Manjeet Chadha

Biodistribution of boronophenylalanine in patients with glioblastoma multiforme: boron concentration correlates with tumor cellularity.

Boron-10 (10B) concentrations were measured in 107 surgical samples from 15 patients with glioblastoma multiforme who were infused with 95 atom% 10B-enriched p-boronophenylalanine (BPA) intravenously for 2 h just prior to surgery at doses ranging from 98 to 290 mg BPA/kg body weight. The blood 10B concentration reached a maximum at the end of the infusion (ranging from 9.3 to 26.0 microg 10B/g) and was proportional to the amount of BPA infused. The boron concentrations in excised tumor samples ranged from 2.7 to 41.3 microg 10B/g over the range of administered BPA doses and varied considerably among multiple samples from individual patients and among patients at the same BPA dose. A morphometric index of the density of viable-appearing tumor cells in histological sections obtained from samples adjacent to, and macroscopically similar to, the tumor samples used for boron analysis correlated linearly with the boron concentrations. From that correlation it is estimated that 10B concentrations in glioblastoma tumor cells were over four times greater than concurrent blood 10B concentrations. Thus, in the dose range of 98 to 290 mg BPA/kg, the accumulation of boron in tumor cells is a linear function of BPA dose and the variations observed in boron concentrations of tumor specimens obtained surgically are largely due to differences in the proportion of nontumor tissue (i.e. necrotic tissue, normal brain) present in the samples submitted for boron analysis. The tumor:blood 10B concentration ratio derived from this analysis provides a rationale for estimating the fraction of the radiation dose to viable tumor cells resulting from the boron neutron capture reaction based on measured boron concentrations in the blood at the time of BNCT without the need for analysis of tumor samples from individual patients.

Boron neutron capture therapy for glioblastoma multiforme using p-boronophenylalanine and epithermal neutrons: trial design and early clinical results.

A Phase I/II clinical trial of boron neutroncapture therapy (BNCT) for glioblastoma multiforme is underwayusing the amino acid analog p-boronophenylalanine (BPA) andthe epithermal neutron beam at the Brookhaven MedicalResearch Reactor. Biodistribution studies were carried out in18 patients at the time of craniotomy usingan i.v. infusion of BPA, solubilized as afructose complex (BPA-F). There were no toxic effectsrelated to the BPA-F administration at doses of130, 170, 210, or 250 mg BPA/kg bodyweight. The tumor/blood, brain/blood and scalp/blood boron concentrationratios were approximately 3.5:1, 1:1 and 1.5:1, respectively.Ten patients have received BNCT following 2-hr infusionsof 250 mg BPA/kg body weight. The averageboron concentration in the blood during the irradiationwas 13.0 ± 1.5 μg 10B/g. The prescribedmaximum dose to normal brain (1 cm3 volume)was 10.5 photon-equivalent Gy (Gy-Eq). Estimated maximum andminimum doses (mean ± sd, n=10)to the tumor volume were 52.6 ± 4.9Gy-Eq (range: 64.4–47.6) and 25.2 ± 4.2 Gy-Eq(range: 32.3–20.0), respectively). The estimated minimum dose tothe target volume (tumor + 2 cm margin)was 12.3 ± 2.7 Gy-Eq (range: 16.2–7.8). Therewere no adverse effects on normal brain. Thescalp showed mild erythema, followed by epilation inthe 8 cm diameter field. Four patients developedrecurrent tumor, apparently in the lower dose (deeper)regions of the target volume, at post-BNCT intervalsof 7, 5, 3.5 and 3 months, respectively.The remaining patients have had less than 4months of post-BNCT follow-up. BNCT, at this startingdose level, appears safe. Plans are underway tobegin the dose escalation phase of this protocol.

Boron Neutron-Capture Therapy (BNCT) for Glioblastoma Multiforme (GBM) Using the Epithermal Neutron Beam at the Brookhaven National Laboratory

OBJECTIVE Boron neutron-capture therapy (BNCT) is a binary form of radiation therapy based on the nuclear reactions that occur when boron (10B) is exposed to thermal neutrons. Preclinical studies have demonstrated the therapeutic efficacy of p-boronophenylalanine (BPA)-based BNCT. The objectives of the Phase I/II trial were to study the feasibility and safety of single-fraction BNCT in patients with GBM. MATERIALS AND METHODS The trial design required (a) a BPA biodistribution study performed at the time of craniotomy; and (b) BNCT within approximately 4 weeks of the biodistribution study. From September 1994 to July 1995, 10 patients were treated. For biodistribution, patients received a 2-hour intravenous (i.v.) infusion of BPA-fructose complex (BPA-F). Blood samples, taken during and after infusion, and multiple tissue samples collected during surgical debulking were analyzed for 10B concentration. For BNCT, all patients received a dose of 250 mg BPA/kg administered by a 2-hour i.v. infusion of BPA-F, followed by neutron beam irradiation at the Brookhaven Medical Research Reactor (BMRR). The average blood 10B concentrations measured before and during treatment were used to calculate the time of reactor irradiation that would deliver the prescribed dose. RESULTS 10B concentrations in specimens of scalp and tumor were higher than in blood by factors of approximately 1.5 and approximately 3.5, respectively. The 10B concentration in the normal brain was < or = that in the blood; however, for purposes of estimating radiation doses to normal brain endothelium, it was always assumed to be equal to blood. BNCT doses are expressed as gray-equivalent (Gy-Eq), which is the sum of the various physical dose components multiplied to appropriate biologic effectiveness factors. The dose to a 1-cm3 volume where the thermal flux reached a maximum was 10.6 +/- 0.3 Gy-Eq in 9 patients and 13.8 Gy-Eq in 1 patient. The minimum dose in tumor ranged from 20 to 32.3 Gy-Eq. The minimum dose in the target volume (tumor plus 2 cm margin) ranged from 7.8 to 16.2 Gy-Eq. Dose to scalp ranged from 10 to 16 Gy-Eq. All patients experienced in-field alopecia. No CNS toxicity attributed to BNCT was observed. The median time to local disease progression following BNCT was 6 months (range 2.7 to 9.0). The median time to local disease progression was longer in patients who received a higher tumor dose. The median survival time from diagnosis was 13.5 months. CONCLUSION It is feasible to safely deliver a single fraction of BPA-based BNCT. At the dose prescribed, the patients did not experience any morbidity. To further evaluate the therapeutic efficacy of BNCT, a dose-escalation study delivering a minimum target volume dose of 17 Gy-Eq is in progress.

Squamous-cell carcinoma of the anus in HIV-positive patients

PURPOSE: Patients diagnosed as having anal cancer and human immunodeficiency virus (HIV)-positive disease were evaluated for response to treatment and its associated toxicity. METHODS: We studied nine HIV-positive patients with squamous-cell carcinoma of the anus. Among them, three patients had acquired immunodeficiency syndrome (AIDS). The stage of disease at presentation included: one Stage 0, two Stage I, two Stage II, and four Stage III patients. Seven patients received combined modality treatment,i.e.,radiation therapy and chemotherapy, and two patients received radiation therapy alone. The radiation therapy field included the pelvis and a conedown boost. Chemotherapy consisted of two cycles of 5-fluorouracil and mitomycin C. Patients have been followed from 2 to 42 (median, 8) months. RE-SULTS: Seven patients achieved a complete response clinically. All Stage I/II patients and one of four Stage III patients remain alive and have no evidence of disease. Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer Grades 3 and 4 skin toxicity were noted in six patients, and Grades 2 and 3 myelosuppression were noted in eight patients. The response rates achieved are comparable to the experience in non-HIV patients reported in the literature, but toxicity seems to be increased. CONCLUSION: It would seem reasonable to offer combined modality treatment to early stage, HIV-positive patients with good performance status and a history of minor opportunistic infections. The value of combined modality in AIDS patients and those who present with advanced stages of the disease is questionable.

Computational dosimetry and treatment planning for Boron Neutron Capture Therapy

The technology for computational dosimetry and treatment planning for Boron Neutron Capture Therapy (BNCT) has advanced significantly over the past few years. Because of the more complex nature of the problem, the computational methods that work well for treatment planning in photon radiotherapy are not applicable to BNCT. The necessary methods have, however, been developed and have been successfully employed both for research applications as well as human trials, although further improvements in speed are needed for routine clinical applications. Computational geometry for BNCT applications can be constructed directly from tomographic medical imagery and computed radiation dose distributions can be readily displayed in formats that are familiar to the radiotherapy community.

The feasibility of a second lumpectomy and breast brachytherapy for localized cancer in a breast previously treated with lumpectomy and radiation therapy for breast cancer

PURPOSE With accumulating evidence supporting partial-breast irradiation, we conducted a Phase I/II study to evaluate the role of a second conservative surgery and brachytherapy for patients presenting with a local recurrence/new primary in a breast who has previously undergone a lumpectomy and external radiation therapy for breast cancer. METHODS AND MATERIALS Fifteen patients with a localized lesion in the breast have undergone a second lumpectomy and received low-dose-rate brachytherapy on protocol. The first 6 patients received a dose of 30Gy. With no unacceptable acute toxicity observed, the brachytherapy dose was increased to 45Gy. Three patients received adjuvant chemotherapy and 8 patients are on antiestrogen therapy. RESULTS The median time interval between the primary breast cancer diagnosis and the second cancer event in the ipsilateral breast is 94 months (range, 28-211). With a median followup of 36 months after brachytherapy, the 3-year Kaplan-Meier overall survival, local disease-free survival and mastectomy-free survival are 100% and 89%, respectively. There was no Grade 3/4 fibrosis or necrosis observed. All patients had baseline asymmetry due to the breast volume deficit from the second lumpectomy. With breast asymmetry as a given, the cosmetic result observed in all patients has been good to excellent. CONCLUSIONS Early results suggest low-complication rates, high rate of local control and freedom from mastectomy. Additional studies are needed to establish whether a second lumpectomy and breast brachytherapy are an acceptable alternative to mastectomy for patients presenting with a localized cancer in a previously irradiated breast.

Early-Stage Breast Cancer Treated With 3-Week Accelerated Whole-Breast Radiation Therapy and Concomitant Boost

PURPOSE To report early outcomes of accelerated whole-breast radiation therapy with concomitant boost. METHODS AND MATERIALS This is a prospective, institutional review board-approved study. Eligibility included stage TisN0, T1N0, and T2N0 breast cancer. Patients receiving adjuvant chemotherapy were ineligible. The whole breast received 40.5 Gy in 2.7-Gy fractions with a concomitant lumpectomy boost of 4.5 Gy in 0.3-Gy fractions. Total dose to the lumpectomy site was 45 Gy in 15 fractions over 19 days. RESULTS Between October 2004 and December 2010, 160 patients were treated; stage distribution was as follows: TisN0, n = 63; T1N0, n = 88; and T2N0, n = 9. With a median follow-up of 3.5 years (range, 1.5-7.8 years) the 5-year overall survival and disease-free survival rates were 90% (95% confidence interval [CI] 0.84-0.94) and 97% (95% CI 0.93-0.99), respectively. Five-year local relapse-free survival was 99% (95% CI 0.96-0.99). Acute National Cancer Institute/Common Toxicity Criteria grade 1 and 2 skin toxicity was observed in 70% and 5%, respectively. Among the patients with ≥ 2-year follow-up no toxicity higher than grade 2 on the Late Effects in Normal Tissues-Subjective, Objective, Management, and Analytic scale was observed. Review of the radiation therapy dose-volume histogram noted that ≥ 95% of the prescribed dose encompassed the lumpectomy target volume in >95% of plans. The median dose received by the heart D05 was 215 cGy, and median lung V20 was 7.6%. CONCLUSIONS The prescribed accelerated schedule of whole-breast radiation therapy with concomitant boost can be administered, achieving acceptable dose distribution. With follow-up to date, the results are encouraging and suggest minimal side effects and excellent local control.

Radiation Therapy of Metastatic Pheochromocytoma: Case Report and Review of the Literature

Malignant pheochromocytomas are rare tumors, which are considered radioresistant on the basis of little information. We report a patient, with cranial nerve deficits from a pheochromocytoma metastatic to the parasellar region, who promptly responded to radiation therapy (2,500 cGy) with reversal of neurologic deficit. The disease recurred 2 years later and again promptly responded upon treatment to 2,000 cGy. Hepatic metastases were controlled for over 1 year with 3,240 cGy. The radiotherapy of pheochromocytoma and chemodectoma is reviewed, and the similarities between the two kinds of tumor are discussed. We speculate that a higher initial radiation dose might have resulted in a more sustained remission in our patient and recommend doses of 4,000-5,000 cGy if they can be safely administered, in 4-5 weeks for pheochromocytomas.

Outcomes of Guided Imagery in Patients Receiving Radiation Therapy for Breast Cancer

Guided imagery is an established intervention in integrative oncology. This study was initiated to evaluate the impact of guided imagery on patients undergoing radiation therapy for breast cancer. Eligible patients receiving guided imagery sessions were monitored via biofeedback before and after each session. Monitored measures included blood pressure, respiration rate, pulse rate, and skin temperature. In addition, the EuroQoL Groups EQ-5D questionnaire was used for subjective assessment and patient feedback was collected at the end of radiation therapy through a satisfaction survey. Measured parameters revealed statistically significant improvement from baseline, with decreases noted in respiration rate and pulse rate as well as systolic and diastolic blood pressure. Skin temperature increased, indicating more peripheral capillary flow secondary to a decrease in the sympathetic response. Overall, 86% of participants described the guided imagery sessions as helpful, and 100% said they would recommend the intervention to others. The results of this study illustrate the positive impact of guided imagery as measured through subjective and objective parameters. Improving the overall care for patients with breast cancer supports the value of incorporating practices of integrative oncology into standard practice.

A Phase 1 Trial of Intravenous Boronophenylalanine-Fructose Complex in Patients with Glioblastoma Multiforme

Boron neutron capture therapy (BNCT) of glioblastoma multiforme was initially performed at the Brookhaven National Laboratory in the early 1950`s While this treatment for malignant brain tumors has continued in Japan, new worldwide interest has been stimulated by the development of new and more selective boron compounds. Boronophenylalanine (BPA) is a blood-brain barrier penetrating compound that has been used in BNCT of malignant melanomas. SPA has been employed experimentally in BNCT of rat gliosarcoma and has potential use in the treatment of human glioblastoma. As a preface to clinical BNCT trials, we studied the biodistribution of SPA in patients with glioblastoma.