Potential hazard due to induced radioactivity secondary to radiotherapy: the report of task group 136 of the American Association of Physicists in Medicine.

External-beam radiation therapy mostly uses high-energy photons (x-rays) produced by medical accelerators, but many facilities now use proton beams, and a few use fast-neutron beams. High-energy photons offer several advantages over lower-energy photons in terms of better dose distributions for deep-seated tumors, lower skin dose, less sensitivity to tissue heterogeneities, etc. However, for beams operating at or above 10 MV, some of the materials in the accelerator room and the radiotherapy patient become radioactive due primarily to photonuclear reactions and neutron capture, exposing therapy staff and patients to unwanted radiation dose. Some recent advances in radiotherapy technology require treatments using a higher number of monitor units and monitor-unit rates for the same delivered dose, and compared to the conventional treatment techniques and fractionation schemes, the activation dose to personnel can be substantially higher. Radiotherapy treatments with proton and neutron beams all result in activated materials in the treatment room. In this report, the authors review critically the published literature on radiation exposures from induced radioactivity in radiotherapy. They conclude that the additional exposure to the patient due to induced radioactivity is negligible compared to the overall radiation exposure as a part of the treatment. The additional exposure to the staff due to induced activity from photon beams is small at an estimated level of about 1 to 2 mSv y. This is well below the allowed occupational exposure limits. Therefore, the potential hazard to staff from induced radioactivity in the use of high-energy x-rays is considered to be low, and no specific actions are considered necessary or mandatory. However, in the spirit of the "As Low as Reasonably Achievable (ALARA)" program, some reasonable steps are recommended that can be taken to reduce this small exposure to an even lower level. The dose reduction strategies suggested should be followed only if these actions are considered reasonable and practical in the individual clinics. Therapists working with proton beam and neutron beam units handle treatment devices that do become radioactive, and they should wear extremity monitors and make handling apertures and boluses their last task upon entering the room following treatment. Personnel doses from neutron-beam units can approach regulatory limits depending on the number of patients and beams, and strategies to reduce doses should be followed.

Correlation of admissions statistics to graduate student success in medical physics.

The purpose of this work is to develop metrics for evaluation of medical physics graduate student performance, assess relationships between success and other quantifiable factors, and determine whether graduate student performance can be accurately predicted by admissions statistics. A cohort of 108 medical physics graduate students from a single institution were rated for performance after matriculation based on final scores in specific courses, first year graduate Grade Point Average (GPA), performance on the program exit exam, performance in oral review sessions, and faculty rating. Admissions statistics including matriculating program (MS vs. PhD); undergraduate degree type, GPA, and country; graduate degree; general and subject GRE scores; traditional vs. nontraditional status; and ranking by admissions committee were evaluated for potential correlation with the performance metrics. GRE verbal and quantitative scores were correlated with higher scores in the most difficult courses in the program and with the program exit exam; however, the GRE section most correlated with overall faculty rating was the analytical writing section. Students with undergraduate degrees in engineering had a higher faculty rating than those from other disciplines and faculty rating was strongly correlated with undergraduate country. Undergraduate GPA was not statistically correlated with any success metrics investigated in this study. However, the high degree of selection on GPA and quantitative GRE scores during the admissions process results in relatively narrow ranges for these quantities. As such, these results do not necessarily imply that one should not strongly consider traditional metrics, such as undergraduate GPA and quantitative GRE score, during the admissions process. They suggest that once applicants have been initially filtered by these metrics, additional selection should be performed via the other metrics shown here to be correlated with success. The parameters used to make admissions decisions for our program are accurate in predicting student success, as illustrated by the very strong statistical correlation between admissions rank and course average, first year graduate GPA, and faculty rating (p < 0.002). Overall, this study indicates that an undergraduate degree in physics should not be considered a fundamental requirement for entry into our program and that within the relatively narrow range of undergraduate GPA and quantitative GRE scores of those admitted into our program, additional variations in these metrics are not important predictors of success. While the high degree of selection on particular statistics involved in the admissions process, along with the relatively small sample size, makes it difficult to draw concrete conclusions about the meaning of correlations here, these results suggest that success in medical physics is based on more than quantitative capabilities. Specifically, they indicate that analytical and communication skills play a major role in student success in our program, as well as predicted future success by program faculty members. Finally, this study confirms that our current admissions process is effective in identifying candidates who will be successful in our program and are expected to be successful after graduation, and provides additional insight useful in improving our admissions selection process.

Characteristic 8 keV X rays possess radiobiological properties of higher-LET radiation.

Electronic brachytherapy systems are being developed that can deliver X rays of varying energy depending on the material of a secondary target. A copper target produces characteristic 8 keV X rays. Our aim was to determine whether 8 keV X rays might deliver greater biological effectiveness than megavoltage photons. Cells of the U251 human glioma cell line were used to compare the biological effects of 8 keV X rays and (60)Co gamma rays in terms of relative biological effectiveness (RBE), oxygen enhancement ratio (OER), and DNA damage. The RBE at 50% and 10% survival was 2.6 and 1.9, respectively. At 50% survival, the OER for cells treated with 8 keV X rays was 1.6 compared with 3.0 for (60)Co gamma rays. The numbers of H2AX foci per Gy after treatment with 8 keV X rays and (60)Co gamma rays were similar; however, the size of the foci generated at 8 keV was significantly larger, possibly indicating more complex DNA damage. The mean area of H2AX foci generated by 8 keV X rays was 0.785 microm(2) (95% CI: 0.756-0.814) compared with 0.491 microm(2) (95% CI: 0.462-0.520) for (60)Co gamma rays (P < 0.0001). Characteristic 8 keV X rays produce two to three times the biological effectiveness of megavoltage photons, with a radiobiological profile similar to higher-LET radiations.

The effect of neutron radiation on conventional and highly cross-linked ultrahigh-molecular-weight polyethylene wear.

The effects of a sarcoma therapy dose level neutron radiation on oxidation and wear were compared between conventional (N2\Vac, Stryker Orthopedics, Mahwah, NJ) and highly cross-linked (Crossfire, Stryker Orthopedics) ultrahigh-molecular-weight polyethylene acetabular liners. Liners were exposed to 15 Gy, a typical sarcoma treatment dose. Wear testing was conducted on a hip simulator. Transvinylene and oxidation indices were measured to determine if significant radiolytic reactions and oxidation occurred after the neutron beam exposure. The neutron bombardment produced further oxidation in both N2\Vac and Crossfire liners. Surprisingly, neutron radiation caused 62% increase in wear for N2\Vac but 0% change for the Crossfire acetabular liners. This study suggested that when joint implants are exposed to neutron beam radiation therapy, the conventional polyethylene liner is at risk for rapid wear.

Intensity modulated neutron radiotherapy for the treatment of adenocarcinoma of the prostate.

PURPOSE: This study investigates the enhanced conformality of neutron dose distributions obtainable through the application of intensity modulated neutron radiotherapy (IMNRT) to the treatment of prostate adenocarcinoma. METHODS AND MATERIALS: An in-house algorithm was used to optimize individual segments for IMNRT generated using an organ-at-risk (OAR) avoidance approach. A number of beam orientation schemes were investigated in an attempt to approach an optimum solution. The IMNRT plans were created retrospectively for 5 patients previously treated for prostate adenocarcinoma using fast neutron therapy (FNT), and a comparison of these plans is presented. Dose distributions and dose-volume histograms (DVHs) were analyzed and plans were evaluated based on percentage volumes of rectum and bladder receiving 95%, 80%, and 50% (V(95), V(80), V(50)) of the prescription dose, and on V(60) for both the femoral heads and GM(muscle) group. RESULTS: Plans were normalized such that the IMNRT DVHs for prostate and seminal vesicles were nearly identical to those for conventional FNT plans. Use of IMNRT provided reductions in rectum V(95) and V(80) of 10% (2-27%) and 13% (5-28%), respectively, and reductions in bladder V(95) and V(80) of 12% (3-26%) and 4% (7-10%), respectively. The average decrease in V(60) for the femoral heads was 4.5% (1-18%), with no significant change in V(60) for the GM(muscle) group. CONCLUSIONS: This study provides the first analysis of the application of intensity modulation to neutron radiotherapy. The IMNRT technique provides a substantial reduction in normal tissue dose in the treatment of prostate cancer. This reduction should result in a significant clinical advantage for this and other treatment sites.

Progression of renal cell carcinoma is inhibited by genistein and radiation in an orthotopic model.

BACKGROUND: We have previously reported the potentiation of radiotherapy by the soy isoflavone genistein for prostate cancer using prostate tumor cells in vitro and orthotopic prostate tumor models in vivo. However, when genistein was used as single therapy in animal models, it promoted metastasis to regional para-aortic lymph nodes. To clarify whether these intriguing adverse effects of genistein are intrinsic to the orthotopic prostate tumor model, or these results could also be recapitulated in another model, we used the orthotopic metastatic KCI-18 renal cell carcinoma (RCC) model established in our laboratory. METHODS: The KCI-18 RCC cell line was generated from a patient with papillary renal cell carcinoma. Following orthotopic renal implantation of KCI-18 RCC cells and serial in vivo kidney passages in nude mice, we have established a reliable and predictable metastatic RCC tumor model. Mice bearing established kidney tumors were treated with genistein combined with kidney tumor irradiation. The effect of the therapy was assessed on the primary tumor and metastases to various organs. RESULTS: In this experimental model, the karyotype and histological characteristics of the human primary tumor are preserved. Tumor cells metastasize from the primary renal tumor to the lungs, liver and mesentery mimicking the progression of RCC in humans. Treatment of established kidney tumors with genistein demonstrated a tendency to stimulate the growth of the primary kidney tumor and increase the incidence of metastasis to the mesentery lining the bowel. In contrast, when given in conjunction with kidney tumor irradiation, genistein significantly inhibited the growth and progression of established kidney tumors. These findings confirm the potentiation of radiotherapy by genistein in the orthotopic RCC model as previously shown in orthotopic models of prostate cancer. CONCLUSION: Our studies in both RCC and prostate tumor models demonstrate that the combination of genistein with primary tumor irradiation is a more effective and safer therapeutic approach as the tumor growth and progression are inhibited both in the primary and metastatic sites.

Boron neutron capture enhancement of fast neutron radiotherapy utilizing a moderated fast neutron beam.

An investigation of the therapeutic potential of boron neutron capture (BNC) enhancement of fast neutron therapy utilizing the Harper University Hospital superconducting cyclotron-produced d(48.5)+Be fast neutron therapy beam is presented. A technique for modification of the fast neutron beam to increase the BNC enhancement is presented along with an evaluation of the effects of beam moderation on the biological effectiveness of the absorbed dose. Characteristics of the photon, neutron, and boron neutron capture components of the absorbed dose are presented. Results demonstrate the possibility of therapeutic gains greater than 50% over conventional fast neutron therapy at depths required to treat brain lesions. This enhancement is estimated assuming currently achievable boron concentrations, and is more than adequate to provide a therapeutic window for the effective treatment of Glioblastoma Multiforme without prohibitive toxicity to the normal brain.

Genistein potentiates inhibition of tumor growth by radiation in a prostate cancer orthotopic model.

OBJECTIVE: We have shown previously that pretreatment with genistein potentiated cell killing induced by radiation in human PC-3 prostate carcinoma cell line in vitro. We tested this approach in vivo using an orthotopic prostate carcinoma model of PC-3 cells in nude mice. METHODS: Established prostate tumors were pretreated with p.o. genistein at a dose of 5 mg/d for 2 days followed by tumor irradiation with 5 Gy photons. One day after radiation, genistein was resumed and given every other day for 4 weeks. RESULTS: Genistein combined with radiation caused a significantly greater inhibition of primary tumor growth (87%) compared with genistein (30%) or radiation (73%) alone. The number of metastatic lymph nodes was also significantly decreased following genistein and radiation. Paradoxically, genistein alone increased the size of lymph nodes associated with heavy tumor infiltration. Genistein-treated prostate tumors were large with necrosis, apoptotic cells, and giant cells and have a lower proliferation index than in control tumors. Following radiation, areas of tumor destruction replaced by fibrotic tissue and inflammatory cells as well as giant cells were observed, which are typical of radiation effect. After radiation and genistein treatment, an increase in giant cells, apoptosis, inflammatory cells, and fibrosis was observed with decreased tumor cell proliferation consistent with increased tumor cell destruction. Long-term therapy with genistein after prostate tumor irradiation significantly increased survival. CONCLUSIONS: Genistein combined with prostate tumor irradiation led to a greater control of the growth of the primary tumor and metastasis to lymph nodes than genistein or radiation alone, resulting in greater survival.

Tumor irradiation followed by intratumoral cytokine gene therapy for murine renal adenocarcinoma.

To circumvent the toxicity caused by systemic injection of cytokines, cytokine cDNA genes encoding the human interleukin IL-2 cDNA (Ad-IL-2) and murine interferon IFN-gamma gene (Ad- IFN-gamma) were inserted into adenoviral vectors. These constructs were used for intratumoral gene therapy of murine renal adenocarcinoma Renca tumors. Treatment with three doses of Ad-IL-2 or Ad- IFN-gamma, given a day apart, was more effective than single-dose gene therapy. We found that tumor irradiation enhanced the therapeutic efficacy of Ad-IL-2 and Ad-IFN-gamma intratumoral gene therapy. Tumor irradiation, administered 1 day prior to three doses of Ad-IL-2 treatment, was more effective than radiation or Ad-IL-2 alone, resulting in tumor growth arrest in all mice, increased survival and a consistent increase in complete tumor regression response rate. Complete responders rejected Renca tumor challenge and demonstrated specific cytotoxic T-cell activity, indicative of specific tumor immunity. The effect of radiation combined with three doses of Ad-IFN-gamma was less pronounced and did not lead to tumor immunity. Histological observations showed that irradiation of the tumor prior to gene therapy increased tumor destruction and inflammatory infiltrates in the tumor nodules. These findings demonstrate that tumor irradiation improves the efficacy of Ad-IL-2 gene therapy for induction of antitumor immune response.

Responsiveness of experimental prostate carcinoma bone tumors to neutron or photon radiation combined with cytokine therapy.

PURPOSE: To improve the outcome of radiotherapy for prostate carcinoma bone tumors, we investigated bone tumor irradiation with photons or neutrons followed by interleukin 2 (IL-2) therapy in a tumor model. METHODS AND MATERIALS: Implantation of PC-3 cells in nude mouse femur cavity induced a bone tumor that progressed to the formation of a palpable tumor, at the hip joint, by Day 20. Established bone tumors were irradiated with photons or neutrons, and a day later, mice were treated with IL-2 therapy for 3 weekly cycles. RESULTS: PC-3 bone tumors responded to radiation with photons or neutrons in a dose-dependent manner. Combination of photon or neutron radiation with IL-2 therapy increased tumor growth delay, compared to that with photons or neutrons alone. Radiation alone or combined with IL-2 significantly increased mouse survival compared to that with IL-2 or no treatment. After combined therapy, a complete inhibition of bone tumor growth was observed in 45% to 50% of the mice. Histologically, the combined therapy resulted in greater tumor destruction associated with fibrosis, new bone formation, and inflammatory infiltrates than that observed with each modality alone. CONCLUSIONS: The efficacy of tumor irradiation with neutrons or photons was enhanced by IL-2 therapy for the treatment of prostate carcinoma bone tumors.

Fast neutron irradiation for prostate cancer.

The purpose of this study was to summarize the progress made using fast neutron irradiation in the treatment of prostate cancer at Wayne State University between 1991 and the year 2001. The results of three Phase II studies and one Phase III st udy involving nearly 700 patients is summarized in this paper. The Phase II studies weredose finding studies looking at doses of 15, 9, 10, and 11 nGy, respectively. The randomized protocol was a study of sequence looking at the results of treating patients with neutron first versus neutron radiation last. The results demonstrated that the best combination of tumor control probabilities and normal tissue complications was found in a mix of approximately 50% neutrons and 50% photons. Thus, the standard doses become 10 nGy and 40 Gy of photons. The randomized trial demonstrated that the sequence has significant importance and the disease-free survival was 93% for patients treated with neutrons first versus 73% for patients treated with neutrons last. There was no difference in the rate of acute or chronic complications. Finally, an analysis was performed demonstrating which patients may best benefit from the use of neutron irradiation. It was shown that patients with one, two, or three adverse risk factors had a significant improvement in disease-free survival when part of the treatment included neutron radiation versus standard photon radiation alone. Neutron radiation can be delivered safely with effort to see that it is superior to that which can be achieved by conformal photon irradiation by itself. Future work will be done to expand the role of neutron radiation in other clinical disease sites.

Design of quality assurance for sonographic prostate brachytherapy needle guides.

OBJECTIVE: Needles are guided to their proper anatomic locations in sonographically guided percutaneous prostate brachytherapy by a mechanical system (template). A quality assurance procedure has been designed to test this template's alignment with the needle position overlay grid displayed in the sonographic image. METHODS: A mechanical arrangement was designed to position the needles properly with respect to the prostate probe's transducer in a liquid-filled test tank. Two liquids were tested: tap water and an ethylene glycol mixture with an acoustic velocity of 1540 m/s. Needle images with the superposed grid were analyzed for needle placement accuracy. RESULTS: The tap water produced misregistration of the needle images. The ethylene glycol mixture yielded images of vertical and horizontal needle positions accurate to 0.3 and 1 mm, respectively. Also, the importance of selecting the lowest possible equipment echo amplitude dynamic range in these tests was shown. CONCLUSIONS: This quality assurance test with the ethylene glycol mixture will permit accurate alignment of the brachytherapy needle position overlay grid for each separate transrectal probe used.

Design considerations for a computer controlled multileaf collimator for the Harper Hospital fast neutron therapy facility.

The d(48.5) + Be neutron beam from the Harper Hospital superconducting cyclotron is collimated using a unique multirod collimator (MRC). A computer controlled multileaf collimator (MLC) is being designed to improve efficiency and allow for the future development of intensity modulated radiation therapy with neutrons. For the current study the use of focused or unfocused collimator leaves has been studied. Since the engineering effort associated with the leaf design and materials choice impacts significantly on cost, it was desirable to determine the clinical impact of using unfocused leaves in the MLC design. The MRC is a useful tool for studying the effects of using focused versus unfocused beams on beam penumbra. The effects of the penumbra for the different leaf designs on tumor and normal tissue DVHs in two selected sites (prostate and head and neck) was investigated. The increase in the penumbra resulting from using unfocused beams was small (approximately 1.5 mm for a 5 x 5 cm2 field and approximately 7.6 mm for a 25 x 25 cm2 field at 10 cm depth) compared to the contribution of phantom scatter to the penumbra width (5.4 and 20 mm for the small and large fields at 10 cm depth, respectively). Comparison of DVHs for tumor and critical normal tissue in a prostate and head and neck case showed that the dosimetric disadvantages of using an unfocused rather than focused beam were minimal and only significant at shallow depths. For the rare cases, where optimum penumbra conditions are required, a MLC incorporating tapered leaves and, thus, providing focused collimation in one plane is necessary.