A New Localization System for Tumor Tracking During External Beam Radiotherapy

Cancer Connect

Richard K. Valicenti, MD, Associate Professor of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University

Adam P. Dicker, PhD, MD, Professor of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University

November 5-9, 2006Philadelphia, PennsylvaniaRichard K. Valicenti, MD, Associate Professor of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University

Adam P. Dicker, PhD, MD, Professor of Radiation Oncology, Jefferson Medical College of Thomas Jefferson UniversityThe content presented here was prepared by independent authors under the editorial supervision of OncoEd and is not endorsed or sanctioned by the 48th Annual Meeting of the American Society for Therapeutic Radiation Oncology.


The goal of image-guided radiation therapy (IGRT) is to direct the radiation treatments (beams) according to specific positional data of the planned and actual treatment targets for an individual patient.  Information that allows decisions as whether to treat, how to treat, delineation of structures of interest, aiding in positioning, verification and monitoring all apply to IGRT.  The thesis of image-guided radiation therapy is to allow for greater sparing of neighboring normal structures and more accurate dose delivery to the target volumes than traditional techniques that rely on historical, population-based margins to ensure radiation dose coverage.  In the population-based approaches, additional margins to account for daily setup error and internal organ motion of the clinical target volume (CTV) are usually derived from studies involving CT scans and daily imaging of groups of patients.[[1]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn1 "_ednref1") A disadvantage of this statistical approach is that, by definition, the positional variation of the CTV of an individual patient is unknown, and that a generalized planning target volume (PTV) must be created to achieve adequate dose coverage in the majority of patients. 

In order to customize radiation treatments to individual patients, IGRT approaches have emerged that localize the CTV by using online imaging data to determine and correct the CTV position for each patient.[[2]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn2 "_ednref2")For prostate cancer patients, established systems to accomplish this goal have consisted of regional irradiation of implanted radio-opaque fiducial markers and real-time ultrasonographic monitoring of pelvic anatomy.[[3]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn3 "_ednref3"),[[4]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn4 "_ednref4") Recently, cone beam (CB) imaging technology with kilovoltage (kV) or megavoltage (MV) X-rays has also been developed.  Limitations to these IGRT methods are the potential for excessive radiation exposure and the inability to continuously image during actual treatment delivery.

The Calypso 4D Localization System is now an FDA approved device for localization of the prostate gland in patients receiving external beam radiation therapy.  This is a novel localization method that uses electromagnetic guidance to accurately and continuously track implanted Beacon electromagnetic transponders without the use of ionizing irradiation.[[5]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn5 "_ednref5"),[[6]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn6 "_ednref6") The transponder measures 1.8 mm x 8.6 mm and is implanted under ultrasound guidance using a 14 gauge needle. Prior to CT-based treatment planning, the Beacon transponders are implanted in the patients prostate using transrectal ultrasound.  When briefly excited by an electromagnetic source, each Beacon transponder emits a unique resonant frequency that can be detected by a tracking array near the patient.  The position of the array relative to the linear accelerators isocenter is determined through the use of infrared cameras that monitor optical targets on the array.  In this system, the target position information is displayed in an easy-to-use interface, with indicators of the offset shift in the lateral, longitudinal, and vertical directions.

The FDA approval of the Calypso 4D Localization System was based on investigational studies conducted under institutional review board-approved protocols at five U.S. Centers, including the M.D. Anderson Cancer Center at Orlando, The Cleveland Clinic, Arizona Oncology Services, Nebraska Medical Center, and Sharp Memorial Hospital. These studies involved 43 prostate cancer patients who had 3 transponders placed within the prostate gland and monitored throughout the course of radiation therapy.  At the recent 48th Annual Meeting of the American Society of Therapeutic Radiology and Oncology, there were eight scientific presentations reporting on the findings of these clinical investigations.  In addition, there were two research studies evaluating bronchoscopic implantation of electromagnetic transponders in canine lung tissue. 

Tolerance, Stability, and Reliability of the Implanted Electromagnetic Transponders in Prostate Cancer Patients 

When the three transponders were implanted using transrectal ultrasound guidance, they were generally placed in the prostate apex, left mid/base, and the right mid/base regions of the prostate.  This procedure was routinely carried out under local anesthesia with antibiotics given for infection prevention.  In order to evaluate the stability of the transponder geometry, Mahadevan et al. evaluated the 3D coordinates of the transponders from the CT simulation scans and the Calypso System during treatment delivery.[[7]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn7 "_ednref7") These coordinates were used to calculate the distance between any two transponders. 

The authors noted that the placement of the transponders was well tolerated, with the procedure taking generally less than 10 minutes.  Post-implant symptoms were minimal and comparable to the typical sequelae purported after placement of other fiducial markers. 

It appears that the transponders did not migrate and remained in a configuration (the inter-transponder distances were typically stable) that was easily localized with the Calypso System.  The transponders were also noted to be reliable over the full duration of the external beam radiation therapy.  In fact, their observations using the Calypso System were similar to that made for other fiducial markers.

Since it is possible that transponder geometry may be affected by androgen suppressive therapy, Weinstein et al. studied the transponder stability in men treated with or without androgen suppression therapy (AST).[[8]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn8 "_ednref8") In the dataset of 41 patients, 13 patients received androgen suppression, with 6 receiving AST 1 to 6 months before starting radiation therapy and 7 received it before and during RT.

In the patients treated with AST, the mean standard deviation of the intertransponder distance was 0.8 mm apex-to-left (A-L), 0.7 mm left-right (L-R), and 0.7 mm right-apex (R-A). These values corresponded to 0.7 mm A-L, 0.7 mm L-R, and 0.8 mm R-A for patients who did not receive AST.  It thus appears that the transponders maintain a stable geometry in patients treated with AST.

Observations on the Efficiency and Precision of the Calypso System

The interface display of the Calypso System continuously displays the offset position of the target position in comparison to other on-line systems that require beam on-time.  The system has the advantage of providing feedback to the therapists as the patient is re-aligned to the machine isocenter and may allow for efficient patient positioning.  In a study designed to evaluate the time to setup a prostate cancer patient with Calypso System, the efficiency of the user interface was assessed.[[9]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn9 "_ednref9")

Using facilities experienced with image guidance for prostate cancer, thirty patients had three electromagnetic transponders implanted into the prostate and had time recorded for setup realignment based on the Calypso System. A total of 1057 treatments were analyzed.  The time for alignment ranged from 34 to 121 seconds, with a mean of 104 seconds (standard deviation of 50 seconds).  There was no observed learning curve, with no change of setup time throughout the course of radiation therapy.  Since the radiation therapists in the study were able to quickly learn the skills to use the Calypso System, the observed efficiencies should be reproducible in the other radiation therapy centers.

In another study, the precision of using the AC electromagnetic device was compared to that of a commercially available stereoscopic KV x-ray system (BrainLab ExacTrac) that was incorporated with a linear accelerator for IGRT.[[10]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn10 "_ednref10") The 41 prostate cancer patients at the 5 institutions underwent implantation of three Beacon transponders 2 weeks prior to CT simulation.  Using the Calypso Systems array, exact location of the implanted markers was identified and the radiation therapists adjusted the treatment couch to eliminate the offsets.  The System performance was verified at an interval of 6 treatments over 8 weeks by imaging the radio-opaque transponders using the ExacTrac X-ray system.  In a total of 1027 comparisons the average differences in lateral, longitudinal, and vertical directions were -0.1, -0.4, and 0.0 mm, with a standard deviation of about 1 mm.  The magnitude of difference was 1.9 + 1.2 mm, indicating good agreement between the two systems. 

Characterization of Prostate Gland Motion During External Beam RT

A unique feature of the Calypso 4D Localization System is an external and independent electronic array, which allows for continuous localization of the transponders.  In such a system, it is possible to specifically evaluate the real-time continuous motion characteristics of the prostate gland during a course of external beam irradiation. 

In a multi-institutional study, Kupelian et al. analyzed such data in 35 prostate cancer patients implanted with 3 transponders each and followed throughout 8 weeks of external beam radiation therapy, involving a total of 1157 sessions.[[11]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn11 "_ednref11") There was daily localization of the intraprostatic transponders, typically lasting 9 to 11 minutes.  This type of information has never captured before and represents the novel type of information that this system can deliver.

During a radiation treatment, prostate motion varied from persistent drifts to transient rapid movements.  At some point in the treatment course, the prostate glands of all 35 patients had displacements greater than 3.0 mm, with 24 of 35 (97%) having displacements of 5 mm or more.  The duration of the displacements was unexpected. In 29 of the 35 patients the prostate was displaced 5 mm or more for more than 30 seconds.  In fact, the range of treatment fractions with displacements greater than 5 mm was 0% to 56% for an individual patient. It appears that the extent and duration of prostate gland motion during radiation therapy can be substantial.

In another multi-institutional study, Djemil et al. studied the rotational changes in 33 prostate cancer patients during daily setup using the Calypso System.[[12]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn12 "_ednref12") The rotations were calculated from the transponder configuration by using criteria for rotation compensation (i.e., > 1.0 cm inter-transponder spacing and non-co-linear transponders). In this patient dataset, they made a total of 1320 observations. The prostate gland rotations were typically less than 10 degrees, with majority less than 5 degrees.  Most of the rotations were about the X-axis as compared to the Y and Z directions. The clinical significance of these findings is unclear. 

Correcting for Positional Changes During Treatment for Prostate Cancer

Due to the unique features of the transponders of the Calypso System to deliver real time positional information, the potential to adapt the radiation therapy treatment to positional changes of the patient represents a potential significant advance in the field.  To assess whether this is possible and the magnitude of changes Willoughby et al. evaluated 35 patients enrolled on a clinical trial.[[13]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn13 "_ednref13") The physicians decided prior to treatment to allow for either a 3 mm or 5 mm limit to positional variance.  In 34/ of 35 patients this was exceeded during one-third of treatments (fractions) ranging from 0 to 85% of fractions for individual patients.  However, due to the real-time information provided, some form of intervention could be performed.  This consisted of either, 1) the radiation therapy stopped (overall 0.4 %), 2) radiation therapy was delayed waiting for spontaneous resolution of the prostate gland motion or drift (2.7%), or 3) the patient was realigned (8.2%).  In a separate study Enke et al. compared the Calypso System to that using gold fiducials for making corrections when threshold limits were reached.[[14]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn14 "_ednref14") Surprisingly, over 42% of patients exhibited movements greater than 3 mm compared to 30%, which exceed a 5 mm threshold.  Interventions were required in one-third of the cases with the total time per patients ranging from 35-120 seconds.  The magnitude of such deviations has not been appreciated before in the field and suggests that we should be aware of the significant motion of the prostate.  This research highlights the potential of the Calypso System to further refine treatment delivery by obtaining real time positional information and correcting for positional changes of the prostate gland that if left uncorrected would lead to suboptimal treatment delivery.

Future Directions for Electromagnetic Tracking in Lung Tissue

The use of smart fiducials is not limited to prostate applications.  Two presentations evaluated the potential for the Calypso System for use in the treatment of lung cancer.[[15]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn15 "_ednref15"),[[16]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_edn16 "_ednref16") The clinical limitation of treating patients with lung cancer with radiation therapy has been the need for large margins to account for the motion of the lungs during breathing.  This increases the probability of normal tissue toxicity and limits the ability of delivering large doses of radiation to the tumor.  Using a canine model, the feasibility of bronchoscopic implantation and evaluation of stability of transponders versus gold fiducials was compared.  Both were successfully placed by an interventional pulmonologist with no untoward sequelae.

The unique feature of the transponders allowed investigators to evaluate motion while animals under general anesthesia had their breathing manipulated to simulate different patient/clinical conditions.  Transponder locations were recorded over a number of sessions and compared to respiratory measurements. Transponders and respiratory measurements correlated well and this type of technology represents a new advance with significant potential for the field of lung cancer. 


[[1]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref1 "_edn1") Bel A, van Herk M, Bartelink H, et al, A Verification Procedure to Improve Patient Set-up Accuracy using Portal Images. Radiother Oncol 1993;29:253-260.

[[2]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref2 "_edn2") Langen KM, Jones DT, Organ Motion and Its Management. Int J Radiat Oncol Biol Phys 2005;50: 265-278.

[[3]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref3 "_edn3") Litzenberg DW, Balter JM, Lam KL, et al, Retrospective Analysis of Prostate Cancer Patients with Implanted Gold Markers using Off-line and Adaptive Therapy Protocols.  Int J Radiat Oncol Biol Phys 2005; 63:123-133.

[[4]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref4 "_edn4") Lattanzi J, McNeeley S, Hanlon A, et al, Ultrasound-based Stereotactic Guidance of Precision Conformal External Beam Radiation Therapy in Clinically Localized Prostate Cancer. Urology 2000;55:73-78.

[[5]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref5 "_edn5") Willoughby TR, Kupelian PA, Pouliot J, et al, Target Localization and Real-time Tracking using the Calypso 4D Localization System in Patients with Localized Prostate Cancer.  Int J Radiat Oncol Biol Phys2006;65:528-534.

[[6]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref6 "_edn6") Balter JM, Wright JN, Newell LJ, et al, Accuracy of a Wireless Localization System for Radiotherapy.  Int J Radiat Oncol Biol Phys 2005;6:933-937. 

[[7]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref7 "_edn7") Mahadevan A, E. Klein E, T. Djemil T, et al. Tolerance, Stability and Reliability of Implanted Electromagnetic Transponders in the Prostate: A Multi-Center Analysis. Proceedings from the 48th Annual Meeting of the American Society for Therapeutic Radiation Oncology. Philadelphia, Penn. 2006. 

[[8]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref8 "_edn8") Weinstein G, Jani S, Kupelian P, et al. Stability of Intraprostatic Electromagnetic Transponders in Patients Receiving Radiation Therapy, With and Without Neoadjuvant and/or Concurrent Androgen Suppression Therapy. Proceedings from the 48th Annual Meeting of the American Society for Therapeutic Radiation Oncology. Philadelphia, Penn. 2006.

[[9]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref9 "_edn9") Beyer D, Liu D, Flores N, et al. Efficiency of a Non-Ionizing Target Localization System for Radiation Therapy. Proceedings from the 48th Annual Meeting of the American Society for Therapeutic Radiation Oncology. Philadelphia, Penn. 2006.

[[10]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref10 "_edn10") Jani S, Weinstein G, Kupelian P, et al. In-Vivo Comparison of an Electromagnetic System to Standard kV X-Rays for Treatment Setup During External Beam Radiotherapy of Patients with Prostate Cancer.  Proceedings from the 48th Annual Meeting of the American Society for Therapeutic Radiation Oncology. Philadelphia, Penn. 2006.

[[11]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref11 "_edn11") Kupelian PA, Willoughby T, Mahadevan A, et al. Characterization of Real Time Motion of the Prostate Gland in Patients Receiving External Radiotherapy for Localization Prostate Cancer: Tracking During 1157 Fractions with the Calypso® System. Proceedings from the 48th Annual Meeting of the American Society for Therapeutic Radiation Oncology. Philadelphia, Penn. 2006.

[[12]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref12 "_edn12") Djemil T, Mahadevan A, Kupelian P, et al. Prostate Rotation Measured by Electromagnetic Tracking System: A Multi-Center Analysis. Proceedings from the 48th Annual Meeting of the American Society for Therapeutic Radiation Oncology. Philadelphia, Penn. 2006.

[[13]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref13 "_edn13") Willoughby T, Kupelian P, Mahadevan A, et al. Position Correction Guidance Utilizing Real-Time Tracking with the Calypso® System for External Radiation Therapy Delivery in Patients with Localized Prostate Cancer. Proceedings from the 48th Annual Meeting of the American Society for Therapeutic Radiation Oncology. Philadelphia, Penn. 2006.

[[14]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref14 "_edn14") Enke CA, Solberg T, Mahadevan A, et al. Clinical Impact of a 3 mm versus 5 mm Action Threshold for Correction of Intrafractional Prostate Motion Identified with Electromagnetic Tracking. Proceedings from the 48th Annual Meeting of the American Society for Therapeutic Radiation Oncology. Philadelphia, Penn. 2006.

[[15]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref15 "_edn15") Parikh Pj, Mayse ML, Chaudhari A, et al. A Comparison of Animal Health Impacts and Implant Stability Between Bronchoscopic Implanted Gold Fiducials and Electromagnetic Transponders in Canine Lung Tissue. Proceedings from the 48th Annual Meeting of the American Society for Therapeutic Radiation Oncology. Philadelphia, Penn. 2006.

[[16]](http://news.cancerconnect.com/a-new-localization-system-for-tumor-tracking-during-external-beam-radiation-therapy/#_ednref16 "_edn16") Lechleiter KM, Low DA, Chaudhari A, et al. Characterization of External Breathing Surrogate using Implanted Electromagnetic Transponders in Canine Lungs. Proceedings from the 48th Annual Meeting of the American Society for Therapeutic Radiation Oncology. Philadelphia, Penn. 2006.


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