Targeting For Cure: Intensity Modulated Radiation Therapy Current Status and Future Directions in the Treatment of Prostate Cancer
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By Lisa M Chaiken, MD and Michael L Steinberg, MD, FACR,
Cancer Care Consultants
Supported by Afshin Safa, MD, David Khan, MD,
Robert Kwon, MD & Uri Zisblatt, MD
Reprinted from PCRI Insights August 2004 vol. 7, no. 3

Introduction

Intensity Modulated Radiation Therapy (IMRT) has had a profound impact on radiation treatment for prostate cancer.

IMRT techniques could be developed because of the recent introduction of powerful computer technology and software, high resolution imaging, and the technical ability to fuse CT and MRI anatomical images. In addition, the positive clinical results associated with dose escalation have further enhanced the apparent efficacy of this treatment modality for prostate cancer. Since the Insights introductory article in April 2000, the use of IMRT for prostate cancer treatment has grown dramatically.6 Community and academic centers alike now offer this modality, with the technical advantages of IMRT considered to be ideal for the application. Today, over four years since the last discussion in this journal, the data has matured, the technique has been refined, and patients have benefited.

IMRT Theory, Technical Considerations, and Dose Escalation

IMRT has revolutionized the delivery of radiation therapy. Although this technique is the logical extension of 3D-conformal radiation treatment, it is unique in offering inverse treatment planning, as compared to traditional forward planning. In so doing, IMRT capitalizes on the basic doctrine of radiation therapy: deliver the dose to the anatomical areas at risk while significantly limiting the radiation dose to normal tissue and critical structures. Forward planning (as utilized in 3D-conformal radiation therapy) sets the fields of radiation and then adjusts the dose weighting and delivery, by trial and error, to refine the radiation plan. Precision and shaping of the radiation dose are limited by this technique (forward planning of 3D-Conformal). Generally no more than six traditional radiation fields are used in total, because there is no further technical benefit gained by adding additional 3D-shaped fields. 3D-Conformal RT with forward planning is thought to be accurate within 7 to 10 millimeters, which means that treatment margins must at least be of that magnitude to safely encompass the treatment target. In contrast, IMRT with inverse treatment planning sets a dose for the tumor/target volume and restricts the dose amount to adjacent structures. It is considered to be accurate within 1-3 millimeters.

The planning computer, through numerous iterations, comes up with the best possible plan that defines radiation treatment delivery in a counterintuitive way. There are literally thousands of beamlets or “pencil beams” coming from every conceivable direction to create radiation dose shapes never before possible. The process involves the physician outlining all the structures in the anatomical area on each 1 mm slice of the CT scan or MRI scan of the patient’s prostate. More recently, fusion of the two scans occurs with sophisticated software to create the most accurate representation of the patient’s anatomy (Figures 1-3).

Chaiken_IMRTFig1and2Chaiken_IMRTFig3

This allows for the most precise representation of the tumor target (the prostate and at times the seminal vesicles), and critical adjacent structures including the rectum, bladder, penile bulb, and hips. The combination of (1) digitally reconstructed radiographs (DRRs) of the 3-dimensional reconstruction of organs and (2) computer- derived dose volume histograms (DVHs) allow the physician to know the exact volume of tissue receiving a specific dose of radiation (Figures 4-7 immediately below and Figures 9-11 – Click the Back button on your browser to return). Treatment plans can then be developed which create a steep dose gradient between the target volume (the prostate), and normal tissue (Figures 4-7). This information is critical to the safe delivery of high doses of radiation to the prostate and target tissue with the least risk of damage to normal structures.

Chaiken_IMRTFig4
Chaiken_IMRTFig5 Chaiken_IMRTFig6
Chaiken_IMRTFig6

IMRT Planning and Delivery Systems

There are numerous IMRT planning and delivery systems currently available. The first IMRT solution to treat patients (and still the only fully dynamic delivery method) was the Nomos Peacock delivery system. With this system, the IMRT beam is modulated in intensity by a multileaf collimator as it moves, at the same time, in a continuous 270-290-degree arc encompassing the patient. This is accomplished by a computercontrolled attachment to a linear accelerator called a MIMiC, which is composed of rapidly moving tungsten leaves called a binary multileaf collimator. This function creates the multitude of the thousands of beamlets required for IMRT and is called dynamic therapy or tomotherapy.

Other systems that use a somewhat fixed delivery techniques are termed “step and shoot” techniques. With “step and shoot” techniques, the conventional multileaf collimator is set in various counterintuitive leaf positions as defined by the computer-generated treatment plan for each of five or (usually) more gantry settings. In so doing, the compilation of various multileaf settings at the various gantry angles creates the equivalent of beam modulation with the associated multiplicity of thousands of beamlets that create the unique IMRT dosimetry.

With regard to technical differences in existing equipment, the multileaf collimator leaf number and leaf size specification may vary among the various IMRT systems. However, contrary to marketing claims of technical superiority made by some vendors or providers, the differences between the various delivery systems are technical in nature only. No proven clinical advantage exists among the various systems for the treatment of prostate cancer.

Computer planning systems also vary in their features, ease of use, and optimization planning. Most use purely inverse-planned IMRT whose dose distribution is tailored over the prostate treatment volumes. This planning technique allows the greatest elasticity of dose to curve around and thereby spare normal structures such as the rectum, while concentrating dose on the tumor target volume, in this case the prostate (Figure 11 – Click the Back button on your browser to return).

A key to optimal outcome in IMRT treatment planning is the iterative process in which sequential clinical evaluation by the radiation oncologist and medical physicist refine the plan to its final iteration. This is an arduous, meticulous, and time-consuming process when done correctly. There is software from at least one vendor, which, although not yet FDA-approved, allows for increased speed and possibly increased accuracy of the iterative process by direct shaping and manipulation of the dosimetry isodose lines.

Safe Escalation of Dose Levels With IMRT

Although it is intuitively obvious that precision in radiation delivery would be beneficial in reducing side effects of treatment, why is all this technology and dose escalation necessary for the treatment of prostate cancer? It is a well known principle of radiobiology that many tumors have a dose response relationship, characterized by a sigmoid (S-shaped) curve.27,28 This means that small changes in dose can lead to large changes in tumor control. Dr. Schellhammer, Chairman of Urology at Virginia Prostate Center, has argued that the curve may level off at some point so that further dose escalation may not contribute to tumor control and cure.30 He also suggests that the addition of hormone ablation therapy may level off the dose response curve earlier, but to date, there is not definitive evidence for that claim.

What we do know is that with prostate cancer there appears to be a significant dose response curve. Doses of 6600-6800 cGy were commonly given for treatment of prostate cancer prior to 1995. Kupelian et al, while at the Cleveland Clinic, published that doses greater than 7200 cGy delivered with conformal type radiation therapy, were associated with improved local control of the prostate tumor.14 In a recent publication of 8-12-year follow-up, Hanks et al at Fox Chase Cancer Center noted a dose response curve with maximal long-term survival for doses greater than 7560 cGy that were delivered with 3D Conformal radiation therapy.9 There was also an absence of biochemical failure after eight years , (Biochemical failure is defined as three consecutive rises in PSA after post-treatment nadir, as defined by ASTRO.) This means the lack of late recurrences and suggests the possibility of long-term cure with dose escalation in patients with intermediate and unfavorable risk disease. For all patients studied, the biochemical PSA relapse free survival was 48% at both 10 and 12 years. However, for patients with PSA in the range of 10-20, the biochemical control was 84% at 8 years with doses above 7560 cGy.

More recently (May 2004), Hanks presented data at the American Radium Society indicating that there is a 26% increase in disease-free survival for all subgroups of prostate cancer patients by escalating the dose from 6800 cGy to 7800 cGy.10 This analysis is based on over 1500 patients treated with dose escalation over the past 20 years, and the results are independent of systemic therapy such as hormone ablation. Pollack et al from MD Anderson Cancer Center published the first randomized trial comparing doses of 7000 to 7800 cGy delivered by 3D-Conformal radiation therapy for patients stratified by risk groups.25 These risk groups were defined in three categories: favorable, intermediate, and unfavorable. The parameters were PSA, clinical stage, and Gleason score. Favorable patients were defined as having PSA </= 10, Gleason < /= 6, and clinical stage T1/T2. If one of these factors is more advanced, the risk is intermediate. If two or more factors are more advanced, the patient risk group is unfavorable. For intermediate and unfavorable risk patients, the high dose patients (7800 cGy) enjoyed a highly significant advantage in terms of freedom from failure. This trial using 3D technology exhibited an increase in rectal toxicity. However, the trial did confirm, with randomized data, the impact and effect of dose escalation. For patients treated with 7800 cGy, the overall freedom from relapse was 70% compared to 64% for those treated with 7000 cGy (p=0.030). For the higher risk patients the difference was even more striking with 62% vs. 43% for 7800 and 7000 cGy respectively. (p=0.01)

Even for favorable groups of patients, some authors advise that dose escalation is also required to achieve maximal tumor control and cure. The dose recommended to achieve this outcome has continued to rise. Zelefsky et al at Memorial Sloan Kettering Cancer Center reported improved outcomes and excellent tolerance for the prostate gland targeted to doses of 8100- 8640 cGy delivered with IMRT as compared with doses of up to 7020-7560 cGy delivered with 3DConformal RT. This is true even for the most favorable early-stage prostate cancer patients.40 Zelefsky et al also noted that the rectal toxicity was not increased and, in fact, was less with IMRT doses of at least 8100 cGy when compared with 3D-Conformal therapy of 7560 cGy to 8100 cGy. Doses of 8100 cGy or greater are commonly used for these patients at Memorial Sloan Kettering. Although Zelefsky does not have 6-8 years or more follow up, the available data is impressive with patients achieving a 3-year PSA control of 81 – 92%. Whether these high numbers hold over time is difficult to predict, but the results are at least as favorable as 3D-Conformal and with less toxicity.41

Although the literature does not agree on a precise dose for all risk groups of prostate cancer patients, all of these authors agree that IMRT provides an important and vital method to safely escalate dose, while at the same time minimizing risk of side effects and complications.1,4,10,12,15,32,34,35,37,39,40,41 IMRT provides the best risk:benefit ratio, and allows for dose escalation, which improves outcome for prostate cancer patients.

IMRT Clinical Outcomes

Since Dr. Brian Butler published the first articles describing IMRT, multiple institutions have published favorable and encouraging results. Butler et al from Baylor College of Medicine published the results of the first 50 patients who were treated to 7000 cGy but with a mean average dose of 7580 cGy (34). In this report, the 7000 cGy was considered as a dose minimum, with substantial parts of the prostate receiving higher dose. This article put forward the notion of “mean average dose”, a dose that is always higher than the prescribed dose because peculiarities of the IMRT planning process cause some sectors of the prostate anatomy to receive substantially higher doses than what is prescribed. Butler noted that patients receiving a higher than standard daily dose still showed excellent tolerance.

Since then, additional patients with both primary and post-prostatectomy radiation have tolerated IMRT well with both modest and extreme dose escalation. Kupelian et al reported excellent control and low complication rates with a hypofractionated regimen, i.e. larger daily doses, with IMRT 2.5 Gy/day to 7000 cGy, doses that are radiobiologically equivalent to approximately 7800 cGy.15 Zelefsky et al published a report on 772 patients treated with IMRT for prostate cancer with dose ranges from 8100-8640 cGy that achieved 81-92% three-year actuarial PSA control for both favorable and unfavorable groups.41

Table 1 - RTOG Late Toxicity Definitions

Our experience at the Santa Monica Cancer Treatment Center (see Table 2) confirms the excellent outcomes with dose escalation and low toxicity profiles in a community setting.4 (Toxicity is defined by the Radiation Therapy Oncology Group (RTOG) as a Grade 1 through 4 system. Please see Table 1 for definitions.)

Table 2 - IMRT Results from Major Studies

In this treatment group, primary prostate patients treated for cure were treated with doses of 7920-8100 cGy depending on individual, clinical, and medical physics factors (Figures 4 and 5 – Click the Back button on your browser to return.). Post-prostatectomy patients were treated to 7020-7200 cGy to the prostate bed. We found that for both the primary and the post-prostatectomy groups of patients, the treatment was extremely well tolerated with minimal acute morbidity. There were no prostate cancer related deaths, and few genitourinary or rectal acute toxicities were noted. Of interest is the substantial decrease in patient reports of treatment-related fatigue (15% for IMRT verses 50% in conventional and 3D treatment patients). No Grade 3 or Grade 4 urinary or gastrointestinal long-term toxicities were noted, and there was a very low incidence of Grade 1 and Grade 2 toxicity reported .

We feel that these excellent outcomes were primarily due to rigorous IMRT treatment planning derived from CT / MRI fusion of 1-mm images, and daily localization with BAT imaging, used on all patients (Figures 8-11). Pollack et al recommend limiting the volume of the rectum exposed to radiation dose above 7000 cGy to 25% and radiation doses above 7560 cGy to 15% rectal volume.1,12

Chaiken_IMRTFig8

Chaiken_IMRTFig9

Chaiken_IMRTFig11

For patients with intact prostates, the Chaiken and Steinberg series by and large limited the rectal volume prescribed to the prostate and target volume to less than 10% for doses of 7000 cGy IMRT, and to less than 5% rectal volume for doses greater than 7560 cGy IMRT (see Figures 6 and 7 – Click the Back button on your browser to return).

In addition, it is noted that for post-prostatectomy patients, the doses to the prostate bed can be escalated to 7020-7200 cGy and 7500 cGy to recurrent tumors in the prostate bed with low morbidity.4,35 Local control has been remarkable (as noted in Table 2 – Click the Back button on your browser to return). Of note, in the Chaiken and Steinberg series, there are two case examples: one patient with a palpable prostate bed recurrence of a 2-cm nodule and another with a 1.5-cm nodule, controlled with radiation alone (no hormonal therapy) for more than three years with clinical and biochemical control. As is always the case with post-prostatectomy treatment, long-term outcomes are dependent on patient selection.

In summary, reported rates of long-term side effects from 3D-Conformal radiation are 2-3 times those reported with IMRT. In a separate report, Zelefsky et al compared the toxicity from 3D-Conformal vs. IMRT delivery in patients treated to doses of 8100 cGy.39 He noted that IMRT reduced late Grade 2 rectal toxicity to 0.5% with doses of 8100 as compared to 13% when the same dose is delivered by 3D-Conformal treatment (p=0.0001). Grade 3 rectal toxicity was reported as 0.5% with IMRT compared with 2% with 3D-Conformal, again when doses of 8100 cGy were used with each technique. IMRT manages to maximize dose to high levels, but when compared to 3D-Conformal, IMRT has significantly lower rectal and genitourinary toxicity.

IMRT Delivery/Localization

With precise IMRT planning methods based on fused contours of CT and MRI, one must be able to reproduce the delivery of the radiation therapy accurately on a daily basis. Differences of only millimeters can significantly affect what area is actually treated. Therefore, along with the technological advances of treatment planning must come an advance in treatment delivery and target localization. This enables one to confirm in real time that the treatment planned for the patient is actually delivered as prescribed.

This factor is extremely important in prostate cancer treatment as the prostate is known to move internally within the patient between treatments. All patients treated with IMRT for prostate cancer should be immobilized using a device or mold, on which the legs and/or pelvis rest. However, this does not impact internal movement, nor does it take into account potential systematic variation of daily set up. Since IMRT accuracy is within 1- 3 millimeters, daily localization and verification of the prostate target is critical.

In a study done by Lattanzi et al at Fox Chase Cancer Center, a combination of CT and ultrasound imaging of prostate cancer patients was performed to determine the correlation of the techniques and to quantify prostate movement.16,17 This study showed that the prostate could move up as much as seven millimeters in an anterior/posterior direction, thereby affecting the areas in the region of the sensitive and dose limiting bladder and rectum structures. In addition, prostate target movements in the superior/inferior directions and in the right and left lateral directions could range between five and nine millimeters. Ultrasound localization was performed utilizing a targeting localization technology called the BAT system (B-Mode Acquisition and Targeting). (See Figure 8 – Click the Back button on your browser to return.)This system recalls the IMRT treatment plan with its initial planning contours and facilitates treatment alignment with the real time ultrasound display of the patients actual anatomy, i.e., prostate, seminal vesicles, rectum, bladder, hips. The ultrasound localization is noninvasive and requires only 2-5 minutes of scanning of the anterior lower abdominal wall.22,23 Lattanzi et al concluded that the BAT had excellent correlation with anatomy when compared to CT and was easier to perform on a daily basis than a daily CT scan.

Others have published on BAT localization for IMRT in the treatment of prostate cancer. Little et al from MD Anderson Cancer Center reported that BAT correlates well with anatomy.18 The authors concluded that without BAT an extra margin of 5.3 – 10.4 mm would be necessary to ensure the target was in the treatment field on a daily basis. These numbers are based on prostate internal movement and movement secondary to variations in daily set up. If this additional margin in the treatment plan were required, it would increase the overall treatment volume and exposure to critical bladder and rectum structures.

Therefore, we concluded that when utilizing significant dose escalation, BAT is necessary to account for organ motion; without it, toxicity would be unacceptably high (meaning more Grade 2 and 3 toxicities). Chandra et al, also from MD Anderson Cancer Center, studied the feasibility of BAT localization for IMRT in the treatment of prostate cancer.5 This article focused on the ability of the technicians to use BAT effectively, to create time efficient clear images, and to have reasonable shifts according to the set up and BAT results. The authors found all factors highly accurate, reproducible, and time-efficient for radiation treatment. Huang et al, again from MD Anderson, studied intrafraction movement with BAT and found this change to be so much less that it was not clinically important, and was independent of the interfraction movement noted above.11

We found that at the Santa Monica Cancer Treatment Center, BAT localization allows for more precise treatment planning, tighter margins, and improved tolerance, as demonstrated in the low frequency of Grade 1 and 2 GI and GU toxicities and the absence of Grade 3 or 4 toxicities as noted in Table 2.4 (Click the Back button on your browser to return).

Other Localization Techniques

Other localization techniques have been reported. Dr. Butler at Baylor uses a rectal balloon inserted on a daily basis and inflated to the same size each day prior to treatment, pinning the prostate to the pubic bone.36 Although the balloon was initially used to fix the prostate into place before each treatment, the authors concluded that the balloon may have decreased the mean dose to the rectum by inflating the rectum and moving it out of the field to a large extent. Patel et al from the University of Wisconsin, Madison, also confirmed these findings, explaining that daily rectal balloon inflation resulted in rectal wall dose sparing.24 They claimed that results were comparable to those achieved with ultrasound localization. However, the rectal balloon does require patients to be treated in a prone position, which is difficult for some patients. In addition, the rectal balloon can be uncomfortable near the end of the treatment course as it is an invasive technique that requires the balloon to be inserted into a potentially sore rectum. In addition, Pollack of MD Anderson has reported increased prostate target movement in the prone position.1

Others have tried permanently placed localization seeds (non-radioactive seeds) into the prostate as a reference for localization. The data is still preliminary but may offer yet another alternative to daily localization. Pouliot et al, in association with Dr. Mack Roach at UCSF, published their experience with these radiopaque marker seeds, which were shown to have no significant migration and had excellent on-line verification with the utilization of three implanted seeds.26 This technique does require surgical implantation of inert metallic seeds into the prostate prior to the commencing the treatment planning, although this is felt to be minimally invasive.

New Localization Techniques

With the increase in precision of radiation therapy delivery associated with IMRT, new strategies and technological solutions are currently in development to refine and verify the delivery of treatment. These treatment-targeting technology solutions include varying the use of CT scan and MRI scan localization on a daily basis for accurate localization of the treatment target. These so-called “scanners on rails” solutions are in development.

Currently, a tomotherapy solution to IMRT includes a real time CT-like image obtained nearly synchronously with treatment. Results from helical tomotherapy have been reported based on a CT scanner modification to deliver radiation therapy. The authors, Mackie from University of Wisconsin and Grigorov et al from London Regional Cancer Center, Canada, have reported experience with this equipment.19,7 Since CT verification is used for all fields with IMRT delivery, this is an example of image-guided radiation therapy (IGRT) with near real-time verification of treatment delivery. This technology is being developed and evaluated for long-term efficacy and effectiveness.

Other applications of IGRT have also been reported. Martinez et al from William Beaumont Cancer Center have reported excellent results by refining their IMRT treatment planning through on-line portal and CT imaging.20 They noted that a 7.5% higher dose could be delivered to the prostate with a mean reduction of 24% in treatment volume by using their image guide technique. A new PTV (planning treatment volume) was developed in the first week of treatments based on CT and portal imaging findings. According to the authors, this allowed for more accurate and higher dose escalation to the prostate target. Treatment strategies that utilize “on-the-run” adjustments to dose or treatment plans are called “adaptive radiotherapy.” A number of these technologies are in development.

In addition, various applications of optical localization technologies are already in use for ultrasound-based target localization systems. CT, infrared, and x-ray based localization systems are in various stages of development. Any localization system must be capable of integrating, fusing, and comparing real-time localization images with the patient’s unique treatment plan. This treatment plan is computed from the initial planning CT and MRI images obtained in the planning phase of treatment development.

All utilization of image-based localization systems require, on some level or another, a subjective interpretation of the image used for localization. In the future, quantitatively objective, anatomical global positioning systems will be developed which will replace the subjective interpretation of image from the process in defining the treatment target. Finally, new imaging isotopes for positron emission tomography (PET) scanning, which may have utility in prostate cancer, will add functional assessment to the planning process for IMRT by fusion of PET images into the CT and MRI planning images. Depending on the sensitivity and resolution of new PET technology, improved planning could result.

Radiobiologic Considerations

Radiobiological research has done much to advance the understanding in such areas as cancer cell and normal cell growth kinetics. In the general knowledge of radiation dose consideration, very few radiobiological principles have turned out to have clinical relevance to the real patient. The benefits of IMRT for prostate cancer treatment are unquestioned, but certain theoretical, biological, and medical physics concerns have been raised about the technique. Monitor units (units of measure of radiation delivered by a linear accelerator) that deliver radiation with IMRT are 2-3 times higher than with conventional or 3D-Conformal radiation therapy. Treatment times are also longer, and there is also radiobiology theory of potential tumor cell repair and healing during protracted treatment times.

IMRT is also thought to expose more normal tissue to radiation but to a very low dose. Questions have been raised as to the significance of this low dose exposure regarding the risk of second malignancies.8,21,36 If this risk in fact exists, its magnitude is thought to be extremely low, far less than a fraction of one percent. These radiobiological concerns have not been observed in clinical outcomes. Of course with all treatment decisions, risk and benefit must be weighed and considered in a patient’s ultimate treatment decision. At this point, the benefits of IMRT are significant and well documented, and far exceed these radiobiologic risks, which remain only theoretical.

Future Directions

Maintenance of potency remains a major quality of life indicator for patients faced with prostate cancer treatment. The exact mechanism for inducing either partial or complete impotence from radiation treatment is not known. At this time, radiation dose to the penile bulb is thought to have a potential impact on long-term sexual function. Since this structure lies approximately 1-cm below the apex of the gland, IMRT planning may allow for partial sparing of this area and thereby may decrease the incidence of impotence. Several authors have investigated this notion. Kao et al from the University of Chicago showed that IMRT could significantly reduce the dose to the penile bulb compared with 3D-Conformal (530 cGy with IMRT vs. 1170 cGy with 3D-Conformal, p=0.003).13 No follow-up as to the clinical outcome of the technique or reported potency rates was reported in this article. Sethi et al from Loyola University Medical Center showed that IMRT reduced doses to penile tissue by a significant amount compared with 3D-Conformal treatment.31 With IMRT, doses were reduced to the proximal penile tissues by over 40%, with significant p values compared to 3DConformal therapy. Again, clinical changes and outcomes have not yet been reported.

Buyyounouski et al from Fox Chase Cancer Center studied IMRT with MRI simulation to spare dose by greater than 50%, to erectile tissue (the penile bulb and corporal bodies) in an effort to impact the incidence of erectile dysfunction after radiation therapy.3 According to the authors, planning in this way did not compromise the dose needed to cover the necessary tumor volume. Steenbakkers et al from the Netherlands Cancer Institute also studied MRI planning for IMRT to reduce both rectal and penile bulb exposure.33 The mean dose to the penile bulb was reduced to 790 cGy with MRI planning compared to 1950 cGy with CT planning. This information about the use of MRI in treatment planning is consistent with previously reported information regarding the anatomic sensitivity of MRI when compared to CT.

It is our opinion that the use of both MRI and CT (with the careful application of fusion software techniques) can best delineate the pertinent anatomy. CT alone tends to overestimate prostate volume, and defines the apical tissue and tissues of erectile function less accurately than MRI.

In a related area, Bastasch et al from Baylor Medical Center found that patients who were potent after nerve-sparing prostatectomy, remained potent after also receiving IMRT post-operatively.2 Of 51 patients studied, 18 retained potency after nerve-sparing prostatectomy. All 18 patients received IMRT (6900 cGy) after surgery, and all 18 maintained potency after 27.2 months of median followup. Neither the neurovascular bundle nor the penile bulb were specifically delineated as to dose. These are encouraging early results, but long term follow-up on a larger group of patients is necessary to confirm these findings. More refined planning recommendations and follow-up may result in improved patient outcomes for maintaining potency. At this point in time, it is simply not known if these IMRT-related techniques will improve erectile function, but the results seem promising.

Treatment of lymph nodes in the management of prostate cancer is controversial at this time. Risk factors for lymph node involvement have been quantified, but the debate continues as to what impact radiation therapy has on outcome when the lymph nodes of the pelvis are treated. Roach et al published the findings of the RTOG 9413 Protocol, a Phase III Study comparing whole pelvis vs. prostate-only radiation therapy with different sequences of hormone ablation therapy.29 The radiation consisted of conventional radiation therapy, not 3DConformal nor IMRT. Whole pelvic radiation provided a significant advantage with regard to progression-free survival for those patients with at least a 15% lymph node involvement risk. However, the volume of radiated tissue certainly increases, especially rectal exposure to radiation dose. This may limit dose escalation. The authors of this paper and others have developed techniques for treating the lymph node-bearing areas that are at highest risk with IMRT. Larger IMRT fields are utilized to a dose of 5040 cGy to encompass the lymph nodes at risk. The prostate is still boosted to doses to 8100 cGy while adhering to critical structure dose/volume limitations.1 Further studies will set guidelines for lymph node treatment with radiation in prostate cancer patients as well as determine clinical outcomes and toxicities of IMRT treatment in this regard.

Conclusions

Although IMRT represents the latest and most advanced technology in radiation treatment delivery for prostate cancer patients, its method and planning represent a logical extension of well known principles of radiation treatment. IMRT represents the most refined and precise form of 3D-Conformal treatment. The long experience with 3D-Conformal provides an important foundation for implementing IMRT. The results with 3D Conformal have been substantial as seen with the data from Hanks and Pollack of biochemical control, ranging from 70 – 84 % depending on patient subgroup analysis, with long term follow up.9,25 While longer follow-up of IMRT patients is needed, the IMRT dose escalation data demonstrates the ability to precisely target tumor-bearing areas, while effectively limiting the dose to critical, sensitive structures that are in close juxtaposition to the target. This technique yields the lowest reported treatment-related morbidity (minimal GI and GU Grade 2 and 3 toxicity) and the highest local tumor control. Although based on 3-year data, Zelefsky reports that the PSA actuarial relapsefree survival rates for favorable, intermediate, and unfavorable groups of patients are 92, 86, and 81% respectively.41 These numbers are at least equivalent and may far surpass the results of 3D Conformal radiation therapy, promising future potential for improving long-term control and cure for prostate cancer patients treated with IMRT.

References

1. ASTRO Practicum 2004: Implementing IMRT into clinical practice. February, 2004, San Diego, CA.

2. Bastasch, M. et al. Post-nerve-sparing prostatectomy, dose escalated intensity modulated radiotherapy: Effect on erectile function. IJROBP 54(1):101- 6, 2002.

3. Buyyounouski, M. et al. Intensity modulated radiotherapy with MRI simulation to reduce doses received by erectile tissue during prostate cancer treatment. IJROBP 58(3): 743-9, 2004.

4. Chaiken, L. et al. Implementation of intensity modulated radiation therapy (IMRT) for prostate cancer in a community practice. Presentation, American Radium Society, Houston, Texas, 2003.

5. Chandra, A. et al. Experience of ultrasound based daily prostate localization. IJROBP 56(2): 436-447, 2003.

6. Gejerman, G. Intensity modulated radiation therapy: A natural progression from 3DCRT. PCRInsights 3(1)3-11, 2000.

7. Grigorov, G. et al. Optimization of helical tomotherapy treatment plans for prostate cancer. Phys Med Biol 48(13): 1933-43, 2003.

8. Hall, E. et al. Radiation induced second cancers: The impact of 3D-CRT and IMRT. IJROBP 56(1): 83-88, 2003.

9. Hanks, G. et al. Dose response in prostate cancer with 8-12 years’ follow-up. IJROBP 54(2): 427-35, 2002.

10. Hanks, Gerald. Panel discussion on prostate cancer. American Radium Society Presentation, Napa Valley, California, May, 2004.

11. Huang, E. et al. Intrafraction prostate motion during IMRT for prostate cancer. IJROBP 53(2): 261-68, 2002.

12. Huang, E. et al. Late rectal toxicity: Dose-volume effects of conformal radiotherapy for prostate cancer. IJROBP 54(5): 1314-21, 2002.

13. Kao, J. et al. Sparing of the penile bulb and proximal penile structures with intensity modulated radiation therapy for prostate cancer. The British Journal of Radiology, 77:129-36, 2004.

14. Kupelian, P. et al. Higher than standard radiation doses (>/= 72 GY) with or without androgen deprivation in the treatment of localized prostate cancer. IJROBP 46(3): 567-74, 2000.

15. Kupelian, P. et al. Preliminary observations on biochemical relapse free survival rates after short course intensity modulated radiotherapy (70 Gy at 2.5 Gy/fraction) for localized prostate cancer. IJROBP 53(4): 904-12, 2002.

16. Lattanzi, J. et al. Ultrasound based stereotactic guidance of precision conformal external beam radiation therapy in clinically localized prostate cancer. Urology 55:73-78, 2000.

17. Lattanzi, J. et al. A comparison of daily CT localization to a daily ultrasound based system in prostate cancer. IJROBP 43(4): 719-25,1999.

18. Little, D. et al. Use of portal images and BAT ultrasonography to measure setup error and organ motion for prostate IMRT: Implications for treatment margins. IJROBP 56(5): 1218-1224, 2003.

19. Mackie, T. Tomotherapy. Presented at the SCROS Midwinter Radiation Oncology Conference, Los Angeles, January 2004.

20. Martinez, A. et al. Improvement in dose escalation using the process of adaptive radiotherapy combined with three-dimensional conformal or intensity-modulated beams for prostate cancer. IJROBP 50(5):1226-34, 2001.

21. Memorial Sloan Kettering Cancer Center, Department of Medical Physics. A Practical Guide to intensity-modulated radiation therapy. Medical Physics Publishing, Madison, WI, 2003.

22. Mohan, D. et al. Short course intensity modulated radiotherapy for localized prostate cancer with daily transabdominal ultrasound localization of the prostate gland. IJROBP 46(3): 575-580, 2000.

23. Morr, J. et al. Implementation and utility of a daily ultrasound-based localization with intensity modulated radiotherapy for prostate cancer. IJROBP 53(5):1124-29,2002.

24. Patel, R. et al. Rectal dose sparing with a balloon catheter and ultrasound localization in conformal radiation therapy for prostate cancer. Radiotherapy and Oncology 67:285-94, 2003.

25. Pollack, A. et al. Prostate cancer radiation dose response: Results of the MD Anderson phase III randomized trial IJROBP 53(5): 1097-1105, 2002.

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