar spine (20%) and cervical spine (10%). Up to 15% of all cancer patients with bone metastasis will suffer compression fracture leading to loss of function and the impairment of mobility, while more than 70% of the patients will experience severe cancer-related pain affecting quality of life. Newer systemic agents targeting specific pathway or molecule within the tumor milieu has led to a dramatic improvement in life expectancy for metastatic patients. Hence, effective palliative treatment options for spinal metastases is an important clinical issue in today's oncologic practice.

Current Practice:

The majority of patients with spinal metastases are initially managed medically with combination of analgesic medication, bisphosphonates, or biologic/chemotherapy agents.

When these patients develop severe pain refractory to medical options or there is a concern for neurologic dysfunction (i.e. vertebrate fracture, nerve root compression), they will be referred for palliative radiotherapy or surgical treatment options.

In the past decade, minimally invasive interventional therapies have become more popular to treat severe pain from spinal metastases, especially in patients with evidence of compression fracture. Vertebroplasty involves the percutaneous injection of cement into the vertebral body with the goals of pain alleviation and preventing further loss of vertebral body height. Similarly, in kyphoplasty (KYPHO), an inflatable balloon is used to create a cavity for the cement deposition, which restores height as well as provides pain relief. However, the immediate goal for both procedures is to achieve stabilization of the vertebral body and prevent further compression.

Investigators assessed the safety and efficacy of vertebroplasty and kyphoplasty for pain palliation in cancer patients. They performed ninety-seven procedures in fifty-six patients. The median age was 62 years. The procedure was well-tolerated and no post-operative complications or death were noted. There was a significant reduction in visual analog pain score (VAS): median pre-and postoperative VAS score was 7 and 2, respectively (P=0.001, student paired t-test). However, there concern for use of kyphoplasty alone in treatment of spinal metastases: the rate of re-treatment and variable duration of pain palliation. The rate of new compression fracture after balloon kyphoplasty in patients with malignant spinal fracture can be as high as 10%.

Non-surgical option to treat spinal metastases usually involves the use of external beam radiotherapy. The goals of radiation therapy are to alleviate pain, stabilize affected bone, and decrease tumor cells within the treated site. Radiotherapy is very effective in pain reduction, as 50-80% of all patients receiving palliative radiation will experience pain reduction. Pain reduction from ionizing radiation, in theory, is due to the direct analgesic effect on the nociceptors in the periosteum and electrolyte shift, which can convert pain-inducing tissue acidosis to tissue alkalosis. Furthermore, stabilization of the vertebral bodies can be achieved by decreasing number of tumor cells and hence, thereby changing the imbalance of osteoclast and osteoblast activity. The latter effect can increase re-mineralization. These effects will occur in 40-50% of patients after radiation therapy, but can take 4-6 weeks after external beam radiation therapy course.

Several issues arise with use of external beam radiation therapy. First, an optimal dose fraction schedule has not been well- established. The most common prescribed dose is 30 grays (Gy) in ten fractions. However, in Radiation Therapy Oncology Group (RTOG) 9714, investigators found no difference between 8Gy in single fraction versus extended 30Gy in 10 fraction schedule in terms of pain relief and narcotic medication usage at three months. Furthermore, an extended radiotherapy course can lead to patient inconvenience, longer hospitalization, and increased toxicity. In the RTOG 9714 trial, patients in the 30-Gy arm had more grade 2-4 toxicities than 8-Gy arm. Furthermore, there is a risk of vertebral fracture for patients treated with radiation therapy for spinal metastases. Researchers reported 31% of their patients with spinal cord compression treated with radiotherapy alone had vertebral collapse.

Hence, to achieve an optimal treatment option for symptomatic cancer patients with spinal metastases, the next logical step would be to combine stabilization (kyphoplasty) technique with direct tumor cell destruction in order to achieve maximum and durable pain palliation, prevent potential neurological dysfunction, and improve quality of life. By combining kyphoplasty with intraoperative radiation, one can achieve the above mentioned goals in a single outpatient procedure.

Combination of Kyphoplasty and Intraoperative Radiation:

During a surgical procedure, the tumor bed and/or the tumor itself can be irradiated with a single dose of radiation. Intraoperative radiation therapy \[IORT\] is the delivery of radiation during a surgical intervention. The advantages of the IORT consist of the high precision combined with optimal protection of the surrounding organs at risk. Hence, a higher dose of radiation can be applied to the target (as compared to external beam), while minimizing the adverse side effects to normal tissue. Furthermore, the single dose corresponds to at least two to three time times higher biological effective dose than conventional fractionated external beam radiotherapy. Another potential advantage is the prevention of tumor cell proliferation during the post-operative period prior to start of adjuvant radiotherapy.

In this study, the investigators will use low energy x-rays (photons) to treat spine lesions during kyphoplasty. The IORT device used will be the Intrabeam®, which is a miniature X-ray generator that produces low-energy X-rays: electrons are accelerated with a voltage of 30-50 kilovolts (kV) and hit a gold target at the tip of the drift tube. At this point the low-energy radiation is generated and emitted isotropically, similar to a point source. Due to its sharp dose fall off, minimal radiation protection is required in the operating room. The ultimate goal is to treat tumor cells with optimal sparing of spinal cord. (Please refer to Section 2.4 for more information on Intrabeam®).

Researchers at the University Medical Center in Mannheim, Germany completed a phase I trial assessing the tolerability of the Kypho-IORT procedure. Investigators reported their experience on performing the Kypho-IORT procedure in 18 patients (twenty-one vertebral lesions) with unstable or painful spinal metastases. The researchers used Intrabeam® to deliver 8Gy at 5mm distance from the spinal applicator surface using 50kV x-rays. The median age was 63 years and median follow up was 4.5 months (range, 1-10 months).

The procedure was well-tolerated. The median surgical time was 70 minutes (range, 53-173 minutes), which included radiation delivery time of approximately two minutes. Of the 21 vertebral lesions, 18 were treated successfully (86%). During the procedure, 78% of patients were noted to have asymptomatic paravertebral para-methoxymethamphetamine (PMMA) cement leakage. None of the treated patients had delayed wound healing, spinal or nerve root compression, paresthesia, new neurological deficit, or skin toxicity.

In terms of pain relief, the median visual analog pain score (VAS) was 5 prior to procedure. The VAS decreased to 2.5 on the first post-procedure day. At six weeks, 12 of the 18 patients were available to be evaluated and reported a median VAS score of 0/10. 67% of the patients required analgesic medication for pain relief prior to procedure, but decreased to just 30% at six weeks. Furthermore, imaging studies were available for 15 of the 18 patients, revealing 93% (14/15) patients had stable disease. Only one patient had progressive disease based on radiographic evidence, but this patient did not require any additional intervention.

INTRABEAM:

The Intrabeam® machine delivers low energy 50-kV photons directly to a target volume. The device generates electrons and then, accelerates them in a sealed vacuum probe (drift tube, measures 10 cm long and 3.2 mm in outer diameter). This drift tube, located within the x-ray spectrometer (XRS) unit, incorporates a gold target on the inside surface of its tip. When the accelerated electrons collide with the gold target at the end of the drift tube, photons are generated and dispersed in an isotropic dose distribution. The X-ray source itself is mounted on a balanced floor stand with six degrees of freedom to provide various treatment positions. The Intrabeam® system is calibrated for quality assurance prior to each treatment.

For the Kypho-IORT procedure, specially designed spinal applicator tip is used. This sterile applicator tip consists of a plastic head, which attaches to the drift tube and is then, placed inside a stainless steel tube (metallic sleeve). The applicator tip protects the drift tube from bending. The applicator is made of plastic in order to minimize the absorption and attenuation of the photons. Under fluoroscopic guidance, the applicator tip is guided though the metallic sleeves to the placed in mid-point/mid-plane of the vertebral lesion.

Due to the steep dose fall-off, a high dose to the vertebral lesion can be delivered, with maximum sparing of spinal cord. A radiation dose of 8 Gy at a distance of 5 mm from the applicator surface will be prescribed. This correlates to an approximate dose of 91 Gy at the applicator surface, 45 Gy at a distance of 1mm (from the applicator surface), 27Gy at 2mm, and 8Gy at 5mm. Further dose fall off is approximated: 2.4Gy at 10mm, 0.8Gy at 15mm, and 0.4Gy at 20mm. Assuming minimal distance of 15mm to the spinal cord, then, the spinal cord would receive less than 1Gy.

Study Design:

The combination of intraoperative radiotherapy with kyphoplasty will provide immediate vertebra stabilization, durable pain relief, and sterilization of tumor cells in a single outpatient procedure. To this date, this procedure has not been performed in the United States. The investigators plan to conduct a phase I trial of Kypho-IORT at the Loyola University Medical Center.

Combining Intraoperative Radiotherapy With Kyphoplasty for Treatment of Spinal Metastases

Patient will rate the severity of pain on a numeric 0-10 scale with higher scores indicating more severe pain. Pain assessment will be done at baseline, day of the procedure, and during follow up visits for up to 52 weeks.

Patients will be classified at week 52 as having (1) disappearance of the treated lesion (i.e., complete response), (2) at least 30% decrease in the diameter of the treated lesion (i.e., partial response), (3) at least 20% increase in the diameter of the treated lesion (i.e., progressive disease), or (4) Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease (i.e., stable disease).

Loyola University

Assistant Professor

Pain

dose-intensified image-guided SBRT using simultaneous integrated boost:

* in the case of no epidural involvement: 40 Gy and 20 Gy in 5 fractions to the high-dose and conventional-dose target volume, respectively.
* In the case epidural involvement: 48.5 Gy and 30 Gy in 10 fractions to the high-dose and conventional-dose target volume, respectively.

External 3-dimensional conformal radiotherapy (3D-CRT):

Homogeneous irradiation of the affected vertebra delivering either

* 20 Gy in 5 fractions or
* 30 Gy in 10 fractions.

Patients eligible for the prospective observational arm will be treated according to the investigational arm (arm A) of the randomised arm of the trial.

dose-intensified image-guided SBRT using simultaneous integrated boost

External 3-dimensional conformal radiotherapy (3D-CRT)

Matthias Guckenberger, Prof. Dr.

This study will compare pain (primary end-point) and local metastatic tumor control (secondary end-point) after dose-intensified image-guided fractionated stereotactic body radiation therapy (SBRT) for painful mass-type spinal metastases versus conventional radiation therapy.

Rationale: Radiation therapy is an effective palliative treatment for painful spinal metastases. A sub-group of patients with mass-type spinal metastases, a factor associated with poor local metastasis control, require treatment optimization ensuring durable pain control and metastatic tumor control.

Proposed solution: To intensify (escalate) radiation dose using simultaneous integrated boost with image-guided hypofractionated SBRT for painful mass-type spinal metastases in a randomized controlled trial. Two experimental fractionation regimes will be tested in the study depending on presence or absence of epidural involvement. Dose intensification is expected to achieve long-term pain control and long-term palliation as well as long-term local metastatic tumor control without adding toxicity as compared to conventional fractionation regimes with conventional radiation therapy.

The study will be carried out as multinational, multicentre phase II clinical controlled trial enrolling patients with painful mass-type spinal metastases who are eligible for radiation therapy without surgery. This study additionally includes a prospective observational arm for patients not eligible for randomisation who are treated in analogy to arm A of the randomised arm.

Clinical Trial Comparing Dose-intensified SBRT With Conventional Radiation Therapy for Spinal Metastases

Dose-intensified Image-guided Fractionated Stereotactic Body Radiation Therapy for Painful Spinal Metastases Versus Conventional Radiation Therapy: a Randomised Controlled Trial (DOSIS RCT)

Local metastasis control is defined from the day of randomization to a day of local (at the site of the treated spinal metastasis) progression, i.e. local failure, determined on control MR images as a change in signal intensity or on CT images as increasing soft-tissue mass. Increased epidural disease or enlargement of paraspinal disease on control images will be documented as progression.

Overall survival is defined from the day of randomization to a day of death of any cause.

Cancer-specific survival is defined from the day of randomization to a day of death due to cancer progression.

Quality-of-life (QoL) as measured by the EORTC QLQ-C15-PL, EORTC-BM22 and EQ-5D-5L patient reported questionnaires

Epidural spinal cord compression (ESCC) will be scored using Bilsky criteria.

Acute aund late toxicity will be assessed in accordance to NCI CTCEA version 4.03 criteria.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of SBRT Efficacy on Intra and Extra -Cranial Tumors or Metastasis in Pediatrics Population (SBRT Pediatrics)	NCT02013297	Brain Metastasi... Spinal Tumors Lung Tumors Ependymoma	SBRT treatment	18 Months - 20 Years	Centre Leon Berard
Combining Intraoperative Radiotherapy With Kyphoplasty for Treatment of Spinal Metastases	NCT02480036	Spinal Metastas...	IORT with Kypho... Intrabeam®	50 Years -	Loyola University
Clinical Trial Comparing Dose-intensified SBRT With Conventional Radiation Therapy for Spinal Metastases	NCT02800551	Spinal Metastas...	dose-intensifie... External 3-dime...	18 Years -	University of Zurich

Spots Global Cancer Trial Database for spinal metastasis