Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer
Introduction
Experimental and clinical data have indicated that the probabilities of tumor control and normal tissue complications after radiation therapy are dose dependent, and that the corresponding dose-response relationships produce sigmoid-shaped curves [19], [33]. The observation that tumor control curves are usually at lower dose levels relative to normal tissue toxicity curves provides the biological basis for curative radiotherapy [19], [33], [35]. When the tumor and normal tissue curves are approximately parallel in shape and sufficiently separated, the doses required for local tumor cure are not associated with significant normal tissue damage [44], [48]. However, for many human cancers the observed tumor control curve represents a population average for clones of different sensitivities. The slopes of such composite curves are frequently less steep (γ50 value of ∼2) than those for normal tissue injury (γ50 value of ∼4) [44], [48], limiting the ability to deliver the high radiation doses required for tumor cure. This problem is further complicated by uncertainties in tumor delineation, organ motion, and in patient positioning from day to day [2], [3], [18], [36], [38], [39], [40], [45], [52]. To compensate for these uncertainties, large safety margins have usually been added to the planning target volume (PTV), extending into surrounding normal tissue, to decrease the risk of a marginal tumor miss. However, since the dose tolerance of critical normal organs is dependent on the volume of the irradiated tissue (the so-called volume effect), the increase in normal tissues within the PTV further constrains the treatment dose. Three-dimensional conformal radiotherapy (3D-CRT) has been developed to address some of these issues [28], [49]. 3D treatment planning uses advanced imaging techniques for tumor and normal organ segmentation, new algorithms for precise dose calculations, and computer-aided optimization to generate treatment plans that confine the prescribed dose to the tumor, while maximally excluding the adjacent normal organs. Patient immobilization and computer-driven beam shaping devices as well as on-line portal imaging are used to decrease treatment uncertainties and assure the quality of treatment delivery. The reduced volume of normal tissues irradiated should hypothetically decrease the risk of treatment toxicity, permit tumor dose escalation, thereby yielding higher rates of local tumor control.
Recent studies have validated this paradigm in the management of prostate cancer [17], [34], [37], [41], [51]. A study of 743 patients with localized prostate cancer treated with 3D-CRT at Memorial Sloan–Kettering Cancer Center [51] demonstrated that both the initial clinical response and the long-term tumor control were dose-dependent. The incidence of an initial complete response (PSA decreasing to ≤1.0 ng/ml) was 90% in patients receiving 75.6 Gy or 81 Gy, as compared with 76 and 56% for those treated to 70.2 and 64.8 Gy, respectively (P<0.001). The 5-year actuarial PSA relapse-free survival for patients with intermediate or unfavorable prognosis receiving ≥75.6 Gy was 78 and 53%, respectively, compared with 54 and 17%, respectively, for those treated to ≤70.2 Gy (P<0.05). When assessed by biopsies obtained at ≥2.5 years after 3D-CRT, only 4% of patients receiving 81 Gy had evidence of relapsing tumor, compared with 27, 36 and 57% for those receiving 75.6, 70.2, and 64.8 Gy, respectively (P<0.05) [51], [57]. However, while the overall rate of late grade 3 and 4 rectal and bladder toxicities was only 1.9%, there was an increase in grade 2 rectal bleeding in patients receiving ≥75.6 Gy to 17%, from the 6% value observed in patients treated with ≤70.2 Gy (P<0.001). Analysis of dose-volume histograms (DVH) in patients receiving 75.6 Gy indicated that the rectal wall volume was significantly higher at each dose of the mean DVH for patients with rectal bleeding as compared with those who did not bleed (P<0.05) [23]. Hence, while doses higher than 75.6 Gy appear to be essential for enhancing the local cure of prostate cancer patients, improved 3D-CRT techniques that more tightly confine the high-dose distribution to the PTV may be necessary to decrease the risk of rectal bleeding.
In a recent paper we demonstrated that 3D-CRT delivered with intensity modulated beams in prostate cancer may provide an approach to improve the conformality of dose distribution around the PTV [29]. We reported on the treatment of a stage T1c prostate cancer patient who was planned part of his 3D-CRT course with an inverse planning algorithm that derived intensity-modulated beam profiles. When six such fields were combined isocentrically, the dose distribution and the DVH for the PTV indicated a significantly improved conformality and increased dose homogeneity than the plan produced by a conventional 3D-CRT technique [29]. The potential of the inverse method for treatment design was first suggested by Brahme [9], [10] and subsequently confirmed by many investigators [16], [21], [32]. These studies clearly demonstrated that beams with non-uniform intensities can produce dose distributions that conform to targets with irregular shapes and suggested an array of inverse planning algorithms, optimization methods and treatment delivery systems for a variety of tumor sites [5], [6], [7], [8], [12], [14], [15], [22], [24], [30], [42], [46], [47]. However, the ability of intensity modulated radiation therapy (IMRT) to improve the outcome in the management of any type of human tumor has not been critically assessed.
In the present study we report preliminary results in a group of 171 prostate cancer patients treated to 81 Gy using IMRT. Treatment was delivered with dynamic multi-leaf collimation (DMLC). When compared with a group of 61 patients treated to 81 Gy delivered with a conventional 3D-CRT approach, the IMRT technique resulted in a decrease in late grade 2 rectal toxicity. The data indicate that this approach offers both improvement in dose distributions and a decrease in normal tissue toxicity, and represents an incremental advance in the ability to deliver the high radiation doses required to improve the local cure of prostate cancer.
Section snippets
Materials and methods
Between September 1992 and February 1998, 232 patients with histologically proven prostate cancer were treated to a dose of 81 Gy. All patients were immobilized in the prone position within a thermoplastic mold as described [50] and simulated on an AcQsim CT simulator. Patients were scanned in the treatment position from the level of L5–S1 to 10 cm caudal to the ischial tuberosities. To produce high resolution 3D images and digitally reconstructed radiographs (DRR), CT slices were reconstructed
Results
Fig. 1 compares the dose distributions from the two types of treatment plans. The treatment planned for conventional 3D-CRT consisted of six co-planar beams carried to 72.0 and a 9 Gy boost delivered via a 5-field plan which the rectum was blocked in each field, while the IMRT plan consisted of five isocentric fields arranged as described in the Materials and methods (Section 2). The isodose distributions in Fig. 1 indicate that the IMRT plan provided improved tumor coverage with 81 Gy. The DVH
Discussion
This report is the first to demonstrate the clinical implementation of IMRT with DMLC in a large group of patients with localized prostate cancer. The use of IMRT was motivated by the recognition that along with the improved local control with high-dose 3D-CRT, there was a higher incidence of late grade 2 rectal bleeding. Further, while there was definitive benefit from the use of 81 Gy, as it was associated with the lowest incidence of positive post-treatment biopsies [51], [57], the planning
Acknowledgements
Supported in part by Grant CA 59017 from the National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland.
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