Global, multicenter, randomized, phase II trial of gemcitabine and gemcitabine plus AGS-1C4D4 in patients with previously untreated, metastatic pancreatic cancer.

BACKGROUND: We evaluated AGS-1C4D4, a fully human monoclonal antibody to prostate stem cell antigen (PSCA), with gemcitabine in a randomized, phase II study of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and previously untreated, metastatic pancreatic adenocarcinoma were randomly assigned 1:2 to gemcitabine (1000 mg/m(2) weekly seven times, 1 week rest, weekly three times q4weeks) or gemcitabine plus AGS-1C4D4 (48 mg/kg loading dose, then 24 mg/kg q3weeks IV). The primary end point was 6-month survival rate (SR). Archived tumor samples were collected for pre-planned analyses by PSCA expression. RESULTS: Between April 2009 and May 2010, 196 patients were randomly assigned to gemcitabine (n = 63) or gemcitabine plus AGS-1C4D4 (n = 133). The 6-month SR was 44.4% (95% CI, 31.9-57.5) in the gemcitabine arm and 60.9% (95% CI, 52.1-69.2) in the gemcitabine plus AGS-1C4D4 arm (P = 0.03), while the median survival was 5.5 versus 7.6 months and the response rate was 13.1% versus 21.6% in the two arms, respectively. The 6-month SR was 57.1% in the gemcitabine arm versus 79.5% in the gemcitabine plus AGS-1C4D4 arm among the PSCA-positive subgroup and 31.6% versus 46.2% among the PSCA-negative subgroup. CONCLUSIONS: This randomized, phase II study achieved its primary end point, demonstrating an improved 6-month SR with addition of AGS-1C4D4 to gemcitabine among patients with previously untreated, metastatic pancreatic adenocarcinoma. ClinicalTrials.gov identifier: NCT00902291.

Impact of sildenafil on marital and sexual adjustment in patients and their wives after radiotherapy and short-term androgen suppression for prostate cancer: analysis of RTOG 0215.

PURPOSE: The Radiation Therapy Oncology Group (RTOG) 0215 investigated the efficacy of sildenafil in improving erectile dysfunction following radiotherapy and neoadjuvant/concurrent androgen deprivation therapy among prostate cancer patients and found a significant improvement on drug but only in 21% of study participants. This paper reports on a secondary aim to investigate the effect of sildenafil on overall sexual and marital adjustment among both patients and their wives. METHODS: RTOG 0215 was a placebo-controlled, double-blind, crossover trial of sildenafil. Participation of wives was optional. Twenty-four married heterosexual couples (33% of heterosexual couples in study) completed the Sexual Adjustment Questionnaire and Locke's Marital Adjustment Test. Treatment differences in mean change scores were evaluated by paired t-tests, and the proportion of patients achieving a clinically meaningful change was evaluated using chi-square tests. Spearman's correlation coefficients were used to determine the association of adjustment between patients and wives. RESULTS: There was no significant change in either sexual or marital adjustment for patients. For wives, there was a trend for improvement in sexual adjustment but no significant change in marital adjustment. Change in marital adjustment between patients and wives was weakly related (r(s) = 0.15, p = 0.48), and for sexual adjustment, there was a moderate, but nonsignificant relationship (r(s) = 0.40, p = 0.09). CONCLUSIONS: Larger studies are warranted to further examine possible differences in sexual experiences and treatment needs between prostate cancer patients and their wives, as well as to assess predictors of sildenafil response.

Case report of a near medical event in stereotactic radiotherapy due to improper units of measure from a treatment planning system.

PURPOSE: The authors hereby notify the Radiation Oncology community of a potentially lethal error due to improper implementation of linear units of measure in a treatment planning system. The authors report an incident in which a patient was nearly mistreated during a stereotactic radiotherapy procedure due to inappropriate reporting of stereotactic coordinates by the radiation therapy treatment planning system in units of centimeter rather than in millimeter. The authors suggest a method to detect such errors during treatment planning so they are caught and corrected prior to the patient positioning for treatment on the treatment machine. METHODS: Using pretreatment imaging, the authors found that stereotactic coordinates are reported with improper linear units by a treatment planning system. The authors have implemented a redundant, independent method of stereotactic coordinate calculation. RESULTS: Implementation of a double check of stereotactic coordinates via redundant, independent calculation is simple and accurate. Use of this technique will avoid any future error in stereotactic treatment coordinates due to improper linear units, transcription, or other similar errors. CONCLUSIONS: The authors recommend an independent double check of stereotactic treatment coordinates during the treatment planning process in order to avoid potential mistreatment of patients.

Radiosurgery for benign tumors and arteriovenous malformations of the central nervous system.

At 5 years, single-fraction stereotactic radiosurgery, alone or in conjunction with subtotal surgical resection, appears to yield local control rates that are comparable to those achieved by complete resection of the meningioma, with progression-free survival at or above 90%. Complication rates are low, as long as doses to critical structures, particularly to the optic apparatus, are maintained below 8.0 Gy in a single fraction. Stereotactic radiotherapy is an alternative treatment with low rates of toxicity for meningiomas in excess of 3.0 cm size, or for those near the optic nerves or other sensitive areas, although follow-up data for treatment efficacy and safety are still very short for this fractionated technique. Given the lack of available long-term follow-up data for stereotactic radiosurgery, complete surgical resection remains the optimal, first choice of treatment for benign meningiomas.

Irradiation of a primary tumor, unlike surgical removal, enhances angiogenesis suppression at a distal site: potential role of host-tumor interaction.

Changes in distal angiogenesis in response to irradiation of primary tumors are not known. To this end, PC-3, a human prostate carcinoma, and FSA-II, a murine fibrosarcoma, were grown in the gastrocnemius muscles of male nude mice. Distal angiogenesis was measured in gel containing human recombinant basic fibroblast growth factor placed in the cranial windows of these mice. PC-3-bearing mice showed inhibition of distal angiogenesis, as compared with non-tumor-bearing controls. Surgical removal of tumors tended to accelerate distal angiogenesis; in comparison, after irradiation of the PC-3 primary tumor, rates of angiogenesis in the cranial window were retarded. Irradiation of the non-tumor-bearing leg or of non-tumor-bearing animals showed no measurable effect on rate of growth of vessels in the cranial window. Similar results were found with the FSA-II tumors, with slowed distal angiogenesis in tumor-bearing animals and further suppression in animals with irradiated tumors. These results demonstrate that the effect of irradiation of a primary tumor on angiogenesis at a distal site may differ from the effect of surgical removal of the primary tumor. Unlike surgery, irradiation of a tumor may enhance angiogenic suppression at a distal site, and this difference may involve host-tumor interaction.

Conformal irradiation of the prostate: estimating long-term rectal bleeding risk using dose-volume histograms.

PURPOSE: Dose-volume histograms (DVHs) may be very useful tools for estimating probability of normal tissue complications (NTCP), but there is not yet an agreed upon method for their analysis. This study introduces a statistical method of aggregating and analyzing primary data from DVHs and associated outcomes. It explores the dose-volume relationship for NTCP of the rectum, using long-term data on rectal wall bleeding following prostatic irradiation. METHODS AND MATERIALS: Previously published data were reviewed and updated on 41 patients with Stages T3 and T4 prostatic carcinoma treated with photons followed by perineal proton boost, including dose-volume histograms (DVHs) of each patient's anterior rectal wall and data on the occurrence of postirradiation rectal bleeding (minimum FU > 4 years). Logistic regression was used to test whether some individual combination of dose and volume irradiated might best separate the DVHs into categories of high or low risk for rectal bleeding. Further analysis explored whether a group of such dose-volume combinations might be superior in predicting complication risk. These results were compared with results of the "critical volume model," a mathematical model based on assumptions of underlying radiobiological interactions. RESULTS: Ten of the 128 tested dose-volume combinations proved to be "statistically significant combinations" (SSCs) distinguishing between bleeders (14 out of 41) and nonbleeders (27 out of 41), ranging contiguously between 60 CGE (Cobalt Gray Equivalent) to 70% of the anterior rectal wall and 75 CGE to 30%. Calculated odds ratios for each SSC were not significantly different across the individual SSCs; however, analysis combining SSCs allowed segregation of DVHs into three risk groups: low, moderate, and high. Estimates of probabilities of normal tissue complications (NTCPs) based on these risk groups correlated strongly with observed data (p = 0.003) and with biomathematical model-generated NTCPs. CONCLUSIONS: There is a dose-volume relationship for rectal mucosal bleeding in the region between 60 and 75 CGE; therefore, efforts to spare rectal wall volume using improved treatment planning and delivery techniques are important. Stratifying dose-volume histograms (DVHs) into risk groups, as done in this study, represents a useful means of analyzing empirical data as a function of hetereogeneous dose distributions. Modeling efforts may extend these results to more heterogeneous treatment techniques. Such analysis of DVH data may allow practicing clinicians to better assess the risk of various treatments, fields, or doses, when caring for an individual patient.

Prostate cancer. Who is best benefited by external beam radiation therapy?

The major indications for radical radiation therapy of prostate cancer for both early-stage and locally advanced disease are discussed. Important issues in the interpretation of long-term treatment series are reviewed. The outcomes of therapy are analyzed for both early-stage and locally advanced disease, including alternative therapeutic strategies. On the basis of this review of the literature, current treatment recommendations delineate patients most likely to benefit from radiation therapy as opposed to alternative therapeutic modalities.

pO(2) measurement in murine tumors by Eppendorf 'Histograph'.

The purpose of this study was to assess the usefulness of the Eppendorf 'Kistograph' as a device for measuring pO(2) in tumor and normal tissues of the laboratory mouse. To determine the appropriate calibration and electrode condition, nitrogen bubbling time was changed, and the current during calibration was recorded. Reproducibility of pO(2) measurements was tested in the series of human xenografts and murine isoplants at different time points or in the same tumor in successive determinations. pO(2) values obtained with the Eppendorf 'Histograph' were compared to those obtained with a manually controlled needle-type electrode manufactured by the Diamond-General Company. The pO(2) values after 9 min of nitrogen bubbling were closer to the expected values than those after 3 min bubbling. The current during nitrogen bubbling in calibration declined following the pO(2) measurement by an amount corresponding to 0.8 mm Hg. Good reproducibility of pO(2) measurement was shown in i) pO(2) values in the same cell line at different time points and ii) pO(2) values in two or three consecutive measurements in related regions within the same tumor. The Eppendorf 'Histograph' and the Diamond-General device showed no significant differences in pO(2) distribution in either subcutaneous tissue or MCaIV tumors. In conclusion, results of the Eppendorf 'Histograph' were consistent and reproducible and were similar to those obtained by the Diamond-General set-up.

Magnetic resonance microscopy of water diffusion and edema during hypothermic preservation of rat kidneys.

Kidney degradation during hypothermic storage was studied on rat kidneys, using magnetic resonance microscopy. Poor storage, modeled by storage with lactated Ringer's solution, resulted in rapid kidney swelling, together with increased signal intensity and water diffusion coefficient in the cortical and medullary regions. Storage of kidneys in Euro-Collins solution resulted in slower swelling and no significant change in signal intensity and in the water diffusion coefficient. Storage with Belzer's solution resulted in shrinkage of the kidneys and no significant change in the diffusion coefficient of water over time. These changes correlated well with kidney degradation observed by histology, and show the potential of magnetic resonance imaging in quality assessment of kidney transplants.

Influence of experimental factors on intrinsic radiosensitivity assays at low doses of radiation: cell multiplicity.

Evaluation of the probability of biological phenomena per cell by colony formation, requires knowledge not only of the number of cells at risk but also of their microdistribution. In the present study, the influence of cellular multiplicity (number of cells per potential colony-forming unit) on the determination of radiation sensitivity is evaluated for a range of multiplicity distributions. Cell surviving fraction was calculated using no multiplicity correction, an average multiplicity correction or the fractional distribution of multiplicities of the control and irradiated population. The results obtained show that: (a) multiplicity corrections are required when the number of cells per potential colony-forming unit is greater than 1.00 either immediately after plating or at the time of irradiation; (b) both the control and irradiated populations must be corrected for multiplicity; (c) multiplicity errors are most pronounced in the low-dose range, e.g. in the survival range with 2 Gy; and (d) the error introduced by using an average vs fractional distribution of multiplicities increases with the multiplicity dispersion. Seemingly small errors due to uncorrected multiplicity effects lead to markedly different predicted isoeffect doses when amplified through multiple (e.g. 30) fractions.

Tumors arising in SCID mice share enhanced radiation sensitivity of SCID normal tissues.

We addressed the question of whether cancers arising in an abnormally radiation sensitive normal tissue are also abnormally sensitive to ionizing irradiation. Germ line mutation-carrying mice with an enhanced radiation sensitivity of the normal tissue, the severe combined immunodeficient (SCID), and normally radiation sensitive mice (C3H) were used to study the sensitivity of normal and tumor tissues in vivo and in vitro. The lethal dose for 50% of the irradiated animals after single dose whole body irradiation was 2.6-fold higher in C3H compared to SCID mice. The dose for an isoeffective acute skin reaction after single dose irradiation was end point dependent 1.7 to 3.7 times higher in C3H than in SCID mice. Embryonic fibroblast and methylcholanthrene induced soft tissue sarcomas derived from C3H and SCID mice were established in vitro and colony-forming assays after single dose irradiation were carried out. Choosing mean inactivation dose as the end point, SCID fibroblast lines were 3.0-fold and SCID tumor cell lines 2.7-fold more radiation sensitive than C3H fibroblast lines and C3H tumor cell lines. Tumor control and growth delay assays for 110-mm3 tumors were used to compare the radiation sensitivity of SCID and C3H tumors in vivo. The doses for 50% local tumor control and a growth delay of 40 days were 2.6 times higher in C3H tumors compared to SCID tumors. Tumors arising in an abnormally radiation sensitive normal tissue are also sensitive to irradiation. The difference in radiation sensitivity of normal tissues predicted the difference in tumor tissues in these two murine systems.