Nilendu Gupta

The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the endometrium

PURPOSE To develop recommendations for use of high-dose-rate (HDR) brachytherapy in patients with endometrial cancer. METHODS A panel of members of the American Brachytherapy Society (ABS) performed a literature review, supplemented their clinical experience, and formulated recommendations for endometrial HDR brachytherapy. RESULTS The ABS endorses the National Comprehensive Cancer Network (NCCN) guidelines for indications for radiation therapy for patients with endometrial cancer and the guidelines on HDR quality assurance of the American Association on Physicists in Medicine (AAPM). The ABS made specific recommendations for HDR applicator selection, insertion techniques, target volume definition, dose fractionation, and specifications for postoperative adjuvant vaginal cuff therapy, for vaginal recurrences, and for medically inoperable primary endometrial cancer patients. The ABS recommends that applicator selection should be based on patient and target volume geometry. The dose prescription point should be clearly specified. The treatment plan should be optimized to conform to the target volume whenever possible while recognizing the limitations of computer optimization. Suggested doses were tabulated for treatment with HDR alone, and in combination with external beam radiation therapy (EBRT), when applicable. For intravaginal brachytherapy, the largest diameter applicator should be selected to ensure close mucosal apposition. Doses should be reported both at the vaginal surface and at 0.5-cm depth irrespective of the dose prescription point. For vaginal recurrences, intracavitary brachytherapy should be restricted to patients with nonbulky (< 0.5-cm thick) disease. Patients with bulky (> 0.5-cm thick) recurrences should be treated with interstitial techniques. For medically inoperable patients, an appropriate applicator that will allow adequate irradiation of the entire uterus should be selected. CONCLUSION Recommendations are made for HDR brachytherapy for endometrial cancer. Practitioners and cooperative groups are encouraged to use these recommendations to formulate their treatment and dose reporting policies. This will lead to meaningful comparisons of reports from different institutions and lead to advances and appropriate use of HDR.

Boron neutron capture therapy of brain tumors: an emerging therapeutic modality.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10, a stable isotope, is irradiated with low-energy thermal neutrons to yield alpha particles and recoiling lithium-7 nuclei. For BNCT to be successful, a large number of 10B atoms must be localized on or preferably within neoplastic cells, and a sufficient number of thermal neutrons must be absorbed by the 10B atoms to sustain a lethal 10B (n, alpha) lithium-7 reaction. There is a growing interest in using BNCT in combination with surgery to treat patients with high-grade gliomas and possibly metastatic brain tumors. The present review covers the biological and radiobiological considerations on which BNCT is based, boron-containing low- and high-molecular weight delivery agents, neutron sources, clinical studies, and future areas of research. Two boron compounds currently are being used clinically, sodium borocaptate and boronophenylalanine, and a number of new delivery agents are under investigation, including boronated porphyrins, nucleosides, amino acids, polyamines, monoclonal and bispecific antibodies, liposomes, and epidermal growth factor. These are discussed, as is optimization of their delivery. Nuclear reactors currently are the only source of neutrons for BNCT, and the fission reaction within the core produces a mixture of lower energy thermal and epithermal neutrons, fast or high-energy neutrons, and gamma-rays. Although thermal neutron beams have been used clinically in Japan to treat patients with brain tumors and cutaneous melanomas, epithermal neutron beams now are being used in the United States and Europe because of their superior tissue-penetrating properties. Currently, there are clinical trials in progress in the United States, Europe, and Japan using a combination of debulking surgery and then BNCT to treat patients with glioblastomas. The American and European studies are Phase I trials using boronophenylalanine and sodium borocaptate, respectively, as capture agents, and the Japanese trial is a Phase II study. Boron compound and neutron dose escalation studies are planned, and these could lead to Phase II and possibly to randomized Phase III clinical trials that should provide data regarding therapeutic efficacy.

A simple method of obtaining equivalent doses for use in HDR brachytherapy

PURPOSE To develop a simple program that can be easily used by clinicians to calculate the tumor and late tissue equivalent doses (as if given in 2 Gy/day fractions) for different high-dose-rate (HDR) brachytherapy regimens. The program should take into account the normal tissue sparing effect of brachytherapy. METHODS AND MATERIALS Using Microsoft Excel, a program was developed incorporating the linear-quadratic (LQ) formula to calculate the biologically equivalent dose (BED). To express the BED in terms more familiar to all clinicians, it was reconverted to equivalent doses as if given as fractionated irradiation at 2 Gy/fraction. Since doses given to normal tissues in HDR brachytherapy treatments are different from those given to tumor, a normal tissue dose modifying factor (DMF) was applied in this spreadsheet (depending on the anticipated dose to normal tissue) to obtain more realistic equivalent normal tissue effects. RESULTS The spreadsheet program created requires the clinician to enter only the external beam total dose and dose/fraction, HDR dose, and the number of HDR fractions. It automatically calculates the equivalent doses for tumor and normal tissue effects, respectively. Generally, the DMF applied is < 1 since the doses to normal tissues are less than the doses to the tumor. However, in certain circumstances, a DMF of > 1 may need to be applied if the dose to critical normal tissues is higher than the dose to tumor. Additionally, the alpha/beta ratios for tumor and normal tissues can be changed from their default values of 10 Gy and 3 Gy, respectively. This program has been used to determine HDR doses needed for treatment of cancers of the cervix, prostate, and other organs. It can also been used to predict the late normal tissue effects, alerting the clinician to the possibility of undue morbidity of a new HDR regimen. CONCLUSION A simple Excel spreadsheet program has been developed to assist clinicians to easily calculate equivalent doses to be used in HDR brachytherapy regimens. The novelty of this program is that the equivalent doses are expressed as if given at 2 Gy per fraction rather than as BED values and a more realistic equivalent normal tissue effect is obtained by applying a DMF. Its ease of use should promote the use of LQ radiobiological modeling to determine doses to be used for HDR brachytherapy. The program is to be used judiciously as a guide only and should be correlated with clinical outcome.

The american brachytherapy society recommendations for low-dose-rate brachytherapy for carcinoma of the cervix

PURPOSE This report presents guidelines for using low-dose-rate (LDR) brachytherapy in the management of patients with cervical cancer. METHODS Members of the American Brachytherapy Society (ABS) with expertise in LDR brachytherapy for cervical cancer performed a literature review, supplemented by their clinical experience, to formulate guidelines for LDR brachytherapy of cervical cancer. RESULTS The ABS strongly recommends that radiation treatment for cervical carcinoma (with or without chemotherapy) should include brachytherapy as a component. Precise applicator placement is essential for improved local control and reduced morbidity. The outcome of brachytherapy depends, in part, on the skill of the brachytherapist. Doses given by external beam radiotherapy and brachytherapy depend upon the initial volume of disease, the ability to displace the bladder and rectum, the degree of tumor regression during pelvic irradiation, and institutional practice. The ABS recognizes that intracavitary brachytherapy is the standard technique for brachytherapy for cervical carcinoma. Interstitial brachytherapy should be considered for patients with disease that cannot be optimally encompassed by intracavitary brachytherapy. The ABS recommends completion of treatment within 8 weeks, when possible. Prolonging total treatment duration can adversely affect local control and survival. Recommendations are made for definitive and postoperative therapy after hysterectomy. Although recognizing that many efficacious LDR dose schedules exist, the ABS presents suggested dose and fractionation schemes for combining external beam radiotherapy with LDR brachytherapy for each stage of disease. The dose prescription point (point A) is defined for intracavitary insertions. Dose rates of 0.50 to 0.65 Gy/h are suggested for intracavitary brachytherapy. Dose rates of 0.50 to 0.70 Gy/h to the periphery of the implant are suggested for interstitial implant. Use of differential source activity or loading minimizes excessive central dose rates. These recommendations are intended only as guidelines. The responsibility for medical decisions ultimately rests with the treating radiation oncologist. CONCLUSION Guidelines are suggested for LDR brachytherapy for cervical cancer. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose-reporting policies.

In vivo imaging of changes in tumor oxygenation during growth and after treatment.

A novel procedure for in vivo imaging of the oxygen partial pressure (pO2) in implanted tumors is reported. The procedure uses electron paramagnetic resonance imaging (EPRI) of oxygen‐sensing nanoprobes embedded in the tumor cells. Unlike existing methods of pO2 quantification, wherein the probes are physically inserted at the time of measurement, the new approach uses cells that are preinternalized (labeled) with the oxygen‐sensing probes, which become permanently embedded in the developed tumor. Radiation‐induced fibrosarcoma (RIF‐1) cells, internalized with nanoprobes of lithium octa‐n‐butoxy‐naphthalocyanine (LiNc‐BuO), were allowed to grow as a solid tumor. In vivo imaging of the growing tumor showed a heterogeneous distribution of the spin probe, as well as oxygenation in the tumor volume. The pO2 images obtained after the tumors were exposed to a single dose of 30‐Gy X‐radiation showed marked redistribution as well as an overall increase in tissue oxygenation, with a maximum increase 6 hr after irradiation. However, larger tumors with a poorly perfused core showed no significant changes in oxygenation. In summary, the use of in vivo EPR technology with embedded oxygen‐sensitive nanoprobes enabled noninvasive visualization of dynamic changes in the intracellular pO2 of growing and irradiated tumors. Magn Reson Med 57:950–959, 2007.

Combination of boron neutron capture therapy and external beam radiotherapy for brain tumors.

PURPOSE Boron neutron capture therapy (BNCT) has been used clinically as a single modality treatment for high-grade gliomas and melanomas metastatic to the brain. The purpose of the present study was to determine whether its efficacy could be enhanced by an X-ray boost administered after BNCT. Two brain tumor models were used, the F98 glioma as a model for primary brain tumors and the MRA 27 human melanoma as a model for metastatic brain tumors. METHODS AND MATERIALS For biodistribution studies, either 10(5) F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats or 10(6) MRA 27 melanoma cells were implanted intracerebrally into National Institutes of Health (NIH)-rnu nude rats. Biodistribution studies were performed 11-13 days after implantation of the F98 glioma and 20-24 days after implantation of the MRA 27 melanoma. Animals bearing the F98 glioma received a combination of two boron-containing drugs, sodium borocaptate at a dose of 30 mg/kg and boron phenylalanine (BPA) at a dose of 250 mg/kg. MRA 27 melanoma-bearing rats received BPA (500 mg/kg) containing an equivalent amount of 10B (27 mg B/kg). The drugs were administered by either intracarotid or i.v. injection. RESULTS The tumor boron concentration after intracarotid injection was approximately 50% greater in the F98 glioma and MRA 27 melanoma after intracarotid injection (20.8 and 36.8 microg/g, respectively) compared with i.v. injection (11.2 and 19.5 microg/g, respectively). BNCT was carried out at the Brookhaven National Laboratory Medical Research Reactor approximately 14 days after tumor implantation of either the F98 glioma or the MRA 27 melanoma. Approximately 7-10 days after BNCT, subsets of animals were irradiated with 6-MV photons, produced by a linear accelerator at a total dose of 15 Gy, delivered in 5-Gy daily fractions. F98 glioma-bearing rats that received intracarotid or i.v. sodium borocaptate plus BPA, followed 2.5 h later by BNCT and 7-10 days later by X-rays, had similar mean survival times (61 days and 53 days, respectively, p = 0.25), and the non X-irradiated, BNCT-treated animals had a mean survival time of 52 and 40 days, respectively, for intracarotid vs. i.v. injection; the latter was equivalent to that of the irradiated animals. The corresponding survival time for MRA 27 melanoma-bearing rats that received intracarotid or i.v. BPA, followed by BNCT and then X-irradiation, was 75 and 82 days, respectively (p = 0.5), 54 days without X-irradiation (p = 0.0002), 37 days for X-irradiation alone, and 24 days for untreated controls. In contrast to the data obtained with the F98 glioma, MRA 27 melanoma-bearing rats that received i.v. BPA, followed by BNCT, had a highly significant difference in mean survival time compared with the irradiated controls (54 vs. 37 days, p = 0.008). CONCLUSION Our data are the first to suggest that a significant therapeutic gain may be obtained when BNCT is combined with an X-ray boost. Additional experimental studies are required to determine the optimal combination of X-radiation and neutron doses and whether it is more advantageous to administer the photon boost before or after BNCT.

Boron Neutron Capture Therapy of Brain Tumors: Biodistribution, Pharmacokinetics, and Radiation Dosimetry of Sodium Borocaptate in Patients with Gliomas

OBJECTIVEThe purpose of this study was to obtain tumor and normal brain tissue biodistribution data and pharmacokinetic profiles for sodium borocaptate (Na2B12H11SH) (BSH), a drug that has been used clinically in Europe and Japan for boron neutron capture therapy of brain tumors. The study was performed with a group of 25 patients who had preoperative diagnoses of either glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) and were candidates for debulking surgery. Nineteen of these patients were subsequently shown to have histopathologically confirmed diagnoses of GBM or AA, and they constituted the study population. METHODSBSH (non-10 B-enriched) was infused intravenously, in a 1-hour period, at doses of 15, 25, and 50 mg boron/kg body weight (corresponding to 26.5, 44.1, and 88.2 mg BSH/kg body weight, respectively) to groups of 3, 3, and 13 patients, respectively. Multiple samples of tumor tissue, brain tissue around the tumors, and normal brain tissue were obtained at either 3 to 7 or 13 to 15 hours after infusion. Blood samples for pharmacokinetic studies were obtained at times up to 120 hours after termination of the infusion. Sixteen of the patients underwent surgery at the Beijing Neurosurgical Institute and three at The Ohio State University, where all tissue samples were subsequently analyzed for boron content by direct current plasma-atomic emission spectroscopy. RESULTSBlood boron values peaked at the end of the infusion and then decreased triexponentially during the 120-hour sampling period. At 6 hours after termination of the infusion, these values had decreased to 20.8, 29.1, and 62.6 &mgr;g/ml for boron doses of 15, 25, and 50 mg/kg body weight, respectively. For a boron dose of 50 mg/kg body weight, the maximum (mean ± standard deviation) solid tumor boron values at 3 to 7 hours after infusion were 17.1 ± 5.8 and 17.3 ± 10.1 &mgr;g/g for GBMs and AAs, respectively, and the mean tumor value averaged across all samples was 11.9 &mgr;g/g for both GBMs and AAs. In contrast, the mean normal brain tissue values, averaged across all samples, were 4.6 ± 5.1 and 5.5 ± 3.9 &mgr;g/g and the tumor/normal brain tissue ratios were 3.8 and 3.2 for patients with GBMs and AAs, respectively. The large standard deviations indicated significant heterogeneity in uptake in both tumor and normal brain tissue. Regions histopathologically classified either as a mixture of tumor and normal brain tissue or as infiltrating tumor exhibited slightly lower boron concentrations than those designated as solid tumor. After a dose of 50 mg/kg body weight, boron concentrations in blood decreased from 104 &mgr;g/ml at 2 hours to 63 &mgr;g/ml at 6 hours and concentrations in skin and muscle were 43.1 and 39.2 &mgr;g/g, respectively, during the 3- to 7-hour sampling period. CONCLUSIONWhen tumor, blood, and normal tissue boron concentrations were taken into account, the most favorable tumor uptake data were obtained with a boron dose of 25 mg/kg body weight, 3 to 7 hours after termination of the infusion. Although blood boron levels were high, normal brain tissue boron levels were almost always lower than tumor levels. However, tumor boron concentrations were less than those necessary for boron neutron capture therapy, and there was significant intratumoral and interpatient variability in the uptake of BSH, which would make estimation of the radiation dose delivered to the tumor very difficult. It is unlikely that intravenous administration of a single dose of BSH would result in therapeutically useful levels of boron. However, combining BSH with boronophenylalanine, the other compound that has been used clinically, and optimizing their delivery could increase tumor boron uptake and potentially improve the efficacy of boron neutron capture therapy.

Predicting outcomes in cervical cancer: a kinetic model of tumor regression during radiation therapy.

Applications of mathematical modeling can improve outcome predictions of cancer therapy. Here we present a kinetic model incorporating effects of radiosensitivity, tumor repopulation, and dead-cell resolving on the analysis of tumor volume regression data of 80 cervical cancer patients (stages 1B2-IVA) who underwent radiation therapy. Regression rates and derived model parameters correlated significantly with clinical outcome (P < 0.001; median follow-up: 6.2 years). The 6-year local tumor control rate was 87% versus 54% using radiosensitivity (2-Gy surviving fraction S(2) < 0.70 vs. S(2) > or = 0.70) as a predictor (P = 0.001) and 89% vs. 57% using dead-cell resolving time (T(1/2) < 22 days versus T(1/2) > or = 22 days, P < 0.001). The 6-year disease-specific survival was 73% versus 41% with S(2) < 0.70 versus S(2) > or = 0.70 (P = 0.025), and 87% vs. 52% with T(1/2) < 22 days versus T(1/2) > or = 22 days (P = 0.002). Our approach illustrates the promise of volume-based tumor response modeling to improve early outcome predictions that can be used to enable personalized adaptive therapy.

Stereotactic radiosurgery with or without whole brain radiotherapy for patients with a single radioresistant brain metastasis.

Purpose:To examine the outcomes of patients with a single brain metastasis from radioresistant histologies (renal cell carcinoma and melanoma) treated with stereotactic radiosurgery (SRS) with or without whole brain radiotherapy (WBRT). Methods and Materials:We reviewed the medical records of 27 patients treated at our institution between 2000 and 2007 with a single radioresistant brain metastasis. Patients were treated with Gamma Knife based SRS. Tumor histologies included renal cell carcinoma and melanoma. Results:Patients were treated to a median marginal dose was 20 Gy (range, 15–22 Gy). At follow-up intervals ranging from 1.8 to 23.2 months, the radiographic responses were as follows: progression in 7 patients; stable in 5 patients; and shrinkage in 15 patients. Fifteen patients (56%) developed distant brain failure. Seven of the 27 patients were alive at last follow-up. The 3-, 6-, 9-, 12-, and 18-months after SRS local control rates were 82.8%, 77.9%, 69.3%, 69.3%, and 55.4%, respectively. None of the 5 patients who received WBRT developed distant brain failure although the follow-up intervals were short (range, 3.5–13.7 months; median, 5.1 months). WBRT did not appear to affect local control, progression free survival, and overall survival (P = 0.32, 0.87, 0.69). One patient developed worsening of symptoms attributable to SRS. Conclusions:Gamma Knife SRS is a safe and feasible strategy for treatment of patients with a single radioresistant brain metastasis. Radiosurgery alone is a reasonable treatment option, but may carry a greater likelihood of distant brain recurrence.

Gamma Knife radiosurgery for intracranial metastatic melanoma: an analysis of survival and prognostic factors

Objective of this study was to evaluate retrospectively the effectiveness of Gamma Knife radiosurgery for intracranial metastatic melanoma and to identify prognostic factors related to survival. Twenty-six patients with intracranial metastases (72 lesions) from melanoma underwent Gamma Knife radiosurgery. In 14 patients (54%) whole-brain radiotherapy (WBRT) was performed as part of the initial treatment, and in 12 patients (38%) immunotherapy and/or chemotherapy was given after Gamma Knife radiosurgery. The median tumor volume for Gamma Knife radiosurgery treated lesions was 1.72 cm3. The median prescribed radiation dose was 18 Gy (range 8–22 Gy) typically prescribed to the isodose at the tumor margin. Univariate and multivariate analyses were used to determine significant prognostic factors affecting survival. Overall median survival was 6 months after Gamma Knife radiosurgery, and 1-year survival was 25%. The median survival from the onset of brain metastases was 9 months and from the original diagnosis of melanoma was 50 months (range 4–160 months). There were no major acute or late GKS complications. In univariate testing, the Karnofsky score equal to or higher than 90% (P < 0.01, log-rank test), supratentorial localization (P < 0.001, log-rank test), intracranial tumor volume less than 1 cm3 (P < 0.02, log-rank test), and absence of neurological signs or symptoms before Gamma Knife radiosurgery (P < 0.003, log-rank test) were significant favorable factors for survival. In multivariate regression analyses, the most important predictors associated with increased survival were a KPS ≥ 90 (P < 0.023), female sex (P < 0.004), supratentorial localization (P < 0.01), and absence of neurological symptoms (P < 0.008). Radiosurgery is a noninvasive, safe, and effective treatment option for patients with single or multiple intracranial metastases from melanoma. Female sex, Karnofsky score ≥90, supratentorial localization and lack of symptoms before the Gamma Knife radiosurgery were good independent predictors of survival.