Spot-scanning-based proton therapy for extracranial chordoma.

PURPOSE: To evaluate effectiveness and safety of spot-scanning-based proton-radiotherapy (PT) for extracranial chordomas (ECC). METHODS AND MATERIAL: Between 1999-2006, 40 patients with chordoma of C-, T-, and L-spine and sacrum were treated at Paul Scherrer Institute (PSI) with PT using spot-scanning. Median patient age was 58 years (range, 10-81 years); 63% were male, and 36% were female. Nineteen patients (47%) had gross residual disease (mean 69 cc; range, 13-495 cc) before PT, and 21 patients (53%) had undergone prior titanium-based surgical stabilization (SS) and reconstruction of the axial skeleton. Proton doses were expressed as Gy(RBE). A conversion factor of 1.1 was used to account for higher relative biological effectiveness (RBE) of protons compared with photons. Mean total dose was 72.5 Gy(RBE) [range, 59.4-75.2 Gy(RBE)] delivered at 1.8-2.0 Gy(RBE) dose per fraction. Median follow-up time was 43 months. RESULTS: In 19 patients without surgical stabilization, actuarial local control (LC) rate at 5 years was 100%. LC for patients with gross residual disease but without surgical stabilization was also 100% at 5 years. In contrast, 12 failures occurred in 21 patients with SS, yielding a significantly decreased 5-year LC rate of 30% (p = 0.0003). For the entire cohort, 5-year LC rates were 62%, disease-free survival rates were 57%, and overall survival rates were 80%. Rates were 100% for patients without SS. No other factor, including dosimetric parameters (V95, V80) were predictive for tumor control on univariate analysis. CONCLUSION: Spot-scanning-based PT at PSI delivered subsequently to function-preserving surgery for tumor debulking, decompression of spinal cord, or biopsy only is safe and highly effective in patients with ECC without major surgical instrumentation even in view of large, unresectable disease.

Effectiveness and safety of spot scanning proton radiation therapy for chordomas and chondrosarcomas of the skull base: first long-term report.

PURPOSE: To evaluate effectiveness and safety of spot-scanning-based proton radiotherapy (PT) in skull-base chordomas and chondrosarcomas. METHODS AND MATERIALS: Between October 1998 and November 2005, 64 patients with skull-base chordomas (n = 42) and chondrosarcomas (n = 22) were treated at Paul Scherrer Institute with PT using spot-scanning technique. Median total dose for chordomas was 73.5 Gy(RBE) and 68.4 Gy(RBE) for chondrosarcomas at 1.8-2.0 Gy(RBE) dose per fraction. Local control (LC), disease specific survival (DSS), and overall survival (OS) rates were calculated. Toxicity was assessed according to CTCAE, v. 3.0. RESULTS: Mean follow-up period was 38 months (range, 14-92 months). Five patients with chordoma and one patient with chondrosarcoma experienced local recurrence. Actuarial 5-year LC rates were 81% for chordomas and 94% for chondrosarcomas. Brainstem compression at the time of PT (p = 0.007) and gross tumor volume >25 mL (p = 0.03) were associated with lower LC rates. Five years rates of DSS and OS were 81% and 62% for chordomas and 100% and 91% for chondrosarcomas, respectively. High-grade late toxicity consisted of one patient with Grade 3 and one patient with Grade 4 unilateral optic neuropathy, and two patients with Grade 3 central nervous system necrosis. No patient experienced brainstem toxicity. Actuarial 5-year freedom from high-grade toxicity was 94%. CONCLUSIONS: Our data indicate safety and efficacy of spot-scanning based PT for skull-base chordomas and chondrosarcomas. With target definition, dose prescription and normal organ tolerance levels similar to passive-scattering based PT series, complication-free, tumor control and survival rates are at present comparable.

Sensitivity of intensity modulated proton therapy plans to changes in patient weight.

PURPOSE: A retrospective study to investigate the sensitivity of intensity modulated proton therapy (IMPT) to changes in body weight occurring during the course of radiotherapy for patients treated in the sacral region. MATERIALS AND METHODS: During therapy, important weight gain and loss were observed for two patients treated to para-spinal tumors, which resulted in both patients being re-scanned and re-planned. Both patients were treated as part of their therapy, with a narrow-angle IMPT (NA-IMPT) plan delivering a 'dose hole' around the cauda equina (CE), which was mainly formed through modulation of Bragg peaks in depth. To investigate the impact of these weight changes on the proton range and delivered dose, the nominal fields were re-calculated on the new CT data sets. Results were analyzed by comparing these new plans with those originally delivered and by calculating changes in range and delivered doses in target volumes and normal tissues. RESULTS: Maximum differences in proton range in the CE region of up to +8 mm and -13 mm, respectively, for the patient who gained weight and for the patient who lost weight, increased the maximum dose to the CE by only 2%. This indicates that both IMPT plans were relatively insensitive to substantial range uncertainties. Even greater differences in range (16 mm) in the planning target volume only slightly affected its dose homogeneity (differences in V(90%) of 6% in the worst case). Nevertheless, some large undesired local dose differences were observed. CONCLUSIONS: We demonstrated, that, at least for the two analyzed cases, NA-IMPT plans are less sensitive to weight variations than one may expect. Still, we would advise to calculate new plans in case of substantial change in weight for patients treated in the sacral region, primarily due to the presence of new hot/cold area.

Postoperative spot-scanning proton radiation therapy for chordoma and chondrosarcoma in children and adolescents: initial experience at paul scherrer institute.

PURPOSE: To evaluate postoperative spot-scanning proton radiation therapy (PT) and intensity-modulated PT (IMPT) for chordoma and chondrosarcoma in pediatric patients. METHODS AND MATERIALS: Between 2000 and 2005, 10 patients (six male patients, four female patients; six chordomas, four chondrosarcomas), aged 10-20 years (median, 16 years), were treated at our institute. Tumor sites were in the brain (one case), skull base (five cases), cervical (three cases), and lumbar spine (one case). Three children had complete resections. In seven children, resection was incomplete, leaving residual tumor behind (range, 2.3-46.3 mL). PT was delivered using spot scanning, with (three patients) or without (seven patients) IMPT. Total dose was 74.0 cobalt Gray equivalents (CGE) for chordoma, and 63.2-68.0 CGE for chondrosarcoma (median, 66.0), depending on histopathological grading and whether the patient had concurrent chemotherapy. RESULTS: Median follow-up time was 36 months (range, 8-77 months). Radiation treatment was well tolerated. All patients remained failure-free at their last follow-up. Late adverse events were reported in three patients and were mild (neurosensory in one patient; alopecia and hypoaccusis in one patient) to moderate (one patient, Grade 2 pituitary insufficiency). CONCLUSIONS: Postoperative spot-scanning PT, delivered in combination with and without IMPT, for chordoma and chondrosarcoma in children and adolescents was tolerated without unacceptable adverse event and initial outcome is perfectly satisfactory in this small cohort. Longer follow-up time and larger cohort are needed to more fully assess tumor control, adverse events, as well as functional and cosmetic outcome.

Spot scanning proton therapy in the curative treatment of adult patients with sarcoma: the Paul Scherrer institute experience.

PURPOSE: To assess the safety and efficacy of spot scanning proton beam therapy (PT) in the curative treatment of soft-tissue sarcoma (STS) in adults patients. PATIENTS AND METHODS: We identified 13 STS patients treated with PT between July 1998 and May 2005 in our institutional database. Tumor histology varied with the most common histologic subtypes including liposarcoma and peripheral nerve sheet tumor. All tumors were located in vicinity of critical structures, such as the spinal cord, optic apparatus, bowel, kidney, or bowel. Of the patients, 6 and 5 patients received PT either as adjuvant therapy for non-R0 resection or for recurrence, respectively. Two patients received radical PT for unresectable disease. The median prescribed dose was 69.4 CGE (CGE = proton Gy x 1.1)-Gy (range, 50.4-76.0) at 1.8 to 2 CGE-Gy (median, 1.9) per fraction. Pre-PT anthracycline-based chemotherapy was delivered to 3 patients only. No patient has been lost to follow-up (median 48.1 months, range, 19.1-100.7 months). RESULTS: Of the 13 patients, all but 2 patients were alive. Local recurrence developed in 3 (23%) patients. The administered dose to these patients was < or =60 Gy-CGE. Distant control was achieved in all but 2 patients (lung metastasis), 1 of whom presented with a concomitant local recurrence. The 4-year local control and metastasis-free survival rates were 74.1% and 84.6%, respectively. Late grade > or =2 toxicity was observed in only 2 patients. CONCLUSIONS: Spot scanning PT is an effective and safe treatment for patient with STS in critical locations. The observed toxicity rate was acceptable.

Extracranial chordoma: Outcome in patients treated with function-preserving surgery followed by spot-scanning proton beam irradiation.

PURPOSE: To evaluate the use of postoperative proton therapy (PT) in extracranial chordoma. PATIENTS AND METHODS: Twenty-six patients were treated. Gross total resection was achieved in 18 patients. Nine patients had cervical, 2 had thoracic, 8 had lumbar, and 7 had sacro-coccygeal chordomas. Thirteen patients had implants. PT was administered after function-preserving surgery, using a gantry and spot scanning, without or with intensity modulation (IMPT; 6 patients), and/or photon-based radiotherapy (RT, 6 patients). Median total dose was 72 cobalt Gray equivalent (CGE; range, 59.4-74.4), with means of 70.5 and 73.2 CGE for patients with and without implants. Median follow-up time was 35 months (range, 13-73 months). Adverse events were scored using the Common Terminology Criteria for Adverse Events grading system (version 3.0). RESULTS: At 3 years, actuarial overall survival (OS) and progression-free survival (PFS) rates were 84% and 77%, respectively. One patient each died of local failure (LF), distant failure (DF), suicide, and secondary tumor. We observed 5 LFs and 3 DFs; 3-year LF-free and DF-free survival rates were 86%. We observed four radiation-induced late adverse events (Grade 2 sensory neuropathy; Grade 3 subcutaneous necrosis, and osteonecrosis; and Grade 5 secondary cancer). In univariate analysis, implants were associated with LF (p = 0.034). Gross residual tumor above 30 mL was negatively associated with OS (p = 0.013) and PFS (p = 0.025). CONCLUSIONS: Postoperative PT for extracranial chordomas delivered with spot scanning offers high local control rates. Toxicity was acceptable. Implants were significantly associated with LF. Residual tumor above 30 mL impacted negatively on OS and PFS.

Spot-scanning proton therapy for malignant soft tissue tumors in childhood: First experiences at the Paul Scherrer Institute.

PURPOSE: Radiotherapy plays a major role in the treatment strategy of childhood sarcomas. Consequences of treatment are likely to affect the survivor's quality of life significantly. We investigated the feasibility of spot-scanning proton therapy (PT) for soft tissue tumors in childhood. METHODS AND MATERIALS: Sixteen children with soft tissue sarcomas were included. Median age at PT was 3.3 years. In 10 children the tumor histology was embryonal rhabdomyosarcoma. All tumors were located in the head or neck, parameningeal, or paraspinal, or pelvic region. In the majority of children, the tumor was initially unresectable (Intergroup Rhabdomyosarcoma Study [IRS] Group III in 75%). In 50% of children the tumors exceeded 5 cm. Fourteen children had chemotherapy before and during PT. Median total dose of radiotherapy was 50 cobalt Gray equivalent (CGE). All 16 children were treated with spot-scanning proton therapy at the Paul Scherrer Institute, and in 3 children the PT was intensity-modulated (IMPT). RESULTS: After median follow-up of 1.5 years, local control was achieved in 12 children. Four children failed locally, 1 at the border of the radiation field and 3 within the field. All 4 children died of tumor recurrence. All 4 showed unfavorable characteristic either of site or histopathology of the tumor. Acute toxicity was low, with Grade 3 or 4 side effects according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria occurring in the bone marrow only. CONCLUSIONS: Proton therapy was feasible and well tolerated. Early local control rates are comparable to those being achieved after conventional radiotherapy. For investigations on late effect, longer follow-up is needed.

Outcome and prognostic factors in cerebellar glioblastoma multiforme in adults: a retrospective study from the Rare Cancer Network.

PURPOSE: The aim of this study was to assess the outcome in patients with cerebellar glioblastoma (GBM) treated in 15 institutions of the Rare Cancer Network. METHODS AND MATERIALS: Data from a series of 45 adult patients with cerebellar GBM were collected in a retrospective multicenter study. Median age was 50.3 years. Brainstem invasion was observed in 9 (20%) patients. Radiotherapy (RT) was administered to 36 patients (with concomitant chemotherapy, 7 patients). Adjuvant chemotherapy after RT was administered in 8 patients. Median RT dose was 59.4 Gy. Median follow-up was 7.2 months (range, 3.4-39.0). RESULTS: The 1-year and 2-year actuarial overall survival rate was 37.8% and 14.7%, respectively, and was significantly influenced by salvage treatment (p = 0.048), tumor volume (p = 0.044), extent of neurosurgical resection (p = 0.019), brainstem invasion (p = 0.0013), additional treatment after surgery (p < 0.001), and completion of the initial treatment (p < 0.001) on univariate analysis. All patients experienced local progression: 8 and 22 had progression with and without a distant failure, respectively. The 1- and 2-year actuarial progression free survival was 25% and 10.7%, respectively, and was significantly influenced by brainstem invasion (p = 0.002), additional treatment after surgery (p = 0.0016), and completion of the initial treatment (p < 0.001). On multivariate analysis, survival was negatively influenced by the extent of surgery (p = 0.03) and brainstem invasion (p = 0.02). CONCLUSIONS: In this multicenter retrospective study, the observed pattern of failure was local in all cases, but approximately 1 patient of 4 presented with an extracerebellar component. Brainstem invasion was observed in a substantial number of patients and was an adverse prognostic factor.

Gefitinib accumulation in glioblastoma tissue.

Therapeutic agents for brain tumors confront multiple physical and metabolic hurdles. These include the blood brain barrier (BBB), vascular and interstitial barriers, clearing by MDR1 and other ABC transporter proteins, and drug catabolism. Here, we report an accumulation of gefitinib in glioblastoma (GBM) tissue to over a dozen times plasma levels, and propose that some mechanisms converge to achieve such accumulation: (1) small molecular size of gefitinib facilitates access by diffusion; (2) its high water solubility enables thermodynamic retention inside malignant cells; and (3) low CYP3A4 activity in GBM tissue, the main enzyme for gefitinib catabolism, prevents metabolic elimination. Our data confirm the capacity of gefitinib to accumulate in solid human tumors in vivo.

Avoiding glucocorticoid administration in a neurooncological case.

Restricting glucocorticoid (GC) use in the treatment of patients with a solid tumor may help improving outcome. Here, we report administration of celecoxib rather than dexamethasone to prevent brain edema in a patient with a cerebellar glioblastoma multiforme WHO grade IV (GBM) upon the patient's request, as well as determining cerebrospinal fluid (CSF) and serum concentrations. CSF concentration (0.04 microM) was 54 times below serum concentration (2.18 microM), or 2500 times below levels inhibiting GBM cells in vitro (100 microM), revealing a blood CSF barrier for celecoxib. The patient did not require dexamethasone for the entire treatment. GC administration hence was avoided successfully in this case. The role of COX-2 inhibitors in treatment of GBM is detailed, leading to the conclusion of a pressing need for a clinical evaluation of non-steroidal COX-2 inhibitors with the ability to penetrate into brain tumors.

Results of spot-scanning proton radiation therapy for chordoma and chondrosarcoma of the skull base: the Paul Scherrer Institut experience.

PURPOSE: To assess the clinical results of spot scanning proton beam radiation therapy (PT) in the treatment of skull base chordomas and low-grade chondrosarcomas (CS). METHODS AND MATERIALS: Between October 1998 and October 2003, 29 patients (median age, 39 years) with chordomas (n = 18) and CS (n = 11) were treated at the Paul Scherrer Institut (PSI) with protons using the main 510-MeV cyclotron. Tumor conformal application of proton beams was realized by spot scanning technology. The median chordoma and CS dose was 74 and 68 cobalt Gy equivalent, respectively (cobalt Gy equivalent = proton Gy x 1.1). Median gross tumor volumes (GTV) were 16.4 mL (range, 1.8-48.1 mL) and 15.2 mL (range, 2.3-57.3 mL) for chordoma and CS, respectively. Late toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v3.0) grading system. The median follow-up time was 29 months (range, 6-68 months). RESULTS: Actuarial 3-year local control rates were 87.5% and 100% for chordoma and CS, respectively. We observed one surgical pathway and one marginal failure in patients with chordomas. No regional failure or distant metastasis was observed. At 3 years, actuarial PFS and OS for the entire cohort was 90% and 93.8%, respectively. Actuarial 3-year complication-free survival was 82.2%. Radiation-induced pituitary dysfunction was observed in 4 (14%) patients (CTCAE Grade 2). No patient presented with post-PT brainstem or optic pathways necrosis or dysfunction. In univariate analysis, age < or =40 years at the time of PT affected favorably on PFS (p = 0.09). CONCLUSION: Spot-scanning PT offers high tumor control rates of skull base chordoma and CS. These results compare favorably to other combined proton-photon or carbon ion irradiation series. Observed toxicity was acceptable. Younger age (< or =40 years) was a favorable prognostic factor of PFS. These preliminary results are encouraging but should be confirmed during a longer follow-up.

Donut-shaped high-dose configuration for proton beam radiation therapy.

BACKGROUND: The authors report on the conception and first clinical application of a donut-shaped high-dose configuration for proton therapy (PT). This approach allows one to intensify target volume dose coverage for targets encompassing a critical, dose-limiting structure--like here, the cauda equina--, whilst delivering minimal dose to other healthy structures surrounding the target, thereby reducing the integral dose. METHODS AND RESULTS: Intensity-modulated PT methods (IMPT) for spot scanning were applied to create and deliver a donut-shaped high-dose configuration with protons, allowing treating > 75% of the target with at least 95% of the prescribed dose of 72.8 CGE, whilst restricting dose to the cauda equina to 60-65 CGE. Integral dose was lower by a factor of 3.3 as compared to intensity-modulated radiotherapy with photons (IMXT). CONCLUSION: IMPT and spot scanning technology allow a potentially clinically useful approach which is also applicable to spare other critical structures passing through a target volume, including spinal cord, optic nerves, chiasm, brain stem, or urethra.

Hydrodynamic consequences of glycolysis: thermodynamic basis and clinical relevance.

Since Warburg's original description of aerobic and anaerobic glycolysis in 1924, the biochemical and molecular bases of glucose metabolism in cells have been characterized. However, its thermodynamic implications have found little attention. Van't Hoff's law of thermodynamics was applied here to describe how glucose metabolism affects intracellular osmotic pressure, hence revealing how glucose metabolism provides cells with osmotic energy as well as chemical energy. Ensuing osmosis-driven movement of free water across membranes affects cell volume and shape, hydration of intracellular components, and interactions of cells with their environment. Comparative analysis of extant data revealed strong evidence for clinically relevant glycolysis-driven effects under hypoxic conditions known to occur in cancer, vascular disease as well as intensive care, including critical and preventable ones affecting treatment effectiveness and thus, clinical outcome. These findings provide the first evidence confirming the existence of glycolysis-driven hydrodynamic effects and suggest that high levels of aerobic and anaerobic glycolysis provide a common biophysical basis in seemingly unrelated medical conditions.

Spot-scanning proton radiation therapy for recurrent, residual or untreated intracranial meningiomas.

BACKGROUND AND PURPOSE: To assess the safety and efficacy of spot scanning proton beam radiation therapy (PRT) in the treatment of intracranial meningiomas. PATIENTS AND METHODS: Sixteen patients with intracranial meningioma (histopathologically proven in 13/16 cases) were treated with PRT between July 1997 and July 2002. Eight patients had skull base lesions. Thirteen patients received PRT after surgery either as adjuvant therapy for incomplete resection (eight patients) or for recurrence (five patients). Three patients received radical PRT after presumptive diagnosis based on imaging. The median prescribed dose was 56 CGE (range, 52.2-64, CGE=proton Gy X 1.1) at 1.8-2.0 CGE (median, 2.0) per fraction. Gross tumor volume and planning target volume ranged from 0.8 to 87.6 cc (median, 17.5) and 4.6-208.1 cc (median 107.7), respectively. Late ophthalmologic and non-ophthalmologic toxicity was assessed using the Subjective, Objective, Management and Analytic scale (SOMA) of the Late Effects of Normal Tissue scoring system and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v3.0) grading system, respectively. The median follow-up time was 34.1 months (range, 6.5-67.8). RESULTS: Cumulative 3-year local control, progression-free survival and overall survival were 91.7, 91.7 and 92.7%, respectively. No patient died from recurrent meningioma. One patient progressed locally after PRT. Radiographic follow-up (median, 34 months) revealed an objective response in three patients and stable disease in 12 patients. Cumulative 3-year toxicity free survival was 76.2%. One patient presented with radiation induced optic neuropathy (SOMA Grade 3) and retinopathy (SOMA Grade 2) 8.8 and 30.4 months after treatment, respectively. These patients with ophthalmologic toxicity received doses higher than those allowed for the optic/ocular structures. Another patient developed a symptomatic brain necrosis (CTCAE Grade 4) 7.2 months after treatment. No radiation-induced hypothalamic/pituitary dysfunction was observed. CONCLUSIONS: Spot-scanning PRT is an effective treatment for patient with untreated, recurrent or incompletely resected intracranial meningiomas. It offers highly conformal irradiation for complex-shaped intracranial meningiomas, while delivering minimal non-target dose. Observed ophthalmologic toxicity is dose-related.

Interference of glucocorticoids with apoptosis signaling and host-tumor interactions.

The cure of cancer is compromised by a variety of factors and mechanisms, which include tissue origin of the malignant cells, tumor load and hypoxia, impediment of drug access, and cellular resistance to treatment. Treatment resistance may be intrinsic, acquired, or induced, and it may occur to either radiation or a single drug alone, or simultaneously to multiple agents. Although the problem of corticosteroid-induced and hence, iatrogenic resistance to the treatment of cancer has continuously gained some interest over the past several years, no measures have been taken yet to diligently examine this problem in the clinical situation. In this review, we address several additional mechanisms through which glucocorticoids may influence the result of cytotoxic therapy of cancer, like: inducible interference of with apoptosis signaling; interference with immune response against malignant cells; issues relating to their impact on glucose metabolism in cancer patients.