Biomedical subjects
Publications and source records attributed to M P Mehta.
We report a case of fibrosarcoma arising in the pineal of a 36-year-old female patient. She died at the age 43 following biopsy, radiation therapy, tumor resection, chemotherapy, and stereotactic radiosurgery. Light microscopic study of all tissues obtained, including immunohistochemistry and electron microscopy of surgically resected tumor and autopsied tissue revealed a slowly progressing primary fibrosarcoma.
The purpose of our study was to examine the extent of patient-independent intrinsic error associated with multiple, repeat remounting of the Laitinen Stereoadapter. The Laitinen frame was repeatedly mounted on a solid water phantom and imaged using computed tomography (CT). The phantom contained five targets located in the center, anterior, right, left, and posterior orientations. The images were processed, fused, and analyzed on the Pinnacle 3-D treatment planning system. The coordinate values (in the x, y, and z directions) for each target were determined for each mounting, and an absolute mean deviation was calculated for 11 repetitions. The mean deviation in the x, y, and z direction for the central and right target, and in the x and y direction for the posterior and anterior target was less than 2.0 mm. However, the mean error in the z direction of the anterior and posterior targets was 1.79 +/- 1.02 mm and 2.20 +/- 1.32 mm, respectively. Rotational misalignment during repeat frame fixation contributed to the observed deviations and in particular affected the antero-posterior plane. With the exception of two occasions where an obvious mounting error occurred, a significant portion of error from remounting the Laitinen Stereoadapter is associated with the operator and the imaging process. The observation of an angular displacement around the axis through the earplugs suggests that a certain degree of rotational misalignment in daily remounting is possible. Targets in the antero-posterior plane are most susceptible to localization error as a consequence of rotational misalignment. In summary, the overall error is within the limits of current imaging technology but not within submillimeter accuracy. Clinical application should take these errors into consideration when designing field margins.
PURPOSE: To estimate the potential improvement in survival for patients with brain metastases, stratified by the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) class and treated with radiosurgery (RS) plus whole brain radiotherapy (WBRT). METHODS AND MATERIALS: An analysis of the RS databases of 10 institutions identified patients with brain metastates treated with RS and WBRT. Patients were stratified into 1 of 3 RPA classes. Survival was evaluated using Kaplan-Meier estimates and proportional hazard regression analysis. A comparison of survival by class was carried out with the RTOG results in similar patients receiving WBRT alone. RESULTS: Five hundred two patients were eligible (261 men and 241 women, median age 59 years, range 26-83). The overall median survival was 10.7 months. A higher Karnofsky performance status (p = 0.0001), a controlled primary (median survival = 11.6 vs. 8.8 months, p = 0.0023), absence of extracranial metastases (median survival 13.4 vs. 9.1 months, p = 0.0001), and lower RPA class (median survival 16.1 months for class I vs. 10.3 months for class II vs. 8.7 months for class III, p = 0.000007) predicted for improved survival. Gender, age, primary site, radiosurgery technique, and institution were not prognostic. The addition of RS boosted results in median survival (16.1, 10.3, and 8.7 months for classes I, II, and III, respectively) compared with the median survival (7.1, 4.2, and 2.3 months, p <0.05) observed in the RTOG RPA analysis for patients treated with WBRT alone. CONCLUSION: In the absence of randomized data, these results suggest that RS may improve survival in patients with BM. The improvement in survival does not appear to be restricted by class for well-selected patients.
PURPOSE: To prospectively evaluate the quality of life (QOL) before, at completion, and after therapy for patients receiving an accelerated fractionation schedule of radiotherapy for advanced, unresectable non-small-cell lung cancer in a Phase II multi-institutional trial. METHODS AND MATERIALS: The Functional Assessment of Cancer Therapy-Lung (FACT-L) patient questionnaire was used to score the QOL in patients enrolled in the Eastern Cooperative Oncology Group Phase II trial (ECOG 4593) of hyperfractionated accelerated radiotherapy in non-small-cell lung cancer. Radiotherapy (total dose 57.6 Gy in 36 fractions) was delivered during 15 days, with three radiation fractions given each treatment day. The protocol was activated in 1993, and 30 patients had accrued by November 1995. The FACT-L questionnaire was administered at study entry (baseline), on the last day of radiotherapy (assessment 2), and 4 weeks after therapy (assessment 3). The FACT-L includes scores for physical, functional, emotional, and social well-being (33 items), and a subscale of lung cancer symptoms (10 additional items). The summation of the physical, functional, and lung cancer symptom subscales (21 items) constitutes the Trial Outcome Index (TOI), considered the most clinically relevant outcome measure in lung cancer treatment trials. RESULTS: The FACT-L completion rates at the designated study time points were as follows: baseline, 30 of 30 (100%); assessment 2, 29 (97%) of 30; and assessment 3, 24 (80%) of 30. At treatment completion, statistically significant declines in QOL scores were noted, compared with baseline for physical and functional well-being. Emotional well-being scores improved at both assessment 2 and assessment 3. The physical and functional scores returned approximately to baseline values at assessment 3. The change in TOI score was evaluated as a function of the clinical response to treatment, toxicity grade, and survival; no clear association was noted. A trend for the largest decrease in QOL was noted for patient groups with shorter survival times. The mean change in the TOI score from baseline to assessment 3 was -8.96 for patients surviving < 52 weeks vs. -0.95 for those surviving > 52 weeks. CONCLUSIONS: The FACT-L questionnaire can be successfully administered to non-small-cell lung cancer patients enrolled in a prospective Phase II trial of accelerated radiation fractionation. The decrement in physical and functional QOL during treatment returned to baseline level at 4 weeks after treatment. Emotional well-being improved at all time points. A trend was noted for shorter survival times in patients with the largest negative change in TOI score. These data suggest that the clinical use of hyperfractionated accelerated radiotherapy did not cause a significant, long-term decrease in the QOL of the treated patients, and that it is feasible to perform a QOL study of patients enrolled in such a trial.
157Gd is a potential agent for neutron capture cancer therapy (GdNCT). We directly observed the microdistribution of Gd in cultured human glioblastoma cells exposed to Gd-diethylenetriaminepentaacetic acid (Gd-DTPA). We demonstrated, with three independent techniques, that Gd-DTPA penetrates the plasma membrane, and we observed no deleterious effect on cell survival. A systematic microchemical analysis revealed a higher Gd accumulation in cell nuclei compared with cytoplasm. This is significant for prospective GdNCT because the proximity of Gd to DNA increases the cell-killing potential of the short-range, high-energy electrons emitted during the neutron capture reaction. We also exposed Gd-containing cells to thermal neutrons and demonstrated the GdNC reaction effectiveness in inducing cell death. These results in vitro stimulated in vivo Gd-DTPA uptake studies, currently underway, in human glioblastoma patients.
PURPOSE: Motexafin gadolinium is a magnetic resonance imaging (MRI)--detectable redox active drug that localizes selectively in tumor cells and enhances the effect of radiation therapy. This phase Ib/II trial of motexafin gadolinium, administered concurrently with 30 Gy in 10 fractions whole-brain radiation therapy (WBRT), was conducted to determine maximum-tolerated dose (MTD), dose-limiting toxicity, pharmacokinetics, and biolocalization in patients with brain metastases. Additional endpoints were radiologic response rate and survival. PATIENTS AND METHODS: Motexafin gadolinium was administered before each radiation treatment in this open-label, multicenter, international trial. In phase Ib, drug dose was escalated until the MTD was exceeded. In phase II, drug was evaluated in a narrow dose range. RESULTS: In phase Ib, the motexafin gadolinium dose was escalated in 39 patients (0.3 mg/kg to 8.4 mg/kg). In phase II, 22 patients received 5 mg/kg to 6.3 mg/kg motexafin gadolinium. Ten once-daily treatments were well tolerated. The MTD was 6.3 mg/kg, with dose-limiting reversible liver toxicity. Motexafin gadolinium's tumor selectivity was established using MRI. The radiologic response rate was 72% in phase II. Median survival was 4.7 months for all patients, 5.4 months for recursive partitioning analysis (RPA) class 2 patients, and 3.8 months for RPA class 3 patients. One-year actuarial survival for all patients was 25%. CONCLUSION: Motexafin gadolinium was well tolerated at doses up to 6.3 mg/kg, was selectively accumulated in tumors, and, when combined with WBRT of 30 Gy in 10 fractions, was associated with a high radiologic response rate.
Lung cancer is the number one worldwide cancer killer, and in spite of therapeutic advances, the overall impact on survival has remained very modest. For both small and non-small-cell lung cancer, treatment trends have shifted toward combined-modality approaches, chemotherapy for the control of systemic micrometastases, and radiotherapy for intrathoracic control. However, on both counts, rates of failure remain unacceptably high, and several novel strategies are currently being explored. The use of altered fractionation, including multiple daily fractions, reflects one approach for modifying radiotherapy. The two most common approaches are hyperfractionation and acceleration, the former designed to reduce late normal tissue toxicities and the latter to counteract accelerated tumor repopulation. Recent randomized trials suggest that such approaches may result not only in lowered rates of intrathoracic failure but also in improved survival.
Late recurrences after therapy are rare in primitive neuro-ectodermal tumor (PNET). Most recurrences occur within the first 2 years after therapy, although a small number of recurrences may occur up to 5 years after therapy. We present a rare case of a recurrence of PNET in a 31-year-old woman 17 years after her initial presentation. The potential biological implications of this late recurrence as well as responses to subsequent therapy, including temozolomide, are discussed.
Over the last 2 years, several advances have been made in the field of radiotherapy for brain tumors. Key advances are summarized in this review. Crucial technologic advances, such as radiosurgery, fractionated stereotactic radiotherapy, and intensity-modulated radiotherapy, are discussed. Better understanding of the interaction between the processes of angiogenesis, apoptosis, cell-cycle regulation, and signal transduction and the effects of ionizing radiation has made it clear that many of these "new agents" are, in fact, valuable modulators of the radiation response. Another exciting molecular discovery is the recognition of radiation-induced promoters that can be exploited to cause spatially and temporally configured expression of selected genes; this approach may represent the ideal application of conformal radiation techniques in the future, yielding well-defined genetic changes in specifically targeted tissues. The final "frontier" covered in this review is the newer categories of radiosensitizers, ranging from topoisomerase-I inhibitors, to expanded metalloporphyrins, to oxygen- dissociating agents.
The North American Brain Tumor Consortium conducted a phase I trial of the combination 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide. Eligibility included a patient with a cancer type that was considered refractory to standard therapy. Prior nitrosourea treatments were not permitted. There were parallel dose escalations in two treatment schedules. Forty-five patients were enrolled during an 18-month period. The maximum tolerated doses (MTDs) when temozolomide followed BCNU (Arm A) were temozolomide at 550 mg/m2/p.o. and BCNU at 150 mg/m2/i.v.), whereas the MTD when temozolomide preceded BCNU (Arm B) was temozolomide at 400 mg/m2/p.o. and BCNU at 100 mg/m2/i.v. Toxicity was predominantly hematologic, although there were three instances of pulmonary toxicity, which in one case could have represented potentiation of nitrosourea-induced pulmonary fibrosis. The half-life of temozolomide was 1.86 (+/-0.31) h. There was a moderate relationship between dose and peak concentration and a strong relationship between dose and plasma concentration time curve. Pharmacokinetic parameters of temozolomide were unaffected by the treatment schedule, so the difference in MTD between the schedules is likely due to a biologic rather than a pharmacokinetic sequence interaction. There were 9 partial responses among 43 patients evaluable for response, including 5 of 25 with a histologic diagnosis of glioblastoma. The recommended dose and schedule for phase II trials of this regimen are BCNU 150 mg/m2/i.v. followed in 2 h by temozolomide 550 mg/m2/p.o. repeated every 6 weeks. We are also recommending screening and periodic pulmonary function testing during treatment to assess the possible potentiation of nitrosourea-induced pulmonary fibrosis.
This article reviews the current role of radiotherapy in the management of non-small-cell lung cancer. This modality is used extensively in lung cancer patients. In a variety of different contexts, the specific indications, results, controversies, and emerging areas are highlighted, with an emphasis on the author's personal techniques and a review of the pertinent literature.
Stereotactic irradiation (radiosurgery) is a method of precisely focusing well-defined beams of radiation at small intracranial targets. The technique has been applied to the treatment of brain lesions that are benign (e.g., arteriovenous malformations, meningiomas, pituitary adenomas) and malignant (e.g., gliomas, metastases). This paper introduces preliminary data suggesting the possible value of radiosurgery in the management of ovarian cancer metastatic to the brain. Among 32 women with ovarian cancer metastatic to the brain treated with whole brain irradiation, nine (29%) experienced a complete radiographic response, compared with two of the five patients (40%) treated with radiosurgery. The 2-year survival rate was 60% among those treated with radiosurgery and 15% among those who received whole brain irradiation without radiosurgical boost. Stereotactic irradiation may be of clinical benefit to select patients with brain metastases resulting from ovarian cancer. A prospective randomized trial has been implemented by the Radiation Therapy Oncology Group (RTOG 95-08) to determine whether such observations are reproducible on a national scale.
OBJECTIVE: To test the spatial accuracy of coordinates generated from magnetic resonance imaging (MRI) scans, using the Brown-Roberts-Wells head frame and localizer system (Radionics, Inc., Burlington, MA). METHODS: An anthropomorphic head phantom, consisting of a two-dimensional lattice of acrylic spheres (4-mm diameter) spaced 10 mm apart and embedded in a brain tissue-mimicking gelatin-agar gel, was constructed. The intersphere distances for the target lattice positions in MRI and computed tomographic scan sets were compared. The data sets were fused, and differences in fiducial marker and intraphantom target positions were measured. RESULTS: Intersphere distances were identical for the MRI and computed tomographic scan sets (10 +/- 0.1 mm). Differences in fiducial marker positions [maximal lateral difference, 0.97 mm; mean absolute lateral difference, 0.69 +/- 0.22 mm; maximal anteroposterior (AP) difference, 1.99 mm; mean absolute AP difference, 1.29 +/- 0.67 mm] were correlated with differences in intraphantom target positions (maximal lateral difference, 0.83 mm; mean absolute lateral difference, 0.28 +/- 0.24 mm; maximal AP difference, -1.97 mm; mean absolute AP difference, 1.63 +/- 25 mm; maximal vertical difference, -0.73 mm; mean absolute vertical difference, 0.34 +/- 0.21 mm). This suggested that improper fiducial rod identification and the subsequent transformation to stereotactic coordinate space were the greatest sources of spatial uncertainty. CONCLUSION: With computed tomographic data as the standard, these differences resulted in maximal and minimal composite uncertainties of 2.06 and 1.17 mm, respectively. The measured uncertainties exceed recommended standards for radiosurgery but allow the possible use of MRI-based stereotactic treatment planning for certain intracranial lesions, if the errors are corrected using appropriate software. Clinicians must recognize that error magnitudes vary for different systems, and they should perform systematic, scheduled, institutional error analyses as part of their ongoing quality assurance processes. This phantom provides one tool for measuring such variances.
PURPOSE: To determine the response rate, time to treatment failure, and toxicity of phenylacetate in patients with recurrent malignant glioma and to identify plasma concentrations achieved during repeated continuous infusion of this agent. PATIENTS AND METHODS: Adult patients with recurrent malignant glioma were treated with phenylacetate. The schedule consisted of a 2-week continuous, intravenous infusion followed by a 2-week rest period (14 days on, 14 days off). A starting dose of 400 mg/kg total body weight per day of phenylacetate was initially used and subsequently changed to 400 mg/kg/d based on ideal body weight. Intrapatient dose escalations were allowed to a maximum of 450 mg/kg ideal body weight/d. Tumor response was assessed every 8 weeks. The National Cancer Institute common toxicity criteria were used to assess toxicity. Plasma concentrations achieved during the patients' first two 14-day infusions were assessed. RESULTS: Forty-three patients were enrolled between December 1994 and December 1996. Of these, 40 patients were assessable for toxicity and response to therapy. Reversible symptoms of fatigue and somnolence were the primary toxicities, with only mild hematologic toxicity. Thirty (75%) of the 40 patients failed treatment within 2 months, seven (17.5%) had stable disease, and three (7.5%) had a response defined as more than 50% reduction in the tumor. Median time to treatment failure was 2 months. Thirty-five patients have died, with a median survival of 8 months. Pharmacokinetic data for this dose schedule showed no difference in the mean plasma concentrations of phenylacetate between weeks 1 and 2 or between weeks 5 and 6. CONCLUSION: Phenylacetate has little activity at this dose schedule in patients with recurrent malignant glioma. Further studies with this drug would necessitate an evaluation of a different dose schedule.
Brain metastases represent the most common intracranial neoplasm, and they have become the most common indication for radiosurgery. The authors present a review summarizing the major issues surrounding the management of brain metastases and an English-language literature review of 21 independent reports, using either Gamma Knife or linear accelerator-based radiosurgery, with over 1700 patients and more than 2700 lesions available for analysis.
Recent interest has focused on the use of amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) as a possible multiorgan combined-modality protector. Amifostine has been shown to selectively protect normal tissues from the cytotoxic and mutagenic effects of alkylating and platinum-based chemotherapy and ionizing radiation. There are a number of approaches to ameliorating therapy-related toxicities, including the use of individual agents that target specific toxicities. However, amifostine is unique in that it possesses a broad range of tissue-protective effects. Amifostine has been studied in clinical trials comprising patients with lung cancer, head and neck cancer, and cancer of the cervix. Results of these trials show that amifostine can be safely administered to patients receiving chemotherapy and radiation therapy. These trials also demonstrate that amifostine has the potential to be a broad-spectrum cytoprotectant of normal tissues from the toxicities of radiation, as well as certain forms of chemotherapy. The selective cytoprotective effects of amifostine allow for the use of higher doses of cytotoxic therapy. Theoretically, this could improve therapeutic outcome in patients with cancer.
Worldwide, approximately 100,000 patients have undergone stereotactic radiosurgery for a variety of intracranial lesions, of which brain metastases represent the most common treatment indication. This article summarizes the major issues surrounding the management of brain metastases, and also analyzes 21 independent reports of Gamma Knife- or linear accelerator-based radiosurgery, representing over 1,700 patients and more than 2,700 lesions. Variable reporting in the studies precludes a definitive, rigorous analysis, but the composite data reveal an average local control rate of 83% and median survival of 9.6 months, both of which are comparable to results in recent surgical reports. The most important prognostic factors for survival appear to be fewer than three lesions, controlled extracranial disease, and Karnofsky performance score (KPS). The exact impact of dose has not been clarified, but a dose-response relationship, especially for > or = 18 Gy, is emerging. The role of whole-brain radiotherapy remains unresolved. It may enhance local control but does not convincingly improve survival and, in some series, is associated with an increased risk of late complications. Chronic steroid dependence and increased intracranial edema do not appear to be common problems. This is an opportune time for the completion of ongoing randomized trials to validate these observations.
BACKGROUND: Electronic tools with substantial educational applications are now widely available. METHODS: In a prospective, randomized study, the value of Web-based educational tools for teaching second-year medical students was evaluated. The 35-hour, image-intensive multifaculty neoplasia course was selected for the experiment, with 103 students assigned to the control group (C) and 61 to the experimental group (E). Representative password-controlled multimedia course modules, accessible via the Internet, were developed. The E cohort was exposed to both classroom and Web-aided materials, whereas the C group had access to the Web modules only after the experiment was concluded (but before the final examination). Pre- and post-exposure questionnaires assessed computer knowledge, familiarity with the Internet, availability of computer access, and the value of Web-based education for both cohorts. Additionally, pre-and post-exposure tests were administered to both cohorts based on educational materials presented in the Web modules. RESULTS: The overall participation rate was 64% (E = 69%; C = 60%). The post-test showed no major performance difference between the two groups. The questionnaires revealed that: less than 1% of the students had not accessed the Internet previously; less than 5% had not used the Internet for medical education before; 34% felt that computer resources on campus were inadequate; and over 75% found Web-based education to be an important additional educational resource. The major negative aspect was the slow pace of data transfer for modem-based home access. Only 1% of students felt that Web-based education could completely replace traditional teaching. CONCLUSION: The potential for incorporating Web-based education in the medical curriculum is considerable.