Don Awood, M.D., Dan Scaperoth, M.D., William McDonald, M.D., Chester Ramsey, Ph.D., Dan Chase, M.S., Edgardo Rodriguez, M.S.
Thompson Cancer Survival Center, Knoxville, Tennessee

Introduction

Over the past ten years, various implementations of three-dimensional conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) have been used to treat thousands of patients. Approximately 80 percent of prostate patients treated in the United States are treated using 3D-CRT techniques and 15 percent are treated with IMRT techniques. The most common IMRT techniques are serial tomotherapy, multiple static segments, and the dynamic window approach.

One recent addition to the intensity modulation family is dynamic arc treatments. In dynamic arc mode, the multileaf collimator moves during gantry rotation to selectively shape the delivered dose. Two types of dynamic arc treatments are currently being used for radiation therapy, stereotactic radiotherapy, and stereotactic radiosurgery. In conformal dynamic arc (CD-ARC) treatments, the MLC moves continuously to conform to the shape of the target volume during gantry rotation. This technique is a natural extension of conventional arc treatments, and has primarily been used for stereotactic treatments. In intensity modulated arc treatments (IMAT), the MLC differentially modulates the intensity across the field during gantry rotation. An extension of the dynamic window techniques, IMAT has been used to generate extremely complex isodose distributions for difficult target volumes. Depending on the treatment complexity and the leaf-sequencing algorithm, IMAT can be delivered in single or multiple arc passes.

At present, there is limited clinical experience with intensity modulated arc treatments (IMAT) for large-field radiation therapy applications. The goal of this work is to investigate the clinical application of IMAT treatments for the prostate.

Materials and Methods

Patient eligibility and pretreatment evaluation
This internal Thompson Cancer Survival Center (TCSC) trial was available for patients previously untreated with biopsy-proven adenocarcinoma of the prostate. All 1992 American Joint Committee on Cancer clinical stages T1 through T3 were eligible. The PSA had to be obtained within 3 months prior to study entry. Neoadjuvant androgen blockade beginning 2 to 6 months prior to registration was deemed acceptable as long as a prehormonal PSA was available. All patients underwent a complete history and physical examination and evaluation of Karnofsky performance status.

Treatment Arms
Two separate treatment arms were used in this study. From 1999 to mid-2001, patients were accrued in a conventional 6-Field conformal treatment arm. From mid-2001 to 2002, patients were accrued in the dose-escalated IMAT treatment arm.

Patient positioning and localization
The treatment planning CT scan was acquired with the patient in the same position as treatment. The scan was to start at or above the level of iliac crest down through the perineum. All tissue to be irradiated was included in the CT scan. CT-scan thickness was required to be 0.5 cm through the region that contained the target volumes. With few exceptions, simulation occurred within 2 weeks of initiation of radiation therapy.

Target volume and critical normal structure definition
The gross tumor volume was defined by the treating physician as encompassing all known disease identified by the planning CT and clinical information. The CTVs were considered to be equal to GTV. The PTV that accounts for variabilities in treatment setup and internal organ motion was added to each CTV and ranged from 5 to 20 mm in all dimensions. Asymmetric margins were allowed within the 5 to10-mm range. The volume of the critical structures intersected by the PTV were considered in the dose-volume histograms (DVHs) of both target and normal tissues. The ICRU reference point doses were to be located in the central part of the PTV on or near the central axis of the beam intersections. Normal tissue volumes contoured included the bladder, rectum, and bilateral femora. The normal tissues were considered as solid organs. The bladder was contoured from its apex to the dome, and the rectum was contoured from the anus (at the level of the ischial tuberosities) for a length of 15 cm or to the point that the rectosigmoid flexure could be identified.

IMAT Treatment Planning
For prostate cases, a class solution was developed for bilateral intensity modulated arcs (IMAT). The treatment consists of 105-degree right and left intensity modulated arcs from 220 to 325-degrees and 35 to 140-degrees (IEC Convention). Treatment planning begins by performing a non-uniform expansion the CTV to account for organ motion and setup error. 1.5 cm of margin is added in all directions except posterior, which has a 1 cm margin. Next, the rectum is contracted by 1-cm anteriorly and expanded by 3 cm posteriorly to create a special rectal block. From gantry angle 35, the CTV is exposed with a 0 cm margin from the BEV. From gantry angles 50, 65, 80, and 125, the PTV is exposed from the BEV. From gantry 95, the PTV is exposed but the special rectal block is used to shield part of the rectum. From gantry angles 110 and 140, the PTV is partially exposed while the entire rectum is blocked. In addition, 45-degree physical wedges are used to conjunction with the dynamic MLC motion to shape the prescribed dose. All regions of interest expansions, beam placements, and MLC shapes are performed automatically using the planning system's scripting utility.

IMAT Treatment Delivery
IMAT treatments were delivered on Clinac 2100CDs (Varian Medical Systems, Palo Alto, CA) with a 52 leaf dMLCs. On Varian dMLCs, dynamic arcs are specified as a range of MLC segments that are defined for specific gantry positions. During gantry rotation, the leaves move between the defined segments with the leaf position linearly interpolated between segments. The MLC controller uses a constant dose rate and a variable leaf speed for each segment during treatment. Although individual leaf speed within a segment is constant, different leaves can travel at different speeds. The speed at which a particular leaf travels within a segment is determined by the total distance that the leaf must travel within the segment and the speed of gantry rotation. The accuracy of the MLC leaf position at isocenter during gantry rotation is defined by a tolerance factor that ranges from 0.05 to 0.50 cm. If this user defined tolerance factor is exceeded, then the treatment cannot be delivered.

Treatment verification
First-day port films or portal images of each field were obtained. Twice weekly verification films or images of orthogonal fields (AP and lateral projection) were required during the first 2 weeks of radiotherapy, and thereafter were required weekly. The portal films or orthogonal setup radiographs were to be reviewed by the treating physician following their acquisition.

Toxicity scoring
Side effects occurring within 120 days from the start of therapy are considered acute radiation morbidity. These acute side effects were scored according to the RTOG acute radiation morbidity scoring criteria (Table I). Late post-treatment gastrointestinal, rectal, or genitourinary complications appearing or persisting greater than 120 days after treatment start were graded according to the RTOG late radiation morbidity scoring scale. Impotence is not analyzed in this report.

TABLE I. RTOG Acute Toxicity Scale

	[ 0 ]	[ 1 ]	[ 2 ]	[ 3 ]
GENITOURINARY	No change	Frequency of urination or nocturia twice pretreatment habit/ dysuria, urgency not requiring medication	Frequency of urination or nocturia which is less frequent than every hour. Dysuria, urgency, bladder spasm requiring local anesthetic (e.g., Pyridium)	Frequency with urgency and nocturia hourly or more frequently/ dysuria, pelvis pain or bladder spasm requiring regular, frequent narcotic/gross hematuria with/ without clot passage
LOWER G.I. INCLUDING PELVIS	No change	Increased frequency or change in quality of bowel habits not requiring medication/ rectal discomfort not requiring analgesics	Diarrhea requiring parasympatholytic drugs (e.g., Lomotil)/ mucous discharge not necessitating sanitary pads/ rectal or abdominal pain requiring analgesics	Diarrhea requiring parenteral support/ severe mucous or blood discharge necessitating sanitary pags/abdominal distention (flat plate radiograph demonstrates distended bowel loops)

Results and Discussion

Between January 1999 and March 2002, fifty cases are analyzable for 6-Field Conformal (25 patients) and IMAT (25 patients) toxicity. Three patients were either cancelled or ineligible and are excluded from this current analysis. Pretreatment patient characteristics of this analysis are listed in Table II. The current study doses reported in Table II represent the minimum dose delivered to the PTV.

The mean minimum peripheral dose (MPD) delivered in the 6-Field treatment arm was 6654 cGy (range 6220 to 6800 cGy). The dose variation for this technique varies by 3 percent across the PTV. The mean MPD in the IMAT arm was gradually escalated over an 18-month period from 6840 to 7400 cGy. The IMAT technique also utilizes a gradual concurrent boost to the prostate. The mean dose to 90% of the prostate and the ICRU reference point for the IMAT technique was 7918 and 8100 cGy respectively (Table III).

TABLE II. Patient Characteristics

6-Field	Mean	Range
Age	71	60-83
Gleason Score	6	3-9
PSA Level	12	3.1-28.9
Dose (cGy)	6654	6220-6800
IMAT	Mean	Range
Age	70	51-80
Gleason Score	6	3-9
PSA Level	8	2.5-18.9
Dose (cGy)	7058	6840-7400

TABLE III. Prostate Dose Variations

6 Field Conformal Technique
Minimum Peripheral Dose (D100)	Dose to 90% of the Prostate Volume (D90)	ICRU Reference Point Dose (Isocenter)
6220 cGy	6350 cGy	6480 cGy
6660 cGy	6700 cGy	6840 cGy
6800 cGy	6880 cGy	7020 cGy
Intensity Modulated Arc Technique
Minimum Peripheral Dose (D100)	Dose to 90% of the Prostate Volume (D90)	ICRU Reference Point Dose (Isocenter)
6840 cGy	7640 cGy	7800 cGy
7020 cGy	7820 cGy	8000 cGy
7400 cGy	8200 cGy	8400 cGy

Acute tolerance to both treatment arms was very good, with 88% of the 6-Field patients and 75% of the IMAT patients having experienced grade 1 or no toxicity (Tables IV and V). Even though the MPD was escalated from 6654 cGy in the 6-Field treatment arm to 7058 in the IMAT treatment arm, the level of grade I rectal toxicities decreased from 71 to 58 percent.

Relatively few patients (0 to 8%) experienced grade 3 acute toxicities. Two patients in the IMAT arm experienced grade 3 urinary toxicities. Both of these patients were treated with a 7400 cGy MPD, which yielded an 8000 to 8400 cGy urethra dose with the concurrent boost (Figure 1).

Table IV. RTOG 6-Field Acute complications

(N=24; Mean Dose: 6654; Range: 6220 to 6800)
6-Field	RTOG Urinary	RTOG Rectal
Grade 0	8%	29%
Grade 1	75%	71%
Grade 2	17%	0%
Grade 3	0%	0%

Table V. RTOG IMAT Acute complications

(N=24; Mean Dose: 7058; Range: 6840-7400)
IMAT	RTOG Urinary	RTOG Rectal
Grade 0	4%	42%
Grade 1	71%	58%
Grade 2	17%	0%
Grade 3	8%	0%