Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

[MRI methods for pulmonary ventilation and perfusion imaging]. / Methoden der MRT zur Ventilations- und Perfusionsbildgebung der Lunge.

CLINICAL/METHODICAL ISSUE: Separate assessment of respiratory mechanics, gas exchange and pulmonary circulation is essential for the diagnosis and therapy of pulmonary diseases. Due to the global character of the information obtained clinical lung function tests are often not sufficiently specific in the differential diagnosis or have a limited sensitivity in the detection of early pathological changes. STANDARD RADIOLOGICAL METHODS: The standard procedures of pulmonary imaging are computed tomography (CT) for depiction of the morphology as well as perfusion/ventilation scintigraphy and single photon emission computed tomography (SPECT) for functional assessment. METHODICAL INNOVATIONS: Magnetic resonance imaging (MRI) with hyperpolarized gases, O2-enhanced MRI, MRI with fluorinated gases and Fourier decomposition MRI (FD-MRI) are available for assessment of pulmonary ventilation. For assessment of pulmonary perfusion dynamic contrast-enhanced MRI (DCE-MRI), arterial spin labeling (ASL) and FD-MRI can be used. PERFORMANCE: Imaging provides a more precise insight into the pathophysiology of pulmonary function on a regional level. The advantages of MRI are a lack of ionizing radiation, which allows a protective acquisition of dynamic data as well as the high number of available contrasts and therefore accessible lung function parameters. ACHIEVEMENTS: Sufficient clinical data exist only for certain applications of DCE-MRI. For the other techniques, only feasibility studies and case series of different sizes are available. The clinical applicability of hyperpolarized gases is limited for technical reasons. PRACTICAL RECOMMENDATIONS: The clinical application of the techniques described, except for DCE-MRI, should be restricted to scientific studies.

Multidisciplinary assessment of fitness to drive in brain tumour patients in southwestern Ontario: a grey matter.

BACKGROUND: Neurocognitive impairments from brain tumours may interfere with the ability to drive safely. In 9 of 13 Canadian provinces and territories, physicians have a legal obligation to report patients who may be medically unfit to drive. To complicate matters, brain tumour patients are managed by a multidisciplinary team; the physician most responsible to make the report of unfitness is often not apparent. The objective of the present study was to determine the attitudes and reporting practices of physicians caring for these patients. METHODS: A 17-question survey distributed to physicians managing brain tumour patients elicited Respondent demographicsKnowledge about legislative requirementsExperience of reportingBarriers and attitudes to reporting Fisher exact tests were performed to assess differences in responses between family physicians (fps) and specialists. RESULTS: Of 467 physicians sent surveys, 194 responded (42%), among whom 81 (42%) were specialists and 113 (58%) were fps. Compared with the specialists, the fps were significantly less comfortable with reporting, less likely to consider reporting, less likely to have patients inquire about driving, and less likely to discuss driving implications. A lack of tools, concern for the patient-physician relationship, and a desire to preserve patient quality of life were the most commonly cited barriers in determining medical fitness of patients to drive. CONCLUSIONS: Legal requirements to report medically unfit drivers put physicians in the difficult position of balancing patient autonomy and public safety. More comprehensive and definitive guidelines would be helpful in assisting physicians with this public health issue.

Assessing fitness to drive in brain tumour patients: a grey matter of law, ethics, and medicine.

BACKGROUND: Neurocognitive deficits from brain tumours may impair the ability to safely operate a motor vehicle. Although certain jurisdictions in Canada legally require that physicians report patients who are unfit to drive, criteria for determining fitness are not clearly defined for brain tumours. METHODS: Patients receiving brain radiotherapy at our institution from January to June 2009 were identified using the Oncology Patient Information System. In addition to descriptive statistics, details of driving assessment were reviewed retrospectively. The Fisher exact test was used to determine factors predictive of reporting a patient to the Ontario Ministry of Transportation (mto) as unfit to drive. A logistic regression model was constructed to further determine factors predictive of reporting. RESULTS: Of the 158 patients available for analysis, 48 (30%) were reported to the mto, and 64 (41%) were advised to stop driving. With respect to the 53 patients with seizures, a report was submitted to the mto for 30 (57%), and a documented discussion about the implications of driving was held with 35 (66%). On univariate analysis, younger age, a central nervous system primary, higher brain radiotherapy dose, unifocal disease, and the presence of seizures were predictive of physician reporting (p < 0.05). On logistic regression modelling, the presence of seizures (odds ratio: 3.9) and a higher radiotherapy dose (odds ratio: 1.3) remained predictive of reporting. INTERPRETATION: Physicians frequently do not discuss the implications of driving with brain tumour patients or are not properly documenting such advice (or both). Clear and concise reporting guidelines need to be drafted given the legal, medical, and ethical concerns surrounding this public health issue.

Consistency check of planned adaptive option on helical tomotherapy.

This study aims to evaluate a new Planned Adaptive software (TomoTherapy Inc., Madison, WI) of the helical tomotherapy system by retrospective verification and adaptive re-planning of radiation treatment. Four patients with different disease sites (brain, nasal cavity, lungs, prostate) were planned in duplicate using the diagnostic planning kVCT data set and MVCT studies of the first treatment fraction with the same optimization parameters for both plan types. The dosimetric characteristics of minimum, maximum, and mean dose to the targets as well as to organs at risk were compared. Both sets of plans were used for calculation of dose distributions in a water-equivalent phantom. Corresponding measurements of these plans in phantom were carried out with the use of radiographic film and ion chamber. In the case of the lung and prostate cancer patients, changes in dosimetric parameters compared to data generated with the kVCT study alone were less than 2%. Certain changes for the nasal cavity and brain cancer patients were greater than 2%, but they were explained in part by anatomy changes that occurred during the time between kVCT and MVCT studies. The Planned Adaptive software allows for adaptive radiotherapy planning using the MVCT studies obtained by the helical tomotherapy imaging system.

Initial Investigation into Microbleeds and White Matter Signal Changes following Radiotherapy for Low-Grade and Benign Brain Tumors Using Ultra-High-Field MRI Techniques.

BACKGROUND AND PURPOSE: External beam radiation therapy is a common treatment for many brain neoplasms. While external beam radiation therapy adheres to dose limits to protect the uninvolved brain, areas of high dose to normal tissue still occur. Patients treated with chemoradiotherapy can have adverse effects such as microbleeds and radiation necrosis, but few studies exist of patients treated without chemotherapy. MATERIALS AND METHODS: Ten patients were treated for low-grade or benign neoplasms with external beam radiation therapy only and scanned within 12-36 months following treatment with a 7T MR imaging scanner. A multiecho gradient-echo sequence was acquired and postprocessed into SWI, quantitative susceptibility mapping, and apparent transverse relaxation maps. Six patients returned for follow-up imaging approximately 18 months following their first research scan and were imaged with the same techniques. RESULTS: At the first visit, 7/10 patients had microbleeds evident on SWI, quantitative susceptibility mapping, and apparent transverse relaxation. All microbleeds were within a dose region of >45 Gy. Additionally, 4/10 patients had asymptomatic WM signal changes evident on standard imaging. Further analysis with our technique revealed that these lesions were venocentric, suggestive of a neuroinflammatory process. CONCLUSIONS: There exists a potential for microbleeds in patients treated with external beam radiation therapy without chemotherapy. This finding is of clinical relevance because it could be a precursor of future neurovascular disease and indicates that additional care should be taken when using therapies such as anticoagulants. Additionally, the appearance of venocentric WM lesions could be suggestive of a neuroinflammatory mechanism that has been suggested in diseases such as MS. Both findings merit further investigation in a larger population set.

Comparison of advanced irradiation techniques with photons for benign intracranial tumours.

BACKGROUND AND PURPOSE: The potential benefits and limitations of different radiation techniques (stereotactic arc therapy (SRS/T), intensity modulated radiotherapy (IMRT), helical tomotherapy (HT), Cyberknife and intensity-modulated multiple arc therapy (AMOA)) have been assessed using comparative treatment planning methods on twelve patients presenting with 'benign' brain tumours. MATERIALS AND METHODS: Plans for five acoustic neurinomas, five meningiomas and two pituitary adenomas were computed to generate dose distributions for all modalities using a common CT dataset to delineate planning target volume and organs at risk. RESULTS: HT, AMOA and IMRT resulted superior to SRS/T and Cyberknife for target coverage. For the first group V(95%) ranged from 98% to 100%, minimum dose ranged from 91% to 96% and standard deviation from 0.84% to 1.67%. For organs at risk all techniques respected planning objectives with a tendency of Cyberknife and SRS/T to better spare the brain stem and the healthy brain tissue (e.g., V(20Gy) of 2.0% and 2.3%, respectively, compared to 3.1-5.0% for the other techniques). AMOA is in general preferable to IMRT for all OARs. Conformity index (CI(95)) was better for HT and Cyberknife (both 1.8) and less for AMOA and IMRT (3.9 and 3.0, respectively). CONCLUSION: All techniques provided good OAR sparing and primarily differed in target coverage indices. For the class of tumours investigated in this report, HT, AMOA and IMRT had better target coverage with HT providing the best combination of indeces. Between AMOA and IMRT, target coverage was comparable and, considering organs at risk, AMOA was slightly preferable.

Assessing the prognostic significance of transrectal ultrasound extracapsular extension in prostate cancer.

AIMS: To determine the prognostic value of transrectal ultrasound (TRUS)-detected extraprostatic disease for prostate cancer in patients receiving radical external-beam radiation therapy (EBRT). MATERIALS AND METHODS: A chart review of 181 patients treated with radical EBRT for prostate cancer was conducted. All patients underwent TRUS assessment by one radiologist. The median radiation dose delivered to the prostate was 66 Gy (range 53-70 Gy) in 33 fractions (range 20-39 fractions). Median follow-up time for all patients was 6.5 years. Sixty-four (35%) out of 181 patients were found to have extracapsular disease on TRUS. Clinical relapse was defined as the first occurrence of either salvage hormonal therapy administration by the treating oncologist or clinical, radiological, and/or pathologic evidence of recurrent or progressive disease. In terms of biochemical failure, two prognostic variable analyses were carried out using both the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus guidelines and the Houston definition of biochemical failure. The primary end point for the prognostic variable analyses was time to first clinical or biochemical failure (CBF). RESULTS: For time to CBF using the ASTRO consensus guidelines for biochemical failure, univariable analysis revealed that the prostate-specific antigen (PSA) (P = 0.018), clinical T stage (P = 0.002), Gleason score (P = 0.021), adjuvant hormonal therapy (P = 0.032) and TRUS T staging (P = 0.0001) were statistically significant prognostic factors. On multivariable analysis, clinical T stage (P = 0.051) was of borderline statistical significance, whereas PSA (P = 0.036), TRUS T stage (P = 0.0002) and adjuvant hormonal therapy (P = 0.015) were found to be independent prognostic factors. For time to CBF using the Houston definition of biochemical failure, univariable analysis revealed that PSA (P = 0.001), Gleason score (P = 0.026) and prostate volume (P = 0.013) were statistically significant prognostic factors. On multivariable analysis, PSA (P = 0.002), Gleason score (P = 0.012), and adjuvant hormonal therapy (P = 0.041) were found to be independent prognostic factors. TRUS T staging was not found to be independently significant. CONCLUSIONS: A clear role for TRUS staging as an independent prognostic factor, in the setting of other more established variables, such as Gleason grade, PSA, and digital rectal examination (DRE) T stage, was not confirmed in this study, population.

Supratentorial low-grade glioma in adults: an analysis of prognostic factors and timing of radiation.

PURPOSE: To review the outcomes of patients with low-grade glioma diagnosed by modern imaging and treated at a center where postponing radiotherapy was common practice. METHODS: We reviewed the records of patients (age > or = 18 years) with pathologically confirmed supratentorial low-grade fibrillary astrocytoma, oligodendroglioma, and mixed glioma treated at a regional cancer center in Canada between 1979 and 1995. RESULTS: Median survival for the entire group (N = 167; mean age 40.6 years) was 10.5 years with 5- and 10-year survival rates of 72% and 50%, respectively. Median progression-free survival was 4.9 years with 5- and 10-year progression-free rates of 50% and 12%, respectively. Overall and progression-free survivals were longer for patients with an oligodendroglioma or mixed glioma than with astrocytoma (median 13 v 7.5 years, P = .003; progression-free 5.6 v 4.4 years, p = .054). Age at diagnosis < or = 40 years, seizures at presentation, minimal residual tumor after surgery, Karnofsky performance status > or = 70, and oligodendroglioma or mixed glioma pathology were associated with significantly longer median survival on univariate and multivariate analyses. Radiotherapy deferred until tumor progression (v immediate radiotherapy) was associated with longer survival on univariate analysis, but an imbalance in other variables accounted for this advantage such that timing of radiotherapy was not an independent (favorable or adverse) prognostic factor on multivariate analysis. CONCLUSION: Patients with low-grade glioma diagnosed by modern imaging can be expected to live a long time; timing of radiotherapy may be a less important determinant of survival than nontreatment variables and residual tumor bulk.

Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial.

PURPOSE: To prospectively compare standard radiation therapy (RT) with an abbreviated course of RT in older patients with glioblastoma multiforme (GBM). PATIENTS AND METHODS: One hundred patients with GBM, age 60 years or older, were randomly assigned after surgery to receive either standard RT (60 Gy in 30 fractions over 6 weeks) or a shorter course of RT (40 Gy in 15 fractions over 3 weeks). The primary end point was overall survival. The secondary end points were proportionate survival at 6 months, health-related quality of life (HRQoL), and corticosteroid requirement. HRQoL was assessed using the Karnofsky performance status (KPS) and Functional Assessment of Cancer Therapy-Brain (FACT-Br). RESULTS: All patients had died at the time of analysis. Overall survival times measured from randomization were similar at 5.1 months for standard RT versus 5.6 months for the shorter course (log-rank test, P =.57). The survival probabilities at 6 months were also similar at 44.7% for standard RT versus 41.7% for the shorter course (lower-bound 95% CI, -13.7). KPS scores varied markedly but were not significantly different between the two groups (Wilcoxon test, P =.63). Low completion rates of the FACT-Br (45%) precluded meaningful comparisons between the two groups. Of patients completing RT as planned, 49% of patients (standard RT) versus 23% required an increase in posttreatment corticosteroid dosage (chi(2) test, P =.02). CONCLUSION: There is no difference in survival between patients receiving standard RT or short-course RT. In view of the similar KPS scores, decreased increment in corticosteroid requirement, and reduced treatment time, the abbreviated course of RT seems to be a reasonable treatment option for older patients with GBM.

Validation of contour-driven thin-plate splines for tracking fraction-to-fraction changes in anatomy and radiation therapy dose mapping.

The goal of this study is to validate a deformable model using contour-driven thin-plate splines for application to radiation therapy dose mapping. Our testing includes a virtual spherical phantom as well as real computed tomography (CT) data from ten prostate cancer patients with radio-opaque markers surgically implanted into the prostate and seminal vesicles. In the spherical mathematical phantom, homologous control points generated automatically given input contour data in CT slice geometry were compared to homologous control point placement using analytical geometry as the ground truth. The dose delivered to specific voxels driven by both sets of homologous control points were compared to determine the accuracy of dose tracking via the deformable model. A 3D analytical spherically symmetric dose distribution with a dose gradient of approximately 10% per mm was used for this phantom. This test showed that the uncertainty in calculating the delivered dose to a tissue element depends on slice thickness and the variation in defining homologous landmarks, where dose agreement of 3-4% in high dose gradient regions was achieved. In the patient data, radio-opaque marker positions driven by the thin-plate spline algorithm were compared to the actual marker positions as identified in the CT scans. It is demonstrated that the deformable model is accurate (approximately 2.5 mm) to within the intra-observer contouring variability. This work shows that the algorithm is appropriate for describing changes in pelvic anatomy and for the dose mapping application with dose gradients characteristic of conformal and intensity modulated radiation therapy.

Dosimetric impact of image-guided 3D conformal radiation therapy of prostate cancer.

The goal of this work is to quantify the impact of image-guided conformal radiation therapy (CRT) on the dose distribution by correcting patient setup uncertainty and inter-fraction tumour motion. This was a retrospective analysis that used five randomly selected prostate cancer patients that underwent approximately 15 computed tomography (CT) scans during their radiation treatment course. The beam arrangement from the treatment plan was imported into each repeat CT study and the dose distribution was recalculated for the new beam setups. Various setup scenarios were then compared to assess the impact of image guidance on radiation treatment precision. These included (1) daily alignment to skin markers, thus representing a conventional beam setup without image guidance, (2) alignment to bony anatomy for correction of daily patient setup error, thus representing on-line portal image guidance, and (3) alignment to the 'CTV of the day' for correction of inter-fraction tumour motion, thus representing on-line CT or ultrasound image guidance. Treatment scenarios (1) and (3) were repeated with a reduced CTV to PTV margin, where the former represents a treatment using small margins without daily image guidance. Daily realignment of the treatment beams to the prostate showed an average increase in minimum tumour dose of 1.5 Gy, in all cases where tumour 'geographic miss' without image guidance was apparent. However, normal tissue sparing did not improve unless the PTV margin was reduced. Daily realignment to the tumour combined with reducing the margin size by a factor of 2 resulted in an average escalation in tumour dose of 9.0 Gy for all five static plans. However, the prescription dose could be escalated by 13.8 Gy when accounting for changes in anatomy by accumulating daily doses using nonlinear image registration techniques. These results provide quantitative information on the effectiveness of image-guided radiation treatment of prostate cancer and demonstrate that the dosimetric impact is patient dependent.

Helical tomotherapy for craniospinal radiation.

Helical tomotherapy (HT) plans for craniospinal radiation were generated for the case of a 4-year-old boy with disseminated ependymoma. The HT plans demonstrated excellent target coverage, homogeneity and organ sparing compared with a conventional linear accelerator based craniospinal radiation plan. On the basis of this case study, further evaluation of HT for craniospinal radiotherapy seems justified.

The significance of circulating tumor cells in prostate cancer patients undergoing adjuvant or salvage radiation therapy.

BACKGROUND: Following radical prostatectomy, success of adjuvant and salvage radiation therapy (RT) is dependent on the absence of micrometastatic disease. However, reliable prognostic/predictive factors for determining this are lacking. Therefore, novel biomarkers are needed to assist with clinical decision-making in this setting. Enumeration of circulating tumor cells (CTCs) using the regulatory-approved CellSearch System (CSS) is prognostic in metastatic prostate cancer. We hypothesize that CTCs may also be prognostic in the post-prostatectomy setting. METHODS: Patient blood samples (n=55) were processed on the CSS to enumerate CTCs at 0, 6, 12 and 24 months after completion of RT. CTC values were correlated with predictive/prognostic factors and progression-free survival. RESULTS: CTC status (presence/absence) correlated significantly with positive margins (increased likelihood of CTC(neg) disease; P=0.032), and trended toward significance with the presence of seminal vesicle invasion (CTC(pos); P=0.113) and extracapsular extension (CTC(neg); P=0.116). Although there was a trend toward a decreased time to biochemical failure (BCF) in baseline CTC-positive patients (n=9), this trend was not significant (hazard ratio (HR)=0.3505; P=0.166). However, CTC-positive status at any point (n=16) predicted for time to BCF (HR=0.2868; P=0.0437). CONCLUSIONS: One caveat of this study is the small sample size utilized (n=55) and the low number of patients with CTC-positive disease (n=16). However, our results suggest that CTCs may be indicative of disseminated disease and assessment of CTCs during RT may be helpful in clinical decision-making to determine, which patients may benefit from RT versus those who may benefit more from systemic treatments.

Multidisciplinary management of adult anaplastic oligodendrogliomas and anaplastic mixed oligo-astrocytomas.

Once thought to be rare, oligodendroglial tumors might actually represent up to 25% of primary glial neoplasms. In recent years, the histologic criteria for the diagnosis of oligodendroglioma have been broadened to include most small cell, monomorphic glial neoplasms. These refinements have led to an increased recognition of oligodendroglial neoplasms, but uniform definitions of pure versus mixed oligodendroglioma as well as the criteria for high-grade (anaplastic) versus low-grade tumors remain elusive. From a prognostic standpoint, the presence of an oligodendroglial component in a malignant glioma predicts longer survivals times for patients treated with surgery, and radiation therapy with or without chemotherapy. High rates of response to PCV (procarbazine, CCNU and Vincristine) chemotherapy also have been noted among patients with anaplastic oligodendroglial neoplasms. Ongoing prospective trials seek to clarify the role of PCV chemotherapy when added to radiation therapy and surgery. In addition, the role of molecular markers as diagnostic aides and guides to therapy and prognosis are being explored for patients with pure and mixed anaplastic oligodendroglial tumors.

Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas.

INTRODUCTION: Allelic loss of the short arm of chromosome 1 predicts radiographic response to chemotherapy and long overall survival times in patients with anaplastic oligodendrogliomas. Using a database of patients with oligodendrogliomas in whom chromosome 1p status was known, we explored whether allelic loss of 1p also predicted longer duration of tumor control when radiotherapy was part of the initial treatment of these patients. MATERIALS AND METHODS: We measured progression-free survival following radiotherapy in a cohort of patients with World Health Organization (WHO) Grade II and WHO Grade III oligodendrogliomas. The effects on progression-free survival of patient age, Karnofsky performance score (KPS), tumor grade when irradiated and chromosome 1p status were examined by univariate and multivariate statistical analyses. For the subset of patients with newly diagnosed anaplastic oligodendrogliomas, relationships between use of chemotherapy, chromosome 1p status and progression-free survival were also examined. RESULTS: Fifty-five patients (29 male, 26 female; ages 18-75 years; median, 44 years; KPS 50-90, median 80) were irradiated for either a WHO Grade II (n = 19) or Grade III (n = 36) oligodendroglioma. Twenty-eight patients had chemotherapy immediately prior to radiotherapy, and 27 had chemotherapy at progression following radiotherapy. The median radiation dose was 54 Gy in 30 fractions. Loss of heterozygosity (LOH) at chromosome 1p was evident in 36 tumors and absent in 19. Overall median progression-free survival after radiotherapy was 40.4 months. Median progression-free survival was 55.0 months for patients whose tumors harbored 1p loss vs. 6.2 months for those patients whose tumors retained both copies of chromosome 1p (p < 0.001). On both univariate and multivariate analyses, chromosome lp loss was the principal independent predictor of longer progression-free survival for patients with Grade II and III oligodendrogliomas. For Grade III oligodendrogliomas, chemotherapy as an adjunct to radiotherapy prolonged tumor control for those patients whose tumors harbored allelic loss of chromosome 1p (p = 0.004). CONCLUSION: These data suggest allelic loss of chromosome 1p in patients with oligodendroglial neoplasms predicts longer progression-free survival among patients receiving radiotherapy +/- chemotherapy as part of their initial treatment. Chromosome 1p loss may be an important stratification variable in future therapeutic trials of oligodendroglioma.

A prospective study of short-course radiotherapy in poor prognosis glioblastoma multiforme.

PURPOSE: Older age and poor performance status at presentation are unfavorable prognostic factors for patients with glioblastoma multiforme. Some studies suggest a shorter, palliative course of radiotherapy may confer similar benefits as compared to a radical course in such patients. We report a prospective, single arm trial, describing the use of a short-course of radiation in patients with glioblastoma and poor prognostic features. METHODS AND MATERIALS: Twenty-nine patients with pathologically confirmed glioblastoma and age > or = 65 years or with initial KPS < or = 50 were treated with a short-course of whole brain radiotherapy (30 Gy/10 fractions/2 weeks). Computer tomography tumor volume, dexamethasone requirements, Spitzer quality of life index, and Karnofsky performance status were measured pre and 1 month postradiation. Overall survival for the study patients was compared with that of radically treated and supportive care only historical controls. RESULTS: Indices of tumor response were stable or improved in 60% of patients evaluable 1 month postradiotherapy. Median survival for all study patients was 6 months. Median survivals in similar groups of radically treated and supportive care only patients were 10 and 1 month(s), respectively. A survival advantage for the radical vs. short-course treatment was observed for the subset of patients with a pretreatment KPS > 50. CONCLUSION: Elderly patients with a low pretreatment KPS (< or = 50) may be treated adequately with a short, palliative course of radiotherapy. Elderly patients with a higher pretreatment KPS (> 50), however, may benefit from a higher dose radiotherapy regimen.

Reirradiation of primary CNS tumors.

PURPOSE: Primary central nervous system (CNS) tumors are seldom reirradiated due to toxicity concerns and sparse clinical data regarding efficacy. METHODS AND MATERIALS: We retrospectively reviewed 34 patients with primary brain tumors retreated with fractionated external beam irradiation at the University of California, San Francisco from 1977-1993. Tumors included 15 medulloblastomas, 10 high-grade gliomas, 7 low-grade gliomas, and 2 meningiomas. RESULTS: Initial course of radiation was radical in intent for all patients. Median age at initial diagnosis was 19.8 years (range: 3.6-67). Median interval between radiation courses was 16.3 months (range: 3.8-166). Median Karnofsky Performance Status (KPS) prior to reirradiation was 80 (range: 40-100). Reirradiation volumes overlapped previous treatment in 30 patients and were nonoverlapping in 4 patients. Fractionation schemes used were hyperfractionated in 17, conventionally fractionated in 9, and hypofractionated in 8. Cumulative maximum overlap dose within the CNS ranged from 43.2-111 Gy (median: 79.7 Gy). Retreatment was completed as planned in 27 out of 34 patients and modified or aborted in 7 (four tumor progression on retreatment, three patient request). As measured from the time of retreatment median progression free and overall survival was 3.3 and 8.3 months. Clinical and radiographic indices were stabilized or improved in about half of patients evaluable at a median of 3 months postretreatment. Complications (early or late) potentially attributable to retreatment were noted in 10 of 34 (29%) of patients. Overt necrosis was noted in 3 of 34 (9%) of patients and the actuarial risk of necrosis was 22% at 1 year following retreatment. CONCLUSIONS: Reirradiation of primary central nervous system tumors was associated with only modest palliative and survival benefits in this retrospective review. Difficulties separating toxicity due to retreatment vs. tumor progression and limited patient survival following retreatment preclude definite conclusions regarding the safety of this practice.

Analysis of the clinical benefit of 5-fluorouracil and radiation treatment in locally advanced pancreatic cancer.

PURPOSE: To assess the palliative benefit of 5-fluorouracil (5-FU) and radiotherapy in patients with surgically unresectable localized pancreatic cancer. METHODS AND MATERIALS: Twenty-five patients with locally advanced surgically unresectable symptomatic pancreatic cancer received 5-FU chemotherapy and local radiation therapy. They were retrospectively reviewed in regard to their clinical benefit response (a composite of measurement of pain assessment, weight, and Karnofsky performance status [KPS]), as well as radiological response, time to progression, and overall survival. RESULTS: Median survival for the 25 patients was 9 months and median progression-free survival was 6 months. Thirty-two percent of patients survived in excess of 1 year. Analgesic requirements increased >50% in 2 patients and KPS deteriorated in 10 patients. Of the 13 remaining patients, 2 sustained a >7% weight loss and 2 gained weight post-treatment. Six patients improved in one parameter of analgesic consumption, weight loss or KPS without deteriorating in any others. Thus, the clinical benefit response index for 5-FU-radiation was 6/25 (24%). In terms of tumor response, 8 patients (44%) demonstrated a reduction in tumor volume post-treatment, 4 of whom (22%) experienced a >50% reduction. Four additional patients had radiologically stable disease. CONCLUSION: In this retrospective analysis, the clinical benefit response index for 5-FU-radiation was 24%, a value similar to the 23.8% reported for single agent gemcitabine. The median survival of 7 months was also similar to the 5.65 months reported for gemcitabine. The radiological partial response rate of 22% and the 1-year survival of 32% were higher for 5-FU-radiation than the reported values for gemcitabine. A randomized trial would be necessary to compare 5-FU-radiation to gemcitabine directly; however, from this review it did not appear that the overall palliative benefit of 5-FU-radiation was inferior to gemcitabine.

Postoperative radiotherapy for Stage I/II seminoma: results for 212 patients.

PURPOSE: A retrospective review of patients with Stage I and II seminoma treated at a regional cancer center was performed to assess the long term efficacy and toxicity associated with post operative radiotherapy. METHODS AND MATERIALS: Between 1950 and 1995, 212 patients seen at the London Regional Cancer Centre received adjuvant radiotherapy following orchiectomy for Stage I (169) and II (43) seminoma. Median follow-up for the group was 7.5 years. RESULTS: Progression free, cause specific, and overall survival were 95%, 98%, and 95% at 5 years, and 94%, 98%, and 94% at 10 years respectively. An increased risk of failure was noted among patients with bulky Stage II disease. No other prognostic factors for relapse were identified. Late toxicity was uncommon with only 12/212 (6%) developing any late GI toxicity potentially attributable to radiotherapy. The incidence of second malignancies (excluding second testicular tumors) was 6/212 (actuarial:1%, 1%, 6% at 5,10,15 years respectively). There was a trend toward increased acute complications for patients treated with larger volumes of radiation. No prognostic factors associated with increased risk of late toxicity or second malignancy were identified, likely a consequence of the small number of these events. CONCLUSION: Survival and toxicity were comparable to that reported in the literature. Post-operative radiotherapy remains a safe and efficacious adjuvant treatment for Stage I and early Stage II seminoma.