Nadeem Riaz

The Stanford University Experience With Conventional-Dose, Total Skin Electron-Beam Therapy in the Treatment of Generalized Patch or Plaque (T2) and Tumor (T3) Mycosis Fungoides

OBJECTIVEnTo review the Stanford University experience with total skin electron-beam therapy (TSEBT) of 30 Gy or greater as monotherapy in patients with mycosis fungoides (MF) and compare with subgroups receiving adjuvant nitrogen mustard (HN2), and further update our experience with repeated courses of TSEBT.nnnDESIGNnRetrospective study.nnnSETTINGnAcademic referral center, multidisciplinary clinic.nnnPATIENTSnA total of 180 patients with MF treated from 1970 through 2007 with T2 MF (103 with generalized patch or plaque disease) or T3 MF (77 with tumor disease). Patients with extracutaneous disease were excluded.nnnINTERVENTIONSnTotal skin electron-beam therapy with or without adjuvant topical HN2.nnnMAIN OUTCOME MEASUREnClinical response rate, freedom from relapse (FFR), overall survival (OS), and progression-free survival (PFS) after TSEBT.nnnRESULTSnThe overall response rate (ORR) was 100%; 60% of patients achieved a complete clinical response (patients with T2 MF = 75%, those with T3 MF = 47%). The 5- and 10-year OS rates of the entire cohort were 59% and 40%, respectively. There were no significant differences in FFR (P = .30 for T2 disease; P = .50 for T3 disease), PFS (P = .10 for T2 disease; P = .40 for T3 disease), or OS (P = .30 for T2 disease; P = .50 for T3 disease) between adjuvant HN2 and TSEBT monotherapy cohorts. The ORR was 100% in patients receiving a second course of TSEBT with median FFR of 6 months.nnnCONCLUSIONSnA TSEBT of 30 Gy or greater is highly effective in treating T2-T3 MF, with better outcomes in T2 disease. There was no clinical advantage to adjuvant HN2 as used in our cohort. Second courses of TSEBT are safe and efficacious and provide clinically meaningful palliation for select patients.

Predicting respiratory tumor motion with multi-dimensional adaptive filters and support vector regression

Intra-fraction tumor tracking methods can improve radiation delivery during radiotherapy sessions. Image acquisition for tumor tracking and subsequent adjustment of the treatment beam with gating or beam tracking introduces time latency and necessitates predicting the future position of the tumor. This study evaluates the use of multi-dimensional linear adaptive filters and support vector regression to predict the motion of lung tumors tracked at 30 Hz. We expand on the prior work of other groups who have looked at adaptive filters by using a general framework of a multiple-input single-output (MISO) adaptive system that uses multiple correlated signals to predict the motion of a tumor. We compare the performance of these two novel methods to conventional methods like linear regression and single-input, single-output adaptive filters. At 400 ms latency the average root-mean-square-errors (RMSEs) for the 14 treatment sessions studied using no prediction, linear regression, single-output adaptive filter, MISO and support vector regression are 2.58, 1.60, 1.58, 1.71 and 1.26 mm, respectively. At 1 s, the RMSEs are 4.40, 2.61, 3.34, 2.66 and 1.93 mm, respectively. We find that support vector regression most accurately predicts the future tumor position of the methods studied and can provide a RMSE of less than 2 mm at 1 s latency. Also, a multi-dimensional adaptive filter framework provides improved performance over single-dimension adaptive filters. Work is underway to combine these two frameworks to improve performance.

Revisiting Low-Dose Total Skin Electron Beam Therapy in Mycosis Fungoides

PURPOSEnTotal skin electron beam therapy (TSEBT) is a highly effective treatment for mycosis fungoides (MF). The standard course consists of 30 to 36 Gy delivered over an 8- to 10-week period. This regimen is time intensive and associated with significant treatment-related toxicities including erythema, desquamation, anhydrosis, alopecia, and xerosis. The aim of this study was to identify a lower dose alternative while retaining a favorable efficacy profile.nnnMETHODS AND MATERIALSnOne hundred two MF patients were identified who had been treated with an initial course of low-dose TSEBT (5-<30 Gy) between 1958 and 1995. Patients had a T stage classification of T2 (generalized patch/plaque, n = 51), T3 (tumor, n = 29), and T4 (erythrodermic, n = 22). Those with extracutaneous disease were excluded.nnnRESULTSnOverall response (OR) rates (>50% improvement) were 90% among patients with T2 to T4 disease receiving 5 to <10 Gy (n = 19). In comparison, OR rates between the 10 to <20 Gy and 20 to <30 Gy subgroups were 98% and 97%, respectively. There was no significant difference in median progression free survival (PFS) in T2 and T3 patients when stratified by dose group, and PFS in each was comparable to that of the standard dose.nnnCONCLUSIONSnOR rates associated with low-dose TSEBT in the ranges of 10 to <20 Gy and 20 to <30 Gy are comparable to that of the standard dose (≥ 30 Gy). Efficacy measures including OS, PFS, and RFS are also favorable. Given that the efficacy profile is similar between 10 and <20 Gy and 20 and <30 Gy, the utility of TSEBT within the lower dose range of 10 to <20 Gy merits further investigation, especially in the context of combined modality treatment.

A fiducial detection algorithm for real-time image guided IMRT based on simultaneous MV and kV imaging

The advantage of highly conformal dose techniques such as 3DCRT and IMRT is limited by intrafraction organ motion. A new approach to gain near real-time 3D positions of internally implanted fiducial markers is to analyze simultaneous onboard kV beam and treatment MV beam images (from fluoroscopic or electronic portal image devices). Before we can use this real-time image guidance for clinical 3DCRT and IMRT treatments, four outstanding issues need to be addressed. (1) How will fiducial motion blur the image and hinder tracking fiducials? kV and MV images are acquired while the tumor is moving at various speeds. We find that a fiducial can be successfully detected at a maximum linear speed of 1.6 cm/s. (2) How does MV beam scattering affect kV imaging? We investigate this by varying MV field size and kV source to imager distance, and find that common treatment MV beams do not hinder fiducial detection in simultaneous kV images. (3) How can one detect fiducials on images from 3DCRT and IMRT treatment beams when the MV fields are modified by a multileaf collimator (MLC)? The presented analysis is capable of segmenting a MV field from the blocking MLC and detecting visible fiducials. This enables the calculation of nearly real-time 3D positions of markers during a real treatment. (4) Is the analysis fast enough to track fiducials in nearly real time? Multiple methods are adopted to predict marker positions and reduce search regions. The average detection time per frame for three markers in a 1024 x 768 image was reduced to 0.1 s or less. Solving these four issues paves the way to tracking moving fiducial markers throughout a 3DCRT or IMRT treatment. Altogether, these four studies demonstrate that our algorithm can track fiducials in real time, on degraded kV images (MV scatter), in rapidly moving tumors (fiducial blurring), and even provide useful information in the case when some fiducials are blocked from view by the MLC. This technique can provide a gating signal or be used for intra-fractional tumor tracking on a Linac equipped with a kV imaging system. Any motion exceeding a preset threshold can warn the therapist to suspend a treatment session and reposition the patient.

Indolent primary cutaneous B-cell lymphoma: experience using systemic rituximab.

BACKGROUNDnOptimal treatment of indolent primary cutaneous B-cell lymphoma (CBCL), marginal zone lymphoma, and follicle center lymphoma, presenting as multiple lesions, has yet to be established. Rituximab is a chimeric monoclonal IgG1 antibody directed against the CD20 antigen of B cells. Clinical efficacy of systemic rituximab in CBCL has yet to be established.nnnOBJECTIVEnWe sought to assess the efficacy of systemic rituximab in the treatment of CBCL.nnnMETHODSnThis was a retrospective study of 15 patients with indolent CBCL treated with intravenous rituximab (375 mg/m(2)) as a single agent. Variable maintenance regimen was used in a subset of patients. Responses were categorized as complete response, partial response, stable disease, or progressive disease. The efficacy end points included were objective response rate, time to response, time to progression, and duration of response.nnnRESULTSnTen patients with follicle center lymphoma and 5 with marginal zone lymphoma were included. The objective response rate was 87% (60% complete response, 27% partial response). All patients with follicle center lymphoma had a response with 80% achieving complete response. Of the patients with marginal zone lymphoma, 3 had a response, one stable disease, and one progressive disease. Median follow-up was 36 months. Median time to response, duration of response, and time to progression was 30 days, 24 months, and 24 months, respectively.nnnLIMITATIONSnThe study was limited by the small sample size and retrospective design.nnnCONCLUSIONSnThis study, although small, suggests that rituximab is a reasonable first-line treatment option for indolent CBCL with multiple lesions where local treatment is not effective or desirable.

IMAGE-GUIDED RADIOTHERAPY IN NEAR REAL TIME WITH INTENSITY- MODULATED RADIOTHERAPY MEGAVOLTAGE TREATMENT BEAM IMAGING

PURPOSEnTo utilize image-guided radiotherapy (IGRT) in near real time by obtaining and evaluating the online positions of implanted fiducials from continuous electronic portal imaging device (EPID) imaging of prostate intensity-modulated radiotherapy (IMRT) delivery.nnnMETHODS AND MATERIALSnUpon initial setup using two orthogonal images, the three-dimensional (3D) positions of all implanted fiducial markers are obtained, and their expected two-dimensional (2D) locations in the beams-eye-view (BEV) projection are calculated for each treatment field. During IMRT beam delivery, EPID images of the megavoltage treatment beam are acquired in cine mode and subsequently analyzed to locate 2D locations of fiducials in the BEV. Simultaneously, 3D positions are estimated according to the current EPID image, information from the setup portal images, and images acquired at other gantry angles (the completed treatment fields). The measured 2D and 3D positions of each fiducial are compared with their expected 2D and 3D setup positions, respectively. Any displacements larger than a predefined tolerance may cause the treatment system to suspend the beam delivery and direct the therapists to reposition the patient.nnnRESULTSnPhantom studies indicate that the accuracy of 2D BEV and 3D tracking are better than 1 mm and 1.4 mm, respectively. A total of 7330 images from prostate treatments were acquired and analyzed, showing a maximum 2D displacement of 6.7 mm and a maximum 3D displacement of 6.9 mm over 34 fractions.nnnCONCLUSIONSnThis EPID-based, real-time IGRT method can be implemented on any external beam machine with portal imaging capabilities without purchasing any additional equipment, and there is no extra dose delivered to the patient.

Use of MV and kV imager correlation for maintaining continuous real-time 3D internal marker tracking during beam interruptions

The integration of onboard kV imaging together with a MV electronic portal imaging device (EPID) on linear accelerators (LINAC) can provide an easy to implement real-time 3D organ position monitoring solution for treatment delivery. Currently, real-time MV-kV tracking has only been demonstrated by simultaneous imagining by both MV and kV imaging devices. However, modalities such as step-and-shoot IMRT (SS-IMRT), which inherently contain MV beam interruptions, can lead to loss of target information necessary for 3D localization. Additionally, continuous kV imaging throughout the treatment delivery can lead to high levels of imaging dose to the patient. This work demonstrates for the first time how full 3D target tracking can be maintained even in the presence of such beam interruption, or MV/kV beam interleave, by use of a relatively simple correlation model together with MV-kV tracking. A moving correlation model was constructed using both present and prior positions of the marker in the available MV or kV image to compute the position of the marker on the interrupted imager. A commercially available radiotherapy system, equipped with both MV and kV imaging devices, was used to deliver typical SS-IMRT lung treatment plans to a 4D phantom containing internally embedded metallic markers. To simulate actual lung tumor motion, previous recorded 4D lung patient motion data were used. Lung tumor motion data of five separate patients were inputted into the 4D phantom, and typical SS-IMRT lung plans were delivered to simulate actual clinical deliveries. Application of the correlation model to SS-IMRT lung treatment deliveries was found to be an effective solution for maintaining continuous 3D tracking during step beam interruptions. For deliveries involving five or more gantry angles with 50 or more fields per plan, the positional errors were found to have < or =1 mm root mean squared error (RMSE) in all three spatial directions. In addition to increasing the robustness of MV-kV tracking against beam interruption, it was also found that use of correlation can be an effective way of lowering kV dose to the patient and for increasing kV image quality by reduction of MV scatter interference.

Target Volume Delineation for Conformal and Intensity-Modulated Radiation Therapy

Head and Neck Cancer: Nasopharynx -- Oropharynx Cancer -- Early Larynx -- Advanced larynx -- Hypopharyngeal Cancer -- Oral Cavity Cancer -- Paranasal Sinuses -- Major Salivary gland -- Thyroid Cancer -- Cranial Nerves -- Unknown Primary.-xa0 Head and Neck -- Neck -- Breast Cancer: Early Breast Cancer -- Locally Advanced Breast -- Thorax: Locally Advanced NSCLC &SCLD -- SBRT and post-OP NSCLC -- Gastrointestinal Cancer: Esophagus -- Gastric -- Pancreatic -- HCC/Cholangiocarcinoma -- Rectal Cancer -- Anal Cancer -- Gynecological Cancer: Cervical Cancer -- Endometrial Cancer -- Ovarian Cancer -- Vaginal Cancer -- Vulvar Cancer -- Genitourinary Cancer: Prostate Cancer -- Bladder Cancer.-Seminoma -- CNS: Brain Metastasis -- Benign -- Low and High Grade Glioma -- Lymphoma: Hodgkins Disease -- Non-Hodgkins Disease -- Musculoskeletal -- Pediatrics: Sarcoma -- Pediatric CNS.

Modeling Dose Response for Late Dysphagia in Patients With Head and Neck Cancer in the Modern Era of Definitive Chemoradiation

PURPOSEnTo develop personalized multivariate dose-response models for late dysphagia in patients with head and neck cancer treated in the modern era of combined chemotherapy with intensity-modulated radiation therapy.nnnPATIENTS AND METHODSnThe analysis included 424 patients (oropharyngeal cancer [n = 295] and nasopharyngeal, hypopharyngeal, or laryngeal cancer [n = 129]) who received definitive chemoradiation between January 2004 and April 2009. The superior, middle, and inferior pharyngeal constrictor muscles were contoured. We calculated generalized equivalent uniform dose (gEUD) for each and the total constrictor muscle volume, with the volume effect parameter a varying from log10 a = -1 to +1 in steps of 0.1. We used the National Cancer Institute Common Toxicity Criteria for Adverse Events (version 3.0) to grade late dysphagia and logistic regression to evaluate the correlation of gEUD( a) with grade 2 or higher (≥ G2) and grade 3 or higher (≥ G3) late dysphagia at each value of a.nnnRESULTSnMedian follow-up was 33.3 months (range, 6 to 69 months). There were 41 cases (10%) of ≥ G2 dysphagia and 22 cases (5%) of ≥ G3 dysphagia. Mean doses to the total constrictor ranged from 30.1 to 85.7 Gy (median, 61.2 Gy). The predicted rate of ≥ G2 dysphagia increased by approximately 3.4% per Gy at the mean dose, for which the probability of ≥ G2 dysphagia is 50%. The threshold mean total constrictor doses that limited rates of ≥ G2 and ≥ G3 dysphagia to < 5% were < 58 Gy and < 61 Gy, respectively. Other significant factors in the multivariate predictive model included disease site, mean dose to total constrictor muscle, and patient age.nnnCONCLUSIONnIncidences of both ≥ G2 and ≥ G3 dysphagia were dependent on the mean radiation dose to the total constrictor muscle volume, disease site, and patient age. Limiting the total volume of constrictor muscle to < 58 Gy could keep the predicted rate of ≥ G2 dysphagia to < 5%.

Patterns of failure in head and neck cancer patients treated with intensity modulated radiation therapy: editorial response

We thank Dr. van der Veen and Dr. Nuyts for their thoughtful discussion and commentary on our recent manuscript as well as placing our results in the broader context of the evolution of target delineation and dosing regimens in head and neck radiotherapy. We herein provide additional clarification to address their comments.