Limb-Salvage Surgery of Soft Tissue Sarcoma with Sciatic Nerve Involvement.

BACKGROUND: The surgical resection of soft tissue sarcomas (STS) with sciatic nerve involvement presents a significant surgical and oncological challenge. Current treatment strategies pursue a multimodal approach with the aim of limb preservation. We aim to evaluate the outcomes of limb-sparing surgery of STS in a patient cohort and to propose a classification for STS with sciatic nerve involvement. METHODS: Patients receiving limb-preserving resections for STS with sciatic nerve involvement between 01/2010 and 01/2017 were included. Clinical and oncological data were prospectively collected in a computerized database and retrospectively analyzed. Sciatic nerve involvement in STS was classified preoperatively as follows: type A for nerve encasement; type B for nerve contact; and type C for no nerve involvement. RESULTS: A total of 364 patients with STS were treated, of which 27 patients had STS with sciatic nerve involvement. Eight patients with type A tumors (29.6%) underwent sciatic nerve resection, and 19 patients with type B tumors (70.4%) received epineural dissections. Disease progression was observed in 8 patients (29.6%) with a local recurrence of 11.1% and distant metastasis in 29.6%. The type of nerve resection significantly influenced leg function but had no impact on disease recurrence or overall survival. CONCLUSION: In a cohort of carefully selected patients with STS and sciatic nerve involvement, the extent of sciatic nerve resection had no significant impact on disease recurrence or survival. Precise classification of neural involvement may therefore be useful in selecting the appropriate degree of nerve resection, without compromising oncological outcome or unnecessarily sacrificing leg function.

High-LET radiotherapy for adenoid cystic carcinoma of the head and neck: 15 years' experience with raster-scanned carbon ion therapy.

PURPOSE: Locoregional control (LC) in malignant salivary gland tumors is dose-dependent, initial results with particle therapy were promising. We report our experience with raster-scanned, intensity-controlled carbon ion therapy (C12) and IMRT in 309 patients with pathologically confirmed adenoid cystic carcinoma (ACC) of the head and neck. PATIENTS AND METHODS: Treatment records of patients treated with C12 between 08/1998 and 05/2013 were evaluated regarding tumor stage, treatment, toxicity (CTCAE v3), LC, progression-free survival (PFS) and overall survival (OS). Response assessment was carried out according to RECIST1.1. RESULTS: Tumor stages were mostly advanced (T4a/b: 60%, macroscopic disease: 71%), most common sites of origin were the paranasal sinus (37%). At a median follow-up at 33.9 months, LC, PFS, and OS at 3 and 5 year estimates are 83.7%/58.5%, 67.8%/56.1%, and 88.9%/74.6%. LC correlates with T-stage but neither nodal stage, age, relapse state, nor margin status. RECIST did not correlate with LC or survival rates. CONCLUSION: IMRT plus C12 boost results in good control and survival rates at moderate toxicity. Margin status did not correlate with LC in T4 tumors, extensive and potentially mutilating surgical procedures may have to be re-evaluated. RECIST assessment did not correlate with either LC or survival rates; potentially more meaningful radiological parameters need to be developed.

Combined intensity-modulated radiotherapy plus raster-scanned carbon ion boost for advanced adenoid cystic carcinoma of the head and neck results in superior locoregional control and overall survival.

BACKGROUND: Local control in patients with adenoid cystic carcinoma (ACC) of the head and neck remains a challenge because of the relative radioresistance of these tumors. This prospective carbon ion pilot project was designed to evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost (C12 therapy). The authors present the first analysis of long-term outcomes of raster-scanned C12 therapy compared with modern photon techniques. METHODS: Patients with inoperable or subtotally resected ACC received C12 therapy within the pilot project. Whenever C12 was not available, patients were offered IMRT or fractionated stereotactic radiotherapy (FSRT). Patients received either C12 therapy at a C12 dose of 3 Gray equivalents (GyE) per fraction up to 18 GyE followed by 54 Gray (Gy) of IMRT or IMRT up to a median total dose of 66 Gy. Toxicity was evaluated according to version 3 of the Common Toxicity Terminology for Adverse Events. Locoregional control (LC), progression-free survival (PFS), and overall survival (OS) were analyzed using the Kaplan-Meier method. RESULTS: Fifty-eight patients received C12 therapy, and 37 received photons (IMRT or FSRT). The median follow-up was 74 months in the C12 group and 63 months in the photon group. Overall, 90% of patients in the C12 group and 94% of those in the photon group had T4 tumors; and the most common disease sites were paranasal sinus, parotid with skull base invasion, and nasopharynx. LC, PFS, and OS at 5 years were significantly higher in the C12 group (59.6%, 48.4%, 76.5%, respectively) compared with the photon group (39.9%, 27%, and 58.7%, respectively). There was no significant difference between patients who had subtotally resected and inoperable ACC. CONCLUSIONS: C12 therapy resulted in superior LC, PFS, and OS without a significant difference between patients with inoperable and partially resected ACC. Extensive and morbid resections in patients with advanced ACC may need to be reconsidered. The most common site of locoregional recurrence remains in field, and further C12 dose escalation should be evaluated.

Clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma: interim analysis.

BACKGROUND: To report an unplanned interim analysis of a prospective, one-armed, single center phase I/II trial (NCT01566123). METHODS: Between 2007 and 2013, 27 patients (pts) with primary/recurrent retroperitoneal sarcomas (size > 5 cm, M0, at least marginally resectable) were enrolled. The protocol attempted neoadjuvant IMRT using an integrated boost with doses of 45-50 Gy to PTV and 50-56 Gy to GTV in 25 fractions, followed by surgery and IOERT (10-12 Gy). Primary endpoint was 5-year-LC, secondary endpoints included PFS, OS, resectability, and acute/late toxicity. The majority of patients showed high grade lesions (FNCLCC G1:18%, G2:52%, G3:30%), predominantly liposarcomas (70%). Median tumor size was 15 cm (6-31). RESULTS: Median follow-up was 33 months (5-75). Neoadjuvant IMRT was performed as planned (median dose 50 Gy, 26-55) in all except 2 pts (93%). Gross total resection was feasible in all except one patient. Final margin status was R0 in 6 (22%) and R1 in 20 pts (74%). Contiguous-organ resection was needed in all grossly resected patients. IOERT was performed in 23 pts (85%) with a median dose of 12 Gy (10-20 Gy).We observed 7 local recurrences, transferring into estimated 3- and 5-year-LC rates of 72%. Two were located outside the EBRT area and two were observed after more than 5 years. Locally recurrent situation had a significantly negative impact on local control. Distant failure was found in 8 pts, resulting in 3- and 5-year-DC rates of 63%. Patients with leiomyosarcoma had a significantly increased risk of distant failure. Estimated 3- and 5-year-rates were 40% for PFS and 74% for OS. Severe acute toxicity (grade 3) was present in 4 pts (15%). Severe postoperative complications were found in 9 pts (33%), of whom 2 finally died after multiple re-interventions. Severe late toxicity (grade 3) was scored in 6% of surviving patients after 1 year and none after 2 years. CONCLUSION: Combination of neoadjuvant IMRT, surgery and IOERT is feasible with acceptable toxicity and yields good results in terms of LC and OS in patients with high-risk retroperitoneal sarcomas. Long term follow-up seems mandatory given the observation of late recurrences. Accrual of patients will be continued with extended follow-up. TRIAL REGISTRATION: NCT01566123.

A clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma.

BACKGROUND: Local control rates in patients with retroperitoneal soft tissue sarcoma (RSTS) remain disappointing even after gross total resection, mainly because wide margins are not achievable in the majority of patients. In contrast to extremity sarcoma, postoperative radiation therapy (RT) has shown limited efficacy due to its limitations in achievable dose and coverage. Although Intraoperative Radiation Therapy (IORT) has been introduced in some centers to overcome the dose limitations and resulted in increased outcome, local failure rates are still high even if considerable treatment related toxicity is accepted. As postoperative administration of RT has some general disadvantages, neoadjuvant approaches could offer benefits in terms of dose escalation, target coverage and reduction of toxicity, especially if highly conformal techniques like intensity-modulated radiation therapy (IMRT) are considered. METHODS/DESIGN: The trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant dose-escalated IMRT (50-56 Gy) followed by surgery and IORT (10-12 Gy) in patients with at least marginally resectable RSTS. The primary objective is the local control rate after five years. Secondary endpoints are progression-free and overall survival, acute and late toxicity, surgical resectability and patterns of failure. The aim of accrual is 37 patients in the per-protocol population. DISCUSSION: The present study evaluates combined neoadjuvant dose-escalated IMRT followed by surgery and IORT concerning its value for improved local control without markedly increased toxicity. TRIAL REGISTRATION: NCT01566123.

Acute toxicity of combined photon IMRT and carbon ion boost for intermediate-risk prostate cancer - acute toxicity of 12C for PC.

BACKGROUND: Carbon ion ((12)C) therapy in the treatment of prostate cancer (PC) might result in an improved outcome as compared to low linear energy transfer irradiation techniques. In this study, we present the first interim report of acute side effects of the first intermediate-risk PC patients treated at the GSI (Gesellschaft für Schwerionenforschung) and the University of Heidelberg in an ongoing clinical phase I/II trial using combined photon intensity modulated radiation therapy (IMRT) and (12)C carbon ion boost. MATERIAL AND METHODS: Fourteen patients (planned accrual: 31 pts) have been treated within this trial so far. IMRT is prescribed to the median PTV at a dose of 30 × 2 Gy; (12)C boost is applied to the prostate (GTV) at a dose of 6 × 3 GyE using raster scan technique. Safety margins added to the clinical target volume were determined individually for each patient based on five independent planning computed tomography (CT)-scans. Acute gastrointestinal (GI) and genitourinary (GU) toxicity was assessed and documented according to the CTCAE Version 3.0. RESULTS: Radiotherapy was very well tolerated without any grade 3 or higher toxicity. Acute anal bleeding grade 2 was observed in 2/14 patients. Rectal tenesmus grade 1 was reported by three other patients. No further GI symptoms have been observed. Most common acute symptoms during radiotherapy were nocturia and dysuria CTC grade 1 and 2 (12/14). There was no severe acute GU toxicity. CONCLUSION: The combination of photon IMRT and carbon ion boost is feasible in patients with intermediate-risk PC. So far, the treatment has been well tolerated. Acute toxicity rates were in good accordance with data reported for high dose IMRT alone.

Improved correlation of the neuropathologic classification according to adapted world health organization classification and outcome after radiotherapy in patients with atypical and anaplastic meningiomas.

PURPOSE: To evaluate the correlation between the 1993 and 2000/2007 World Health Organization (WHO) classification with the outcome in patients with high-grade meningiomas. PATIENTS AND METHODS: Between 1985 and 2004, 73 patients diagnosed with atypical or anaplastic meningiomas were treated with radiotherapy. Sections from the paraffin-embedded tumor material from 66 patients (90%) from 13 different pathology departments were re-evaluated according to the first revised WHO classification from 1993 and the revised classifications from 2000/2007. In 4 cases, the initial diagnosis meningioma was not reproducible (5%). Therefore, 62 patients with meningiomas were analyzed. RESULTS: All 62 tumors were reclassified according to the 1993 and 2000/2007 WHO classification systems. Using the 1993 system, 7 patients were diagnosed with WHO grade I meningioma (11%), 23 with WHO grade II (37%), and 32 with WHO grade III meningioma (52%). After scoring using the 2000/2007 system, we found 17 WHO grade I meningiomas (27%), 32 WHO grade II meningiomas (52%), and 13 WHO grade III meningiomas (21%). According to the 1993 classification, the difference in overall survival was not statistically significant among the histologic subgroups (p=.96). Using the 2000/2007 WHO classifications, the difference in overall survival became significant (p=.02). Of the 62 reclassified patients 29 developed tumor progression (47%). No difference in progression-free survival was observed among the histologic subgroups (p=.44). After grading according to the 2000/2007 WHO classifications, significant differences in progression-free survival were observed among the three histologic groups (p=.005). CONCLUSION: The new 2000/2007 WHO classification for meningiomas showed an improved correlation between the histologic grade and outcome. This classification therefore provides a useful basis to determine the postoperative indication for radiotherapy. According to our results, a comparison of the published data for future treatment decision-making remains difficult when the histologic diagnosis has not been based on the new improved classification system.

Temporal lobe reactions after radiotherapy with carbon ions: incidence and estimation of the relative biological effectiveness by the local effect model.

PURPOSE: To identify predictors for the development of temporal lobe reactions (TLR) after carbon ion radiation therapy (RT) for radiation-resistant tumors in the central nervous system and to evaluate the predictions of the local effect model (LEM) used for calculation of the biologically effective dose. METHODS AND MATERIALS: This retrospective study reports the TLR rates in patients with skull base chordomas and chondrosarcomas irradiated with carbon ions at GSI, Darmstadt, Germany, in the years 2002 and 2003. Calculation of the relative biological effectiveness and dose optimization of treatment plans were performed on the basis of the LEM. Clinical examinations and magnetic resonance imaging (MRI) were performed at 3, 6, and 12 months after RT and annually thereafter. Local contrast medium enhancement in temporal lobes, as detected on MRI, was regarded as radiation-induced TLR. Dose-volume histograms of 118 temporal lobes in 59 patients were analyzed, and 16 therapy-associated and 2 patient-associated factors were statistically evaluated for their predictive value for the occurrence of TLR. RESULTS: Median follow-up was 2.5 years (range, 0.3-6.6 years). Age and maximum dose applied to at least 1 cm(3) of the temporal lobe (D(max,V - 1 cm)3, maximum dose in the remaining temporal lobe volume, excluding the volume 1 cm(3) with the highest dose) were found to be the most important predictors for TLR. Dose response curves of D(max,V - 1 cm)3 were calculated. The biologically equivalent tolerance doses for the 5% and 50% probabilities to develop TLR were 68.8 ± 3.3 Gy equivalents (GyE) and 87.3 ± 2.8 GyE, respectively. CONCLUSIONS: D(max,V - 1 cm)3 is predictive for radiation-induced TLR. The tolerance doses obtained seem to be consistent with published data for highly conformal photon and proton irradiations. We could not detect any clinically relevant deviations between clinical findings and expectations based on predictions of the LEM.

Long term outcome of adolescent and adult patients with pineal parenchymal tumors treated with fractionated radiotherapy between 1982 and 2003--a single institution's experience.

BACKGROUND: To evaluate the effectivity of fractionated radiotherapy in adolescent and adult patients with pineal parenchymal tumors (PPT). METHODS: Between 1982 and 2003, 14 patients with PPTs were treated with fractionated radiotherapy. 4 patients had a pineocytoma (PC), one a PPT with intermediate differentiation (PPTID) and 9 patients a pineoblastoma (PB), 2 of which were recurrences. All patients underwent radiotherapy on the primary tumor site with a median total dose of 54 Gy. In 9 patients with primary PB treatment included whole brain irradiation (3 patients) or irradiation of the craniospinal axis (6 patients) with a median total dose of 35 Gy. RESULTS: Median follow-up was 123 months in the PC patients and 109 months in the patients with primary PB. 7 patients were free from relapse at the end of follow-up. One PC patient died from spinal seeding. Among 5 PB patients treated with radiotherapy without chemotherapy, 3 developed local or spinal tumor recurrence. Both patients treated for PB recurrences died. The patient with PPTID is free of disease 7 years after radiotherapy. CONCLUSION: Local radiotherapy seems to be effective in patients with PC and some PPTIDs. Diagnosis and treatment of patients with more aggressive variants of PPTIDs as well as treatment of PB needs to be further improved, since local and spinal failure even despite craniospinal irradiation (CSI) is common. As PPT are very rare tumors, treatment within multi-institutional trials remains necessary.

Radiotherapy in the treatment of primary osteosarcoma--a single center experience.

PURPOSE: To analyze our experiences concerning radiation treatment in patients with osteosarcoma. MATERIALS AND METHODS: Since 1981, 40 patients with osteosarcoma have undergone radiotherapy in Heidelberg; 3 of them were immediately lost to follow-up. Twenty patients with metastases were treated palliatively and 17 patients were treated with a curative intent. RESULTS: Interestingly, 14 of the 17 patients treated with a curative intent were referred to our clinic during the last 8 years, whereas the number of patients referred for palliation decreased. The mean dose applied for palliation was 47 Gy (range, 26 Gy to > 70 GyE), for cure was 59 Gy (range, 45 Gy to > 70 GyE). Local control until death could be achieved in 15 of the 20 palliatively treated patients, with a mean survival of 7 months after radiation. Five patients experienced local failure with symptom recurrence, and 3 of them had received doses > 60 Gy. At last follow-up, 3 of the 17 curatively treated patients had experienced local recurrence. Median follow-up was 32 months (range, 3-144). Estimated 5-year overall survival and local control rates were 38% and 68%, respectively. Local disease-free survival was shorter in patients treated for recurrent, inoperable or incompletely resected tumors and doses below 60 Gy. CONCLUSIONS: With adequate doses, long-term local control is possible even in inoperable or incompletely resected tumors. Improvements of systemic therapy and modern radiation techniques have begun to bring the possibly curative role of radiation treatment back to the fore. However, in disseminated tumors, even doses beyond 60 Gy do not guarantee local control, suggesting an extremely low radiosensitivity of certain kinds of osteosarcoma.

Non-randomized therapy trial to determine the safety and efficacy of heavy ion radiotherapy in patients with non-resectable osteosarcoma.

BACKGROUND: Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. For effective treatment, local control of the tumor is absolutely critical, because the chances of long term survival are <10% and might effectively approach zero if a complete surgical resection of the tumor is not possible. Up to date there is no curative treatment protocol for patients with non-resectable osteosarcomas, who are excluded from current osteosarcoma trials, e.g. EURAMOS1. Local photon radiotherapy has previously been used in small series and in an uncontrolled, highly individualized fashion, which, however, documented that high dose radiotherapy can, in principle, be used to achieve local control. Generally the radiation dose that is necessary for a curative approach can hardly be achieved with conventional photon radiotherapy in patients with non-resectable tumors that are usually located near radiosensitive critical organs such as the brain, the spine or the pelvis. In these cases particle Radiotherapy (proton therapy (PT)/heavy ion therapy (HIT) may offer a promising new alternative. Moreover, compared with photons, heavy ion beams provide a higher physical selectivity because of their finite depth coverage in tissue. They achieve a higher relative biological effectiveness. Phase I/II dose escalation studies of HIT in adults with non-resectable bone and soft tissue sarcomas have already shown favorable results. METHODS/DESIGN: This is a monocenter, single-arm study for patients > or = 6 years of age with non-resectable osteosarcoma. Desired target dose is 60-66 Cobalt Gray Equivalent (Gy E) with 45 Gy PT (proton therapy) and a carbon ion boost of 15-21 GyE. Weekly fractionation of 5-6 x 3 Gy E is used. PT/HIT will be administered exclusively at the Ion Radiotherapy Center in Heidelberg. Furthermore, FDG-PET imaging characteristics of non-resectable osteosarcoma before and after PT/HIT will be investigated prospectively. Systemic disease before and after PT/HIT is targeted by standard chemotherapy protocols and is not part of this trial. DISCUSSION: The primary objectives of this trial are the determination of feasibility and toxicity of HIT. Secondary objectives are tumor response, disease free survival and overall survival. The aim is to improve outcome for patients with non-resectable osteosarcoma. TRIAL REGISTRATION: Registration number (ClinicalTrials.gov): NCT01005043.

Carbon ion radiation therapy for high-risk meningiomas.

BACKGROUND: We analyzed outcome after a carbon ion boost in combination with precision photon radiation therapy in patients with meningiomas. PATIENTS AND METHODS: Ten patients with meningiomas were treated with carbon ion RT as part of a Phase I/II trial. Carbon ion RT was conducted in conjunction with fractionated stereotactic RT (FSRT) or intensity-modulated RT (IMRT). Eight patients were treated as primary RT, in 2 patients carbon ion RT was performed as re-irradiation. Carbon ion RT was applied with a median dose of 18 GyE, and photon RT was applied with a median dose of 50.4 Gy. Two patients with a history of former irradiation received 18GyE of carbon ion RT and a reduced dose of photon treatment. RESULTS: The median follow-up time was 77 months. Five patients died during follow-up, of which four died of tumor progression. In the group treated in the primary situation, actuarial survival rates after RT were 75% and 63% at 5 and 7 years. After re-irradiation, both patients died at 10 and 67 months, respectively. Actuarial local control rates after primary RT were 86% and 72% at 5 and 7 years. Two patients developed tumor recurrence after re-irradiation, 6 and 67 months after treatment. CONCLUSION: In conclusion, carbon ion radiation shows promising results in patients with atypical or anaplastic meningiomas. Further evaluation in a larger, prospective study in comparison to proton RT or modern photon RT is needed to corroborate these results.

Differences in clinical results after LINAC-based single-dose radiosurgery versus fractionated stereotactic radiotherapy for patients with vestibular schwannomas.

PURPOSE: To evaluate the outcomes of patients with vestibular schwannoma (VS) treated with fractionated stereotactic radiotherapy (FSRT) vs. those treated with stereotactic radiosurgery (SRS). METHODS AND MATERIALS: This study is based on an analysis of 200 patients with 202 VSs treated with FSRT (n = 172) or SRS (n = 30). Patients with tumor progression and/or progression of clinical symptoms were selected for treatment. In 165 out of 202 VSs (82%), RT was performed as the primary treatment for VS, and for 37 VSs (18%), RT was conducted for tumor progression after neurosurgical intervention. For patients receiving FSRT, a median total dose of 57.6 Gy was prescribed, with a median fractionation of 5 x 1.8 Gy per week. For patients who underwent SRS, a median single dose of 13 Gy was prescribed to the 80% isodose. RESULTS: FSRT and SRS were well tolerated. Median follow-up time was 75 months. Local control was not statistically different for both groups. The probability of maintaining the pretreatment hearing level after SRS with doses of < or =13 Gy was comparable to that of FSRT. The radiation dose for the SRS group (< or =13 Gy vs. >13 Gy) significantly influenced hearing preservation rates (p = 0.03). In the group of patients treated with SRS doses of < or =13 Gy, cranial nerve toxicity was comparable to that of the FSRT group. CONCLUSIONS: FSRT and SRS are both safe and effective alternatives for the treatment of VS. Local control rates are comparable in both groups. SRS with doses of < or =13 Gy is a safe alternative to FSRT. While FSRT can be applied safely for the treatment of VSs of all sizes, SRS should be reserved for smaller lesions.

Chromosomal aberrations in peripheral blood lymphocytes of prostate cancer patients treated with IMRT and carbon ions.

BACKGROUND AND PURPOSE: To investigate the cytogenetic damage in blood lymphocytes of patients treated for prostate cancer with different radiation qualities and target volumes. MATERIALS AND METHODS: Twenty patients receiving carbon-ion boost irradiation followed by IMRT or IMRT alone for the treatment of prostate cancer entered the study. Cytogenetic damage induced in peripheral blood lymphocytes of these patients was investigated at different times during the radiotherapy course using Giemsa staining and mFISH. A blood sample from each patient was taken before initiation of radiation therapy and irradiated in vitro to test for individual radiosensitivity. In addition, in vitro dose-effect curves for the induction of chromosomal exchanges by X-rays and carbon ions of different energies were measured. RESULTS: The yield of chromosome aberrations increased during the therapy course, and the frequency was lower in patients irradiated with carbon ions as compared to patients treated with IMRT with similar target volumes. A higher frequency of aberrations was measured by increasing the target volume. In vitro, high-LET carbon ions were more effective than X-rays in inducing aberrations and yielded a higher fraction of complex exchanges. The yield of complex aberrations observed in vivo was very low. CONCLUSION: The investigation showed no higher aberration yield induced by treatment with a carbon-ion boost. In contrast, the reduced integral dose to the normal tissue is reflected in a lower chromosomal aberration yield when a carbon-ion boost is used instead of IMRT alone. No cytogenetic "signature" of exposure to densely ionizing carbon ions could be detected in vivo.

Long-term outcome of postoperative irradiation in patients with newly diagnosed WHO grade III anaplastic gliomas.

PURPOSE: Patients with anaplastic gliomas have a more favorable overall survival than patients with glioblastomas. In most analyses, WHO grade III and 1V tumors are not analyzed separately. The present analysis reports outcome after postoperative radiotherapy in patients with WHO grade III gliomas. PATIENTS AND METHODS: Between January 1988 and January 2007, 127 patients with WHO grade III tumors were treated with radiotherapy; the histological classification was pure astrocytoma in 104 patients, oligoastrocytoma in 12 and pure oligodendroglioma in 11 patients. Median age was 48 years. After the primary diagnosis, a biopsy had been performed in 72 patients; subtotal and total resections were performed in 37 and 18 patients, respectively. In all patients radiotherapy was applied with a median dose of 60 Gy in conventional fractionation. The median follow-up time was 18 months. RESULTS: Median overall survival was 17 months. Overall survival was significantly influenced by the extent of surgery. Median overall survival was 32 months after complete resection, 36 months after subtotal resection, and 12 months after biopsy. Median overall survival was 7 months for patients with anaplastic astrocytomas, 44 months for patients with mixed tumors, and 47 months for those with pure oligodendrogliomas. Age significantly influenced overall survival. Median progression-free survival was 9 months; the extent of neurosurgical resection significantly influenced progression-free survival. CONCLUSION: Patients with WHO grade III anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas show favorable overall survival after postoperative radiotherapy compared with glioblastoma patients and should therefore be analyzed separately. Radiochemotherapy might further improve outcome.

The clinical experience with particle therapy in adults.

Radiation therapy with charged particles, such as protons and heavier ions, provides physical selectivity and therefore allows for favorable dose distributions in comparison with conventional photon radiotherapy. Carbon ions furthermore exhibit biologic advantages related to their high linear energy transfer properties in a number of tumors known to be relatively insensitive to low-linear energy transfer radiation therapy. Over the last 2 decades, major developments in the fields of accelerator technology, diagnostic techniques, and beam delivery methods have been made. These developments formed the basis for the application of particle beams in clinical surroundings. Many clinical centers are already considering the introduction of radiation therapy with charged particles. This article reviews the clinical experience with particle therapy in adults available so far.

Long-term outcome of high-precision radiotherapy in patients with brain stem gliomas: results from a difficult-to-treat patient population using fractionated stereotactic radiotherapy.

INTRODUCTION: To assess long-term outcome in 85 patients with brain stem gliomas treated with fractionated stereotactic radiation therapy (FSRT). PATIENT AND METHODS: Thirty-nine patients were females, and 46 were males. Median age at primary diagnosis was 26 years. Thirty-one patients were younger than 18 years. Histopathological examination confirmed a low-grade glioma in 57 patients. Of the group of high-grade gliomas, six were anaplastic astrocytomas, and two were classified as glioblastoma. Radiation therapy was performed as FSRT. The median target volume was 101 ml. We applied a median dose of 54 Gy in conventional fractionation of 1.8 Gy. In seven of 85 patients (8%) FSRT was performed as re-irradiation. RESULTS: The median follow-up time was 42 months. Median overall survival (OS) was 81 months. OS rates were 77% at 12 months, 70% at 24 months, and 63% at 36 months. Significant impact on OS could be shown for pilocytic histology, age, neurosurgical resection as well as for the presence of cyst on MR-imaging. Median progression-free survival (PFS) after FSRT was 52 months. PFS rates at 12 months were 70%, and 63% and 58% at 24 and 36 months, respectively. Histology, partial neurosurgical resection and the duration of symptoms could be identified as significant prognostic factors. CONCLUSION: Long-term outcome of FSRT in patients with brain stem gliomas is acceptable with low rates of side effects. Significant impact on outcome could be shown for histology, age, extent of neurosurgical resection as well as for cyst formation. No dose-response relationship could be observed.

Radiobiological evaluation and correlation with the local effect model (LEM) of carbon ion radiation therapy and temozolomide in glioblastoma cell lines.

PURPOSE: To investigate the cytotoxic effect of high linear-energy transfer (LET) carbon irradiation on glioblastoma cells lines in combination with temozolomide (TMZ). METHODS AND MATERIALS: The cell lines U87-MG expressing wild-type p53 and LN229 expressing both mutant and wild-type p53 were irradiated with monoenergetic carbon ion beams (LET 172 keV/microm) or an extended Bragg peak (LET 103 keV/microm) after treatment with 10 microM or 20 microM TMZ. Cytotoxicity was measured by a clonogenic survival assay, and cell growth as well as cell cycle progression, were examined. RESULTS: The p53 mutant was more sensitive to X-ray irradiation than the p53 wild type cell line, which was also expressed in a shorter G2 block. High LET carbon ions show an increased biological effectiveness in both cell lines, which is consistent with the predictive calculations by the Local Effect Model (LEM) introduced by Scholz et al. The cell line LN229 was more sensitive to TMZ treatment than the U87MG cell line expressing wild-type p53 only. The combination of TMZ and irradiation showed an additive effect in both cell lines. CONCLUSION: High LET carbon ion irradiation is significantly more effective for glioblastoma cell lines compared to photon irradiation. An additional treatment with TMZ may offer a great chance especially for several tumor types.

Carbon ion radiotherapy for pediatric patients and young adults treated for tumors of the skull base.

BACKGROUND: The current study was conducted to evaluate the outcome of carbon ion radiotherapy (RT) in children and young adults with skull base chordomas and chondrosarcomas. METHODS: Between 1997 and 2007, 394 patients were treated with carbon ion RT at Gesellschaft für Schwerionenforschung in Darmstadt, Germany. Of these patients, 17 patients were aged

Radiochemotherapy with temozolomide as re-irradiation using high precision fractionated stereotactic radiotherapy (FSRT) in patients with recurrent gliomas.

PURPOSE: To evaluate outcome after fractionated stereotactic radiotherapy (FSRT) and concomitant daily temozolomide (TMZ) in patients with recurrent gliomas. MATERIALS AND METHODS: Twenty-five patients with recurrent or progressive gliomas were treated with FSRT in combination with TMZ at the Department of Radiation Oncology, University of Heidelberg. Histologic classification at primary diagnosis included low-grade astrocytoma in 7 patients (28%), grade III gliomas in 10 patients (40%) and glioblastoma in 8 patients (32%). All patients had undergone at least one neurosurgical resection, which was complete in 5 patients (20%), subtotal in 13 patients (52%) and a biopsy only in 7 patients (28%). Nineteen patients (76%) had undergone neurosurgical resection for tumor recurrence. All patients had received radiation therapy with a median dose of 60 Gy. The median time interval between primary RT and re-irradiation was 36 months. Using FSRT, we applied a median total dose of 36 Gy in a median fractionation of 5 x 2 Gy/week. Chemotherapy with TMZ was applied in a median dose of 50 mg/m(2). RESULTS: Median overall survival was 59 months. Median survival from re-irradiation was 8 months. Actuarial survival rates at 6 and 12 months were 81% and 25%. Median PFS was 5 months; actuarial PFS rates at 6 and 12 months were 48% and 16%. Treatment could be completed in all patients as scheduled without interruptions >3 days. No severe treatment-related side effects could be observed. CONCLUSION: Re-irradiation and TMZ is safe and effective in a subgroup of patients with recurrent gliomas. Further evaluation of radiochemotherapy regimens for recurrent or progressive gliomas is warranted.