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.

Heidelberg Ion Therapy Center (HIT): Initial clinical experience in the first 80 patients.

UNLABELLED: The Heidelberg Ion Therapy Center (HIT) started clinical operation in November 2009. In this report we present the first 80 patients treated with proton and carbon ion radiotherapy and describe patient selection, treatment planning and daily treatment for different indications. PATIENTS AND METHODS: Between November 15, 2009 and April 15, 2010, 80 patients were treated at the Heidelberg Ion Therapy Center (HIT) with carbon ion and proton radiotherapy. Main treated indications consisted of skull base chordoma (n = 9) and chondrosarcoma (n = 18), malignant salivary gland tumors (n=29), chordomas of the sacrum (n = 5), low grade glioma (n=3), primary and recurrent malignant astrocytoma and glioblastoma (n=7) and well as osteosarcoma (n = 3). Of these patients, four pediatric patients aged under 18 years were treated. RESULTS: All patients were treated using the intensity-modulated rasterscanning technique. Seventy six patients were treated with carbon ions (95%), and four patients were treated with protons. In all patients x-ray imaging was performed prior to each fraction. Treatment concepts were based on the initial experiences with carbon ion therapy at the Gesellschaft für Schwerionenforschung (GSI) including carbon-only treatments and carbon-boost treatments with photon-IMRT. The average time per fraction in the treatment room per patient was 29 minutes; for irradiation only, the mean time including all patients was 16 minutes. Position verification was performed prior to every treatment fraction with orthogonal x-ray imaging. CONCLUSION: Particle therapy could be included successfully into the clinical routine at the Department of Radiation Oncology in Heidelberg. Numerous clinical trials will subsequently be initiated to precisely define the role of proton and carbon ion radiotherapy in radiation oncology.

Improved target volume definition for fractionated stereotactic radiotherapy in patients with intracranial meningiomas by correlation of CT, MRI, and [68Ga]-DOTATOC-PET.

PURPOSE: To evaluate the influence of 68-Ga-labeled DOTA (0)-D-Phe (1)-Tyr (3)-Octreotide positron emission tomography ([68Ga]-DOTATOC-PET) for target definition for fractionated stereotactic radiotherapy (FSRT) as a complementary modality to computed tomography (CT) and magnetic resonance imaging (MRI). Because meningiomas show a high expression of somatostatin receptor subtype 2, somatostatin analogs such as DOTATOC offer the possibility of receptor-targeted imaging. PATIENTS AND METHODS: Twenty-six patients received stereotactic CT, MRI, and [68Ga]-DOTATOC-PET as part of their treatment planning. Histology was: World Health Organization (WHO) Grade 1 61.5%, WHO Grade 2 7.7%, WHO Grade 3 3.9%, and undetermined 26.9%. Six patients received radiotherapy as primary treatment, 2 after subtotal resection; 17 patients were treated for recurrent disease. Dynamic PET scans were acquired before radiotherapy over 60 min after intravenous injection of 156 +/- 29 MBq [68Ga]-DOTATOC. These PET images were imported in the planning software for FSRT. Planning target volume (PTV)-I outlined on CT and contrast-enhanced MRI was compared with PTV-II outlined on PET. PTV-III was defined with CT, MRI, and PET and was actually used for radiotherapy treatment. RESULTS: PTV-III was smaller than PTV-I in 9 patients, the same size in 7 patients, and larger in 10 patients. Median PTV-I was 49.6 cc, median PTV-III was 57.2 cc. In all patients [68Ga]-DOTATOC-PET delivered additional information concerning tumor extension. PTV-III was significantly modified based on DOTATOC-PET data in 19 patients. In 1 patient no tumor was exactly identified on CT/MRI but was visible on PET. CONCLUSION: These data demonstrate that [68Ga]-DOTATOC-PET improves target definition for FSRT in patients with intracranial meningiomas. Radiation targeting with fused DOTATOC-PET, CT, and MRI resulted in significant alterations in target definition in 73%.

Stereotactic single-dose radiotherapy of stage I non-small-cell lung cancer (NSCLC).

PURPOSE: The treatment of early-stage lung cancers is a primary domain of thoracic surgery, leading to persuasive results. In patients with medical contraindications, radiotherapy is an alternative, although with considerably worse outcome. Radiotherapy is associated with the risk of severe acute side effects and a permanent decrease of lung function. By the introduction of an extracranial stereotactic treatment technique, the amount of normal tissue in the high-dose region can be reduced, allowing the performance of single-dose treatment with high, biologically effective doses. METHODS AND MATERIALS: Between October 1998 and May 2001, 10 patients with histologically confirmed Stage I non-small-cell lung cancer were treated with stereotactic single-dose radiotherapy. A self-developed stereotactic frame was used for patient positioning and navigation. Total doses applied ranged from 19 to 26 Gy. After treatment, regular CT-based follow-up was performed. RESULTS: During a median follow-up period of 14.9 months, the tumors in 8 of 10 patients were locally controlled. The actuarial overall survival was 80% and 64%, respectively, 12 and 24 months after therapy. Actuarial local recurrence-free survival reached 88.9% and 71.1%, respectively. Therapy-related perifocal normal-tissue reaction occurred in 70% of all treated patients, although no major clinical symptoms were seen. In 5 patients, systemic metastases were found during follow-up; 1 patient developed suspect mediastinal lymph nodes. CONCLUSION: Stereotactic single-fraction radiotherapy is a feasible, safe, and effective procedure for the treatment of Stage I non-small-cell lung cancer. It promises high local control with a reduced overall treatment time. However, further investigation in a larger patient collective with extended follow-up is necessary.

Inversely planned intensity modulated radiotherapy of the breast including the internal mammary chain: a plan comparison study.

The aim of this paper is to evaluate the benefit of inversely planned intensity modulated radiotherapy (IMRT) in the adjuvant irradiation of breast cancer when internal mammary lymph nodes are included in the treatment volume. 20 patients treated with 3D-planned conventional radiotherapy (CRT) following breast conserving surgery were included in the study. We chose 10 patients with left-sided and 10 patients with right-sided tumors. All treatment volumes included the internal mammary chain. For plan comparison to the applied CRT plan an inverse IMRT-plan in, step-and-shoot'-technique was calculated. For all patients IMRT resulted in an improved conformity of dose distribution to the target volume compared to CRT (mean COIN95: 0.798 vs. 0.514 with COIN95 = C1 * C2 (C1= fraction of CTV that is covered by > 95% of the prescribed dose and C2 = volume of CTV that is covered by > 95% of the prescribed dose/total volume that is covered by > 95% of the prescribed dose). In all cases with matching adjacent beams, the homogeneity in the target volume was improved. The volume of the ipsilateral lung irradiated with a dose higher than 20 Gy was reduced with IMRT from 24.6% to 13.1% compared to CRT. For left-sided target volume the heart volume with a dose higher than 30 Gy was reduced from 6.2% to 0.2%. The presented plan comparison study for irradiation of the breast and the parasternal lymph nodes showed a substantial improvement of the dose distribution by inversely planned IMRT compared to CRT. This is visible for the target volume, the ipsilateral lung and, in case of left-sided target volume, the heart. Despite an increase in integral dose to the entire normal tissue, the application of IMRT might be clinically advantageous in cases where no satisfying dose distribution can be obtained by CRT.

Intensity-modulated radiotherapy of the female breast.

Current methods for intensity-modulated radiotherapy (IMRT) in breast cancer use forward planning based on equivalent radiological path length to design intensity modulated tangential beams. Compared to conventional tangential techniques, dose reduction of organs at risk is limited using these techniques. We developed a method for intensity modulation of multiple beams for adjuvant radiotherapy of breast cancer by application of a virtual bolus defined on CT for inverse optimization. This method enables multibeam IMRT, which provides improved sparing of lung and heart tissue. In this paper, we present the general aspects of this approach and an evaluation of the optimum beam configuration for IMRT based on inverse treatment planning. We compared this method to conventional techniques. Different clinical examples illustrate the possible indications and feasibility of this new approach. This method is superior to conventional techniques because of the reduction of high-dose area of a substantial cardiac volume in those cases where the parasternal lymph nodes are part of the target volume.

Treatment of pediatric patients and young adults with particle therapy at the Heidelberg Ion Therapy Center (HIT): establishment of workflow and initial clinical data.

BACKGROUND: To report on establishment of workflow and clinical results of particle therapy at the Heidelberg Ion Therapy Center. MATERIALS AND METHODS: We treated 36 pediatric patients (aged 21 or younger) with particle therapy at HIT. Median age was 12 years (range 2-21 years), five patients (14%) were younger than 5 years of age. Indications included pilocytic astrocytoma, parameningeal and orbital rhabdomyosarcoma, skull base and cervical chordoma, osteosarcoma and adenoid-cystic carcinoma (ACC), as well as one patient with an angiofibroma of the nasopharynx. For the treatment of small children, an anesthesia unit at HIT was established in cooperation with the Department of Anesthesiology. RESULTS: Treatment concepts depended on tumor type, staging, age of the patient, as well as availability of specific study protocols. In all patients, particle radiotherapy was well tolerated and no interruptions due to toxicity had to be undertaken. During follow-up, only mild toxicites were observed. Only one patient died of tumor progression: Carbon ion radiotherapy was performed as an individual treatment approach in a child with a skull base recurrence of the previously irradiated rhabdomyosarcoma. Besides this patient, tumor recurrence was observed in two additional patients. CONCLUSION: Clinical protocols have been generated to evaluate the real potential of particle therapy, also with respect to carbon ions in distinct pediatric patient populations. The strong cooperation between the pediatric department and the department of radiation oncology enable an interdisciplinary treatment and stream-lined workflow and acceptance of the treatment for the patients and their parents.

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.

Time- and dose-dependency of radiographic normal tissue changes of the lung after stereotactic radiotherapy.

PURPOSE: Normal tissue changes (NTC) of the normal lung parenchyma are commonly seen after stereotactic single-dose radiotherapy (radiosurgery) of lung tumors. The aim of this study was to investigate the extent and dynamics of NTCs after radiosurgery. METHODS AND MATERIALS: Fifty lung tumors in 49 patients were treated with radiosurgery. Follow-up CTs were anatomically matched to the treatment planning CTs, incorporating the treatment plan and enabling spatial correlation of initial radiation dose distribution and subsequent NTCs of the lung. Lung parenchyma was divided into nine areas of different radiation dose exposures (range, 6-35 Gy). Areas were investigated and compared at different time points according to the development of NTCs. RESULTS: Twenty-six patients developed NTCs during follow-up. The evaluation of the dependency of the extent of NTCs on the amount of radiation dose lead to a linear model for the fixed effects: Fraction of reacting volume =Intercept(T) +0.0208 * Dose ("Dose" should be given in Gy). Dose had a slope of 0.0208 (fraction of normal tissue reaction/Gy) (SE 0.000804, p < 0.0001), implying a significant correlation between dose level and the extent of NTC. CONCLUSION: For radiosurgery of lung tumors, a significant correlation of radiation dose and the extent of NTCs could be demonstrated. Using the introduced formula, a preview on the extent of NTCs to develop in normal lung parenchyma according to the dose level can be performed.

Quantitative assessment of image-guided radiotherapy for paraspinal tumors.

PURPOSE: To evaluate stereotactic positioning uncertainties of patients with paraspinal tumors treated with fractionated intensity-modulated radiotherapy; and to determine whether target-point correction via rigid registration is sufficient for daily patient positioning. PATIENTS AND METHODS: Forty-five patients with tumors at the cervical, thoracic, and lumbar spine received regular control computed-tomography (CT) scans using an in-room CT scanner. All patients were immobilized with the combination of Scotch cast torso and head masks. The positioning was evaluated regarding translational and rotational errors by applying a rigid registration algorithm based on mutual information. The registration box was fitted to the target volume for optimal registration in the high-dose area. To evaluate the suitability of the rigid registration result for correcting the target volume position we subsequently registered three small subsections of the upper, middle, and lower target volume. The resulting residual deviations reflect the extent of the elastic deformations, which cannot be covered by the rigid-body registration procedure. RESULTS: A total of 321 control CT scans were evaluated. The rotational errors were negligible. Translational errors were smallest for cervical tumors (-0.1 +/- 1.1, 0.3 +/- 0.8, and 0.1 +/- 0.9 mm along left-right, anterior-posterior, and superior-inferior axes), followed by thoracic (0.8 +/- 1.1, 0.3 +/- 0.8, and 1.1 +/- 1.3 mm) and lumbar tumors (-0.7 +/- 1.3, 0.0 +/- 0.9, and 0.5 +/- 1.6 mm). The residual deviations of the three subsections were <1 mm. CONCLUSIONS: The applied stereotactic patient setup resulted in small rotational errors. However, considerable translational positioning errors may occur; thus, on the basis of these data daily control CT scans are recommended. Rigid transformation is adequate for correcting the target volume position.

Stereotactic single-dose radiotherapy of lung metastases.

BACKGROUND: Stereotactic treatment approaches lead to a significant reduction of irradiated volumes, which should make pulmonary targets more accessible to radiotherapy. PATIENTS AND METHODS: Between May 1997 and December 2005, 61 patients received stereotactic single-dose dose treatment for 71 pulmonary metastases. Doses to the isocenter ranged from 12 to 30 Gy. Survival and local tumor control rates were evaluated prospectively. RESULTS: After a median follow-up period of 14 months the actuarial overall survival was 78.4%, 65.1%, and 47.8% 12, 24, and 36 months after therapy, respectively. There was a significantly better survival (p = 0.023) for patients not developing further metastases during follow-up. The actuarial local progression-free rate was 88.6%, 73.7%, and 63.1% 12, 24, and 36 months after therapy. Although the majority of patients (70.4%) developed perifocal normal-tissue changes, these were not related to clinically relevant toxicities. CONCLUSION: Stereotactic single-dose radiotherapy is a feasible, safe and effective local treatment option for solitary pulmonary metastases in patients with contraindications to surgery or for palliation of symptomatic pulmonary metastases.

Stereotactic single-dose radiotherapy (radiosurgery) of early stage nonsmall-cell lung cancer (NSCLC).

BACKGROUND: The clinical results after stereotactic single-dose radiotherapy of nonsmall-cell lung cancer (NSCLC) stages I and II were evaluated. METHODS: Forty-two patients with biopsy-proven NSCLC received stereotactic radiotherapy. Patients were treated in a stereotactic body frame and breathing motion was reduced by abdominal compression. The single doses used ranged between 19 and 30 Gy/isocenter. RESULTS: After a median follow-up period of 15 months (range, 1.5-72 months) the actuarial overall survival rates and disease-free survival rates were 74.5%, 65.4%, 37.4%, and 70.2%, 49.1%, 49.1% at 12, 24, and 36 months after therapy, respectively. The actuarial local tumor control rates were 89.5%, 67.9%, and 67.9% at 12, 24, and 36 months after therapy, respectively. A significant difference (P = .032) in local tumor control was found for patients receiving 26-30 Gy (n = 32) compared with doses of less than 26 Gy (n = 10). The effect of the tumor volume on local tumor control was also evaluated. Although the difference was not statistically significant (P = .078), the subgroup of tumors with a tumor volume of less than 12 cm(3) (n = 10) experienced no tumor recurrence. Thirteen (31%) patients developed metastases during follow-up, whereas isolated regional lymph node recurrence was only encountered in 2 patients. No clinically significant treatment-associated side effects were documented. CONCLUSIONS: Stereotactic single-dose radiotherapy is a safe and effective treatment option for patients with early stage NSCLC not suitable for surgery. Especially for small tumor volumes it seems to be equally effective as hypofractionated radiotherapy, while minimizing the overall treatment time.

Achievement of long-term local control in patients with craniopharyngiomas using high precision stereotactic radiotherapy.

BACKGROUND: The long-term outcome in patients with craniopharyngiomas treated with fractionated stereotactic radiotherapy (FSRT) was evaluated. METHODS: A total of 40 patients with craniopharyngiomas were treated between May 1989 and July 2006 with FSRT. Most patients were treated for tumor progression after surgery. A median target dose of 52.2 grays (Gy) (range, 50.4-56 Gy) was applied in a median conventional fractionation of 5 x 1.8 Gy per week. Follow-up examinations included thorough clinical assessment as well as contrast-enhanced magnetic resonance imaging scans. RESULTS: After a median follow-up of 98 months (range, 3-326 months), local control was 100% at both 5 years and 10 years. Overall survival rates at 5 years and 10 years were 97% and 89%, respectively. A complete response was observed in 4 patients and partial responses were noted in 25 patients. Eleven patients presented with stable disease during follow-up. Acute toxicity was mild in all patients. Long-term toxicity included enlargement of cysts requiring drainage 3 months after FSRT. No visual impairment, radionecrosis, or development of secondary malignancies were observed. CONCLUSIONS: The long-term outcome of FSRT for craniopharyngiomas is excellent with regard to local control as well as treatment-related side effects.

Results of three-dimensional stereotactically-guided radiotherapy in recurrent medulloblastoma.

PURPOSE: To evaluate survival rates and side effects after stereotactically-guided radiotherapy (SRT) in patients with recurrent medulloblastoma of the brain. METHODS AND MATERIALS: Between 1992 and 2000, 20 patients with 29 radiological manifestations were treated with fractionated SRT (n = 21) or radiosurgery (n = 8). Median age was 16 years with 6 patients < or = 14 years. All patients had prior cranio-spinal radiotherapy plus boost to the posterior fossa with a total dose of 54 Gy. Time to recurrence was 33 months mean. Eighteen of the 29 lesions were located within the boost volume. Chemotherapy was given according to current international study protocols (HIT) in all patients. Mean total dose for re-irradiation was 24 Gy for fractionated stereotactically-guided radiotherapy, and 15 Gy for radiosurgery. Mean follow-up was 88.5 months. RESULTS: Overall local control was 89.7%. Thirteen recurrences showed partial or complete response in CT/MR-imaging, 13 showed stable disease. Local tumor progression was seen 5 months mean after radiotherapy in three cases. A multifocal intracranial progression was seen in 9 patients, 5 patients developed additional spinal metastases. Thirteen patients died with disseminated cranio-spinal progression, after 72.6 months median. No late toxicity > CTC II(o) especially no brain radionecrosis was seen after radiotherapy. CONCLUSION: SRT is effective and safe in the treatment of recurrent medulloblastoma to improve local control without evident side effects. The main problem remains the control of subclinical cranio-spinal dissemination.