Charles A. Enke

Phase I Trial of Iodine-131 Tositumomab With High-Dose Chemotherapy and Autologous Stem-Cell Transplantation for Relapsed Non-Hodgkin's Lymphoma

PURPOSE To determine the maximum outpatient dose of iodine-131 tositumomab (up to 0.75 Gy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem-cell transplantation (ASCT) for the treatment of chemotherapy-resistant relapsed or refractory B-cell non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS Twenty-three patients with chemotherapy-refractory or multiply-relapsed B-cell NHL were treated in a phase I trial combining iodine-131 tositumomab (ranging from 0.30 to 0.75 Gy total-body dose [TBD]) with high-dose BEAM followed by ASCT. RESULTS The complete response rate after transplantation was 57%, and the overall response rate was 65%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 38 months (range, 27 to 60 months), the overall survival (OS) rate was 55%, and the event-free survival (EFS) rate was 39%. CONCLUSION There were no significant added toxicities apparent with the addition of iodine-131 tositumomab up to a dose of 0.75 Gy TBD to high-dose BEAM chemotherapy followed by ASCT. The EFS and OS were encouraging in this group of chemotherapy-resistant or refractory B-cell NHL patients. A follow-up phase II trial with iodine-131 tositumomab at the dose of 0.75 Gy TBD with BEAM is currently ongoing.

DOSIMETRIC CONSEQUENCES OF INTRAFRACTION PROSTATE MOTION

PURPOSE To analyze characteristics of intrafraction prostate motion, monitored using the Calypso system, and investigate dosimetric consequences of the motion for different clinical target volume (CTV) to planning target volume (PTV) margins. METHODS AND MATERIALS Motion characteristics were analyzed for 1,267 tracking sessions and 35 patients. Using prostate-PTV margins of 0, 1, 2, 3, and 5 mm, dose metrics for the prostate gland, bladder, and rectum were evaluated for scenarios including patient population, individual patients showing the greatest motion during the course of treatment, and the individual session with the largest overall movement. Composite dose distributions incorporating motion blurring were calculated by convolving static intensity-modulated radiotherapy plans with corresponding motion probability functions. RESULTS For prostate-PTV margins of 2 mm or greater, intrafraction motion did not compromise prostate dose coverage for either the patient population or individual patients. For the patient showing the largest overall movement, the prostate equivalent uniform dose was reduced by only 17.4 cGy (0.23%), and the minimum prostate dose remained greater than 95% of the nominal dose. For margins less than 2 mm, the prostate dose-volume histogram in the same patient was slightly compromised, and the equivalent uniform dose was reduced by 38.5 cGy (0.51%). Sparing of the bladder and rectum was improved substantially by reducing margins. CONCLUSIONS Although significant motion can be observed during individual fractions, the dosimetric consequences are insignificant during a typical course of radiotherapy (30-40 fractions) with CTV-PTV margins of 2 mm or greater provided that the Calypso system is applied for pretreatment localization. Further reduction of the margin is possible if intrafraction realignment is performed.

Hepatic irradiation augments engraftment of donor cells following hepatocyte transplantation

Engraftment of donor hepatocytes is a critical step that determines the success of hepatocyte transplantation. Rapid and efficient integration of donor cells would enable prompt liver repopulation of these cells in response to selective proliferative stimuli offered by a preparative regimen. We have earlier demonstrated that hepatic irradiation (HIR) in combination with a variety of hepatotrophic growth signals, such as partial hepatectomy and hepatocyte growth factor, can be used as a preparative regimen for liver repopulation of transplanted hepatocytes. In this study, we investigated the effects of HIR on engraftment of transplanted dipeptidyl peptidase IV (DPPIV)–positive hepatocytes in congeneic DPPIV‐deficient rats. HIR‐induced apoptosis of hepatic sinusoidal endothelial cells (SEC) within 6 hours of HIR resulted in dehiscence of the SEC lining in 24 hours. Although there was no change of the number of Kupffer cells after HIR, colloidal carbon clearance decreased 24 hours post HIR, indicating a suppression of phagocytic function. DPPIV+ donor cells were transplanted 24 hours after HIR (0–50 Gy). There was an HIR dose‐dependent increase in the donor hepatocyte mass engrafted in the liver parenchyma. The number of viable transplanted hepatocytes present in hepatic sinusoids or integrated in the parenchyma was greater in the HIR‐treated group at 3 and 7 days after transplantation compared with the sham controls. Finally, we validated these rodent studies in cynomolgus monkeys, demonstrating that a single 10‐Gy dose of HIR was sufficient to enhance engraftment of donor porcine hepatocytes. These data indicate that transient disruption of the SEC barrier and inhibition of the phagocytic function of Kupffer cells by HIR enhances hepatocyte engraftment and the integrated donor cell mass. Thus, preparative HIR could be potentially useful to augment hepatocyte transplantation. (HEPATOLOGY 2009;49:258‐267.)

Hodgkin’s Disease in the Elderly: Improved Treatment Outcome With a Doxorubicin-Containing Regimen

PURPOSE Hodgkins disease (HD) is a malignancy that displays a bimodal age distribution. Previous reports of treatment in patients greater-than-or-equal 60 years have found a poor outcome, particularly in patients with advanced disease. Because of an improved side-effect profile, the regimen of chlorambucil, vinblastine, procarbazine, and prednisone (ChlVPP) has been proposed for use in elderly patients. PATIENTS AND METHODS From September 1982 to May 1998, 262 patients with previously untreated HD received either ChlVPP (n = 176) or ChlVPP plus doxorubicin/bleomycin/vincristine (ChlVPP/ABV hybrid; n = 86). Fifty-six patients were greater-than-or-equal 60 years old, and 206 were younger than 60 years. RESULTS The 5-year overall survival (OS; 87% v 39%) and the 5-year event-free survival (EFS; 75% v 31%) favored patients younger than 60 years of age. Prognostic factors analyzed in patients greater-than-or-equal 60 years of age, other than type of therapy, included sex, stage, Karnofsky performance score, lactic dehydrogenase, number of extranodal sites, B symptoms, size of largest mass, and histologic subtype. In patients older than 60 years, none of the clinical features was a statistically significant predictor of EFS; however, ChlVPP/ABV hybrid was associated with a decreased risk of an event (relative risk, 0.40; 95% confidence interval, 0.19 to 0.83; P =.014) compared with ChlVPP. The 5-year OS for patients greater-than-or-equal 60 years who received ChlVPP was 30%, compared with 67% for those patients receiving the ChlVPP/ABV regimen (P =.0086) CONCLUSION Patients greater-than-or-equal 60 years with HD who require chemotherapy are better treated with ChlVPP/ABV hybrid than with ChlVPP alone.

Effect of Platelet-Derived Growth Factor Receptor-β Inhibition with STI571 on Radioimmunotherapy

Whereas radioimmunotherapy of hematologic malignancies has evolved into a viable treatment option, the responses of solid tumors to radioimmunotherapy are discouraging. The likely cause of this problem is the interstitial hypertension inherent to all solid tumors. Remarkable improvements in tumor responses to radioimmunotherapy were discovered after the inclusion of STI571 in the therapy regimen. A combination of the tumor stroma-reactive STI571, a potent platelet-derived growth factor receptor-beta (PDGFr-beta) antagonist, and the tumor-seeking radiolabeled antibody B72.3 yielded long-lasting growth arrest of the human colorectal adenocarcinoma LS174T grown as s.c. xenografts in athymic mice. The interaction of STI571 with the stromal PDGFr-beta reduced tumor interstitial fluid pressure (P(IF)) by >50% and in so doing improved the uptake of B72.3. The attenuation of P(IF) also had a positive effect on the homogeneity of antibody distribution. These effects were dose-dependent and under optimized dosing conditions allowed for a 2.45 times increase in the tumor uptake of B72.3 as determined in the biodistribution studies. Single-photon emission computed tomography imaging studies substantiated these results and indicated that the homogeneity of the radioisotope distribution was also much improved when compared with the control mice. The increased uptake of radioimmunotherapy into the tumor resulted in >400% increase in the tumor absorbed radiation doses in STI571 + radioimmunotherapy-treated mice compared with PBS + radioimmunotherapy-treated mice. The improved antibody uptake in response to the attenuation of tumor P(IF) was identified as the primary reason for the growth arrest of the STI571 + radioimmunotherapy-treated tumors. Two related causes were also identified: (a) the improved homogeneity of monoclonal antibody distribution in tumor and (b) the increased tumor radiosensitivity resulting from the improved tumor oxygenation.

Prediction of Intrafraction Prostate Motion: Accuracy of Pre- and Post-Treatment Imaging and Intermittent Imaging

PURPOSE To evaluate whether pre- and post-treatment imaging (immediately before and after a radiation therapy treatment fraction) and intermittent imaging (at intervals during a treatment fraction) are accurate predictors of prostate motion during the delivery of radiation. METHODS AND MATERIALS The Calypso 4D Localization System was used to continuously track the prostate during radiation delivery in 35 prostate cancer patients, for a total of 1,157 fractions (28-45 per patient). Predictions of prostate motion away from isocenter were modeled for a pre- and post-treatment imaging schedule and for multiple intermittent intrafraction imaging schedules and compared with the actual continuous tracking data. The endpoint was drift of the prostate beyond a certain radial displacement for a duration of more than 30 s, 1 min, and 2 min. Results were used to evaluate the sensitivity and specificity of these models as an evaluation of intrafraction prostate motion. RESULTS The sensitivity of pre- and post-treatment imaging in determining 30 s of intrafraction prostate motion greater than 3, 5, or 7 mm for all fractions was low, with values of 53%, 49%, and 39%, respectively. The specificity of pre- and post-treatment imaging was high for all displacements. The sensitivity of intermittent imaging improved with increasing sampling rate. CONCLUSIONS These results suggest that pre- and post-treatment imaging is not a sensitive method of assessing intrafraction prostate motion, and that intermittent imaging is sufficiently sensitive only at a high sampling rate. These findings support the value of continuous, real-time tracking in prostate cancer radiation therapy.

Effect of Radiotherapy Techniques (IMRT vs. 3D-CRT) on Outcome in Patients With Intermediate-Risk Rhabdomyosarcoma Enrolled in COG D9803—A Report From the Children’s Oncology Group

PURPOSE To compare the dosimetric parameters of intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) in patients with intermediate-risk rhabdomyosarcoma and to analyze their effect on locoregional control and failure-free survival (FFS). METHODS AND MATERIALS The study population consisted of 375 patients enrolled in the Childrens Oncology Group protocol D9803 study, receiving IMRT or 3D-CRT. Dosimetric data were collected from 179 patients with an available composite plan. The chi-square test or Fishers exact test was used to compare the patient characteristics and radiotherapy parameters between the two groups. The interval-to-event outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests. Cox proportional hazards regression analysis was used to examine the effect of the treatment technique on FFS after adjusting for primary site and risk group. RESULTS The median follow-up time was 5.7 and 4.2 years for patients receiving 3D-CRT and IMRT, respectively. No differences in the 5-year failure of locoregional control (18% vs. 15%) or FFS (72% vs. 76%) rates were noted between the two groups. Multivariate analysis revealed no association between the two techniques and FFS. Patients with primary tumors in parameningeal sites were more likely to receive IMRT than 3D-CRT. IMRT became more common during the later years of the study. Patients receiving IMRT were more likely to receive >50 Gy, photon energy of ≤6 MV, and >5 radiation fields than those who received 3D-CRT. The coverage of the IMRT planning target volume by the prescription dose was improved compared with the coverage using 3D-CRT with similar target dose heterogeneity. CONCLUSIONS IMRT improved the target dose coverage compared with 3D-CRT, although an improvement in locoregional control or FFS could not be demonstrated in this population. Future studies comparing the integral dose to nontarget tissue and late radiation toxicity between the two groups are warranted.

Immobilization devices for intensity-modulated radiation therapy (IMRT)

Three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) plans show radiation dose distribution that is highly conformal to the target volume. The successful clinical implementation of these radiotherapy modalities requires precise positioning of the target to avoid a geographical miss. Effective reduction in target positional inaccuracies can be achieved with the proper use of immobilization devices. This paper reviews some of the immobilization devices that have been used and/or have the potential of being used for IMRT. The immobilization devices being reviewed include stereotactic frame, Talon system, thermoplastic molds, Alpha Cradles, and Vac-Lok system. The implementation of these devices at various anatomical sites is discussed.

DOSIMETRIC EVALUATION OF ABUTTED FIELDS USING ASYMMETRIC COLLIMATORS FOR TREATMENT OF HEAD AND NECK

PURPOSE The objective of this study was to reevaluate the dose nonuniformity of abutted fields defined using asymmetric collimators and one isocenter for treatment of the head and neck region. METHODS AND MATERIALS Bilateral parallel-opposed fields abutted to the anterior field at one isocenter were implemented in the treatment of head and neck. The effect of digital display tolerance can produce dose nonuniformity at the junction of the abutted fields. The amount of dose nonuniformity was quantified using both mathematical summation of dose profiles and by direct measurement of doses at the junction of the two abutted fields. The dose nonuniformity was obtained by irradiating the superior part of a film using bilateral parallel-opposed fields and the inferior part by an anterior field with a gap or an overlap. Dose profiles were taken at the depth of maximum dose for the anterior field across the abutted fields. The dose nonuniformity was determined for the case where the asymmetric jaw was set at -2 mm, -1 mm, 0, +1 mm, and +2 mm from the beam central axis. RESULTS The dose at the junction increases systematically as the abutment of the fields changes from a gap to an overlap. The dose nonuniformity with 1-mm gap and 1-mm overlap is about 15% underdose and overdose, respectively. CONCLUSION Imperfect abutment of split fields due to digital display tolerance (+/-1 mm) of asymmetric collimator can cause an underdose or overdose of 15% of the delivered dose.

Clinical implementation of intensity-modulated radiation therapy

The clinical implementation of intensity-modulated radiation therapy (IMRT) is a complex process because of the introduction of new treatment planning algorithms and beam delivery systems compared to conventional 3-dimensional conformal radiation therapy (3D-CRT) and the lack of established national performance protocols. IMRT uses an inverse-planning algorithm to create nonuniform fields that are only deliverable through a newly designed beam-modulating delivery system. The intent of this paper is to describe our experience and to elucidate the new clinical procedures that must be executed to have a successful IMRT program. Patients who undergo IMRT at our institution are immobilized and simulated before proceeding to computed tomography scan for patient data acquisition. Treatment planning involves the use of different prescription dose formats and different planning techniques compared to 3D-CRT. The desired dose goals for the target and sensitive structures must be specified before initiating the planning process, which is computer intensive. After the plan is completed, the delivery instructions are transferred to the delivery system via either a floppy disk for MIMiC-based IMRT or through the network for MLC-based IMRT. Target localizations are carried out using orthogonal radiographs. Ultrasound imaging system (BAT) is used to localize the prostate. Dose validation is performed using films, ion chambers or dose-calculation-based techniques.