Mark Yudelev

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

BackgroundWe 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.MethodsThe 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.ResultsIn 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.ConclusionOur 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.

CONFORMAL MIXED NEUTRON AND PHOTON IRRADIATION IN LOCALIZED AND LOCALLY ADVANCED PROSTATE CANCER: PRELIMINARY ESTIMATES OF THE THERAPEUTIC RATIO

PURPOSE To determine the incidence of chronic toxicity and the probability of biochemical and histologic complete response among patients with nonmetastatic prostate cancer, treated with three dimensional (3D) conformal mixed neutron and photon irradiation. METHODS AND MATERIALS Between November 1991 and December 1994, 151 patients with prostate cancer were entered in three prospective dose-finding studies of conformal mixed neutron and photon irradiation. Patients with low stage, low to intermediate grade prostate cancer (T1-2NXM0, Gleason Score < or = 7) received 38 Photon Gy (PhGy) plus 9 (51 patients) or 10 (53 patients) Neutron Gy (NGy) to the prostate and seminal vesicles. Forty-seven patients with locally advanced prostate cancer (T3-4 N0-1 M0 and/or Gleason Score > or = 8) received 15 NGy + 18 PhGy to the prostate and seminal vesicles and 9 NGy + 18 PhGy to the pelvic lymph nodes. RESULTS The median follow-up was 16 months (range: 3-30 months). There was no Grade 3-5 GI or GU toxicity recorded. At 20 months, the actuarial rates of Grade 2 GI morbidity were 6 and 29% for the 9-10 and 15 NGy protocols, respectively (p = 0.07). At 20 months, the incidences of Grade 2 GU morbidity were 4 and 16%, respectively (p = 0.08). Stiffness in flexing or abducting the hips was seen in 20 and 42% of patients receiving 9-10 and 15 NGy, respectively (p = 0.01). Potency was maintained in 65% of all patients. Among patients with an initial PSA < or = 10, 100% had a 12-month PSA < 2 and 78% < 1 ng/ml. Negative postradiation biopsies were seen in 30% of patients 6 months, 79% at 12 months, and 84% of patients at 18 months. CONCLUSION The use of conformal mixed neutron and photon irradiation has been well tolerated with no severe bladder or rectal complications observed. However, because of the enhanced toxicity seen with 15 NGy, the current maximum dose levels of neutron irradiation have been limited to 11 NGy.

Neutron dosimetry with planar silicon p-i-n diodes

New nonionizing energy losses (NIEL) sensors based on silicon planar p-i-n diodes of different geometry have been investigated and their response to fast neutron field compared with bulk diodes. The possibility of obtaining a wide range of sensitivities in these NIEL sensors simultaneously with measurements of IEL has been demonstrated.

Simultaneous macro and micro dosimetry with MOSFETs

The application of MOSFET dosimeters in complicated mixed radiation fields for measurement of absorbed dose distribution in tissue equivalent phantoms has been studied. The spectra of secondary charged particles have been measured simultaneously with average absorbed doses by the same MOSFET dosimeter. A good correlation has been observed between neutron depth dose distribution in a water phantom obtained using MOSFETs in integral mode and a tissue equivalent (T.E.) ionisation chamber. Such MOSFET dosimeters are a promising tool for micro-macro dosimetry in Boron Neutron Capture Therapy (BNCT) and Fast Neutron Therapy (FNT). Paired MOSFETs with one of the dosimeters covered by /sup 10/B have been applied for measuring of average boron dose distribution and microdosimetric spectra due to alpha particles and /sup 7/Li ions throughout a perspex phantom exposed in the epithermal neutron beam at the Brookhaven Medical Research Reactor (BMRR).

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 study involving nearly 700 patients is summarized in this paper. The Phase II studies were dose 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.

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-γ gene (Ad- IFN-γ) 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-γ, 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-γ 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-γ 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.

Hip stiffness following mixed conformal neutron and photon radiotherapy: A dose-volume relationship

PURPOSE To determine the relationship between dose, volume, and the incidence of hip stiffness in patients who received conformal neutron irradiation for prostate cancer. METHODS AND MATERIALS A series of dose-searching studies using neutron irradiation for prostate cancer were performed to determine the optimal dose, fraction size, field size, technique, and proportions of photon and neutron dose. Neutron doses ranged from 9 to 20 Gy and photon doses ranged from 0 to 38 Gy. Data were analyzed by using a hip stiffness grading scale. RESULTS Hip stiffness was recorded on follow-up examination in 30% of patients (40 out of 132) treated with fast neutrons or mixtures of fast neutron and photon radiation for prostate cancer. Hip stiffness was categorized as none (Grade 0, 92 patients), mild (Grade 1, 24 patients), moderate (Grade 2, 10 patients), or severe (Grade 3, 6 patients). The incidence of hip stiffness differed significantly by dose and volume in the five dose levels studied (p < 0.001). CONCLUSIONS By using a mixture of conformal neutron and photon irradiation and limiting the total neutron dose to less than 13 Gy, hip stiffness toxicity could be reduced to acceptable levels.

A multirod collimator for neutron therapy

PURPOSE To design, construct, and commission a multirod collimator for producing irregularly shaped fields in neutron radiation therapy. To demonstrate the reliability and applicability of this device to routine use with a superconducting cyclotron for neutron therapy. METHODS AND MATERIALS A multirod collimator has been designed, constructed, and thoroughly tested to investigate its radiological properties; neutron transmission characteristics, beam profiles, and penumbral widths as a function of field size and depth in a phantom, and the spatial resolution of the rod array, have been measured. A wide variety of irregularly shaped fields, used routinely in neutron radiation therapy, have been produced, including fields that incorporate partial transmission blocks. The performance of the collimator has been closely monitored over a period of 20 months to accurately assess reliability. RESULTS The multirod collimator has been in routine use for 32 months, and during this time a total of 7025 neutron fields has been treated. For the latter 20 months of this period, detailed performance records show that collimator failure has caused 28.4 h of downtime during the patient treatment day. Only 5.25 h of this downtime was experienced in the last 12 months (0.22% of the available treatment time). The results of collimator attenuation and beam profile measurements show that the radiological properties of the collimator are comparable to those of other collimator systems used for neutron radiation therapy. Isodose measurements in a water phantom show that the spatial resolution of the rods is superior to that of the leaves used in neutron multileaf collimators. The ability of the multirod collimator to produce many irregularly shaped fields commonly encountered in neutron radiation therapy has been demonstrated. Shaped fields for prostate, head and neck, soft tissue sarcomas, lung, thyroid, rectum, bladder, colon, breast, pancreas, and gynecological tumors have been produced. For some prostate cases, the device has been used to produce partial transmission blocks. CONCLUSIONS A novel multirod collimator has been designed, constructed, and successfully applied in the routine treatment of neutron radiation therapy patients.

Physical characteristics of a clinical d(48.5)+Be neutron therapy beam produced by a superconducting cyclotron

The Harper Hospital and Wayne State University fast neutron therapy facility is the only one in the world to use a compact superconducting cyclotron and multirod collimator. Neutrons are produced by the interaction of the 48.5-MeV deuteron beam with a thick internal beryllium target and the compact accelerator is gantry mounted to allow full 360 degrees rotation of the neutron beam about the therapy couch. The deuteron beam strikes the beryllium target at a glancing angle. A flattening filter is used to flatten the asymmetric neutron beam which results from this geometry. Details of the flattening filter design and construction are discussed. The physical characteristics of the resulting neutron therapy beam were measured. The central axis depth-dose values are approximately equivalent to those of a 4-MV photon beam. The dose buildup curve reaches its maximum value at a depth of 9 mm in a water phantom and the surface dose is approximately 42%. The beam penumbra produced by the multirod collimator has been measured in terms of the distance between the 20% and 80% isodose lines. The penumbra width for a 10 x 10-cm2 field at a depth of 10 cm in a water phantom is 1.65 +/- 0.1 cm, and is comparable to that achieved with other high-energy neutron beams. The long-term stability of the dose monitoring system has been measured and found to be satisfactory. The physical characteristics of the neutron beam are comparable with those of other modern fast neutron therapy facilities.

RBE variation between fast neutron beams as a function of energy. Intercomparison involving 7 neutrontherapy facilities.

In fast neutron therapy, the relative biological effectiveness (RBE) of a given beam varies to a large extent with the neutron energy spectrum. This spectrum depends primarily on the energy of the incident particles and on the nuclear reaction used for neutron production. However, it also depends on other factors which are specific to the local facility, eg, target, collimation system, etc. Therefore direct radiobiological intercomparisons are justified. The present paper reports the results of an intercomparison performed at seven neutrontherapy centres: Orléans, France (p(34)+Be), Riyadh, Saudi Arabia (p(26)+Be), Ghent, Belgium (d(14.5)+Be), Faure, South Africa (p(66)+Be), Detroit, USA (d(48)+Be), Nice, France (p(65)+Be) and Louvain-la-Neuve, Belgium (p(65)+Be). The selected radiobiological system was intestinal crypt regeneration in mice after single fraction irradiation. The observed RBE values (ref cobalt-60 gamma-rays) were 1.79 +/- 0.10, 1.84 +/- 0.07, 2.24 +/- 0.11, 1.55 +/- 0.04, 1.51 +/- 0.03, 1.50 +/- 0.04 and 1.52 +/- 0.04, respectively. When machine availability permitted, additional factors were studied: two vs one fraction (Ghent, Louvain-la-Neuve), dose rate (Detroit), influence of depth in phantom (Faure, Detroit, Nice, Louvain-la-Neuve). In addition, at Orléans and Ghent, RBEs were also determined for LD50 at 6 days after selective abdominal irradiation and were found to be equal to the RBEs for crypt regeneration. The radiobiological intercomparisons were always combined with direct dosimetric intercomparisons and, when possible in some centres, with microdosimetric investigations.