The use of 3D conformal radiotherapy (3D CRT) to spare the cochlea in patients with medulloblastoma.

PURPOSE: Radiation therapy in combination with cis-platinum chemotherapy is associated with ototoxicity due to destruction of cochlear hair cells. This is a significant problem, especially in pediatric patients, because it may lead to difficulties with communication, speech, language, and development of learning skills. The use of 3D conformal radiotherapy (3D CRT) may be useful in sparing auditory structures. This paper discusses a technique using 3D CRT to spare the cochlea in patients with medulloblastoma. METHODS AND MATERIALS: Five pediatric patients with medulloblastoma were planned using 3D CRT. All had MRI and CT obtained specifically for treatment planning. Multiple structures were contoured, including the cochlea and posterior fossa, and conformal beams designed in beam's eye view and dose distribution analysis were edited to provide 3D dose coverage to the target while sparing the inner ear. Patients received 36 Gy to the craniospinal axis followed by an 18-20 Gy boost to the posterior fossa. RESULTS: A 3D CRT cochlear sparing technique was designed, using an axial pair of posterior oblique fields to treat the posterior fossa while sparing the cochlea for all patients in this analysis. Dose-volume information, obtained from 3D calculations, demonstrates that the average dose received by the cochlea was 65% of the prescribed dose using the cochlear sparing plan, as compared to 101% using standard opposed-lateral beams. Both plans delivered > or = 100% of the prescribed dose to the posterior fossa. CONCLUSION: 3D CRT allows for cochlear sparing in the treatment of medulloblastoma. Further follow-up is necessary to determine the long-term benefit in these patients.

Patterns of failure following treatment for medulloblastoma: is it necessary to treat the entire posterior fossa?

PURPOSE: Craniospinal radiation (CSRT) followed by a boost to the entire posterior fossa (PF) is standard postoperative therapy for patients with medulloblastoma. A large proportion of recurrences after treatment are local, with approximately 50-70% of recurrences occurring in the PF. It is unclear, however, whether these failures are occurring in the original tumor bed or outside the tumor bed, but still within the PF. With improved diagnostic imaging, better definition of tumor volumes, and the use of three-dimensional conformal therapy (3D CRT), we may be able to restrict the boost volume to the tumor bed plus a margin without compromising local control. This retrospective study analyzes the patterns of failure within the PF in a series of patients treated with radiation therapy (RT). METHODS: From July 1986 through February 1996, 114 patients >18 months and <18 years with medulloblastoma were treated at the University of Michigan and Children's Hospital of Philadelphia, with RT following surgical resection. Of 114, 27 (24%) were found to have a recurrence and form the basis for this study. RT consisted of CSRT followed by a boost to the entire posterior fossa. Some patients received adjuvant chemotherapy. Patient's preoperative magnetic resonance imaging (MRI) and/or computerized tomography (CT) studies were used to compare the original tumor volume with the specific region of local relapse. Failure was defined as MRI or CT evidence of recurrence or positive cerebrospinal fluid cytology. Relapse was scored as local, if it was within the original tumor bed, and regional if it was outside of the tumor bed but still within the PF. RESULTS: The median age of the 27 patients who relapsed was 8.6 years. Three patients were <3 years old. Of 27, 21 had disease localized to the PF. Of 26, 22 patients received chemotherapy during their treatment regimen; 1 patient did not have information on systemic treatment. The median dose of RT to the craniospinal axis was 32.5 Gy and to the PF was 55.2 Gy. The median time to recurrence was 19.5 months. Local failure within the tumor bed as any component of first failure occurred in 52% (14 of 27) of all failures, but as the solitary site of first failure in only 2 of 27 failures. Of 14 patients who failed in the tumor bed, 11 also failed in the spine, 8 of 14 also failed within the PF but outside the tumor bed, and 7 of 14 failed in all three locations. Local failure within the PF but outside the tumor bed as any component of first failure occurred in 41% (11 of 27) of all failures, but as the solitary site of first failure in only 1 of 27 failures. Of 11 patients who failed in the PF but outside the tumor bed, 9 also failed in the spine, 8 also failed within the tumor bed, and 7 failed in the all three locations. Of the failures outside the tumor bed but still within the PF, 7 of 11 failed in the leptomeninges, 1 in the brainstem parenchyma, and 3 in the PF parenchyma. Of 7 who failed in the PF leptomeninges, 6 also failed within the spine. Failure within the spine as any component of first failure occurred in 70% (19 of 27) of all failures and as the only site of first failure in 5 of 27 patients. Of 19 patients who failed in the spine, 11 also failed in the tumor bed, 9 also failed within the PF but outside the tumor bed, and 9 failed in the all three locations. CONCLUSIONS: Leptomeningeal failure is a common component of failure and occurs in the leptomeninges of the PF, as well as the spine. Isolated tumor bed failure is a rarely observed event and occurred in only 2 of 27 failures described here. Similarly, parenchymal (nonleptomeningeal) failures in the PF but outside of the tumor bed were rare: 4 patients recurred in this manner, only 1 of whom was an isolated event without other sites of recurrence. Our data suggest that, when the entire PF is treated, very few failures develop in isolation in the PF outside the tumor bed. Further studies will be necessary to determine if RT to the tu

Results of 3D conformal radiotherapy in the treatment of localized prostate cancer.

PURPOSE: 3D conformal radiotherapy (3D CRT) has been shown to decrease acute morbidity in the treatment of prostate cancer. Therapeutic outcome and late morbidity data have been accumulating. To evaluate the results of 3D CRT for the treatment of prostate cancer, we analyzed the outcome of a large series of patients treated with conformal techniques. MATERIAL AND METHODS: From January 1987 through June 1994, 707 patients with localized prostate cancer were treated with 3D CRT. Patients with pathologically-confirmed pelvic lymph node metastasis, treated with pre-irradiation (preRT) androgen ablation, or treated post-prostatectomy were excluded. All had CT obtained specifically for treatment planning, multiple structures contoured on the axial images, and beam's-eye view conformal beams edited to provide 3D dose coverage. Median follow-up is 36 mos; 70 patients have been followed longer than 5.5 years. Six hundred three had T1-T2 tumors. PreRT prostate specific antigen (PSA) was available for 649 patients: median preRT PSA was 12.9 ng/ml, 209 patients had preRT PSA > 20 ng/ml. The median dose of radiation was 69 Gy; 102 patients received > or = 69 Gy. Biochemical failure was defined as: 1) two consecutive PSA rises over 2.0 ng/ml if nadir PSA < or = 2.0 ng/ml, 2) two consecutive PSA rises over nadir if nadir PSA > 2.0 ng/ml, or 3) initiation of hormonal therapy after RT. Complications were graded using the RTOG system. RESULTS: PreRT PSA and Gleason score emerged as independent indicators of biochemical control (bNED). Patients with preRT PSA > 10 had a significantly worse bNED at 5 years than patients with preRT PSA < or = 10. Five-year bNED was determined according to preRT PSA: PSA < or = 4, 88%; PSA > 4 < or = 10, 72%; PSA > 10 < or = 20, 43%; and PSA > 20, 30%. Patients with Gleason score > or = 7 also had a significantly worse bNED than patients with Gleason score < 7. Patients were divided into two prognostic groups: a favorable group with PSA < or = 10, Gleason score < 7, and T1-T2 tumors, and an unfavorable group with PSA > 10, Gleason score > or = 7 or T3-T4 tumors and studied for the effect of dose on bNED status. The bNED at 5 years was 75% for the favorable group and 37% for the unfavorable group. In addition, a group that might be considered a surgical subset was reviewed: patients with PSA < or = 10, Gleason score < or = 7, and T1-T2 tumors who were < 70 years old. This subset had an 84% 5-year bNED rate and 98% 5-year overall survival. Complications with the techniques used here are very low: 3% risk at 7 years of Grade 3-4 complications and 1% risk at 7 years of Grade 3 bladder complications (no Grade 4). CONCLUSION: 3D CRT allows for treatment of prostate cancers with a very low risk of complications. Patients with relatively early disease as defined by preRT PSA, Gleason score < 7, and T1-2 tumors and patients who are candidates for radical prostatectomy have excellent 5-year bNED rates. Patients with adverse prognostic factors have a high risk of biochemical recurrence and are candidates for innovative therapy.

Molecular analysis of a gene, BB1, overexpressed in bladder and breast carcinoma.

The AN43 antigen is a new bladder tumor marker which is present in bladder cancer specimens as well as breast cancer specimens (1). Our objective was to clone the AN43 gene and determine its possible role in bladder and breast tumorigenesis. A bladder tumor cell cDNA expression library was made and screened with a murine monoclonal antibody to the AN43 antigen. A 1897 bp cDNA clone was isolated following expression screening with the AN43 antibody and named BB1. Following DNA sequencing, the BB1 cDNA clone was determined to have no homology to any known gene when screened through GenBank. RNA analysis demonstrated increased expression of BB1 mRNA in metastatic breast and bladder carcinomas relative to normal breast epithelium and urothelium. Treatment with gamma-interferon resulted in decreased mRNA expression. BB1 mRNA expression is increased in malignant cells relative to normal cells and is down-regulated following gamma-interferon treatment and therefore may have a role in tumor progression. Further characterization and functional analysis of this novel gene will be useful in understanding tumor development and metastatic potential.

Bcl-2 protects murine erythroleukemia cells from p53-dependent and -independent radiation-induced cell death.

To better understand the molecular basis of radiation-induced cell death, we studied the role of the bcl-2 oncogene and the p53 tumor suppressor gene in this process. A temperature-sensitive mutant of murine p53 (p53Val-135) and/or bcl-2 was transfected into murine erythroleukemia cells (MEL, DP16-1, which are null in p53). We demonstrate that radiation-induced cell death occurs by both p53-dependent and -independent pathways and overexpression of bcl-2 modulates both pathways. When viability was measured 24 h post-radiation, cells that had been briefly exposed to wtp53 immediately after X-ray irradiation had decreased survival as compared to unirradiated cells expressing wtp53 or X-ray irradiated DP16-1 cells. However, at later times X-ray irradiated parental DP16-1 cells also had decreased survival compared to the unirradiated control. This decrease in survival began 48 h following radiation. Bcl-2 prevented radiation-induced cell death in DP16-1 cells expressing wtp53 and delayed radiation-induced cell death in DP16-1 cells without wtp53. X-ray irradiated cells expressing wtp53 displayed microscopic and biochemical characteristics consistent with cell death due to apoptosis. DP16-1 cells which were untransfected or co-transfected with wtp53 and bcl-2 displayed characteristics of cells undergoing necrosis. These results suggest that radiation-induced cell death occurs by both p53-dependent and p53-independent pathways. The p53-dependent pathway results in cell death via apoptosis and occurs approximately 24 h following radiation. The p53-independent pathway does not appear to involve apoptosis and occurs at a later time, starting 48 h after X-ray exposure. Thus, bcl-2 protects cells from p53-dependent radiation-induced apoptotic cell death and attenuates p53-independent radiation-induced cell death.