Author: C. D. Buckner, MD

Introduction

Intensity modulated radiation therapy (IMRT) is a relatively new way of delivering radiation that theoretically delivers more radiation to cancers while delivering less radiation to normal tissues than conventional three-dimensional conformal radiation (3D-CRT). IMRT developed through improvements and a decrease in the cost of server type computers; the development of multi-leaf collimators with multiple tungsten shields, which allowed the delivery of radiation through multiple ports (often referred to as “beamlets”); and the development of software that combined computerized tomography (CT) or other imaging of the cancer with control of the radiation delivered. The equipment allows for intensity modulation of the radiation beam during treatment. This is accomplished by the computer telling the machine to shield or not shield various ports with the tungsten shields. ¹

In 3D-CRT, the cancer is imaged in three dimensions by CT or magnetic resonance imaging (MRI) and the radiation oncologist calculates the dose to be delivered to the cancer. The dose of radiation is then delivered through a fairly large port from several different angles. Using 3D-CRT, there invariably are varying degrees of exposure of normal tissues to radiation near cancer sites that can be dose limiting. At most cancer sites, the amount of radiation tolerated by normal tissue determines the total dose that can be delivered, but the primary calculations are based on the dose to the tumor. In IMRT, the process is reversed and the radiation oncologist has to perform what is called inverse planning. The radiation oncologist programs in the maximum dose wanted for the tissues adjacent to the tumor, as well as for the tumor. For example, in prostate cancer, the dose of radiation desired for the bladder and rectum would be entered into the computer and the program would modulate the dose to these areas. This also means that a treatment plan might be designed to deliver a higher dose to certain areas of the tumor at high risk of progression and a lower dose to areas at lower risk of progression. Areas of normal tissue adjacent to the tumor can be selectively spared to avoid side effects. In practical terms this means that the volume of the tumor is divided into a series of regions of greater or lesser desired treatment intensity. ²

In practice, IMRT requires more planning time and more time to actually deliver the radiation compared to 3D-CRT. ³However, with 3D-CRT, hyperfractionation (2-3 fractions per day) is often used to allow normal tissues to recover between fractions. With IMRT, hypofractionation (once per day) is used and there are usually fewer overall treatment days than for hyperfractionated 3D-CRT.

At the present time, the costs of a treatment with IMRT are still higher than for 3D-CRT. Currently, Medicare and most insurance companies pay for IMRT. There never was a formal approval process for IMRT, as this technique just gradually replaced 3D-CRT in most radiation centers. At the present time, 30-40% of patients receiving radiation therapy at the Swedish Cancer Center in Seattle receive IMRT and this is probably true for most major radiation therapy centers.

What is the data to support the use of IMRT over 3D-CRT? There have been no published randomized controlled trials comparing IMRT to 3D-CRT. The extended use of and enthusiasm for this technology rests on observations of phase II trials and simulation results where radiation to normal tissue was calculated to be less than for 3D-CRT under the same circumstances. Since this technology has apparently replaced 3D-CRT, it is unlikely that randomized trials will be performed in the future.

Simulation Results

Much of the enthusiasm for IMRT rests on the confidence that radiation physicists and radiation oncologists have the ability to simulate ahead of time the doses of radiation that various tissues will receive during the course of treatment. Researchers in Germany found that IMRT increased target coverage an average of 36% and conformality by 10% compared to 3D-CRT. ⁴Where dose escalation was a goal, the use of IMRT allowed an increased mean dose by 4-6 Gy and target coverage by 19% with the same degree of conformality. They also found that rotational IMRT was slightly superior to fixed-field IMRT.

In one study of ten patients with breast cancer, simulation showed that a median of only 0.1% of the treatment volume received more than 110% of the prescribed dose with IMRT, versus 10% with standard wedge radiation therapy. ⁵In a study from Memorial Sloan-Kettering Cancer Center, IMRT of the breast reduced the dose to the coronary arteries, ipsilateral lung, contralateral breast, and surrounding soft tissues compared to conventional techniques. ⁶Researchers at Emory University compared simulation results of IMRT with standard 3D-CRT in 10 patients with pancreatic cancer. ⁷They found that IMRT plans were more conformal than 3D-CRT plans. The average dose delivered to one-third of the small bowel was lower with the IMRT plan compared to 3D-CRT. Using a modeling system, it was predicted that small bowel complications would occur in 9.3% of patients with IMRT compared to 24.4% of patients with 3D-CRT delivery. They concluded that the IMRT using an inverse treatment plan has the potential to significantly improve radiation therapy of pancreatic cancers by reducing the dose to normal tissue and simultaneously allowing dose escalation to the cancer.

Researchers from France compared the simulation results for treating 8 brain tumors with IMRT or 3D-CRT. ⁸They were able to demonstrate advantages for the IMRT system although the healthy tissues were less exposed to radiation with 3D-CRT. They concluded that IMRT makes it possible to reduce the number of fields used and to optimize the orientations in the case of target volumes of complex shape or when volumes at risk are in the vicinity of the target.

Clinical Results

There are no randomized clinical trials comparing IMRT to 3D-CRT, but there are some retrospective comparisons and one concurrent but non-randomized comparison for the treatment of prostate cancer. ⁹Researchers at Baylor Medical Center have reported the largest number of patients treated with IMRT. ¹⁰They treated 185 patients with a variety of malignancies and concluded that IMRT will allow dose escalation and better tumor control with less toxicity to normal tissues. Their results are included below in summaries by disease.

Prostate Cancer

Researchers at the Cleveland Clinic Foundation compared a short-course IMRT delivering 70 Gy in 28 fractions with 3D-CRT delivering 78 Gy in 39 fractions in patients with localized prostate cancer. ⁹They treated 166 patients with IMRT and 116 with 3D-CRT. The biochemical relapse-free survival rate at 30 months for 3D-CRT was 88%, compared to 94% for the IMRT group, which was not statistically different. In multivariate analysis, IMRT showed a trend toward a better outcome (p = 0.058). Late rectal toxicity at 30 months was 5% for IMRT and 12% for 3D-CRT (p = 0.24). Late urinary toxicity was rare in both groups. They concluded that both treatments had a comparable recurrence rate and that there was suggestive evidence for less rectal toxicity.

Researchers from Baylor Medical Center treated 77 men with localized prostate cancer with IMRT. ¹⁰When they compared their results to conventional radiation therapy and to six-field 3D-CRT, they found less toxicity to the bladder and lower gastrointestinal track than with IMRT. Late toxicity and tumor control has yet to be assessed. The authors demonstrated that 17.8% of the rectum received more than 65 Gy following IMRT compared to 29.5% for convention conformal radiation. They also estimated that 13.4% of the rectum received more than 70 Gy of radiation following IMRT, compared to 17.9% with conventional conformal radiation.

Head and Neck Cancer

Treatment of head and neck cancers offers an opportunity to decrease the dose of radiation to the tumor while sparing the parotid gland. Researchers at Baylor Medical Center treated 28 patients with IMRT and found less toxicity compared to previous experience with conventional radiation therapy techniques. ¹⁰There were only 3 cases of severe xerostomia. In this study, 25 of 28 patients had a complete response to IMRT alone without chemotherapy. The authors claim that the lack of xerostomia was due to the ability to selectively spare the parotid gland from high doses of radiation.

Pediatric Brain and Head and Neck Tumors

Researchers at Baylor MedicalCenter used IMRT to treat 40 children, ages 10 months to 20 years, with various tumors in the brain and head and neck. ¹⁰The authors presented data suggesting that normal tissues are spared more than with other forms of radiation therapy. Eighty-nine percent demonstrated a CR and three additional patients demonstrated a PR.

Adult Brain Tumor

Researchers at Baylor Medical Center used IMRT to treat 30 patients with adult brain tumors with IMRT. ⁹The treated group was extremely heterogenous and there were no meaningful comparisons made, except that in certain situations vital structures, such as the optic nerve, received less radiation than they would have by other radiation techniques.

Cancers Involving the Spinal Cord

The spinal cord is easily damaged by relatively low doses of radiation and methods to deliver effective doses to this area without damage would be a significant advance in treatment. IMRT offers the capability of delivering high doses to targets near the spine without exceeding spinal cord tolerance. Researchers at the University of California, Irvine treated 8 patients for a variety of primary and metastatic cancers of the spine. ¹¹Five cases had 6 courses given for re-irradiation of symptomatic disease and 3 cases had 4 courses of IMRT as primary management. For the re-irradiation patients, the mean follow-up interval was 4 months and the local control was estimated at 14%. Of the patients treated with primary intent, the mean follow-up was 9 months and the local control rate 75%. No patients developed spinal cord complications.

Nasopharyngeal Cancer

Researchers at UCSF used IMRT alone or with chemotherapy to treat 67 patients with stage I-IV nasopharyngeal cancer. ¹²Fifty patients received concomitant cisplatinum and adjuvant cisplatinum and 5-FU chemotherapy. Twenty-six patients also had fractionated high-dose-rate intracavitary brachytherapy and 1 patient had gamma knife radiosurgery boost after external beam radiotherapy. With a median follow-up of 31 months, there were two local-regional recurrences, while 17 had distant metastases. The local control rate at 4 years was 97%. The 4-year estimate of overall survival was 88%. There were no severe toxicities. It was concluded that IMRT provided excellent local control for nasopharyngeal cancer while sparing the salivary glands and other nearby critical normal tissues.

Summary

At the present time, it appears that IMRT will or has replaced 3D-CRT for the treatment of cancers where these are the appropriate choices. It is unlikely that there will be any significant number of formal randomized trials to confirm the superiority of IMRT over other technologies. Most major radiation oncology centers believe this technique to be superior and have already invested heavily in this technology.

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