Neoplasms

Symptoms and General Pathology

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Nervous System Diseases

Neoplasm Metastasis

Brain Neoplasms

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Cyberknife SRS of all suspect intracranial lesions visible in SPACE up to 10 simultaneous lesions

Cyberknife SRS of all suspect intracranial lesions visible in MPRAGE up to 10 simultaneous lesions

All patients will receive a pre-treatment cranial MRI for diagnostic and treatment planning purposes.

In Arm A, the contrast-based T1-weighted SPACE sequence is utilized for GTV definition. In Arm B, the contrast-based T1-weighted three-dimensional MPRAGE sequence is utilized for GTV definition. In both cases the GTV consists of all contrasted tissue associated with the target lesion and all additional tissue judged by an experienced physician to be part of the suspect target lesion. To the GTV a PTV margin of 1 mm is added by isotropic expansion that can be slightly modified if deemed necessary by the treating physician (e.g. intersection with adjoining OAR).

Dose prescription to the PTV for target lesions will be as follows:

* 20 Gy to the 70%-isodose (lesions \< 2 cm max. diameter)
* 18 Gy to the 70%-isodose (lesions 2 - 3 cm max. diameter)
* 6 x 5 Gy to the conformally surrounding isodose (lesions \> 3 cm max. diameter)

stereotactic radiosurgery (SRS)

Juergen Debus, Prof. Dr.Dr.

For patients with cerebral oligometastases who are in adequate clinical condition stereotactic radiosurgery (SRS) is the treatment of choice, being recommended by international guidelines for the treatment of one to four lesions. Newer findings have shown that for patients with more than four lesions SRS can be considered as a favorable alternative to whole-brain radiotherapy (WBRT), the currently established standard-of-care treatment. With modern techniques highly conformal SRS of multiple lesions has become feasible with comparable clinical effort and minimal toxicity as compared to WBRT. Developments in magnetic resonance imaging (MRI- imaging) have produced highly sensitive contrast-enhanced three-dimensional fast spin echo sequences such as SPACE that facilitate the detection of very small and early-stage lesions in a fashion superior to the established Magnetization Prepared Rapid Gradient Echo (MPRAGE) series.

Since it has been established that the response of brain metastases to SRS is better for smaller lesions and that WBRT can come at the price of significant neurotoxicity, the investigators hypothesize that 1) earlier detection of small brain metastases and 2) early and aggressive treatment of those by SRS will result in an overall clinical benefit by delaying the failure of repeated localized therapy and thus preserving quality of life and potentially prolonging overall survival. On the other hand however, overtreatment might be a valid concern with this approach since it has yet to be proved that a clinical benefit can be achieved.

The current study aims to stretch the boundaries of the term "cerebral oligometastases" by performing SRS for up to ten cerebral metastases, compared to the established clinical standard of four, given that existing data supports the non-inferiority of this approach and given that modern Cyberknife SRS facilitates the treatment of multiple lesions with minimal treatment-associated toxicity.

Scientific Background: Brain metastases are the most common intracranial cancer manifestations, affecting up to one third of adult cancer patients with systemic spread. Prognosis is generally poor with overall survival ranging below 6 months on average. However, a more detailed inspection reveals a prognostic subgroup, for which improved overall survival and clinical symptom control can be achieved and that is most descriptively characterized by favorable clinical performance (KPI ≥ 70%) and extracranially controlled disease. Whereas for most patients with brain metastases whole-brain radiotherapy, steroids or best supportive care represent the palliation treatment of choice, the abovementioned subgroup is eligible to profit from a locally radical therapy concept and in those cases neurosurgical resection and stereotactic radiosurgery have both produced favorable results. In patients unsuitable for neurosurgical resection, single- or multifraction, SRS has several distinct advantages over WBRT, the most significant being short treatment time, less posttherapeutic neurocognitive impairment, better local tumor control and little to no hair loss. Furthermore, SRS can be repeated multiple times or performed before or after WBRT. Current clinical guidelines recommend SRS in cases of cerebral oligometastases, defined as one to four intracranial lesions with an extracranially controlled systemic disease status. However, recent data suggests that it may be a suitable treatment for patients with five to ten or even more than ten lesions, being non-inferior to the SRS of four or less lesions. There are several factors supporting this rationale: On the one hand technical improvements in the field of SRS have significantly facilitated the treatment of a higher number of target lesions with little to no increase in toxicity and comparable clinical effort. On the other hand, the ever improving sensitivity of medical imaging has caused an increase in the detection of oligometastatic constellations, enabling their treatment in an earlier stage. For a long time the contrast-based high-resolution cranial computer tomography (cCT) had been the gold standard of detecting cerebral metastases. This was significantly improved by the introduction of magnetic resonance imaging (MRI) with contrast-enhanced T1-weighted sequences. Sensitivity was further improved with the introduction of 3T MRI into clinical routine and the development of high-resolution three-dimensional gradient-echo sequences such as the contrast-based T1-weighted MPRAGE, featuring a slice thickness of 0.9 mm and multiplanar reconstruction, thus enabling the detection of very small sized lesions in the range of one to a few millimeters. However, the use of gradient-echo (GE) techniques to obtain three-dimensional high-spatial-resolution images comes at the cost of inferior contrast enhancement and higher susceptibility to artifacts than is the case with two-dimensional spin-echo (SE) techniques. Recent developments in MRI research have produced another sequence that might prove even superior to MPRAGE in the specific detection of very small and early brain metastases: Sampling perfection with application-optimized contrasts by using different flip angle evolutions (SPACE) is a three-dimensional fast SE sequence that combines high contrast enhancement superior to MPRAGE with a high spatial resolution and multiplanar reconstruction. Kato et al. have found this sequence to be significantly superior to MPRAGE in the detection of contrast enhanced parenchymal lesions, especially if those are \< 5mm in size as is characteristic of small very-early-stage cerebral metastases.

Trial Objectives: It is the purpose of this study to evaluate treatment response and toxicity after SRS of up to ten simultaneous cerebral metastases, treating either all lesions visible in the highly sensitive SPACE MRI sequence or only those visible in the conventional contrast-based MPRAGE sequence. Treatment response is evaluated with respect to the ineligibility for further cerebral SRS at 12 months after initial SRS, defined by simultaneous new occurrence or progression of \> 10 brain metastases (as a surrogate parameter for overall local control), furthermore overall survival and cognitive function and quality of life.

Patients´Selection: A total of n=200 patients will be enrolled into the trial (n=100 per treatment group). All patients fulfilling the inclusion and exclusion criteria will be informed about the study and included into the study if they declare informed consent. Registration for the study must be performed before the start of RT.

Trial Design: The trial will be performed as a single-center two-armed prospective randomized Phase II study. Patients will be randomized into an experimental arm and a control arm. All patients will receive pre-therapeutic MRI imaging as described in (Chapter 6) and imaging will be assessed by a radiologist. For patients in the experimental arm, all available MRI series, including SPACE will be taken into consideration for the definition of treatment target lesions. For patients in the control arm the assessing radiologist will be blinded with respect to the SPACE sequence and for the definition of treatment target lesions primarily contrast-based three-dimensional MPRAGE, complemented by all non-SPACE MRI sequences will be taken into consideration.

Cyberknife Radiosurgery for Patients With Brain Metastases Diagnosed With Either SPACE or MPRAGE Sequence

Cyberknife Radiosurgery for Patients With Brain Metastases Diagnosed With Either SPACE or MPRAGE Sequence - A Prospective Randomized Evaluation of Response and Toxicity

simultaneous new occurrence or progression of \> 10 brain metastases

Time interval between the date of RT begin and the date of death or date of leaving the study e.g., lost to follow up) whatever occurs first.

CANTAB Test (Cambridge Neuropsychological Test Automated Battery )

EORTC QLQ-C30 questionnaire to assess the QoL of cancer patients, clinical assessment

Heidelberg University

Juergen Debus

Prof. Dr.Dr. Jürgen Debus

High-resolution contrast-enhanced post-operative MRI imaging in preparation for Cyberknife SRS. Cyberknife SRS of the resection cavity and all potential additional metastases diagnosed in the treatment planning MRI (up to 10 lesions)

Resection cavity:

7 x 5 Gy @ 95%-isodose

Potential additional brain metastases:

20 Gy @ 70%-isodose (lesions \< 2 cm max. diameter) 18 Gy @ 70%-isodose (lesions 2 - 3 cm max. diameter) 6 x 5 Gy @ 70%-isodose (lesions \> 3 cm max. diameter)

Post-operative WBRT will be performed according to the following dose regimen: 10 x 3 Gy

For radiosurgery, patients will be immobilized. Treatment planning including the MRI and planning CT should be performed 1 -2 weeks before SRT and treatment finished at latest 3-4 weeks after surgery. Planning should be as close to SRT as possible.

Organs at risk such as the brain stem, optic nerves, chiasm and spinal cord will be contoured. The Clinical Target Volume 1 (CTV1) will be defined as the resection cavity based on MRI and CT including T1 contrast enhanced changes around the resection cavity. The Clinical Target Volume 2 (CTV2) will be defined as a 3mm margin added to CTV1 by isotropic expansion and slightly adjusted as deemed appropriated by the experienced contouring physician. The Planning Target Volume (PTV) will be an additional margin of 1mm added to CTV2 by isotropic expansion.

Treatment planning will be performed using Accuray's Multiplan or subsequent approved treatment planning systems for Cyberknife.

post-operative stereotactic radiosurgery (SRS)

For WBRT, an individual head fixation mask is manufactured for each patient, and treatment planning is performed as virtual simulation or 3D-conformal RT planning based on CT-imaging. The portals include the whole brain with special focus as including the skull base areas and lamina cribrosa. For low infratentorial lesions, the treatment volume may include the whole brain down to the second cervical vertbra.

RT will be applied with two portals (e.g. 87°and 273°) using a 6 MeV linear accelerator.

For WBRT, a total dose of 30 Gy in 3 Gy fractions will be applied.

Whole brain radiotherapy (WBRT)

Juergen Debus, Prof. Dr. Dr.

In advanced cancer disease brain metastases are common, difficult to treat, and are associated with a poor prognosis. As new local and systemic therapies are eventually resulting in improved survival and quality of life for patients with brain metastases, negative neurocognitive effects of radiation therapy are becoming increasingly important as well as good loco-regional disease control of brain metastases.

Concerning treatment, brain metastases remain a major clinical problem and a multidisciplinary approach to management should be adopted. Neurosurgical resection with postoperative whole brain radiotherapy (WBRT) is one major treatment option in solitary or symptomatic brain metastases. Furthermore, WBRT is recommended for multiple brain metastases. For a limited number of brain metastases stereotactic radiosurgery (SRS) has been established as a highly effective treatment alternative.

Recently, a new treatment approach combing neurosurgery with postoperative stereotactic radiotherapy (SRT) of the resection cavity is emerging. Based on available evidence, postoperative SRT of the resection cavity improves local control following surgery, reduces the number of patients who require whole brain radiotherapy, and is well tolerated (1).

This protocol is aimed at primarily evaluating the safety and toxicity profile of SRT to the resection cavity following neurosurgical resection combined with SRT of potentially further unresected brain metastases, compared to postoperative whole-brain radiotherapy (WBRT). Secondary, the local effect of SRT in patients with brain metastases will be assessed by measuring time to local recurrence (LR), local and loco-regional progression-free survival (PFS).

Additional systemic treatment will be carried out according to the standards of the National Center for Tumor Therapy (NCT).

Scientific Background: Brain metastases (BM) represent a significant healthcare problem. It is estimated that 20% to 40% of patients with cancer will develop metastatic cancer to the brain during the course of their illness 1. The most common primary sites are lung, melanoma, renal, breast and colorectal cancer 2. Options for patients with brain metastases had been limited to whole brain radiotherapy (WBRT) or supportive care alone, and systemic chemotherapy was often discontinued. Historically, the best possible supportive care or whole-brain radiotherapy (WBRT) were the standard of care 1 aiming at temporary symptom relief. For WBRT, efficacy in symptom relief but also in prolongation of the median survival time by 3-6 months is well documented. To date, microsurgical approaches and SRS, both proved to be safe and efficient, offer alternative treatment options that potentially meet these concerns 6,7. After proving its efficacy in achieving local tumor control in the treated volume, SRS was used as a stand-alone treatment option in patients with oligometastases (one to four metastases) in the brain. There is a rapidly expanding recent body of literature on outcomes of single-fraction SRS or hypofractionated SRS targeting the resection cavity after surgical resection of BM. Several retrospective series assessed the efficacy and safety of postoperative SRS to the resection cavity 9 aiming at an enhanced local tumor control but also at avoidance of the neurotoxic late effects of WBRT. WBRT followed by SRS of the tumor bed leads to 1-year local control rates of 70-93 %, which is comparable to results after surgery followed by WBRT. Median survival was 12-18 months with a 1-year incidence of new metastases in the brain of 45-60 %.

Trial Objectives: This protocol is primarily aimed at evaluating the safety and toxicity profile of SRS following neurosurgical resection and compares it to that of WBRT as the established standard of care. Secondary, the local effect of radiation therapy in patients with brain metastases will be assessed by measuring time to local and loco-regional recurrence, local and loco-regional PFS and overall survival at 12 months after treatment.

Patients´Selection: Patients with the diagnosis of brain metastases from solid tumors that have undergone neurosurgical resection of one brain metastasis will be evaluated and screened for the protocol. All patients fulfilling the inclusion and exclusion criteria will be informed about the study and included into the study if they declare informed consent. Registration for the study must be performed before the start of RT.

Trial Design: The trial will be performed as a single-center two-armed prospective randomized Phase II study. Patients will be randomized into an experimental arm and a control arm. All patients will receive post-operative contrast-enhanced cranial MRI imaging and imaging will be assessed by a radiologist. All available MRI sequences, including SPACE will be taken into consideration for the definition of treatment target lesions. Patients for whom the post-operative MRI reveals more than 10 suspect intracranial lesions (all sequences taken into account) will not be included in the trial.

Stereotactic Radiotherapy of the Resection Cavity of Brain Metastases vs. Post-operative Whole-brain Radiotherapy

Evaluation of Stereotactic Radiotherapy of the Resection Cavity After Surgery of Brain Metastases Compared to Post-operative Whole-brain Radiotherapy

Neurologic progression-free survival in follow-up imaging is the primary endpoint of the study. The duration is defined as the time interval between the date start of RT and the date of local and loco-regional progression or death, or the date of leaving the study without local and loco-regional progression (e.g., lost to follow up non-local progression) whatever occurs first. Patients not reported local and loco-regional progressive or dead, or lost to follow-up or non-local progressive will be censored at the date of the last follow-up examination where no signs of local and loco-regional progression were observed.

Time interval (days) between the date of RT begin and the date of death or date of leaving the study e.g., lost to follow up) whatever occurs first. Patients not reported dead or lost to follow-up will be censored at the date of the last follow-up or the time when last seen alive.

lenght of time (days) till local disease progression

lenght of time (days) till loco-regional disease progression

Prof. Dr. Dr. Jürgen Debus

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Small Cell Lung Carcinoma

Lung Neoplasms

Small Cell Lung Cancer

Patient receive stereotactic radiosurgery (SRS), dose prescription according to the size of radiated brain metastases

Patients receive whole brain radiotherapy (WBRT)

For SRS the dose prescription to the PTV will be as follows:

* 20 Gy to the 70%-isodose (lesions \< 2 cm max. diameter)
* 18 Gy to the 70%-isodose (lesions 2 - 3 cm max. diameter)
* 6 x 5 Gy to the conformally surrounding isodose (lesions \> 3 cm max. diameter)

WBRT will be applied in 10 fractions with single doses of 3 Gy to the whole brain.

WBRT

Stefan Rieken, PD.Dr.

Patients suffering from small cell lung cancer (SCLC) are at high risk for developing brain metastases (BM). To prevent a clinical manifestation of preexisting microscopic brain dissemination, prophylactic cranial irradiation (PCI) is offered to both limited and extensive disease patients, if they respond to first line regime, thus being at risk or at chance to develop clinical brain metastases. However, up to 10-15% of patients present with BM at initial diagnosis. If MRI is used as a diagnostic tool for initial staging the number even increases up to 15-20%. Additionally, between 40 - 50% of patients develop BM until time of death and the risk of developing BM further increases with prolonged survival. Treatment options are usually limited to WBRT and palliative chemotherapy but the actual effect of therapeutic WBRT has mainly been studied in small retrospective and nonrandomized studies. WBRT has been established as the treatment standard in patients with cerebral metastases from SCLC, however, it has only modest efficacy. Results might be improved by additional dose escalation. A SRS to cerebral metastases may be indicated in patients with intracranial disease, and the current protocol is aimed at exploring the neurocognition and efficacy of SCLC in patients with brain metastases treated with SRS or WBRT.

The present trial aims to exploratory investigate the treatment response to ´conventional whole brain radiotherapy´ (WBRT) and ´stereotactic radiotherapy´(SRS) in SCLC patients.

Scientific Background: Patients suffering from BM from SCLC have a poor prognosis with a median survival ranging between 2-14 months. Treatment options for BM in SCLC are usually limited to WBRT, steroids or palliative chemotherapy. SCLC patients demonstrate an exception in the treatment of BM, because treatment options for a limited number of BM from other solid tumors commonly include surgery or SRS with or without WBRT. Even though SCLC is a radiosensitive tumor, higher doses are commonly not applied. Locally ablative treatments like SRS or surgery are less frequently used in patients with BM from SCLC as compared to other types of cancer due to the high incidence of brain metastases in SCLC and the increased likelihood of a diffuse failure pattern. It is of general belief that BM from SCLC are rarely solitary and usually occur at multiple sites. The investigators could not confirm these findings from this analysis as they found 1-5 BM in 39 % of their patients. WBRT, with a treatment time of about two weeks, is commonly the technique of choice for SCLC patients with any number of BM. In a recent Japanese trial, prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with early disease (ED) SCLC. PCI is therefore no longer recommended for patients with ED SCLC when patients receive regularly MRI examinations during follow-up.

Though, the initial response to cranial irradiation is good, especially in the synchronous setting, SCLC patients are at high risk of developing intracranial recurrence. In the investigators´ retrospective analysis median Overall survival (OS) after re-WBRT was only 2 months and the median OS after SRS was 6 months. These results are similar as compared to results for re-irradiation after PCI. In a recent analysis the investigators reported a prolonged survival for patients treated with SRS in the recurrent setting after previous PCI with a median survival of 5 months.

Therefore, the number of patients with oligometastatic cerebral disease might rise. Based on recursive partitioning Analysis (RPA) classification, the investigators found a median survival after WBRT of 17 months in RPA class I, 7 months in class II and 3 months in class III (p\<0.0001), which is comparable to previous analyses using graded prognostic assessment (GPA) scoring. This is further of special interest as patients in RPA class I had a comparable or even better outcome than patients with non-cerebral disease treated with PCI. On the other hand, patients with RPA class III should be carefully selected for WBRT and treatment should be weighed against supportive therapy with steroids alone. This implicates that patient selection is mandatory, even in SCLC, and that the general paradigm of WBRT needs to be reevaluated.

Trial Objectives: The purpose of this trial is to explore the neurocognitive response in patients with brain metastases from SCLC treated with WBRT or SRS. The investigators proposed that patients treated with SRS would have inferior neurocognitive function based on the Hopkins Verbal Learning Test-Revised (HVLT-R) compared with patients treated with SRS alone.

Patients Selection: Patients with a diagnosis of brain metastases from SCLC will be evaluated and screened based on the protocol. All patients fulfilling the inclusion and exclusion criteria will be informed about the possibility to participate in the study. Registration for the study must be performed prior to beginning of RT. 56 patients will be enrolled in this exploratory clinical trial.

Trial Design: This pilot trial will be conducted as a single-center prospective, randomized, two-arm Phase II study.

Whole Brain Radiation Therapy Alone vs. Radiosurgery for SCLC Patients With 1-10 Brain Metastases

Whole Brain Radiation Therapy (WBRT) Alone Versus Radiosurgery (SRS) for Patients With 1-10 Brain Metastases From Small Cell Lung Cancer

Drop of at least 5 Points from baseline in HVLT-R test (Hopkins Verbal Learning Test-Revised)

Duration of survival defined as the interval between the date of RT begin and the date of death or date of leaving the study e.g., lost to follow up) whatever occurs first.

Death which directly connects to existing brain metastases

12 month Progression-fee survival referring to local tumour progression

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cyberknife Radiosurgery for Patients With Brain Metastases Diagnosed With Either SPACE or MPRAGE Sequence	NCT03303365	Brain Metastase... Adult Solid Tum...	stereotactic ra...	18 Years -	University Hospital Heidelberg
Stereotactic Radiotherapy of the Resection Cavity of Brain Metastases vs. Post-operative Whole-brain Radiotherapy	NCT03285932	Brain Metastase...	post-operative ... Whole brain rad...	18 Years -	University Hospital Heidelberg
Whole Brain Radiation Therapy Alone vs. Radiosurgery for SCLC Patients With 1-10 Brain Metastases	NCT03297788	SCLC Brain Metastase...	SRS WBRT	18 Years -	University Hospital Heidelberg

Spots Global Cancer Trial Database for wbrt (whole brain radiotherapy)