PURPOSE: Institutional structure, function, and philosophy reflect the organizational needs, and tend to mirror societal values of the times. For many years, the field of radiation oncology had among its major academic centers, an organization that served as a model for collaboration among health care institutions in an effort to serve the common good of its patients, hospitals, professional colleagues, and community. For over three decades, the Joint Center for Radiation Therapy (JCRT) was a leader in developing new organizational approaches for academic and clinical radiation oncology through the philosophy of collaboration in patient care, education, and research. METHODS AND RESULTS: In tracing the development and changes in organizational philosophy and structure of the JCRT, one can see the impact on academic oncology and cancer care through the emergence of both radiation and medical oncology as independent subspecialties, the importance of the National Cancer Act of 1971 accompanied by the growth of the NIH research and training programs and, more recently, the effect of the changing attitudes and approaches of hospitals, academicians, practitioners, and policy makers to health care delivery, structures, and cooperation. CONCLUSION: Lessons learned from the 31-year history of the JCRT may help provide organizational insight useful in guiding academic oncology and academic medical centers through periods of change.

Boston↗

PubMed2000

Report of the 1997 SCAROP survey on resident training. Society of Chairmen of Academic Radiation Oncology Programs.

RATIONALE AND OBJECTIVES: Members of the Society of Chairmen of Academic Radiation Oncology Programs (SCAROP) were surveyed in November 1997 to evaluate the current status of radiation oncology training in the United States and to help determine how it should be carried out in the coming decade. MATERIALS AND METHODS: A detailed questionnaire was sent to all members of SCAROP; 68 of 82 questionnaires were returned, for a response rate of 83%. RESULTS: The responses to the survey show a serious shortage of radiation oncologists in university settings, despite an apparent surplus in private practice. Although recent changes in health care have added additional clinical responsibilities for radiation oncologists in university practices, approximately 75% of the chairpersons answering the survey continue to give their faculty protected time for research. Even with additional research and teaching responsibilities, the average radiation oncologist in university practice saw 206 patients per year in 1997, a number similar to that reported by the Patterns of Care Study for radiation oncologists overall. Approximately two-thirds of respondents believe that academic chairs should strive to have all clinical faculty members participating in research. Nevertheless, most think that basic research is better performed by dedicated researchers with PhD degrees rather than radiologists with MD degrees. Most respondents believe that the training programs adequately prepare radiation oncologists for a career in academic medicine but do not provide good training in research. Eighty-four percent agreed that resident performance on the American Board of Radiology examination should be considered in the accreditation of residency programs in radiation oncology but should not be the major criterion. CONCLUSION: There is a shortage of academic radiation oncologists in the United States despite the large number of radiation oncologists completing training. This probably is due to a variety of factors, including a relatively small pool of candidates for academic positions, increasing demands for performance from academic physicians (to see more patients, perform research, publish, write grants, and teach), and competition from the private sector for recruitment of these individuals.

Data Collection↗

PubMed1999

Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen.

Apoptotic pathways controlled by the Rel/NF-kappaB family of transcription factors may regulate the response of cells to DNA damage. Here, we have examined the NF-kappaB status of several prostate tumor cell lines. In the androgen-independent prostate tumor cells PC-3 and DU-145, the DNA-binding activity of NF-kappaB was constitutively activated and IkappaB-alpha levels were decreased. In contrast, the androgen-sensitive prostate tumor cell line LNCaP had low levels of NF-kappaB which were upregulated following exposure to cytokines or DNA damage. The activity of the IkappaB-alpha kinase, IKKalpha, which mediates NF-kappaB activation, was also measured. In PC-3 cells, IKKalpha activity was constitutively active, whereas LNCaP cells had minimal IKKalpha activity that was activated by cytokines. The anti-inflammatory agent ibuprofen inhibited the constitutive activation of NF-kappaB and IKKalpha in PC-3 and DU-145 cells, and blocked stimulated activation of NF-kappaB in LNCaP cells. However, ibuprofen did not directly inhibit IkappaB-alpha kinase. The results demonstrate that NF-kappaB is constitutively activated in the hormone-insensitive prostate tumor cell lines PC-3 and DU-145, but not in the hormone responsive LNCaP cell line. The constitutive activation of NF-kappaB in prostate tumor cells may increase expression of anti-apoptotic proteins, thereby decreasing the effectiveness of anti-tumor therapy and contributing to the development of the malignant phenotype.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1999

Salicylic acid and aspirin inhibit the activity of RSK2 kinase and repress RSK2-dependent transcription of cyclic AMP response element binding protein- and NF-kappa B-responsive genes.

Sodium salicylate (NaSal) and other nonsteroidal anti-inflammatory drugs (NSAIDs) coordinately inhibit the activity of NF-kappa B, activate heat shock transcription factor 1 and suppress cytokine gene expression in activated monocytes and macrophages. Because our preliminary studies indicated that these effects could be mimicked by inhibitors of signal transduction, we have studied the effects of NSAIDs on signaling molecules potentially downstream of LPS receptors in activated macrophages. Our findings indicate that ribosomal S6 kinase 2 (RSK2), a 90-kDa ribosomal S6 kinase with a critical role as an effector of the RAS-mitogen-activated protein kinase pathway and a regulator of immediate early gene transcription is a target for inhibition by the NSAIDs. NSAIDs inhibited the activity of purified RSK2 kinase in vitro and of RSK2 in mammalian cells and suppressed the phosphorylation of RSK2 substrates cAMP response element binding protein (CREB) and I-kappa B alpha in vivo. Additionally, NaSal inhibited the phosphorylation by RSK2 of CREB and I-kappa B alpha on residues crucial for their transcriptional activity in vivo and thus repressed CREB and NF-kappa B-dependent transcription. These experiments suggest that RSK2 is a target for NSAIDs in the inhibition of monocyte-specific gene expression and indicate the importance of RSK2 and related kinases in cell regulation, indicating a new area for anti-inflammatory drug discovery.

3T3 Cells↗

PubMed1999

Phase I trial of the hypoxic cell cytotoxin tirapazamine with concurrent radiation therapy in the treatment of refractory solid tumors.

PURPOSE: Patients with refractory solid tumors were treated with the combination of fractionated radiation therapy and multiple-dose intravenous tirapazamine to determine the toxicities and maximum tolerated dose of tirapazamine when given concurrently with radiation therapy. METHODS: Patients received radiation therapy in accordance with standard treatment practice in relation to fraction size and number of fractions for their particular cancer. In all cases, the course of radiation therapy exceeded the time of tirapazamine administration. Initially, tirapazamine was administered 5 days per week for 2 weeks for a total of 10 doses. After the first 8 patients, the schedule was changed to 3 times per week (Monday, Wednesday, Friday) for 4 weeks for a total of 12 doses. Between 3 and 6 patients were treated at each dose level. RESULTS: A total of 43 patients were treated in the study between 1991 and 1995. All patients were 18 years old or older, had a Karnofsky performance status of > or = 60% and had adequate hematologic, hepatic, and renal function. Dose escalation began at 9 mg/m(2)/dose and was increased using a modified Fibonacci schema. The maximum tolerated dose was not reached and dose escalation was stopped at 260 mg/m(2) because of other data that became available suggesting 330 mg/m(2) was associated with dose-limiting toxicity (1, 2). CONCLUSION: Tirapazamine in doses of up to 260 mg/m(2) times 12 doses can be given safely with fractionated radiation therapy. This dose appears to result in adequate plasma exposure (2) for radiation sensitization, and this schedule is being tested in a Phase II trial by the Radiation Therapy Oncology Group to determine if tirapazamine is a radiation enhancer in the clinic.

Adult↗

PubMed1999

Molecular biology in radiation oncology. Radiation oncology perspective of BRCA1 and BRCA2.

The breast cancer susceptibility genes, BRCA1 and BRCA2, are used to illustrate the application of molecular biology to clinical radiation oncology. Identified by linkage analysis and cloned, the structure of the genes and the numerous mutations are determined by molecular biology techniques that examine the structure of the DNA and the proteins made by the normal and mutant alleles. Mutations in the non-transcribed portion of the gene will not be found in protein structure assays and may be important in gene function. In addition to potential deleterious mutations, normal polymorphisms of the gene will also be detected, therefore not all differences in gene sequence may represent important mutations, a finding that complicates genetic screening and counseling. The localization of the protein in the nucleus, the expression in relation to cell cycle and the association with RAD51 led to the discovery that the two BRCA genes may be involved in transcriptional regulation and DNA repair. The defect in DNA repair can increase radiosensitivity which might improve local control using breast-conserving treatment in a tumor which is homozygous for the loss of the gene (i.e., BRCA1 and BRCA2 are tumor suppressor genes). This is supported by the early reports of a high rate of local control with breast-conserving therapy. Nonetheless, this radiosensitivity theoretically may also lead to increased susceptibility to carcinogenic effects in surviving cells, a finding that might not be observed for decades. The susceptibility to radiation-induced DNA damage appears also to make the cells more sensitive to chemotherapy. Understanding the role of the normal BRCA genes in DNA repair might help define a novel mechanism for radiation sensitization by interfering with the normal gene function using a variety of molecular or biochemical therapies.

BRCA2 Protein↗

PubMed1999

Clinical radiosensitization: why it does and does not work.

Explore the source record for details and available documents.

Antineoplastic Agents↗

PubMed1999

Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer.

PURPOSE: To present nomograms providing estimates of prostate-specific antigen (PSA) failure-free survival after radical prostatectomy (RP) or external-beam radiation therapy (RT) for men diagnosed during the PSA era with clinically localized disease. PATIENTS AND METHODS: A Cox regression multivariable analysis was used to determine the prognostic significance of the pretreatment PSA level, 1992 American Joint Committee on Cancer (AJCC) clinical stage, and biopsy Gleason score in predicting the time to posttherapy PSA failure in 1,654 men with T1c,2 prostate cancer managed with either RP or RT. RESULTS: Pretherapy PSA, AJCC clinical stage, and biopsy Gleason score were independent predictors (P < .0001) of time to posttherapy PSA failure in patients managed with either RP or RT. Two-year PSA failure rates derived from the Cox regression model and bootstrap estimates of the 95% confidence intervals are presented in the format of a nomogram stratified by the pretreatment PSA, AJCC clinical stage, biopsy Gleason score, and local treatment modality. CONCLUSION: Men at high risk (> 50%) for early (< or = 2 years) PSA failure could be identified on the basis of the type of local therapy received and the clinical information obtained as part of the routine work-up for localized prostate cancer. Selection of these men for trials evaluating adjuvant systemic and improved local therapies may be justified.

Humans↗

PubMed1998

Chemical sensitizers and protectors.

Explore the source record for details and available documents.

Radiation-Protective Agents↗

PubMed1998

Real-time magnetic resonance image-guided interstitial brachytherapy in the treatment of select patients with clinically localized prostate cancer.

PURPOSE: This study was performed to establish the dose-localization capability and acute toxicity of a real-time intraoperative magnetic resonance (MR) image-guided approach to prostate brachytherapy in select patients with clinically localized prostate cancer. METHODS AND MATERIALS: Nine patients with 1997 American Joint Commission on Cancer (AJCC) clinical stage T1cNxM0 prostate cancer, prostate-specific antigen (PSA) < 10 ng/ml, biopsy Gleason score not exceeding 3 + 4, and endorectal coil MR stage T2 disease were enrolled into this study. The prescribed minimum peripheral dose was 160 Gy to the clinical target volume (CTV), which was the MR-defined peripheral zone (PZ) of the prostate gland. Using a real-time 0.5 Tesla intraoperative MR imaging unit, 5-mm image planes were obtained throughout the prostate gland. The PZ of the prostate gland, anterior rectal wall, and prostatic urethra were identified on the T2 weighted axial images by an MR radiologist. An optimized treatment plan for catheter insertion was generated intraoperatively. Each catheter containing the 125Iodine sources was placed under real-time MR guidance to ensure that its position in the coronal, sagittal, and axial planes was in agreement with the planned trajectory. Real-time dose- volume histogram analyses were used intraoperatively to optimize the dosimetry. RESULTS: For the 9 study patients, 89-99% (median 94%) of the CTV received a minimum peripheral dose of 160 Gy and > or = 95% of the volume of the prostatic urethra and 42-89% (median 70%) of the volume of the anterior rectal wall received doses that were below the reported tolerance. All patients voided spontaneously within 3 h after discontinuation of the Foley catheter and no patient required more than a limited course (< or = 3 weeks) of oral alpha-1 blockers for postimplant urethritis. CONCLUSIONS: Real-time MR-guided interstitial radiation therapy provided the ability to achieve the planned optimized dose-volume histogram profiles to the CTV and healthy juxtaposed structures intraoperatively, with minimal acute morbidity.

Aged↗

PubMed1998

Calculated prostate carcinoma volume: The optimal predictor of 3-year prostate specific antigen (PSA) failure free survival after surgery or radiation therapy of patients with pretreatment PSA levels of 4-20 nanograms per milliliter.

BACKGROUND: In this study, the authors evaluated whether a clinically relevant stratification of prostate specific antigen (PSA) failure free survival (bNED) after definitive local therapy could be made for patients with prostate carcinoma clinically classified as T1 or T2 and pretreatment PSA levels of 4-20 ng/mL. METHODS: Multivariate Cox regression analysis and Kaplan-Meier analysis were performed for clinically localized prostate carcinoma patients who presented with PSA levels of 4-20 ng/mL. Three hundred forty-eight of the patients were managed definitively with conventional external beam radiation therapy (median dose, 67 gray), whereas 547 of the patients were managed definitively with a radical retropubic prostatectomy. The outcome tested was time to posttreatment PSA failure. The clinical predictors evaluated included the standard paradigm (PSA, biopsy Gleason score, and clinical stage); type of local therapy; and a newly defined factor, the calculated prostate cancer volume (cV[Ca]). RESULTS: Time to posttreatment PSA failure was equivalent (P = 0.52) independent of the type of local therapy. The cV(Ca) (P < 0.0001), pretreatment PSA (P = 0.003), and clinical classification of T2c (P = 0.04) remained significant predictors of time to posttreatment PSA failure in multivariate analysis. CONCLUSIONS: The staging system described herein, which is based on cV(Ca) and PSA, may optimize patient selection for definitive local therapy and entry onto randomized clinical trials examining the use of adjuvant hormonal or chemotherapy in patients with clinically localized disease who present with PSA levels of 4-20 ng/mL. Validation of this staging system by other investigators is currently underway.

Antineoplastic Agents, Hormonal↗

PubMed1998

Survival results from a phase I study of etanidazole (SR2508) and radiotherapy in patients with malignant glioma.

PURPOSE: To report the survival results from a previous Phase I study of etanidazole (ETA) and radiotherapy in patients with glioblastoma multiforme (GBM n = 50) or anaplastic astrocytoma (AA n = 19) and examine survival according to age, Karnofsky performance status (KPS), and implant status. PATIENTS AND METHODS: In a previous Phase I study, 70 previously untreated patients (median age 49) with malignant gliomas were accrued. One patient was excluded from analysis because pathology was unverifiable. All had KPS > or = 70. Prior to initiation of treatment, patients were stratified according to whether they were candidates for interstitial implantation. The implant patients (IMP n = 14) received accelerated fractionation radiotherapy (XRT) 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m2 x 6 doses, a 2 week break, and then interstitial implant for an additional 50 Gy (4-7 days) with a continuous infusion of ETA over 90-96 hours. There were 55 patients treated on two sequentially conducted non-implant arms. These patients started with accelerated fractionation XRT 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m2 x 4-5 doses/week. Non-IMP1 arm (n = 41) received a 2-week break before standard fractionated boost XRT of 2 Gy/day for 2 weeks to a total dose of 60 Gy with ETA. Non-IMP2 arm (n = 14) did not have the 2-week break. All patients had plasma pharmacokinetic monitoring of ETA. Subsequent follow-up study provided information regarding long-term survival status of this group of patients. The Phase I toxicity evaluation was conducted according to the RTOG toxicity scale and was found well tolerated in both groups. Overall actuarial survival was plotted for all patients, by histologic group, and by implant status. Subset analyses of GBM patients by age (< or = 49 or > 49 years), KPS (< or = 80 or > 80) and implant versus non-implant were also performed. RESULTS: Median survival of GBM patients was 1.1 years and that of anaplastic astrocytoma patients was 3.1 years (p = 0.0001). In GBM patients, KPS > 80, implanted patients, and age < or = 49 were factors found not to be associated with a statistically improved survival. CONCLUSION: The results of survival in this Phase I etanidazole study of patients with anaplastic astrocytoma are comparable to the results from other studies using bromodeoxyuridine, iododeoxyuridine, or procarbazine, lomustine (CCNU), and vincristine. The use of etanidazole with accelerated radiotherapy does not appear to improve survival in patients with glioblastoma multiforme compared to those treated with conventional therapies.

Adult↗