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Prostate Cancer

  Submitted By:  V. Elayne Arterbery, M.D.

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Author: V. Elayne Arterbery , M.D.

It is estimated that one out of three persons in the United States will be diagnosed with cancer in their lifetimes. More than half of these patients will receive some form of radiation therapy. The goal of radiotherapy of malignant tumor is to administer a sufficient dose of radiation to kill cancerous cells within a given target volume. A high enough dose of radiation can eradicate any cancerous mass. The catch is that injury to the surrounding normal tissue limits the delivery of high radiation doses in many settings. Intensity modulated radiation therapy, or IMRT, is a refinement over existing conformal radiotherapy modalities, rather than a breakthrough technology. IMRT represents an advance in the means that radiation is delivered to the target, and it is believed that IMRT offers an improvement over conventional and conformal radiation in its ability to provide higher dose irradiation of tumor mass, while exposing the surrounding normal tissue to less radiation. IMRT may be especially useful in the treatment of concave tumors, and tumors that are surrounded by or are adjacent to sensitive normal tissue. This enhancement in accuracy is achieved by the delivery of thousands of tiny pencil-thin radiation beams, rather than a single large radiation beam passing through the body, and by the enhanced ability of the radiation oncologist to “map” the direction of beamlet travel so that dose distribution to cancer cells is maximized and normal tissue exposure is minimized. Because prostate cancer fits the ideal target criteria for IMRT of adjacent sensitive dose-limiting tissue (rectal and bladder), and since prostate cancer has been the most widely used application of IMRT with the longest follow-up periods, this paper will emphasize the role of IMRT in the treatment of prostate cancer.


Radiation therapy has been used to treat cancer for over a century. The first recorded case of radiation treatment in the literature occurred in January 1896, just several weeks after Nobel laureate Wilhelm Roentgen reported his discover of the X-ray. The discovery of radioactivity and X-rays led to the knowledge that radiation could be used to damage cells. Cancer cells reproduce at a greater rate than normal cells, and thus are vulnerable to the effects of radiation. Normal cells, while also affected by radiation, have a greater ability to regenerate than cancerous cells1.

First developed and marketed in the 1950’s, the medical linear accelerator represented a technological breakthrough in the way that radiation was delivered to treat cancer. These machines operate by using microwave energy to accelerate electrons to nearly the speed of light over a short distance, usually one meter or less. As the electrons reach maximum speed they collide into a tungsten target, which releases photons as the result of the bombardment. As the photons, or X-rays, hit human tissue, they produce highly energized ions that are lethal to both malignant and benign tissue. However, unlike cancer cells, non-cancerous tissue can adapt over successive regenerative cycles, leading to the practice of administering repeated radiation treatments rather than a single massive dose2.

Radiation treatment underwent a major progression when it evolved from generic radiation of the entire pelvis to an approach known as conformal radiation therapy. The technique, known as three-dimensional conformal radiation therapy, or 3D-CRT, was introduced in the 1980’s, and was the first radiation therapy that had the ability to conform the shape of the radiation beam to that of the tumor. The objective of 3D-CRT is to irradiate a target volume that is the result of a three-dimensional study, rather than the two dimensional dose planning system it replaces. Several randomized trials have shown that, compared with conventional radiation therapy of prostate cancer, 3D-CRT reduces the radiation volume to the adjacent normal tissue, while the higher dose delivery allows for improved efficacy rates3.

Because of the proximity of the prostate to the rectum and bladder, radiation oncologists have been reluctant to irradiate prostate tumors with doses higher than 70 Gy, out of a fear of radiation toxicity. However, in many cases, 70 Gy is a suboptimal dose, either due to radioresistance, poor vascularization, or local hypoxia4.

3D-CRT, despite its name, cannot conform well to three-dimensional objects, largely because of the uniformity of beam strength. This can pose a significant problem in tumor control. Researchers in the field of radiation oncology estimate that approximately 30% of tumors exhibit concave features, thereby posing difficulty for treatment with conventional conformal radiotherapy5.


IMRT is the latest technological advance in conformal radiation therapy. IMRT evolved from the inability of 3D-CRT to irradiate tumors that are concave, surrounded by normal tissue, or in very close proximity to sensitive normal tissue, without causing excessive radiation exposure of adjacent normal tissue. IMRT aims to overcome the limitations of 3D-CRT by adding modulation of beam intensity to beam shaping. In fact, it is the use of non-uniform intensity fields that most differentiates IMRT from 3D-CRT.

IMRT incorporates two distinct features over 3D-CRT, inverse treatment planning, and computer-controlled intensity modulation of the radiation beam6.

The conventional forward planning that is used with 3D-CRT is not feasible with IMRT. Instead, IMRT employs the use of “inverse” planning, a method that has a greater capability of integrating the very large number of possible beam profiles. This technique begins with the required dose distribution and a set of planning parameters. The planning computer then designs the beam profiles necessary to produce their distribution5.

Conventional conformal beam radiation is characterized by a constant fluence. IMRT differs in that the radiation fluence varies across the beam, a phenomenon termed beam intensity modulation or BEM. Intensity modulated beams can be produced by a variety of methods, including the use of metal compensators, sequential delivery of smaller segments or subfields (termed the “step and shoot” method), the “sliding window” technique which uses pairs of moving dynamic multileaf collimators (dMLC), and the irradiation of the target slice by slice, termed tomotherapy5.


IMRT allows for varying intensities of radiation to produce dose distribution that is significantly more precise than 3D-CRT. Since IMRT has the ability to deliver radiotherapy that is highly conformal to the target tumor volume, dose escalation, with the resultant improved local control and cure, is more feasible. With conventional radiotherapy, the average intensity of the radiation dose to the prostate has been 65-70 Gy. The problem is that subpopulations of prostate tumor cells are radioresistant to doses of this intensity. Doses greater than 70 Gy are needed to achieve local control, but the rates of severe complications double when the dose is escalated beyond 70 Gy. IMRT offers the potential advantage of dose escalation without a corresponding increase in radiotherapy-associated toxicity to surrounding tissue7.

Several potential advantages of IMRT over conventional radiotherapy include greater latitude for dose escalation which may lead to improved local control and cure, the ability to deliver differential dose rates, a possible reduction in acute and late radiation toxicity, the potential to approach any complex problem regardless of shape, and the empowerment of clinicians who use low doses of radiation to elevate doses to appropriate levels8.


Compared with conventional radiotherapy, there are several potential disadvantages of IMRT, including dose heterogeneity within the target that is the result of the tradeoff of higher conformality with multiple beam delivery, increased volume of normal tissue exposure that is the consequence of improved dose distribution around the target, inefficiency of beam delivery and beam leakage that may result in a total body dose that is significantly higher than in conventional radiotherapy, prolonged treatment delivery time that is inherent in the inefficiency of the beam delivery, and the greater sensitivity of IMRT over other radiotherapies to any degree of internal movement of the targeted tumor region, which can confound calculations of dose and arbitrarily defined margins6,8.

Other potential concerns over IMRT include a higher risk of error due to the complexity of planning and delivery, and difficulties in quality assurance, radiation safety, and portal verification. IMRT is time-consuming, expensive, complex, and may not necessarily offer an advantage over more conventional techniques for some patients. Long-term follow-up of patients treated with IMRT is necessary to resolve these issues9.


Although IMRT has been used clinically in the treatment of tumors of the brain, breast, head and neck, liver, lung, nasopharynx, pancreas, prostate, and uterus, the primary focus of research involving IMRT in the United States has been on prostate cancer. Additionally, prostate cancer is the only application involving comparisons with conventional radiotherapy, with an emphasis on comparative morbidity between IMRT and 3D-CRT.

Zelefsky et al.10 followed a series of 772 prostate cancer patients for a median of 24 months who were treated with a dose of either 81.0 or 86.4 Gy. 1.5% of the patients experienced moderate (grade 2) rectal toxicity ( usually rectal bleeding and pain) and 0.5% experienced serious (grade 3) rectal toxicity. Grade 3 rectal toxicity is rectal ulceration as seen on colonoscopy. The 3 year actuarial rate of >= grade 2 rectal bleeding was 4%. Also they found no difference in the rate of toxicity between the two treatment groups. The 3-year actuarial PSA relapse-free survival rates among patients wth low, medium, and high risk for biochemical relapse treated with 81 Gy were 93%, 84%, and 81%, respectively.

Zelefsky et al.3 compared the acute and late toxicities of patients with locally confined to locally advanced (T1c-T3) prostate cancer receiving high-dose (81 Gy) 3D-CRT (n=61) and IMRT (n=171). The median follow-up period was 39 months for 3D-CRT and 12 months for IMRT. The authors found that IMRT significantly reduced the incidence of acute mild to moderate rectal toxicity compared with 3D-CCRT, and that there was a corresponding increase in the number of patients who did not exhibit rectal toxicity with IMRT. Additionally, there were fewer cases of moderately severe late rectal toxicity with IMRT than 3D-CRT, and there were fewer total number of cases of late rectal toxicity with IMRT.

To quantitatively evaluate the differences between IMRT and 3D-CRT, 20 randomly selected patients in the Zelefsky study3 were planned concomitantly with both methods. Histogram analysis revealed that IMRT planning resulted in a larger volume of targeted malignant tissue received the prescribed dose relative to 3D-CRT. The authors believe that this provides evidence that IMRT provides greater conformality in the treatment of prostate cancer than 3D-CRT. However, planning studies such as this do not provide clinical data and is no substitute for appropriate clinical trials5.

A study with long-term follow-up was published Zelefsky et al11 in 2001. Although the outcome figures of IMRT were combined with those of 3D-CRT, the authors did follow 40 patients who received high dose radiotherapy delivered by IMRT for a median of 31 months. They found that 5% developed late-onset moderate rectal toxicity and 20% developed moderate urinary toxicity. The authors conclude that IMRT allows the delivery of high dose radiotherapy unattainable by 3D-CRT without significant compromise to adjacent tissue.

A study comparing the side effects of high dose (82 Gy or more) IMRT with 3D-CRT was published by Shu and colleagues12. At a median follow-up of 18.7 months and 30.1 months for IMRT and 3D-CRT, respectively, the authors found that IMRT produced significantly greater rates of acute rectal toxicity than those treated with 3D-CRT. However, the results were confounded by a higher degree of tumor aggressiveness among the IMRT patients, and a higher rate of whole pelvic irradiation among IMRT recipients.

In summary, the body of research of IMRT treatment of prostate cancer suggests that IMRT can achieve similar rates of efficacy as 3D-CRT, but with lower rates of acute and late-onset toxicity


As is often the case with any new medical technology, there is a lack of medical consensus surrounding issues such as patient selection criteria, target selection and delineation, target dose prescription strategies, and non-involved organ dose constraints that are defined for IMRT9. Although there is no medical consensus on exactly which patient populations IMRT is appropriate treatment, IMRT is most likely to benefit patients with tumor targets that are concave, and where the avoidance of normal tissue irradiation is paramount. Patient selectivity is important with IMRT because of its higher cost, increased treatment time, and increased demands on physician, physicists, and therapists relative to conventional radiotherapy. Zhen et al.6 propose a set of disease and patient-related characteristics that should be considered prior to IMRT treatment. Patient-related factors include performance status, age, tolerance for prolonged daily treatment, and history of previous radiation therapy. Disease-related factors include curability with radiotherapy, potential improvement over conventional radiotherapy, histology, site or location of the tumor, and tumor motion.

Zen et al.6 conclude that priority for IMRT treatment should be reserved for patients with good performance status, absence of significant co-morbidity, and reasonable life expectancy.

Third party reimbursement can be a contentious issue surrounding new medical technologies. The reimbursement policy for IMRT that is established by Pennsylvania Medicare13 may serve as an example of how third parties may implement coverage for IMRT for prostate and other cancers. In their policy, they state that “IMRT is considered to be reasonable and necessary in instances where sparing the surrounding normal tissue is essential and the patient has at least one of the following conditions:

• Important dose limiting structures adjacent to, but outside the planned treatment volume are sufficiently close and require IMRT to assure for safety and morbidity reduction.
• An immediate adjacent volume has been irradiated and abutting portals must be established with high precision.
• Gross tumor volume margins are concave or convex and in close proximity to critical structures that must be protected to avoid unacceptable morbidity.
• Non-IMRT techniques would increase the probability of grade 2 or grade 3 radiation toxicity by greater than 15 percent of radiated similar cases.
• The volume of interest is in such location that its parameters are not assessed by simple two dimensional imaging techniques but rather by three dimensional reconstructions.
• IMRT is covered when the tumor tissue lies in areas associated with target motion caused by cardiac and pulmonary cycles, and the IMRT is necessary in order to protect adjacent normal tissues.”

Additionally, they state that IMRT is not covered “in situations where sparring surrounding normal tissue is not essential.”

Often, there is the temptation to assume that improvements in technology automatically translate into improvements in patient outcome. Preliminary evidence suggests that IMRT treatment can provide similar efficacy with less acute and long-term rectal toxicity than 3D-CRT. However, the body of clinical research on IMRT treatment of prostate cancer is quite limited. Issues that need to be addressed by future research should include clinical outcome data, the establishment and refinement of patient selection criteria, optimal treatment planning and delivery, cost analysis, and impact on quality of life. Of particular interest is whether IMRT can reduce the rate of late toxicity and risk of complications that are found in conventional radiotherapy6. Additionally, there is wide variation in response among tumors that are identical by location and pathological type. The factors associated with these variations should be examined so that dose modulation can be implemented4.

In conclusion, preliminary evidence suggests that IMRT can play a valuable role in reducing radiation toxicity to sensitive normal tissue adjacent to the targeted tumor, with no loss in efficacy. However, more comprehensive and longer-term data will be necessary before IMRT can shown to be superior to conventional three dimensional therapy in regards to survival.  


Additional Authors:  

Works Cited:  

1 IMRT: Intensity Modulated Radiation Therapy. Buffalo Niagara Cancer Consortium. 2002;1(3). Available online at http://www.bnpcc.org/document_2_3.html

2 Varian SmartBeam™ IMRT. Cancer Cure for the Next Generation. Available at http://www.varian.com/index2.html

3 Zelefsky MJ, Fuks Z, Happersett L, et al. Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer. Radiother Oncol. 2000;55:241-249.

4 Tubiana M, Eschwege F. Conformal radiotherapy and intensity-modulated radiotherapy. Acta Oncologica. 2000;39(5):555-567.

5 Nutting C, Dearnaley DP, Webb S. Intensity modulated radiation therapy: a clinical review. Br J Radiol. 2000;73:459-469.

6 Zhen W, Thompson RB, Enke CA. Intensity modulated radiation therapy (IMRT): The radiation oncologist’s perspective. Medical Dosimetry. 2002;27:155-159.

7 Zelefsky MJ, Fuks Z, Leibel SA. Intensity modulated radiation therapy for prostate cancer, Sem Radiat Oncol. 2002;12:229-237.

8 Glatstein E. Intensity-modulated radiation therapy: The inverse, the converse, and the perverse. Sem Radiat Oncol. 2002;12:272-281.

9 Eisbruch A. Seminars in Radiation Oncology: Introduction. Sem Radiat Oncol. 2002;12:197-198.

10 Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity –modulated radiation therapy for prostate cancer: Early toxicity and biochemical outcome in 772 patients. In press. Reported in Zelefsky MJ, Fuks Z, Leibel SA. Intensity modulated radiation therapy for prostate cancer, Sem Radiat Oncol. 2002;12:229-237.

11 Zelefsky MJ, Fuks Z, Hunt M, et. High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol. 2001;166:876-881.

12 Shu H-K G, Lee TT, Vignealt E, et al. Toxicity following high-dose three-dimensional conformal and intensity-modulated radiation therapy for clinically localized prostate cancer. Urology. 2001;57:102-107.

13 HGSA 2002. Medicare Medical Policy Bulletin. Intensity modulated radiation therapy (IMRT). Accessed at http://www.hgsa.com/professionals/policy-notice/r10.html


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