Long-term results of a prospective multicenter phase II study to preserve the larynx function using concomitant boost radiochemotherapy with Carboplatin.

PURPOSE: This prospective phase II study was undertaken to assess the feasibility of a larynx preservation protocol with simultaneous radiochemotherapy. PATIENTS AND METHODS: Between 3/1998 and 10/2000, 42 patients with moderately advanced cancer of the larynx (n=25) and hypopharynx (n=17) eligible for total laryngectomy (LE) were treated in a prospective larynx preservation study. The study protocol scheduled 66Gy in 5 weeks using a concomitant boost technique and 70mg/m(2) Carboplatin on days 1-5 in weeks 1 and 5. RESULTS: The median follow-up time of the censored study patients was 41 months (9-95 months). The 5-year overall survival was 0.66 (95% CI 0.48-0.84), the 5-year laryngectomy-free survival 0.60 (95% CI 0.42-0.78), and the laryngeal preservation rate at 5 years 0.67 (95% CI 0.49-0.85). Cox multivariate regression analysis showed the total tumor volume to be the only statistically significant factor on locoregional failure-free survival. Six of 23 tumor-free long-term survivors received a tracheotomy because of late laryngeal toxicity associated with dysphagia 30-79 months after radiochemotherapy. CONCLUSIONS: Due to the late laryngeal toxicity observed the value of this regimen for larynx preservation is limited.

Temozolomide combined with irradiation as postoperative treatment of primary glioblastoma multiforme. Phase I/II study.

BACKGROUND AND PURPOSE: The role of radiochemotherapy in the treatment of primary glioblastoma multiforme is still discussed controversially. To evaluate the feasibility and toxicity of irradiation and concomitant administration of 50 mg/m(2) temozolomide in patients with primary malignant glioma, this phase I/II study was conducted. PATIENTS AND METHODS: 53 Patients with histologically confirmed WHO grade IV malignant glioma were enrolled into the study. All patients were treated with radiation therapy up to a total dose of 60 Gy using conventional fractionation of 5 x 2.0 Gy/week. Temozolomide was administered orally each therapy day at a dose of 50 mg/m(2). RESULTS: Prior to radiochemotherapy, complete resection (n = 14), subtotal resection (n = 22) or a biopsy (n = 17) of the tumor was performed. The median time interval between surgery and radiochemotherapy was 21 days. Treatment-related toxicity was very mild. Acute toxicity > grade 2 was observed in one patient who developed grade 4 hemotoxicity. Minor side effects of chemotherapy included nausea and vomiting. No severe late effects were observed. Median progression-free and overall survival were 8 and 19 months, respectively. The overall survival rate was 72% at 1 and 26% at 2 years. Age and extent of surgery significantly influenced survival. CONCLUSION: The combination of temozolomide plus radiation therapy is feasible and safe in terms of toxicity. Overall survival times were relatively long compared to survival times reported for radiotherapy alone. The application of 50 mg/m(2) of temozolomide can be performed throughout the whole time course without interruption due to side effects and might largely contribute to the prolonged overall survival. Further evaluation is warranted as to which dose of temozolomide is optimal with regard to tumor response and toxicity.

External beam radiotherapy in the treatment of male breast carcinoma: patterns of failure in a single institute experience.

AIMS AND BACKGROUND: We analyzed our own results in the treatment of male breast cancer patients with respect to local control, overall survival and possible prognostic factors for local and distant control. METHODS: Thirty-one patients with 32 carcinomas of the male breast were treated with radiotherapy. Twenty-five patients received radiotherapy to the chest wall including or not regional lymphatics after initial mastectomy (n = 23) or after surgery for local recurrence (n = 2). Median total dose was 60 Gy to the chest wall and 46 Gy to regional lymphatics. Seven patients with metastatic disease were referred for palliative radiotherapy. RESULTS: Overall survival after postoperative radiotherapy was 40% after a median follow-up of 4.3 years. Actuarial 3-, 5- and 10-year survival was 82.6%, 56.5% and 43.5%, respectively. Five-year progression-free survival was 62.5%. Survival was significantly affected by the presence of lymph node metastases (P <0.001). Local recurrence was seen in one patient after 29 months. CONCLUSIONS: Postoperative radiotherapy is important in the management of male breast cancer to improve local control and progression-free survival, resulting in one local failure in our analysis. The presence of lymph node metastases significantly impairs survival.

Fractionated stereotactic radiotherapy in patients with benign or atypical intracranial meningioma: long-term experience and prognostic factors.

PURPOSE: To analyze our long-term experience and prognostic factors after fractionated stereotactic radiotherapy (FSRT) in patients with benign or atypical intracranial meningioma. METHODS AND MATERIALS: Between January 1985 and December 2001, 317 patients with a median age of 55.7 years were treated with FSRT for intracranial meningioma. The tumor distribution was World Health Organization (WHO) Grade 1 in 48.3%, WHO Grade 2 in 8.2%, and unknown in 43.5%. Of the 317 patients, 97 underwent RT as their primary treatment, 79 underwent postoperative RT (subtotal resection in 38 and biopsy only in 41), and 141 were treated for recurrent disease. The median target volume was 33.6 cm(3) (range, 1.0-412.6 cm(3)). The median total dose was 57.6 Gy at 1.8 Gy/fraction five times weekly. RESULTS: The median follow-up was 5.7 years (range, 1.2-14.3 years). The overall local tumor control rate was 93.1% (295 of 317). Of the 317 patients, 72 had a partial response on CT/MRI and 223 (70.4%) remained stable. At a median of 4.5 years after FSRT, 22 patients (6.9%) had local tumor progression on MRI. Local tumor failure was significantly greater in patients with WHO Grade 2 meningioma (p <0.002) than in patients with WHO Grade 1 or unknown histologic features. Patients treated for recurrent meningioma showed a trend toward decreased progression-free survival compared with patients treated with primary therapy, after biopsy, or after subtotal resection (p <0.06). Patients with a tumor volume >60 cm(3) had a recurrence rate of 15.5% vs. 4.3% for those with a tumor volume of < or =60 cm(3) (p <0.001). In 42.9% of the patients, preexisting neurologic deficits improved. Worsening of preexisting neurologic symptoms occurred in 8.2%. Eight patients developed new clinical symptoms, such as reduced vision, trigeminal neuralgia, and intermittent tinnitus located at the side of the irradiated meningioma after FSRT. CONCLUSION: These data have demonstrated that FSRT is an effective and safe treatment modality for local control of meningioma with a low risk of significant late toxicity. We identified the tumor volume, indication for FSRT, and histologic features of the meningioma as statistically significant prognostic factors.

Stereotactic conformal radiotherapy in patients with growth hormone-secreting pituitary adenoma.

PURPOSE: To evaluate the reduction of hormonal overproduction and side effects as well as survival rates after fractionated stereotactic conformal radiotherapy (FSRT) and radiosurgery in patients with growth hormone (GH)-secreting pituitary adenoma. METHODS AND MATERIALS: Between January 1989 and May 2001, 25 consecutive patients were treated with FSRT (n = 20) or radiosurgery (n = 5) for GH-secreting pituitary adenoma. Nine patients were treated for recurrent disease after primary surgery. One patient had primary radiotherapy because of inoperability, and 15 patients received radiotherapy after subtotal resection due to increased GH level. Median total dose was 52.2 Gy for FSRT and 15 Gy for radiosurgery. RESULTS: Radiologic local tumor control was 100% after a median follow-up of 59.8 months (range, 20.3-168.2 months). Seventeen patients had stable disease on CT/MRI, and eight showed a reduction of tumor volume on MRI scans. Endocrinologic control was 92% (23 of 25 patients). Two patients had an endocrinologic recurrence 21 and 54 months after FSRT. A normalization of preexisting acromegalic symptoms was seen in 1 patient, 4.5 years after FSRT. GH level normalized in 21 of 25 patients after 26 months median. Five of these patients underwent concurrent Octreotid therapy because of increased insulin-like growth factor I levels. Improvement of visual acuity was seen in 1 patient. New onset of clinically evident hypopituitarism as an adverse reaction of stereotactic radiotherapy was only infrequently observed in this series. CONCLUSION: Stereotactic conformal radiotherapy is effective and safe in the treatment of GH-secreting pituitary adenoma to reduce hormonal overproduction and to improve local control. It is an alternative option to surgery especially for patients at high risk of surgical complications due to comorbidity.

External beam radiotherapy fails to prevent restenosis after iliac or femoropopliteal percutaneous transluminal angioplasty: results of a prospective randomized double-blind study.

PURPOSE: Early restenosis is one of the major complications after successful percutaneous transluminal angioplasty (PTA), in main, as well as peripheral, arteries. The effectiveness of hypofractionated external beam radiotherapy (EBRT) as a prophylaxis for restenosis was examined in a prospective, randomized, double-blind, clinical trial. METHODS AND MATERIALS: Forty-eight patients underwent sham RT and 47 were treated with daily RT in 3-Gy fractions, to a total dose of 21 Gy. The follow-up lasted for 12 months, and the examinations included pressure measurements and calculations of the ankle-brachial index or duplex sonography ("peak velocity ratio"). If restenosis was suspected, additional angiography was performed. RESULTS: No statistically significant difference was found between the treatment groups: sham RT 16 failures (33.3%) and EBRT group 21 failures (45.7%; p = 0.292). EBRT also showed no substantial effects on subgroups classified by the specific length of the lesion or in diabetic patients. CONCLUSION: External beam radiotherapy does not prevent restenosis. A reduction in the failure rate >8% using fractionated EBRT with doses aimed at keloid prevention can be ruled out with a probability of 97.5%. Endovascular brachytherapy remains the preferred therapeutic method for achieving restenosis prophylaxis through RT.

Prognostic factors for brain metastases after whole brain radiotherapy. Data from a single institution.

PURPOSE: Prognostic factors for overall survival of patients treated for brain metastases with whole brain radiotherapy (WBRT) at a single institution were retrospectively evaluated, and the validity of the RTOG recursive partitioning analysis (RPA) for prognostic classes was assessed. PATIENTS AND METHODS: The data of all patients (n = 268) with brain metastases from solid tumors homogeneously treated between 01/1997 and 09/1999 at the University of Heidelberg, Germany, with WBRT without surgery or radiosurgery were reviewed. 13 different patient- and therapy-related variables were evaluated for prognosis. Second, a grouping of the study cohort was performed according to the RTOG RPA prognostic classes. RESULTS: Median survival of the whole population after the start of WBRT was 3.8 months. The 1-year survival rate was 19%. Multivariate analysis revealed that only the Karnofsky performance status, control of the primary and no extracranial disease were independent prognostic factors for overall survival. These are also the main determinants of the RTOG RPA classes. Applying the RTOG RPA classes to the authors' data set revealed three subgroups with significantly different prognosis. CONCLUSION: Based on this analysis, prognostic factors for survival after WBRT in patients with brain metastases could be identified. A total of 19% (n = 44/232) survived > or = 1 year, whereas overall survival was poor. The potential value of the RPA classes in estimating the patient's prognosis could be confirmed.

Fractionated stereotactic conformal radiotherapy in the management of large chemodectomas of the skull base.

PURPOSE: To evaluate the role of fractionated stereotactic conformal radiotherapy (FSRT) as a noninvasive method in the management of large chemodectomas of the skull base. METHODS AND MATERIALS: Twenty-two patients with chemodectomas of the skull base were treated with FSRT at our institution. Ten patients received primary RT, and 12 patients were treated for recurrent or progressive disease after primary surgery (8 patients) or embolization (4 patients). The median total dose was 57.6 Gy, with a median of 1.8 Gy/fraction. The median target volume was 71.8 cm3 (range, 10.5-212.2 cm3). The most common symptoms at the initial diagnosis were pulsatile tinnitus (16 patients), hearing loss (14 patients), and balance disturbance (14 patients). Twelve patients had additional cranial nerve deficits. RESULTS: The median follow-up was 5.7 years (range, 19-177 months). The actuarial overall survival rate was 89.5% at 5 and 10 years. The actuarial local control rate was 90.4% at 5 and 10 years. Seven patients (32%) had a partial response and 13 (59%) had stable disease of the irradiated chemodectoma. Two symptomatic patients developed recurrence after 19 and 32 months. Neurologic dysfunction improved or completely resolved in 59% and stabilized in 32%; 9% of patients experienced impairment of preexisting neurologic dysfunction. No patient developed new neurologic deficits after FSRT. RT was interrupted in 1 patient because of a maxillary bone abscess. In all other patients, no acute or late adverse reactions greater than Common Toxicity Criteria Grade 2 were seen. CONCLUSION: Fractionated stereotactic conformal radiotherapy is an effective and well-tolerated noninvasive treatment for chemodectomas, with excellent tumor control rates and a low risk of morbidity. It is an option for patients at greater risk of microsurgical resection or with residual and recurrent tumors.

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.

Results of carbon ion radiotherapy in 152 patients.

PURPOSE: This study summarizes the experience with raster scanned carbon ion radiation therapy (RT) at the Gesellschaft für Schwerionenforschung (GSI), Darmstadt, Germany since 1997. METHODS AND MATERIALS: Between December 1997 and December 2002, 152 patients were treated at GSI with carbon ion RT. Eighty-seven patients with chordomas and low-grade chondrosarcomas of the skull base received carbon ion RT alone (median dose 60 GyE); 21 patients with unfavorable adenoid cystic carcinomas and 17 patients with spinal (n = 9) and sacrococcygeal (n = 8) chordomas and chondrosarcomas were treated with combined photon and carbon ion RT. Twelve patients received reirradiation with carbon ions with or without photon RT for recurrent tumors. Furthermore, 15 patients with skull base tumors other than chordoma and low-grade chondrosarcoma were treated with carbon ions. RESULTS: Actuarial 3-year local control was 81% for chordomas, 100% for chondrosarcomas, and 62% for adenoid cystic carcinomas. Local control was obtained in 15/17 patients with spinal (8/9) and sacral (7/8) chordomas or chondrosarcomas and in 11/15 patients with skull base tumors other than chordomas and low-grade chondrosarcomas, respectively. Six of 12 patients who received reirradiation are still alive without signs of tumor progression. Common Toxicity Criteria Grade 4 or Grade 5 toxicity was not observed. CONCLUSION: Carbon ion therapy is safe with respect to toxicity and offers high local control rates for skull base tumors such as chordomas, low-grade chondrosarcomas, and unfavorable adenoid cystic carcinomas.

Evaluation of therapeutic potential of heavy ion therapy for patients with locally advanced prostate cancer.

PURPOSE: To investigate the feasibility of raster scanned heavy charged particle therapy in the treatment of prostate cancer (PCa,) with special regard to the influence of internal organ motion on the dose distribution. METHODS AND MATERIALS: The CT data of 8 patients with PCa who underwent three-dimensional conformal radiotherapy (RT) were chosen. In addition to the routine treatment planning scan, three to five additional positioning control CT scans were performed. The organs at risk and the target volumes were defined on all CT scans. Primary and boost carbon ion plans were calculated to deliver 66 Gy to the clinical target volume/planning target volume, with an additional 10 Gy to the gross tumor volume (GTV). To estimate the influence of internal organ motion on plan quality, the dose was recalculated on the basis of the control CT scans. The comparative analysis was based on the dose-volume histogram-derived physical parameters. RESULTS: The average 90% target coverage was 99.1% for the GTV. The maximal dose to the rectum was 71.8 Gy. The average rectal mean dose was 19 Gy. The volume of the rectum receiving 70 and 68 Gy was 0.1 and 0.3 cm3. The average difference in the 90% coverage for the GTV on control CT cubes was 3.6%. The maximal rectal dose increased to 76.2 Gy. The deviation in the mean rectal dose was <1 Gy on average. The rectal volume receiving 70 and 68 Gy increased to 2.5 and 3.3 cm3. CONCLUSION: The investigation demonstrated the feasibility of raster scanned carbon ions for PCa RT. Excellent coverage of the target volume and optimal sparing of the rectum were acquired. The combination of photon intensity-modulated RT and a carbon ion boost to the GTV is the most rational solution for the gain of clinical experience in heavy ion RT for PCa patients.

Evaluation of salivary gland function after treatment of head-and-neck tumors with intensity-modulated radiotherapy by quantitative pertechnetate scintigraphy.

PURPOSE: To evaluate salivary gland function after inversely planned stereotactic intensity-modulated radiotherapy (IMRT) for tumors of the head-and-neck region using quantitative pertechnetate scintigraphy. METHODS AND MATERIALS: Since January 2000, 18 patients undergoing IMRT for cancer of the head and neck underwent pre- and posttherapeutic scintigraphy to examine salivary gland function. The mean dose to the primary planning target volume was 61.5 Gy (range 50.4-73.2), and the median follow-up was 23 months. In all cases, the parotid glands were directly adjacent to the planning target volume. The treatment planning goal was for at least one parotid gland to receive a mean dose of <26 Gy. Two quantitative parameters (change in maximal uptake and change in the relative excretion rate before and after IMRT) characterizing the change in salivary gland function after radiotherapy were determined. These parameters were compared with respect to the dose thresholds of 26 and 30 Gy for the mean dose. In addition, dose-response curves were calculated. RESULTS: Using IMRT, it was possible in 16 patients to reduce the dose for at least one parotid gland to < or =26 Gy. In 7 patients, protection of both parotid glands was possible. No recurrent disease adjacent to the protected parotid glands was observed. Using the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer scoring system, only 3 patients had Grade 2 xerostomia. No greater toxicity was seen for the salivary glands. The change in the relative excretion rate was significantly greater, if the parotid glands received a mean dose of > or =26 Gy or > or =30 Gy. For the change in maximal uptake, a statistically significant difference was seen only for the parotid glands and a dose threshold of 30 Gy. For the end point of a reduction in the parotid excretion rate of >50% and 75%, the dose-response curves yielded a dose at 50% complication probability of 34.8 +/- 3.6 and 40.8 +/- 5.3 Gy, respectively. CONCLUSION: Using IMRT, it is possible to protect the parotid glands and reduce the incidence and severity of xerostomia in patients. Doses <26-30 Gy significantly preserve salivary gland function. The results support the hypothesis that application of IMRT does not lead to increased local failure rates.

Neuropsychological outcome after fractionated stereotactic radiotherapy (FSRT) for base of skull meningiomas: a prospective 1-year follow-up.

PURPOSE: The purpose of this study was to evaluate the cognitive outcome after fractionated stereotactic radiotherapy (FSRT) in patients with base of skull meningiomas. METHODS AND MATERIAL: A total of 40 patients with base of skull meningiomas were neuropsychologically evaluated before, after the first fraction (1.8 Gy), at the end of FSRT (n=37), 6 weeks (n=24), 6 (n=18) and 12 months (n=14) after FSRT. A comprehensive test battery including assessment of general intelligence, attention and memory functions was used. Alternate forms were used and current mood state was controlled. RESULTS: After the first fraction a transient decline in memory function and simultaneous improvements in attention functions were observed. No cognitive deteriorations were seen during further follow-up, but increases in attention and memory functions were observed. Mood state improved after the first fraction, at the end of radiotherapy and 6 weeks after radiotherapy. CONCLUSION: The present data support the conclusion that the probability for the development of permanent cognitive dysfunctions appears to be very low after FSRT. The transient memory impairments on day 1 are interpreted as most likely related to an increase of a preexisting peritumoral edema, whereas the significant acute improvements in attention functions are interpreted as practice effects. An analysis of localization specific effects of radiation failed to show clear hemisphere specific cognitive changes.

[Male gonadal dose in adjuvant 3-d-pelvic irradiation after anterior resection of rectal cancer. Influence to fertility]. / Radiogene Hodenbelastung durch Streustrahlung bei adjuvanter 3-D-Beckenbestrahlung nach anteriorer Resektion beim RektumkarzinomEinfluss auf die Fertilität.

BACKGROUND: Rectal cancer is a common malignant disease and occurs not infrequently in younger men. We verified the dose to the testes from scattered radiation in adjuvant pelvic irradiation following anterior resection of rectal cancer. PATIENTS AND METHOD: We measured the scattered gonadal dose of 18 patients in vivo with thermoluminescence detectors, which were fixed on four defined points on the scrotum during radiation on three consecutive days. All patients were treated three-dimensionally planned using a three-field box lying in prone position in a bellyboard. A total dose of 50.4 Gy was given in 28 fractions of 1.8 Gy. From 45 up to 50.4 Gy the radiation fields were modified to lateral-opposing fields which were shortened from the top to protect the small bowel. RESULTS: The mean gonadal dose per fraction of all patients was 0.057 Gy (median 0.05 Gy) with a range between 0.035 and 0.114 Gy. The standard deviation was 0.02 Gy. The calculated cumulative mean gonadal dose after 28 fractions was 1.60 Gy (0.98-3.19 Gy). CONCLUSIONS: Germinal epithelium is very sensitive to low-dose irradiation, according to a negative fractionation effect. It is known that gonadal total doses of 1 Gy with single doses of 0.03-0.05 Gy can result in a temporary azoospermia with following recovery in most cases. If gonadal total doses exceed 1.5 Gy a substantial increase in irreversible azoospermia must be expected. With respect to the data reported in the literature our measured mean gonadal total dose of 1.60 Gy will lead with high probability to an irreversible infertility. Because of the small number of patients in our study, the data must be interpreted with caution, however, it is very important in patient's informed consent to draw attention to the high risk of infertility. The possibility of sperm cryoconservation should be discussed with the patient.

Carbon ion radiotherapy for chordomas and low-grade chondrosarcomas of the skull base. Results in 67 patients.

PURPOSE: To prospectively evaluate outcome and toxicity after carbon ion radiotherapy (RT) in chordomas and low-grade chondrosarcomas. PATIENTS AND METHODS: Between September 1998 and December 2001, 74 patients were treated for chordomas and chondrosarcomas with carbon ion RT at the "Gesellschaft für Schwerionenforschung" (GSI). Seven patients reirradiated with reduced carbon ion doses after conventional RT were excluded from the analysis, leaving 67 evaluable patients (44 chordomas and 23 chondrosarcomas) who received a full course of carbon ion therapy. Tumor-conform application of carbon ion beams was realized by intensity-controlled raster scanning with active energy variation. Three-dimensional treatment planning included intensity modulation and biological plan optimization. A median dose of 60 GyE was applied to the target volume within 20 consecutive days at a dose of 3.0 GyE per fraction. RESULTS: Median follow-up was 15 months (range 3-46 months). At 3 years, actuarial local control was 100% for chondrosarcomas and 87% for chordomas, respectively. Partial tumor remission was observed in 14/44 (31%) chordoma patients and in 4/23 (17%) chondrosarcoma patients. At 3 years, actuarial overall survival was 100% for chondrosarcomas and 89% for chordomas, respectively. No severe side effects > CTC degrees III have been observed. CONCLUSIONS: These data demonstrate the clinical efficiency and safety of scanning beam delivery of carbon ion beams in patients with skull base chordomas and chondrosarcomas. The observation of tumor regressions at a dose level of 60 GyE may indicate that the biological effectiveness of carbon ions in chordomas and chondrosarcomas is higher than initially estimated.

Radiation tolerance of the rat spinal cord after single and split doses of photons and carbon ions.

The sensitivity of the rat spinal cord to single and split doses of radiation and the resulting relative biological effectiveness (RBE) were determined for carbon-ion irradiations (12C) in the plateau and Bragg-peak regions. The cranial part of the cervical and thoracic spinal cords of 180 rats were irradiated with one or two fractions of 12C ions or photons, respectively. Dose-response curves for the end point symptomatic myelopathy were established, and the resulting values for the ED50 (dose for 50% complication probability) were used to determine the RBEs. A median latency for myelopathy of 167 days (range, 121-288 days) was found. The ED50 values were 17.1 +/- 0.8 Gy, 24.9 +/- 0.7 Gy (one and two fractions, 12C plateau) and 13.9 +/- 0.8, 15.8 +/- 0.7 Gy (one and two fractions, 12C Bragg peak), respectively. For photons we obtained ED50 values of 24.5 +/- 0.8 Gy for single doses and 34.2 +/- 0.7 Gy when two fractions were applied. The corresponding RBEs were 1.43 +/- 0.08, 1.37 +/- 0.12 (one and two fractions, 12C plateau) and 1.76 +/- 0.05, 2.16 +/- 0.11 (one and two fractions, 12C Bragg peak), respectively. Hematoxylin and eosin staining revealed necrosis of the white matter in the spinal cord in all symptomatic animals. In summary, from one- and two-fraction photon, 12C plateau and Bragg-peak irradiation of the rat spinal cord, we have established RBEs as well as the individual ED50's. From the latter there is a clear indication of repair processes for fractionated photons and 12C plateau ions which are significantly reduced by using Bragg-peak ions. Additional studies are being carried with 6 and 18 fractions to further refine and define the RBE and ED50 values and estimate the alpha/beta ratios.

Fractionated stereotactic radiotherapy in low-grade astrocytomas: long-term outcome and prognostic factors.

PURPOSE: To evaluate outcome after fractionated stereotactic radiotherapy (RT) of patients with World Health Organization Grade 2 astrocytoma in terms of progression-free survival, overall survival, toxicity, quality of life, and prognostic factors. METHODS AND MATERIALS: Between 1984 and 2000, 143 patients with histologically proven Grade 2 astrocytoma were treated with fractionated stereotactic RT at our institution. The evaluation of the quality of life and toxicity was based on neurologic examinations and the Karnofsky performance score. Univariate analysis was performed on seven potential prognosticators and multivariate analysis on four prognosticators. RESULTS: The median follow-up was 44 months. The actuarial overall survival and progression-free survival was 58% and 39% at 5 years, respectively. Out-of-field recurrences occurred in 1 patient (1.2%). We did not observe a dose-response relationship. Overall survival and progression-free survival were significantly correlated with the absence of contrast media enhancement before RT (p <0.01). Toxicity was mild and included severe side effects of European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group Grade 3 in only 4 patients (2.8%). The Karnofsky performance score improved in most patients. CONCLUSION: Fractionated stereotactic RT is effective and has low toxicity in the treatment of Grade 2 gliomas. The rate of field border recurrences was not increased compared with after conventional RT. Exceeding the tumor dose did not improve the tumor control rate but did enhance toxicity. Pretherapeutic contrast media enhancement should be interpreted as a sign of higher grade tumor elements.

Number and orientation of beams in inversely planned intensity-modulated radiotherapy of the female breast and the parasternal lymph nodes.

Intensity-modulated radiotherapy (IMRT) provides better sparing of normal tissue. We evaluated the optimum beam configuration for IMRT based on inverse treatment planning in adjuvant radiotherapy for breast cancer in a case of left-sided tumor. In addition to radiotherapy planning with the conventional technique of tangential wedged 6-MV photon beams and an oblique 15-MeV electron beam, we performed inversely planned IMRT with the step-and-shoot-technique. Dose calculation was carried out using the treatment planning system Virtuos with the inverse optimization module KonRad adapted to it. IMRT plans were generated for 2 to 16 beams. The results were compared with conventional techniques. For a maximum treatment time of 20 minutes, it is shown that IMRT with 12 modulated photon beams and 7 intensity steps is best suited for treatment in the presented case. Compared with a conventional technique with photons combined with electrons, dose conformality and homogeneity of the planning target volume was increased. The mean heart dose was reduced from 9.1 Gy to 6.1 Gy. The volume of heart irradiated with a dose higher than 30 Gy was reduced from 7.6% to 1.9%, and the volume of the left lung from 13.6% to 11.5% as well. Inverse optimization for IMRT with multiple beams is feasible in the adjuvant treatment of breast cancer. Because of the reduction of the high-dose area of a substantial cardiac volume, it is superior to conventional techniques in cases where the parasternal lymph nodes should be integrated into the target volume. Here, a clinical advantage might be detectable.

Combination of early bisphosphonate administration and irradiation leads to improved remineralization and restabilization of osteolytic bone metastases in an animal tumor model.

BACKGROUND: The goal of the current study was to analyze the combined effect of bisphosphonates (BPs) and irradiation on remineralization and restabilization of osteolytic bone metastases in an animal tumor model. METHODS: Bone metastases were induced in male Wistar rats via intraosseous injection of the Walker carcinosarcoma 256B cell line into both proximal tibia metaphyses on Day 1 of the study. Three treatment groups were analyzed. All animals received a single radiation dose of 17 grays (in the form of 6-megaelectron-volt electrons) on Day 7 and were sacrificed on Day 49. Group 1 (the control group) was treated with irradiation only. Groups 2 and 3 received additional BPs (clodronate; daily intraperitoneal injection dose, 20 mg/kg per day). In Group 2, BPs were given before irradiation, on Days 3-6; this schedule later was referred to as early BP treatment. In Group 3, BPs were administered simultaneously with irradiation, on Days 7-10; this schedule later was referred to as simultaneous BP treatment. The endpoints of the study were bone density and microstructural parameters of bone on Day 49. Bone density was measured using X-ray absorption. Microstructural parameters of bone were assessed using histomorphometry. A total of thirty tibiae were analyzed in each group. RESULTS: After irradiation, bone density was significantly higher among animals in the early BP treatment group compared with those in the control group and those in the simultaneous BP treatment group (P = 0.001). Histomorphometric analysis of bone showed significantly better-preserved (P < 0.001) microstructural parameters (bone area, trabecular number, and trabecular separation) in the early BP treatment group compared with the control and simultaneous BP treatment groups. CONCLUSIONS: Early BP administration in combination with irradiation led to improved remineralization and restabilization of osteolytic bone metastases in an animal tumor model.

Assessment of focal liver reaction by multiphasic CT after stereotactic single-dose radiotherapy of liver tumors.

PURPOSE: To characterize and quantitatively assess focal radiation reactions in the liver after stereotactic single-dose radiotherapy for liver malignancies. METHODS AND MATERIALS: A total of 131 multiphasic CT scans were performed in 36 patients before and after stereotactic radiotherapy for liver tumors. The examination protocol included a nonenhanced scan and contrast-enhanced scans at different times after contrast injection. The volume of the reaction was determined in each scan and the threshold dose calculated using the dose-volume histogram of the treatment plan. RESULTS: Every patient showed a focal radiation reaction on at least one follow-up examination. In 74% of the posttherapeutic scans, a sharply demarcated hypodense area surrounded the treated tumor in the nonenhanced scans. The reaction occurred at a median of 1.8 months (range 1.2-4.6) after radiotherapy. The median threshold dose was 13.7 Gy (range 8.9-19.2). The threshold dose strongly correlated with the time of detection after therapy (r = 0.7). Radiologically, three reaction types were found on the enhanced scans: type 1, portal-venous phase: hypodense and late phase: isodense; type 2, portal-venous phase: hypodense and late phase: hyperdense; and type 3, portal-venous phase: isodense/hyperdense and late phase: hyperdense. Type 1 or 2 reactions were observed significantly earlier than type 3 (p <0.05). The median threshold dose for type 1 or 2 reactions was significantly lower than for type 3 (p <0.05). The reaction volume decreased with longer follow-up (2-4 months: median 40% of initial volume). The reaction types shifted with follow-up: 58% were of type 1 at the initial manifestation and 58% were of type 3 at the next examination thereafter. CONCLUSION: A focal radiation reaction occurs after stereotactic single-dose therapy in the liver. The volume of the reaction decreases and changes its radiologic appearance during follow-up. This reaction has to be differentiated from recurrent tumor.