Mubina Quader

International spine radiosurgery consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery

PURPOSE Spinal stereotactic radiosurgery (SRS) is increasingly used to manage spinal metastases. However, target volume definition varies considerably and no consensus target volume guidelines exist. This study proposes consensus target volume definitions using common scenarios in metastatic spine radiosurgery. METHODS AND MATERIALS Seven radiation oncologists and 3 neurological surgeons with spinal radiosurgery expertise independently contoured target and critical normal structures for 10 cases representing common scenarios in metastatic spine radiosurgery. Each set of volumes was imported into the Computational Environment for Radiotherapy Research. Quantitative analysis was performed using an expectation maximization algorithm for Simultaneous Truth and Performance Level Estimation (STAPLE) with kappa statistics calculating agreement between physicians. Optimized confidence level consensus contours were identified using histogram agreement analysis and characterized to create target volume definition guidelines. RESULTS Mean STAPLE agreement sensitivity and specificity was 0.76 (range, 0.67-0.84) and 0.97 (range, 0.94-0.99), respectively, for gross tumor volume (GTV) and 0.79 (range, 0.66-0.91) and 0.96 (range, 0.92-0.98), respectively, for clinical target volume (CTV). Mean kappa agreement was 0.65 (range, 0.54-0.79) for GTV and 0.64 (range, 0.54-0.82) for CTV (P<.01 for GTV and CTV in all cases). STAPLE histogram agreement analysis identified optimal consensus contours (80% confidence limit). Consensus recommendations include that the CTV should include abnormal marrow signal suspicious for microscopic invasion and an adjacent normal bony expansion to account for subclinical tumor spread in the marrow space. No epidural CTV expansion is recommended without epidural disease, and circumferential CTVs encircling the cord should be used only when the vertebral body, bilateral pedicles/lamina, and spinous process are all involved or there is extensive metastatic disease along the circumference of the epidural space. CONCLUSIONS This report provides consensus guidelines for target volume definition for spinal metastases receiving upfront SRS in common clinical situations.

Testicular recovery after irradiation differs in prepubertal and pubertal non-human primates, and can be enhanced by autologous germ cell transplantation

BACKGROUND Although infertility is a serious concern in survivors of pediatric cancers, little is known about the influence of the degree of sexual maturation at the time of irradiation on spermatogenic recovery after treatment. Thus, we address this question in a non-human primate model, the rhesus monkey (Macaca mulatta). METHODS Two pubertal (testis size 3 and 6.5 ml, no sperm in ejaculate) and four prepubertal (testis size 1 ml, no sperm in ejaculate) macaques were submitted to a single fraction of testicular irradiation (10 Gy). Unilateral autologous transfer of cryopreserved testis cells was performed 2 months after irradiation. Testicular volume, histology and semen parameters were analyzed to assess irradiation effects and testicular recovery. RESULTS Irradiation provoked acute testis involution only in the two pubertal monkeys. Subsequently, testis sizes recovered and sperm was present in the ejaculates. Longitudinal outgrowth of seminiferous tubules continued, and, in testes without autologous cell transfer, 4-22% of tubular cross sections showed spermatogenesis 2 years after irradiation. In contrast, the four prepubertal monkeys showed neither a detectable involution as direct response to irradiation, nor a detectable growth of seminiferous tubules later. However, two of these animals showed spermarche 2 years after irradiation, and 8-12% of tubules presented spermatogenesis. One prepubertally irradiated monkey presented fast growth of one testis after cell transfer, and showed spermarche 1 year after irradiation. The infused testis had spermatogenesis in 70% of the tubules. The contralateral testis remained smaller. CONCLUSION We conclude that irradiation before puberty has a severe detrimental effect on outgrowth of seminiferous tubules. But, within the seminiferous epithelium, spermatogenetic recovery occurs at a low rate with no detectable relation to the maturity of the epithelium at irradiation. We also show that autologous testis cell transplantation can enhance spermatogenesis, but only in isolated cases.

Dosimetric comparison of the Leksell Gamma Knife Perfexion and 4C

OBJECT The recently introduced Leksell Gamma Knife (LGK) Perfexion is an entirely new system with a different beam geometry compared with the LGK 4C. The new Perfexion system has 192 cobalt-60 sources that are fixed on 8 sectors (each sector has 24 sources). Each sector can be moved independently of the others and can be set to 1 of 5 different positions: 3 positions defining collimator sizes of 4, 8, and 16 mm; an off position (sources are blocked); and a home position. The purpose of this study is to compare the dosimetric characteristics of the GK 4C and the Perfexion models. This comparison is important especially for the treatment of functional disorders when only a single shot with the 4- or 8-mm collimator is used. METHODS A 160-mm-diameter spherical polystyrene phantom was used for all measurements and calculations. The irradiation geometry consisted of the placement of a single shot at the center of this phantom. Comparisons were made among different dosimetric parameters obtained from calculations performed using Leksell GammaPlan v. 8.0 and measurements performed using film dosimetry. The dosimetric parameters investigated were dose profiles for all collimators in all 3 stereotactic planes (x, y, and z) including the full width at half maximum and the penumbra for each profile, cumulative dose-volume histograms, the volume encompassed by the 50% isodose surface, the mean doses delivered to a defined matrix volume, and relative output factors for all collimator sizes. RESULTS There was excellent agreement between the dosimetric parameters of GK 4C and Perfexion for the 4- and 8-mm collimators. CONCLUSIONS The results of this study suggest that consistent treatments of functional disorders will be delivered using either GK 4C or Perfexion.

Setup accuracy of spine radiosurgery using cone beam computed tomography image guidance in patients with spinal implants.

OBJECT Cone beam computed tomography (CBCT) image guidance technology has been adopted for use in spine radiosurgery. There is concern regarding the ability to safely and accurately perform spine radiosurgery without the use of implanted fiducials for image guidance in postsurgical cases in which titanium instrumentation and/or methylmethacrylate (MMA) has been implanted. In this study the authors prospectively evaluated the accuracy of the patient setup for spine radiosurgery by using CBCT image guidance in the context of orthopedic hardware at the site of disease. METHODS The positioning deviations of 31 single-fraction spine radiosurgery treatments in patients with spinal implants were prospectively evaluated using the Elekta Synergy S 6-MV linear accelerator with a beam modulator and CBCT image guidance combined with a robotic couch that allows positioning correction in 3 translational and 3 rotational directions. To measure patient movement, 3 quality-assurance CBCT studies were performed and recorded: before, halfway through, and after radiosurgical treatment. The positioning data and fused images of planning CTs and CBCTs from the treatments were analyzed to determine intrafractional patient movements. From each of 3 CBCTs, 3 translational and 3 rotational coordinates were obtained. RESULTS The prescribed dose to the gross tumor volume for the cohort was 12-18 Gy (mean 14 Gy) utilizing 9-14 coplanar intensity-modulated radiation therapy (IMRT) beams (mean 10 beams). At the halfway point of the radiosurgery, the translational variations and standard deviations were 0.6 +/- 0.6, 0.4 +/- 0.4, and 0.5 +/- 0.5 mm in the lateral (X), longitudinal (Y), and anteroposterior (Z) directions, respectively. The magnitude of the 3D vector (X,Y,Z) was 1.1 +/- 0.7 mm. Similarly, the variations immediately after treatment were 0.5 +/- 0.3, 0.4 +/- 0.4, and 0.5 +/- 0.6 mm along the X, Y, and Z directions, respectively. The 3D vector was 1.0 +/- 0.6 mm. The mean rotational angles were 0.3 +/- 0.4, 0.5 +/- 0.6, and 0.3 +/- 0.4 degrees along yaw, roll, and pitch, respectively, at the halfway point and 0.3 +/- 0.4, 0.6 +/- 0.6, and 0.4 +/- 0.5 degrees immediately after treatment. CONCLUSIONS Cone beam CT image guidance used for patient setup for spine radiosurgery was highly accurate despite the presence of spinal instrumentation and/or MMA at the level of the target volume. The presence of such spinal implants does not preclude safe treatment via spine radiosurgery in these patients.

Radiosurgery for benign tumors of the spine: clinical experience and current trends.

In distinction to the development of the clinical indications for intracranial radiosurgery, spine radiosurgerys initial primary focus was and still remains the treatment of malignant disease. The role of stereotactic radiosurgery for the treatment of intracranial benign tumors has been well established. However, there is much less experience and much more controversy regarding the use of radiosurgery for the treatment of benign tumors of the spine. This study presents the clinical experience and current trends of radiosurgery in the treatment paradigm of benign tumors of the spine as part of a dedicated spine radiosurgery program. Forty consecutive benign spine tumors were treated using cone beam computed tomography (CBCT) image guidance technology for target localization. Lesion location included 13 cervical, 9 thoracic, 11 lumbar, and 7 sacral tumors. Thirty-four cases (85%) were intradural. The most common tumor histologies were schwannoma (15 cases), neurofibroma (7 cases), and meningioma (8 cases). Eighteen cases (45%) had previously undergone open surgical resection, and 4 lesions (10%) had previously been treated with conventional fractionated external beam irradiation techniques. This cohort was compared to a prior institutional experience of 73 consecutive benign spine tumors treated with radiosurgery. No subacute or long term spinal cord or cauda equina toxicity occurred during the follow-up period (median 26 months). Radiosurgery was used as the primary treatment modality in 22 cases (55%) and for recurrence after prior open surgical resection in 18 cases (45%). The mean prescribed dose to the gross tumor volume (GTV) was 14 Gy (range 11 to 17) delivered in a single fraction in 35 cases. In 5 cases in which the tumor was found to be intimately associated with the spinal cord with distortion of the spinal cord itself, the prescribed dose to the GTV was 18 to 21 Gy delivered in 3 fractions. The GTV ranged from 0.37 to 94.5 cm3 (mean 13.2 cm3, median 5.1 cm3). No evidence of tumor growth was seen on serial imaging in any case. Compared to the prior cohort, there was a trend towards increased patient age, GTV, and use of radiosurgery in the post-surgical setting, as well as a simultaneous decrease in the prescription dose. Radiosurgery is a safe and clinically effective treatment alternative for benign spinal neoplasms. While surgical extirpation is currently felt to be the best initial treatment option for most benign spinal tumors, spine radiosurgery has been demonstrated to have long-term clinical and radiographic benefit for the treatment of such lesions. In a similar manner in which spine radiosurgery has become a primary treatment option for a variety of intracranial benign tumors, radiosurgery may become the most favorable treatment alternative for similar histologies when found in the spine. The application of radiosurgery for non-neoplastic spine disease deserves future investigation.

Radiosurgery for benign tumors of the spine using the Synergy S with cone-beam computed tomography image guidance.

OBJECT There is a growing body of evidence to support the safe and effective use of spine radiosurgery. However, there is much less experience regarding the use of radiosurgery for the treatment of benign as opposed to malignant spine tumors. This study represents an evaluation of, and reporting on, the technical aspects of using a dedicated radiosurgery system for the treatment of benign spine tumors. METHODS Forty-five consecutive benign spine tumors were treated using the Elekta Synergy S 6-MV linear accelerator with a beam modulator and cone-beam computed tomography (CBCT) image guidance technology for target localization. The study cohort included 16 men and 29 women, ranging in age from 23 to 88 years (mean age 52 years). There were 14 cervical, 12 thoracic, 14 lumbar, and 5 sacral tumors. Forty-one lesions (91%) were intradural. The most common histological types of tumor were schwannoma, neurofibroma, and meningioma. Indications for radiosurgery included primary treatment in 24 cases (53%) and treatment of recurrent or residual tumor after open resection in 21 cases (47%). RESULTS No subacute or long-term spinal cord or cauda equina toxicity occurred during the follow-up period (median 32 months). The mean maximum dose received by the gross tumor volume (GTV) was 16 Gy (range 12-24 Gy) delivered in a single fraction in 39 cases. The mean lowest dose received to the GTV was 12 Gy (range 8-16 Gy). The GTV ranged from 0.37 to 94.5 cm(3) (mean 13.7 cm(3), median 5.9 cm(3)). In the majority of cases, a planning target volume expansion of 2 mm was employed (38 cases; 84%). The mean maximum point dose delivered to the spinal cord was 8.7 Gy (range 4-11.5 Gy); the mean volume of the spinal cord that received greater than 8 Gy was 0.9 cm(3) (range 0.0-5.1 cm(3)); and the mean dose delivered to 0.1 cm(3) of the spinal cord was 7.5 Gy (range 3-10.5 Gy). The mean maximum point dose delivered to the cauda equina was 10 Gy (range 0-13 Gy); the mean volume of the cauda equina that received greater than 8 Gy was 1.45 cm(3) (range 0.0-10.6 cm(3)); and the mean dose delivered to 0.1 cm(3) of the cauda equina was 8 Gy (range 0.5-11 Gy). CONCLUSIONS In this study the authors describe the contouring and prescribed dose techniques used in the treatment planning and delivery of radiosurgery for benign neoplasms of the spine using CBCT image guidance. This technique may serve as an important reference for the performance of radiosurgery when one believes it is clinically indicated as a treatment modality for a benign spine tumor that is associated with both a high safety profile and a strong positive clinical outcome.

A multi-national report on methods for institutional credentialing for spine radiosurgery

BackgroundStereotactic body radiotherapy and radiosurgery are rapidly emerging treatment options for both malignant and benign spine tumors. Proper institutional credentialing by physicians and medical physicists as well as other personnel is important for the safe and effective adoption of spine radiosurgery. This article describes the methods for institutional credentialing for spine radiosurgery at seven highly experienced international institutions.MethodsAll institutions (n = 7) are members of the Elekta Spine Radiosurgery Research Consortium and have a dedicated research and clinical focus on image-guided spine radiosurgery. A questionnaire consisting of 24 items covering various aspects of institutional credentialing for spine radiosurgery was completed by all seven institutions.ResultsClose agreement was observed in most aspects of spine radiosurgery credentialing at each institution. A formal credentialing process was believed to be important for the implementation of a new spine radiosurgery program, for patient safety and clinical outcomes. One institution has a written policy specific for spine radiosurgery credentialing, but all have an undocumented credentialing system in place. All institutions rely upon an in-house proctoring system for the training of both physicians and medical physicists. Four institutions require physicians and medical physicists to attend corporate sponsored training. Two of these 4 institutions also require attendance at a non-corporate sponsored academic society radiosurgery course. Corporate as well as non-corporate sponsored training were believed to be complimentary and both important for training. In 5 centers, all cases must be reviewed at a multidisciplinary conference prior to radiosurgery treatment. At 3 centers, neurosurgeons are not required to be involved in all cases if there is no evidence for instability or spinal cord compression. Backup physicians and physicists are required at only 1 institution, but all institutions have more than one specialist trained to perform spine radiosurgery. All centers believed that credentialing should also be device specific, and all believed that professional societies should formulate guidelines for institutions on the requirements for spine radiosurgery credentialing. Finally, in 4 institutions radiation therapists were required to attend corporate-sponsored device specific training for credentialing, and in only 1 institution were radiation therapists required to also attend academic society training for credentialing.ConclusionsThis study represents the first multi-national report of the current practice of institutional credentialing for spine radiosurgery. Key methodologies for safe implementation and credentialing of spine radiosurgery have been identified. There is strong agreement among experienced centers that credentialing is an important component of the safe and effective implementation of a spine radiosurgery program.

Unintended attenuation in the Leksell Gamma Knife® Perfexion™ calibration-phantom adaptor and its effect on dose calibration

The calibration of Leksell Gamma Knife Perfexion (LGK PFX) is performed using a spherical polystyrene phantom 160 mm in diameter, which is provided by the manufacturer. This is the same phantom that has been used with LGK models U, B, C, and 4C. The polystyrene phantom is held in irradiation position by an aluminum adaptor, which has stainless steel side-fixation screws. The phantom adaptor partially attenuates the beams from sectors 3 and 7 by 3.2% and 4.6%, respectively. This unintended attenuation introduces a systematic error in dose calibration. The overall effect of phantom-adaptor attenuation on output calibration of the LGK PFX unit is to underestimate output by about 1.0%.

Host conditioning and rejection monitoring in hepatocyte transplantation in humans

BACKGROUND & AIMS Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. METHODS Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. RESULTS Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343±48μM (normal 30-119μM) to 854±25μM (treatment goal ≤360μM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900μM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. CONCLUSIONS Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. LAY SUMMARY Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.

Hematopoietic chimerism following allotransplantation of the spleen, splenocytes or kidney in pigs.

BACKGROUND Mixed chimerism is associated with donor-specific tolerance. Spleen or splenocyte allotransplantation (Tx) is recognized as potentially tolerogenic. There is no definitive report comparing chimerism levels following spleen and splenocyte Tx in a large animal model. We have compared chimerism after spleen, splenocyte, or kidney Tx in pigs. METHODS Outbred (n = 5) and MHC-defined miniature (n = 1) pigs underwent orthotopic spleen Tx. Outbred pigs received splenocytes through a systemic vein (n = 1) or the portal vein (n = 3). Kidney Tx (n = 2) or concomitant Tx of spleen+kidney (n = 2) was carried out. All except one recipient pigs were irradiated (700 cGy thymic and 100-125 cGy whole body) on day-2. Cyclosporine or tacrolimus was administered for 42 days. All donors were males and all recipients were females; chimerism in the blood was determined by Quantification-PCR for the donor Y chromosome. Mixed lymphocyte reaction (MLR) was performed before and after Tx. RESULTS One week after spleen Tx in outbred and MHC-defined pigs, chimerism ranged between 0.8 and 22.5%, and 5.4-20.1%, respectively, and remained between 17.7 and 67.4%, and 2.2-7.4%, respectively, until day 28. One week after splenocyte Tx, chimerism ranged between 0.1 and 8.5%, and decreased to 0.1-0.8% at 3-4 weeks. There was no detectable chimerism 14 days after kidney Tx. The response on MLR of all recipient pigs to donor cells was decreased after Tx, except in one case of splenocyte Tx, indicating that this pig might have become sensitized. After discontinuation of immunosuppression, most isolated spleen or kidney grafts were not rejected, but the kidney was rejected after concomitant spleen+kidney Tx. CONCLUSIONS There was a significantly higher level of blood chimerism following spleen Tx compared to splenocyte or kidney Tx. However, concomitant Tx of spleen+kidney may be associated with accelerated kidney graft rejection.